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b172af122daf1a6146bfa18486ef10dee5bbd479	wikidoc	Angiotensin	Angiotensin Angiotensin is a peptide hormone that causes vasoconstriction and an increase in blood pressure. It is part of the renin–angiotensin system, which regulates blood pressure. Angiotensin also stimulates the release of aldosterone from the adrenal cortex to promote sodium retention by the kidneys. An oligopeptide, angiotensin is a hormone and a dipsogen. It is derived from the precursor molecule angiotensinogen, a serum globulin produced in the liver. Angiotensin was isolated in the late 1930s (first named 'angiotonin' or 'hypertensin') and subsequently characterized and synthesized by groups at the Cleveland Clinic and Ciba laboratories. # Precursor and types ## Angiotensinogen Angiotensinogen is an α-2-globulin produced constitutively and released into the circulation mainly by the liver. It is a member of the serpin family, although it is not known to inhibit other enzymes, unlike most serpins. Plasma angiotensinogen levels are increased by plasma corticosteroid, estrogen, thyroid hormone, and angiotensin II levels. Angiotensinogen is also known as renin substrate. Human angiotensinogen is 452 amino acids long, but other species have angiotensinogen of varying sizes. The first 12 amino acids are the most important for activity. ## Angiotensin I Angiotensin I (CAS# 11128-99-7), also called proangiotensin, is formed by the action of renin on angiotensinogen. Renin cleaves the peptide bond between the leucine (Leu) and valine (Val) residues on angiotensinogen, creating the decapeptide (ten amino acid) (des-Asp) angiotensin I. Renin is produced in the kidneys in response to renal sympathetic activity, decreased intrarenal blood pressure (<90mmHg systolic blood pressure ) at the juxtaglomerular cells, or decreased delivery of Na+ and Cl- to the macula densa. If a reduced NaCl concentration in the distal tubule is sensed by the macula densa, renin release by juxtaglomerular cells is increased. This sensing mechanism for macula densa-mediated renin secretion appears to have a specific dependency on chloride ions rather than sodium ions. Studies using isolated preparations of thick ascending limb with glomerulus attached in low NaCl perfusate were unable to inhibit renin secretion when various sodium salts were added but could inhibit renin secretion with the addition of chloride salts. This, and similar findings obtained in vivo, has led some to believe that perhaps "the initiating signal for MD control of renin secretion is a change in the rate of NaCl uptake predominantly via a luminal Na,K,2Cl co-transporter whose physiological activity is determined by a change in luminal Cl concentration." Angiotensin I appears to have no direct biological activity and exists solely as a precursor to angiotensin II. ## Angiotensin II Angiotensin I is converted to angiotensin II (AII) through removal of two C-terminal residues by the enzyme angiotensin-converting enzyme (ACE), primarily through ACE within the lung (but also present in endothelial cells, kidney epithelial cells, and the brain). Angiotensin II acts on the CNS to increase vasopressin production, and also acts on venous and arterial smooth muscle to cause vasoconstriction. Angiotensin II also increases aldosterone secretion, therefore, it acts as an endocrine, autocrine/paracrine, and intracrine hormone. ACE is a target of ACE inhibitor drugs, which decrease the rate of angiotensin II production. Angiotensin II increases blood pressure by stimulating the Gq protein in vascular smooth muscle cells (which in turn activates an IP3-dependent mechanism leading to a rise in intracellular calcium levels and ultimately causing contraction). In addition, angiotensin II acts at the Na+/H+ exchanger in the proximal tubules of the kidney to stimulate Na reabsorption and H+ excretion which is coupled to bicarbonate reabsorption. This ultimately results in an increase in blood volume, pressure, and pH. Hence, ACE inhibitors are major anti-hypertensive drugs. Other cleavage products of ACE, seven or 9 amino acids long, are also known; they have differential affinity for angiotensin receptors, although their exact role is still unclear. The action of AII itself is targeted by angiotensin II receptor antagonists, which directly block angiotensin II AT1 receptors. Angiotensin II is degraded to angiotensin III by angiotensinases located in red blood cells and the vascular beds of most tissues. It has a half-life in circulation of around 30 seconds, whereas, in tissue, it may be as long as 15–30 minutes. Angiotensin II results in increased inotropy, chronotropy, catecholamine (norepinephrine) release, catecholamine sensitivity, aldosterone levels, vasopressin levels, and cardiac remodeling and vasoconstriction through AT1 receptors on peripheral vessels (conversely, AT2 receptors impair cardiac remodeling). This is why ACE inhibitors and ARBs help to prevent remodeling that occurs secondary to angiotensin II and are beneficial in CHF. ## Angiotensin III Angiotensin III has 40% of the pressor activity of angiotensin II, but 100% of the aldosterone-producing activity. Increases mean arterial pressure. ## Angiotensin IV Angiotensin IV is a hexapeptide that, like angiotensin III, has some lesser activity. Angiotensin IV has a wide range of activities in the central nervous system. The exact identity of AT4 receptors has not been established. There is evidence that the AT4 receptor is insulin-regulated aminopeptidase (IRAP). There is also evidence that angiotensin IV interacts with the HGF system through the c-Met receptor. Synthetic small molecule analogues of angiotensin IV with the ability to penetrate through blood brain barrier have been developed. # Effects Angiotensins II, III and IV have a number of effects throughout the body: ## Adipic Angiotensins "modulate fat mass expansion through upregulation of adipose tissue lipogenesis ... and downregulation of lipolysis " ## Cardiovascular They are potent direct vasoconstrictors, constricting arteries and veins and increasing blood pressure. This effect is achieved through activation of the GPCR AT1, which signals through a Gq protein to activate Phospholipase C, and subsequently increase intracellular calcium. Angiotensin II has prothrombotic potential through adhesion and aggregation of platelets and stimulation of PAI-1 and PAI-2. When cardiac cell growth is stimulated, a local (autocrine-paracrine) renin–angiotensin system is activated in the cardiac myocyte, which stimulates cardiac cell growth through protein kinase C. The same system can be activated in smooth muscle cells in conditions of hypertension, atherosclerosis, or endothelial damage. Angiotensin II is the most important Gq stimulator of the heart during hypertrophy, compared to endothelin-1 and α1 adrenoreceptors. ## Neural Angiotensin II increases thirst sensation (dipsogen) through the area postrema and subfornical organ of the brain, decreases the response of the baroreceptor reflex, increases the desire for salt, increases secretion of ADH from the posterior pituitary, and increases secretion of ACTH from the anterior pituitary. It also potentiates the release of norepinephrine by direct action on postganglionic sympathetic fibers. ## Adrenal Angiotensin II acts on the adrenal cortex, causing it to release aldosterone, a hormone that causes the kidneys to retain sodium and lose potassium. Elevated plasma angiotensin II levels are responsible for the elevated aldosterone levels present during the luteal phase of the menstrual cycle. ## Renal Angiotensin II has a direct effect on the proximal tubules to increase Na+ reabsorption. It has a complex and variable effect on glomerular filtration and renal blood flow depending on the setting. Increases in systemic blood pressure will maintain renal perfusion pressure; however, constriction of the afferent and efferent glomerular arterioles will tend to restrict renal blood flow. The effect on the efferent arteriolar resistance is, however, markedly greater, in part due to its smaller basal diameter; this tends to increase glomerular capillary hydrostatic pressure and maintain glomerular filtration rate. A number of other mechanisms can affect renal blood flow and GFR. High concentrations of Angiotensin II can constrict the glomerular mesangium, reducing the area for glomerular filtration. Angiotensin II is a sensitizer to tubuloglomerular feedback, preventing an excessive rise in GFR. Angiotensin II causes the local release of prostaglandins, which, in turn, antagonize renal vasoconstriction. The net effect of these competing mechanisms on glomerular filtration will vary with the physiological and pharmacological environment.	Angiotensin Angiotensin is a peptide hormone that causes vasoconstriction and an increase in blood pressure. It is part of the renin–angiotensin system, which regulates blood pressure. Angiotensin also stimulates the release of aldosterone from the adrenal cortex to promote sodium retention by the kidneys. An oligopeptide, angiotensin is a hormone and a dipsogen. It is derived from the precursor molecule angiotensinogen, a serum globulin produced in the liver. Angiotensin was isolated in the late 1930s (first named 'angiotonin' or 'hypertensin') and subsequently characterized and synthesized by groups at the Cleveland Clinic and Ciba laboratories.[1] # Precursor and types ## Angiotensinogen Angiotensinogen is an α-2-globulin produced constitutively and released into the circulation mainly by the liver. It is a member of the serpin family, although it is not known to inhibit other enzymes, unlike most serpins. Plasma angiotensinogen levels are increased by plasma corticosteroid, estrogen, thyroid hormone, and angiotensin II levels. Angiotensinogen is also known as renin substrate. Human angiotensinogen is 452 amino acids long, but other species have angiotensinogen of varying sizes. The first 12 amino acids are the most important for activity. ## Angiotensin I Angiotensin I (CAS# 11128-99-7), also called proangiotensin, is formed by the action of renin on angiotensinogen. Renin cleaves the peptide bond between the leucine (Leu) and valine (Val) residues on angiotensinogen, creating the decapeptide (ten amino acid) (des-Asp) angiotensin I. Renin is produced in the kidneys in response to renal sympathetic activity, decreased intrarenal blood pressure (<90mmHg systolic blood pressure[2] ) at the juxtaglomerular cells, or decreased delivery of Na+ and Cl- to the macula densa.[3] If a reduced NaCl concentration[4] in the distal tubule is sensed by the macula densa, renin release by juxtaglomerular cells is increased. This sensing mechanism for macula densa-mediated renin secretion appears to have a specific dependency on chloride ions rather than sodium ions. Studies using isolated preparations of thick ascending limb with glomerulus attached in low NaCl perfusate were unable to inhibit renin secretion when various sodium salts were added but could inhibit renin secretion with the addition of chloride salts.[5] This, and similar findings obtained in vivo,[6] has led some to believe that perhaps "the initiating signal for MD control of renin secretion is a change in the rate of NaCl uptake predominantly via a luminal Na,K,2Cl co-transporter whose physiological activity is determined by a change in luminal Cl concentration."[7] Angiotensin I appears to have no direct biological activity and exists solely as a precursor to angiotensin II. ## Angiotensin II Angiotensin I is converted to angiotensin II (AII) through removal of two C-terminal residues by the enzyme angiotensin-converting enzyme (ACE), primarily through ACE within the lung (but also present in endothelial cells, kidney epithelial cells, and the brain). Angiotensin II acts on the CNS to increase vasopressin production, and also acts on venous and arterial smooth muscle to cause vasoconstriction. Angiotensin II also increases aldosterone secretion, therefore, it acts as an endocrine, autocrine/paracrine, and intracrine hormone. ACE is a target of ACE inhibitor drugs, which decrease the rate of angiotensin II production. Angiotensin II increases blood pressure by stimulating the Gq protein in vascular smooth muscle cells (which in turn activates an IP3-dependent mechanism leading to a rise in intracellular calcium levels and ultimately causing contraction). In addition, angiotensin II acts at the Na+/H+ exchanger in the proximal tubules of the kidney to stimulate Na reabsorption and H+ excretion which is coupled to bicarbonate reabsorption. This ultimately results in an increase in blood volume, pressure, and pH.[8] Hence, ACE inhibitors are major anti-hypertensive drugs. Other cleavage products of ACE, seven or 9 amino acids long, are also known; they have differential affinity for angiotensin receptors, although their exact role is still unclear. The action of AII itself is targeted by angiotensin II receptor antagonists, which directly block angiotensin II AT1 receptors. Angiotensin II is degraded to angiotensin III by angiotensinases located in red blood cells and the vascular beds of most tissues. It has a half-life in circulation of around 30 seconds, whereas, in tissue, it may be as long as 15–30 minutes. Angiotensin II results in increased inotropy, chronotropy, catecholamine (norepinephrine) release, catecholamine sensitivity, aldosterone levels, vasopressin levels, and cardiac remodeling and vasoconstriction through AT1 receptors on peripheral vessels (conversely, AT2 receptors impair cardiac remodeling). This is why ACE inhibitors and ARBs help to prevent remodeling that occurs secondary to angiotensin II and are beneficial in CHF. [7] ## Angiotensin III Angiotensin III has 40% of the pressor activity of angiotensin II, but 100% of the aldosterone-producing activity. Increases mean arterial pressure. ## Angiotensin IV Angiotensin IV is a hexapeptide that, like angiotensin III, has some lesser activity. Angiotensin IV has a wide range of activities in the central nervous system.[9][10] The exact identity of AT4 receptors has not been established. There is evidence that the AT4 receptor is insulin-regulated aminopeptidase (IRAP).[11] There is also evidence that angiotensin IV interacts with the HGF system through the c-Met receptor.[12][13] Synthetic small molecule analogues of angiotensin IV with the ability to penetrate through blood brain barrier have been developed.[13] # Effects Angiotensins II, III and IV have a number of effects throughout the body: ## Adipic Angiotensins "modulate fat mass expansion through upregulation of adipose tissue lipogenesis ... and downregulation of lipolysis " [14] ## Cardiovascular They are potent direct vasoconstrictors, constricting arteries and veins and increasing blood pressure. This effect is achieved through activation of the GPCR AT1, which signals through a Gq protein to activate Phospholipase C, and subsequently increase intracellular calcium.[15] Angiotensin II has prothrombotic potential through adhesion and aggregation of platelets and stimulation of PAI-1 and PAI-2.[16][17] When cardiac cell growth is stimulated, a local (autocrine-paracrine) renin–angiotensin system is activated in the cardiac myocyte, which stimulates cardiac cell growth through protein kinase C. The same system can be activated in smooth muscle cells in conditions of hypertension, atherosclerosis, or endothelial damage. Angiotensin II is the most important Gq stimulator of the heart during hypertrophy, compared to endothelin-1 and α1 adrenoreceptors.[citation needed] ## Neural Angiotensin II increases thirst sensation (dipsogen) through the area postrema and subfornical organ of the brain,[18][19][20] decreases the response of the baroreceptor reflex, increases the desire for salt, increases secretion of ADH from the posterior pituitary, and increases secretion of ACTH from the anterior pituitary.[18] It also potentiates the release of norepinephrine by direct action on postganglionic sympathetic fibers.[citation needed] ## Adrenal Angiotensin II acts on the adrenal cortex, causing it to release aldosterone, a hormone that causes the kidneys to retain sodium and lose potassium. Elevated plasma angiotensin II levels are responsible for the elevated aldosterone levels present during the luteal phase of the menstrual cycle. ## Renal Angiotensin II has a direct effect on the proximal tubules to increase Na+ reabsorption. It has a complex and variable effect on glomerular filtration and renal blood flow depending on the setting. Increases in systemic blood pressure will maintain renal perfusion pressure; however, constriction of the afferent and efferent glomerular arterioles will tend to restrict renal blood flow. The effect on the efferent arteriolar resistance is, however, markedly greater, in part due to its smaller basal diameter; this tends to increase glomerular capillary hydrostatic pressure and maintain glomerular filtration rate. A number of other mechanisms can affect renal blood flow and GFR. High concentrations of Angiotensin II can constrict the glomerular mesangium, reducing the area for glomerular filtration. Angiotensin II is a sensitizer to tubuloglomerular feedback, preventing an excessive rise in GFR. Angiotensin II causes the local release of prostaglandins, which, in turn, antagonize renal vasoconstriction. The net effect of these competing mechanisms on glomerular filtration will vary with the physiological and pharmacological environment.	https://www.wikidoc.org/index.php/Angiotensin
3ec63532183ab9abb1cbcf00907e12ec7ab9a202	wikidoc	Anglophobia	Anglophobia # Overview Anti-English sentiment or Anglophobia (from Latin Anglus "English" and Greek φόβος, phobos, "fear") means opposition to, dislike of, fear of, or hatred towards England or the English people. The term is sometimes used more loosely for general anti-British sentiment. Its opposite is Anglophile\|Anglophilia. # Within the United Kingdom In his essay "Notes on Nationalism", written in May 1945 and published in the first issue of the intellectual magazine Polemic (magazine)\|Polemic (October 1945),George Orwell wrote that 'Welsh, Irish and Scottish nationalism have points of difference but are alike in their anti-English orientation.' ## Scotland In a 2003 survey of 500 English people living in Scotland, one quarter said that they had been harassed or discriminated against by the Scots. A 2005 study by Hussain and Millar of the Department of Politics at the University of Glasgow examined the prevalence of Anglophobia in relation to Islamophobia in Scotland. One finding of the report suggested that national "phobias" have common roots independent of the nations they are directed toward. The study states that: Scottish identity comes close to rivalling low levels of education as an influence towards Anglophobia. Beyond that, having an English friend reduces Anglophobia by about as much as having a Muslim friend reduces Islamophobia. And lack of knowledge about Islam probably indicates a broader rejection of the ‘other’, for it has as much impact on Anglophobia as on Islamophobia. The study goes on to say: (of the English living in Scotland) "Few of the English (only 16 percent) see conflict between Scots and English as even 'fairly serious'". Hussain and Millar's study found that Anglophobia was slightly less prevalent than Islamophobia, but that unlike Islamophobia, Anglophobia correlated with a strong sense of Scottish identity. In 1999 an Inspector and race relations officer with Lothian and Borders Police said that a correlation had been noticed between the establishment of the Scottish Parliament and anti-English incidents. However, Hussain and Millar's research suggested that Anglophobia had fallen slightly since the introduction of Devolution in the United Kingdom\|devolution. In 2009 a woman originally from England was assaulted in an allegedly anti-English racially motivated attack. Similar cases have been connected with major football matches and tournaments, particularly international tournaments where the English and Scottish football teams often compete with each other. A spate of anti-English attacks occurred in 2006 during the football World Cup 2006\|World Cup, in one incident a 7 year old boy wearing an England shirt was punched in the head in an Edinburgh park. ## Wales The Laws in Wales Acts 1535–1542 also known as the "Acts of Union", passed by the Parliament of England, annexed Wales to the Kingdom of England, and replaced the Welsh language and Welsh law with the English language and English law. In particular, Section 20 of the 1535 Act made English the only language of the law courts and stated that those who used Welsh would not be appointed to any public office in Wales. The Welsh language was supplanted in many public spheres, with, for example, the use of the Welsh Not in some schools. This would later be adopted as a symbol of English oppression, although evidence suggests its enforcement may have been largely voluntary. Since the Glyndŵr Rising of the early 15th century, Welsh nationalism has been primarily nonviolent. However, the Welsh militant group Meibion Glyndŵr (Template:Lang-en) were responsible for arson attacks on English-owned second homes in Wales from 1979–1994, motivated by cultural anti-English sentiment. Meibion Glyndŵr also attempted arson against several estate agents in Wales and England, and against the offices of the Conservative Party (UK)\|Conservative Party in London. In 2000, the Chairman of Swansea Bay Race Equality Council said that "Devolution has brought a definite increase in anti-English behaviour" citing three women who believed that they were being discriminated against in their careers because they could not speak Welsh. Author Simon Brooks recommended that English-owned homes in Wales be "peacefully occupied". In 2001 Dafydd Elis-Thomas, a former leader of Plaid Cymru, said that there was an anti-English strand to Welsh nationalism. ## Northern Ireland During the Troubles, the IRA exclusively attacked targets located in Northern Ireland and England, not Scotland or Wales. In the Protestant community, the English are identified with British politicians, and are sometimes resented for their perceived abandonment of loyalist communities. # Outside the United Kingdom In 1859, in his essay A Few Words on Non-Intervention, John Stuart Mill notes that England "finds itself, in respect of its foreign policy, held up to obloquy as the type of egoism and selfishness; as a nation which thinks of nothing but of out-witting and out-generalling its neighbours" and urges his fellow countrymen against "the mania of professing to act from meaner motives than those by which we are really actuated". ## Ireland There is a long tradition of Anglophobia within Irish nationalism. Much of this was grounded in the hostility felt by the largely Catholic poor for the Anglo-Irish gentry, which was mainly Anglican. In Ireland before the Great Famine (Ireland)\|Great Famine, anti-English hostility was deep seated and was manifested in increased anti-English hostility organised by Society of United Irishmen\|United Irishmen. In post-famine Ireland, anti-English hostility was adopted into the philosophy and foundation of the Irish nationalist movement. At the turn of the 20th century, the Celtic Revival movement associated the search for a cultural and national identity with an increasing anti-colonial and anti-English sentiment. Anti-English themes manifested in national organisations seen as promoting native Irish values, with the emergence of groups like Sinn Féin. The Gaelic Athletic Association (GAA) was itself founded in 1884 as a countermeasure against the Anglo-Irish Athletic Association, which promoted and supervised British sports such as English Association football\|football in Ireland. The GAA was founded in the anti-English ideas of Thomas Croke, Archbishop of Roman Catholic Archdiocese of Cashel and Emly\|Cashel and Emly. From 1886 to 1971 the GAA focused national pride into distinctly non-English activities. Members were forbidden to belong to organisations that played "English" games, and the organisation countered the Anglicisation in Irish society. With the development across Ireland of Irish games and the arts, the Celtic revivalists and nationalists identified characteristics of what they defined as the "Irish Race". A nationalistic identity developed, as being the polar opposite of the Anglo-Saxons, and untainted by the Anglo-Irish community. A sense of national identity and Irish distinctiveness as well as an anti-English assertiveness was reinforced to Catholics by teachers in hedge schools. A feeling of anti-English sentiment intensified within Irish nationalism during the Boer wars\|Boer War leading to xenophobia underlined by Anglophobia. Resulting in two units of Irish commandos who fought with the Boeragainst British forces during the Second Boer War (1899–1902). J. Donnolly a member of the brigade wrote to the editor of Irish News in 1901 stating; "It was not for the love of the Boer war we were fighting; it was for the hatred of the English."J. Donnolly letter to the Irish News 1901 The pro-Boer movement gained widespread support in Ireland and over 20.000 supporters demonstrated in Dublin in 1899 where Irish nationalism, anti-English and pro-Boer attitudes were one and the same. There was a pro-Boer movement in England however the English pro-Boer movement was not based on anti-English sentiments. These opposing views and animosity led the English and Irish pro-Boer groups to maintain a distance from one another. The William Butler Yeats\|W. B. Yeats play The Countess Cathleen, written in 1892, has anti-English overtones comparing the English gentry to demons who come for Irish souls. Films set during the Irish War of Independence, such as The Informer (1935 film)\|The Informer (1935) and the The Plough and the Stars (film)\|Plough and the Stars (1936), were criticised by the British Board of Film Classification\|BBFC for the director John Ford's anti-English content, and, in recent years, Michael Collins (film)\|Michael Collins and The Wind That Shakes the Barley (film)\|The Wind That Shakes the Barley (despite being a joint British-Irish production) have led to accusations of Anglophobia in the British press. In 2006, Antony Booth, the father-in law of Tony Blair, claimed he was the victim of anti-English vandalism and discrimination while living in County Cavan, Ireland, with his wife. In addition, in August 2008 an English pipefitter based in Dublin was awarded €20,000 for the racial abuse and discrimination he received at his workplace. In 2011, tensions and anti-English or anti-British feelings flared in relation to the proposed visit of Elizabeth II, the first Monarchy of the United Kingdom\|British monarch to visit Ireland in 101 years. The direct invitation by the President of Ireland, Mary McAleese, and the Irish government, was hailed by the Irish press as a historic visit, but was criticised by Sinn Féin President Gerry Adams. An anti-Queen demonstration was held at the GPO Dublin by a small group of Irish Republicans on 26 February 2011, and a mock trial and decapitation of an effigy of Queen Elizabeth II were carried out by socialist republican group Éirígí. Other protests included one Dublin publican (the father of Celtic player Anthony Stokes) hanging a banner declaring "the Queen will never be welcome in this country". ## France After the Norman conquest in 1066, Anglo-Norman replaced English as the official language of England. However, in the thirteenth and fourteenth centuries, the Plantagenet kings of England lost most of their possessions in France, began to consider England to be their primary domain, and turned to the English language. King Edward I, when issuing writs for summoning parliament in 1295, claimed that the King of France planned to invade England and extinguish the English language, "a truly detestable plan which may God avert". In 1338, Philip VI of France authored the Ordinance of Normandy, which again called for the destruction and elimination of the English nation and language. The Hundred Years' War (1337–1453) between England and France changed societies on both sides of the Channel. The English and French were engaged in numerous wars in the following centuries. England's ongoing conflict with Scotland provided France with an opportunity to destabilise England, and there was a firm friendship (known as the Auld Alliance) between France and Scotland from the late-thirteenth century to the mid-sixteenth century. The alliance eventually foundered because of growing Protestantism in Scotland. Opposition to Protestantism became a major feature of later French Anglophobia (and conversely, fear of Catholicism was a hallmark of Francophobia). Antipathy and intermittent hostilities between France and Britain, as distinct from England, continued during later centuries. It has become more and more political. ## United States In 2002, academic John Moser said that, although anglophobia is now "almost completely absent" from United States society, this was not always the case. He stated that "there were strains of anglophobia present in virtually every populist movement of the late 19th and early 20th centuries", with the Populist Party, for example, "referring to England as a 'monster' that had 'seized upon the fresh energy of America and is steadily fixing its fangs into our social life.'" Reasons suggested for the decline in anglophobia included the impact of the Second World War, and reduced political support for Irish nationalist movements compared with that in earlier periods. Moser also said: "In an age when the wealthiest and most influential Americans tended to be associated with things British—the vast majority were of Anglo-Saxon descent, wore English-tailored suits, drove British-made automobiles, and even spoke with affected British accents—it was quite natural for Great Britain to fall within the sights of disaffected populists. In more recent years, however, this has changed. When one thinks of wealth and influence in contemporary America, particularly when one considers those who have made their fortunes in the past thirty years, English culture does not immediately spring to mind. The film industry is widely perceived to give a British nationality to a disproportionate number of villains. Lyndon LaRouche, a perennial candidate for US President and a movement leader known for theories of conspiracies, has been called the "most illustrious" Anglophobe in American politics. ### Anglophobia in the Irish-American community The Irish-American community in the United States has historically shown antipathy towards the English in particular. Anglophobia has been a defining feature of the post-famine Irish-American experience. Bolstered by their support of Irish nationalism, Irish-American communities have been staunchly anti-English since the 1850s and this sentiment is fostered within the Irish-American identity. Irish immigrants who settled in the United States often prospered there, retained the bitterest animosity to England and many of them subscribed from their weekly wage to keep up the anti-English agitation. This was due in part to the nature of their history and manner of their emigration, when they brought with them a strong specific sense of Anglophobia. Irish-American newspapers, like the pro-Catholic "Truth Teller" which was founded in 1825 by an anti-English priest, were influential in the identity of the community. Anglophobia in print was also seen in the autobiographies of noted Irish-Americans; Elizabeth Gurley a leading American socialist, and William Z. Foster who reported in his own memoirs his own father died at over eighty, he never said the word England without adding “God damn her!”. In 1842, the first national gathering of Irish-Americans took place in Philadelphia: The convention ended with anti-English speeches and three cheers for Ireland……Thus they influenced the progress of nationalism in Ireland and shaped their Irish-American identity Anti-English feelings among Irish-Americans spread to American culture through Irish-American performers in popular Blackface minstral shows. These imparted both elements of the Irish-Americans performers own national bias, and the popular stereotypical image that the English people were bourgeois aloof or upper class. Sentiments quickly turned into direct and volent action when in the 1860s the Fenian Brotherhood Society invaded Canada to provoke a United States-British war in hope it would lead to Irish freedom. Violence is said to have included direct action by Fenian sympathisers, with the assassination of Thomas D'Arcy McGee himself an Irish-Canadian and Irish nationalist who was against the invasion, although he was very critical of the Orange Order, and it has long been suspected they were his true killers. Goldwin Smith, Professor at Cornell University, wrote in the North American Review that ‘hatred of England’ was used as a tool to win the Irish-American vote. An observation shared in 1900 by the Secretary of State for the United States John Hay who openly criticise the Prairie Populist and his own Democratic Parties political pandering to attract the support of the Irish diaspora: "state conventions put on an anti-English plank in their platforms to curry favor with the Irish (whom they want to keep) and the Germans whom they want to seduce. It is too disgusting to have to deal with such sordid lies."John Hay Secretary of State for the United States in 1900 Well into the early 20th century anti-English sentiment was increasing with famine memorials in the Irish-American communities, quote “served as a wellspring for their obsessive and often corrosive antipathy”, as noted in the British Parliament in 1915: There is no part of the world where anti-English influences worked so powerfully than in the United States. Almost every Irishman there is the son or grandson of an evicted tenant – evicted in all the horrors of the black 40s. And most of them have heard stories of them from their mother’s knee. Some newspapers, including the San Francisco Leader and New York Irish World, first published in 1823, were renowned for their anti-English articles. The Irish World blamed the mainland United Kingdom for the depopulation and desolate state of Ireland's industries. One newspaper, the Gaelic American, called a student performance of the British national anthem by some girls of Irish heritage from a convent school an act of disloyalty, where they were taught to reverence the traditions of the hereditary enemy of their race and religion. A commemorative stamp by philanthropist Andrew Carnegie on a century of peace between America and Great Britain was criticised by the Irish-American press. In recent years American political commentators, such as Pat Buchanan, have highlighted the anti-English stance of the Irish Diaspora in the United States of America. ## Iran Anti-British sentiment has been described as "deeply entrenched in Iranian culture", and reported to be increasingly prevalent in Iran. In July 2009, an adviser to Ali Khamenei called Britain "worse than America" for its alleged interference in Iran's post-election affairs. Animosity has been dated back to the early 19th century, when a British diplomat, Sir Gore Ouseley, was responsible for drawing up the country's boundaries after the First Russo-Persian War. In the first half of the 20th century, the British Empire exerted political influence over Iran (Persia) in order to control the profits from the Anglo-Iranian Oil Company. As a result, British influence was widely known to have been behind the overthrow of the Qajar Dynasty in the 1920s, the subsequent rise of Reza Shah Pahlavi, and the successful coup d'etat overthrowing prime minister Mohammad Mosaddeq in 1953. In November 2011, attacks on the UK's embassy in Tehran led to the closure of the embassy and the expulsion of Iranian diplomats from the UK, with the Iranian parliamentary chairman Ali Larijani stating that the incident was the outcome of "decades of domineering moves by the British in Iran". The classic Iranian novel My Uncle Napoleon, published in 1973, lampoons the widespread belief that the English are responsible for events that occur in Iran. ## Australia and New Zealand "Pommy" or "Pom" (probably derived from "pomegranate", rhyming slang for "immigrant") is a common Australasian and South African slang word for the English, often combined with "whinging" (complaining) to make the expression "whingeing Pom" – an English immigrant who stereotypically complains about everything. Although the term is sometimes applied to British immigrants generally, it is usually applied specifically to the English, by both Australians and New Zealanders. From the 19th century onwards, there were feelings among established Australians that many immigrants from England were poorly skilled, unwanted by their home country, and unappreciative of the benefits of their new country. In recent years, complaints about two newspaper articles blaming English tourists for littering a local beach, and headed "Filthy Poms" and "Poms fill the summer of our discontent", were accepted as complaints and settled through conciliation by the Australian Human Rights Commission when the newspapers published apologies. However, letters and articles which referred to English people as "Poms" or "Pommies" did not meet the threshold for racial hatred. In 2007 a complaint to Australia's Advertising Standards Bureau about a television commercial using the term "Pom" was upheld and the commercial was withdrawn. Films such as Gallipoli and Breaker Morant have highlighted anti-British sentiment felt by some Australians.	Anglophobia Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview Anti-English sentiment or Anglophobia (from Latin Anglus "English" and Greek φόβος, phobos, "fear") means opposition to, dislike of, fear of, or hatred towards England or the English people.[1] The term is sometimes used more loosely for general anti-British sentiment.[1] Its opposite is Anglophile\|Anglophilia. # Within the United Kingdom In his essay "Notes on Nationalism", written in May 1945 and published in the first issue of the intellectual magazine Polemic (magazine)\|Polemic (October 1945),George Orwell wrote that 'Welsh, Irish and Scottish nationalism have points of difference but are alike in their anti-English orientation.'[2] ## Scotland In a 2003 survey of 500 English people living in Scotland, one quarter said that they had been harassed or discriminated against by the Scots.[3] A 2005 study by Hussain and Millar of the Department of Politics at the University of Glasgow examined the prevalence of Anglophobia in relation to Islamophobia in Scotland. One finding of the report suggested that national "phobias" have common roots independent of the nations they are directed toward. The study states that: Scottish identity comes close to rivalling low levels of education as an influence towards Anglophobia. Beyond that, having an English friend reduces Anglophobia by about as much as having a Muslim friend reduces Islamophobia. And lack of knowledge about Islam probably indicates a broader rejection of the ‘other’, for it has as much impact on Anglophobia as on Islamophobia.[4] The study goes on to say: (of the English living in Scotland) "Few of the English (only 16 percent) see conflict between Scots and English as even 'fairly serious'". Hussain and Millar's study found that Anglophobia was slightly less prevalent than Islamophobia, but that unlike Islamophobia, Anglophobia correlated with a strong sense of Scottish identity. In 1999 an Inspector and race relations officer with Lothian and Borders Police said that a correlation had been noticed between the establishment of the Scottish Parliament and anti-English incidents.[5] However, Hussain and Millar's research suggested that Anglophobia had fallen slightly since the introduction of Devolution in the United Kingdom\|devolution. In 2009 a woman originally from England was assaulted in an allegedly anti-English racially motivated attack.[6] Similar cases have been connected with major football matches and tournaments, particularly international tournaments where the English and Scottish football teams often compete with each other.[7][8][9] A spate of anti-English attacks occurred in 2006 during the football World Cup 2006\|World Cup,[10] in one incident a 7 year old boy wearing an England shirt was punched in the head in an Edinburgh park.[11] ## Wales The Laws in Wales Acts 1535–1542 also known as the "Acts of Union", passed by the Parliament of England, annexed Wales to the Kingdom of England, and replaced the Welsh language and Welsh law with the English language and English law.[12][13] In particular, Section 20 of the 1535 Act made English the only language of the law courts and stated that those who used Welsh would not be appointed to any public office in Wales.[12] The Welsh language was supplanted in many public spheres, with, for example, the use of the Welsh Not in some schools. This would later be adopted as a symbol of English oppression, although evidence suggests its enforcement may have been largely voluntary.[14] Since the Glyndŵr Rising of the early 15th century, Welsh nationalism has been primarily nonviolent.[15] However, the Welsh militant group Meibion Glyndŵr (Template:Lang-en) were responsible for arson attacks on English-owned second homes in Wales from 1979–1994, motivated by cultural anti-English sentiment.[15] Meibion Glyndŵr also attempted arson against several estate agents in Wales and England, and against the offices of the Conservative Party (UK)\|Conservative Party in London.[16][16][17] In 2000, the Chairman of Swansea Bay Race Equality Council said that "Devolution has brought a definite increase in anti-English behaviour" citing three women who believed that they were being discriminated against in their careers because they could not speak Welsh.[18] Author Simon Brooks recommended that English-owned homes in Wales be "peacefully occupied".[16] In 2001 Dafydd Elis-Thomas, a former leader of Plaid Cymru, said that there was an anti-English strand to Welsh nationalism.[19] ## Northern Ireland During the Troubles, the IRA exclusively attacked targets located in Northern Ireland and England, not Scotland or Wales.[20] In the Protestant community, the English are identified with British politicians, and are sometimes resented for their perceived abandonment of loyalist communities.[21] # Outside the United Kingdom In 1859, in his essay A Few Words on Non-Intervention, John Stuart Mill notes that England "finds itself, in respect of its foreign policy, held up to obloquy as the type of egoism and selfishness; as a nation which thinks of nothing but of out-witting and out-generalling its neighbours" and urges his fellow countrymen against "the mania of professing to act from meaner motives than those by which we are really actuated".[22] ## Ireland There is a long tradition of Anglophobia within Irish nationalism. Much of this was grounded in the hostility felt by the largely Catholic poor for the Anglo-Irish gentry, which was mainly Anglican. In Ireland before the Great Famine (Ireland)\|Great Famine, anti-English hostility was deep seated[23] and was manifested in increased anti-English hostility organised by Society of United Irishmen\|United Irishmen.[24][25] In post-famine Ireland, anti-English hostility was adopted into the philosophy and foundation of the Irish nationalist movement. At the turn of the 20th century, the Celtic Revival movement associated the search for a cultural and national identity with an increasing anti-colonial and anti-English sentiment.[26] Anti-English themes manifested in national organisations seen as promoting native Irish values, with the emergence of groups like Sinn Féin. The Gaelic Athletic Association (GAA) was itself founded in 1884 as a countermeasure against the Anglo-Irish Athletic Association, which promoted and supervised British sports such as English Association football\|football in Ireland. The GAA was founded in the anti-English ideas of Thomas Croke, Archbishop of Roman Catholic Archdiocese of Cashel and Emly\|Cashel and Emly.[27] From 1886 to 1971 the GAA focused national pride into distinctly non-English activities.[28] Members were forbidden to belong to organisations that played "English" games, and the organisation countered the Anglicisation in Irish society.[29][30][31] With the development across Ireland of Irish games and the arts, the Celtic revivalists and nationalists identified characteristics of what they defined as the "Irish Race". A nationalistic identity developed, as being the polar opposite of the Anglo-Saxons, and untainted by the Anglo-Irish community.[32] A sense of national identity and Irish distinctiveness as well as an anti-English assertiveness was reinforced to Catholics by teachers in hedge schools.[33] A feeling of anti-English sentiment intensified within Irish nationalism during the Boer wars\|Boer War leading to xenophobia underlined by Anglophobia.[34] Resulting in two units of Irish commandos who fought with the Boeragainst British forces during the Second Boer War (1899–1902). J. Donnolly a member of the brigade wrote to the editor of Irish News in 1901 stating; "It was not for the love of the Boer war we were fighting; it was for the hatred of the English."J. Donnolly letter to the Irish News 1901[35] The pro-Boer movement gained widespread support in Ireland and over 20.000 supporters demonstrated in Dublin in 1899 where Irish nationalism, anti-English and pro-Boer attitudes were one and the same. There was a pro-Boer movement in England however the English pro-Boer movement was not based on anti-English sentiments. These opposing views and animosity led the English and Irish pro-Boer groups to maintain a distance from one another.[36] The William Butler Yeats\|W. B. Yeats play The Countess Cathleen, written in 1892, has anti-English overtones comparing the English gentry to demons who come for Irish souls.[37] Films set during the Irish War of Independence, such as The Informer (1935 film)\|The Informer (1935) and the The Plough and the Stars (film)\|Plough and the Stars (1936), were criticised by the British Board of Film Classification\|BBFC for the director John Ford's anti-English content,[38] and, in recent years, Michael Collins (film)\|Michael Collins[39][40] and The Wind That Shakes the Barley (film)\|The Wind That Shakes the Barley[41][42] (despite being a joint British-Irish production) have led to accusations of Anglophobia in the British press. In 2006, Antony Booth, the father-in law of Tony Blair, claimed he was the victim of anti-English vandalism and discrimination while living in County Cavan, Ireland, with his wife.[43] In addition, in August 2008 an English pipefitter based in Dublin was awarded €20,000 for the racial abuse and discrimination he received at his workplace.[44] In 2011, tensions and anti-English or anti-British feelings flared in relation to the proposed visit of Elizabeth II, the first Monarchy of the United Kingdom\|British monarch to visit Ireland in 101 years. The direct invitation by the President of Ireland, Mary McAleese, and the Irish government, was hailed by the Irish press as a historic visit,[45] but was criticised by Sinn Féin President Gerry Adams.[46] An anti-Queen demonstration was held at the GPO Dublin by a small group of Irish Republicans on 26 February 2011,[citation needed] and a mock trial and decapitation of an effigy of Queen Elizabeth II were carried out by socialist republican group Éirígí.[47] Other protests included one Dublin publican (the father of Celtic player Anthony Stokes) hanging a banner declaring "the Queen will never be welcome in this country".[48][49] ## France After the Norman conquest in 1066, Anglo-Norman replaced English as the official language of England. However, in the thirteenth and fourteenth centuries, the Plantagenet kings of England lost most of their possessions in France, began to consider England to be their primary domain, and turned to the English language. King Edward I, when issuing writs for summoning parliament in 1295, claimed that the King of France planned to invade England and extinguish the English language, "a truly detestable plan which may God avert".[50][51] In 1338, Philip VI of France authored the Ordinance of Normandy, which again called for the destruction and elimination of the English nation and language. The Hundred Years' War (1337–1453) between England and France changed societies on both sides of the Channel. The English and French were engaged in numerous wars in the following centuries. England's ongoing conflict with Scotland provided France with an opportunity to destabilise England, and there was a firm friendship (known as the Auld Alliance) between France and Scotland from the late-thirteenth century to the mid-sixteenth century. The alliance eventually foundered because of growing Protestantism in Scotland. Opposition to Protestantism became a major feature of later French Anglophobia (and conversely, fear of Catholicism was a hallmark of Francophobia). Antipathy and intermittent hostilities between France and Britain, as distinct from England, continued during later centuries. It has become more and more political. ## United States In 2002, academic John Moser said that, although anglophobia is now "almost completely absent" from United States society, this was not always the case. He stated that "there were strains of anglophobia present in virtually every populist movement of the late 19th and early 20th centuries", with the Populist Party, for example, "referring to England as a 'monster' that had 'seized upon the fresh energy of America and is steadily fixing its fangs into our social life.'" Reasons suggested for the decline in anglophobia included the impact of the Second World War, and reduced political support for Irish nationalist movements compared with that in earlier periods. Moser also said:[52] "In an age when the wealthiest and most influential Americans tended to be associated with things British—the vast majority were of Anglo-Saxon descent, wore English-tailored suits, drove British-made automobiles, and even spoke with affected British accents—it was quite natural for Great Britain to fall within the sights of disaffected populists. In more recent years, however, this has changed. When one thinks of wealth and influence in contemporary America, particularly when one considers those who have made their fortunes in the past thirty years, English culture does not immediately spring to mind. The film industry is widely perceived to give a British nationality to a disproportionate number of villains.[53] Lyndon LaRouche, a perennial candidate for US President and a movement leader known for theories of conspiracies, has been called the "most illustrious" Anglophobe in American politics.[54] ### Anglophobia in the Irish-American community The Irish-American community in the United States has historically shown antipathy towards the English in particular.[55] Anglophobia has been a defining feature of the post-famine Irish-American experience. Bolstered by their support of Irish nationalism, Irish-American communities have been staunchly anti-English since the 1850s and this sentiment is fostered within the Irish-American identity.[56][57] Irish immigrants who settled in the United States often prospered there, retained the bitterest animosity to England and many of them subscribed from their weekly wage to keep up the anti-English agitation.[58] This was due in part to the nature of their history and manner of their emigration, when they brought with them a strong specific sense of Anglophobia.[55][56] Irish-American newspapers, like the pro-Catholic "Truth Teller" which was founded in 1825 by an anti-English priest, were influential in the identity of the community.[59] Anglophobia in print was also seen in the autobiographies of noted Irish-Americans; Elizabeth Gurley a leading American socialist,[60] and William Z. Foster who reported in his own memoirs his own father died at over eighty, he never said the word England without adding “God damn her!”.[60] In 1842, the first national gathering of Irish-Americans took place in Philadelphia: The convention ended with anti-English speeches and three cheers for Ireland…[]…Thus they influenced the progress of nationalism in Ireland and shaped their Irish-American identity[60] Anti-English feelings among Irish-Americans spread to American culture through Irish-American performers in popular Blackface minstral shows. These imparted both elements of the Irish-Americans performers own national bias, and the popular stereotypical image that the English people were bourgeois aloof or upper class.[61] Sentiments quickly turned into direct and volent action when in the 1860s the Fenian Brotherhood Society invaded Canada to provoke a United States-British war in hope it would lead to Irish freedom.[62] Violence is said to have included direct action by Fenian sympathisers, with the assassination of Thomas D'Arcy McGee himself an Irish-Canadian and Irish nationalist who was against the invasion, although he was very critical of the Orange Order, and it has long been suspected they were his true killers.[63] Goldwin Smith, Professor at Cornell University, wrote in the North American Review that ‘hatred of England’ was used as a tool to win the Irish-American vote.[64] An observation shared in 1900 by the Secretary of State for the United States John Hay who openly criticise the Prairie Populist and his own Democratic Parties political pandering to attract the support of the Irish diaspora: "state conventions put on an anti-English plank in their platforms to curry favor with the Irish (whom they want to keep) and the Germans whom they want to seduce. It is too disgusting to have to deal with such sordid lies."John Hay Secretary of State for the United States in 1900[62] Well into the early 20th century anti-English sentiment was increasing with famine memorials in the Irish-American communities, quote “served as a wellspring for their obsessive and often corrosive antipathy”, as noted in the British Parliament in 1915: There is no part of the world where anti-English influences worked so powerfully than in the United States. Almost every Irishman there is the son or grandson of an evicted tenant – evicted in all the horrors of the black 40s. And most of them have heard stories of them from their mother’s knee. [65] Some newspapers, including the San Francisco Leader and New York Irish World, first published in 1823, were renowned for their anti-English articles.[66] The Irish World blamed the mainland United Kingdom for the depopulation and desolate state of Ireland's industries.[67] One newspaper, the Gaelic American, called a student performance of the British national anthem by some girls of Irish heritage from a convent school an act of disloyalty, where they were taught to reverence the traditions of the hereditary enemy of their race and religion.[67] A commemorative stamp by philanthropist Andrew Carnegie on a century of peace between America and Great Britain was criticised by the Irish-American press.[67] In recent years American political commentators, such as Pat Buchanan, have highlighted the anti-English stance of the Irish Diaspora in the United States of America.[62] ## Iran Anti-British sentiment has been described as "deeply entrenched in Iranian culture",[68] and reported to be increasingly prevalent in Iran. In July 2009, an adviser to Ali Khamenei called Britain "worse than America" for its alleged interference in Iran's post-election affairs. Animosity has been dated back to the early 19th century, when a British diplomat, Sir Gore Ouseley, was responsible for drawing up the country's boundaries after the First Russo-Persian War.[69] In the first half of the 20th century, the British Empire exerted political influence over Iran (Persia) in order to control the profits from the Anglo-Iranian Oil Company. As a result, British influence was widely known to have been behind the overthrow of the Qajar Dynasty in the 1920s, the subsequent rise of Reza Shah Pahlavi, and the successful coup d'etat overthrowing prime minister Mohammad Mosaddeq in 1953.[70][71][72] In November 2011, attacks on the UK's embassy in Tehran led to the closure of the embassy and the expulsion of Iranian diplomats from the UK, with the Iranian parliamentary chairman Ali Larijani stating that the incident was the outcome of "decades of domineering moves by the British in Iran".[69] The classic Iranian novel My Uncle Napoleon, published in 1973, lampoons the widespread belief that the English are responsible for events that occur in Iran.[citation needed] ## Australia and New Zealand "Pommy" or "Pom" (probably derived from "pomegranate", rhyming slang for "immigrant")[73] is a common Australasian and South African slang word for the English, often combined with "whing[e]ing" (complaining) to make the expression "whingeing Pom" – an English immigrant who stereotypically complains about everything. Although the term is sometimes applied to British immigrants generally, it is usually applied specifically to the English, by both Australians and New Zealanders.[74][75] From the 19th century onwards, there were feelings among established Australians that many immigrants from England were poorly skilled, unwanted by their home country, and unappreciative of the benefits of their new country.[76] In recent years, complaints about two newspaper articles blaming English tourists for littering a local beach, and headed "Filthy Poms" and "Poms fill the summer of our discontent", were accepted as complaints and settled through conciliation by the Australian Human Rights Commission when the newspapers published apologies. However, letters and articles which referred to English people as "Poms" or "Pommies" did not meet the threshold for racial hatred.[77] In 2007 a complaint to Australia's Advertising Standards Bureau about a television commercial using the term "Pom" was upheld and the commercial was withdrawn.[78] Films such as Gallipoli and Breaker Morant have highlighted anti-British sentiment felt by some Australians.[citation needed]	https://www.wikidoc.org/index.php/Anglophobia
1d27d3bcb704ba8bfade242301fd64ce2b973c02	wikidoc	Exoskeleton	Exoskeleton An exoskeleton is an external anatomical feature that supports and protects an animal's body, in contrast to the internal endoskeleton of, for example, a human. Whilst many many other invertebrate animals (such as shelled mollusks) have exoskeletons in the sense of external hard parts, the character is most associated with the arthropods (i.e. insects, spiders, myriapods and crustaceans). Exoskeletons contain rigid and resistant components that fulfil a set of functional roles including protection, excretion, sensing, support, feeding and (for terrestrial organisms) acting as a barrier against desiccation. Exoskeletons first appeared in the fossil record about 550 million years ago, and their evolution has been seen as critical as a driving role in the Cambrian explosion of animals that took place subsequent to this time. # Arthropod exoskeletons ## Microscopic structure A typical arthropod exoskeleton is a multi-layered structure with four functional regions: epicuticle, procuticle, epidermis and basement membrane.. Of these, the epicuticle is a multi-layered external barrier that, especially in terrestrial arthropods, acts as a barrier against dessiccation. The strength of the exoskeleton is provided by the underlying procuticle, which is in turn secreted by the epidermis. Arthropod cuticle is a biological composite material, consisting of two main portions: fibrous chains of alpha-chitin within a matrix of silk-like and globular proteins, of which the most well-known is the rubbery protein called resilin. The relative abundance of these two main components varies from approximately 50/50 to 70/30 protein/chitin, with softer parts of the exoskeleton having a higher proportion of chitin. Although the cuticle is relatively soft when first secreted, it soon hardens in a poorly-understood process that involves dehydration and/or tanning mediated by hydrophobic chemicals called phenolics. Different types of interaction between the proteins and chitin leads to varying mechanical properties of the exoskeleton. In addition to the chitino-proteinaceous composite of the cuticle, many crustaceans, some myriapods and the extinct trilobites further impregnate the cuticle with mineral salts, above all calcium carbonate, which can make up up to 40% of the cuticle. This can lead to great mechanical strength. ## Organisation The arthropod exoskeleton is typically divided into different functional units to allow flexibility in an often otherwise rigid structure. For example, the head is a fused capsule; and the trunk is often divided into a series of articulating sclerites called tergites. In addition, the characteristic limbs of arthropods need to be jointed. The internal surface of the exoskeleton is often elaborated into a set of specialised structures called apodemes that allow the attachment of muscles. Such endoskeletal components of the arthropod skeleton can be highly complex, as in crabs and lobsters. ## Ecdysis - See also main article: Ecdysis The relative rigidity of the exoskeleton means that continuous growth of arthropods is not possible. Therefore, growth is periodic and concentrated into a period of time when the exoskeleton is shed, called moulting or ecdysis, which is under the control of a hormone called ecdysone. Moulting is a complex process that is invariably dangerous for the arthropod involved. Before the old exoskeleton is shed, the cuticle separates from the epidermis through a process called apolysis. New cuticle is excreted by the underlying epidermis, and mineral salts are usually withdrawn from the old cuticle for re-use. After the old cuticle is shed, the arthropod typically pumps up its body (for example, by air or water intake) to allow the new cuticle to expand to a larger size: the process of hardening by dehydration of the cuticle then takes place. Newly molted arthropods typically appear pale or white, and darken as the cuticle hardens. # Natural exoskeletons Excellent as defensive adaptation, exoskeletons may nevertheless cause problems where entities carry an excessive weight to surface-area ratio or whenever organism growth requires an enlargement of the exoskeleton. Exoskeletons are found on many different types of organisms including shellfish and insects. ## Types - Bone and cartilage Ostracoderms (extinct armoured fish) Turtles, Terrapins and Tortoises - Ostracoderms (extinct armoured fish) - Turtles, Terrapins and Tortoises - Chitin Arthropods some Bacteria - Arthropods - some Bacteria - Calcium compounds Corals Echinoderms Mollusks some Polychaetes - Corals - Echinoderms - Mollusks - some Polychaetes - Silicate Diatoms Radiolaria - Diatoms - Radiolaria # Artificial human exoskeletons Humans have long used armour as an artificial exoskeleton for protection, especially in combat. Exoskeletal machines are also starting to be used for medical and industrial purposes, while Powered human exoskeletons are a feature of science fiction writing, but are currently moving into prototype stage. Orthoses are a limited, medical form of exoskeleton. ## In history Medieval armour (in the case of mounted knights) is not load-bearing, but furnishes the appearance of an artificial human exoskeleton. ## In medicine An orthosis (plural orthoses) is a device which attaches to a limb, or the torso, to support the function or correct the shape of that limb or the spine. Orthotics is the field dealing with orthoses, their use, and their manufacture. An orthotist is a person who designs and fits orthoses. A limb prosthesis (plural prostheses) is a device that substitutes for a missing part of a limb. If the prosthesis is a hollow shell and self-carrying, it is exoskeletal. If internal tubes are used in the device and the cover (cosmesis) to create the outside shape is made of a soft, non-carrying material, it is endoskeletal. Prosthetics is the field that deals with prostheses, use, and their manufacture. A prosthetist is a person who designs and fits prostheses. ## In modern and near-future technology	Exoskeleton An exoskeleton is an external anatomical feature that supports and protects an animal's body, in contrast to the internal endoskeleton of, for example, a human. Whilst many many other invertebrate animals (such as shelled mollusks) have exoskeletons in the sense of external hard parts, the character is most associated with the arthropods (i.e. insects, spiders, myriapods and crustaceans). Exoskeletons contain rigid and resistant components that fulfil a set of functional roles including protection, excretion, sensing, support, feeding and (for terrestrial organisms) acting as a barrier against desiccation. Exoskeletons first appeared in the fossil record about 550 million years ago, and their evolution has been seen as critical as a driving role in the Cambrian explosion of animals that took place subsequent to this time. # Arthropod exoskeletons ## Microscopic structure A typical arthropod exoskeleton is a multi-layered structure with four functional regions: epicuticle, procuticle, epidermis and basement membrane.[1]. Of these, the epicuticle is a multi-layered external barrier that, especially in terrestrial arthropods, acts as a barrier against dessiccation. The strength of the exoskeleton is provided by the underlying procuticle, which is in turn secreted by the epidermis. Arthropod cuticle is a biological composite material, consisting of two main portions: fibrous chains of alpha-chitin within a matrix of silk-like and globular proteins, of which the most well-known is the rubbery protein called resilin. The relative abundance of these two main components varies from approximately 50/50 to 70/30 protein/chitin, with softer parts of the exoskeleton having a higher proportion of chitin. Although the cuticle is relatively soft when first secreted, it soon hardens in a poorly-understood process that involves dehydration and/or tanning mediated by hydrophobic chemicals called phenolics. Different types of interaction between the proteins and chitin leads to varying mechanical properties of the exoskeleton. In addition to the chitino-proteinaceous composite of the cuticle, many crustaceans, some myriapods and the extinct trilobites further impregnate the cuticle with mineral salts, above all calcium carbonate, which can make up up to 40% of the cuticle. This can lead to great mechanical strength. ## Organisation The arthropod exoskeleton is typically divided into different functional units to allow flexibility in an often otherwise rigid structure. For example, the head is a fused capsule; and the trunk is often divided into a series of articulating sclerites called tergites. In addition, the characteristic limbs of arthropods need to be jointed. The internal surface of the exoskeleton is often elaborated into a set of specialised structures called apodemes that allow the attachment of muscles. Such endoskeletal components of the arthropod skeleton can be highly complex, as in crabs and lobsters. ## Ecdysis - See also main article: Ecdysis The relative rigidity of the exoskeleton means that continuous growth of arthropods is not possible. Therefore, growth is periodic and concentrated into a period of time when the exoskeleton is shed, called moulting or ecdysis, which is under the control of a hormone called ecdysone. Moulting is a complex process that is invariably dangerous for the arthropod involved. Before the old exoskeleton is shed, the cuticle separates from the epidermis through a process called apolysis. New cuticle is excreted by the underlying epidermis, and mineral salts are usually withdrawn from the old cuticle for re-use. After the old cuticle is shed, the arthropod typically pumps up its body (for example, by air or water intake) to allow the new cuticle to expand to a larger size: the process of hardening by dehydration of the cuticle then takes place. Newly molted arthropods typically appear pale or white, and darken as the cuticle hardens. # Natural exoskeletons Template:Sect-stub Excellent as defensive adaptation, exoskeletons may nevertheless cause problems where entities carry an excessive weight to surface-area ratio or whenever organism growth requires an enlargement of the exoskeleton. Exoskeletons are found on many different types of organisms including shellfish and insects. ## Types - Bone and cartilage Ostracoderms (extinct armoured fish) Turtles, Terrapins and Tortoises - Ostracoderms (extinct armoured fish) - Turtles, Terrapins and Tortoises - Chitin Arthropods some Bacteria - Arthropods - some Bacteria - Calcium compounds Corals Echinoderms Mollusks some Polychaetes - Corals - Echinoderms - Mollusks - some Polychaetes - Silicate Diatoms Radiolaria - Diatoms - Radiolaria # Artificial human exoskeletons Humans have long used armour as an artificial exoskeleton for protection, especially in combat. Exoskeletal machines are also starting to be used for medical and industrial purposes, while Powered human exoskeletons are a feature of science fiction writing, but are currently moving into prototype stage. Orthoses are a limited, medical form of exoskeleton. ## In history Medieval armour (in the case of mounted knights) is not load-bearing, but furnishes the appearance of an artificial human exoskeleton. ## In medicine An orthosis (plural orthoses) is a device which attaches to a limb, or the torso, to support the function or correct the shape of that limb or the spine. Orthotics is the field dealing with orthoses, their use, and their manufacture. An orthotist is a person who designs and fits orthoses. A limb prosthesis (plural prostheses) is a device that substitutes for a missing part of a limb. If the prosthesis is a hollow shell and self-carrying, it is exoskeletal. If internal tubes are used in the device and the cover (cosmesis) to create the outside shape is made of a soft, non-carrying material, it is endoskeletal. Prosthetics is the field that deals with prostheses, use, and their manufacture. A prosthetist is a person who designs and fits prostheses. ## In modern and near-future technology	https://www.wikidoc.org/index.php/Animal_shell
9da246b71a9fe5df387ef61a70b12ae1b304e799	wikidoc	Aniseikonia	Aniseikonia Aniseikonia is a binocular condition in which the two eyes perceive images of different size. These unequal images can be caused by a difference in: - optical magnification (i.e. different retinal image sizes) - retinal receptor distribution (i.e. a different sampling of the retinal images) - cortical processing (i.e. different processing of the sampled retinal images) # Patients at risk of aniseikonia Aniseikonia is often associated with unequal refractive errors between the eyes (anisometropia). However, there are several other patient groups at risk. For example, research has shown that appr. 40% of the patients that underwent cataract surgery/surgeries and who had an intra-ocular lens(es) implanted, have complaints referable to aniseikonia. This also makes one wonder how much aniseikonia is induced with refractive surgery such as LASIK. Another group of patients at risk are patients who have a retinal condition or who underwent retinal surgery. For example with an epiretinal membrane (macular pucker) or after a retinal detachment surgery. The aniseikonia in these patients may be complicated because the aniseikonia is field-dependent (variable over the retina), but fortunately also these patients often can get more comfortable binocular vision by optically correcting the aniseikonia. # Symptoms Most aniseikonic symptoms are quite general (a-specific), for example: headaches, asthenopia (ocular fatigue, burning, tearing, pain, pulling, etc.), light sensitivity, reading difficulty, nausea, and double images (diplopia). This is one of the reasons why aniseikonia is sometimes overseen by the treating eye care provider. Only, if the aniseikonia is severe, the patient could also actually see an image size difference by closing one eye at a time. However, symptoms usually occur already with much less aniseikonia. # Clinically significant aniseikonia values Aniseikonia of 3% or more is generally considered clinically significant, but sensitive individuals may have symptoms with less aniseikonia. # Testing for aniseikonia Testing for aniseikonia is important. In older books sometimes rules of thumb are given based on retinal images size differences alone. However, research has shown that even in anisometropia the retinal receptor distribution may be different between the eyes, making aniseikonia management based on calculated retinal image sizes inaccurate. Testing for aniseikonia can be done using a space eikonometric method (based on space distortions accompanying the aniseikonia) or a direct comparison method. The space eikonometric method is sometimes still used in research, but it is less suited for clinical purposes (and commercially unavailable). There are two commerically available aniseikonia tests: the New Aniseikonia Test1 (NAT, 1982) and the Aniseikonia Inspector2 (2003-2007). The first is a booklet and the second is software. The two tests are based on the same principle, but the Aniseikonia Inspector has several advanges due to the interactive possibilities when using a computer. Also, the Aniseikonia Inspector contains a module to calculate aniseikonia correcting prescriptions. # Correcting aniseikonia Aniseikonia can be corrected by changing the optical magnification properties of the auxilary optics (glasses, contact lenses). For example, if the curvature or thickness of a spectacle lens is changed (without changing its refractive power, so there will still be a good visual acuity), the optical magnification will change. Also, the distance between the spectacle lens and the eye (vertex distance) affects the optical magnification. Therefore, contact lenses will in general give a different aniseikonia than glasses. It might even be possible to correct aniseikonia by fitting a contact lens together with a spectacle lens, creating a weak telescope system. What solution is best depends on the amount of aniseikonia, type of aniseikonia (optical-induced or retinally-induced), the refraction, and the importance of cosmetics. For more information on aniseikonia and possible correction options, see Optical Diagnostics' aniseikonia webpage3.	Aniseikonia Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Aniseikonia is a binocular condition in which the two eyes perceive images of different size. These unequal images can be caused by a difference in: - optical magnification (i.e. different retinal image sizes) - retinal receptor distribution (i.e. a different sampling of the retinal images) - cortical processing (i.e. different processing of the sampled retinal images) # Patients at risk of aniseikonia Aniseikonia is often associated with unequal refractive errors between the eyes (anisometropia). However, there are several other patient groups at risk. For example, research has shown that appr. 40% of the patients that underwent cataract surgery/surgeries and who had an intra-ocular lens(es) implanted, have complaints referable to aniseikonia. This also makes one wonder how much aniseikonia is induced with refractive surgery such as LASIK. Another group of patients at risk are patients who have a retinal condition or who underwent retinal surgery. For example with an epiretinal membrane (macular pucker) or after a retinal detachment surgery. The aniseikonia in these patients may be complicated because the aniseikonia is field-dependent (variable over the retina), but fortunately also these patients often can get more comfortable binocular vision by optically correcting the aniseikonia. # Symptoms Most aniseikonic symptoms are quite general (a-specific), for example: headaches, asthenopia (ocular fatigue, burning, tearing, pain, pulling, etc.), light sensitivity, reading difficulty, nausea, and double images (diplopia). This is one of the reasons why aniseikonia is sometimes overseen by the treating eye care provider. Only, if the aniseikonia is severe, the patient could also actually see an image size difference by closing one eye at a time. However, symptoms usually occur already with much less aniseikonia. # Clinically significant aniseikonia values Aniseikonia of 3% or more is generally considered clinically significant, but sensitive individuals may have symptoms with less aniseikonia. # Testing for aniseikonia Testing for aniseikonia is important. In older books sometimes rules of thumb are given based on retinal images size differences alone. However, research has shown that even in anisometropia the retinal receptor distribution may be different between the eyes, making aniseikonia management based on calculated retinal image sizes inaccurate. Testing for aniseikonia can be done using a space eikonometric method (based on space distortions accompanying the aniseikonia) or a direct comparison method. The space eikonometric method is sometimes still used in research, but it is less suited for clinical purposes (and commercially unavailable). There are two commerically available aniseikonia tests: the New Aniseikonia Test1 (NAT, 1982) and the Aniseikonia Inspector2 (2003-2007). The first is a booklet and the second is software. The two tests are based on the same principle, but the Aniseikonia Inspector has several advanges due to the interactive possibilities when using a computer. Also, the Aniseikonia Inspector contains a module to calculate aniseikonia correcting prescriptions. # Correcting aniseikonia Aniseikonia can be corrected by changing the optical magnification properties of the auxilary optics (glasses, contact lenses). For example, if the curvature or thickness of a spectacle lens is changed (without changing its refractive power, so there will still be a good visual acuity), the optical magnification will change. Also, the distance between the spectacle lens and the eye (vertex distance) affects the optical magnification. Therefore, contact lenses will in general give a different aniseikonia than glasses. It might even be possible to correct aniseikonia by fitting a contact lens together with a spectacle lens, creating a weak telescope system. What solution is best depends on the amount of aniseikonia, type of aniseikonia (optical-induced or retinally-induced), the refraction, and the importance of cosmetics. For more information on aniseikonia and possible correction options, see Optical Diagnostics' aniseikonia webpage3. # External links 1. New Aniseikonia Test 2. Aniseikonia Inspector 3. More information on aniseikonia. Template:WS	https://www.wikidoc.org/index.php/Aniseikonia
c927774deba735cf3550ea6dfa2258424b5c1458	wikidoc	Homatropine	Homatropine # Disclaimer WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here. # Overview Homatropine is a anticholinergic agent that is FDA approved for the treatment of inflammatory conditions of the uveal tract, for cycloplegic refraction and as an optical aid in some cases of axial lens opacities. Common adverse reactions include stinging and burning sensation in eye. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) ### Indications - A moderately long-acting mydriatic and cycloplegic for cycloplegic refraction and in the treatment of inflammatory conditions of the uveal tract. For pre- and postoperative states when mydriasis is required. Use as an optical aid in some cases of axial lens opacities. ### Dosage - For refraction, instill one or two drops topically in the eye(s). May be repeated in five to ten minutes if necessary. For uveitis, instill one or two drops topically up to every three to four hours. Individuals with heavily pigmented irides may require larger doses. Only the 2% strength should be used in pediatric patients. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Homatropine in adult patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Homatropine in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) There is limited information regarding FDA-Labeled Use of Homatropine in pediatric patients. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Homatropine in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Homatropine in pediatric patients. # Contraindications - Contraindicated in persons with primary glaucoma or a tendency toward glaucoma, e.g., narrow anterior chamber angle, and in those persons showing hypersensitivity to any component of this preparation. # Warnings - FOR TOPICAL OPHTHALMIC USE ONLY - NOT FOR INJECTION. Risk-benefit should be considered when the following medical problems exist: keratoconus (homatropine may produce fixed dilated pupil); Down’s syndrome, children with brain damage and the elderly (increased susceptibility). In infants and small children, use with extreme caution. ### Precautions - To avoid excessive systemic absorption, the lacrimal sac should be compressed by digital pressure for two to three minutes after instillation. To avoid inducing angle closure glaucoma, an estimation of the depth of the angle of the anterior chamber should be made. Excessive topical use of this drug can potentially lead to a confusional state characterized by delirium, agitation, and rarely coma. This state is more apt to occur in the pediatric and geriatric age groups. The specific antidote for this systemic anticholinergic syndrome is injectable physostigmine salicylate. # Adverse Reactions ## Clinical Trials Experience - Transient symptoms of stinging and burning] may occur. Prolonged use may produce local irritation characterized by follicular conjunctivitis, vascular congestion, edema, exudate, and an eczematoid dermatitis. Thirst or dryness of mouth, eye irritation not present before therapy, or increased sensitivity of eyes to light may occur. - Systemic homatropine toxicity is manifested by flushing and dryness of the skin (a rash may be present in children), blurred vision, a rapid and irregular pulse, fever, abdominal distention in infants, mental aberration (hallucinosis) and loss of neuro-muscular coordination. Atropine poisoning, although distressing, is rarely fatal even with large doses of atropine, and is self-limited if the cause is recognized and the homatropine medication is discontinued. Treatment includes supportive measures including maintaining a patent airway and assisting respiration if needed. Treat hyperthermia, coma and seizures if they occur (1). In infants and children, the body surface must be kept moist. Excitement may be controlled by diazepam or a short-acting barbiturate. For ingestion, activated charcoal can be used to prevent drug absorption. If necessary, ipecac or another cathartic may be useful for drug removal during initial treatment (1, 2). Physostigmine is used as an antidote to the systemic effects of atropine and may be administered parenterally to provide more prompt relief of intoxication. Parenteral physostigmine may be particularly useful in cases of pronounced hallucinations, agitation in which a patient may be dangerous to himself or others, arrhythmias resulting in uncontrolled hemodynamic instability, and intractable seizures. ## Postmarketing Experience There is limited information regarding Postmarketing Experience of Homatropine in the drug label. # Drug Interactions There is limited information regarding Homatropine Drug Interactions in the drug label. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): C - Animal reproduction studies have not been conducted with homatropine hydrobromide. It is also not known whether homatropine hydrobromide can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Homatropine hydrobromide should be given to a pregnant woman only if clearly needed. Pregnancy Category (AUS): - Australian Drug Evaluation Committee (ADEC) Pregnancy Category There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Homatropine in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Homatropine during labor and delivery. ### Nursing Mothers - It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when homatropine hydrobromide is administered to a nursing woman. ### Pediatric Use - Safety and effectiveness in pediatric patients have not been established. ### Geriatic Use - No overall differences in safety or effectiveness have been observed between elderly and younger patients. ### Gender There is no FDA guidance on the use of Homatropine with respect to specific gender populations. ### Race There is no FDA guidance on the use of Homatropine with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Homatropine in patients with renal impairment. ### Hepatic Impairment There is no FDA guidance on the use of Homatropine in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Homatropine in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Homatropine in patients who are immunocompromised. # Administration and Monitoring ### Administration - topical eye drops ### Monitoring There is limited information regarding Monitoring of Homatropine in the drug label. # IV Compatibility There is limited information regarding IV Compatibility of Homatropine in the drug label. # Overdosage - Systemic homatropine toxicity is manifested by flushing and dryness of the skin (a rash may be present in children), blurred vision, a rapid and irregular pulse, fever, abdominal distention in infants, mental aberration (hallucinosis) and loss of neuro-muscular coordination. Atropine poisoning, although distressing, is rarely fatal even with large doses of atropine, and is self-limited if the cause is recognized and the homatropine medication is discontinued. Treatment includes supportive measures including maintaining a patent airway and assisting respiration if needed. Treat hyperthermia, coma and seizures if they occur (1). In infants and children, the body surface must be kept moist. Excitement may be controlled by diazepam or a short-acting barbiturate. For ingestion, activated charcoal can be used to prevent drug absorption. If necessary, ipecac or another cathartic may be useful for drug removal during initial treatment (1, 2). Physostigmine is used as an antidote to the systemic effects of atropine and may be administered parenterally to provide more prompt relief of intoxication. Parenteral physostigmine may be particularly useful in cases of pronounced hallucinations, agitation in which a patient may be dangerous to himself or others, arrhythmias resulting in uncontrolled hemodynamic instability, and intractable seizures. # Pharmacology ## Mechanism of Action - This anticholinergic preparation blocks the responses of the sphincter muscle of the iris and the accommodative muscle of the ciliary body to cholinergic stimulation, producing pupillary dilation (mydriasis) and paralysis of accommodation (cycloplegia). ## Structure - ISOPTO® Homatropine (homatropine hydrobromide ophthalmic solution) is an anticholinergic prepared as a sterile topical ophthalmic solution supplied in two strengths. The active ingredient is represented by the chemical structure: - Established name: Homatropine Hydrobromide - Chemical name: Benzeneacetic acid, α-hydroxy-, 8-methyl-8-azabicyclo-oct-3-yl ester, hydrobromide, endo-(±)-. - Each mL contains: Active: homatropine hydrobromide 2.0% or 5.0%. Preservatives: benzalkonium chloride 0.01% in 2% strength, benzethonium chloride 0.005% in 5% strength. Vehicle: hypromellose 0.5%. Inactives: sodium chloride, polysorbate 80 (in 2% strength), sodium hydroxide and/or hydrochloric acid (to adjust pH), purified water. ## Pharmacodynamics There is limited information regarding Pharmacodynamics of Homatropine in the drug label. ## Pharmacokinetics There is limited information regarding Pharmacokinetics of Homatropine in the drug label. ## Nonclinical Toxicology - There have been no long-term studies done using homatropine hydrobromide in animals to evaluate carcinogenic potential. # Clinical Studies There is limited information regarding Clinical Studies of Homatropine in the drug label. # How Supplied - 5 mL in plastic DROP-TAINER® Dispensers. ## Storage - Store at 8° - 24°C (46° - 75°F). # Images ## Drug Images ## Package and Label Display Panel ### PRINCIPAL DISPLAY PANEL NDC 0998-0311-05 Alcon® Isopto® Homatropine 2% (homatropine hydrobromide ophthalmic solution) 5 mL Sterile ### Ingredients and Appearance # Patient Counseling Information - Patient should be advised not to drive or engage in other hazardous activities while pupils are dilated. Patient may experience sensitivity to light and should protect eyes in bright illumination during dilation. Parents should be warned not to get this preparation in their child’s mouth and to wash their own hands and the child’s hands following administration. Do not touch dropper tip to any surface, as this may contaminate the solution. # Precautions with Alcohol - Alcohol-Homatropine interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - ISOPTO HOMATROPINE® # Look-Alike Drug Names There is limited information regarding Homatropine Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	Homatropine Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Rabin Bista, M.B.B.S. [2] # Disclaimer WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here. # Overview Homatropine is a anticholinergic agent that is FDA approved for the treatment of inflammatory conditions of the uveal tract, for cycloplegic refraction and as an optical aid in some cases of axial lens opacities. Common adverse reactions include stinging and burning sensation in eye. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) ### Indications - A moderately long-acting mydriatic and cycloplegic for cycloplegic refraction and in the treatment of inflammatory conditions of the uveal tract. For pre- and postoperative states when mydriasis is required. Use as an optical aid in some cases of axial lens opacities. ### Dosage - For refraction, instill one or two drops topically in the eye(s). May be repeated in five to ten minutes if necessary. For uveitis, instill one or two drops topically up to every three to four hours. Individuals with heavily pigmented irides may require larger doses. Only the 2% strength should be used in pediatric patients. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Homatropine in adult patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Homatropine in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) There is limited information regarding FDA-Labeled Use of Homatropine in pediatric patients. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Homatropine in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Homatropine in pediatric patients. # Contraindications - Contraindicated in persons with primary glaucoma or a tendency toward glaucoma, e.g., narrow anterior chamber angle, and in those persons showing hypersensitivity to any component of this preparation. # Warnings - FOR TOPICAL OPHTHALMIC USE ONLY - NOT FOR INJECTION. Risk-benefit should be considered when the following medical problems exist: keratoconus (homatropine may produce fixed dilated pupil); Down’s syndrome, children with brain damage and the elderly (increased susceptibility). In infants and small children, use with extreme caution. ### Precautions - To avoid excessive systemic absorption, the lacrimal sac should be compressed by digital pressure for two to three minutes after instillation. To avoid inducing angle closure glaucoma, an estimation of the depth of the angle of the anterior chamber should be made. Excessive topical use of this drug can potentially lead to a confusional state characterized by delirium, agitation, and rarely coma. This state is more apt to occur in the pediatric and geriatric age groups. The specific antidote for this systemic anticholinergic syndrome is injectable physostigmine salicylate. # Adverse Reactions ## Clinical Trials Experience - Transient symptoms of stinging and burning] may occur. Prolonged use may produce local irritation characterized by follicular conjunctivitis, vascular congestion, edema, exudate, and an eczematoid dermatitis. Thirst or dryness of mouth, eye irritation not present before therapy, or increased sensitivity of eyes to light may occur. - Systemic homatropine toxicity is manifested by flushing and dryness of the skin (a rash may be present in children), blurred vision, a rapid and irregular pulse, fever, abdominal distention in infants, mental aberration (hallucinosis) and loss of neuro-muscular coordination. Atropine poisoning, although distressing, is rarely fatal even with large doses of atropine, and is self-limited if the cause is recognized and the homatropine medication is discontinued. Treatment includes supportive measures including maintaining a patent airway and assisting respiration if needed. Treat hyperthermia, coma and seizures if they occur (1). In infants and children, the body surface must be kept moist. Excitement may be controlled by diazepam or a short-acting barbiturate. For ingestion, activated charcoal can be used to prevent drug absorption. If necessary, ipecac or another cathartic may be useful for drug removal during initial treatment (1, 2). Physostigmine is used as an antidote to the systemic effects of atropine and may be administered parenterally to provide more prompt relief of intoxication. Parenteral physostigmine may be particularly useful in cases of pronounced hallucinations, agitation in which a patient may be dangerous to himself or others, arrhythmias resulting in uncontrolled hemodynamic instability, and intractable seizures. ## Postmarketing Experience There is limited information regarding Postmarketing Experience of Homatropine in the drug label. # Drug Interactions There is limited information regarding Homatropine Drug Interactions in the drug label. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): C - Animal reproduction studies have not been conducted with homatropine hydrobromide. It is also not known whether homatropine hydrobromide can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Homatropine hydrobromide should be given to a pregnant woman only if clearly needed. Pregnancy Category (AUS): - Australian Drug Evaluation Committee (ADEC) Pregnancy Category There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Homatropine in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Homatropine during labor and delivery. ### Nursing Mothers - It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when homatropine hydrobromide is administered to a nursing woman. ### Pediatric Use - Safety and effectiveness in pediatric patients have not been established. ### Geriatic Use - No overall differences in safety or effectiveness have been observed between elderly and younger patients. ### Gender There is no FDA guidance on the use of Homatropine with respect to specific gender populations. ### Race There is no FDA guidance on the use of Homatropine with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Homatropine in patients with renal impairment. ### Hepatic Impairment There is no FDA guidance on the use of Homatropine in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Homatropine in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Homatropine in patients who are immunocompromised. # Administration and Monitoring ### Administration - topical eye drops ### Monitoring There is limited information regarding Monitoring of Homatropine in the drug label. # IV Compatibility There is limited information regarding IV Compatibility of Homatropine in the drug label. # Overdosage - Systemic homatropine toxicity is manifested by flushing and dryness of the skin (a rash may be present in children), blurred vision, a rapid and irregular pulse, fever, abdominal distention in infants, mental aberration (hallucinosis) and loss of neuro-muscular coordination. Atropine poisoning, although distressing, is rarely fatal even with large doses of atropine, and is self-limited if the cause is recognized and the homatropine medication is discontinued. Treatment includes supportive measures including maintaining a patent airway and assisting respiration if needed. Treat hyperthermia, coma and seizures if they occur (1). In infants and children, the body surface must be kept moist. Excitement may be controlled by diazepam or a short-acting barbiturate. For ingestion, activated charcoal can be used to prevent drug absorption. If necessary, ipecac or another cathartic may be useful for drug removal during initial treatment (1, 2). Physostigmine is used as an antidote to the systemic effects of atropine and may be administered parenterally to provide more prompt relief of intoxication. Parenteral physostigmine may be particularly useful in cases of pronounced hallucinations, agitation in which a patient may be dangerous to himself or others, arrhythmias resulting in uncontrolled hemodynamic instability, and intractable seizures. # Pharmacology ## Mechanism of Action - This anticholinergic preparation blocks the responses of the sphincter muscle of the iris and the accommodative muscle of the ciliary body to cholinergic stimulation, producing pupillary dilation (mydriasis) and paralysis of accommodation (cycloplegia). ## Structure - ISOPTO® Homatropine (homatropine hydrobromide ophthalmic solution) is an anticholinergic prepared as a sterile topical ophthalmic solution supplied in two strengths. The active ingredient is represented by the chemical structure: - Established name: Homatropine Hydrobromide - Chemical name: Benzeneacetic acid, α-hydroxy-, 8-methyl-8-azabicyclo[3.2.1]-oct-3-yl ester, hydrobromide, endo-(±)-. - Each mL contains: Active: homatropine hydrobromide 2.0% or 5.0%. Preservatives: benzalkonium chloride 0.01% in 2% strength, benzethonium chloride 0.005% in 5% strength. Vehicle: hypromellose 0.5%. Inactives: sodium chloride, polysorbate 80 (in 2% strength), sodium hydroxide and/or hydrochloric acid (to adjust pH), purified water. ## Pharmacodynamics There is limited information regarding Pharmacodynamics of Homatropine in the drug label. ## Pharmacokinetics There is limited information regarding Pharmacokinetics of Homatropine in the drug label. ## Nonclinical Toxicology - There have been no long-term studies done using homatropine hydrobromide in animals to evaluate carcinogenic potential. # Clinical Studies There is limited information regarding Clinical Studies of Homatropine in the drug label. # How Supplied - 5 mL in plastic DROP-TAINER® Dispensers. ## Storage - Store at 8° - 24°C (46° - 75°F). # Images ## Drug Images ## Package and Label Display Panel ### PRINCIPAL DISPLAY PANEL NDC 0998-0311-05 Alcon® Isopto® Homatropine 2% (homatropine hydrobromide ophthalmic solution) 5 mL Sterile ### Ingredients and Appearance # Patient Counseling Information - Patient should be advised not to drive or engage in other hazardous activities while pupils are dilated. Patient may experience sensitivity to light and should protect eyes in bright illumination during dilation. Parents should be warned not to get this preparation in their child’s mouth and to wash their own hands and the child’s hands following administration. Do not touch dropper tip to any surface, as this may contaminate the solution. # Precautions with Alcohol - Alcohol-Homatropine interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - ISOPTO HOMATROPINE®[1] # Look-Alike Drug Names There is limited information regarding Homatropine Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	https://www.wikidoc.org/index.php/Anisotropine_Methylbromide
2a42134889adbb9767b056afe732c05c503bebce	wikidoc	Annexin A11	Annexin A11 Annexin A11 is a protein that in humans is encoded by the ANXA11 gene. # Function This gene encodes a member of the annexin family, a group of calcium-dependent phospholipid-binding proteins. Annexins have unique N-terminal domains and conserved C-terminal domains, which contain the calcium-dependent phospholipid-binding sites. The encoded protein is a 56-kD antigen recognized by sera from patients with various autoimmune diseases. Transcript variants encoding the same isoform have been identified. # Interactions ANXA11 has been shown to interact with PDCD6 and ALG2. # Clinical significance It is shown that over-expression of the ANXA11 is involved in apoptotic alterations in schizophrenia and contribute to pathomechanisms of this disorder.	Annexin A11 Annexin A11 is a protein that in humans is encoded by the ANXA11 gene.[1][2][3] # Function This gene encodes a member of the annexin family, a group of calcium-dependent phospholipid-binding proteins. Annexins have unique N-terminal domains and conserved C-terminal domains, which contain the calcium-dependent phospholipid-binding sites. The encoded protein is a 56-kD antigen recognized by sera from patients with various autoimmune diseases. Transcript variants encoding the same isoform have been identified.[3] # Interactions ANXA11 has been shown to interact with PDCD6[4] and ALG2.[5] # Clinical significance It is shown that over-expression of the ANXA11 is involved in apoptotic alterations in schizophrenia and contribute to pathomechanisms of this disorder.[6]	https://www.wikidoc.org/index.php/Annexin_A11
1b89e1131781c61297794641d15fa84e5a717317	wikidoc	Anosognosia	Anosognosia Anosognosia is a condition in which a person who suffers disability due to brain injury seems unaware of or denies the existence of their handicap. This may include unawareness of quite dramatic impairments, such as blindness or paralysis. It was first named by neurologist Joseph Babinski in 1914, although relatively little has been discovered about the cause of the condition since its initial identification. The word comes from the Greek words "nosos" disease and "gnosis" knowledge. # Neurology Anosognosia is relatively common following brain injury (e.g. 20-30% in the case of hemiplegia/hemiparesis after stroke), but can appear to occur in conjunction with virtually any neurological impairment. However, it is not related to global mental confusion (see delirium), cognitive flexibility, or other major intellectual disturbance. Anosognosia can be selective in that an affected person with multiple impairments may only seem unaware of one handicap, while appearing to be fully aware of any others. Those diagnosed with dementia of the Alzheimer's type often display this lack of awareness and insist that "There is nothing wrong with me!" The condition does not seem to be directly related to sensory loss and is thought to be caused by damage to higher level neurocognitive processes which are involved in integrating sensory information with processes which support spatial or bodily representations (including the somatosensory system). Anosognosia is thought to be related to unilateral neglect, a condition often found after damage to the non-dominant (usually the right) hemisphere of the cerebral cortex in which sufferers seem unable to attend to, or sometimes comprehend, anything on a certain side of their body (usually the left). # Psychiatry Although largely used to describe unawareness of impairment after brain injury, the term 'anosognosia' is now also used to describe the lack of insight shown by some people who suffer from psychosis, and who may be unaware that their outlandish beliefs and experiences are in any way unusual. Those in a manic phase of bipolar disorder may also exhibit anosognosia. The Treatment Advocacy Center has compiled information that Anosognosia is the most likely reason individuals with severe psychiatric conditions such as disorders do not take their psychiatric medication as prescribed. Further, a collection of studies show that close to 50 percent of those diagnosed with schizophrenia or bipolar disorder, including those who have never been treated, show signs of anosognosia. # Differential Diagnosis of Anosognosia # Treatment There are currently no long-term treatments for anosognosia, although, like unilateral neglect, Caloric reflex testing (squirting ice cold water into the left ear) is known to temporarily ameliorate unawareness of impairment. It is not entirely clear how this works, although it is thought that the unconscious shift of attention or focus caused by the intense stimulation of the vestibular system temporarily influences awareness. Most cases of anosognosia appear to simply disappear over time, while other cases can last indefinitely. Normally, long-term cases are treated with cognitive therapy to train the patient to adjust for their inoperable limbs (though it is believed that these patients still are not "aware" of their disability).	Anosognosia Template:DiseaseDisorder infobox Template:Search infobox Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Anosognosia is a condition in which a person who suffers disability due to brain injury seems unaware of or denies the existence of their handicap. This may include unawareness of quite dramatic impairments, such as blindness or paralysis. It was first named by neurologist Joseph Babinski in 1914, although relatively little has been discovered about the cause of the condition since its initial identification. The word comes from the Greek words "nosos" disease and "gnosis" knowledge. # Neurology Anosognosia is relatively common following brain injury (e.g. 20-30% in the case of hemiplegia/hemiparesis after stroke), but can appear to occur in conjunction with virtually any neurological impairment. However, it is not related to global mental confusion (see delirium), cognitive flexibility, or other major intellectual disturbance. Anosognosia can be selective in that an affected person with multiple impairments may only seem unaware of one handicap, while appearing to be fully aware of any others. Those diagnosed with dementia of the Alzheimer's type often display this lack of awareness and insist that "There is nothing wrong with me!" The condition does not seem to be directly related to sensory loss and is thought to be caused by damage to higher level neurocognitive processes which are involved in integrating sensory information with processes which support spatial or bodily representations (including the somatosensory system). Anosognosia is thought to be related to unilateral neglect, a condition often found after damage to the non-dominant (usually the right) hemisphere of the cerebral cortex in which sufferers seem unable to attend to, or sometimes comprehend, anything on a certain side of their body (usually the left). # Psychiatry Although largely used to describe unawareness of impairment after brain injury, the term 'anosognosia' is now also used to describe the lack of insight shown by some people who suffer from psychosis, and who may be unaware that their outlandish beliefs and experiences are in any way unusual. Those in a manic phase of bipolar disorder may also exhibit anosognosia. The Treatment Advocacy Center has compiled information that Anosognosia is the most likely reason individuals with severe psychiatric conditions such as disorders do not take their psychiatric medication as prescribed.[1] Further, a collection of studies show that close to 50 percent of those diagnosed with schizophrenia or bipolar disorder, including those who have never been treated, show signs of anosognosia.[2] # Differential Diagnosis of Anosognosia # Treatment There are currently no long-term treatments for anosognosia, although, like unilateral neglect, Caloric reflex testing (squirting ice cold water into the left ear) is known to temporarily ameliorate unawareness of impairment. It is not entirely clear how this works, although it is thought that the unconscious shift of attention or focus caused by the intense stimulation of the vestibular system temporarily influences awareness. Most cases of anosognosia appear to simply disappear over time, while other cases can last indefinitely. Normally, long-term cases are treated with cognitive therapy to train the patient to adjust for their inoperable limbs (though it is believed that these patients still are not "aware" of their disability).	https://www.wikidoc.org/index.php/Anosognosia
1ee673e48578933b600781c6e3988582a3b6f226	wikidoc	Answers.com	Answers.com Answers.com is a website that presents reference content in over four million entries, collected from multiple sources. The site was launched in January 2005. The website is the primary product of the Answers Corporation(Template:NASDAQ), previously GuruNet, an Israel-based Internet reference company with offices in New York City and Jerusalem, founded by Bob Rosenschein in 1999. # WikiAnswers Answers Corporation also owns Wikianswers, a Q&A site that uses a wiki engine to improve questions and answers. It is the second-largest Q&A site after Yahoo! Answers. Answers has stated that it intends to bring the two sites much closer together in order to provide various types of answers to its visitors -- both encyclopedic and "community-based". # Staff - Robert S Rosenschein, chairman of the board, president, chief executive officer - Steven Steinberg, chief financial officer, secretary - Bruce D Smith, chief strategic officer - Jeff Schneiderman, chief technical officer	Answers.com Template:Primarysources Template:Infobox Website Answers.com is a website that presents reference content in over four million entries, collected from multiple sources. The site was launched in January 2005. The website is the primary product of the Answers Corporation(Template:NASDAQ), previously GuruNet, an Israel-based Internet reference company with offices in New York City and Jerusalem, founded by Bob Rosenschein in 1999.[1] # WikiAnswers Answers Corporation also owns Wikianswers, a Q&A site that uses a wiki engine to improve questions and answers. It is the second-largest Q&A site after Yahoo! Answers.[citation needed] Answers has stated that it intends to bring the two sites much closer together in order to provide various types of answers to its visitors -- both encyclopedic and "community-based". # Staff - Robert S Rosenschein, chairman of the board, president, chief executive officer - Steven Steinberg, chief financial officer, secretary - Bruce D Smith, chief strategic officer - Jeff Schneiderman, chief technical officer	https://www.wikidoc.org/index.php/Answers.com
d95122a1cb58a9e61602bcea5585313ca5447aa2	wikidoc	Fenofibrate	Fenofibrate # Disclaimer WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here. # Overview Fenofibrate is a peroxisome proliferator receptor alpha agonist that is FDA approved for the treatment of primary hypercholesterolemia or mixed dyslipidemia, severe hypertriglyceridemia. Common adverse reactions include abdominal pain, nausea, AST/SGOT level raised, abnormal liver function tests , backache, rhinitis. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) ### General Considerations (tablet) - Patients should be placed on an appropriate lipid-lowering diet before receiving fenofibrate tablets, and should continue this diet during treatment with fenofibrate tablets. Fenofibrate tablets can be given without regard to meals. - The initial treatment for dyslipidemia is dietary therapy specific for the type of lipoprotein abnormality. Excess body weight and excess alcoholic intake may be important factors in hypertriglyceridemia and should be addressed prior to any drug therapy. Physical exercise can be an important ancillary measure. Diseases contributory to hyperlipidemia, such as hypothyroidism or diabetes mellitus should be looked for and adequately treated. Estrogen therapy, thiazide diuretics and beta-blockers, are sometimes associated with massive rises in plasma triglycerides, especially in subjects with familial hypertriglyceridemia. In such cases, discontinuation of the specific etiologic agent may obviate the need for specific drug therapy of hypertriglyceridemia. - Lipid levels should be monitored periodically and consideration should be given to reducing the dosage of fenofibrate tablets if lipid levels fall significantly below the targeted range. - Therapy should be withdrawn in patients who do not have an adequate response after two months of treatment with the maximum recommended dose of 145 mg once daily. ### General Considerations (capsule) - Fenofibrate capsules should be given with meals thereby optimizing the absorption of the medication. - Patients should be advised to swallow fenofibrate capsules whole. Do not open, crush, dissolve or chew capsules. - Patients should be placed on an appropriate lipid-lowering diet before receiving fenofibrate capsules, and should continue this diet during treatment with fenofibrate capsules. - The initial treatment for dyslipidemia is dietary therapy specific for the type of lipoprotein abnormality. Excess body weight and excess alcoholic intake may be important factors in hypertriglyceridemia and should be addressed prior to any drug therapy. Physical exercise can be an important ancillary measure. Diseases contributory to hyperlipidemia, such as hypothyroidism or diabetes mellitus should be looked for and adequately treated. Estrogen therapy, thiazide diuretics and beta-blockers, are sometimes associated with massive rises in plasma triglycerides, especially in subjects with familial hypertriglyceridemia. In such cases, discontinuation of the specific etiologic agent may obviate the need for specific drug therapy of hypertriglyceridemia. - Periodic determination of serum lipids should be obtained during initial therapy in order to establish the lowest effective dose of fenofibrate. Therapy should be withdrawn in patients who do not have an adequate response after two months of treatment with the maximum recommended dose of 150 mg per day. - Consideration should be given to reducing the dosage of fenofibrate if lipid levels fall significantly below the targeted range. ### Primary Hypercholesterolemia or Mixed Dyslipidemia - Indication - Fenofibrate tablets are indicated as adjunctive therapy to diet to reduce elevated low-density lipoprotein cholesterol (LDL-C), total cholesterol (Total-C), triglycerides (TG) and apolipoprotein B (Apo B), and to increase high-density lipoprotein cholesterol (HDL-C) in adult patients with primary hypercholesterolemia or mixed dyslipidemia. - Dosing Information (tablet) - Initial dosage: 145 mg PO qd - Dosing Information (capsule) - Initial dosage: 150 mg PO qd ### Severe Hypertriglyceridemia - Indication - Fenofibrate tablets are also indicated as adjunctive therapy to diet for treatment of adult patients with severe hypertriglyceridemia. Improving glycemic control in diabetic patients showing fasting chylomicronemia will usually obviate the need for pharmacologic intervention. - Markedly elevated levels of serum triglycerides (e.g. >2000 mg/dL) may increase the risk of developing pancreatitis. The effect of fenofibrate therapy on reducing this risk has not been adequately studied. - Dosing Information (tablet) - Initial dosage: 48 -145 mg/day. Dosage should be individualized according to patient response, and should be adjusted if necessary following repeat lipid determinations at 4 to 8 week intervals. - Maximum dosage: 145 mg PO qd - Dosing Information (capsule) - Initial dosage: 50-150 mg/day. Dosage should be individualized according to patient response, and should be adjusted if necessary following repeat lipid determination at 4 to 8 week intervals. - Maximum dosage: 150 mg PO qd ### Impaired Renal Function - Dosing information (tablet) - In patients having mild to moderately impaired renal function: - Initial dosage: 48 mg/day , and increased only after evaluation of the effects on renal function and lipid levels at this dose. - The use of fenofibrate tablets should be avoided in patients with severe renal impairment. - Dosing Information (capsule) - In patients having mild to moderately impaired renal function: - Initial dosage: 50 mg/day , and increased only after evaluation of the effects on renal function and lipid levels at this dose. - The use of fenofibrate tablets should be avoided in patients with severe renal impairment. ### Geriatric Patients - Dosing Information - Dose selection for the elderly should be made on the basis of renal function. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use - Developed by: American College of Rheumatology (ACR) - Class of Recommendation: Not Applicable - Level of Evidence: Level B - Dosing Information - Not Applicable ### Non–Guideline-Supported Use There is limited information about Off-Label Non–Guideline-Supported Use of fenofibrate in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) FDA package insert for fenofibrate contains no information regarding FDA-labeled indications and dosage information for children. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information about Off-Label Guideline-Supported Use of fenofibrate sandbox in pediatric patients. ### Non–Guideline-Supported Use There is limited information about Off-Label Non–Guideline-Supported Use of fenofibrate sandbox in pediatric patients. # Contraindications - Patients with severe renal impairment, including those receiving dialysis. - Patients with active liver disease, including those with primary biliary cirrhosis and unexplained persistent liver function abnormalities. - Patients with pre-existing gallbladder disease. - Nursing mothers. - Patients with known hypersensitivity to fenofibric acid or fenofibrate. # Warnings ## Mortality and Coronary Heart Disease Morbidity - The effect of Antara on coronary heart disease morbidity and mortality and non-cardiovascular mortality has not been established. - The Action to Control Cardiovascular Risk in Diabetes Lipid (ACCORD Lipid) trial was a randomized placebo-controlled study of 5518 patients with type 2 diabetes mellitus on background statin therapy treated with fenofibrate. The mean duration of follow-up was 4.7 years. Fenofibrate plus statin combination therapy showed a non significant 8% relative risk reduction in the primary outcome of major adverse cardiovascular events (MACE), a composite of non-fatal myocardial infarction, non fatal stroke, and cardiovascular disease death (hazard ratio 0.92, 95% CI 0.79- 1.08) (p=0.32) as compared to statin monotherapy. In a gender subgroup analysis, the hazard ratio for MACE in men receiving combination therapy versus statin monotherapy was 0.82 (95% CI 0.69-0.99), and the hazard ratio for MACE in women receiving combination therapy versus statin monotherapy was 1.38 (95% CI 0.98-1.94) (interaction p=0.01). The clinical significance of this subgroup finding is unclear. - The fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study was a 5-year randomized, placebo-controlled study of 9795 patients with type 2 diabetes mellitus treated with fenofibrate. Fenofibrate demonstrated a non-significant 11% relative reduction in the primary outcome of coronary heart disease events (hazard ratio 0.89, 95% CI 0.75-1.05, p=0.16) and a significant 11% reduction in the secondary outcome of total cardiovascular disease events (HR 0.89 , p=0.04). There was a non-significant 11% (HR 1.11 , p=0.18) and 19% (HR 1.19 , p=0.22) increase in total and coronary heart disease mortality, respectively, with fenofibrate as compared to placebo. - Because of chemical, pharmacological, and clinical similarities between TRICOR (fenofibrate tablets), clofibrate, and gemfibrozil, the adverse findings in 4 large randomized, placebo-controlled clinical studies with these other fibrate drugs may also apply to Antara. - In the Coronary Drug Project, a large study of post myocardial infarction of patients treated for 5 years with clofibrate, there was no difference in mortality seen between the clofibrate group and the placebo group. There was however, a difference in the rate of cholelithiasis and cholecystitis requiring surgery between the two groups (3.0% vs. 1.8%). - In a study conducted by the World Health Organization (WHO), 5000 subjects without known coronary artery disease were treated with placebo or clofibrate for 5 years and followed for an additional one year. There was a statistically significant, higher age-adjusted all-cause mortality in the clofibrate group compared with the placebo group (5.70% vs. 3.96%, p≤0.01). Excess mortality was due to a 33% increase in non-cardiovascular causes, including malignancy, post-cholecystectomy complications, and pancreatitis. This appeared to confirm the higher risk of gallbladder disease seen in clofibrate-treated patients studied in the Coronary Drug Project. - The Helsinki Heart Study was a large (n=4081) study of middle-aged men without a history of coronary artery disease. Subjects received either placebo or gemfibrozil for 5 years, with a 3.5 year open extension afterward. Total mortality was numerically higher in the gemfibrozil randomization group but did not achieve statistical significance (p=0.19, 95% confidence interval for relative risk G:P=0.91-1.64). Although cancer deaths trended higher in the gemfibrozil group (p=0.11), cancers (excluding basal cell carcinoma) were diagnosed with equal frequency in both study groups. Due to the limited size of the study, the relative risk of death from any cause was not shown to be different than that seen in the 9 year follow-up data from the WHO study (RR=1.29) - A secondary prevention component of the Helsinki Heart Study enrolled middle-aged men excluded from the primary prevention study because of known or suspected coronary heart disease. Subjects received gemfibrozil or placebo for 5 years. Although cardiac deaths trended higher in the gemfibrozil group, this was not statistically significant (hazard ratio 2.2, 95% confidence interval: 0.94-5.05). ## Skeletal Muscle - Fibrates increase the risk for myopathy, and have been associated with rhabdomyolysis. The risk for serious muscle toxicity appears to be increased in elderly patients and in patients with diabetes,renal failure, or hypothyroidism. - Data from observational studies suggest that the risk for rhabdomyolysis is increased when fibrates, in particularly gemfibrozil, are co-administered with an HMG-CoA reductase inhibitor (statin). The combination should be avoided unless the benefit of further alterations in lipid levels is likely to outweigh the increased risk of this drug combination. - Myopathy should be considered in any patient with diffuse myalgias, muscle tenderness or weakness, and/or marked elevations of creatine phosphokinase (CPK) levels. - Patients should be advised to report promptly unexplained muscle pain, tenderness or weakness, particularly if accompanied by malaise or fever. CPK levels should be assessed in patients reporting these symptoms, and Antara therapy should be discontinued if markedly elevated CPK levels occur or myopathy/myositis is suspected or diagnosed. - Cases of myopathy, including rhabdomyolysis, have been reported with fenofibrates co-administered with colchicine, and caution should be exercised when prescribing fenofibrate with colchicine. ## Liver Function - Fenofibrate at doses equivalent to 90 mg Antara per day has been associated with increases in serum transaminases (AST (SGOT) or ALT (SGPT)). - In a pooled analysis of 10 placebo-controlled trials, increases to >3 times the upper limit of normal occurred in 5.3% of patients taking fenofibrate versus 1.1% of patients treated with placebo. When transaminase determinations were followed either after discontinuation of treatment or during continued treatment, a return to normal limits was usually observed. The incidence of increases in transaminases levels related to fenofibrate therapy appears to be dose related. - Hepatocellular, chronic active and cholestatic hepatitis associated with fenofibrate therapy have been reported after exposures of weeks to several years. In extremely rare cases, cirrhosis has been reported in association with chronic active hepatitis. - Baseline and regular periodic monitoring of liver function, including serum ALT (SGPT) should be performed for the duration of therapy with Antara, and therapy discontinued if enzyme levels persist above three times the normal limit. ## Serum Creatinine - Elevations in serum creatinine have been reported in patients on fenofibrate. These elevations tend to return to baseline following discontinuation of fenofibrate. The clinical significance of these observations is unknown. Monitor renal function in patients with renal impairment taking Antara. Renal monitoring should also be considered for patients taking Antara at risk for renal insufficiency such as the elderly and patients with diabetes. ## Cholelithiasis - Fenofibrate, like clofibrate and gemfibrozil, may increase cholesterol excretion into the bile, leading to cholelithiasis. If cholelithiasis is suspected, gallbladder studies are indicated. Antara therapy should be discontinued if gallstones are found. ## Coumarin Anticoagulants - Caution should be exercised when anticoagulants are given in conjunction with Antara because of the potentiation of coumarin-type anti-coagulants in prolonging the prothrombin time/International Normalized Ratio (INR/INR). To prevent bleeding complications, frequent monitoring of PT/INR and dose adjustment of the anticoagulant are recommended until PT/INR has stabilized. ## Pancreatitis - Pancreatitis has been reported in patients taking fenofibrate, gemfibrozil, and clofibrate. This occurrence may represent a failure of efficacy in patients with severe hypertriglyceridemia, a direct drug effect, or a secondary phenomenon mediated through biliary tract stone or sludge formation with obstruction of the common bile duct. ## Hematologic Changes - Mild to moderate hemoglobin, hematocrit, and white blood cell decreases have been observed in patients following initiation of fenofibrate therapy. However, these levels stabilize during long-term administration. Thrombocytopenia and agranulocytosis have been reported in individuals treated with fenofibrate. Periodic monitoring of red and white blood cell counts are recommended during the first 12 months of Antara administration. ## Hypersensitivity Reactions - Acute hypersensitivity reactions such as stevens-johnson syndrome and toxic necrolysis requiring patient hospitalization and treatment with steroids have been reported in individuals treated with fenofibrates. Urticaria was seen in 1.1 vs. 0%, and rash in 1.4 vs. 0.8% of fenofibrate and placebo patients, respectively, in controlled trials. ## Veno Thromboembolic Disease - In the FIELD trial, pulmonary embolus (PE) and deep vein thrombosis (DVT) were observed at higher rates in the fenofibrate than the placebo-treated group. Of 9795 patients enrolled in FIELD, there were 4900 in the placebo group and 4895 in the fenofibrate group. For DVT, there were 48 events (1%) in the placebo group and 67 (1%) in the fenofibrate group (p = 0.074); and for PE, there were 32 (0.7%) events in the placebo group and 53 (1%) in the fenofibrate group (p = 0.022). - In the Coronary Drug Project, a higher proportion of the clofibrate group experienced definite or suspected fatal or non fatal pulmonary embolism or thrombophlebitis than the placebo group (5.2% vs. 3.3% at five years; p < 0.01). ## Paradoxical Decreases in HDL Cholesterol Levels - There have been post marketing and clinical trial reports of severe decreases in HDL cholesterol levels (as low as 2 mg/dL) occurring in diabetic and non-diabetic patients initiated on fibrate therapy. The decrease in HDL-C is mirrored by a decrease in apolipoprotein A1. This decrease has been reported to occur within 2 weeks to years after initiation of fibrate therapy. The HDL-C levels remain depressed until fibrate therapy has been withdrawn; the response to withdrawal of fibrate therapy is rapid and sustained. The clinical significance of this decrease in HDL-C is unknown. It is recommended that HDL-C levels be checked within the first few months after initiation of fibrate therapy. If a severely depressed HDL-C level is detected, fibrate therapy should be withdrawn, and the HDL-C level monitored until it has returned to baseline, and fibrate therapy should not be re-initiated. # Adverse Reactions ## Clinical Trials Experience - Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect rates observed in clinical practice. - Adverse events reported by 2% or more of patients treated with fenofibrate and greater than placebo during double-blind, placebo-controlled trials, regardless of causality, are listed in Table 1. Adverse reactions led to discontinuation of treatment in 5.0% of patients treated with fenofibrate and in 3.0% treated with placebo. Increases in liver function tests were the most frequent events, causing discontinuation of fenofibrate treatment in 1.6% of patients in double-blind trials. ## Postmarketing Experience - The following adverse reactions have been identified during post approval use of fenofibrate:myalgia, rhabdomyolysis, pancreatitis, renal failure, muscle spasms,acute renal failure, hepatitis, cirrhosis, anemia, arthralgia, asthenia and severely depressed HDL-cholesterol levels. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a casual relationship to drug exposure. # Drug Interactions ## Coumarin Anticoagulants - Potentiation of coumarin-type anticoagulant effects has been observed with prolongation of the PT/INR. - Caution should be exercised when coumarin anticoagulants are given in conjunction with Antara. The dosage of the anticoagulants should be reduced to maintain the PT/INR at the desired level to prevent bleeding complications. Frequent PT/INR determinations are advisable until it has been definitely determined that the PT/INR has stabilized . ## Immunosuppressants - Immunosuppressants such as cyclosporine and tacrolimus can produce nephrotoxicity with decreases in creatinine clearance and because renal excretion is the primary elimination route of fibrate drugs including Antara, there is a risk that an interaction will lead to deterioration of renal function. The benefits and risks of using Antara with immunosuppressants and other potentially nephrotoxic agents should be carefully considered, and the lowest effective dose employed. ## Bile-Acid Binding Resins Since bile acid binding resins may bind other drugs given concurrently, patients should take Antara at least 1 hour before or 4 to 6 hours after a bile acid binding resin to avoid impeding its absorption. ## Colchicine - Cases of myopathy, including rhabdomyolysis, have been reported with fenofibrates co-administered with colchicine, and caution should be exercised when prescribing fenofibrate with colchicine. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): C - Safety in pregnant women has not been established. There are no adequate and well controlled studies of fenofibrate in pregnant women. - Fenofibrate should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. - In female rats given oral dietary doses of 15, 75, and 300 mg/kg/day of fenofibrate from 15 days prior to mating through weaning, maternal toxicity was observed at 0.3 times the maximum recommended human dose (MRHD), based on body surface area comparisons; mg/m2. - In pregnant rats given oral dietary doses of 14, 127, and 361 mg/kg/day from gestation day 6-15 during the period of organogenesis, adverse developmental findings were not observed at 14 mg/kg/day (less than 1 times the MRHD, based on body surface area comparisons; mg/m2). At higher multiples of human doses, evidence of maternal toxicity was observed. - In pregnant rabbits given oral gavage doses of 15, 150, and 300 mg/kg/day from gestation day 6 to 18 during the period of organogenesis and allowed to deliver, aborted litters were observed at 150 mg/kg/day (10 times the MRHD, based on body surface area comparisons: mg/m2). No developmental findings were observed at 15 mg/kg/day (at less than 1 times the MRHD, based on body surface area comparisons; mg/m2). - In pregnant rats given oral dietary doses of 15, 75, and 300 mg/kg/day from gestation day 15 through lactation day 21 (weaning), maternal toxicity was observed at less than 1 times the MRHD, based on body surface area comparisons; mg/m2. Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Fenofibrate in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Fenofibrate during labor and delivery. ### Nursing Mothers - Fenofibrate should not be used in nursing mothers. A decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. ### Pediatric Use Safety and effectiveness have not been established in pediatric patients. ### Geriatic Use - Fenofibric acid is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Fenofibric acid exposure is not influenced by age. Since elderly patients have a higher incidence of renal impairment, dose selection for the elderly should be made on the basis of renal function. Elderly patients with normal renal function should require no dose modifications. Consider monitoring renal function in elderly patients taking Antara. ### Gender No pharmacokinetic difference between males and females has been observed for fenofibrate. ### Race - The influence of race on the pharmacokinetics of fenofibrate has not been studied; however, fenofibrate is not metabolized by enzymes known for exhibiting inter-ethnic variability. ### Renal Impairment - Fenofibrate should be avoided in patients with severe renal impairment. Dose reduction is required in patients with mild to moderate renal impairment. Monitoring renal function in patients with renal impairment is recommended. ### Hepatic Impairment The use of Antara has not been evaluated in subjects with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Fenofibrate in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Fenofibrate in patients who are immunocompromised. # Administration and Monitoring ### Administration Oral ### Monitoring FDA package insert for fenofibrate contains no information regarding drug monitoring. # IV Compatibility FDA package insert for fenofibrate contains no information regarding IV compatibility. # Overdosage - There is no specific treatment for overdose with Antara. General supportive care of the patient is indicated, including monitoring of vital signs and observation of clinical status, should an overdose occur. If indicated, elimination of unabsorbed drug should be achieved by emesis or gastric lavage; usual precautions should be observed to maintain the airway. Because fenofibrate is highly bound to plasma proteins, hemodialysis should not be considered. # Pharmacology ## Mechanism of Action - The active moiety of Antara is fenofibric acid. The pharmacological effects of fenofibric acid in both animals and humans have been extensively studied through oral administration of fenofibrate. - The lipid lowering effects of fenofibric acid seen in clinical practice have been explained in vivo in transgenic mice and in vitro in human hepatocyte cultures by the activation of peroxisome proliferator activated receptor α (PPARα). Through this mechanism, fenofibrate increases lipolysis and elimination of triglyceride-rich particles from plasma by activating lipoprotein lipase and reducing production of apoprotein C-III (an inhibitor of lipoprotein lipase activity). The resulting decrease in triglycerides produces an alteration in the size and composition of LDL from small, dense particles (which are thought to be atherogenic due to their susceptibility to oxidation), to large buoyant particles. These larger particles have a greater affinity for cholesterol receptors and are catabolized rapidly. Activation of PPARα also induces an increase in the synthesis of apoproteins A-I, A-II and HDL-cholesterol. - Fenofibrate also reduces serum uric acid levels in hyperuricemic and normal individuals by increasing the urinary excretion of uric acid. ## Structure - Antara (fenofibrate) Capsules, is a lipid regulating agent available as capsules for oral administration. Each capsule contains 30 mg or 90 mg of micronized fenofibrate. The chemical name for fenofibrate is 2- 2-methyl-propanoic acid, l-methylethyl ester with the following structural formula: - The empirical formula is C20H21O4Cl and the molecular weight is 360.83; fenofibrate is insoluble in water. The melting point is 79°-82°C. Fenofibrate is a white solid which is stable under ordinary conditions. - Inactive Ingredients: Each gelatin capsule contains hypromellose, simethicone emulsion, sodium lauryl sulphate, sugar spheres and talc. The capsule shell contains the following inactive ingredients: black iron oxide, D & C Yellow 10, potassium hydroxide, propylene glycol, gelatin, shellac, sodium lauryl sulphate, titanium dioxide. The 30 mg capsule shell contains following additional inactive ingredients: FD & C Blue 2, yellow iron oxide. The 90 mg capsule shell contains following additional inactive ingredients: FD & C Blue 1, FD & C Yellow 6. ## Pharmacodynamics - A variety of clinical studies have demonstrated that elevated levels of total-C, DL-C, and Apo B, an LDL membrane complex, are associated with human atherosclerosis. Similarly, decreased levels of HDL-C and its transport complex, apolipoprotein A (Apo AI and Apo All) are associated with the development of atherosclerosis. Epidemiologic investigations have established that cardiovascular morbidity and mortality vary directly with the level of total-C, LDL-C, and triglycerides, and inversely with the level of HDL-C. The independent effect of raising HDL-C or lowering TG on the risk of cardiovascular morbidity and mortality has not been determined. - Fenofibric acid, the active metabolite of fenofibrate, produces reductions in total cholesterol, LDL cholesterol, apolipoprotein B, total triglycerides, and triglyceride-rich lipoprotein (VLDL) in treated patients. In addition, treatment with fenofibrate results in increases in high density lipoprotein (HDL) and apoproteins Apo AI and Apo AII. ## Pharmacokinetics - Fenofibrate is a pro-drug of the active chemical moiety fenofibric acid. Fenofibrate is converted by ester hydrolysis in the body to fenofibric acid which is the active constituent measurable in the circulation. ## Absorption - The absolute bioavailability of fenofibrate cannot be determined as the compound is virtually insoluble in aqueous media suitable for injection. However, fenofibrate is well absorbed from the gastrointestinal tract. Following oral administration in healthy volunteers, approximately 60% of a single dose of radiolabelled fenofibrate appeared in urine, primarily as fenofibric acid and its glucuronate conjugate, and 25% was excreted in the feces. Peak plasma levels of fenofibric acid from Antara capsules 90 mg occur within 2 to 6 hours after administration. - In the presence of a high-fat meal, there was a 26.7% increase in AUC and 15.35% increase in Cmax of fenofibric acid from Antara capsule 30mg relative to fasting state, ## Distribution - In healthy volunteers, steady-state plasma levels of fenofibric acid were shown to be achieved within a week of dosing and did not demonstrate accumulation across time following multiple dose administration. Serum protein binding was approximately 99% in normal and hyperlipidemic subjects. ## Metabolism - Following oral administration, fenofibrate is rapidly hydrolyzed by esterases to the active metabolite, fenofibric acid; no unchanged fenofibrate is detected in plasma. - Fenofibric acid is primarily conjugated with glucuronic acid and then excreted in urine. A small amount of fenofibric acid is reduced at the carbonyl moiety to a benzhydrol metabolite which is, in turn, conjugated with glucuronic acid and excreted in urine. - In vivo metabolism data indicate that neither fenofibrate nor fenofibric acid undergo oxidative metabolism (e.g., cytochrome P450) to a significant extent. ## Elimination - After absorption, fenofibrate is mainly excreted in the urine in the form of metabolites, primarily fenofibric acid and fenofibric acid glucuronide. After administration of radiolabeled fenofibrate, approximately 60% of the dose appeared in the urine and 25% was excreted in the feces. - Fenofibrate acid from Antara is eliminated with a half-life of 23 hours, allowing once daily administration in a clinical setting. ## Geriatrics - In elderly volunteers 77 to 87 years of age, the oral clearance of fenofibric acid following a single oral dose of fenofibrate was 1.2 L/h, which compares to 1.1 L/h in young adults. This indicates that a similar dosage regimen can be used in the elderly with normal renal function, without increasing accumulation of the drug or metabolites. ## Pediatrics - The pharmacokinetics of Antara has not been studied in pediatric populations. ## Nonclinical Toxicology ## Carcinogenesis, Mutagenesis, Impairment Of Fertility - Two dietary carcinogenicity studies have been conducted in rats with fenofibrate. In the first 24-month study, Wistar rats were dosed with fenofibrate at 10, 45, and 200 mg/kg/day, approximately 0.3, 1, and 6 times the maximum recommended human dose (MRHD), based on body surface area comparisons (mg/m2). At a dose of 200 mg/kg/day (at 6 times the MRHD), the incidence of liver carcinomas was significantly increased in both sexes. A statistically significant increase in pancreatic carcinomas was observed in males at 1 and 6 times the MRHD; an increase in pancreatic adenomas and benign testicular interstitial cell tumors was observed at 6 times the MRHD in males. In a second 24-month rat carcinogenicity study in a different strain of rats (Sprague-Dawley), doses of 10 and 60 mg/kg/day (0.3 and 2 times the MRHD) produced significant increases in the incidence of pancreatic acinar adenomas in both sexes and increases in testicular interstitial cell tumors in males at 2 times the MRHD. - A 117-week carcinogenicity study was conducted in rats comparing three drugs: fenofibrate 10 and 60 mg/kg/day (0.3 and 2 times the MRHD), clofibrate (400 mg/kg/day; 2 times the human dose), and gemfibrozil (250 mg/kg/day; 2 times the human dose, based on mg/m2 surface area). Fenofibrate increased pancreatic acinar adenomas in both sexes. clofibrate increased hepatocellular carcinoma and pancreatic acinar adenomas in males and hepatic neoplastic nodules in females. gemfibrozil increased hepatic neoplastic nodules in males and females, while all three drugs increased testicular interstitial cell tumors in males. - In a 21-month study in CF-1 mice, fenofibrate 10, 45, and 200 mg/kg/day (approximately 0.2, 1, and 3 times the MRHD on the basis of mg/m2 surface area) significantly increased the liver carcinomas in both sexes at 3 times the MRHD. In a second 18-month study at 10, 60, and 200 mg/kg/day, fenofibrate significantly increased the liver carcinomas in male mice and liver adenomas in female mice at 3 times the MRHD. - Electron microscopy studies have demonstrated peroxisomal proliferation following fenofibrate administration to the rat. An adequate study to test for peroxisome proliferation in humans has not been done, but changes in peroxisome morphology and numbers have been observed in humans after treatment with other members of the fibrate class when liver biopsies were compared before and after treatment in the same individual. ## Mutagenesis - Fenofibrate has been demonstrated to be devoid of mutagenic potential in the following tests: Ames, mouse lymphoma, chromosomal aberration and unscheduled DNA synthesis in primary rat hepatocytes. ## Impairment of Fertility - In fertility studies rats were given oral dietary doses of fenofibrate, males received 61 days prior to mating and females 15 days prior to mating through weaning which resulted in no adverse effect on fertility at doses up to 300 mg/kg/day (~10 times the MRHD, based on mg/m2surface area comparisons) # Clinical Studies ## Primary Hypercholesterolemia (Heterozygous Familial and Non familial) and Mixed Dyslipidemia - The effects of fenofibrate at a dose equivalent to 90 mg Antara per day were assessed from four randomized, placebo-controlled, double-blind, parallel group studies including patients with the following mean baseline lipid values: total-C 306.9 mg/dL; LDL-C 213.8 mg/dL; HDL-C 52.3 mg/dL; and triglycerides 191.0 mg/dL. Fenofibrate therapy lowered LDL-C, Total-C, and the LDL-C/HDL-C ratio. Fenofibrate therapy also lowered triglycerides and raised HDL-C. - In a subset of the subjects, measurements of Apo B were conducted. Fenofibrate treatment significantly reduced Apo B from baseline to endpoint as compared with placebo (-25.1% vs. 2.4%, p<0.0001, n=213 and 143 respectively). ## Severe Hypertriglyceridemia - The effects of fenofibrate on serum triglycerides were studied in two randomized, double-blind, placebo-controlled clinical trials of 147 hypertriglyceridemic patients. Patients were treated for eight weeks under protocols that differed only in that one entered patients with baseline TG levels of 500 to 1500 mg/dL, and the other TG levels of 350 to 499 mg/dL. In patients with hypertriglyceridemia and normal cholesterolemia with or without hyperchylomicronemia , treatment with fenofibrate at dosages equivalent to 90 mg Antara per day decreased primarily very low density lipoprotein (VLDL) triglycerides and VLDL cholesterol Treatment of patients with elevated triglycerides often results in an increase of LDL-C. # How Supplied ## Fenofibrate Tablet - Fenofibrate tablets are available in two strengths: ## Fenofibrate Capsule - Fenofibrate Capsules, USP are available in two strengths: ## Storage ## Fenofibrate Tablet - Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F). . Keep out of the reach of children. Protect from moisture. ## Fenofibrate Capsule - Store at Controlled Room Temperature, 15°C - 30°C (59°F - 86°F). Keep out of the reach of children. Protect from moisture and light. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information - Patients should be advised: - Of the potential benefits and risks of fenofibrate capsules. - Not to use fenofibrate capsules if there is a known hypersensitivity to fenofibrate or fenofibric acid. - Of medications that should not be taken in combination with fenofibrate capsules. - That if they are taking coumarin anticoagulants, fenofibrate capsules may increase their anti-coagulant effect, and increased monitoring may be necessary. - To inform their physician of all medications, supplements, and herbal preparations they are taking and any change in their medical condition. - To inform a physician prescribing a new medication, that they are taking fenofibrate capsules. - To continue to follow an appropriate lipid-modifying diet while taking fenofibrate capsules. - To take fenofibrate capsules once daily at the prescribed dose, swallowing each capsule whole. - To inform their physician of any muscle pain, tenderness, or weakness; onset of abdominal pain; or any other new symptoms. - To return to their physician's office for routine monitoring. # Precautions with Alcohol Excess body weight and excess alcoholic intake may be important factors in hypertriglyceridemia and should be addressed prior to any drug therapy. # Brand Names There is limited information regarding Fenofibrate Brand Names in the drug label. # Look-Alike Drug Names Tricor - Tracleer # Drug Shortage Status # Price	Fenofibrate Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Sheng Shi, M.D. [2]; Rabin Bista, M.B.B.S. [3] # Disclaimer WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here. # Overview Fenofibrate is a peroxisome proliferator receptor alpha agonist that is FDA approved for the treatment of primary hypercholesterolemia or mixed dyslipidemia, severe hypertriglyceridemia. Common adverse reactions include abdominal pain, nausea, AST/SGOT level raised, abnormal liver function tests , backache, rhinitis. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) ### General Considerations (tablet) - Patients should be placed on an appropriate lipid-lowering diet before receiving fenofibrate tablets, and should continue this diet during treatment with fenofibrate tablets. Fenofibrate tablets can be given without regard to meals. - The initial treatment for dyslipidemia is dietary therapy specific for the type of lipoprotein abnormality. Excess body weight and excess alcoholic intake may be important factors in hypertriglyceridemia and should be addressed prior to any drug therapy. Physical exercise can be an important ancillary measure. Diseases contributory to hyperlipidemia, such as hypothyroidism or diabetes mellitus should be looked for and adequately treated. Estrogen therapy, thiazide diuretics and beta-blockers, are sometimes associated with massive rises in plasma triglycerides, especially in subjects with familial hypertriglyceridemia. In such cases, discontinuation of the specific etiologic agent may obviate the need for specific drug therapy of hypertriglyceridemia. - Lipid levels should be monitored periodically and consideration should be given to reducing the dosage of fenofibrate tablets if lipid levels fall significantly below the targeted range. - Therapy should be withdrawn in patients who do not have an adequate response after two months of treatment with the maximum recommended dose of 145 mg once daily. ### General Considerations (capsule) - Fenofibrate capsules should be given with meals thereby optimizing the absorption of the medication. - Patients should be advised to swallow fenofibrate capsules whole. Do not open, crush, dissolve or chew capsules. - Patients should be placed on an appropriate lipid-lowering diet before receiving fenofibrate capsules, and should continue this diet during treatment with fenofibrate capsules. - The initial treatment for dyslipidemia is dietary therapy specific for the type of lipoprotein abnormality. Excess body weight and excess alcoholic intake may be important factors in hypertriglyceridemia and should be addressed prior to any drug therapy. Physical exercise can be an important ancillary measure. Diseases contributory to hyperlipidemia, such as hypothyroidism or diabetes mellitus should be looked for and adequately treated. Estrogen therapy, thiazide diuretics and beta-blockers, are sometimes associated with massive rises in plasma triglycerides, especially in subjects with familial hypertriglyceridemia. In such cases, discontinuation of the specific etiologic agent may obviate the need for specific drug therapy of hypertriglyceridemia. - Periodic determination of serum lipids should be obtained during initial therapy in order to establish the lowest effective dose of fenofibrate. Therapy should be withdrawn in patients who do not have an adequate response after two months of treatment with the maximum recommended dose of 150 mg per day. - Consideration should be given to reducing the dosage of fenofibrate if lipid levels fall significantly below the targeted range. ### Primary Hypercholesterolemia or Mixed Dyslipidemia - Indication - Fenofibrate tablets are indicated as adjunctive therapy to diet to reduce elevated low-density lipoprotein cholesterol (LDL-C), total cholesterol (Total-C), triglycerides (TG) and apolipoprotein B (Apo B), and to increase high-density lipoprotein cholesterol (HDL-C) in adult patients with primary hypercholesterolemia or mixed dyslipidemia. - Dosing Information (tablet) - Initial dosage: 145 mg PO qd - Dosing Information (capsule) - Initial dosage: 150 mg PO qd ### Severe Hypertriglyceridemia - Indication - Fenofibrate tablets are also indicated as adjunctive therapy to diet for treatment of adult patients with severe hypertriglyceridemia. Improving glycemic control in diabetic patients showing fasting chylomicronemia will usually obviate the need for pharmacologic intervention. - Markedly elevated levels of serum triglycerides (e.g. >2000 mg/dL) may increase the risk of developing pancreatitis. The effect of fenofibrate therapy on reducing this risk has not been adequately studied. - Dosing Information (tablet) - Initial dosage: 48 -145 mg/day. Dosage should be individualized according to patient response, and should be adjusted if necessary following repeat lipid determinations at 4 to 8 week intervals. - Maximum dosage: 145 mg PO qd - Dosing Information (capsule) - Initial dosage: 50-150 mg/day. Dosage should be individualized according to patient response, and should be adjusted if necessary following repeat lipid determination at 4 to 8 week intervals. - Maximum dosage: 150 mg PO qd ### Impaired Renal Function - Dosing information (tablet) - In patients having mild to moderately impaired renal function: - Initial dosage: 48 mg/day , and increased only after evaluation of the effects on renal function and lipid levels at this dose. - The use of fenofibrate tablets should be avoided in patients with severe renal impairment. - Dosing Information (capsule) - In patients having mild to moderately impaired renal function: - Initial dosage: 50 mg/day , and increased only after evaluation of the effects on renal function and lipid levels at this dose. - The use of fenofibrate tablets should be avoided in patients with severe renal impairment. ### Geriatric Patients - Dosing Information - Dose selection for the elderly should be made on the basis of renal function. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use - Developed by: American College of Rheumatology (ACR) - Class of Recommendation: Not Applicable - Level of Evidence: Level B - Dosing Information - Not Applicable ### Non–Guideline-Supported Use There is limited information about Off-Label Non–Guideline-Supported Use of fenofibrate in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) FDA package insert for fenofibrate contains no information regarding FDA-labeled indications and dosage information for children. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information about Off-Label Guideline-Supported Use of fenofibrate sandbox in pediatric patients. ### Non–Guideline-Supported Use There is limited information about Off-Label Non–Guideline-Supported Use of fenofibrate sandbox in pediatric patients. # Contraindications - Patients with severe renal impairment, including those receiving dialysis. - Patients with active liver disease, including those with primary biliary cirrhosis and unexplained persistent liver function abnormalities. - Patients with pre-existing gallbladder disease. - Nursing mothers. - Patients with known hypersensitivity to fenofibric acid or fenofibrate. # Warnings ## Mortality and Coronary Heart Disease Morbidity - The effect of Antara on coronary heart disease morbidity and mortality and non-cardiovascular mortality has not been established. - The Action to Control Cardiovascular Risk in Diabetes Lipid (ACCORD Lipid) trial was a randomized placebo-controlled study of 5518 patients with type 2 diabetes mellitus on background statin therapy treated with fenofibrate. The mean duration of follow-up was 4.7 years. Fenofibrate plus statin combination therapy showed a non significant 8% relative risk reduction in the primary outcome of major adverse cardiovascular events (MACE), a composite of non-fatal myocardial infarction, non fatal stroke, and cardiovascular disease death (hazard ratio [HR] 0.92, 95% CI 0.79- 1.08) (p=0.32) as compared to statin monotherapy. In a gender subgroup analysis, the hazard ratio for MACE in men receiving combination therapy versus statin monotherapy was 0.82 (95% CI 0.69-0.99), and the hazard ratio for MACE in women receiving combination therapy versus statin monotherapy was 1.38 (95% CI 0.98-1.94) (interaction p=0.01). The clinical significance of this subgroup finding is unclear. - The fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study was a 5-year randomized, placebo-controlled study of 9795 patients with type 2 diabetes mellitus treated with fenofibrate. Fenofibrate demonstrated a non-significant 11% relative reduction in the primary outcome of coronary heart disease events (hazard ratio [HR] 0.89, 95% CI 0.75-1.05, p=0.16) and a significant 11% reduction in the secondary outcome of total cardiovascular disease events (HR 0.89 [0.80-0.99], p=0.04). There was a non-significant 11% (HR 1.11 [0.95, 1.29], p=0.18) and 19% (HR 1.19 [0.90, 1.57], p=0.22) increase in total and coronary heart disease mortality, respectively, with fenofibrate as compared to placebo. - Because of chemical, pharmacological, and clinical similarities between TRICOR (fenofibrate tablets), clofibrate, and gemfibrozil, the adverse findings in 4 large randomized, placebo-controlled clinical studies with these other fibrate drugs may also apply to Antara. - In the Coronary Drug Project, a large study of post myocardial infarction of patients treated for 5 years with clofibrate, there was no difference in mortality seen between the clofibrate group and the placebo group. There was however, a difference in the rate of cholelithiasis and cholecystitis requiring surgery between the two groups (3.0% vs. 1.8%). - In a study conducted by the World Health Organization (WHO), 5000 subjects without known coronary artery disease were treated with placebo or clofibrate for 5 years and followed for an additional one year. There was a statistically significant, higher age-adjusted all-cause mortality in the clofibrate group compared with the placebo group (5.70% vs. 3.96%, p≤0.01). Excess mortality was due to a 33% increase in non-cardiovascular causes, including malignancy, post-cholecystectomy complications, and pancreatitis. This appeared to confirm the higher risk of gallbladder disease seen in clofibrate-treated patients studied in the Coronary Drug Project. - The Helsinki Heart Study was a large (n=4081) study of middle-aged men without a history of coronary artery disease. Subjects received either placebo or gemfibrozil for 5 years, with a 3.5 year open extension afterward. Total mortality was numerically higher in the gemfibrozil randomization group but did not achieve statistical significance (p=0.19, 95% confidence interval for relative risk G:P=0.91-1.64). Although cancer deaths trended higher in the gemfibrozil group (p=0.11), cancers (excluding basal cell carcinoma) were diagnosed with equal frequency in both study groups. Due to the limited size of the study, the relative risk of death from any cause was not shown to be different than that seen in the 9 year follow-up data from the WHO study (RR=1.29) - A secondary prevention component of the Helsinki Heart Study enrolled middle-aged men excluded from the primary prevention study because of known or suspected coronary heart disease. Subjects received gemfibrozil or placebo for 5 years. Although cardiac deaths trended higher in the gemfibrozil group, this was not statistically significant (hazard ratio 2.2, 95% confidence interval: 0.94-5.05). ## Skeletal Muscle - Fibrates increase the risk for myopathy, and have been associated with rhabdomyolysis. The risk for serious muscle toxicity appears to be increased in elderly patients and in patients with diabetes,renal failure, or hypothyroidism. - Data from observational studies suggest that the risk for rhabdomyolysis is increased when fibrates, in particularly gemfibrozil, are co-administered with an HMG-CoA reductase inhibitor (statin). The combination should be avoided unless the benefit of further alterations in lipid levels is likely to outweigh the increased risk of this drug combination. - Myopathy should be considered in any patient with diffuse myalgias, muscle tenderness or weakness, and/or marked elevations of creatine phosphokinase (CPK) levels. - Patients should be advised to report promptly unexplained muscle pain, tenderness or weakness, particularly if accompanied by malaise or fever. CPK levels should be assessed in patients reporting these symptoms, and Antara therapy should be discontinued if markedly elevated CPK levels occur or myopathy/myositis is suspected or diagnosed. - Cases of myopathy, including rhabdomyolysis, have been reported with fenofibrates co-administered with colchicine, and caution should be exercised when prescribing fenofibrate with colchicine. ## Liver Function - Fenofibrate at doses equivalent to 90 mg Antara per day has been associated with increases in serum transaminases (AST (SGOT) or ALT (SGPT)). - In a pooled analysis of 10 placebo-controlled trials, increases to >3 times the upper limit of normal occurred in 5.3% of patients taking fenofibrate versus 1.1% of patients treated with placebo. When transaminase determinations were followed either after discontinuation of treatment or during continued treatment, a return to normal limits was usually observed. The incidence of increases in transaminases levels related to fenofibrate therapy appears to be dose related. - Hepatocellular, chronic active and cholestatic hepatitis associated with fenofibrate therapy have been reported after exposures of weeks to several years. In extremely rare cases, cirrhosis has been reported in association with chronic active hepatitis. - Baseline and regular periodic monitoring of liver function, including serum ALT (SGPT) should be performed for the duration of therapy with Antara, and therapy discontinued if enzyme levels persist above three times the normal limit. ## Serum Creatinine - Elevations in serum creatinine have been reported in patients on fenofibrate. These elevations tend to return to baseline following discontinuation of fenofibrate. The clinical significance of these observations is unknown. Monitor renal function in patients with renal impairment taking Antara. Renal monitoring should also be considered for patients taking Antara at risk for renal insufficiency such as the elderly and patients with diabetes. ## Cholelithiasis - Fenofibrate, like clofibrate and gemfibrozil, may increase cholesterol excretion into the bile, leading to cholelithiasis. If cholelithiasis is suspected, gallbladder studies are indicated. Antara therapy should be discontinued if gallstones are found. ## Coumarin Anticoagulants - Caution should be exercised when anticoagulants are given in conjunction with Antara because of the potentiation of coumarin-type anti-coagulants in prolonging the prothrombin time/International Normalized Ratio (INR/INR). To prevent bleeding complications, frequent monitoring of PT/INR and dose adjustment of the anticoagulant are recommended until PT/INR has stabilized. ## Pancreatitis - Pancreatitis has been reported in patients taking fenofibrate, gemfibrozil, and clofibrate. This occurrence may represent a failure of efficacy in patients with severe hypertriglyceridemia, a direct drug effect, or a secondary phenomenon mediated through biliary tract stone or sludge formation with obstruction of the common bile duct. ## Hematologic Changes - Mild to moderate hemoglobin, hematocrit, and white blood cell decreases have been observed in patients following initiation of fenofibrate therapy. However, these levels stabilize during long-term administration. Thrombocytopenia and agranulocytosis have been reported in individuals treated with fenofibrate. Periodic monitoring of red and white blood cell counts are recommended during the first 12 months of Antara administration. ## Hypersensitivity Reactions - Acute hypersensitivity reactions such as stevens-johnson syndrome and toxic necrolysis requiring patient hospitalization and treatment with steroids have been reported in individuals treated with fenofibrates. Urticaria was seen in 1.1 vs. 0%, and rash in 1.4 vs. 0.8% of fenofibrate and placebo patients, respectively, in controlled trials. ## Veno Thromboembolic Disease - In the FIELD trial, pulmonary embolus (PE) and deep vein thrombosis (DVT) were observed at higher rates in the fenofibrate than the placebo-treated group. Of 9795 patients enrolled in FIELD, there were 4900 in the placebo group and 4895 in the fenofibrate group. For DVT, there were 48 events (1%) in the placebo group and 67 (1%) in the fenofibrate group (p = 0.074); and for PE, there were 32 (0.7%) events in the placebo group and 53 (1%) in the fenofibrate group (p = 0.022). - In the Coronary Drug Project, a higher proportion of the clofibrate group experienced definite or suspected fatal or non fatal pulmonary embolism or thrombophlebitis than the placebo group (5.2% vs. 3.3% at five years; p < 0.01). ## Paradoxical Decreases in HDL Cholesterol Levels - There have been post marketing and clinical trial reports of severe decreases in HDL cholesterol levels (as low as 2 mg/dL) occurring in diabetic and non-diabetic patients initiated on fibrate therapy. The decrease in HDL-C is mirrored by a decrease in apolipoprotein A1. This decrease has been reported to occur within 2 weeks to years after initiation of fibrate therapy. The HDL-C levels remain depressed until fibrate therapy has been withdrawn; the response to withdrawal of fibrate therapy is rapid and sustained. The clinical significance of this decrease in HDL-C is unknown. It is recommended that HDL-C levels be checked within the first few months after initiation of fibrate therapy. If a severely depressed HDL-C level is detected, fibrate therapy should be withdrawn, and the HDL-C level monitored until it has returned to baseline, and fibrate therapy should not be re-initiated. # Adverse Reactions ## Clinical Trials Experience - Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect rates observed in clinical practice. - Adverse events reported by 2% or more of patients treated with fenofibrate and greater than placebo during double-blind, placebo-controlled trials, regardless of causality, are listed in Table 1. Adverse reactions led to discontinuation of treatment in 5.0% of patients treated with fenofibrate and in 3.0% treated with placebo. Increases in liver function tests were the most frequent events, causing discontinuation of fenofibrate treatment in 1.6% of patients in double-blind trials. ## Postmarketing Experience - The following adverse reactions have been identified during post approval use of fenofibrate:myalgia, rhabdomyolysis, pancreatitis, renal failure, muscle spasms,acute renal failure, hepatitis, cirrhosis, anemia, arthralgia, asthenia and severely depressed HDL-cholesterol levels. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a casual relationship to drug exposure. # Drug Interactions ## Coumarin Anticoagulants - Potentiation of coumarin-type anticoagulant effects has been observed with prolongation of the PT/INR. - Caution should be exercised when coumarin anticoagulants are given in conjunction with Antara. The dosage of the anticoagulants should be reduced to maintain the PT/INR at the desired level to prevent bleeding complications. Frequent PT/INR determinations are advisable until it has been definitely determined that the PT/INR has stabilized . ## Immunosuppressants - Immunosuppressants such as cyclosporine and tacrolimus can produce nephrotoxicity with decreases in creatinine clearance and because renal excretion is the primary elimination route of fibrate drugs including Antara, there is a risk that an interaction will lead to deterioration of renal function. The benefits and risks of using Antara with immunosuppressants and other potentially nephrotoxic agents should be carefully considered, and the lowest effective dose employed. ## Bile-Acid Binding Resins Since bile acid binding resins may bind other drugs given concurrently, patients should take Antara at least 1 hour before or 4 to 6 hours after a bile acid binding resin to avoid impeding its absorption. ## Colchicine - Cases of myopathy, including rhabdomyolysis, have been reported with fenofibrates co-administered with colchicine, and caution should be exercised when prescribing fenofibrate with colchicine. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): C - Safety in pregnant women has not been established. There are no adequate and well controlled studies of fenofibrate in pregnant women. * Fenofibrate should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. - In female rats given oral dietary doses of 15, 75, and 300 mg/kg/day of fenofibrate from 15 days prior to mating through weaning, maternal toxicity was observed at 0.3 times the maximum recommended human dose (MRHD), based on body surface area comparisons; mg/m2. - In pregnant rats given oral dietary doses of 14, 127, and 361 mg/kg/day from gestation day 6-15 during the period of organogenesis, adverse developmental findings were not observed at 14 mg/kg/day (less than 1 times the MRHD, based on body surface area comparisons; mg/m2). At higher multiples of human doses, evidence of maternal toxicity was observed. - In pregnant rabbits given oral gavage doses of 15, 150, and 300 mg/kg/day from gestation day 6 to 18 during the period of organogenesis and allowed to deliver, aborted litters were observed at 150 mg/kg/day (10 times the MRHD, based on body surface area comparisons: mg/m2). No developmental findings were observed at 15 mg/kg/day (at less than 1 times the MRHD, based on body surface area comparisons; mg/m2). - In pregnant rats given oral dietary doses of 15, 75, and 300 mg/kg/day from gestation day 15 through lactation day 21 (weaning), maternal toxicity was observed at less than 1 times the MRHD, based on body surface area comparisons; mg/m2. Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Fenofibrate in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Fenofibrate during labor and delivery. ### Nursing Mothers - Fenofibrate should not be used in nursing mothers. A decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. ### Pediatric Use Safety and effectiveness have not been established in pediatric patients. ### Geriatic Use - Fenofibric acid is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Fenofibric acid exposure is not influenced by age. Since elderly patients have a higher incidence of renal impairment, dose selection for the elderly should be made on the basis of renal function. Elderly patients with normal renal function should require no dose modifications. Consider monitoring renal function in elderly patients taking Antara. ### Gender No pharmacokinetic difference between males and females has been observed for fenofibrate. ### Race - The influence of race on the pharmacokinetics of fenofibrate has not been studied; however, fenofibrate is not metabolized by enzymes known for exhibiting inter-ethnic variability. ### Renal Impairment - Fenofibrate should be avoided in patients with severe renal impairment. Dose reduction is required in patients with mild to moderate renal impairment. Monitoring renal function in patients with renal impairment is recommended. ### Hepatic Impairment The use of Antara has not been evaluated in subjects with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Fenofibrate in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Fenofibrate in patients who are immunocompromised. # Administration and Monitoring ### Administration Oral ### Monitoring FDA package insert for fenofibrate contains no information regarding drug monitoring. # IV Compatibility FDA package insert for fenofibrate contains no information regarding IV compatibility. # Overdosage - There is no specific treatment for overdose with Antara. General supportive care of the patient is indicated, including monitoring of vital signs and observation of clinical status, should an overdose occur. If indicated, elimination of unabsorbed drug should be achieved by emesis or gastric lavage; usual precautions should be observed to maintain the airway. Because fenofibrate is highly bound to plasma proteins, hemodialysis should not be considered. # Pharmacology ## Mechanism of Action - The active moiety of Antara is fenofibric acid. The pharmacological effects of fenofibric acid in both animals and humans have been extensively studied through oral administration of fenofibrate. - The lipid lowering effects of fenofibric acid seen in clinical practice have been explained in vivo in transgenic mice and in vitro in human hepatocyte cultures by the activation of peroxisome proliferator activated receptor α (PPARα). Through this mechanism, fenofibrate increases lipolysis and elimination of triglyceride-rich particles from plasma by activating lipoprotein lipase and reducing production of apoprotein C-III (an inhibitor of lipoprotein lipase activity). The resulting decrease in triglycerides produces an alteration in the size and composition of LDL from small, dense particles (which are thought to be atherogenic due to their susceptibility to oxidation), to large buoyant particles. These larger particles have a greater affinity for cholesterol receptors and are catabolized rapidly. Activation of PPARα also induces an increase in the synthesis of apoproteins A-I, A-II and HDL-cholesterol. - Fenofibrate also reduces serum uric acid levels in hyperuricemic and normal individuals by increasing the urinary excretion of uric acid. ## Structure - Antara (fenofibrate) Capsules, is a lipid regulating agent available as capsules for oral administration. Each capsule contains 30 mg or 90 mg of micronized fenofibrate. The chemical name for fenofibrate is 2-[4-(4-chlorobenzoyl) phenoxy] 2-methyl-propanoic acid, l-methylethyl ester with the following structural formula: - The empirical formula is C20H21O4Cl and the molecular weight is 360.83; fenofibrate is insoluble in water. The melting point is 79°-82°C. Fenofibrate is a white solid which is stable under ordinary conditions. - Inactive Ingredients: Each gelatin capsule contains hypromellose, simethicone emulsion, sodium lauryl sulphate, sugar spheres and talc. The capsule shell contains the following inactive ingredients: black iron oxide, D & C Yellow 10, potassium hydroxide, propylene glycol, gelatin, shellac, sodium lauryl sulphate, titanium dioxide. The 30 mg capsule shell contains following additional inactive ingredients: FD & C Blue 2, yellow iron oxide. The 90 mg capsule shell contains following additional inactive ingredients: FD & C Blue 1, FD & C Yellow 6. ## Pharmacodynamics - A variety of clinical studies have demonstrated that elevated levels of total-C, DL-C, and Apo B, an LDL membrane complex, are associated with human atherosclerosis. Similarly, decreased levels of HDL-C and its transport complex, apolipoprotein A (Apo AI and Apo All) are associated with the development of atherosclerosis. Epidemiologic investigations have established that cardiovascular morbidity and mortality vary directly with the level of total-C, LDL-C, and triglycerides, and inversely with the level of HDL-C. The independent effect of raising HDL-C or lowering TG on the risk of cardiovascular morbidity and mortality has not been determined. - Fenofibric acid, the active metabolite of fenofibrate, produces reductions in total cholesterol, LDL cholesterol, apolipoprotein B, total triglycerides, and triglyceride-rich lipoprotein (VLDL) in treated patients. In addition, treatment with fenofibrate results in increases in high density lipoprotein (HDL) and apoproteins Apo AI and Apo AII. ## Pharmacokinetics - Fenofibrate is a pro-drug of the active chemical moiety fenofibric acid. Fenofibrate is converted by ester hydrolysis in the body to fenofibric acid which is the active constituent measurable in the circulation. ## Absorption - The absolute bioavailability of fenofibrate cannot be determined as the compound is virtually insoluble in aqueous media suitable for injection. However, fenofibrate is well absorbed from the gastrointestinal tract. Following oral administration in healthy volunteers, approximately 60% of a single dose of radiolabelled fenofibrate appeared in urine, primarily as fenofibric acid and its glucuronate conjugate, and 25% was excreted in the feces. Peak plasma levels of fenofibric acid from Antara capsules 90 mg occur within 2 to 6 hours after administration. - In the presence of a high-fat meal, there was a 26.7% increase in AUC and 15.35% increase in Cmax of fenofibric acid from Antara capsule 30mg relative to fasting state, ## Distribution - In healthy volunteers, steady-state plasma levels of fenofibric acid were shown to be achieved within a week of dosing and did not demonstrate accumulation across time following multiple dose administration. Serum protein binding was approximately 99% in normal and hyperlipidemic subjects. ## Metabolism - Following oral administration, fenofibrate is rapidly hydrolyzed by esterases to the active metabolite, fenofibric acid; no unchanged fenofibrate is detected in plasma. - Fenofibric acid is primarily conjugated with glucuronic acid and then excreted in urine. A small amount of fenofibric acid is reduced at the carbonyl moiety to a benzhydrol metabolite which is, in turn, conjugated with glucuronic acid and excreted in urine. - In vivo metabolism data indicate that neither fenofibrate nor fenofibric acid undergo oxidative metabolism (e.g., cytochrome P450) to a significant extent. ## Elimination - After absorption, fenofibrate is mainly excreted in the urine in the form of metabolites, primarily fenofibric acid and fenofibric acid glucuronide. After administration of radiolabeled fenofibrate, approximately 60% of the dose appeared in the urine and 25% was excreted in the feces. - Fenofibrate acid from Antara is eliminated with a half-life of 23 hours, allowing once daily administration in a clinical setting. ## Geriatrics - In elderly volunteers 77 to 87 years of age, the oral clearance of fenofibric acid following a single oral dose of fenofibrate was 1.2 L/h, which compares to 1.1 L/h in young adults. This indicates that a similar dosage regimen can be used in the elderly with normal renal function, without increasing accumulation of the drug or metabolites. ## Pediatrics - The pharmacokinetics of Antara has not been studied in pediatric populations. ## Nonclinical Toxicology ## Carcinogenesis, Mutagenesis, Impairment Of Fertility - Two dietary carcinogenicity studies have been conducted in rats with fenofibrate. In the first 24-month study, Wistar rats were dosed with fenofibrate at 10, 45, and 200 mg/kg/day, approximately 0.3, 1, and 6 times the maximum recommended human dose (MRHD), based on body surface area comparisons (mg/m2). At a dose of 200 mg/kg/day (at 6 times the MRHD), the incidence of liver carcinomas was significantly increased in both sexes. A statistically significant increase in pancreatic carcinomas was observed in males at 1 and 6 times the MRHD; an increase in pancreatic adenomas and benign testicular interstitial cell tumors was observed at 6 times the MRHD in males. In a second 24-month rat carcinogenicity study in a different strain of rats (Sprague-Dawley), doses of 10 and 60 mg/kg/day (0.3 and 2 times the MRHD) produced significant increases in the incidence of pancreatic acinar adenomas in both sexes and increases in testicular interstitial cell tumors in males at 2 times the MRHD. - A 117-week carcinogenicity study was conducted in rats comparing three drugs: fenofibrate 10 and 60 mg/kg/day (0.3 and 2 times the MRHD), clofibrate (400 mg/kg/day; 2 times the human dose), and gemfibrozil (250 mg/kg/day; 2 times the human dose, based on mg/m2 surface area). Fenofibrate increased pancreatic acinar adenomas in both sexes. clofibrate increased hepatocellular carcinoma and pancreatic acinar adenomas in males and hepatic neoplastic nodules in females. gemfibrozil increased hepatic neoplastic nodules in males and females, while all three drugs increased testicular interstitial cell tumors in males. - In a 21-month study in CF-1 mice, fenofibrate 10, 45, and 200 mg/kg/day (approximately 0.2, 1, and 3 times the MRHD on the basis of mg/m2 surface area) significantly increased the liver carcinomas in both sexes at 3 times the MRHD. In a second 18-month study at 10, 60, and 200 mg/kg/day, fenofibrate significantly increased the liver carcinomas in male mice and liver adenomas in female mice at 3 times the MRHD. - Electron microscopy studies have demonstrated peroxisomal proliferation following fenofibrate administration to the rat. An adequate study to test for peroxisome proliferation in humans has not been done, but changes in peroxisome morphology and numbers have been observed in humans after treatment with other members of the fibrate class when liver biopsies were compared before and after treatment in the same individual. ## Mutagenesis - Fenofibrate has been demonstrated to be devoid of mutagenic potential in the following tests: Ames, mouse lymphoma, chromosomal aberration and unscheduled DNA synthesis in primary rat hepatocytes. ## Impairment of Fertility - In fertility studies rats were given oral dietary doses of fenofibrate, males received 61 days prior to mating and females 15 days prior to mating through weaning which resulted in no adverse effect on fertility at doses up to 300 mg/kg/day (~10 times the MRHD, based on mg/m2surface area comparisons) # Clinical Studies ## Primary Hypercholesterolemia (Heterozygous Familial and Non familial) and Mixed Dyslipidemia - The effects of fenofibrate at a dose equivalent to 90 mg Antara per day were assessed from four randomized, placebo-controlled, double-blind, parallel group studies including patients with the following mean baseline lipid values: total-C 306.9 mg/dL; LDL-C 213.8 mg/dL; HDL-C 52.3 mg/dL; and triglycerides 191.0 mg/dL. Fenofibrate therapy lowered LDL-C, Total-C, and the LDL-C/HDL-C ratio. Fenofibrate therapy also lowered triglycerides and raised HDL-C. - In a subset of the subjects, measurements of Apo B were conducted. Fenofibrate treatment significantly reduced Apo B from baseline to endpoint as compared with placebo (-25.1% vs. 2.4%, p<0.0001, n=213 and 143 respectively). ## Severe Hypertriglyceridemia - The effects of fenofibrate on serum triglycerides were studied in two randomized, double-blind, placebo-controlled clinical trials of 147 hypertriglyceridemic patients. Patients were treated for eight weeks under protocols that differed only in that one entered patients with baseline TG levels of 500 to 1500 mg/dL, and the other TG levels of 350 to 499 mg/dL. In patients with hypertriglyceridemia and normal cholesterolemia with or without hyperchylomicronemia , treatment with fenofibrate at dosages equivalent to 90 mg Antara per day decreased primarily very low density lipoprotein (VLDL) triglycerides and VLDL cholesterol Treatment of patients with elevated triglycerides often results in an increase of LDL-C. # How Supplied ## Fenofibrate Tablet - Fenofibrate tablets are available in two strengths: ## Fenofibrate Capsule - Fenofibrate Capsules, USP are available in two strengths: ## Storage ## Fenofibrate Tablet - Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F). [see USP Controlled Room Temperature]. Keep out of the reach of children. Protect from moisture. ## Fenofibrate Capsule - Store at Controlled Room Temperature, 15°C - 30°C (59°F - 86°F). Keep out of the reach of children. Protect from moisture and light. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information - Patients should be advised: - Of the potential benefits and risks of fenofibrate capsules. - Not to use fenofibrate capsules if there is a known hypersensitivity to fenofibrate or fenofibric acid. - Of medications that should not be taken in combination with fenofibrate capsules. - That if they are taking coumarin anticoagulants, fenofibrate capsules may increase their anti-coagulant effect, and increased monitoring may be necessary. - To inform their physician of all medications, supplements, and herbal preparations they are taking and any change in their medical condition. - To inform a physician prescribing a new medication, that they are taking fenofibrate capsules. - To continue to follow an appropriate lipid-modifying diet while taking fenofibrate capsules. - To take fenofibrate capsules once daily at the prescribed dose, swallowing each capsule whole. - To inform their physician of any muscle pain, tenderness, or weakness; onset of abdominal pain; or any other new symptoms. - To return to their physician's office for routine monitoring. # Precautions with Alcohol Excess body weight and excess alcoholic intake may be important factors in hypertriglyceridemia and should be addressed prior to any drug therapy. # Brand Names There is limited information regarding Fenofibrate Brand Names in the drug label. # Look-Alike Drug Names Tricor - Tracleer[1] # Drug Shortage Status # Price	https://www.wikidoc.org/index.php/Antara
4cab0c6d81f7b2de2774616340a85958ed291763	wikidoc	Natalizumab	Natalizumab # Disclaimer WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here. # Black Box Warning # Overview Natalizumab is a monoclonal antibody that is FDA approved for the treatment of multiple sclerosis (MS) and Crohn's disease (CD). There is a Black Box Warning for this drug as shown here. Common adverse reactions include headache, fatigue, arthralgia, urinary tract infection, lower respiratory tract infection, gastroenteritis, vaginitis, depression, pain in extremity, abdominal discomfort, diarrhea NOS, and rash. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) ### Multiple Sclerosis (MS) - Is indicated as monotherapy for the treatment of patients with relapsing forms of multiple sclerosis. - Natalizumab increases the risk of PML. - When initiating and continuing treatment with natalizumab, physicians should consider whether the expected benefit of natalizumab is sufficient to offset this risk. - Dosage: - 300 mg intravenous infusion over one hour every four weeks. ### Crohn's Disease (CD) - Is indicated for inducing and maintaining clinical response and remission in adult patients with moderately to severely active Crohn's disease with evidence of inflammation who have had an inadequate response to, or are unable to tolerate, conventional CD therapies and inhibitors of TNF-α. - Natalizumab should not be used in combination with immunosuppressants (e.g., 6-mercaptopurine, azathioprine, cyclosporine, or methotrexate) or inhibitors of TNF-α. - Dosage: - 300 mg intravenous infusion over one hour every four weeks ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Natalizumab in adult patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Natalizumab in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) There is limited information regarding Natalizumab FDA-Labeled Indications and Dosage (Pediatric) in the drug label. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Natalizumab in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Natalizumab in pediatric patients. # Contraindications - natalizumab is contraindicated in patients who have or have had progressive multifocal leukoencephalopathy (PML). - natalizumab should not be administered to a patient who has had a hypersensitivity reaction to natalizumab. Observed reactions range from urticaria to anaphylaxis # Warnings ### Progressive Multifocal Leukoencephalopathy Progressive multifocal leukoencephalopathy (PML), an opportunistic viral infection of the brain caused by the JC virus (JCV) that typically only occurs in patients who are immunocompromised, and that usually leads to death or severe disability, has occurred in patients who have received natalizumab. Three factors that are known to increase the risk of PML in natalizumab-treated patients have been identified: - Longer treatment duration, especially beyond 2 years. There is limited experience in patients who have received more than 6 years of natalizumab treatment. - Prior treatment with an immunosuppressant (e.g., mitoxantrone, azathioprine, methotrexate, cyclophosphamide, mycophenolate mofetil). - The presence of anti-JCV antibodies. Patients who are anti-JCV antibody positive have a higher risk for developing PML. These factors should be considered in the context of expected benefit when initiating and continuing treatment with natalizumab. Infection by the JC virus is required for the development of PML. Anti-JCV antibody testing should not be used to diagnose PML. Anti-JCV antibody negative status indicates that exposure to the JC virus has not been detected. Patients who are anti-JCV antibody negative have a lower risk of PML than those who are positive. Patients who are anti-JCV antibody negative are still at risk for the development of PML due to the potential for a new JCV infection or a false negative test result. The reported rate of seroconversion in patients with MS (changing from anti-JCV antibody negative to positive and remaining positive in subsequent testing) is 3 to 8 percent annually. In addition, some patients' serostatus may change intermittently. Therefore, patients with a negative anti-JCV antibody test result should be retested periodically. For purposes of risk assessment, a patient with a positive anti-JCV antibody test at any time is considered anti-JCV antibody positive regardless of the results of any prior or subsequent anti-JCV antibody testing. When assessed, anti-JCV antibody status should be determined using an analytically and clinically validated immunoassay. Anti-JCV antibody testing should not be performed for at least two weeks following plasma exchange due to the removal of antibodies from the serum. There are no known interventions that can reliably prevent PML or adequately treat PML if it occurs. It is not known whether early detection of PML and discontinuation of natalizumab will mitigate the disease. PML has been reported following discontinuation of natalizumab in patients who did not have findings suggestive of PML at the time of discontinuation. Patients should continue to be monitored for any new signs or symptoms that may be suggestive of PML for at least six months following discontinuation of natalizumab. Ordinarily, patients receiving chronic immunosuppressant or immunomodulatory therapy or who have systemic medical conditions resulting in significantly compromised immune system function should not be treated with natalizumab. Because of the risk of PML, natalizumab is available only under a restricted distribution program, the TOUCH® Prescribing Program. In multiple sclerosis patients, an MRI scan should be obtained prior to initiating therapy with natalizumab. This MRI may be helpful in differentiating subsequent multiple sclerosis symptoms from PML. In Crohn's disease patients, a baseline brain MRI may also be helpful to distinguish pre-existent lesions from newly developed lesions, but brain lesions at baseline that could cause diagnostic difficulty while on natalizumab therapy are uncommon. Healthcare professionals should monitor patients on natalizumab for any new sign or symptom suggestive of PML. Typical symptoms associated with PML are diverse, progress over days to weeks, and include progressive weakness on one side of the body or clumsiness of limbs, disturbance of vision, and changes in thinking, memory, and orientation leading to confusion and personality changes. The progression of deficits usually leads to death or severe disability over weeks or months. Withhold natalizumab dosing immediately at the first sign or symptom suggestive of PML. For diagnosis of PML, an evaluation including a gadolinium-enhanced MRI scan of the brain and, when indicated, cerebrospinal fluid analysis for JC viral DNA are recommended. If the initial evaluations for PML are negative but clinical suspicion for PML remains, continue to withhold natalizumab dosing and repeat the evaluations. There are no known interventions that can adequately treat PML if it occurs. Three sessions of plasma exchange over 5 to 8 days were shown to accelerate natalizumab clearance in a study of 12 patients with MS who did not have PML, although in the majority of patients alpha-4 integrin receptor binding remained high. Adverse events which may occur during plasma exchange include clearance of other medications and volume shifts, which have the potential to lead to hypotension or pulmonary edema. Although plasma exchange has not been studied in natalizumab treated patients with PML, it has been used in such patients in the postmarketing setting to remove natalizumab more quickly from the circulation. Anti-JCV antibody testing should not be performed during or for at least two weeks following plasma exchange due to the removal of antibodies from the serum. Immune reconstitution inflammatory syndrome (IRIS) has been reported in the majority of natalizumab treated patients who developed PML and subsequently discontinued natalizumab. In almost all cases, IRIS occurred after plasma exchange was used to eliminate circulating natalizumab. It presents as a clinical decline in the patient's condition after natalizumab removal (and in some cases after apparent clinical improvement) that may be rapid, can lead to serious neurological complications or death and is often associated with characteristic changes in the MRI. natalizumab has not been associated with IRIS in patients discontinuing treatment with natalizumab for reasons unrelated to PML. In natalizumab-treated patients with PML, IRIS has been reported within days to several weeks after plasma exchange. Monitoring for development of IRIS and appropriate treatment of the associated inflammation should be undertaken. ### natalizumab TOUCH Prescribing Program natalizumab is available only through a restricted program under a REMS called the TOUCH® Prescribing Program because of the risk of PML. For prescribers and patients, the TOUCH® Prescribing Program has two components: MS TOUCH® (for patients with multiple sclerosis) and CD TOUCH® (for patients with Crohn's disease). Selected requirements of the TOUCH® Prescribing Program include the following: - Prescribers must be certified and comply with the following: - Review the TOUCH Prescribing Program prescriber educational materials, including the full prescribing information. - Educate patients on the benefits and risks of treatment with natalizumab, ensure that patients receive the Medication Guide, and encourage them to ask questions. - Review, complete, and sign the Patient-Prescriber Enrollment Form. - Evaluate patients three months after the first infusion, six months after the first infusion, every six months thereafter, and for at least six months after discontinuing natalizumab. - Determine every six months whether patients should continue on treatment and, if so, authorize treatment for another six months. - Submit to Biogen Idec the “natalizumab Patient Status Report and Reauthorization Questionnaire” six months after initiating treatment and every six months thereafter. - Complete an “Initial Discontinuation Questionnaire” when natalizumab is discontinued and a “6-Month Discontinuation Questionnaire” following discontinuation of natalizumab. - Report cases of PML, hospitalizations due to opportunistic infections, or deaths to Biogen Idec at 1-800-456-2255 as soon as possible. - Patients must be enrolled in the TOUCH Prescribing Program, read the Medication Guide, understand the risks associated with natalizumab and complete and sign the Patient-Prescriber Enrollment Form. - Pharmacies and infusion centers must be specially certified to dispense or infuse natalizumab. ### Herpes Encephalitis and Meningitis Natalizumab increases the risk of developing encephalitis and meningitis caused by herpes simplex and varicella zoster viruses. Serious, life-threatening, and sometimes fatal cases have been reported in the postmarketing setting in multiple sclerosis patients receiving natalizumab. Laboratory confirmation in those cases was based on positive PCR for viral DNA in the cerebrospinal fluid. The duration of treatment with natalizumab prior to onset ranged from a few months to several years. Monitor patients receiving natalizumab for signs and symptoms of meningitis and encephalitis. If herpes encephalitis or meningitis occurs, TYSBARI should be discontinued, and appropriate treatment for herpes encephalitis/meningitis should be administered. ### Hepatotoxicity Clinically significant liver injury, including acute liver failure requiring transplant, has been reported in patients treated with natalizumab in the postmarketing setting. Signs of liver injury, including markedly elevated serum hepatic enzymes and elevated total bilirubin, occurred as early as six days after the first dose; signs of liver injury have also been reported for the first time after multiple doses. In some patients, liver injury recurred upon rechallenge, providing evidence that natalizumab caused the injury. The combination of transaminase elevations and elevated bilirubin without evidence of obstruction is generally recognized as an important predictor of severe liver injury that may lead to death or the need for a liver transplant in some patients. Natalizumab should be discontinued in patients with jaundice or other evidence of significant liver injury (e.g., laboratory evidence). ### Hypersensitivity/Antibody Formation Hypersensitivity reactions have occurred in patients receiving natalizumab, including serious systemic reactions (e.g., anaphylaxis) which occurred at an incidence of <1%. These reactions usually occur within two hours of the start of the infusion. Symptoms associated with these reactions can include urticaria, dizziness, fever, rash, rigors, pruritus, nausea, flushing, hypotension, dyspnea, and chest pain. Generally, these reactions are associated with antibodies to natalizumab. If a hypersensitivity reaction occurs, discontinue administration of natalizumab and initiate appropriate therapy. Patients who experience a hypersensitivity reaction should not be re-treated with natalizumab. Hypersensitivity reactions were more frequent in patients with antibodies to natalizumab compared to patients who did not develop antibodies to natalizumab in both MS and CD studies. Therefore, the possibility of antibodies to natalizumab should be considered in patients who have hypersensitivity reactions. Antibody testing: If the presence of persistent antibodies is suspected, antibody testing should be performed. Antibodies may be detected and confirmed with sequential serum antibody tests. Antibodies detected early in the treatment course (e.g., within the first six months) may be transient and disappear with continued dosing. Repeat testing at three months after the initial positive result is recommended in patients in whom antibodies are detected to confirm that antibodies are persistent. Prescribers should consider the overall benefits and risks of natalizumab in a patient with persistent antibodies. Experience with monoclonal antibodies, including natalizumab, suggests that patients who receive therapeutic monoclonal antibodies after an extended period without treatment may be at higher risk of hypersensitivity reactions than patients who received regularly scheduled treatment. Given that patients with persistent antibodies to natalizumab experience reduced efficacy, and that hypersensitivity reactions are more common in such patients, consideration should be given to testing for the presence of antibodies in patients who wish to recommence therapy following a dose interruption. Following a period of dose interruption, patients testing negative for antibodies prior to re-dosing have a risk of antibody development with re-treatment that is similar to natalizumab naïve patients. ### Immunosuppression/Infections The immune system effects of natalizumab may increase the risk for infections. In Study MS1, certain types of infections, including pneumonias and urinary tract infections (including serious cases), gastroenteritis, vaginal infections, tooth infections, tonsillitis, and herpes infections, occurred more often in natalizumab-treated patients than in placebo-treated patients. One opportunistic infection, a cryptosporidial gastroenteritis with a prolonged course, was observed in a patient who received natalizumab in Study MS1. In Studies MS1 and MS2, an increase in infections was seen in patients concurrently receiving short courses of corticosteroids. However, the increase in infections in natalizumab-treated patients who received steroids was similar to the increase in placebo-treated patients who received steroids. In CD clinical studies, opportunistic infections (pneumocystis carinii pneumonia, pulmonary mycobacterium avium intracellulare, bronchopulmonary aspergillosis, and burkholderia cepacia) have been observed in <1% of natalizumab-treated patients; some of these patients were receiving concurrent immunosuppressants. In Studies CD1 and CD2, an increase in infections was seen in patients concurrently receiving corticosteroids. However, the increase in infections was similar in placebo-treated and natalizumab-treated patients who received steroids. Concurrent use of antineoplastic, immunosuppressant, or immunomodulating agents may further increase the risk of infections, including PML and other opportunistic infections, over the risk observed with use of natalizumab alone. The safety and efficacy of natalizumab in combination with antineoplastic, immunosuppressant, or immunomodulating agents have not been established. Patients receiving chronic immunosuppressant or immunomodulatory therapy or who have systemic medical conditions resulting in significantly compromised immune system function should not ordinarily be treated with natalizumab. The risk of PML is also increased in patients who have been treated with an immunosuppressant prior to receiving natalizumab. For patients with Crohn's disease who start natalizumab while on chronic corticosteroids, commence steroid withdrawal as soon as a therapeutic benefit has occurred. If the patient cannot discontinue systemic corticosteroids within six months, discontinue natalizumab. ### Laboratory Test Abnormalities In clinical trials, natalizumab was observed to induce increases in circulating lymphocytes, monocytes, eosinophils, basophils, and nucleated red blood cells. Observed changes persisted during natalizumab exposure, but were reversible, returning to baseline levels usually within 16 weeks after the last dose. Elevations of neutrophils were not observed. natalizumab induces mild decreases in hemoglobin levels that are frequently transient. ### Immunizations No data are available on the effects of vaccination in patients receiving natalizumab. No data are available on the secondary transmission of infection by live vaccines in patients receiving natalizumab. # Adverse Reactions ## Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The most common adverse reactions (incidence ≥ 10%) were headache and fatigue in both the multiple sclerosis (MS) and Crohn's disease (CD) studies. Other common adverse reactions (incidence ≥ 10%) in the MS population were arthralgia, urinary tract infection, lower respiratory tract infection, gastroenteritis, vaginitis, depression, pain in extremity, abdominal discomfort, diarrhea NOS, and rash. Other common adverse reactions (incidence ≥ 10%) in the CD population were upper respiratory tract infections and nausea. The most frequently reported adverse reactions resulting in clinical intervention (i.e., discontinuation of natalizumab), in the MS studies were urticaria (1%) and other hypersensitivity reactions (1%), and in the CD studies (Studies CD1 and CD2) were the exacerbation of Crohn's disease (4.2%) and acute hypersensitivity reactions (1.5%). A total of 1617 multiple sclerosis patients in controlled studies received natalizumab, with a median duration of exposure of 28 months. A total of 1563 patients received natalizumab in all CD studies for a median exposure of 5 months; of these patients, 33% (n=518) received at least one year of treatment and 19% (n=297) received at least two years of treatment. ### Multiple Sclerosis Clinical Studies The most frequently reported serious adverse reactions in Study MS1 with natalizumab were infections (3.2% versus 2.6% in placebo, including urinary tract infection and pneumonia ), acute hypersensitivity reactions (1.1% versus 0.3%, including naphylaxis/anaphylactoid reaction ), depression (1.0% versus 1.0%, including suicidal ideation or attempt ), and cholelithiasis (1.0% versus 0.3%). In Study MS2, serious adverse reactions of appendicitis were also more common in patients who received natalizumab (0.8% versus 0.2% in placebo). TABLE 2 enumerates adverse reactions and selected laboratory abnormalities that occurred in Study MS1 at an incidence of at least 1 percentage point higher in natalizumab-treated patients than was observed in placebo-treated patients. In Study MS2, peripheral edema was more common in patients who received natalizumab (5% versus 1% in placebo). ### Crohn's Disease Clinical Studies The following serious adverse events in the induction Studies CD1 and CD2 were reported more commonly with natalizumab than placebo and occurred at an incidence of at least 0.3%: intestinal obstruction or stenosis (2% vs. 1% in placebo), acute hypersensitivity reactions (0.5% vs. 0%), abdominal adhesions (0.3% vs. 0%), and cholelithiasis (0.3% vs. 0%). Similar serious adverse events were seen in the maintenance Study CD3. TABLE 3 enumerates adverse drug reactions that occurred in Studies CD1 and CD2 (median exposure of 2.8 months). TABLE 4 enumerates adverse drug reactions that occurred in Study CD3 (median exposure of 11.0 months). ### Infections Progressive Multifocal Leukoencephalopathy (PML) occurred in three patients who received natalizumab in clinical trials. Two cases of PML were observed in the 1869 patients with multiple sclerosis who were treated for a median of 120 weeks. These two patients had received natalizumab in addition to interferon beta-1a. The third case occurred after eight doses in one of the 1043 patients with Crohn's disease who were evaluated for PML. In the postmarketing setting, additional cases of PML have been reported in natalizumab-treated multiple sclerosis and Crohn's disease patients who were not receiving concomitant immunomodulatory therapy. In Studies MS1 and MS2, the rate of any type of infection was approximately 1.5 per patient-year in both natalizumab-treated patients and placebo-treated patients. The infections were predominately upper respiratory tract infections, influenza, and urinary tract infections. In Study MS1, the incidence of serious infection was approximately 3% in natalizumab-treated patients and placebo-treated patients. Most patients did not interrupt treatment with natalizumab during infections. The only opportunistic infection in the multiple sclerosis clinical trials was a case of cryptosporidial gastroenteritis with a prolonged course. In Studies CD1 and CD2, the rate of any type of infection was 1.7 per patient-year in natalizumab-treated patients and 1.4 per patient-year in placebo-treated patients. In Study CD3, the incidence of any type of infection was 1.7 per patient-year in natalizumab-treated patients and was similar in placebo-treated patients. The most common infections were nasopharyngitis, upper respiratory tract infection, and influenza. The majority of patients did not interrupt natalizumab therapy during infections and recovery occurred with appropriate treatment. Concurrent use of natalizumab in CD clinical trials with chronic steroids and/or methotrexate, 6-MP, and azathioprine did not result in an increase in overall infections compared to natalizumab alone; however, the concomitant use of such agents could lead to an increased risk of serious infections. In Studies CD1 and CD2, the incidence of serious infection was approximately 2.1% in both natalizumab-treated patients and placebo-treated patients. In Study CD3, the incidence of serious infection was approximately 3.3% in natalizumab-treated patients and approximately 2.8% in placebo-treated patients. In clinical studies for CD, opportunistic infections (pneumocystis carinii pneumonia, pulmonary mycobacterium avium intracellulare, bronchopulmonary aspergillosis, and burkholderia cepacia) have been observed in <1% of natalizumab-treated patients; some of these patients were receiving concurrent immunosuppressants. Two serious non-bacterial meningitides occurred in natalizumab-treated patients compared to none in placebo-treated patients. ### Infusion-related Reactions An infusion-related reaction was defined in clinical trials as any adverse event occurring within two hours of the start of an infusion. In MS clinical trials, approximately 24% of natalizumab-treated multiple sclerosis patients experienced an infusion-related reaction, compared to 18% of placebo-treated patients. In the controlled CD clinical trials, infusion-related reactions occurred in approximately 11% of patients treated with natalizumab compared to 7% of placebo-treated patients. Reactions more common in the natalizumab-treated MS patients compared to the placebo-treated MS patients included headache, dizziness, fatigue, urticaria, pruritus, and rigors. Acute urticaria was observed in approximately 2% of patients. Other hypersensitivity reactions were observed in 1% of patients receiving natalizumab. Serious systemic hypersensitivity infusion reactions occurred in <1% of patients. All patients recovered with treatment and/or discontinuation of the infusion. Infusion-related reactions more common in CD patients receiving natalizumab than those receiving placebo included headache, nausea, urticaria, pruritus, and flushing. Serious infusion reactions occurred in Studies CD1, CD2, and CD3 at an incidence of <1% in natalizumab-treated patients. MS and CD patients who became persistently positive for antibodies to natalizumab were more likely to have an infusion-related reaction than those who were antibody-negative. ## Postmarketing Experience There is limited information regarding Natalizumab Postmarketing Experience in the drug label. # Drug Interactions Because of the potential for increased risk of PML and other infections, Crohn's disease patients receiving natalizumab should not be treated with concomitant immunosuppressants (e.g., 6-mercaptopurine, azathioprine, cyclosporine, or methotrexate) or inhibitors of TNF-α, and corticosteroids should be tapered in those patients with Crohn's disease who are on chronic corticosteroids when they start natalizumab therapy. Ordinarily, MS patients receiving chronic immunosuppressant or immunomodulatory therapy should not be treated with natalizumab. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): C Natalizumab has been shown to reduce pup survival in guinea pigs when given in doses 7 times the human dose, and has been shown to have hematologic effects on the fetus in monkeys when given in doses 2.3 times the human dose. There are no adequate and well-controlled studies in pregnant women. natalizumab should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Pregnancy Category (AUS): C There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Natalizumab in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Natalizumab during labor and delivery. ### Nursing Mothers Natalizumab has been detected in human milk. The effects of this exposure on infants are unknown. ### Pediatric Use Safety and effectiveness of natalizumab in pediatric patients with multiple sclerosis or Crohn's disease below the age of 18 years have not been established. natalizumab is not indicated for use in pediatric patients. ### Geriatic Use Clinical studies of natalizumab did not include sufficient numbers of patients aged 65 years and over to determine whether they respond differently than younger patients. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. ### Gender There is no FDA guidance on the use of Natalizumab with respect to specific gender populations. ### Race There is no FDA guidance on the use of Natalizumab with respect to specific racial populations. ### Renal Impairment Pharmacokinetics of natalizumab in patients with renal or hepatic insufficiency have not been studied. ### Hepatic Impairment Pharmacokinetics of natalizumab in patients with renal or hepatic insufficiency have not been studied. ### Females of Reproductive Potential and Males Natalizumab did not affect male fertility at doses up to 7-fold the clinical dose. ### Immunocompromised Patients There is no FDA guidance one the use of Natalizumab in patients who are immunocompromised. # Administration and Monitoring ### Administration Intravenous ### Monitoring There is limited information regarding Natalizumab Monitoring in the drug label. # IV Compatibility There is limited information regarding the compatibility of Natalizumab and IV administrations. # Overdosage Safety of doses higher than 300 mg has not been adequately evaluated. The maximum amount of natalizumab that can be safely administered has not been determined. # Pharmacology ## Mechanism of Action Natalizumab binds to the α4-subunit of α4β1 and α4β7 integrins expressed on the surface of all leukocytes except neutrophils, and inhibits the α4-mediated adhesion of leukocytes to their counter-receptor(s). The receptors for the α4 family of integrins include vascular cell adhesion molecule-1 (VCAM-1), which is expressed on activated vascular endothelium, and mucosal addressin cell adhesion molecule-1 (MAdCAM-1) present on vascular endothelial cells of the gastrointestinal tract. Disruption of these molecular interactions prevents transmigration of leukocytes across the endothelium into inflamed parenchymal tissue. In vitro, anti-α4-integrin antibodies also block α4-mediated cell binding to ligands such as osteopontin and an alternatively spliced domain of fibronectin, connecting segment-1 (CS-1). In vivo, natalizumab may further act to inhibit the interaction of α4-expressing leukocytes with their ligand(s) in the extracellular matrix and on parenchymal cells, thereby inhibiting further recruitment and inflammatory activity of activated immune cells. The specific mechanism(s) by which natalizumab exerts its effects in multiple sclerosis and Crohn's disease have not been fully defined. In multiple sclerosis, lesions are believed to occur when activated inflammatory cells, including T-lymphocytes, cross the blood-brain barrier (BBB). Leukocyte migration across the BBB involves interaction between adhesion molecules on inflammatory cells and their counter-receptors present on endothelial cells of the vessel wall. The clinical effect of natalizumab in multiple sclerosis may be secondary to blockade of the molecular interaction of α4β1-integrin expressed by inflammatory cells with VCAM-1 on vascular endothelial cells, and with CS-1 and/or osteopontin expressed by parenchymal cells in the brain. Data from an experimental autoimmune encephalitis animal model of multiple sclerosis demonstrate reduction of leukocyte migration into brain parenchyma and reduction of plaque formation detected by magnetic resonance imaging (MRI) following repeated administration of natalizumab. The clinical significance of these animal data is unknown. In Crohn's disease, the interaction of the α4β7 integrin with the endothelial receptor MAdCAM-1 has been implicated as an important contributor to the chronic inflammation that is a hallmark of the disease. MAdCAM-1 is mainly expressed on gut endothelial cells and plays a critical role in the homing of T lymphocytes to gut lymph tissue found in Peyer's patches. MAdCAM-1 expression has been found to be increased at active sites of inflammation in patients with CD, which suggests it may play a role in the recruitment of leukocytes to the mucosa and contribute to the inflammatory response characteristic of CD. The clinical effect of natalizumab in CD may therefore be secondary to blockade of the molecular interaction of the α4ß7-integrin receptor with MAdCAM-1 expressed on the venular endothelium at inflammatory foci. VCAM-1 expression has been found to be upregulated on colonic endothelial cells in a mouse model of IBD and appears to play a role in leukocyte recruitment to sites of inflammation. The role of VCAM-1 in CD, however, is not clear. ## Structure Natalizumab is a recombinant humanized IgG4ϰ monoclonal antibody produced in murine myeloma cells. Natalizumab contains human framework regions and the complementarity-determining regions of a murine antibody that binds to α4-integrin. The molecular weight of natalizumab is 149 kilodaltons ## Pharmacodynamics Natalizumab administration increases the number of circulating leukocytes (including lymphocytes, monocytes, basophils, and eosinophils) due to inhibition of transmigration out of the vascular space. natalizumab does not affect the absolute count of circulating neutrophils. ## Pharmacokinetics ### Multiple Sclerosis (MS) Patients In patients with MS, following the repeat intravenous administration of a 300 mg dose of natalizumab, the mean ± SD maximum observed serum concentration was 110 ± 52 mcg/mL. Mean average steady-state trough concentrations ranged from 23 mcg/mL to 29 mcg/mL. The observed time to steady-state was approximately 24 weeks after every four weeks of dosing. The mean ± SD half-life, volume of distribution, and clearance of natalizumab were 11 ± 4 days, 5.7 ± 1.9 L, and 16 ± 5 mL/hour, respectively. The effects of covariates such as body weight, age, gender, and presence of anti-natalizumab antibodies on natalizumab pharmacokinetics were investigated in a population pharmacokinetic study (n=2195). Natalizumab clearance increased with body weight in a less than proportional manner such that a 43% increase in body weight resulted in a 32% increase in clearance. The presence of persistent anti-natalizumab antibodies increased natalizumab clearance approximately 3-fold. ### Crohn's Disease (CD) Patients In patients with CD, following the repeat intravenous administration of a 300 mg dose of natalizumab, the mean ± SD maximum observed serum concentration was 101 ± 34 mcg/mL. The mean ± SD average steady-state trough concentration was 10 ± 9 mcg/mL. The estimated time to steady-state was approximately 16 to 24 weeks after every four weeks of dosing. The mean ± SD half-life, volume of distribution, and clearance of natalizumab were 10 ± 7 days, 5.2 ± 2.8 L, and 22 ± 22 mL/hour, respectively. The effects of total body weight, age, gender, race, selected hematology and serum chemistry measures, co-administered medications (infliximab, immunosuppressants, or steroids), and the presence of anti-natalizumab antibodies were investigated in a population pharmacokinetic analysis (n=1156). The presence of anti-natalizumab antibodies was observed to increase natalizumab clearance. ## Nonclinical Toxicology ### Carcinogenesis, Mutagenesis, Impairment of Fertility No clastogenic or mutagenic effects of natalizumab were observed in the Ames test or in vitro chromosomal aberration assay in human lymphocytes. Natalizumab showed no effects in in vitro assays of α4-integrin positive human tumor line proliferation/cytotoxicity. Xenograft transplantation models in SCID and nude mice with two α4-integrin positive human tumor lines (leukemia, melanoma) demonstrated no increase in tumor growth rates or metastasis resulting from natalizumab treatment. Reductions in female guinea pig fertility were observed in one study at dose levels of 30 mg/kg, but not at the 10 mg/kg dose level (2.3-fold the clinical dose). A 47% reduction in pregnancy rate was observed in guinea pigs receiving 30 mg/kg relative to control. Implantations were seen in only 36% of animals having corpora lutea in the 30 mg/kg group versus 66 to 72% in the other groups. Natalizumab did not affect male fertility at doses up to 7-fold the clinical dose. ### Animal Toxicology and/or Pharmacology In reproductive studies in monkeys and guinea pigs, there was no evidence of teratogenic effects at doses up to 30 mg/kg (7 times the human clinical dose based on a body weight comparison). In one study where female guinea pigs were exposed to natalizumab during the second half of pregnancy, a small reduction in pup survival was noted at post-natal day 14 with respect to control (3 pups/litter for the group treated with 30 mg/kg natalizumab and 4.3 pups/litter for the control group). In one of five studies that exposed monkeys or guinea pigs during pregnancy, the number of abortions in treated (30 mg/kg) monkeys was 33% versus 17% in controls. No effects on abortion rates were noted in any other study. natalizumab underwent trans-placental transfer and produced in utero exposure in developing guinea pigs and cynomolgus monkeys. When pregnant dams were exposed to natalizumab at approximately 7-fold the clinical dose, serum levels in fetal animals at delivery were approximately 35% of maternal serum natalizumab levels. A study in pregnant cynomolgus monkeys treated at 2.3-fold the clinical dose demonstrated natalizumab-related changes in the fetus. These changes included mild anemia, reduced platelet count, increased spleen weights, and reduced liver and thymus weights associated with increased splenic extramedullary hematopoiesis, thymic atrophy, and decreased hepatic hematopoiesis. In offspring born to mothers treated with natalizumab at 7-fold the clinical dose, platelet counts were also reduced. This effect was reversed upon clearance of natalizumab. There was no evidence of anemia in these offspring. Offspring exposed in utero and via breast milk had no natalizumab-related changes in the lymphoid organs and had normal immune response to challenge with a T-cell dependent antigen. # Clinical Studies ### Multiple Sclerosis natalizumab was evaluated in two randomized, double-blind, placebo-controlled trials in patients with multiple sclerosis. Both studies enrolled patients who experienced at least one clinical relapse during the prior year and had a Kurtzke Expanded Disability Status Scale (EDSS) score between 0 and 5.0. Results for each study are shown in TABLE 5 and TABLE 6. Median time on study drug was 120 weeks in each study. In both studies, neurological evaluations were performed every 12 weeks and at times of suspected relapse. Magnetic resonance imaging evaluations for T1-weighted gadolinium (Gd)-enhancing lesions and T2-hyperintense lesions were performed annually. Study MS1 enrolled patients who had not received any interferon-beta or glatiramer acetate for at least the previous 6 months; approximately 94% had never been treated with these agents. Median age was 37, with a median disease duration of 5 years. Patients were randomized in a 2:1 ratio to receive natalizumab 300 mg intravenous infusion (n=627) or placebo (n=315) every 4 weeks for up to 28 months (30 infusions). Study MS2 enrolled patients who had experienced one or more relapses while on treatment with AVONEX® (Interferon beta-1a) 30 mcg intramuscularly (IM) once weekly during the year prior to study entry. Median age was 39, with a median disease duration of 7 years. Patients were evenly randomized to receive natalizumab 300 mg (n=589) or placebo (n=582) every 4 weeks for up to 28 months (30 infusions). All patients continued to receive AVONEX 30 mcg IM once weekly. The efficacy of natalizumab alone was not compared with the efficacy of natalizumab plus AVONEX. The primary endpoint at 2 years was time to onset of sustained increase in disability, defined as an increase of at least 1 point on the EDSS from baseline EDSS ≥ 1.0 that was sustained for 12 weeks, or at least a 1.5 point increase on the EDSS from baseline EDSS=0 that was sustained for 12 weeks. Time to onset of sustained increase in disability was longer in natalizumab-treated patients than in placebo-treated patients in Studies MS1 (FIGURE 1) and MS2. The proportion of patients with increased disability and the annualized relapse rate were also lower in natalizumab-treated patients than in placebo-treated patients in Studies MS1 and MS2. ### Crohn's Disease The safety and efficacy of natalizumab were evaluated in three randomized, double-blind, placebo-controlled clinical trials in 1414 adult patients with moderately to severely active Crohn's disease (Crohn's Disease Activity Index ≥220 and ≤450). Concomitant inhibitors of TNF-α were not permitted. Concomitant stable doses of aminosalicylates, corticosteroids, and/or immunosuppressants (e.g., 6-mercatopurine, azathioprine, or methotrexate) were permitted, and 89% of patients continued to receive at least one of these medications. Although permitted in the clinical trials, combination therapy with immunosuppressants is not recommended. Overall, approximately two-thirds of patients were not taking concomitant immunosuppressants, and approximately one-third of patients were taking neither concomitant immunosuppressants nor concomitant corticosteroids. Induction of clinical response (defined as ≥70-point decrease in CDAI from baseline) was evaluated in two studies. In Study CD1, 896 patients were randomized 4:1 to receive three monthly infusions of either 300 mg natalizumab or placebo. Clinical results were assessed at Week 10, and patients with incomplete information were considered as not having a clinical response. At Week 10, 56% of the 717 patients receiving natalizumab were in response compared to 49% of the 179 patients receiving placebo (treatment effect: 7%; 95% confidence interval (CI): ; p=0.067). In a post hoc analysis of the subset of 653 patients with elevated baseline C-reactive protein (CRP), indicative of active inflammation, 57% of natalizumab patients were in response compared to 45% of those receiving placebo (treatment effect: 12%; 95% CI: ; nominal p=0.01). In the second induction trial, Study CD2, only patients with elevated serum C-reactive Protein (CRP) were studied. A total of 509 patients were randomized 1:1 to receive three monthly infusions of either 300 mg natalizumab or placebo. In Study CD2, in contrast to Study CD1, clinical response and clinical remission (defined as CDAI score <150) were required to be met at both Weeks 8 and 12, rather than at a single time-point; patients with incomplete information were considered as not having a response. In studies CD1 and CD2, for subgroups defined by prior use of, or by inadequate response to prior therapies (i.e., corticosteroids, immunosuppressants, and inhibitors of TNF-α), the treatment effect was generally similar to that seen in the whole study population. In the subgroup of patients that were taking neither concomitant immunosuppressants nor concomitant corticosteroids, the treatment effect was generally similar to that seen in the whole study population. Patients with inadequate response to inhibitors of TNF-α appeared to have lower clinical response and lower clinical remission in both the treatment and placebo groups. For patients in Study CD2 with an inadequate response to prior treatment with inhibitors of TNF-α, clinical response at both Weeks 8 and 12 was seen in 38% of those randomized to natalizumab, and clinical remission at both Weeks 8 and 12 was seen in 17%. Maintenance therapy was evaluated in Study CD3. In this study, 331 patients from Study CD1 that had had a clinical response to natalizumab at both Weeks 10 and 12 were re-randomized 1:1 to treatment with continuing monthly infusions of either 300 mg natalizumab or placebo. Maintenance of response was assessed by the proportion of patients who did not lose clinical response at any study visit for an additional 6 and 12 months of treatment (i.e., Month 9 and Month 15 after initial treatment with natalizumab). The study also assessed the proportion of patients who did not lose clinical remission at any study visit within the subset of those who were in remission at study entry. Requiring maintenance of response or remission at each visit, as opposed to just at Month 9 or Month 15, may result in lower proportions meeting endpoint criteria, and may make a comparison of these results with those of other products used to treat Crohn's disease misleading. For subgroups in study CD3 defined by prior use of, or by inadequate response to prior therapies (i.e., corticosteroids, immunosuppressants, and inhibitors of TNF-α), the treatment effect was generally similar to that seen in the whole study population. In the subgroup of patients that were taking neither concomitant immunosuppressants nor concomitant corticosteroids, the treatment effect was generally similar to that seen in the whole study population. Patients with inadequate response to inhibitors of TNF-α appeared to have lower maintenance of clinical response and lower maintenance of clinical remission in both the treatment and placebo groups. For patients in study CD3 with an inadequate response to prior treatment with inhibitors of TNF-α, maintenance of clinical response through Month 9 was seen in 52% of those randomized to natalizumab, and maintenance of clinical remission through Month 9 was seen in 30%. Given the requirement to discontinue chronic steroids it is important to note that in the subgroup of patients (n=65) who were receiving corticosteroid medication at baseline, responded to natalizumab in Study CD1, and were re-randomized to natalizumab in Study CD3, approximately two-thirds were able to discontinue steroids within 10 weeks of initiating a steroid taper. # How Supplied - 300 mg natalizumab in 15 mL - In a sterile single-use vial free of preservatives - NDC 64406-008-01 ## Storage - Must be refrigerated between 2 to 8°C (36° to 46°F) # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information ### General Counseling Information Counsel patients to understand the risks and benefits of natalizumab before an initial prescription is written. The patient may be educated by either the enrolled prescriber or a healthcare provider under that prescriber's direction. Instruct patients using natuzimab to: - Read the Medication Guide before starting natalizumab and before each natalizumab infusion. - Promptly report any new or continuously worsening symptoms that persist over several days to their prescriber. - Inform all of their physicians that they are receiving natalizumab. - Plan to see their prescriber three months after the first infusion, six months after the first infusion, every six months thereafter, and for at least six months after discontinuing natalizumab. ### Progressive Multifocal Leukoencephalopathy Inform patients that Progressive Multifocal Leukoencephalopathy (PML) has occurred in patients who received natalizumab. Instruct the patient of the importance of contacting their doctor if they develop any symptoms suggestive of PML. Instruct the patient that typical symptoms associated with PML are diverse, progress over days to weeks, and include progressive weakness on one side of the body or clumsiness of limbs, disturbance of vision, and changes in thinking, memory, and orientation leading to confusion and personality changes. Instruct the patient that the progression of deficits usually leads to death or severe disability over weeks or months. Instruct patients to continue to look for new signs and symptoms suggestive of PML for approximately 6 months following discontinuation of natalizumab. ### natalizumab TOUCH Prescribing Program Advise the patient that natalizumab is only available through a restricted program called the TOUCH Prescribing Program. Inform the patient of the following requirements: Patients must read the Medication Guide and sign the Patient Prescriber Enrollment Form. Advise patients that natalizumab is available only from certified pharmacies and infusion centers participating in the program. ### Herpes Encephalitis/Meningitis Inform patients that natalizumab increases the risk of developing encephalitis and meningitis caused by herpes simplex and varicella zoster viruses. Instruct patients to report immediately if they experience symptoms such as fever, headache and confusion. ### Hepatotoxicity Inform patients that natalizumab may cause liver injury. Instruct patients treated with natalizumab to report promptly any symptoms that may indicate liver injury, including fatigue, anorexia, right upper abdominal discomfort, dark urine or jaundice. ### Hypersensitivity Reactions Instruct patients to report immediately if they experience symptoms consistent with a hypersensitivity reaction (e.g., urticaria with or without associated symptoms) during or following an infusion of natalizumab. ### Immunosuppression/Infections Inform patients that natalizumab may lower the ability of their immune system to fight infections. Instruct the patient of the importance of contacting their doctor if they develop any symptoms of infection. # Precautions with Alcohol Alcohol-Natalizumab interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - Tysabri # Look-Alike Drug Names There is limited information regarding Natalizumab Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	Natalizumab Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Gloria Picoy [2] # Disclaimer WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here. # Black Box Warning # Overview Natalizumab is a monoclonal antibody that is FDA approved for the treatment of multiple sclerosis (MS) and Crohn's disease (CD). There is a Black Box Warning for this drug as shown here. Common adverse reactions include headache, fatigue, arthralgia, urinary tract infection, lower respiratory tract infection, gastroenteritis, vaginitis, depression, pain in extremity, abdominal discomfort, diarrhea NOS, and rash. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) ### Multiple Sclerosis (MS) - Is indicated as monotherapy for the treatment of patients with relapsing forms of multiple sclerosis. - Natalizumab increases the risk of PML. - When initiating and continuing treatment with natalizumab, physicians should consider whether the expected benefit of natalizumab is sufficient to offset this risk. - Dosage: - 300 mg intravenous infusion over one hour every four weeks. ### Crohn's Disease (CD) - Is indicated for inducing and maintaining clinical response and remission in adult patients with moderately to severely active Crohn's disease with evidence of inflammation who have had an inadequate response to, or are unable to tolerate, conventional CD therapies and inhibitors of TNF-α. - Natalizumab should not be used in combination with immunosuppressants (e.g., 6-mercaptopurine, azathioprine, cyclosporine, or methotrexate) or inhibitors of TNF-α. - Dosage: - 300 mg intravenous infusion over one hour every four weeks ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Natalizumab in adult patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Natalizumab in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) There is limited information regarding Natalizumab FDA-Labeled Indications and Dosage (Pediatric) in the drug label. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Natalizumab in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Natalizumab in pediatric patients. # Contraindications - natalizumab is contraindicated in patients who have or have had progressive multifocal leukoencephalopathy (PML). - natalizumab should not be administered to a patient who has had a hypersensitivity reaction to natalizumab. Observed reactions range from urticaria to anaphylaxis # Warnings ### Progressive Multifocal Leukoencephalopathy Progressive multifocal leukoencephalopathy (PML), an opportunistic viral infection of the brain caused by the JC virus (JCV) that typically only occurs in patients who are immunocompromised, and that usually leads to death or severe disability, has occurred in patients who have received natalizumab. Three factors that are known to increase the risk of PML in natalizumab-treated patients have been identified: - Longer treatment duration, especially beyond 2 years. There is limited experience in patients who have received more than 6 years of natalizumab treatment. - Prior treatment with an immunosuppressant (e.g., mitoxantrone, azathioprine, methotrexate, cyclophosphamide, mycophenolate mofetil). - The presence of anti-JCV antibodies. Patients who are anti-JCV antibody positive have a higher risk for developing PML. These factors should be considered in the context of expected benefit when initiating and continuing treatment with natalizumab. Infection by the JC virus is required for the development of PML. Anti-JCV antibody testing should not be used to diagnose PML. Anti-JCV antibody negative status indicates that exposure to the JC virus has not been detected. Patients who are anti-JCV antibody negative have a lower risk of PML than those who are positive. Patients who are anti-JCV antibody negative are still at risk for the development of PML due to the potential for a new JCV infection or a false negative test result. The reported rate of seroconversion in patients with MS (changing from anti-JCV antibody negative to positive and remaining positive in subsequent testing) is 3 to 8 percent annually. In addition, some patients' serostatus may change intermittently. Therefore, patients with a negative anti-JCV antibody test result should be retested periodically. For purposes of risk assessment, a patient with a positive anti-JCV antibody test at any time is considered anti-JCV antibody positive regardless of the results of any prior or subsequent anti-JCV antibody testing. When assessed, anti-JCV antibody status should be determined using an analytically and clinically validated immunoassay. Anti-JCV antibody testing should not be performed for at least two weeks following plasma exchange due to the removal of antibodies from the serum. There are no known interventions that can reliably prevent PML or adequately treat PML if it occurs. It is not known whether early detection of PML and discontinuation of natalizumab will mitigate the disease. PML has been reported following discontinuation of natalizumab in patients who did not have findings suggestive of PML at the time of discontinuation. Patients should continue to be monitored for any new signs or symptoms that may be suggestive of PML for at least six months following discontinuation of natalizumab. Ordinarily, patients receiving chronic immunosuppressant or immunomodulatory therapy or who have systemic medical conditions resulting in significantly compromised immune system function should not be treated with natalizumab. Because of the risk of PML, natalizumab is available only under a restricted distribution program, the TOUCH® Prescribing Program. In multiple sclerosis patients, an MRI scan should be obtained prior to initiating therapy with natalizumab. This MRI may be helpful in differentiating subsequent multiple sclerosis symptoms from PML. In Crohn's disease patients, a baseline brain MRI may also be helpful to distinguish pre-existent lesions from newly developed lesions, but brain lesions at baseline that could cause diagnostic difficulty while on natalizumab therapy are uncommon. Healthcare professionals should monitor patients on natalizumab for any new sign or symptom suggestive of PML. Typical symptoms associated with PML are diverse, progress over days to weeks, and include progressive weakness on one side of the body or clumsiness of limbs, disturbance of vision, and changes in thinking, memory, and orientation leading to confusion and personality changes. The progression of deficits usually leads to death or severe disability over weeks or months. Withhold natalizumab dosing immediately at the first sign or symptom suggestive of PML. For diagnosis of PML, an evaluation including a gadolinium-enhanced MRI scan of the brain and, when indicated, cerebrospinal fluid analysis for JC viral DNA are recommended. If the initial evaluations for PML are negative but clinical suspicion for PML remains, continue to withhold natalizumab dosing and repeat the evaluations. There are no known interventions that can adequately treat PML if it occurs. Three sessions of plasma exchange over 5 to 8 days were shown to accelerate natalizumab clearance in a study of 12 patients with MS who did not have PML, although in the majority of patients alpha-4 integrin receptor binding remained high. Adverse events which may occur during plasma exchange include clearance of other medications and volume shifts, which have the potential to lead to hypotension or pulmonary edema. Although plasma exchange has not been studied in natalizumab treated patients with PML, it has been used in such patients in the postmarketing setting to remove natalizumab more quickly from the circulation. Anti-JCV antibody testing should not be performed during or for at least two weeks following plasma exchange due to the removal of antibodies from the serum. Immune reconstitution inflammatory syndrome (IRIS) has been reported in the majority of natalizumab treated patients who developed PML and subsequently discontinued natalizumab. In almost all cases, IRIS occurred after plasma exchange was used to eliminate circulating natalizumab. It presents as a clinical decline in the patient's condition after natalizumab removal (and in some cases after apparent clinical improvement) that may be rapid, can lead to serious neurological complications or death and is often associated with characteristic changes in the MRI. natalizumab has not been associated with IRIS in patients discontinuing treatment with natalizumab for reasons unrelated to PML. In natalizumab-treated patients with PML, IRIS has been reported within days to several weeks after plasma exchange. Monitoring for development of IRIS and appropriate treatment of the associated inflammation should be undertaken. ### natalizumab TOUCH Prescribing Program natalizumab is available only through a restricted program under a REMS called the TOUCH® Prescribing Program because of the risk of PML. For prescribers and patients, the TOUCH® Prescribing Program has two components: MS TOUCH® (for patients with multiple sclerosis) and CD TOUCH® (for patients with Crohn's disease). Selected requirements of the TOUCH® Prescribing Program include the following: - Prescribers must be certified and comply with the following: - Review the TOUCH Prescribing Program prescriber educational materials, including the full prescribing information. - Educate patients on the benefits and risks of treatment with natalizumab, ensure that patients receive the Medication Guide, and encourage them to ask questions. - Review, complete, and sign the Patient-Prescriber Enrollment Form. - Evaluate patients three months after the first infusion, six months after the first infusion, every six months thereafter, and for at least six months after discontinuing natalizumab. - Determine every six months whether patients should continue on treatment and, if so, authorize treatment for another six months. - Submit to Biogen Idec the “natalizumab Patient Status Report and Reauthorization Questionnaire” six months after initiating treatment and every six months thereafter. - Complete an “Initial Discontinuation Questionnaire” when natalizumab is discontinued and a “6-Month Discontinuation Questionnaire” following discontinuation of natalizumab. - Report cases of PML, hospitalizations due to opportunistic infections, or deaths to Biogen Idec at 1-800-456-2255 as soon as possible. - Patients must be enrolled in the TOUCH Prescribing Program, read the Medication Guide, understand the risks associated with natalizumab and complete and sign the Patient-Prescriber Enrollment Form. - Pharmacies and infusion centers must be specially certified to dispense or infuse natalizumab. ### Herpes Encephalitis and Meningitis Natalizumab increases the risk of developing encephalitis and meningitis caused by herpes simplex and varicella zoster viruses. Serious, life-threatening, and sometimes fatal cases have been reported in the postmarketing setting in multiple sclerosis patients receiving natalizumab. Laboratory confirmation in those cases was based on positive PCR for viral DNA in the cerebrospinal fluid. The duration of treatment with natalizumab prior to onset ranged from a few months to several years. Monitor patients receiving natalizumab for signs and symptoms of meningitis and encephalitis. If herpes encephalitis or meningitis occurs, TYSBARI should be discontinued, and appropriate treatment for herpes encephalitis/meningitis should be administered. ### Hepatotoxicity Clinically significant liver injury, including acute liver failure requiring transplant, has been reported in patients treated with natalizumab in the postmarketing setting. Signs of liver injury, including markedly elevated serum hepatic enzymes and elevated total bilirubin, occurred as early as six days after the first dose; signs of liver injury have also been reported for the first time after multiple doses. In some patients, liver injury recurred upon rechallenge, providing evidence that natalizumab caused the injury. The combination of transaminase elevations and elevated bilirubin without evidence of obstruction is generally recognized as an important predictor of severe liver injury that may lead to death or the need for a liver transplant in some patients. Natalizumab should be discontinued in patients with jaundice or other evidence of significant liver injury (e.g., laboratory evidence). ### Hypersensitivity/Antibody Formation Hypersensitivity reactions have occurred in patients receiving natalizumab, including serious systemic reactions (e.g., anaphylaxis) which occurred at an incidence of <1%. These reactions usually occur within two hours of the start of the infusion. Symptoms associated with these reactions can include urticaria, dizziness, fever, rash, rigors, pruritus, nausea, flushing, hypotension, dyspnea, and chest pain. Generally, these reactions are associated with antibodies to natalizumab. If a hypersensitivity reaction occurs, discontinue administration of natalizumab and initiate appropriate therapy. Patients who experience a hypersensitivity reaction should not be re-treated with natalizumab. Hypersensitivity reactions were more frequent in patients with antibodies to natalizumab compared to patients who did not develop antibodies to natalizumab in both MS and CD studies. Therefore, the possibility of antibodies to natalizumab should be considered in patients who have hypersensitivity reactions. Antibody testing: If the presence of persistent antibodies is suspected, antibody testing should be performed. Antibodies may be detected and confirmed with sequential serum antibody tests. Antibodies detected early in the treatment course (e.g., within the first six months) may be transient and disappear with continued dosing. Repeat testing at three months after the initial positive result is recommended in patients in whom antibodies are detected to confirm that antibodies are persistent. Prescribers should consider the overall benefits and risks of natalizumab in a patient with persistent antibodies. Experience with monoclonal antibodies, including natalizumab, suggests that patients who receive therapeutic monoclonal antibodies after an extended period without treatment may be at higher risk of hypersensitivity reactions than patients who received regularly scheduled treatment. Given that patients with persistent antibodies to natalizumab experience reduced efficacy, and that hypersensitivity reactions are more common in such patients, consideration should be given to testing for the presence of antibodies in patients who wish to recommence therapy following a dose interruption. Following a period of dose interruption, patients testing negative for antibodies prior to re-dosing have a risk of antibody development with re-treatment that is similar to natalizumab naïve patients. ### Immunosuppression/Infections The immune system effects of natalizumab may increase the risk for infections. In Study MS1, certain types of infections, including pneumonias and urinary tract infections (including serious cases), gastroenteritis, vaginal infections, tooth infections, tonsillitis, and herpes infections, occurred more often in natalizumab-treated patients than in placebo-treated patients. One opportunistic infection, a cryptosporidial gastroenteritis with a prolonged course, was observed in a patient who received natalizumab in Study MS1. In Studies MS1 and MS2, an increase in infections was seen in patients concurrently receiving short courses of corticosteroids. However, the increase in infections in natalizumab-treated patients who received steroids was similar to the increase in placebo-treated patients who received steroids. In CD clinical studies, opportunistic infections (pneumocystis carinii pneumonia, pulmonary mycobacterium avium intracellulare, bronchopulmonary aspergillosis, and burkholderia cepacia) have been observed in <1% of natalizumab-treated patients; some of these patients were receiving concurrent immunosuppressants. In Studies CD1 and CD2, an increase in infections was seen in patients concurrently receiving corticosteroids. However, the increase in infections was similar in placebo-treated and natalizumab-treated patients who received steroids. Concurrent use of antineoplastic, immunosuppressant, or immunomodulating agents may further increase the risk of infections, including PML and other opportunistic infections, over the risk observed with use of natalizumab alone. The safety and efficacy of natalizumab in combination with antineoplastic, immunosuppressant, or immunomodulating agents have not been established. Patients receiving chronic immunosuppressant or immunomodulatory therapy or who have systemic medical conditions resulting in significantly compromised immune system function should not ordinarily be treated with natalizumab. The risk of PML is also increased in patients who have been treated with an immunosuppressant prior to receiving natalizumab. For patients with Crohn's disease who start natalizumab while on chronic corticosteroids, commence steroid withdrawal as soon as a therapeutic benefit has occurred. If the patient cannot discontinue systemic corticosteroids within six months, discontinue natalizumab. ### Laboratory Test Abnormalities In clinical trials, natalizumab was observed to induce increases in circulating lymphocytes, monocytes, eosinophils, basophils, and nucleated red blood cells. Observed changes persisted during natalizumab exposure, but were reversible, returning to baseline levels usually within 16 weeks after the last dose. Elevations of neutrophils were not observed. natalizumab induces mild decreases in hemoglobin levels that are frequently transient. ### Immunizations No data are available on the effects of vaccination in patients receiving natalizumab. No data are available on the secondary transmission of infection by live vaccines in patients receiving natalizumab. # Adverse Reactions ## Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The most common adverse reactions (incidence ≥ 10%) were headache and fatigue in both the multiple sclerosis (MS) and Crohn's disease (CD) studies. Other common adverse reactions (incidence ≥ 10%) in the MS population were arthralgia, urinary tract infection, lower respiratory tract infection, gastroenteritis, vaginitis, depression, pain in extremity, abdominal discomfort, diarrhea NOS, and rash. Other common adverse reactions (incidence ≥ 10%) in the CD population were upper respiratory tract infections and nausea. The most frequently reported adverse reactions resulting in clinical intervention (i.e., discontinuation of natalizumab), in the MS studies were urticaria (1%) and other hypersensitivity reactions (1%), and in the CD studies (Studies CD1 and CD2) were the exacerbation of Crohn's disease (4.2%) and acute hypersensitivity reactions (1.5%). A total of 1617 multiple sclerosis patients in controlled studies received natalizumab, with a median duration of exposure of 28 months. A total of 1563 patients received natalizumab in all CD studies for a median exposure of 5 months; of these patients, 33% (n=518) received at least one year of treatment and 19% (n=297) received at least two years of treatment. ### Multiple Sclerosis Clinical Studies The most frequently reported serious adverse reactions in Study MS1 with natalizumab were infections (3.2% versus 2.6% in placebo, including urinary tract infection [0.8% versus 0.3%] and pneumonia [0.6% versus 0%]), acute hypersensitivity reactions (1.1% versus 0.3%, including naphylaxis/anaphylactoid reaction [0.8% versus 0%]), depression (1.0% versus 1.0%, including suicidal ideation or attempt [0.6% versus 0.3%]), and cholelithiasis (1.0% versus 0.3%). In Study MS2, serious adverse reactions of appendicitis were also more common in patients who received natalizumab (0.8% versus 0.2% in placebo). TABLE 2 enumerates adverse reactions and selected laboratory abnormalities that occurred in Study MS1 at an incidence of at least 1 percentage point higher in natalizumab-treated patients than was observed in placebo-treated patients. In Study MS2, peripheral edema was more common in patients who received natalizumab (5% versus 1% in placebo). ### Crohn's Disease Clinical Studies The following serious adverse events in the induction Studies CD1 and CD2 were reported more commonly with natalizumab than placebo and occurred at an incidence of at least 0.3%: intestinal obstruction or stenosis (2% vs. 1% in placebo), acute hypersensitivity reactions (0.5% vs. 0%), abdominal adhesions (0.3% vs. 0%), and cholelithiasis (0.3% vs. 0%). Similar serious adverse events were seen in the maintenance Study CD3. TABLE 3 enumerates adverse drug reactions that occurred in Studies CD1 and CD2 (median exposure of 2.8 months). TABLE 4 enumerates adverse drug reactions that occurred in Study CD3 (median exposure of 11.0 months). ### Infections Progressive Multifocal Leukoencephalopathy (PML) occurred in three patients who received natalizumab in clinical trials. Two cases of PML were observed in the 1869 patients with multiple sclerosis who were treated for a median of 120 weeks. These two patients had received natalizumab in addition to interferon beta-1a. The third case occurred after eight doses in one of the 1043 patients with Crohn's disease who were evaluated for PML. In the postmarketing setting, additional cases of PML have been reported in natalizumab-treated multiple sclerosis and Crohn's disease patients who were not receiving concomitant immunomodulatory therapy. In Studies MS1 and MS2, the rate of any type of infection was approximately 1.5 per patient-year in both natalizumab-treated patients and placebo-treated patients. The infections were predominately upper respiratory tract infections, influenza, and urinary tract infections. In Study MS1, the incidence of serious infection was approximately 3% in natalizumab-treated patients and placebo-treated patients. Most patients did not interrupt treatment with natalizumab during infections. The only opportunistic infection in the multiple sclerosis clinical trials was a case of cryptosporidial gastroenteritis with a prolonged course. In Studies CD1 and CD2, the rate of any type of infection was 1.7 per patient-year in natalizumab-treated patients and 1.4 per patient-year in placebo-treated patients. In Study CD3, the incidence of any type of infection was 1.7 per patient-year in natalizumab-treated patients and was similar in placebo-treated patients. The most common infections were nasopharyngitis, upper respiratory tract infection, and influenza. The majority of patients did not interrupt natalizumab therapy during infections and recovery occurred with appropriate treatment. Concurrent use of natalizumab in CD clinical trials with chronic steroids and/or methotrexate, 6-MP, and azathioprine did not result in an increase in overall infections compared to natalizumab alone; however, the concomitant use of such agents could lead to an increased risk of serious infections. In Studies CD1 and CD2, the incidence of serious infection was approximately 2.1% in both natalizumab-treated patients and placebo-treated patients. In Study CD3, the incidence of serious infection was approximately 3.3% in natalizumab-treated patients and approximately 2.8% in placebo-treated patients. In clinical studies for CD, opportunistic infections (pneumocystis carinii pneumonia, pulmonary mycobacterium avium intracellulare, bronchopulmonary aspergillosis, and burkholderia cepacia) have been observed in <1% of natalizumab-treated patients; some of these patients were receiving concurrent immunosuppressants. Two serious non-bacterial meningitides occurred in natalizumab-treated patients compared to none in placebo-treated patients. ### Infusion-related Reactions An infusion-related reaction was defined in clinical trials as any adverse event occurring within two hours of the start of an infusion. In MS clinical trials, approximately 24% of natalizumab-treated multiple sclerosis patients experienced an infusion-related reaction, compared to 18% of placebo-treated patients. In the controlled CD clinical trials, infusion-related reactions occurred in approximately 11% of patients treated with natalizumab compared to 7% of placebo-treated patients. Reactions more common in the natalizumab-treated MS patients compared to the placebo-treated MS patients included headache, dizziness, fatigue, urticaria, pruritus, and rigors. Acute urticaria was observed in approximately 2% of patients. Other hypersensitivity reactions were observed in 1% of patients receiving natalizumab. Serious systemic hypersensitivity infusion reactions occurred in <1% of patients. All patients recovered with treatment and/or discontinuation of the infusion. Infusion-related reactions more common in CD patients receiving natalizumab than those receiving placebo included headache, nausea, urticaria, pruritus, and flushing. Serious infusion reactions occurred in Studies CD1, CD2, and CD3 at an incidence of <1% in natalizumab-treated patients. MS and CD patients who became persistently positive for antibodies to natalizumab were more likely to have an infusion-related reaction than those who were antibody-negative. ## Postmarketing Experience There is limited information regarding Natalizumab Postmarketing Experience in the drug label. # Drug Interactions Because of the potential for increased risk of PML and other infections, Crohn's disease patients receiving natalizumab should not be treated with concomitant immunosuppressants (e.g., 6-mercaptopurine, azathioprine, cyclosporine, or methotrexate) or inhibitors of TNF-α, and corticosteroids should be tapered in those patients with Crohn's disease who are on chronic corticosteroids when they start natalizumab therapy. Ordinarily, MS patients receiving chronic immunosuppressant or immunomodulatory therapy should not be treated with natalizumab. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): C Natalizumab has been shown to reduce pup survival in guinea pigs when given in doses 7 times the human dose, and has been shown to have hematologic effects on the fetus in monkeys when given in doses 2.3 times the human dose. There are no adequate and well-controlled studies in pregnant women. natalizumab should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Pregnancy Category (AUS): C There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Natalizumab in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Natalizumab during labor and delivery. ### Nursing Mothers Natalizumab has been detected in human milk. The effects of this exposure on infants are unknown. ### Pediatric Use Safety and effectiveness of natalizumab in pediatric patients with multiple sclerosis or Crohn's disease below the age of 18 years have not been established. natalizumab is not indicated for use in pediatric patients. ### Geriatic Use Clinical studies of natalizumab did not include sufficient numbers of patients aged 65 years and over to determine whether they respond differently than younger patients. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. ### Gender There is no FDA guidance on the use of Natalizumab with respect to specific gender populations. ### Race There is no FDA guidance on the use of Natalizumab with respect to specific racial populations. ### Renal Impairment Pharmacokinetics of natalizumab in patients with renal or hepatic insufficiency have not been studied. ### Hepatic Impairment Pharmacokinetics of natalizumab in patients with renal or hepatic insufficiency have not been studied. ### Females of Reproductive Potential and Males Natalizumab did not affect male fertility at doses up to 7-fold the clinical dose. ### Immunocompromised Patients There is no FDA guidance one the use of Natalizumab in patients who are immunocompromised. # Administration and Monitoring ### Administration Intravenous ### Monitoring There is limited information regarding Natalizumab Monitoring in the drug label. # IV Compatibility There is limited information regarding the compatibility of Natalizumab and IV administrations. # Overdosage Safety of doses higher than 300 mg has not been adequately evaluated. The maximum amount of natalizumab that can be safely administered has not been determined. # Pharmacology ## Mechanism of Action Natalizumab binds to the α4-subunit of α4β1 and α4β7 integrins expressed on the surface of all leukocytes except neutrophils, and inhibits the α4-mediated adhesion of leukocytes to their counter-receptor(s). The receptors for the α4 family of integrins include vascular cell adhesion molecule-1 (VCAM-1), which is expressed on activated vascular endothelium, and mucosal addressin cell adhesion molecule-1 (MAdCAM-1) present on vascular endothelial cells of the gastrointestinal tract. Disruption of these molecular interactions prevents transmigration of leukocytes across the endothelium into inflamed parenchymal tissue. In vitro, anti-α4-integrin antibodies also block α4-mediated cell binding to ligands such as osteopontin and an alternatively spliced domain of fibronectin, connecting segment-1 (CS-1). In vivo, natalizumab may further act to inhibit the interaction of α4-expressing leukocytes with their ligand(s) in the extracellular matrix and on parenchymal cells, thereby inhibiting further recruitment and inflammatory activity of activated immune cells. The specific mechanism(s) by which natalizumab exerts its effects in multiple sclerosis and Crohn's disease have not been fully defined. In multiple sclerosis, lesions are believed to occur when activated inflammatory cells, including T-lymphocytes, cross the blood-brain barrier (BBB). Leukocyte migration across the BBB involves interaction between adhesion molecules on inflammatory cells and their counter-receptors present on endothelial cells of the vessel wall. The clinical effect of natalizumab in multiple sclerosis may be secondary to blockade of the molecular interaction of α4β1-integrin expressed by inflammatory cells with VCAM-1 on vascular endothelial cells, and with CS-1 and/or osteopontin expressed by parenchymal cells in the brain. Data from an experimental autoimmune encephalitis animal model of multiple sclerosis demonstrate reduction of leukocyte migration into brain parenchyma and reduction of plaque formation detected by magnetic resonance imaging (MRI) following repeated administration of natalizumab. The clinical significance of these animal data is unknown. In Crohn's disease, the interaction of the α4β7 integrin with the endothelial receptor MAdCAM-1 has been implicated as an important contributor to the chronic inflammation that is a hallmark of the disease. MAdCAM-1 is mainly expressed on gut endothelial cells and plays a critical role in the homing of T lymphocytes to gut lymph tissue found in Peyer's patches. MAdCAM-1 expression has been found to be increased at active sites of inflammation in patients with CD, which suggests it may play a role in the recruitment of leukocytes to the mucosa and contribute to the inflammatory response characteristic of CD. The clinical effect of natalizumab in CD may therefore be secondary to blockade of the molecular interaction of the α4ß7-integrin receptor with MAdCAM-1 expressed on the venular endothelium at inflammatory foci. VCAM-1 expression has been found to be upregulated on colonic endothelial cells in a mouse model of IBD and appears to play a role in leukocyte recruitment to sites of inflammation. The role of VCAM-1 in CD, however, is not clear. ## Structure Natalizumab is a recombinant humanized IgG4ϰ monoclonal antibody produced in murine myeloma cells. Natalizumab contains human framework regions and the complementarity-determining regions of a murine antibody that binds to α4-integrin. The molecular weight of natalizumab is 149 kilodaltons ## Pharmacodynamics Natalizumab administration increases the number of circulating leukocytes (including lymphocytes, monocytes, basophils, and eosinophils) due to inhibition of transmigration out of the vascular space. natalizumab does not affect the absolute count of circulating neutrophils. ## Pharmacokinetics ### Multiple Sclerosis (MS) Patients In patients with MS, following the repeat intravenous administration of a 300 mg dose of natalizumab, the mean ± SD maximum observed serum concentration was 110 ± 52 mcg/mL. Mean average steady-state trough concentrations ranged from 23 mcg/mL to 29 mcg/mL. The observed time to steady-state was approximately 24 weeks after every four weeks of dosing. The mean ± SD half-life, volume of distribution, and clearance of natalizumab were 11 ± 4 days, 5.7 ± 1.9 L, and 16 ± 5 mL/hour, respectively. The effects of covariates such as body weight, age, gender, and presence of anti-natalizumab antibodies on natalizumab pharmacokinetics were investigated in a population pharmacokinetic study (n=2195). Natalizumab clearance increased with body weight in a less than proportional manner such that a 43% increase in body weight resulted in a 32% increase in clearance. The presence of persistent anti-natalizumab antibodies increased natalizumab clearance approximately 3-fold. ### Crohn's Disease (CD) Patients In patients with CD, following the repeat intravenous administration of a 300 mg dose of natalizumab, the mean ± SD maximum observed serum concentration was 101 ± 34 mcg/mL. The mean ± SD average steady-state trough concentration was 10 ± 9 mcg/mL. The estimated time to steady-state was approximately 16 to 24 weeks after every four weeks of dosing. The mean ± SD half-life, volume of distribution, and clearance of natalizumab were 10 ± 7 days, 5.2 ± 2.8 L, and 22 ± 22 mL/hour, respectively. The effects of total body weight, age, gender, race, selected hematology and serum chemistry measures, co-administered medications (infliximab, immunosuppressants, or steroids), and the presence of anti-natalizumab antibodies were investigated in a population pharmacokinetic analysis (n=1156). The presence of anti-natalizumab antibodies was observed to increase natalizumab clearance. ## Nonclinical Toxicology ### Carcinogenesis, Mutagenesis, Impairment of Fertility No clastogenic or mutagenic effects of natalizumab were observed in the Ames test or in vitro chromosomal aberration assay in human lymphocytes. Natalizumab showed no effects in in vitro assays of α4-integrin positive human tumor line proliferation/cytotoxicity. Xenograft transplantation models in SCID and nude mice with two α4-integrin positive human tumor lines (leukemia, melanoma) demonstrated no increase in tumor growth rates or metastasis resulting from natalizumab treatment. Reductions in female guinea pig fertility were observed in one study at dose levels of 30 mg/kg, but not at the 10 mg/kg dose level (2.3-fold the clinical dose). A 47% reduction in pregnancy rate was observed in guinea pigs receiving 30 mg/kg relative to control. Implantations were seen in only 36% of animals having corpora lutea in the 30 mg/kg group versus 66 to 72% in the other groups. Natalizumab did not affect male fertility at doses up to 7-fold the clinical dose. ### Animal Toxicology and/or Pharmacology In reproductive studies in monkeys and guinea pigs, there was no evidence of teratogenic effects at doses up to 30 mg/kg (7 times the human clinical dose based on a body weight comparison). In one study where female guinea pigs were exposed to natalizumab during the second half of pregnancy, a small reduction in pup survival was noted at post-natal day 14 with respect to control (3 pups/litter for the group treated with 30 mg/kg natalizumab and 4.3 pups/litter for the control group). In one of five studies that exposed monkeys or guinea pigs during pregnancy, the number of abortions in treated (30 mg/kg) monkeys was 33% versus 17% in controls. No effects on abortion rates were noted in any other study. natalizumab underwent trans-placental transfer and produced in utero exposure in developing guinea pigs and cynomolgus monkeys. When pregnant dams were exposed to natalizumab at approximately 7-fold the clinical dose, serum levels in fetal animals at delivery were approximately 35% of maternal serum natalizumab levels. A study in pregnant cynomolgus monkeys treated at 2.3-fold the clinical dose demonstrated natalizumab-related changes in the fetus. These changes included mild anemia, reduced platelet count, increased spleen weights, and reduced liver and thymus weights associated with increased splenic extramedullary hematopoiesis, thymic atrophy, and decreased hepatic hematopoiesis. In offspring born to mothers treated with natalizumab at 7-fold the clinical dose, platelet counts were also reduced. This effect was reversed upon clearance of natalizumab. There was no evidence of anemia in these offspring. Offspring exposed in utero and via breast milk had no natalizumab-related changes in the lymphoid organs and had normal immune response to challenge with a T-cell dependent antigen. # Clinical Studies ### Multiple Sclerosis natalizumab was evaluated in two randomized, double-blind, placebo-controlled trials in patients with multiple sclerosis. Both studies enrolled patients who experienced at least one clinical relapse during the prior year and had a Kurtzke Expanded Disability Status Scale (EDSS) score between 0 and 5.0. Results for each study are shown in TABLE 5 and TABLE 6. Median time on study drug was 120 weeks in each study. In both studies, neurological evaluations were performed every 12 weeks and at times of suspected relapse. Magnetic resonance imaging evaluations for T1-weighted gadolinium (Gd)-enhancing lesions and T2-hyperintense lesions were performed annually. Study MS1 enrolled patients who had not received any interferon-beta or glatiramer acetate for at least the previous 6 months; approximately 94% had never been treated with these agents. Median age was 37, with a median disease duration of 5 years. Patients were randomized in a 2:1 ratio to receive natalizumab 300 mg intravenous infusion (n=627) or placebo (n=315) every 4 weeks for up to 28 months (30 infusions). Study MS2 enrolled patients who had experienced one or more relapses while on treatment with AVONEX® (Interferon beta-1a) 30 mcg intramuscularly (IM) once weekly during the year prior to study entry. Median age was 39, with a median disease duration of 7 years. Patients were evenly randomized to receive natalizumab 300 mg (n=589) or placebo (n=582) every 4 weeks for up to 28 months (30 infusions). All patients continued to receive AVONEX 30 mcg IM once weekly. The efficacy of natalizumab alone was not compared with the efficacy of natalizumab plus AVONEX. The primary endpoint at 2 years was time to onset of sustained increase in disability, defined as an increase of at least 1 point on the EDSS from baseline EDSS ≥ 1.0 that was sustained for 12 weeks, or at least a 1.5 point increase on the EDSS from baseline EDSS=0 that was sustained for 12 weeks. Time to onset of sustained increase in disability was longer in natalizumab-treated patients than in placebo-treated patients in Studies MS1 (FIGURE 1) and MS2. The proportion of patients with increased disability and the annualized relapse rate were also lower in natalizumab-treated patients than in placebo-treated patients in Studies MS1 and MS2. ### Crohn's Disease The safety and efficacy of natalizumab were evaluated in three randomized, double-blind, placebo-controlled clinical trials in 1414 adult patients with moderately to severely active Crohn's disease (Crohn's Disease Activity Index [CDAI] ≥220 and ≤450). Concomitant inhibitors of TNF-α were not permitted. Concomitant stable doses of aminosalicylates, corticosteroids, and/or immunosuppressants (e.g., 6-mercatopurine, azathioprine, or methotrexate) were permitted, and 89% of patients continued to receive at least one of these medications. Although permitted in the clinical trials, combination therapy with immunosuppressants is not recommended. Overall, approximately two-thirds of patients were not taking concomitant immunosuppressants, and approximately one-third of patients were taking neither concomitant immunosuppressants nor concomitant corticosteroids. Induction of clinical response (defined as ≥70-point decrease in CDAI from baseline) was evaluated in two studies. In Study CD1, 896 patients were randomized 4:1 to receive three monthly infusions of either 300 mg natalizumab or placebo. Clinical results were assessed at Week 10, and patients with incomplete information were considered as not having a clinical response. At Week 10, 56% of the 717 patients receiving natalizumab were in response compared to 49% of the 179 patients receiving placebo (treatment effect: 7%; 95% confidence interval (CI): [-1%, 16%]; p=0.067). In a post hoc analysis of the subset of 653 patients with elevated baseline C-reactive protein (CRP), indicative of active inflammation, 57% of natalizumab patients were in response compared to 45% of those receiving placebo (treatment effect: 12%; 95% CI: [3%, 22%]; nominal p=0.01). In the second induction trial, Study CD2, only patients with elevated serum C-reactive Protein (CRP) were studied. A total of 509 patients were randomized 1:1 to receive three monthly infusions of either 300 mg natalizumab or placebo. In Study CD2, in contrast to Study CD1, clinical response and clinical remission (defined as CDAI score <150) were required to be met at both Weeks 8 and 12, rather than at a single time-point; patients with incomplete information were considered as not having a response. In studies CD1 and CD2, for subgroups defined by prior use of, or by inadequate response to prior therapies (i.e., corticosteroids, immunosuppressants, and inhibitors of TNF-α), the treatment effect was generally similar to that seen in the whole study population. In the subgroup of patients that were taking neither concomitant immunosuppressants nor concomitant corticosteroids, the treatment effect was generally similar to that seen in the whole study population. Patients with inadequate response to inhibitors of TNF-α appeared to have lower clinical response and lower clinical remission in both the treatment and placebo groups. For patients in Study CD2 with an inadequate response to prior treatment with inhibitors of TNF-α, clinical response at both Weeks 8 and 12 was seen in 38% of those randomized to natalizumab, and clinical remission at both Weeks 8 and 12 was seen in 17%. Maintenance therapy was evaluated in Study CD3. In this study, 331 patients from Study CD1 that had had a clinical response to natalizumab at both Weeks 10 and 12 were re-randomized 1:1 to treatment with continuing monthly infusions of either 300 mg natalizumab or placebo. Maintenance of response was assessed by the proportion of patients who did not lose clinical response at any study visit for an additional 6 and 12 months of treatment (i.e., Month 9 and Month 15 after initial treatment with natalizumab). The study also assessed the proportion of patients who did not lose clinical remission at any study visit within the subset of those who were in remission at study entry. Requiring maintenance of response or remission at each visit, as opposed to just at Month 9 or Month 15, may result in lower proportions meeting endpoint criteria, and may make a comparison of these results with those of other products used to treat Crohn's disease misleading. For subgroups in study CD3 defined by prior use of, or by inadequate response to prior therapies (i.e., corticosteroids, immunosuppressants, and inhibitors of TNF-α), the treatment effect was generally similar to that seen in the whole study population. In the subgroup of patients that were taking neither concomitant immunosuppressants nor concomitant corticosteroids, the treatment effect was generally similar to that seen in the whole study population. Patients with inadequate response to inhibitors of TNF-α appeared to have lower maintenance of clinical response and lower maintenance of clinical remission in both the treatment and placebo groups. For patients in study CD3 with an inadequate response to prior treatment with inhibitors of TNF-α, maintenance of clinical response through Month 9 was seen in 52% of those randomized to natalizumab, and maintenance of clinical remission through Month 9 was seen in 30%. Given the requirement to discontinue chronic steroids it is important to note that in the subgroup of patients (n=65) who were receiving corticosteroid medication at baseline, responded to natalizumab in Study CD1, and were re-randomized to natalizumab in Study CD3, approximately two-thirds were able to discontinue steroids within 10 weeks of initiating a steroid taper. # How Supplied - 300 mg natalizumab in 15 mL - In a sterile single-use vial free of preservatives - NDC 64406-008-01 ## Storage - Must be refrigerated between 2 to 8°C (36° to 46°F) # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information ### General Counseling Information Counsel patients to understand the risks and benefits of natalizumab before an initial prescription is written. The patient may be educated by either the enrolled prescriber or a healthcare provider under that prescriber's direction. Instruct patients using natuzimab to: - Read the Medication Guide before starting natalizumab and before each natalizumab infusion. - Promptly report any new or continuously worsening symptoms that persist over several days to their prescriber. - Inform all of their physicians that they are receiving natalizumab. - Plan to see their prescriber three months after the first infusion, six months after the first infusion, every six months thereafter, and for at least six months after discontinuing natalizumab. ### Progressive Multifocal Leukoencephalopathy Inform patients that Progressive Multifocal Leukoencephalopathy (PML) has occurred in patients who received natalizumab. Instruct the patient of the importance of contacting their doctor if they develop any symptoms suggestive of PML. Instruct the patient that typical symptoms associated with PML are diverse, progress over days to weeks, and include progressive weakness on one side of the body or clumsiness of limbs, disturbance of vision, and changes in thinking, memory, and orientation leading to confusion and personality changes. Instruct the patient that the progression of deficits usually leads to death or severe disability over weeks or months. Instruct patients to continue to look for new signs and symptoms suggestive of PML for approximately 6 months following discontinuation of natalizumab. ### natalizumab TOUCH Prescribing Program Advise the patient that natalizumab is only available through a restricted program called the TOUCH Prescribing Program. Inform the patient of the following requirements: Patients must read the Medication Guide and sign the Patient Prescriber Enrollment Form. Advise patients that natalizumab is available only from certified pharmacies and infusion centers participating in the program. ### Herpes Encephalitis/Meningitis Inform patients that natalizumab increases the risk of developing encephalitis and meningitis caused by herpes simplex and varicella zoster viruses. Instruct patients to report immediately if they experience symptoms such as fever, headache and confusion. ### Hepatotoxicity Inform patients that natalizumab may cause liver injury. Instruct patients treated with natalizumab to report promptly any symptoms that may indicate liver injury, including fatigue, anorexia, right upper abdominal discomfort, dark urine or jaundice. ### Hypersensitivity Reactions Instruct patients to report immediately if they experience symptoms consistent with a hypersensitivity reaction (e.g., urticaria with or without associated symptoms) during or following an infusion of natalizumab. ### Immunosuppression/Infections Inform patients that natalizumab may lower the ability of their immune system to fight infections. Instruct the patient of the importance of contacting their doctor if they develop any symptoms of infection. # Precautions with Alcohol Alcohol-Natalizumab interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - Tysabri [1] # Look-Alike Drug Names There is limited information regarding Natalizumab Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	https://www.wikidoc.org/index.php/Antegren
2399c9187ef684ac6744567c4d3832ccc28b941c	wikidoc	Facial vein	Facial vein The anterior facial vein (facial vein) commences at the side of the root of the nose, and is a direct continuation of the angular vein. It lies behind the facial artery and follows a less tortuous course. It usually either joins the anterior branch of the retromandibular vein to form the common facial vein, or drains directly into the internal jugular vein. # Path From its origin it runs obliquely downward and backward, beneath the Zygomaticus and zygomatic head of the Quadratus labii superioris, descends along the anterior border and then on the superficial surface of the Masseter, crosses over the body of the mandible, and passes obliquely backward, beneath the Platysma and cervical fascia, superficial to the submaxillary gland, the Digastricus and Stylohyoideus. The facial vein has no valves, and its walls are not so flaccid as most superficial veins. # Additional images - Bloodvessels of the eyelids, front view.	Facial vein Template:Infobox Vein Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] The anterior facial vein (facial vein) commences at the side of the root of the nose, and is a direct continuation of the angular vein. It lies behind the facial artery and follows a less tortuous course. It usually either joins the anterior branch of the retromandibular vein to form the common facial vein, or drains directly into the internal jugular vein. # Path From its origin it runs obliquely downward and backward, beneath the Zygomaticus and zygomatic head of the Quadratus labii superioris, descends along the anterior border and then on the superficial surface of the Masseter, crosses over the body of the mandible, and passes obliquely backward, beneath the Platysma and cervical fascia, superficial to the submaxillary gland, the Digastricus and Stylohyoideus. The facial vein has no valves, and its walls are not so flaccid as most superficial veins. # Additional images - Bloodvessels of the eyelids, front view. # External links - Template:EMedicineDictionary - Template:NormanAnatomy (Template:NormanAnatomyFig) Template:Gray's Template:VeinsHeadNeck Template:WikiDoc Sources	https://www.wikidoc.org/index.php/Anterior_facial_vein
169d5f4222ed7cf105e8585b407b64d83b9682bb	wikidoc	Antianginal	Antianginal # Overview An antianginal is any drug used in the treatment of angina pectoris, a symptom of ischaemic heart disease. Drugs used are nitrates such as nitroglycerin (glyceryl trinitrate) or pentaerythritol tetranitrate; beta blockers, either cardioselectives such as acebutolol or metoprolol, or non-cardioselectives such as oxprenolol or sotalol; or calcium channel blockers, either Class I agents (e.g., verapamil), Class II agents (e.g., amlodipine, nifedipine), or the Class III agent diltiazem. Nitrates cause vasodilation of the venous capacitance vessels by simulating the endothelium-derived relaxing factor (EDRF). Used to relieve both exertional and vasospastic angina by allowing venous pooling, reducing the pressure in the ventricles and so reducing wall tension and oxygen requirements in the heart. Short-acting nitrates are used to abort angina attacks that have occurred, while longer-acting nitrates are used in the prophylactic management of the condition. Beta blockers are used in the prophylaxis of exertional angina by reducing the work the heart is allowed to perform below the level that would provoke an angina attack. They cannot be used in vasospastic angina and can precipitate heart failure. Calcium ion (Ca++) antagonists (Calcium channel blockers) are used in the treatment of both exertional and vasospastic angina. In vitro, they dilate the coronary and peripheral arteries and have negative inotropic and chronotropic effects - decreasing afterload, improving myocardial efficiency, reducing heart rate and improving coronary blood flow. In vivo, the vasodilation and hypotension trigger the baroreceptor reflex. Therefore the net effect is the interplay of direct and reflex actions. Class I antiarrhythmic agents have the most potent negative inotropic effect and may cause heart failure; Class II agents do not depress conduction or contractility; the Class III agent has negligible inotropic effect and causes almost no reflex tachycardia.	Antianginal # Overview An antianginal is any drug used in the treatment of angina pectoris, a symptom of ischaemic heart disease. Drugs used are nitrates such as nitroglycerin (glyceryl trinitrate) or pentaerythritol tetranitrate; beta blockers, either cardioselectives such as acebutolol or metoprolol, or non-cardioselectives such as oxprenolol or sotalol; or calcium channel blockers, either Class I agents (e.g., verapamil), Class II agents (e.g., amlodipine, nifedipine), or the Class III agent diltiazem. Nitrates cause vasodilation of the venous capacitance vessels by simulating the endothelium-derived relaxing factor (EDRF). Used to relieve both exertional and vasospastic angina by allowing venous pooling, reducing the pressure in the ventricles and so reducing wall tension and oxygen requirements in the heart. Short-acting nitrates are used to abort angina attacks that have occurred, while longer-acting nitrates are used in the prophylactic management of the condition. Beta blockers are used in the prophylaxis of exertional angina by reducing the work the heart is allowed to perform below the level that would provoke an angina attack. They cannot be used in vasospastic angina and can precipitate heart failure. Calcium ion (Ca++) antagonists (Calcium channel blockers) are used in the treatment of both exertional and vasospastic angina. In vitro, they dilate the coronary and peripheral arteries and have negative inotropic and chronotropic effects - decreasing afterload, improving myocardial efficiency, reducing heart rate and improving coronary blood flow. In vivo, the vasodilation and hypotension trigger the baroreceptor reflex. Therefore the net effect is the interplay of direct and reflex actions. Class I antiarrhythmic agents have the most potent negative inotropic effect and may cause heart failure; Class II agents do not depress conduction or contractility; the Class III agent has negligible inotropic effect and causes almost no reflex tachycardia. Template:Major Drug Groups Template:WH Template:WS	https://www.wikidoc.org/index.php/Anti-anginal
3878ac296a1cb477ab86145759a48dd7c3121ba9	wikidoc	Anxiolytics	Anxiolytics # Overview An anxiolytic is a drug prescribed for the treatment of symptoms of anxiety. Some anxiolytics have been shown to be useful in the treatment of anxiety disorders as have antidepressants such as the class of selective serotonin reuptake inhibitors (SSRIs). Though not anxiolytics, beta-receptor blockers such as propranolol and oxprenolol can be used to combat the somatic symptoms of anxiety. # Types of Anxiolytics Anxiolytics are generally divided into two groups of medication, benzodiazepines and non-benzodiazepines. ## Benzodiazepines - Main article: Benzodiazepine Benzodiazepines are prescribed for short-term relief of severe and disabling anxiety. Common medications are lorazepam (Ativan), clonazepam (Klonopin), alprazolam (Xanax), and diazepam (Valium). Benzodiazepines may also be indicated to cover the latent periods associated with the medications prescribed to treat an underlying anxiety disorder. They are used to treat a wide variety of conditions and symptoms and are usually a first choice when short-term CNS sedation is needed. Longer term uses include treatment for severe anxiety and psychosis. There is a risk of withdrawal symptoms and rebound syndrome after continuous usage past two weeks. There is also the added problem of the accumulation of drug metabolites and adverse effects. ## Non-Benzodiazepines Buspirone (Buspar) is a serotonin 1A agonist. It lacks the sedation and the dependence associated with benzodiazepines and causes much less cognitive impairment. It may be less effective than benzodiazepines in patients who have been previously treated with benzodiazepines as the medication does not provide the sedation that these patients may expect or equate with anxiety relief. ## Barbiturates Barbiturates and meprobamate exert an anxiolytic effect linked to the sedation they cause. The risk of abuse and addiction is high. Many experts consider these drugs as obsolete for treating anxiety, although they may be valuable for the short term treatment of severe insomnia. ## Herbal Treatments Certain herbs, such as St. John's wort, kava (kava kava), chamomile, bacopa monniera and Valerian are reputed to have anxiolytic properties. With the exception of kava kava, only limited evidence exists for their efficacy. Use of marijuana as an anxiolytic has seen promising results in regions where its practical study is possible, but its status as a controlled substance in many countries make its study as such difficult. # Alternatives to Medication Psychotherapy (e.g. cognitive or behavior therapy) is often useful as an adjunct to pharmacotherapy or as an alternative to medication. # Anxiolytic Withdrawal ## Differential Diagnosis - Alcohol withdrawal - Anxiety disorders - Essential tremor - Hypoglycemia - Diabetic ketoacidosis - Seizure due to infections, head injury, poisonings ## DSM-V Diagnostic Criteria for Sedative, Hypnotic, or Anxiolytic Withdrawal # Anxiolytic Intoxication ## Differential Diagnosis - Alcohol use disorders - Alcohol intoxication - Delirium - Traumatic brain injury ## DSM-V Diagnostic Criteria for Sedative, Hypnotic, or Anxiolytic Intoxication # Anxiolytic Use Disorder ## Differential Diagnosis - Alcohol use disorder - Clinically appropriate use of the medication - Generalized anxiety disorder - Multiple sclerosis - Subdural hematoma ## Epidemiology and Demographics of Sedative, Hypnotic, or Anxiolytic Use Disorder ### Prevalence The 12 month prevalence of hypnotic or anxiolytic use disorder is: - 300 per 100,000 (0.3%) among adults 12-17 years old - 200 per 100,000 among adults 18 years and older ## Risk Factors - Availability of the substances - Alcohol use disorder - Environmental factors - Early onset of use - Genetic predisposition - Peer use of the substance ## DSM-V Diagnostic Criteria for Sedative, Hypnotic, or Anxiolytic Use Disorder	Anxiolytics Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Kiran Singh, M.D. [2] # Overview An anxiolytic is a drug prescribed for the treatment of symptoms of anxiety. Some anxiolytics have been shown to be useful in the treatment of anxiety disorders as have antidepressants such as the class of selective serotonin reuptake inhibitors (SSRIs). Though not anxiolytics, beta-receptor blockers such as propranolol and oxprenolol can be used to combat the somatic symptoms of anxiety. # Types of Anxiolytics Anxiolytics are generally divided into two groups of medication, benzodiazepines and non-benzodiazepines. ## Benzodiazepines - Main article: Benzodiazepine Benzodiazepines are prescribed for short-term relief of severe and disabling anxiety. Common medications are lorazepam (Ativan), clonazepam (Klonopin), alprazolam (Xanax), and diazepam (Valium). Benzodiazepines may also be indicated to cover the latent periods associated with the medications prescribed to treat an underlying anxiety disorder. They are used to treat a wide variety of conditions and symptoms and are usually a first choice when short-term CNS sedation is needed. Longer term uses include treatment for severe anxiety and psychosis. There is a risk of withdrawal symptoms and rebound syndrome after continuous usage past two weeks. There is also the added problem of the accumulation of drug metabolites and adverse effects. ## Non-Benzodiazepines Template:Seealso Buspirone (Buspar) is a serotonin 1A agonist. It lacks the sedation and the dependence associated with benzodiazepines and causes much less cognitive impairment. It may be less effective than benzodiazepines in patients who have been previously treated with benzodiazepines as the medication does not provide the sedation that these patients may expect or equate with anxiety relief. ## Barbiturates Barbiturates and meprobamate exert an anxiolytic effect linked to the sedation they cause. The risk of abuse and addiction is high. Many experts consider these drugs as obsolete for treating anxiety, although they may be valuable for the short term treatment of severe insomnia. ## Herbal Treatments Certain herbs, such as St. John's wort, kava (kava kava), chamomile, bacopa monniera and Valerian are reputed to have anxiolytic properties. With the exception of kava kava, only limited evidence exists for their efficacy.[1][2] Use of marijuana as an anxiolytic has seen promising results in regions where its practical study is possible, but its status as a controlled substance in many countries make its study as such difficult. # Alternatives to Medication Psychotherapy (e.g. cognitive or behavior therapy) is often useful as an adjunct to pharmacotherapy or as an alternative to medication. # Anxiolytic Withdrawal ## Differential Diagnosis - Alcohol withdrawal - Anxiety disorders - Essential tremor - Hypoglycemia - Diabetic ketoacidosis - Seizure due to infections, head injury, poisonings[3] ## DSM-V Diagnostic Criteria for Sedative, Hypnotic, or Anxiolytic Withdrawal[3] # Anxiolytic Intoxication ## Differential Diagnosis - Alcohol use disorders - Alcohol intoxication - Delirium - Traumatic brain injury[3] ## DSM-V Diagnostic Criteria for Sedative, Hypnotic, or Anxiolytic Intoxication[3] # Anxiolytic Use Disorder ## Differential Diagnosis - Alcohol use disorder - Clinically appropriate use of the medication - Generalized anxiety disorder - Multiple sclerosis - Subdural hematoma[3] ## Epidemiology and Demographics of Sedative, Hypnotic, or Anxiolytic Use Disorder ### Prevalence The 12 month prevalence of hypnotic or anxiolytic use disorder is: - 300 per 100,000 (0.3%) among adults 12-17 years old - 200 per 100,000 among adults 18 years and older[3] ## Risk Factors - Availability of the substances - Alcohol use disorder - Environmental factors - Early onset of use - Genetic predisposition - Peer use of the substance[3] ## DSM-V Diagnostic Criteria for Sedative, Hypnotic, or Anxiolytic Use Disorder[3]	https://www.wikidoc.org/index.php/Anti-anxiety_drugs
83b1b6b93197ca87830d9e970e8eb8990fa8f76b	wikidoc	Vasopressin	Vasopressin Vasopressin, also called antidiuretic hormone (ADH), arginine vasopressin (AVP) or argipressin, is a hormone synthesized as a peptide prohormone in neurons in the hypothalamus, and is converted to AVP. It then travels down the axon of that cell, which terminates in the posterior pituitary, and is released from vesicles into the circulation in response to extracellular fluid hypertonicity (hyperosmolality). AVP has two primary functions. First, it increases the amount of solute-free water reabsorbed back into the circulation from the filtrate in the kidney tubules of the nephrons. Second, AVP constricts arterioles, which increases peripheral vascular resistance and raises arterial blood pressure. A third function is possible. Some AVP may be released directly into the brain from the hypothalamus, and may play an important role in social behavior, sexual motivation and pair bonding, and maternal responses to stress. Vasopressin induces differential of stem cells into cardiomyocytes and promotes heart muscle homeostasis. It has a very short half-life, between 16–24 minutes. # Physiology ## Function Vasopressin regulates the tonicity of body fluids. It is released from the posterior pituitary in response to hypertonicity and causes the kidneys to reabsorb solute-free water and return it to the circulation from the tubules of the nephron, thus returning the tonicity of the body fluids toward normal. An incidental consequence of this renal reabsorption of water is concentrated urine and reduced urine volume. AVP released in high concentrations may also raise blood pressure by inducing moderate vasoconstriction. AVP also may have a variety of neurological effects on the brain. It may influence pair-bonding in voles. The high-density distributions of vasopressin receptor AVPr1a in prairie vole ventral forebrain regions have been shown to facilitate and coordinate reward circuits during partner preference formation, critical for pair bond formation. A very similar substance, lysine vasopressin (LVP) or lypressin, has the same function in pigs and is used in human AVP deficiency. ### Kidney Vasopressin has three main effects which are - Increasing the water permeability of initial and cortical collecting tubules (ICT & CCT), as well as outer and inner medullary collecting duct (OMCD & IMCD) in the kidney, thus allowing water reabsorption and excretion of more concentrated urine, i.e., antidiuresis. This occurs through increased transcription and insertion of water channels (Aquaporin-2) into the apical membrane of collecting tubule and collecting duct epithelial cells. Aquaporins allow water to move down their osmotic gradient and out of the nephron, increasing the amount of water re-absorbed from the filtrate (forming urine) back into the bloodstream. Important for bowen students, this effect is mediated by V2 receptors. Vasopressin also increases the concentration of calcium in the collecting duct cells, by episodic release from intracellular stores. Vasopressin, acting through cAMP, also increases transcription of the aquaporin-2 gene, thus increasing the total number of aquaporin-2 molecules in collecting duct cells. - Increasing permeability of the inner medullary portion of the collecting duct to urea by regulating the cell surface expression of urea transporters, which facilitates its reabsorption into the medullary interstitium as it travels down the concentration gradient created by removing water from the connecting tubule, cortical collecting duct, and outer medullary collecting duct. - Acute increase of sodium absorption across the ascending loop of henle. This adds to the countercurrent multiplication which aids in proper water reabsorption later in the distal tubule and collecting duct. ### Central nervous system Vasopressin released within the brain may have several actions: - Vasopressin is released into the brain in a circadian rhythm by neurons of the suprachiasmatic nucleus. - Vasopressin released from centrally projecting hypothalamic neurons is involved in aggression, blood pressure regulation, and temperature regulation.--> - Recent evidence suggests that vasopressin may have analgesic effects. The analgesia effects of vasopressin were found to be dependent on both stress and sex. ## Regulation Many factors influence the secretion of vasopressin: - Ethanol (alcohol) reduces the calcium-dependent secretion of AVP by blocking voltage-gated calcium channels in neurohypophyseal nerve terminals in rats. - Angiotensin II stimulates AVP secretion, in keeping with its general pressor and pro-volumic effects on the body. - Atrial natriuretic peptide inhibits AVP secretion, in part by inhibiting Angiotensin II-induced stimulation of AVP secretion. - Cortisol inhibits secretion of antidiuretic hormone. ## Production and secretion The physiologic stimulus for secretion of vasopressin is increased osmolality of the plasma, monitored by the hypothalamus. A decreased arterial blood volume, (such as can occur in cirrhosis, nephrosis and heart failure), stimulates secretion, even in the face of decreased osmolality of the plasma: it supersedes osmolality, but with a milder effect. In other words, vasopressin is secreted in spite of the presence of hypoosmolality (hyponatremia) when the arterial blood volume is low. The AVP that is measured in peripheral blood is almost all derived from secretion from the posterior pituitary gland (except in cases of AVP-secreting tumours). Vasopressin is produced by magnocellular neurosecretory neurons in the Paraventricular nucleus of hypothalamus (PVN) and Supraoptic nucleus (SON). It then travels down the axon through the infundibulum within neurosecretory granules that are found within Herring bodies, localized swellings of the axons and nerve terminals. These carry the peptide directly to the posterior pituitary gland, where it is stored until released into the blood. There are other sources of AVP, beyond the hypothalamic magnocellular neurons. For example, AVP is also synthesized by parvocellular neurosecretory neurons of the PVN, transported and released at the median eminence, from which it travels through the hypophyseal portal system to the anterior pituitary, where it stimulates corticotropic cells synergistically with CRH to produce ACTH (by itself it is a weak secretagogue). ## Vasopressin during surgery and anaesthesia Vasopressin is used for measurement of surgical stress at evaluation of surgical techniques. Plasma vasopressin concentration is elevated at noxious stimuli, predominantly during abdominal surgery, especially at gut manipulation and traction of viscera. In a study on dogs, plasma vasopressin concentration increased at removal of both ovaries, with a 15 minute pause between ovary removal. Blood pressure and vasopressin concentrations changed in parallel at use of z‐scores (standard scores) for comparison. In a human study, two different approaches for lumbar spine surgery were compared. An intraoperative increase of vasopressin levels was observed in one of the groups and this group required more postoperative analgesics. ## Receptors The following describes the actions of AVP: ## Structure and relation to oxytocin The vasopressins are peptides consisting of nine amino acids (nonapeptides). (NB: the value in the table above of 164 amino acids is that obtained before the hormone is activated by cleavage.) The amino acid sequence of arginine vasopressin (argipressin) is Cys-Tyr-Phe-Gln-Asn-Cys-Pro-Arg-Gly-NH2, with the cysteine residues forming a disulfide bond and the C-terminus of the sequence converted to a primary amide. Lysine vasopressin (lypressin) has a lysine in place of the arginine as the eighth amino acid, and is found in pigs and some related animals, whereas arginine vasopressin is found in humans. The structure of oxytocin is very similar to that of the vasopressins: It is also a nonapeptide with a disulfide bridge and its amino acid sequence differs at only two positions (see table below). The two genes are located on the same chromosome separated by a relatively small distance of less than 15,000 bases in most species. The magnocellular neurons that secrete vasopressin are adjacent to magnocellular neurons that secrete oxytocin, and are similar in many respects. The similarity of the two peptides can cause some cross-reactions: oxytocin has a slight antidiuretic function, and high levels of AVP can cause uterine contractions. Below is a table showing the superfamily of vasopressin and oxytocin neuropeptides: # Medical use Vasopressin is used to manage anti-diuretic hormone deficiency. It has off-label uses and is used in the treatment of vasodilatory shock, gastrointestinal bleeding, ventricular tachycardia and ventricular fibrillation. Vasopressin is used to treat diabetes insipidus related to low levels of antiduretic hormone. It is available as Pressyn. Vasopressin agonists are used therapeutically in various conditions, and its long-acting synthetic analogue desmopressin is used in conditions featuring low vasopressin secretion, as well as for control of bleeding (in some forms of von Willebrand disease and in mild haemophilia A) and in extreme cases of bedwetting by children. Terlipressin and related analogues are used as vasoconstrictors in certain conditions. Use of vasopressin analogues for esophageal varices commenced in 1970. Vasopressin infusions are also used as second line therapy for septic shock patients not responding to fluid resuscitation or infusions of catecholamines (e.g., dopamine or norepinephrine) to increase the blood pressure while sparing the use of catecholamines. These argipressins have much shorter elimination half-life (around 20 minutes) comparing to synthetic non-arginine vasopresines with much longer elimination half-life of many hours. Further, argipressins act on V1a, V1b, and V2 reseptors which consequently lead to higher eGFR and lower vascular resistance in the lungs. A number of injectable arginine vasopressins are currently in clinical use in the United States and in Europe. ## Pharmacokinetics Vasopressin is administered through an intravenous device, intramuscular injection or a subcutaneous injection. The duration of action depends on the mode of administration and ranges from thirty minutes to two hours. It has a half life of ten to twenty minutes. It is widely distributed throughout the body and remains in the extracellular fluid. It is degraded by the liver and excreted through the kidneys.. Arginin vasopressins for use in septic shock are intended for intravenous use only. ## Side effects The most common side effects during treatment with vasopressin are dizziness, angina, chest pain, abdominal cramps, heartburn, nausea, vomiting, trembling, fever, water intoxication, pounding sensation in the head, diarrhea, sweating, paleness, and flatulence. The most severe adverse reactions are myocardial infarction and hypersensitivy. ## Contraindications The use of lysine vasopressin is contraindicated in the presence of hypersentivity to beef or pork proteins, increased BUN and chronic renal failure. It is recommended that it be cautiously used in instances of perioperative polyuria, sensitivity to the drug, asthma, seizures, heart failure, a comatose state, migraine headaches, and cardiovascular disease. ## Interactions - alcohol - may lower the antidiuretic effect - carbamazepine, chloropropamide, clofibrate, tricyclic antidepressants fludrocortisone may raise the diuretic effect - lithium, demeclocycline, heparin or norepinephrine may lower the antidiuretic effect - vasopressor effect may be higher with the concurrent use of ganglionic blocking medications # Role in disease There may be a connection between arginine vasopressin and autism. ## Deficiency Decreased AVP release (neurogenic — i.e. due to alcohol intoxication or tumour) or decreased renal sensitivity to AVP (nephrogenic, i.e. by mutation of V2 receptor or AQP) leads to diabetes insipidus, a condition featuring hypernatremia (increased blood sodium concentration), polyuria (excess urine production), and polydipsia (thirst). ## Excess Syndrome of Inappropriate Antidiuretic Hormone secretion (SIADH) in turn can be caused by a number of problems. Some forms of cancer can cause SIADH, particularly small cell lung carcinoma but also a number of other tumors. A variety of diseases affecting the brain or the lung (infections, bleeding) can be the driver behind SIADH. A number of drugs has been associated with SIADH, such as certain antidepressants (serotonin reuptake inhibitors and tricyclic antidepressants), the anticonvulsant carbamazepine, oxytocin (used to induce and stimulate labor), and the chemotherapy drug vincristine. It has also been associated with fluoroquinolones (including ciprofloxacin and moxifloxacin). Finally, it can occur without a clear explanation. Hyponatremia can be treated pharmaceutically through the use of vasopressin receptor antagonists. # History Vasopressin was elucidated and synthesized for the first time by Vincent du Vigneaud. # Animal studies Evidence for an effect of AVP on monogamy vs promiscuity comes from experimental studies in several species, which indicate that the precise distribution of vasopressin and vasopressin receptors in the brain is associated with species-typical patterns of social behavior. In particular, there are consistent differences between monogamous species and promiscuous species in the distribution of AVP receptors, and sometimes in the distribution of vasopressin-containing axons, even when closely related species are compared. # Human studies Vasopressin has shown nootropic effects on pain perception and cognitive function. Vasopressin also plays a role in autism, major depressive disorder, bipolar disorder, and schizophrenia.	Vasopressin Vasopressin, also called antidiuretic hormone (ADH), arginine vasopressin (AVP) or argipressin,[1] is a hormone synthesized as a peptide prohormone in neurons in the hypothalamus, and is converted to AVP. It then travels down the axon of that cell, which terminates in the posterior pituitary, and is released from vesicles into the circulation in response to extracellular fluid hypertonicity (hyperosmolality). AVP has two primary functions. First, it increases the amount of solute-free water reabsorbed back into the circulation from the filtrate in the kidney tubules of the nephrons. Second, AVP constricts arterioles, which increases peripheral vascular resistance and raises arterial blood pressure.[2][3][4] A third function is possible. Some AVP may be released directly into the brain from the hypothalamus, and may play an important role in social behavior, sexual motivation and pair bonding, and maternal responses to stress.[5] Vasopressin induces differential of stem cells into cardiomyocytes and promotes heart muscle homeostasis.[6] It has a very short half-life, between 16–24 minutes.[4] # Physiology ## Function Vasopressin regulates the tonicity of body fluids. It is released from the posterior pituitary in response to hypertonicity and causes the kidneys to reabsorb solute-free water and return it to the circulation from the tubules of the nephron, thus returning the tonicity of the body fluids toward normal. An incidental consequence of this renal reabsorption of water is concentrated urine and reduced urine volume. AVP released in high concentrations may also raise blood pressure by inducing moderate vasoconstriction. AVP also may have a variety of neurological effects on the brain. It may influence pair-bonding in voles. The high-density distributions of vasopressin receptor AVPr1a in prairie vole ventral forebrain regions have been shown to facilitate and coordinate reward circuits during partner preference formation, critical for pair bond formation.[7] A very similar substance, lysine vasopressin (LVP) or lypressin, has the same function in pigs and is used in human AVP deficiency.[8] ### Kidney Vasopressin has three main effects which are - Increasing the water permeability of initial and cortical collecting tubules (ICT & CCT), as well as outer and inner medullary collecting duct (OMCD & IMCD) in the kidney, thus allowing water reabsorption and excretion of more concentrated urine, i.e., antidiuresis. This occurs through increased transcription and insertion of water channels (Aquaporin-2) into the apical membrane of collecting tubule and collecting duct epithelial cells. [9] Aquaporins allow water to move down their osmotic gradient and out of the nephron, increasing the amount of water re-absorbed from the filtrate (forming urine) back into the bloodstream. Important for bowen students, this effect is mediated by V2 receptors. Vasopressin also increases the concentration of calcium in the collecting duct cells, by episodic release from intracellular stores. Vasopressin, acting through cAMP, also increases transcription of the aquaporin-2 gene, thus increasing the total number of aquaporin-2 molecules in collecting duct cells.[citation needed] - Increasing permeability of the inner medullary portion of the collecting duct to urea by regulating the cell surface expression of urea transporters,[10] which facilitates its reabsorption into the medullary interstitium as it travels down the concentration gradient created by removing water from the connecting tubule, cortical collecting duct, and outer medullary collecting duct. - Acute increase of sodium absorption across the ascending loop of henle. This adds to the countercurrent multiplication which aids in proper water reabsorption later in the distal tubule and collecting duct.[11] ### Central nervous system Vasopressin released within the brain may have several actions: - Vasopressin is released into the brain in a circadian rhythm by neurons of the suprachiasmatic nucleus.[12] - Vasopressin released from centrally projecting hypothalamic neurons is involved in aggression, blood pressure regulation, and temperature regulation.[citation needed]--> - Recent evidence suggests that vasopressin may have analgesic effects. The analgesia effects of vasopressin were found to be dependent on both stress and sex.[13] ## Regulation Many factors influence the secretion of vasopressin: - Ethanol (alcohol) reduces the calcium-dependent secretion of AVP by blocking voltage-gated calcium channels in neurohypophyseal nerve terminals in rats.[14] - Angiotensin II stimulates AVP secretion, in keeping with its general pressor and pro-volumic effects on the body.[15] - Atrial natriuretic peptide inhibits AVP secretion, in part by inhibiting Angiotensin II-induced stimulation of AVP secretion.[15] - Cortisol inhibits secretion of antidiuretic hormone.[16] ## Production and secretion The physiologic stimulus for secretion of vasopressin is increased osmolality of the plasma, monitored by the hypothalamus. A decreased arterial blood volume, (such as can occur in cirrhosis, nephrosis and heart failure), stimulates secretion, even in the face of decreased osmolality of the plasma: it supersedes osmolality, but with a milder effect. In other words, vasopressin is secreted in spite of the presence of hypoosmolality (hyponatremia) when the arterial blood volume is low. The AVP that is measured in peripheral blood is almost all derived from secretion from the posterior pituitary gland (except in cases of AVP-secreting tumours). Vasopressin is produced by magnocellular neurosecretory neurons in the Paraventricular nucleus of hypothalamus (PVN) and Supraoptic nucleus (SON). It then travels down the axon through the infundibulum within neurosecretory granules that are found within Herring bodies, localized swellings of the axons and nerve terminals. These carry the peptide directly to the posterior pituitary gland, where it is stored until released into the blood. There are other sources of AVP, beyond the hypothalamic magnocellular neurons. For example, AVP is also synthesized by parvocellular neurosecretory neurons of the PVN, transported and released at the median eminence, from which it travels through the hypophyseal portal system to the anterior pituitary, where it stimulates corticotropic cells synergistically with CRH to produce ACTH (by itself it is a weak secretagogue).[17] ## Vasopressin during surgery and anaesthesia Vasopressin is used for measurement of surgical stress at evaluation of surgical techniques. Plasma vasopressin concentration is elevated at noxious stimuli,[18] predominantly during abdominal surgery,[19][20][21] especially at gut manipulation and traction of viscera.[22][23][24] In a study on dogs, plasma vasopressin concentration increased at removal of both ovaries, with a 15 minute pause between ovary removal. Blood pressure and vasopressin concentrations changed in parallel at use of z‐scores (standard scores) for comparison.[25] In a human study, two different approaches for lumbar spine surgery were compared. An intraoperative increase of vasopressin levels was observed in one of the groups and this group required more postoperative analgesics.[26] ## Receptors The following describes the actions of AVP: ## Structure and relation to oxytocin The vasopressins are peptides consisting of nine amino acids (nonapeptides). (NB: the value in the table above of 164 amino acids is that obtained before the hormone is activated by cleavage.) The amino acid sequence of arginine vasopressin (argipressin) is Cys-Tyr-Phe-Gln-Asn-Cys-Pro-Arg-Gly-NH2, with the cysteine residues forming a disulfide bond and the C-terminus of the sequence converted to a primary amide.[35] Lysine vasopressin (lypressin) has a lysine in place of the arginine as the eighth amino acid, and is found in pigs and some related animals, whereas arginine vasopressin is found in humans.[36] The structure of oxytocin is very similar to that of the vasopressins: It is also a nonapeptide with a disulfide bridge and its amino acid sequence differs at only two positions (see table below). The two genes are located on the same chromosome separated by a relatively small distance of less than 15,000 bases in most species. The magnocellular neurons that secrete vasopressin are adjacent to magnocellular neurons that secrete oxytocin, and are similar in many respects. The similarity of the two peptides can cause some cross-reactions: oxytocin has a slight antidiuretic function, and high levels of AVP can cause uterine contractions.[37][38] Below is a table showing the superfamily of vasopressin and oxytocin neuropeptides: # Medical use Vasopressin is used to manage anti-diuretic hormone deficiency. It has off-label uses and is used in the treatment of vasodilatory shock, gastrointestinal bleeding, ventricular tachycardia and ventricular fibrillation. Vasopressin is used to treat diabetes insipidus related to low levels of antiduretic hormone. It is available as Pressyn.[40] Vasopressin agonists are used therapeutically in various conditions, and its long-acting synthetic analogue desmopressin is used in conditions featuring low vasopressin secretion, as well as for control of bleeding (in some forms of von Willebrand disease and in mild haemophilia A) and in extreme cases of bedwetting by children. Terlipressin and related analogues are used as vasoconstrictors in certain conditions. Use of vasopressin analogues for esophageal varices commenced in 1970.[41] Vasopressin infusions are also used as second line therapy for septic shock patients not responding to fluid resuscitation or infusions of catecholamines (e.g., dopamine or norepinephrine) to increase the blood pressure while sparing the use of catecholamines. These argipressins have much shorter elimination half-life (around 20 minutes) comparing to synthetic non-arginine vasopresines with much longer elimination half-life of many hours. Further, argipressins act on V1a, V1b, and V2 reseptors which consequently lead to higher eGFR and lower vascular resistance in the lungs. A number of injectable arginine vasopressins are currently in clinical use in the United States and in Europe. ## Pharmacokinetics Vasopressin is administered through an intravenous device, intramuscular injection or a subcutaneous injection. The duration of action depends on the mode of administration and ranges from thirty minutes to two hours. It has a half life of ten to twenty minutes. It is widely distributed throughout the body and remains in the extracellular fluid. It is degraded by the liver and excreted through the kidneys.[40]. Arginin vasopressins for use in septic shock are intended for intravenous use only. ## Side effects The most common side effects during treatment with vasopressin are dizziness, angina, chest pain, abdominal cramps, heartburn, nausea, vomiting, trembling, fever, water intoxication, pounding sensation in the head, diarrhea, sweating, paleness, and flatulence. The most severe adverse reactions are myocardial infarction and hypersensitivy.[40] ## Contraindications The use of lysine vasopressin is contraindicated in the presence of hypersentivity to beef or pork proteins, increased BUN and chronic renal failure. It is recommended that it be cautiously used in instances of perioperative polyuria, sensitivity to the drug, asthma, seizures, heart failure, a comatose state, migraine headaches, and cardiovascular disease.[40] ## Interactions - alcohol - may lower the antidiuretic effect - carbamazepine, chloropropamide, clofibrate, tricyclic antidepressants fludrocortisone may raise the diuretic effect - lithium, demeclocycline, heparin or norepinephrine may lower the antidiuretic effect - vasopressor effect may be higher with the concurrent use of ganglionic blocking medications[40] # Role in disease There may be a connection between arginine vasopressin and autism.[42] ## Deficiency Decreased AVP release (neurogenic — i.e. due to alcohol intoxication or tumour) or decreased renal sensitivity to AVP (nephrogenic, i.e. by mutation of V2 receptor or AQP) leads to diabetes insipidus, a condition featuring hypernatremia (increased blood sodium concentration), polyuria (excess urine production), and polydipsia (thirst). ## Excess Syndrome of Inappropriate Antidiuretic Hormone secretion (SIADH) in turn can be caused by a number of problems. Some forms of cancer can cause SIADH, particularly small cell lung carcinoma but also a number of other tumors. A variety of diseases affecting the brain or the lung (infections, bleeding) can be the driver behind SIADH. A number of drugs has been associated with SIADH, such as certain antidepressants (serotonin reuptake inhibitors and tricyclic antidepressants), the anticonvulsant carbamazepine, oxytocin (used to induce and stimulate labor), and the chemotherapy drug vincristine. It has also been associated with fluoroquinolones (including ciprofloxacin and moxifloxacin).[4] Finally, it can occur without a clear explanation.[43] Hyponatremia can be treated pharmaceutically through the use of vasopressin receptor antagonists.[43] # History Vasopressin was elucidated and synthesized for the first time by Vincent du Vigneaud. # Animal studies Evidence for an effect of AVP on monogamy vs promiscuity comes from experimental studies in several species, which indicate that the precise distribution of vasopressin and vasopressin receptors in the brain is associated with species-typical patterns of social behavior. In particular, there are consistent differences between monogamous species and promiscuous species in the distribution of AVP receptors, and sometimes in the distribution of vasopressin-containing axons, even when closely related species are compared.[44] # Human studies Vasopressin has shown nootropic effects on pain perception and cognitive function.[45] Vasopressin also plays a role in autism, major depressive disorder, bipolar disorder, and schizophrenia.[46]	https://www.wikidoc.org/index.php/Anti-diuretic_hormone
0a5043f3a5eb5a3f7a1bd529509cb12b94d54cd3	wikidoc	Antioxidant	Antioxidant # Overview An antioxidant is a molecule capable of slowing or preventing the oxidation of other molecules. Oxidation is a chemical reaction that transfers electrons from a substance to an oxidizing agent. Oxidation reactions can produce free radicals, which start chain reactions that damage cells. Antioxidants terminate these chain reactions by removing free radical intermediates, and inhibit other oxidation reactions by being oxidized themselves. As a result, antioxidants are often reducing agents such as thiols or polyphenols. Although oxidation reactions are crucial for life, they can also be damaging; hence, plants and animals maintain complex systems of multiple types of antioxidants, such as glutathione, vitamin C, and vitamin E as well as enzymes such as catalase, superoxide dismutase and various peroxidases. Low levels of antioxidants, or inhibition of the antioxidant enzymes, causes oxidative stress and may damage or kill cells. As oxidative stress might be an important part of many human diseases, the use of antioxidants in pharmacology is intensively studied, particularly as treatments for stroke and neurodegenerative diseases. However, it is unknown whether oxidative stress is the cause or the consequence of disease. Antioxidants are also widely used as ingredients in dietary supplements in the hope of maintaining health and preventing diseases such as cancer and coronary heart disease. Although some studies have suggested antioxidant supplements have health benefits, other large clinical trials did not detect any benefit for the formulations tested, and excess supplementation may be harmful. In addition to these uses in medicine, antioxidants have many industrial uses, such as preservatives in food and cosmetics and preventing the degradation of rubber and gasoline. # History The term antioxidant originally was used to refer specifically to a chemical that prevented the consumption of oxygen. In the late 19th and early 20th century, extensive study was devoted to the uses of antioxidants in important industrial processes, such as the prevention of metal corrosion, the vulcanization of rubber, and the polymerization of fuels in the fouling of internal combustion engines. Early research on the role of antioxidants in biology focused on their use in preventing the oxidation of unsaturated fats, which is the cause of rancidity. Antioxidant activity could be measured simply by placing the fat in a closed container with oxygen and measuring the rate of oxygen consumption. However, it was the identification of vitamins A, C, and E as antioxidants that revolutionized the field and led to the realization of the importance of antioxidants in biochemistry of living organisms. The possible mechanisms of action of antioxidants were first explored when it was recognized that a substance with anti-oxidative activity is likely to be one that is itself readily oxidized. Research into how vitamin E prevents the process of lipid peroxidation led to the identification of antioxidants as reducing agents that prevent oxidative reactions, often by scavenging reactive oxygen species before they can damage cells. # The oxidative challenge in biology A paradox in metabolism is that while the vast majority of complex life requires oxygen for its existence, oxygen is a highly reactive molecule that damages living organisms by producing reactive oxygen species. Consequently, organisms contain a complex network of antioxidant metabolites and enzymes that work together to prevent oxidative damage to cellular components such as DNA, proteins and lipids. In general, antioxidant systems either prevent these reactive species from being formed, or remove them before they can damage vital components of the cell. The reactive oxygen species produced in cells include hydrogen peroxide (H2O2), hypochlorous acid (HClO), and free radicals such as the hydroxyl radical (·OH) and the superoxide anion (O2−). The hydroxyl radical is particularly unstable and will react rapidly and non-specifically with most biological molecules. This species is produced from hydrogen peroxide in metal-catalyzed redox reactions such as the Fenton reaction. These oxidants can damage cells by starting chemical chain reactions such as lipid peroxidation, or by oxidizing DNA or proteins. Damage to DNA can cause mutations and possibly cancer, if not reversed by DNA repair mechanisms, while damage to proteins causes enzyme inhibition, denaturation and protein degradation. The use of oxygen as part of the process for generating metabolic energy produces reactive oxygen species. In this process, the superoxide anion is produced as a by-product of several steps in the electron transport chain. Particularly important is the reduction of coenzyme Q in complex III, since a highly reactive free radical is formed as an intermediate (Q·−). This unstable intermediate can lead to electron "leakage", when electrons jump directly to oxygen and form the superoxide anion, instead of moving through the normal series of well-controlled reactions of the electron transport chain. In a similar set of reactions in plants, reactive oxygen species are also produced during photosynthesis under conditions of high light intensity. This effect is partly offset by the involvement of carotenoids in photoinhibition, which involves these antioxidants reacting with over-reduced forms of the photosynthetic reaction centres to prevent the production of reactive oxygen species. # Metabolites ## Overview Antioxidants are classified into two broad divisions, depending on whether they are soluble in water (hydrophilic) or in lipids (hydrophobic). In general, water-soluble antioxidants react with oxidants in the cell cytoplasm and the blood plasma, while lipid-soluble antioxidants protect cell membranes from lipid peroxidation. These compounds may be synthesized in the body or obtained from the diet. The different antioxidants are present at a wide range of concentrations in body fluids and tissues, with some such as glutathione or ubiquinone mostly present within cells, while others such as uric acid are more evenly distributed (see table below). The relative importance and interactions between these different antioxidants is a very complex question, with the various metabolites and enzyme systems having synergistic and interdependent effects on one another. The action of one antioxidant may therefore depend on the proper function of other members of the antioxidant system. The amount of protection provided by any one antioxidant will also depend on its concentration, its reactivity towards the particular reactive oxygen species being considered, and the status of the antioxidants with which it interacts. Some compounds contribute to antioxidant defense by chelating transition metals and preventing them from catalyzing the production of free radicals in the cell. Particularly important is the ability to sequester iron, which is the function of iron-binding proteins such as transferrin and ferritin. Selenium and zinc are commonly referred to as antioxidant nutrients, but these chemical elements have no antioxidant action themselves and are instead required for the activity of some antioxidant enzymes, as is discussed below. ## Ascorbic acid Ascorbic acid or "vitamin C" is a monosaccharide antioxidant found in both animals and plants. As it cannot be synthesised in humans and must be obtained from the diet, it is a vitamin. Most other animals are able to produce this compound in their bodies and do not require it in their diets. In cells, it is maintained in its reduced form by reaction with glutathione, which can be catalysed by protein disulfide isomerase and glutaredoxins. Ascorbic acid is a reducing agent and can reduce and thereby neutralize reactive oxygen species such as hydrogen peroxide. In addition to its direct antioxidant effects, ascorbic acid is also a substrate for the antioxidant enzyme ascorbate peroxidase, a function that is particularly important in stress resistance in plants. ## Glutathione Glutathione is a cysteine-containing peptide found in most forms of aerobic life. It is not required in the diet and is instead synthesized in cells from its constituent amino acids. Glutathione has antioxidant properties since the thiol group in its cysteine moiety is a reducing agent and can be reversibly oxidized and reduced. In cells, glutathione is maintained in the reduced form by the enzyme glutathione reductase and in turn reduces other metabolites and enzyme systems as well as reacting directly with oxidants. Due to its high concentration and its central role in maintaining the cell's redox state, glutathione is one of the most important cellular antioxidants. ## Melatonin Melatonin is a powerful antioxidant that can easily cross cell membranes and the blood-brain barrier. Unlike other antioxidants, melatonin does not undergo redox cycling, which is the ability of a molecule to undergo repeated reduction and oxidation. Redox cycling may allow other antioxidants (such as vitamin C) to act as pro-oxidants and promote free radical formation. Melatonin, once oxidized, cannot be reduced to its former state because it forms several stable end-products upon reacting with free radicals. Therefore, it has been referred to as a terminal (or suicidal) antioxidant. ## Tocopherols and tocotrienols (vitamin E) Vitamin E is the collective name for a set of eight related tocopherols and tocotrienols, which are fat-soluble vitamins with antioxidant properties. Of these, α-tocopherol has been most studied as it has the highest bioavailability, with the body preferentially absorbing and metabolising this form. It has been claimed that the α-tocopherol form is the most important lipid-soluble antioxidant, and that it protects membranes from oxidation by reacting with lipid radicals produced in the lipid peroxidation chain reaction. This removes the free radical intermediates and prevents the propagation reaction from continuing. This reaction produces oxidised α-tocopheroxyl radicals that can be recycled back to the active reduced form through reduction by other antioxidants, such as ascorbate, retinol or ubiquinol. However, the roles and importance of the various forms of vitamin E are presently unclear, and it has even been suggested that the most important function of α-tocopherol is as a signaling molecule, with this molecule having no significant role in antioxidant metabolism. The functions of the other forms of vitamin E are even less well-understood, although γ-tocopherol is a nucleophile that may react with electrophilic mutagens, and tocotrienols may be important in protecting neurons from damage. # Pro-oxidant activities Antioxidants that are reducing agents can also act as pro-oxidants. For example, vitamin C has antioxidant activity when it reduces oxidizing substances such as hydrogen peroxide, however, it will also reduce metal ions that generate free radicals through the Fenton reaction. The relative importance of the antioxidant and pro-oxidant activities of antioxidants are an area of current research, but vitamin C, for example, appears to have a mostly antioxidant action in the body. However, fewer data are available for other dietary antioxidants, such as vitamin E. # Enzyme systems ## Overview As with the chemical antioxidants, cells are protected against oxidative stress by an interacting network of antioxidant enzymes. Here, the superoxide released by processes such as oxidative phosphorylation is first converted to hydrogen peroxide and then further reduced to give water. This detoxification pathway is the result of multiple enzymes, with superoxide dismutases catalysing the first step and then catalases and various peroxidases removing hydrogen peroxide. As with antioxidant metabolites, the contributions of these enzymes to the antioxidant defenses of a cell can be hard to separate from one another, but the generation of transgenic mice lacking just one antioxidant enzyme can be informative. ## Superoxide dismutase, catalase and peroxiredoxins Superoxide dismutases (SODs) are a class of closely related enzymes that catalyse the breakdown of the superoxide anion into oxygen and hydrogen peroxide. SOD enzymes are present in almost all aerobic cells and in extracellular fluids. Superoxide dismutase enzymes contain metal ion cofactors that, depending on the isozyme, can be copper, zinc, manganese or iron. In humans, the copper/zinc SOD is present in the cytosol, while manganese SOD is present in the mitochondrion. There also exists a third form of SOD in extracellular fluids, which contains copper and zinc in its active sites. The mitochondrial isozyme seems to be the most biologically important of these three, since mice lacking this enzyme die soon after birth. In contrast, the mice lacking copper/zinc SOD are viable but have lowered fertility, while mice without the extracellular SOD have minimal defects. In plants, SOD isozymes are present in the cytosol and mitochondria, with an iron SOD found in chloroplasts that is absent from vertebrates and yeast. Catalases are enzymes that catalyse the conversion of hydrogen peroxide to water and oxygen, using either an iron or manganese cofactor. This protein is localized to peroxisomes in most eukaryotic cells. Catalase is an unusual enzyme since, although hydrogen peroxide is its only substrate, it follows a ping-pong mechanism. Here, its cofactor is oxidised by one molecule of hydrogen peroxide and then regenerated by transferring the bound oxygen to a second molecule of substrate. Despite its apparent importance in hydrogen peroxide removal, humans with genetic deficiency of catalase — "acatalasemia" — or mice genetically engineered to lack catalase completely, suffer few ill effects. Peroxiredoxins are peroxidases that catalyze the reduction of hydrogen peroxide, organic hydroperoxides, as well as peroxynitrite. They are divided into three classes: typical 2-cysteine peroxiredoxins; atypical 2-cysteine peroxiredoxins; and 1-cysteine peroxiredoxins. These enzymes share the same basic catalytic mechanism, in which a redox-active cysteine (the peroxidatic cysteine) in the active site is oxidized to a sulfenic acid by the peroxide substrate. Peroxiredoxins seem to be important in antioxidant metabolism, as mice lacking peroxiredoxin 1 or 2 have shortened lifespan and suffer from hemolytic anaemia, while plants use peroxiredoxins to remove hydrogen peroxide generated in chloroplasts. ## Thioredoxin and glutathione systems The thioredoxin system contains the 12-kDa protein thioredoxin and its companion thioredoxin reductase. Proteins related to thioredoxin are present in all sequenced organisms, with plants such as Arabidopsis thaliana having a particularly great diversity of isoforms. The active site of thioredoxin consists of two neighboring cysteines, as part of a highly-conserved CXXC motif, that can cycle between an active dithiol form (reduced) and an oxidized disulfide form. In its active state, thioredoxin acts as an efficient reducing agent, scavenging reactive oxygen species and maintaining other proteins in their reduced state. After being oxidized, the active thioredoxin is regenerated by the action of thioredoxin reductase, using NADPH as an electron donor. The glutathione system includes glutathione, glutathione reductase, glutathione peroxidases and glutathione S-transferases. This system is found in animals, plants and microorganisms. Glutathione peroxidase is an enzyme containing four selenium-cofactors that catalyzes the breakdown of hydrogen peroxide and organic hydroperoxides. There are at least four different glutathione peroxidase isozymes in animals. Glutathione peroxidase 1 is the most abundant and is a very efficient scavenger of hydrogen peroxide, while glutathione peroxidase 4 is most active with lipid hydroperoxides. Surprisingly, glutathione peroxidase 1 is dispensable, as mice lacking this enzyme have normal lifespans, but they are hypersensitive to induced oxidative stress. In addition, the glutathione S-transferases are another class of glutathione-dependent antioxidant enzymes that show high activity with lipid peroxides. These enzymes are at particularly high levels in the liver and also serve in detoxification metabolism. # Oxidative stress in disease Oxidative stress is thought to contribute to the development of a wide range of diseases including Alzheimer's disease, Parkinson's disease, the pathologies caused by diabetes, rheumatoid arthritis, and neurodegeneration in motor neurone diseases. In many of these cases, it is unclear if oxidants trigger the disease, or if they are produced as a consequence of the disease and cause the disease symptoms; as a plausible alternative, a neurodegenerative disease might result from defective axonal transport of mitochondria, which carry out oxidation reactions. One case in which this link is particularly well-understood is the role of oxidative stress in cardiovascular disease. Here, low density lipoprotein (LDL) oxidation appears to trigger the process of atherogenesis, which results in atherosclerosis, and finally cardiovascular disease. A low calorie diet extends median and maximum lifespan in many animals. This effect may involve a reduction in oxidative stress. While there is good evidence to support the role of oxidative stress in aging in model organisms such as Drosophila melanogaster and Caenorhabditis elegans, the evidence in mammals is less clear. Diets high in fruit and vegetables, which are high in antioxidants, promote health and reduce the effects of aging, however antioxidant vitamin supplementation has no detectable effect on the aging process, so the effects of fruit and vegetables may be unrelated to their antioxidant contents. One reason for this might be the fact that consuming antioxidant molecules such as polyphenols and vitamin E will produce changes in other parts of metabolism, so it may be these other non-antioxidant effects that are the real reason they are important in human nutrition. # Health effects ## Disease treatment The brain is uniquely vulnerable to oxidative injury, due to its high metabolic rate and elevated levels of polyunsaturated lipids, the target of lipid peroxidation. Consequently, antioxidants are commonly used as medications to treat various forms of brain injury. Here, superoxide dismutase mimetics, sodium thiopental and propofol are used to treat reperfusion injury and traumatic brain injury, while the experimental drug NXY-059 and ebselen are being applied in the treatment of stroke. These compounds appear to prevent oxidative stress in neurons and prevent apoptosis and neurological damage. Antioxidants are also being investigated as possible treatments for neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis, and as a way to prevent noise-induced hearing loss. ## Disease prevention Antioxidants can cancel out the cell-damaging effects of free radicals. Furthermore, people who eat fruits and vegetables, which are good sources of antioxidants, have a lower risk of heart disease and some neurological diseases, and there is evidence that some types of vegetables, and fruits in general, probably protect against a number of cancers. These observations suggested that antioxidants might help prevent these conditions. There is some evidence that antioxidants might help prevent diseases such as macular degeneration, suppressed immunity due to poor nutrition, and neurodegeneration. However, despite the clear role of oxidative stress in cardiovascular disease, controlled studies using antioxidant vitamins have observed no reduction in either the risk of developing heart disease, or the rate of progression of existing disease. This suggests that other substances in fruit and vegetables (possibly flavonoids), or a complex mix of substances, may contribute to the better cardiovascular health of those who consume more fruit and vegetables. It is thought that oxidation of low density lipoprotein in the blood contributes to heart disease, and initial observational studies found that people taking Vitamin E supplements had a lower risk of developing heart disease. Consequently, at least seven large clinical trials were conducted to test the effects of antioxidant supplement with Vitamin E, in doses ranging from 50 to 600 mg per day. However, none of these trials found a statistically significant effect of Vitamin E on overall number of deaths or on deaths due to heart disease. It is not clear if the doses used in these trials or in most dietary supplements are capable of producing any significant decrease in oxidative stress. While several trials have investigated supplements with high doses of antioxidants, the "Supplémentation en Vitamines et Mineraux Antioxydants" (SU.VI.MAX) study tested the effect of supplementation with doses comparable to those in a healthy diet. Over 12,500 French men and women took either low-dose antioxidants (120 mg of ascorbic acid, 30 mg of vitamin E, 6 mg of beta carotene, 100 \mug of selenium, and 20 mg of zinc) or placebo pills for an average of 7.5 years. The investigators found there was no statistically significant effect of the antioxidants on overall survival, cancer, or heart disease. However, a subgroup analysis showed a 31% reduction in the risk of cancer in men, but not women. Many nutraceutical and health food companies now sell formulations of antioxidants as dietary supplements and these are widely used in industrialized countries. These supplements may include specific antioxidant chemicals, like resveratrol (from grape seeds), combinations of antioxidants, like the "ACES" products that contain beta carotene (provitamin A), vitamin C, vitamin E and Selenium, or herbs that contain antioxidants - such as green tea and jiaogulan. Although some levels of antioxidant vitamins and minerals in the diet are required for good health, there is considerable doubt as to whether antioxidant supplementation is beneficial, and if so, which antioxidant(s) are beneficial and in what amounts. It has been suggested that moderate levels of oxidative stress may increase life expectancy of in the worm Caenorhabditis elegans, by inducing a protective response to increased levels of reactive oxygen species. However, the suggestion that increased life expectancy comes from increased oxidative stress conflicts with results seen in the yeast Saccharomyces cerevisiae, and the situation in mammals is even less clear. ## Physical exercise During exercise, oxygen consumption can increase by a factor of more than 10. This leads to a large increase in the production of oxidants and results in damage that contributes to muscular fatigue during and after exercise. The inflammatory response that occurs after strenuous exercise is also associated with oxidative stress, especially in the 24 hours after an exercise session. The immune system response to damage done by exercise peaks 2 to 7 days after exercise, the period during which adaptation resulting in greater fitness is greatest. During this process, free radicals are produced by neutrophils to remove damaged tissue. As a result, excessive antioxidant levels have the potential to inhibit recovery and adaptation mechanisms. The evidence for benefits from antioxidant supplementation in vigorous exercise is mixed. There is strong evidence that one of the adaptations resulting from exercise is a strengthening of the body's antioxidant defenses, particularly the glutathione system, to deal with the increased oxidative stress. It is possible that this effect may be to some extent protective against diseases which are associated with oxidative stress, which would provide a partial explanation for the lower incidence of major diseases and better health of those who undertake regular exercise. However, no benefits to athletes are seen with vitamin A or E supplementation. For example, despite its key role in preventing lipid membrane peroxidation, 6 weeks of vitamin E supplementation had no effect on muscle damage in ultramarathon runners. Although there appears to be no increased requirement for vitamin C in athletes, there is some evidence that vitamin C supplementation increased the amount of intense exercise that can be done and vitamin C supplementation before strenuous exercise may reduce the amount of muscle damage. However, other studies found no such effects, and some research suggests that supplementation with amounts as high as 1000 mg inhibits recovery. ## Adverse effects Relatively strong reducing acids can have anti-nutritional effects by binding to dietary minerals such as iron and zinc in the gastrointestinal tract and preventing them from being absorbed. Notable examples are oxalic acid, tannins and phytic acid, which are high in plant-based diets. Calcium and iron deficiencies are not uncommon in diets in developing countries where less meat is eaten and there is high consumption of phytic acid from beans and unleavened whole grain bread. Nonpolar antioxidants such as eugenol, a major component of oil of cloves have toxicity limits that can be exceeded with the misuse of undiluted essential oils. Toxicity associated with high doses of water-soluble antioxidants such as ascorbic acid are less of a concern, as these compounds can be excreted rapidly in urine. More seriously, very high doses of some antioxidants may have harmful long-term effects. The beta-Carotene and Retinol Efficacy Trial (CARET) study of lung cancer patients found that smokers given supplements containing beta-carotene and vitamin A had increased rates of lung cancer. Subsequent studies confirmed these adverse effects. These harmful effects may also be seen in non-smokers, as a recent meta-analysis including data from approximately 230,000 patients showed that β-carotene, vitamin A or vitamin E supplementation is associated with increased mortality but saw no significant effect from vitamin C. No health risk was seen when all the randomized controlled studies were examined together, but an increase in mortality was detected only when the high-quality and low-bias risk trials were examined separately. However, as the majority of these low-bias trials dealt with either elderly people, or people already suffering disease, these results may not apply to the general population. This meta-analysis was later repeated and extended by the same authors, with the new analysis published by the Cochrane Collaboration; confirming the previous results. These two publications are consistent with some previous meta-analyzes that also suggested that Vitamin E supplementation increased mortality, and that antioxidant supplements increased the risk of colon cancer. However, the results of this meta-analysis are inconsistent with other studies such as the SU.VI.MAX trial, which suggested that antioxidants have no effect on cause-all mortality. Overall, the large number of clinical trials carried out on antioxidant supplements suggest that either these products have no effect on health, or that they cause a small increase in mortality in elderly or vulnerable populations. While antioxidant supplementation is widely used in attempts to prevent the development of cancer, it has been proposed that antioxidants may, paradoxically, interfere with cancer treatments. This was thought to occur since the environment of cancer cells causes high levels of oxidative stress, making these cells more susceptible to the further oxidative stress induced by treatments. As a result, by reducing the redox stress in cancer cells, antioxidant supplements were thought to decrease the effectiveness of radiotherapy and chemotherapy. However, this concern appears not to be valid, as it has been addressed by multiple clinical trials that indicate that antioxidants are either neutral or beneficial in cancer therapy. # Measurement and levels in food Measurement of antioxidants is not a straightforward process, as this is a diverse group of compounds with different reactivities to different reactive oxygen species. In food science, the oxygen radical absorbance capacity (ORAC) has become the current industry standard for assessing antioxidant strength of whole foods, juices and food additives. Other measurement tests include the Folin-Ciocalteu reagent, and the trolox equivalent antioxidant capacity assay. In medicine, a range of different assays are used to assess the antioxidant capability of blood plasma and of these, the ORAC assay may be the most reliable. Antioxidants are found in varying amounts in foods such as vegetables, fruits, grain cereals, legumes and nuts. Some antioxidants such as lycopene and ascorbic acid can be destroyed by long-term storage or prolonged cooking. Other antioxidant compounds are more stable, such as the polyphenolic antioxidants in foods such as whole-wheat cereals and tea. In general, processed foods contain less antioxidants than fresh and uncooked foods, since the preparation processes may expose the food to oxygen. Some antioxidants are made in the body and are not absorbed from the intestine. One example is glutathione, which is made from amino acids. As any glutathione in the gut is broken down to free cysteine, glycine and glutamic acid before being absorbed, even large oral doses have little effect on the concentration of glutathione in the body. Ubiquinol (coenzyme Q) is also poorly absorbed from the gut and is made in humans through the mevalonate pathway. # Uses in technology ## Food preservatives Antioxidants are used as food additives to help guard against food deterioration. Exposure to oxygen and sunlight are the two main factors in the oxidation of food, so food is preserved by keeping in the dark and sealing it in containers or even coating it in wax, as with cucumbers. However, as oxygen is also important for plant respiration, storing plant materials in anaerobic conditions produces unpleasant flavors and unappealing colors. Consequently, packaging of fresh fruits and vegetables contains an ~8% oxygen atmosphere. Antioxidants are an especially important class of preservatives as, unlike bacterial or fungal spoilage, oxidation reactions still occur relatively rapidly in frozen or refrigerated food. These preservatives include ascorbic acid (AA, E300), propyl gallate (PG, E310), tocopherols (E306), tertiary butylhydroquinone (TBHQ), butylated hydroxyanisole (BHA, E320) and butylated hydroxytoluene (BHT, E321). The most common molecules attacked by oxidation are unsaturated fats; oxidation causes them to turn rancid. Since oxidized lipids are often discolored and usually have unpleasant tastes such as metallic or sulfurous flavors, it is important to avoid oxidation in fat-rich foods. Thus, these foods are rarely preserved by drying; instead, they are preserved by smoking, salting or fermenting. Even less fatty foods such as fruits are sprayed with sulfurous antioxidants prior to air drying. Oxidation is often catalyzed by metals, which is why fats such as butter should never be wrapped in aluminium foil or kept in metal containers. Some fatty foods such as olive oil are partially protected from oxidation by their natural content of antioxidants, but remain sensitive to photooxidation. ## Industrial uses Some antioxidants are added to industrial products. A common use is as stabilizers in fuels and lubricants to prevent oxidation, and in gasolines to prevent the polymerization that leads to the formation of engine-fouling residues. They are also used to prevent the oxidative degradation of rubber, plastics and adhesives that causes a loss of strength and flexibility in these materials. Antioxidant preservatives are also added to fat-based cosmetics such as lipstick and moisturizers to prevent rancidity.	Antioxidant Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview An antioxidant is a molecule capable of slowing or preventing the oxidation of other molecules. Oxidation is a chemical reaction that transfers electrons from a substance to an oxidizing agent. Oxidation reactions can produce free radicals, which start chain reactions that damage cells. Antioxidants terminate these chain reactions by removing free radical intermediates, and inhibit other oxidation reactions by being oxidized themselves. As a result, antioxidants are often reducing agents such as thiols or polyphenols. Although oxidation reactions are crucial for life, they can also be damaging; hence, plants and animals maintain complex systems of multiple types of antioxidants, such as glutathione, vitamin C, and vitamin E as well as enzymes such as catalase, superoxide dismutase and various peroxidases. Low levels of antioxidants, or inhibition of the antioxidant enzymes, causes oxidative stress and may damage or kill cells. As oxidative stress might be an important part of many human diseases, the use of antioxidants in pharmacology is intensively studied, particularly as treatments for stroke and neurodegenerative diseases. However, it is unknown whether oxidative stress is the cause or the consequence of disease. Antioxidants are also widely used as ingredients in dietary supplements in the hope of maintaining health and preventing diseases such as cancer and coronary heart disease. Although some studies have suggested antioxidant supplements have health benefits, other large clinical trials did not detect any benefit for the formulations tested, and excess supplementation may be harmful.[1] In addition to these uses in medicine, antioxidants have many industrial uses, such as preservatives in food and cosmetics and preventing the degradation of rubber and gasoline. # History The term antioxidant originally was used to refer specifically to a chemical that prevented the consumption of oxygen. In the late 19th and early 20th century, extensive study was devoted to the uses of antioxidants in important industrial processes, such as the prevention of metal corrosion, the vulcanization of rubber, and the polymerization of fuels in the fouling of internal combustion engines.[2] Early research on the role of antioxidants in biology focused on their use in preventing the oxidation of unsaturated fats, which is the cause of rancidity.[3] Antioxidant activity could be measured simply by placing the fat in a closed container with oxygen and measuring the rate of oxygen consumption. However, it was the identification of vitamins A, C, and E as antioxidants that revolutionized the field and led to the realization of the importance of antioxidants in biochemistry of living organisms.[4][5] The possible mechanisms of action of antioxidants were first explored when it was recognized that a substance with anti-oxidative activity is likely to be one that is itself readily oxidized.[6] Research into how vitamin E prevents the process of lipid peroxidation led to the identification of antioxidants as reducing agents that prevent oxidative reactions, often by scavenging reactive oxygen species before they can damage cells.[7] # The oxidative challenge in biology A paradox in metabolism is that while the vast majority of complex life requires oxygen for its existence, oxygen is a highly reactive molecule that damages living organisms by producing reactive oxygen species.[8] Consequently, organisms contain a complex network of antioxidant metabolites and enzymes that work together to prevent oxidative damage to cellular components such as DNA, proteins and lipids.[9][10] In general, antioxidant systems either prevent these reactive species from being formed, or remove them before they can damage vital components of the cell.[9][8] The reactive oxygen species produced in cells include hydrogen peroxide (H2O2), hypochlorous acid (HClO), and free radicals such as the hydroxyl radical (·OH) and the superoxide anion (O2−).[11] The hydroxyl radical is particularly unstable and will react rapidly and non-specifically with most biological molecules. This species is produced from hydrogen peroxide in metal-catalyzed redox reactions such as the Fenton reaction.[12] These oxidants can damage cells by starting chemical chain reactions such as lipid peroxidation, or by oxidizing DNA or proteins.[9] Damage to DNA can cause mutations and possibly cancer, if not reversed by DNA repair mechanisms,[13][14] while damage to proteins causes enzyme inhibition, denaturation and protein degradation.[15] The use of oxygen as part of the process for generating metabolic energy produces reactive oxygen species.[16] In this process, the superoxide anion is produced as a by-product of several steps in the electron transport chain.[17] Particularly important is the reduction of coenzyme Q in complex III, since a highly reactive free radical is formed as an intermediate (Q·−). This unstable intermediate can lead to electron "leakage", when electrons jump directly to oxygen and form the superoxide anion, instead of moving through the normal series of well-controlled reactions of the electron transport chain.[18] In a similar set of reactions in plants, reactive oxygen species are also produced during photosynthesis under conditions of high light intensity.[19] This effect is partly offset by the involvement of carotenoids in photoinhibition, which involves these antioxidants reacting with over-reduced forms of the photosynthetic reaction centres to prevent the production of reactive oxygen species.[20] # Metabolites ## Overview Antioxidants are classified into two broad divisions, depending on whether they are soluble in water (hydrophilic) or in lipids (hydrophobic). In general, water-soluble antioxidants react with oxidants in the cell cytoplasm and the blood plasma, while lipid-soluble antioxidants protect cell membranes from lipid peroxidation.[9] These compounds may be synthesized in the body or obtained from the diet.[10] The different antioxidants are present at a wide range of concentrations in body fluids and tissues, with some such as glutathione or ubiquinone mostly present within cells, while others such as uric acid are more evenly distributed (see table below). The relative importance and interactions between these different antioxidants is a very complex question, with the various metabolites and enzyme systems having synergistic and interdependent effects on one another.[21][22] The action of one antioxidant may therefore depend on the proper function of other members of the antioxidant system.[10] The amount of protection provided by any one antioxidant will also depend on its concentration, its reactivity towards the particular reactive oxygen species being considered, and the status of the antioxidants with which it interacts.[10] Some compounds contribute to antioxidant defense by chelating transition metals and preventing them from catalyzing the production of free radicals in the cell. Particularly important is the ability to sequester iron, which is the function of iron-binding proteins such as transferrin and ferritin.[23] Selenium and zinc are commonly referred to as antioxidant nutrients, but these chemical elements have no antioxidant action themselves and are instead required for the activity of some antioxidant enzymes, as is discussed below. ## Ascorbic acid Ascorbic acid or "vitamin C" is a monosaccharide antioxidant found in both animals and plants. As it cannot be synthesised in humans and must be obtained from the diet, it is a vitamin.[36] Most other animals are able to produce this compound in their bodies and do not require it in their diets.[37] In cells, it is maintained in its reduced form by reaction with glutathione, which can be catalysed by protein disulfide isomerase and glutaredoxins.[38][39] Ascorbic acid is a reducing agent and can reduce and thereby neutralize reactive oxygen species such as hydrogen peroxide.[40] In addition to its direct antioxidant effects, ascorbic acid is also a substrate for the antioxidant enzyme ascorbate peroxidase, a function that is particularly important in stress resistance in plants.[41] ## Glutathione Glutathione is a cysteine-containing peptide found in most forms of aerobic life.[42] It is not required in the diet and is instead synthesized in cells from its constituent amino acids.[43] Glutathione has antioxidant properties since the thiol group in its cysteine moiety is a reducing agent and can be reversibly oxidized and reduced. In cells, glutathione is maintained in the reduced form by the enzyme glutathione reductase and in turn reduces other metabolites and enzyme systems as well as reacting directly with oxidants.[38] Due to its high concentration and its central role in maintaining the cell's redox state, glutathione is one of the most important cellular antioxidants.[42] ## Melatonin Melatonin is a powerful antioxidant that can easily cross cell membranes and the blood-brain barrier.[44] Unlike other antioxidants, melatonin does not undergo redox cycling, which is the ability of a molecule to undergo repeated reduction and oxidation. Redox cycling may allow other antioxidants (such as vitamin C) to act as pro-oxidants and promote free radical formation. Melatonin, once oxidized, cannot be reduced to its former state because it forms several stable end-products upon reacting with free radicals. Therefore, it has been referred to as a terminal (or suicidal) antioxidant.[45] ## Tocopherols and tocotrienols (vitamin E) Vitamin E is the collective name for a set of eight related tocopherols and tocotrienols, which are fat-soluble vitamins with antioxidant properties.[46][47] Of these, α-tocopherol has been most studied as it has the highest bioavailability, with the body preferentially absorbing and metabolising this form.[48] It has been claimed that the α-tocopherol form is the most important lipid-soluble antioxidant, and that it protects membranes from oxidation by reacting with lipid radicals produced in the lipid peroxidation chain reaction.[46][49] This removes the free radical intermediates and prevents the propagation reaction from continuing. This reaction produces oxidised α-tocopheroxyl radicals that can be recycled back to the active reduced form through reduction by other antioxidants, such as ascorbate, retinol or ubiquinol.[50] However, the roles and importance of the various forms of vitamin E are presently unclear,[51][52] and it has even been suggested that the most important function of α-tocopherol is as a signaling molecule, with this molecule having no significant role in antioxidant metabolism.[53][54] The functions of the other forms of vitamin E are even less well-understood, although γ-tocopherol is a nucleophile that may react with electrophilic mutagens,[48] and tocotrienols may be important in protecting neurons from damage.[55] # Pro-oxidant activities Antioxidants that are reducing agents can also act as pro-oxidants. For example, vitamin C has antioxidant activity when it reduces oxidizing substances such as hydrogen peroxide,[56] however, it will also reduce metal ions that generate free radicals through the Fenton reaction.[57][58] The relative importance of the antioxidant and pro-oxidant activities of antioxidants are an area of current research, but vitamin C, for example, appears to have a mostly antioxidant action in the body.[59][57] However, fewer data are available for other dietary antioxidants, such as vitamin E.[60] # Enzyme systems ## Overview As with the chemical antioxidants, cells are protected against oxidative stress by an interacting network of antioxidant enzymes.[9][8] Here, the superoxide released by processes such as oxidative phosphorylation is first converted to hydrogen peroxide and then further reduced to give water. This detoxification pathway is the result of multiple enzymes, with superoxide dismutases catalysing the first step and then catalases and various peroxidases removing hydrogen peroxide. As with antioxidant metabolites, the contributions of these enzymes to the antioxidant defenses of a cell can be hard to separate from one another, but the generation of transgenic mice lacking just one antioxidant enzyme can be informative.[61] ## Superoxide dismutase, catalase and peroxiredoxins Superoxide dismutases (SODs) are a class of closely related enzymes that catalyse the breakdown of the superoxide anion into oxygen and hydrogen peroxide.[62][63] SOD enzymes are present in almost all aerobic cells and in extracellular fluids.[64] Superoxide dismutase enzymes contain metal ion cofactors that, depending on the isozyme, can be copper, zinc, manganese or iron. In humans, the copper/zinc SOD is present in the cytosol, while manganese SOD is present in the mitochondrion.[63] There also exists a third form of SOD in extracellular fluids, which contains copper and zinc in its active sites.[65] The mitochondrial isozyme seems to be the most biologically important of these three, since mice lacking this enzyme die soon after birth.[66] In contrast, the mice lacking copper/zinc SOD are viable but have lowered fertility, while mice without the extracellular SOD have minimal defects.[61][67] In plants, SOD isozymes are present in the cytosol and mitochondria, with an iron SOD found in chloroplasts that is absent from vertebrates and yeast.[68] Catalases are enzymes that catalyse the conversion of hydrogen peroxide to water and oxygen, using either an iron or manganese cofactor.[69][70] This protein is localized to peroxisomes in most eukaryotic cells.[71] Catalase is an unusual enzyme since, although hydrogen peroxide is its only substrate, it follows a ping-pong mechanism. Here, its cofactor is oxidised by one molecule of hydrogen peroxide and then regenerated by transferring the bound oxygen to a second molecule of substrate.[72] Despite its apparent importance in hydrogen peroxide removal, humans with genetic deficiency of catalase — "acatalasemia" — or mice genetically engineered to lack catalase completely, suffer few ill effects.[73][74] Peroxiredoxins are peroxidases that catalyze the reduction of hydrogen peroxide, organic hydroperoxides, as well as peroxynitrite.[76] They are divided into three classes: typical 2-cysteine peroxiredoxins; atypical 2-cysteine peroxiredoxins; and 1-cysteine peroxiredoxins.[77] These enzymes share the same basic catalytic mechanism, in which a redox-active cysteine (the peroxidatic cysteine) in the active site is oxidized to a sulfenic acid by the peroxide substrate.[78] Peroxiredoxins seem to be important in antioxidant metabolism, as mice lacking peroxiredoxin 1 or 2 have shortened lifespan and suffer from hemolytic anaemia, while plants use peroxiredoxins to remove hydrogen peroxide generated in chloroplasts.[79][80][81] ## Thioredoxin and glutathione systems The thioredoxin system contains the 12-kDa protein thioredoxin and its companion thioredoxin reductase.[82] Proteins related to thioredoxin are present in all sequenced organisms, with plants such as Arabidopsis thaliana having a particularly great diversity of isoforms.[83] The active site of thioredoxin consists of two neighboring cysteines, as part of a highly-conserved CXXC motif, that can cycle between an active dithiol form (reduced) and an oxidized disulfide form. In its active state, thioredoxin acts as an efficient reducing agent, scavenging reactive oxygen species and maintaining other proteins in their reduced state.[84] After being oxidized, the active thioredoxin is regenerated by the action of thioredoxin reductase, using NADPH as an electron donor.[85] The glutathione system includes glutathione, glutathione reductase, glutathione peroxidases and glutathione S-transferases.[42] This system is found in animals, plants and microorganisms.[86][42] Glutathione peroxidase is an enzyme containing four selenium-cofactors that catalyzes the breakdown of hydrogen peroxide and organic hydroperoxides. There are at least four different glutathione peroxidase isozymes in animals.[87] Glutathione peroxidase 1 is the most abundant and is a very efficient scavenger of hydrogen peroxide, while glutathione peroxidase 4 is most active with lipid hydroperoxides. Surprisingly, glutathione peroxidase 1 is dispensable, as mice lacking this enzyme have normal lifespans,[88] but they are hypersensitive to induced oxidative stress.[89] In addition, the glutathione S-transferases are another class of glutathione-dependent antioxidant enzymes that show high activity with lipid peroxides.[90] These enzymes are at particularly high levels in the liver and also serve in detoxification metabolism.[91] # Oxidative stress in disease Oxidative stress is thought to contribute to the development of a wide range of diseases including Alzheimer's disease,[92][93] Parkinson's disease,[94] the pathologies caused by diabetes,[95][96] rheumatoid arthritis,[97] and neurodegeneration in motor neurone diseases.[98] In many of these cases, it is unclear if oxidants trigger the disease, or if they are produced as a consequence of the disease and cause the disease symptoms;[11] as a plausible alternative, a neurodegenerative disease might result from defective axonal transport of mitochondria, which carry out oxidation reactions. One case in which this link is particularly well-understood is the role of oxidative stress in cardiovascular disease. Here, low density lipoprotein (LDL) oxidation appears to trigger the process of atherogenesis, which results in atherosclerosis, and finally cardiovascular disease.[99][100] A low calorie diet extends median and maximum lifespan in many animals. This effect may involve a reduction in oxidative stress.[101] While there is good evidence to support the role of oxidative stress in aging in model organisms such as Drosophila melanogaster and Caenorhabditis elegans,[102][103] the evidence in mammals is less clear.[104][105][106] Diets high in fruit and vegetables, which are high in antioxidants, promote health and reduce the effects of aging, however antioxidant vitamin supplementation has no detectable effect on the aging process, so the effects of fruit and vegetables may be unrelated to their antioxidant contents.[107][108] One reason for this might be the fact that consuming antioxidant molecules such as polyphenols and vitamin E will produce changes in other parts of metabolism, so it may be these other non-antioxidant effects that are the real reason they are important in human nutrition.[109][53] # Health effects ## Disease treatment The brain is uniquely vulnerable to oxidative injury, due to its high metabolic rate and elevated levels of polyunsaturated lipids, the target of lipid peroxidation.[110] Consequently, antioxidants are commonly used as medications to treat various forms of brain injury. Here, superoxide dismutase mimetics,[111] sodium thiopental and propofol are used to treat reperfusion injury and traumatic brain injury,[112] while the experimental drug NXY-059[113][114] and ebselen[115] are being applied in the treatment of stroke. These compounds appear to prevent oxidative stress in neurons and prevent apoptosis and neurological damage. Antioxidants are also being investigated as possible treatments for neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis,[116][117] and as a way to prevent noise-induced hearing loss.[118] ## Disease prevention Antioxidants can cancel out the cell-damaging effects of free radicals.[9] Furthermore, people who eat fruits and vegetables, which are good sources of antioxidants, have a lower risk of heart disease and some neurological diseases,[119] and there is evidence that some types of vegetables, and fruits in general, probably protect against a number of cancers.[120] These observations suggested that antioxidants might help prevent these conditions. There is some evidence that antioxidants might help prevent diseases such as macular degeneration,[121] suppressed immunity due to poor nutrition,[122] and neurodegeneration.[123] However, despite the clear role of oxidative stress in cardiovascular disease, controlled studies using antioxidant vitamins have observed no reduction in either the risk of developing heart disease, or the rate of progression of existing disease.[124][125] This suggests that other substances in fruit and vegetables (possibly flavonoids), or a complex mix of substances, may contribute to the better cardiovascular health of those who consume more fruit and vegetables.[126][127] It is thought that oxidation of low density lipoprotein in the blood contributes to heart disease, and initial observational studies found that people taking Vitamin E supplements had a lower risk of developing heart disease.[128] Consequently, at least seven large clinical trials were conducted to test the effects of antioxidant supplement with Vitamin E, in doses ranging from 50 to 600 mg per day. However, none of these trials found a statistically significant effect of Vitamin E on overall number of deaths or on deaths due to heart disease.[129] It is not clear if the doses used in these trials or in most dietary supplements are capable of producing any significant decrease in oxidative stress.[130] While several trials have investigated supplements with high doses of antioxidants, the "Supplémentation en Vitamines et Mineraux Antioxydants" (SU.VI.MAX) study tested the effect of supplementation with doses comparable to those in a healthy diet.[131] Over 12,500 French men and women took either low-dose antioxidants (120 mg of ascorbic acid, 30 mg of vitamin E, 6 mg of beta carotene, 100 <math>\mu</math>g of selenium, and 20 mg of zinc) or placebo pills for an average of 7.5 years. The investigators found there was no statistically significant effect of the antioxidants on overall survival, cancer, or heart disease. However, a subgroup analysis showed a 31% reduction in the risk of cancer in men, but not women. Many nutraceutical and health food companies now sell formulations of antioxidants as dietary supplements and these are widely used in industrialized countries.[132] These supplements may include specific antioxidant chemicals, like resveratrol (from grape seeds), combinations of antioxidants, like the "ACES" products that contain beta carotene (provitamin A), vitamin C, vitamin E and Selenium, or herbs that contain antioxidants - such as green tea and jiaogulan. Although some levels of antioxidant vitamins and minerals in the diet are required for good health, there is considerable doubt as to whether antioxidant supplementation is beneficial, and if so, which antioxidant(s) are beneficial and in what amounts.[133][134][119] It has been suggested that moderate levels of oxidative stress may increase life expectancy of in the worm Caenorhabditis elegans, by inducing a protective response to increased levels of reactive oxygen species.[135] However, the suggestion that increased life expectancy comes from increased oxidative stress conflicts with results seen in the yeast Saccharomyces cerevisiae,[136] and the situation in mammals is even less clear.[104][137][138] ## Physical exercise During exercise, oxygen consumption can increase by a factor of more than 10.[139] This leads to a large increase in the production of oxidants and results in damage that contributes to muscular fatigue during and after exercise. The inflammatory response that occurs after strenuous exercise is also associated with oxidative stress, especially in the 24 hours after an exercise session. The immune system response to damage done by exercise peaks 2 to 7 days after exercise, the period during which adaptation resulting in greater fitness is greatest. During this process, free radicals are produced by neutrophils to remove damaged tissue. As a result, excessive antioxidant levels have the potential to inhibit recovery and adaptation mechanisms.[140] The evidence for benefits from antioxidant supplementation in vigorous exercise is mixed. There is strong evidence that one of the adaptations resulting from exercise is a strengthening of the body's antioxidant defenses, particularly the glutathione system, to deal with the increased oxidative stress.[141] It is possible that this effect may be to some extent protective against diseases which are associated with oxidative stress, which would provide a partial explanation for the lower incidence of major diseases and better health of those who undertake regular exercise.[142] However, no benefits to athletes are seen with vitamin A or E supplementation.[143] For example, despite its key role in preventing lipid membrane peroxidation, 6 weeks of vitamin E supplementation had no effect on muscle damage in ultramarathon runners.[144] Although there appears to be no increased requirement for vitamin C in athletes, there is some evidence that vitamin C supplementation increased the amount of intense exercise that can be done and vitamin C supplementation before strenuous exercise may reduce the amount of muscle damage.[145][146] However, other studies found no such effects, and some research suggests that supplementation with amounts as high as 1000 mg inhibits recovery.[147] ## Adverse effects Relatively strong reducing acids can have anti-nutritional effects by binding to dietary minerals such as iron and zinc in the gastrointestinal tract and preventing them from being absorbed.[148] Notable examples are oxalic acid, tannins and phytic acid, which are high in plant-based diets.[149] Calcium and iron deficiencies are not uncommon in diets in developing countries where less meat is eaten and there is high consumption of phytic acid from beans and unleavened whole grain bread.[150] Nonpolar antioxidants such as eugenol, a major component of oil of cloves have toxicity limits that can be exceeded with the misuse of undiluted essential oils.[154] Toxicity associated with high doses of water-soluble antioxidants such as ascorbic acid are less of a concern, as these compounds can be excreted rapidly in urine.[155] More seriously, very high doses of some antioxidants may have harmful long-term effects. The beta-Carotene and Retinol Efficacy Trial (CARET) study of lung cancer patients found that smokers given supplements containing beta-carotene and vitamin A had increased rates of lung cancer.[156] Subsequent studies confirmed these adverse effects.[157] These harmful effects may also be seen in non-smokers, as a recent meta-analysis including data from approximately 230,000 patients showed that β-carotene, vitamin A or vitamin E supplementation is associated with increased mortality but saw no significant effect from vitamin C.[158] No health risk was seen when all the randomized controlled studies were examined together, but an increase in mortality was detected only when the high-quality and low-bias risk trials were examined separately. However, as the majority of these low-bias trials dealt with either elderly people, or people already suffering disease, these results may not apply to the general population.[159] This meta-analysis was later repeated and extended by the same authors, with the new analysis published by the Cochrane Collaboration; confirming the previous results.[160] These two publications are consistent with some previous meta-analyzes that also suggested that Vitamin E supplementation increased mortality,[161] and that antioxidant supplements increased the risk of colon cancer.[162] However, the results of this meta-analysis are inconsistent with other studies such as the SU.VI.MAX trial, which suggested that antioxidants have no effect on cause-all mortality.[131][163][164][165] Overall, the large number of clinical trials carried out on antioxidant supplements suggest that either these products have no effect on health, or that they cause a small increase in mortality in elderly or vulnerable populations.[133][119][158] While antioxidant supplementation is widely used in attempts to prevent the development of cancer, it has been proposed that antioxidants may, paradoxically, interfere with cancer treatments.[166] This was thought to occur since the environment of cancer cells causes high levels of oxidative stress, making these cells more susceptible to the further oxidative stress induced by treatments. As a result, by reducing the redox stress in cancer cells, antioxidant supplements were thought to decrease the effectiveness of radiotherapy and chemotherapy.[167] However, this concern appears not to be valid, as it has been addressed by multiple clinical trials that indicate that antioxidants are either neutral or beneficial in cancer therapy.[168][169] # Measurement and levels in food Measurement of antioxidants is not a straightforward process, as this is a diverse group of compounds with different reactivities to different reactive oxygen species. In food science, the oxygen radical absorbance capacity (ORAC) has become the current industry standard for assessing antioxidant strength of whole foods, juices and food additives.[170][171] Other measurement tests include the Folin-Ciocalteu reagent, and the trolox equivalent antioxidant capacity assay.[172] In medicine, a range of different assays are used to assess the antioxidant capability of blood plasma and of these, the ORAC assay may be the most reliable.[173] Antioxidants are found in varying amounts in foods such as vegetables, fruits, grain cereals, legumes and nuts. Some antioxidants such as lycopene and ascorbic acid can be destroyed by long-term storage or prolonged cooking.[174][175] Other antioxidant compounds are more stable, such as the polyphenolic antioxidants in foods such as whole-wheat cereals and tea.[176][177] In general, processed foods contain less antioxidants than fresh and uncooked foods, since the preparation processes may expose the food to oxygen.[178] Some antioxidants are made in the body and are not absorbed from the intestine. One example is glutathione, which is made from amino acids. As any glutathione in the gut is broken down to free cysteine, glycine and glutamic acid before being absorbed, even large oral doses have little effect on the concentration of glutathione in the body.[181] Ubiquinol (coenzyme Q) is also poorly absorbed from the gut and is made in humans through the mevalonate pathway.[35] # Uses in technology ## Food preservatives Antioxidants are used as food additives to help guard against food deterioration. Exposure to oxygen and sunlight are the two main factors in the oxidation of food, so food is preserved by keeping in the dark and sealing it in containers or even coating it in wax, as with cucumbers. However, as oxygen is also important for plant respiration, storing plant materials in anaerobic conditions produces unpleasant flavors and unappealing colors.[182] Consequently, packaging of fresh fruits and vegetables contains an ~8% oxygen atmosphere. Antioxidants are an especially important class of preservatives as, unlike bacterial or fungal spoilage, oxidation reactions still occur relatively rapidly in frozen or refrigerated food.[183] These preservatives include ascorbic acid (AA, E300), propyl gallate (PG, E310), tocopherols (E306), tertiary butylhydroquinone (TBHQ), butylated hydroxyanisole (BHA, E320) and butylated hydroxytoluene (BHT, E321).[184][185] The most common molecules attacked by oxidation are unsaturated fats; oxidation causes them to turn rancid.[186] Since oxidized lipids are often discolored and usually have unpleasant tastes such as metallic or sulfurous flavors, it is important to avoid oxidation in fat-rich foods. Thus, these foods are rarely preserved by drying; instead, they are preserved by smoking, salting or fermenting. Even less fatty foods such as fruits are sprayed with sulfurous antioxidants prior to air drying. Oxidation is often catalyzed by metals, which is why fats such as butter should never be wrapped in aluminium foil or kept in metal containers. Some fatty foods such as olive oil are partially protected from oxidation by their natural content of antioxidants, but remain sensitive to photooxidation.[187] ## Industrial uses Some antioxidants are added to industrial products. A common use is as stabilizers in fuels and lubricants to prevent oxidation, and in gasolines to prevent the polymerization that leads to the formation of engine-fouling residues.[188] They are also used to prevent the oxidative degradation of rubber, plastics and adhesives that causes a loss of strength and flexibility in these materials.[189] Antioxidant preservatives are also added to fat-based cosmetics such as lipstick and moisturizers to prevent rancidity.	https://www.wikidoc.org/index.php/Anti-oxidant
2c53d29ffd7f535e047f091c6c730e3511d78ffd	wikidoc	Antipyretic	Antipyretic Antipyretics are drugs that reduce body temperature in situations such as fever. However, they will not affect the normal body temperature if one does not have fever. Antipyretics cause the hypothalamus to override an interleukin-induced increase in temperature. The body will then work to lower the temperature and the result is a reduction in fever. Most are also used for other purposes. For example, the most common antipyretics in the United States are aspirin and paracetamol (acetaminophen), which are used primarily as pain relievers. NSAIDs are antipyretic, anti-inflammatory, and pain relievers. There is some debate over the appropriate use of such medications: fever is part of the body's immune response to infection. Herbal remedies with a fever-reducing effect are called febrifuges, and include catnip, chamomile, sage and yarrow. However, the term febrifuge can also refer to a refrigerant, such as topical alcohol, which cools the body by physically removing heat rather than modifying the body's responses. This is not recommended now because alcohol can be transferred through the skin and affect the liver. In addition, alcohol slightly raises the body temperature before it brings it down, which, if the fever is already very high could cause permanent damage..	Antipyretic Antipyretics are drugs that reduce body temperature in situations such as fever.[1] However, they will not affect the normal body temperature if one does not have fever. Antipyretics cause the hypothalamus to override an interleukin-induced increase in temperature. The body will then work to lower the temperature and the result is a reduction in fever. Most are also used for other purposes. For example, the most common antipyretics in the United States are aspirin and paracetamol (acetaminophen), which are used primarily as pain relievers. NSAIDs are antipyretic, anti-inflammatory, and pain relievers. There is some debate over the appropriate use of such medications: fever is part of the body's immune response to infection. Herbal remedies with a fever-reducing effect are called febrifuges, and include catnip, chamomile, sage and yarrow. However, the term febrifuge can also refer to a refrigerant, such as topical alcohol, which cools the body by physically removing heat rather than modifying the body's responses. This is not recommended now because alcohol can be transferred through the skin and affect the liver. In addition, alcohol slightly raises the body temperature before it brings it down, which, if the fever is already very high could cause permanent damage.[citation needed].	https://www.wikidoc.org/index.php/Anti-pyretic
602fff41c5df3950003db39f832a0a69d8cfd5d3	wikidoc	Antibiogram	Antibiogram # Overview An antibiogram is the result of a laboratory testing for the sensitivity of an isolated bacterial strain to different antibiotics. It is by definition an in vitro-sensitivity. In clinical practice, antibiotics are most frequently prescribed on the basis of general guidelines and knowledge about sensitivity: e.g. uncomplicated urinary tract infections can be treated with a first generation quinolone, etc. This is because Escherichia coli is the most likely causative pathogen, and it is known to be sensitive to quinolone treatment. Infections that are not acquired in the hospital, are called "community acquired" infections. However, many bacteria are known to be resistant to several classes of antibiotics, and treatment is not so straight-forward. This is especially the case in vulnerable patients, such as patients in the intensive care unit. When these patients develop a "hospital-acquired" (or "nosocomial") pneumonia, more hardy bacteria like Pseudomonas aeruginosa are potentially involved. Treatment is then generally started on the basis of surveillance data about the local pathogens probably involved. This first treatment, based on statistical information about former patients, and aimed at a large group of potentially involved microbes, is called "empirical treatment". Before starting this treatment, the physician will collect a sample from a suspected contaminated compartment: a blood sample when bacteria possibly have invaded the bloodstream, a sputum sample, a urine sample,... This samples are transferred to the microbiology lab, which looks at the sample under the microscope, and tries to culture the bacteria. This can help in the diagnosis. Once a culture is established, there are two possible ways to get an antibiogram: - a semi-quantitative way based on diffusion (Kirby-Bauer method); small discs containing different antibiotics, or impregnated paper discs, are dropped in different zones of the culture in the petri dish. The antibiotic will diffuse in the area surrounding each tablet, and a disc of bacterial lysis will become visible. Since the concentration of the antibiotic was the highest at the centre, and the lowest at the edge of this zone, the diameter is suggestive for the Minimum Inhibitory Concentration (conversion of the diameter in millimeter to the MIC, in µg/ml, is based on known linear regression curves). - a quantitative way based on dilution: a dilution series of antibiotics is established (this is a series of reaction vials with progressively lower concentrations of antibiotic substance). The last vial in which no bacteria grow contains the antibiotic at the Minimal Inhibiting Concentration. Once the MIC is calculated, it can be compared to know values for a given bacterium and antibiotic: e.g. a MIC > 0,06µg/ml may be interpreted as a penicillin-resistant Streptococcus pneumoniae. Such information may be useful to the clinician, who can change the empirical treatment, to a more custom-tailored treatment that is directed only at the causative bacterium. it:Antibiogramma - Antibiogram technique video (diffusion method)	Antibiogram # Overview An antibiogram is the result of a laboratory testing for the sensitivity of an isolated bacterial strain to different antibiotics. It is by definition an in vitro-sensitivity. In clinical practice, antibiotics are most frequently prescribed on the basis of general guidelines and knowledge about sensitivity: e.g. uncomplicated urinary tract infections can be treated with a first generation quinolone, etc. This is because Escherichia coli is the most likely causative pathogen, and it is known to be sensitive to quinolone treatment. Infections that are not acquired in the hospital, are called "community acquired" infections. However, many bacteria are known to be resistant to several classes of antibiotics, and treatment is not so straight-forward. This is especially the case in vulnerable patients, such as patients in the intensive care unit. When these patients develop a "hospital-acquired" (or "nosocomial") pneumonia, more hardy bacteria like Pseudomonas aeruginosa are potentially involved. Treatment is then generally started on the basis of surveillance data about the local pathogens probably involved. This first treatment, based on statistical information about former patients, and aimed at a large group of potentially involved microbes, is called "empirical treatment". Before starting this treatment, the physician will collect a sample from a suspected contaminated compartment: a blood sample when bacteria possibly have invaded the bloodstream, a sputum sample, a urine sample,... This samples are transferred to the microbiology lab, which looks at the sample under the microscope, and tries to culture the bacteria. This can help in the diagnosis. Once a culture is established, there are two possible ways to get an antibiogram: - a semi-quantitative way based on diffusion (Kirby-Bauer method); small discs containing different antibiotics, or impregnated paper discs, are dropped in different zones of the culture in the petri dish. The antibiotic will diffuse in the area surrounding each tablet, and a disc of bacterial lysis will become visible. Since the concentration of the antibiotic was the highest at the centre, and the lowest at the edge of this zone, the diameter is suggestive for the Minimum Inhibitory Concentration (conversion of the diameter in millimeter to the MIC, in µg/ml, is based on known linear regression curves). - a quantitative way based on dilution: a dilution series of antibiotics is established (this is a series of reaction vials with progressively lower concentrations of antibiotic substance). The last vial in which no bacteria grow contains the antibiotic at the Minimal Inhibiting Concentration. Once the MIC is calculated, it can be compared to know values for a given bacterium and antibiotic: e.g. a MIC > 0,06µg/ml may be interpreted as a penicillin-resistant Streptococcus pneumoniae. Such information may be useful to the clinician, who can change the empirical treatment, to a more custom-tailored treatment that is directed only at the causative bacterium. it:Antibiogramma - Antibiogram technique video (diffusion method) Template:WH Template:WS	https://www.wikidoc.org/index.php/Antibiogram
985ffbb0d870ae23081af18b1773feb4ad5cd518	wikidoc	Antimycin A	Antimycin A Antimycin A is a chemical compound produced by streptomyces bacteria. # Uses It is the active ingredient in Fintrol(R), a chemical piscicide (fish poison) used in fisheries management and in the catfish industry. It is also used as an antibiotic. # Mechanism Antimycin A functions by inhibiting the oxidation of ubiquinol in the electron transport chain, ultimately preventing the formation of ATP. More specifically, Antimycin A binds to the Qi site of Complex III (the enzyme cytochrome c oxidoreductase), in the cytochrome b subunit. The inhibition of Complex III by Antimycin A result in the formation of large quantities of the toxic free radical, Superoxide. It has also been found to inhibit the cyclic electron flow within photosynthetic systems along the proposed ferredoxin quinone reductase pathway. Antimycin blocks the flow of electrons from semiquinone to ubiquinone in the Q-cycle of complex III in oxidative phosphorylation. By doing so it inhibits the electron transport pathway thus preventing the consumption of oxygen (which occurs at Complex IV) and disrupting the proton gradient across the inner membrane. It is the disruption of the proton gradient that prevents the production of ATP as protons are unable to flow through the ATP synthase complex.	Antimycin A Template:Chembox new Antimycin A is a chemical compound produced by streptomyces bacteria. # Uses It is the active ingredient in Fintrol(R), a chemical piscicide (fish poison) used in fisheries management and in the catfish industry. It is also used as an antibiotic. # Mechanism Antimycin A functions by inhibiting the oxidation of ubiquinol in the electron transport chain, ultimately preventing the formation of ATP. More specifically, Antimycin A binds to the Qi site of Complex III (the enzyme cytochrome c oxidoreductase), in the cytochrome b subunit. The inhibition of Complex III by Antimycin A result in the formation of large quantities of the toxic free radical, Superoxide. It has also been found to inhibit the cyclic electron flow within photosynthetic systems along the proposed ferredoxin quinone reductase pathway. Antimycin blocks the flow of electrons from semiquinone to ubiquinone in the Q-cycle of complex III in oxidative phosphorylation. By doing so it inhibits the electron transport pathway thus preventing the consumption of oxygen (which occurs at Complex IV) and disrupting the proton gradient across the inner membrane. It is the disruption of the proton gradient that prevents the production of ATP as protons are unable to flow through the ATP synthase complex. # External links de:Antimycin A Template:WH Template:WS	https://www.wikidoc.org/index.php/Antimycin_A
def5432eff22711815e144b83f9bfbb44af8fcd8	wikidoc	Antlophobia	Antlophobia # Overview Antlophobia is a specific phobia—an irrational fear of floods. The term comes from the Greek word antlia, meaning "pump", and phobos, meaning "fear". Antlophobic people usually fear the power of floods that can cause property damage or loss of life. # Causes Antlophobia develops from past traumatic experiences with floods; either personal experiences or through knowing survivors of a flood. # Symptoms and treatment People who are severely antlophobic may feel anxious, be filled with dread, or have panic attacks. Mild sufferers may have shakiness, breathlessness, irregular heartbeat, discomfort, etc. As with other specific phobias, antlophobia is treated through psychotherapy, talk therapy, support groups, cognitive-behavioral therapy, exposure therapy, and for severe sufferers anti-anxiety medication.	Antlophobia Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview Antlophobia is a specific phobia—an irrational fear of floods. The term comes from the Greek word antlia, meaning "pump", and phobos, meaning "fear". Antlophobic people usually fear the power of floods that can cause property damage or loss of life.[1] # Causes Antlophobia develops from past traumatic experiences with floods; either personal experiences or through knowing survivors of a flood.[1] # Symptoms and treatment People who are severely antlophobic may feel anxious, be filled with dread, or have panic attacks. Mild sufferers may have shakiness, breathlessness, irregular heartbeat, discomfort, etc.[1] As with other specific phobias, antlophobia is treated through psychotherapy, talk therapy, support groups, cognitive-behavioral therapy, exposure therapy, and for severe sufferers anti-anxiety medication.[1]	https://www.wikidoc.org/index.php/Antlophobia
db1d89023d660e9d653c1cfde7790f83ce78e53f	wikidoc	Aortic arch	Aortic arch The arch of the aorta (Transverse Aorta) begins at the level of the upper border of the second sternocostal articulation of the right side, and runs at first upward, backward, and to the left in front of the trachea; it is then directed backward on the left side of the trachea and finally passes downward on the left side of the body of the fourth thoracic vertebra, at the lower border of which it becomes continuous with the descending aorta. It thus forms two curvatures: one with its convexity upward, the other with its convexity forward and to the left. Its upper border is usually about 2.5 cm. below the superior border to the manubrium sterni. # Relations The arch of the aorta is covered anteriorly by the pleura and anterior margins of the lungs, and by the remains of the thymus. As the vessel runs backward its left side is in contact with the left lung and pleura. Passing downward on the left side of this part of the arch are four nerves; in order from before backward these are, the left phrenic, the lower of the superior cardiac branches of the left vagus, the superior cardiac branch of the left sympathetic, and the trunk of the left vagus. As the left vagus nerve crosses the arch, it gives off its recurrent branch, which hooks around below the vessel and then passes upward on its right side. The highest left intercostal vein runs obliquely upward and forward on the left side of the arch, between the phrenic and vagus nerves. On the right are the deep part of the cardiac plexus, the left recurrent nerve, the esophagus, and the thoracic duct; the trachea lies behind and to the right of the vessel. Above are the innominate, left common carotid, and left subclavian arteries, which arise from the convexity of the arch and are crossed close to their origins by the left innominate vein. Below are the bifurcation of the pulmonary artery, the left bronchus, the ligamentum arteriosum, the superficial part of the cardiac plexus, and the left recurrent nerve. The ligamentum arteriosum connects the commencement of the left pulmonary artery to the aortic arch. # Additional images - Diagram showing the origins of the main branches of the carotid arteries. - Front view of heart and lungs. - Course and distribution of the glossopharyngeal, vagus, and accessory nerves. da:Arcus aortae hr:Luk aorte	Aortic arch Template:Infobox Artery Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] The arch of the aorta (Transverse Aorta) begins at the level of the upper border of the second sternocostal articulation of the right side, and runs at first upward, backward, and to the left in front of the trachea; it is then directed backward on the left side of the trachea and finally passes downward on the left side of the body of the fourth thoracic vertebra, at the lower border of which it becomes continuous with the descending aorta. It thus forms two curvatures: one with its convexity upward, the other with its convexity forward and to the left. Its upper border is usually about 2.5 cm. below the superior border to the manubrium sterni. # Relations The arch of the aorta is covered anteriorly by the pleura and anterior margins of the lungs, and by the remains of the thymus. As the vessel runs backward its left side is in contact with the left lung and pleura. Passing downward on the left side of this part of the arch are four nerves; in order from before backward these are, the left phrenic, the lower of the superior cardiac branches of the left vagus, the superior cardiac branch of the left sympathetic, and the trunk of the left vagus. As the left vagus nerve crosses the arch, it gives off its recurrent branch, which hooks around below the vessel and then passes upward on its right side. The highest left intercostal vein runs obliquely upward and forward on the left side of the arch, between the phrenic and vagus nerves. On the right are the deep part of the cardiac plexus, the left recurrent nerve, the esophagus, and the thoracic duct; the trachea lies behind and to the right of the vessel. Above are the innominate, left common carotid, and left subclavian arteries, which arise from the convexity of the arch and are crossed close to their origins by the left innominate vein. Below are the bifurcation of the pulmonary artery, the left bronchus, the ligamentum arteriosum, the superficial part of the cardiac plexus, and the left recurrent nerve. The ligamentum arteriosum connects the commencement of the left pulmonary artery to the aortic arch. # Additional images - Diagram showing the origins of the main branches of the carotid arteries. - Front view of heart and lungs. - Course and distribution of the glossopharyngeal, vagus, and accessory nerves. Template:Gray's Template:Arteries of chest da:Arcus aortae hr:Luk aorte Template:WikiDoc Sources	https://www.wikidoc.org/index.php/Aortic_arch
28ea2d3aca3976b9b63ace0a08b4e0375d2a4a3d	wikidoc	Aortic body	Aortic body In the human heart, the aortic body is one of several small cluster of chemoreceptors, baroreceptors, and supporting cells located along the aortic arch. # Function It measures changes in blood pressure and the composition of arterial blood flowing past it, including the partial pressures of oxygen and carbon dioxide but not pH. The chemoreceptors responsible for sensing changes in blood gases are called glomus cells. It gives feedback to the medulla oblongata via the afferent branches of the vagus nerve (X). The medulla, in turn, regulates breathing and blood pressure. # Disorders A paraganglioma is a tumor that may involve the aortic body. Swelling can also occur. # Nomenclature Some sources equate the "aortic bodies" and "paraaortic bodies", while other sources explicitly distinguish between the two. When a distinction is made, the "aortic bodies" are chemoreceptors which regulate circulation, while the "paraaortic bodies" are the chromaffin cells which manufacture catecholamines.	Aortic body Template:Infobox Anatomy Template:WikiDoc Cardiology News Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] In the human heart, the aortic body is one of several small cluster of chemoreceptors, baroreceptors, and supporting cells located along the aortic arch. # Function It measures changes in blood pressure and the composition of arterial blood flowing past it, including the partial pressures of oxygen and carbon dioxide but not pH. The chemoreceptors responsible for sensing changes in blood gases are called glomus cells. It gives feedback to the medulla oblongata via the afferent branches of the vagus nerve (X). The medulla, in turn, regulates breathing and blood pressure. # Disorders A paraganglioma is a tumor that may involve the aortic body. Swelling can also occur. # Nomenclature Some sources equate the "aortic bodies" and "paraaortic bodies",[1] while other sources explicitly distinguish between the two.[2][3] When a distinction is made, the "aortic bodies" are chemoreceptors which regulate circulation, while the "paraaortic bodies" are the chromaffin cells which manufacture catecholamines.	https://www.wikidoc.org/index.php/Aortic_bodies
fc292d8d5553e1522c01957f2dc46b212baf1183	wikidoc	Aortography	Aortography # Ascending Aortography The ascending aorta is best visualized in the 45 degrees LAO, 0 degrees cranial or causal projection. This view of the aortic root optimizes the evaluation of aortic insufficiency. Placement of the catheter in the ascending aorta prior to the great vessels demonstrates the aortic arch and the origin of the vessels which is useful in planing the approach prior to percutaneous revascularization of these vessels. Dissection of the ascending aorta as well as some visualization of anomalous coronary origins. Some operators prefer to engage saphenous bypass grafts in this projection. The RAO projection is optimal for left ventriculography (30 degrees RAO and 0 degrees cranial) and visualization of saphenous grafts. ## Technique A 4-6 F pigtail catheter is generally used to perform aortography. However, any non-end hole catheter may be used to perform the procedure. End hole catheters may risk aortic dissection or aortic valve damage during power injection. For aortic insufficiency quantification and bypass/anomalous vessel origination, the catheter is placed in the aortic root approximately 2 cm above the aortic valve. To delineate the great vessels, the catheter is placed proximal to the origin of the innominate artery. To optimize the origins of the vessels, the amount of LAO angulation is adjusted to maximize the elongation of the arch and the vessels. ## Settings Optimal aortography requires the use of a power injector to adequately opacify and fill the aorta. Adjustable settings on the power injector include pressure and flow rates, volume, rate of pressure rise. Each patient may require slight variation in the settings based on the size of the root and the presence of any aneurysmal dilatation or insufficiency, catheter type and patient size. Generally, 20-25 ml/sec for 40-50 cc will be sufficient to image a normal aorta. A rate of rise of 0.4 cc/sec should prevent forward lunging of the catheter. The pressure rate setting is typically 600 psi for a 6 F, 900 psi for a 5 F system and 1200 psi for a 4F system. Careful attention is required to remove air from the injector system prior to use to prevent catastrophic air embolism during aortograpahy. # Quantification of Aortic Insufficiency The pigtail catheter is placed a few centimeters above the aortic root. Grading the amount of aortic regurgitation is based on the amount of opacification of the ventricle 2 complete cardiac cycles after injection compared to that of the aortic root. ## Normal (No Regurgitation) There is no sign of ventricular opacification during and after contrast injection to aortic root. ## Grade 1 Brief and incomplete ventricular opacification. Clears rapidly. ## Grade 2 Moderate opacification of the ventricle that clears in less that 2 cycles. Never greater than aortic root opacification. Video below shows grade 2 aortic insufficiency in patient with marfan syndrome. ## Grade 3 Opacification of the ventricle equal to aortic root opacification within 2 cycles. Delayed clearing of ventricle over several cycles. ## Grade 4 Opacification of the ventricle almost immediately that is greater than that of the aortic root with delayed clearing of the ventricle. # Additional Reading - Braunwald's Heart Disease, Libby P, 8th ed., 2007, ISBN 978-1-41-604105-4 - Hurst's the Heart, Fuster V, 12th ed. 2008, ISBN 978-0-07-149928-6 - Willerson JT, Cardiovascular Medicine, 3rd ed., 2007, ISBN 978-1-84628-188-4 # Related Chapters - Aortic insufficiency - Aortic stenosis - Aorta	Aortography Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor-In-Chief: Cafer Zorkun, M.D., Ph.D. [2] # Ascending Aortography The ascending aorta is best visualized in the 45 degrees LAO, 0 degrees cranial or causal projection. This view of the aortic root optimizes the evaluation of aortic insufficiency. Placement of the catheter in the ascending aorta prior to the great vessels demonstrates the aortic arch and the origin of the vessels which is useful in planing the approach prior to percutaneous revascularization of these vessels. Dissection of the ascending aorta as well as some visualization of anomalous coronary origins. Some operators prefer to engage saphenous bypass grafts in this projection. The RAO projection is optimal for left ventriculography (30 degrees RAO and 0 degrees cranial) and visualization of saphenous grafts. ## Technique A 4-6 F pigtail catheter is generally used to perform aortography. However, any non-end hole catheter may be used to perform the procedure. End hole catheters may risk aortic dissection or aortic valve damage during power injection. For aortic insufficiency quantification and bypass/anomalous vessel origination, the catheter is placed in the aortic root approximately 2 cm above the aortic valve. To delineate the great vessels, the catheter is placed proximal to the origin of the innominate artery. To optimize the origins of the vessels, the amount of LAO angulation is adjusted to maximize the elongation of the arch and the vessels. ## Settings Optimal aortography requires the use of a power injector to adequately opacify and fill the aorta. Adjustable settings on the power injector include pressure and flow rates, volume, rate of pressure rise. Each patient may require slight variation in the settings based on the size of the root and the presence of any aneurysmal dilatation or insufficiency, catheter type and patient size. Generally, 20-25 ml/sec for 40-50 cc will be sufficient to image a normal aorta. A rate of rise of 0.4 cc/sec should prevent forward lunging of the catheter. The pressure rate setting is typically 600 psi for a 6 F, 900 psi for a 5 F system and 1200 psi for a 4F system. Careful attention is required to remove air from the injector system prior to use to prevent catastrophic air embolism during aortograpahy. # Quantification of Aortic Insufficiency The pigtail catheter is placed a few centimeters above the aortic root. Grading the amount of aortic regurgitation is based on the amount of opacification of the ventricle 2 complete cardiac cycles after injection compared to that of the aortic root. ## Normal (No Regurgitation) There is no sign of ventricular opacification during and after contrast injection to aortic root. ## Grade 1 Brief and incomplete ventricular opacification. Clears rapidly. ## Grade 2 Moderate opacification of the ventricle that clears in less that 2 cycles. Never greater than aortic root opacification. Video below shows grade 2 aortic insufficiency in patient with marfan syndrome. ## Grade 3 Opacification of the ventricle equal to aortic root opacification within 2 cycles. Delayed clearing of ventricle over several cycles. ## Grade 4 Opacification of the ventricle almost immediately that is greater than that of the aortic root with delayed clearing of the ventricle. # Additional Reading - Braunwald's Heart Disease, Libby P, 8th ed., 2007, ISBN 978-1-41-604105-4 - Hurst's the Heart, Fuster V, 12th ed. 2008, ISBN 978-0-07-149928-6 - Willerson JT, Cardiovascular Medicine, 3rd ed., 2007, ISBN 978-1-84628-188-4 # Related Chapters - Aortic insufficiency - Aortic stenosis - Aorta # External links - Clinical Trial Results: An up to dated resource of Cardiovascular Research	https://www.wikidoc.org/index.php/Aortogram
52ebd703c215945e3d8d02f6e3889a8c1868bfaa	wikidoc	Apalutamide	Apalutamide # Disclaimer WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here. # Overview Apalutamide is an androgen receptor inhibitor that is FDA approved for the treatment of non-metastatic castration-resistant prostate cancer. Common adverse reactions include fatigue, hypertension, rash, diarrhea, nausea, weight decreased, arthralgia, fall, hot flush, decreased appetite, fracture, and peripheral edema. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - For the treatment of patients with non-metastatic, castration-resistant prostate cancer (NM-CRPC). - The recommended dose of ERLEADA is 240 mg (four 60 mg tablets) administered orally once daily. Swallow the tablets whole. ERLEADA can be taken with or without food. - Patients should also receive a gonadotropin-releasing hormone (GnRH) analog concurrently or should have had a bilateral orchiectomy. ### Dose Modification - If a patient experiences a greater than or equal to Grade 3 toxicity or an intolerable side effect, hold dosing until symptoms improve to less than or equal to Grade 1 or original grade, then resume at the same dose or a reduced dose (180 mg or 120 mg), if warranted. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding apalutamide Off-Label Guideline-Supported Use and Dosage (Adult) in the drug label. ### Non–Guideline-Supported Use There is limited information regarding apalutamide Off-Label Non-Guideline-Supported Use and Dosage (Adult) in the drug label. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) There is limited information regarding Apalutamide FDA-Labeled Indications and Dosage (Pediatric) in the drug label. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding apalutamide Off-Label Guideline-Supported Use and Dosage (Pediatric) in the drug label. ### Non–Guideline-Supported Use There is limited information regarding apalutamide Off-Label Non-Guideline-Supported Use and Dosage (Pediatric) in the drug label. # Contraindications ### Pregnancy - Apalutamide can cause fetal harm and potential loss of pregnancy. # Warnings - Falls and fractures occurred in patients receiving apalutamide. Evaluate patients for fracture and fall risk. Monitor and manage patients at risk for fractures according to established treatment guidelines and consider use of bone targeted agents. - In a randomized study (SPARTAN), falls occurred in 16% of patients treated with apalutamide compared to 9% of patients treated with placebo. Falls were not associated with loss of consciousness or seizure. Fractures occurred in 12% of patients treated with apalutamide and in 7% of patients treated with placebo. Grade 3–4 fractures occurred in 3% of patients treated with apalutamide and in 1% of patients treated with placebo. The median time to onset of fracture was 314 days (range: 20 to 953 days) for patients treated with apalutamide. Routine bone density assessment and treatment of osteoporosis with bone targeted agents were not performed in the SPARTAN study. - Seizure occurred in patients receiving apalutamide. Permanently discontinue apalutamide in patients who develop a seizure during treatment. It is unknown whether anti-epileptic medications will prevent seizures with apalutamide. Advise patients of the risk of developing a seizure while receiving apalutamide and of engaging in any activity where sudden loss of consciousness could cause harm to themselves or others. - In a randomized study (SPARTAN), two patients (0.2%) treated with apalutamide experienced a seizure. Seizure occurred from 354 to 475 days after initiation of apalutamide. No seizures occurred in patients treated with placebo. Patients with a history of seizure, predisposing factors for seizure, or receiving drugs known to decrease the seizure threshold or to induce seizure were excluded. There is no clinical experience in re-administering apalutamide to patients who experienced a seizure. # Adverse Reactions ## Clinical Trials Experience - Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. - SPARTAN, a randomized (2:1), double-blind, placebo-controlled, multi-center clinical study, enrolled patients who had non-metastatic, castration-resistant prostate cancer (NM-CRPC). In this study, patients received either apalutamide at a dose of 240 mg daily or a placebo. All patients in the SPARTAN study received a concomitant gonadotropin-releasing hormone (GnRH) analog or had a bilateral orchiectomy. The median duration of exposure was 16.9 months (range: 0.1 to 42 months) in patients who received apalutamide and 11.2 months (range: 0.1 to 37 months) in patients who received placebo. - Overall, 8 patients (1%) who were treated with apalutamide died from adverse reactions. The reasons for death were infection (n=4), myocardial infarction (n=3), and cerebral hemorrhage (n=1). One patient (0.3%) treated with placebo died from an adverse reaction of cardiopulmonary arrest (n=1). Apalutamide was discontinued due to adverse reactions in 11% of patients, most commonly from rash (3%). Adverse reactions leading to dose interruption or reduction of apalutamide occurred in 33% of patients; the most common (>1%) were rash, diarrhea, fatigue, nausea, vomiting, hypertension, and hematuria. Serious adverse reactions occurred in 25% of apalutamide-treated patients and 23% in patients receiving placebo. The most common serious adverse reactions (>2%) were fracture (3%) in the apalutamide arm and urinary retention (4%) in the placebo arm. - Table 1 shows adverse reactions occurring in ≥10% on the apalutamide arm in SPARTAN that occurred with a 2% absolute increase in frequency compared to placebo. Table 2 shows laboratory abnormalities that occurred in ≥15% of patients, and more frequently (>5%) in the apalutamide arm compared to placebo. - Additional clinically significant adverse reactions occurring in 2% or more of patients treated with apalutamide included hypothyroidism (8.1% versus 2% on placebo), pruritus (6.2% versus 2% on placebo), ischemic heart disease (3.7% versus 2% on placebo), and heart failure (2.2% versus 1% on placebo). ### Rash - In SPARTAN, rash associated with apalutamide was most commonly described as macular or maculo-papular. Adverse reactions of rash were reported for 24% of patients treated with apalutamide versus 6% of patients treated with placebo. Grade 3 rashes (defined as covering > 30% body surface area ) were reported with apalutamide treatment (5%) versus placebo (0.3%). - The onset of rash occurred at a median of 82 days of apalutamide treatment. Rash resolved in 81% of patients within a median of 60 days (range: 2 to 709 days) from onset of rash. Four (4%) of patients treated with apalutamide received systemic corticosteroids for treatment of rash. Rash recurred in approximately half of patients who were re-challenged with apalutamide. ### Hypothyroidism - Hypothyroidism was reported for 8% of patients treated with apalutamide and 2% of patients treated with placebo based on assessments of thyroid-stimulating hormone (TSH) every 4 months. Elevated TSH occurred in 25% of patients treated with apalutamide and 7% of patients treated with placebo. The median onset was Day 113. There were no Grade 3 or 4 adverse reactions. Thyroid replacement therapy was initiated in 7% of patients treated with apalutamide. Thyroid replacement therapy, when clinically indicated, should be initiated or dose-adjusted. ## Postmarketing Experience There is limited information regarding Apalutamide Postmarketing Experience in the drug label. # Drug Interactions - Strong CYP2C8 or CYP3A4 Inhibitors - CYP3A4, CYP2C9, CYP2C19 and UGT Substrates - P-gp, BCRP or OATP1B1 Substrates ### Effect of Other Drugs on apalutamide Strong CYP2C8 or CYP3A4 Inhibitors - Co-administration of a strong CYP2C8 or CYP3A4 inhibitor is predicted to increase the steady-state exposure of the active moieties (sum of unbound apalutamide plus the potency-adjusted unbound N-desmethyl-apalutamide). No initial dose adjustment is necessary however, reduce the apalutamide dose based on tolerability. Mild or moderate inhibitors of CYP2C8 or CYP3A4 are not expected to affect the exposure of apalutamide. ### Effect of apalutamide on Other Drugs CYP3A4, CYP2C9, CYP2C19 and UGT Substrates - Apalutamide is a strong inducer of CYP3A4 and CYP2C19, and a weak inducer of CYP2C9 in humans. Concomitant use of apalutamide with medications that are primarily metabolized by CYP3A4, CYP2C19, or CYP2C9 can result in lower exposure to these medications. Substitution for these medications is recommended when possible or evaluate for loss of activity if medication is continued. Concomitant administration of apalutamide with medications that are substrates of UDP-glucuronosyl transferase (UGT) can result in decreased exposure. Use caution if substrates of UGT must be co-administered with apalutamide and evaluate for loss of activity. P-gp, BCRP or OATP1B1 Substrates - Apalutamide was shown to be a weak inducer of P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), and organic anion transporting polypeptide 1B1 (OATP1B1) clinically. At steady-state, apalutamide reduced the plasma exposure to fexofenadine (a P-gp substrate) and rosuvastatin (a BCRP/OATP1B1 substrate). Concomitant use of apalutamide with medications that are substrates of P-gp, BCRP, or OATP1B1 can result in lower exposure of these medications. Use caution if substrates of P-gp, BCRP or OATP1B1 must be co-administered with apalutamide and evaluate for loss of activity if medication is continued. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): - Apalutamide is contraindicated for use in pregnant women because the drug can cause fetal harm and potential loss of pregnancy. Apalutamide is not indicated for use in females, so animal embryo-fetal developmental toxicology studies were not conducted with apalutamide. There are no human data on the use of apalutamide in pregnant women. Based on its mechanism of action, apalutamide may cause fetal harm when administered during pregnancy. Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Apalutamide in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Apalutamide during labor and delivery. ### Nursing Mothers - Apalutamide is not indicated for use in females. There are no data on the presence of apalutamide or its metabolites in human milk, the effect on the breastfed child, or the effect on milk production. ### Pediatric Use - Safety and effectiveness of apalutamide in pediatric patients have not been established. ### Geriatic Use - Of the 803 patients who received apalutamide in SPARTAN, 87% of patients were 65 years and over and 49% were 75 years and over. Grade 3–4 adverse reactions occurred in 46% (323/697) of patients 65 years or older and in 51% (197/391) of patients 75 years or older treated with apalutamide compared to 35% (124/355) of patients 65 years or older and 37% (70/187) of patients 75 years or older treated with placebo. No overall differences in effectiveness were observed between these patients and younger patients. ### Gender There is no FDA guidance on the use of Apalutamide with respect to specific gender populations. ### Race There is no FDA guidance on the use of Apalutamide with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Apalutamide in patients with renal impairment. ### Hepatic Impairment There is no FDA guidance on the use of Apalutamide in patients with hepatic impairment. ### Females of Reproductive Potential and Males Contraception (Males) - Based on the mechanism of action and findings in an animal reproduction study, advise male patients with female partners of reproductive potential to use effective contraception during treatment and for 3 months after the last dose of apalutamide. Infertility (Males) - Based on animal studies, apalutamide may impair fertility in males of reproductive potential. ### Immunocompromised Patients There is no FDA guidance one the use of Apalutamide in patients who are immunocompromised. # Administration and Monitoring ### Administration - May be given with or without food. ### Monitoring - Prolongation in the time to PSA progression and the time to symptomatic disease progression may indicate efficacy. - Fracture and fall risk: Evaluate for risk and monitor during therapy. # IV Compatibility There is limited information regarding the compatibility of Apalutamide and IV administrations. # Overdosage - There is no known specific antidote for apalutamide overdose. In the event of an overdose, stop apalutamide, undertake general supportive measures until clinical toxicity has been diminished or resolved. # Pharmacology ## Mechanism of Action - Apalutamide is an Androgen Receptor (AR) inhibitor that binds directly to the ligand-binding domain of the AR. Apalutamide inhibits AR nuclear translocation, inhibits DNA binding, and impedes AR-mediated transcription. A major metabolite, N-desmethyl apalutamide, is a less potent inhibitor of AR, and exhibited one-third the activity of apalutamide in an in vitro transcriptional reporter assay. Apalutamide administration caused decreased tumor cell proliferation and increased apoptosis leading to decreased tumor volume in mouse xenograft models of prostate cancer. ## Structure ## Pharmacodynamics ### Cardiac Electrophysiology - The effect of apalutamide 240 mg once daily on the QTc interval was assessed in an open-label, uncontrolled, multi-center, single-arm dedicated QT study in 45 patients with CRPC. The maximum mean QTcF change from baseline was 12.4 ms (2-sided 90% upper CI: 16.0 ms). An exposure-QT analysis suggested a concentration-dependent increase in QTcF for apalutamide and its active metabolite. ## Pharmacokinetics - Apalutamide pharmacokinetic parameters are presented as the mean unless otherwise specified. Apalutamide Cmax and area under the concentration curve (AUC) increased proportionally following repeated once-daily dosing of 30 to 480 mg (0.125 to 2 times the recommended dosage). Following administration of the recommended dosage, apalutamide steady-state was achieved after 4 weeks and the mean accumulation ratio was approximately 5-fold. Apalutamide Cmax was 6.0 mcg/mL (1.7) and AUC was 100 mcg∙h/mL (32) at steady-state. Daily fluctuations in apalutamide plasma concentrations were low, with mean peak-to-trough ratio of 1.63. An increase in apparent clearance (CL/F) was observed with repeat dosing, likely due to induction of apalutamide's own metabolism. The auto-induction effect likely reached its maximum at the recommended dosage because exposure of apalutamide across the dose range of 30 to 480 mg is dose-proportional. - The major active metabolite N-desmethyl apalutamide Cmax was 5.9 mcg/mL (1.0) and AUC was 124 mcg∙h/mL (23) at steady-state after the recommended dosage. N-desmethyl apalutamide was characterized by a flat concentration-time profile at steady-state with a mean peak-to-trough ratio of 1.27. Mean AUC metabolite/parent drug ratio for N-desmethyl apalutamide following repeat-dose administration was 1.3. Based on systemic exposure, relative potency, and pharmacokinetic properties, N-desmethyl apalutamide likely contributed to the clinical activity of apalutamide. ### Absorption - Mean absolute oral bioavailability was approximately 100%. Median time to achieve peak plasma concentration (tmax) was 2 hours (range: 1 to 5 hours). Effect of Food - Administration of apalutamide to healthy subjects under fasting conditions and with a high-fat meal (approximately 500 to 600 fat calories, 250 carbohydrate calories, and 150 protein calories) resulted in no clinically relevant changes in Cmax and AUC. Median time to reach tmax was delayed approximately 2 hours with food. ### Distribution - The mean apparent volume of distribution at steady-state of apalutamide was approximately 276 L. - Apalutamide was 96% and N-desmethyl apalutamide was 95% bound to plasma proteins with no concentration dependency. ### Elimination - The CL/F of apalutamide was 1.3 L/h after single dosing and increased to 2.0 L/h at steady-state after once-daily dosing likely due to CYP3A4 auto-induction. The mean effective half-life for apalutamide in patients was approximately 3 days at steady-state. ### Metabolism - Metabolism is the main route of elimination of apalutamide. Apalutamide is primarily metabolized by CYP2C8 and CYP3A4 to form active metabolite, N-desmethyl apalutamide. The contribution of CYP2C8 and CYP3A4 in the metabolism of apalutamide is estimated to be 58% and 13% following single dose but changes to 40% and 37%, respectively at steady-state. - Apalutamide represented 45% and N-desmethyl apalutamide represented 44% of the total AUC following a single oral administration of radiolabeled apalutamide 240 mg. ### Excretion - Up to 70 days following a single oral administration of radiolabeled apalutamide, 65% of the dose was recovered in urine (1.2% of dose as unchanged apalutamide and 2.7% as N-desmethyl apalutamide) and 24% was recovered in feces (1.5% of dose as unchanged apalutamide and 2% as N-desmethyl apalutamide). ### Specific Populations - No clinically significant differences in the pharmacokinetics of apalutamide or N-desmethyl apalutamide were observed based on age (18–94 years), race (Black, non-Japanese Asian, Japanese), mild to moderate (eGFR 30–89 mL/min/1.73m2, estimated by the modification of diet in renal disease equation) renal impairment, or mild (Child-Pugh A) to moderate (Child-Pugh B) hepatic impairment. - The effect of severe renal impairment or end stage renal disease (eGFR ≤29 mL/min/1.73m2, MDRD) or severe hepatic impairment (Child-Pugh C) on apalutamide pharmacokinetics is unknown. ### Drug Interactions Strong CYP2C8 inhibitors - Apalutamide Cmax decreased by 21% while AUC increased by 68% following co-administration of apalutamide as a 240 mg single dose with gemfibrozil (a strong CYP2C8 inhibitor). Gemfibrozil is predicted to increase the steady-state apalutamide Cmax by 32% and AUC by 44%. For the active moieties (sum of unbound apalutamide plus the potency-adjusted unbound N-desmethyl apalutamide), the predicted steady-state Cmax increased by 19% and AUC by 23%. Strong CYP3A4 inhibitors - Apalutamide Cmax decreased by 22% while AUC was similar following co-administration of apalutamide as a 240 mg single dose with itraconazole (a strong CYP3A4 inhibitor). Ketoconazole (a strong CYP3A4 inhibitor) is predicted to increase the single-dose apalutamide AUC by 24% but have no impact on Cmax. Ketoconazole is predicted to increase the steady-state apalutamide Cmax by 38% and AUC by 51%. For the active moieties, the predicted steady-state Cmax increased by 23% and AUC by 28%. CYP3A4/CYP2C8 inducers - Rifampin (a strong CYP3A4 and moderate CYP2C8 inducer) is predicted to decrease the steady-state apalutamide Cmax by 25% and AUC by 34%. For the active moieties, the predicted steady-state Cmax decreased by 15% and AUC by 19%. Acid lowering agents - Apalutamide is not ionizable under relevant physiological pH condition, therefore acid lowering agents (e.g. proton pump inhibitor, H2-receptor antagonist, antacid) are not expected to affect the solubility and bioavailability of apalutamide. Drugs affecting transporters - In vitro, apalutamide and N-desmethyl apalutamide are substrates for P-gp but not BCRP, OATP1B1, and OATP1B3. Because apalutamide is completely absorbed after oral administration, P-gp does not limit the absorption of apalutamide and therefore, inhibition or induction of P-gp is not expected to affect the bioavailability of apalutamide. CYP substrates - In vitro studies showed that apalutamide and N-desmethyl apalutamide are moderate to strong CYP3A4 and CYP2B6 inducers, are moderate inhibitors of CYP2B6 and CYP2C8, and weak inhibitors of CYP2C9, CYP2C19, and CYP3A4. Apalutamide and N-desmethyl apalutamide do not affect CYP1A2 and CYP2D6 at therapeutically relevant concentrations. - Co-administration of apalutamide with single oral doses of sensitive CYP substrates resulted in a 92% decrease in the AUC of midazolam (a CYP3A4 substrate), 85% decrease in the AUC of omeprazole (a CYP2C19 substrate), and 46% decrease in the AUC of S-warfarin (a CYP2C9 substrate). Apalutamide did not cause clinically significant changes in exposure to a CYP2C8 substrate. P-gp, BCRP and OATP1B1 substrates - Co-administration of apalutamide with single oral doses of transporter substrates resulted in a 30% decrease in the AUC of fexofenadine (a P-gp substrate) and 41% decrease in the AUC of rosuvastatin (a BCRP/OATP1B1 substrate) but had no impact on Cmax. GT substrates - Apalutamide may induce UGT. Concomitant administration of apalutamide with medications that are substrates of UGT may result in lower exposure to these medications. OCT2, OAT1, OAT3 and MATEs substrates - In vitro, apalutamide and N-desmethyl apalutamide inhibit organic cation transporter 2 (OCT2), organic anion transporter 3 (OAT3) and multidrug and toxin extrusions (MATEs), and do not inhibit organic anion transporter 1. Apalutamide is not predicted to cause clinically significant changes in exposure to an OAT3 substrate. ## Nonclinical Toxicology ### Carcinogenesis, Mutagenesis, Impairment of Fertility - Long-term animal studies have not been conducted to evaluate the carcinogenic potential of apalutamide. Apalutamide did not induce mutations in the bacterial reverse mutation (Ames) assay and was not genotoxic in either in vitro chromosome aberration assay or the in vivo rat bone marrow micronucleus assay or the in vivo rat Comet assay. - In repeat-dose toxicity studies in male rats (up to 26 weeks) and dogs (up to 39 weeks), atrophy of the prostate gland and seminal vesicles, aspermia/hypospermia, tubular degeneration and/or hyperplasia or hypertrophy of the interstitial cells in the reproductive system were observed at ≥ 25 mg/kg/day in rats (1.4 times the human exposure based on AUC) and ≥ 2.5 mg/kg/day in dogs (0.9 times the human exposure based on AUC). - In a fertility study in male rats, a decrease in sperm concentration and motility, increased abnormal sperm morphology, lower copulation and fertility rates (upon pairing with untreated females) along with reduced weights of the secondary sex glands and epididymis were observed following 4 weeks of dosing at ≥ 25 mg/kg/day (0.8 times the human exposure based on AUC). A reduced number of live fetuses due to increased pre- and/or post-implantation loss was observed following 4 weeks of 150 mg/kg/day administration (5.7 times the human exposure based on AUC). Effects on male rats were reversible after 8 weeks from the last apalutamide administration. # Clinical Studies - SPARTAN (NCT01946204) was a multicenter, double-blind, randomized (2:1), placebo-controlled clinical trial in which 1207 patients with NM-CRPC were randomized (2:1) to receive either apalutamide orally at a dose of 240 mg once daily (N = 806) or placebo once daily (N = 401). All patients in the SPARTAN trial received a concomitant gonadotropin-releasing hormone (GnRH) analog or had a bilateral orchiectomy. Patients were stratified by Prostate Specific Antigen (PSA) Doubling Time (PSADT), the use of bone-sparing agents, and locoregional disease. Patients were required to have a PSADT ≤ 10 months and confirmation of non-metastatic disease by blinded independent central review (BICR). PSA results were blinded and were not used for treatment discontinuation. Patients randomized to either arm discontinued treatment for radiographic disease progression confirmed by BICR, locoregional-only progression, initiation of new treatment, unacceptable toxicity, or withdrawal. - The following patient demographics and baseline disease characteristics were balanced between the treatment arms. The median age was 74 years (range 48–97) and 26% of patients were 80 years of age or older. The racial distribution was 66% Caucasian, 12% Asian, and 6% Black. Seventy-seven percent (77%) of patients in both treatment arms had prior surgery or radiotherapy of the prostate. A majority of patients had a Gleason score of 7 or higher (78%). Fifteen percent (15%) of patients had <2 cm pelvic lymph nodes at study entry. Seventy-three percent (73%) of patients received prior treatment with an anti-androgen; 69% of patients received bicalutamide and 10% of patients received flutamide. All patients had an Eastern Cooperative Oncology Group Performance Status (ECOG PS) score of 0 or 1 at study entry. Among the patients who discontinued study treatment (N = 279 for placebo and N = 314 for apalutamide), a greater proportion (80%) of patients treated with placebo received subsequent therapy compared to patients treated with apalutamide (56%). Locoregional-only progression occurred in 2% of patients overall. - The major efficacy outcome measure of the study was metastasis-free survival (MFS), defined as the time from randomization to the time of first evidence of BICR-confirmed distant metastasis, defined as new bone or soft tissue lesions or enlarged lymph nodes above the iliac bifurcation, or death due to any cause, whichever occurred first. Additional efficacy endpoints were time to metastasis (TTM), progression-free survival (PFS) which also includes locoregional progression, time to symptomatic progression, and overall survival (OS). - A statistically significant improvement in MFS was demonstrated in patients randomized to receive apalutamide compared with patients randomized to receive placebo. Consistent results were observed across patient subgroups including PSADT (≤ 6 months or > 6 months), use of a prior bone-sparing agent (yes or no), and locoregional disease (N0 or N1). The major efficacy outcome was supported by statistically significant improvements in TTM, PFS, and time to symptomatic progression. Overall survival (OS) data were not mature at the time of final MFS analysis (24% of the required number of events). The efficacy results of MFS, TTM, and PFS from SPARTAN are summarized in Figure 1 and Table 3. # How Supplied - Apalutamide (apalutamide) 60 mg film-coated tablets are slightly yellowish to greyish green, oblong-shaped tablets debossed with "AR 60" on one side. Apalutamide 60 mg tablets are available in bottles of 120 tablets. Each bottle contains silica gel desiccant. - NDC Number is 59676-600-12 ## Storage - Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F). - Store in the original package. Do not discard desiccant. Protect from light and moisture. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information ### Falls and Fractures - Inform patients that apalutamide is associated with an increased incidence of falls and fractures. ### Seizures - Inform patients that apalutamide has been associated with an increased risk of seizure. Discuss conditions that may predispose to seizures and medications that may lower the seizure threshold. Advise patients of the risk of engaging in any activity where sudden loss of consciousness could cause serious harm to themselves or others. Inform patients to contact their healthcare provider right away if they experience a seizure. ### Rash - Inform patients that apalutamide is associated with rashes and to inform their healthcare provider if they develop a rash. ### Dosage and Administration - Inform patients receiving concomitant gonadotropin-releasing hormone (GnRH) analog therapy that they need to maintain this treatment during the course of treatment with apalutamide. - Instruct patients to take their dose at the same time each day (once daily). Apalutamide can be taken with or without food. Each tablet should be swallowed whole. - Inform patients that in the event of a missed daily dose of apalutamide, they should take their normal dose as soon as possible on the same day with a return to the normal schedule on the following day. The patient should not take extra tablets to make up the missed dose. ### Embryo-Fetal Toxicity - Inform patients that apalutamide can be harmful to a developing fetus. Advise patients having sex with female partners of reproductive potential to use effective contraception during treatment and for 3 months after the last dose of apalutamide. Advise male patients to use a condom if having sex with a pregnant woman. ### Infertility - Advise male patients that apalutamide may impair fertility and not to donate sperm during therapy and for 3 months following the last dose of apalutamide. # Precautions with Alcohol Alcohol-Apalutamide interaction has not been established. Talk to your doctor regarding the effects of taking alcohol with this medication. # Brand Names - Erleada # Look-Alike Drug Names There is limited information regarding Apalutamide Look-Alike Drug Names in the drug label. # Drug Shortage Status Drug Shortage # Price	Apalutamide Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Yashasvi Aryaputra[2], Anmol Pitliya, M.B.B.S. M.D.[3] # Disclaimer WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here. # Overview Apalutamide is an androgen receptor inhibitor that is FDA approved for the treatment of non-metastatic castration-resistant prostate cancer. Common adverse reactions include fatigue, hypertension, rash, diarrhea, nausea, weight decreased, arthralgia, fall, hot flush, decreased appetite, fracture, and peripheral edema. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - For the treatment of patients with non-metastatic, castration-resistant prostate cancer (NM-CRPC). - The recommended dose of ERLEADA is 240 mg (four 60 mg tablets) administered orally once daily. Swallow the tablets whole. ERLEADA can be taken with or without food. - Patients should also receive a gonadotropin-releasing hormone (GnRH) analog concurrently or should have had a bilateral orchiectomy. ### Dose Modification - If a patient experiences a greater than or equal to Grade 3 toxicity or an intolerable side effect, hold dosing until symptoms improve to less than or equal to Grade 1 or original grade, then resume at the same dose or a reduced dose (180 mg or 120 mg), if warranted. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding apalutamide Off-Label Guideline-Supported Use and Dosage (Adult) in the drug label. ### Non–Guideline-Supported Use There is limited information regarding apalutamide Off-Label Non-Guideline-Supported Use and Dosage (Adult) in the drug label. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) There is limited information regarding Apalutamide FDA-Labeled Indications and Dosage (Pediatric) in the drug label. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding apalutamide Off-Label Guideline-Supported Use and Dosage (Pediatric) in the drug label. ### Non–Guideline-Supported Use There is limited information regarding apalutamide Off-Label Non-Guideline-Supported Use and Dosage (Pediatric) in the drug label. # Contraindications ### Pregnancy - Apalutamide can cause fetal harm and potential loss of pregnancy. # Warnings - Falls and fractures occurred in patients receiving apalutamide. Evaluate patients for fracture and fall risk. Monitor and manage patients at risk for fractures according to established treatment guidelines and consider use of bone targeted agents. - In a randomized study (SPARTAN), falls occurred in 16% of patients treated with apalutamide compared to 9% of patients treated with placebo. Falls were not associated with loss of consciousness or seizure. Fractures occurred in 12% of patients treated with apalutamide and in 7% of patients treated with placebo. Grade 3–4 fractures occurred in 3% of patients treated with apalutamide and in 1% of patients treated with placebo. The median time to onset of fracture was 314 days (range: 20 to 953 days) for patients treated with apalutamide. Routine bone density assessment and treatment of osteoporosis with bone targeted agents were not performed in the SPARTAN study. - Seizure occurred in patients receiving apalutamide. Permanently discontinue apalutamide in patients who develop a seizure during treatment. It is unknown whether anti-epileptic medications will prevent seizures with apalutamide. Advise patients of the risk of developing a seizure while receiving apalutamide and of engaging in any activity where sudden loss of consciousness could cause harm to themselves or others. - In a randomized study (SPARTAN), two patients (0.2%) treated with apalutamide experienced a seizure. Seizure occurred from 354 to 475 days after initiation of apalutamide. No seizures occurred in patients treated with placebo. Patients with a history of seizure, predisposing factors for seizure, or receiving drugs known to decrease the seizure threshold or to induce seizure were excluded. There is no clinical experience in re-administering apalutamide to patients who experienced a seizure. # Adverse Reactions ## Clinical Trials Experience - Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. - SPARTAN, a randomized (2:1), double-blind, placebo-controlled, multi-center clinical study, enrolled patients who had non-metastatic, castration-resistant prostate cancer (NM-CRPC). In this study, patients received either apalutamide at a dose of 240 mg daily or a placebo. All patients in the SPARTAN study received a concomitant gonadotropin-releasing hormone (GnRH) analog or had a bilateral orchiectomy. The median duration of exposure was 16.9 months (range: 0.1 to 42 months) in patients who received apalutamide and 11.2 months (range: 0.1 to 37 months) in patients who received placebo. - Overall, 8 patients (1%) who were treated with apalutamide died from adverse reactions. The reasons for death were infection (n=4), myocardial infarction (n=3), and cerebral hemorrhage (n=1). One patient (0.3%) treated with placebo died from an adverse reaction of cardiopulmonary arrest (n=1). Apalutamide was discontinued due to adverse reactions in 11% of patients, most commonly from rash (3%). Adverse reactions leading to dose interruption or reduction of apalutamide occurred in 33% of patients; the most common (>1%) were rash, diarrhea, fatigue, nausea, vomiting, hypertension, and hematuria. Serious adverse reactions occurred in 25% of apalutamide-treated patients and 23% in patients receiving placebo. The most common serious adverse reactions (>2%) were fracture (3%) in the apalutamide arm and urinary retention (4%) in the placebo arm. - Table 1 shows adverse reactions occurring in ≥10% on the apalutamide arm in SPARTAN that occurred with a 2% absolute increase in frequency compared to placebo. Table 2 shows laboratory abnormalities that occurred in ≥15% of patients, and more frequently (>5%) in the apalutamide arm compared to placebo. - Additional clinically significant adverse reactions occurring in 2% or more of patients treated with apalutamide included hypothyroidism (8.1% versus 2% on placebo), pruritus (6.2% versus 2% on placebo), ischemic heart disease (3.7% versus 2% on placebo), and heart failure (2.2% versus 1% on placebo). ### Rash - In SPARTAN, rash associated with apalutamide was most commonly described as macular or maculo-papular. Adverse reactions of rash were reported for 24% of patients treated with apalutamide versus 6% of patients treated with placebo. Grade 3 rashes (defined as covering > 30% body surface area [BSA]) were reported with apalutamide treatment (5%) versus placebo (0.3%). - The onset of rash occurred at a median of 82 days of apalutamide treatment. Rash resolved in 81% of patients within a median of 60 days (range: 2 to 709 days) from onset of rash. Four (4%) of patients treated with apalutamide received systemic corticosteroids for treatment of rash. Rash recurred in approximately half of patients who were re-challenged with apalutamide. ### Hypothyroidism - Hypothyroidism was reported for 8% of patients treated with apalutamide and 2% of patients treated with placebo based on assessments of thyroid-stimulating hormone (TSH) every 4 months. Elevated TSH occurred in 25% of patients treated with apalutamide and 7% of patients treated with placebo. The median onset was Day 113. There were no Grade 3 or 4 adverse reactions. Thyroid replacement therapy was initiated in 7% of patients treated with apalutamide. Thyroid replacement therapy, when clinically indicated, should be initiated or dose-adjusted. ## Postmarketing Experience There is limited information regarding Apalutamide Postmarketing Experience in the drug label. # Drug Interactions - Strong CYP2C8 or CYP3A4 Inhibitors - CYP3A4, CYP2C9, CYP2C19 and UGT Substrates - P-gp, BCRP or OATP1B1 Substrates ### Effect of Other Drugs on apalutamide Strong CYP2C8 or CYP3A4 Inhibitors - Co-administration of a strong CYP2C8 or CYP3A4 inhibitor is predicted to increase the steady-state exposure of the active moieties (sum of unbound apalutamide plus the potency-adjusted unbound N-desmethyl-apalutamide). No initial dose adjustment is necessary however, reduce the apalutamide dose based on tolerability. Mild or moderate inhibitors of CYP2C8 or CYP3A4 are not expected to affect the exposure of apalutamide. ### Effect of apalutamide on Other Drugs CYP3A4, CYP2C9, CYP2C19 and UGT Substrates - Apalutamide is a strong inducer of CYP3A4 and CYP2C19, and a weak inducer of CYP2C9 in humans. Concomitant use of apalutamide with medications that are primarily metabolized by CYP3A4, CYP2C19, or CYP2C9 can result in lower exposure to these medications. Substitution for these medications is recommended when possible or evaluate for loss of activity if medication is continued. Concomitant administration of apalutamide with medications that are substrates of UDP-glucuronosyl transferase (UGT) can result in decreased exposure. Use caution if substrates of UGT must be co-administered with apalutamide and evaluate for loss of activity. P-gp, BCRP or OATP1B1 Substrates - Apalutamide was shown to be a weak inducer of P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), and organic anion transporting polypeptide 1B1 (OATP1B1) clinically. At steady-state, apalutamide reduced the plasma exposure to fexofenadine (a P-gp substrate) and rosuvastatin (a BCRP/OATP1B1 substrate). Concomitant use of apalutamide with medications that are substrates of P-gp, BCRP, or OATP1B1 can result in lower exposure of these medications. Use caution if substrates of P-gp, BCRP or OATP1B1 must be co-administered with apalutamide and evaluate for loss of activity if medication is continued. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): - Apalutamide is contraindicated for use in pregnant women because the drug can cause fetal harm and potential loss of pregnancy. Apalutamide is not indicated for use in females, so animal embryo-fetal developmental toxicology studies were not conducted with apalutamide. There are no human data on the use of apalutamide in pregnant women. Based on its mechanism of action, apalutamide may cause fetal harm when administered during pregnancy. Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Apalutamide in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Apalutamide during labor and delivery. ### Nursing Mothers - Apalutamide is not indicated for use in females. There are no data on the presence of apalutamide or its metabolites in human milk, the effect on the breastfed child, or the effect on milk production. ### Pediatric Use - Safety and effectiveness of apalutamide in pediatric patients have not been established. ### Geriatic Use - Of the 803 patients who received apalutamide in SPARTAN, 87% of patients were 65 years and over and 49% were 75 years and over. Grade 3–4 adverse reactions occurred in 46% (323/697) of patients 65 years or older and in 51% (197/391) of patients 75 years or older treated with apalutamide compared to 35% (124/355) of patients 65 years or older and 37% (70/187) of patients 75 years or older treated with placebo. No overall differences in effectiveness were observed between these patients and younger patients. ### Gender There is no FDA guidance on the use of Apalutamide with respect to specific gender populations. ### Race There is no FDA guidance on the use of Apalutamide with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Apalutamide in patients with renal impairment. ### Hepatic Impairment There is no FDA guidance on the use of Apalutamide in patients with hepatic impairment. ### Females of Reproductive Potential and Males Contraception (Males) - Based on the mechanism of action and findings in an animal reproduction study, advise male patients with female partners of reproductive potential to use effective contraception during treatment and for 3 months after the last dose of apalutamide. Infertility (Males) - Based on animal studies, apalutamide may impair fertility in males of reproductive potential. ### Immunocompromised Patients There is no FDA guidance one the use of Apalutamide in patients who are immunocompromised. # Administration and Monitoring ### Administration - May be given with or without food. ### Monitoring - Prolongation in the time to PSA progression and the time to symptomatic disease progression may indicate efficacy. - Fracture and fall risk: Evaluate for risk and monitor during therapy. # IV Compatibility There is limited information regarding the compatibility of Apalutamide and IV administrations. # Overdosage - There is no known specific antidote for apalutamide overdose. In the event of an overdose, stop apalutamide, undertake general supportive measures until clinical toxicity has been diminished or resolved. # Pharmacology ## Mechanism of Action - Apalutamide is an Androgen Receptor (AR) inhibitor that binds directly to the ligand-binding domain of the AR. Apalutamide inhibits AR nuclear translocation, inhibits DNA binding, and impedes AR-mediated transcription. A major metabolite, N-desmethyl apalutamide, is a less potent inhibitor of AR, and exhibited one-third the activity of apalutamide in an in vitro transcriptional reporter assay. Apalutamide administration caused decreased tumor cell proliferation and increased apoptosis leading to decreased tumor volume in mouse xenograft models of prostate cancer. ## Structure ## Pharmacodynamics ### Cardiac Electrophysiology - The effect of apalutamide 240 mg once daily on the QTc interval was assessed in an open-label, uncontrolled, multi-center, single-arm dedicated QT study in 45 patients with CRPC. The maximum mean QTcF change from baseline was 12.4 ms (2-sided 90% upper CI: 16.0 ms). An exposure-QT analysis suggested a concentration-dependent increase in QTcF for apalutamide and its active metabolite. ## Pharmacokinetics - Apalutamide pharmacokinetic parameters are presented as the mean [standard deviation (SD)] unless otherwise specified. Apalutamide Cmax and area under the concentration curve (AUC) increased proportionally following repeated once-daily dosing of 30 to 480 mg (0.125 to 2 times the recommended dosage). Following administration of the recommended dosage, apalutamide steady-state was achieved after 4 weeks and the mean accumulation ratio was approximately 5-fold. Apalutamide Cmax was 6.0 mcg/mL (1.7) and AUC was 100 mcg∙h/mL (32) at steady-state. Daily fluctuations in apalutamide plasma concentrations were low, with mean peak-to-trough ratio of 1.63. An increase in apparent clearance (CL/F) was observed with repeat dosing, likely due to induction of apalutamide's own metabolism. The auto-induction effect likely reached its maximum at the recommended dosage because exposure of apalutamide across the dose range of 30 to 480 mg is dose-proportional. - The major active metabolite N-desmethyl apalutamide Cmax was 5.9 mcg/mL (1.0) and AUC was 124 mcg∙h/mL (23) at steady-state after the recommended dosage. N-desmethyl apalutamide was characterized by a flat concentration-time profile at steady-state with a mean peak-to-trough ratio of 1.27. Mean AUC metabolite/parent drug ratio for N-desmethyl apalutamide following repeat-dose administration was 1.3. Based on systemic exposure, relative potency, and pharmacokinetic properties, N-desmethyl apalutamide likely contributed to the clinical activity of apalutamide. ### Absorption - Mean absolute oral bioavailability was approximately 100%. Median time to achieve peak plasma concentration (tmax) was 2 hours (range: 1 to 5 hours). Effect of Food - Administration of apalutamide to healthy subjects under fasting conditions and with a high-fat meal (approximately 500 to 600 fat calories, 250 carbohydrate calories, and 150 protein calories) resulted in no clinically relevant changes in Cmax and AUC. Median time to reach tmax was delayed approximately 2 hours with food. ### Distribution - The mean apparent volume of distribution at steady-state of apalutamide was approximately 276 L. - Apalutamide was 96% and N-desmethyl apalutamide was 95% bound to plasma proteins with no concentration dependency. ### Elimination - The CL/F of apalutamide was 1.3 L/h after single dosing and increased to 2.0 L/h at steady-state after once-daily dosing likely due to CYP3A4 auto-induction. The mean effective half-life for apalutamide in patients was approximately 3 days at steady-state. ### Metabolism - Metabolism is the main route of elimination of apalutamide. Apalutamide is primarily metabolized by CYP2C8 and CYP3A4 to form active metabolite, N-desmethyl apalutamide. The contribution of CYP2C8 and CYP3A4 in the metabolism of apalutamide is estimated to be 58% and 13% following single dose but changes to 40% and 37%, respectively at steady-state. - Apalutamide represented 45% and N-desmethyl apalutamide represented 44% of the total AUC following a single oral administration of radiolabeled apalutamide 240 mg. ### Excretion - Up to 70 days following a single oral administration of radiolabeled apalutamide, 65% of the dose was recovered in urine (1.2% of dose as unchanged apalutamide and 2.7% as N-desmethyl apalutamide) and 24% was recovered in feces (1.5% of dose as unchanged apalutamide and 2% as N-desmethyl apalutamide). ### Specific Populations - No clinically significant differences in the pharmacokinetics of apalutamide or N-desmethyl apalutamide were observed based on age (18–94 years), race (Black, non-Japanese Asian, Japanese), mild to moderate (eGFR 30–89 mL/min/1.73m2, estimated by the modification of diet in renal disease [MDRD] equation) renal impairment, or mild (Child-Pugh A) to moderate (Child-Pugh B) hepatic impairment. - The effect of severe renal impairment or end stage renal disease (eGFR ≤29 mL/min/1.73m2, MDRD) or severe hepatic impairment (Child-Pugh C) on apalutamide pharmacokinetics is unknown. ### Drug Interactions Strong CYP2C8 inhibitors - Apalutamide Cmax decreased by 21% while AUC increased by 68% following co-administration of apalutamide as a 240 mg single dose with gemfibrozil (a strong CYP2C8 inhibitor). Gemfibrozil is predicted to increase the steady-state apalutamide Cmax by 32% and AUC by 44%. For the active moieties (sum of unbound apalutamide plus the potency-adjusted unbound N-desmethyl apalutamide), the predicted steady-state Cmax increased by 19% and AUC by 23%. Strong CYP3A4 inhibitors - Apalutamide Cmax decreased by 22% while AUC was similar following co-administration of apalutamide as a 240 mg single dose with itraconazole (a strong CYP3A4 inhibitor). Ketoconazole (a strong CYP3A4 inhibitor) is predicted to increase the single-dose apalutamide AUC by 24% but have no impact on Cmax. Ketoconazole is predicted to increase the steady-state apalutamide Cmax by 38% and AUC by 51%. For the active moieties, the predicted steady-state Cmax increased by 23% and AUC by 28%. CYP3A4/CYP2C8 inducers - Rifampin (a strong CYP3A4 and moderate CYP2C8 inducer) is predicted to decrease the steady-state apalutamide Cmax by 25% and AUC by 34%. For the active moieties, the predicted steady-state Cmax decreased by 15% and AUC by 19%. Acid lowering agents - Apalutamide is not ionizable under relevant physiological pH condition, therefore acid lowering agents (e.g. proton pump inhibitor, H2-receptor antagonist, antacid) are not expected to affect the solubility and bioavailability of apalutamide. Drugs affecting transporters - In vitro, apalutamide and N-desmethyl apalutamide are substrates for P-gp but not BCRP, OATP1B1, and OATP1B3. Because apalutamide is completely absorbed after oral administration, P-gp does not limit the absorption of apalutamide and therefore, inhibition or induction of P-gp is not expected to affect the bioavailability of apalutamide. CYP substrates - In vitro studies showed that apalutamide and N-desmethyl apalutamide are moderate to strong CYP3A4 and CYP2B6 inducers, are moderate inhibitors of CYP2B6 and CYP2C8, and weak inhibitors of CYP2C9, CYP2C19, and CYP3A4. Apalutamide and N-desmethyl apalutamide do not affect CYP1A2 and CYP2D6 at therapeutically relevant concentrations. - Co-administration of apalutamide with single oral doses of sensitive CYP substrates resulted in a 92% decrease in the AUC of midazolam (a CYP3A4 substrate), 85% decrease in the AUC of omeprazole (a CYP2C19 substrate), and 46% decrease in the AUC of S-warfarin (a CYP2C9 substrate). Apalutamide did not cause clinically significant changes in exposure to a CYP2C8 substrate. P-gp, BCRP and OATP1B1 substrates - Co-administration of apalutamide with single oral doses of transporter substrates resulted in a 30% decrease in the AUC of fexofenadine (a P-gp substrate) and 41% decrease in the AUC of rosuvastatin (a BCRP/OATP1B1 substrate) but had no impact on Cmax. GT substrates - Apalutamide may induce UGT. Concomitant administration of apalutamide with medications that are substrates of UGT may result in lower exposure to these medications. OCT2, OAT1, OAT3 and MATEs substrates - In vitro, apalutamide and N-desmethyl apalutamide inhibit organic cation transporter 2 (OCT2), organic anion transporter 3 (OAT3) and multidrug and toxin extrusions (MATEs), and do not inhibit organic anion transporter 1. Apalutamide is not predicted to cause clinically significant changes in exposure to an OAT3 substrate. ## Nonclinical Toxicology ### Carcinogenesis, Mutagenesis, Impairment of Fertility - Long-term animal studies have not been conducted to evaluate the carcinogenic potential of apalutamide. Apalutamide did not induce mutations in the bacterial reverse mutation (Ames) assay and was not genotoxic in either in vitro chromosome aberration assay or the in vivo rat bone marrow micronucleus assay or the in vivo rat Comet assay. - In repeat-dose toxicity studies in male rats (up to 26 weeks) and dogs (up to 39 weeks), atrophy of the prostate gland and seminal vesicles, aspermia/hypospermia, tubular degeneration and/or hyperplasia or hypertrophy of the interstitial cells in the reproductive system were observed at ≥ 25 mg/kg/day in rats (1.4 times the human exposure based on AUC) and ≥ 2.5 mg/kg/day in dogs (0.9 times the human exposure based on AUC). - In a fertility study in male rats, a decrease in sperm concentration and motility, increased abnormal sperm morphology, lower copulation and fertility rates (upon pairing with untreated females) along with reduced weights of the secondary sex glands and epididymis were observed following 4 weeks of dosing at ≥ 25 mg/kg/day (0.8 times the human exposure based on AUC). A reduced number of live fetuses due to increased pre- and/or post-implantation loss was observed following 4 weeks of 150 mg/kg/day administration (5.7 times the human exposure based on AUC). Effects on male rats were reversible after 8 weeks from the last apalutamide administration. # Clinical Studies - SPARTAN (NCT01946204) was a multicenter, double-blind, randomized (2:1), placebo-controlled clinical trial in which 1207 patients with NM-CRPC were randomized (2:1) to receive either apalutamide orally at a dose of 240 mg once daily (N = 806) or placebo once daily (N = 401). All patients in the SPARTAN trial received a concomitant gonadotropin-releasing hormone (GnRH) analog or had a bilateral orchiectomy. Patients were stratified by Prostate Specific Antigen (PSA) Doubling Time (PSADT), the use of bone-sparing agents, and locoregional disease. Patients were required to have a PSADT ≤ 10 months and confirmation of non-metastatic disease by blinded independent central review (BICR). PSA results were blinded and were not used for treatment discontinuation. Patients randomized to either arm discontinued treatment for radiographic disease progression confirmed by BICR, locoregional-only progression, initiation of new treatment, unacceptable toxicity, or withdrawal. - The following patient demographics and baseline disease characteristics were balanced between the treatment arms. The median age was 74 years (range 48–97) and 26% of patients were 80 years of age or older. The racial distribution was 66% Caucasian, 12% Asian, and 6% Black. Seventy-seven percent (77%) of patients in both treatment arms had prior surgery or radiotherapy of the prostate. A majority of patients had a Gleason score of 7 or higher (78%). Fifteen percent (15%) of patients had <2 cm pelvic lymph nodes at study entry. Seventy-three percent (73%) of patients received prior treatment with an anti-androgen; 69% of patients received bicalutamide and 10% of patients received flutamide. All patients had an Eastern Cooperative Oncology Group Performance Status (ECOG PS) score of 0 or 1 at study entry. Among the patients who discontinued study treatment (N = 279 for placebo and N = 314 for apalutamide), a greater proportion (80%) of patients treated with placebo received subsequent therapy compared to patients treated with apalutamide (56%). Locoregional-only progression occurred in 2% of patients overall. - The major efficacy outcome measure of the study was metastasis-free survival (MFS), defined as the time from randomization to the time of first evidence of BICR-confirmed distant metastasis, defined as new bone or soft tissue lesions or enlarged lymph nodes above the iliac bifurcation, or death due to any cause, whichever occurred first. Additional efficacy endpoints were time to metastasis (TTM), progression-free survival (PFS) which also includes locoregional progression, time to symptomatic progression, and overall survival (OS). - A statistically significant improvement in MFS was demonstrated in patients randomized to receive apalutamide compared with patients randomized to receive placebo. Consistent results were observed across patient subgroups including PSADT (≤ 6 months or > 6 months), use of a prior bone-sparing agent (yes or no), and locoregional disease (N0 or N1). The major efficacy outcome was supported by statistically significant improvements in TTM, PFS, and time to symptomatic progression. Overall survival (OS) data were not mature at the time of final MFS analysis (24% of the required number of events). The efficacy results of MFS, TTM, and PFS from SPARTAN are summarized in Figure 1 and Table 3. # How Supplied - Apalutamide (apalutamide) 60 mg film-coated tablets are slightly yellowish to greyish green, oblong-shaped tablets debossed with "AR 60" on one side. Apalutamide 60 mg tablets are available in bottles of 120 tablets. Each bottle contains silica gel desiccant. - NDC Number is 59676-600-12 ## Storage - Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F). - Store in the original package. Do not discard desiccant. Protect from light and moisture. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information ### Falls and Fractures - Inform patients that apalutamide is associated with an increased incidence of falls and fractures. ### Seizures - Inform patients that apalutamide has been associated with an increased risk of seizure. Discuss conditions that may predispose to seizures and medications that may lower the seizure threshold. Advise patients of the risk of engaging in any activity where sudden loss of consciousness could cause serious harm to themselves or others. Inform patients to contact their healthcare provider right away if they experience a seizure. ### Rash - Inform patients that apalutamide is associated with rashes and to inform their healthcare provider if they develop a rash. ### Dosage and Administration - Inform patients receiving concomitant gonadotropin-releasing hormone (GnRH) analog therapy that they need to maintain this treatment during the course of treatment with apalutamide. - Instruct patients to take their dose at the same time each day (once daily). Apalutamide can be taken with or without food. Each tablet should be swallowed whole. - Inform patients that in the event of a missed daily dose of apalutamide, they should take their normal dose as soon as possible on the same day with a return to the normal schedule on the following day. The patient should not take extra tablets to make up the missed dose. ### Embryo-Fetal Toxicity - Inform patients that apalutamide can be harmful to a developing fetus. Advise patients having sex with female partners of reproductive potential to use effective contraception during treatment and for 3 months after the last dose of apalutamide. Advise male patients to use a condom if having sex with a pregnant woman. ### Infertility - Advise male patients that apalutamide may impair fertility and not to donate sperm during therapy and for 3 months following the last dose of apalutamide. # Precautions with Alcohol Alcohol-Apalutamide interaction has not been established. Talk to your doctor regarding the effects of taking alcohol with this medication. # Brand Names - Erleada # Look-Alike Drug Names There is limited information regarding Apalutamide Look-Alike Drug Names in the drug label. # Drug Shortage Status Drug Shortage # Price	https://www.wikidoc.org/index.php/Apalutamide
409395c8a48284758698ac58f9028c29dc1e5697	wikidoc	Apgar score	Apgar score # Overview The Apgar score was devised in 1952 by Dr. Virginia Apgar as a simple and repeatable method to quickly and summarily assess the health of newborn children immediately after childbirth. Virginia Apgar was a pediatrician and anesthesiologist who developed the score to ascertain the effects of anaesthetic agents on neonates. The Apgar score is determined by evaluating the newborn baby on five simple criteria on a scale from zero to two and summing up the five values thus obtained. The resulting Apgar score ranges from zero to 10. The five criteria were used as a mnemonic learning aid. # Apgar Score Calculator The Apgar score was devised in 1952 by Dr. Virginia Apgar as a simple and repeatable method to quickly and summarily assess the health of newborn children immediately after childbirth. Virginia Apgar was a pediatrician and anesthesiologist who developed the score to ascertain the effects of anaesthetic agents on neonates. The Apgar score is determined by evaluating the newborn baby on five simple criteria on a scale from zero to two and summing up the five values thus obtained. The resulting Apgar score ranges from zero to 10. The five criteria were used as a mnemonic learning aid. ## Acronym Some ten years after the initial publication, the acronym APGAR was coined in the US as a mnemonic learning aid: Appearance (skin color), Pulse (heart rate), Grimace (reflex irritability), Activity (muscle tone), and Respiration. The mnemonic was introduced in 1963 by the pediatrician Dr. Joseph Butterfield. The same acronym is used in German (Atmung, Puls, Grundtonus, Aussehen, Reflexe), Spanish (Apariencia, Pulso, Gesticulación, Actividad, Respiración) and French (Apparence, Pouls, Grimace, Activité et Respiration) although the letters have different meanings. Another such backformation attempting to make Apgar an acronym is American Pediatric Gross Assessment Record. The test, however, is named for Dr. Apgar, making Apgar an eponymous backronym. The test has also been reformulated with a different mnemonic, How Ready Is This Child, but the criteria are essentially the same: Heart rate, Respiratory effort, Irritability, Tone, and Color. ## Calculation of the Apgar Score function calcScore(){ var score = 0; if(document.forms.checked == 1){score += 2;} if(document.forms.checked == 1){score += 1;} if(document.forms.checked == 1){score += 0;} if(document.forms.checked == 1){score += 2;} if(document.forms.checked == 1){score += 1;} if(document.forms.checked == 1){score += 0;} if(document.forms.checked == 1){score += 2;} if(document.forms.checked == 1){score += 1;} if(document.forms.checked == 1){score += 0;} if(document.forms.checked == 1){score += 2;} if(document.forms.checked == 1){score += 1;} if(document.forms.checked == 1){score += 0;} if(document.forms.checked == 1){score += 2;} if(document.forms.checked == 1){score += 1;} if(document.forms.checked == 1){score += 0;} document.forms.value = score; if(score <=3){document.forms.value = "Critically low; Neonate requires medical attention";} if(score >= 4 && score <= 6){document.forms.value = "Fairly low";} if(score >= 7){document.forms.value = "Normal";} ## Interpretation of the Apgar Score The test is generally done at one and five minutes after birth, and may be repeated later if the score is and remains low. Scores below 3 are generally regarded as critically low, 4 to 6 fairly low, and over 7 generally normal. A low score on the one-minute test may show that the neonate requires medical attention but is not necessarily an indication that there will be long-term problems, particularly if there is an improvement by the stage of the five-minute test. If the Apgar score remains below 3 at later times such as 10, 15, or 30 minutes, there is a risk that the child will suffer longer-term neurological damage. There is also a small but significant increase of the risk of cerebral palsy. However, the purpose of the Apgar test is to determine quickly whether a newborn needs immediate medical care; it was not designed to make long-term predictions on a child's health. Contrary to popular opinion the APGAR score is no longer used to decide if a neonate requires resuscitation. That decision is based on the emergency assessment of airway, breathing, and circulation ("ABC").	Apgar score Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview The Apgar score was devised in 1952 by Dr. Virginia Apgar as a simple and repeatable method to quickly and summarily assess the health of newborn children immediately after childbirth. Virginia Apgar was a pediatrician and anesthesiologist who developed the score to ascertain the effects of anaesthetic agents on neonates. The Apgar score is determined by evaluating the newborn baby on five simple criteria on a scale from zero to two and summing up the five values thus obtained. The resulting Apgar score ranges from zero to 10. The five criteria were used as a mnemonic learning aid. # Apgar Score Calculator The Apgar score was devised in 1952 by Dr. Virginia Apgar as a simple and repeatable method to quickly and summarily assess the health of newborn children immediately after childbirth. Virginia Apgar was a pediatrician and anesthesiologist who developed the score to ascertain the effects of anaesthetic agents on neonates. The Apgar score is determined by evaluating the newborn baby on five simple criteria on a scale from zero to two and summing up the five values thus obtained. The resulting Apgar score ranges from zero to 10. The five criteria were used as a mnemonic learning aid.[1][2] ## Acronym Some ten years after the initial publication, the acronym APGAR was coined in the US as a mnemonic learning aid: Appearance (skin color), Pulse (heart rate), Grimace (reflex irritability), Activity (muscle tone), and Respiration. The mnemonic was introduced in 1963 by the pediatrician Dr. Joseph Butterfield. The same acronym is used in German (Atmung, Puls, Grundtonus, Aussehen, Reflexe), Spanish (Apariencia, Pulso, Gesticulación, Actividad, Respiración) and French (Apparence, Pouls, Grimace, Activité et Respiration) although the letters have different meanings. Another such backformation attempting to make Apgar an acronym is American Pediatric Gross Assessment Record. The test, however, is named for Dr. Apgar, making Apgar an eponymous backronym. The test has also been reformulated with a different mnemonic, How Ready Is This Child, but the criteria are essentially the same: Heart rate, Respiratory effort, Irritability, Tone, and Color. ## Calculation of the Apgar Score function calcScore(){ var score = 0; if(document.forms["Apgarscore"]["input1"].checked == 1){score += 2;} if(document.forms["Apgarscore"]["input2"].checked == 1){score += 1;} if(document.forms["Apgarscore"]["input3"].checked == 1){score += 0;} if(document.forms["Apgarscore"]["input4"].checked == 1){score += 2;} if(document.forms["Apgarscore"]["input5"].checked == 1){score += 1;} if(document.forms["Apgarscore"]["input6"].checked == 1){score += 0;} if(document.forms["Apgarscore"]["input7"].checked == 1){score += 2;} if(document.forms["Apgarscore"]["input8"].checked == 1){score += 1;} if(document.forms["Apgarscore"]["input9"].checked == 1){score += 0;} if(document.forms["Apgarscore"]["input10"].checked == 1){score += 2;} if(document.forms["Apgarscore"]["input11"].checked == 1){score += 1;} if(document.forms["Apgarscore"]["input12"].checked == 1){score += 0;} if(document.forms["Apgarscore"]["input13"].checked == 1){score += 2;} if(document.forms["Apgarscore"]["input14"].checked == 1){score += 1;} if(document.forms["Apgarscore"]["input15"].checked == 1){score += 0;} document.forms["Apgarscore"]["result"].value = score; if(score <=3){document.forms["Apgarscore"]["longanswer"].value = "Critically low; Neonate requires medical attention";} if(score >= 4 && score <= 6){document.forms["Apgarscore"]["longanswer"].value = "Fairly low";} if(score >= 7){document.forms["Apgarscore"]["longanswer"].value = "Normal";} } ## Interpretation of the Apgar Score The test is generally done at one and five minutes after birth, and may be repeated later if the score is and remains low. Scores below 3 are generally regarded as critically low, 4 to 6 fairly low, and over 7 generally normal. A low score on the one-minute test may show that the neonate requires medical attention but is not necessarily an indication that there will be long-term problems, particularly if there is an improvement by the stage of the five-minute test. If the Apgar score remains below 3 at later times such as 10, 15, or 30 minutes, there is a risk that the child will suffer longer-term neurological damage. There is also a small but significant increase of the risk of cerebral palsy. However, the purpose of the Apgar test is to determine quickly whether a newborn needs immediate medical care; it was not designed to make long-term predictions on a child's health.[3] Contrary to popular opinion the APGAR score is no longer used to decide if a neonate requires resuscitation. That decision is based on the emergency assessment of airway, breathing, and circulation ("ABC").	https://www.wikidoc.org/index.php/Apgar_score
af96b464e27ea35accb1d34b6f825d28686a74df	wikidoc	Aphasiology	Aphasiology # Overview Aphasiology is the study of linguistics problems resulting from brain damage. It is also the name of a scientific journal covering the area. These specific deficits, termed aphasias, may be defined as impairments of language production or comprehension that cannot be attributed to trivial causes such as deafness or oral paralysis. A number of aphasias have been described, but two are best known: Broca's aphasia (expressive aphasia) and Wernicke's aphasia (receptive or sensory aphasia). Most commonly, aphasias are the result of tissue damage following a stroke. # Broca's Aphasia Broca's aphasia, first described by the French neurologist Paul Broca in the nineteenth century, causes the speech of its sufferers to have a considerable vocabulary but lack even basic grammar. It is characterized by a halting speech consisting mainly of content words, i.e. nouns and verbs, and, at least in English, distinctly lacking small grammatical function words such as articles and prepositions. This observation gave rise to the terms telegraphic speech and, more recently, agrammatism. The extent to which Broca's aphasics retain knowledge of grammar is a matter of considerable controversy. Nonetheless, because their comprehension of spoken language is mostly preserved, and because their speech is usually good enough to get their point across, the agrammatic nature of their speech suggests that the disorder chiefly involves the expressive mechanisms of language that turn thoughts into well-formed sentences. The view of Broca's aphasia as an expressive disorder is supported by its frequent co-occurrence with facial motor difficulties, and its anatomical localization. Although brain damage to many regions may cause it, it is most commonly associated with the inferior frontal gyrus, a region that overlaps with motor cortex controlling the mouth and tongue. Not surprisingly, this region has come to be known as "Broca's area." However, an intriguing line of research has demonstrated specific comprehension deficits in Broca's aphasics as well. These deficits generally involve sentences that are grammatical, but atypical in their word order. The simplest example is sentences in the passive voice, such as "The boy was chased by the girl." Broca's aphasics may have quite a hard time realizing that the girl is doing the chasing, but they do much better with "The mouse was chased by the cat," where world knowledge constraints contribute to the correct interpretation. However, "The cat was chased by the mouse" would likewise be incomprehensible. This evidence suggests that grammatical competence may be a specific function of Broca's area. # Wernicke's Aphasia Such a view is supported by the complementary nature of Wernicke's aphasia, described by the German neurologist Karl Wernicke, a contemporary of Broca. Wernicke's aphasics produce speech that seems fluent and grammatical, but is largely devoid of sensible content. Comprehension is severely impaired. Wernicke's aphasia is associated with the posterior superior temporal gyrus, known as "Wernicke's area", an area adjacent to cortex responsible for auditory processing. Therefore, the localization of the two best-known aphasias mirrors the grossest dichotomy in brain organization: anterior areas are specialized for motor output, and posterior areas for sensory processing. A fascinating corollary of this has come from research on aphasias in deaf users of sign language, who can show deficits in signing and comprehension analogous to Broca's and Wernicke's aphasias in hearing populations. These studies demonstrate that the grammatical functions of Broca's area and the semantic functions of Wernicke's area are indeed deep, abstract properties of the language system independent of its modality of expression.	Aphasiology Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview Aphasiology is the study of linguistics problems resulting from brain damage. It is also the name of a scientific journal covering the area. These specific deficits, termed aphasias, may be defined as impairments of language production or comprehension that cannot be attributed to trivial causes such as deafness or oral paralysis. A number of aphasias have been described, but two are best known: Broca's aphasia (expressive aphasia) and Wernicke's aphasia (receptive or sensory aphasia). Most commonly, aphasias are the result of tissue damage following a stroke. # Broca's Aphasia Broca's aphasia, first described by the French neurologist Paul Broca in the nineteenth century, causes the speech of its sufferers to have a considerable vocabulary but lack even basic grammar. It is characterized by a halting speech consisting mainly of content words, i.e. nouns and verbs, and, at least in English, distinctly lacking small grammatical function words such as articles and prepositions. This observation gave rise to the terms telegraphic speech and, more recently, agrammatism. The extent to which Broca's aphasics retain knowledge of grammar is a matter of considerable controversy. Nonetheless, because their comprehension of spoken language is mostly preserved, and because their speech is usually good enough to get their point across, the agrammatic nature of their speech suggests that the disorder chiefly involves the expressive mechanisms of language that turn thoughts into well-formed sentences. The view of Broca's aphasia as an expressive disorder is supported by its frequent co-occurrence with facial motor difficulties, and its anatomical localization. Although brain damage to many regions may cause it, it is most commonly associated with the inferior frontal gyrus, a region that overlaps with motor cortex controlling the mouth and tongue. Not surprisingly, this region has come to be known as "Broca's area." However, an intriguing line of research has demonstrated specific comprehension deficits in Broca's aphasics as well. These deficits generally involve sentences that are grammatical, but atypical in their word order. The simplest example is sentences in the passive voice, such as "The boy was chased by the girl." Broca's aphasics may have quite a hard time realizing that the girl is doing the chasing, but they do much better with "The mouse was chased by the cat," where world knowledge constraints contribute to the correct interpretation. However, "The cat was chased by the mouse" would likewise be incomprehensible. This evidence suggests that grammatical competence may be a specific function of Broca's area. # Wernicke's Aphasia Such a view is supported by the complementary nature of Wernicke's aphasia, described by the German neurologist Karl Wernicke, a contemporary of Broca. Wernicke's aphasics produce speech that seems fluent and grammatical, but is largely devoid of sensible content. Comprehension is severely impaired. Wernicke's aphasia is associated with the posterior superior temporal gyrus, known as "Wernicke's area", an area adjacent to cortex responsible for auditory processing. Therefore, the localization of the two best-known aphasias mirrors the grossest dichotomy in brain organization: anterior areas are specialized for motor output, and posterior areas for sensory processing. A fascinating corollary of this has come from research on aphasias in deaf users of sign language, who can show deficits in signing and comprehension analogous to Broca's and Wernicke's aphasias in hearing populations. These studies demonstrate that the grammatical functions of Broca's area and the semantic functions of Wernicke's area are indeed deep, abstract properties of the language system independent of its modality of expression.	https://www.wikidoc.org/index.php/Aphasiology
0977baae0a2ff602395b9cdf61b29f5bf9f302bb	wikidoc	Aphidicolin	Aphidicolin Aphidicolin is defined as a tetracyclic diterpene antibiotic with antiviral and antimitotical properties. Aphidicolin is a reversible inhibitor of eukaryotic nuclear DNA replication. It blocks the cell cycle at early S-phase. It is a specific inhibitor of DNA polymerase A,D in eukaryotic cells and in some viruses and an Apoptosis inducer in HeLa cells. # Further reading - Dhillon VS, Husain SA, Ray GN. in Teratog Carcinog Mutagen. 2003 Expression of aphidicolin-induced fragile sites and their relationship between genetic susceptibility in breast cancer, ovarian cancer, and non-small-cell lung cancer patients	Aphidicolin Aphidicolin is defined as a tetracyclic diterpene antibiotic with antiviral and antimitotical properties. Aphidicolin is a reversible inhibitor of eukaryotic nuclear DNA replication. It blocks the cell cycle at early S-phase. It is a specific inhibitor of DNA polymerase A,D in eukaryotic cells and in some viruses and an Apoptosis inducer in HeLa cells. # Further reading - Dhillon VS, Husain SA, Ray GN. in Teratog Carcinog Mutagen. 2003 Expression of aphidicolin-induced fragile sites and their relationship between genetic susceptibility in breast cancer, ovarian cancer, and non-small-cell lung cancer patients # External links Template:WS	https://www.wikidoc.org/index.php/Aphidicolin
e66bf11ec181135ebeb6fae0cddcee3469394f08	wikidoc	Apicomplexa	Apicomplexa # Overview The Apicomplexa are a large group of protists, characterized by the presence of a unique organelle called an apical complex. They are unicellular, spore-forming, and exclusively parasites of animals. Motile structures such as flagella or pseudopods are absent except in certain gamete stages. This is a diverse group including organisms such as coccidia, gregarines, piroplasms, haemogregarines, and malarias; some diseases caused by apicomplexan organisms include: - Babesiosis (Babesia) - Malaria (Plasmodium) - Cryptosporidiosis (Cryptosporidium) - Coccidian diseases including: Cryptosporidiosis (Cryptosporidium parvum) Cyclosporiasis (Cyclospora cayetanensis) Toxoplasmosis (Toxoplasma gondii) - Cryptosporidiosis (Cryptosporidium parvum) - Cyclosporiasis (Cyclospora cayetanensis) - Toxoplasmosis (Toxoplasma gondii) Most members have a complex life-cycle, involving both asexual and sexual reproduction. Typically, a host is infected by ingesting cysts, which divide to produce sporozoites that enter its cells. Eventually, the cells burst, releasing merozoites which infect new cells. This may occur several times, until gamonts are produced, forming gametes that fuse to create new cysts. There are many variations on this basic pattern, however, and many Apicomplexa have more than one host. The apical complex includes vesicles called rhoptries and micronemes, which open at the anterior of the cell. These secrete enzymes that allow the parasite to enter other cells. The tip is surrounded by a band of microtubules, called the polar ring, and among the Conoidasida there is also a funnel of rods called the conoid.. Over the rest of the cell, except for a diminished mouth called the micropore, the membrane is supported by vesicles called alveoli, forming a semi-rigid pellicle. The presence of alveoli and other traits place the Apicomplexa among a group called the alveolates. Several related flagellates, such as Perkinsus and Colpodella have structures similar to the polar ring and were formerly included here, but most appear to be closer relatives of the dinoflagellates. They are probably similar to the common ancestor of the two groups. Another similarity is that apicomplexan cells contain a single plastid, called the apicoplast, surrounded by either 3 or four membranes. Its functions are thought to include tasks such as lipid synthesis, it appears to be necessary for survival. They are generally considered to share a common origin with the chloroplasts of dinoflagellates, although some studies suggest they are ultimately derived from green rather than red algae. The Apicomplexa comprise the bulk of what used to be called the Sporozoa, a group for parasitic protozoans without flagella, pseudopods, or cilia. Most of the Apicomplexa are motile however. The other main lines were the Ascetosporea, the Myxozoa (now known to be derived from animals), and the Microsporidia (now known to be derived from fungi). Sometimes the name Sporozoa is taken as a synonym for the Apicomplexa, or occasionally as a subset. # Blood borne genera Within the Apicomplexa there are three groups of blood borne parasites. These species lie within in three suborders. - suborder Adeleorina - 8 genera - suborder Haemosporina - all genera in this suborder - suborder Eimeriorina - 2 genera (Lankesterella and Schellackia) Blood parasites belonging to the suborder Adeleorina are collectively known as haemogregarines. Currently their sister group is thought to be the piroplasms. Suborder Adeleorina has ~400 species and has been organised into four large and 4 small genera. The larger genera are: - family Haemogregarinidae - taxon created by Neveu-Lemaire in 1901 genera: - Haemogregarina - taxon created by Danilewsky in 1885 - Cyrilia - taxon created by Lainson in 1981 - family Karyolysidae - taxon created by Wenyon in 1926 genera: - Karyolysus - taxon created by Labbe in 1894 - family Hepatozoidae - taxon created by Wenyon in 1926 genera: - Hepatozoon - taxon created by Miller in 1908 The smaller genera are : - Hemolivia - taxon created by Petit et al in 1990 - Desseria - taxon created by Siddall in 1995 - family Dactylosomatidae genera: - Dactylosoma - Babesiosoma Notes: Species of the genus Desseria infect fish and lack erythrocytic merogony. The species of the genera Dactylosoma and Babesiosoma infect fish and reptiles. Leeches are the only known vectors for these species and their vertebrate hosts are aquatic. # Disease Genomics As noted above, many of the apicomplexan parasites are important pathogens of human and domestic animals. In contrast to bacterial pathogens, these apicomplexan parasites are eukaryotes and share many metabolic pathways with their animal hosts. This fact makes therapeutic target development extremely difficult – a drug that harms an apicomplexan parasite is also likely to harm its human host. Currently there are no effective vaccines or treatments available for most diseases caused by these parasites. Biomedical research on these parasites is challenging because it is often difficult, if not impossible, to maintain live parasite cultures in the laboratory and to genetically manipulate these organisms. In the recent years, several of the apicomplexan species have been selected for genome sequencing. The availability of genome sequences provides a new opportunity for scientists to learn more about the evolution and biochemical capacity of these parasite. A NIH-funded database, ApiDB.org, provides public access to currently available genomic data sets.	Apicomplexa Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview The Apicomplexa are a large group of protists, characterized by the presence of a unique organelle called an apical complex. They are unicellular, spore-forming, and exclusively parasites of animals. Motile structures such as flagella or pseudopods are absent except in certain gamete stages. This is a diverse group including organisms such as coccidia, gregarines, piroplasms, haemogregarines, and malarias; some diseases caused by apicomplexan organisms include: - Babesiosis (Babesia) - Malaria (Plasmodium) - Cryptosporidiosis (Cryptosporidium) - Coccidian diseases including: Cryptosporidiosis (Cryptosporidium parvum) Cyclosporiasis (Cyclospora cayetanensis) Toxoplasmosis (Toxoplasma gondii) - Cryptosporidiosis (Cryptosporidium parvum) - Cyclosporiasis (Cyclospora cayetanensis) - Toxoplasmosis (Toxoplasma gondii) Most members have a complex life-cycle, involving both asexual and sexual reproduction. Typically, a host is infected by ingesting cysts, which divide to produce sporozoites that enter its cells. Eventually, the cells burst, releasing merozoites which infect new cells. This may occur several times, until gamonts are produced, forming gametes that fuse to create new cysts. There are many variations on this basic pattern, however, and many Apicomplexa have more than one host. The apical complex includes vesicles called rhoptries and micronemes, which open at the anterior of the cell. These secrete enzymes that allow the parasite to enter other cells. The tip is surrounded by a band of microtubules, called the polar ring, and among the Conoidasida there is also a funnel of rods called the conoid..[1] Over the rest of the cell, except for a diminished mouth called the micropore, the membrane is supported by vesicles called alveoli, forming a semi-rigid pellicle. The presence of alveoli and other traits place the Apicomplexa among a group called the alveolates. Several related flagellates, such as Perkinsus and Colpodella have structures similar to the polar ring and were formerly included here, but most appear to be closer relatives of the dinoflagellates. They are probably similar to the common ancestor of the two groups. Another similarity is that apicomplexan cells contain a single plastid, called the apicoplast, surrounded by either 3 or four membranes. Its functions are thought to include tasks such as lipid synthesis, it appears to be necessary for survival. They are generally considered to share a common origin with the chloroplasts of dinoflagellates, although some studies suggest they are ultimately derived from green rather than red algae. The Apicomplexa comprise the bulk of what used to be called the Sporozoa, a group for parasitic protozoans without flagella, pseudopods, or cilia. Most of the Apicomplexa are motile however. The other main lines were the Ascetosporea, the Myxozoa (now known to be derived from animals), and the Microsporidia (now known to be derived from fungi). Sometimes the name Sporozoa is taken as a synonym for the Apicomplexa, or occasionally as a subset. # Blood borne genera Within the Apicomplexa there are three groups of blood borne parasites. These species lie within in three suborders. - suborder Adeleorina - 8 genera - suborder Haemosporina - all genera in this suborder - suborder Eimeriorina - 2 genera (Lankesterella and Schellackia) Blood parasites belonging to the suborder Adeleorina are collectively known as haemogregarines. Currently their sister group is thought to be the piroplasms. Suborder Adeleorina has ~400 species and has been organised into four large and 4 small genera. The larger genera are: - family Haemogregarinidae - taxon created by Neveu-Lemaire in 1901 genera: - Haemogregarina - taxon created by Danilewsky in 1885 - Cyrilia - taxon created by Lainson in 1981 - family Karyolysidae - taxon created by Wenyon in 1926 genera: - Karyolysus - taxon created by Labbe in 1894 - family Hepatozoidae - taxon created by Wenyon in 1926 genera: - Hepatozoon - taxon created by Miller in 1908 The smaller genera are : - Hemolivia - taxon created by Petit et al in 1990 - Desseria - taxon created by Siddall in 1995 - family Dactylosomatidae genera: - Dactylosoma - Babesiosoma Notes: Species of the genus Desseria infect fish and lack erythrocytic merogony. The species of the genera Dactylosoma and Babesiosoma infect fish and reptiles. Leeches are the only known vectors for these species and their vertebrate hosts are aquatic. # Disease Genomics As noted above, many of the apicomplexan parasites are important pathogens of human and domestic animals. In contrast to bacterial pathogens, these apicomplexan parasites are eukaryotes and share many metabolic pathways with their animal hosts. This fact makes therapeutic target development extremely difficult – a drug that harms an apicomplexan parasite is also likely to harm its human host. Currently there are no effective vaccines or treatments available for most diseases caused by these parasites. Biomedical research on these parasites is challenging because it is often difficult, if not impossible, to maintain live parasite cultures in the laboratory and to genetically manipulate these organisms. In the recent years, several of the apicomplexan species have been selected for genome sequencing. The availability of genome sequences provides a new opportunity for scientists to learn more about the evolution and biochemical capacity of these parasite. A NIH-funded database, ApiDB.org, provides public access to currently available genomic data sets.	https://www.wikidoc.org/index.php/Apicomplexa
65aff35cece90f35af4f29929a59eb63036df34e	wikidoc	Apis cerana	Apis cerana Apis cerana, or the Asiatic honey bee (or the Eastern honey bee), are small honey bees of southern and southeastern Asia, such as China, India, Japan, Malaysia, Nepal, Bangladesh and Papua New Guinea. This species is the sister species of Apis koschevnikovi, and both are in the same subgenus as the Western (European) honey bee, Apis mellifera. In the wild, they prefer to nest in small spaces, such as hollowed out tree trunks. Like the Western honey bee, they are sometimes domesticated and used in apiculture, mostly in wooden boxes with fixed frames. Their size is similar or somewhat smaller than Apis mellifera, and they also have a more prominent abdominal stripes. Their honey yield is smaller, because they form smaller colonies. In folk medicine, their beeswax is used to treat and heal wounds. Apis cerana is the natural host to the mite Varroa jacobsoni and the parasite Nosema ceranae, both serious pests of the Western honey bee. Having coevolved with these parasites, A. cerana exhibits more careful grooming than A. mellifera, and thus has an effective defense mechanism against Varroa that keeps the mite from devastating colonies. Other than defensive behaviors such as these, much of their behavior and biology (at least in the wild) is very similar to that of A. mellifera. - Thermal defense: When an Apis cerana hive is invaded by the Japanese giant hornet (Vespa mandarinia), about 500 Japanese honey bees (A. cerana japonica) surround the hornet and vibrate their flight muscles until the temperature is raised to 47°C (117°F), heating the hornet to death, but keeping the temperature still under their own lethal limit (48-50°C). European honey bees (A. mellifera) lack this behavior. # Subspecies (following Engel, 1999). - Apis cerana cerana Fabricius ( = "sinensis") - Afghanistan, Pakistan, north India, China and north Vietnam - Apis cerana heimifeng Engel - Apis cerana indica - Fabricius South India, Sri Lanka, Bangladesh, Burma, Malaysia, Indonesia and the Philippines - Apis cerana japonica Fabricius - Japan - Apis cerana javana Enderlein - Apis cerana johni Skorikov - Apis cerana nuluensis Tingek, Koeniger and Koeniger - Apis cerana skorikovi Engel ( = "himalaya") - Central and east Himalayan mountains (Ruttner, 1987) # Sources - BIODIVERSITY OF HONEYBEES, M.R.Srinivasan, Department of Agricultural Entomology - Tamil Nadu Agricultural University accessed Oct 2005 - Engel, M.S. (1999) The taxonomy of recent and fossil honey bees (Hymenoptera: Apidae: Apis). Journal of Hymenoptera Research 8: 165-196.	Apis cerana Apis cerana, or the Asiatic honey bee (or the Eastern honey bee), are small honey bees of southern and southeastern Asia, such as China, India, Japan, Malaysia, Nepal, Bangladesh and Papua New Guinea. This species is the sister species of Apis koschevnikovi, and both are in the same subgenus as the Western (European) honey bee, Apis mellifera. In the wild, they prefer to nest in small spaces, such as hollowed out tree trunks. Like the Western honey bee, they are sometimes domesticated and used in apiculture, mostly in wooden boxes with fixed frames. Their size is similar or somewhat smaller than Apis mellifera, and they also have a more prominent abdominal stripes. Their honey yield is smaller, because they form smaller colonies. In folk medicine, their beeswax is used to treat and heal wounds. Apis cerana is the natural host to the mite Varroa jacobsoni and the parasite Nosema ceranae, both serious pests of the Western honey bee. [1] Having coevolved with these parasites, A. cerana exhibits more careful grooming than A. mellifera, and thus has an effective defense mechanism against Varroa that keeps the mite from devastating colonies. Other than defensive behaviors such as these, much of their behavior and biology (at least in the wild) is very similar to that of A. mellifera. - Thermal defense: When an Apis cerana hive is invaded by the Japanese giant hornet (Vespa mandarinia), about 500 Japanese honey bees (A. cerana japonica) surround the hornet and vibrate their flight muscles until the temperature is raised to 47°C (117°F), heating the hornet to death, but keeping the temperature still under their own lethal limit (48-50°C). European honey bees (A. mellifera) lack this behavior. # Subspecies (following Engel, 1999). - Apis cerana cerana Fabricius ( = "sinensis") - Afghanistan, Pakistan, north India, China and north Vietnam - Apis cerana heimifeng Engel - Apis cerana indica - Fabricius South India, Sri Lanka, Bangladesh, Burma, Malaysia, Indonesia and the Philippines - Apis cerana japonica Fabricius - Japan - Apis cerana javana Enderlein - Apis cerana johni Skorikov - Apis cerana nuluensis Tingek, Koeniger and Koeniger - Apis cerana skorikovi Engel ( = "himalaya") - Central and east Himalayan mountains (Ruttner, 1987) # Sources - BIODIVERSITY OF HONEYBEES, M.R.Srinivasan, Department of Agricultural Entomology - Tamil Nadu Agricultural University accessed Oct 2005 - Engel, M.S. (1999) The taxonomy of recent and fossil honey bees (Hymenoptera: Apidae: Apis). Journal of Hymenoptera Research 8: 165-196. # External links - Photos of Apis cerana - Apis cerana' "cooking" a hornet to death - Video	https://www.wikidoc.org/index.php/Apis_cerana
f12d67d61162985df43441ddbded490af71700af	wikidoc	Apocynaceae	Apocynaceae # Overview The Apocynaceae or dogbane family is a family of flowering plants, including trees, shrubs, herbs, or lianas. Many species are tall trees found in the tropical rainforest, and most are from the tropics and subtropics, but some come from tropical dry, xeric environments. There are also some perennial herbs from temperate zones. Many of these plants have milky sap; and many species are poisonous if ingested. Some genera of Apocynaceae, such as Adenium however, have either clear and milky, latex sap, and others, such as Pachypodium, always have clear sap. # Uses Several plants of this family had economic uses in the past. The genera Carpodinus, Landolphia, Hancornia, Funtumia and Mascarenhasia were used as a commercial source of inferior rubber. The juice of Acokanthera species such as A. venenata and the milky juice of the Namibian Pachypodium has been used as venom for arrow tips by the Bushmen. Some sources (Rapananrivo et al. on p. 5) state that Pachypodium do not have a milky sap. Several genera are grown as ornamental plants, including Amsonia (bluestar), Nerium (oleander), Vinca (periwinkle), Carissa (Natal plum, an edible fruit), Allamanda (golden trumpet), Plumeria (frangipani), Thevetia (lucky nut), Mandevilla (Savannah flower). Rauvolfia cafra is the Quinine tree. Rauvolfia serpentina or Indian Snakeroot yields the alkaloids reserpine and rescinnamine. Some are sources of drugs, such as cardiac glycosides, affecting the heart function, including Acokanthera, Apocynum, Cerbera, Nerium, Thevetia and Strophantus. The genus Apocynum was used as a source of fiber by Native Americans. The edible flower of Fernaldia pandurata (common name: Loroco) is a popular part of El Salvadorian and Guatemalan cooking.	Apocynaceae Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview The Apocynaceae or dogbane family is a family of flowering plants, including trees, shrubs, herbs, or lianas. Many species are tall trees found in the tropical rainforest, and most are from the tropics and subtropics, but some come from tropical dry, xeric environments. There are also some perennial herbs from temperate zones. Many of these plants have milky sap; and many species are poisonous if ingested. Some genera of Apocynaceae, such as Adenium however, have either clear and milky, latex sap, and others, such as Pachypodium, always have clear sap. # Uses Several plants of this family had economic uses in the past. The genera Carpodinus, Landolphia, Hancornia, Funtumia and Mascarenhasia were used as a commercial source of inferior rubber. The juice of Acokanthera species such as A. venenata and the milky juice of the Namibian Pachypodium has been used as venom for arrow tips by the Bushmen. Some sources (Rapananrivo et al. on p. 5) state that Pachypodium do not have a milky sap. Several genera are grown as ornamental plants, including Amsonia (bluestar), Nerium (oleander), Vinca (periwinkle), Carissa (Natal plum, an edible fruit), Allamanda (golden trumpet), Plumeria (frangipani), Thevetia (lucky nut), Mandevilla (Savannah flower). Rauvolfia cafra is the Quinine tree. Rauvolfia serpentina or Indian Snakeroot yields the alkaloids reserpine and rescinnamine. Some are sources of drugs, such as cardiac glycosides, affecting the heart function, including Acokanthera, Apocynum, Cerbera, Nerium, Thevetia and Strophantus. The genus Apocynum was used as a source of fiber by Native Americans. The edible flower of Fernaldia pandurata (common name: Loroco) is a popular part of El Salvadorian and Guatemalan cooking.	https://www.wikidoc.org/index.php/Apocynaceae
efc3570e4235324985d812009d19bbf43ba2ca4d	wikidoc	Aponeurosis	Aponeurosis # Overview Aponeuroses (απο, "away" or "of", and νευρον, "sinew") are membranes separating muscles from each other. They have a shiny, whitish-silvery color, and are histologically similar to tendons, but are very sparingly supplied with blood vessels and nerves. When dissected, aponeuroses are papery, and peel off by sections. The primary regions with thick aponeurosis is in the ventral abdominal region, the dorsal lumbar region, and in the palmar region. # Ventral abdominal aponeuroses The ventral abdominal aponeuroses are located just on top of the rectus abdominis muscle. It has for its borders the external oblique, pectoralis muscles, and the latissimus dorsi. # Dorsal lumbar aponeuroses The dorsal lumbar aponeuroses are situated just on top of the epaxial muscles of the thorax, which are multifidus spinae and Sacrospinalis. # Palmar aponeuroses The palmar aponeuroses occur on the palms of the hands, and are referred to in the Patrick O'Brian Aubrey–Maturin series of books. # Scalp aponeuroses The aponeurosis (or galea aponeurotica) is a tough layer of dense fibrous tissue which runs from the frontalis muscle anteriorly to the occipitalis posteriorly.	Aponeurosis # Overview Aponeuroses (απο, "away" or "of", and νευρον, "sinew") are membranes separating muscles from each other. They have a shiny, whitish-silvery color, and are histologically similar to tendons, but are very sparingly supplied with blood vessels and nerves. When dissected, aponeuroses are papery, and peel off by sections. The primary regions with thick aponeurosis is in the ventral abdominal region, the dorsal lumbar region, and in the palmar region. # Ventral abdominal aponeuroses The ventral abdominal aponeuroses are located just on top of the rectus abdominis muscle. It has for its borders the external oblique, pectoralis muscles, and the latissimus dorsi. # Dorsal lumbar aponeuroses The dorsal lumbar aponeuroses are situated just on top of the epaxial muscles of the thorax, which are multifidus spinae and Sacrospinalis. # Palmar aponeuroses The palmar aponeuroses occur on the palms of the hands, and are referred to in the Patrick O'Brian Aubrey–Maturin series of books. # Scalp aponeuroses The aponeurosis (or galea aponeurotica) is a tough layer of dense fibrous tissue which runs from the frontalis muscle anteriorly to the occipitalis posteriorly.	https://www.wikidoc.org/index.php/Aponeuroses
0e0971c27328c74552e87f73f5214557dae103c0	wikidoc	Aquaporin 2	Aquaporin 2 AQP2 is found in the apical cell membranes of the kidney's collecting duct principal cells and in intracellular vesicles located throughout the cell. # Regulation It is the only aquaporin regulated by vasopressin. The basic job of aquaporin 2 is to reabsorb water from the urine while its being removed from the blood by the kidney. Aquaporin 2 is in kidney epithelial cells and usually lies dormant in intracellular vesicle membranes. When it is needed, vasopressin binds to the cell surface vasopressin receptor thereby activating a signaling pathway that causes the aquaporin 2 containing vesicles to fuse with the plasma membrane, so the aquaporin 2 can be used by the cell. This aquaporin is regulated in two ways by the peptide hormone vasopressin: - short-term regulation (minutes) through trafficking of AQP2 vesicles to the apical region where they fuse with the apical plasma membrane - long-term regulation (days) through an increase in AQP2 gene expression. This aquaporin is also regulated by food intake. Fasting reduces expression of this aquaporin independently of vasopressin. # Clinical significance Mutations in this channel are associated with nephrogenic diabetes insipidus, which can be autosomal dominant or recessive. Mutations in the vasopressin receptor cause a similar X-linked phenotype. Lithium, which is often used to treat bipolar disorder, can cause acquired diabetes insipidus (characterized by the excretion of large volumes of dilute urine) by decreasing the expression of the AQP2 gene. The expression of the AQP2 gene is increased during conditions associated with water retention such as pregnancy and congestive heart failure.	Aquaporin 2 AQP2 is found in the apical cell membranes of the kidney's collecting duct principal cells and in intracellular vesicles located throughout the cell. # Regulation It is the only aquaporin regulated by vasopressin.[1] The basic job of aquaporin 2 is to reabsorb water from the urine while its being removed from the blood by the kidney. Aquaporin 2 is in kidney epithelial cells and usually lies dormant in intracellular vesicle membranes. When it is needed, vasopressin binds to the cell surface vasopressin receptor thereby activating a signaling pathway that causes the aquaporin 2 containing vesicles to fuse with the plasma membrane, so the aquaporin 2 can be used by the cell.[2] This aquaporin is regulated in two ways by the peptide hormone vasopressin: - short-term regulation (minutes) through trafficking of AQP2 vesicles to the apical region where they fuse with the apical plasma membrane - long-term regulation (days) through an increase in AQP2 gene expression. This aquaporin is also regulated by food intake. Fasting reduces expression of this aquaporin independently of vasopressin. # Clinical significance Mutations in this channel are associated with nephrogenic diabetes insipidus, which can be autosomal dominant or recessive. Mutations in the vasopressin receptor cause a similar X-linked phenotype. Lithium, which is often used to treat bipolar disorder, can cause acquired diabetes insipidus (characterized by the excretion of large volumes of dilute urine) by decreasing the expression of the AQP2 gene. The expression of the AQP2 gene is increased during conditions associated with water retention such as pregnancy and congestive heart failure.	https://www.wikidoc.org/index.php/Aquaporin-2
2558858f49f154468a184c5586cd9f0208cc603f	wikidoc	Aquaporin 3	Aquaporin 3 Aquaporin 3 is found in the basolateral cell membrane of principal collecting duct cells and provides a pathway for water to exit these cells. In the kidney, AQP3 is regulated by vasopressin (ADH). This protein is also a determinant for the GIL blood group system. Suberoylanilide hydroxamic acid (SAHA) (a HDAC inhibitor) increases expression of aquaporin-3 in normal skin cells (keratinocytes). # Clinical significance AQP3 levels are often lower in psoriasis than in healthy skin. AQP3 is expressed more in atopic eczema.	Aquaporin 3 Aquaporin 3 is found in the basolateral cell membrane of principal collecting duct cells and provides a pathway for water to exit these cells.[1] In the kidney, AQP3 is regulated by vasopressin (ADH).[2] This protein is also a determinant for the GIL blood group system.[3] Suberoylanilide hydroxamic acid (SAHA) (a HDAC inhibitor) increases expression of aquaporin-3 in normal skin cells (keratinocytes).[4] # Clinical significance AQP3 levels are often lower in psoriasis than in healthy skin.[4] AQP3 is expressed more in atopic eczema.[5]	https://www.wikidoc.org/index.php/Aquaporin_3
c19747e6e55bb475702b8a8c7e7a49b9a055aa60	wikidoc	Aquaporin 4	Aquaporin 4 Aquaporin-4, also known as AQP4, is a water channel protein encoded by the AQP4 gene in humans. AQP4 belongs to the aquaporin family of integral membrane proteins that conduct water through the cell membrane. A limited number of aquaporins are found within the central nervous system (CNS): AQP1, 3, 4, 5, 8, 9, and 11, but more exclusive representation of AQP1, 4, and 9 are found in the brain and spinal cord. In the CNS, AQP4 is the most prevalent aquaporin channel, specifically located at the perimicrovessel astrocyte foot processes, glia limitans, and ependyma. Aquaporin-4 was first identified in 1986. It was the first evidence of the existence of water transport channels. The method that was used to discover the existence of the transport channels was through knockout experiments. With this technique they were able to show the significant role of AQP4 in CNS injuries and brain water imbalances. # Structure The structure of AQP4 consists of six-transmembrane domains and five connecting loops to form the channel. Through x-ray crystallography, it was found that “each AQP4 monomer consists of six helical, membrane-spanning domains and two short helical segments surrounding a narrow aqueous pore.” Similar to other aquaporin channels, the monomers of AQP4 assemble into tetramers. In addition, AQP4 has two distinct structural isoforms located in the CNS: M1 and M23. Both form homo- and hetero-tetramers that are permeable to water. M23 isoforms are larger square arrays in the endfoot membranes of astrocytes compared to M1 isoforms, which are smaller and more unstable. The aquaporin-4 tetramers accumulate to transform into orthogonal arrays of particle (OAPs) in the cell plasma membrane. # Tissue and cellular distribution Aquaporin-4 is highly expressed in the human body primarily at the end-feet of astrocytes. Additionally, AQP4 can also be located in epithelial cells of many organs throughout the human body, such as the kidney, intestine, salivary glands, sensory organs, and skeletal muscles. In these specific cases of epithelial cell expression, AQP4 is concentrated within the basolateral membrane layer of these locations. Furthermore, AQP4 also plays a role in the supportive cells of sensory organs, such as the retina, inner ear, and olfactory epithelium. Within the retina, AQP4 is highly concentrated where the processes of Muller cells have a basal lamina around blood vessels and inner limiting membrane. AQP4 is also expressed in astrocytes and is upregulated by direct insult to the central nervous system. Specifically within the central nervous system (CNS), AQP4 can be found along the spinal cord and serves as the main water channel. The AQP4 channels are highly concentrated in the blood-brain barrier (BBB), as well as in other cerebrospinal fluid barriers. In the kidneys, AQP4 is constitutively expressed in the basolateral cell membrane of principal collecting duct cells and provide a pathway for water to exit these cells. # Function Aquaporin-4’s overall function is to provide fast water transportation as well as maintain homeostatic balance within the central nervous system. It is the primary water channel protein that reconciles the homeostasis of water in the CNS. AQP4 may be involved in a variety of physiological processes such as waste removal and fine-tuning of potassium homeostasis. Water flowing into and out of the brain or spinal cord is assisted by AQP4. Here, AQP4 channels respond passively to osmotic gradients. In addition, they play a role in brain water transport, cell migration, brain edema, metabolism and cell homeostasis. Other systems are also regulated by AQP4. Within the inner ear, the main role is to provide osmotic balance in supporting epithelium cells within the organ of Corti by recycling K+. Another specific role AQP4 plays is to help odorant molecules bind to target receptors and binding proteins within olfactory epithelium. Within the retina, the role of AQP-4 is to maintain homeostasis. Aquaporin-4 is essential in the formation of memory as well as synaptic plasticity. Other performances that aquaporin-4 is involved in are synaptic plasticity, astrocyte migration, regulation of extracellular space volume, and the homeostasis of potassium. # Clinical significance The condition known as neuromyelitis optica, NMO, is a rare demyelinating, inflammatory disorder of the CNS that primarily affects the optic nerves and spinal cord of individuals. Aquaporin-4 is the predominant autoimmune target in neuromyelitis optica, or NMO, since a specific AQP4 IgG autoantibody, or NMO-IgG, binds to the extracellular surface of AQP4. This binding provides an opening for the development of targeted therapeutics in NMO. As of right now, some therapy options are immunosuppression, such as corticosteroids and azathioprine immunosuppressive drugs, immunomodulation, and plasma exchange. A recent serum has been detected for patients with NMO, which is currently used to diagnose this condition. Other clinical significant implications of AQP4 in the human body is the role in the regulation of cerebrospinal fluid (CSF) in the ventricles. Within the ventricles of the brain, AQP4 can be utilized in the removal of excess CSF in conditions such as hydrocephaly. The primary treatment for individuals with hydrocephaly is through the implementation of mechanical shunts into the ventricles to drain the excess fluid. With further research into the role of AQP4, it may be possible to modify the human body's system of upregulation of these channels to help in the reabsorption of CSF without the need to use physically invasive treatments. # Research Based on work in animal models, aquaporin-4 may have a role in several other diseases including Alzheimer's disease, amyotrophic lateral sclerosis, Parkinson's disease, multiple sclerosis, and epilepsy, and appears to have a role in pathological response to traumatic brain injury and stroke. In rodent models, AQP4 appears plays a role in both the development and resolution of the cerebral edema that occurs following an injury like TBI or stroke and around brain tumors. In comparison with wild-type mice, double knockout mice exhibited different diseases course post brain injury. It indicated reduced intracranial pressure, cell death, water accumulation, astrogliosis, and lesion volume. The expression of aquaporin 4 is reliant on the disease stage of TBI. In an acute stage of TBI, the lack of aquaporin 4 causes an decrease of excess water removal while for later stage TBI results in prevention of severe damage and swelling. In people who suffer from Alzheimer's disease, amyloid plaques sometimes develop in brain arteries—a condition is referred to as cerebral amyloid angiopathy, or CAA. Animal studies have found that the severity of CAA increases or decreases depending on aquaporin-4 expression. When there is an decrease in AQP4, CAA severity increases and vice versa; it is not known what causes changes in AQP4 expression levels, nor whether this is part of the disease process or an effort of the brain to adapt. In animal models of amyotrophic lateral sclerosis, AQP4 is overexpressed in the brainstem, cortex, and gray matter of the spinal cord which results in swollen astrocytes; the reason for this is not understood. Knockout mice display cognition problems; there is disruption in memory consolidation as well as disruption between memory acquisition, spatial recognition, and memory of where an object was after it has been moved.	Aquaporin 4 Aquaporin-4, also known as AQP4, is a water channel protein encoded by the AQP4 gene in humans.[1] AQP4 belongs to the aquaporin family of integral membrane proteins that conduct water through the cell membrane. A limited number of aquaporins are found within the central nervous system (CNS): AQP1, 3, 4, 5, 8, 9, and 11, but more exclusive representation of AQP1, 4, and 9 are found in the brain and spinal cord.[2] In the CNS, AQP4 is the most prevalent aquaporin channel, specifically located at the perimicrovessel astrocyte foot processes, glia limitans, and ependyma.[3] Aquaporin-4 was first identified in 1986. It was the first evidence of the existence of water transport channels.[4] The method that was used to discover the existence of the transport channels was through knockout experiments. With this technique they were able to show the significant role of AQP4 in CNS injuries and brain water imbalances.[2] # Structure The structure of AQP4 consists of six-transmembrane domains and five connecting loops to form the channel. Through x-ray crystallography, it was found that “each AQP4 monomer consists of six helical, membrane-spanning domains and two short helical segments surrounding a narrow aqueous pore.”[5] Similar to other aquaporin channels, the monomers of AQP4 assemble into tetramers.[6] In addition, AQP4 has two distinct structural isoforms located in the CNS: M1 and M23.[2] Both form homo- and hetero-tetramers that are permeable to water.[2] M23 isoforms are larger square arrays in the endfoot membranes of astrocytes compared to M1 isoforms, which are smaller and more unstable. The aquaporin-4 tetramers accumulate to transform into orthogonal arrays of particle (OAPs) in the cell plasma membrane.[5] # Tissue and cellular distribution Aquaporin-4 is highly expressed in the human body primarily at the end-feet of astrocytes.[5] Additionally, AQP4 can also be located in epithelial cells of many organs throughout the human body, such as the kidney, intestine, salivary glands, sensory organs, and skeletal muscles.[4] In these specific cases of epithelial cell expression, AQP4 is concentrated within the basolateral membrane layer of these locations.[6] Furthermore, AQP4 also plays a role in the supportive cells of sensory organs, such as the retina, inner ear, and olfactory epithelium.[5] Within the retina, AQP4 is highly concentrated where the processes of Muller cells have a basal lamina around blood vessels and inner limiting membrane.[4] AQP4 is also expressed in astrocytes and is upregulated by direct insult to the central nervous system.[7] Specifically within the central nervous system (CNS), AQP4 can be found along the spinal cord and serves as the main water channel.[2] The AQP4 channels are highly concentrated in the blood-brain barrier (BBB), as well as in other cerebrospinal fluid barriers.[8] In the kidneys, AQP4 is constitutively expressed in the basolateral cell membrane of principal collecting duct cells and provide a pathway for water to exit these cells.[9] # Function Aquaporin-4’s overall function is to provide fast water transportation as well as maintain homeostatic balance within the central nervous system. It is the primary water channel protein that reconciles the homeostasis of water in the CNS.[2] AQP4 may be involved in a variety of physiological processes such as waste removal and fine-tuning of potassium homeostasis.[8] Water flowing into and out of the brain or spinal cord is assisted by AQP4.[2] Here, AQP4 channels respond passively to osmotic gradients. In addition, they play a role in brain water transport, cell migration, brain edema, metabolism and cell homeostasis.[10] Other systems are also regulated by AQP4. Within the inner ear, the main role is to provide osmotic balance in supporting epithelium cells within the organ of Corti by recycling K+.[4] Another specific role AQP4 plays is to help odorant molecules bind to target receptors and binding proteins within olfactory epithelium.[4] Within the retina, the role of AQP-4 is to maintain homeostasis.[4] Aquaporin-4 is essential in the formation of memory as well as synaptic plasticity.[8] Other performances that aquaporin-4 is involved in are synaptic plasticity, astrocyte migration, regulation of extracellular space volume, and the homeostasis of potassium.[8] # Clinical significance The condition known as neuromyelitis optica, NMO, is a rare demyelinating, inflammatory disorder of the CNS that primarily affects the optic nerves and spinal cord of individuals.[11] Aquaporin-4 is the predominant autoimmune target in neuromyelitis optica, or NMO, since a specific AQP4 IgG autoantibody, or NMO-IgG, binds to the extracellular surface of AQP4.[5] This binding provides an opening for the development of targeted therapeutics in NMO.[5] As of right now, some therapy options are immunosuppression, such as corticosteroids and azathioprine immunosuppressive drugs, immunomodulation, and plasma exchange.[5] A recent serum has been detected for patients with NMO, which is currently used to diagnose this condition.[3] Other clinical significant implications of AQP4 in the human body is the role in the regulation of cerebrospinal fluid (CSF) in the ventricles. Within the ventricles of the brain, AQP4 can be utilized in the removal of excess CSF in conditions such as hydrocephaly.[10] The primary treatment for individuals with hydrocephaly is through the implementation of mechanical shunts into the ventricles to drain the excess fluid. With further research into the role of AQP4, it may be possible to modify the human body's system of upregulation of these channels to help in the reabsorption of CSF without the need to use physically invasive treatments.[10] # Research Based on work in animal models, aquaporin-4 may have a role in several other diseases including Alzheimer's disease, amyotrophic lateral sclerosis, Parkinson's disease, multiple sclerosis, and epilepsy, and appears to have a role in pathological response to traumatic brain injury and stroke.[8] In rodent models, AQP4 appears plays a role in both the development and resolution of the cerebral edema that occurs following an injury like TBI or stroke and around brain tumors.[3][6] In comparison with wild-type mice, double knockout mice exhibited different diseases course post brain injury.[8] It indicated reduced intracranial pressure, cell death, water accumulation, astrogliosis, and lesion volume.[8] The expression of aquaporin 4 is reliant on the disease stage of TBI.[8] In an acute stage of TBI, the lack of aquaporin 4 causes an decrease of excess water removal while for later stage TBI results in prevention of severe damage and swelling.[8] In people who suffer from Alzheimer's disease, amyloid plaques sometimes develop in brain arteries—a condition is referred to as cerebral amyloid angiopathy, or CAA. Animal studies have found that the severity of CAA increases or decreases depending on aquaporin-4 expression. When there is an decrease in AQP4, CAA severity increases and vice versa; it is not known what causes changes in AQP4 expression levels, nor whether this is part of the disease process or an effort of the brain to adapt.[8] In animal models of amyotrophic lateral sclerosis, AQP4 is overexpressed in the brainstem, cortex, and gray matter of the spinal cord which results in swollen astrocytes; the reason for this is not understood.[8] Knockout mice display cognition problems; there is disruption in memory consolidation as well as disruption between memory acquisition, spatial recognition, and memory of where an object was after it has been moved.[8]	https://www.wikidoc.org/index.php/Aquaporin_4
2914cd1cd98b32849256bd0bb4cb5db0a068ec35	wikidoc	Chloroquine	Chloroquine # Disclaimer WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here. # Black Box Warning # Overview Chloroquine is a aminoquinoline antimalarial that is FDA approved for the treatment of for the suppressive treatment and for acute attacks of malaria due to P. vivax, P. malariae, P. ovale, and susceptible strains of P. falciparum. The drug is also indicated for the treatment of extraintestinal amebiasis.. There is a Black Box Warning for this drug as shown here. Common adverse reactions include cardiovascular, dermatological, immunological, neurological and ophthalmological (see Adverse Reactions section). # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - Chloroquine phosphate tablets are indicated for the suppressive treatment and for acute attacks of malaria due to P. vivax, P. malariae, P. ovale, and susceptible strains of P. falciparum. The drug is also indicated for the treatment of extraintestinal amebiasis. - Chloroquine phosphate tablets does not prevent relapses in patients with vivax or malariae malaria because it is not effective against exoerythrocytic forms of the parasite, nor will it prevent vivax or malariae infection when administered as a prophylactic. It is highly effective as a suppressive agent in patients with vivax or malariae malaria, in terminating acute attacks, and significantly lengthening the interval between treatment and relapse. In patients with falciparum malaria it abolishes the acute attack and effects complete cure of the infection, unless due to a resistant strain of P. falciparum. - The dosage of chloroquine phosphate is often expressed or calculated as the base. Each 250 mg tablet of chloroquine phosphate is equivalent to 150 mg base. In infants and children the dosage is preferably calculated on the body weight. - Malaria: - Suppression— Adult Dose: 500 mg (= 300 mg base) on exactly the same day of each week. - If circumstances permit, suppressive therapy should begin two weeks prior to exposure. However, failing this in adults, an initial double (loading) dose of 1 g (= 400 mg base), or in children 10 mg base/kg may be taken in two divided doses, six hours apart. The suppressive therapy should be continued for eight weeks after leaving the endemic area. - For Treatment of Acute Attack: - An initial dose of 1 g (= 400 mg base) followed by an additional 500 mg (= 300 mg base) after six to eight hours and a single dose of 500 mg (= 300 mg base) on each of two consecutive days. This represents a total dose of 2.5 g chloroquine phosphate or 1.5 g base in three days. - The dosage for adults of low body weight and for infants and children should be determined as follows: First dose: 10 mg base per kg (but not exceeding a single dose of 400 mg base). Second dose: (6 hours after first dose) 5 mg base per kg (but not exceeding a single dose of 300 mg base). Third dose: (24 hours after first dose) 5 mg base per kg. - First dose: 10 mg base per kg (but not exceeding a single dose of 400 mg base). - Second dose: (6 hours after first dose) 5 mg base per kg (but not exceeding a single dose of 300 mg base). - Third dose: (24 hours after first dose) 5 mg base per kg. - Fourth dose: (36 hours after first dose) 5 mg base per kg. - Fourth dose: (36 hours after first dose) 5 mg base per kg. - For radical cure of vivax and malariae malaria concomitant therapy with an 8-aminoquinoline compound is necessary. - Extraintestinal Amebiasis: - Adults:1 g (400 mg base) daily for two days, followed by 500 mg (300 mg base) daily for at least two to three weeks. Treatment is usually combined with an effective intestinal amebicide. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Chloroquine in adult patients. ### Non–Guideline-Supported Use - Hemophagocytic syndrome - Porphyria cutanea tarda - Sarcoidosis - Ulcerative colitis # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) - Malaria: - The dosage of chloroquine phosphate is often expressed or calculated as the base. Each 250 mg tablet of chloroquine phosphate is equivalent to 150 mg base. In infants and children the dosage is preferably calculated on the body weight. - The weekly suppressive dosage is 5 mg calculated as base, per kg of body weight, but should not exceed the adult dose regardless of weight. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Chloroquine in pediatric patients. ### Non–Guideline-Supported Use - Hemophagocytic syndrome - Porphyria cutanea tarda # Contraindications - Use of this drug is contraindicated in the presence of retinal or visual field changes either attributable to 4-aminoquinoline compounds or to any other etiology, and in patients with known hypersensitivity to 4-aminoquinoline compounds. However, in the treatment of acute attacks of malaria caused by susceptible strains of plasmodia, the physician may elect to use this drug after carefully weighing the possible benefits and risks to the patient. # Warnings - It has been found that certain strains of P. falciparum have become resistant to 4- aminoquinoline compounds (including chloroquine and hydroxychloroquine). Chloroquine resistance is widespread and, at present, is particularly prominent in various parts of the world including sub-Saharan Africa, Southeast Asia, the Indian subcontinent, and over large portions of South America, including the Amazon basin1. - Before using chloroquine for prophylaxis, it should be ascertained whether chloroquine is appropriate for use in the region to be visited by the traveler. Chloroquine should not be used for treatment of P.falciparum infections acquired in areas of chloroquine resistance or malaria occurring in patients where chloroquine prophylaxis has failed. - Patients infected with a resistant strain of plasmodia as shown by the fact that normally adequate doses have failed to prevent or cure clinical malaria or parasitemia should be treated with another form of antimalarial therapy. - Retinopathy/maculopathy, as well as macular degeneration have been reported, and irreversible retinal damage has been observed in some patients who had received long-term or high-dosage 4-aminoquinoline therapy. Retinopathy has been reported to be dose related. Risk factors for the development of retinopathy include age, duration of treatment, high daily and/or cumulated doses. - When prolonged therapy with any antimalarial compound is contemplated, initial (base line) and periodic ophthalmologic examinations (including visual acuity, expert slit-lamp, funduscopic, and visual field tests) should be performed. - If there is any indication (past or present) of abnormality in the visual acuity, visual field, or retinal macular areas (such as pigmentary changes, loss of foveal reflex), or any visual symptoms (such as light flashes and streaks) which are not fully explainable by difficulties of accommodation or corneal opacities, the drug should be discontinued immediately and the patient closely observed for possible progression. Retinal changes (and visual disturbances) may progress even after cessation of therapy. - Acute extrapyramidal disorders may occur with chloroquine. These adverse reactions usually resolve after treatment discontinuation and/or symptomatic treatment. - All patients on long-term therapy with this preparation should be questioned and examined periodically, including testing knee and ankle reflexes, to detect any evidence of muscular weakness. If weakness occurs, discontinue the drug. - A number of fatalities have been reported following the accidental ingestion of chloroquine, sometimes in relatively small doses (0.75 g or 1 g chloroquine phosphate in one 3-year-old child). Patients should be strongly warned to keep this drug out of the reach of children because they are especially sensitive to the 4-aminoquinoline compounds. - Use of chloroquine phosphate in patients with psoriasis may precipitate a severe attack of psoriasis. When used in patients with porphyria the condition may be exacerbated. The drug should not be used in these conditions unless in the judgment of the physician the benefit to the patient outweighs the potential risks. - Usage in Pregnancy: Radioactively tagged chloroquine administered intravenously to pregnant pigmented CBA mice passed rapidly across the placenta and accumulated selectively in the melanin structures of the fetal eyes. It was retained in the ocular tissues for five months after the drug had been eliminated from the rest of the body. There are no adequate and well-controlled studies evaluating the safety and efficacy of chloroquine in pregnant women. Usage of chloroquine during pregnancy should be avoided except in the suppression or treatment of malaria when in the judgment of the physician the benefit outweighs the potential risk to the fetus. - Hematological Effects/Laboratory Tests - Complete blood cell counts should be made periodically if patients are given prolonged therapy. If any severe blood disorder appears which is not attributable to the disease under treatment, discontinuance of the drug should be considered. - The drug should be administered with caution to patients having G-6-PD (glucose-6 phosphate dehydrogenase) deficiency. - Auditory Effects - In patients with preexisting auditory damage, chloroquine should be administered with caution. In case of any defects in hearing, chloroquine should be immediately discontinued, and the patient closely observed. - Hepatic Effects - Since this drug is known to concentrate in the liver, it should be used with caution in patients with hepatic disease or alcoholism or in conjunction with known hepatotoxic drugs. - Central Nervous System Effects - Patients with a history of epilepsy should be advised about the risk of chloroquine provoking seizures. # Adverse Reactions ## Clinical Trials Experience ### Special Senses:Ocular:= - Maculopathy and macular degeneration have been reported and may be irreversible; irreversible retinal damage in patients receiving long-term or high-dosage 4-aminoquinoline therapy; visual disturbances (blurring of vision and difficulty of focusing or accommodation); nyctalopia; scotomatous vision with field defects of paracentral, pericentral ring types, and typically temporal scotomas, e.g., difficulty in reading with words tending to disappear, seeing half an object, misty vision, and fog before the eyes. Reversible corneal opacities have also been reported. - Nerve type deafness; tinnitus, reduced hearing in patients with preexisting auditory damage. - Skeletal muscle myopathy or neuromyopathy leading to progressive weakness and atrophy of proximal muscle groups, which may be associated with mild sensory changes, depression of tendon reflexes and abnormal nerve conduction, have been noted. - Hepatitis, increased liver enzymes, anorexia, nausea, vomiting, diarrhea, abdominal cramps. - Rare reports of erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis, exfoliative dermatitis and similar desquamation-type events. Pleomorphic skin eruptions, skin and mucosal pigmentary changes; lichen planus-like eruptions, pruritus, urticaria, anaphylactic/anaphylactoid reaction including angioedema; drug rash with eosinophilia and systemic symptoms (DRESS syndrome); photosensitivity and hair loss and bleaching of hair pigment. - Rarely, pancytopenia, aplastic anemia, reversible agranulocytosis, thrombocytopenia and neutropenia. - Convulsive seizures, mild and transient headache, polyneuritis. Acute extrapyramidal disorders (such as dystonia, dyskinesia, tongue protrusion, torticollis). Neuropsychiatric changes including psychosis, delirium, anxiety, agitation, insomnia, confusion, hallucinations, personality changes, and depression. - Rarely, hypotension, electrocardiographic change particularly, inversion or depression of the T-wave with widening of the QRS complex prolonged QT interval, atrioventricular block, heart failure and cardiomyopathy. ## Postmarketing Experience There is limited information regarding Postmarketing Experience of Chloroquine phosphate in the drug label. # Drug Interactions ### Antacids and kaolin:= - Antacids and kaolin can reduce absorption of chloroquine; an interval of at least 4 hours between intake of these agents and chloroquine should be observed. - Cimetidine can inhibit the metabolism of chloroquine, increasing its plasma level. Concomitant use of cimetidine should be avoided. - In a study of healthy volunteers, chloroquine significantly reduced the bioavailability of ampicillin. An interval of at least two hours between intake of this agent and chloroquine should be observed. - After introduction of chloroquine (oral form), a sudden increase in serum cyclosporine level has been reported. Therefore, close monitoring of serum cyclosporine level is recommended and, if necessary, chloroquine should be discontinued. - Co-administration of chloroquine and mefloquine may increase the risk of convulsions. - The blood concentrations of chloroquine and desethylchloroquine (the major metabolite of chloroquine, which also has antimalarial properties) were negatively associated with log antibody titers. Chloroquine taken in the dose recommended for malaria prophylaxis can reduce the antibody response to primary immunization with intradermal human diploid-cell rabies vaccine. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): C - Radioactively tagged chloroquine administered intravenously to pregnant pigmented CBA mice passed rapidly across the placenta and accumulated selectively in the melanin structures of the fetal eyes. It was retained in the ocular tissues for five months after the drug had been eliminated from the rest of the body. There are no adequate and well-controlled studies evaluating the safety and efficacy of chloroquine in pregnant women. Usage of chloroquine during pregnancy should be avoided except in the suppression or treatment of malaria when in the judgment of the physician the benefit outweighs the potential risk to the fetus. Pregnancy Category (AUS): - Australian Drug Evaluation Committee (ADEC) Pregnancy Category There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Chloroquine phosphate in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Chloroquine phosphate during labor and delivery. ### Nursing Mothers - Because of the potential for serious adverse reactions in nursing infants from chloroquine, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the potential clinical benefit of the drug to the mother. - The excretion of chloroquine and the major metabolite, desethylchloroquine, in breast milk was investigated in eleven lactating mothers following a single oral dose of chloroquine (400 mg base). The maximum daily dose of the drug that the infant can receive from breastfeeding was about 0.7% of the maternal start dose of the drug in malaria chemotherapy. Separate chemoprophylaxis for the infant is required. ### Pediatric Use - A number of fatalities have been reported following the accidental ingestion of chloroquine, sometimes in relatively small doses (0.75 g or 1 g chloroquine phosphate in one 3-year-old child). Patients should be strongly warned to keep this drug out of the reach of children because they are especially sensitive to the 4-aminoquinoline compounds. ### Geriatic Use - Clinical studies of chloroquine phosphate did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. However, this drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection and it may be useful to monitor renal function. ### Gender There is no FDA guidance on the use of Chloroquine phosphate with respect to specific gender populations. ### Race There is no FDA guidance on the use of Chloroquine phosphate with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Chloroquine phosphate in patients with renal impairment. ### Hepatic Impairment - Since this drug is known to concentrate in the liver, it should be used with caution in patients with hepatic disease or alcoholism or in conjunction with known hepatotoxic drugs. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Chloroquine phosphate in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Chloroquine phosphate in patients who are immunocompromised. # Administration and Monitoring ### Administration - Oral ### Monitoring ### Cyclosporine= - After introduction of chloroquine (oral form), a sudden increase in serum cyclosporine level has been reported. Therefore, close monitoring of serum cyclosporine level is recommended and, if necessary, chloroquine should be discontinued. - Clinical studies of chloroquine phosphate did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. However, this drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection and it may be useful to monitor renal function. # IV Compatibility There is limited information regarding IV Compatibility of Chloroquine phosphatein the drug label. # Overdosage ### Symptoms:= - Chloroquine is very rapidly and completely absorbed after ingestion. Toxic doses of chloroquine can be fatal. As little as 1 g may be fatal in children. Toxic symptoms can occur within minutes. These consist of headache, drowsiness, visual disturbances, nausea and vomiting, cardiovascular collapse, shock and convulsions followed by sudden and early respiratory and cardiac arrest. Hypokalemia has been observed with arrhythmias in cases of intoxication. The electrocardiogram may reveal atrial standstill, nodal rhythm, prolonged intraventricular conduction time, and progressive bradycardia leading to ventricular fibrillation and/or arrest. Cases of extrapyramidal disorders have also been reported in the context of chloroquine overdose. - Treatment is symptomatic and must be prompt with immediate evacuation of the stomach by emesis (at home, before transportation to the hospital) or gastric lavage until the stomach is completely emptied. If finely powdered, activated charcoal is introduced by stomach tube, after lavage, and within 30 minutes after ingestion of the antimalarial, it may inhibit further intestinal absorption of the drug. To be effective, the dose of activated charcoal should be at least five times the estimated dose of chloroquine ingested. - Convulsions, if present, should be controlled before attempting gastric lavage. If due to cerebral stimulation, cautious administration of an ultra short-acting barbiturate may be tried but, if due to anoxia, it should be corrected by oxygen administration and artificial respiration, monitor ECG. In shock with hypotension, a potent vasopressor should be administered. Replace fluids and electrolytes as needed. Cardiac compressing or pacing may be indicated to sustain the circulation. Because of the importance of supporting respiration, tracheal intubation or tracheostomy, followed by gastric lavage, may also be necessary. Peritoneal dialysis and exchange transfusions have also been suggested to reduce the level of the drug in the blood. - Intervention options can involve: diazepam for life-threatening symptoms, seizures and sedation, epinephrine for treatment of vasodilation and myocardial depression, potassium replacement with close monitoring of serum potassium levels. - A patient who survives the acute phase and is asymptomatic should be closely observed for at least six hours. Fluids may be forced, and sufficient ammonium chloride (8 g daily in divided doses for adults) may be administered for a few days to acidify the urine to help promote urinary excretion in cases of both overdosage or sensitivity. # Pharmacology ## Mechanism of Action ### Microbiology= - Mechanism of Action: Chloroquine is an antimalarial agent. While the drug can inhibit certain enzymes, its effect is believed to result, at least in part from its interaction with DNA. However, the mechanism of plasmodicidal action of chloroquine is not completely certain. - Activity in vitro and in vivo: Chloroquine is active against the erythrocytic forms of Plasmodium vivax, Plasmodium malariae, and susceptible strains of Plasmodium falciparum (but not the gametocytes of P. falciparum). It is not effective against exoerythrocytic forms of the parasite. - In vitro studies with trophozoites of Entamoeba histolytica have demonstrated that chloroquine phosphate also possesses amebicidal activity comparable to that of emetine. - Drug Resistance: Resistance of Plasmodium falciparum to chloroquine is widespread and cases of Plasmodium vivax have been reported. ## Structure - Chloroquine phosphate, USP is a 4-aminoquinoline compound for oral administration. It is a white crystalline powder; odorless; has a bitter taste, and is discolored slowly on exposure to light. It is freely soluble in water, practically insoluble in alcohol, in chloroform and in ether. - Each tablet, for oral administration, contains 250 mg of chloroquine phosphate, USP (equivalent to 150 mg base). - Inactive ingredients: colloidal silicon dioxide, corn starch, hypromellose, magnesium stearate, microcrystalline cellulose, polyethylene glycol 400, polyethylene glycol 3350, polysorbate 80, povidone, sodium starch glycolate, talc, and titanium dioxide. - Chemically, it is 7-chloro-4-((4-(diethylamino)-1-methylbutyl)amino) quinoline phosphate (1:2) and has the following molecular structure: ## Pharmacodynamics There is limited information regarding Pharmacodynamics of Chloroquine phosphate in the drug label. ## Pharmacokinetics - Chloroquine is rapidly and almost completely absorbed from the gastrointestinal tract, and only a small proportion of the administered dose is found in the stools. Approximately 55% of the drug in the plasma is bound to nondiffusible plasma constituents. Excretion of chloroquine is quite slow, but is increased by acidification of the urine. Chloroquine is deposited in the tissues in considerable amounts. In animals, from 200 to 700 times the plasma concentration may be found in the liver, spleen, kidney, and lung; leukocytes also concentrate the drug. The brain and spinal cord, in contrast, contain only 10 to 30 times the amount present in plasma. - Chloroquine undergoes appreciable degradation in the body. The main metabolite is desethylchloroquine, which accounts for one fourth of the total material appearing in the urine; bisdesethylchloroquine, a carboxylic acid derivative, and other metabolic products as yet uncharacterized are found in small amounts. Slightly more than half of the urinary drug products can be accounted for as unchanged chloroquine. ## Nonclinical Toxicology There is limited information regarding Nonclinical Toxicology of Chloroquine phosphate in the drug label. # Clinical Studies There is limited information regarding Clinical Studies of Chloroquine phosphate in the drug label. # How Supplied Chloroquine phosphate tablets, USP 250 mg are white to off-white, round, film-coated tablets, debossed with “RF” and “27” on one side and break line on the other side. NDC 63304-460-03 Bottles of 10 NDC 63304-460-50 Bottles of 50 NDC 63304-460-10 Bottles of 1000 Dispense in a tight, light-resistant container as defined in the USP using a child-resistant closure. Protect from light and moisture. You may report side effects to FDA at 1-800-FDA-1088. ## Storage - Store at 20 - 25° C (68 - 77° F). # Images ## Drug Images ## Package and Label Display Panel NDC 63304-460-03 CHLOROQUINE PHOSPHATE TABLETS,USP 250 mg For Use in Malaria and Extraintestinal Amebiasis Only Rx only 10 Tablets # Patient Counseling Information There is limited information regarding Patient Counseling Information of Chloroquine phosphate in the drug label. # Precautions with Alcohol - Since this drug is known to concentrate in the liver, it should be used with caution in patients with hepatic disease or alcoholism or in conjunction with known hepatotoxic drugs. # Brand Names - Aralen Phosphate® # Look-Alike Drug Names There is limited information regarding Chloroquine Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	Chloroquine Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Adeel Jamil, M.D. [2] # Disclaimer WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here. # Black Box Warning # Overview Chloroquine is a aminoquinoline antimalarial that is FDA approved for the treatment of for the suppressive treatment and for acute attacks of malaria due to P. vivax, P. malariae, P. ovale, and susceptible strains of P. falciparum. The drug is also indicated for the treatment of extraintestinal amebiasis.. There is a Black Box Warning for this drug as shown here. Common adverse reactions include cardiovascular, dermatological, immunological, neurological and ophthalmological (see Adverse Reactions section). # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - Chloroquine phosphate tablets are indicated for the suppressive treatment and for acute attacks of malaria due to P. vivax, P. malariae, P. ovale, and susceptible strains of P. falciparum. The drug is also indicated for the treatment of extraintestinal amebiasis. - Chloroquine phosphate tablets does not prevent relapses in patients with vivax or malariae malaria because it is not effective against exoerythrocytic forms of the parasite, nor will it prevent vivax or malariae infection when administered as a prophylactic. It is highly effective as a suppressive agent in patients with vivax or malariae malaria, in terminating acute attacks, and significantly lengthening the interval between treatment and relapse. In patients with falciparum malaria it abolishes the acute attack and effects complete cure of the infection, unless due to a resistant strain of P. falciparum. - The dosage of chloroquine phosphate is often expressed or calculated as the base. Each 250 mg tablet of chloroquine phosphate is equivalent to 150 mg base. In infants and children the dosage is preferably calculated on the body weight. - Malaria: - Suppression— Adult Dose: 500 mg (= 300 mg base) on exactly the same day of each week. - If circumstances permit, suppressive therapy should begin two weeks prior to exposure. However, failing this in adults, an initial double (loading) dose of 1 g (= 400 mg base), or in children 10 mg base/kg may be taken in two divided doses, six hours apart. The suppressive therapy should be continued for eight weeks after leaving the endemic area. - For Treatment of Acute Attack: - An initial dose of 1 g (= 400 mg base) followed by an additional 500 mg (= 300 mg base) after six to eight hours and a single dose of 500 mg (= 300 mg base) on each of two consecutive days. This represents a total dose of 2.5 g chloroquine phosphate or 1.5 g base in three days. - The dosage for adults of low body weight and for infants and children should be determined as follows: First dose: 10 mg base per kg (but not exceeding a single dose of 400 mg base). Second dose: (6 hours after first dose) 5 mg base per kg (but not exceeding a single dose of 300 mg base). Third dose: (24 hours after first dose) 5 mg base per kg. - First dose: 10 mg base per kg (but not exceeding a single dose of 400 mg base). - Second dose: (6 hours after first dose) 5 mg base per kg (but not exceeding a single dose of 300 mg base). - Third dose: (24 hours after first dose) 5 mg base per kg. - Fourth dose: (36 hours after first dose) 5 mg base per kg. - Fourth dose: (36 hours after first dose) 5 mg base per kg. - For radical cure of vivax and malariae malaria concomitant therapy with an 8-aminoquinoline compound is necessary. - Extraintestinal Amebiasis: - Adults:1 g (400 mg base) daily for two days, followed by 500 mg (300 mg base) daily for at least two to three weeks. Treatment is usually combined with an effective intestinal amebicide. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Chloroquine in adult patients. ### Non–Guideline-Supported Use - Hemophagocytic syndrome - Porphyria cutanea tarda - Sarcoidosis - Ulcerative colitis # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) - Malaria: - The dosage of chloroquine phosphate is often expressed or calculated as the base. Each 250 mg tablet of chloroquine phosphate is equivalent to 150 mg base. In infants and children the dosage is preferably calculated on the body weight. - The weekly suppressive dosage is 5 mg calculated as base, per kg of body weight, but should not exceed the adult dose regardless of weight. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Chloroquine in pediatric patients. ### Non–Guideline-Supported Use - Hemophagocytic syndrome - Porphyria cutanea tarda # Contraindications - Use of this drug is contraindicated in the presence of retinal or visual field changes either attributable to 4-aminoquinoline compounds or to any other etiology, and in patients with known hypersensitivity to 4-aminoquinoline compounds. However, in the treatment of acute attacks of malaria caused by susceptible strains of plasmodia, the physician may elect to use this drug after carefully weighing the possible benefits and risks to the patient. # Warnings - It has been found that certain strains of P. falciparum have become resistant to 4- aminoquinoline compounds (including chloroquine and hydroxychloroquine). Chloroquine resistance is widespread and, at present, is particularly prominent in various parts of the world including sub-Saharan Africa, Southeast Asia, the Indian subcontinent, and over large portions of South America, including the Amazon basin1. - Before using chloroquine for prophylaxis, it should be ascertained whether chloroquine is appropriate for use in the region to be visited by the traveler. Chloroquine should not be used for treatment of P.falciparum infections acquired in areas of chloroquine resistance or malaria occurring in patients where chloroquine prophylaxis has failed. - Patients infected with a resistant strain of plasmodia as shown by the fact that normally adequate doses have failed to prevent or cure clinical malaria or parasitemia should be treated with another form of antimalarial therapy. - Retinopathy/maculopathy, as well as macular degeneration have been reported, and irreversible retinal damage has been observed in some patients who had received long-term or high-dosage 4-aminoquinoline therapy. Retinopathy has been reported to be dose related. Risk factors for the development of retinopathy include age, duration of treatment, high daily and/or cumulated doses. - When prolonged therapy with any antimalarial compound is contemplated, initial (base line) and periodic ophthalmologic examinations (including visual acuity, expert slit-lamp, funduscopic, and visual field tests) should be performed. - If there is any indication (past or present) of abnormality in the visual acuity, visual field, or retinal macular areas (such as pigmentary changes, loss of foveal reflex), or any visual symptoms (such as light flashes and streaks) which are not fully explainable by difficulties of accommodation or corneal opacities, the drug should be discontinued immediately and the patient closely observed for possible progression. Retinal changes (and visual disturbances) may progress even after cessation of therapy. - Acute extrapyramidal disorders may occur with chloroquine. These adverse reactions usually resolve after treatment discontinuation and/or symptomatic treatment. - All patients on long-term therapy with this preparation should be questioned and examined periodically, including testing knee and ankle reflexes, to detect any evidence of muscular weakness. If weakness occurs, discontinue the drug. - A number of fatalities have been reported following the accidental ingestion of chloroquine, sometimes in relatively small doses (0.75 g or 1 g chloroquine phosphate in one 3-year-old child). Patients should be strongly warned to keep this drug out of the reach of children because they are especially sensitive to the 4-aminoquinoline compounds. - Use of chloroquine phosphate in patients with psoriasis may precipitate a severe attack of psoriasis. When used in patients with porphyria the condition may be exacerbated. The drug should not be used in these conditions unless in the judgment of the physician the benefit to the patient outweighs the potential risks. - Usage in Pregnancy: Radioactively tagged chloroquine administered intravenously to pregnant pigmented CBA mice passed rapidly across the placenta and accumulated selectively in the melanin structures of the fetal eyes. It was retained in the ocular tissues for five months after the drug had been eliminated from the rest of the body. There are no adequate and well-controlled studies evaluating the safety and efficacy of chloroquine in pregnant women. Usage of chloroquine during pregnancy should be avoided except in the suppression or treatment of malaria when in the judgment of the physician the benefit outweighs the potential risk to the fetus. - Hematological Effects/Laboratory Tests - Complete blood cell counts should be made periodically if patients are given prolonged therapy. If any severe blood disorder appears which is not attributable to the disease under treatment, discontinuance of the drug should be considered. - The drug should be administered with caution to patients having G-6-PD (glucose-6 phosphate dehydrogenase) deficiency. - Auditory Effects - In patients with preexisting auditory damage, chloroquine should be administered with caution. In case of any defects in hearing, chloroquine should be immediately discontinued, and the patient closely observed. - Hepatic Effects - Since this drug is known to concentrate in the liver, it should be used with caution in patients with hepatic disease or alcoholism or in conjunction with known hepatotoxic drugs. - Central Nervous System Effects - Patients with a history of epilepsy should be advised about the risk of chloroquine provoking seizures. # Adverse Reactions ## Clinical Trials Experience ### Special Senses:Ocular:= - Maculopathy and macular degeneration have been reported and may be irreversible; irreversible retinal damage in patients receiving long-term or high-dosage 4-aminoquinoline therapy; visual disturbances (blurring of vision and difficulty of focusing or accommodation); nyctalopia; scotomatous vision with field defects of paracentral, pericentral ring types, and typically temporal scotomas, e.g., difficulty in reading with words tending to disappear, seeing half an object, misty vision, and fog before the eyes. Reversible corneal opacities have also been reported. - Nerve type deafness; tinnitus, reduced hearing in patients with preexisting auditory damage. - Skeletal muscle myopathy or neuromyopathy leading to progressive weakness and atrophy of proximal muscle groups, which may be associated with mild sensory changes, depression of tendon reflexes and abnormal nerve conduction, have been noted. - Hepatitis, increased liver enzymes, anorexia, nausea, vomiting, diarrhea, abdominal cramps. - Rare reports of erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis, exfoliative dermatitis and similar desquamation-type events. Pleomorphic skin eruptions, skin and mucosal pigmentary changes; lichen planus-like eruptions, pruritus, urticaria, anaphylactic/anaphylactoid reaction including angioedema; drug rash with eosinophilia and systemic symptoms (DRESS syndrome); photosensitivity and hair loss and bleaching of hair pigment. - Rarely, pancytopenia, aplastic anemia, reversible agranulocytosis, thrombocytopenia and neutropenia. - Convulsive seizures, mild and transient headache, polyneuritis. Acute extrapyramidal disorders (such as dystonia, dyskinesia, tongue protrusion, torticollis). Neuropsychiatric changes including psychosis, delirium, anxiety, agitation, insomnia, confusion, hallucinations, personality changes, and depression. - Rarely, hypotension, electrocardiographic change particularly, inversion or depression of the T-wave with widening of the QRS complex prolonged QT interval, atrioventricular block, heart failure and cardiomyopathy. ## Postmarketing Experience There is limited information regarding Postmarketing Experience of Chloroquine phosphate in the drug label. # Drug Interactions ### Antacids and kaolin:= - Antacids and kaolin can reduce absorption of chloroquine; an interval of at least 4 hours between intake of these agents and chloroquine should be observed. - Cimetidine can inhibit the metabolism of chloroquine, increasing its plasma level. Concomitant use of cimetidine should be avoided. - In a study of healthy volunteers, chloroquine significantly reduced the bioavailability of ampicillin. An interval of at least two hours between intake of this agent and chloroquine should be observed. - After introduction of chloroquine (oral form), a sudden increase in serum cyclosporine level has been reported. Therefore, close monitoring of serum cyclosporine level is recommended and, if necessary, chloroquine should be discontinued. - Co-administration of chloroquine and mefloquine may increase the risk of convulsions. - The blood concentrations of chloroquine and desethylchloroquine (the major metabolite of chloroquine, which also has antimalarial properties) were negatively associated with log antibody titers. Chloroquine taken in the dose recommended for malaria prophylaxis can reduce the antibody response to primary immunization with intradermal human diploid-cell rabies vaccine. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): C - Radioactively tagged chloroquine administered intravenously to pregnant pigmented CBA mice passed rapidly across the placenta and accumulated selectively in the melanin structures of the fetal eyes. It was retained in the ocular tissues for five months after the drug had been eliminated from the rest of the body. There are no adequate and well-controlled studies evaluating the safety and efficacy of chloroquine in pregnant women. Usage of chloroquine during pregnancy should be avoided except in the suppression or treatment of malaria when in the judgment of the physician the benefit outweighs the potential risk to the fetus. Pregnancy Category (AUS): - Australian Drug Evaluation Committee (ADEC) Pregnancy Category There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Chloroquine phosphate in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Chloroquine phosphate during labor and delivery. ### Nursing Mothers - Because of the potential for serious adverse reactions in nursing infants from chloroquine, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the potential clinical benefit of the drug to the mother. - The excretion of chloroquine and the major metabolite, desethylchloroquine, in breast milk was investigated in eleven lactating mothers following a single oral dose of chloroquine (400 mg base). The maximum daily dose of the drug that the infant can receive from breastfeeding was about 0.7% of the maternal start dose of the drug in malaria chemotherapy. Separate chemoprophylaxis for the infant is required. ### Pediatric Use - A number of fatalities have been reported following the accidental ingestion of chloroquine, sometimes in relatively small doses (0.75 g or 1 g chloroquine phosphate in one 3-year-old child). Patients should be strongly warned to keep this drug out of the reach of children because they are especially sensitive to the 4-aminoquinoline compounds. ### Geriatic Use - Clinical studies of chloroquine phosphate did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. However, this drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection and it may be useful to monitor renal function. ### Gender There is no FDA guidance on the use of Chloroquine phosphate with respect to specific gender populations. ### Race There is no FDA guidance on the use of Chloroquine phosphate with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Chloroquine phosphate in patients with renal impairment. ### Hepatic Impairment - Since this drug is known to concentrate in the liver, it should be used with caution in patients with hepatic disease or alcoholism or in conjunction with known hepatotoxic drugs. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Chloroquine phosphate in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Chloroquine phosphate in patients who are immunocompromised. # Administration and Monitoring ### Administration - Oral ### Monitoring ### Cyclosporine= - After introduction of chloroquine (oral form), a sudden increase in serum cyclosporine level has been reported. Therefore, close monitoring of serum cyclosporine level is recommended and, if necessary, chloroquine should be discontinued. - Clinical studies of chloroquine phosphate did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. However, this drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection and it may be useful to monitor renal function. # IV Compatibility There is limited information regarding IV Compatibility of Chloroquine phosphatein the drug label. # Overdosage ### Symptoms:= - Chloroquine is very rapidly and completely absorbed after ingestion. Toxic doses of chloroquine can be fatal. As little as 1 g may be fatal in children. Toxic symptoms can occur within minutes. These consist of headache, drowsiness, visual disturbances, nausea and vomiting, cardiovascular collapse, shock and convulsions followed by sudden and early respiratory and cardiac arrest. Hypokalemia has been observed with arrhythmias in cases of intoxication. The electrocardiogram may reveal atrial standstill, nodal rhythm, prolonged intraventricular conduction time, and progressive bradycardia leading to ventricular fibrillation and/or arrest. Cases of extrapyramidal disorders have also been reported in the context of chloroquine overdose. - Treatment is symptomatic and must be prompt with immediate evacuation of the stomach by emesis (at home, before transportation to the hospital) or gastric lavage until the stomach is completely emptied. If finely powdered, activated charcoal is introduced by stomach tube, after lavage, and within 30 minutes after ingestion of the antimalarial, it may inhibit further intestinal absorption of the drug. To be effective, the dose of activated charcoal should be at least five times the estimated dose of chloroquine ingested. - Convulsions, if present, should be controlled before attempting gastric lavage. If due to cerebral stimulation, cautious administration of an ultra short-acting barbiturate may be tried but, if due to anoxia, it should be corrected by oxygen administration and artificial respiration, monitor ECG. In shock with hypotension, a potent vasopressor should be administered. Replace fluids and electrolytes as needed. Cardiac compressing or pacing may be indicated to sustain the circulation. Because of the importance of supporting respiration, tracheal intubation or tracheostomy, followed by gastric lavage, may also be necessary. Peritoneal dialysis and exchange transfusions have also been suggested to reduce the level of the drug in the blood. - Intervention options can involve: diazepam for life-threatening symptoms, seizures and sedation, epinephrine for treatment of vasodilation and myocardial depression, potassium replacement with close monitoring of serum potassium levels. - A patient who survives the acute phase and is asymptomatic should be closely observed for at least six hours. Fluids may be forced, and sufficient ammonium chloride (8 g daily in divided doses for adults) may be administered for a few days to acidify the urine to help promote urinary excretion in cases of both overdosage or sensitivity. # Pharmacology ## Mechanism of Action ### Microbiology= - Mechanism of Action: Chloroquine is an antimalarial agent. While the drug can inhibit certain enzymes, its effect is believed to result, at least in part from its interaction with DNA. However, the mechanism of plasmodicidal action of chloroquine is not completely certain. - Activity in vitro and in vivo: Chloroquine is active against the erythrocytic forms of Plasmodium vivax, Plasmodium malariae, and susceptible strains of Plasmodium falciparum (but not the gametocytes of P. falciparum). It is not effective against exoerythrocytic forms of the parasite. - In vitro studies with trophozoites of Entamoeba histolytica have demonstrated that chloroquine phosphate also possesses amebicidal activity comparable to that of emetine. - Drug Resistance: Resistance of Plasmodium falciparum to chloroquine is widespread and cases of Plasmodium vivax have been reported. ## Structure - Chloroquine phosphate, USP is a 4-aminoquinoline compound for oral administration. It is a white crystalline powder; odorless; has a bitter taste, and is discolored slowly on exposure to light. It is freely soluble in water, practically insoluble in alcohol, in chloroform and in ether. - Each tablet, for oral administration, contains 250 mg of chloroquine phosphate, USP (equivalent to 150 mg base). - Inactive ingredients: colloidal silicon dioxide, corn starch, hypromellose, magnesium stearate, microcrystalline cellulose, polyethylene glycol 400, polyethylene glycol 3350, polysorbate 80, povidone, sodium starch glycolate, talc, and titanium dioxide. - Chemically, it is 7-chloro-4-((4-(diethylamino)-1-methylbutyl)amino) quinoline phosphate (1:2) and has the following molecular structure: ## Pharmacodynamics There is limited information regarding Pharmacodynamics of Chloroquine phosphate in the drug label. ## Pharmacokinetics - Chloroquine is rapidly and almost completely absorbed from the gastrointestinal tract, and only a small proportion of the administered dose is found in the stools. Approximately 55% of the drug in the plasma is bound to nondiffusible plasma constituents. Excretion of chloroquine is quite slow, but is increased by acidification of the urine. Chloroquine is deposited in the tissues in considerable amounts. In animals, from 200 to 700 times the plasma concentration may be found in the liver, spleen, kidney, and lung; leukocytes also concentrate the drug. The brain and spinal cord, in contrast, contain only 10 to 30 times the amount present in plasma. - Chloroquine undergoes appreciable degradation in the body. The main metabolite is desethylchloroquine, which accounts for one fourth of the total material appearing in the urine; bisdesethylchloroquine, a carboxylic acid derivative, and other metabolic products as yet uncharacterized are found in small amounts. Slightly more than half of the urinary drug products can be accounted for as unchanged chloroquine. ## Nonclinical Toxicology There is limited information regarding Nonclinical Toxicology of Chloroquine phosphate in the drug label. # Clinical Studies There is limited information regarding Clinical Studies of Chloroquine phosphate in the drug label. # How Supplied Chloroquine phosphate tablets, USP 250 mg are white to off-white, round, film-coated tablets, debossed with “RF” and “27” on one side and break line on the other side. NDC 63304-460-03 Bottles of 10 NDC 63304-460-50 Bottles of 50 NDC 63304-460-10 Bottles of 1000 Dispense in a tight, light-resistant container as defined in the USP using a child-resistant closure. Protect from light and moisture. You may report side effects to FDA at 1-800-FDA-1088. ## Storage - Store at 20 - 25° C (68 - 77° F). # Images ## Drug Images ## Package and Label Display Panel NDC 63304-460-03 CHLOROQUINE PHOSPHATE TABLETS,USP 250 mg For Use in Malaria and Extraintestinal Amebiasis Only Rx only 10 Tablets # Patient Counseling Information There is limited information regarding Patient Counseling Information of Chloroquine phosphate in the drug label. # Precautions with Alcohol - Since this drug is known to concentrate in the liver, it should be used with caution in patients with hepatic disease or alcoholism or in conjunction with known hepatotoxic drugs. # Brand Names - Aralen Phosphate® # Look-Alike Drug Names There is limited information regarding Chloroquine Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	https://www.wikidoc.org/index.php/Aralen_Phosphate
b9bb4ac302aaa04a117d60070d6b4244ce15a179	wikidoc	Archaeology	Archaeology Archaeology "studies human cultures through the recovery, documentation and analysis of material remains and environmental data, including architecture, artifacts, ecofacts, human remains, and landscapes." It is the study of human activity in the past, primarily through the recovery and analysis of the material culture and environmental data that they have left behind, which includes artifacts, architecture, biofacts and cultural landscapes (the archaeological record). Because archaeology employs a wide range of different procedures, it can be considered to be both a science and a humanity. Archaeology studies human history from the development of the first stone tools in eastern Africa 3.4 million years ago up until recent decades. (Archaeology does not include the discipline of paleontology.) It is of most importance for learning about prehistoric societies, when there are no written records for historians to study, making up over 99% of total human history, from the Palaeolithic until the advent of literacy in any given society. # Theoretical archaeology Def. the "period of time that has already happened" is called the past. Def. the "study of the past through material remains" is called archaeology, or archeology. # Entities "ominant groups create and control the meanings and uses of material culture. If other groups wish to be understood by the dominant group, they must express themselves through the goods controlled by the dominant group." "But, the privilege afforded a certain dominant group of 'normal' archaeologists in terms of their ways of constructing the past influences all aspects of archaeological practice." "However, some answers to these questions may emerge from a consideration of the dominant group, that is, the five institutions whose scholars published the most articles in the two periodicals." # Landscape archaeology Def. an assemblage of surfaces that are a portion of land, region, or territory, observable in its entirety is called a landscape. Landscape comprises the visible features of an area of land, including the physical elements of landforms such as (ice-capped) mountains, hills, water bodies such as rivers, lakes, ponds and the sea, living elements of land cover including indigenous vegetation, human elements including different forms of land use, buildings and structures, and transitory elements such as lighting and weather conditions. Landscape archaeology is the study of the ways in which people in the past constructed and used the environment around them. Landscape archaeology is inherently multidisciplinary in its approach to the study of culture, and is used by both pre-historical, classic, and historic archaeologists. The key feature that distinguishes landscape archaeology from other archaeological approaches to sites is that there is an explicit emphasis on the study of the relationships between material culture, human alteration of land/cultural modifications to landscape, and the natural environment. # Sources Archaeological field survey is the method by which archaeologists (often landscape archaeologists) search for archaeological sites and collect information about the location, distribution and organization of past human cultures across a large area (e.g. typically in excess of one hectare, and often in excess of many km2). Surveys are conducted to search for particular archaeological sites or kinds of sites, to detect patterns in the distribution of material culture over regions, to make generalizations or test hypotheses about past cultures, and to assess the risks that development projects will have adverse impacts on archaeological heritage. The surveys may be: (a) intrusive or non-intrusive, depending on the needs of the survey team (and the risk of destroying archaeological evidence if intrusive methods are used) and; (b) extensive or intensive, depending on the types of research questions being asked of the landscape in question. Surveys can be a practical way to decide whether or not to carry out an excavation (as a way of recording the basic details of a possible site), but may also be ends in themselves, as they produce important information about past human activities in a regional context. Excavation is the exposure, processing and recording of archaeological remains. An excavation site or "dig" is a site being studied. # Objects Def. an "object, such as a tool, weapon or ornament, structure or finding in an experiment or investigation ... made or shaped by some agent or intelligence, ... a result of external action, the test arrangement, or an experimental error ... rather than an inherent element" is called an artifact, or artefact. In June 2014, the Precolumbian Chiefdom Settlements with Stone Spheres of the Diquis was added to the UNESCO list of World Heritage Sites. The spheres range in size from a few centimetres to over 2 metres (6.5616798 ft) in diameter, and weigh up to 15 tons. Most are sculpted from gabbro. The culture of the people who made them disappeared after the Spanish conquest. The first scientific investigation of the spheres was undertaken shortly after their discovery and published in 1943 in American Antiquity, attracting the attention of Samuel Kirkland Lothrop of the Peabody Museum of Archaeology and Ethnology at Harvard University. In 1948, he and his wife attempted to excavate an unrelated archaeological site in the northern region of Costa Rica. In San José he met Doris Stone, who directed the group toward the Diquís Delta region in the southwest ("Valle de Diquís" refers to the valley of the lower Río Grande de Térraba, including the Osa Canton towns of Puerto Cortés, Palmar Norte, and Sierpe. The Dropa stones or discs may be a series of at least 716 circular stone discs, dating back 12,000 years, on which tiny hieroglyph-like markings may be found. Each disc is claimed to measure up to 1 foot (30.48 cm) in diameter and carry two grooves, originating from a hole in their center, in the form of a double spiral. # Coppers In "Serbia the oldest copper implements in the world. Some 7000 years ago, tradesmen of great wealth flourished on the Balkan peninsula." "The soil around Plonik is rich in copper - the metal in a pure state lays often directly at the surface." The so-called "copper-violets" "are related to the Alpine violets, which we know in Germany from flower pots. But they grow only in a soil with a very high copper content. There - where the soil is too poisonous for the other plants, they blossom in wide carpets - and in so doing point to the presence of copper." In "the late stone age people picked up the beautiful stones. For instance, malachite. The green-hued mineral belongs to the class of carbonates. Copper content: 57 percent. Our ancestors made experiments with different stones over the fire. From there, it was only a small step to jewels and to more practical objects." On "the Black Sea Coast in today's Bulgaria, there flourished a prosperous, big city, quite close to today's Varna. Archaeologists have found the cemetary of this settlement. The graves were loaded with treasures: jewels - mostly gold, but also copper - sea shells from the Aegean and tools made of types of stone which must have come from far away." "In the 5. Millennium BC people lived there in complex, centralized settlements of up to a thousand inhabitants. They invented a new ceramic oven with two chambers which was remarkably well suited to the extraction of metal. We must strongly surmise that there existed relations between the Balkans and Northern Mesopotamia." "An enormous fire unleashed itself around 5000 BC in the city . The earth carbonized. The houses collapsed and buried all the possessions of the inhabitants under their walls. When the flame died down, the city had ceased to exist." # Tools In "the deep Southeast of Europe, near today's village of Plonik in Serbia, there existed 7000 years ago a major city. Its inhabitants lived in closely assembled huts and they melted copper to make jewels, tools and weapons." "The age of the oldest pieces which they have found up to now in the settlement is up to 7300 years. That's a good 800 years older as any other copper implements which have been found anywhere on Earth to this day." # Weapons "The people of the Balkan peninsula had a good knowledge of how they could create jewels, tools and weapons out of earth with a high copper content." "In Plonik, excavators found hatchets of copper. And weapons: axes and maces. With them a new area began. The stone age was gone, the copper age - chalcolithic - had begun." # Jewelry "From one grave, the excavator dug 1,516 K of gold jewelry. This is more gold than has been found in all the rest of the world for this particular epoch." # Materials "In order to interpret archaeological ceramic assemblages in terms of social identities, a method was developed consists in sorting the potsherds according to, successively, technical, techno-petrographic and morpho-stylistic criteria." # Heritage management "Rare, though, is the country where ethnic groups balance each other in terms of numbers, wealth or political influence and, consequently, it is not uncommon for the dominant group to use its power to push its own heritage to the fore, minimizing or denying the significance of subordinate groups as it crafts a national identity in its own image." # Historical archaeology Historical archaeology is a form of archaeology dealing with places, things, and issues from the past or present when written records and oral traditions can inform and contextualize cultural material. These records can both complement and conflict with the archaeological evidence found at a particular site. Studies focus on literate, historical-period societies as opposed to non-literate, prehistoric societies. While they may not have generated the records, the lives of people for whom there was little need for written records, such as the working class, slaves, indentured labourers, and children but who live in the historical period can also be the subject of study. The sites are found on land and underwater. Industrial archaeology, unless practiced at industrial sites from the prehistoric era, is a form of historical archaeology concentrating on the remains and products of industry and the Industrial era. # Maya civilization In the image on the right, dense forest surrounds the city center of this Classic-era Maya site (top) Tikal. Laser mapping of the same view (bottom) reveals structures and causeways hidden by the jungle. "Lidar (a type of airborne laser scanning) provides a powerful technique for three-dimensional mapping of topographic features." "Lowland Maya civilization flourished from 1000 BCE to 1500 CE in and around the Yucatan Peninsula." "In 2016, the Pacunam Lidar Initiative (PLI) undertook the largest lidar survey to date of the Maya region, mapping 2144 km2 of the Maya Biosphere Reserve in Guatemala." "Analysis identified 61,480 ancient structures in the survey region, resulting in a density of 29 structures/km2. Controlling for a number of complex variables, we estimate an average density of ~80 to 120 persons/km2 at the height of the Late Classic period (650 to 800 CE). Extrapolation of this settlement density to the entire 95,000 km2 of the central lowlands produces a population range of 7 million to 11 million." "Settlement distribution is not homogeneous, however; we found evidence of (i) rural areas with low overall density, (ii) periurban zones with small urban centers and dispersed populations, and (iii) urban zones where a single, large city integrated a wider population." "The PLI survey revealed a landscape heavily modified for intensive agriculture, necessary to sustain populations on this scale. Lidar shows field systems in the low-lying wetlands and terraces in the upland areas. The scale of wetland systems and their association with dense populations suggest centralized planning, whereas upland terraces cluster around residences, implying local management. Analysis identified 362 km2 of deliberately modified agricultural terrain and another 952 km2 of unmodified uplands for potential swidden use. Approximately 106 km of causeways within and between sites constitute evidence of inter- and intracommunity connectivity. In contrast, sizable defensive features point to societal disconnection and large-scale conflict." “The new lidar data show that interconnected Maya cities go back to at least 300 B.C.” # Prehistory The prehistory period dates from around 7 x 106 b2k to about 7,000 b2k. Def. the "history of human culture prior to written records" is called prehistory. # 21st Century "During an underwater expedition in 2000, divers saw a large stone head emerge from the murky dark waters . It was the head of the god Hapi, the personification of the Nile’s annual flood." Heracleion, also known by its Egyptian name Thonis, and sometimes called Thonis-Heracleion, was an ancient Egyptian city located near the Canopic Mouth of the Nile, about 32 km northeast of Alexandria. Its ruins are located in Abu Qir Bay, currently 2.5 km off the coast, under 10 m (30 ft) of water. A stele found on the site indicates that it was one single city known by both its Egyptian and Greek names. # 20th Century Manned spaceflight on an individual basis has only been achieved with experimental aircraft such as the X-15. "In 1933 British RAF Group-Captain Cull was flying his plane over Aboukir, a Royal Air Force base east of Alexandria in Egypt, when he glimpsed something in the water below him. From his vantage point, Cull could make out the outlines of structures beneath the water. Unbeknownst to him, Cull had located Heracleion, an important ancient Egyptian city that had lain hidden beneath the water for nearly 1500 years." Heracleion is located at 31°18'15"N 30°06'02"E. "According to legend, this lost metropolis had hosted its namesake, Heracles, and lovers Paris and Helen before they fled to Troy. Cleopatra, Egypt’s most famous queen, had even been crowned in one of the temples there." "Before its discovery, Heracleion (which was also known in the ancient world by its Egyptian name, Thonis) was almost the stuff of mythology. Though it is now buried several miles off the coast, Thonis-Heracleion was once a thriving port city." The ruins submerged in the sea were located and explored by the French underwater archaeologist Franck Goddio in 1999, after a five-year search. # 19th Century The Covered Bridge on the right was built in 1867 near the town of Cedarburg, Wisconsin. "In 1866 Mahmoud Bey El-Falaki, the official astronomer to the Viceroy of Egypt, had published a map that located the nearby ancient town of Canopus on the edge of the coastline." # 18th Century Taken from the observation platform at the top of the Jantar Mantar, the image on the right shows smaller architectural sundials. The Jantar Mantar is a collection of architectural astronomical instruments, built by Maharaja Jai Singh II at his then new capital of Jaipur between 1727 and 1733. The City Palace is behind then Govindji Temple. Nahargarh Fort is on the Hill. # 17th Century The Keplerian Telescope was invented by Johannes Kepler in 1611. # 16th Century The images on the right shows the sphere without sighting tubes or any device for observing astronomical objects and dates from 1547. # 15th Century The image at the right dating from c. 1480 shows the sphere without sighting tube or any device for observing astronomical objects. # 14th Century The image at the left shows a sceptre dated to before 1380. "According to written records, a steady succession of earthquakes, perhaps as many as 23, struck North Africa between A.D. 323-1303." # 13th Century The ruin tower on the right is apparently dated to the 13th Century and was built by the Anasazi. # 12th Century Romanesque apses and brick towers of the Church of San Tirso, Sahagún, are shown on the right, dated to the 12th Century. # 11th Century The star map on the right, which features a cylindrical projection, was published in 1092 and has a corrected position for the pole star using Shen Kuo's astronomical observations. # 10th Century Visby was founded in the 10th century, on the then independent Baltic Sea island of Gotland. The Hansaetic League formed it during ensuing centuries, during which it came to Denmark. In 1645, it came into Swedish occupation, in which it has remained until today. There is more about lenses more recently from Visby, Gotland. "What intrigues the researchers is that the lenses are of such high quality that they could have been used to make a telescope some 500 years before the first known crude telescopes were constructed in Europe in the last few years of the 16th century." "Made from rock-crystal, the lenses have an accurate shape that betrays the work of a master craftsman. The best example of the lenses measures 50 mm (2 inches) in diameter and 30 mm (1 inch) thick at its centre." "The Gotland crystals provide the first evidence that sophisticated lens-making techniques were being used by craftsmen over a 1,000 years ago." # 9th Century There was an inscription which placed the foundation of the nilometer in 861. Cobá is a former pre-Columbian Mayan city on the Yucatán Peninsula southeast of Valladolid located in the state of Quintana Roo, Mexico. In Cobá, the temple pyramid Nohoch-Mul (also known as Castillo, or the climbing pyramid shown on the left) is 42 meters high. The city was founded shortly after the beginning of the year and expanded into a city state that peaked between 600 and 800 (1400 and 1200 b2k). # 8th Century The Dunhuang map from the Tang Dynasty of the North Polar region at right is thought to date from the reign of Emperor Zhongzong of Tang (705–710). Constellations of the three schools are distinguished with different colors: white, black and yellow for stars of Wu Xian, Gan De and Shi Shen respectively. The whole set of star maps contains 1,300 stars. The Dunhuang Star Atlas, the last section of manuscript Or.8210/S.3326. It is "the oldest manuscript star atlas known today from any civilisation, probably dating from around AD 700. It shows a complete representation of the Chinese sky in 13 charts with over 1300 stars named and accurately presented." "The Dunhuang Star Atlas forms the second part of a longer scroll (Or.8210/S.3326) that measures 210 cm long by 24.4 cm wide and is made of fine paper in thirteen separate panels." "The first part of the scroll is a manual for divination based on the shape of clouds. The twelve charts showing different sections of the sky follow these. The stars are named and there is also explanatory text. The final chart is of the north-polar region. The chart is detailed, showing a total of 1345 stars in 257 clearly marked and named asterisms, or constellations, including all twenty-eight mansions." "The importance of the chart lies in both its accuracy and graphic quality. The chart includes both bright and faint stars, visible to the naked eye from north central China". # 7th Century Sambor Pre Kuk, with its N16 Sanctuary imaged on the right, is an archaeological complex formed by the remains of the city of Isanapura, the capital of the kingdom of Chenla, an immediate predecessor of the Khmer Empire (pre-Angkorian). This city was built during the reign of Isanavarman I (616-635). At this time, several constructions, clear predecessors of Khmer architecture, were erected in Angkor. Cantona is a Mesoamerican archaeological site in the state of Puebla, Mexico. It was a fortified city with a high urbanization level at prehispanic times, probably founded by Olmec-Xicalanca groups towards the late Classical Period. It sat astride an old trading route between the Gulf Coast and the Central Highlands and was a prominent, if isolated, Mesoamerican city between 600 and 1000 CE. After Chichimec's invasions in the 11th century, Cantona was abandoned. Cantona's inhabitants were mainly agricultural farmers and traders, particularly for obsidian, obtained from Oyameles-Zaragoza mountains surrounding the city. Additionally, they may have been supplying the lowlands with a derivative of the maguey plant, pulque. Cantona's population is estimated at about 80,000 inhabitants at its peak. Cantona may well be the largest prehispanic city yet discovered in Mesoamerica. Limited archaeological work has been done at the site, and only about 10% of the site can be seen. The Pre-Columbian settlement area occupies approximately 12 km², distributed in three units, of which the largest is at the south, with a surface of 5 km². The site comprises a road network with over 500 cobblestone causeways, more than 3,000 individual patios, residences, and 24 ball courts - more than in any other mesoamerican site. It has an elevated Acropolis over the rest of the city in which the main buildings of the city were built. This was used for the ruling elite and priests, and was where the temples of the most important deities where located. These impressive buildings were constructed with carved stones (one atop the other) without any stucco or cement mortar. Cantona certainly was built with a definite urban design and walkways connecting each and every part of the city. The "First Avenue" is 563 meters in length. # 6th Century On the right is the Basilica Cistern in Constantinople, Turkey. It has been dated to the 6th century. Dzibanche is an archaeological site which includes the Temple of the Owl pyramid. It is an ancient Maya site located in southern Quintana Roo, in the Yucatan Peninsula of southeastern Mexico. Structures at Dzibanche include the Temple of the Captives, the Temple of the Lintels and the Temple of the Owl, on the left. # 5th Century Ancient India was an early leader in metallurgy, as evidenced by the wrought-iron Pillar of Delhi in the image on the right, dated to about 415 or 1585 b2k. # 4th Century The House of Peter in Capernaum, Israel, has been dated to the 4th century. "The most severe occurred in A.D. 365. The coastline fell and the cluster of cities that lay in the Canopic branch of the Nile vanished into the Mediterranean." # 3rd Century The last known celestial globe shown at the right dates from 1850 to 1780 b2k. The constellation illustrations from the Mainz celestial globe are shown at the left. # 2nd Century On the right is an image of the oldest extant diagram of Euclid's Elements, found at Oxyrhynchus and dated to c. 100 AD. # 1st Century Pompeii lens (plano-convex) from the excavations of the Via Stabia, "House of the Engraver" dated to 79 AD per E. Gerspach, L'art de la verrerie (Paris 1885) 41-42. Roman London lens (fragmentary biconvex glass lens of light green color), from Roman London, dated to 43-50 AD per H. Syer Cuming, "On Spectacles," The Journal of the British Archaeological Association 11 (1855) 144-49. # -1st Century The "Late La Tène time span between the conquests of 55 BC and 54 BC under Julius Caesar (100-44 BC) and the time of Christ. In the rare cases where pottery and tableware are attributed to Saxons of the 4th/5th c. AD, "astonishingly La Tène art styles re-emerge as dominant in the northern and western zone." (Hines 1996, 260)" "Stamped pottery has had a long and varied history in Britain. There have been periods when it flourished and periods when it almost totally disappeared. This article considers two variations of the rosette motif (A 5) and their fortunes from the late Iron Age to the Early Saxon period. The La Tène ring stamps are found in a range of designs, from the simple negative ring (= AASPS Classification A 1bi) to four concentric negative rings (= AASPS A 2di). These motifs are also found in the early Roman period . The 'dot rosettes' (= AASPS A 9di) -n bowls from the Hunsbury hill-fort (Fell 1937) use the same sort of technique as the dimple decoration on 4th-century 'Romano-Saxon' wares." In "Šarnjaka kod Šemovca (Dalmatia/Croatia), e.g., contain 700-year-older La Tène and Imperial period items (1st century BC to 3rd century AD) :" "A large dugout house (SU 9) was discovered in the course of the investigation in 2006. Its dimensions are 4.8 by 2.1 metres, with a depth of 34 centimetres, and an east-west orientation, deviating slightly along the NE-SW line. It contained numerous sherds of Early Medieval pottery, two fragments of glass, and a small iron spike. Three sherds of Roman pottery and ten sherds of La Tène pottery were also recovered from the house." "The contemporaneity of Rome’s Imperial period textbook-dated to the 1st-3rd century AD with the Early Middle Ages (8th-10th century AD) is also confirmed for Poland . There, too, Late Latène (conventionally ending 1st c. BC) immediately precedes the Early Medieval period of the 8th-10th c. CE." "In capital cities, Rome and Constantinople (Heinsohn 2016) build residential quarters, streets, latrines, aqueducts, ports etc. only in one of the three periods—Imperial Antiquity, Late Antiquity, and Early Middle Ages—dated between 1 and 930s AD. In Rome, they are assigned to Imperial Antiquity (1st-3rd c.); in Constantinople, to Late Antiquity (4th-6th c.)." "Roman churches of Late Antiquity and the Early Middle Ages would suffice to confirm the existence of these two periods. The churches are there. However, we never find churches of the 8th or 9th century superimposed on churches of the 4th or 5th century that, in turn, are superimposed on pagan basilicas of the 1st or 2nd century. They all share the same stratigraphic level of the 1st and 2nd/early 3rd century. Moreover, the ground plans of the 4th/5th—as well as the 8th/9th—century churches slavishly repeat the ground plans of 1st/2nd century basilicas, as already pointed out 75 years ago by Richard Krautheimer (1897-1994). It is this period of Imperial Antiquity (with its internal evolution from the 1st to 3rd centuries) that alone builds the residential quarters, latrines, streets, and aqueducts so desperately looked for in Late Antiquity and the Early Middle Ages. Thus, Rome does not have more stratigraphy for the first millennium AD than England or Poland." "Germanic tribes, not only Anglo-Saxons and Frisians but also Franks, had been competing with Rome for the conquest of the British Isles since the 1st century BC". "1st century BC "Astonishingly LA TÈNE art styles" (Hines 1996) dominate pottery of SAXONS Powerful LA TÈNE Celts with King Aththe-Domarous of Camulodunum greatest ruler." "Saxons begin their attack on Britain as early as the 1st century BC. They compete with the Romans, who may have employed Germanic Franks as auxiliary forces. The Saxons invade from the East, i.e., from the German Bight." From "the stratigraphy of the Saxon homeland, located around Bremen/Weser inside today’s Lower Saxony is mainly inhabited by Chauci and Bructeri Saxon tribes that are at war with the Romans in the time of Augustus (31 BC-14 AD) and Aththe-Domaros of Camulodunum (Aθθe-Domaros, also read as Addedom-Arus; c. 15-5 BC)." On the right is an Indian-standard coin of King Maues. On the obverse is a rejoicing elephant holding a wreath, a symbol of victory. The Greek legend reads ΒΑΣΙΛΕΩΣ ΒΑΣΙΛΕΩΝ ΜΕΓΑΛΟΥ ΜΑΥΟΥ (Great King of Kings Maues). The reverse shows the seated king Maues. Kharoshthi legend: RAJATIRAJASA MAHATASA MOASA (Great King of Kings Maues). # -2nd Century The "fragments contain at least 30 interlocking gear-wheels, along with copious astronomical inscriptions. Before its sojourn on the sea bed, it computed and displayed the movement of the Sun, the Moon and possibly the planets around Earth, and predicted the dates of future eclipses." The Winged Nike of Samothrace is made from Parian marble, ca. 190 BC? and found in Samothrace in 1863 by the archaeological expedition of Charles Champoiseau, 1863 and 1879. Cleopatra II on the left was involved in the ruling of Egypt apparently from c. 175 BC to until she died in 116 BC. # -3rd Century A Sea Island survey diagram shown on the right was first written of by the Chinese mathematician Liu Hui during the Three Kingdoms era (220–280 CE). "Jastorf (La Tène) culture with bronze and iron technology. Rich building evidence in downtown Bremen." "Many of the coins found at Heracleion date to the time of King Ptolemy II, who ruled Egypt from 283 to 246 B.C." # -4th Century A 3rd century BCE dioptra in the image at the right is an astronomical and surveying instrument, a sighting tube if fitted with protractors, it could be used to measure angles. Numerous finds from the site have indicated that the city's period of major activity ran from the 6th to the 4th century BC, with finds of pottery and coins appearing to stop at the end of the 2nd century BC. Goddio's finds have also included incomplete statues of the god Serapis and the queen Arsinoe II. No more than 5% of the city's area was explored by the archaeologist. # -5th Century Edzná is a Mayan archaeological site in the north of the Mexican state of Campeche. The Gran Acropolis is on the right. Edzná was already inhabited in 400 BC (2400 b2k). Apparently construction on the Parthenon is dated to have begun in 447 BC (2447 b2k) and was completed in 438 BC (2438 b2k) although decoration continued until 432 BC (2432 b2k). "The fifth-century B.C. historian Herodotus writes that the Temple of Heracles was a refuge for runaway slaves. Herodotus notes that if a slave took refuge there and had the “sacred marks” set on them it would not be lawful for the slave’s original owner to claim them." # -6th Century The map on the right shows Assyria, Babylonia and Armenia. Croesus, 595 BC – c. 546 BC, was king of Lydia for apparently 14 years: from 560 BC until his defeat by the Persian king Cyrus the Great in 546 BC, or 547 BC. He issued gold-silver alloy coins as on the left. Based on the pottery shown in the image on the right, Croesus was burned to death. "Sappho of Eresos" is shown center holding a lyre and plectrum, and turning toward a bearded man with a lyre partially visible on the left. # -7th Century Amulet in the image on the right dates from 800 BC-612 BC for warding off plague. Esarhaddon, portrayed on a stone stele, dated after 671 BC on the right, apparently ruled Assyria between 681 – 669 BC. The black basalt monument of king Esarhaddon on the left narrates Esarhaddon's restoration of Babylon, ca. 670 BCE, from Babylon, Mesopotamia, Iraq, now in The British Museum, London. # -8th Century Nimrud lens is plano-convex, Neo-Assyrian, from the North West Palace, Room AB, dated to 750–710 BC, discovered by Austen Henry Layard at the Assyrian palace of Nimrud, in modern-day Iraq. The ""Loupe of Sargon," a piano-convex rock-crystal lentoid excavated by Layard at Nimrud in the 1850s .28 The object is oval (40 x 35 mm) and of uneven thickness (max. th. 22.5 mm) This Dipylon Vase on the right is apparently from the late Geometric period, or the beginning of the Archaic period, c. 750 BC (2750 b2k). Prothesis scene is exposure of the dead and mourning. The low-relief from the L wall of the palace of Sargon II at Dur Sharrukin in Assyria (now Khorsabad in Iraq) is apparently dated to c. 716–713 BC. It is the image on the left. In the center is an image of the upper portion of a statue of Elissa, Queen of Carthage, apparently from the early 8th century or late ninth century. "The founding of the Phoenician colony of Toscanos would have come a bit later; its earliest levels (Strata I/II) would date from the years 805–780 cal BC.6" # -9th Century In 842 BC the Kingdom of Israel and the Phoenician cities sent tributes to Shalmaneser III. The image on the right is from the Black Obelisk of Shalmaneser III and depicts King Jehu of the Kingdom of Israel bowing before Shalmaneser III of Assyria. Carthage was founded in 814 BC. "The recent radiocarbon dates from the earliest levels in Carthage situate the founding of this Tyrian colony in the years 835–800 cal BC,4 which coincides with the dates handed down by Flavius Josephus and Timeus for the founding of the city." The "dates for the founding of Carthage coincide with dates established for the Phoenician colony of Morro de Mezquitilla, which situate the most ancient occupation levels (Strata B1a and B2) in the years 807–802 cal BC.5" The "founding of the first Phoenician colonies at the end of the ninth century coincides with the radio-carbon chronology attributed to the most ancient Phoenician imports recorded in the indigenous Portuguese settlements and in the south of Spain, like Acinipo, Alcáçova de Santarem or Cerro de la Mora.7" # -10th Century The 10th century BC is equivalent to 3,000 to 2,900 b2k. On the right is the burial mask for the Pharaoh Psusennes I exhumed from Tomb III at Tanis (Nile delta). The material used is gold (different pieces were assembled using nails). The eyebrows and eye shadows are lapis lazuli. The eyes are glass paste. There is a cobra on the forehead. The ritual beard is braided to symbolize the death of the sovereign. It is kept in the Egyptian Museum of Cairo. Dynasty is the XXI, dated to c. 1039 BC-990 BC. In the left image is the burial mask for pharaoh Amenemope of the 21st Dynasty of Egypt, dated to 1001 – 992 BC or 993 – 984 BC. # -11th Century # -12th Century Thongs-Heracleion's legendary beginnings go back to as early as the 12th century BC, and it is mentioned by ancient Greek historians. Its importance grew particularly during the waning days of the Pharaohs. "Until very recently the site had been known only from a few literary and epigraphic sources, one of which interestingly mentions the site as an emporion, just like Naukratis." The city was mentioned by the ancient historians Diodorus (1.19.4) and Strabo (17.1.16). Herodotus was told that Thonis was the warden of the Canopic mouth of the Nile: Thonis arrested Alexander (Paris), the son of Priam, because Alexander had abducted Helen of Troy and taken much wealth. Heracleion is also mentioned in the twin steles of the Decree of Nectanebo I (the first of which is known as the 'Stele of Naukratis'), which specify that one tenth of the taxes on imports passing through the town of Thonis/Herakleion were to be given to the sanctuary of Neith of Sais. The city is also mentioned in the Decree of Canopus honoring Pharaoh Ptolemy III, which describes donations, sacrifices and a procession on water. # -50th Century The "Dolmen of Guadalperal the “Spanish Stonehenge,” the monument is a circle of more than 100 standing rocks dating back to 7,000 years ago." "Originally constructed from granite that was likely transported from miles away, the stones are porous and already falling over, cracking, and eroding." The "dolmen’s most notable feature is a large stone that marks its entrance and features a squiggly line. Some believe it is a map of the Tagus River, which would make it one of the oldest maps on Earth." # Hypotheses - Archaeology of Scandinavia will eventually show it to have been occupied 40,000 b2k.	Archaeology Editor-In-Chief: Henry A. Hoff Archaeology "studies human cultures through the recovery, documentation and analysis of material remains and environmental data, including architecture, artifacts, ecofacts, human remains, and landscapes."[1] It is the study of human activity in the past, primarily through the recovery and analysis of the material culture and environmental data that they have left behind, which includes artifacts, architecture, biofacts and cultural landscapes (the archaeological record). Because archaeology employs a wide range of different procedures, it can be considered to be both a science and a humanity.[2] Archaeology studies human history from the development of the first stone tools in eastern Africa 3.4 million years ago up until recent decades.[3] (Archaeology does not include the discipline of paleontology.) It is of most importance for learning about prehistoric societies, when there are no written records for historians to study, making up over 99% of total human history, from the Palaeolithic until the advent of literacy in any given society.[2] # Theoretical archaeology Def. the "period of time that has already happened"[4] is called the past. Def. the "study of the past through material remains"[5] is called archaeology, or archeology. # Entities "[D]ominant groups create and control the meanings and uses of material culture. If other groups wish to be understood by the dominant group, they must express themselves through the goods controlled by the dominant group."[6] "But, the privilege afforded a certain dominant group of 'normal' archaeologists in terms of their ways of constructing the past influences all aspects of archaeological practice."[7] "However, some answers to these questions may emerge from a consideration of the dominant group, that is, the five institutions whose scholars published the most articles in the two periodicals."[8] # Landscape archaeology Def. an assemblage of surfaces that are a portion of land, region, or territory, observable in its entirety is called a landscape. Landscape comprises the visible features of an area of [terrestrial ecoregion] land, including the physical elements of landforms such as (ice-capped) mountains, hills, water bodies such as rivers, lakes, ponds and the sea, living elements of land cover including indigenous vegetation, human elements including different forms of land use, buildings and structures, and transitory elements such as lighting and weather conditions. Landscape archaeology is the study of the ways in which people in the past constructed and used the environment around them. Landscape archaeology is inherently multidisciplinary in its approach to the study of culture, and is used by both pre-historical, classic, and historic archaeologists. The key feature that distinguishes landscape archaeology from other archaeological approaches to sites is that there is an explicit emphasis on the study of the relationships between material culture, human alteration of land/cultural modifications to landscape, and the natural environment. # Sources Archaeological field survey is the method by which archaeologists (often landscape archaeologists) search for archaeological sites and collect information about the location, distribution and organization of past human cultures across a large area (e.g. typically in excess of one hectare, and often in excess of many km2). Surveys are conducted to search for particular archaeological sites or kinds of sites, to detect patterns in the distribution of material culture over regions, to make generalizations or test hypotheses about past cultures, and to assess the risks that development projects will have adverse impacts on archaeological heritage.[9] The surveys may be: (a) intrusive or non-intrusive, depending on the needs of the survey team (and the risk of destroying archaeological evidence if intrusive methods are used) and; (b) extensive or intensive, depending on the types of research questions being asked of the landscape in question. Surveys can be a practical way to decide whether or not to carry out an excavation (as a way of recording the basic details of a possible site), but may also be ends in themselves, as they produce important information about past human activities in a regional context. Excavation is the exposure, processing and recording of archaeological remains. An excavation site or "dig" is a site being studied. # Objects Def. an "object, such as a tool, weapon or ornament, [ceramics or pottery,] structure or finding in an experiment or investigation ... made or shaped by some agent or intelligence, ... [as] a result of external action, the test arrangement, or an experimental error ... rather than an inherent element"[10] is called an artifact, or artefact. In June 2014, the Precolumbian Chiefdom Settlements with Stone Spheres of the Diquis was added to the UNESCO list of World Heritage Sites.[11] The spheres range in size from a few centimetres to over 2 metres (6.5616798 ft) in diameter, and weigh up to 15 tons.[12] Most are sculpted from gabbro.[12] The culture of the people who made them disappeared after the Spanish conquest.[13] The first scientific investigation of the spheres was undertaken shortly after their discovery and published in 1943 in American Antiquity, attracting the attention of Samuel Kirkland Lothrop[14] of the Peabody Museum of Archaeology and Ethnology at Harvard University.[15] In 1948, he and his wife attempted to excavate an unrelated archaeological site in the northern region of Costa Rica.[16] In San José he met Doris Stone, who directed the group toward the Diquís Delta region in the southwest ("Valle de Diquís" refers to the valley of the lower Río Grande de Térraba, including the Osa Canton towns of Puerto Cortés, Palmar Norte, and Sierpe.[17] The Dropa stones or discs may be a series of at least 716 circular stone discs, dating back 12,000 years, on which tiny hieroglyph-like markings may be found.[18][19] Each disc is claimed to measure up to 1 foot (30.48 cm) in diameter and carry two grooves, originating from a hole in their center, in the form of a double spiral.[20] # Coppers In "Serbia [are] the oldest copper implements in the world. Some 7000 years ago, tradesmen of great wealth flourished on the Balkan peninsula."[21] "The soil around Plonik is rich in copper - the metal in a pure state lays often directly at the surface."[22] The so-called "copper-violets" "are related to the Alpine violets, which we know in Germany from flower pots. But they grow only in a soil with a very high copper content. There - where the soil is too poisonous for the other plants, they blossom in wide carpets - and in so doing point to the presence of copper."[22] In "the late stone age people picked up the beautiful stones. For instance, malachite. The green-hued mineral belongs to the class of carbonates. Copper content: 57 percent. Our ancestors made experiments with different stones over the fire. From there, it was only a small step to jewels and to more practical objects."[21] On "the Black Sea Coast in today's Bulgaria, there flourished a prosperous, big city, quite close to today's Varna. Archaeologists have found the cemetary of this settlement. The graves were loaded with treasures: jewels - mostly gold, but also copper - sea shells from the Aegean and tools made of types of stone which must have come from far away."[21] "In the 5. Millennium BC people lived there in complex, centralized settlements of up to a thousand inhabitants. They invented a new ceramic oven with two chambers which was remarkably well suited to the extraction of metal. We must strongly surmise that there existed relations between the Balkans and Northern Mesopotamia."[21] "An enormous fire unleashed itself around 5000 BC in the city [of Plonik]. The earth carbonized. The houses collapsed and buried all the possessions of the inhabitants under their walls. When the flame died down, the city had ceased to exist."[21] # Tools In "the deep Southeast of Europe, near today's village of Plonik in Serbia, there existed 7000 years ago a major city. Its inhabitants lived in closely assembled huts and they melted copper to make jewels, tools and weapons."[21] "The age of the oldest pieces which they have found up to now in the settlement is up to 7300 years. That's a good 800 years older as any other copper implements which have been found anywhere on Earth to this day."[21] # Weapons "The people of the Balkan peninsula had a good knowledge of how they could create jewels, tools and weapons out of earth with a high copper content."[21] "In Plonik, excavators found hatchets of copper. And weapons: axes and maces. With them a new area began. The stone age was gone, the copper age - chalcolithic - had begun."[21] # Jewelry "From one grave, the excavator dug 1,516 K of gold jewelry. This is more gold than has been found in all the rest of the world for this particular epoch."[21] # Materials "In order to interpret archaeological ceramic assemblages in terms of social identities, a method was developed [that] consists in sorting the potsherds according to, successively, technical, techno-petrographic and morpho-stylistic criteria."[23] # Heritage management "Rare, though, is the country where ethnic groups balance each other in terms of numbers, wealth or political influence and, consequently, it is not uncommon for the dominant group to use its power to push its own heritage to the fore, minimizing or denying the significance of subordinate groups as it crafts a national identity in its own image."[24] # Historical archaeology Historical archaeology is a form of archaeology dealing with places, things, and issues from the past or present when written records and oral traditions can inform and contextualize cultural material. These records can both complement and conflict with the archaeological evidence found at a particular site. Studies focus on literate, historical-period societies as opposed to non-literate, prehistoric societies. While they may not have generated the records, the lives of people for whom there was little need for written records, such as the working class, slaves, indentured labourers, and children but who live in the historical period can also be the subject of study. The sites are found on land and underwater. Industrial archaeology, unless practiced at industrial sites from the prehistoric era, is a form of historical archaeology concentrating on the remains and products of industry and the Industrial era. # Maya civilization In the image on the right, dense forest surrounds the city center of this Classic-era Maya site (top) Tikal. Laser mapping of the same view (bottom) reveals structures and causeways hidden by the jungle. "Lidar (a type of airborne laser scanning) provides a powerful technique for three-dimensional mapping of topographic features."[25] "Lowland Maya civilization flourished from 1000 BCE to 1500 CE in and around the Yucatan Peninsula."[25] "In 2016, the Pacunam Lidar Initiative (PLI) undertook the largest lidar survey to date of the Maya region, mapping 2144 km2 of the Maya Biosphere Reserve in Guatemala."[25] "Analysis identified 61,480 ancient structures in the survey region, resulting in a density of 29 structures/km2. Controlling for a number of complex variables, we estimate an average density of ~80 to 120 persons/km2 at the height of the Late Classic period (650 to 800 CE). Extrapolation of this settlement density to the entire 95,000 km2 of the central lowlands produces a population range of 7 million to 11 million."[25] "Settlement distribution is not homogeneous, however; we found evidence of (i) rural areas with low overall density, (ii) periurban zones with small urban centers and dispersed populations, and (iii) urban zones where a single, large city integrated a wider population."[25] "The PLI survey revealed a landscape heavily modified for intensive agriculture, necessary to sustain populations on this scale. Lidar shows field systems in the low-lying wetlands and terraces in the upland areas. The scale of wetland systems and their association with dense populations suggest centralized planning, whereas upland terraces cluster around residences, implying local management. Analysis identified 362 km2 of deliberately modified agricultural terrain and another 952 km2 of unmodified uplands for potential swidden use. Approximately 106 km of causeways within and between sites constitute evidence of inter- and intracommunity connectivity. In contrast, sizable defensive features point to societal disconnection and large-scale conflict."[25] “The new lidar data show that interconnected Maya cities go back to at least 300 B.C.”[26] # Prehistory The prehistory period dates from around 7 x 106 b2k to about 7,000 b2k. Def. the "history of human culture prior to written records"[27] is called prehistory. # 21st Century "During an underwater expedition in 2000, divers saw a large stone head emerge from the murky dark waters [over Heracleion]. It was the head of the god Hapi, the personification of the Nile’s annual flood."[28] Heracleion, also known by its Egyptian name Thonis,[29] and sometimes called Thonis-Heracleion, was an ancient Egyptian city located near the Canopic Mouth of the Nile, about 32 km northeast of Alexandria. Its ruins are located in Abu Qir Bay, currently 2.5 km off the coast, under 10 m (30 ft) of water.[30] A stele found on the site indicates that it was one single city known by both its Egyptian and Greek names.[31] # 20th Century Manned spaceflight on an individual basis has only been achieved with experimental aircraft such as the X-15. "In 1933 British RAF Group-Captain Cull was flying his plane over Aboukir, a Royal Air Force base east of Alexandria in Egypt, when he glimpsed something in the water below him. From his vantage point, Cull could make out the outlines of structures beneath the water. Unbeknownst to him, Cull had located Heracleion, an important ancient Egyptian city that had lain hidden beneath the water for nearly 1500 years."[28] Heracleion is located at 31°18'15"N 30°06'02"E. "According to legend, this lost metropolis had hosted its namesake, Heracles, and lovers Paris and Helen before they fled to Troy. Cleopatra, Egypt’s most famous queen, had even been crowned in one of the temples there."[28] "Before its discovery, Heracleion (which was also known in the ancient world by its Egyptian name, Thonis) was almost the stuff of mythology. Though it is now buried several miles off the coast, Thonis-Heracleion was once a thriving port city."[28] The ruins submerged in the sea were located and explored by the French underwater archaeologist Franck Goddio in 1999, after a five-year search.[32] # 19th Century The Covered Bridge on the right was built in 1867 near the town of Cedarburg, Wisconsin. "In 1866 Mahmoud Bey El-Falaki, the official astronomer to the Viceroy of Egypt, had published a map that located the nearby ancient town of [...] Canopus on the edge of the coastline."[28] # 18th Century Taken from the observation platform at the top of the Jantar Mantar, the image on the right shows smaller architectural sundials. The Jantar Mantar is a collection of architectural astronomical instruments, built by Maharaja Jai Singh II at his then new capital of Jaipur between 1727 and 1733. The City Palace is behind then Govindji Temple. Nahargarh Fort is on the Hill. # 17th Century The Keplerian Telescope was invented by Johannes Kepler in 1611.[33] # 16th Century The images on the right shows the sphere without sighting tubes or any device for observing astronomical objects and dates from 1547. # 15th Century The image at the right dating from c. 1480 shows the sphere without sighting tube or any device for observing astronomical objects. # 14th Century The image at the left shows a sceptre dated to before 1380. "According to written records, a steady succession of earthquakes, perhaps as many as 23, struck North Africa between A.D. 323-1303."[28] # 13th Century The ruin tower on the right is apparently dated to the 13th Century and was built by the Anasazi. # 12th Century Romanesque apses and brick towers of the Church of San Tirso, Sahagún, are shown on the right, dated to the 12th Century. # 11th Century The star map on the right, which features a cylindrical projection, was published in 1092 and has a corrected position for the pole star using Shen Kuo's astronomical observations.[34] # 10th Century Visby was founded in the 10th century, on the then independent Baltic Sea island of Gotland. The Hansaetic League formed it during ensuing centuries, during which it came to Denmark. In 1645, it came into Swedish occupation, in which it has remained until today. There is more about lenses more recently from Visby, Gotland. "What intrigues the researchers is that the lenses are of such high quality that they could have been used to make a telescope some 500 years before the first known crude telescopes were constructed in Europe in the last few years of the 16th century."[35] "Made from rock-crystal, the lenses have an accurate shape that betrays the work of a master craftsman. The best example of the lenses measures 50 mm (2 inches) in diameter and 30 mm (1 inch) thick at its centre."[35] "The [Visby] Gotland crystals provide the first evidence that sophisticated lens-making techniques were being used by craftsmen over a 1,000 years ago."[35] # 9th Century There was an inscription which placed the foundation of the nilometer in 861. Cobá is a former pre-Columbian Mayan city on the Yucatán Peninsula southeast of Valladolid located in the state of Quintana Roo, Mexico. In Cobá, the temple pyramid Nohoch-Mul (also known as Castillo, or the climbing pyramid shown on the left) is 42 meters high. The city was founded shortly after the beginning of the year and expanded into a city state that peaked between 600 and 800 (1400 and 1200 b2k). # 8th Century The Dunhuang map from the Tang Dynasty of the North Polar region at right is thought to date from the reign of Emperor Zhongzong of Tang (705–710). Constellations of the three schools are distinguished with different colors: white, black and yellow for stars of Wu Xian, Gan De and Shi Shen respectively. The whole set of star maps contains 1,300 stars. The Dunhuang Star Atlas, the last section of manuscript Or.8210/S.3326. It is "the oldest manuscript star atlas known today from any civilisation, probably dating from around AD 700. It shows a complete representation of the Chinese sky in 13 charts with over 1300 stars named and accurately presented."[36] "The Dunhuang Star Atlas [above center] forms the second part of a longer scroll (Or.8210/S.3326) that measures 210 cm long by 24.4 cm wide and is made of fine paper in thirteen separate panels."[36] "The first part of the scroll is a manual for divination based on the shape of clouds. The twelve charts showing different sections of the sky follow these. The stars are named and there is also explanatory text. The final chart is of the north-polar region. The chart is detailed, showing a total of 1345 stars in 257 clearly marked and named asterisms, or constellations, including all twenty-eight mansions."[36] "The importance of the chart lies in both its accuracy and graphic quality. The chart includes both bright and faint stars, visible to the naked eye from north central China".[36] # 7th Century Sambor Pre Kuk, with its N16 Sanctuary imaged on the right, is an archaeological complex formed by the remains of the city of Isanapura, the capital of the kingdom of Chenla, an immediate predecessor of the Khmer Empire (pre-Angkorian). This city was built during the reign of Isanavarman I (616-635). At this time, several constructions, clear predecessors of Khmer architecture, were erected in Angkor. Cantona is a Mesoamerican archaeological site in the state of Puebla, Mexico. It was a fortified city with a high urbanization level at prehispanic times, probably founded by Olmec-Xicalanca groups towards the late Classical Period. It sat astride an old trading route between the Gulf Coast and the Central Highlands and was a prominent, if isolated, Mesoamerican city between 600 and 1000 CE. After Chichimec's invasions in the 11th century, Cantona was abandoned. Cantona's inhabitants were mainly agricultural farmers and traders, particularly for obsidian, obtained from Oyameles-Zaragoza mountains surrounding the city. Additionally, they may have been supplying the lowlands with a derivative of the maguey plant, pulque. Cantona's population is estimated at about 80,000 inhabitants at its peak. Cantona may well be the largest prehispanic city yet discovered in Mesoamerica. Limited archaeological work has been done at the site, and only about 10% of the site can be seen. The Pre-Columbian settlement area occupies approximately 12 km², distributed in three units, of which the largest is at the south, with a surface of 5 km². The site comprises a road network with over 500 cobblestone causeways, more than 3,000 individual patios, residences, and 24 ball courts - more than in any other mesoamerican site. It has an elevated Acropolis over the rest of the city in which the main buildings of the city were built. This was used for the ruling elite and priests, and was where the temples of the most important deities where located. These impressive buildings were constructed with carved stones (one atop the other) without any stucco or cement mortar. Cantona certainly was built with a definite urban design and walkways connecting each and every part of the city. The "First Avenue" is 563 meters in length. # 6th Century On the right is the Basilica Cistern in Constantinople, Turkey. It has been dated to the 6th century. Dzibanche is an archaeological site which includes the Temple of the Owl pyramid. It is an ancient Maya site located in southern Quintana Roo, in the Yucatan Peninsula of southeastern Mexico. Structures at Dzibanche include the Temple of the Captives, the Temple of the Lintels and the Temple of the Owl, on the left. # 5th Century Ancient India was an early leader in metallurgy, as evidenced by the wrought-iron Pillar of Delhi in the image on the right, dated to about 415 or 1585 b2k. # 4th Century The House of Peter in Capernaum, Israel, has been dated to the 4th century. "The most severe [earthquake of North Africa] occurred in A.D. 365. The coastline fell and the cluster of cities that lay in the Canopic branch of the Nile vanished into the Mediterranean."[28] # 3rd Century The last known celestial globe shown at the right dates from 1850 to 1780 b2k. The constellation illustrations from the Mainz celestial globe are shown at the left. # 2nd Century On the right is an image of the oldest extant diagram of Euclid's Elements, found at Oxyrhynchus and dated to c. 100 AD.[37] # 1st Century Pompeii lens (plano-convex) from the excavations of the Via Stabia, "House of the Engraver" dated to 79 AD per E. Gerspach, L'art de la verrerie (Paris 1885) 41-42. Roman London lens (fragmentary biconvex glass lens of light green color), from Roman London, dated to 43-50 AD per H. Syer Cuming, "On Spectacles," The Journal of the British Archaeological Association 11 (1855) 144-49. # -1st Century The "Late La Tène time span [is] between the conquests of 55 BC and 54 BC [2055 and 2054 b2k] under Julius Caesar (100-44 BC) and the time of Christ. In the rare cases where pottery and tableware are attributed to Saxons of the 4th/5th c. AD, "astonishingly La Tène art styles [more than 300 years out of fashion] re-emerge as dominant in the northern and western zone." (Hines 1996, 260)"[38] "Stamped pottery has had a long and varied history in Britain. There have been periods when it flourished and periods when it almost totally disappeared. This article considers two variations of the rosette motif (A 5) and their fortunes from the late Iron Age to the Early Saxon period. [...] The La Tène ring stamps [which end in the 1st century BC; GH ] are found in a range of designs, from the simple negative ring (= AASPS Classification A 1bi) to four concentric negative rings (= AASPS A 2di). These motifs are also found in the early Roman period [1st century AD; GH]. [...] The 'dot rosettes' (= AASPS A 9di) on bowls from the [Late Latène] Hunsbury hill-fort (Fell 1937) use the same sort of technique as the dimple decoration on 4th-century 'Romano-Saxon' wares."[39] In "Šarnjaka kod Šemovca (Dalmatia/Croatia), e.g., contain 700-year-older La Tène and Imperial period items (1st century BC to 3rd century AD) [...]:"[38] "A large dugout house (SU 9) was discovered in the course of the investigation in 2006. Its dimensions are 4.8 by 2.1 metres, with a depth of 34 centimetres, and an east-west orientation, deviating slightly along the NE-SW line. It contained numerous sherds of Early Medieval pottery, two fragments of glass, and a small iron spike. Three sherds of Roman pottery [1st-3rd c. CE; GH] and ten sherds of La Tène pottery [ending 1st c. BCE; GH] were also recovered from the house."[40] "The contemporaneity of Rome’s Imperial period textbook-dated to the 1st-3rd century AD with the Early Middle Ages (8th-10th century AD) is also confirmed for Poland [in the stratigraphic table above]. There, too, Late Latène (conventionally ending 1st c. BC) immediately precedes the Early Medieval period of the 8th-10th c. CE."[38] "In [the Roman Empire] capital cities, Rome and Constantinople (Heinsohn 2016) [they] build residential quarters, streets, latrines, aqueducts, ports etc. only in one of the three periods—Imperial Antiquity, Late Antiquity, and Early Middle Ages—dated between 1 and 930s AD. In Rome, they are assigned to Imperial Antiquity (1st-3rd c.); in Constantinople, to Late Antiquity (4th-6th c.)."[38] "Roman churches of Late Antiquity and the Early Middle Ages [...] would suffice to confirm the existence of these two periods. The churches are there. However, we never find churches of the 8th or 9th century superimposed on churches of the 4th or 5th century that, in turn, are superimposed on pagan basilicas of the 1st or 2nd century. They all share the same stratigraphic level of the 1st and 2nd/early 3rd century. Moreover, the ground plans of the 4th/5th—as well as the 8th/9th—century churches slavishly repeat the ground plans of 1st/2nd century basilicas, as already pointed out 75 years ago by Richard Krautheimer (1897-1994). It is this period of Imperial Antiquity (with its internal evolution from the 1st to 3rd centuries) that alone builds the residential quarters, latrines, streets, and aqueducts so desperately looked for in Late Antiquity and the Early Middle Ages. Thus, Rome does not have more stratigraphy for the first millennium AD than England or Poland."[38] "Germanic tribes, not only Anglo-Saxons and Frisians but also Franks, had been competing with Rome for the conquest of the British Isles since the 1st century BC".[38] "1st century BC "Astonishingly LA TÈNE art styles" (Hines 1996) dominate pottery of SAXONS [and] Powerful LA TÈNE Celts with King Aththe-Domarous of Camulodunum [is the] greatest ruler."[38] "Saxons begin their attack on Britain as early as the 1st century BC. They compete with the Romans, who may have employed Germanic Franks as auxiliary forces. The Saxons invade from the East, i.e., from the German Bight."[38] From "the stratigraphy of the Saxon homeland, located around Bremen/Weser inside today’s Lower Saxony [it] is mainly inhabited by Chauci and Bructeri [...] Saxon tribes that are [...] at war with the Romans in the time of Augustus (31 BC-14 AD) and Aththe-Domaros of Camulodunum (Aθθe-Domaros, also read as Addedom-Arus; c. 15-5 BC)."[38] On the right is an Indian-standard coin of King Maues. On the obverse is a rejoicing elephant holding a wreath, a symbol of victory. The Greek legend reads ΒΑΣΙΛΕΩΣ ΒΑΣΙΛΕΩΝ ΜΕΓΑΛΟΥ ΜΑΥΟΥ (Great King of Kings Maues). The reverse shows the seated king Maues. Kharoshthi legend: RAJATIRAJASA MAHATASA MOASA (Great King of Kings Maues). # -2nd Century The "fragments [of the Antikythera Mechanism] contain at least 30 interlocking gear-wheels, along with copious astronomical inscriptions. Before its sojourn on the sea bed, it computed and displayed the movement of the Sun, the Moon and possibly the planets around Earth, and predicted the dates of future eclipses."[41] The Winged Nike of Samothrace is made from Parian marble, ca. 190 BC? and found in Samothrace in 1863 by the archaeological expedition of Charles Champoiseau, 1863 and 1879. Cleopatra II on the left was involved in the ruling of Egypt apparently from c. 175 BC to until she died in 116 BC. # -3rd Century A Sea Island survey diagram shown on the right was first written of by the Chinese mathematician Liu Hui during the Three Kingdoms era (220–280 CE). "Jastorf (La Tène) culture [3rd to 1st century BC] with bronze and iron technology. Rich building evidence in downtown Bremen."[38] "Many of the coins found at Heracleion date to the time of King Ptolemy II, who ruled Egypt from 283 to 246 B.C."[28] # -4th Century A 3rd century BCE dioptra in the image at the right is an astronomical and surveying instrument, a sighting tube if fitted with protractors, it could be used to measure angles. Numerous finds from the [Thonis-Heracleion] site have indicated that the city's period of major activity ran from the 6th to the 4th century BC,[42] with finds of pottery and coins appearing to stop at the end of the 2nd century BC.[31] Goddio's finds have also included incomplete statues of the god Serapis and the queen Arsinoe II.[43] No more than 5% of the city's area was explored by the archaeologist.[31] # -5th Century Edzná is a Mayan archaeological site in the north of the Mexican state of Campeche. The Gran Acropolis is on the right. Edzná was already inhabited in 400 BC (2400 b2k). Apparently construction on the Parthenon is dated to have begun in 447 BC (2447 b2k) and was completed in 438 BC (2438 b2k) although decoration continued until 432 BC (2432 b2k). "The fifth-century B.C. historian Herodotus writes that the Temple of Heracles [in Thonis (Heracleion)] was a refuge for runaway slaves. Herodotus notes that if a slave took refuge there and had the “sacred marks” set on them it would not be lawful for the slave’s original owner to claim them."[28] # -6th Century The map on the right shows Assyria, Babylonia and Armenia. Croesus, 595 BC – c. 546 BC, was king of Lydia for apparently 14 years: from 560 BC until his defeat by the Persian king Cyrus the Great in 546 BC, or 547 BC. He issued gold-silver alloy coins as on the left. Based on the pottery shown in the image on the right, Croesus was burned to death. "Sappho of Eresos" is shown center holding a lyre and plectrum, and turning toward a bearded man with a lyre partially visible on the left. # -7th Century Amulet in the image on the right dates from 800 BC-612 BC for warding off plague. Esarhaddon, portrayed on a stone stele, dated after 671 BC on the right, apparently ruled Assyria between 681 – 669 BC. The black basalt monument of king Esarhaddon on the left narrates Esarhaddon's restoration of Babylon, ca. 670 BCE, from Babylon, Mesopotamia, Iraq, now in The British Museum, London. # -8th Century Nimrud lens is plano-convex, Neo-Assyrian, from the North West Palace, Room AB, dated to 750–710 BC, discovered by Austen Henry Layard at the Assyrian palace of Nimrud, in modern-day Iraq.[44] The ""Loupe of Sargon," a piano-convex rock-crystal lentoid [was] excavated by Layard at Nimrud in the 1850s [on the right].28 The object is oval (40 x 35 mm) and of uneven thickness (max. th. 22.5 mm) [centered and including the maximum convexness as shown edge-on in the image on the left. Its focal length has been calculated at 112.5 mm. Its nominal magnification is about 2 x but, owing to its imperfect surface, it would be useless as a tool."[45] This Dipylon Vase on the right is apparently from the late Geometric period, or the beginning of the Archaic period, c. 750 BC (2750 b2k). Prothesis scene is exposure of the dead and mourning. The low-relief from the L wall of the palace of Sargon II at Dur Sharrukin in Assyria (now Khorsabad in Iraq) is apparently dated to c. 716–713 BC. It is the image on the left. In the center is an image of the upper portion of a statue of Elissa, Queen of Carthage, apparently from the early 8th century or late ninth century. "The founding of the Phoenician colony of Toscanos would have come a bit later; its earliest levels (Strata I/II) would date from the years 805–780 cal BC.6"[46] # -9th Century In 842 BC the Kingdom of Israel and the Phoenician cities sent tributes to Shalmaneser III. The image on the right is from the Black Obelisk of Shalmaneser III and depicts King Jehu of the Kingdom of Israel bowing before Shalmaneser III of Assyria. Carthage was founded in 814 BC.[47] "The recent radiocarbon dates from the earliest levels in Carthage situate the founding of this Tyrian colony in the years 835–800 cal BC,4 which coincides with the dates handed down by Flavius Josephus and Timeus for the founding of the city."[46] The "dates for the founding of Carthage coincide with dates established for the Phoenician colony of Morro de Mezquitilla, which situate the most ancient occupation levels (Strata B1a and B2) in the years 807–802 cal BC.5"[46] The "founding of the first Phoenician colonies at the end of the ninth century coincides with the radio-carbon chronology attributed to the most ancient Phoenician imports recorded in the indigenous Portuguese settlements and in the south of Spain, like Acinipo, Alcáçova de Santarem or Cerro de la Mora.7"[46] # -10th Century The 10th century BC is equivalent to 3,000 to 2,900 b2k. On the right is the burial mask for the Pharaoh Psusennes I exhumed from Tomb III at Tanis (Nile delta). The material used is gold (different pieces were assembled using nails). The eyebrows and eye shadows are lapis lazuli. The eyes are glass paste. There is a cobra on the forehead. The ritual beard is braided to symbolize the death of the sovereign. It is kept in the Egyptian Museum of Cairo. Dynasty is the XXI, dated to c. 1039 BC-990 BC. In the left image is the burial mask for pharaoh Amenemope of the 21st Dynasty of Egypt, dated to 1001 – 992 BC or 993 – 984 BC. # -11th Century # -12th Century Thongs-Heracleion's legendary beginnings go back to as early as the 12th century BC, and it is mentioned by ancient Greek historians. Its importance grew particularly during the waning days of the Pharaohs.[48] "Until very recently the site had been known only from a few literary and epigraphic sources, one of which interestingly mentions the site as an emporion, just like Naukratis."[49] The city was mentioned by the ancient historians Diodorus (1.19.4) and Strabo (17.1.16). Herodotus was told that Thonis was the warden of the Canopic mouth of the Nile: Thonis arrested Alexander (Paris), the son of Priam, because Alexander had abducted Helen of Troy and taken much wealth.[49][50] Heracleion is also mentioned in the twin steles of the Decree of Nectanebo I (the first of which is known as the 'Stele of Naukratis'), which specify that one tenth of the taxes on imports passing through the town of Thonis/Herakleion were to be given to the sanctuary of Neith of Sais.[49] The city is also mentioned in the Decree of Canopus honoring Pharaoh Ptolemy III, which describes donations, sacrifices and a procession on water.[48] # -50th Century The "Dolmen of Guadalperal [dubbed] the “Spanish Stonehenge,” the monument is a circle of more than 100 standing rocks dating back to 7,000 years ago."[51] "Originally constructed from granite that was likely transported from miles away, the stones are porous and already falling over, cracking, and eroding."[51] The "dolmen’s most notable feature is a large stone that marks its entrance and features a squiggly line. Some believe it is a map of the Tagus River, which would make it one of the oldest maps on Earth."[51] # Hypotheses - Archaeology of Scandinavia will eventually show it to have been occupied 40,000 b2k.	https://www.wikidoc.org/index.php/Archaeology
911c62a213c5a6a5e68f9ac5337f4f44f0c52186	wikidoc	Minocycline	Minocycline # Disclaimer WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here. # Overview Minocycline is a tetracycline antiobiotic that is FDA approved for the treatment of is indicated as an adjunct to scaling and root planing procedures for reduction of pocket depth in patients with adult periodontitis. Minocycline may be used as part of a periodontal maintenance program which includes good oral hygiene, and scaling and root planing. Common adverse reactions include the most frequently reported nondental treatment-emergent adverse events in the 3 multicenter US trials were headache, infection, flu syndrome, and pain. Dental conditions include peritonitis, gingivitis, stomatitis, pharyngitis. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) Minocycline is indicated as an adjunct to scaling and root planing procedures for reduction of pocket depth in patients with adult periodontitis. Minocycline may be used as part of a periodontal maintenance program which includes good oral hygiene, and scaling and root planing. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Minocycline in adult patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Minocycline in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) There is limited information regarding Minocycline FDA-Labeled Indications and Dosage (Pediatric) in the drug label. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Minocycline in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Minocycline in pediatric patients. # Contraindications It should not be used in any patient who has a known sensitivity to tetracyclines. # Warnings There is limited information regarding Minocycline Warnings' in the drug label. # Adverse Reactions ## Clinical Trials Experience - This medication may cause upset stomach, diarrhea, dizziness, unsteadiness, drowsiness, headache or vomiting. If these symptoms persist or worsen, one should notify their doctor. Minocycline increases sensitivity to sunlight. Prolonged sun exposure should be avoided. Wear protective clothing and use a sunscreen if needed. Very unlikely but should be reported: fever, yellowing of the eyes or skin, stomach pain, sore throat, vision changes and mental changes. - In those cases where this drug must be used for extended periods, blue-gray skin discoloration may occur. In the unlikely event one has an allergic reaction to this drug, immediate medical attention should be sought. Symptoms of an allergic reaction include rash, itching, swelling, severe dizziness, trouble breathing. Other effects not listed above should be reported to the doctor or pharmacist. ## Postmarketing Experience There is limited information regarding Minocycline Postmarketing Experience in the drug label. # Drug Interactions There is limited information regarding Minocycline Drug Interactions in the drug label. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): There is no FDA guidance on usage of Minocycline in women who are pregnant. Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Minocycline in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Minocycline during labor and delivery. ### Nursing Mothers There is no FDA guidance on the use of Minocycline in women who are nursing. ### Pediatric Use There is no FDA guidance on the use of Minocycline in pediatric settings. ### Geriatic Use There is no FDA guidance on the use of Minocycline in geriatric settings. ### Gender There is no FDA guidance on the use of Minocycline with respect to specific gender populations. ### Race There is no FDA guidance on the use of Minocycline with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Minocycline in patients with renal impairment. ### Hepatic Impairment There is no FDA guidance on the use of Minocycline in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Minocycline in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Minocycline in patients who are immunocompromised. # Administration and Monitoring ### Administration - Oral ### Monitoring There is limited information regarding Minocycline Monitoring in the drug label. # IV Compatibility There is limited information regarding the compatibility of Minocycline and IV administrations. # Overdosage There is limited information regarding Minocycline overdosage. If you suspect drug poisoning or overdose, please contact the National Poison Help hotline (1-800-222-1222) immediately. # Pharmacology ## Mechanism of Action There is limited information regarding Minocycline Mechanism of Action in the drug label. ## Structure There is limited information regarding Minocycline Structure in the drug label. ## Pharmacodynamics There is limited information regarding Minocycline Pharmacodynamics in the drug label. ## Pharmacokinetics There is limited information regarding Minocycline Pharmacokinetics in the drug label. ## Nonclinical Toxicology There is limited information regarding Minocycline Nonclinical Toxicology in the drug label. # Clinical Studies There is limited information regarding Minocycline Clinical Studies in the drug label. # How Supplied - Minocycline equivalent to 50 mg minocycline are opaque white capsules imprinted "0487" and "DYNACIN® 50 mg" and are supplied as follows: NDC 99207-487-10 Bottles of 100 NDC 99207-487-11 Bottle of 1000. - Minocycline equivalent to 75 mg minocycline are light gray opaque capsules imprinted "0489" and "DYNACIN® 75 mg" and are supplied as follows: NDC 99207-489-10 Bottles of 100 NDC 99207-489-11 Bottle of 1000. - Minocycline equivalent to 100 mg minocycline are opaque dark gray and opaque white capsules imprinted "0488" and "DYNACIN® 100 mg" and are supplied as follows: NDC 99207-488-05 Bottles of 50 NDC 99207-488-11 Bottle of 1000. - Dispense in tight, light-resistant container with child-resistant closure. - Store at 20º–25ºC (68º–77ºF). - Protect from light, moisture and excessive heat. ## Storage There is limited information regarding Minocycline Storage in the drug label. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information There is limited information regarding Minocycline Patient Counseling Information in the drug label. # Precautions with Alcohol Alcohol-Minocycline interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - MINOCYCLINE HYDROCHLORIDE ® # Look-Alike Drug Names There is limited information regarding Minocycline Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	Minocycline Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Ammu Susheela, M.D. [2] # Disclaimer WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here. # Overview Minocycline is a tetracycline antiobiotic that is FDA approved for the treatment of is indicated as an adjunct to scaling and root planing procedures for reduction of pocket depth in patients with adult periodontitis. Minocycline may be used as part of a periodontal maintenance program which includes good oral hygiene, and scaling and root planing. Common adverse reactions include the most frequently reported nondental treatment-emergent adverse events in the 3 multicenter US trials were headache, infection, flu syndrome, and pain. Dental conditions include peritonitis, gingivitis, stomatitis, pharyngitis. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) Minocycline is indicated as an adjunct to scaling and root planing procedures for reduction of pocket depth in patients with adult periodontitis. Minocycline may be used as part of a periodontal maintenance program which includes good oral hygiene, and scaling and root planing. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Minocycline in adult patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Minocycline in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) There is limited information regarding Minocycline FDA-Labeled Indications and Dosage (Pediatric) in the drug label. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Minocycline in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Minocycline in pediatric patients. # Contraindications It should not be used in any patient who has a known sensitivity to tetracyclines. # Warnings There is limited information regarding Minocycline Warnings' in the drug label. # Adverse Reactions ## Clinical Trials Experience - This medication may cause upset stomach, diarrhea, dizziness, unsteadiness, drowsiness, headache or vomiting. If these symptoms persist or worsen, one should notify their doctor. Minocycline increases sensitivity to sunlight. Prolonged sun exposure should be avoided. Wear protective clothing and use a sunscreen if needed. Very unlikely but should be reported: fever, yellowing of the eyes or skin, stomach pain, sore throat, vision changes and mental changes. - In those cases where this drug must be used for extended periods, blue-gray skin discoloration may occur. In the unlikely event one has an allergic reaction to this drug, immediate medical attention should be sought. Symptoms of an allergic reaction include rash, itching, swelling, severe dizziness, trouble breathing. Other effects not listed above should be reported to the doctor or pharmacist. ## Postmarketing Experience There is limited information regarding Minocycline Postmarketing Experience in the drug label. # Drug Interactions There is limited information regarding Minocycline Drug Interactions in the drug label. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): There is no FDA guidance on usage of Minocycline in women who are pregnant. Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Minocycline in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Minocycline during labor and delivery. ### Nursing Mothers There is no FDA guidance on the use of Minocycline in women who are nursing. ### Pediatric Use There is no FDA guidance on the use of Minocycline in pediatric settings. ### Geriatic Use There is no FDA guidance on the use of Minocycline in geriatric settings. ### Gender There is no FDA guidance on the use of Minocycline with respect to specific gender populations. ### Race There is no FDA guidance on the use of Minocycline with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Minocycline in patients with renal impairment. ### Hepatic Impairment There is no FDA guidance on the use of Minocycline in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Minocycline in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Minocycline in patients who are immunocompromised. # Administration and Monitoring ### Administration - Oral ### Monitoring There is limited information regarding Minocycline Monitoring in the drug label. # IV Compatibility There is limited information regarding the compatibility of Minocycline and IV administrations. # Overdosage There is limited information regarding Minocycline overdosage. If you suspect drug poisoning or overdose, please contact the National Poison Help hotline (1-800-222-1222) immediately. # Pharmacology ## Mechanism of Action There is limited information regarding Minocycline Mechanism of Action in the drug label. ## Structure There is limited information regarding Minocycline Structure in the drug label. ## Pharmacodynamics There is limited information regarding Minocycline Pharmacodynamics in the drug label. ## Pharmacokinetics There is limited information regarding Minocycline Pharmacokinetics in the drug label. ## Nonclinical Toxicology There is limited information regarding Minocycline Nonclinical Toxicology in the drug label. # Clinical Studies There is limited information regarding Minocycline Clinical Studies in the drug label. # How Supplied - Minocycline equivalent to 50 mg minocycline are opaque white capsules imprinted "0487" and "DYNACIN® 50 mg" and are supplied as follows: NDC 99207-487-10 Bottles of 100 NDC 99207-487-11 Bottle of 1000. - Minocycline equivalent to 75 mg minocycline are light gray opaque capsules imprinted "0489" and "DYNACIN® 75 mg" and are supplied as follows: NDC 99207-489-10 Bottles of 100 NDC 99207-489-11 Bottle of 1000. - Minocycline equivalent to 100 mg minocycline are opaque dark gray and opaque white capsules imprinted "0488" and "DYNACIN® 100 mg" and are supplied as follows: NDC 99207-488-05 Bottles of 50 NDC 99207-488-11 Bottle of 1000. - Dispense in tight, light-resistant container with child-resistant closure. - Store at 20º–25ºC (68º–77ºF). - Protect from light, moisture and excessive heat. ## Storage There is limited information regarding Minocycline Storage in the drug label. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information There is limited information regarding Minocycline Patient Counseling Information in the drug label. # Precautions with Alcohol Alcohol-Minocycline interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - MINOCYCLINE HYDROCHLORIDE ®[2] # Look-Alike Drug Names There is limited information regarding Minocycline Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	https://www.wikidoc.org/index.php/Arestin
2f055f133441dc2f197d98200575d2af22311547	wikidoc	Argininemia	Argininemia # Overview Argininemia, also called arginase deficiency, is an autosomal recessive urea cycle disorder where a deficiency of the enzyme arginase causes a build up of arginine and ammonia in the blood. Ammonia, which is formed when proteins are broken down in the body, is toxic if levels become too high. The nervous system is especially sensitive to the effects of excess ammonia. # Historical Perspective # Classification # Pathophysiology ## Genetics Mutations in the ARG1 gene cause argininemia. Argininemia belongs to a class of genetic diseases called urea cycle disorders. The urea cycle is a sequence of reactions that occurs in liver cells. This cycle processes excess nitrogen, generated when protein is used by the body, to make a compound called urea that is excreted by the kidneys. The ARG1 gene provides instructions for making an enzyme called arginase. This enzyme controls the final step of the urea cycle, which produces urea by removing nitrogen from arginine. In people with arginase deficiency, arginase is damaged or missing, and arginine is not broken down properly. As a result, urea cannot be produced normally, and excess nitrogen accumulates in the blood in the form of ammonia. The accumulation of ammonia and arginine are believed to cause the neurological problems and other signs and symptoms of arginase deficiency. This condition is an autosomal recessive disorder, which means the defective gene is located on an autosome, and two copies of the defective gene are required to inherit the disorder. Both parents of an individual with an autosomal recessive disorder are carriers of one copy of the gene, but usually do not have the disorder. # Causes # Differentiating Argininemia from Other Diseases # Epidemiology and Demographics # Risk Factors # Screening # Natural History, Complications, and Prognosis # Diagnosis Argininemia usually becomes evident by about the age of 3. It most often appears as stiffness, especially in the legs, caused by abnormal tensing of the muscles (spasticity). Other symptoms may include slower than normal growth, developmental delay and eventual loss of developmental milestones, mental retardation, seizures, tremor, and difficulty with balance and coordination (ataxia). Occasionally, high protein meals or stress caused by illness or periods without food (fasting) may cause ammonia to accumulate more quickly in the blood. This rapid increase in ammonia may lead to episodes of irritability, refusal to eat, and vomiting. In some affected individuals, signs and symptoms of argininemia may be less severe, and may not appear until later in life. ## Diagnostic Criteria ## History and Symptoms ## Physical Examination ## Laboratory Findings ## Imaging Findings ## Other Diagnostic Studies # Treatment ## Medical Therapy ## Surgery ## Prevention	Argininemia Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: # Overview Argininemia, also called arginase deficiency,[1] is an autosomal recessive[2] urea cycle disorder where a deficiency of the enzyme arginase causes a build up of arginine and ammonia in the blood. Ammonia, which is formed when proteins are broken down in the body, is toxic if levels become too high. The nervous system is especially sensitive to the effects of excess ammonia. # Historical Perspective # Classification # Pathophysiology ## Genetics Mutations in the ARG1 gene cause argininemia. Argininemia belongs to a class of genetic diseases called urea cycle disorders. The urea cycle is a sequence of reactions that occurs in liver cells. This cycle processes excess nitrogen, generated when protein is used by the body, to make a compound called urea that is excreted by the kidneys. The ARG1 gene provides instructions for making an enzyme called arginase. This enzyme controls the final step of the urea cycle, which produces urea by removing nitrogen from arginine. In people with arginase deficiency, arginase is damaged or missing, and arginine is not broken down properly. As a result, urea cannot be produced normally, and excess nitrogen accumulates in the blood in the form of ammonia. The accumulation of ammonia and arginine are believed to cause the neurological problems and other signs and symptoms of arginase deficiency. This condition is an autosomal recessive disorder, which means the defective gene is located on an autosome, and two copies of the defective gene are required to inherit the disorder. Both parents of an individual with an autosomal recessive disorder are carriers of one copy of the gene, but usually do not have the disorder. # Causes # Differentiating Argininemia from Other Diseases # Epidemiology and Demographics # Risk Factors # Screening # Natural History, Complications, and Prognosis # Diagnosis Argininemia usually becomes evident by about the age of 3. It most often appears as stiffness, especially in the legs, caused by abnormal tensing of the muscles (spasticity). Other symptoms may include slower than normal growth, developmental delay and eventual loss of developmental milestones, mental retardation, seizures, tremor, and difficulty with balance and coordination (ataxia). Occasionally, high protein meals or stress caused by illness or periods without food (fasting) may cause ammonia to accumulate more quickly in the blood. This rapid increase in ammonia may lead to episodes of irritability, refusal to eat, and vomiting. In some affected individuals, signs and symptoms of argininemia may be less severe, and may not appear until later in life. ## Diagnostic Criteria ## History and Symptoms ## Physical Examination ## Laboratory Findings ## Imaging Findings ## Other Diagnostic Studies # Treatment ## Medical Therapy ## Surgery ## Prevention # External links - Argininemia at NLM Genetics Home Reference	https://www.wikidoc.org/index.php/Argininemia
a1bc297406c36a4fff70a6676b20506ccf8d936b	wikidoc	Arimoclomol	Arimoclomol Arimoclomol is an experimental drug compound developed by CytRx Corporation, a biopharmaceutical company based in Los Angeles, California. The orally administered drug is intended to treat amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig's disease, a neurodegenerative disease with no effective treatment. # Mechanism of Action The drug is designed to stimulate a natural cellular repair pathway by activating compounds called “molecular chaperones.” Arimoclomol uses a unique 'molecular chaperone' co-induction mechanism. The small molecule drug candidate is believed to function by stimulating a normal cellular protein repair pathway through the activation of "molecular chaperones." Since damaged proteins called aggregates are thought to play a role in many diseases, CytRx believes that activation of molecular chaperones could have therapeutic efficacy for a broad range of diseases. # History Arimolclomol has been shown to extend life in ALS-affected mice and was well tolerated in healthy human volunteers in a recently completed Phase I study. The drug was cited in the fifth annual report on "100 Great Investigational Drugs in Development," published in the March 2006 issue of the pharmaceutical industry magazine R&D Directions. CytRx is currently conducting a Phase II clinical trial at ten centers across the U.S. Arimoclomol was discovered by Hungarian researchers, as a drug candidate to treat insulin resistance, and diabetic complications, such as retinopathy. neuropathy and nephropathy. Later the compound with other small molecules were synthetised and screened for further development, by Biorex (a firm seatled in Hungary) was sold to CytRx Corporation, who developed it toward a different, but very promising direction, from 2003. Hungarian institutional code of Arimoclomol was: BRX-220. Publication date of the patent: 2001-12-03 Publication number: SK11582001 Inventor: KURTHY MARIA (HU); BIRO KATALIN (HU); NAGY KAROLY (HU); UROGDI LASZLO (HU); CSAKAI ZITA (HU); SZILBEREKY JENO (HU); MOGYOROSI TAMAS (HU); TOROK MAGDOLNA (HU); KOMAROMI ANDRAS (HU); MARVANYOS EDE (HU); BARABAS MIHALY (HU); KARDOS MIHALYNE (HU); NAGY ZOLTAN (HU); KORANYI LASZLO (HU); NAGY MELINDA (HU) Applicant: BIOREX KUTATO FEJLESZTOE KFT (HU) Classification: - international: A61P3/10; C07D213/89; A61P3/00; C07D213/00; (IPC1-7): C07D213/89; A61K31/44; A61P3/10 - European: C07D213/89B Application number: SK20010001158 20000224 Priority number(s): HU19990000475 19990226; WO2000HU00015 20000224 Abstract of corresponding document: WO0050403 The invention relates to N--pyridine-1-oxide-3-carboximidoyl chloride, its stereoisomers and the acid addition salts thereof, pharmaceutical compositions containing the same, the use of these compounds in the treatment of pathological insulin resistance, and for the treatment of pathological conditions associated therewith, by simultaneous treatment and prevention of diabetes-induced chronic complications, especially retinopathy, neuropathy and nephropathy and/or with simultaneous increasing pathologically decreased peripheral neuroregeneration caused by diabetes and methods of treatment. List of publications: Source: Key word: Arimoclomol in PubMed: 1: Traynor BJ, Bruijn L, Conwit R, Beal F, O'Neill G, Fagan SC, Cudkowicz ME. Neuroprotective agents for clinical trials in ALS: a systematic assessment. 2: Benn SC, Brown RH Jr. Putting the heat on ALS. 3: Kieran D, Kalmar B, Dick JR, Riddoch-Contreras J, Burnstock G, Greensmith L. Key word: BRX-220 in PubMed: 1: Kalmar B, Greensmith L, Malcangio M, McMahon SB, Csermely P, Burnstock G. 2: Kalmar B, Burnstock G, Vrbova G, Urbanics R, Csermely P, Greensmith L. R Upregulation of heat shock proteins rescues motoneurones from axotomy-induced cell 3: Kurthy M, Mogyorosi T, Nagy K, Kukorelli T, Jednakovits A, Talosi L, Biro K. 4: Sebokova E, Kurthy M, Mogyorosi T, Nagy K, Demcakova E, Ukropec J, Koranyi L, Klimes I. Nontoxic heat shock protein coinducer BRX-220 protects against acute pancreatitis in rats.	Arimoclomol Arimoclomol is an experimental drug compound developed by CytRx Corporation, a biopharmaceutical company based in Los Angeles, California. The orally administered drug is intended to treat amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig's disease, a neurodegenerative disease with no effective treatment. # Mechanism of Action The drug is designed to stimulate a natural cellular repair pathway by activating compounds called “molecular chaperones.” Arimoclomol uses a unique 'molecular chaperone' co-induction mechanism. The small molecule drug candidate is believed to function by stimulating a normal cellular protein repair pathway through the activation of "molecular chaperones." Since damaged proteins called aggregates are thought to play a role in many diseases, CytRx believes that activation of molecular chaperones could have therapeutic efficacy for a broad range of diseases. # History Arimolclomol has been shown to extend life in ALS-affected mice and was well tolerated in healthy human volunteers in a recently completed Phase I study. The drug was cited in the fifth annual report on "100 Great Investigational Drugs in Development," published in the March 2006 issue of the pharmaceutical industry magazine R&D Directions. CytRx is currently conducting a Phase II clinical trial at ten centers across the U.S. Arimoclomol was discovered by Hungarian researchers, as a drug candidate to treat insulin resistance, and diabetic complications, such as retinopathy. neuropathy and nephropathy. Later the compound with other small molecules were synthetised and screened for further development, by Biorex (a firm seatled in Hungary) was sold to CytRx Corporation, who developed it toward a different, but very promising direction, from 2003. Hungarian institutional code of Arimoclomol was: BRX-220. Publication date of the patent: 2001-12-03 Publication number: SK11582001 Inventor: KURTHY MARIA (HU); BIRO KATALIN (HU); NAGY KAROLY (HU); UROGDI LASZLO (HU); CSAKAI ZITA (HU); SZILBEREKY JENO (HU); MOGYOROSI TAMAS (HU); TOROK MAGDOLNA (HU); KOMAROMI ANDRAS (HU); MARVANYOS EDE (HU); BARABAS MIHALY (HU); KARDOS MIHALYNE (HU); NAGY ZOLTAN (HU); KORANYI LASZLO (HU); NAGY MELINDA (HU) Applicant: BIOREX KUTATO FEJLESZTOE KFT (HU) Classification: - international: A61P3/10; C07D213/89; A61P3/00; C07D213/00; (IPC1-7): C07D213/89; A61K31/44; A61P3/10 - European: C07D213/89B Application number: SK20010001158 20000224 Priority number(s): HU19990000475 19990226; WO2000HU00015 20000224 Abstract of corresponding document: WO0050403 The invention relates to N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboximidoyl chloride, its stereoisomers and the acid addition salts thereof, pharmaceutical compositions containing the same, the use of these compounds in the treatment of pathological insulin resistance, and for the treatment of pathological conditions associated therewith, by simultaneous treatment and prevention of diabetes-induced chronic complications, especially retinopathy, neuropathy and nephropathy and/or with simultaneous increasing pathologically decreased peripheral neuroregeneration caused by diabetes and methods of treatment. List of publications: Source: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?DB=pubmed Key word: Arimoclomol in PubMed: 1: Traynor BJ, Bruijn L, Conwit R, Beal F, O'Neill G, Fagan SC, Cudkowicz ME. Neuroprotective agents for clinical trials in ALS: a systematic assessment. 2: Benn SC, Brown RH Jr. Putting the heat on ALS. 3: Kieran D, Kalmar B, Dick JR, Riddoch-Contreras J, Burnstock G, Greensmith L. Key word: BRX-220 in PubMed: 1: Kalmar B, Greensmith L, Malcangio M, McMahon SB, Csermely P, Burnstock G. 2: Kalmar B, Burnstock G, Vrbova G, Urbanics R, Csermely P, Greensmith L. R Upregulation of heat shock proteins rescues motoneurones from axotomy-induced cell 3: Kurthy M, Mogyorosi T, Nagy K, Kukorelli T, Jednakovits A, Talosi L, Biro K. 4: Sebokova E, Kurthy M, Mogyorosi T, Nagy K, Demcakova E, Ukropec J, Koranyi L, Klimes I. Nontoxic heat shock protein coinducer BRX-220 protects against acute pancreatitis in rats. # External links - Template:PubChem	https://www.wikidoc.org/index.php/Arimoclomol
d17e62fee1477225c2fe8fea963529a550a174ae	wikidoc	Armodafinil	Armodafinil # Disclaimer WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here. # Overview Armodafinil is a central nervous system agent that is FDA approved for the treatment of obstructive sleep apnea (OSA), narcolepsy, or shift work disorder (SWD). Common adverse reactions include headache, nausea, dizziness, and insomnia. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - NUVIGIL is indicated to improve wakefulness in adult patients with excessive sleepiness associated with obstructive sleep apnea (OSA), narcolepsy, or shift work disorder (SWD). - In OSA, NUVIGIL is indicated to treat excessive sleepiness and not as treatment for the underlying obstruction. If continuous positive airway pressure (CPAP) is the treatment of choice for a patient, a maximal effort to treat with CPAP for an adequate period of time should be made prior to initiating NUVIGIL for excessive sleepiness. If NUVIGIL is used adjunctively with CPAP, the encouragement of and periodic assessment of CPAP compliance is necessary. - In all cases, careful attention to the diagnosis and treatment of the underlying sleep disorder(s) is of utmost importance. Prescribers should be aware that some patients may have more than one sleep disorder contributing to their excessive sleepiness. - The effectiveness of NUVIGIL in long-term use (greater than 12 weeks) has not been systematically evaluated in placebo-controlled trials. The physician who elects to prescribe NUVIGIL for an extended time in patients should periodically re-evaluate long-term usefulness for the individual patient. - Dosing Information - The recommended dose of NUVIGIL for patients with OSA or narcolepsy is 150 mg to 250 mg given once daily in the morning. In patients with OSA, doses up to 250 mg/day, given as a single dose, have been well tolerated, but there is no consistent evidence that these doses confer additional benefit beyond that of the 150 mg/day dose. - Dosing Information - The recommended dose of NUVIGIL for patients with SWD is 150 mg given daily approximately 1 hour prior to the start of their work shift. Hepatic Impairment - The dose of NUVIGIL should be reduced in patients with severe hepatic impairment, with or without cirrhosis. Use in Geriatric Patients - Consideration should be given to the use of lower doses and close monitoring in geriatric patients. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use - There is limited information regarding Off-Label Guideline-Supported Use of Armodafinil in adult patients. ### Non–Guideline-Supported Use - There is limited information regarding Off-Label Non–Guideline-Supported Use of Armodafinil in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) - There is limited information regarding FDA-Labeled Use of Armodafinil in pediatric patients. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use - There is limited information regarding Off-Label Guideline-Supported Use of Armodafinil in pediatric patients. ### Non–Guideline-Supported Use - There is limited information regarding Off-Label Non–Guideline-Supported Use of Armodafinil in pediatric patients. # Contraindications - NUVIGIL is contraindicated in patients with known hypersensitivity to modafinil or armodafinil or its inactive ingredients. # Warnings Serious Rash, including Stevens-Johnson Syndrome - Serious rash requiring hospitalization and discontinuation of treatment has been reported in association with the use of NUVIGIL (armodafinil) or modafinil (the racemic mixture of S- and R-enantiomers). - NUVIGIL has not been studied in pediatric patients in any setting and is not approved for use in pediatric patients for any indication. - In clinical trials of modafinil, the incidence of rash resulting in discontinuation was approximately 0.8% (13 per 1,585) in pediatric patients (age <17 years); these rashes included 1 case of possible Stevens-Johnson Syndrome (SJS) and 1 case of apparent multi-organ hypersensitivity reaction. Several of the cases were associated with fever and other abnormalities (e.g., vomiting, leukopenia). The median time to rash that resulted in discontinuation was 13 days. No such cases were observed among 380 pediatric patients who received placebo. No serious skin rashes have been reported in adult clinical trials (0 per 4,264) of modafinil. Rare cases of serious or life-threatening rash, including SJS, Toxic Epidermal Necrolysis (TEN), and Drug Rash with Eosinophilia and Systemic Symptoms (DRESS) have been reported in adults and children in worldwide post-marketing experience. The reporting rate of TEN and SJS associated with modafinil use, which is generally accepted to be an underestimate due to underreporting, exceeds the background incidence rate. Estimates of the background incidence rate for these serious skin reactions in the general population range between 1 to 2 cases per million-person years. - Cases of serious rash similar to those observed with modafinil including skin and mouth blistering have been reported in adults in postmarketing experience with NUVIGIL. - There are no factors that are known to predict the risk of occurrence or the severity of rash associated with modafinil or armodafinil. Nearly all cases of serious rash associated with these drugs occurred within 1 to 5 weeks after treatment initiation. However, isolated cases have been reported after prolonged treatment (e.g., 3 months). Accordingly, duration of therapy cannot be relied upon as a means to predict the potential risk heralded by the first appearance of a rash. - Although benign rashes also occur with NUVIGIL, it is not possible to reliably predict which rashes will prove to be serious. Accordingly, NUVIGIL should be discontinued at the first sign of rash, unless the rash is clearly not drug-related. Discontinuation of treatment may not prevent a rash from becoming life-threatening or permanently disabling or disfiguring. Angioedema and Anaphylactoid Reactions - Angioedema and hypersensitivity (with rash, dysphagia, and bronchospasm), were observed with NUVIGIL. Patients should be advised to discontinue therapy and immediately report to their physician any signs or symptoms suggesting angioedema or anaphylaxis (e.g., swelling of face, eyes, lips, tongue or larynx; difficulty in swallowing or breathing; hoarseness). Multi-organ Hypersensitivity Reactions - Multi-organ hypersensitivity reactions, including at least one fatality in post-marketing experience, have occurred in close temporal association (median time to detection 13 days: range 4-33) to the initiation of modafinil. A similar risk of multi-organ hypersensitivity reactions with armodafinil cannot be ruled out. - Although there have been a limited number of reports, multi-organ hypersensitivity reactions may result in hospitalization or be life-threatening. There are no factors that are known to predict the risk of occurrence or the severity of multi-organ hypersensitivity reactions. Signs and symptoms of this disorder were diverse; however, patients typically, although not exclusively, presented with fever and rash associated with other organ system involvement. Other associated manifestations included myocarditis, hepatitis, liver function test abnormalities, hematological abnormalities (e.g., eosinophilia, leukopenia, thrombocytopenia), pruritus, and asthenia. Because multi-organ hypersensitivity is variable in its expression, other organ system symptoms and signs, not noted here, may occur. - If a multi-organ hypersensitivity reaction is suspected, NUVIGIL should be discontinued. Although there are no case reports to indicate cross-sensitivity with other drugs that produce this syndrome, the experience with drugs associated with multi-organ hypersensitivity would indicate this to be a possibility. Persistent Sleepiness - Patients with abnormal levels of sleepiness who take NUVIGIL should be advised that their level of wakefulness may not return to normal. Patients with excessive sleepiness, including those taking NUVIGIL, should be frequently reassessed for their degree of sleepiness and, if appropriate, advised to avoid driving or any other potentially dangerous activity. Prescribers should also be aware that patients may not acknowledge sleepiness or drowsiness until directly questioned about drowsiness or sleepiness during specific activities. Psychiatric Symptoms - In pre-approval narcolepsy, OSA and SWD controlled trials of NUVIGIL, anxiety, agitation, nervousness, and irritability were reasons for treatment discontinuation more often in patients on NUVIGIL compared to placebo (NUVIGIL 1.2% and placebo 0.3%). Depression was also a reason for treatment discontinuation more often in patients on NUVIGIL compared to placebo (NUVIGIL 0.6% and placebo 0.2%). Cases of suicide ideation were observed in clinical trials. - Caution should be exercised when NUVIGIL is given to patients with a history of psychosis, depression, or mania. If psychiatric symptoms develop in association with NUVIGIL administration, consider discontinuing NUVIGIL. - Psychiatric adverse experiences have been reported in patients treated with modafinil. Modafinil and armodafinil (NUVIGIL) are very closely related. Therefore, the incidence and type of psychiatric symptoms associated with NUVIGIL are expected to be similar to the incidence and type of these events with modafinil. - Post-marketing adverse events associated with the use of modafinil have included mania, delusions, hallucinations, suicidal ideation, and aggression, some resulting in hospitalization. Many, but not all, patients had a prior psychiatric history. One healthy male volunteer developed ideas of reference, paranoid delusions, and auditory hallucinations in association with multiple daily 600 mg doses of modafinil and sleep deprivation. There was no evidence of psychosis 36 hours after drug discontinuation. Diagnosis of Sleep Disorders - NUVIGIL should be used only in patients who have had a complete evaluation of their excessive sleepiness, and in whom a diagnosis of narcolepsy, OSA, or SWD has been made in accordance with International Classification of Sleep Disorders (ICSD) or Diagnostic and Statistical Manual of Mental Disorders (DSM) diagnostic criteria. Such an evaluation usually consists of a complete history and physical examination, and it may be supplemented with testing in a laboratory setting. Some patients may have more than one sleep disorder contributing to their excessive sleepiness (e.g., OSA and SWD coincident in the same patient). CPAP Use in Patients with OSA - In OSA, NUVIGIL is not indicated as treatment for the underlying obstruction. If continuous positive airway pressure (CPAP) is the treatment of choice for a patient, a maximal effort to treat with CPAP for an adequate period of time should be made prior to initiating NUVIGIL for excessive sleepiness. If NUVIGIL is used adjunctively with CPAP, the encouragement of and periodic assessment of CPAP compliance is necessary. There was a slight trend for reduced CPAP use over time (mean reduction of 18 minutes for patients treated with NUVIGIL and a 6-minute reduction for placebo-treated patients from a mean baseline use of 6.9 hours per night) in NUVIGIL trials. Effects on Ability to Drive and Use Machinery - Although NUVIGIL has not been shown to produce functional impairment, any drug affecting the CNS may alter judgment, thinking or motor skills. Patients should be cautioned about operating an automobile or other hazardous machinery until it is reasonably certain that NUVIGIL therapy will not adversely affect their ability to engage in such activities. Cardiovascular System - NUVIGIL has not been evaluated or used to any appreciable extent in patients with a recent history of myocardial infarction or unstable angina, and such patients should be treated with caution. - In clinical studies of modafinil, cardiovascular adverse events, including chest pain, palpitations, dyspnea and transient ischemic T-wave changes on ECG were observed in three subjects in association with mitral valve prolapse or left ventricular hypertrophy. It is recommended that NUVIGIL tablets not be used in patients with a history of left ventricular hypertrophy or in patients with mitral valve prolapse who have experienced the mitral valve prolapse syndrome when previously receiving CNS stimulants. Findings suggestive of mitral valve prolapse syndrome include but are not limited to ischemic ECG changes, chest pain, or arrhythmia. If new onset of any of these findings occurs, consider cardiac evaluation. - Blood pressure monitoring in short term (≤ 3 months) pre-approval controlled trials of OSA, SWD, and narcolepsy showed small average increases in mean systolic and diastolic blood pressure in patients receiving NUVIGIL as compared to placebo (1.2 to 4.3 mmHg in the various experimental groups). There was also a slightly greater proportion of patients on NUVIGIL requiring new or increased use of antihypertensive medications (2.9%) compared to patients on placebo (1.8%). There was a small, but consistent, average increase in pulse rate over placebo in pre-approval controlled trials. This increase varied from 0.9 to 3.5 BPM. Increased monitoring of heart rate and blood pressure may be appropriate in patients on NUVIGIL. Caution should be exercised when prescribing NUVIGIL to patients with known cardiovascular disease. DRUG ABUSE AND DEPENDENCE Controlled Substance - Armodafinil (NUVIGIL) is a Schedule IV controlled substance. Abuse - Although the abuse potential of armodafinil has not been specifically studied, its abuse potential is likely to be similar to that of modafinil. In humans, modafinil produces psychoactive and euphoric effects, alterations in mood, perception, thinking and feelings typical of other CNS stimulants. In in vitro binding studies, modafinil binds to the dopamine reuptake site and causes an increase in extracellular dopamine, but no increase in dopamine release. Modafinil is reinforcing, as evidenced by its self-administration in monkeys previously trained to self-administer cocaine. In some studies, modafinil was also partially discriminated as stimulant-like. Physicians should follow patients closely, especially those with a history of drug and/or stimulant (e.g., methylphenidate, amphetamine, or cocaine) abuse. Patients should be observed for signs of misuse or abuse (e.g., incrementation of doses or drug-seeking behavior). - The abuse potential of modafinil (200, 400, and 800 mg) was assessed relative to methylphenidate (45 and 90 mg) in an inpatient study in individuals experienced with drugs of abuse. Results from this clinical study demonstrated that modafinil produced psychoactive and euphoric effects and feelings consistent with other scheduled CNS stimulants (methylphenidate). # Adverse Reactions ## Clinical Trials Experience - The following serious adverse reactions are described below and elsewhere in the labeling: - Serious Rash, including Stevens-Johnson Syndrome - Angioedema and Anaphylactoid Reactions - Multi-organ Hypersensitivity Reactions - Persistent Sleepiness - Psychiatric Symptoms - Diagnosis of Sleep Disorders - CPAP Use in Patients with OSA - Effects on Ability to Drive and Use Machinery - Cardiovascular System Clinical Trials Experience - Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. OSA, SWD, and Narcolepsy - NUVIGIL has been evaluated for safety in over 1100 patients with excessive sleepiness associated with OSA, SWD, and narcolepsy. - In the pre-approval controlled clinical trials, the most commonly observed adverse events (≥ 5%) associated with the use of NUVIGIL occurring more frequently than in the placebo-treated patients were headache, nausea, dizziness, and insomnia. The adverse event profile was similar across the studies. - In the pre-approval controlled clinical trials, 44 of the 645 patients (7%) who received NUVIGIL discontinued due to an adverse experience compared to 16 of the 445 (4%) of patients that received placebo. The most frequent reason for discontinuation was headache (1%). Incidence in Controlled Trials - The following table (Table 1) presents the adverse experiences that occurred at a rate of 1% or more and were more frequent in patients treated with NUVIGIL than in placebo group patients in the pre-approval controlled clinical trials. - The prescriber should be aware that the figures provided below cannot be used to predict the frequency of adverse experiences in the course of usual medical practice, where patient characteristics and other factors may differ from those occurring during clinical studies. Similarly, the cited frequencies cannot be directly compared with figures obtained from other clinical investigations involving different treatments, uses, or investigators. Review of these frequencies, however, provides prescribers with a basis to estimate the relative contribution of drug and non-drug factors to the incidence of adverse events in the population studied. Dose Dependency of Adverse Events - In the pre-approval controlled clinical trials which compared doses of 150 mg/day and 250 mg/day of NUVIGIL and placebo, the only adverse events that appeared to be dose-related were headache, rash, depression, dry mouth, insomnia, and nausea. See Table 2 for additional information. Laboratory Changes - Clinical chemistry, hematology, and urinalysis parameters were monitored in the studies. Mean plasma levels of gamma glutamyltransferase (GGT) and alkaline phosphatase (AP) were found to be higher following administration of NUVIGIL, but not placebo. Few subjects, however, had GGT or AP elevations outside of the normal range. No differences were apparent in alanine aminotransferase (ALT), aspartate aminotransferase (AST), total protein, albumin, or total bilirubin, although there were rare cases of isolated elevations of AST and/or ALT. A single case of mild pancytopenia was observed after 35 days of treatment and resolved with drug discontinuation. A small mean decrease from baseline in serum uric acid compared to placebo was seen in clinical trials. The clinical significance of this finding is unknown. Vital Sign Changes - Blood pressure monitoring in pre-approval controlled trials of OSA, SWD, and narcolepsy showed small average increases in mean systolic and diastolic blood pressure in patients receiving NUVIGIL as compared to placebo (1.2 to 4.3 mmHg in the various experimental groups). There was also a slightly greater proportion of patients on NUVIGIL requiring new or increased use of antihypertensive medications (2.9%) compared to patients on placebo (1.8%). There was a small, but consistent, average increase in pulse rate over placebo in pre-approval controlled trials. This increase varied from 0.9 to 3.5 BPM. ## Postmarketing Experience - There is limited information regarding Postmarketing Experience of Armodafinil in the drug label. # Drug Interactions - The clearance of drugs that are substrates for CYP3A4/5 (e.g., steroidal contraceptives, cyclosporine, midazolam, and triazolam) may be increased by NUVIGIL via induction of metabolic enzymes, which results in lower systemic exposure. Dosage adjustment of these drugs should be considered when these drugs are used concomitantly with NUVIGIL . - The effectiveness of steroidal contraceptives may be reduced when used with NUVIGIL and for one month after discontinuation of therapy. Alternative or concomitant methods of contraception are recommended for patients taking steroidal contraceptives (e.g., ethinyl estradiol) when treated concomitantly with NUVIGIL and for one month after discontinuation of NUVIGIL treatment. - Blood levels of cyclosporine may be reduced when used with NUVIGIL. Monitoring of circulating cyclosporine concentrations and appropriate dosage adjustment for cyclosporine should be considered when used concomitantly with NUVIGIL. - Elimination of drugs that are substrates for CYP2C19 (e.g., phenytoin, diazepam, propranolol, omeprazole, and clomipramine) may be prolonged by NUVIGIL via inhibition of metabolic enzymes, with resultant higher systemic exposure. Dose reduction of these drugs may be required when these drugs are used concomitantly with NUVIGIL. - More frequent monitoring of prothrombin times/INR should be considered whenever NUVIGIL is coadministered with warfarin. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): C Pregnancy Category C - There are no adequate and well-controlled studies of armodafinil in pregnant women. Intrauterine growth restriction and spontaneous abortion have been reported in association with armodafinil and modafinil. Although the pharmacology of armodafinil is not identical to that of the sympathomimetic amines, it does share some pharmacologic properties with this class. Certain of these drugs have been associated with intrauterine growth restriction and spontaneous abortions. Whether the cases reported with armodafinil are drug-related is unknown. In studies of armodafinil (R-modafinil) and modafinil (a mixture of R- and S-modafinil) conducted in rats (armodafinil, modafinil) and rabbits (modafinil), developmental toxicity was observed at clinically relevant plasma exposures. NUVIGIL should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. - Oral administration of armodafinil (60, 200, or 600 mg/kg/day) to pregnant rats throughout organogenesis resulted in increased incidences of fetal visceral and skeletal variations and decreased fetal body weight at the highest dose. The highest no-effect dose for embryofetal developmental toxicity in rat (200 mg/kg/day) was associated with a plasma armodafinil exposure (AUC) less than that in humans at the maximum recommended human dose (MRHD) of NUVIGIL (250 mg/day). - Modafinil (50, 100, or 200 mg/kg/day) administered orally to pregnant rats throughout organogenesis caused, in the absence of maternal toxicity, an increase in resorptions and an increased incidence of visceral and skeletal variations in the offspring at the highest dose tested. The higher no-effect dose for embryofetal developmental toxicity in rat (100 mg/kg/day) was associated with a plasma armodafinil AUC less than that in humans at the MRHD of NUVIGIL. However, in a subsequent study of up to 480 mg/kg/day of modafinil, no adverse effects on embryofetal development were observed. - Modafinil administered orally to pregnant rabbits throughout organogenesis at doses of up to 100 mg/kg/day had no effect on embryofetal development; however, the doses used were too low to adequately assess the effects of modafinil on embryofetal development. In a subsequent developmental toxicity study evaluating doses of 45, 90, and 180 mg/kg/day in pregnant rabbits, the incidences of fetal structural alterations and embryofetal death were increased at the highest dose. The highest no-effect dose for developmental toxicity (100 mg/kg/day) was associated with a plasma armodafinil AUC less than that in humans at the MRHD of NUVIGIL. - Modafinil administration to rats throughout gestation and lactation at oral doses of up to 200 mg/kg/day resulted in decreased viability in the offspring at doses greater than 20 mg/kg/day, a dose resulting in a plasma armodafinil AUC less than that in humans at the MRHD of NUVIGIL. No effects on postnatal developmental and neurobehavioral parameters were observed in surviving offspring. - Pregnancy Registry: A pregnancy registry has been established to collect information on the pregnancy outcomes of women exposed to NUVIGIL. Healthcare providers are encouraged to register pregnant patients, or pregnant women may enroll themselves in the registry by calling 1-866-404-4106 (toll free). Pregnancy Category (AUS): - Australian Drug Evaluation Committee (ADEC) Pregnancy Category - There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Armodafinil in women who are pregnant. ### Labor and Delivery - There is no FDA guidance on use of Armodafinil during labor and delivery. ### Nursing Mothers - It is not known whether armodafinil or its metabolites are excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when NUVIGIL is administered to a nursing woman. ### Pediatric Use - Safety and effectiveness in pediatric patients have not been established. Serious rash has been seen in pediatric patients receiving modafinil. ### Geriatic Use - In elderly patients, elimination of armodafinil and its metabolites may be reduced as a consequence of aging. Therefore, consideration should be given to the use of lower doses and close monitoring in this population. ### Gender - There is no FDA guidance on the use of Armodafinil with respect to specific gender populations. ### Race - There is no FDA guidance on the use of Armodafinil with respect to specific racial populations. ### Renal Impairment - There is inadequate information to determine safety and efficacy of dosing in patients with severe renal impairment. ### Hepatic Impairment - The dose of NUVIGIL should be reduced in patients with severe hepatic impairment, with or without cirrhosis. ### Females of Reproductive Potential and Males - There is no FDA guidance on the use of Armodafinil in women of reproductive potentials and males. ### Immunocompromised Patients - There is no FDA guidance one the use of Armodafinil in patients who are immunocompromised. # Administration and Monitoring ### Administration Obstructive Sleep Apnea (OSA) and Narcolepsy - The recommended dose of NUVIGIL for patients with OSA or narcolepsy is 150 mg to 250 mg given once daily in the morning. In patients with OSA, doses up to 250 mg/day, given as a single dose, have been well tolerated, but there is no consistent evidence that these doses confer additional benefit beyond that of the 150 mg/day dose. Shift Work Disorder (SWD) - The recommended dose of NUVIGIL for patients with SWD is 150 mg given daily approximately 1 hour prior to the start of their work shift. Hepatic Impairment - The dose of NUVIGIL should be reduced in patients with severe hepatic impairment, with or without cirrhosis. Use in Geriatric Patients - Consideration should be given to the use of lower doses and close monitoring in geriatric patients. DOSAGE FORMS AND STRENGTHS - 50 mg – round, white to off-white tablet with - stylized c - on one side and "205" on the other - 150 mg – oval, white to off-white tablet with - stylized c - on one side and "215" on the other - 200 mg – rounded, rectangular, white to off-white tablet with - stylized c - on one side and "220" on the other - 250 mg – oval, white to off-white tablet with - stylized c - on one side and "225" on the other ### Monitoring - There is limited information regarding Monitoring of Armodafinil in the drug label. # IV Compatibility - There is limited information regarding IV Compatibility of Armodafinil in the drug label. # Overdosage Human Experience - There were no overdoses reported in the NUVIGIL clinical studies. - Symptoms of NUVIGIL overdose are likely to be similar to those of modafinil. Symptoms of overdose in modafinil clinical trials included excitation or agitation, insomnia, and slight or moderate elevations in hemodynamic parameters. From post-marketing experience with modafinil, there have been no reports of fatal overdoses involving modafinil alone (doses up to 12 grams). Overdoses involving multiple drugs, including modafinil, have resulted in fatal outcomes. Symptoms most often accompanying modafinil overdose, alone or in combination with other drugs have included insomnia; central nervous system symptoms such as restlessness, disorientation, confusion, excitation and hallucination; digestive changes such as nausea and diarrhea; and cardiovascular changes such as tachycardia, bradycardia, hypertension and chest pain. Overdose Management - No specific antidote exists for the toxic effects of a NUVIGIL overdose. Such overdoses should be managed with primarily supportive care, including cardiovascular monitoring. If there are no contraindications, induced emesis or gastric lavage should be considered. There are no data to suggest the utility of dialysis or urinary acidification or alkalinization in enhancing drug elimination. The physician should consider contacting a poison-control center for advice in the treatment of any overdose. # Pharmacology ## Mechanism of Action - The mechanism(s) through which armodafinil promotes wakefulness is unknown. Armodafinil (R-modafinil) has pharmacological properties similar to those of modafinil (a mixture of R- and S-modafinil), to the extent tested in animal and in vitro studies. The R- and S-enantiomers have similar pharmacological actions in animals. - Armodafinil and modafinil have wake-promoting actions similar to sympathomimetic agents including amphetamine and methylphenidate, although their pharmacologic profile is not identical to that of the sympathomimetic amines. - Modafinil-induced wakefulness can be attenuated by the α1-adrenergic receptor antagonist, prazosin; however, modafinil is inactive in other in vitro assay systems known to be responsive to α-adrenergic agonists such as the rat vas deferens preparation. - Armodafinil is an indirect dopamine receptor agonist; both armodafinil and modafinil bind in vitro to the dopamine transporter and inhibit dopamine reuptake. For modafinil, this activity has been associated in vivo with increased extracellular dopamine levels in some brain regions of animals. In genetically engineered mice lacking the dopamine transporter (DAT), modafinil lacked wake-promoting activity, suggesting that this activity was DAT-dependent. However, the wake-promoting effects of modafinil, unlike those of amphetamine, were not antagonized by the dopamine receptor antagonist haloperidol in rats. In addition, alpha-methyl-p-tyrosine, a dopamine synthesis inhibitor, blocks the action of amphetamine, but does not block locomotor activity induced by modafinil. - In addition to its wake-promoting effects and ability to increase locomotor activity in animals, modafinil produces psychoactive and euphoric effects, alterations in mood, perception, thinking, and feelings typical of other CNS stimulants in humans. Modafinil has reinforcing properties, as evidenced by its self-administration in monkeys previously trained to self-administer cocaine; modafinil was also partially discriminated as stimulant-like. - Based on nonclinical studies, two major metabolites, acid and sulfone, of modafinil or armodafinil, do not appear to contribute to the CNS-activating properties of the parent compounds. ## Structure - NUVIGIL (armodafinil) is a wakefulness-promoting agent for oral administration. Armodafinil is the R-enantiomer of modafinil which is a 1:1 mixture of the R- and S-enantiomers. The chemical name for armodafinil is 2-acetamide. The molecular formula is C15H15NO2S and the molecular weight is 273.35. - The chemical structure is: - Armodafinil exists in multiple crystalline forms. Form I, which is used in NUVIGIL, is the least soluble form of armodafinil and is a white to off-white, crystalline powder that is slightly soluble in water, sparingly soluble in acetone and soluble in methanol. At least 90% of the armodafinil particles used in NUVIGIL have a diameter of less than 200 microns. - NUVIGIL tablets contain 50, 150, 200 or 250 mg of armodafinil and the following inactive ingredients: croscarmellose sodium, lactose monohydrate, magnesium stearate, microcrystalline cellulose, povidone, and pregelatinized starch. ## Pharmacodynamics - There is limited information regarding Pharmacodynamics of Armodafinil in the drug label. ## Pharmacokinetics - Armodafinil exhibits linear time-independent kinetics following single and multiple oral dose administration. Increase in systemic exposure is proportional over the dose range of 50 to 400 mg. No time-dependent change in kinetics was observed through 12 weeks of dosing. Apparent steady state for armodafinil was reached within 7 days of dosing. At steady state, the systemic exposure for armodafinil is 1.8 times the exposure observed after a single dose. The concentration-time profiles of the R-enantiomer following administration of a single-dose of 50 mg NUVIGIL or 100 mg PROVIGIL (modafinil, a 1:1 mixture of R- and S-enantiomers) are nearly superimposable. However, the Cmax and AUC0-∞, of armodafinil at steady-state were approximately 37% and 70% higher, respectively, following administration of 200 mg NUVIGIL than the corresponding values of modafinil following administration of 200 mg PROVIGIL due to the more rapid clearance of the S-enantiomer (elimination half-life approximately 4 hours) as compared to the R-enantiomer. Absorption - NUVIGIL is readily absorbed after oral administration. The absolute oral bioavailability was not determined due to the aqueous insolubility of armodafinil, which precluded intravenous administration. Peak plasma concentrations are attained at approximately 2 hours in the fasted state. Food effect on the overall bioavailability of NUVIGIL is considered minimal; however, time to reach peak concentration (tmax) may be delayed by approximately 2-4 hours in the fed state. Since the delay in tmax is also associated with elevated plasma concentrations later in time, food can potentially affect the onset and time course of pharmacologic action for NUVIGIL. Distribution - NUVIGIL has an apparent volume of distribution of approximately 42 L. Data specific to armodafinil protein binding are not available. However, modafinil is moderately bound to plasma protein (approximately 60%), mainly to albumin. The potential for interactions of NUVIGIL with highly protein-bound drugs is considered to be minimal. Metabolism - In vitro and in vivo data show that armodafinil undergoes hydrolytic deamidation, S-oxidation, and aromatic ring hydroxylation, with subsequent glucuronide conjugation of the hydroxylated products. Amide hydrolysis is the single most prominent metabolic pathway, with sulfone formation by cytochrome P450 (CYP) 3A4/5 being next in importance. The other oxidative products are formed too slowly in vitro to enable identification of the enzyme(s) responsible. Only two metabolites reach appreciable concentrations in plasma (i.e., R-modafinil acid and modafinil sulfone). - Data specific to NUVIGIL disposition are not available. However, modafinil is mainly eliminated via metabolism, predominantly in the liver, with less than 10% of the parent compound excreted in the urine. A total of 81% of the administered radioactivity was recovered in 11 days post-dose, predominantly in the urine (80% vs. 1.0% in the feces). Elimination - After oral administration of NUVIGIL, armodafinil exhibits an apparent monoexponential decline from the peak plasma concentration. The apparent terminal t½ is approximately 15 hours. The oral clearance of NUVIGIL is approximately 33 mL/min. Specific Populations Age - In a clinical study, systemic exposure of armodafinil was approximately 15% higher in elderly subjects (≥65 years of age, N=24), corresponding to approximately 12% lower oral clearance (CL/F), as compared to young subjects (18-45 years of age, N=25). Systemic exposure of armodafinil acid (metabolite) was approximately 61% and 73% greater for Cmax and AUC0-τ, respectively, compared to young subjects. Systemic exposure of the sulfone metabolite was approximately 20% lower for elderly subjects compared with young subjects. A subgroup analysis of elderly subjects demonstrated elderly subjects ≥75 and 65-74 years of age had approximately 21% and 9% lower oral clearance, respectively, compared to young subjects. Systemic exposure was approximately 10% greater in subjects 65-74 years of age (N=17) and 27% greater in subjects ≥75 years of age (N=7), respectively, when compared to young subjects. The change is considered not likely to be clinically significant for elderly patients, however, because some elderly patients have greater exposure to armodafinil, consideration should be given to the use of lower doses. Gender - Population pharmacokinetic analysis suggests no gender effect on the pharmacokinetics of armodafinil. Race - The influence of race on the pharmacokinetics of armodafinil has not been studied. Hepatic Impairment - The pharmacokinetics and metabolism of modafinil were examined in patients with cirrhosis of the liver (6 men and 3 women). Three patients had stage B or B+ cirrhosis and 6 patients had stage C or C+ cirrhosis (per the Child-Pugh score criteria). Clinically 8 of 9 patients were icteric and all had ascites. In these patients, the oral clearance of modafinil was decreased by about 60% and the steady state concentration was doubled compared to normal patients. The dose of NUVIGIL should be reduced in patients with severe hepatic impairment. Renal Impairment - In a single dose 200 mg modafinil study, severe chronic renal failure (creatinine clearance ≤20 mL/min) did not significantly influence the pharmacokinetics of modafinil, but exposure to modafinil acid (metabolite) was increased 9-fold. Drug Interactions - In vitro data demonstrated that armodafinil weakly induces CYP1A2 and possibly CYP3A activities in a concentration-related manner and that CYP2C19 activity is reversibly inhibited by armodafinil. Other CYP activities did not appear to be affected by armodafinil. An in vitro study demonstrated that armodafinil is a substrate of P-glycoprotein. - Potential Interactions with Drugs That Inhibit, Induce, or Are Metabolized by Cytochrome P450 Isoenzymes and Other Hepatic Enzymes - The existence of multiple pathways for armodafinil metabolism, as well as the fact that a non-CYP-related pathway is the most rapid in metabolizing armodafinil, suggest that there is a low probability of substantive effects on the overall pharmacokinetic profile of NUVIGIL due to CYP inhibition by concomitant medications. However, due to the partial involvement of CYP3A enzymes in the metabolic elimination of armodafinil, coadministration of potent inducers of CYP3A4/5 (e.g., carbamazepine, phenobarbital, rifampin) or inhibitors of CYP3A4/5 (e.g., ketoconazole, erythromycin) could alter the plasma concentrations of armodafinil. - The Potential of NUVIGIL to Alter the Metabolism of Other Drugs by Enzyme Induction or Inhibition Drugs Metabolized by CYP3A4/5 - In vitro data demonstrated that armodafinil is a weak inducer of CYP3A activity in a concentration-related manner. In a clinical study, concomitant administration of NUVIGIL 250 mg resulted in a reduction in systemic exposure to midazolam by 32% after a single oral dose (5 mg) and 17% after a single intravenous dose (2 mg). Therefore, the blood levels and effectiveness of drugs that are substrates for CYP3A enzymes (e.g., steroidal contraceptives, cyclosporine, midazolam, and triazolam) may be reduced after initiation of concomitant treatment with NUVIGIL, and dose adjustment may be required. - In a separate clinical study, concomitant administration of NUVIGIL 250 mg with quetiapine (300 mg to 600 mg daily doses) resulted in a reduction in the mean systemic exposure of quetiapine by approximately 29%. No dose adjustment is required. Drugs Metabolized by CYP1A2 - In vitro data demonstrated that armodafinil is a weak inducer of CYP1A2 in a concentration-related manner. However, in a clinical study using caffeine as a probe substrate, no significant effect on CYP1A2 activity was observed. Drugs Metabolized by CYP2C19 - In vitro data demonstrated that armodafinil is a reversible inhibitor of CYP2C19 activity. In a clinical study, concomitant administration of NUVIGIL 400 mg resulted in a 40% increase in exposure to omeprazole after a single oral dose (40 mg), as a result of moderate inhibition of CYP2C19 activity. Therefore, dose reduction may be required for some drugs that are substrates for CYP2C19 (e.g., phenytoin, diazepam, and propranolol, omeprazole, and clomipramine) when used concomitantly with NUVIGIL. Interactions with CNS Active Drugs - Concomitant administration of NUVIGIL with quetiapine reduced the systemic exposure of quetiapine. - Data specific to NUVIGIL drug-drug interaction potential with other CNS active drugs are not available. However, the following available drug-drug interaction information on modafinil should be applicable to NUVIGIL. - Concomitant administration of modafinil with methylphenidate or dextroamphetamine produced no significant alterations on the pharmacokinetic profile of modafinil or either stimulant, even though the absorption of modafinil was delayed for approximately one hour. - Concomitant modafinil or clomipramine did not alter the pharmacokinetic profile of either drug; however, one incident of increased levels of clomipramine and its active metabolite desmethylclomipramine was reported in a patient with narcolepsy during treatment with modafinil. - Data specific to NUVIGIL or modafinil drug-drug interaction potential with monoamine oxidase (MAO) inhibitors are not available. Therefore, caution should be used when concomitantly administering MAO inhibitors and NUVIGIL. Interaction with P-Glycoprotein - An in vitro study demonstrated that armodafinil is a substrate of P-glycoprotein. The impact of inhibition of P-glycoprotein is not known. Interactions with Other Drugs - Data specific to NUVIGIL drug-drug interaction potential for additional other drugs are not available. However, the following available drug-drug interaction information on modafinil should be applicable to NUVIGIL. - Warfarin - Concomitant administration of modafinil with warfarin did not produce significant changes in the pharmacokinetic profiles of R- and S-warfarin. However, since only a single dose of warfarin was tested in this study, an interaction cannot be ruled out. Therefore, more frequent monitoring of prothrombin times/INR should be considered whenever NUVIGIL is coadministered with warfarin. ## Nonclinical Toxicology Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis - Carcinogenicity studies were conducted in which modafinil (a mixture of R- and S-modafinil) was administered in the diet to mice for 78 weeks and to rats for 104 weeks at doses of 6, 30, and 60 mg/kg/day. At the highest dose studied in rat, the plasma armodafinil exposure (AUC) was less than that in humans at the MRHD of NUVIGIL. There was no evidence of tumorigenesis associated with modafinil administration in these studies. However, since the mouse study used an inadequate high dose that was not representative of a maximum tolerated dose, a subsequent carcinogenicity study was conducted in the Tg.AC transgenic mouse. Doses evaluated in the Tg.AC assay were 125, 250, and 500 mg/kg/day, administered dermally. There was no evidence of tumorigenicity associated with modafinil administration; however, this dermal model may not have adequately assessed the carcinogenic potential of an orally administered drug. Mutagenesis - Armodafinil was negative in an in vitro bacterial reverse mutation assay and in an in vitro chromosomal aberration assay in human lymphocytes. - Modafinil was negative in a series of in vitro (i.e., bacterial reverse mutation, mouse lymphoma tk, chromosomal aberration in human lymphocytes, cell transformation in BALB/3T3 mouse embryo cells) or in vivo (mouse bone marrow micronucleus) assays. Impairment of Fertility - A fertility and early embryonic development (to implantation) study was not conducted with armodafinil alone. - Oral administration of modafinil (doses of up to 480 mg/kg/day) to male and female rats prior to and throughout mating, and continuing in females through day 7 of gestation produced an increase in the time to mate at the highest dose; no effects were observed on other fertility or reproductive parameters. The no-effect dose of 240 mg/kg/day was associated with a plasma armodafinil AUC less than that in humans at the MRHD of NUVIGIL. # Clinical Studies - The effectiveness of NUVIGIL in improving wakefulness has been established in the following sleep disorders: obstructive sleep apnea (OSA), narcolepsy, and shift work disorder (SWD). - For each clinical trial, a p-value of ≤ 0.05 was required for statistical significance. Obstructive Sleep Apnea (OSA) - The effectiveness of NUVIGIL in improving wakefulness in patients with excessive sleepiness associated with OSA was established in two 12-week, multi-center, placebo-controlled, parallel-group, double-blind studies of outpatients who met the International Classification of Sleep Disorders (ICSD) criteria for OSA (which are also consistent with the American Psychiatric Association DSM-IV-TR criteria). These criteria include either: 1) excessive sleepiness or insomnia, plus frequent episodes of impaired breathing during sleep, and associated features such as loud snoring, morning headaches or dry mouth upon awakening; or 2) excessive sleepiness or insomnia; and polysomnography demonstrating one of the following: more than five obstructive apneas, each greater than 10 seconds in duration, per hour of sleep; and one or more of the following: frequent arousals from sleep associated with the apneas, bradytachycardia, or arterial oxygen desaturation in association with the apneas. In addition, for entry into these studies, all patients were required to have excessive sleepiness as demonstrated by a score ≥ 10 on the Epworth Sleepiness Scale, despite treatment with continuous positive airway pressure (CPAP). Evidence that CPAP was effective in reducing episodes of apnea/hypopnea was required along with documentation of CPAP use. - Patients were required to be compliant with CPAP, defined as CPAP use ≥ 4 hours/night on ≥ 70% of nights. CPAP use continued throughout the study. In both studies, the primary measures of effectiveness were 1) sleep latency, as assessed by the Maintenance of Wakefulness Test (MWT) and 2) the change in the patient’s overall disease status, as measured by the Clinical Global Impression of Change (CGI-C) at the final visit. For a successful trial both measures had to show statistically significant improvement. - The MWT measures latency (in minutes) to sleep onset. An extended MWT was performed with test sessions at 2 hour intervals between 9AM and 7PM. The primary analysis was the average of the sleep latencies from the first four test sessions (9AM to 3PM). For each test session, the subject was asked to attempt to remain awake without using extraordinary measures. Each test session was terminated after 30 minutes if no sleep occurred or immediately after sleep onset. The CGI-C is a 7-point scale, centered at No Change, and ranging from Very Much Worse to Very Much Improved. Evaluators were not given any specific guidance about the criteria they were to apply when rating patients. - In the first study, a total of 395 patients with OSA were randomized to receive NUVIGIL 150 mg/day, NUVIGIL 250 mg/day or matching placebo. Patients treated with NUVIGIL showed a statistically significant improvement in the ability to remain awake compared to placebo-treated patients as measured by the MWT at final visit. A statistically significant greater number of patients treated with NUVIGIL showed improvement in overall clinical condition as rated by the CGI-C scale at final visit. The average sleep latencies (in minutes) in the MWT at baseline for the trials are shown in Table 3 below, along with the average change from baseline on the MWT at final visit. The percentages of patients who showed any degree of improvement on the CGI-C in the clinical trials are shown in Table 4 below. The two doses of NUVIGIL produced statistically significant effects of similar magnitudes on the MWT, and also on the CGI-C. - In the second study, 263 patients with OSA were randomized to either NUVIGIL 150 mg/day or placebo. Patients treated with NUVIGIL showed a statistically significant improvement in the ability to remain awake compared to placebo-treated patients as measured by the MWT . A statistically significant greater number of patients treated with NUVIGIL showed improvement in overall clinical condition as rated by the CGI-C scale . - Nighttime sleep measured with polysomnography was not affected by the use of NUVIGIL in either study. Narcolepsy - The effectiveness of NUVIGIL in improving wakefulness in patients with excessive sleepiness (ES) associated with narcolepsy was established in one 12-week, multi-center, placebo-controlled, parallel-group, double-blind study of outpatients who met the ICSD criteria for narcolepsy. A total of 196 patients were randomized to receive NUVIGIL 150 or 250 mg/day, or matching placebo. The ICSD criteria for narcolepsy include either: 1) recurrent daytime naps or lapses into sleep that occur almost daily for at least three months, plus sudden bilateral loss of postural muscle tone in association with intense emotion (cataplexy); or 2) a complaint of excessive sleepiness or sudden muscle weakness with associated features: sleep paralysis, hypnagogic hallucinations, automatic behaviors, disrupted major sleep episode; and polysomnography demonstrating one of the following: sleep latency less than 10 minutes or rapid eye movement (REM) sleep latency less than 20 minutes and a Multiple Sleep Latency Test (MSLT) that demonstrates a mean sleep latency of less than 5 minutes and two or more sleep onset REM periods and no medical or mental disorder accounts for the symptoms. For entry into these studies, all patients were required to have objectively documented excessive daytime sleepiness, via MSLT with a sleep latency of 6 minutes or less and the absence of any other clinically significant active medical or psychiatric disorder. The MSLT, an objective polysomnographic assessment of the patient’s ability to fall asleep in an unstimulating environment, measured latency (in minutes) to sleep onset averaged over 4 test sessions at 2-hour intervals. For each test session, the subject was told to lie quietly and attempt to sleep. Each test session was terminated after 20 minutes if no sleep occurred or immediately after sleep onset. - The primary measures of effectiveness were: 1) sleep latency as assessed by the Maintenance of Wakefulness Test (MWT); and 2) the change in the patient’s overall disease status, as measured by the CGI-C at the final visit for a description of these measures]. Each MWT test session was terminated after 20 minutes if no sleep occurred or immediately after sleep onset in this study. - Patients treated with NUVIGIL showed a statistically significantly enhanced ability to remain awake on the MWT at each dose compared to placebo at final visit . A statistically significant greater number of patients treated with NUVIGIL at each dose showed improvement in overall clinical condition as rated by the CGI-C scale at final visit . - The two doses of NUVIGIL produced statistically significant effects of similar magnitudes on the CGI-C. Although a statistically significant effect on the MWT was observed for each dose, the magnitude of effect was observed to be greater for the higher dose. - Nighttime sleep measured with polysomnography was not affected by the use of NUVIGIL. Shift Work Disorder (SWD) - The effectiveness of NUVIGIL in improving wakefulness in patients with excessive sleepiness associated with SWD was demonstrated in a 12-week, multi-center, double-blind, placebo-controlled, parallel-group clinical trial. A total of 254 patients with chronic SWD were randomized to receive NUVIGIL 150 mg/day or placebo. All patients met the ICSD criteria for chronic SWD . These criteria include: 1) either, a) a primary complaint of excessive sleepiness or insomnia which is temporally associated with a work period (usually night work) that occurs during the habitual sleep phase, or b) polysomnography and the MSLT demonstrate loss of a normal sleep-wake pattern (i.e., disturbed chronobiological rhythmicity); and 2) no other medical or mental disorder accounts for the symptoms; and 3) the symptoms do not meet criteria for any other sleep disorder producing insomnia or excessive sleepiness (e.g., time zone change syndrome). - It should be noted that not all patients with a complaint of sleepiness who are also engaged in shift work meet the criteria for the diagnosis of SWD. In the clinical trial, only patients who were symptomatic for at least 3 months were enrolled. - Enrolled patients were also required to work a minimum of 5 night shifts per month, have excessive sleepiness at the time of their night shifts (MSLT score ≤ 6 minutes), and have daytime insomnia documented by a daytime polysomnogram (PSG). - The primary measures of effectiveness were: 1) sleep latency, as assessed by the Multiple Sleep Latency Test (MSLT) performed during a simulated night shift at the final visit; and 2) the change in the patient’s overall disease status, as measured by the CGI-C at the final visit. - Patients treated with NUVIGIL showed a statistically significant prolongation in the time to sleep onset compared to placebo-treated patients, as measured by the nighttime MSLT at final visit . A statistically significant greater number of patients treated with NUVIGIL showed improvement in overall clinical condition as rated by the CGI-C scale at final visit . - Daytime sleep measured with polysomnography was not affected by the use of NUVIGIL. # How Supplied How Supplied - NUVIGIL® (armodafinil) Tablets are available as follows: - 50 mg: Each round, white to off-white tablet is debossed with stylized c on one side and "205" on the other. - NDC 63459-205-30 – Bottles of 30 - 150 mg: Each oval, white to off-white tablet is debossed with stylized c on one side and "215" on the other. - NDC 63459-215-30 – Bottles of 30 - 200 mg: Each rounded, rectangular, white to off-white tablet is debossed with stylized c on one side and "220" on the other. - NDC 63459-220-30 – Bottles of 30 - 250 mg: Each oval, white to off-white tablet is debossed with stylized c on one side and "225" on the other. - NDC 63459-225-30 – Bottles of 30 ## Storage - Store at 20o - 25o C (68o - 77o F). # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information - See FDA-approved patient labeling (Medication Guide). - Inform patients of the availability of a Medication Guide, and instruct them to read it prior to taking NUVIGIL. Wakefulness - NUVIGIL is indicated for patients who have abnormal levels of sleepiness. NUVIGIL has been shown to improve, but not eliminate, this abnormal tendency to fall asleep. Therefore, patients should not alter their previous behavior with regard to potentially dangerous activities (e.g., driving, operating machinery) or other activities requiring appropriate levels of wakefulness, until and unless treatment with NUVIGIL has been shown to produce levels of wakefulness that permit such activities. Advise patients that NUVIGIL is not a replacement for sleep. Continuing Previously Prescribed Treatments - Inform patients that it may be critical that they continue to take their previously prescribed treatments (e.g., patients with OSA receiving CPAP should continue to do so). Discontinuing Drug Due to Adverse Reactions - Advise patients to stop taking NUVIGIL and contact their physician right away if they experience rash, depression, anxiety, or signs of psychosis or mania. Pregnancy - Advise patients to notify their physician if they become pregnant or intend to become pregnant during therapy. Caution patients regarding the potential increased risk of pregnancy when using steroidal contraceptives (including depot or implantable contraceptives) with NUVIGIL and for one month after discontinuation of therapy. Nursing - Advise patients to notify their physician if they are breastfeeding an infant. Concomitant Medication - Advise patients to inform their physician if they are taking, or plan to take, any prescription or over-the-counter drugs, because of the potential for interactions between NUVIGIL and other drugs. Alcohol - Advise patients that the use of NUVIGIL in combination with alcohol has not been studied. Advise patients that it is prudent to avoid alcohol while taking NUVIGIL. Allergic Reactions - Advise patients to stop taking NUVIGIL and to notify their physician right away if they develop a rash, hives, mouth sores, blisters, peeling skin, trouble swallowing or breathing or a related allergic phenomenon. # Precautions with Alcohol - Alcohol-Armodafinil interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names Nuvigil # Look-Alike Drug Names - A® — B® # Drug Shortage Status # Price	Armodafinil Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Deepika Beereddy, MBBS [2] # Disclaimer WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here. # Overview Armodafinil is a central nervous system agent that is FDA approved for the treatment of obstructive sleep apnea (OSA), narcolepsy, or shift work disorder (SWD). Common adverse reactions include headache, nausea, dizziness, and insomnia. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - NUVIGIL is indicated to improve wakefulness in adult patients with excessive sleepiness associated with obstructive sleep apnea (OSA), narcolepsy, or shift work disorder (SWD). - In OSA, NUVIGIL is indicated to treat excessive sleepiness and not as treatment for the underlying obstruction. If continuous positive airway pressure (CPAP) is the treatment of choice for a patient, a maximal effort to treat with CPAP for an adequate period of time should be made prior to initiating NUVIGIL for excessive sleepiness. If NUVIGIL is used adjunctively with CPAP, the encouragement of and periodic assessment of CPAP compliance is necessary. - In all cases, careful attention to the diagnosis and treatment of the underlying sleep disorder(s) is of utmost importance. Prescribers should be aware that some patients may have more than one sleep disorder contributing to their excessive sleepiness. - The effectiveness of NUVIGIL in long-term use (greater than 12 weeks) has not been systematically evaluated in placebo-controlled trials. The physician who elects to prescribe NUVIGIL for an extended time in patients should periodically re-evaluate long-term usefulness for the individual patient. - Dosing Information - The recommended dose of NUVIGIL for patients with OSA or narcolepsy is 150 mg to 250 mg given once daily in the morning. In patients with OSA, doses up to 250 mg/day, given as a single dose, have been well tolerated, but there is no consistent evidence that these doses confer additional benefit beyond that of the 150 mg/day dose. - Dosing Information - The recommended dose of NUVIGIL for patients with SWD is 150 mg given daily approximately 1 hour prior to the start of their work shift. Hepatic Impairment - The dose of NUVIGIL should be reduced in patients with severe hepatic impairment, with or without cirrhosis. Use in Geriatric Patients - Consideration should be given to the use of lower doses and close monitoring in geriatric patients. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use - There is limited information regarding Off-Label Guideline-Supported Use of Armodafinil in adult patients. ### Non–Guideline-Supported Use - There is limited information regarding Off-Label Non–Guideline-Supported Use of Armodafinil in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) - There is limited information regarding FDA-Labeled Use of Armodafinil in pediatric patients. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use - There is limited information regarding Off-Label Guideline-Supported Use of Armodafinil in pediatric patients. ### Non–Guideline-Supported Use - There is limited information regarding Off-Label Non–Guideline-Supported Use of Armodafinil in pediatric patients. # Contraindications - NUVIGIL is contraindicated in patients with known hypersensitivity to modafinil or armodafinil or its inactive ingredients. # Warnings Serious Rash, including Stevens-Johnson Syndrome - Serious rash requiring hospitalization and discontinuation of treatment has been reported in association with the use of NUVIGIL (armodafinil) or modafinil (the racemic mixture of S- and R-enantiomers). - NUVIGIL has not been studied in pediatric patients in any setting and is not approved for use in pediatric patients for any indication. - In clinical trials of modafinil, the incidence of rash resulting in discontinuation was approximately 0.8% (13 per 1,585) in pediatric patients (age <17 years); these rashes included 1 case of possible Stevens-Johnson Syndrome (SJS) and 1 case of apparent multi-organ hypersensitivity reaction. Several of the cases were associated with fever and other abnormalities (e.g., vomiting, leukopenia). The median time to rash that resulted in discontinuation was 13 days. No such cases were observed among 380 pediatric patients who received placebo. No serious skin rashes have been reported in adult clinical trials (0 per 4,264) of modafinil. Rare cases of serious or life-threatening rash, including SJS, Toxic Epidermal Necrolysis (TEN), and Drug Rash with Eosinophilia and Systemic Symptoms (DRESS) have been reported in adults and children in worldwide post-marketing experience. The reporting rate of TEN and SJS associated with modafinil use, which is generally accepted to be an underestimate due to underreporting, exceeds the background incidence rate. Estimates of the background incidence rate for these serious skin reactions in the general population range between 1 to 2 cases per million-person years. - Cases of serious rash similar to those observed with modafinil including skin and mouth blistering have been reported in adults in postmarketing experience with NUVIGIL. - There are no factors that are known to predict the risk of occurrence or the severity of rash associated with modafinil or armodafinil. Nearly all cases of serious rash associated with these drugs occurred within 1 to 5 weeks after treatment initiation. However, isolated cases have been reported after prolonged treatment (e.g., 3 months). Accordingly, duration of therapy cannot be relied upon as a means to predict the potential risk heralded by the first appearance of a rash. - Although benign rashes also occur with NUVIGIL, it is not possible to reliably predict which rashes will prove to be serious. Accordingly, NUVIGIL should be discontinued at the first sign of rash, unless the rash is clearly not drug-related. Discontinuation of treatment may not prevent a rash from becoming life-threatening or permanently disabling or disfiguring. Angioedema and Anaphylactoid Reactions - Angioedema and hypersensitivity (with rash, dysphagia, and bronchospasm), were observed with NUVIGIL. Patients should be advised to discontinue therapy and immediately report to their physician any signs or symptoms suggesting angioedema or anaphylaxis (e.g., swelling of face, eyes, lips, tongue or larynx; difficulty in swallowing or breathing; hoarseness). Multi-organ Hypersensitivity Reactions - Multi-organ hypersensitivity reactions, including at least one fatality in post-marketing experience, have occurred in close temporal association (median time to detection 13 days: range 4-33) to the initiation of modafinil. A similar risk of multi-organ hypersensitivity reactions with armodafinil cannot be ruled out. - Although there have been a limited number of reports, multi-organ hypersensitivity reactions may result in hospitalization or be life-threatening. There are no factors that are known to predict the risk of occurrence or the severity of multi-organ hypersensitivity reactions. Signs and symptoms of this disorder were diverse; however, patients typically, although not exclusively, presented with fever and rash associated with other organ system involvement. Other associated manifestations included myocarditis, hepatitis, liver function test abnormalities, hematological abnormalities (e.g., eosinophilia, leukopenia, thrombocytopenia), pruritus, and asthenia. Because multi-organ hypersensitivity is variable in its expression, other organ system symptoms and signs, not noted here, may occur. - If a multi-organ hypersensitivity reaction is suspected, NUVIGIL should be discontinued. Although there are no case reports to indicate cross-sensitivity with other drugs that produce this syndrome, the experience with drugs associated with multi-organ hypersensitivity would indicate this to be a possibility. Persistent Sleepiness - Patients with abnormal levels of sleepiness who take NUVIGIL should be advised that their level of wakefulness may not return to normal. Patients with excessive sleepiness, including those taking NUVIGIL, should be frequently reassessed for their degree of sleepiness and, if appropriate, advised to avoid driving or any other potentially dangerous activity. Prescribers should also be aware that patients may not acknowledge sleepiness or drowsiness until directly questioned about drowsiness or sleepiness during specific activities. Psychiatric Symptoms - In pre-approval narcolepsy, OSA and SWD controlled trials of NUVIGIL, anxiety, agitation, nervousness, and irritability were reasons for treatment discontinuation more often in patients on NUVIGIL compared to placebo (NUVIGIL 1.2% and placebo 0.3%). Depression was also a reason for treatment discontinuation more often in patients on NUVIGIL compared to placebo (NUVIGIL 0.6% and placebo 0.2%). Cases of suicide ideation were observed in clinical trials. - Caution should be exercised when NUVIGIL is given to patients with a history of psychosis, depression, or mania. If psychiatric symptoms develop in association with NUVIGIL administration, consider discontinuing NUVIGIL. - Psychiatric adverse experiences have been reported in patients treated with modafinil. Modafinil and armodafinil (NUVIGIL) are very closely related. Therefore, the incidence and type of psychiatric symptoms associated with NUVIGIL are expected to be similar to the incidence and type of these events with modafinil. - Post-marketing adverse events associated with the use of modafinil have included mania, delusions, hallucinations, suicidal ideation, and aggression, some resulting in hospitalization. Many, but not all, patients had a prior psychiatric history. One healthy male volunteer developed ideas of reference, paranoid delusions, and auditory hallucinations in association with multiple daily 600 mg doses of modafinil and sleep deprivation. There was no evidence of psychosis 36 hours after drug discontinuation. Diagnosis of Sleep Disorders - NUVIGIL should be used only in patients who have had a complete evaluation of their excessive sleepiness, and in whom a diagnosis of narcolepsy, OSA, or SWD has been made in accordance with International Classification of Sleep Disorders (ICSD) or Diagnostic and Statistical Manual of Mental Disorders (DSM) diagnostic criteria. Such an evaluation usually consists of a complete history and physical examination, and it may be supplemented with testing in a laboratory setting. Some patients may have more than one sleep disorder contributing to their excessive sleepiness (e.g., OSA and SWD coincident in the same patient). CPAP Use in Patients with OSA - In OSA, NUVIGIL is not indicated as treatment for the underlying obstruction. If continuous positive airway pressure (CPAP) is the treatment of choice for a patient, a maximal effort to treat with CPAP for an adequate period of time should be made prior to initiating NUVIGIL for excessive sleepiness. If NUVIGIL is used adjunctively with CPAP, the encouragement of and periodic assessment of CPAP compliance is necessary. There was a slight trend for reduced CPAP use over time (mean reduction of 18 minutes for patients treated with NUVIGIL and a 6-minute reduction for placebo-treated patients from a mean baseline use of 6.9 hours per night) in NUVIGIL trials. Effects on Ability to Drive and Use Machinery - Although NUVIGIL has not been shown to produce functional impairment, any drug affecting the CNS may alter judgment, thinking or motor skills. Patients should be cautioned about operating an automobile or other hazardous machinery until it is reasonably certain that NUVIGIL therapy will not adversely affect their ability to engage in such activities. Cardiovascular System - NUVIGIL has not been evaluated or used to any appreciable extent in patients with a recent history of myocardial infarction or unstable angina, and such patients should be treated with caution. - In clinical studies of modafinil, cardiovascular adverse events, including chest pain, palpitations, dyspnea and transient ischemic T-wave changes on ECG were observed in three subjects in association with mitral valve prolapse or left ventricular hypertrophy. It is recommended that NUVIGIL tablets not be used in patients with a history of left ventricular hypertrophy or in patients with mitral valve prolapse who have experienced the mitral valve prolapse syndrome when previously receiving CNS stimulants. Findings suggestive of mitral valve prolapse syndrome include but are not limited to ischemic ECG changes, chest pain, or arrhythmia. If new onset of any of these findings occurs, consider cardiac evaluation. - Blood pressure monitoring in short term (≤ 3 months) pre-approval controlled trials of OSA, SWD, and narcolepsy showed small average increases in mean systolic and diastolic blood pressure in patients receiving NUVIGIL as compared to placebo (1.2 to 4.3 mmHg in the various experimental groups). There was also a slightly greater proportion of patients on NUVIGIL requiring new or increased use of antihypertensive medications (2.9%) compared to patients on placebo (1.8%). There was a small, but consistent, average increase in pulse rate over placebo in pre-approval controlled trials. This increase varied from 0.9 to 3.5 BPM. Increased monitoring of heart rate and blood pressure may be appropriate in patients on NUVIGIL. Caution should be exercised when prescribing NUVIGIL to patients with known cardiovascular disease. DRUG ABUSE AND DEPENDENCE Controlled Substance - Armodafinil (NUVIGIL) is a Schedule IV controlled substance. Abuse - Although the abuse potential of armodafinil has not been specifically studied, its abuse potential is likely to be similar to that of modafinil. In humans, modafinil produces psychoactive and euphoric effects, alterations in mood, perception, thinking and feelings typical of other CNS stimulants. In in vitro binding studies, modafinil binds to the dopamine reuptake site and causes an increase in extracellular dopamine, but no increase in dopamine release. Modafinil is reinforcing, as evidenced by its self-administration in monkeys previously trained to self-administer cocaine. In some studies, modafinil was also partially discriminated as stimulant-like. Physicians should follow patients closely, especially those with a history of drug and/or stimulant (e.g., methylphenidate, amphetamine, or cocaine) abuse. Patients should be observed for signs of misuse or abuse (e.g., incrementation of doses or drug-seeking behavior). - The abuse potential of modafinil (200, 400, and 800 mg) was assessed relative to methylphenidate (45 and 90 mg) in an inpatient study in individuals experienced with drugs of abuse. Results from this clinical study demonstrated that modafinil produced psychoactive and euphoric effects and feelings consistent with other scheduled CNS stimulants (methylphenidate). # Adverse Reactions ## Clinical Trials Experience - The following serious adverse reactions are described below and elsewhere in the labeling: - Serious Rash, including Stevens-Johnson Syndrome - Angioedema and Anaphylactoid Reactions - Multi-organ Hypersensitivity Reactions - Persistent Sleepiness - Psychiatric Symptoms - Diagnosis of Sleep Disorders - CPAP Use in Patients with OSA - Effects on Ability to Drive and Use Machinery - Cardiovascular System Clinical Trials Experience - Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. OSA, SWD, and Narcolepsy - NUVIGIL has been evaluated for safety in over 1100 patients with excessive sleepiness associated with OSA, SWD, and narcolepsy. - In the pre-approval controlled clinical trials, the most commonly observed adverse events (≥ 5%) associated with the use of NUVIGIL occurring more frequently than in the placebo-treated patients were headache, nausea, dizziness, and insomnia. The adverse event profile was similar across the studies. - In the pre-approval controlled clinical trials, 44 of the 645 patients (7%) who received NUVIGIL discontinued due to an adverse experience compared to 16 of the 445 (4%) of patients that received placebo. The most frequent reason for discontinuation was headache (1%). Incidence in Controlled Trials - The following table (Table 1) presents the adverse experiences that occurred at a rate of 1% or more and were more frequent in patients treated with NUVIGIL than in placebo group patients in the pre-approval controlled clinical trials. - The prescriber should be aware that the figures provided below cannot be used to predict the frequency of adverse experiences in the course of usual medical practice, where patient characteristics and other factors may differ from those occurring during clinical studies. Similarly, the cited frequencies cannot be directly compared with figures obtained from other clinical investigations involving different treatments, uses, or investigators. Review of these frequencies, however, provides prescribers with a basis to estimate the relative contribution of drug and non-drug factors to the incidence of adverse events in the population studied. Dose Dependency of Adverse Events - In the pre-approval controlled clinical trials which compared doses of 150 mg/day and 250 mg/day of NUVIGIL and placebo, the only adverse events that appeared to be dose-related were headache, rash, depression, dry mouth, insomnia, and nausea. See Table 2 for additional information. Laboratory Changes - Clinical chemistry, hematology, and urinalysis parameters were monitored in the studies. Mean plasma levels of gamma glutamyltransferase (GGT) and alkaline phosphatase (AP) were found to be higher following administration of NUVIGIL, but not placebo. Few subjects, however, had GGT or AP elevations outside of the normal range. No differences were apparent in alanine aminotransferase (ALT), aspartate aminotransferase (AST), total protein, albumin, or total bilirubin, although there were rare cases of isolated elevations of AST and/or ALT. A single case of mild pancytopenia was observed after 35 days of treatment and resolved with drug discontinuation. A small mean decrease from baseline in serum uric acid compared to placebo was seen in clinical trials. The clinical significance of this finding is unknown. Vital Sign Changes - Blood pressure monitoring in pre-approval controlled trials of OSA, SWD, and narcolepsy showed small average increases in mean systolic and diastolic blood pressure in patients receiving NUVIGIL as compared to placebo (1.2 to 4.3 mmHg in the various experimental groups). There was also a slightly greater proportion of patients on NUVIGIL requiring new or increased use of antihypertensive medications (2.9%) compared to patients on placebo (1.8%). There was a small, but consistent, average increase in pulse rate over placebo in pre-approval controlled trials. This increase varied from 0.9 to 3.5 BPM. ## Postmarketing Experience - There is limited information regarding Postmarketing Experience of Armodafinil in the drug label. # Drug Interactions - The clearance of drugs that are substrates for CYP3A4/5 (e.g., steroidal contraceptives, cyclosporine, midazolam, and triazolam) may be increased by NUVIGIL via induction of metabolic enzymes, which results in lower systemic exposure. Dosage adjustment of these drugs should be considered when these drugs are used concomitantly with NUVIGIL [see Clinical Pharmacology (12.3)]. - The effectiveness of steroidal contraceptives may be reduced when used with NUVIGIL and for one month after discontinuation of therapy. Alternative or concomitant methods of contraception are recommended for patients taking steroidal contraceptives (e.g., ethinyl estradiol) when treated concomitantly with NUVIGIL and for one month after discontinuation of NUVIGIL treatment. - Blood levels of cyclosporine may be reduced when used with NUVIGIL. Monitoring of circulating cyclosporine concentrations and appropriate dosage adjustment for cyclosporine should be considered when used concomitantly with NUVIGIL. - Elimination of drugs that are substrates for CYP2C19 (e.g., phenytoin, diazepam, propranolol, omeprazole, and clomipramine) may be prolonged by NUVIGIL via inhibition of metabolic enzymes, with resultant higher systemic exposure. Dose reduction of these drugs may be required when these drugs are used concomitantly with NUVIGIL. - More frequent monitoring of prothrombin times/INR should be considered whenever NUVIGIL is coadministered with warfarin. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): C Pregnancy Category C - There are no adequate and well-controlled studies of armodafinil in pregnant women. Intrauterine growth restriction and spontaneous abortion have been reported in association with armodafinil and modafinil. Although the pharmacology of armodafinil is not identical to that of the sympathomimetic amines, it does share some pharmacologic properties with this class. Certain of these drugs have been associated with intrauterine growth restriction and spontaneous abortions. Whether the cases reported with armodafinil are drug-related is unknown. In studies of armodafinil (R-modafinil) and modafinil (a mixture of R- and S-modafinil) conducted in rats (armodafinil, modafinil) and rabbits (modafinil), developmental toxicity was observed at clinically relevant plasma exposures. NUVIGIL should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. - Oral administration of armodafinil (60, 200, or 600 mg/kg/day) to pregnant rats throughout organogenesis resulted in increased incidences of fetal visceral and skeletal variations and decreased fetal body weight at the highest dose. The highest no-effect dose for embryofetal developmental toxicity in rat (200 mg/kg/day) was associated with a plasma armodafinil exposure (AUC) less than that in humans at the maximum recommended human dose (MRHD) of NUVIGIL (250 mg/day). - Modafinil (50, 100, or 200 mg/kg/day) administered orally to pregnant rats throughout organogenesis caused, in the absence of maternal toxicity, an increase in resorptions and an increased incidence of visceral and skeletal variations in the offspring at the highest dose tested. The higher no-effect dose for embryofetal developmental toxicity in rat (100 mg/kg/day) was associated with a plasma armodafinil AUC less than that in humans at the MRHD of NUVIGIL. However, in a subsequent study of up to 480 mg/kg/day of modafinil, no adverse effects on embryofetal development were observed. - Modafinil administered orally to pregnant rabbits throughout organogenesis at doses of up to 100 mg/kg/day had no effect on embryofetal development; however, the doses used were too low to adequately assess the effects of modafinil on embryofetal development. In a subsequent developmental toxicity study evaluating doses of 45, 90, and 180 mg/kg/day in pregnant rabbits, the incidences of fetal structural alterations and embryofetal death were increased at the highest dose. The highest no-effect dose for developmental toxicity (100 mg/kg/day) was associated with a plasma armodafinil AUC less than that in humans at the MRHD of NUVIGIL. - Modafinil administration to rats throughout gestation and lactation at oral doses of up to 200 mg/kg/day resulted in decreased viability in the offspring at doses greater than 20 mg/kg/day, a dose resulting in a plasma armodafinil AUC less than that in humans at the MRHD of NUVIGIL. No effects on postnatal developmental and neurobehavioral parameters were observed in surviving offspring. - Pregnancy Registry: A pregnancy registry has been established to collect information on the pregnancy outcomes of women exposed to NUVIGIL. Healthcare providers are encouraged to register pregnant patients, or pregnant women may enroll themselves in the registry by calling 1-866-404-4106 (toll free). Pregnancy Category (AUS): - Australian Drug Evaluation Committee (ADEC) Pregnancy Category - There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Armodafinil in women who are pregnant. ### Labor and Delivery - There is no FDA guidance on use of Armodafinil during labor and delivery. ### Nursing Mothers - It is not known whether armodafinil or its metabolites are excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when NUVIGIL is administered to a nursing woman. ### Pediatric Use - Safety and effectiveness in pediatric patients have not been established. Serious rash has been seen in pediatric patients receiving modafinil. ### Geriatic Use - In elderly patients, elimination of armodafinil and its metabolites may be reduced as a consequence of aging. Therefore, consideration should be given to the use of lower doses and close monitoring in this population. ### Gender - There is no FDA guidance on the use of Armodafinil with respect to specific gender populations. ### Race - There is no FDA guidance on the use of Armodafinil with respect to specific racial populations. ### Renal Impairment - There is inadequate information to determine safety and efficacy of dosing in patients with severe renal impairment. ### Hepatic Impairment - The dose of NUVIGIL should be reduced in patients with severe hepatic impairment, with or without cirrhosis. ### Females of Reproductive Potential and Males - There is no FDA guidance on the use of Armodafinil in women of reproductive potentials and males. ### Immunocompromised Patients - There is no FDA guidance one the use of Armodafinil in patients who are immunocompromised. # Administration and Monitoring ### Administration Obstructive Sleep Apnea (OSA) and Narcolepsy - The recommended dose of NUVIGIL for patients with OSA or narcolepsy is 150 mg to 250 mg given once daily in the morning. In patients with OSA, doses up to 250 mg/day, given as a single dose, have been well tolerated, but there is no consistent evidence that these doses confer additional benefit beyond that of the 150 mg/day dose. Shift Work Disorder (SWD) - The recommended dose of NUVIGIL for patients with SWD is 150 mg given daily approximately 1 hour prior to the start of their work shift. Hepatic Impairment - The dose of NUVIGIL should be reduced in patients with severe hepatic impairment, with or without cirrhosis. [see Clinical Pharmacology (12.3)] Use in Geriatric Patients - Consideration should be given to the use of lower doses and close monitoring in geriatric patients. [see Use in Specific Populations (8.5)] DOSAGE FORMS AND STRENGTHS - 50 mg – round, white to off-white tablet with - stylized c - on one side and "205" on the other - 150 mg – oval, white to off-white tablet with - stylized c - on one side and "215" on the other - 200 mg – rounded, rectangular, white to off-white tablet with - stylized c - on one side and "220" on the other - 250 mg – oval, white to off-white tablet with - stylized c - on one side and "225" on the other ### Monitoring - There is limited information regarding Monitoring of Armodafinil in the drug label. # IV Compatibility - There is limited information regarding IV Compatibility of Armodafinil in the drug label. # Overdosage Human Experience - There were no overdoses reported in the NUVIGIL clinical studies. - Symptoms of NUVIGIL overdose are likely to be similar to those of modafinil. Symptoms of overdose in modafinil clinical trials included excitation or agitation, insomnia, and slight or moderate elevations in hemodynamic parameters. From post-marketing experience with modafinil, there have been no reports of fatal overdoses involving modafinil alone (doses up to 12 grams). Overdoses involving multiple drugs, including modafinil, have resulted in fatal outcomes. Symptoms most often accompanying modafinil overdose, alone or in combination with other drugs have included insomnia; central nervous system symptoms such as restlessness, disorientation, confusion, excitation and hallucination; digestive changes such as nausea and diarrhea; and cardiovascular changes such as tachycardia, bradycardia, hypertension and chest pain. Overdose Management - No specific antidote exists for the toxic effects of a NUVIGIL overdose. Such overdoses should be managed with primarily supportive care, including cardiovascular monitoring. If there are no contraindications, induced emesis or gastric lavage should be considered. There are no data to suggest the utility of dialysis or urinary acidification or alkalinization in enhancing drug elimination. The physician should consider contacting a poison-control center for advice in the treatment of any overdose. # Pharmacology ## Mechanism of Action - The mechanism(s) through which armodafinil promotes wakefulness is unknown. Armodafinil (R-modafinil) has pharmacological properties similar to those of modafinil (a mixture of R- and S-modafinil), to the extent tested in animal and in vitro studies. The R- and S-enantiomers have similar pharmacological actions in animals. - Armodafinil and modafinil have wake-promoting actions similar to sympathomimetic agents including amphetamine and methylphenidate, although their pharmacologic profile is not identical to that of the sympathomimetic amines. - Modafinil-induced wakefulness can be attenuated by the α1-adrenergic receptor antagonist, prazosin; however, modafinil is inactive in other in vitro assay systems known to be responsive to α-adrenergic agonists such as the rat vas deferens preparation. - Armodafinil is an indirect dopamine receptor agonist; both armodafinil and modafinil bind in vitro to the dopamine transporter and inhibit dopamine reuptake. For modafinil, this activity has been associated in vivo with increased extracellular dopamine levels in some brain regions of animals. In genetically engineered mice lacking the dopamine transporter (DAT), modafinil lacked wake-promoting activity, suggesting that this activity was DAT-dependent. However, the wake-promoting effects of modafinil, unlike those of amphetamine, were not antagonized by the dopamine receptor antagonist haloperidol in rats. In addition, alpha-methyl-p-tyrosine, a dopamine synthesis inhibitor, blocks the action of amphetamine, but does not block locomotor activity induced by modafinil. - In addition to its wake-promoting effects and ability to increase locomotor activity in animals, modafinil produces psychoactive and euphoric effects, alterations in mood, perception, thinking, and feelings typical of other CNS stimulants in humans. Modafinil has reinforcing properties, as evidenced by its self-administration in monkeys previously trained to self-administer cocaine; modafinil was also partially discriminated as stimulant-like. - Based on nonclinical studies, two major metabolites, acid and sulfone, of modafinil or armodafinil, do not appear to contribute to the CNS-activating properties of the parent compounds. ## Structure - NUVIGIL (armodafinil) is a wakefulness-promoting agent for oral administration. Armodafinil is the R-enantiomer of modafinil which is a 1:1 mixture of the R- and S-enantiomers. The chemical name for armodafinil is 2-[(R)-(diphenylmethyl)sulfinyl]acetamide. The molecular formula is C15H15NO2S and the molecular weight is 273.35. - The chemical structure is: - Armodafinil exists in multiple crystalline forms. Form I, which is used in NUVIGIL, is the least soluble form of armodafinil and is a white to off-white, crystalline powder that is slightly soluble in water, sparingly soluble in acetone and soluble in methanol. At least 90% of the armodafinil particles used in NUVIGIL have a diameter of less than 200 microns. - NUVIGIL tablets contain 50, 150, 200 or 250 mg of armodafinil and the following inactive ingredients: croscarmellose sodium, lactose monohydrate, magnesium stearate, microcrystalline cellulose, povidone, and pregelatinized starch. ## Pharmacodynamics - There is limited information regarding Pharmacodynamics of Armodafinil in the drug label. ## Pharmacokinetics - Armodafinil exhibits linear time-independent kinetics following single and multiple oral dose administration. Increase in systemic exposure is proportional over the dose range of 50 to 400 mg. No time-dependent change in kinetics was observed through 12 weeks of dosing. Apparent steady state for armodafinil was reached within 7 days of dosing. At steady state, the systemic exposure for armodafinil is 1.8 times the exposure observed after a single dose. The concentration-time profiles of the R-enantiomer following administration of a single-dose of 50 mg NUVIGIL or 100 mg PROVIGIL (modafinil, a 1:1 mixture of R- and S-enantiomers) are nearly superimposable. However, the Cmax and AUC0-∞, of armodafinil at steady-state were approximately 37% and 70% higher, respectively, following administration of 200 mg NUVIGIL than the corresponding values of modafinil following administration of 200 mg PROVIGIL due to the more rapid clearance of the S-enantiomer (elimination half-life approximately 4 hours) as compared to the R-enantiomer. Absorption - NUVIGIL is readily absorbed after oral administration. The absolute oral bioavailability was not determined due to the aqueous insolubility of armodafinil, which precluded intravenous administration. Peak plasma concentrations are attained at approximately 2 hours in the fasted state. Food effect on the overall bioavailability of NUVIGIL is considered minimal; however, time to reach peak concentration (tmax) may be delayed by approximately 2-4 hours in the fed state. Since the delay in tmax is also associated with elevated plasma concentrations later in time, food can potentially affect the onset and time course of pharmacologic action for NUVIGIL. Distribution - NUVIGIL has an apparent volume of distribution of approximately 42 L. Data specific to armodafinil protein binding are not available. However, modafinil is moderately bound to plasma protein (approximately 60%), mainly to albumin. The potential for interactions of NUVIGIL with highly protein-bound drugs is considered to be minimal. Metabolism - In vitro and in vivo data show that armodafinil undergoes hydrolytic deamidation, S-oxidation, and aromatic ring hydroxylation, with subsequent glucuronide conjugation of the hydroxylated products. Amide hydrolysis is the single most prominent metabolic pathway, with sulfone formation by cytochrome P450 (CYP) 3A4/5 being next in importance. The other oxidative products are formed too slowly in vitro to enable identification of the enzyme(s) responsible. Only two metabolites reach appreciable concentrations in plasma (i.e., R-modafinil acid and modafinil sulfone). - Data specific to NUVIGIL disposition are not available. However, modafinil is mainly eliminated via metabolism, predominantly in the liver, with less than 10% of the parent compound excreted in the urine. A total of 81% of the administered radioactivity was recovered in 11 days post-dose, predominantly in the urine (80% vs. 1.0% in the feces). Elimination - After oral administration of NUVIGIL, armodafinil exhibits an apparent monoexponential decline from the peak plasma concentration. The apparent terminal t½ is approximately 15 hours. The oral clearance of NUVIGIL is approximately 33 mL/min. Specific Populations Age - In a clinical study, systemic exposure of armodafinil was approximately 15% higher in elderly subjects (≥65 years of age, N=24), corresponding to approximately 12% lower oral clearance (CL/F), as compared to young subjects (18-45 years of age, N=25). Systemic exposure of armodafinil acid (metabolite) was approximately 61% and 73% greater for Cmax and AUC0-τ, respectively, compared to young subjects. Systemic exposure of the sulfone metabolite was approximately 20% lower for elderly subjects compared with young subjects. A subgroup analysis of elderly subjects demonstrated elderly subjects ≥75 and 65-74 years of age had approximately 21% and 9% lower oral clearance, respectively, compared to young subjects. Systemic exposure was approximately 10% greater in subjects 65-74 years of age (N=17) and 27% greater in subjects ≥75 years of age (N=7), respectively, when compared to young subjects. The change is considered not likely to be clinically significant for elderly patients, however, because some elderly patients have greater exposure to armodafinil, consideration should be given to the use of lower doses. Gender - Population pharmacokinetic analysis suggests no gender effect on the pharmacokinetics of armodafinil. Race - The influence of race on the pharmacokinetics of armodafinil has not been studied. Hepatic Impairment - The pharmacokinetics and metabolism of modafinil were examined in patients with cirrhosis of the liver (6 men and 3 women). Three patients had stage B or B+ cirrhosis and 6 patients had stage C or C+ cirrhosis (per the Child-Pugh score criteria). Clinically 8 of 9 patients were icteric and all had ascites. In these patients, the oral clearance of modafinil was decreased by about 60% and the steady state concentration was doubled compared to normal patients. The dose of NUVIGIL should be reduced in patients with severe hepatic impairment. Renal Impairment - In a single dose 200 mg modafinil study, severe chronic renal failure (creatinine clearance ≤20 mL/min) did not significantly influence the pharmacokinetics of modafinil, but exposure to modafinil acid (metabolite) was increased 9-fold. Drug Interactions - In vitro data demonstrated that armodafinil weakly induces CYP1A2 and possibly CYP3A activities in a concentration-related manner and that CYP2C19 activity is reversibly inhibited by armodafinil. Other CYP activities did not appear to be affected by armodafinil. An in vitro study demonstrated that armodafinil is a substrate of P-glycoprotein. - Potential Interactions with Drugs That Inhibit, Induce, or Are Metabolized by Cytochrome P450 Isoenzymes and Other Hepatic Enzymes - The existence of multiple pathways for armodafinil metabolism, as well as the fact that a non-CYP-related pathway is the most rapid in metabolizing armodafinil, suggest that there is a low probability of substantive effects on the overall pharmacokinetic profile of NUVIGIL due to CYP inhibition by concomitant medications. However, due to the partial involvement of CYP3A enzymes in the metabolic elimination of armodafinil, coadministration of potent inducers of CYP3A4/5 (e.g., carbamazepine, phenobarbital, rifampin) or inhibitors of CYP3A4/5 (e.g., ketoconazole, erythromycin) could alter the plasma concentrations of armodafinil. - The Potential of NUVIGIL to Alter the Metabolism of Other Drugs by Enzyme Induction or Inhibition Drugs Metabolized by CYP3A4/5 - In vitro data demonstrated that armodafinil is a weak inducer of CYP3A activity in a concentration-related manner. In a clinical study, concomitant administration of NUVIGIL 250 mg resulted in a reduction in systemic exposure to midazolam by 32% after a single oral dose (5 mg) and 17% after a single intravenous dose (2 mg). Therefore, the blood levels and effectiveness of drugs that are substrates for CYP3A enzymes (e.g., steroidal contraceptives, cyclosporine, midazolam, and triazolam) may be reduced after initiation of concomitant treatment with NUVIGIL, and dose adjustment may be required. - In a separate clinical study, concomitant administration of NUVIGIL 250 mg with quetiapine (300 mg to 600 mg daily doses) resulted in a reduction in the mean systemic exposure of quetiapine by approximately 29%. No dose adjustment is required. Drugs Metabolized by CYP1A2 - In vitro data demonstrated that armodafinil is a weak inducer of CYP1A2 in a concentration-related manner. However, in a clinical study using caffeine as a probe substrate, no significant effect on CYP1A2 activity was observed. Drugs Metabolized by CYP2C19 - In vitro data demonstrated that armodafinil is a reversible inhibitor of CYP2C19 activity. In a clinical study, concomitant administration of NUVIGIL 400 mg resulted in a 40% increase in exposure to omeprazole after a single oral dose (40 mg), as a result of moderate inhibition of CYP2C19 activity. Therefore, dose reduction may be required for some drugs that are substrates for CYP2C19 (e.g., phenytoin, diazepam, and propranolol, omeprazole, and clomipramine) when used concomitantly with NUVIGIL. Interactions with CNS Active Drugs - Concomitant administration of NUVIGIL with quetiapine reduced the systemic exposure of quetiapine. - Data specific to NUVIGIL drug-drug interaction potential with other CNS active drugs are not available. However, the following available drug-drug interaction information on modafinil should be applicable to NUVIGIL. - Concomitant administration of modafinil with methylphenidate or dextroamphetamine produced no significant alterations on the pharmacokinetic profile of modafinil or either stimulant, even though the absorption of modafinil was delayed for approximately one hour. - Concomitant modafinil or clomipramine did not alter the pharmacokinetic profile of either drug; however, one incident of increased levels of clomipramine and its active metabolite desmethylclomipramine was reported in a patient with narcolepsy during treatment with modafinil. - Data specific to NUVIGIL or modafinil drug-drug interaction potential with monoamine oxidase (MAO) inhibitors are not available. Therefore, caution should be used when concomitantly administering MAO inhibitors and NUVIGIL. Interaction with P-Glycoprotein - An in vitro study demonstrated that armodafinil is a substrate of P-glycoprotein. The impact of inhibition of P-glycoprotein is not known. Interactions with Other Drugs - Data specific to NUVIGIL drug-drug interaction potential for additional other drugs are not available. However, the following available drug-drug interaction information on modafinil should be applicable to NUVIGIL. - Warfarin - Concomitant administration of modafinil with warfarin did not produce significant changes in the pharmacokinetic profiles of R- and S-warfarin. However, since only a single dose of warfarin was tested in this study, an interaction cannot be ruled out. Therefore, more frequent monitoring of prothrombin times/INR should be considered whenever NUVIGIL is coadministered with warfarin. ## Nonclinical Toxicology Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis - Carcinogenicity studies were conducted in which modafinil (a mixture of R- and S-modafinil) was administered in the diet to mice for 78 weeks and to rats for 104 weeks at doses of 6, 30, and 60 mg/kg/day. At the highest dose studied in rat, the plasma armodafinil exposure (AUC) was less than that in humans at the MRHD of NUVIGIL. There was no evidence of tumorigenesis associated with modafinil administration in these studies. However, since the mouse study used an inadequate high dose that was not representative of a maximum tolerated dose, a subsequent carcinogenicity study was conducted in the Tg.AC transgenic mouse. Doses evaluated in the Tg.AC assay were 125, 250, and 500 mg/kg/day, administered dermally. There was no evidence of tumorigenicity associated with modafinil administration; however, this dermal model may not have adequately assessed the carcinogenic potential of an orally administered drug. Mutagenesis - Armodafinil was negative in an in vitro bacterial reverse mutation assay and in an in vitro chromosomal aberration assay in human lymphocytes. - Modafinil was negative in a series of in vitro (i.e., bacterial reverse mutation, mouse lymphoma tk, chromosomal aberration in human lymphocytes, cell transformation in BALB/3T3 mouse embryo cells) or in vivo (mouse bone marrow micronucleus) assays. Impairment of Fertility - A fertility and early embryonic development (to implantation) study was not conducted with armodafinil alone. - Oral administration of modafinil (doses of up to 480 mg/kg/day) to male and female rats prior to and throughout mating, and continuing in females through day 7 of gestation produced an increase in the time to mate at the highest dose; no effects were observed on other fertility or reproductive parameters. The no-effect dose of 240 mg/kg/day was associated with a plasma armodafinil AUC less than that in humans at the MRHD of NUVIGIL. # Clinical Studies - The effectiveness of NUVIGIL in improving wakefulness has been established in the following sleep disorders: obstructive sleep apnea (OSA), narcolepsy, and shift work disorder (SWD). - For each clinical trial, a p-value of ≤ 0.05 was required for statistical significance. Obstructive Sleep Apnea (OSA) - The effectiveness of NUVIGIL in improving wakefulness in patients with excessive sleepiness associated with OSA was established in two 12-week, multi-center, placebo-controlled, parallel-group, double-blind studies of outpatients who met the International Classification of Sleep Disorders (ICSD) criteria for OSA (which are also consistent with the American Psychiatric Association DSM-IV-TR criteria). These criteria include either: 1) excessive sleepiness or insomnia, plus frequent episodes of impaired breathing during sleep, and associated features such as loud snoring, morning headaches or dry mouth upon awakening; or 2) excessive sleepiness or insomnia; and polysomnography demonstrating one of the following: more than five obstructive apneas, each greater than 10 seconds in duration, per hour of sleep; and one or more of the following: frequent arousals from sleep associated with the apneas, bradytachycardia, or arterial oxygen desaturation in association with the apneas. In addition, for entry into these studies, all patients were required to have excessive sleepiness as demonstrated by a score ≥ 10 on the Epworth Sleepiness Scale, despite treatment with continuous positive airway pressure (CPAP). Evidence that CPAP was effective in reducing episodes of apnea/hypopnea was required along with documentation of CPAP use. - Patients were required to be compliant with CPAP, defined as CPAP use ≥ 4 hours/night on ≥ 70% of nights. CPAP use continued throughout the study. In both studies, the primary measures of effectiveness were 1) sleep latency, as assessed by the Maintenance of Wakefulness Test (MWT) and 2) the change in the patient’s overall disease status, as measured by the Clinical Global Impression of Change (CGI-C) at the final visit. For a successful trial both measures had to show statistically significant improvement. - The MWT measures latency (in minutes) to sleep onset. An extended MWT was performed with test sessions at 2 hour intervals between 9AM and 7PM. The primary analysis was the average of the sleep latencies from the first four test sessions (9AM to 3PM). For each test session, the subject was asked to attempt to remain awake without using extraordinary measures. Each test session was terminated after 30 minutes if no sleep occurred or immediately after sleep onset. The CGI-C is a 7-point scale, centered at No Change, and ranging from Very Much Worse to Very Much Improved. Evaluators were not given any specific guidance about the criteria they were to apply when rating patients. - In the first study, a total of 395 patients with OSA were randomized to receive NUVIGIL 150 mg/day, NUVIGIL 250 mg/day or matching placebo. Patients treated with NUVIGIL showed a statistically significant improvement in the ability to remain awake compared to placebo-treated patients as measured by the MWT at final visit. A statistically significant greater number of patients treated with NUVIGIL showed improvement in overall clinical condition as rated by the CGI-C scale at final visit. The average sleep latencies (in minutes) in the MWT at baseline for the trials are shown in Table 3 below, along with the average change from baseline on the MWT at final visit. The percentages of patients who showed any degree of improvement on the CGI-C in the clinical trials are shown in Table 4 below. The two doses of NUVIGIL produced statistically significant effects of similar magnitudes on the MWT, and also on the CGI-C. - In the second study, 263 patients with OSA were randomized to either NUVIGIL 150 mg/day or placebo. Patients treated with NUVIGIL showed a statistically significant improvement in the ability to remain awake compared to placebo-treated patients as measured by the MWT [Table 3]. A statistically significant greater number of patients treated with NUVIGIL showed improvement in overall clinical condition as rated by the CGI-C scale [Table 4]. - Nighttime sleep measured with polysomnography was not affected by the use of NUVIGIL in either study. Narcolepsy - The effectiveness of NUVIGIL in improving wakefulness in patients with excessive sleepiness (ES) associated with narcolepsy was established in one 12-week, multi-center, placebo-controlled, parallel-group, double-blind study of outpatients who met the ICSD criteria for narcolepsy. A total of 196 patients were randomized to receive NUVIGIL 150 or 250 mg/day, or matching placebo. The ICSD criteria for narcolepsy include either: 1) recurrent daytime naps or lapses into sleep that occur almost daily for at least three months, plus sudden bilateral loss of postural muscle tone in association with intense emotion (cataplexy); or 2) a complaint of excessive sleepiness or sudden muscle weakness with associated features: sleep paralysis, hypnagogic hallucinations, automatic behaviors, disrupted major sleep episode; and polysomnography demonstrating one of the following: sleep latency less than 10 minutes or rapid eye movement (REM) sleep latency less than 20 minutes and a Multiple Sleep Latency Test (MSLT) that demonstrates a mean sleep latency of less than 5 minutes and two or more sleep onset REM periods and no medical or mental disorder accounts for the symptoms. For entry into these studies, all patients were required to have objectively documented excessive daytime sleepiness, via MSLT with a sleep latency of 6 minutes or less and the absence of any other clinically significant active medical or psychiatric disorder. The MSLT, an objective polysomnographic assessment of the patient’s ability to fall asleep in an unstimulating environment, measured latency (in minutes) to sleep onset averaged over 4 test sessions at 2-hour intervals. For each test session, the subject was told to lie quietly and attempt to sleep. Each test session was terminated after 20 minutes if no sleep occurred or immediately after sleep onset. - The primary measures of effectiveness were: 1) sleep latency as assessed by the Maintenance of Wakefulness Test (MWT); and 2) the change in the patient’s overall disease status, as measured by the CGI-C at the final visit for a description of these measures]. Each MWT test session was terminated after 20 minutes if no sleep occurred or immediately after sleep onset in this study. - Patients treated with NUVIGIL showed a statistically significantly enhanced ability to remain awake on the MWT at each dose compared to placebo at final visit [Table 3]. A statistically significant greater number of patients treated with NUVIGIL at each dose showed improvement in overall clinical condition as rated by the CGI-C scale at final visit [Table 4]. - The two doses of NUVIGIL produced statistically significant effects of similar magnitudes on the CGI-C. Although a statistically significant effect on the MWT was observed for each dose, the magnitude of effect was observed to be greater for the higher dose. - Nighttime sleep measured with polysomnography was not affected by the use of NUVIGIL. Shift Work Disorder (SWD) - The effectiveness of NUVIGIL in improving wakefulness in patients with excessive sleepiness associated with SWD was demonstrated in a 12-week, multi-center, double-blind, placebo-controlled, parallel-group clinical trial. A total of 254 patients with chronic SWD were randomized to receive NUVIGIL 150 mg/day or placebo. All patients met the ICSD criteria for chronic SWD [which are consistent with the American Psychiatric Association DSM-IV-TR criteria for Circadian Rhythm Sleep Disorder: Shift Work Type]. These criteria include: 1) either, a) a primary complaint of excessive sleepiness or insomnia which is temporally associated with a work period (usually night work) that occurs during the habitual sleep phase, or b) polysomnography and the MSLT demonstrate loss of a normal sleep-wake pattern (i.e., disturbed chronobiological rhythmicity); and 2) no other medical or mental disorder accounts for the symptoms; and 3) the symptoms do not meet criteria for any other sleep disorder producing insomnia or excessive sleepiness (e.g., time zone change [jet lag] syndrome). - It should be noted that not all patients with a complaint of sleepiness who are also engaged in shift work meet the criteria for the diagnosis of SWD. In the clinical trial, only patients who were symptomatic for at least 3 months were enrolled. - Enrolled patients were also required to work a minimum of 5 night shifts per month, have excessive sleepiness at the time of their night shifts (MSLT score ≤ 6 minutes), and have daytime insomnia documented by a daytime polysomnogram (PSG). - The primary measures of effectiveness were: 1) sleep latency, as assessed by the Multiple Sleep Latency Test (MSLT) performed during a simulated night shift at the final visit; and 2) the change in the patient’s overall disease status, as measured by the CGI-C at the final visit. - Patients treated with NUVIGIL showed a statistically significant prolongation in the time to sleep onset compared to placebo-treated patients, as measured by the nighttime MSLT at final visit [Table 3]. A statistically significant greater number of patients treated with NUVIGIL showed improvement in overall clinical condition as rated by the CGI-C scale at final visit [Table 4]. - Daytime sleep measured with polysomnography was not affected by the use of NUVIGIL. # How Supplied How Supplied - NUVIGIL® (armodafinil) Tablets are available as follows: - 50 mg: Each round, white to off-white tablet is debossed with stylized c on one side and "205" on the other. - NDC 63459-205-30 – Bottles of 30 - 150 mg: Each oval, white to off-white tablet is debossed with stylized c on one side and "215" on the other. - NDC 63459-215-30 – Bottles of 30 - 200 mg: Each rounded, rectangular, white to off-white tablet is debossed with stylized c on one side and "220" on the other. - NDC 63459-220-30 – Bottles of 30 - 250 mg: Each oval, white to off-white tablet is debossed with stylized c on one side and "225" on the other. - NDC 63459-225-30 – Bottles of 30 ## Storage - Store at 20o - 25o C (68o - 77o F). # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information - See FDA-approved patient labeling (Medication Guide). - Inform patients of the availability of a Medication Guide, and instruct them to read it prior to taking NUVIGIL. Wakefulness - NUVIGIL is indicated for patients who have abnormal levels of sleepiness. NUVIGIL has been shown to improve, but not eliminate, this abnormal tendency to fall asleep. Therefore, patients should not alter their previous behavior with regard to potentially dangerous activities (e.g., driving, operating machinery) or other activities requiring appropriate levels of wakefulness, until and unless treatment with NUVIGIL has been shown to produce levels of wakefulness that permit such activities. Advise patients that NUVIGIL is not a replacement for sleep. Continuing Previously Prescribed Treatments - Inform patients that it may be critical that they continue to take their previously prescribed treatments (e.g., patients with OSA receiving CPAP should continue to do so). Discontinuing Drug Due to Adverse Reactions - Advise patients to stop taking NUVIGIL and contact their physician right away if they experience rash, depression, anxiety, or signs of psychosis or mania. Pregnancy - Advise patients to notify their physician if they become pregnant or intend to become pregnant during therapy. Caution patients regarding the potential increased risk of pregnancy when using steroidal contraceptives (including depot or implantable contraceptives) with NUVIGIL and for one month after discontinuation of therapy. Nursing - Advise patients to notify their physician if they are breastfeeding an infant. Concomitant Medication - Advise patients to inform their physician if they are taking, or plan to take, any prescription or over-the-counter drugs, because of the potential for interactions between NUVIGIL and other drugs. Alcohol - Advise patients that the use of NUVIGIL in combination with alcohol has not been studied. Advise patients that it is prudent to avoid alcohol while taking NUVIGIL. Allergic Reactions - Advise patients to stop taking NUVIGIL and to notify their physician right away if they develop a rash, hives, mouth sores, blisters, peeling skin, trouble swallowing or breathing or a related allergic phenomenon. # Precautions with Alcohol - Alcohol-Armodafinil interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names Nuvigil # Look-Alike Drug Names - A® — B®[1] # Drug Shortage Status # Price	https://www.wikidoc.org/index.php/Armodafinil
f7589f9fd601e7a61a35628ba643798186460640	wikidoc	Aromaticity	Aromaticity # Overview Aromaticity is a chemical property in which a conjugated ring of unsaturated bonds, lone pairs, or empty orbitals exhibit a stabilization stronger than would be expected by the stabilization of conjugation alone. It can also be considered a manifestation of cyclic delocalization and of resonance. This is usually considered to be because electrons are free to cycle around circular arrangements of atoms, which are alternately single- and double-bonded to one another. These bonds may be seen as a hybrid of a single bond and a double bond, each bond in the ring identical to every other. This commonly-seen model of aromatic rings, namely the idea that benzene was formed from a six-membered carbon ring with alternating single and double bonds (cyclohexatriene), was developed by Kekulé (see "History" section below). The model for benzene consists of two resonance forms, which corresponds to the double and single bonds' switching positions. Benzene is a more stable molecule than would be expected without accounting for charge delocalization. # Theory By convention, the double-headed arrow indicates that the two structures are simply hypothetical, since neither is an accurate representation of the actual compound. The actual molecule is best represented by a hybrid (average) of these structures, which can be seen at right. A C=C bond is shorter than a C−C bond, but benzene is perfectly hexagonal--all six carbon-carbon bonds have the same length, intermediate between that of a single and that of a double bond. A better representation is that of the circular π bond (Armstrong's inner cycle), in which the electron density is evenly distributed through a π bond above and below the ring. This model more correctly represents the location of electron density within the aromatic ring. The single bonds are formed with electrons in line between the carbon nuclei--these are called sigma bonds. Double bonds consist of a sigma bond and another bond--a π bond. The π-bonds are formed from overlap of atomic p-orbitals above and below the plane of the ring. The following diagram shows the positions of these p-orbitals: Since they are out of the plane of the atoms, these orbitals can interact with each other freely, and become delocalised. This means that instead of being tied to one atom of carbon, each electron is shared by all six in the ring. Thus, there are not enough electrons to form double bonds on all the carbon atoms, but the "extra" electrons strengthen all of the bonds on the ring equally. The resulting molecular orbital has π symmetry. # History The first known use of the word "aromatic" as a chemical term -- namely, to apply to compounds that contain the phenyl radical -- occurs in an article by August Wilhelm Hofmann in 1855. If this is indeed the earliest introduction of the term, it is curious that Hofmann says nothing about why he introduced an adjective indicating olfactory character to apply to a group of chemical substances, only some of which have notable aromas. Ironically, many of the most odoriferous organic substances known are terpenes, which are not aromatic in the chemical sense. But terpenes and benzenoid substances do have a chemical characteristic in common, namely higher unsaturation indexes than many aliphatic compounds, and Hofmann may not have been making a distinction between the two categories. The cyclohexatriene structure for benzene was first proposed by August Kekulé in 1865. Over the next few decades, most chemists readily accepted this structure, since it accounted for most of the known isomeric relationships of aromatic chemistry. However, it was always puzzling that this purportedly highly unsaturated molecule was so unreactive toward addition reactions. The discoverer of the electron J. J. Thomson, in 1921 placed three equivalent electrons between each carbon atom in benzene. An explanation for the exceptional stability of benzene is conventionally attributed to Sir Robert Robinson, who was apparently the first (in 1925) to coin the term aromatic sextet as a group of six electrons that resists disruption. In fact, this concept can be traced further back, via Ernest Crocker in 1922, to Henry Edward Armstrong, who in 1890, in an article entitled The structure of cycloid hydrocarbons, wrote the (six) centric affinities act within a cycle...benzene may be represented by a double ring (sic) ... and when an additive compound is formed, the inner cycle of affinity suffers disruption, the contiguous carbon-atoms to which nothing has been attached of necessity acquire the ethylenic condition. Here, Armstrong is describing at least four modern concepts. Firstly, his "affinity" is better known nowadays as the electron, which was only to be discovered seven years later by J. J. Thomson. Secondly, he is describing electrophilic aromatic substitution, proceeding (thirdly) through a Wheland intermediate, in which (fourthly) the conjugation of the ring is broken. He introduced the symbol C centered on the ring as a shorthand for the inner cycle, thus anticipating Eric Clar's notation. Arguably, he also anticipated the nature of wave mechanics, since he recognized that his affinities had direction, not merely being point particles, and collectively having a distribution that could be altered by introducing substituents onto the benzene ring (much as the distribution of the electric charge in a body is altered by bringing it near to another body). The quantum mechanical origins of this stability, or aromaticity, were first modelled by Hückel in 1931. He was the first to separate the bonding electrons in sigma and pi electrons. # Characteristics of aromatic (Aryl) compounds An aromatic compound contains a set of covalently-bound atoms with specific characteristics: - A delocalized conjugated π system, most commonly an arrangement of alternating single and double bonds - Coplanar structure, with all the contributing atoms in the same plane - Contributing atoms arranged in one or more rings - A number of π delocalized electrons that is even, but not a multiple of 4. This is known as Hückel's rule. Permissible numbers of π electrons include 2, 6, 10, 14, and so on - Special reactivity in organic reactions such as electrophilic aromatic substitution and nucleophilic aromatic substitution Whereas benzene is aromatic (6 electrons, from 3 double bonds), cyclobutadiene is not, since the number of π delocalized electrons is 4, which of course is a multiple of 4. The cyclobutadienide (2−) ion, however, is aromatic (6 electrons). An atom in an aromatic system can have other electrons that are not part of the system, and are therefore ignored for the 4n + 2 rule. In furan, the oxygen atom is sp² hybridized. One lone pair is in the π system and the other in the plane of the ring (analogous to C-H bond on the other positions). There are 6 π electrons, so furan is aromatic. Aromatic molecules typically display enhanced chemical stability, compared to similar non-aromatic molecules. The circulating π electrons in an aromatic molecule produce ring currents that oppose the applied magnetic field in NMR. The NMR signal of protons in the plane of an aromatic ring are shifted substantially further down-field than those on non-aromatic sp² carbons. This is an important way of detecting aromaticity. By the same mechanism, the signals of protons located near the ring axis are shifted up-field. Planar monocyclic molecules containing 4n π electrons are called antiaromatic and are, in general, destabilized. Molecules that could be antiaromatic will tend to alter their electronic or conformational structure to avoid this situation, thereby becoming non-aromatic. For example, cyclooctatetraene (COT) distorts itself out of planarity, breaking π overlap between adjacent double bonds. Aromatic molecules are able to interact with each other in so-called π-π stacking: the π systems form two parallel rings overlap in a "face-to-face" orientation. Aromatic molecules are also able to interact with each other in an "edge-to-face" orientation: the slight positive charge of the substituents on the ring atoms of one molecule are attracted to the slight negative charge of the aromatic system on another molecule. Many of the earliest-known examples of aromatic compounds, such as benzene and toluene, have distinctive pleasant smells. This property led to the term "aromatic" for this class of compounds, and hence to "aromaticity" being the eventually-discovered electronic property of them. # Aromatic compound classifications The key aromatic hydrocarbons of commercial interest are benzene, toluene, ortho-xylene and para-xylene. About 35 million tonnes are produced worldwide every year. They are extracted from complex mixtures obtained by the refining of oil or by distillation of coal tar, and are used to produce a range of important chemicals and polymers, including styrene, phenol, aniline, polyester and nylon. ## Heterocyclics In heterocyclic aromatics, one or more of the atoms in the aromatic ring is of an element other than carbon. This can lessen the ring's aromaticity, and thus (as in the case of furan) increase its reactivity. Other examples include pyridine, imidazole, pyrazole, oxazole, thiophene, and their benzannulated analogs (benzimidazole, for example). ## Polycyclics Polycyclic aromatic hydrocarbons (PAH) are molecules containing two or more simple aromatic rings fused together by sharing two neighboring carbon atoms (see also simple aromatic rings). Examples are naphthalene, anthracene and phenanthrene. ## Substituted aromatics Many chemical compounds contain simple aromatic rings in their structure. Examples are DNA which contains purine and pyrimidine, trinitrotoluene (TNT), acetylsalicylic acid (aspirin) and paracetamol. # Aromaticity in other systems Aromaticity is found in ions as well: the cyclopropenyl cation (2e system), the cyclopentadienyl anion (6e system), the tropylium ion (6e) and the cyclooctatetraene dianion (10e). Aromatic properties have been attributed to non-benzenoid compounds such as tropone. Aromatic properties are tested to the limit in a class of compounds called cyclophanes. A special case of aromaticity is found in homoaromaticity where conjugation is interrupted by a single sp³ hybridized carbon atom. When carbon in benzene is replaced by other elements in borabenzene, silabenzene, germanabenzene, stannabenzene, phosphorine or pyrylium salts the aromaticity is still retained. Aromaticity is also not limited to compounds of carbon, oxygen and nitrogen. Metal aromaticity is believed to exist in certain metal clusters of aluminium. Möbius aromaticity occurs when a cyclic system of molecular orbitals formed from pπ atomic orbitals and populated in a closed shell by 4n (n is an integer) electrons is given a single half-twist to correspond to a Möbius topology. Because the twist can be left-handed or right-handed, the resulting Möbius aromatics are dissymmetric or chiral. Up to now there is no doubtless proof, that a Möbius aromatic molecule was synthesized. Aromatics with two half-twists corresponding to the paradromic topologies first suggested by Johann Listing have been proposed by Rzepa in 2005. In carbo-benzene the ring bonds are extended with alkyne and allene groups.	Aromaticity Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview Aromaticity is a chemical property in which a conjugated ring of unsaturated bonds, lone pairs, or empty orbitals exhibit a stabilization stronger than would be expected by the stabilization of conjugation alone. It can also be considered a manifestation of cyclic delocalization and of resonance.[1][2][3] This is usually considered to be because electrons are free to cycle around circular arrangements of atoms, which are alternately single- and double-bonded to one another. These bonds may be seen as a hybrid of a single bond and a double bond, each bond in the ring identical to every other. This commonly-seen model of aromatic rings, namely the idea that benzene was formed from a six-membered carbon ring with alternating single and double bonds (cyclohexatriene), was developed by Kekulé (see "History" section below). The model for benzene consists of two resonance forms, which corresponds to the double and single bonds' switching positions. Benzene is a more stable molecule than would be expected without accounting for charge delocalization. # Theory By convention, the double-headed arrow indicates that the two structures are simply hypothetical, since neither is an accurate representation of the actual compound. The actual molecule is best represented by a hybrid (average) of these structures, which can be seen at right. A C=C bond is shorter than a C−C bond, but benzene is perfectly hexagonal--all six carbon-carbon bonds have the same length, intermediate between that of a single and that of a double bond. A better representation is that of the circular π bond (Armstrong's inner cycle), in which the electron density is evenly distributed through a π bond above and below the ring. This model more correctly represents the location of electron density within the aromatic ring. The single bonds are formed with electrons in line between the carbon nuclei--these are called sigma bonds. Double bonds consist of a sigma bond and another bond--a π bond. The π-bonds are formed from overlap of atomic p-orbitals above and below the plane of the ring. The following diagram shows the positions of these p-orbitals: Since they are out of the plane of the atoms, these orbitals can interact with each other freely, and become delocalised. This means that instead of being tied to one atom of carbon, each electron is shared by all six in the ring. Thus, there are not enough electrons to form double bonds on all the carbon atoms, but the "extra" electrons strengthen all of the bonds on the ring equally. The resulting molecular orbital has π symmetry. # History The first known use of the word "aromatic" as a chemical term -- namely, to apply to compounds that contain the phenyl radical -- occurs in an article by August Wilhelm Hofmann in 1855.[4] If this is indeed the earliest introduction of the term, it is curious that Hofmann says nothing about why he introduced an adjective indicating olfactory character to apply to a group of chemical substances, only some of which have notable aromas. Ironically, many of the most odoriferous organic substances known are terpenes, which are not aromatic in the chemical sense. But terpenes and benzenoid substances do have a chemical characteristic in common, namely higher unsaturation indexes than many aliphatic compounds, and Hofmann may not have been making a distinction between the two categories. The cyclohexatriene structure for benzene was first proposed by August Kekulé in 1865. Over the next few decades, most chemists readily accepted this structure, since it accounted for most of the known isomeric relationships of aromatic chemistry. However, it was always puzzling that this purportedly highly unsaturated molecule was so unreactive toward addition reactions. The discoverer of the electron J. J. Thomson, in 1921 placed three equivalent electrons between each carbon atom in benzene. An explanation for the exceptional stability of benzene is conventionally attributed to Sir Robert Robinson, who was apparently the first (in 1925)[5] to coin the term aromatic sextet as a group of six electrons that resists disruption. In fact, this concept can be traced further back, via Ernest Crocker in 1922,[6] to Henry Edward Armstrong, who in 1890, in an article entitled The structure of cycloid hydrocarbons, wrote the (six) centric affinities act within a cycle...benzene may be represented by a double ring (sic) ... and when an additive compound is formed, the inner cycle of affinity suffers disruption, the contiguous carbon-atoms to which nothing has been attached of necessity acquire the ethylenic condition.[7] Here, Armstrong is describing at least four modern concepts. Firstly, his "affinity" is better known nowadays as the electron, which was only to be discovered seven years later by J. J. Thomson. Secondly, he is describing electrophilic aromatic substitution, proceeding (thirdly) through a Wheland intermediate, in which (fourthly) the conjugation of the ring is broken. He introduced the symbol C centered on the ring as a shorthand for the inner cycle, thus anticipating Eric Clar's notation. Arguably, he also anticipated the nature of wave mechanics, since he recognized that his affinities had direction, not merely being point particles, and collectively having a distribution that could be altered by introducing substituents onto the benzene ring (much as the distribution of the electric charge in a body is altered by bringing it near to another body). The quantum mechanical origins of this stability, or aromaticity, were first modelled by Hückel in 1931. He was the first to separate the bonding electrons in sigma and pi electrons. # Characteristics of aromatic (Aryl) compounds An aromatic compound contains a set of covalently-bound atoms with specific characteristics: - A delocalized conjugated π system, most commonly an arrangement of alternating single and double bonds - Coplanar structure, with all the contributing atoms in the same plane - Contributing atoms arranged in one or more rings - A number of π delocalized electrons that is even, but not a multiple of 4. This is known as Hückel's rule. Permissible numbers of π electrons include 2, 6, 10, 14, and so on - Special reactivity in organic reactions such as electrophilic aromatic substitution and nucleophilic aromatic substitution Whereas benzene is aromatic (6 electrons, from 3 double bonds), cyclobutadiene is not, since the number of π delocalized electrons is 4, which of course is a multiple of 4. The cyclobutadienide (2−) ion, however, is aromatic (6 electrons). An atom in an aromatic system can have other electrons that are not part of the system, and are therefore ignored for the 4n + 2 rule. In furan, the oxygen atom is sp² hybridized. One lone pair is in the π system and the other in the plane of the ring (analogous to C-H bond on the other positions). There are 6 π electrons, so furan is aromatic. Aromatic molecules typically display enhanced chemical stability, compared to similar non-aromatic molecules. The circulating π electrons in an aromatic molecule produce ring currents that oppose the applied magnetic field in NMR. The NMR signal of protons in the plane of an aromatic ring are shifted substantially further down-field than those on non-aromatic sp² carbons. This is an important way of detecting aromaticity. By the same mechanism, the signals of protons located near the ring axis are shifted up-field. Planar monocyclic molecules containing 4n π electrons are called antiaromatic and are, in general, destabilized. Molecules that could be antiaromatic will tend to alter their electronic or conformational structure to avoid this situation, thereby becoming non-aromatic. For example, cyclooctatetraene (COT) distorts itself out of planarity, breaking π overlap between adjacent double bonds. Aromatic molecules are able to interact with each other in so-called π-π stacking: the π systems form two parallel rings overlap in a "face-to-face" orientation. Aromatic molecules are also able to interact with each other in an "edge-to-face" orientation: the slight positive charge of the substituents on the ring atoms of one molecule are attracted to the slight negative charge of the aromatic system on another molecule. Many of the earliest-known examples of aromatic compounds, such as benzene and toluene, have distinctive pleasant smells. This property led to the term "aromatic" for this class of compounds, and hence to "aromaticity" being the eventually-discovered electronic property of them. # Aromatic compound classifications The key aromatic hydrocarbons of commercial interest are benzene, toluene, ortho-xylene and para-xylene. About 35 million tonnes are produced worldwide every year. They are extracted from complex mixtures obtained by the refining of oil or by distillation of coal tar, and are used to produce a range of important chemicals and polymers, including styrene, phenol, aniline, polyester and nylon. ## Heterocyclics In heterocyclic aromatics, one or more of the atoms in the aromatic ring is of an element other than carbon. This can lessen the ring's aromaticity, and thus (as in the case of furan) increase its reactivity. Other examples include pyridine, imidazole, pyrazole, oxazole, thiophene, and their benzannulated analogs (benzimidazole, for example). ## Polycyclics Polycyclic aromatic hydrocarbons (PAH) are molecules containing two or more simple aromatic rings fused together by sharing two neighboring carbon atoms (see also simple aromatic rings). Examples are naphthalene, anthracene and phenanthrene. ## Substituted aromatics Many chemical compounds contain simple aromatic rings in their structure. Examples are DNA which contains purine and pyrimidine, trinitrotoluene (TNT), acetylsalicylic acid (aspirin) and paracetamol. # Aromaticity in other systems Aromaticity is found in ions as well: the cyclopropenyl cation (2e system), the cyclopentadienyl anion (6e system), the tropylium ion (6e) and the cyclooctatetraene dianion (10e). Aromatic properties have been attributed to non-benzenoid compounds such as tropone. Aromatic properties are tested to the limit in a class of compounds called cyclophanes. A special case of aromaticity is found in homoaromaticity where conjugation is interrupted by a single sp³ hybridized carbon atom. When carbon in benzene is replaced by other elements in borabenzene, silabenzene, germanabenzene, stannabenzene, phosphorine or pyrylium salts the aromaticity is still retained. Aromaticity is also not limited to compounds of carbon, oxygen and nitrogen. Metal aromaticity is believed to exist in certain metal clusters of aluminium. Möbius aromaticity occurs when a cyclic system of molecular orbitals formed from pπ atomic orbitals and populated in a closed shell by 4n (n is an integer) electrons is given a single half-twist to correspond to a Möbius topology. Because the twist can be left-handed or right-handed, the resulting Möbius aromatics are dissymmetric or chiral. Up to now there is no doubtless proof, that a Möbius aromatic molecule was synthesized.[8][9] Aromatics with two half-twists corresponding to the paradromic topologies first suggested by Johann Listing have been proposed by Rzepa in 2005.[10] In carbo-benzene the ring bonds are extended with alkyne and allene groups.	https://www.wikidoc.org/index.php/Aromatic
dabaa12677757b2f17bbaa83c0e3ee984bf27764	wikidoc	Art therapy	Art therapy Art therapy is a form of expressive therapy that uses art materials, such as paints, chalk and markers. Art therapy combines traditional psychotherapeutic theories and techniques with an understanding of the psychological aspects of the creative process, especially the affective properties of the different art materials. As a mental health profession, art therapy is employed in many clinical settings with diverse populations. Art therapy can be found in non-clinical settings as well, such as in art studios and in workshops that focus on creativity development. Art therapists work with children, adolescents, and adults and provide services to individuals, couples, families, groups, and communities. According to the American Art Therapy Association, art therapy is based on the belief that the creative process involved in making art is on a basic level healing and life-enhancing. Art therapists use the creative process and the issues that come up during art therapy to help their clients increase insight and judgment, cope better with stress, work through traumatic experiences, increase cognitive abilities, have better relationships with family and friends, and to just be able to enjoy the life-affirming pleasures of the creative experience. The term art therapist is reserved for those that are professionals trained in both art and therapy and hold a master's degree in art therapy or a related field. # Purpose of Art Therapy The purpose of art therapy is much the same as in any other psychotherapeutic modality, to improve or maintain mental health and emotional well- being. But whereas some of the other expressive therapies utilize the performing arts for expressive purposes, art therapy generally utilizes drawing, painting, sculpture, photography, and other forms of visual art expression. For that reason art therapists are trained to recognize the nonverbal symbols and metaphors that are communicated within the creative process, symbols and metaphors which might be difficult to express in words or in other modalities. By helping their clients to discover what underlying thoughts and feelings are being communicated in the artwork and what it means to them, it is hoped that clients will not only gain insight and judgment, but perhaps develop a better understanding of themselves and the way they relate to the people around them. According to Ed Beeson, "Art therapists stress that it is not their job to interpret or read meaning into patients’ art"(2006). # Art-Based Assessments There are many psychological assessments that utilize artmaking to analyze various types of mental functioning (Betts, 2005). Art therapists are trained to administer and interpret a number of these assessments, most of which rely on simple directives and a standardized array of art materials (Malchiodi 1998, 2003; Betts 2005). The first drawing assessment for psychological purposes was created in 1906 by German psychiatrist Fritz Mohr (Malchiodi 1998). In 1926, researcher Florence Goodenough created a drawing test to measure the intelligence in children called the Draw–A–Man Test (Malchiodi 1998). The key to interpreting the Draw-A-Man Test was that the more details a child incorporated into the drawing, the more intelligent they were (Malchiodi). Goodenough and other researchers realized the test had just as much to do with personality as it did intelligence (Malchiodi). Several other psychiatric art assessments were created in the 1940s, and have been used ever since (Malchiodi 1998). Notwithstanding, many art therapists eschew diagnostic testing and indeed some writers (Hogan 1997) question the validity of therapists making interpretative assumptions. Below are a few of the most common art therapy assessments: ## The Diagnostic Drawing Series (DDS) The Diagnostic Drawing Series is an art therapy assessment that assesses for a range of major psychiatric disorders. (Malchiodi 1998). There are three parts to the DDS (Malchiodi 1998). In the first part, the patient is asked to draw any picture using colored chalk pastels on an 18x24 inch piece of paper (Malchiodi 1998). Then they are asked to draw a tree in the second part. In the last part of the test, the patient is asked to show how they are feeling using lines, shapes, and colors (Malchiodi 1998). The series of pictures are interpreted based on a combination of many different factors, such as use of color, amount of blending, and placement of the images on the paper. ## The Mandala Assessment Research Instrument (MARI) In this assessment, a person is asked to select a card from a deck with different mandalas; designs enclosed in a geometric shape, and then must choose a color from a set of colored cards (Malchiodi 1998). The person is then asked to draw the mandala from the card they choose with an oil pastel of the color of their choice (Malchiodi 1998). The artist is then asked to explain if there were any meanings, experiences, or related information related to the mandala they drew (Malchiodi 1998). This test is based on the beliefs of Joan Kellogg, who sees a reoccurring correlation between the images, pattern and shapes in the mandalas that people draw and the personalities of the artists (Malchiodi 1998). This test assesses and gives clues to a person's psychological progressions and their current psychological condition (Malchiodi 1998). ## House–Tree–Person (HTP) In this assessment, the patient is asked to draw a picture with a house, a tree, and a person in it (Malchiodi 1998). After the patient has finished the drawing, the therapist asks questions like, “How old is the person in your drawing? What is he or she doing? What is the house made of? What is the weather in this picture?” (Malchiodi 1998). This is a projective assessment and the house, the tree, and person in the drawing represent different aspects of the artist and the way the artist feels about him or herself (Malchiodi 1998). # Art Therapy Certification and Registration ## Board Certification and Registration In the United States, art therapists may become Registered (ATR) and Board Certified (ATR-BC). For more information on these credentials, art therapists in the US should contact the Art Therapy Credentials Board (ATCB) at www.atcb.org. A Code of Professional Practice, a 17 page document summarizing the standards of practice for professional art therapists. The ATCB Code of Professional Practice is comprised of five main categories; General Ethical Principles, Independent Practitioner, Eligibility for Credentials, Standards of Conduct, and Disciplinary Procedures (ATCB 2005). ## General Ethical Principles One topic covered in this section describes the responsibility art therapist have to their patients (ATCB 2005). According to the ATCB, art therapists must strive to advance the wellness of their clients, respect the rights of the client, and make sure they are providing a useful service (2005). They cannot discriminate against patient whatsoever, and may never desert or neglect patients receiving therapy (2005). Art therapist must fully explain to their patients what their expectations of the patients will be at the outset of the professional relationship between the two (ATCB 2005). Art therapists should continue therapy with a patient only if the client is benefiting from the therapy (ATCB 2005). It’s against the principles established by the ATCB for art therapist to have patients only for financial reasons (ATCB 2005). Another topic of this section discuses the competency and integrity art therapist must possess (ATCB 2005). The ATCB states art therapist must be professionally proficient and have integrity (2005). Art therapist must keep up dated on new developments in art therapy. They are only supposed to treat cases in which they are qualified as established by their training, education, and experience (ATCB 2005). They are not allowed to treat patients currently seeing another therapist without the other therapist’s permission (ATCB 2005). Art therapist must observe patient confidentiality (ATCB 2005). Other topics covered in this section discuss other responsibilities of art therapists. This responsibilities include, “responsibility to students and supervisees, responsibility to research participants, responsibility to the profession” (ATCB 2005). This section also establishes the rules by which art therapists must follow when making financial arrangements and when they chose to advertise their service (ATCB 2005) ## Independent Practitioner Independent practitioners are art therapists who are practicing independently or responsible for the service they are providing to paying clients. This section covers the credentials for independent practitioners. Independent practitioners must provide a safe and functional environment to conduct art therapy sessions (ATCB 2005). According to ATCB, "this includes but is not limited to: proper ventilation, adequate lighting, access to water supply, knowledge of hazards or toxicity of art materials and the effort need to safeguard the health of clients, storage space for art projects and secured areas for any hazardous materials, monitored use of sharp objects, allowance for privacy and confidentiality, and compliance with any other health and safety requirements according to state and federal agencies which regulate comparable businesses" (2005). This section also establishes the standards for independent practitioners to follow when dealing with financial arrangements (ATCB 2005). Basically it states that the art therapist must provide a straight forward contract to the payer of the therapy sessions (ATCB 2005). It also states that the art therapist must not deceive the payers or exploit clients financially (ATCB 2005). The last topics this section sets standards for address treatment planning and documentation (ATCB 2005). Art therapists must provide a treatment plan that assists the patients to reach or maintain the highest level of quality of life and functioning (ATCB 2005). This involves using the clients’ strengths to help them reach their goals and address their needs (ATCB 2005). Art therapists are also required to record and take notes that reflect the proceedings of the events of therapy sessions (ATCB 2005). According to ATCB, the following is the minimum of which must be documented: “the current goals of any treatment plan, verbal content of art therapy sessions relevant to client behavior and goals, artistic expression relevant to client behavior and goals, changes (or lack of change) in affect, thought process, and behavior, suicidal or homicidal intent or ideation” (2005) and a summary of the “clients response to treatment and future treatment recommendations” (2005). ## Eligibility for Credentials This section of the ATCB Code of Professional Practice outlines the process by which art therapy students receive their credentials. It discusses the standards for eligibility and describes the application process. It also states that the ATCB certificates are the property of the ATCB and that any art therapist who loses their certificate and still claim to have ATCB credentials can be punished legally. It also discusses the procedure to follow when accused of wrong doing related to art therapy. Lastly, it discusses the wrong doings related to art therapy that therapists can be convicted for with a felony or another criminal conviction. These wrong doings include rape, sexual abuse, assault, battery, prostitution, or the sale of controlled substances to patients. ## Standards of Conduct This section of the ATCB Code of Professional Practice addresses in detail confidentiality, use of clients’ artwork, professional relationships, and grounds for discipline (ATCB 2005). Art therapists are permitted to disclosing information about the clients’ therapy sessions. This includes “all verbal and/or artistic expression occurring within a client-therapist relationship” (ATCB 2005). Art therapist are only allowed to release confidential information if they have explicit written consent by the patient of if the therapist has reason to believe the patient needs immediate help to address a severe danger to the patients life (ATCB 2005). Also, therapists are not allowed to publish or display any of the patients work without the expressed written consent of the patient (ATCB 2005). The standards of a professional relationship between art therapists and clients are covered in this section. Within a professional relationship, art therapists are banned from engaging in exploitative relationships with current and former patients, students, inters trainees, supervisors, or co-workers (ATCB 2005). The ATCB defines an exploitative relationship as anything involving sexual intimacy, romance, or borrowing or loaning money (ATCB 2005). Within professional relationships, therapists are to do what they feel is best in the clients interest, shall not advance a professional relationship for their own benefit, and shall not steer their patients in the wrong direction (ATCB 2005). The breaking of any of the standards established in this section is grounds for discipline (ATCB 2005). ## Disciplinary Procedures The content contained in this section of the ATCB Code of Professional Practice specifically discusses in legal and technical detail the entire disciplinary procedures for wrong doings in art therapy (2005). Main topics covered in this section cover: “submission of allegations, procedures of the Disciplinary Hearing Committees, sanctions, release of information, waivers, reconsideration of eligibility and reinstatement of credentials, deadlines, bias, prejudice, and impartiality” (ATCB 2005).	Art therapy Template:Psychology Art therapy is a form of expressive therapy that uses art materials, such as paints, chalk and markers. Art therapy combines traditional psychotherapeutic theories and techniques with an understanding of the psychological aspects of the creative process, especially the affective properties of the different art materials. As a mental health profession, art therapy is employed in many clinical settings with diverse populations. Art therapy can be found in non-clinical settings as well, such as in art studios and in workshops that focus on creativity development. Art therapists work with children, adolescents, and adults and provide services to individuals, couples, families, groups, and communities. According to the American Art Therapy Association, art therapy is based on the belief that the creative process involved in making art is on a basic level healing and life-enhancing. Art therapists use the creative process and the issues that come up during art therapy to help their clients increase insight and judgment, cope better with stress, work through traumatic experiences, increase cognitive abilities, have better relationships with family and friends, and to just be able to enjoy the life-affirming pleasures of the creative experience. The term art therapist is reserved for those that are professionals trained in both art and therapy and hold a master's degree in art therapy or a related field. # Purpose of Art Therapy The purpose of art therapy is much the same as in any other psychotherapeutic modality, to improve or maintain mental health and emotional well- being. But whereas some of the other expressive therapies utilize the performing arts for expressive purposes, art therapy generally utilizes drawing, painting, sculpture, photography, and other forms of visual art expression. For that reason art therapists are trained to recognize the nonverbal symbols and metaphors that are communicated within the creative process, symbols and metaphors which might be difficult to express in words or in other modalities. By helping their clients to discover what underlying thoughts and feelings are being communicated in the artwork and what it means to them, it is hoped that clients will not only gain insight and judgment, but perhaps develop a better understanding of themselves and the way they relate to the people around them. According to Ed Beeson, "Art therapists stress that it is not their job to interpret or read meaning into patients’ art"(2006). # Art-Based Assessments There are many psychological assessments that utilize artmaking to analyze various types of mental functioning (Betts, 2005). Art therapists are trained to administer and interpret a number of these assessments, most of which rely on simple directives and a standardized array of art materials (Malchiodi 1998, 2003; Betts 2005). The first drawing assessment for psychological purposes was created in 1906 by German psychiatrist Fritz Mohr (Malchiodi 1998). In 1926, researcher Florence Goodenough created a drawing test to measure the intelligence in children called the Draw–A–Man Test (Malchiodi 1998). The key to interpreting the Draw-A-Man Test was that the more details a child incorporated into the drawing, the more intelligent they were (Malchiodi). Goodenough and other researchers realized the test had just as much to do with personality as it did intelligence (Malchiodi). Several other psychiatric art assessments were created in the 1940s, and have been used ever since (Malchiodi 1998). Notwithstanding, many art therapists eschew diagnostic testing and indeed some writers (Hogan 1997) question the validity of therapists making interpretative assumptions. Below are a few of the most common art therapy assessments: ## The Diagnostic Drawing Series (DDS) The Diagnostic Drawing Series is an art therapy assessment that assesses for a range of major psychiatric disorders. (Malchiodi 1998). There are three parts to the DDS (Malchiodi 1998). In the first part, the patient is asked to draw any picture using colored chalk pastels on an 18x24 inch piece of paper (Malchiodi 1998). Then they are asked to draw a tree in the second part. In the last part of the test, the patient is asked to show how they are feeling using lines, shapes, and colors (Malchiodi 1998). The series of pictures are interpreted based on a combination of many different factors, such as use of color, amount of blending, and placement of the images on the paper. ## The Mandala Assessment Research Instrument (MARI) In this assessment, a person is asked to select a card from a deck with different mandalas; designs enclosed in a geometric shape, and then must choose a color from a set of colored cards (Malchiodi 1998). The person is then asked to draw the mandala from the card they choose with an oil pastel of the color of their choice (Malchiodi 1998). The artist is then asked to explain if there were any meanings, experiences, or related information related to the mandala they drew (Malchiodi 1998). This test is based on the beliefs of Joan Kellogg, who sees a reoccurring correlation between the images, pattern and shapes in the mandalas that people draw and the personalities of the artists (Malchiodi 1998). This test assesses and gives clues to a person's psychological progressions and their current psychological condition (Malchiodi 1998). ## House–Tree–Person (HTP) In this assessment, the patient is asked to draw a picture with a house, a tree, and a person in it (Malchiodi 1998). After the patient has finished the drawing, the therapist asks questions like, “How old is the person in your drawing? What is he or she doing? What is the house made of? What is the weather in this picture?” (Malchiodi 1998). This is a projective assessment and the house, the tree, and person in the drawing represent different aspects of the artist and the way the artist feels about him or herself (Malchiodi 1998). # Art Therapy Certification and Registration ## Board Certification and Registration In the United States, art therapists may become Registered (ATR) and Board Certified (ATR-BC). For more information on these credentials, art therapists in the US should contact the Art Therapy Credentials Board (ATCB) at www.atcb.org. A Code of Professional Practice, a 17 page document summarizing the standards of practice for professional art therapists. The ATCB Code of Professional Practice is comprised of five main categories; General Ethical Principles, Independent Practitioner, Eligibility for Credentials, Standards of Conduct, and Disciplinary Procedures (ATCB 2005). ## General Ethical Principles One topic covered in this section describes the responsibility art therapist have to their patients (ATCB 2005). According to the ATCB, art therapists must strive to advance the wellness of their clients, respect the rights of the client, and make sure they are providing a useful service (2005). They cannot discriminate against patient whatsoever, and may never desert or neglect patients receiving therapy (2005). Art therapist must fully explain to their patients what their expectations of the patients will be at the outset of the professional relationship between the two (ATCB 2005). Art therapists should continue therapy with a patient only if the client is benefiting from the therapy (ATCB 2005). It’s against the principles established by the ATCB for art therapist to have patients only for financial reasons (ATCB 2005). Another topic of this section discuses the competency and integrity art therapist must possess (ATCB 2005). The ATCB states art therapist must be professionally proficient and have integrity (2005). Art therapist must keep up dated on new developments in art therapy. They are only supposed to treat cases in which they are qualified as established by their training, education, and experience (ATCB 2005). They are not allowed to treat patients currently seeing another therapist without the other therapist’s permission (ATCB 2005). Art therapist must observe patient confidentiality (ATCB 2005). Other topics covered in this section discuss other responsibilities of art therapists. This responsibilities include, “responsibility to students and supervisees, responsibility to research participants, responsibility to the profession” (ATCB 2005). This section also establishes the rules by which art therapists must follow when making financial arrangements and when they chose to advertise their service (ATCB 2005) ## Independent Practitioner Independent practitioners are art therapists who are practicing independently or responsible for the service they are providing to paying clients. This section covers the credentials for independent practitioners. Independent practitioners must provide a safe and functional environment to conduct art therapy sessions (ATCB 2005). According to ATCB, "this includes but is not limited to: proper ventilation, adequate lighting, access to water supply, knowledge of hazards or toxicity of art materials and the effort need to safeguard the health of clients, storage space for art projects and secured areas for any hazardous materials, monitored use of sharp objects, allowance for privacy and confidentiality, and compliance with any other health and safety requirements according to state and federal agencies which regulate comparable businesses" (2005). This section also establishes the standards for independent practitioners to follow when dealing with financial arrangements (ATCB 2005). Basically it states that the art therapist must provide a straight forward contract to the payer of the therapy sessions (ATCB 2005). It also states that the art therapist must not deceive the payers or exploit clients financially (ATCB 2005). The last topics this section sets standards for address treatment planning and documentation (ATCB 2005). Art therapists must provide a treatment plan that assists the patients to reach or maintain the highest level of quality of life and functioning (ATCB 2005). This involves using the clients’ strengths to help them reach their goals and address their needs (ATCB 2005). Art therapists are also required to record and take notes that reflect the proceedings of the events of therapy sessions (ATCB 2005). According to ATCB, the following is the minimum of which must be documented: “the current goals of any treatment plan, verbal content of art therapy sessions relevant to client behavior and goals, artistic expression relevant to client behavior and goals, changes (or lack of change) in affect, thought process, and behavior, suicidal or homicidal intent or ideation” (2005) and a summary of the “clients response to treatment and future treatment recommendations” (2005). ## Eligibility for Credentials This section of the ATCB Code of Professional Practice outlines the process by which art therapy students receive their credentials. It discusses the standards for eligibility and describes the application process. It also states that the ATCB certificates are the property of the ATCB and that any art therapist who loses their certificate and still claim to have ATCB credentials can be punished legally. It also discusses the procedure to follow when accused of wrong doing related to art therapy. Lastly, it discusses the wrong doings related to art therapy that therapists can be convicted for with a felony or another criminal conviction. These wrong doings include rape, sexual abuse, assault, battery, prostitution, or the sale of controlled substances to patients. ## Standards of Conduct This section of the ATCB Code of Professional Practice addresses in detail confidentiality, use of clients’ artwork, professional relationships, and grounds for discipline (ATCB 2005). Art therapists are permitted to disclosing information about the clients’ therapy sessions. This includes “all verbal and/or artistic expression occurring within a client-therapist relationship” (ATCB 2005). Art therapist are only allowed to release confidential information if they have explicit written consent by the patient of if the therapist has reason to believe the patient needs immediate help to address a severe danger to the patients life (ATCB 2005). Also, therapists are not allowed to publish or display any of the patients work without the expressed written consent of the patient (ATCB 2005). The standards of a professional relationship between art therapists and clients are covered in this section. Within a professional relationship, art therapists are banned from engaging in exploitative relationships with current and former patients, students, inters trainees, supervisors, or co-workers (ATCB 2005). The ATCB defines an exploitative relationship as anything involving sexual intimacy, romance, or borrowing or loaning money (ATCB 2005). Within professional relationships, therapists are to do what they feel is best in the clients interest, shall not advance a professional relationship for their own benefit, and shall not steer their patients in the wrong direction (ATCB 2005). The breaking of any of the standards established in this section is grounds for discipline (ATCB 2005). ## Disciplinary Procedures The content contained in this section of the ATCB Code of Professional Practice specifically discusses in legal and technical detail the entire disciplinary procedures for wrong doings in art therapy (2005). Main topics covered in this section cover: “submission of allegations, procedures of the Disciplinary Hearing Committees, sanctions, release of information, waivers, reconsideration of eligibility and reinstatement of credentials, deadlines, bias, prejudice, and impartiality” (ATCB 2005).	https://www.wikidoc.org/index.php/Art_therapy
ad0530e71a9a310a529356dc6ff53357fc8a944c	wikidoc	Artemisinin	Artemisinin # Overview Artemisinin (IPA: Template:IPA) is a drug used to treat multi-drug resistant strains of falciparum malaria. The compound (a sesquiterpene lactone) is isolated from the shrub Artemisia annua long used in traditional Chinese medicine. Not all shrubs of this species contain artemisinin. Apparently it is only produced when the plant is subjected to certain conditions. It can be synthesized from artemisinic acid. # History Artemisia has been used by Chinese herbalists for more than a thousand years in the treatment of many illnesses, such as skin diseases and malaria. The earliest record dates back to 200 BC , in the "Fifty two Prescriptions" unearthed from the Mawangdui Han Dynasty Tombs. Its antimalarial application was first described in Zhouhou Beji Fang ("The Handbook of Prescriptions for Emergencies"), edited in the middle of fourth century by Ge Hong. In the 1960s a research program was set up by the Chinese army to find an adequate treatment for malaria. In 1972, in the course of this research, Tu Youyou discovered artemisinin in the leaves of Artemisia annua. The drug is named Qinghaosu in Chinese. It was one of many candidates then tested by Chinese scientists from a list of nearly 200 traditional Chinese medicines for treating malaria. It was the only one that was effective. It remained largely unknown to the rest of the world for about ten years, until results were published in a Chinese medical journal. The report was met with skepticism at first, because the Chinese had made unsubstantiated claims about having found treatments for malaria before. In addition, the chemical structure of artemisinin, particularly the peroxide, appeared to be too unstable to be a viable drug. For many years, access to the purified drug and the plant it was extracted from were restricted by the Chinese government. However, Artemisia annua is a common shrub and has been found in many parts of the world, including along the Potomac River, in Washington, D.C. Currently, artemisinin is widely used in China and Southeast Asia for treatment of malaria. It is often used without taking precautions against conditions that might lead to resistance of the malaria parasite to this drug, leading to concern that the effectiveness of artemisinin may be reduced in the near future, as is the case with other classes of antimalarial drugs. Because artemisinin itself has physical properties such as poor bioavailability that limit its effectiveness, semi-synthetic derivatives of artemisinin, including artemether and artesunate, have been developed. However, their activity is not long lasting, with significant decreases in effectiveness after one to two hours. To counter this drawback, artemisinin is given alongside lumefantrine to treat uncomplicated falciparum malaria. Lumefantrine has a half-life of about 3 to 6 days. Such a treatment is called ACT (artemisinin-based combination therapy); other examples are artemether-lumefantrine, artesunate-mefloquine, artesunate-amodiaquine, and artesunate-sulfadoxine/pyrimethamine. Recent trials have shown that ACT is more than 90% effective, with a recovery of malaria after three days, especially for the chloroquine-resistant Plasmodium falciparum. The World Health Organisation has recommended that a switch to ACT should be made in all countries where the malaria parasite has developed resistance to chloroquine. Artemisinin and its derivatives are now standard components of malaria treatment in China, Vietnam, and some other countries in Asia and Africa, where they have proved to be safe and effective anti-malarial drugs. They have minimal adverse side effects. Currently, artemisinin is not widely available in the United States or Canada, but is easy to find in Africa and Asia. There have been some concerns about the quality of some products on offer in Africa. To counter the present shortage in leaves of Artemisia annua, researchers have been searching for a way to develop artemisinin artificially in the laboratory. A recent paper in Nature presented a genetically engineered yeast that can synthesize a precursor called artemisinic acid which can be chemically converted to Artemisinin. The compound called OZ-277 (also known as RBx11160), developed by Jonathan Vennerstrom at the University of Nebraska, has proved to be even more effective than the natural product in test-tube trials. A six month trial of the drug on human subjects in Thailand was started in January 2005. There are also plans to have the plant grow in other areas of the world (outside Vietnam and China). # Analogues There are a number of derivatives and analogues within the artemisinin family: - Artesunate (water-soluble: for oral, rectal, intramuscular, or intravenous use) - Artemether (lipid-soluble: for oral, rectal or intramuscular use) - Arteether - Dihydroartemisinin - Artelinic acid # Cancer Treatment Artemisinin is under early research and testing for treatment of cancer, primarily by researchers at the University of Washington . Artemisinin has a peroxide lactone group in its structure. It is thought that when the peroxide comes into contact with high iron concentrations (common in cancerous cells), the molecule becomes unstable and releases reactive oxygen species. It has been shown to reduce angiogenesis and the expression of vascular endothelial growth factor in some tissue cultures. # Mechanism of action The specific mechanism of action of artemisinin is not well understood, and there is ongoing research directed at elucidating it. When the parasite that causes malaria infects a red blood cell, it consumes hemoglobin and liberates free heme, an iron-porphyrin complex. The iron reduces the peroxide bond in artemisinin generating high-valent iron-oxo species, resulting in a cascade of reactions that produce reactive oxygen radicals which damage the parasite leading to its death. Numerous studies have investigated the type of damage that these oxygen radicals may induce. For example, Pandey et al. have observed inhibition of digestive vacuole cysteine protease activity of malarial parasite by artemisinin. These observations were further confirmed by ex vivo experiments showing accumulation of hemoglobin in the parasites treated with artemisinin, suggesting inhibition of hemoglobin degradation. They found artemisinin to be a potent inhibitor of hemeozoin formation activity of malaria parasite. A 2005 study investigating the mode of action of artemisinin using a yeast model demonstrated that the drug acts on the electron transport chain, generates local reactive oxygen species, and causes the depolarization of the mitochondrial membrane. Artemisinins have also been shown to inhibit PfATP6, a SERCA-type enzyme (calcium transporter) and artemisinin has been shown to compete with thapsigargin for SERCA binding, though artemesinin is much less toxic to mammalian cells. Resistance to artemisinin is conferred by a single mutation in the calcium transporter (PfATP6). This mutation has been studied in the laboratory but recently a study from French Guiana in field isolates of malaria parasites has identified a different mutation in the calcium transporter (PfATP6) that is associated with resistance to artemether, lending support to the idea that PfATP6 is the target for artemisinins. # Dosing The WHO approved adult dose of co-artemether (artemether-lumofantrine) for malaria is 4 tablets at 0, 8, 24, 36,48 and 60 hours (six doses). This has been proven to be superior to regimens based on amodiaquine. Artemesinin is not soluble in water and therefore Artemesia annua tea was postulated not to contain pharmacologically significant amounts of artemesinin.. However, this conclusion was rebuked by several experts who stated that hot water (85 oC), and not boiling water, should be used to prepare the tea. Although Artemisia tea is not recommended as a substitute for the ACT (artemisinin combination therapies) more clinical studies on artemisia tea preparation are in need (). The artemesinins are not used for malaria prophylaxis (prevention) because to be efficacious, they must be taken twice or three times a day throughout the risk period. # Synthesis In 2006 a team from Berkeley have published an article claiming that they have engineered Saccharomyces cerevisiae microbes that can produce the precursor artemisinic acid. The synthesized artemisinic acid can then be transported out, purified and turned into a drug that they claim will cost roughly 0.25 cents. Details of the formation of artemisinic acid involves a mevalonate pathway, expression of amorphadiene synthase, a novel cytochrome P450 monooxygenase (CYP71AV1) and its redox partner from A. annua. A three-step oxidation of amorpha-4,11-diene gives the resulting artemisinic acid. Amyris Biotechnologies is collaborating with UC Berkeley and the Institute for One World Health to further develop this technology. Using seed supplied by Action for Natural Medicine (ANAMED), the World Agroforestry Centre (ICRAF) has developed a hybrid, dubbed A3, which can grow to a height of 3 m and which produces 20 times more artemisinin than wild varieties. In northwestern Mozambique, ICRAF is working together with a medical organisation, Médecins sans frontières (MSF), ANAMED and the Ministry of Agriculture and Rural Development to train farmers on how to grow the shrub from cuttings, and to harvest and dry the leaves to make artemisia tea. Cultivation of this crop may well prove a valuable niche market for Africa, given the strong demand for the plant from pharmaceutical laboratories. The biosynthesis of artemisinin is shown at the bottom in three parts: The formation of IPP and DMAPP, the formation of E,Z-FPP and finally the formation of Artemisinin. The total synthesis of Artemisinin can also be performed using basic organic reagents. In 1982, G. Schmid and W. Hofheinz published a paper showing the complete synthesis of artemisinin. Their starting material was (-)-Isopulegol (2) which as converted to methoxymethyl ether (3). The ether was hydroborated and then underwent oxidative workup to give (4). The primary hydroxyl group was then benzylated and the methoxymethyl ether was cleaved resulting in (5) which would be oxidized to (6). Next, the compound was protonated and treated with (E)-(3-iodo-1-methyl-1-propenyl)-trimethylsilane to give (7). This resulting ketone was reacted with lithium methoxy(trimethylsily)methylide to obtain two diastereomeric alcohols, (8a) and (8b). 8a was then debenzylated using (Li, NH3) to give lactone (9). The vinylsilane was then oxidized to ketone (10). The ketone was then reacted with fluoride ion that caused it to undergo desilylation, enol ether formation and carboxylic acid formation to give (11). An introduction of a hydroperoxide function at C(3) of 11 gives rise to (12). Finally, this underwent photooxygenation and then treated with acid to produce artemisinin.	Artemisinin # Overview Artemisinin (IPA: Template:IPA) is a drug used to treat multi-drug resistant strains of falciparum malaria. The compound (a sesquiterpene lactone) is isolated from the shrub Artemisia annua long used in traditional Chinese medicine. Not all shrubs of this species contain artemisinin. Apparently it is only produced when the plant is subjected to certain conditions. It can be synthesized from artemisinic acid.[1] # History Artemisia has been used by Chinese herbalists for more than a thousand years in the treatment of many illnesses, such as skin diseases and malaria. The earliest record dates back to 200 BC , in the "Fifty two Prescriptions" unearthed from the Mawangdui Han Dynasty Tombs. Its antimalarial application was first described in Zhouhou Beji Fang ("The Handbook of Prescriptions for Emergencies"), edited in the middle of fourth century by Ge Hong. In the 1960s a research program was set up by the Chinese army to find an adequate treatment for malaria. In 1972, in the course of this research, Tu Youyou [1] discovered artemisinin in the leaves of Artemisia annua. The drug is named Qinghaosu in Chinese. It was one of many candidates then tested by Chinese scientists from a list of nearly 200 traditional Chinese medicines for treating malaria. It was the only one that was effective. It remained largely unknown to the rest of the world for about ten years, until results were published in a Chinese medical journal. The report was met with skepticism at first, because the Chinese had made unsubstantiated claims about having found treatments for malaria before. In addition, the chemical structure of artemisinin, particularly the peroxide, appeared to be too unstable to be a viable drug. For many years, access to the purified drug and the plant it was extracted from were restricted by the Chinese government. However, Artemisia annua is a common shrub and has been found in many parts of the world, including along the Potomac River, in Washington, D.C. Currently, artemisinin is widely used in China and Southeast Asia for treatment of malaria. It is often used without taking precautions against conditions that might lead to resistance of the malaria parasite to this drug, leading to concern that the effectiveness of artemisinin may be reduced in the near future, as is the case with other classes of antimalarial drugs. Because artemisinin itself has physical properties such as poor bioavailability that limit its effectiveness, semi-synthetic derivatives of artemisinin, including artemether and artesunate, have been developed. However, their activity is not long lasting, with significant decreases in effectiveness after one to two hours. To counter this drawback, artemisinin is given alongside lumefantrine to treat uncomplicated falciparum malaria. Lumefantrine has a half-life of about 3 to 6 days. Such a treatment is called ACT (artemisinin-based combination therapy); other examples are artemether-lumefantrine, artesunate-mefloquine, artesunate-amodiaquine, and artesunate-sulfadoxine/pyrimethamine. Recent trials have shown that ACT is more than 90% effective, with a recovery of malaria after three days, especially for the chloroquine-resistant Plasmodium falciparum. The World Health Organisation has recommended that a switch to ACT should be made in all countries where the malaria parasite has developed resistance to chloroquine. Artemisinin and its derivatives are now standard components of malaria treatment in China, Vietnam, and some other countries in Asia and Africa, where they have proved to be safe and effective anti-malarial drugs. They have minimal adverse side effects. Currently, artemisinin is not widely available in the United States or Canada, but is easy to find in Africa and Asia. There have been some concerns about the quality of some products on offer in Africa[citation needed]. To counter the present shortage in leaves of Artemisia annua, researchers have been searching for a way to develop artemisinin artificially in the laboratory. A recent paper in Nature[2] presented a genetically engineered yeast that can synthesize a precursor called artemisinic acid which can be chemically converted to Artemisinin. The compound called OZ-277 (also known as RBx11160), developed by Jonathan Vennerstrom at the University of Nebraska, has proved to be even more effective than the natural product in test-tube trials. A six month trial of the drug on human subjects in Thailand was started in January 2005. There are also plans to have the plant grow in other areas of the world (outside Vietnam and China). # Analogues There are a number of derivatives and analogues within the artemisinin family: - Artesunate (water-soluble: for oral, rectal, intramuscular, or intravenous use) - Artemether (lipid-soluble: for oral, rectal or intramuscular use) - Arteether - Dihydroartemisinin - Artelinic acid # Cancer Treatment Artemisinin is under early research and testing for treatment of cancer, primarily by researchers at the University of Washington [2] [3]. Artemisinin has a peroxide lactone group in its structure. It is thought that when the peroxide comes into contact with high iron concentrations (common in cancerous cells), the molecule becomes unstable and releases reactive oxygen species. It has been shown to reduce angiogenesis and the expression of vascular endothelial growth factor in some tissue cultures. # Mechanism of action The specific mechanism of action of artemisinin is not well understood, and there is ongoing research directed at elucidating it. When the parasite that causes malaria infects a red blood cell, it consumes hemoglobin and liberates free heme, an iron-porphyrin complex. The iron reduces the peroxide bond in artemisinin generating high-valent iron-oxo species, resulting in a cascade of reactions that produce reactive oxygen radicals which damage the parasite leading to its death.[3] Numerous studies have investigated the type of damage that these oxygen radicals may induce. For example, Pandey et al. have observed inhibition of digestive vacuole cysteine protease activity of malarial parasite by artemisinin.[4] These observations were further confirmed by ex vivo experiments showing accumulation of hemoglobin in the parasites treated with artemisinin, suggesting inhibition of hemoglobin degradation. They found artemisinin to be a potent inhibitor of hemeozoin formation activity of malaria parasite. A 2005 study investigating the mode of action of artemisinin using a yeast model demonstrated that the drug acts on the electron transport chain, generates local reactive oxygen species, and causes the depolarization of the mitochondrial membrane.[5] Artemisinins have also been shown to inhibit PfATP6, a SERCA-type enzyme (calcium transporter) and artemisinin has been shown to compete with thapsigargin for SERCA binding, though artemesinin is much less toxic to mammalian cells. Resistance to artemisinin is conferred by a single mutation in the calcium transporter (PfATP6). This mutation has been studied in the laboratory but recently a study from French Guiana in field isolates of malaria parasites has identified a different mutation in the calcium transporter (PfATP6) that is associated with resistance to artemether, lending support to the idea that PfATP6 is the target for artemisinins.[6] # Dosing The WHO approved adult dose of co-artemether (artemether-lumofantrine) for malaria is 4 tablets at 0, 8, 24, 36,48 and 60 hours (six doses).[7][8] This has been proven to be superior to regimens based on amodiaquine.[9] Artemesinin is not soluble in water and therefore Artemesia annua tea was postulated not to contain pharmacologically significant amounts of artemesinin.[10]. However, this conclusion was rebuked by several experts who stated that hot water (85 oC), and not boiling water, should be used to prepare the tea. Although Artemisia tea is not recommended as a substitute for the ACT (artemisinin combination therapies) more clinical studies on artemisia tea preparation are in need (http://www.bioline.org.br/request?tc07001). The artemesinins are not used for malaria prophylaxis (prevention) because to be efficacious, they must be taken twice or three times a day throughout the risk period. # Synthesis In 2006 a team from Berkeley have published an article claiming that they have engineered Saccharomyces cerevisiae microbes that can produce the precursor artemisinic acid. The synthesized artemisinic acid can then be transported out, purified and turned into a drug that they claim will cost roughly 0.25 cents. Details of the formation of artemisinic acid involves a mevalonate pathway, expression of amorphadiene synthase, a novel cytochrome P450 monooxygenase (CYP71AV1) and its redox partner from A. annua. A three-step oxidation of amorpha-4,11-diene gives the resulting artemisinic acid. [11] Amyris Biotechnologies is collaborating with UC Berkeley and the Institute for One World Health to further develop this technology. [12] Using seed supplied by Action for Natural Medicine (ANAMED), the World Agroforestry Centre (ICRAF) has developed a hybrid, dubbed A3, which can grow to a height of 3 m and which produces 20 times more artemisinin than wild varieties. In northwestern Mozambique, ICRAF is working together with a medical organisation, Médecins sans frontières (MSF), ANAMED and the Ministry of Agriculture and Rural Development to train farmers on how to grow the shrub from cuttings, and to harvest and dry the leaves to make artemisia tea. Cultivation of this crop may well prove a valuable niche market for Africa, given the strong demand for the plant from pharmaceutical laboratories. The biosynthesis of artemisinin is shown at the bottom in three parts: The formation of IPP and DMAPP, the formation of E,Z-FPP and finally the formation of Artemisinin. The total synthesis of Artemisinin can also be performed using basic organic reagents. In 1982, G. Schmid and W. Hofheinz published a paper showing the complete synthesis of artemisinin. Their starting material was (-)-Isopulegol (2) which as converted to methoxymethyl ether (3). The ether was hydroborated and then underwent oxidative workup to give (4). The primary hydroxyl group was then benzylated and the methoxymethyl ether was cleaved resulting in (5) which would be oxidized to (6). Next, the compound was protonated and treated with (E)-(3-iodo-1-methyl-1-propenyl)-trimethylsilane to give (7). This resulting ketone was reacted with lithium methoxy(trimethylsily)methylide to obtain two diastereomeric alcohols, (8a) and (8b). 8a was then debenzylated using (Li, NH3) to give lactone (9). The vinylsilane was then oxidized to ketone (10). The ketone was then reacted with fluoride ion that caused it to undergo desilylation, enol ether formation and carboxylic acid formation to give (11). An introduction of a hydroperoxide function at C(3) of 11 gives rise to (12). Finally, this underwent photooxygenation and then treated with acid to produce artemisinin.[13]	https://www.wikidoc.org/index.php/Artemesinin
c45ce956f6d50cdebbf144bffc8072e1a9f528b3	wikidoc	Arthrodesis	Arthrodesis Arthrodesis, also known as artificial ankylosis or syndesis, is the artificial induction of joint ossification between two bones via surgery. This is done to relieve intractable pain in a joint which cannot be managed by pain medication, splints, or other normally-indicated treatments. The typical causes of such pain are fractures which disrupt the joint, and arthritis. It is most commonly performed on joints in the spine, hand, ankle, and foot. Historically, knee and hip arthrodeses were also performed as pain relieving procedures, however with the great successes achieved in hip and knee arthroplasty, arthrodesis of these large joints has fallen out of favour as a primary procedure, and now are only used as procedures of last-resort in some failed arthroplasties. It can be done in several ways: - A bone graft can be created between the two bones using a bone from elsewhere in the person's body (autograft) or using donor bone (allograft) from a bone bank. Bone autograft is generally preferred by surgeons because, as well as eliminating the risks associated with allografts, bone autograft contains native bone-forming cells (osteoblasts), so the graft actually forms new bone itself (osteoinductive), as well as acting as a matrix or scaffold to new bone growing from the bones being bridged (osteoconductive). The main drawback of bone autograft is the limited supply available for harvest. Bone allograft has the advantage of being available in far larger quantities than autograft; however, the treatment process the bone goes through following harvest, which usually involves irradiation and deep-freezing, kills the bone forming cells. This significantly reduces the immunogenicity (risk of graft rejection) such that no anti rejection drugs are needed. The process also makes the allograft function only as an osteoconductive matrix. - Bone autograft is generally preferred by surgeons because, as well as eliminating the risks associated with allografts, bone autograft contains native bone-forming cells (osteoblasts), so the graft actually forms new bone itself (osteoinductive), as well as acting as a matrix or scaffold to new bone growing from the bones being bridged (osteoconductive). The main drawback of bone autograft is the limited supply available for harvest. - Bone allograft has the advantage of being available in far larger quantities than autograft; however, the treatment process the bone goes through following harvest, which usually involves irradiation and deep-freezing, kills the bone forming cells. This significantly reduces the immunogenicity (risk of graft rejection) such that no anti rejection drugs are needed. The process also makes the allograft function only as an osteoconductive matrix. - A variety of synthetic bone substitutes are commercially available. These are usually hydroxyapatite based granules formed into a coralline or trabecular structure to mimic the structure of cancellous bone. They act solely as an osteoconductive matrix. Some manufacturers have recently begun supplying these products with soluble bone-forming factors such as bone morphogenetic protein to attempt to create a synthetic product with osteoinductive properties. - Metal implants can be attached to the two bones to hold them together in a position which favors bone growth. - A combination of the above methods is also commonly employed to facilitate bony fusion. At the completion of surgery and healing, which takes place over a period of several months to over a year, the two adjoining bones are fused and no motion takes place between them. This can have the effect of actually strengthening the bones, as in anterior cervical fusion.	Arthrodesis Arthrodesis, also known as artificial ankylosis or syndesis, is the artificial induction of joint ossification between two bones via surgery. This is done to relieve intractable pain in a joint which cannot be managed by pain medication, splints, or other normally-indicated treatments. The typical causes of such pain are fractures which disrupt the joint, and arthritis. It is most commonly performed on joints in the spine, hand, ankle, and foot. Historically, knee and hip arthrodeses were also performed as pain relieving procedures, however with the great successes achieved in hip and knee arthroplasty, arthrodesis of these large joints has fallen out of favour as a primary procedure, and now are only used as procedures of last-resort in some failed arthroplasties. It can be done in several ways: - A bone graft can be created between the two bones using a bone from elsewhere in the person's body (autograft) or using donor bone (allograft) from a bone bank. Bone autograft is generally preferred by surgeons because, as well as eliminating the risks associated with allografts, bone autograft contains native bone-forming cells (osteoblasts), so the graft actually forms new bone itself (osteoinductive), as well as acting as a matrix or scaffold to new bone growing from the bones being bridged (osteoconductive). The main drawback of bone autograft is the limited supply available for harvest. Bone allograft has the advantage of being available in far larger quantities than autograft; however, the treatment process the bone goes through following harvest, which usually involves irradiation and deep-freezing, kills the bone forming cells. This significantly reduces the immunogenicity (risk of graft rejection) such that no anti rejection drugs are needed. The process also makes the allograft function only as an osteoconductive matrix. - Bone autograft is generally preferred by surgeons because, as well as eliminating the risks associated with allografts, bone autograft contains native bone-forming cells (osteoblasts), so the graft actually forms new bone itself (osteoinductive), as well as acting as a matrix or scaffold to new bone growing from the bones being bridged (osteoconductive). The main drawback of bone autograft is the limited supply available for harvest. - Bone allograft has the advantage of being available in far larger quantities than autograft; however, the treatment process the bone goes through following harvest, which usually involves irradiation and deep-freezing, kills the bone forming cells. This significantly reduces the immunogenicity (risk of graft rejection) such that no anti rejection drugs are needed. The process also makes the allograft function only as an osteoconductive matrix. - A variety of synthetic bone substitutes are commercially available. These are usually hydroxyapatite based granules formed into a coralline or trabecular structure to mimic the structure of cancellous bone. They act solely as an osteoconductive matrix. Some manufacturers have recently begun supplying these products with soluble bone-forming factors such as bone morphogenetic protein to attempt to create a synthetic product with osteoinductive properties. - Metal implants can be attached to the two bones to hold them together in a position which favors bone growth. - A combination of the above methods is also commonly employed to facilitate bony fusion. At the completion of surgery and healing, which takes place over a period of several months to over a year, the two adjoining bones are fused and no motion takes place between them. This can have the effect of actually strengthening the bones, as in anterior cervical fusion.	https://www.wikidoc.org/index.php/Arthrodesis
1e11e533b1aaaf560c95c7736567cd8ef28f3275	wikidoc	Arthropathy	Arthropathy # Overview An arthropathy is a disease of a joint. Although the terms "arthropathy" and arthritis have very similar meanings, the former is traditionally used to describe the following conditions: - Reactive arthropathy (M02-M03) is caused by an infection, but not a direct infection of the synovial space. (See also Reactive arthritis) - Enteropathic arthropathy (M07) is caused by colitis and related conditions. - Crystal arthropathy (also known as crystal arthritis) (M10-M11) involves the deposition of crystals in the joint. In gout, the crystal is uric acid. In pseudogout/chondrocalcinosis/calcium pyrophosphate deposition disease, the crystal is calcium pyrophosphate. - In gout, the crystal is uric acid. - In pseudogout/chondrocalcinosis/calcium pyrophosphate deposition disease, the crystal is calcium pyrophosphate. - Diabetic arthropathy (M14.2, E10-E14) is caused by diabetes. - Neuropathic arthropathy (M14.6) is associated with a loss of sensation.	Arthropathy Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview An arthropathy is a disease of a joint. Although the terms "arthropathy" and arthritis have very similar meanings, the former is traditionally used to describe the following conditions: - Reactive arthropathy (M02-M03) is caused by an infection, but not a direct infection of the synovial space. (See also Reactive arthritis) - Enteropathic arthropathy (M07) is caused by colitis and related conditions. - Crystal arthropathy (also known as crystal arthritis) (M10-M11) involves the deposition of crystals in the joint. In gout, the crystal is uric acid. In pseudogout/chondrocalcinosis/calcium pyrophosphate deposition disease, the crystal is calcium pyrophosphate. - In gout, the crystal is uric acid. - In pseudogout/chondrocalcinosis/calcium pyrophosphate deposition disease, the crystal is calcium pyrophosphate. - Diabetic arthropathy (M14.2, E10-E14) is caused by diabetes. - Neuropathic arthropathy (M14.6) is associated with a loss of sensation. Template:Diseases of the musculoskeletal system and connective tissue Template:WS	https://www.wikidoc.org/index.php/Arthropathies
9bb451ce8f10edd1eefcc89eeb2509ab3b665fe7	wikidoc	Arthroscopy	Arthroscopy # Overview Arthroscopy (also called arthroscopic surgery) is a minimally invasive surgical procedure in which an examination and sometimes treatment of damage of the interior of a joint is performed using an arthroscope, a type of endoscope that is inserted into the joint through a small incision. Arthroscopic procedures can be performed either to evaluate or to treat many orthopaedic conditions including torn floating cartilage, torn surface cartilage, ACL reconstruction, and trimming damaged cartilage. The advantage of arthroscopy over traditional, open surgery is that the joint does not have to be opened up fully. Instead, only two small incisions are made - one for the arthroscope and one for the surgical instruments. This reduces recovery time and may increase the rate of surgical success due to less trauma to the connective tissue. It is especially useful for professional athletes, who frequently injure knee joints and require fast healing time. There is also less scarring, because of the smaller incisions. The surgical instruments used are smaller than traditional instruments. Surgeons view the joint area on a video monitor, and can diagnose and repair torn joint tissue, such as ligaments and menisci. Arthroscopy is used for joints of the knee, shoulder, elbow, wrist, ankle and hip. # Historical Perspective 2000 marks the end of the third decade of arthroscopic surgery, although pioneering work in the field began as early as the 1920s with the work of Eugen Bircher. Arthroscopic surgery was begun by a Japanese surgeon (Masaki Watanabe, MD); however, inspired by the work and teaching of a Japanese surgeon, Dr. Richard O'Connor and later Dr. Heshmat Shahriaree began experimenting with ways to excise fragments of menisci in the early 1970s. Largely through his effort in the ensuing years, arthroscopic surgery was developed and advanced. Dr. O'Connor paved the way for arthroscopic surgery and did more to pioneer and develop the techniques of arthroscopic meniscectomy than any other person in North America. No wonder Dr. Masaki Watanabe wrote: "From his efforts, I was convinced that O'Connor would be the man to perfect the methodology of arthroscopic meniscectomy, bringing most types of meniscectomy within the scope of arthroscopic control." Together both doctors fashioned the first operating arthroscope and helped to generate and produce the first high-quality color intraarticular photography. Dr. O'Connor wrote the first book under the title, Arthroscopy. Dr. Shahriaree has written three books on arthroscopic surgery: Arthroscopic Surgery, First Edition (1984); Arthroscopic Surgery, Second Edition (1992) both of which were published by J.B. Lippincott Company. His third book was a rendition of his Second Edition, which was translated in Chinese. # Knee Arthroscopy Knee arthroscopy has in many cases replaced the classic arthrotomy that was performed in the past. Today knee arthroscopy is commonly performed for treating with damaged meniscus cartilage, reconstruction of the anterior cruciate ligament and for cartilage microfracturing. Arthroscopy can also be performed just for diagnosing and checking of the knee; however, the latter use has been mainly replaced by magnetic resonance imaging. During an average knee arthroscopy a small fiberoptic camera, the endoscope, is inserted in the joint through a small incision that has an approximate size of 1/8 inch long. A special fluid is used to visualize the joint parts. More incisions might be performed in order to check other parts of the knee. Then other miniature instruments are used and the surgery is performed Recovery after a knee arthroscopy is a lot faster compared to arthrotomy. Most patients can return home and walk using crutches the same or the next day after the surgery. Usually after a month a patient can fully load his leg and after a few weeks the joint function can fully recover. It is not uncommon for athletes who have a beyond average physical condition to return to normal athletic activities within a few weeks. However the recovery time also depends on the diagnosis that the arthroscopy was performed for, thus each case is unique and the patient must consult his personal doctor and physician regarding his physiotherapy. A double-blind placebo-controlled study on arthroscopic surgery for osteoarthritis of the knee was published in the New England Journal of Medicine in July 2002 and concluded that the group that received actual arthroscopy did not report better function or pain than the placebo group." # Spinal Arthroscopy Many invasive spine procedures involve the removal of bone, muscle, and ligaments to access and treat problematic areas. In some cases, thoracic (mid-spine) conditions requires a surgeon to access the problem area through the rib cage, dramatically lengthening recovery time. Arthroscopic (also endoscopic) spinal procedures allow a surgeon to access and treat a variety of spinal conditions with minimal damage to surrounding tissues. Recovery times are greatly reduced due to the relatively small size of incision(s) required, and many patients are treated on an outpatient basis. Arthroscopic procedures treat: - Bulging discs / herniated discs - Degenerative discs - Spinal deformity - tumors - General spine trauma Similar to knee arthroscopy, recovery rates and times vary according to condition severity and patient's overall health. Any patient considering surgery should consult his or her physician/specialist for further education, evaluation, & treatment options.	Arthroscopy Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview Arthroscopy (also called arthroscopic surgery) is a minimally invasive surgical procedure in which an examination and sometimes treatment of damage of the interior of a joint is performed using an arthroscope, a type of endoscope that is inserted into the joint through a small incision. Arthroscopic procedures can be performed either to evaluate or to treat many orthopaedic conditions including torn floating cartilage, torn surface cartilage, ACL reconstruction, and trimming damaged cartilage. The advantage of arthroscopy over traditional, open surgery is that the joint does not have to be opened up fully. Instead, only two small incisions are made - one for the arthroscope and one for the surgical instruments. This reduces recovery time and may increase the rate of surgical success due to less trauma to the connective tissue. It is especially useful for professional athletes, who frequently injure knee joints and require fast healing time. There is also less scarring, because of the smaller incisions. The surgical instruments used are smaller than traditional instruments. Surgeons view the joint area on a video monitor, and can diagnose and repair torn joint tissue, such as ligaments and menisci. Arthroscopy is used for joints of the knee, shoulder, elbow, wrist, ankle and hip. # Historical Perspective 2000 marks the end of the third decade of arthroscopic surgery, although pioneering work in the field began as early as the 1920s with the work of Eugen Bircher.[2] Arthroscopic surgery was begun by a Japanese surgeon (Masaki Watanabe, MD)[1]; however, inspired by the work and teaching of a Japanese surgeon, Dr. Richard O'Connor and later Dr. Heshmat Shahriaree began experimenting with ways to excise fragments of menisci[2] in the early 1970s. Largely through his effort in the ensuing years, arthroscopic surgery was developed and advanced[3]. Dr. O'Connor paved the way for arthroscopic surgery[4] and did more to pioneer and develop the techniques of arthroscopic meniscectomy than any other person in North America[5]. No wonder Dr. Masaki Watanabe wrote: "From his efforts, I was convinced that O'Connor would be the man to perfect the methodology of arthroscopic meniscectomy, bringing most types of meniscectomy within the scope of arthroscopic control."[1] Together both doctors fashioned the first operating arthroscope and helped to generate and produce the first high-quality color intraarticular photography[6]. Dr. O'Connor wrote the first book under the title, Arthroscopy. Dr. Shahriaree has written three books on arthroscopic surgery: Arthroscopic Surgery, First Edition (1984); Arthroscopic Surgery, Second Edition (1992) both of which were published by J.B. Lippincott Company. His third book was a rendition of his Second Edition, which was translated in Chinese. # Knee Arthroscopy Knee arthroscopy has in many cases replaced the classic arthrotomy that was performed in the past. Today knee arthroscopy is commonly performed for treating with damaged meniscus cartilage, reconstruction of the anterior cruciate ligament and for cartilage microfracturing. Arthroscopy can also be performed just for diagnosing and checking of the knee; however, the latter use has been mainly replaced by magnetic resonance imaging. During an average knee arthroscopy a small fiberoptic camera, the endoscope, is inserted in the joint through a small incision that has an approximate size of 1/8 inch long. A special fluid is used to visualize the joint parts. More incisions might be performed in order to check other parts of the knee. Then other miniature instruments are used and the surgery is performed Recovery after a knee arthroscopy is a lot faster compared to arthrotomy. Most patients can return home and walk using crutches the same or the next day after the surgery. Usually after a month a patient can fully load his leg and after a few weeks the joint function can fully recover. It is not uncommon for athletes who have a beyond average physical condition to return to normal athletic activities within a few weeks. However the recovery time also depends on the diagnosis that the arthroscopy was performed for, thus each case is unique and the patient must consult his personal doctor and physician regarding his physiotherapy. A double-blind placebo-controlled study on arthroscopic surgery for osteoarthritis of the knee was published in the New England Journal of Medicine in July 2002 and concluded that the group that received actual arthroscopy did not report better function or pain than the placebo group."[7] # Spinal Arthroscopy Many invasive spine procedures involve the removal of bone, muscle, and ligaments to access and treat problematic areas. In some cases, thoracic (mid-spine) conditions requires a surgeon to access the problem area through the rib cage, dramatically lengthening recovery time. Arthroscopic (also endoscopic) spinal procedures allow a surgeon to access and treat a variety of spinal conditions with minimal damage to surrounding tissues. Recovery times are greatly reduced due to the relatively small size of incision(s) required, and many patients are treated on an outpatient basis.[8] Arthroscopic procedures treat: - Bulging discs / herniated discs - Degenerative discs - Spinal deformity - tumors - General spine trauma Similar to knee arthroscopy, recovery rates and times vary according to condition severity and patient's overall health. Any patient considering surgery should consult his or her physician/specialist for further education, evaluation, & treatment options. # External Links - Shoulder Arthroscopy - Ankle Arthroscopy - Shoulder SLAP tear images - Knee 3D Presentation - American Medical Group article - History, future of, general information about arthroscopy - SpineUniverse Minimally Invasive Spine Surgery Information Center - Collection of articles from different institutes, organizations, and spine professionals	https://www.wikidoc.org/index.php/Arthroscopic
52e0a2b31e090aabddeabd84374ad162d642a464	wikidoc	Ashwagandha	Ashwagandha Ashwagandha (Withania somnifera), also known as Indian ginseng, Winter cherry, Ajagandha, Kanaje Hindi and Samm Al Ferakh, is a plant in Solanaceae or nightshade family. It grows as a stout shrub that reaches a height of 170cm. Like the tomato which belongs to the same family, ashwagandha bears yellow flowers and red fruit, though its fruit is berry-like in size and shape. Ashwagandha grows prolifically in India, Pakistan, and Sri Lanka. # Medicinal use In Ayurveda ashwaganda is considered a rasayana herb, a herb that works on a nonspecific basis to increase health and longevity. This herb is also considered an adaptogen which is a nontoxic herb that works on a nonspecific basis to normalize physiological function, working on the HPA axis and the neuroendocrine system. The roots and berries of the plant are used in herbal medicine. In Ayurveda, the fresh roots are sometimes boiled in milk, prior to drying, in order to leach out undesirable constituents. {ref} The berries are used as a substitute for rennet, to coagulate milk in cheese making. Ashwagandha in Sanskrit means "horse's smell", probably originating from the odor of its root which resembles that of sweaty horse. The species name somnifera means "sleep-bearing" in Latin, indicating it was considered a sedative, but it has been also used for sexual vitality and as an adaptogen. Some herbalists refer to ashwagandha as Indian ginseng, since it is used in ayurvedic medicine in a way similar to that ginseng is used in traditional Chinese medicine. Seven American and four Japanese firms have filed for grant of patents on formulations containing extracts of the herb Ashwagandha. Fruits, leaves and seeds of the Indian medicinal plant withania somnifera have been traditionally used for the Ayurvedic system as aphrodisiacs, diuretics and for treating memory loss. The Japanese patent applications are related to the use of the herb as a skin ointment and for promoting reproductive fertility. The U.S based company Natreon has also obtained a patent for an Ashwagandha extract. Another US establishment, the New England Deaconess Hospital, has taken a patent on an Ashwagandha formulation claimed to alleviate symptoms associated with arthritis.. The product called "ashwagandha oil" is a combination of ashwagandha with almond oil and rose water designed to be used as a facial toner, therefore should not be consumed. ## Active Constituents All chemicals listed pertain to the root unless otherwise specified, as the root is the part used. Anaferine (Alkaloid), Anahygrine (Alkaloid), Beta-Sisterol, Chlorogenic acid (in leaf only), Cysteine (in fruit), Cuscohygrine (Alkaloid), Iron, Pseudotropine (Alkaloid), Scopoletin, Somniferinine (Alkaloid), Somniferiene (Alkaloid), Tropanol (Alkaloid), Withanine (Alkaloid), Withananine (Alkaloid) and Withanolides A-Y(Steroidal lactones) # History Robin Lane Fox, in his biography of Alexander the Great, claims Withania somnifera was used in wine in ancient times. According to Anne Van Arsdall, Withania somnifera was called apollinaris and also glofwyrt in The Old English Herbarium, and had a legend that Apollo found it first and gave it to the healer Aesculapius. The main constituents of ashwagandha are alkaloids and steroidal lactones. Among the various alkaloids, withanine is the main constituent. The other alkaloids are somniferine, somnine, somniferinine, withananine, pseudo-withanine, tropine, pseudo-tropine, 3-a-gloyloxytropane, choline, cuscohygrine, isopelletierine, anaferine and anahydrine. Two acyl steryl glucoside viz. Sitoindoside VII and sitoindoside VIII have been isolated from root. The leaves contain steroidal lactones, which are commonly called withanolides. The withanolides have C28 steroidal nucleus with C9 side chain, having six membered lactone ring. Thakur ''et al.( 1987) has described Withania somnifera in their book on major medicinal plants of India, while Puri (2002) has given various recipes in which ashwagndha is an important ingredient Puri (2003) in his book on RASAYANA has given monographic account of this adaptogenic plant. After botanical study, he has given various uses of this herb in Ayurveda, important Ayurvedic preparations and therapeutic indications and pharmacological activities. The author has cited about a hundred references. # Other species There are over 20 other species of the Withania genus that occur in the dry parts of India, North Africa, Middle East, and the Mediterranean. These include Withania coagulens and Withania simonii, the roots of which are sometimes used interchangeably with those of Withania somnifera. Withania somnifera itself has been extensively domesticated from the wild form. In India, at least five different cultivars have been developed for increased root size and adaptation to different climates.	Ashwagandha Ashwagandha (Withania somnifera), also known as Indian ginseng, Winter cherry, Ajagandha, Kanaje Hindi and Samm Al Ferakh, is a plant in Solanaceae or nightshade family. It grows as a stout shrub that reaches a height of 170cm. Like the tomato which belongs to the same family, ashwagandha bears yellow flowers and red fruit, though its fruit is berry-like in size and shape. Ashwagandha grows prolifically in India, Pakistan, and Sri Lanka. # Medicinal use In Ayurveda ashwaganda is considered a rasayana herb, a herb that works on a nonspecific basis to increase health and longevity. This herb is also considered an adaptogen which is a nontoxic herb that works on a nonspecific basis to normalize physiological function, working on the HPA axis and the neuroendocrine system. The roots and berries of the plant are used in herbal medicine. In Ayurveda, the fresh roots are sometimes boiled in milk, prior to drying, in order to leach out undesirable constituents. {ref} The berries are used as a substitute for rennet, to coagulate milk in cheese making. Ashwagandha in Sanskrit means "horse's smell", probably originating from the odor of its root which resembles that of sweaty horse.[1] The species name somnifera means "sleep-bearing" in Latin, indicating it was considered a sedative, but it has been also used for sexual vitality and as an adaptogen. Some herbalists refer to ashwagandha as Indian ginseng, since it is used in ayurvedic medicine in a way similar to that ginseng is used in traditional Chinese medicine. Seven American and four Japanese firms have filed for grant of patents on formulations containing extracts of the herb Ashwagandha. Fruits, leaves and seeds of the Indian medicinal plant withania somnifera have been traditionally used for the Ayurvedic system as aphrodisiacs, diuretics and for treating memory loss. The Japanese patent applications are related to the use of the herb as a skin ointment and for promoting reproductive fertility. The U.S based company Natreon has also obtained a patent for an Ashwagandha extract. Another US establishment, the New England Deaconess Hospital, has taken a patent on an Ashwagandha formulation claimed to alleviate symptoms associated with arthritis.[1]. The product called "ashwagandha oil" is a combination of ashwagandha with almond oil and rose water designed to be used as a facial toner, therefore should not be consumed. ## Active Constituents All chemicals listed pertain to the root unless otherwise specified, as the root is the part used. Anaferine (Alkaloid), Anahygrine (Alkaloid), Beta-Sisterol, Chlorogenic acid (in leaf only), Cysteine (in fruit), Cuscohygrine (Alkaloid), Iron, Pseudotropine (Alkaloid), Scopoletin, Somniferinine (Alkaloid), Somniferiene (Alkaloid), Tropanol (Alkaloid), Withanine (Alkaloid), Withananine (Alkaloid) and Withanolides A-Y(Steroidal lactones)[2][3] # History Robin Lane Fox, in his biography of Alexander the Great, claims Withania somnifera was used in wine in ancient times. According to Anne Van Arsdall, Withania somnifera was called apollinaris and also glofwyrt in The Old English Herbarium, and had a legend that Apollo found it first and gave it to the healer Aesculapius. The main constituents of ashwagandha are alkaloids and steroidal lactones. Among the various alkaloids, withanine is the main constituent. The other alkaloids are somniferine, somnine, somniferinine, withananine, pseudo-withanine, tropine, pseudo-tropine, 3-a-gloyloxytropane, choline, cuscohygrine, isopelletierine, anaferine and anahydrine. Two acyl steryl glucoside viz. Sitoindoside VII and sitoindoside VIII have been isolated from root. The leaves contain steroidal lactones, which are commonly called withanolides. The withanolides have C28 steroidal nucleus with C9 side chain, having six membered lactone ring. Thakur ''et al.( 1987) has described Withania somnifera in their book on major medicinal plants of India, while Puri (2002) has given various recipes in which ashwagndha is an important ingredient Puri (2003) in his book on RASAYANA has given monographic account of this adaptogenic plant. After botanical study, he has given various uses of this herb in Ayurveda, important Ayurvedic preparations and therapeutic indications and pharmacological activities. The author has cited about a hundred references. # Other species There are over 20 other species of the Withania genus that occur in the dry parts of India, North Africa, Middle East, and the Mediterranean. These include Withania coagulens and Withania simonii, the roots of which are sometimes used interchangeably with those of Withania somnifera. Withania somnifera itself has been extensively domesticated from the wild form. In India, at least five different cultivars have been developed for increased root size and adaptation to different climates. # External links - Aashwagandha Information	https://www.wikidoc.org/index.php/Ashwagandha
30d91b7f640b566417122c309b003401c4d5570c	wikidoc	Aspergillus	Aspergillus # Overview Aspergillosis is caused by the fungus Aspergillus, commonly A. fumigatus. Aspergillus is ubiquitous in the environment. # Causes Aspergillosis is caused by the fungus Aspergillus: Common Aspergillus species involved in human disease include the following: - A. fumigatus (most common) - A. flavus - A. clavatus - A. parasiticus - A. oryzae - A. terreus - A. nidulans - A. niger # Taxonomy Eukaryota; Fungi/Metazoa group; Fungi; Ascomycota; Pezizomycotina; Eurotiomycetes; Eurotiales; Trichocomaceae; mitosporic Trichomaceae # Reservoir - Aspergillus is ubiquitous in the environment. - Aspergillus can be found in soil, decomposing plant matter, household dust, building materials, plants, food, and water. # Transmission - Transmission occurs through inhalation of airborne conidia. - Hospital-acquired infections may be sporadic or may be associated with dust exposure during building renovation or construction. - Occasional outbreaks of cutaneous infection have been traced to contaminated biomedical devices. # Incubation Period The incubation period for aspergillosis is unclear and likely varies depending on the dose of Aspergillus and the host immune response. # Associated Diseases Aspergillus may cause any of the following clinical syndromes depending on the host immune responses: - Allergic bronchopulmonary aspergillosis - Allergic Aspergillus sinusitis - Aspergilloma - Chronic pulmonary aspergillosis - Invasive aspergillosis - Cutaneous aspergillosis To learn how to distinguish between the Aspergillus clinical syndromes, click here. # Gallery - This micrograph reveals a fertilized egg of the round worm Ascaris lumbricoides; Mag. 400X. From Public Health Image Library (PHIL). - Under a relatively low magnification of 30X, this micrograph of a growing colony of Aspergillus alliaceus revealed some of the ultrastructural characteristics including the presence of sclerotia and conidial heads. From Public Health Image Library (PHIL). - This photomicrograph reveals some of the ultrastructural morphology displayed by the fungal organism Aspergillus fumigatus. Of particular importance is the filamentous conidiophore, which ends in a bulbous, spheroid-shaped vesicle. From Public Health Image Library (PHIL). - Under a magnification of 125X, this illustration depicts the ultrastructural details found in the common mold, Aspergillus including the organism’s septate hyphae, conidiophores, which support the apparatus. From Public Health Image Library (PHIL). - This digitally-colorized scanning electron micrograph (SEM) depicts numbers of chains of Aspergillus specie fungal conidiospores. From Public Health Image Library (PHIL). - This digitally-colorized scanning electron micrograph (SEM) depicts numbers of chains of Aspergillus specie fungal conidiospores. From Public Health Image Library (PHIL). - This scanning electron micrograph (SEM) depicts numbers of round asexual Aspergillus sp. fungal fruiting bodies situated amongst a patch of the organism’s septate hyphae. Numbers of chains of conidiospores are visible in this view. From Public Health Image Library (PHIL). - This scanning electron micrograph (SEM) depicts numbers of round asexual Aspergillus sp. fungal fruiting bodies situated amongst a patch of the organism’s septate hyphae. From Public Health Image Library (PHIL). - Magnified 562X this photomicrograph, stained using a fluorescent antibody (FA) staining technique (NOT stained using a “Candida” conjugate) revealed the presence of Aspergillus sp. organisms, in a case of aspergillosis. From Public Health Image Library (PHIL). - Magnified 562X this photomicrograph, stained using an “Aspergillus” conjugate fluorescent antibody (FA) staining technique, revealed the presence of Aspergillus sp. organisms, in a case of aspergillosis. From Public Health Image Library (PHIL). - This photomicrograph revealed the presence of Aspergillus fumigatus fungal organisms in a brain tissue, methenamine silver-stained specimen harvested from a turkey poult that had contracted this infection. From Public Health Image Library (PHIL). - This micrograph depicts the histopathologic features of aspergillosis including the presence of fungal hyphae. From Public Health Image Library (PHIL). - This micrograph depicts the histopathologic features of aspergillosis including the presence of conidia-laden conidiophores. From Public Health Image Library (PHIL). - This micrograph depicts the histopathologic features of aspergillosis including the presence of conidial heads.From Public Health Image Library (PHIL). - Note the histopathologic changes seen in aspergillosis of the lung of a caged parrot using H&E stain, which shows fungal hyphae. From Public Health Image Library (PHIL). - Note the histopathologic changes seen in aspergillosis of the lung of a caged parrot using PAS stain, which shows fungal hyphae. From Public Health Image Library (PHIL). - This was a case of pulmonary aspergillosis found in a caged sulfur-crested cockatoo due to Aspergillosis fumigatus. From Public Health Image Library (PHIL). - This photomicrograph depicts the appearance of a “rough” conidiophore of the fungus Aspergillus flavus. From Public Health Image Library (PHIL). - This photomicrograph depicts the appearance of a conidiophore of the fungus Aspergillus flavus. From Public Health Image Library (PHIL). - This photomicrograph depicts the appearance of a conidiophore of the fungus Aspergillus flavus. From Public Health Image Library (PHIL). - Note the aspergillosis associated histopathologic changes in this turkey poult brain tissue due to Aspergillus fumigatus. From Public Health Image Library (PHIL). - This photomicrograph reveals a conidiophore filament of the fungus Aspergillus fumigatus. From Public Health Image Library (PHIL). - Conidial head of an Aspergillus niger fungal organism showing a double row of sterigmata. From Public Health Image Library (PHIL). - Conidial head of an Aspergillus niger fungal organism showing a double row of sterigmata. From Public Health Image Library (PHIL). - This scanning electron micrograph (SEM) depicts numbers of chains of Aspergillus specie fungal conidiospores. From Public Health Image Library (PHIL).	Aspergillus Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Yazan Daaboul, M.D.; Haytham Allaham, M.D. [2]; Serge Korjian M.D. # Overview Aspergillosis is caused by the fungus Aspergillus, commonly A. fumigatus. Aspergillus is ubiquitous in the environment. # Causes Aspergillosis is caused by the fungus Aspergillus: Common Aspergillus species involved in human disease include the following: - A. fumigatus (most common) - A. flavus - A. clavatus - A. parasiticus - A. oryzae - A. terreus - A. nidulans - A. niger # Taxonomy Eukaryota; Fungi/Metazoa group; Fungi; Ascomycota; Pezizomycotina; Eurotiomycetes; Eurotiales; Trichocomaceae; mitosporic Trichomaceae # Reservoir - Aspergillus is ubiquitous in the environment. - Aspergillus can be found in soil, decomposing plant matter, household dust, building materials, plants, food, and water. # Transmission - Transmission occurs through inhalation of airborne conidia. - Hospital-acquired infections may be sporadic or may be associated with dust exposure during building renovation or construction. - Occasional outbreaks of cutaneous infection have been traced to contaminated biomedical devices. # Incubation Period The incubation period for aspergillosis is unclear and likely varies depending on the dose of Aspergillus and the host immune response. # Associated Diseases Aspergillus may cause any of the following clinical syndromes depending on the host immune responses: - Allergic bronchopulmonary aspergillosis - Allergic Aspergillus sinusitis - Aspergilloma - Chronic pulmonary aspergillosis - Invasive aspergillosis - Cutaneous aspergillosis To learn how to distinguish between the Aspergillus clinical syndromes, click here. # Gallery - This micrograph reveals a fertilized egg of the round worm Ascaris lumbricoides; Mag. 400X. From Public Health Image Library (PHIL). [1] - Under a relatively low magnification of 30X, this micrograph of a growing colony of Aspergillus alliaceus revealed some of the ultrastructural characteristics including the presence of sclerotia and conidial heads. From Public Health Image Library (PHIL). [1] - This photomicrograph reveals some of the ultrastructural morphology displayed by the fungal organism Aspergillus fumigatus. Of particular importance is the filamentous conidiophore, which ends in a bulbous, spheroid-shaped vesicle. From Public Health Image Library (PHIL). [1] - Under a magnification of 125X, this illustration depicts the ultrastructural details found in the common mold, Aspergillus including the organism’s septate hyphae, conidiophores, which support the apparatus. From Public Health Image Library (PHIL). [1] - This digitally-colorized scanning electron micrograph (SEM) depicts numbers of chains of Aspergillus specie fungal conidiospores. From Public Health Image Library (PHIL). [1] - This digitally-colorized scanning electron micrograph (SEM) depicts numbers of chains of Aspergillus specie fungal conidiospores. From Public Health Image Library (PHIL). [1] - This scanning electron micrograph (SEM) depicts numbers of round asexual Aspergillus sp. fungal fruiting bodies situated amongst a patch of the organism’s septate hyphae. Numbers of chains of conidiospores are visible in this view. From Public Health Image Library (PHIL). [1] - This scanning electron micrograph (SEM) depicts numbers of round asexual Aspergillus sp. fungal fruiting bodies situated amongst a patch of the organism’s septate hyphae. From Public Health Image Library (PHIL). [1] - Magnified 562X this photomicrograph, stained using a fluorescent antibody (FA) staining technique (NOT stained using a “Candida” conjugate) revealed the presence of Aspergillus sp. organisms, in a case of aspergillosis. From Public Health Image Library (PHIL). [1] - Magnified 562X this photomicrograph, stained using an “Aspergillus” conjugate fluorescent antibody (FA) staining technique, revealed the presence of Aspergillus sp. organisms, in a case of aspergillosis. From Public Health Image Library (PHIL). [1] - This photomicrograph revealed the presence of Aspergillus fumigatus fungal organisms in a brain tissue, methenamine silver-stained specimen harvested from a turkey poult that had contracted this infection. From Public Health Image Library (PHIL). [1] - This micrograph depicts the histopathologic features of aspergillosis including the presence of fungal hyphae. From Public Health Image Library (PHIL). [1] - This micrograph depicts the histopathologic features of aspergillosis including the presence of conidia-laden conidiophores. From Public Health Image Library (PHIL). [1] - This micrograph depicts the histopathologic features of aspergillosis including the presence of conidial heads.From Public Health Image Library (PHIL). [1] - Note the histopathologic changes seen in aspergillosis of the lung of a caged parrot using H&E stain, which shows fungal hyphae. From Public Health Image Library (PHIL). [1] - Note the histopathologic changes seen in aspergillosis of the lung of a caged parrot using PAS stain, which shows fungal hyphae. From Public Health Image Library (PHIL). [1] - This was a case of pulmonary aspergillosis found in a caged sulfur-crested cockatoo due to Aspergillosis fumigatus. From Public Health Image Library (PHIL). [1] - This photomicrograph depicts the appearance of a “rough” conidiophore of the fungus Aspergillus flavus. From Public Health Image Library (PHIL). [1] - This photomicrograph depicts the appearance of a conidiophore of the fungus Aspergillus flavus. From Public Health Image Library (PHIL). [1] - This photomicrograph depicts the appearance of a conidiophore of the fungus Aspergillus flavus. From Public Health Image Library (PHIL). [1] - Note the aspergillosis associated histopathologic changes in this turkey poult brain tissue due to Aspergillus fumigatus. From Public Health Image Library (PHIL). [1] - This photomicrograph reveals a conidiophore filament of the fungus Aspergillus fumigatus. From Public Health Image Library (PHIL). [1] - Conidial head of an Aspergillus niger fungal organism showing a double row of sterigmata. From Public Health Image Library (PHIL). [1] - Conidial head of an Aspergillus niger fungal organism showing a double row of sterigmata. From Public Health Image Library (PHIL). [1] - This scanning electron micrograph (SEM) depicts numbers of chains of Aspergillus specie fungal conidiospores. From Public Health Image Library (PHIL). [1]	https://www.wikidoc.org/index.php/Aspergillosis_causes
177071a2d476770682e2adae72ba97efff0fddc3	wikidoc	Interneuron	Interneuron # Overview An interneuron (also called relay neuron, association neuron or bipolar neuron) is a term used to describe a neuron which has two different common meanings. # PNS In the peripheral nervous system, an interneuron is a neuron that communicates only to other neurons. Interneurons are the neurons that provide connections between sensory and motor neurons, as well as between themselves. Contrast to sensory neurons or motor neurons, which respectively provide input from and output to the rest of the body. Interneurons are found in the grey matter. One type of peripheral interneuron is the Renshaw cell. # CNS According to the PNS definition, the neurons of the central nervous system, including the brain, are all interneurons. However, in the CNS, the term interneurons is also used for the general group of small, locally projecting neurons of the central nervous system. These neurons are typically inhibitory, and use the neurotransmitter GABA. However, excitatory interneurons also exist. One example of interneurons are inhibitory interneurons in the neocortex which selectively inhibit sections of the thalamus based on synaptic input both from other parts of the neocortex and from the thalamus itself. This is theorized to help focus higher attention on relevant sensory input and help block out behavioraly irrelevant or unchanging input, such as the sensation of the backs of your thighs on a chair. A human brain contains about 100 billion interneurons.	Interneuron Template:Infobox Anatomy Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview An interneuron (also called relay neuron, association neuron or bipolar neuron) is a term used to describe a neuron which has two different common meanings. # PNS In the peripheral nervous system, an interneuron is a neuron that communicates only to other neurons. Interneurons are the neurons that provide connections between sensory and motor neurons, as well as between themselves. Contrast to sensory neurons or motor neurons, which respectively provide input from and output to the rest of the body. Interneurons are found in the grey matter. One type of peripheral interneuron is the Renshaw cell. # CNS According to the PNS definition, the neurons of the central nervous system, including the brain, are all interneurons. However, in the CNS, the term interneurons is also used for the general group of small, locally projecting neurons of the central nervous system. These neurons are typically inhibitory, and use the neurotransmitter GABA. However, excitatory interneurons also exist. One example of interneurons are inhibitory interneurons in the neocortex which selectively inhibit sections of the thalamus based on synaptic input both from other parts of the neocortex and from the thalamus itself. This is theorized to help focus higher attention on relevant sensory input and help block out behavioraly irrelevant or unchanging input, such as the sensation of the backs of your thighs on a chair. A human brain contains about 100 billion interneurons. # External links - Template:EMedicineDictionary Template:Neuroanatomy-stub Template:Spinal cord de:Interneuron nl:Interneuron Template:WH Template:WS	https://www.wikidoc.org/index.php/Association_neurons
da9512d97763816662709ed0571c52c3546cca34	wikidoc	Astigmatism	Astigmatism In optics, astigmatism (from Greek: α- a- "without" + στίγματος stigmatos, gen. of στίγμα stigma "a mark, spot, puncture") is when an optical system has different foci for rays that propagate in two perpendicular planes. If an optical system with astigmatism is used to form an image of a cross, the vertical and horizontal lines will be in sharp focus at two different distances. # Forms of astigmatism There are two distinct forms of astigmatism. The first is a third-order aberration, which occurs for objects (or parts of objects) away from the optical axis. This form of aberration occurs even when the optical system is perfectly symmetrical. This is often referred to as a "monochromatic aberration", because it occurs even for light of a single wavelength. This terminology may be misleading, however, as the amount of aberration can vary strongly with wavelength in an optical system. The second form of astigmatism occurs when the optical system is not symmetric about the optical axis. This may be by design (as in the case of a cylindrical lens), or due to manufacturing error in the surfaces of the components or misalignment of the components. In this case, astigmatism is observed even for rays from on-axis object points. This form of astigmatism is extremely important in ophthalmology, since the human eye often exhibits this aberration due to imperfections in the shape of the cornea or the lens. ## Third-order astigmatism In the analysis of this form of astigmatism, it is most common to consider rays from a given point on the object, which propagate in two special planes. The first plane is the tangential plane. This is the plane which includes both the object point being considered and the axis of symmetry. Rays that propagate in this plane are called tangential rays. Planes that include the optical axis are meridional planes. It is common to simplify problems in radially-symmetric optical systems by choosing object points in the vertical ("y") plane only. This plane is then sometimes referred to as the meridional plane. The second special plane is the sagittal plane. This is defined as the plane, orthogonal to the tangential plane, which contains the object point being considered and intersects the optical axis at the entrance pupil of the optical system. This plane contains the chief ray, but does not contain the optic axis. It is therefore a skew plane, in other words not a meridional plane. Rays propagating in this plane are called sagittal rays. In third-order astigmatism, the sagittal and transverse rays form foci at different distances along the optic axis. These foci are called the sagittal focus and the transverse focus, respectively. In the presence of astigmatism, an off-axis point on the object is not sharply imaged by the optical system. Instead, sharp lines are formed at the sagittal and transverse foci. The image at the transverse focus is a short line, oriented in the direction of the sagittal plane; images of circles centered on the optic axis, or lines tangential to such circles, will be sharp in this plane. The image at the sagittal focus is a short line, oriented in the tangential direction; images of spokes radiating from the center are sharp at this focus. In between these two foci, a round but "blurry" image is formed. This is called the medial focus or circle of least confusion. This plane often represents the best compromise image location in a system with astigmatism. The amount of aberration due to astigmatism is proportional to the square of the angle between the rays from the object and the optical axis of the system. With care, an optical system can be designed to reduce or eliminate astigmatism. Such systems are called anastigmats. ## Astigmatism in systems that are not rotationally symmetric If an optical system is not axisymmetric, either due to an error in the shape of the optical surfaces or due to misalignment of the components, astigmatism can occur even for on-axis object points. This effect is often used deliberately in complex optical systems, especially certain types of telescope. In the analysis of these systems, it is common to consider tangential rays (as defined above), and rays in a meridional plane (a plane containing the optic axis) perpendicular to the tangential plane. This plane is called either the sagittal meridional plane or, confusingly, just the sagittal plane. ### Ophthalmic astigmatism In ophthalmology, the vertical and horizontal planes are identified as tangential and sagittal meridians, respectively. Ophthalmic astigmatism is a refraction error of the eye in which there is a difference in degree of refraction in different meridians. It is typically characterized by an aspherical, non-figure of revolution cornea in which the corneal profile slope and refractive power in one meridian is greater than that of the perpendicular axis. Astigmatism causes difficulties in seeing fine detail. In some cases vertical lines and objects such as walls may appear to the patient to be leaning over like the Tower of Pisa. Astigmatism can be often corrected by glasses with a lens that has different radii of curvature in different planes (a cylindrical lens), contact lenses, or refractive surgery. Astigmatism is quite common. Studies have shown that about one in three people suffers from it . The prevalence of astigmatism increases with age . Although a person may not notice mild astigmatism, higher amounts of astigmatism may cause blurry vision, squinting, asthenopia, fatigue, or headaches There are a number of tests used by ophthalmologists and optometrists during eye examinations to determine the presence of astigmatism and to quantify the amount and axis of the astigmatism. A Snellen chart or other eye chart may initially reveal reduced visual acuity. A keratometer may be used to measure the curvature of the steepest and flattest meridians in the cornea's front surface. A corneal topographer may also be used to obtain a more accurate representation of the cornea's shape . An autorefractor or retinoscopy may provide an objective estimate of the eye's refractive error and the use of Jackson cross cylinders in a phoropter may be used to subjectively refine those measurements . An alternative technique with the phoropter requires the use of a "clock dial" or "sunburst" chart to determine the astigmatic axis and power. ### Astigmatism due to misaligned or malformed lenses and mirrors Grinding and polishing of precision optical parts, either by hand or machine, typically employs significant downward pressure, which in turn creates significant frictional side pressures during polishing strokes that can combine to locally flex and distort the parts. These distortions generally do not possess figure-of-revolution symmetry and are thus astigmatic, and slowly become permanently polished into the surface if the problems causing the distortion are not corrected. Astigmatic, distorted surfaces potentially introduce serious degradations in optical system performance. Surface distortion due to grinding or polishing increases with the aspect ratio of the part (diameter to thickness ratio). To a first order, glass strength increases as the cube of the thickness. Thick lenses at 4:1 to 6:1 aspect ratios will flex much less than high aspect ratio parts, such as optical windows, which can have aspect ratios of 15:1 or higher. The combination of surface or wavefront error precision requirements and part aspect ratio drives the degree of back support uniformity required, especially during the higher down pressures and side forces during polishing. Optical working typically involves a degree of randomness that helps greatly in preserving figure-of-revolution surfaces, provided the part is not flexing during the grind/polish process. ### Deliberate astigmatism in optical systems Compact disc players use an astigmatic lens for focusing. When one axis is more in focus than the other, dot-like features on the disc project to oval shapes. The orientation of the oval indicates which axis is more in focus, and thus which direction the lens needs to move. A square arrangement of only four sensors can observe this bias and use it to bring the read lens to best focus, without being fooled by oblong pits or other features on the disc surface. Some telescopes use deliberately astigmatic optics.	Astigmatism Template:Seealso In optics, astigmatism (from Greek: α- a- "without" + στίγματος stigmatos, gen. of στίγμα stigma "a mark, spot, puncture"[1]) is when an optical system has different foci for rays that propagate in two perpendicular planes. If an optical system with astigmatism is used to form an image of a cross, the vertical and horizontal lines will be in sharp focus at two different distances. # Forms of astigmatism There are two distinct forms of astigmatism. The first is a third-order aberration, which occurs for objects (or parts of objects) away from the optical axis. This form of aberration occurs even when the optical system is perfectly symmetrical. This is often referred to as a "monochromatic aberration", because it occurs even for light of a single wavelength. This terminology may be misleading, however, as the amount of aberration can vary strongly with wavelength in an optical system. The second form of astigmatism occurs when the optical system is not symmetric about the optical axis. This may be by design (as in the case of a cylindrical lens), or due to manufacturing error in the surfaces of the components or misalignment of the components. In this case, astigmatism is observed even for rays from on-axis object points. This form of astigmatism is extremely important in ophthalmology, since the human eye often exhibits this aberration due to imperfections in the shape of the cornea or the lens. ## Third-order astigmatism In the analysis of this form of astigmatism, it is most common to consider rays from a given point on the object, which propagate in two special planes. The first plane is the tangential plane. This is the plane which includes both the object point being considered and the axis of symmetry. Rays that propagate in this plane are called tangential rays. Planes that include the optical axis are meridional planes. It is common to simplify problems in radially-symmetric optical systems by choosing object points in the vertical ("y") plane only. This plane is then sometimes referred to as the meridional plane. The second special plane is the sagittal plane. This is defined as the plane, orthogonal to the tangential plane, which contains the object point being considered and intersects the optical axis at the entrance pupil of the optical system. This plane contains the chief ray, but does not contain the optic axis. It is therefore a skew plane, in other words not a meridional plane. Rays propagating in this plane are called sagittal rays. In third-order astigmatism, the sagittal and transverse rays form foci at different distances along the optic axis. These foci are called the sagittal focus and the transverse focus, respectively. In the presence of astigmatism, an off-axis point on the object is not sharply imaged by the optical system. Instead, sharp lines are formed at the sagittal and transverse foci. The image at the transverse focus is a short line, oriented in the direction of the sagittal plane; images of circles centered on the optic axis, or lines tangential to such circles, will be sharp in this plane. The image at the sagittal focus is a short line, oriented in the tangential direction; images of spokes radiating from the center are sharp at this focus. In between these two foci, a round but "blurry" image is formed. This is called the medial focus or circle of least confusion. This plane often represents the best compromise image location in a system with astigmatism. The amount of aberration due to astigmatism is proportional to the square of the angle between the rays from the object and the optical axis of the system. With care, an optical system can be designed to reduce or eliminate astigmatism. Such systems are called anastigmats. Template:Section-stub ## Astigmatism in systems that are not rotationally symmetric If an optical system is not axisymmetric, either due to an error in the shape of the optical surfaces or due to misalignment of the components, astigmatism can occur even for on-axis object points. This effect is often used deliberately in complex optical systems, especially certain types of telescope. In the analysis of these systems, it is common to consider tangential rays (as defined above), and rays in a meridional plane (a plane containing the optic axis) perpendicular to the tangential plane. This plane is called either the sagittal meridional plane or, confusingly, just the sagittal plane. ### Ophthalmic astigmatism In ophthalmology, the vertical and horizontal planes are identified as tangential and sagittal meridians, respectively. Ophthalmic astigmatism is a refraction error of the eye in which there is a difference in degree of refraction in different meridians. It is typically characterized by an aspherical, non-figure of revolution cornea in which the corneal profile slope and refractive power in one meridian is greater than that of the perpendicular axis. Astigmatism causes difficulties in seeing fine detail. In some cases vertical lines and objects such as walls may appear to the patient to be leaning over like the Tower of Pisa. Astigmatism can be often corrected by glasses with a lens that has different radii of curvature in different planes (a cylindrical lens), contact lenses, or refractive surgery. Astigmatism is quite common. Studies have shown that about one in three people suffers from it [1][2][3]. The prevalence of astigmatism increases with age [4]. Although a person may not notice mild astigmatism, higher amounts of astigmatism may cause blurry vision, squinting, asthenopia, fatigue, or headaches [5] [6] [7]. There are a number of tests used by ophthalmologists and optometrists during eye examinations to determine the presence of astigmatism and to quantify the amount and axis of the astigmatism[8]. A Snellen chart or other eye chart may initially reveal reduced visual acuity. A keratometer may be used to measure the curvature of the steepest and flattest meridians in the cornea's front surface[9]. A corneal topographer may also be used to obtain a more accurate representation of the cornea's shape [10]. An autorefractor or retinoscopy may provide an objective estimate of the eye's refractive error and the use of Jackson cross cylinders in a phoropter may be used to subjectively refine those measurements[11] [12] [13]. An alternative technique with the phoropter requires the use of a "clock dial" or "sunburst" chart to determine the astigmatic axis and power[14][15]. ### Astigmatism due to misaligned or malformed lenses and mirrors Grinding and polishing of precision optical parts, either by hand or machine, typically employs significant downward pressure, which in turn creates significant frictional side pressures during polishing strokes that can combine to locally flex and distort the parts. These distortions generally do not possess figure-of-revolution symmetry and are thus astigmatic, and slowly become permanently polished into the surface if the problems causing the distortion are not corrected. Astigmatic, distorted surfaces potentially introduce serious degradations in optical system performance. Surface distortion due to grinding or polishing increases with the aspect ratio of the part (diameter to thickness ratio). To a first order, glass strength increases as the cube of the thickness. Thick lenses at 4:1 to 6:1 aspect ratios will flex much less than high aspect ratio parts, such as optical windows, which can have aspect ratios of 15:1 or higher. The combination of surface or wavefront error precision requirements and part aspect ratio drives the degree of back support uniformity required, especially during the higher down pressures and side forces during polishing. Optical working typically involves a degree of randomness that helps greatly in preserving figure-of-revolution surfaces, provided the part is not flexing during the grind/polish process. ### Deliberate astigmatism in optical systems Compact disc players use an astigmatic lens for focusing. When one axis is more in focus than the other, dot-like features on the disc project to oval shapes. The orientation of the oval indicates which axis is more in focus, and thus which direction the lens needs to move. A square arrangement of only four sensors can observe this bias and use it to bring the read lens to best focus, without being fooled by oblong pits or other features on the disc surface. Some telescopes use deliberately astigmatic optics. Template:Section-stub	https://www.wikidoc.org/index.php/Astigmatism
27ab6565cab3dda10831c968ddc393af199152b7	wikidoc	Astraphobia	Astraphobia # Overview Astraphobia, also known as astrapophobia, brontophobia, keraunophobia, or tonitrophobia, is an abnormal fear of thunder and lightning, a type of specific phobia. It is a treatable phobia that both humans and animals can develop. The term astraphobia derives from the Greek words ἀστραπή (astrape; lightning) and φόβος (phobos; fear). # Symptoms A person with astraphobia will often feel anxious during a thunderstorm even when they understand that the threat to them is minimal. Some symptoms are those accompanied with many phobias, such as trembling, crying, sweating, panicked reactions, the sudden feeling of using the bathroom, nausea, the feeling of dread, and rapid heartbeat. However, there are some reactions that are unique to astraphobia. For instance, reassurance from other people is usually sought, and symptoms worsen when alone. Many people who have astraphobia will look for extra shelter from the storm. They might hide underneath a bed, under the covers, in a closet, in a basement, or any other space where they feel safer. Efforts are usually made to smother the sound of the thunder; the person may cover their ears or curtain the windows. A sign that someone has astraphobia is a very heightened interest in Weather forecasting\|weather forecasts. An astraphobic person will be alert for news of incoming storms. They may watch the weather on television constantly during rainy bouts and may even track thunderstorms online. This can become severe enough that the person may not go outside without checking the weather first. In very extreme cases, astraphobia can lead to agoraphobia, the fear of leaving the home. # Children A 2007 study found astraphobia the third most prevalent phobia in the US. It can occur in people of any age. It occurs in many children, and should not be immediately identified as a phobia because children naturally go through many fears as they mature. Their fear of thunder and lightning cannot be considered a fully developed phobia unless it persists for more than six months. In this case, the child's phobia should be addressed, for it may become a serious problem in adulthood. To lessen a child's fear during thunderstorms, the child can be distracted by games and activities. A bolder approach is to treat the storm as an entertainment; a fearless adult is an excellent role model for children. Sometimes children cannot be attracted to video games and activities while a thunderstorm is happening. Some children usually go to basements and other places that are quiet. # Treatment The most widely used and possibly the most effective treatment for astraphobia is exposure to thunderstorms and eventually building an immunity. Cognitive behavioral therapy is also often used to treat astraphobia. The patient will in many cases be instructed to repeat phrases to himself or herself in order to become calm during a storm. Heavy breathing exercises can reinforce this effort. # Dogs and cats Dogs may exhibit severe anxiety during thunderstorms; between 15 and 30 percent may be affected. Research confirms high levels of cortisol - a hormone associated with stress - affects dogs during and after thunderstorms. Remedies include behavioral therapies such as counter conditioning and desensitization, anti-anxiety medications, and Dog Appeasing Pheromone, a synthetic analogue of a hormone secreted by nursing canine mothers. Studies have also shown that cats can be afraid of thunderstorms. Whilst it is very rare, cats have been known to hide under a table or behind a couch during a thunderstorm. Generally if any animal is anxious during a thunderstorm or any similar, practically harmless event (e.g. fireworks display), it is advised to simply continue behaving normally, instead of attempting to comfort animals. Showing fearlessness is, arguably, the best method to "cure" the anxiety.	Astraphobia Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview Astraphobia, also known as astrapophobia, brontophobia, keraunophobia, or tonitrophobia, is an abnormal fear of thunder and lightning, a type of specific phobia. It is a treatable phobia that both humans and animals can develop. The term astraphobia derives from the Greek words ἀστραπή (astrape; lightning) and φόβος (phobos; fear). # Symptoms A person with astraphobia will often feel anxious during a thunderstorm even when they understand that the threat to them is minimal. Some symptoms are those accompanied with many phobias, such as trembling, crying, sweating, panicked reactions, the sudden feeling of using the bathroom, nausea, the feeling of dread, and rapid heartbeat. However, there are some reactions that are unique to astraphobia. For instance, reassurance from other people is usually sought, and symptoms worsen when alone. Many people who have astraphobia will look for extra shelter from the storm.[1] They might hide underneath a bed, under the covers, in a closet, in a basement, or any other space where they feel safer. Efforts are usually made to smother the sound of the thunder; the person may cover their ears or curtain the windows. A sign that someone has astraphobia is a very heightened interest in Weather forecasting\|weather forecasts. An astraphobic person will be alert for news of incoming storms. They may watch the weather on television constantly during rainy bouts and may even track thunderstorms online. This can become severe enough that the person may not go outside without checking the weather first. In very extreme cases, astraphobia can lead to agoraphobia, the fear of leaving the home. # Children A 2007 study found astraphobia the third most prevalent phobia in the US.[2] It can occur in people of any age. It occurs in many children, and should not be immediately identified as a phobia because children naturally go through many fears as they mature. Their fear of thunder and lightning cannot be considered a fully developed phobia unless it persists for more than six months. In this case, the child's phobia should be addressed, for it may become a serious problem in adulthood. To lessen a child's fear during thunderstorms, the child can be distracted by games and activities. A bolder approach is to treat the storm as an entertainment; a fearless adult is an excellent role model for children. Sometimes children cannot be attracted to video games and activities while a thunderstorm is happening. Some children usually go to basements and other places that are quiet. # Treatment The most widely used and possibly the most effective treatment for astraphobia is exposure to thunderstorms and eventually building an immunity. Cognitive behavioral therapy is also often used to treat astraphobia.[3] The patient will in many cases be instructed to repeat phrases to himself or herself in order to become calm during a storm. Heavy breathing exercises can reinforce this effort. # Dogs and cats Dogs may exhibit severe anxiety during thunderstorms; between 15 and 30 percent may be affected.[4] Research confirms high levels of cortisol - a hormone associated with stress - affects dogs during and after thunderstorms.[4] Remedies include behavioral therapies such as counter conditioning and desensitization, anti-anxiety medications, and Dog Appeasing Pheromone, a synthetic analogue of a hormone secreted by nursing canine mothers.[5] Studies have also shown that cats can be afraid of thunderstorms. Whilst it is very rare, cats have been known to hide under a table or behind a couch during a thunderstorm.[6] Generally if any animal is anxious during a thunderstorm or any similar, practically harmless event (e.g. fireworks display), it is advised to simply continue behaving normally, instead of attempting to comfort animals. Showing fearlessness is, arguably, the best method to "cure" the anxiety.	https://www.wikidoc.org/index.php/Astraphobia
36555394ba6b9989341d24bb60013523c27b67af	wikidoc	Atelophobia	Atelophobia # Overview Atelophobia is the fear of not being good enough or imperfection. Atelophobia is classified as an anxiety disorder that can affect relationships and makes the afflicted person feel like everything they do is wrong. The term comes from the Template:Language with name atelès, meaning "imperfect" or "incomplete" and φόβος, phóbos, "fear". # Symptoms Symptoms of atelophobia can be mental, emotional, and physical. The severity of the symptoms varies, but because atelophobia is a mental illness, problems are created in the mind and the body reacts with physical symptoms such as sweating. Following is a list of various symptoms: ## Mental - Difficulty thinking about anything other than the fear - Feelings of unreality or of being detached from oneself - Fear of failing - Pessimistic view on the outcome of situations before it happens - Low self-esteem - Extreme disappointment if one fails at something - Responding unrealistically to a situation ## Emotional - Constant worrying about upcoming activities - An overbearing amount of fear - Unhealthy emotions, such as anger, sadness, jealousy and hurt - The desire to abruptly leave the situation ## Physical - Perspiration due to stress - Nausea - Panic attacks - Dizziness - Accelerated heart rate - Chest pains - Hot or cold flashes - Numbness or tingling feelings - Trembling or shaking - Shortness of breath - Insomnia - Increased muscle tension - Dryness of mouth - Constant restlessness These symptoms are important to pay attention to because mental illness is harder to recognize within patients than physical ailments. In order to diagnose a person with atelophobia, it is important to observe their reactions to failure. # Treatment When a patient suspects that they have a phobia the first step to recovery is talking to a health care professional. To help a patient deal with their mental disorder there are an array of methods. ## Exposure therapy The type of therapy most often used in the treatment of phobias is called exposure therapy. Exposure therapy is a form of cognitive-behavioral therapy. The treatment involves the patient exposing themselves to highly stressful situations involving the distinct phobia to overcome their anxiety. The technique involves five steps; evaluations, feedback, develop fear hierarchy, exposure and building. The evaluation step involves describing the specific fear to a therapist and recollecting events in their past that may have contributed to it. Next the therapist offers an evaluation of the particular phobia and proposes a plan for treatment. The patient then needs to develop fear hierarchy. This is when the patient and therapist create a list of scenarios involving the fear, each more intense than the last. The exposure step is when patients expose themselves to their lists of fears with the hope that encountering them one by one will lessen the panic they feel. Lastly, a patient builds upon their skills by facing more difficult situations as their tolerance grows. The effectiveness of exposure therapy is dependent on the patient, the therapist, and their working relationship, but with time many people are successful. The difficulty with this therapy is finding a trustworthy therapist who can help the patient through these intensely difficult situations. Using additional cognitive-behavioral therapy techniques can help. Therapists can help patients through breathing and relaxation exercises to reduce fear while teaching them that their thoughts of perfection are unrealistic. The problems with exposure therapy are the techniques used may be unnecessary and cruel and in certain patients become more paranoid. Other therapies available are self-help, talk therapy, behavioral therapy and medication. Self-help is when people take their problem into their own hands. The benefit of this is that the patient is the only person who can cure their disease, rather than a temporary fix. Talk therapy is when the patient talks out their problems to a psychiatrist. ## Behavior therapy Behavior therapy involves exercises to alter the patient’s inappropriate patterns of thinking they have developed and the behavior that stems from them. Lastly, if all else fails patients can turn to medication monitored by a medical professional. # Coping Like any other phobia, atelophobia is an obstacle in the path of normal life. While normal people compete with others, win and lose, show off their talents and communicate with one another with ease, an atelophobic person finds their life in jeopardy when they have to face other people. This makes living with atelophobia very difficult. While competition may be considered a natural thing for most people, it may be problematic for an atelophobic person. When a normal person loses, they may be disappointed, but they overcome it and are able to control their feelings. When a person living with atelophobia faces a failure, they are unable to bear it. They become extremely disappointed and start doubting their own abilities. They start to think that they will never be able to do that thing properly. They consider themselves to be stupid and to not have the capability to do anything properly. This doubt further masks their abilities. While an atelophobic person might have talents and intelligence, this lack of self-confidence negates them. A person with atelophobia will hold grudges and will be hurt, mad, and depressed. A person afflicted with atelophobia is able to do little to help themselves as they move further into depression with every disappointment. Living with atelophobia gets worse as the person is unable to cope with other people in their surrounding and cannot communicate with friends or relatives, thus relationships end up in a state of disrepair.	Atelophobia Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview Atelophobia is the fear of not being good enough or imperfection.[1] Atelophobia is classified as an anxiety disorder that can affect relationships and makes the afflicted person feel like everything they do is wrong.[citation needed] The term comes from the Template:Language with name atelès, meaning "imperfect" or "incomplete" and φόβος, phóbos, "fear". # Symptoms Symptoms of atelophobia can be mental, emotional, and physical. The severity of the symptoms varies, but because atelophobia is a mental illness, problems are created in the mind and the body reacts with physical symptoms such as sweating. Following is a list of various symptoms: ## Mental - Difficulty thinking about anything other than the fear - Feelings of unreality or of being detached from oneself - Fear of failing - Pessimistic view on the outcome of situations before it happens - Low self-esteem - Extreme disappointment if one fails at something - Responding unrealistically to a situation ## Emotional - Constant worrying about upcoming activities - An overbearing amount of fear - Unhealthy emotions, such as anger, sadness, jealousy and hurt - The desire to abruptly leave the situation ## Physical - Perspiration due to stress - Nausea - Panic attacks - Dizziness - Accelerated heart rate - Chest pains - Hot or cold flashes - Numbness or tingling feelings - Trembling or shaking - Shortness of breath - Insomnia - Increased muscle tension - Dryness of mouth - Constant restlessness These symptoms are important to pay attention to because mental illness is harder to recognize within patients than physical ailments. In order to diagnose a person with atelophobia, it is important to observe their reactions to failure.[citation needed] # Treatment When a patient suspects that they have a phobia the first step to recovery is talking to a health care professional. To help a patient deal with their mental disorder there are an array of methods. ## Exposure therapy The type of therapy most often used in the treatment of phobias is called exposure therapy.[citation needed] Exposure therapy is a form of cognitive-behavioral therapy. The treatment involves the patient exposing themselves to highly stressful situations involving the distinct phobia to overcome their anxiety. The technique involves five steps; evaluations, feedback, develop fear hierarchy, exposure and building. The evaluation step involves describing the specific fear to a therapist and recollecting events in their past that may have contributed to it. Next the therapist offers an evaluation of the particular phobia and proposes a plan for treatment. The patient then needs to develop fear hierarchy. This is when the patient and therapist create a list of scenarios involving the fear, each more intense than the last. The exposure step is when patients expose themselves to their lists of fears with the hope that encountering them one by one will lessen the panic they feel. Lastly, a patient builds upon their skills by facing more difficult situations as their tolerance grows. The effectiveness of exposure therapy is dependent on the patient, the therapist, and their working relationship, but with time many people are successful. The difficulty with this therapy is finding a trustworthy therapist who can help the patient through these intensely difficult situations. Using additional cognitive-behavioral therapy techniques can help. Therapists can help patients through breathing and relaxation exercises to reduce fear while teaching them that their thoughts of perfection are unrealistic. The problems with exposure therapy are the techniques used may be unnecessary and cruel and in certain patients become more paranoid. Other therapies available are self-help, talk therapy, behavioral therapy and medication. Self-help is when people take their problem into their own hands. The benefit of this is that the patient is the only person who can cure their disease, rather than a temporary fix. Talk therapy is when the patient talks out their problems to a psychiatrist. ## Behavior therapy Behavior therapy involves exercises to alter the patient’s inappropriate patterns of thinking they have developed and the behavior that stems from them. Lastly, if all else fails patients can turn to medication monitored by a medical professional. # Coping Like any other phobia, atelophobia is an obstacle in the path of normal life. While normal people compete with others, win and lose, show off their talents and communicate with one another with ease, an atelophobic person finds their life in jeopardy when they have to face other people. This makes living with atelophobia very difficult. While competition may be considered a natural thing for most people, it may be problematic for an atelophobic person. When a normal person loses, they may be disappointed, but they overcome it and are able to control their feelings. When a person living with atelophobia faces a failure, they are unable to bear it. They become extremely disappointed and start doubting their own abilities. They start to think that they will never be able to do that thing properly. They consider themselves to be stupid and to not have the capability to do anything properly. This doubt further masks their abilities. While an atelophobic person might have talents and intelligence, this lack of self-confidence negates them. A person with atelophobia will hold grudges and will be hurt, mad, and depressed. A person afflicted with atelophobia is able to do little to help themselves as they move further into depression with every disappointment. Living with atelophobia gets worse as the person is unable to cope with other people in their surrounding and cannot communicate with friends or relatives, thus relationships end up in a state of disrepair.[citation needed]	https://www.wikidoc.org/index.php/Atelophobia
624145b91ecf4f2546dbaf03ea65ddfdf501a2d1	wikidoc	Athymhormia	Athymhormia # Overview Athymhormia is a disorder of motivation, one of that class of neuro-psychiatric conditions marked by abnormalities or deficiencies in motivation. Symptoms include the loss or reduction of desire and interest toward previous motivations, loss of drive and the desire for satisfaction, curiosity, the loss of tastes and preferences, and flat affect. In athymhormia, however, these phenomena are not accompanied by the characterizing features of depression nor by any notable abnormality in intellectual or cognitive function. # Historical Perspective The diagnostic category was coined in 1922 by the French psychiatrists Dide and Guiraud, originally in reference to the behavior identified in some schizophrenic patients. # Etiology The etiology of this condition has been hypothesised to derive from abnormalities in the limbic frontal cortex, the striatum, globus pallidus, and dorso-medial thalamic nucleus. In the context of the theory of those who propose the existence of a distinct neural pathway for mood and interest, or the "hormothymic" system, athymhormia may be a disorder of this system. # Further Reading - Patrick Verstichel and Pascale Larrouy. "Drowning Mr. M." Scientific American Mind. April 2005.	Athymhormia Template:Search infobox Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview Athymhormia is a disorder of motivation, one of that class of neuro-psychiatric conditions marked by abnormalities or deficiencies in motivation. Symptoms include the loss or reduction of desire and interest toward previous motivations, loss of drive and the desire for satisfaction, curiosity, the loss of tastes and preferences, and flat affect. In athymhormia, however, these phenomena are not accompanied by the characterizing features of depression nor by any notable abnormality in intellectual or cognitive function. # Historical Perspective The diagnostic category was coined in 1922 by the French psychiatrists Dide and Guiraud, originally in reference to the behavior identified in some schizophrenic patients. # Etiology The etiology of this condition has been hypothesised to derive from abnormalities in the limbic frontal cortex, the striatum, globus pallidus, and dorso-medial thalamic nucleus. In the context of the theory of those who propose the existence of a distinct neural pathway for mood and interest, or the "hormothymic" system, athymhormia may be a disorder of this system. # Further Reading - Patrick Verstichel and Pascale Larrouy. "Drowning Mr. M." Scientific American Mind. April 2005. # External Links - Habib M, Poncet M. Loss of vitality, of interest and of the affect (athymhormia syndrome) in lacunar lesions of the corpus striatum. Rev Neurol (Paris). 1988;144(10):571-7. (article in French, abstract in English) - Current Journal: Current Opinion in Neurology - Volume 15(1) - Text of the William Feinberg Lecture 2002 - "Athymhormia and Disorders of Motivation in Basal Ganglia Disease" Template:WikiDoc Sources	https://www.wikidoc.org/index.php/Athymhormia
8ef8eea7d20157ed2ef429ec23fee7248d300802	wikidoc	Atomexitine	Atomexitine # Overview Atomoxetine is a drug approved for the treatment of attention-deficit hyperactivity disorder (ADHD). It is a selective norepinephrine reuptake inhibitor or NRI, not to be confused with selective serotonin and norepinephrine reuptake inhibitors (SNRIs) or selective serotonin reuptake inhibitors (SSRIs), both of which are currently the most prescribed form of antidepressants. This compound is manufactured, marketed and sold in the United States under the brand name Strattera by Eli Lilly and Company as a hydrochloride salt (atomoxetine HCl), the original patent filing company, and current U.S. patent owner. Generics of atomoxetine are sold in all other countries; they are manufactured by Torrent Pharmaceuticals using the label Tomoxetin, Ranbaxy Laboratories (through its Division: Solus) using the label Attentin, Sun Pharmaceuticals (through its Division: Milmet Pharmaceuticals), and Intas Biopharmaceuticals. There is currently no generic manufactured directly in the United States since it is under patent until 2017. On August 12, 2010, Lilly lost a lawsuit that challenged Lilly's patent on Strattera, increasing the likelihood of an earlier entry of a generic into the US market. On September 1, 2010, Sun Pharmaceuticals announced it would begin manufacturing a generic in the United States. In a July 29, 2011 conference call, however, Sun Pharmaceutical's Chairman stated "Lilly won that litigation on appeal so I think ’s deferred." # Use Classified as a norepinephrine (noradrenaline) reuptake inhibitor, atomoxetine is approved for use in children, adolescents, and adults. However, its efficacy has not been studied in children under six years old. Its advantage over stimulants for the treatment of ADHD is that it has less abuse potential than stimulants, is not scheduled as a controlled substance, and has shown in clinical trials to offer 24-hour coverage of symptoms associated with ADHD in adults and children. Initial therapeutic effects of atomoxetine may take at least a week to be felt. Atomoxetine should be taken for 6–8 weeks before deciding whether it is effective or not. Many people respond to atomoxetine who don't respond to stimulants (for ADHD). Atomoxetine may be preferred over amphetamine-based stimulants in patients with psychiatric disorders, those who cannot tolerate stimulants, and those with a substance misuse recurring history. Stimulant drugs are not recommended for ADHD patients who suffer from nervous disorders like facial tics, spasms, etc. In such cases Atomoxetine is the better choice. Therapy is usually initiated by gradually increasing the dose to minimize typically minor side effects. As well, some individuals are sensitive to lower doses. If the individual is on stimulants, a gradual titration down of the stimulant dose may be prescribed to minimize side effects. Another benefit of this drug is that even if discontinued, there are no known withdrawal symptoms. Strattera was originally intended to be a new antidepressant drug; however, in clinical trials, no such benefits could be proven. Since norepinephrine is believed to play a role in ADHD, Strattera was tested – and subsequently approved – as an ADHD treatment. # Nomenclature Atomoxetine was originally known as "tomoxetine". However, the U.S. Food and Drug Administration (FDA) requested the name be changed because, in their opinion, the similarity of "tomoxetine" to "tamoxifen" (a breast cancer drug) could lead to dispensing errors at pharmacies. # Pharmacology Atomoxetine inhibits NET, SERT and DAT with respective Ki values of 5, 77 and 1451 nM. In microdialysis studies it increased NE and DA levels by 3 fold in the prefrontal cortices but did not alter DA levels in the striatum or nucleus accumbens. Atomoxetine also acts as an NMDA-receptor antagonist at clinically relevant doses. The role of NMDA-receptor antagonism in atomoxetine's therapeutic profile remains to be further elucidated, however recent literature has further implicated glutaminergic dysfunction as central in ADHD pathophysiology and etiology. Atomoxetine has little affinity for serotonergic, cholinergic, and adrenergic receptors. # Chemistry and composition Atomoxetine is designated chemically as (-)-N-methyl-3-phenyl-3-(o-tolyloxy)-propylamine hydrochloride, and has a molecular mass of 291.82. It has a solubility of 27.8 mg/mL in water. Atomoxetine is a white solid that exists as a granular powder inside the capsule, along with pre-gelatinized starch and dimethicone. The capsule shells contain gelatin, sodium lauryl sulfate, FD&C Blue No. 2, synthetic yellow iron oxide, titanium dioxide, red iron oxide, edible black ink, and trace amounts of other inactive ingredients. # Therapeutic efficacy Once- or twice-daily atomoxetine was effective in the short-term treatment of ADHD in children and adolescents, as observed in several placebo-controlled trials. A single morning dose was shown to be effective into the evening, and discontinuation of atomoxetine was not associated with symptom rebound. # Side effects The side effects include, dry mouth, tiredness, irritability, nausea, decreased appetite, constipation, dizziness, sweating, dysuria, sexual problems, decreased libido, urinary retention or hesitancy, increased obsessive behavior, weight changes, slowed growth in children, palpitations, increases in heart rate and blood pressure. Confirmed cases of severe liver damage have been reported by Eli Lilly and Company. A black box warning was issued by the FDA in 2004. Other side effects can include psychosis, mood swings, mood disorders, depression, abnormal thought patterns, suicidal thoughts or tendencies, and self injury. ## Discontinuation effects Strattera can be discontinued without being tapered. ## Psychiatric reactions Strattera is included on the Black Triangle List for drugs under intensive surveillance, maintained by the British Medicines and Healthcare Products Regulatory Agency (MHRA). It has had this listing since 2004. "The MHRA assesses the Black Triangle status of a product usually two years after marketing. However, there is no standard time for a product to retain Black Triangle status. The symbol is not removed until the safety of the drug is well established." In a further release by the MHRA of the Strattera (Atomoxetine) Risk Benefit Assessment, under the Freedom of Information act, on 9 December 2005, it was noted: In the March 2009 issue of its Drug Safety Update, the MHRA declared that, after "continued case reports of possible nervous-system and psychiatric adverse effects prompted a review of data from all sources", it advised, "Atomoxetine is associated with treatment-emergent psychotic or manic symptoms in children and adolescents without a history of such disorders." On 1 August 2006, an article was published by Janne Larsson, in which he states an MHRA document was ordered made public by a court in Sweden. In it is revealed, according to Larsson, that Eli Lilly received 10,998 reports of adverse psychiatric reactions in a period of three years. # Potential for abuse To date, the potential for abuse of Strattera has not been researched extensively. The two studies that have been performed suggest that atomoxetine has a low to moderate risk for abuse, since it has a long titration time (meaning that it may have no effect on the user unless they've been taking it regularly for days) and does not produce strong stimulating effects like most other ADHD medications. Monkeys will not self-administer atomoxetine at the doses tested. However, rats, pigeons and monkeys trained to distinguish cocaine or methamphetamine from saline indicate that atomoxetine produces effects indistinguishable from low doses of cocaine or methamphetamine, but not at all like high doses of cocaine. # Off-label uses Atomoxetine, which inhibits the reuptake of norepinephrine, was originally explored by Eli Lilly as a treatment for depression, but did not show a favorable benefit-to-risk ratio in trials. Failed clinical trials are not submitted to drug regulatory agencies and are considered trade secrets. Subsequently, Lilly then chose to pursue an ADHD treatment route for atomoxetine. Many patients have seen a pronounced anti-depressive effect in conjunction with other antidepressants. More study is needed to understand the full pharmacodynamics. # Experimental uses In 2007, 40-participant, 10-week, double-blind clinical trial was reported in the Journal of Clinical Psychiatry on the effectiveness of atomoxetine for treating binge eating disorder. The average daily dose given was 106 mg/day. At the conclusion of the trial, it was reported that atomoxetine was "associated with a significantly greater rate of reduction in binge-eating episode frequency, weight, body mass index." The authors concluded that atomoxetine is effective for short term treatment of binge eating disorder. A preliminary 12-week, randomized, double-blind, placebo-controlled trial was conducted at Duke University Medical Center which studied the effectiveness of atomoxetine on adult obese women. The study included 30 obese women with an average body mass index of 36.1. Fifteen women were given atomoxetine therapy starting at 25 mg/day with a gradual increase to 100 mg/day over 1 week. Fifteen women were given a placebo with identical dosing. By the end of the trial, the atomoxetine group lost an average of 3.6 kg (3.7% of their body mass) vs a 0.1 kg gain in the placebo group (0.2% gain). Three participants in the atomoxetine group and none in the placebo group lost greater than 5% of their mass. # Overdose Somnolence is the most common symptom of acute or chronic overdose. Other signs may include agitation, hyperactivity, abnormal behavior and gastrointestinal symptoms. Mydriasis causing blurred vision, tachycardia and dry mouth occasionally occurs as a result of overdose. Treatment of atomoxetine overdose may include gastric emptying and repeated doses of activated charcoal. However, lavage or "stomach pumping", is no longer an accepted procedure in emergency departments for overdose. Atomoxetine is highly protein bound so dialysis is unlikely to be of benefit. # Detection in biological fluids Atomoxetine may be quantitated in plasma, serum or whole blood in order to distinguish extensive versus poor metabolizers in those receiving the drug therapeutically, to confirm the diagnosis in potential poisoning victims or to assist in the forensic investigation in a case of fatal overdosage. # Synthesis First step appears to be a Mannich reaction between acetophenone, paraformaldehyde and dimethylamine, although not formally written in the scheme. Foster, B. J.; Lavagnino, E. R.; European Patent, 1982, EP 0052492 .	Atomexitine Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview Atomoxetine is a drug approved for the treatment of attention-deficit hyperactivity disorder (ADHD). It is a selective norepinephrine reuptake inhibitor or NRI, not to be confused with selective serotonin and norepinephrine reuptake inhibitors (SNRIs) or selective serotonin reuptake inhibitors (SSRIs), both of which are currently the most prescribed form of antidepressants. This compound is manufactured, marketed and sold in the United States under the brand name Strattera by Eli Lilly and Company as a hydrochloride salt (atomoxetine HCl), the original patent filing company, and current U.S. patent owner. Generics of atomoxetine are sold in all other countries; they are manufactured by Torrent Pharmaceuticals using the label Tomoxetin, Ranbaxy Laboratories (through its Division: Solus) using the label Attentin, Sun Pharmaceuticals (through its Division: Milmet Pharmaceuticals), and Intas Biopharmaceuticals. There is currently no generic manufactured directly in the United States since it is under patent until 2017.[1] On August 12, 2010, Lilly lost a lawsuit that challenged Lilly's patent on Strattera, increasing the likelihood of an earlier entry of a generic into the US market.[2] On September 1, 2010, Sun Pharmaceuticals announced it would begin manufacturing a generic in the United States.[3] In a July 29, 2011 conference call, however, Sun Pharmaceutical's Chairman stated "Lilly won that litigation on appeal so I think [generic Strattera]’s deferred."[4] # Use Classified as a norepinephrine (noradrenaline) reuptake inhibitor, atomoxetine is approved for use in children, adolescents, and adults. However, its efficacy has not been studied in children under six years old. Its advantage over stimulants for the treatment of ADHD is that it has less abuse potential than stimulants,[5][6] is not scheduled as a controlled substance, and has shown in clinical trials to offer 24-hour coverage of symptoms associated with ADHD in adults and children.[7] Initial therapeutic effects of atomoxetine may take at least a week to be felt. Atomoxetine should be taken for 6–8 weeks before deciding whether it is effective or not. Many people respond to atomoxetine who don't respond to stimulants (for ADHD). Atomoxetine may be preferred over amphetamine-based stimulants in patients with psychiatric disorders, those who cannot tolerate stimulants, and those with a substance misuse recurring history. Stimulant drugs are not recommended for ADHD patients who suffer from nervous disorders like facial tics, spasms, etc. In such cases Atomoxetine is the better choice. Therapy is usually initiated by gradually increasing the dose to minimize typically minor side effects. As well, some individuals are sensitive to lower doses. If the individual is on stimulants, a gradual titration down of the stimulant dose may be prescribed to minimize side effects.[8][9] Another benefit of this drug is that even if discontinued, there are no known withdrawal symptoms. Strattera was originally intended to be a new antidepressant drug; however, in clinical trials, no such benefits could be proven. Since norepinephrine is believed to play a role in ADHD, Strattera was tested – and subsequently approved – as an ADHD treatment. # Nomenclature Atomoxetine was originally known as "tomoxetine". However, the U.S. Food and Drug Administration (FDA) requested the name be changed because, in their opinion, the similarity of "tomoxetine" to "tamoxifen" (a breast cancer drug) could lead to dispensing errors at pharmacies. # Pharmacology Atomoxetine inhibits NET, SERT and DAT with respective Ki values of 5, 77 and 1451 nM. In microdialysis studies it increased NE and DA levels by 3 fold in the prefrontal cortices but did not alter DA levels in the striatum or nucleus accumbens.[10] Atomoxetine also acts as an NMDA-receptor antagonist at clinically relevant doses.[11] The role of NMDA-receptor antagonism in atomoxetine's therapeutic profile remains to be further elucidated, however recent literature has further implicated glutaminergic dysfunction as central in ADHD pathophysiology and etiology[citation needed]. Atomoxetine has little affinity for serotonergic, cholinergic, and adrenergic receptors.[12] # Chemistry and composition Atomoxetine is designated chemically as (-)-N-methyl-3-phenyl-3-(o-tolyloxy)-propylamine hydrochloride, and has a molecular mass of 291.82. It has a solubility of 27.8 mg/mL in water. Atomoxetine is a white solid that exists as a granular powder inside the capsule, along with pre-gelatinized starch and dimethicone. The capsule shells contain gelatin, sodium lauryl sulfate, FD&C Blue No. 2, synthetic yellow iron oxide, titanium dioxide, red iron oxide, edible black ink, and trace amounts of other inactive ingredients. # Therapeutic efficacy Once- or twice-daily atomoxetine was effective in the short-term treatment of ADHD in children and adolescents, as observed in several placebo-controlled trials. A single morning dose was shown to be effective into the evening, and discontinuation of atomoxetine was not associated with symptom rebound.[13] # Side effects The side effects include, dry mouth, tiredness, irritability, nausea, decreased appetite, constipation, dizziness, sweating, dysuria, sexual problems, decreased libido, urinary retention or hesitancy, increased obsessive behavior, weight changes, slowed growth in children, palpitations, increases in heart rate and blood pressure.[14][15][16] Confirmed cases of severe liver damage have been reported by Eli Lilly and Company. A black box warning was issued by the FDA in 2004.[17][18][19] Other side effects can include psychosis, mood swings, mood disorders, depression, abnormal thought patterns, suicidal thoughts or tendencies, and self injury.[20] ## Discontinuation effects Strattera can be discontinued without being tapered.[21] ## Psychiatric reactions Strattera is included on the Black Triangle List for drugs under intensive surveillance, maintained by the British Medicines and Healthcare Products Regulatory Agency (MHRA). It has had this listing since 2004.[citation needed] "The MHRA assesses the Black Triangle status of a product usually two years after marketing. However, there is no standard time for a product to retain Black Triangle status. The symbol is not removed until the safety of the drug is well established."[22] In a further release by the MHRA of the Strattera (Atomoxetine) Risk Benefit Assessment, under the Freedom of Information act, on 9 December 2005, it was noted: In the March 2009 issue of its Drug Safety Update, the MHRA declared that, after "continued case reports of possible nervous-system and psychiatric adverse effects prompted a review of data from all sources", it advised, "Atomoxetine is associated with treatment-emergent psychotic or manic symptoms in children and adolescents without a history of such disorders."[27] On 1 August 2006, an article was published by Janne Larsson, in which he states an MHRA document was ordered made public by a court in Sweden. In it is revealed, according to Larsson, that Eli Lilly received 10,998 reports of adverse psychiatric reactions in a period of three years.[28] # Potential for abuse To date, the potential for abuse of Strattera has not been researched extensively. The two studies that have been performed suggest that atomoxetine has a low to moderate risk for abuse, since it has a long titration time (meaning that it may have no effect on the user unless they've been taking it regularly for days) and does not produce strong stimulating effects like most other ADHD medications. Monkeys will not self-administer atomoxetine at the doses tested.[5][6] However, rats, pigeons and monkeys trained to distinguish cocaine or methamphetamine from saline indicate that atomoxetine produces effects indistinguishable from low doses of cocaine or methamphetamine, but not at all like high doses of cocaine.[29][30] # Off-label uses Atomoxetine, which inhibits the reuptake of norepinephrine, was originally explored by Eli Lilly as a treatment for depression, but did not show a favorable benefit-to-risk ratio in trials. Failed clinical trials are not submitted to drug regulatory agencies and are considered trade secrets. Subsequently, Lilly then chose to pursue an ADHD treatment route for atomoxetine. Many patients have seen a pronounced anti-depressive effect in conjunction with other antidepressants. More study is needed to understand the full pharmacodynamics.[31][32][33][34] # Experimental uses In 2007, 40-participant, 10-week, double-blind clinical trial was reported in the Journal of Clinical Psychiatry on the effectiveness of atomoxetine for treating binge eating disorder. The average daily dose given was 106 mg/day. At the conclusion of the trial, it was reported that atomoxetine was "associated with a significantly greater rate of reduction in binge-eating episode frequency, weight, [and] body mass index." The authors concluded that atomoxetine is effective for short term treatment of binge eating disorder.[35] A preliminary 12-week, randomized, double-blind, placebo-controlled trial was conducted at Duke University Medical Center which studied the effectiveness of atomoxetine on adult obese women. The study included 30 obese women with an average body mass index of 36.1. Fifteen women were given atomoxetine therapy starting at 25 mg/day with a gradual increase to 100 mg/day over 1 week. Fifteen women were given a placebo with identical dosing. By the end of the trial, the atomoxetine group lost an average of 3.6 kg (3.7% of their body mass) vs a 0.1 kg gain in the placebo group (0.2% gain). Three participants in the atomoxetine group and none in the placebo group lost greater than 5% of their mass.[36] # Overdose Somnolence is the most common symptom of acute or chronic overdose. Other signs may include agitation, hyperactivity, abnormal behavior and gastrointestinal symptoms. Mydriasis causing blurred vision, tachycardia and dry mouth occasionally occurs as a result of overdose. Treatment of atomoxetine overdose may include gastric emptying and repeated doses of activated charcoal. However, lavage or "stomach pumping", is no longer an accepted procedure in emergency departments for overdose. Atomoxetine is highly protein bound so dialysis is unlikely to be of benefit.[8] # Detection in biological fluids Atomoxetine may be quantitated in plasma, serum or whole blood in order to distinguish extensive versus poor metabolizers in those receiving the drug therapeutically, to confirm the diagnosis in potential poisoning victims or to assist in the forensic investigation in a case of fatal overdosage.[37] # Synthesis First step appears to be a Mannich reaction between acetophenone, paraformaldehyde and dimethylamine, although not formally written in the scheme. Foster, B. J.; Lavagnino, E. R.; European Patent, 1982, EP 0052492 .	https://www.wikidoc.org/index.php/Atomexitine
b281071ffd029b5a86d19c34b81d616c986c82f4	wikidoc	Atomic mass	Atomic mass The atomic mass (ma) is the mass of an atom at rest, most often expressed in unified atomic mass units. The atomic mass may be considered to be the total mass of protons, neutrons and electrons in a single atom (when the atom is motionless). The atomic mass is sometimes incorrectly used as a synonym of relative atomic mass, average atomic mass and atomic weight; however, these differ subtly from the atomic mass. The atomic mass is defined as the mass of an atom, which can only be one isotope at a time and is not an abundance-weighted average. The actual numerical difference is usually very small such that it does not affect most bulk calculations but such an error can be critical when considering individual atoms. The relative atomic mass (Ar) (also known as atomic weight and average atomic mass) is the average of the atomic masses of all the chemical element's isotopes as found in a particular environment, weighted by isotopic abundance. This is frequently used as a synonym for the standard atomic weight and is not incorrect to do so since the standard atomic weights are relative atomic masses, although it is less specific to do so. Relative atomic mass also refers to non-terrestrial environments and highly specific terrestrial environments that deviate from the average or have different certainties (number of significant figures) than the standard atomic weights. The standard atomic weight refers to the mean relative atomic mass of an element in the local environment of the Earth's crust and atmosphere as determined by the IUPAC Commission on Atomic Weights and Isotopic Abundances. These are what are included in a standard periodic table and is what is used in most bulk calculations. An uncertainty in brackets is included which often reflects natural variability in isotopic distribution rather than uncertainty in measurement. For synthetic elements the isotope formed depends on the means of synthesis, so the concept of natural isotope abundance has no meaning. Therefore, for synthetic elements the total nucleon count of the most stable isotope (ie, the isotope with the longest half-life) is listed in brackets in place of the standard atomic weight. Lithium represents a unique case where the natural abundances of the isotopes have been perturbed by human activities to the point of affecting the uncertainty in its standard atomic weight, even in samples obtained from natural sources such as rivers. The relative isotopic mass is the relative mass of the isotope, scaled with carbon-12 as exactly 12. No other isotopes have whole number masses due to the different mass of neutrons and protons, as well as loss/gain of mass to binding energy. However, since mass defect due to binding energy is minimal compared to the mass of a nucleon, rounding the atomic mass of an isotope tells you the total nucleon count. Neutron count can then be derived by subtracting the atomic number. # Mass defects in atomic masses The pattern in the amounts the atomic masses deviate from their mass numbers is as follows: the deviation starts positive at hydrogen-1, becomes negative until a minimum is reached at iron-56, iron-58 and nickel-62, then increases to positive values in the heavy isotopes, with increasing atomic number. This corresponds to the following: nuclear fission in an element heavier than iron produces energy, and fission in any element lighter than iron requires energy. The opposite is true of nuclear fusion reactions: fusion in elements lighter than iron produces energy, and fusion in elements heavier than iron requires energy. # Measurement of atomic masses Direct comparison and measurement of the masses of atoms is achieved with mass spectrometry. # Conversion factor between atomic mass units and grams The standard scientific unit for dealing with atoms in macroscopic quantities is the mole (mol), which is defined arbitrarily as the amount of a substance with as many atoms or other units as there are in 12 grams of the carbon isotope C-12. The number of atoms in a mole is called Avogadro's number, the value of which is approximately 6.022 × 10Template:Smsup. One mole of a substance always contains almost exactly the relative atomic mass or molar mass of that substance (which is the concept of molar mass), expressed in grams; however, this is almost never true for the atomic mass. For example, the standard atomic weight of iron is 55.847 g/mol, and therefore one mole of iron as commonly found on earth has a mass of 55.847 grams. The atomic mass of an 56Fe isotope is 55.935 u and one mole of 56Fe will in theory weigh 55.935g, but such amounts of pure 56Fe has never existed. The formulaic conversion between atomic mass and SI mass in grams for a single atom is: where \rm{u} is the atomic mass unit and N_A is Avogadro's number. # Relationship between atomic and molecular masses Similar definitions apply to molecules. One can compute the molecular mass of a compound by adding the atomic masses of its constituent atoms (nuclides). One can compute the molar mass of a compound by adding the relative atomic masses of the elements given in the chemical formula. In both cases the multiplicity of the atoms (the number of times it occurs) must be taken into account, usually by multiplication of each unique mass by its multiplicity. # History Before the 1960s, this was expressed so that the oxygen-16 isotope received the atomic weight 16, however, the proportions of oxygen-17 and oxygen-18 present in natural oxygen, which were also used to calculate atomic mass led to two different tables of atomic mass. Formerly chemists and physicists used two different atomic mass scales. The chemists used a scale such that the natural mixture of oxygen isotopes had an atomic mass 16, while the physicists assigned the same number 16 to the atomic mass of the most common oxygen isotope (containing eight protons and eight neutrons). The unified scale based on carbon-12, 12C, met the physicists' need to base the scale on a pure isotope, while being numerically close to the old chemists' scale. The term atomic weight is being phased out slowly and being replaced by relative atomic mass, in most current usage. The history of this shift in nomenclature reaches back to the 1960's and has been the source of much debate in the scientific community. The debate was largely created by the adoption of the unified atomic mass unit and the realization that weight was in some ways an inappropriate term. The argument for keeping the term "atomic weight" was primarily that it was a well understood term to those in the field, that the term "atomic mass" was already in use (as it is currently defined) and that the term "relative atomic mass" was in some ways redundant. In 1979, in a compromise move, the definition was refined and the term "relative atomic mass" was introduced as a secondary synonym. Twenty years later the primacy of these synonyms was reversed and the term "relative atomic mass" is now the preferred term; however the "standard atomic weights" have maintained the same name. # Table of standard atomic weights ms:Jisim atom/Jadual	Atomic mass Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] The atomic mass (ma) is the mass of an atom at rest, most often expressed in unified atomic mass units.[1] The atomic mass may be considered to be the total mass of protons, neutrons and electrons in a single atom (when the atom is motionless). The atomic mass is sometimes incorrectly used as a synonym of relative atomic mass, average atomic mass and atomic weight; however, these differ subtly from the atomic mass. The atomic mass is defined as the mass of an atom, which can only be one isotope at a time and is not an abundance-weighted average. The actual numerical difference is usually very small such that it does not affect most bulk calculations but such an error can be critical when considering individual atoms. The relative atomic mass (Ar) (also known as atomic weight and average atomic mass) is the average of the atomic masses of all the chemical element's isotopes as found in a particular environment, weighted by isotopic abundance.[2] This is frequently used as a synonym for the standard atomic weight and is not incorrect to do so since the standard atomic weights are relative atomic masses, although it is less specific to do so. Relative atomic mass also refers to non-terrestrial environments and highly specific terrestrial environments that deviate from the average or have different certainties (number of significant figures) than the standard atomic weights. The standard atomic weight refers to the mean relative atomic mass of an element in the local environment of the Earth's crust and atmosphere as determined by the IUPAC Commission on Atomic Weights and Isotopic Abundances.[3] These are what are included in a standard periodic table and is what is used in most bulk calculations. An uncertainty in brackets is included which often reflects natural variability in isotopic distribution rather than uncertainty in measurement.[4] For synthetic elements the isotope formed depends on the means of synthesis, so the concept of natural isotope abundance has no meaning. Therefore, for synthetic elements the total nucleon count of the most stable isotope (ie, the isotope with the longest half-life) is listed in brackets in place of the standard atomic weight. Lithium represents a unique case where the natural abundances of the isotopes have been perturbed by human activities to the point of affecting the uncertainty in its standard atomic weight, even in samples obtained from natural sources such as rivers. The relative isotopic mass is the relative mass of the isotope, scaled with carbon-12 as exactly 12. No other isotopes have whole number masses due to the different mass of neutrons and protons, as well as loss/gain of mass to binding energy. However, since mass defect due to binding energy is minimal compared to the mass of a nucleon, rounding the atomic mass of an isotope tells you the total nucleon count. Neutron count can then be derived by subtracting the atomic number. # Mass defects in atomic masses The pattern in the amounts the atomic masses deviate from their mass numbers is as follows: the deviation starts positive at hydrogen-1, becomes negative until a minimum is reached at iron-56, iron-58 and nickel-62, then increases to positive values in the heavy isotopes, with increasing atomic number. This corresponds to the following: nuclear fission in an element heavier than iron produces energy, and fission in any element lighter than iron requires energy. The opposite is true of nuclear fusion reactions: fusion in elements lighter than iron produces energy, and fusion in elements heavier than iron requires energy. # Measurement of atomic masses Direct comparison and measurement of the masses of atoms is achieved with mass spectrometry. # Conversion factor between atomic mass units and grams The standard scientific unit for dealing with atoms in macroscopic quantities is the mole (mol), which is defined arbitrarily as the amount of a substance with as many atoms or other units as there are in 12 grams of the carbon isotope C-12. The number of atoms in a mole is called Avogadro's number, the value of which is approximately 6.022 × 10Template:Smsup. One mole of a substance always contains almost exactly the relative atomic mass or molar mass of that substance (which is the concept of molar mass), expressed in grams; however, this is almost never true for the atomic mass. For example, the standard atomic weight of iron is 55.847 g/mol, and therefore one mole of iron as commonly found on earth has a mass of 55.847 grams. The atomic mass of an 56Fe isotope is 55.935 u and one mole of 56Fe will in theory weigh 55.935g, but such amounts of pure 56Fe has never existed. The formulaic conversion between atomic mass and SI mass in grams for a single atom is: where <math>\rm{u}</math> is the atomic mass unit and <math>N_A</math> is Avogadro's number. # Relationship between atomic and molecular masses Similar definitions apply to molecules. One can compute the molecular mass of a compound by adding the atomic masses of its constituent atoms (nuclides). One can compute the molar mass of a compound by adding the relative atomic masses of the elements given in the chemical formula. In both cases the multiplicity of the atoms (the number of times it occurs) must be taken into account, usually by multiplication of each unique mass by its multiplicity. # History Before the 1960s, this was expressed so that the oxygen-16 isotope received the atomic weight 16, however, the proportions of oxygen-17 and oxygen-18 present in natural oxygen, which were also used to calculate atomic mass led to two different tables of atomic mass. Formerly chemists and physicists used two different atomic mass scales. The chemists used a scale such that the natural mixture of oxygen isotopes had an atomic mass 16, while the physicists assigned the same number 16 to the atomic mass of the most common oxygen isotope (containing eight protons and eight neutrons). The unified scale based on carbon-12, 12C, met the physicists' need to base the scale on a pure isotope, while being numerically close to the old chemists' scale. The term atomic weight is being phased out slowly and being replaced by relative atomic mass, in most current usage. The history of this shift in nomenclature reaches back to the 1960's and has been the source of much debate in the scientific community. The debate was largely created by the adoption of the unified atomic mass unit and the realization that weight was in some ways an inappropriate term. The argument for keeping the term "atomic weight" was primarily that it was a well understood term to those in the field, that the term "atomic mass" was already in use (as it is currently defined) and that the term "relative atomic mass" was in some ways redundant. In 1979, in a compromise move, the definition was refined and the term "relative atomic mass" was introduced as a secondary synonym. Twenty years later the primacy of these synonyms was reversed and the term "relative atomic mass" is now the preferred term; however the "standard atomic weights" have maintained the same name. [5] # Table of standard atomic weights Template:PeriodicTablesKey ms:Jisim atom/Jadual Template:WikiDoc Sources	https://www.wikidoc.org/index.php/Atomic_mass
08fec7fdfa052376b906521051bd2ca7479e49f0	wikidoc	Atomization	Atomization In atomic spectroscopy, atomization stands for the conversion of a vaporized sample into atomic components. Liquid samples are first nebulized, the fine mist is transported into the atomization source (flame or plasma), where the solvent evaporates and the analyte is vaporized, then atomized. Atomization also refers to the conversion of bulk liquid into a spray or mist (i.e. collection of drops), often by passing the liquid through a nozzle. Despite the name, it does not usually imply that the particles are reduced to atomic sizes. The process can also be described as nebulization. By convention, "nebulize", "nebulization", and "nebulizer" are terms used more often in the medical/science fields. An atomizer is an atomization apparatus; carburetors, airbrushes, misters, and spray bottles are only a few examples of atomizers used ubiquitously. In internal combustion engines, fine-grained fuel atomization is instrumental to efficient combustion. In some manufacturing processes, fine powder is produced by spraying molten or dissolved materials through an atomizer and solidifying the droplets.	Atomization In atomic spectroscopy, atomization stands for the conversion of a vaporized sample into atomic components. Liquid samples are first nebulized, the fine mist is transported into the atomization source (flame or plasma), where the solvent evaporates and the analyte is vaporized, then atomized. Atomization also refers to the conversion of bulk liquid into a spray or mist (i.e. collection of drops), often by passing the liquid through a nozzle.[1] Despite the name, it does not usually imply that the particles are reduced to atomic sizes. The process can also be described as nebulization. By convention, "nebulize", "nebulization", and "nebulizer" are terms used more often in the medical/science fields. An atomizer is an atomization apparatus; carburetors, airbrushes, misters, and spray bottles are only a few examples of atomizers used ubiquitously. In internal combustion engines, fine-grained fuel atomization is instrumental to efficient combustion. In some manufacturing processes, fine powder is produced by spraying molten or dissolved materials through an atomizer and solidifying the droplets.	https://www.wikidoc.org/index.php/Atomization
48f69275c97af98490f1761ac6955a8230d45142	wikidoc	Atomoxetine	Atomoxetine # Disclaimer WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here. # Black Box Warning # Overview Atomoxetine is a selective norepinephrine reuptake inhibitor that is FDA approved for the treatment of attention-deficit/hyperactivity disorder(ADHD). There is a Black Box Warning for this drug as shown here. Common adverse reactions include nausea, vomiting, fatigue, decreased appetite, abdominal pain, and somnolence. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - Dosing Information - Acute Treatment - Atomoxetine should be initiated at a total daily dose of 40 mg and increased after a minimum of 3 days to a target total daily dose of approximately 80 mg administered either as a single daily dose in the morning or as evenly divided doses in the morning and late afternoon/early evening. After 2 to 4 additional weeks, the dose may be increased to a maximum of 100 mg in patients who have not achieved an optimal response. There are no data that support increased effectiveness at higher doses. - The maximum recommended total daily dose in adults is 100 mg. - Maintenance/Extended Treatment - It is generally agreed that pharmacological treatment of ADHD may be needed for extended periods. Patients assigned to Atomoxetine in the maintenance phase were generally continued on the same dose used to achieve a response in the open label phase. The physician who elects to use Atomoxetine for extended periods should periodically reevaluate the long-term usefulness of the drug for the individual patient. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Atomoxetine in adult patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Atomoxetine in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) - The efficacy of Atomoxetine Capsules was established in seven clinical trials in outpatients with ADHD: four 6 to 9-week trials in pediatric patients (ages 6 to 18), two 10-week trial in adults, and one maintenance trial in pediatrics (ages 6 to 15). - Diagnostic Considerations - A diagnosis of ADHD (DSM-IV) implies the presence of hyperactive-impulsive or inattentive symptoms that cause impairment and that were present before age 7 years. The symptoms must be persistent, must be more severe than is typically observed in individuals at a comparable level of development, must cause clinically significant impairment, e.g., in social, academic, or occupational functioning, and must be present in 2 or more settings, e.g., school (or work) and at home. The symptoms must not be better accounted for by another mental disorder. - The specific etiology of ADHD is unknown, and there is no single diagnostic test. Adequate diagnosis requires the use not only of medical but also of special psychological, educational, and social resources. Learning may or may not be impaired. The diagnosis must be based upon a complete history and evaluation of the patient and not solely on the presence of the required number of DSM-IV characteristics. - For the Inattentive Type, at least 6 of the following symptoms must have persisted for at least 6 months: lack of attention to details/careless mistakes, lack of sustained attention, poor listener, failure to follow through on tasks, poor organization, avoids tasks requiring sustained mental effort, loses things, easily distracted, forgetful. For the Hyperactive-Impulsive Type, at least 6 of the following symptoms must have persisted for at least 6 months: fidgeting/squirming, leaving seat, inappropriate running/climbing, difficulty with quiet activities, “on the go,” excessive talking, blurting answers, can't wait turn, intrusive. For a Combined Type diagnosis, both inattentive and hyperactive-impulsive criteria must be met. - Need for Comprehensive Treatment Program - Atomoxetine is indicated as an integral part of a total treatment program for ADHD that may include other measures (psychological, educational, social) for patients with this syndrome. Drug treatment may not be indicated for all patients with this syndrome. Drug treatment is not intended for use in the patient who exhibits symptoms secondary to environmental factors and/or other primary psychiatric disorders, including psychosis. Appropriate educational placement is essential in children and adolescents with this diagnosis and psychosocial intervention is often helpful. When remedial measures alone are insufficient, the decision to prescribe drug treatment medication will depend upon the physician's assessment of the chronicity and severity of the patient's symptoms - Dosing Information - Acute Treatment - Dosing of children and adolescents up to 70 kg body weight Atomoxetine should be initiated at a total daily dose of approximately 0.5 mg/kg and increased after a minimum of 3 days to a target total daily dose of approximately 1.2 mg/kg administered either as a single daily dose in the morning or as evenly divided doses in the morning and late afternoon/early evening. No additional benefit has been demonstrated for doses higher than 1.2 mg/kg/day. The total daily dose in children and adolescents should not exceed 1.4 mg/kg or 100 mg, whichever is less. - Atomoxetine should be initiated at a total daily dose of approximately 0.5 mg/kg and increased after a minimum of 3 days to a target total daily dose of approximately 1.2 mg/kg administered either as a single daily dose in the morning or as evenly divided doses in the morning and late afternoon/early evening. No additional benefit has been demonstrated for doses higher than 1.2 mg/kg/day. - The total daily dose in children and adolescents should not exceed 1.4 mg/kg or 100 mg, whichever is less. - Dosing of children and adolescents over 70 kg body weight Atomoxetine should be initiated at a total daily dose of 40 mg and increased after a minimum of 3 days to a target total daily dose of approximately 80 mg administered either as a single daily dose in the morning or as evenly divided doses in the morning and late afternoon/early evening. After 2 to 4 additional weeks, the dose may be increased to a maximum of 100 mg in patients who have not achieved an optimal response. There are no data that support increased effectiveness at higher doses. The maximum recommended total daily dose in children and adolescents over 70 kg. - Atomoxetine should be initiated at a total daily dose of 40 mg and increased after a minimum of 3 days to a target total daily dose of approximately 80 mg administered either as a single daily dose in the morning or as evenly divided doses in the morning and late afternoon/early evening. After 2 to 4 additional weeks, the dose may be increased to a maximum of 100 mg in patients who have not achieved an optimal response. There are no data that support increased effectiveness at higher doses. - The maximum recommended total daily dose in children and adolescents over 70 kg. - Maintenance/Extended Treatment - It is generally agreed that pharmacological treatment of ADHD may be needed for extended periods. The benefit of maintaining pediatric patients (ages 6-15 years) with ADHD on Atomoxetine after achieving a response in a dose range of 1.2 to 1.8 mg/kg/day was demonstrated in a controlled trial. Patients assigned to Atomoxetine in the maintenance phase were generally continued on the same dose used to achieve a response in the open label phase. The physician who elects to use Atomoxetine for extended periods should periodically reevaluate the long-term usefulness of the drug for the individual patient. - Dosing in Specific Populations - Dosing adjustment for hepatically impaired patients — For those ADHD patients who have hepatic insufficiency (HI), dosage adjustment is recommended as follows: For patients with moderate HI (Child-Pugh Class B), initial and target doses should be reduced to 50% of the normal dose (for patients without HI). For patients with severe HI (Child-Pugh Class C), initial dose and target doses should be reduced to 25% of normal. - Dosing adjustment for use with a strong CYP2D6 inhibitor or in patients who are known to be CYP2D6 PMs — In children and adolescents up to 70 kg body weight administered strong CYP2D6 inhibitors, e.g., paroxetine, fluoxetine, and quinidine, or in patients who are known to be CYP2D6 PMs, Atomoxetine should be initiated at 0.5 mg/kg/day and only increased to the usual target dose of 1.2 mg/kg/day if symptoms fail to improve after 4 weeks and the initial dose is well tolerated. - In children and adolescents over 70 kg body weight and adults administered strong CYP2D6 inhibitors, e.g., paroxetine, fluoxetine, and quinidine, Atomoxetine should be initiated at 40 mg/day and only increased to the usual target dose of 80 mg/day if symptoms fail to improve after 4 weeks and the initial dose is well tolerated. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Atomoxetine in pediatric patients. ### Non–Guideline-Supported Use - Dosing Information - 0.5 mg/kg daily for 3 days, followed by 1 mg/kg/day for the next 3 days and then increased to 1.5 mg/kg/day. # Contraindications - Hypersensitivity - Atomoxetine is contraindicated in patients known to be hypersensitive to atomoxetine or other constituents of the product. - Monoamine Oxidase Inhibitors (MAOI) - Atomoxetine should not be taken with an MAOI, or within 2 weeks after discontinuing an MAOI. Treatment with an MAOI should not be initiated within 2 weeks after discontinuing Atomoxetine. With other drugs that affect brain monoamine concentrations, there have been reports of serious, sometimes fatal reactions (including hyperthermia, rigidity, myoclonus, autonomic instability with possible rapid fluctuations of vital signs, and mental status changes that include extreme agitation progressing to delirium and coma) when taken in combination with an MAOI. Some cases presented with features resembling neuroleptic malignant syndrome. Such reactions may occur when these drugs are given concurrently or in close proximity. - Narrow Angle Glaucoma - In clinical trials, Atomoxetine use was associated with an increased risk of mydriasis and therefore its use is not recommended in patients with narrow angle glaucoma. - Pheochromocytoma - Serious reactions, including elevated blood pressure and tachyarrhythmia, have been reported in patients with pheochromocytoma or a history of pheochromocytoma who received Atomoxetine. Therefore, Atomoxetine should not be taken by patients with pheochromocytoma or a history of pheochromocytoma. - Severe Cardiovascular Disorders - Atomoxetine should not be used in patients with severe cardiac or vascular disorders whose condition would be expected to deteriorate if they experience increases in blood pressure or heart rate that could be clinically important (for example, 15 to 20 mm Hg in blood pressure or 20 beats per minute in heart rate). # Warnings ### Precautions - Suicidal Ideation - Atomoxetine increased the risk of suicidal ideation in short-term studies in children and adolescents with Attention-Deficit/Hyperactivity Disorder (ADHD). Pooled analyses of short-term (6 to 18 weeks) placebo-controlled trials of Atomoxetine in children and adolescents have revealed a greater risk of suicidal ideation early during treatment in those receiving Atomoxetine. There were a total of 12 trials (11 in ADHD and 1 in enuresis) involving over 2200 patients (including 1357 patients receiving Atomoxetine and 851 receiving placebo). The average risk of suicidal ideation in patients receiving Atomoxetine was 0.4% (5/1357 patients), compared to none in placebo-treated patients. There was 1 suicide attempt among these approximately 2200 patients, occurring in a patient treated with Atomoxetine. No suicides occurred in these trials. All reactions occurred in children 12 years of age or younger. All reactions occurred during the first month of treatment. It is unknown whether the risk of suicidal ideation in pediatric patients extends to longer-term use. A similar analysis in adult patients treated with Atomoxetine for either ADHD or major depressive disorder (MDD) did not reveal an increased risk of suicidal ideation or behavior in association with the use of Atomoxetine. - All pediatric patients being treated with Atomoxetine should be monitored appropriately and observed closely for clinical worsening, suicidality, and unusual changes in behavior, especially during the initial few months of a course of drug therapy, or at times of dose changes, either increases or decreases. - The following symptoms have been reported with Atomoxetine: anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania and mania. Although a causal link between the emergence of such symptoms and the emergence of suicidal impulses has not been established, there is a concern that such symptoms may represent precursors to emerging suicidality. Thus, patients being treated with Atomoxetine should be observed for the emergence of such symptoms. - Consideration should be given to changing the therapeutic regimen, including possibly discontinuing the medication, in patients who are experiencing emergent suicidality or symptoms that might be precursors to emerging suicidality, especially if these symptoms are severe or abrupt in onset, or were not part of the patient's presenting symptoms. - Families and caregivers of pediatric patients being treated with Atomoxetine should be alerted about the need to monitor patients for the emergence of agitation, irritability, unusual changes in behavior, and the other symptoms described above, as well as the emergence of suicidality, and to report such symptoms immediately to healthcare providers. Such monitoring should include daily observation by families and caregivers. - Severe Liver Injury - Postmarketing reports indicate that Atomoxetine can cause severe liver injury. Although no evidence of liver injury was detected in clinical trials of about 6000 patients, there have been rare cases of clinically significant liver injury that were considered probably or possibly related to Atomoxetine use in postmarketing experience. Rare cases of liver failure have also been reported, including a case that resulted in a liver transplant. Because of probable underreporting, it is impossible to provide an accurate estimate of the true incidence of these reactions. Reported cases of liver injury occurred within 120 days of initiation of atomoxetine in the majority of cases and some patients presented with markedly elevated liver enzymes , and jaundice with significantly elevated bilirubin levels (>2 X ULN), followed by recovery upon atomoxetine discontinuation. In one patient, liver injury, manifested by elevated hepatic enzymes up to 40 X ULN and jaundice with bilirubin up to 12 X ULN, recurred upon rechallenge, and was followed by recovery upon drug discontinuation, providing evidence that Atomoxetine likely caused the liver injury. Such reactions may occur several months after therapy is started, but laboratory abnormalities may continue to worsen for several weeks after drug is stopped. The patient described above recovered from his liver injury, and did not require a liver transplant. - Atomoxetine should be discontinued in patients with jaundice or laboratory evidence of liver injury, and should not be restarted. Laboratory testing to determine liver enzyme levels should be done upon the first symptom or sign of liver dysfunction (e.g., pruritus, dark urine, jaundice, right upper quadrant tenderness, or unexplained “flu like” symptoms). - Serious Cardiovascular Events - Sudden Death and Pre-existing Structural Cardiac Abnormalities or Other Serious Heart Problems - Children and Adolescents — Sudden death has been reported in association with atomoxetine treatment at usual doses in children and adolescents with structural cardiac abnormalities or other serious heart problems. Although some serious heart problems alone carry an increased risk of sudden death, atomoxetine generally should not be used in children or adolescents with known serious structural cardiac abnormalities, cardiomyopathy, serious heart rhythm abnormalities, or other serious cardiac problems that may place them at increased vulnerability to the noradrenergic effects of atomoxetine. - Adults — Sudden deaths, stroke, and myocardial infarction have been reported in adults taking atomoxetine at usual doses for ADHD. Although the role of atomoxetine in these adult cases is also unknown, adults have a greater likelihood than children of having serious structural cardiac abnormalities, cardiomyopathy, serious heart rhythm abnormalities, coronary artery disease, or other serious cardiac problems. Consideration should be given to not treating adults with clinically significant cardiac abnormalities. - Assessing Cardiovascular Status in Patients being Treated with Atomoxetine - Children, adolescents, or adults who are being considered for treatment with atomoxetine should have a careful history (including assessment for a family history of sudden death or ventricular arrhythmia) and physical exam to assess for the presence of cardiac disease, and should receive further cardiac evaluation if findings suggest such disease (e.g., electrocardiogram and echocardiogram). Patients who develop symptoms such as exertional chest pain, unexplained syncope, or other symptoms suggestive of cardiac disease during atomoxetine treatment should undergo a prompt cardiac evaluation. - Effects on Blood Pressure and Heart Rate - Atomoxetine should be used with caution in patients whose underlying medical conditions could be worsened by increases in blood pressure or heart rate such as certain patients with hypertension, tachycardia, or cardiovascular or cerebrovascular disease. It should not be used in patients with severe cardiac or vascular disorders whose condition would be expected to deteriorate if they experienced clinically important increases in blood pressure or heart rate. Pulse and blood pressure should be measured at baseline, following Atomoxetine dose increases, and periodically while on therapy to detect possible clinically important increases. - The following table provides short-term, placebo-controlled clinical trial data for the proportions of patients having an increase in: diastolic blood pressure ≥15 mm Hg; systolic blood pressure ≥20 mm Hg; heart rate greater than or equal to 20 bpm, in both the pediatric and adult populations (see Table 1). - In placebo-controlled registration studies involving pediatric patients, tachycardia was identified as an adverse event for 0.3% (5/1597) of these Atomoxetine patients compared with 0% (0/934) of placebo patients. The mean heart rate increase in extensive metabolizer (EM) patients was 5.0 beats/minute, and in poor metabolizer (PM) patients 9.4 beats/minute. - In adult clinical trials where EM/PM status was available, the mean heart rate increase in PM patients was significantly higher than in EM patients (11 beats/minute versus 7.5 beats/minute). The heart rate effects could be clinically important in some PM patients. - In placebo-controlled registration studies involving adult patients, tachycardia was identified as an adverse event for 1.5% (8/540) of Atomoxetine patients compared with 0.5% (2/402) of placebo patients. - In adult clinical trials where EM/PM status was available, the mean change from baseline in diastolic blood pressure in PM patients was higher than in EM patients (4.21 versus 2.13 mm Hg) as was the mean change from baseline in systolic blood pressure (PM: 2.75 versus EM: 2.40 mm Hg). The blood pressure effects could be clinically important in some PM patients. - Orthostatic hypotension and syncope have been reported in patients taking Atomoxetine. In child and adolescent registration studies, 0.2% (12/5596) of Atomoxetine-treated patients experienced orthostatic hypotension and 0.8% (46/5596) experienced syncope. In short-term child and adolescent registration studies, 1.8% (6/340) of Atomoxetine-treated patients experienced orthostatic hypotension compared with 0.5% (1/207) of placebo-treated patients. Syncope was not reported during short-term child and adolescent placebo-controlled ADHD registration studies. Atomoxetine should be used with caution in any condition that may predispose patients to hypotension, or conditions associated with abrupt heart rate or blood pressure changes. - Emergence of New Psychotic or Manic Symptoms - Treatment emergent psychotic or manic symptoms, e.g., hallucinations, delusional thinking, or mania in children and adolescents without a prior history of psychotic illness or mania can be caused by atomoxetine at usual doses. If such symptoms occur, consideration should be given to a possible causal role of atomoxetine, and discontinuation of treatment should be considered. In a pooled analysis of multiple short-term, placebo-controlled studies, such symptoms occurred in about 0.2% (4 patients with reactions out of 1939 exposed to atomoxetine for several weeks at usual doses) of atomoxetine-treated patients compared to 0 out of 1056 placebo-treated patients. - Screening Patients for Bipolar Disorder - In general, particular care should be taken in treating ADHD in patients with comorbid bipolar disorder because of concern for possible induction of a mixed/manic episode in patients at risk for bipolar disorder. Whether any of the symptoms described above represent such a conversion is unknown. However, prior to initiating treatment with Atomoxetine, patients with comorbid depressive symptoms should be adequately screened to determine if they are at risk for bipolar disorder; such screening should include a detailed psychiatric history, including a family history of suicide, bipolar disorder, and depression. - Aggressive Behavior or Hostility - Patients beginning treatment for ADHD should be monitored for the appearance or worsening of aggressive behavior or hostility. Aggressive behavior or hostility is often observed in children and adolescents with ADHD. In pediatric short-term controlled clinical trials, 21/1308 (1.6%) of atomoxetine patients versus 9/806 (1.1%) of placebo-treated patients spontaneously reported treatment emergent hostility-related adverse events (overall risk ratio of 1.33 ). In adult placebo-controlled clinical trials, 6/1697 (0.35%) of atomoxetine patients versus 4/1560 (0.26%) of placebo-treated patients spontaneously reported treatment emergent hostility-related adverse events (overall risk ratio of 1.38 ). Although this is not conclusive evidence that Atomoxetine causes aggressive behavior or hostility, these behaviors were more frequently observed in clinical trials among children, adolescents, and adults treated with Atomoxetine compared to placebo. - Allergic Events - Although uncommon, allergic reactions, including anaphylactic reactions, angioneurotic edema, urticaria, and rash, have been reported in patients taking Atomoxetine. - Effects on Urine Outflow from the Bladder - In adult ADHD controlled trials, the rates of urinary retention (1.7%, 9/540) and urinary hesitation (5.6%, 30/540) were increased among atomoxetine subjects compared with placebo subjects (0%, 0/402 ; 0.5%, 2/402, respectively). Two adult atomoxetine subjects and no placebo subjects discontinued from controlled clinical trials because of urinary retention. A complaint of urinary retention or urinary hesitancy should be considered potentially related to atomoxetine. - Priapism - Rare postmarketing cases of priapism, defined as painful and nonpainful penile erection lasting more than 4 hours, have been reported for pediatric and adult patients treated with Atomoxetine. The erections resolved in cases in which follow-up information was available, some following discontinuation of Atomoxetine. Prompt medical attention is required in the event of suspected priapism. - Effects on Growth - Data on the long-term effects of Atomoxetine on growth come from open-label studies, and weight and height changes are compared to normative population data. In general, the weight and height gain of pediatric patients treated with Atomoxetine lags behind that predicted by normative population data for about the first 9-12 months of treatment. Subsequently, weight gain rebounds and at about 3 years of treatment, patients treated with Atomoxetine have gained 17.9 kg on average, 0.5 kg more than predicted by their baseline data. After about 12 months, gain in height stabilizes, and at 3 years, patients treated with Atomoxetine have gained 19.4 cm on average, 0.4 cm less than predicted by their baseline data (see Figure 1 below). - This growth pattern was generally similar regardless of pubertal status at the time of treatment initiation. Patients who were pre-pubertal at the start of treatment (girls ≤8 years old, boys ≤9 years old) gained an average of 2.1 kg and 1.2 cm less than predicted after three years. Patients who were pubertal (girls >8 to ≤13 years old, boys >9 to ≤14 years old) or late pubertal (girls >13 years old, boys >14 years old) had average weight and height gains that were close to or exceeded those predicted after three years of treatment. - Growth followed a similar pattern in both extensive and poor metabolizers (EMs, PMs). PMs treated for at least two years gained an average of 2.4 kg and 1.1 cm less than predicted, while EMs gained an average of 0.2 kg and 0.4 cm less than predicted. - In short-term controlled studies (up to 9 weeks), Atomoxetine-treated patients lost an average of 0.4 kg and gained an average of 0.9 cm, compared to a gain of 1.5 kg and 1.1 cm in the placebo-treated patients. In a fixed-dose controlled trial, 1.3%, 7.1%, 19.3%, and 29.1% of patients lost at least 3.5% of their body weight in the placebo, 0.5, 1.2, and 1.8 mg/kg/day dose groups. - Growth should be monitored during treatment with Atomoxetine. - Laboratory Tests - Routine laboratory tests are not required. - CYP2D6 metabolism — Poor metabolizers (PMs) of CYP2D6 have a 10-fold higher AUC and a 5-fold higher peak concentration to a given dose of Atomoxetine compared with extensive metabolizers (EMs). Approximately 7% of a Caucasian population are PMs. Laboratory tests are available to identify CYP2D6 PMs. The blood levels in PMs are similar to those attained by taking strong inhibitors of CYP2D6. The higher blood levels in PMs lead to a higher rate of some adverse effects of Atomoxetine. - Concomitant Use of Potent CYP2D6 Inhibitors or Use in patients who are known to be CYP2D6 PMs - Atomoxetine is primarily metabolized by the CYP2D6 pathway to 4-hydroxyatomoxetine. Dosage adjustment of Atomoxetine may be necessary when coadministered with potent CYP2D6 inhibitors (e.g., paroxetine, fluoxetine, and quinidine) or when administered to CYP2D6 PMs. # Adverse Reactions ## Clinical Trials Experience - Atomoxetine was administered to 5382 children or adolescent patients with ADHD and 1007 adults with ADHD in clinical studies. During the ADHD clinical trials, 1625 children and adolescent patients were treated for longer than 1 year and 2529 children and adolescent patients were treated for over 6 months. - Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. - Reasons for discontinuation of treatment due to adverse reactions in child and adolescent clinical trials — In acute child and adolescent placebo-controlled trials, 3.0% (48/1613) of atomoxetine subjects and 1.4% (13/945) placebo subjects discontinued for adverse reactions. For all studies, (including open-label and long-term studies), 6.3% of extensive metabolizer (EM) patients and 11.2% of poor metabolizer (PM) patients discontinued because of an adverse reaction. Among Atomoxetine-treated patients, irritability (0.3%, N=5); somnolence (0.3%, N=5); aggression (0.2%, N=4); nausea (0.2%, N=4); vomiting (0.2%, N=4); abdominal pain (0.2%, N=4); constipation (0.1%, N=2); fatigue (0.1%, N=2); feeling abnormal (0.1%, N=2); and headache (0.1%, N=2) were the reasons for discontinuation reported by more than 1 patient. - Seizures — Atomoxetine has not been systematically evaluated in pediatric patients with seizure disorder as these patients were excluded from clinical studies during the product's premarket testing. In the clinical development program, seizures were reported in 0.2% (12/5073) of children whose average age was 10 years (range 6 to 16 years). In these clinical trials, the seizure risk among poor metabolizers was 0.3% (1/293) compared to 0.2% (11/4741) for extensive metabolizers. - Commonly observed adverse reactions in acute child and adolescent, placebo-controlled trials — Commonly observed adverse reactions associated with the use of Atomoxetine (incidence of 2% or greater) and not observed at an equivalent incidence among placebo-treated patients (Atomoxetine incidence greater than placebo) are listed in Table 2. Results were similar in the BID and the QD trial except as shown in Table 3, which shows both BID and QD results for selected adverse reactions based on statistically significant Breslow-Day tests. The most commonly observed adverse reactions in patients treated with Atomoxetine (incidence of 5% or greater and at least twice the incidence in placebo patients, for either BID or QD dosing) were: nausea, vomiting, fatigue, decreased appetite, abdominal pain, and somnolence (see Tables 2 and 3). - Additional data from ADHD clinical trials (controlled and uncontrolled) has shown that approximately 5 to 10% of pediatric patients experienced potentially clinically important changes in heart rate (≥20 beats per min) or blood pressure (≥15 to 20 mm Hg). - The following adverse reactions occurred in at least 2% of child and adolescent CYP2D6 PM patients and were statistically significantly more frequent in PM patients compared with CYP2D6 EM patients: insomnia (11% of PMs, 6% of EMs); weight decreased (7% of PMs, 4% of EMs); constipation (7% of PMs, 4% of EMs); depression (7% of PMs, 4% of EMs); tremor (5% of PMs, 1% of EMs); excoriation (4% of PMs, 2% of EMs); middle insomnia (3% of PMs, 1% of EMs); conjunctivitis (3% of PMs, 1% of EMs); syncope (3% of PMs, 1% of EMs); early morning awakening (2% of PMs, 1% of EMs); mydriasis (2% of PMs, 1% of EMs); sedation (4% of PMs, 2% of EMs). - Depression includes the following terms: depression, major depression, depressive symptoms, depressed mood, dysphoria. - Reasons for discontinuation of treatment due to adverse reactions in acute adult placebo-controlled trials — In the acute adult placebo-controlled trials, 11.3% (61/541) atomoxetine subjects and 3.0% (12/405) placebo subjects discontinued for adverse reactions. Among Atomoxetine-treated patients, insomnia (0.9%, N=5); nausea (0.9%, N=5); chest pain (0.6%, N=3); fatigue (0.6%, N=3); anxiety (0.4%, N=2); erectile dysfunction (0.4%, N=2); mood swings (0.4%, N=2); nervousness (0.4%, N=2); palpitations (0.4%, N=2); and urinary retention (0.4%, N=2) were the reasons for discontinuation reported by more than 1 patient. - Seizures — Atomoxetine has not been systematically evaluated in adult patients with a seizure disorder as these patients were excluded from clinical studies during the product's premarket testing. In the clinical development program, seizures were reported on 0.1% (1/748) of adult patients. In these clinical trials, no poor metabolizers (0/43) reported seizures compared to 0.1% (1/705) for extensive metabolizers. - Commonly observed adverse reactions in acute adult placebo-controlled trials — Commonly observed adverse reactions associated with the use of Atomoxetine (incidence of 2% or greater) and not observed at an equivalent incidence among placebo-treated patients (Atomoxetine incidence greater than placebo) are listed in Table 4. The most commonly observed adverse reactions in patients treated with Atomoxetine (incidence of 5% or greater and at least twice the incidence in placebo patients) were: constipation, dry mouth, nausea, decreased appetite, dizziness, erectile dysfunction, and urinary hesitation (see Table 4). - Additional data from ADHD clinical trials (controlled and uncontrolled) has shown that approximately 5 to 10% of adult patients experienced potentially clinically important changes in heart rate (≥20 beats per min) or blood pressure (≥15 to 20 mm Hg). - The following adverse events occurred in at least 2% of adult CYP2D6 poor metaboliser (PM) patients and were statistically significantly more frequent in PM patients compared to CYP2D6 extensive metaboliser (EM) patients: vision blurred (4% of PMs, 1% of EMs); dry mouth (35% of PMs, 17% of EMs); constipation (11% of PMs, 7% of EMs); feeling jittery (5% of PMs, 2% of EMs); decreased appetite (23% of PMs, 15% of EMs); tremor (5% of PMs, 1% of EMs); insomnia (19% of PMs, 11% of EMs); sleep disorder (7% of PMs, 3% of EMs); middle insomnia (5% of PMs, 3% of EMs); terminal insomnia (3% of PMs, 1% of EMs); urinary retention (6% of PMs, 1% of EMs); erectile dysfunction (21% of PMs, 9% of EMs); ejaculation disorder (6% of PMs, 2% of EMs); hyperhidrosis(15% of PMs, 7% of EMs); peripheral coldness (3% of PMs, 1% of EMs). - Male and female sexual dysfunction — Atomoxetine appears to impair sexual function in some patients. Changes in sexual desire, sexual performance, and sexual satisfaction are not well assessed in most clinical trials because they need special attention and because patients and physicians may be reluctant to discuss them. Accordingly, estimates of the incidence of untoward sexual experience and performance cited in product labeling are likely to underestimate the actual incidence. Table 4 above displays the incidence of sexual side effects reported by at least 2% of adult patients taking Atomoxetine in placebo-controlled trials. - There are no adequate and well-controlled studies examining sexual dysfunction with Atomoxetine treatment. While it is difficult to know the precise risk of sexual dysfunction associated with the use of Atomoxetine, physicians should routinely inquire about such possible side effects. ## Postmarketing Experience - The following adverse reactions have been identified during post approval use of Atomoxetine. Unless otherwise specified, these adverse reactions have occurred in adults and children and adolescents. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. QT prolongation, syncope. Raynaud's phenomenon. Lethargy. Hypoaesthesia; paraesthesia in children and adolescents; sensory disturbances; tics. Depression and depressed mood; anxiety, libido changes. - Seizures - Seizures have been reported in the postmarketing period. The postmarketing seizure cases include patients with pre-existing seizure disorders and those with identified risk factors for seizures, as well as patients with neither a history of nor identified risk factors for seizures. The exact relationship between Atomoxetine and seizures is difficult to evaluate due to uncertainty about the background risk of seizures in ADHD patients. Hyperhidrosis. Male pelvic pain; urinary hesitation in children and adolescents; urinary retention in children and adolescents. # Drug Interactions - Monoamine Oxidase Inhibitors - With other drugs that affect brain monoamine concentrations, there have been reports of serious, sometimes fatal reactions (including hyperthermia, rigidity, myoclonus, autonomic instability with possible rapid fluctuations of vital signs, and mental status changes that include extreme agitation progressing to delirium and coma) when taken in combination with an MAOI. Some cases presented with features resembling neuroleptic malignant syndrome. Such reactions may occur when these drugs are given concurrently or in close proximity. - Effect of CYP2D6 Inhibitors on Atomoxetine - In extensive metabolizers (EMs), inhibitors of CYP2D6 (e.g., paroxetine, fluoxetine, and quinidine) increase atomoxetine steady-state plasma concentrations to exposures similar to those observed in poor metabolizers (PMs). In EM individuals treated with paroxetine or fluoxetine, the AUC of atomoxetine is approximately 6- to 8-fold and Css, max is about 3- to 4-fold greater than atomoxetine alone. - In vitro studies suggest that coadministration of cytochrome P450 inhibitors to PMs will not increase the plasma concentrations of atomoxetine. - Antihypertensive Drugs and Pressor Agents - Because of possible effects on blood pressure, Atomoxetine should be used cautiously with antihypertensive drugs and pressor agents (e.g., dopamine, dobutamine) or other drugs that increase blood pressure. - Albuterol - Atomoxetine should be administered with caution to patients being treated with systemically-administered (oral or intravenous) albuterol (or other beta2 agonists) because the action of albuterol on the cardiovascular system can be potentiated resulting in increases in heart rate and blood pressure. Albuterol (600 mcg iv over 2 hours) induced increases in heart rate and blood pressure. These effects were potentiated by atomoxetine (60 mg BID for 5 days) and were most marked after the initial coadministration of albuterol and atomoxetine. However, these effects on heart rate and blood pressure were not seen in another study after the coadministration with inhaled dose of albuterol (200-800 mcg) and atomoxetine (80 mg QD for 5 days) in 21 healthy Asian subjects who were excluded for poor metabolizer status. - Effect of Atomoxetine on P450 Enzymes - Atomoxetine did not cause clinically important inhibition or induction of cytochrome P450 enzymes, including CYP1A2, CYP3A, CYP2D6, and CYP2C9. - CYP3A Substrate (e.g., Midazolam) — Coadministration of Atomoxetine (60 mg BID for 12 days) with midazolam, a model compound for CYP3A4 metabolized drugs (single dose of 5 mg), resulted in 15% increase in AUC of midazolam. No dose adjustment is recommended for drugs metabolized by CYP3A. - CYP2D6 Substrate (e.g., Desipramine) — Coadministration of Atomoxetine (40 or 60 mg BID for 13 days) with desipramine, a model compound for CYP2D6 metabolized drugs (single dose of 50 mg), did not alter the pharmacokinetics of desipramine. No dose adjustment is recommended for drugs metabolized by CYP2D6. - Alcohol - Consumption of ethanol with Atomoxetine did not change the intoxicating effects of ethanol. - Methylphenidate - Coadministration of methylphenidate with Atomoxetine did not increase cardiovascular effects beyond those seen with methylphenidate alone. - Drugs Highly Bound to Plasma Protein - In vitro drug-displacement studies were conducted with atomoxetine and other highly-bound drugs at therapeutic concentrations. Atomoxetine did not affect the binding of warfarin, acetylsalicylic acid, phenytoin, or diazepam to human albumin. Similarly, these compounds did not affect the binding of atomoxetine to human albumin. - Drugs that Affect Gastric pH - Drugs that elevate gastric pH (magnesium hydroxide/aluminum hydroxide, omeprazole) had no effect on Atomoxetine bioavailability. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): - Pregnancy Category C - Pregnant rabbits were treated with up to 100 mg/kg/day of atomoxetine by gavage throughout the period of organogenesis. At this dose, in 1 of 3 studies, a decrease in live fetuses and an increase in early resorptions was observed. Slight increases in the incidences of atypical origin of carotid artery and absent subclavian artery were observed. These findings were observed at doses that caused slight maternal toxicity. The no-effect dose for these findings was 30 mg/kg/day. The 100 mg/kg dose is approximately 23 times the maximum human dose on a mg/m2 basis; plasma levels (AUC) of atomoxetine at this dose in rabbits are estimated to be 3.3 times (extensive metabolizers) or 0.4 times (poor metabolizers) those in humans receiving the maximum human dose. - Rats were treated with up to approximately 50 mg/kg/day of atomoxetine (approximately 6 times the maximum human dose on a mg/m2 basis) in the diet from 2 weeks (females) or 10 weeks (males) prior to mating through the periods of organogenesis and lactation. In 1 of 2 studies, decreases in pup weight and pup survival were observed. The decreased pup survival was also seen at 25 mg/kg (but not at 13 mg/kg). In a study in which rats were treated with atomoxetine in the diet from 2 weeks (females) or 10 weeks (males) prior to mating throughout the period of organogenesis, a decrease in fetal weight (female only) and an increase in the incidence of incomplete ossification of the vertebral arch in fetuses were observed at 40 mg/kg/day (approximately 5 times the maximum human dose on a mg/m2 basis) but not at 20 mg/kg/day. - No adverse fetal effects were seen when pregnant rats were treated with up to 150 mg/kg/day (approximately 17 times the maximum human dose on a mg/m2 basis) by gavage throughout the period of organogenesis. - No adequate and well-controlled studies have been conducted in pregnant women. Atomoxetine should not be used during pregnancy unless the potential benefit justifies the potential risk to the fetus. Pregnancy Category (AUS): - Australian Drug Evaluation Committee (ADEC) Pregnancy Category There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Atomoxetine in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Atomoxetine during labor and delivery. ### Nursing Mothers - Atomoxetine and/or its metabolites were excreted in the milk of rats. It is not known if atomoxetine is excreted in human milk. Caution should be exercised if Atomoxetine is administered to a nursing woman. ### Pediatric Use - Anyone considering the use of Atomoxetine in a child or adolescent must balance the potential risks with the clinical need. - The pharmacokinetics of atomoxetine in children and adolescents are similar to those in adults. The safety, efficacy, and pharmacokinetics of Atomoxetine in pediatric patients less than 6 years of age have not been evaluated. - A study was conducted in young rats to evaluate the effects of atomoxetine on growth and neurobehavioral and sexual development. Rats were treated with 1, 10, or 50 mg/kg/day (approximately 0.2, 2, and 8 times, respectively, the maximum human dose on a mg/m2 basis) of atomoxetine given by gavage from the early postnatal period (Day 10 of age) through adulthood. Slight delays in onset of vaginal patency (all doses) and preputial separation (10 and 50 mg/kg), slight decreases in epididymal weight and sperm number (10 and 50 mg/kg), and a slight decrease in corpora lutea (50 mg/kg) were seen, but there were no effects on fertility or reproductive performance. A slight delay in onset of incisor eruption was seen at 50 mg/kg. A slight increase in motor activity was seen on Day 15 (males at 10 and 50 mg/kg and females at 50 mg/kg) and on Day 30 (females at 50 mg/kg) but not on Day 60 of age. There were no effects on learning and memory tests. The significance of these findings to humans is unknown. ### Geriatic Use There is no FDA guidance on the use of Atomoxetine with respect to geriatric patients. ### Gender There is no FDA guidance on the use of Atomoxetine with respect to specific gender populations. ### Race There is no FDA guidance on the use of Atomoxetine with respect to specific racial populations. ### Renal Impairment - EM subjects with end stage renal disease had higher systemic exposure to atomoxetine than healthy subjects (about a 65% increase), but there was no difference when exposure was corrected for mg/kg dose. Atomoxetine can therefore be administered to ADHD patients with end stage renal disease or lesser degrees of renal insufficiency using the normal dosing regimen. ### Hepatic Impairment - Atomoxetine exposure (AUC) is increased, compared with normal subjects, in EM subjects with moderate (Child-Pugh Class B) (2-fold increase) and severe (Child-Pugh Class C) (4-fold increase) hepatic insufficiency. Dosage adjustment is recommended for patients with moderate or severe hepatic insufficiency. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Atomoxetine in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Atomoxetine in patients who are immunocompromised. # Administration and Monitoring ### Administration - Oral ### Monitoring There is limited information regarding Monitoring of Atomoxetine in the drug label. - Description # IV Compatibility There is limited information regarding IV Compatibility of Atomoxetine in the drug label. # Overdosage ## Acute Overdose ### Signs and Symptoms - No fatal overdoses occurred in clinical trials. There is limited clinical trial experience with Atomoxetine overdose. During postmarketing, there have been fatalities reported involving a mixed ingestion overdose of Atomoxetine and at least one other drug. There have been no reports of death involving overdose of Atomoxetine alone, including intentional overdoses at amounts up to 1400 mg. In some cases of overdose involving Atomoxetine, seizures have been reported. The most commonly reported symptoms accompanying acute and chronic overdoses of Atomoxetine were gastrointestinal symptoms, somnolence, dizziness, tremor, and abnormal behavior. Hyperactivity and agitation have also been reported. Signs and symptoms consistent with mild to moderate sympathetic nervous system activation (e.g., tachycardia, blood pressure increased, mydriasis, dry mouth) have also been observed. Most events were mild to moderate. Less commonly, there have been reports of QT prolongation and mental changes, including disorientation and hallucinations. ### Management - Consult with a Certified Poison Control Center for up to date guidance and advice. Because atomoxetine is highly protein-bound, dialysis is not likely to be useful in the treatment of overdose. ## Chronic Overdose There is limited information regarding Chronic Overdose of Atomoxetine in the drug label. # Pharmacology ## Mechanism of Action - The precise mechanism by which atomoxetine produces its therapeutic effects in Attention-Deficit/Hyperactivity Disorder (ADHD) is unknown, but is thought to be related to selective inhibition of the pre-synaptic norepinephrine transporter, as determined in ex vivo uptake and neurotransmitter depletion studies. ## Structure - Atomoxetine® (atomoxetine) is a selective norepinephrine reuptake inhibitor. Atomoxetine HCl is the R(-) isomer as determined by x-ray diffraction. The chemical designation is (-)-N-Methyl-3-phenyl-3-(o-tolyloxy)-propylamine hydrochloride. The molecular formula is C17H21NOHCl, which corresponds to a molecular weight of 291.82. The chemical structure is: - Atomoxetine HCl is a white to practically white solid, which has a solubility of 27.8 mg/mL in water. - Atomoxetine capsules are intended for oral administration only. - Each capsule contains atomoxetine HCl equivalent to 10, 18, 25, 40, 60, 80, or 100 mg of atomoxetine. The capsules also contain pregelatinized starch and dimethicone. The capsule shells contain gelatin, sodium lauryl sulfate, and other inactive ingredients. The capsule shells also contain one or more of the following: - FD&C Blue No. 2, synthetic yellow iron oxide, titanium dioxide, red iron oxide. The capsules are imprinted with edible black ink. ## Pharmacodynamics - An exposure-response analysis encompassing doses of atomoxetine (0.5, 1.2 or 1.8 mg/kg/day) or placebo demonstrated atomoxetine exposure correlates with efficacy as measured by the Attention-Deficit/Hyperactivity Disorder Rating Scale-IV-Parent Version: Investigator administered and scored. The exposure-efficacy relationship was similar to that observed between dose and efficacy with median exposures at the two highest doses resulting in near maximal changes from baseline. - Cardiac Electrophysiology — The effect of Atomoxetine on QT prolongation was evaluated in a randomized, double-blinded, positive-(moxifloxacin 400 mg) and placebo-controlled, cross-over study in healthy male CYP2D6 poor metabolizers. A total of 120 healthy subjects were administered Atomoxetine (20 mg and 60 mg) twice daily for 7 days. No large changes in QTc interval (i.e., increases >60 msec from baseline, absolute QTc >480 msec) were observed in the study. However, small changes in QTc interval cannot be excluded from the current study, because the study failed to demonstrate assay sensitivity. There was a slight increase in QTc interval with increased atomoxetine concentration. ## Pharmacokinetics - Atomoxetine is well-absorbed after oral administration and is minimally affected by food. It is eliminated primarily by oxidative metabolism through the cytochrome P450 2D6 (CYP2D6) enzymatic pathway and subsequent glucuronidation. Atomoxetine has a half-life of about 5 hours. A fraction of the population (about 7% of Caucasians and 2% of African Americans) are poor metabolizers (PMs) of CYP2D6 metabolized drugs. These individuals have reduced activity in this pathway resulting in 10-fold higher AUCs, 5-fold higher peak plasma concentrations, and slower elimination (plasma half-life of about 24 hours) of atomoxetine compared with people with normal activity . Drugs that inhibit CYP2D6, such as fluoxetine, paroxetine, and quinidine, cause similar increases in exposure. - The pharmacokinetics of atomoxetine have been evaluated in more than 400 children and adolescents in selected clinical trials, primarily using population pharmacokinetic studies. Single-dose and steady-state individual pharmacokinetic data were also obtained in children, adolescents, and adults. When doses were normalized to a mg/kg basis, similar half-life, Cmax, and AUC values were observed in children, adolescents, and adults. Clearance and volume of distribution after adjustment for body weight were also similar. - Absorption and distribution — Atomoxetine is rapidly absorbed after oral administration, with absolute bioavailability of about 63% in EMs and 94% in PMs. Maximal plasma concentrations (Cmax) are reached approximately 1 to 2 hours after dosing. - Atomoxetine can be administered with or without food. Administration of Atomoxetine with a standard high-fat meal in adults did not affect the extent of oral absorption of atomoxetine (AUC), but did decrease the rate of absorption, resulting in a 37% lower Cmax, and delayed Tmax by 3 hours. In clinical trials with children and adolescents, administration of Atomoxetine with food resulted in a 9% lower Cmax. - The steady-state volume of distribution after intravenous administration is 0.85 L/kg indicating that atomoxetine distributes primarily into total body water. Volume of distribution is similar across the patient weight range after normalizing for body weight. - At therapeutic concentrations, 98% of atomoxetine in plasma is bound to protein, primarily albumin. - Metabolism and elimination — Atomoxetine is metabolized primarily through the CYP2D6 enzymatic pathway. People with reduced activity in this pathway (PMs) have higher plasma concentrations of atomoxetine compared with people with normal activity (EMs). For PMs, AUC of atomoxetine is approximately 10-fold and Css, max is about 5-fold greater than EMs. Laboratory tests are available to identify CYP2D6 PMs. Coadministration of Atomoxetine with potent inhibitors of CYP2D6, such as fluoxetine, paroxetine, or quinidine, results in a substantial increase in atomoxetine plasma exposure, and dosing adjustment may be necessary. Atomoxetine did not inhibit or induce the CYP2D6 pathway. - The major oxidative metabolite formed, regardless of CYP2D6 status, is 4-hydroxyatomoxetine, which is glucuronidated. 4-Hydroxyatomoxetine is equipotent to atomoxetine as an inhibitor of the norepinephrine transporter but circulates in plasma at much lower concentrations (1% of atomoxetine concentration in EMs and 0.1% of atomoxetine concentration in PMs). 4-Hydroxyatomoxetine is primarily formed by CYP2D6, but in PMs, 4-hydroxyatomoxetine is formed at a slower rate by several other cytochrome P450 enzymes. N-Desmethylatomoxetine is formed by CYP2C19 and other cytochrome P450 enzymes, but has substantially less pharmacological activity compared with atomoxetine and circulates in plasma at lower concentrations (5% of atomoxetine concentration in EMs and 45% of atomoxetine concentration in PMs). - Mean apparent plasma clearance of atomoxetine after oral administration in adult EMs is 0.35 L/hr/kg and the mean half-life is 5.2 hours. Following oral administration of atomoxetine to PMs, mean apparent plasma clearance is 0.03 L/hr/kg and mean half-life is 21.6 hours. For PMs, AUC of atomoxetine is approximately 10-fold and Css, max is about 5-fold greater than EMs. The elimination half-life of 4-hydroxyatomoxetine is similar to that of N-desmethylatomoxetine (6 to 8 hours) in EM subjects, while the half-life of N-desmethylatomoxetine is much longer in PM subjects (34 to 40 hours). - Atomoxetine is excreted primarily as 4-hydroxyatomoxetine-O-glucuronide, mainly in the urine (greater than 80% of the dose) and to a lesser extent in the feces (less than 17% of the dose). Only a small fraction of the Atomoxetine dose is excreted as unchanged atomoxetine (less than 3% of the dose), indicating extensive biotransformation. ## Nonclinical Toxicology - Carcinogenesis — Atomoxetine HCl was not carcinogenic in rats and mice when given in the diet for 2 years at time-weighted average doses up to 47 and 458 mg/kg/day, respectively. The highest dose used in rats is approximately 8 and 5 times the maximum human dose in children and adults, respectively, on a mg/m2 basis. Plasma levels (AUC) of atomoxetine at this dose in rats are estimated to be 1.8 times (extensive metabolizers) or 0.2 times (poor metabolizers) those in humans receiving the maximum human dose. The highest dose used in mice is approximately 39 and 26 times the maximum human dose in children and adults, respectively, on a mg/m2 basis. - Mutagenesis — Atomoxetine HCl was negative in a battery of genotoxicity studies that included a reverse point mutation assay (Ames Test), an in vitro mouse lymphoma assay, a chromosomal aberration test in Chinese hamster ovary cells, an unscheduled DNA synthesis test in rat hepatocytes, and an in vivo micronucleus test in mice. However, there was a slight increase in the percentage of Chinese hamster ovary cells with diplochromosomes, suggesting endoreduplication (numerical aberration). - The metabolite N-desmethylatomoxetine HCl was negative in the Ames Test, mouse lymphoma assay, and unscheduled DNA synthesis test. - Impairment of fertility — Atomoxetine HCl did not impair fertility in rats when given in the diet at doses of up to 57 mg/kg/day, which is approximately 6 times the maximum human dose on a mg/m2 basis. # Clinical Studies - Acute Studies — The effectiveness of Atomoxetine in the treatment of ADHD was established in 4 randomized, double-blind, placebo-controlled studies of pediatric patients (ages 6 to 18). Approximately one-third of the patients met DSM-IV criteria for inattentive subtype and two-thirds met criteria for both inattentive and hyperactive/impulsive subtypes. - Signs and symptoms of ADHD were evaluated by a comparison of mean change from baseline to endpoint for Atomoxetine- and placebo-treated patients using an intent-to-treat analysis of the primary outcome measure, the investigator administered and scored ADHD Rating Scale-IV-Parent Version (ADHDRS) total score including hyperactive/impulsive and inattentive subscales. Each item on the ADHDRS maps directly to one symptom criterion for ADHD in the DSM-IV. - In Study 1, an 8-week randomized, double-blind, placebo-controlled, dose-response, acute treatment study of children and adolescents aged 8 to 18 (N=297), patients received either a fixed dose of Atomoxetine (0.5, 1.2, or 1.8 mg/kg/day) or placebo. Atomoxetine was administered as a divided dose in the early morning and late afternoon/early evening. At the 2 higher doses, improvements in ADHD symptoms were statistically significantly superior in Atomoxetine-treated patients compared with placebo-treated patients as measured on the ADHDRS scale. The 1.8 mg/kg/day Atomoxetine dose did not provide any additional benefit over that observed with the 1.2 mg/kg/day dose. The 0.5 mg/kg/day Atomoxetine dose was not superior to placebo. - In Study 2, a 6-week randomized, double-blind, placebo-controlled, acute treatment study of children and adolescents aged 6 to 16 (N=171), patients received either Atomoxetine or placebo. Atomoxetine was administered as a single dose in the early morning and titrated on a weight-adjusted basis according to clinical response, up to a maximum dose of 1.5 mg/kg/day. The mean final dose of Atomoxetine was approximately 1.3 mg/kg/day. ADHD symptoms were statistically significantly improved on Atomoxetine compared with placebo, as measured on the ADHDRS scale. This study shows that Atomoxetine is effective when administered once daily in the morning. - In 2 identical, 9-week, acute, randomized, double-blind, placebo-controlled studies of children aged 7 to 13 (Study 3, N=147; Study 4, N=144), Atomoxetine and methylphenidate were compared with placebo. Atomoxetine was administered as a divided dose in the early morning and late afternoon (after school) and titrated on a weight-adjusted basis according to clinical response. The maximum recommended Atomoxetine dose was 2.0 mg/kg/day. The mean final dose of Atomoxetine for both studies was approximately 1.6 mg/kg/day. In both studies, ADHD symptoms statistically significantly improved more on Atomoxetine than on placebo, as measured on the ADHDRS scale. - Examination of population subsets based on gender and age (<12 and 12 to 17) did not reveal any differential responsiveness on the basis of these subgroupings. There was not sufficient exposure of ethnic groups other than Caucasian to allow exploration of differences in these subgroups. - Maintenance Study — The effectiveness of Atomoxetine in the maintenance treatment of ADHD was established in an outpatient study of children and adolescents (ages 6-15 years). Patients meeting DSM-IV criteria for ADHD who showed continuous response for about 4 weeks during an initial 10 week open-label treatment phase with Atomoxetine (1.2 to 1.8 mg/kg/day) were randomized to continuation of their current dose of Atomoxetine (N=292) or to placebo (N=124) under double-blind treatment for observation of relapse. Response during the open-label phase was defined as CGI-ADHD-S score ≤2 and a reduction of at least 25% from baseline in ADHDRS-IV-Parent:Inv total score. Patients who were assigned to Atomoxetine and showed continuous response for approximately 8 months during the first double-blind treatment phase were again randomized to continuation of their current dose of Atomoxetine (N=81) or to placebo (N=82) under double-blind treatment for observation of relapse. Relapse during the double-blind phase was defined as CGI-ADHD-S score increases of at least 2 from the end of open-label phase and ADHDRS-IV-Parent:Inv total score returns to ≥90% of study entry score for 2 consecutive visits. In both double-blind phases, patients receiving continued Atomoxetine treatment experienced significantly longer times to relapse than those receiving placebo. - The effectiveness of Atomoxetine in the treatment of ADHD was established in 2 randomized, double-blind, placebo-controlled clinical studies of adult patients, age 18 and older, who met DSM-IV criteria for ADHD. - Signs and symptoms of ADHD were evaluated using the investigator-administered Conners Adult ADHD Rating Scale Screening Version (CAARS), a 30-item scale. The primary effectiveness measure was the 18-item Total ADHD Symptom score (the sum of the inattentive and hyperactivity/impulsivity subscales from the CAARS) evaluated by a comparison of mean change from baseline to endpoint using an intent-to-treat analysis. - In 2 identical, 10-week, randomized, double-blind, placebo-controlled acute treatment studies (Study 5, N=280; Study 6, N=256), patients received either Atomoxetine or placebo. Atomoxetine was administered as a divided dose in the early morning and late afternoon/early evening and titrated according to clinical response in a range of 60 to 120 mg/day. The mean final dose of Atomoxetine for both studies was approximately 95 mg/day. In both studies, ADHD symptoms were statistically significantly improved on Atomoxetine, as measured on the ADHD Symptom score from the CAARS scale. - Examination of population subsets based on gender and age (<42 and ≥42) did not reveal any differential responsiveness on the basis of these subgroupings. There was not sufficient exposure of ethnic groups other than Caucasian to allow exploration of differences in these subgroups. # How Supplied - Store at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F). ## Storage There is limited information regarding Atomoxetine Storage in the drug label. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information - Physicians should instruct their patients to read the Medication Guide before starting therapy with Atomoxetine and to reread it each time the prescription is renewed. - Prescribers or other health professionals should inform patients, their families, and their caregivers about the benefits and risks associated with treatment with Atomoxetine and should counsel them in its appropriate use. The prescriber or health professional should instruct patients, their families, and their caregivers to read the Medication Guide and should assist them in understanding its contents. Patients should be given the opportunity to discuss the contents of the Medication Guide and to obtain answers to any questions they may have. - Patients should be advised of the following issues and asked to alert their prescriber if these occur while taking Atomoxetine. - Patients, their families, and their caregivers should be encouraged to be alert to the emergence of anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, mania, other unusual changes in behavior, depression, and suicidal ideation, especially early during Atomoxetine treatment and when the dose is adjusted. Families and caregivers of patients should be advised to observe for the emergence of such symptoms on a day-to-day basis, since changes may be abrupt. Such symptoms should be reported to the patient's prescriber or health professional, especially if they are severe, abrupt in onset, or were not part of the patient's presenting symptoms. Symptoms such as these may be associated with an increased risk for suicidal thinking and behavior and indicate a need for very close monitoring and possibly changes in the medication. - Patients initiating Atomoxetine should be cautioned that severe liver injury may develop. Patients should be instructed to contact their physician immediately should they develop pruritus, dark urine, jaundice, right upper quadrant tenderness, or unexplained “flu-like” symptoms. - Patients should be instructed to call their doctor as soon as possible should they notice an increase in aggression or hostility. - Rare postmarketing cases of priapism, defined as painful and nonpainful penile erection lasting more than 4 hours, have been reported for pediatric and adult patients treated with Atomoxetine. The parents or guardians of pediatric patients taking Atomoxetine and adult patients taking Atomoxetine should be instructed that priapism requires prompt medical attention. - Atomoxetine is an ocular irritant. Atomoxetine capsules are not intended to be opened. In the event of capsule content coming in contact with the eye, the affected eye should be flushed immediately with water, and medical advice obtained. Hands and any potentially contaminated surfaces should be washed as soon as possible. - Patients should be instructed to consult a physician if they are taking or plan to take any prescription or over-the-counter medicines, dietary supplements, or herbal remedies. - Patients should be instructed to consult a physician if they are nursing, pregnant, or thinking of becoming pregnant while taking Atomoxetine. - Patients may take Atomoxetine with or without food. - If patients miss a dose, they should be instructed to take it as soon as possible, but should not take more than the prescribed total daily amount of Atomoxetine in any 24-hour period. - Patients should be instructed to use caution when driving a car or operating hazardous machinery until they are reasonably certain that their performance is not affected by atomoxetine. # Precautions with Alcohol - Alcohol-Atomoxetine interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - STRATTERA® # Look-Alike Drug Names There is limited information regarding Atomoxetine Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	Atomoxetine Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Vignesh Ponnusamy, M.B.B.S. [2] # Disclaimer WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here. # Black Box Warning # Overview Atomoxetine is a selective norepinephrine reuptake inhibitor that is FDA approved for the treatment of attention-deficit/hyperactivity disorder(ADHD). There is a Black Box Warning for this drug as shown here. Common adverse reactions include nausea, vomiting, fatigue, decreased appetite, abdominal pain, and somnolence. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - Dosing Information - Acute Treatment - Atomoxetine should be initiated at a total daily dose of 40 mg and increased after a minimum of 3 days to a target total daily dose of approximately 80 mg administered either as a single daily dose in the morning or as evenly divided doses in the morning and late afternoon/early evening. After 2 to 4 additional weeks, the dose may be increased to a maximum of 100 mg in patients who have not achieved an optimal response. There are no data that support increased effectiveness at higher doses. - The maximum recommended total daily dose in adults is 100 mg. - Maintenance/Extended Treatment - It is generally agreed that pharmacological treatment of ADHD may be needed for extended periods. Patients assigned to Atomoxetine in the maintenance phase were generally continued on the same dose used to achieve a response in the open label phase. The physician who elects to use Atomoxetine for extended periods should periodically reevaluate the long-term usefulness of the drug for the individual patient. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Atomoxetine in adult patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Atomoxetine in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) - The efficacy of Atomoxetine Capsules was established in seven clinical trials in outpatients with ADHD: four 6 to 9-week trials in pediatric patients (ages 6 to 18), two 10-week trial in adults, and one maintenance trial in pediatrics (ages 6 to 15). - Diagnostic Considerations - A diagnosis of ADHD (DSM-IV) implies the presence of hyperactive-impulsive or inattentive symptoms that cause impairment and that were present before age 7 years. The symptoms must be persistent, must be more severe than is typically observed in individuals at a comparable level of development, must cause clinically significant impairment, e.g., in social, academic, or occupational functioning, and must be present in 2 or more settings, e.g., school (or work) and at home. The symptoms must not be better accounted for by another mental disorder. - The specific etiology of ADHD is unknown, and there is no single diagnostic test. Adequate diagnosis requires the use not only of medical but also of special psychological, educational, and social resources. Learning may or may not be impaired. The diagnosis must be based upon a complete history and evaluation of the patient and not solely on the presence of the required number of DSM-IV characteristics. - For the Inattentive Type, at least 6 of the following symptoms must have persisted for at least 6 months: lack of attention to details/careless mistakes, lack of sustained attention, poor listener, failure to follow through on tasks, poor organization, avoids tasks requiring sustained mental effort, loses things, easily distracted, forgetful. For the Hyperactive-Impulsive Type, at least 6 of the following symptoms must have persisted for at least 6 months: fidgeting/squirming, leaving seat, inappropriate running/climbing, difficulty with quiet activities, “on the go,” excessive talking, blurting answers, can't wait turn, intrusive. For a Combined Type diagnosis, both inattentive and hyperactive-impulsive criteria must be met. - Need for Comprehensive Treatment Program - Atomoxetine is indicated as an integral part of a total treatment program for ADHD that may include other measures (psychological, educational, social) for patients with this syndrome. Drug treatment may not be indicated for all patients with this syndrome. Drug treatment is not intended for use in the patient who exhibits symptoms secondary to environmental factors and/or other primary psychiatric disorders, including psychosis. Appropriate educational placement is essential in children and adolescents with this diagnosis and psychosocial intervention is often helpful. When remedial measures alone are insufficient, the decision to prescribe drug treatment medication will depend upon the physician's assessment of the chronicity and severity of the patient's symptoms - Dosing Information - Acute Treatment - Dosing of children and adolescents up to 70 kg body weight Atomoxetine should be initiated at a total daily dose of approximately 0.5 mg/kg and increased after a minimum of 3 days to a target total daily dose of approximately 1.2 mg/kg administered either as a single daily dose in the morning or as evenly divided doses in the morning and late afternoon/early evening. No additional benefit has been demonstrated for doses higher than 1.2 mg/kg/day. The total daily dose in children and adolescents should not exceed 1.4 mg/kg or 100 mg, whichever is less. - Atomoxetine should be initiated at a total daily dose of approximately 0.5 mg/kg and increased after a minimum of 3 days to a target total daily dose of approximately 1.2 mg/kg administered either as a single daily dose in the morning or as evenly divided doses in the morning and late afternoon/early evening. No additional benefit has been demonstrated for doses higher than 1.2 mg/kg/day. - The total daily dose in children and adolescents should not exceed 1.4 mg/kg or 100 mg, whichever is less. - Dosing of children and adolescents over 70 kg body weight Atomoxetine should be initiated at a total daily dose of 40 mg and increased after a minimum of 3 days to a target total daily dose of approximately 80 mg administered either as a single daily dose in the morning or as evenly divided doses in the morning and late afternoon/early evening. After 2 to 4 additional weeks, the dose may be increased to a maximum of 100 mg in patients who have not achieved an optimal response. There are no data that support increased effectiveness at higher doses. The maximum recommended total daily dose in children and adolescents over 70 kg. - Atomoxetine should be initiated at a total daily dose of 40 mg and increased after a minimum of 3 days to a target total daily dose of approximately 80 mg administered either as a single daily dose in the morning or as evenly divided doses in the morning and late afternoon/early evening. After 2 to 4 additional weeks, the dose may be increased to a maximum of 100 mg in patients who have not achieved an optimal response. There are no data that support increased effectiveness at higher doses. - The maximum recommended total daily dose in children and adolescents over 70 kg. - Maintenance/Extended Treatment - It is generally agreed that pharmacological treatment of ADHD may be needed for extended periods. The benefit of maintaining pediatric patients (ages 6-15 years) with ADHD on Atomoxetine after achieving a response in a dose range of 1.2 to 1.8 mg/kg/day was demonstrated in a controlled trial. Patients assigned to Atomoxetine in the maintenance phase were generally continued on the same dose used to achieve a response in the open label phase. The physician who elects to use Atomoxetine for extended periods should periodically reevaluate the long-term usefulness of the drug for the individual patient. - Dosing in Specific Populations - Dosing adjustment for hepatically impaired patients — For those ADHD patients who have hepatic insufficiency (HI), dosage adjustment is recommended as follows: For patients with moderate HI (Child-Pugh Class B), initial and target doses should be reduced to 50% of the normal dose (for patients without HI). For patients with severe HI (Child-Pugh Class C), initial dose and target doses should be reduced to 25% of normal. - Dosing adjustment for use with a strong CYP2D6 inhibitor or in patients who are known to be CYP2D6 PMs — In children and adolescents up to 70 kg body weight administered strong CYP2D6 inhibitors, e.g., paroxetine, fluoxetine, and quinidine, or in patients who are known to be CYP2D6 PMs, Atomoxetine should be initiated at 0.5 mg/kg/day and only increased to the usual target dose of 1.2 mg/kg/day if symptoms fail to improve after 4 weeks and the initial dose is well tolerated. - In children and adolescents over 70 kg body weight and adults administered strong CYP2D6 inhibitors, e.g., paroxetine, fluoxetine, and quinidine, Atomoxetine should be initiated at 40 mg/day and only increased to the usual target dose of 80 mg/day if symptoms fail to improve after 4 weeks and the initial dose is well tolerated. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Atomoxetine in pediatric patients. ### Non–Guideline-Supported Use - Dosing Information - 0.5 mg/kg daily for 3 days, followed by 1 mg/kg/day for the next 3 days and then increased to 1.5 mg/kg/day. # Contraindications - Hypersensitivity - Atomoxetine is contraindicated in patients known to be hypersensitive to atomoxetine or other constituents of the product. - Monoamine Oxidase Inhibitors (MAOI) - Atomoxetine should not be taken with an MAOI, or within 2 weeks after discontinuing an MAOI. Treatment with an MAOI should not be initiated within 2 weeks after discontinuing Atomoxetine. With other drugs that affect brain monoamine concentrations, there have been reports of serious, sometimes fatal reactions (including hyperthermia, rigidity, myoclonus, autonomic instability with possible rapid fluctuations of vital signs, and mental status changes that include extreme agitation progressing to delirium and coma) when taken in combination with an MAOI. Some cases presented with features resembling neuroleptic malignant syndrome. Such reactions may occur when these drugs are given concurrently or in close proximity. - Narrow Angle Glaucoma - In clinical trials, Atomoxetine use was associated with an increased risk of mydriasis and therefore its use is not recommended in patients with narrow angle glaucoma. - Pheochromocytoma - Serious reactions, including elevated blood pressure and tachyarrhythmia, have been reported in patients with pheochromocytoma or a history of pheochromocytoma who received Atomoxetine. Therefore, Atomoxetine should not be taken by patients with pheochromocytoma or a history of pheochromocytoma. - Severe Cardiovascular Disorders - Atomoxetine should not be used in patients with severe cardiac or vascular disorders whose condition would be expected to deteriorate if they experience increases in blood pressure or heart rate that could be clinically important (for example, 15 to 20 mm Hg in blood pressure or 20 beats per minute in heart rate). # Warnings ### Precautions - Suicidal Ideation - Atomoxetine increased the risk of suicidal ideation in short-term studies in children and adolescents with Attention-Deficit/Hyperactivity Disorder (ADHD). Pooled analyses of short-term (6 to 18 weeks) placebo-controlled trials of Atomoxetine in children and adolescents have revealed a greater risk of suicidal ideation early during treatment in those receiving Atomoxetine. There were a total of 12 trials (11 in ADHD and 1 in enuresis) involving over 2200 patients (including 1357 patients receiving Atomoxetine and 851 receiving placebo). The average risk of suicidal ideation in patients receiving Atomoxetine was 0.4% (5/1357 patients), compared to none in placebo-treated patients. There was 1 suicide attempt among these approximately 2200 patients, occurring in a patient treated with Atomoxetine. No suicides occurred in these trials. All reactions occurred in children 12 years of age or younger. All reactions occurred during the first month of treatment. It is unknown whether the risk of suicidal ideation in pediatric patients extends to longer-term use. A similar analysis in adult patients treated with Atomoxetine for either ADHD or major depressive disorder (MDD) did not reveal an increased risk of suicidal ideation or behavior in association with the use of Atomoxetine. - All pediatric patients being treated with Atomoxetine should be monitored appropriately and observed closely for clinical worsening, suicidality, and unusual changes in behavior, especially during the initial few months of a course of drug therapy, or at times of dose changes, either increases or decreases. - The following symptoms have been reported with Atomoxetine: anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania and mania. Although a causal link between the emergence of such symptoms and the emergence of suicidal impulses has not been established, there is a concern that such symptoms may represent precursors to emerging suicidality. Thus, patients being treated with Atomoxetine should be observed for the emergence of such symptoms. - Consideration should be given to changing the therapeutic regimen, including possibly discontinuing the medication, in patients who are experiencing emergent suicidality or symptoms that might be precursors to emerging suicidality, especially if these symptoms are severe or abrupt in onset, or were not part of the patient's presenting symptoms. - Families and caregivers of pediatric patients being treated with Atomoxetine should be alerted about the need to monitor patients for the emergence of agitation, irritability, unusual changes in behavior, and the other symptoms described above, as well as the emergence of suicidality, and to report such symptoms immediately to healthcare providers. Such monitoring should include daily observation by families and caregivers. - Severe Liver Injury - Postmarketing reports indicate that Atomoxetine can cause severe liver injury. Although no evidence of liver injury was detected in clinical trials of about 6000 patients, there have been rare cases of clinically significant liver injury that were considered probably or possibly related to Atomoxetine use in postmarketing experience. Rare cases of liver failure have also been reported, including a case that resulted in a liver transplant. Because of probable underreporting, it is impossible to provide an accurate estimate of the true incidence of these reactions. Reported cases of liver injury occurred within 120 days of initiation of atomoxetine in the majority of cases and some patients presented with markedly elevated liver enzymes [>20 X upper limit of normal (ULN)], and jaundice with significantly elevated bilirubin levels (>2 X ULN), followed by recovery upon atomoxetine discontinuation. In one patient, liver injury, manifested by elevated hepatic enzymes up to 40 X ULN and jaundice with bilirubin up to 12 X ULN, recurred upon rechallenge, and was followed by recovery upon drug discontinuation, providing evidence that Atomoxetine likely caused the liver injury. Such reactions may occur several months after therapy is started, but laboratory abnormalities may continue to worsen for several weeks after drug is stopped. The patient described above recovered from his liver injury, and did not require a liver transplant. - Atomoxetine should be discontinued in patients with jaundice or laboratory evidence of liver injury, and should not be restarted. Laboratory testing to determine liver enzyme levels should be done upon the first symptom or sign of liver dysfunction (e.g., pruritus, dark urine, jaundice, right upper quadrant tenderness, or unexplained “flu like” symptoms). - Serious Cardiovascular Events - Sudden Death and Pre-existing Structural Cardiac Abnormalities or Other Serious Heart Problems - Children and Adolescents — Sudden death has been reported in association with atomoxetine treatment at usual doses in children and adolescents with structural cardiac abnormalities or other serious heart problems. Although some serious heart problems alone carry an increased risk of sudden death, atomoxetine generally should not be used in children or adolescents with known serious structural cardiac abnormalities, cardiomyopathy, serious heart rhythm abnormalities, or other serious cardiac problems that may place them at increased vulnerability to the noradrenergic effects of atomoxetine. - Adults — Sudden deaths, stroke, and myocardial infarction have been reported in adults taking atomoxetine at usual doses for ADHD. Although the role of atomoxetine in these adult cases is also unknown, adults have a greater likelihood than children of having serious structural cardiac abnormalities, cardiomyopathy, serious heart rhythm abnormalities, coronary artery disease, or other serious cardiac problems. Consideration should be given to not treating adults with clinically significant cardiac abnormalities. - Assessing Cardiovascular Status in Patients being Treated with Atomoxetine - Children, adolescents, or adults who are being considered for treatment with atomoxetine should have a careful history (including assessment for a family history of sudden death or ventricular arrhythmia) and physical exam to assess for the presence of cardiac disease, and should receive further cardiac evaluation if findings suggest such disease (e.g., electrocardiogram and echocardiogram). Patients who develop symptoms such as exertional chest pain, unexplained syncope, or other symptoms suggestive of cardiac disease during atomoxetine treatment should undergo a prompt cardiac evaluation. - Effects on Blood Pressure and Heart Rate - Atomoxetine should be used with caution in patients whose underlying medical conditions could be worsened by increases in blood pressure or heart rate such as certain patients with hypertension, tachycardia, or cardiovascular or cerebrovascular disease. It should not be used in patients with severe cardiac or vascular disorders whose condition would be expected to deteriorate if they experienced clinically important increases in blood pressure or heart rate. Pulse and blood pressure should be measured at baseline, following Atomoxetine dose increases, and periodically while on therapy to detect possible clinically important increases. - The following table provides short-term, placebo-controlled clinical trial data for the proportions of patients having an increase in: diastolic blood pressure ≥15 mm Hg; systolic blood pressure ≥20 mm Hg; heart rate greater than or equal to 20 bpm, in both the pediatric and adult populations (see Table 1). - In placebo-controlled registration studies involving pediatric patients, tachycardia was identified as an adverse event for 0.3% (5/1597) of these Atomoxetine patients compared with 0% (0/934) of placebo patients. The mean heart rate increase in extensive metabolizer (EM) patients was 5.0 beats/minute, and in poor metabolizer (PM) patients 9.4 beats/minute. - In adult clinical trials where EM/PM status was available, the mean heart rate increase in PM patients was significantly higher than in EM patients (11 beats/minute versus 7.5 beats/minute). The heart rate effects could be clinically important in some PM patients. - In placebo-controlled registration studies involving adult patients, tachycardia was identified as an adverse event for 1.5% (8/540) of Atomoxetine patients compared with 0.5% (2/402) of placebo patients. - In adult clinical trials where EM/PM status was available, the mean change from baseline in diastolic blood pressure in PM patients was higher than in EM patients (4.21 versus 2.13 mm Hg) as was the mean change from baseline in systolic blood pressure (PM: 2.75 versus EM: 2.40 mm Hg). The blood pressure effects could be clinically important in some PM patients. - Orthostatic hypotension and syncope have been reported in patients taking Atomoxetine. In child and adolescent registration studies, 0.2% (12/5596) of Atomoxetine-treated patients experienced orthostatic hypotension and 0.8% (46/5596) experienced syncope. In short-term child and adolescent registration studies, 1.8% (6/340) of Atomoxetine-treated patients experienced orthostatic hypotension compared with 0.5% (1/207) of placebo-treated patients. Syncope was not reported during short-term child and adolescent placebo-controlled ADHD registration studies. Atomoxetine should be used with caution in any condition that may predispose patients to hypotension, or conditions associated with abrupt heart rate or blood pressure changes. - Emergence of New Psychotic or Manic Symptoms - Treatment emergent psychotic or manic symptoms, e.g., hallucinations, delusional thinking, or mania in children and adolescents without a prior history of psychotic illness or mania can be caused by atomoxetine at usual doses. If such symptoms occur, consideration should be given to a possible causal role of atomoxetine, and discontinuation of treatment should be considered. In a pooled analysis of multiple short-term, placebo-controlled studies, such symptoms occurred in about 0.2% (4 patients with reactions out of 1939 exposed to atomoxetine for several weeks at usual doses) of atomoxetine-treated patients compared to 0 out of 1056 placebo-treated patients. - Screening Patients for Bipolar Disorder - In general, particular care should be taken in treating ADHD in patients with comorbid bipolar disorder because of concern for possible induction of a mixed/manic episode in patients at risk for bipolar disorder. Whether any of the symptoms described above represent such a conversion is unknown. However, prior to initiating treatment with Atomoxetine, patients with comorbid depressive symptoms should be adequately screened to determine if they are at risk for bipolar disorder; such screening should include a detailed psychiatric history, including a family history of suicide, bipolar disorder, and depression. - Aggressive Behavior or Hostility - Patients beginning treatment for ADHD should be monitored for the appearance or worsening of aggressive behavior or hostility. Aggressive behavior or hostility is often observed in children and adolescents with ADHD. In pediatric short-term controlled clinical trials, 21/1308 (1.6%) of atomoxetine patients versus 9/806 (1.1%) of placebo-treated patients spontaneously reported treatment emergent hostility-related adverse events (overall risk ratio of 1.33 [95% C.I. 0.67-2.64 – not statistically significant]). In adult placebo-controlled clinical trials, 6/1697 (0.35%) of atomoxetine patients versus 4/1560 (0.26%) of placebo-treated patients spontaneously reported treatment emergent hostility-related adverse events (overall risk ratio of 1.38 [95% C.I. 0.39-4.88 – not statistically significant]). Although this is not conclusive evidence that Atomoxetine causes aggressive behavior or hostility, these behaviors were more frequently observed in clinical trials among children, adolescents, and adults treated with Atomoxetine compared to placebo. - Allergic Events - Although uncommon, allergic reactions, including anaphylactic reactions, angioneurotic edema, urticaria, and rash, have been reported in patients taking Atomoxetine. - Effects on Urine Outflow from the Bladder - In adult ADHD controlled trials, the rates of urinary retention (1.7%, 9/540) and urinary hesitation (5.6%, 30/540) were increased among atomoxetine subjects compared with placebo subjects (0%, 0/402 ; 0.5%, 2/402, respectively). Two adult atomoxetine subjects and no placebo subjects discontinued from controlled clinical trials because of urinary retention. A complaint of urinary retention or urinary hesitancy should be considered potentially related to atomoxetine. - Priapism - Rare postmarketing cases of priapism, defined as painful and nonpainful penile erection lasting more than 4 hours, have been reported for pediatric and adult patients treated with Atomoxetine. The erections resolved in cases in which follow-up information was available, some following discontinuation of Atomoxetine. Prompt medical attention is required in the event of suspected priapism. - Effects on Growth - Data on the long-term effects of Atomoxetine on growth come from open-label studies, and weight and height changes are compared to normative population data. In general, the weight and height gain of pediatric patients treated with Atomoxetine lags behind that predicted by normative population data for about the first 9-12 months of treatment. Subsequently, weight gain rebounds and at about 3 years of treatment, patients treated with Atomoxetine have gained 17.9 kg on average, 0.5 kg more than predicted by their baseline data. After about 12 months, gain in height stabilizes, and at 3 years, patients treated with Atomoxetine have gained 19.4 cm on average, 0.4 cm less than predicted by their baseline data (see Figure 1 below). - This growth pattern was generally similar regardless of pubertal status at the time of treatment initiation. Patients who were pre-pubertal at the start of treatment (girls ≤8 years old, boys ≤9 years old) gained an average of 2.1 kg and 1.2 cm less than predicted after three years. Patients who were pubertal (girls >8 to ≤13 years old, boys >9 to ≤14 years old) or late pubertal (girls >13 years old, boys >14 years old) had average weight and height gains that were close to or exceeded those predicted after three years of treatment. - Growth followed a similar pattern in both extensive and poor metabolizers (EMs, PMs). PMs treated for at least two years gained an average of 2.4 kg and 1.1 cm less than predicted, while EMs gained an average of 0.2 kg and 0.4 cm less than predicted. - In short-term controlled studies (up to 9 weeks), Atomoxetine-treated patients lost an average of 0.4 kg and gained an average of 0.9 cm, compared to a gain of 1.5 kg and 1.1 cm in the placebo-treated patients. In a fixed-dose controlled trial, 1.3%, 7.1%, 19.3%, and 29.1% of patients lost at least 3.5% of their body weight in the placebo, 0.5, 1.2, and 1.8 mg/kg/day dose groups. - Growth should be monitored during treatment with Atomoxetine. - Laboratory Tests - Routine laboratory tests are not required. - CYP2D6 metabolism — Poor metabolizers (PMs) of CYP2D6 have a 10-fold higher AUC and a 5-fold higher peak concentration to a given dose of Atomoxetine compared with extensive metabolizers (EMs). Approximately 7% of a Caucasian population are PMs. Laboratory tests are available to identify CYP2D6 PMs. The blood levels in PMs are similar to those attained by taking strong inhibitors of CYP2D6. The higher blood levels in PMs lead to a higher rate of some adverse effects of Atomoxetine. - Concomitant Use of Potent CYP2D6 Inhibitors or Use in patients who are known to be CYP2D6 PMs - Atomoxetine is primarily metabolized by the CYP2D6 pathway to 4-hydroxyatomoxetine. Dosage adjustment of Atomoxetine may be necessary when coadministered with potent CYP2D6 inhibitors (e.g., paroxetine, fluoxetine, and quinidine) or when administered to CYP2D6 PMs. # Adverse Reactions ## Clinical Trials Experience - Atomoxetine was administered to 5382 children or adolescent patients with ADHD and 1007 adults with ADHD in clinical studies. During the ADHD clinical trials, 1625 children and adolescent patients were treated for longer than 1 year and 2529 children and adolescent patients were treated for over 6 months. - Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. - Reasons for discontinuation of treatment due to adverse reactions in child and adolescent clinical trials — In acute child and adolescent placebo-controlled trials, 3.0% (48/1613) of atomoxetine subjects and 1.4% (13/945) placebo subjects discontinued for adverse reactions. For all studies, (including open-label and long-term studies), 6.3% of extensive metabolizer (EM) patients and 11.2% of poor metabolizer (PM) patients discontinued because of an adverse reaction. Among Atomoxetine-treated patients, irritability (0.3%, N=5); somnolence (0.3%, N=5); aggression (0.2%, N=4); nausea (0.2%, N=4); vomiting (0.2%, N=4); abdominal pain (0.2%, N=4); constipation (0.1%, N=2); fatigue (0.1%, N=2); feeling abnormal (0.1%, N=2); and headache (0.1%, N=2) were the reasons for discontinuation reported by more than 1 patient. - Seizures — Atomoxetine has not been systematically evaluated in pediatric patients with seizure disorder as these patients were excluded from clinical studies during the product's premarket testing. In the clinical development program, seizures were reported in 0.2% (12/5073) of children whose average age was 10 years (range 6 to 16 years). In these clinical trials, the seizure risk among poor metabolizers was 0.3% (1/293) compared to 0.2% (11/4741) for extensive metabolizers. - Commonly observed adverse reactions in acute child and adolescent, placebo-controlled trials — Commonly observed adverse reactions associated with the use of Atomoxetine (incidence of 2% or greater) and not observed at an equivalent incidence among placebo-treated patients (Atomoxetine incidence greater than placebo) are listed in Table 2. Results were similar in the BID and the QD trial except as shown in Table 3, which shows both BID and QD results for selected adverse reactions based on statistically significant Breslow-Day tests. The most commonly observed adverse reactions in patients treated with Atomoxetine (incidence of 5% or greater and at least twice the incidence in placebo patients, for either BID or QD dosing) were: nausea, vomiting, fatigue, decreased appetite, abdominal pain, and somnolence (see Tables 2 and 3). - Additional data from ADHD clinical trials (controlled and uncontrolled) has shown that approximately 5 to 10% of pediatric patients experienced potentially clinically important changes in heart rate (≥20 beats per min) or blood pressure (≥15 to 20 mm Hg). - The following adverse reactions occurred in at least 2% of child and adolescent CYP2D6 PM patients and were statistically significantly more frequent in PM patients compared with CYP2D6 EM patients: insomnia (11% of PMs, 6% of EMs); weight decreased (7% of PMs, 4% of EMs); constipation (7% of PMs, 4% of EMs); depression (7% of PMs, 4% of EMs); tremor (5% of PMs, 1% of EMs); excoriation (4% of PMs, 2% of EMs); middle insomnia (3% of PMs, 1% of EMs); conjunctivitis (3% of PMs, 1% of EMs); syncope (3% of PMs, 1% of EMs); early morning awakening (2% of PMs, 1% of EMs); mydriasis (2% of PMs, 1% of EMs); sedation (4% of PMs, 2% of EMs). - Depression includes the following terms: depression, major depression, depressive symptoms, depressed mood, dysphoria. - Reasons for discontinuation of treatment due to adverse reactions in acute adult placebo-controlled trials — In the acute adult placebo-controlled trials, 11.3% (61/541) atomoxetine subjects and 3.0% (12/405) placebo subjects discontinued for adverse reactions. Among Atomoxetine-treated patients, insomnia (0.9%, N=5); nausea (0.9%, N=5); chest pain (0.6%, N=3); fatigue (0.6%, N=3); anxiety (0.4%, N=2); erectile dysfunction (0.4%, N=2); mood swings (0.4%, N=2); nervousness (0.4%, N=2); palpitations (0.4%, N=2); and urinary retention (0.4%, N=2) were the reasons for discontinuation reported by more than 1 patient. - Seizures — Atomoxetine has not been systematically evaluated in adult patients with a seizure disorder as these patients were excluded from clinical studies during the product's premarket testing. In the clinical development program, seizures were reported on 0.1% (1/748) of adult patients. In these clinical trials, no poor metabolizers (0/43) reported seizures compared to 0.1% (1/705) for extensive metabolizers. - Commonly observed adverse reactions in acute adult placebo-controlled trials — Commonly observed adverse reactions associated with the use of Atomoxetine (incidence of 2% or greater) and not observed at an equivalent incidence among placebo-treated patients (Atomoxetine incidence greater than placebo) are listed in Table 4. The most commonly observed adverse reactions in patients treated with Atomoxetine (incidence of 5% or greater and at least twice the incidence in placebo patients) were: constipation, dry mouth, nausea, decreased appetite, dizziness, erectile dysfunction, and urinary hesitation (see Table 4). - Additional data from ADHD clinical trials (controlled and uncontrolled) has shown that approximately 5 to 10% of adult patients experienced potentially clinically important changes in heart rate (≥20 beats per min) or blood pressure (≥15 to 20 mm Hg). - The following adverse events occurred in at least 2% of adult CYP2D6 poor metaboliser (PM) patients and were statistically significantly more frequent in PM patients compared to CYP2D6 extensive metaboliser (EM) patients: vision blurred (4% of PMs, 1% of EMs); dry mouth (35% of PMs, 17% of EMs); constipation (11% of PMs, 7% of EMs); feeling jittery (5% of PMs, 2% of EMs); decreased appetite (23% of PMs, 15% of EMs); tremor (5% of PMs, 1% of EMs); insomnia (19% of PMs, 11% of EMs); sleep disorder (7% of PMs, 3% of EMs); middle insomnia (5% of PMs, 3% of EMs); terminal insomnia (3% of PMs, 1% of EMs); urinary retention (6% of PMs, 1% of EMs); erectile dysfunction (21% of PMs, 9% of EMs); ejaculation disorder (6% of PMs, 2% of EMs); hyperhidrosis(15% of PMs, 7% of EMs); peripheral coldness (3% of PMs, 1% of EMs). - Male and female sexual dysfunction — Atomoxetine appears to impair sexual function in some patients. Changes in sexual desire, sexual performance, and sexual satisfaction are not well assessed in most clinical trials because they need special attention and because patients and physicians may be reluctant to discuss them. Accordingly, estimates of the incidence of untoward sexual experience and performance cited in product labeling are likely to underestimate the actual incidence. Table 4 above displays the incidence of sexual side effects reported by at least 2% of adult patients taking Atomoxetine in placebo-controlled trials. - There are no adequate and well-controlled studies examining sexual dysfunction with Atomoxetine treatment. While it is difficult to know the precise risk of sexual dysfunction associated with the use of Atomoxetine, physicians should routinely inquire about such possible side effects. ## Postmarketing Experience - The following adverse reactions have been identified during post approval use of Atomoxetine. Unless otherwise specified, these adverse reactions have occurred in adults and children and adolescents. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. QT prolongation, syncope. Raynaud's phenomenon. Lethargy. Hypoaesthesia; paraesthesia in children and adolescents; sensory disturbances; tics. Depression and depressed mood; anxiety, libido changes. - Seizures - Seizures have been reported in the postmarketing period. The postmarketing seizure cases include patients with pre-existing seizure disorders and those with identified risk factors for seizures, as well as patients with neither a history of nor identified risk factors for seizures. The exact relationship between Atomoxetine and seizures is difficult to evaluate due to uncertainty about the background risk of seizures in ADHD patients. Hyperhidrosis. Male pelvic pain; urinary hesitation in children and adolescents; urinary retention in children and adolescents. # Drug Interactions - Monoamine Oxidase Inhibitors - With other drugs that affect brain monoamine concentrations, there have been reports of serious, sometimes fatal reactions (including hyperthermia, rigidity, myoclonus, autonomic instability with possible rapid fluctuations of vital signs, and mental status changes that include extreme agitation progressing to delirium and coma) when taken in combination with an MAOI. Some cases presented with features resembling neuroleptic malignant syndrome. Such reactions may occur when these drugs are given concurrently or in close proximity. - Effect of CYP2D6 Inhibitors on Atomoxetine - In extensive metabolizers (EMs), inhibitors of CYP2D6 (e.g., paroxetine, fluoxetine, and quinidine) increase atomoxetine steady-state plasma concentrations to exposures similar to those observed in poor metabolizers (PMs). In EM individuals treated with paroxetine or fluoxetine, the AUC of atomoxetine is approximately 6- to 8-fold and Css, max is about 3- to 4-fold greater than atomoxetine alone. - In vitro studies suggest that coadministration of cytochrome P450 inhibitors to PMs will not increase the plasma concentrations of atomoxetine. - Antihypertensive Drugs and Pressor Agents - Because of possible effects on blood pressure, Atomoxetine should be used cautiously with antihypertensive drugs and pressor agents (e.g., dopamine, dobutamine) or other drugs that increase blood pressure. - Albuterol - Atomoxetine should be administered with caution to patients being treated with systemically-administered (oral or intravenous) albuterol (or other beta2 agonists) because the action of albuterol on the cardiovascular system can be potentiated resulting in increases in heart rate and blood pressure. Albuterol (600 mcg iv over 2 hours) induced increases in heart rate and blood pressure. These effects were potentiated by atomoxetine (60 mg BID for 5 days) and were most marked after the initial coadministration of albuterol and atomoxetine. However, these effects on heart rate and blood pressure were not seen in another study after the coadministration with inhaled dose of albuterol (200-800 mcg) and atomoxetine (80 mg QD for 5 days) in 21 healthy Asian subjects who were excluded for poor metabolizer status. - Effect of Atomoxetine on P450 Enzymes - Atomoxetine did not cause clinically important inhibition or induction of cytochrome P450 enzymes, including CYP1A2, CYP3A, CYP2D6, and CYP2C9. - CYP3A Substrate (e.g., Midazolam) — Coadministration of Atomoxetine (60 mg BID for 12 days) with midazolam, a model compound for CYP3A4 metabolized drugs (single dose of 5 mg), resulted in 15% increase in AUC of midazolam. No dose adjustment is recommended for drugs metabolized by CYP3A. - CYP2D6 Substrate (e.g., Desipramine) — Coadministration of Atomoxetine (40 or 60 mg BID for 13 days) with desipramine, a model compound for CYP2D6 metabolized drugs (single dose of 50 mg), did not alter the pharmacokinetics of desipramine. No dose adjustment is recommended for drugs metabolized by CYP2D6. - Alcohol - Consumption of ethanol with Atomoxetine did not change the intoxicating effects of ethanol. - Methylphenidate - Coadministration of methylphenidate with Atomoxetine did not increase cardiovascular effects beyond those seen with methylphenidate alone. - Drugs Highly Bound to Plasma Protein - In vitro drug-displacement studies were conducted with atomoxetine and other highly-bound drugs at therapeutic concentrations. Atomoxetine did not affect the binding of warfarin, acetylsalicylic acid, phenytoin, or diazepam to human albumin. Similarly, these compounds did not affect the binding of atomoxetine to human albumin. - Drugs that Affect Gastric pH - Drugs that elevate gastric pH (magnesium hydroxide/aluminum hydroxide, omeprazole) had no effect on Atomoxetine bioavailability. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): - Pregnancy Category C - Pregnant rabbits were treated with up to 100 mg/kg/day of atomoxetine by gavage throughout the period of organogenesis. At this dose, in 1 of 3 studies, a decrease in live fetuses and an increase in early resorptions was observed. Slight increases in the incidences of atypical origin of carotid artery and absent subclavian artery were observed. These findings were observed at doses that caused slight maternal toxicity. The no-effect dose for these findings was 30 mg/kg/day. The 100 mg/kg dose is approximately 23 times the maximum human dose on a mg/m2 basis; plasma levels (AUC) of atomoxetine at this dose in rabbits are estimated to be 3.3 times (extensive metabolizers) or 0.4 times (poor metabolizers) those in humans receiving the maximum human dose. - Rats were treated with up to approximately 50 mg/kg/day of atomoxetine (approximately 6 times the maximum human dose on a mg/m2 basis) in the diet from 2 weeks (females) or 10 weeks (males) prior to mating through the periods of organogenesis and lactation. In 1 of 2 studies, decreases in pup weight and pup survival were observed. The decreased pup survival was also seen at 25 mg/kg (but not at 13 mg/kg). In a study in which rats were treated with atomoxetine in the diet from 2 weeks (females) or 10 weeks (males) prior to mating throughout the period of organogenesis, a decrease in fetal weight (female only) and an increase in the incidence of incomplete ossification of the vertebral arch in fetuses were observed at 40 mg/kg/day (approximately 5 times the maximum human dose on a mg/m2 basis) but not at 20 mg/kg/day. - No adverse fetal effects were seen when pregnant rats were treated with up to 150 mg/kg/day (approximately 17 times the maximum human dose on a mg/m2 basis) by gavage throughout the period of organogenesis. - No adequate and well-controlled studies have been conducted in pregnant women. Atomoxetine should not be used during pregnancy unless the potential benefit justifies the potential risk to the fetus. Pregnancy Category (AUS): - Australian Drug Evaluation Committee (ADEC) Pregnancy Category There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Atomoxetine in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Atomoxetine during labor and delivery. ### Nursing Mothers - Atomoxetine and/or its metabolites were excreted in the milk of rats. It is not known if atomoxetine is excreted in human milk. Caution should be exercised if Atomoxetine is administered to a nursing woman. ### Pediatric Use - Anyone considering the use of Atomoxetine in a child or adolescent must balance the potential risks with the clinical need. - The pharmacokinetics of atomoxetine in children and adolescents are similar to those in adults. The safety, efficacy, and pharmacokinetics of Atomoxetine in pediatric patients less than 6 years of age have not been evaluated. - A study was conducted in young rats to evaluate the effects of atomoxetine on growth and neurobehavioral and sexual development. Rats were treated with 1, 10, or 50 mg/kg/day (approximately 0.2, 2, and 8 times, respectively, the maximum human dose on a mg/m2 basis) of atomoxetine given by gavage from the early postnatal period (Day 10 of age) through adulthood. Slight delays in onset of vaginal patency (all doses) and preputial separation (10 and 50 mg/kg), slight decreases in epididymal weight and sperm number (10 and 50 mg/kg), and a slight decrease in corpora lutea (50 mg/kg) were seen, but there were no effects on fertility or reproductive performance. A slight delay in onset of incisor eruption was seen at 50 mg/kg. A slight increase in motor activity was seen on Day 15 (males at 10 and 50 mg/kg and females at 50 mg/kg) and on Day 30 (females at 50 mg/kg) but not on Day 60 of age. There were no effects on learning and memory tests. The significance of these findings to humans is unknown. ### Geriatic Use There is no FDA guidance on the use of Atomoxetine with respect to geriatric patients. ### Gender There is no FDA guidance on the use of Atomoxetine with respect to specific gender populations. ### Race There is no FDA guidance on the use of Atomoxetine with respect to specific racial populations. ### Renal Impairment - EM subjects with end stage renal disease had higher systemic exposure to atomoxetine than healthy subjects (about a 65% increase), but there was no difference when exposure was corrected for mg/kg dose. Atomoxetine can therefore be administered to ADHD patients with end stage renal disease or lesser degrees of renal insufficiency using the normal dosing regimen. ### Hepatic Impairment - Atomoxetine exposure (AUC) is increased, compared with normal subjects, in EM subjects with moderate (Child-Pugh Class B) (2-fold increase) and severe (Child-Pugh Class C) (4-fold increase) hepatic insufficiency. Dosage adjustment is recommended for patients with moderate or severe hepatic insufficiency. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Atomoxetine in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Atomoxetine in patients who are immunocompromised. # Administration and Monitoring ### Administration - Oral ### Monitoring There is limited information regarding Monitoring of Atomoxetine in the drug label. - Description # IV Compatibility There is limited information regarding IV Compatibility of Atomoxetine in the drug label. # Overdosage ## Acute Overdose ### Signs and Symptoms - No fatal overdoses occurred in clinical trials. There is limited clinical trial experience with Atomoxetine overdose. During postmarketing, there have been fatalities reported involving a mixed ingestion overdose of Atomoxetine and at least one other drug. There have been no reports of death involving overdose of Atomoxetine alone, including intentional overdoses at amounts up to 1400 mg. In some cases of overdose involving Atomoxetine, seizures have been reported. The most commonly reported symptoms accompanying acute and chronic overdoses of Atomoxetine were gastrointestinal symptoms, somnolence, dizziness, tremor, and abnormal behavior. Hyperactivity and agitation have also been reported. Signs and symptoms consistent with mild to moderate sympathetic nervous system activation (e.g., tachycardia, blood pressure increased, mydriasis, dry mouth) have also been observed. Most events were mild to moderate. Less commonly, there have been reports of QT prolongation and mental changes, including disorientation and hallucinations. ### Management - Consult with a Certified Poison Control Center for up to date guidance and advice. Because atomoxetine is highly protein-bound, dialysis is not likely to be useful in the treatment of overdose. ## Chronic Overdose There is limited information regarding Chronic Overdose of Atomoxetine in the drug label. # Pharmacology ## Mechanism of Action - The precise mechanism by which atomoxetine produces its therapeutic effects in Attention-Deficit/Hyperactivity Disorder (ADHD) is unknown, but is thought to be related to selective inhibition of the pre-synaptic norepinephrine transporter, as determined in ex vivo uptake and neurotransmitter depletion studies. ## Structure - Atomoxetine® (atomoxetine) is a selective norepinephrine reuptake inhibitor. Atomoxetine HCl is the R(-) isomer as determined by x-ray diffraction. The chemical designation is (-)-N-Methyl-3-phenyl-3-(o-tolyloxy)-propylamine hydrochloride. The molecular formula is C17H21NO•HCl, which corresponds to a molecular weight of 291.82. The chemical structure is: - Atomoxetine HCl is a white to practically white solid, which has a solubility of 27.8 mg/mL in water. - Atomoxetine capsules are intended for oral administration only. - Each capsule contains atomoxetine HCl equivalent to 10, 18, 25, 40, 60, 80, or 100 mg of atomoxetine. The capsules also contain pregelatinized starch and dimethicone. The capsule shells contain gelatin, sodium lauryl sulfate, and other inactive ingredients. The capsule shells also contain one or more of the following: - FD&C Blue No. 2, synthetic yellow iron oxide, titanium dioxide, red iron oxide. The capsules are imprinted with edible black ink. ## Pharmacodynamics - An exposure-response analysis encompassing doses of atomoxetine (0.5, 1.2 or 1.8 mg/kg/day) or placebo demonstrated atomoxetine exposure correlates with efficacy as measured by the Attention-Deficit/Hyperactivity Disorder Rating Scale-IV-Parent Version: Investigator administered and scored. The exposure-efficacy relationship was similar to that observed between dose and efficacy with median exposures at the two highest doses resulting in near maximal changes from baseline. - Cardiac Electrophysiology — The effect of Atomoxetine on QT prolongation was evaluated in a randomized, double-blinded, positive-(moxifloxacin 400 mg) and placebo-controlled, cross-over study in healthy male CYP2D6 poor metabolizers. A total of 120 healthy subjects were administered Atomoxetine (20 mg and 60 mg) twice daily for 7 days. No large changes in QTc interval (i.e., increases >60 msec from baseline, absolute QTc >480 msec) were observed in the study. However, small changes in QTc interval cannot be excluded from the current study, because the study failed to demonstrate assay sensitivity. There was a slight increase in QTc interval with increased atomoxetine concentration. ## Pharmacokinetics - Atomoxetine is well-absorbed after oral administration and is minimally affected by food. It is eliminated primarily by oxidative metabolism through the cytochrome P450 2D6 (CYP2D6) enzymatic pathway and subsequent glucuronidation. Atomoxetine has a half-life of about 5 hours. A fraction of the population (about 7% of Caucasians and 2% of African Americans) are poor metabolizers (PMs) of CYP2D6 metabolized drugs. These individuals have reduced activity in this pathway resulting in 10-fold higher AUCs, 5-fold higher peak plasma concentrations, and slower elimination (plasma half-life of about 24 hours) of atomoxetine compared with people with normal activity [extensive metabolizers (EMs)]. Drugs that inhibit CYP2D6, such as fluoxetine, paroxetine, and quinidine, cause similar increases in exposure. - The pharmacokinetics of atomoxetine have been evaluated in more than 400 children and adolescents in selected clinical trials, primarily using population pharmacokinetic studies. Single-dose and steady-state individual pharmacokinetic data were also obtained in children, adolescents, and adults. When doses were normalized to a mg/kg basis, similar half-life, Cmax, and AUC values were observed in children, adolescents, and adults. Clearance and volume of distribution after adjustment for body weight were also similar. - Absorption and distribution — Atomoxetine is rapidly absorbed after oral administration, with absolute bioavailability of about 63% in EMs and 94% in PMs. Maximal plasma concentrations (Cmax) are reached approximately 1 to 2 hours after dosing. - Atomoxetine can be administered with or without food. Administration of Atomoxetine with a standard high-fat meal in adults did not affect the extent of oral absorption of atomoxetine (AUC), but did decrease the rate of absorption, resulting in a 37% lower Cmax, and delayed Tmax by 3 hours. In clinical trials with children and adolescents, administration of Atomoxetine with food resulted in a 9% lower Cmax. - The steady-state volume of distribution after intravenous administration is 0.85 L/kg indicating that atomoxetine distributes primarily into total body water. Volume of distribution is similar across the patient weight range after normalizing for body weight. - At therapeutic concentrations, 98% of atomoxetine in plasma is bound to protein, primarily albumin. - Metabolism and elimination — Atomoxetine is metabolized primarily through the CYP2D6 enzymatic pathway. People with reduced activity in this pathway (PMs) have higher plasma concentrations of atomoxetine compared with people with normal activity (EMs). For PMs, AUC of atomoxetine is approximately 10-fold and Css, max is about 5-fold greater than EMs. Laboratory tests are available to identify CYP2D6 PMs. Coadministration of Atomoxetine with potent inhibitors of CYP2D6, such as fluoxetine, paroxetine, or quinidine, results in a substantial increase in atomoxetine plasma exposure, and dosing adjustment may be necessary. Atomoxetine did not inhibit or induce the CYP2D6 pathway. - The major oxidative metabolite formed, regardless of CYP2D6 status, is 4-hydroxyatomoxetine, which is glucuronidated. 4-Hydroxyatomoxetine is equipotent to atomoxetine as an inhibitor of the norepinephrine transporter but circulates in plasma at much lower concentrations (1% of atomoxetine concentration in EMs and 0.1% of atomoxetine concentration in PMs). 4-Hydroxyatomoxetine is primarily formed by CYP2D6, but in PMs, 4-hydroxyatomoxetine is formed at a slower rate by several other cytochrome P450 enzymes. N-Desmethylatomoxetine is formed by CYP2C19 and other cytochrome P450 enzymes, but has substantially less pharmacological activity compared with atomoxetine and circulates in plasma at lower concentrations (5% of atomoxetine concentration in EMs and 45% of atomoxetine concentration in PMs). - Mean apparent plasma clearance of atomoxetine after oral administration in adult EMs is 0.35 L/hr/kg and the mean half-life is 5.2 hours. Following oral administration of atomoxetine to PMs, mean apparent plasma clearance is 0.03 L/hr/kg and mean half-life is 21.6 hours. For PMs, AUC of atomoxetine is approximately 10-fold and Css, max is about 5-fold greater than EMs. The elimination half-life of 4-hydroxyatomoxetine is similar to that of N-desmethylatomoxetine (6 to 8 hours) in EM subjects, while the half-life of N-desmethylatomoxetine is much longer in PM subjects (34 to 40 hours). - Atomoxetine is excreted primarily as 4-hydroxyatomoxetine-O-glucuronide, mainly in the urine (greater than 80% of the dose) and to a lesser extent in the feces (less than 17% of the dose). Only a small fraction of the Atomoxetine dose is excreted as unchanged atomoxetine (less than 3% of the dose), indicating extensive biotransformation. ## Nonclinical Toxicology - Carcinogenesis — Atomoxetine HCl was not carcinogenic in rats and mice when given in the diet for 2 years at time-weighted average doses up to 47 and 458 mg/kg/day, respectively. The highest dose used in rats is approximately 8 and 5 times the maximum human dose in children and adults, respectively, on a mg/m2 basis. Plasma levels (AUC) of atomoxetine at this dose in rats are estimated to be 1.8 times (extensive metabolizers) or 0.2 times (poor metabolizers) those in humans receiving the maximum human dose. The highest dose used in mice is approximately 39 and 26 times the maximum human dose in children and adults, respectively, on a mg/m2 basis. - Mutagenesis — Atomoxetine HCl was negative in a battery of genotoxicity studies that included a reverse point mutation assay (Ames Test), an in vitro mouse lymphoma assay, a chromosomal aberration test in Chinese hamster ovary cells, an unscheduled DNA synthesis test in rat hepatocytes, and an in vivo micronucleus test in mice. However, there was a slight increase in the percentage of Chinese hamster ovary cells with diplochromosomes, suggesting endoreduplication (numerical aberration). - The metabolite N-desmethylatomoxetine HCl was negative in the Ames Test, mouse lymphoma assay, and unscheduled DNA synthesis test. - Impairment of fertility — Atomoxetine HCl did not impair fertility in rats when given in the diet at doses of up to 57 mg/kg/day, which is approximately 6 times the maximum human dose on a mg/m2 basis. # Clinical Studies - Acute Studies — The effectiveness of Atomoxetine in the treatment of ADHD was established in 4 randomized, double-blind, placebo-controlled studies of pediatric patients (ages 6 to 18). Approximately one-third of the patients met DSM-IV criteria for inattentive subtype and two-thirds met criteria for both inattentive and hyperactive/impulsive subtypes. - Signs and symptoms of ADHD were evaluated by a comparison of mean change from baseline to endpoint for Atomoxetine- and placebo-treated patients using an intent-to-treat analysis of the primary outcome measure, the investigator administered and scored ADHD Rating Scale-IV-Parent Version (ADHDRS) total score including hyperactive/impulsive and inattentive subscales. Each item on the ADHDRS maps directly to one symptom criterion for ADHD in the DSM-IV. - In Study 1, an 8-week randomized, double-blind, placebo-controlled, dose-response, acute treatment study of children and adolescents aged 8 to 18 (N=297), patients received either a fixed dose of Atomoxetine (0.5, 1.2, or 1.8 mg/kg/day) or placebo. Atomoxetine was administered as a divided dose in the early morning and late afternoon/early evening. At the 2 higher doses, improvements in ADHD symptoms were statistically significantly superior in Atomoxetine-treated patients compared with placebo-treated patients as measured on the ADHDRS scale. The 1.8 mg/kg/day Atomoxetine dose did not provide any additional benefit over that observed with the 1.2 mg/kg/day dose. The 0.5 mg/kg/day Atomoxetine dose was not superior to placebo. - In Study 2, a 6-week randomized, double-blind, placebo-controlled, acute treatment study of children and adolescents aged 6 to 16 (N=171), patients received either Atomoxetine or placebo. Atomoxetine was administered as a single dose in the early morning and titrated on a weight-adjusted basis according to clinical response, up to a maximum dose of 1.5 mg/kg/day. The mean final dose of Atomoxetine was approximately 1.3 mg/kg/day. ADHD symptoms were statistically significantly improved on Atomoxetine compared with placebo, as measured on the ADHDRS scale. This study shows that Atomoxetine is effective when administered once daily in the morning. - In 2 identical, 9-week, acute, randomized, double-blind, placebo-controlled studies of children aged 7 to 13 (Study 3, N=147; Study 4, N=144), Atomoxetine and methylphenidate were compared with placebo. Atomoxetine was administered as a divided dose in the early morning and late afternoon (after school) and titrated on a weight-adjusted basis according to clinical response. The maximum recommended Atomoxetine dose was 2.0 mg/kg/day. The mean final dose of Atomoxetine for both studies was approximately 1.6 mg/kg/day. In both studies, ADHD symptoms statistically significantly improved more on Atomoxetine than on placebo, as measured on the ADHDRS scale. - Examination of population subsets based on gender and age (<12 and 12 to 17) did not reveal any differential responsiveness on the basis of these subgroupings. There was not sufficient exposure of ethnic groups other than Caucasian to allow exploration of differences in these subgroups. - Maintenance Study — The effectiveness of Atomoxetine in the maintenance treatment of ADHD was established in an outpatient study of children and adolescents (ages 6-15 years). Patients meeting DSM-IV criteria for ADHD who showed continuous response for about 4 weeks during an initial 10 week open-label treatment phase with Atomoxetine (1.2 to 1.8 mg/kg/day) were randomized to continuation of their current dose of Atomoxetine (N=292) or to placebo (N=124) under double-blind treatment for observation of relapse. Response during the open-label phase was defined as CGI-ADHD-S score ≤2 and a reduction of at least 25% from baseline in ADHDRS-IV-Parent:Inv total score. Patients who were assigned to Atomoxetine and showed continuous response for approximately 8 months during the first double-blind treatment phase were again randomized to continuation of their current dose of Atomoxetine (N=81) or to placebo (N=82) under double-blind treatment for observation of relapse. Relapse during the double-blind phase was defined as CGI-ADHD-S score increases of at least 2 from the end of open-label phase and ADHDRS-IV-Parent:Inv total score returns to ≥90% of study entry score for 2 consecutive visits. In both double-blind phases, patients receiving continued Atomoxetine treatment experienced significantly longer times to relapse than those receiving placebo. - The effectiveness of Atomoxetine in the treatment of ADHD was established in 2 randomized, double-blind, placebo-controlled clinical studies of adult patients, age 18 and older, who met DSM-IV criteria for ADHD. - Signs and symptoms of ADHD were evaluated using the investigator-administered Conners Adult ADHD Rating Scale Screening Version (CAARS), a 30-item scale. The primary effectiveness measure was the 18-item Total ADHD Symptom score (the sum of the inattentive and hyperactivity/impulsivity subscales from the CAARS) evaluated by a comparison of mean change from baseline to endpoint using an intent-to-treat analysis. - In 2 identical, 10-week, randomized, double-blind, placebo-controlled acute treatment studies (Study 5, N=280; Study 6, N=256), patients received either Atomoxetine or placebo. Atomoxetine was administered as a divided dose in the early morning and late afternoon/early evening and titrated according to clinical response in a range of 60 to 120 mg/day. The mean final dose of Atomoxetine for both studies was approximately 95 mg/day. In both studies, ADHD symptoms were statistically significantly improved on Atomoxetine, as measured on the ADHD Symptom score from the CAARS scale. - Examination of population subsets based on gender and age (<42 and ≥42) did not reveal any differential responsiveness on the basis of these subgroupings. There was not sufficient exposure of ethnic groups other than Caucasian to allow exploration of differences in these subgroups. # How Supplied - Store at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F). ## Storage There is limited information regarding Atomoxetine Storage in the drug label. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information - Physicians should instruct their patients to read the Medication Guide before starting therapy with Atomoxetine and to reread it each time the prescription is renewed. - Prescribers or other health professionals should inform patients, their families, and their caregivers about the benefits and risks associated with treatment with Atomoxetine and should counsel them in its appropriate use. The prescriber or health professional should instruct patients, their families, and their caregivers to read the Medication Guide and should assist them in understanding its contents. Patients should be given the opportunity to discuss the contents of the Medication Guide and to obtain answers to any questions they may have. - Patients should be advised of the following issues and asked to alert their prescriber if these occur while taking Atomoxetine. - Patients, their families, and their caregivers should be encouraged to be alert to the emergence of anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, mania, other unusual changes in behavior, depression, and suicidal ideation, especially early during Atomoxetine treatment and when the dose is adjusted. Families and caregivers of patients should be advised to observe for the emergence of such symptoms on a day-to-day basis, since changes may be abrupt. Such symptoms should be reported to the patient's prescriber or health professional, especially if they are severe, abrupt in onset, or were not part of the patient's presenting symptoms. Symptoms such as these may be associated with an increased risk for suicidal thinking and behavior and indicate a need for very close monitoring and possibly changes in the medication. - Patients initiating Atomoxetine should be cautioned that severe liver injury may develop. Patients should be instructed to contact their physician immediately should they develop pruritus, dark urine, jaundice, right upper quadrant tenderness, or unexplained “flu-like” symptoms. - Patients should be instructed to call their doctor as soon as possible should they notice an increase in aggression or hostility. - Rare postmarketing cases of priapism, defined as painful and nonpainful penile erection lasting more than 4 hours, have been reported for pediatric and adult patients treated with Atomoxetine. The parents or guardians of pediatric patients taking Atomoxetine and adult patients taking Atomoxetine should be instructed that priapism requires prompt medical attention. - Atomoxetine is an ocular irritant. Atomoxetine capsules are not intended to be opened. In the event of capsule content coming in contact with the eye, the affected eye should be flushed immediately with water, and medical advice obtained. Hands and any potentially contaminated surfaces should be washed as soon as possible. - Patients should be instructed to consult a physician if they are taking or plan to take any prescription or over-the-counter medicines, dietary supplements, or herbal remedies. - Patients should be instructed to consult a physician if they are nursing, pregnant, or thinking of becoming pregnant while taking Atomoxetine. - Patients may take Atomoxetine with or without food. - If patients miss a dose, they should be instructed to take it as soon as possible, but should not take more than the prescribed total daily amount of Atomoxetine in any 24-hour period. - Patients should be instructed to use caution when driving a car or operating hazardous machinery until they are reasonably certain that their performance is not affected by atomoxetine. # Precautions with Alcohol - Alcohol-Atomoxetine interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - STRATTERA®[4] # Look-Alike Drug Names There is limited information regarding Atomoxetine Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	https://www.wikidoc.org/index.php/Atomoxetine
f727ea6b1ac28871366fa8ce2577b3e3cac3c4bf	wikidoc	Heart valve	Heart valve # Overview In anatomy, the heart valves are valves in the heart that maintain the unidirectional flow of blood by opening and closing depending on the difference in pressure on each side. The mechanical equivalent of the heart valves would be the reed valves. There are four valves of the heart (not counting the valve of the coronary sinus and valve of the inferior vena cava): - The two atrioventricular (AV) valves ensure blood flows from the atria to the ventricles, and not the other way. - The two semilunar (SL) valves are present in the arteries leaving the heart, and they prevent blood flowing back from the arteries into the ventricles. The sound of the heart valves shutting causes the heart sounds. # Atrioventricular valves The atrioventricular valves are large, multicusped valves that prevent backflow from the ventricles into the atria during systole. They are anchored to the wall of the ventricle by chordae tendinae, that prevent the valve from inverting. The chordae tendinae are attached to papillary muscles that cause tension to better hold the valve. Together, the papillary muscles and the chordae tendinae are known as the subvalvular apparatus. The function of the subvalvular apparatus is to keep the valves from prolapsing into the atria when they close. The subvalvular apparatus have no effect on the opening and closure of the valves, however. This is caused entirely by the pressure gradient across the valve. ## Mitral valve Also known as the bicuspid valve, the mitral valve gets its name from the resemblance to a bishop's mitre (a type of hat). It prevents blood flowing from the left ventricle into the left atrium. It is on the left side of the heart and has two leaflets. A common complication of rheumatic fever is thickening and stenosis of the mitral valve. ## Tricuspid valve The tricuspid valve is on the right side of the heart, between the right atrium and the right ventricle. # Semilunar valves The semilunar vlalves are positioned on the pulmonary artery and the aorta. These valves do not have chordae tendinae, but are more similar to valves in veins. ## Aortic valve The aortic valve lies between the left ventricle and the aorta. The aortic valve has three cusps. During ventricular systole, pressure rises in the left ventricle. When the pressure in the left ventricle rises above the pressure in the aorta, the aortic valve opens, allowing blood to exit the left ventricle into the aorta. When ventricular systole ends, pressure in the left ventricle rapidly drops. When the pressure in the left ventricle decreases, the aortic pressure forces the aortic valve to close. The closure of the aortic valve contributes the A2 component of the second heart sound (S2). The most common congenital abnormality of the heart is the bicuspid aortic valve. In this condition, instead of three cusps, the aortic valve has two cusps. This condition is often undiagnosed until the person develops calcific aortic stenosis. Aortic stenosis occurs in this condition usually in patients in their 40s or 50s, an average of over 10 years earlier than in people with normal aortic valves. ## Pulmonic valve The pulmonic valve lies between the right ventricle and the pulmonary artery and also has three cusps. # Pathology of the valves - Endocarditis - inflammation of the inner layer of the endocardium. - Stenosis - a constricture of the heart valve, making it hard for blood to get through. - Insufficiency (also regurgitation or incompetence) - the inability of the heart valve to close properly, meaning some blood can flow the wrong way. - An artificial heart valve may be used to surgically replace a patient's damaged valve. - MV: Mitral valve, TV: Tricuspid valve, AV: Aortic valve, Septum: Interventricular septum. Continuous lines demarkates septum and free wall seen in echocardiogram, dotted line is a suggestion of where the free wall of the right ventricle should be. The red line represents where the upper left loop in the echocardiogram transects the 3D-loop, the blue line represents the lower loop.	Heart valve Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview In anatomy, the heart valves are valves in the heart that maintain the unidirectional flow of blood by opening and closing depending on the difference in pressure on each side. The mechanical equivalent of the heart valves would be the reed valves. There are four valves of the heart (not counting the valve of the coronary sinus and valve of the inferior vena cava): - The two atrioventricular (AV) valves ensure blood flows from the atria to the ventricles, and not the other way. - The two semilunar (SL) valves are present in the arteries leaving the heart, and they prevent blood flowing back from the arteries into the ventricles. The sound of the heart valves shutting causes the heart sounds. # Atrioventricular valves The atrioventricular valves are large, multicusped valves that prevent backflow from the ventricles into the atria during systole. They are anchored to the wall of the ventricle by chordae tendinae, that prevent the valve from inverting. The chordae tendinae are attached to papillary muscles that cause tension to better hold the valve. Together, the papillary muscles and the chordae tendinae are known as the subvalvular apparatus. The function of the subvalvular apparatus is to keep the valves from prolapsing into the atria when they close. The subvalvular apparatus have no effect on the opening and closure of the valves, however. This is caused entirely by the pressure gradient across the valve. ## Mitral valve Also known as the bicuspid valve, the mitral valve gets its name from the resemblance to a bishop's mitre (a type of hat). It prevents blood flowing from the left ventricle into the left atrium. It is on the left side of the heart and has two leaflets. A common complication of rheumatic fever is thickening and stenosis of the mitral valve. ## Tricuspid valve The tricuspid valve is on the right side of the heart, between the right atrium and the right ventricle. # Semilunar valves The semilunar vlalves are positioned on the pulmonary artery and the aorta. These valves do not have chordae tendinae, but are more similar to valves in veins. ## Aortic valve The aortic valve lies between the left ventricle and the aorta. The aortic valve has three cusps. During ventricular systole, pressure rises in the left ventricle. When the pressure in the left ventricle rises above the pressure in the aorta, the aortic valve opens, allowing blood to exit the left ventricle into the aorta. When ventricular systole ends, pressure in the left ventricle rapidly drops. When the pressure in the left ventricle decreases, the aortic pressure forces the aortic valve to close. The closure of the aortic valve contributes the A2 component of the second heart sound (S2). The most common congenital abnormality of the heart is the bicuspid aortic valve. In this condition, instead of three cusps, the aortic valve has two cusps. This condition is often undiagnosed until the person develops calcific aortic stenosis. Aortic stenosis occurs in this condition usually in patients in their 40s or 50s, an average of over 10 years earlier than in people with normal aortic valves. ## Pulmonic valve The pulmonic valve lies between the right ventricle and the pulmonary artery and also has three cusps. # Pathology of the valves - Endocarditis - inflammation of the inner layer of the endocardium. - Stenosis - a constricture of the heart valve, making it hard for blood to get through. - Insufficiency (also regurgitation or incompetence) - the inability of the heart valve to close properly, meaning some blood can flow the wrong way. - An artificial heart valve may be used to surgically replace a patient's damaged valve. - MV: Mitral valve, TV: Tricuspid valve, AV: Aortic valve, Septum: Interventricular septum. Continuous lines demarkates septum and free wall seen in echocardiogram, dotted line is a suggestion of where the free wall of the right ventricle should be. The red line represents where the upper left loop in the echocardiogram transects the 3D-loop, the blue line represents the lower loop.	https://www.wikidoc.org/index.php/Atrioventricular_valves
93e083dd7da88dae1971f6aaa7fc7f7b90d47b94	wikidoc	Atropisomer	Atropisomer Atropisomers are stereoisomers resulting from hindered rotation about single bonds where the steric strain barrier to rotation is high enough to allow for the isolation of the conformers . The word atropisomer is derived from the Greek a which means not and tropos which translates as turn. The name was coined by Kuhn in 1933, but atropisomerism was first detected in 6,6’-dinitro-2,2’-diphenic acid by Cristie in 1922. Oki defined atropisomers as conformers that interconvert with a half-life of more than 1000 seconds at a given temperature. Atropisomers are an important class of compounds because they display axial chirality. They differ from other chiral compounds in that they can be equilibrated thermally whereas in the other forms of chirality isomerization is usually only possible chemically. The most important class of atropisomers are biaryls such as the aforementioned diphenic acid which is a derivative of biphenyl with a complete set of ortho substituents. Others are dimers of naphthalene derivatives such as 1,1'-bi-2-naphthol. In a similar way aliphatic ring systems like cyclohexanes linked through a single bond may display atropisomerism provided that bulky substituents are present. Examples of naturally occurring atropisomers include vancomycin and knipholone which is found in the roots of Kniphofia Foliosa of the family Asphodelaceae. Separation of atropisomers is possibly by chiral resolution methods such as selective crystallization. In an atropo-enantioselective or atropselective synthesis one atropisomer is formed at the expense of the other. Atroposelective synthesis may be carried out by use of chiral auxiliaries like a CBS catalyst in the total synthesis of knipholone or by approaches based on thermodynamic equilibration when an isomerization reaction favors one atropisomer over the other. # Scope In one application the asymmetry in an atropisomer is transferred in a chemical reaction to a new stereocenter . The atropisomer is an iodoaryl compound synthesised starting from (S)-valine and exists as the (M,S) isomer and the (P,S) isomer. The interconversion barrier between the two is 24.3 kcal/mol (101.7 kJ/mol). The (M,S) isomer can be obtained exclusively from this mixture by recrystallisation from hexanes. The iodine group is homolytically removed to form an aryl radical by a tributyltin hydride/triethylboron/oxygen mixture as in the Barton-McCombie reaction. Although the hindered rotation is now removed in the aryl radical the intermolecular reaction with the alkene is so much faster than rotation of the carbon-nitrogen bond that the stereochemistry is preserved. In this way the (M,S) isomer yields the (S,S) dihydroindolone. An axial chirality switch is reported for a diol prepared from intramolecular pinacol coupling of the corresponding di-aldehyde with samarium(II) iodide. In methanol this compound has the two alcohol groups in equatorial positions but in hexane helicity is reversed with both groups in axial positions.	Atropisomer Atropisomers are stereoisomers resulting from hindered rotation about single bonds where the steric strain barrier to rotation is high enough to allow for the isolation of the conformers [1]. The word atropisomer is derived from the Greek a which means not and tropos which translates as turn. The name was coined by Kuhn in 1933, but atropisomerism was first detected in 6,6’-dinitro-2,2’-diphenic acid by Cristie in 1922. Oki defined atropisomers as conformers that interconvert with a half-life of more than 1000 seconds at a given temperature.[2] Atropisomers are an important class of compounds because they display axial chirality. They differ from other chiral compounds in that they can be equilibrated thermally whereas in the other forms of chirality isomerization is usually only possible chemically. The most important class of atropisomers are biaryls such as the aforementioned diphenic acid which is a derivative of biphenyl with a complete set of ortho substituents. Others are dimers of naphthalene derivatives such as 1,1'-bi-2-naphthol. In a similar way aliphatic ring systems like cyclohexanes linked through a single bond may display atropisomerism provided that bulky substituents are present. Examples of naturally occurring atropisomers include vancomycin and knipholone which is found in the roots of Kniphofia Foliosa of the family Asphodelaceae. Separation of atropisomers is possibly by chiral resolution methods such as selective crystallization. In an atropo-enantioselective or atropselective synthesis one atropisomer is formed at the expense of the other. Atroposelective synthesis may be carried out by use of chiral auxiliaries like a CBS catalyst in the total synthesis of knipholone or by approaches based on thermodynamic equilibration when an isomerization reaction favors one atropisomer over the other. # Scope In one application the asymmetry in an atropisomer is transferred in a chemical reaction to a new stereocenter [3]. The atropisomer is an iodoaryl compound synthesised starting from (S)-valine and exists as the (M,S) isomer and the (P,S) isomer. The interconversion barrier between the two is 24.3 kcal/mol (101.7 kJ/mol). The (M,S) isomer can be obtained exclusively from this mixture by recrystallisation from hexanes. The iodine group is homolytically removed to form an aryl radical by a tributyltin hydride/triethylboron/oxygen mixture as in the Barton-McCombie reaction. Although the hindered rotation is now removed in the aryl radical the intermolecular reaction with the alkene is so much faster than rotation of the carbon-nitrogen bond that the stereochemistry is preserved. In this way the (M,S) isomer yields the (S,S) dihydroindolone. An axial chirality switch is reported [4] for a diol prepared from intramolecular pinacol coupling of the corresponding di-aldehyde with samarium(II) iodide. In methanol this compound has the two alcohol groups in equatorial positions but in hexane helicity is reversed with both groups in axial positions. # External links - Selective atropisomer preparation in natural product synthesis reported by Kevin M. Peese 2002 Website	https://www.wikidoc.org/index.php/Atropisomer
93e00624ad5aced2164b410675b6b301ccbc44a6	wikidoc	Attack rate	Attack rate An attack rate in epidemiology is the incidence of infection in a group of people over a period of time, usually in relation to foodborne illness. It is defined as the number of exposed persons infected with the disease divided by the total number of exposed persons. This ratio is measured from the beginning of an outbreak to the end of the outbreak.	Attack rate An attack rate in epidemiology is the incidence of infection in a group of people over a period of time, usually in relation to foodborne illness. It is defined as the number of exposed persons infected with the disease divided by the total number of exposed persons. This ratio is measured from the beginning of an outbreak to the end of the outbreak. Template:WH Template:WS	https://www.wikidoc.org/index.php/Attack_rate
11c5d5fcc21454496e0a1c7faf3ef5bb1ee95f50	wikidoc	Attenuation	Attenuation Attenuation is the reduction in amplitude and intensity of a signal. Signals may be attenuated exponentially by transmission through a medium, in which case attenuation is usually reported in dB with respect to distance traveled through the medium. Attenuation can also be understood to be the opposite of amplification. Attenuation is an important property in telecommunications and ultrasound applications because of its importance in determining signal strength as a function of distance. Attenuation is usually measured in units of decibels per unit length of medium (dB/cm, dB/km, etc) and is represented by the attenuation coefficient of the medium in question. # Ultrasound One area of research in which attenuation figures strongly is in ultrasound physics. Attenuation in ultrasound is the reduction in amplitude of the ultrasound beam as a function of distance through the imaging medium. Accounting for attenuation effects in ultrasound is important because a reduced signal amplitude can affect the quality of the image produced. By knowing the attenuation that an ultrasound beam experiences travelling through a medium, one can adjust the input signal amplitude to compensate for any loss of energy at the desired imaging depth. - Ultrasound attenuation measurement in heterogeneous systems, like emulsions or colloids yields information on particle size distribution. There is ISO standard on this technique. - Ultrasound attenuation can be used for extensional rheology measurement. There are acoustic rheometers that employ Stokes' law for measuring extensional viscosity and volume viscosity. ## Attenuation coefficient Attenuation coefficients are used to quantify different media according to how strongly the transmitted ultrasound amplitude decreases as a function of frequency. The attenuation coefficient (\alpha) can be used to determine total attenuation in dB/cm in the medium using the following formula: \mathrm{Attenuation} = \alpha\mathrm{}\cdot\mathit{l}\mathrm{}\cdot\mathrm{f} As this equation shows, besides the medium length and attenuation coefficient, attenuation is also linearly dependent on the frequency of the incident ultrasound beam. Attenuation coefficients vary widely for different media. In biomedical ultrasound imaging however, biological materials and water are the most commonly used media. The attenuation coefficients of common biological materials at a frequency of 1 MHz are listed below: There are two general ways of acoustic energy losses: absorption and scattering, for instance light scattering. Ultrasound propagation through homogeneous media is associated only with absorption and can be characterised with absorption coefficient only. Propagation through heterogeneous media requires taking into account scattering. # Earthquake The energy with which an earthquake affects a location depends on the running distance. The attenuation in the signal of ground motion intensity plays an important role in the assessment of possible strong ground shaking. A seismic wave loses energy as it propagates through the earth (attenuation). This phenomenon is tied in to the dispersion of the seismic energy with the distance. There are two types of dissipated energy: - geometric dispersion caused by distribution of the seismic energy to greater volumes - dispersion as heat # Electromagnetic Attenuation decreases the intensity of electromagnetic radiation due to absorption or scattering of photons. Attenuation does not include the decrease in intensity due to inverse-square law geometric spreading. Therefore, calculation of the total change in intensity involves both the inverse-square law and an estimation of attenuation over the path. The primary causes of attenuation in matter are the photoelectric effect, compton scattering and, for photon energies of above 1.022MeV, pair production. ## Radiography See Attenuation coefficient article. ## Optics Attenuation of light by cloudy water is called turbidity, and by interstellar dust, extinction (astronomy). Attenuation in glass or other solid medium is usually studied by telecommunication engineers, hence is called by the same names as the attenuation of electrical signals. Attenuation is caused by several different factors, but primarily scattering and absorption.The scattering of light is caused due to molecular level irregularities in the glass structure.Further attenuation is caused by light absorbed by residual materials, such as metals or water ions, within the fiber core and inner cladding.Light leakage due to bending, splices, connectors, or other outside forces are other factors resulting in attenuation.Attenuation in fibre optics, also known as transmission loss, is the reduction in intensity of the light beam with respect to distance travelled through a transparent medium. Attenuation coefficients in fibre optics usually use units of dB/km through the medium due to the great transparency of modern optical media. The medium is usually a fibre of silica glass that confines the incident light beam to the inside. Attenuation is an important factor limiting the transmission of a light pulse across far distances, and as a result much research has gone into both limiting the attenuation and maximizing the amplification of the fibre optic light beam. Attenuation in fibre optics can be quantified using the following equation: \mathrm{Attenuation(dB)} = 10\times\log_{10}\left(\frac{\mathrm{Input\ Intensity(W)}}{\mathrm{Output\ Intensity(W)}}\right) ## Applications In optical fibers, attenuation is the rate at which the signal light decreases in intensity. For this reason, glass fiber (which has a low attenuation) is used for long-distance fiber optic cables; plastic fiber has a higher attenuation and hence shorter range. There also exist optical attenuators which decrease the signal in a fiber optic cable intentionally. Attenuation of light is also important in physical oceanography. Here, attenuation is the decrease in light intensity with depth due to absorption by water molecules and scattering by suspended particulates. This same effect is an important consideration in weather radar as rain drops absorb a part of the emitted beam that is more or less significant depending on the wavelength used. The attenuation of photons, particularly of those in the x-ray spectrum, is important in the field of medical physics. Due to the damaging effects of high energy photons, it is necessary to know how much energy is deposited in tissue during diagnostic treatments involving such radiation. Additionally gamma radiation is used in cancer treatments where it is important to know how much energy will be deposited in healthy and in tumorous tissue. ## Radio Attenuation is an important consideration in the modern world of wireless telecommunication. People are daily affected by it as they rely more and more on mobile phones, television, satellite communication, and wireless internet. Attenuation limits the range of radio signals and is affected by the materials a signal must travel through (e.g. air, wood, concrete, rain). See the article on path loss for more information on signal loss in wireless communication.	Attenuation Template:This Attenuation is the reduction in amplitude and intensity of a signal. Signals may be attenuated exponentially by transmission through a medium, in which case attenuation is usually reported in dB with respect to distance traveled through the medium. Attenuation can also be understood to be the opposite of amplification. Attenuation is an important property in telecommunications and ultrasound applications because of its importance in determining signal strength as a function of distance. Attenuation is usually measured in units of decibels per unit length of medium (dB/cm, dB/km, etc) and is represented by the attenuation coefficient of the medium in question.[1] # Ultrasound One area of research in which attenuation figures strongly is in ultrasound physics. Attenuation in ultrasound is the reduction in amplitude of the ultrasound beam as a function of distance through the imaging medium. Accounting for attenuation effects in ultrasound is important because a reduced signal amplitude can affect the quality of the image produced. By knowing the attenuation that an ultrasound beam experiences travelling through a medium, one can adjust the input signal amplitude to compensate for any loss of energy at the desired imaging depth.[2] - Ultrasound attenuation measurement in heterogeneous systems, like emulsions or colloids yields information on particle size distribution. There is ISO standard on this technique.[3] - Ultrasound attenuation can be used for extensional rheology measurement. There are acoustic rheometers that employ Stokes' law for measuring extensional viscosity and volume viscosity. ## Attenuation coefficient Attenuation coefficients are used to quantify different media according to how strongly the transmitted ultrasound amplitude decreases as a function of frequency. The attenuation coefficient (<math>\alpha</math>) can be used to determine total attenuation in dB/cm in the medium using the following formula: <math>\mathrm{Attenuation[dB]} = \alpha\mathrm{[dB/(MHz*cm)]}\cdot\mathit{l}\mathrm{[cm]}\cdot\mathrm{f[MHz]}</math> As this equation shows, besides the medium length and attenuation coefficient, attenuation is also linearly dependent on the frequency of the incident ultrasound beam. Attenuation coefficients vary widely for different media. In biomedical ultrasound imaging however, biological materials and water are the most commonly used media. The attenuation coefficients of common biological materials at a frequency of 1 MHz are listed below:[2] There are two general ways of acoustic energy losses: absorption and scattering, for instance light scattering.[4] Ultrasound propagation through homogeneous media is associated only with absorption and can be characterised with absorption coefficient only. Propagation through heterogeneous media requires taking into account scattering.[5] # Earthquake The energy with which an earthquake affects a location depends on the running distance. The attenuation in the signal of ground motion intensity plays an important role in the assessment of possible strong ground shaking. A seismic wave loses energy as it propagates through the earth (attenuation). This phenomenon is tied in to the dispersion of the seismic energy with the distance. There are two types of dissipated energy: - geometric dispersion caused by distribution of the seismic energy to greater volumes - dispersion as heat # Electromagnetic Attenuation decreases the intensity of electromagnetic radiation due to absorption or scattering of photons. Attenuation does not include the decrease in intensity due to inverse-square law geometric spreading. Therefore, calculation of the total change in intensity involves both the inverse-square law and an estimation of attenuation over the path. The primary causes of attenuation in matter are the photoelectric effect, compton scattering and, for photon energies of above 1.022MeV, pair production. ## Radiography See Attenuation coefficient article. ## Optics Attenuation of light by cloudy water is called turbidity, and by interstellar dust, extinction (astronomy). Attenuation in glass or other solid medium is usually studied by telecommunication engineers, hence is called by the same names as the attenuation of electrical signals. Attenuation is caused by several different factors, but primarily scattering and absorption.The scattering of light is caused due to molecular level irregularities in the glass structure.Further attenuation is caused by light absorbed by residual materials, such as metals or water ions, within the fiber core and inner cladding.Light leakage due to bending, splices, connectors, or other outside forces are other factors resulting in attenuation.Attenuation in fibre optics, also known as transmission loss, is the reduction in intensity of the light beam with respect to distance travelled through a transparent medium. Attenuation coefficients in fibre optics usually use units of dB/km through the medium due to the great transparency of modern optical media. The medium is usually a fibre of silica glass that confines the incident light beam to the inside. Attenuation is an important factor limiting the transmission of a light pulse across far distances, and as a result much research has gone into both limiting the attenuation and maximizing the amplification of the fibre optic light beam.[6] Attenuation in fibre optics can be quantified using the following equation:[7] <math>\mathrm{Attenuation(dB)} = 10\times\log_{10}\left(\frac{\mathrm{Input\ Intensity(W)}}{\mathrm{Output\ Intensity(W)}}\right)</math> ## Applications In optical fibers, attenuation is the rate at which the signal light decreases in intensity. For this reason, glass fiber (which has a low attenuation) is used for long-distance fiber optic cables; plastic fiber has a higher attenuation and hence shorter range. There also exist optical attenuators which decrease the signal in a fiber optic cable intentionally. Attenuation of light is also important in physical oceanography. Here, attenuation is the decrease in light intensity with depth due to absorption by water molecules and scattering by suspended particulates. This same effect is an important consideration in weather radar as rain drops absorb a part of the emitted beam that is more or less significant depending on the wavelength used. The attenuation of photons, particularly of those in the x-ray spectrum, is important in the field of medical physics. Due to the damaging effects of high energy photons, it is necessary to know how much energy is deposited in tissue during diagnostic treatments involving such radiation. Additionally gamma radiation is used in cancer treatments where it is important to know how much energy will be deposited in healthy and in tumorous tissue. ## Radio Attenuation is an important consideration in the modern world of wireless telecommunication. People are daily affected by it as they rely more and more on mobile phones, television, satellite communication, and wireless internet. Attenuation limits the range of radio signals and is affected by the materials a signal must travel through (e.g. air, wood, concrete, rain). See the article on path loss for more information on signal loss in wireless communication.	https://www.wikidoc.org/index.php/Attenuation
f038863c51e60a7a40f5b1fdbc98e36a607d11c2	wikidoc	Mirtazapine	Mirtazapine # Disclaimer WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here. # Black Box Warning # Overview Mirtazapine is a noradrenergic and specific serotonergic antidepressant that is FDA approved for the {{{indicationType}}} of major depressive disorder. There is a Black Box Warning for this drug as shown here. Common adverse reactions include increased appetite, serum triglycerides raised, weight gain, constipation, xerostomia, ALT/SGPT level raised, asthenia, dizziness, somnolence, disturbance in thinking. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - Major depression - 15 mg/day PO at bedtime, increase every 1-2 weeks to a max dose of 45 mg/day. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information about Off-Label Guideline-Supported Use of Mirtazapine in adult patients. ### Non–Guideline-Supported Use - Anxiety - Cancer - Dysthymia - Obsessive-compulsive disorder - Panic disorder There is limited information about Off-Label Non–Guideline-Supported Use of Mirtazapine in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) Safety in pediatric patient has not been established. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information about Off-Label Guideline-Supported Use of Mirtazapine in pediatric patients. ### Non–Guideline-Supported Use There is limited information about Off-Label Non–Guideline-Supported Use of Mirtazapine in pediatric patients. # Contraindications - Hypersensitivity - Mirtazapine orally disintegrating tablets are contraindicated in patients with a known hypersensitivity to mirtazapine or to any of the excipients. - Monoamine Oxidase Inhibitors - The use of monoamine oxidase inhibitors (MAOIs) intended to treat psychiatric disorders with mirtazapine orally disintegrating tablets or within 14 days of stopping treatment with mirtazapine orally disintegrating tablets is contraindicated because of an increased risk of serotonin syndrome. The use of mirtazapine orally disintegrating tablets within 14 days of stopping an MAOI intended to treat psychiatric disorders is also contraindicated. - Starting mirtazapine orally disintegrating tablets in a patient who is being treated with MAOIs such as linezolid or intravenous methylene blue is also contraindicated because of an increased risk of serotonin syndrome # Warnings - Clinical Worsening and Suicide Risk - Patients with major depressive disorder (MDD), both adult and pediatric, may experience worsening of their depression and/or the emergence of suicidal ideation and behavior (suicidality) or unusual changes in behavior, whether or not they are taking antidepressant medications, and this risk may persist until significant remission occurs. Suicide is a known risk of depression and certain other psychiatric disorders, and these disorders themselves are the strongest predictors of suicide. There has been a long-standing concern, however, that antidepressants may have a role in inducing worsening of depression and the emergence of suicidality in certain patients during the early phases of treatment. Pooled analyses of short-term placebo-controlled trials of antidepressant drugs (SSRIs and others) showed that these drugs increase the risk of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults (ages 18–24) with major depressive disorder (MDD) and other psychiatric disorders. Short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24; there was a reduction in risk with antidepressants compared to placebo in adults aged 65 and older. - The pooled analyses of placebo-controlled trials in children and adolescents with MDD, obsessive compulsive disorder (OCD), or other psychiatric disorders included a total of 24 short-term trials of 9 antidepressant drugs in over 4400 patients. The pooled analyses of placebo-controlled trials in adults with MDD or other psychiatric disorders included a total of 295 short-term trials (median duration of 2 months) of 11 antidepressant drugs in over 77,000 patients. There was considerable variation in risk of suicidality among drugs, but a tendency toward an increase in the younger patients for almost all drugs studied. There were differences in absolute risk of suicidality across different indications, with the highest incidence in MDD. The risk differences (drug vs. placebo), however, were relatively stable within age strata and across indications. These risk differences (drug-placebo difference in the number of cases of suicidality per 1000 patients treated) are provided in Table 1. - No suicides occurred in any of the pediatric trials. There were suicides in the adult trials, but the number was not sufficient to reach any conclusion about drug effect on suicide. - It is unknown whether the suicidality risk extends to longer-term use, i.e., beyond several months. However, there is substantial evidence from placebo-controlled maintenance trials in adults with depression that the use of antidepressants can delay the recurrence of depression. - All patients being treated with antidepressants for any indication should be monitored appropriately and observed closely for clinical worsening, suicidality, and unusual changes in behavior, especially during the initial few months of a course of drug therapy, or at times of dose changes, either increases or decreases. - The following symptoms, anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, and mania, have been reported in adult and pediatric patients being treated with antidepressants for major depressive disorder as well as for other indications, both psychiatric and nonpsychiatric. Although a causal link between the emergence of such symptoms and either the worsening of depression and/or the emergence of suicidal impulses has not been established, there is concern that such symptoms may represent precursors to emerging suicidality. - Consideration should be given to changing the therapeutic regimen, including possibly discontinuing the medication, in patients whose depression is persistently worse, or who are experiencing emergent suicidality or symptoms that might be precursors to worsening depression or suicidality, especially if these symptoms are severe, abrupt in onset, or were not part of the patient’s presenting symptoms. - Families and caregivers of patients being treated with antidepressants for major depressive disorder or other indications, both psychiatric and nonpsychiatric, should be alerted about the need to monitor patients for the emergence of agitation, irritability, unusual changes in behavior, and the other symptoms described above, as well as the emergence of suicidality, and to report such symptoms immediately to health care providers. Such monitoring should include daily observation by families and caregivers. Prescriptions for mirtazapine orally disintegrating tablets should be written for the smallest quantity of tablets consistent with good patient management, in order to reduce the risk of overdose. - Screening Patients for Bipolar Disorder: - A major depressive episode may be the initial presentation of bipolar disorder. It is generally believed (though not established in controlled trials) that treating such an episode with an antidepressant alone may increase the likelihood of precipitation of a mixed/manic episode in patients at risk for bipolar disorder. Whether any of the symptoms described above represent such a conversion is unknown. However, prior to initiating treatment with an antidepressant, patients with depressive symptoms should be adequately screened to determine if they are at risk for bipolar disorder; such screening should include a detailed psychiatric history, including a family history of suicide, bipolar disorder, and depression. It should be noted that mirtazapine orally disintegrating tablets are not approved for use in treating bipolar depression. - Agranulocytosis - In premarketing clinical trials, 2 (1 with Sjögren’s Syndrome) out of 2796 patients treated with mirtazapine tablets developed agranulocytosis and a third patient developed severe neutropenia (ANC <500/mm3 without any associated symptoms). For these 3 patients, onset of severe neutropenia was detected on days 61, 9, and 14 of treatment, respectively. All 3 patients recovered after mirtazapine was stopped. These 3 cases yield a crude incidence of severe neutropenia (with or without associated infection) of approximately 1.1 per thousand patients exposed, with a very wide 95% confidence interval, i.e., 2.2 cases per 10,000 to 3.1 cases per 1000. If a patient develops a sore throat, fever, stomatitis, or other signs of infection, along with a low WBC count, treatment with mirtazapine orally disintegrating tablets should be discontinued and the patient should be closely monitored. - Serotonin Syndrome - The development of a potentially life-threatening serotonin syndrome has been reported with SNRIs and SSRIs, including mirtazapine orally disintegrating tablets, alone but particularly with concomitant use of serotonergic drugs (including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, and St. John"s wort) and with drugs that impair metabolism of serotonin (in particular, MAOIs, both those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue). - Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, delirium, and coma), autonomic instability (e.g., tachycardia, labile blood pressure, dizziness, diaphoresis, flusing, hyperthermia), neuromuscular symptoms (e.g., tremor, rigidity, myoclonus, hyperreflexia, incoordination), seizures, and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). Patients should be monitored for the emergence of serotonin syndrome. - The concomitant use of mirtazapine orally disintegrating tablets with MAOIs intended to treat psychiatric disorders is contraindicated. Mirtazapine orally disintegrating tablets should also not be started in a patient who is being treated with MAOIs such as linezolid or intravenous methylene blue. All reports with methylene blue that provided information on the route of administration involved intravenous administration in the dose range of 1 mg/kg to 8 mg/kg. No reports involved the administration of methylene blue by other routes (such as oral tablets or local tissue injection) or at lower doses. There may be circumstances when it is necessary to initiate treatment with an MAOI such as linezolid or intravenous methylene blue in a patient taking mirtazapine orally disintegrating tablets. Mirtazapine orally disintegrating tablets should be discontinued before initiating treatment with the MAOI (see CONTRAINDICATIONS and DOSAGE AND ADMINISTRATION). - If concomitant use of mirtazapine orally disintegrating tablets with other serotonergic drugs, including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, buspirone, tryptophan, and St. John"s wort, is clinically warranted, be aware of a potential increased risk for serotonin syndrome, particularly during treatment initiation and dose increases. - Treatment with mirtazapine orally disintegrating tablets and any concomitant serotonergic agents should be discontinued immediately if the above events occur and supportive symptomatic treatment should be initiated. - General - Discontinuation Symptoms There have been reports of adverse reactions upon the discontinuation of mirtazapine/mirtazapine orally disintegrating tablets (particularly when abrupt), including but not limited to the following: dizziness, abnormal dreams, sensory disturbances (including paresthesia and electric shock sensations), agitation, anxiety, fatigue, confusion, headache, tremor, nausea, vomiting, and sweating, or other symptoms which may be of clinical significance. The majority of the reported cases are mild and self-limiting. Even though these have been reported as adverse reactions, it should be realized that these symptoms may be related to underlying disease. - Patients currently taking mirtazapine should NOT discontinue treatment abruptly, due to risk of discontinuation symptoms. At the time that a medical decision is made to discontinue treatment with mirtazapine, a gradual reduction in the dose, rather than an abrupt cessation, is recommended. - Akathisia/Psychomotor Restlessness - The use of antidepressants has been associated with the development of akathisia, characterized by a subjectively unpleasant or distressing restlessness and need to move often accompanied by an inability to sit or stand still. This is most likely to occur within the first few weeks of treatment. In patients who develop these symptoms, increasing the dose may be detrimental. - Hyponatremia - Hyponatremia has been reported very rarely with the use of mirtazapine. Caution should be exercised in patients at risk, such as elderly patients or patients concomitantly treated with medications known to cause hyponatremia. - Somnolence - In US controlled studies, somnolence was reported in 54% of patients treated with mirtazapine tablets, compared to 18% for placebo and 60% for amitriptyline. In these studies, somnolence resulted in discontinuation for 10.4% of mirtazapine-treated patients, compared to 2.2% for placebo. It is unclear whether or not tolerance develops to the somnolent effects of mirtazapine. Because of the potentially significant effects of mirtazapine on impairment of performance, patients should be cautioned about engaging in activities requiring alertness until they have been able to assess the drug’s effect on their own psychomotor performance. - Dizziness - In US controlled studies, dizziness was reported in 7% of patients treated with mirtazapine, compared to 3% for placebo and 14% for amitriptyline. It is unclear whether or not tolerance develops to the dizziness observed in association with the use of mirtazapine. - Increased Appetite/Weight Gain - In US controlled studies, appetite increase was reported in 17% of patients treated with mirtazapine, compared to 2% for placebo and 6% for amitriptyline. In these same trials, weight gain of ≥7% of body weight was reported in 7.5% of patients treated with mirtazapine, compared to 0% for placebo and 5.9% for amitriptyline. In a pool of premarketing US studies, including many patients for long-term, open-label treatment, 8% of patients receiving mirtazapine discontinued for weight gain. In an 8-week-long pediatric clinical trial of doses between 15 to 45 mg/day, 49% of mirtazapine-treated patients had a weight gain of at least 7%, compared to 5.7% of placebo-treated patients (see PRECAUTIONS: Pediatric Use). - Cholesterol/Triglycerides - In US controlled studies, nonfasting cholesterol increases to ≥20% above the upper limits normal were observed in 15% of patients treated with mirtazapine, compared to 7% for placebo and 8% for amitriptyline. In these same studies, nonfasting triglyceride increases to ≥500 mg/dL were observed in 6% of patients treated with mirtazapine, compared to 3% for placebo and 3% for amitriptyline. - Transaminase Elevations - Clinically significant ALT (SGPT) elevations (≥3 times the upper limit of the normal range) were observed in 2.0% (8/424) of patients exposed to mirtazapine in a pool of short-term US controlled trials, compared to 0.3% (1/328) of placebo patients and 2.0% (3/181) of amitriptyline patients. Most of these patients with ALT increases did not develop signs or symptoms associated with compromised liver function. While some patients were discontinued for the ALT increases, in other cases, the enzyme levels returned to normal despite continued mirtazapine treatment. Mirtazapine orally disintegrating tablets should be used with caution in patients with impaired hepatic function. - Activation of Mania/Hypomania - Mania/hypomania occurred in approximately 0.2% (3/1299 patients) of mirtazapine-treated patients in US studies. Although the incidence of mania/hypomania was very low during treatment with mirtazapine, it should be used carefully in patients with a history of mania/hypomania. - Seizure - In premarketing clinical trials, only 1 seizure was reported among the 2796 US and non-US patients treated with mirtazapine. However, no controlled studies have been carried out in patients with a history of seizures. Therefore, care should be exercised when mirtazapine is used in these patients. - Use in Patients with Concomitant Illness - Clinical experience with mirtazapine orally disintegrating tablets in patients with concomitant systemic illness is limited. Accordingly, care is advisable in prescribing mirtazapine for patients with diseases or conditions that affect metabolism or hemodynamic responses. Mirtazapine orally disintegrating tablets have not been systematically evaluated or used to any appreciable extent in patients with a recent history of myocardial infarction or other significant heart disease. Mirtazapine was associated with significant orthostatic hypotension in early clinical pharmacology trials with normal volunteers. Orthostatic hypotension was infrequently observed in clinical trials with depressed patients. Mirtazapine orally disintegrating tablets should be used with caution in patients with known cardiovascular or cerebrovascular disease that could be exacerbated by hypotension (history of myocardial infarction, angina, or ischemic stroke) and conditions that would predispose patients to hypotension (dehydration, hypovolemia, and treatment with antihypertensive medication). - Mirtazapine clearance is decreased in patients with moderate and severe renal impairment, and also in patients with hepatic impairment. Caution is indicated in administering mirtazapine orally disintegrating tablets to such patients # Adverse Reactions ## Clinical Trials Experience - Associated with Discontinuation of Treatment - Approximately 16% of the 453 patients who received mirtazapine tablets in US 6-week controlled clinical trials discontinued treatment due to an adverse experience, compared to 7% of the 361 placebo-treated patients in those studies. The most common events (≥1%) associated with discontinuation and considered to be drug related (i.e., those events associated with dropout at a rate at least twice that of placebo) are included in Table 2. - Commonly Observed Adverse Events in US Controlled Clinical Trials The most commonly observed adverse events associated with the use of mirtazapine tablets (incidence of 5% or greater) and not observed at an equivalent incidence among placebo-treated patients (mirtazapine incidence at least twice that for placebo) are listed in Table 3. - Adverse Events Occurring at an Incidence of 1% or More Among Mirtazapine *Tablets-Treated Patients - Table 4 enumerates adverse events that occurred at an incidence of 1% or more, and were more frequent than in the placebo group, among mirtazapine tablets-treated patients who participated in short-term US placebo-controlled trials in which patients were dosed in a range of 5 to 60 mg/day. This table shows the percentage of patients in each group who had at least 1 episode of an event at some time during their treatment. Reported adverse events were classified using a standard COSTART-based dictionary terminology. - The prescriber should be aware that these figures cannot be used to predict the incidence of side effects in the course of usual medical practice where patient characteristics and other factors differ from those which prevailed in the clinical trials. Similarly, the cited frequencies cannot be compared with figures obtained from other investigations involving different treatments, uses, and investigators. The cited figures, however, do provide the prescribing physician with some basis for estimating the relative contribution of drug and nondrug factors to the side-effect incidence rate in the population studied. - ECG Changes - The electrocardiograms for 338 patients who received mirtazapine tablets and 261 patients who received placebo in 6-week, placebo-controlled trials were analyzed. Prolongation in QTc ≥500 msec was not observed among mirtazapine-treated patients; mean change in QTc was +1.6 msec for mirtazapine and –3.1 msec for placebo. Mirtazapine was associated with a mean increase in heart rate of 3.4 bpm, compared to 0.8 bpm for placebo. The clinical significance of these changes is unknown. - Other Adverse Events Observed During the Premarketing Evaluation of Mirtazapine - During its premarketing assessment, multiple doses of mirtazapine tablets were administered to 2796 patients in clinical studies. The conditions and duration of exposure to mirtazapine varied greatly, and included (in overlapping categories) open and double-blind studies, uncontrolled and controlled studies, inpatient and outpatient studies, fixed-dose and titration studies. Untoward events associated with this exposure were recorded by clinical investigators using terminology of their own choosing. Consequently, it is not possible to provide a meaningful estimate of the proportion of individuals experiencing adverse events without first grouping similar types of untoward events into a smaller number of standardized event categories. - In the tabulations that follow, reported adverse events were classified using a standard COSTART-based dictionary terminology. The frequencies presented, therefore, represent the proportion of the 2796 patients exposed to multiple doses of mirtazapine who experienced an event of the type cited on at least 1 occasion while receiving mirtazapine. All reported events are included except those already listed in Table 4, those adverse experiences subsumed under COSTART terms that are either overly general or excessively specific so as to be uninformative, and those events for which a drug cause was very remote. - It is important to emphasize that, although the events reported occurred during treatment with mirtazapine, they were not necessarily caused by it. - Events are further categorized by body system and listed in order of decreasing frequency according to the following definitions: frequent adverse events are those occurring on 1 or more occasions in at least 1/100 patients; infrequent adverse events are those occurring in 1/100 to 1/1000 patients; rare events are those occurring in fewer than 1/1000 patients. Only those events not already listed in Table 4 appear in this listing. Events of major clinical importance are also described in the WARNINGS and PRECAUTIONS sections. - Body as a Whole - Frequent: malaise, abdominal pain, abdominal syndrome acute; infrequent: chills, fever, face edema, ulcer, photosensitivity reaction, neck rigidity, neck pain, abdomen enlarged; rare: cellulitis, chest pain substernal. - Cardiovascular System - Frequent: hypertension, vasodilatation; infrequent: angina pectoris, myocardial infarction, bradycardia, ventricular extrasystoles, syncope, migraine, hypotension; rare: atrial arrhythmia, bigeminy, vascular headache, pulmonary embolus, cerebral ischemia, cardiomegaly, phlebitis, left heart failure. - Digestive System - Frequent: vomiting, anorexia; infrequent: eructation, glossitis, cholecystitis, nausea and vomiting, gum hemorrhage, stomatitis, colitis, liver function tests abnormal; rare: tongue discoloration, ulcerative stomatitis, salivary gland enlargement, increased salivation, intestinal obstruction, pancreatitis, aphthous stomatitis, cirrhosis of liver, gastritis, gastroenteritis, oral moniliasis, tongue edema. - Endocrine System - Rare: goiter, hypothyroidism. - Hemic and Lymphatic System: rare: lymphadenopathy, leukopenia, petechia, anemia, thrombocytopenia, lymphocytosis, pancytopenia. - Metabolic and Nutritional Disorders: frequent: thirst; infrequent: dehydration, weight loss; rare: gout, SGOT increased, healing abnormal, acid phosphatase increased, SGPT increased, diabetes mellitus, hyponatremia. - Musculoskeletal System: frequent: myasthenia, arthralgia; infrequent: arthritis, tenosynovitis; rare: pathologic fracture, osteoporosis fracture, bone pain, myositis, tendon rupture, arthrosis, bursitis. - Nervous System: frequent - Hypesthesia, apathy, depression, hypokinesia, vertigo, twitching, agitation, anxiety, amnesia, hyperkinesia, paresthesia; infrequent: ataxia, delirium, delusions, depersonalization, dyskinesia, extrapyramidal syndrome, libido increased, coordination abnormal, dysarthria, hallucinations, manic reaction, neurosis, dystonia, hostility, reflexes increased, emotional lability, euphoria, paranoid reaction; rare: aphasia, nystagmus, akathisia (psychomotor restlessness), stupor, dementia, diplopia, drug dependence, paralysis, grand mal convulsion, hypotonia, myoclonus, psychotic depression, withdrawal syndrome, serotonin syndrome. - Respiratory System - Frequent: cough increased, sinusitis; infrequent: epistaxis, bronchitis, asthma, pneumonia; rare: asphyxia, laryngitis, pneumothorax, hiccup. - Skin and Appendages: frequent: pruritus, rash; infrequent: acne, exfoliative dermatitis, dry skin, herpes simplex, alopecia; rare: urticaria, herpes zoster, skin hypertrophy, seborrhea, skin ulcer. - Special Senses: infrequent: eye pain, abnormality of accommodation, conjunctivitis, deafness, keratoconjunctivitis, lacrimation disorder, glaucoma, hyperacusis, ear pain; rare: blepharitis, partial transitory deafness, otitis media, taste loss, parosmia. - Urogenital System: frequent: urinary tract infection; infrequent: kidney calculus, cystitis, dysuria, urinary incontinence, urinary retention, vaginitis, hematuria, breast pain, amenorrhea, dysmenorrhea, leukorrhea, impotence; rare: polyuria, urethritis, metrorrhagia, menorrhagia, abnormal ejaculation, breast engorgement, breast enlargement, urinary urgency. - Other Adverse Events Observed During Postmarketing Evaluation of Mirtazapine - Adverse events reported since market introduction, which were temporally (but not necessarily causally) related to mirtazapine therapy, include 4 cases of the ventricular arrhythmia torsades de pointes. In 3 of the 4 cases, however, concomitant drugs were implicated. All patients recovered. - Cases of severe skin reactions, including Stevens-Johnson syndrome, bullous dermatitis, erythema multiforme and toxic epidermal necrolysis have also been reported. ## Postmarketing Experience There is limited information regarding Mirtazapine Postmarketing Experience in the drug label. # Drug Interactions - As with other drugs, the potential for interaction by a variety of mechanisms (e.g., pharmacodynamic, pharmacokinetic inhibition or enhancement, etc.) is a possibility. - Monoamine Oxidase Inhibitors - Serotonergic Drugs - Drugs Affecting Hepatic Metabolism The metabolism and pharmacokinetics of mirtazapine orally disintegrating tablets may be affected by the induction or inhibition of drug-metabolizing enzymes. ### Drugs that are Metabolized by and/or Inhibit Cytochrome P450 Enzymes CYP Enzyme Inducers (these studies used both drugs at steady state) - Phenytoin - In healthy male patients (n=18), phenytoin (200 mg daily) increased mirtazapine (30 mg daily) clearance about 2-fold, resulting in a decrease in average plasma mirtazapine concentrations of 45%. Mirtazapine did not significantly affect the pharmacokinetics of phenytoin. - Carbamazepine - In healthy male patients (n=24), carbamazepine (400 mg b.i.d.) increased mirtazapine (15 mg b.i.d.) clearance about 2-fold, resulting in a decrease in average plasma mirtazapine concentrations of 60%. - When phenytoin, carbamazepine, or another inducer of hepatic metabolism (such as rifampicin) is added to mirtazapine therapy, the mirtazapine dose may have to be increased. If treatment with such a medicinal product is discontinued, it may be necessary to reduce the mirtazapine dose. ### CYP Enzyme Inhibitors - Cimetidine - In healthy male patients (n=12), when cimetidine, a weak inhibitor of CYP1A2, CYP2D6, and CYP3A4, given at 800 mg b.i.d. at steady state was coadministered with mirtazapine (30 mg daily) at steady state, the Area Under the Curve (AUC) of mirtazapine increased more than 50%. Mirtazapine did not cause relevant changes in the pharmacokinetics of cimetidine. The mirtazapine dose may have to be decreased when concomitant treatment with cimetidine is started, or increased when cimetidine treatment is discontinued. - Ketoconazole - In healthy, male, Caucasian patients (n=24), coadministration of the potent CYP3A4 inhibitor ketoconazole (200 mg b.i.d. for 6.5 days) increased the peak plasma levels and the AUC of a single 30-mg dose of mirtazapine by approximately 40% and 50%, respectively. - Caution should be exercised when coadministering mirtazapine with potent CYP3A4 inhibitors, HIV protease inhibitors, azole antifungals, erythromycin, or nefazodone. - Paroxetine - In an in vivo interaction study in healthy, CYP2D6 extensive metabolizer patients (n=24), mirtazapine (30 mg/day), at steady state, did not cause relevant changes in the pharmacokinetics of steady state paroxetine (40 mg/day), a CYP2D6 inhibitor. - Amitriptyline - In healthy, CYP2D6 extensive metabolizer patients (n=32), amitriptyline (75 mg daily), at steady state, did not cause relevant changes to the pharmacokinetics of steady state mirtazapine (30 mg daily); mirtazapine also did not cause relevant changes to the pharmacokinetics of amitriptyline. - Warfarin - In healthy male subjects (n=16), mirtazapine (30 mg daily), at steady state, caused a small (0.2) but statistically significant increase in the International Normalized Ratio (INR) in subjects treated with warfarin. As at a higher dose of mirtazapine, a more pronounced effect can not be excluded, it is advisable to monitor the INR in case of concomitant treatment of warfarin with mirtazapine. - Lithium - No relevant clinical effects or significant changes in pharmacokinetics have been observed in healthy male subjects on concurrent treatment with subtherapeutic levels of lithium (600 mg/day for 10 days) at steady state and a single 30 mg dose of mirtazapine. The effects of higher doses of lithium on the pharmacokinetics of mirtazapine are unknown. - Risperidone - In an in vivo, nonrandomized, interaction study, subjects (n=6) in need of treatment with an antipsychotic and antidepressant drug, showed that mirtazapine (30 mg daily) at steady state did not influence the pharmacokinetics of risperidone (up to 3 mg b.i.d.). - Alcohol - Concomitant administration of alcohol (equivalent to 60 g) had a minimal effect on plasma levels of mirtazapine (15 mg) in 6 healthy male subjects. However, the impairment of cognitive and motor skills produced by mirtazapine were shown to be additive with those produced by alcohol. Accordingly, patients should be advised to avoid alcohol while taking mirtazapine orally disintegrating tablets. - Diazepam - Concomitant administration of diazepam (15 mg) had a minimal effect on plasma levels of mirtazapine (15 mg) in 12 healthy subjects. However, the impairment of motor skills produced by mirtazapine has been shown to be additive with those caused by diazepam. Accordingly, patients should be advised to avoid diazepam and other similar drugs while taking mirtazapine orally disintegrating tablets. - Carcinogenesis - Carcinogenicity studies were conducted with mirtazapine given in the diet at doses of 2, 20, and 200 mg/kg/day to mice and 2, 20, and 60 mg/kg/day to rats. The highest doses used are approximately 20 and 12 times the maximum recommended human dose (MRHD) of 45 mg/day on an mg/m2 basis in mice and rats, respectively. There was an increased incidence of hepatocellular adenoma and carcinoma in male mice at the high dose. In rats, there was an increase in hepatocellular adenoma in females at the mid and high doses and in hepatocellular tumors and thyroid follicular adenoma/cystadenoma and carcinoma in males at the high dose. The data suggest that the above effects could possibly be mediated by non-genotoxic mechanisms, the relevance of which to humans is not known. - The doses used in the mouse study may not have been high enough to fully characterize the carcinogenic potential of mirtazapine tablets. - Mutagenesis - Mirtazapine was not mutagenic or clastogenic and did not induce general DNA damage as determined in several genotoxicity tests: Ames test, in vitro gene mutation assay in Chinese hamster V 79 cells, in vitro sister chromatid exchange assay in cultured rabbit lymphocytes, in vivo bone marrow micronucleus test in rats, and unscheduled DNA synthesis assay in HeLa cells. - Impairment of Fertility - In a fertility study in rats, mirtazapine was given at doses up to 100 mg/kg . Mating and conception were not affected by the drug, but estrous cycling was disrupted at doses that were 3 or more times the MRHD, and pre-implantation losses occurred at 20 times the MRHD. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): C Reproduction studies in pregnant rats and rabbits at doses up to 100 mg/kg and 40 mg/kg, respectively , have revealed no evidence of teratogenic effects. However, in rats, there was an increase in postimplantation losses in dams treated with mirtazapine. There was an increase in pup deaths during the first 3 days of lactation and a decrease in pup birth weights. The cause of these deaths is not known. The effects occurred at doses that were 20 times the MRHD, but not at 3 times the MRHD, on an mg/m2 basis. There are no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed. Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Mirtazapine in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Mirtazapine during labor and delivery. ### Nursing Mothers Because some mirtazapine may be excreted in breast milk, caution should be exercised when mirtazapine orally disintegrating tablets are administered to nursing women. ### Pediatric Use - Safety and effectiveness in the pediatric population have not been established. Two placebo-controlled trials in 258 pediatric patients with MDD have been conducted with mirtazapine tablets, and the data were not sufficient to support a claim for use in pediatric patients. Anyone considering the use of mirtazapine orally disintegrating tablets in a child or adolescent must balance the potential risks with the clinical need. - In an 8-week-long pediatric clinical trial of doses between 15 to 45 mg/day, 49% of mirtazapine-treated patients had a weight gain of at least 7%, compared to 5.7% of placebo-treated patients. The mean increase in weight was 4 kg (2 kg SD) for mirtazapine-treated patients versus 1 kg (2 kg SD) for placebo-treated patients. ### Geriatic Use - Following oral administration of mirtazapine tablets 20 mg/day for 7 days to subjects of varying ages (range, 25–74), oral clearance of mirtazapine was reduced in the elderly compared to the younger subjects. The differences were most striking in males, with a 40% lower clearance in elderly males compared to younger males, while the clearance in elderly females was only 10% lower compared to younger females. Caution is indicated in administering mirtazapine orally disintegrating tablets to elderly patients. - Approximately 190 elderly individuals (≥65 years of age) participated in clinical studies with mirtazapine tablets. This drug is known to be substantially excreted by the kidney (75%), and the risk of decreased clearance of this drug is greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection. Sedating drugs may cause confusion and over-sedation in the elderly. No unusual adverse age-related phenomena were identified in this group. Pharmacokinetic studies revealed a decreased clearance in the elderly. Caution is indicated in administering mirtazapine orally disintegrating tablets to elderly patients ### Gender The mean elimination half-life of mirtazapine after oral administration ranges from approximately 20 to 40 hours across age and gender subgroups, with females of all ages exhibiting significantly longer elimination half-lives than males (mean half-life of 37 hours for females vs. 26 hours for males) ### Race There have been no clinical studies to evaluate the effect of race on the pharmacokinetics of mirtazapine orally disintegrating tablets. ### Renal Impairment The disposition of mirtazapine was studied in patients with varying degrees of renal function. Elimination of mirtazapine is correlated with creatinine clearance. Total body clearance of mirtazapine was reduced approximately 30% in patients with moderate (Clcr = 11–39 mL/min/1.73 m2) and approximately 50% in patients with severe (Clcr = <10 mL/min/1.73 m2) renal impairment when compared to normal subjects. Caution is indicated in administering mirtazapine orally disintegrating tablets to patients with compromised renal function. ### Hepatic Impairment Following a single 15-mg oral dose of mirtazapine, the oral clearance of mirtazapine was decreased by approximately 30% in hepatically impaired patients compared to subjects with normal hepatic function. Caution is indicated in administering mirtazapine orally disintegrating tablets to patients with compromised hepatic function. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Mirtazapine in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Mirtazapine in patients who are immunocompromised. # Administration and Monitoring ### Administration - Initial Treatment - The recommended starting dose for mirtazapine orally disintegrating tablets is 15 mg/day, administered in a single dose, preferably in the evening prior to sleep. In the controlled clinical trials establishing the efficacy of mirtazapine in the treatment of major depressive disorder, the effective dose range was generally 15 to 45 mg/day. While the relationship between dose and satisfactory response in the treatment of major depressive disorder for mirtazapine has not been adequately explored, patients not responding to the initial 15-mg dose may benefit from dose increases up to a maximum of 45 mg/day. Mirtazapine has an elimination half-life of approximately 20 to 40 hours; therefore, dose changes should not be made at intervals of less than 1 to 2 weeks in order to allow sufficient time for evaluation of the therapeutic response to a given dose. - Administration of Mirtazapine Orally Disintegrating Tablets - Patients should be instructed to open tablet blister pack with dry hands and place the tablet on the tongue. The tablet should be used immediately after removal from its blister; once removed, it cannot be stored. Mirtazapine orally disintegrating tablets will disintegrate rapidly on the tongue and can be swallowed with saliva. No water is needed for taking the tablet. Patients should not attempt to split the tablet. - Elderly and Patients with Renal or Hepatic Impairment - The clearance of mirtazapine is reduced in elderly patients and in patients with moderate to severe renal or hepatic impairment. Consequently, the prescriber should be aware that plasma mirtazapine levels may be increased in these patient groups, compared to levels observed in younger adults without renal or hepatic impairment. ### Monitoring - Maintenance/Extended Treatment - It is generally agreed that acute episodes of depression require several months or longer of sustained pharmacological therapy beyond response to the acute episode. Systematic evaluation of mirtazapine tablets has demonstrated that its efficacy in major depressive disorder is maintained for periods of up to 40 weeks following 8 to 12 weeks of initial treatment at a dose of 15 to 45 mg/day. Based on these limited data, it is unknown whether or not the dose of mirtazapine needed for maintenance treatment is identical to the dose needed to achieve an initial response. Patients should be periodically reassessed to determine the need for maintenance treatment and the appropriate dose for such treatment. - Switching Patients To or From a Monoamine Oxidase Inhibitor (MAOI) Intended to Treat Psychiatric Disorders - At least 14 days should elapse between discontinuation of an MAOI intended to treat psychiatric disorders and initiation of therapy with mirtazapine orally disintegrating tablets. Conversely, at least 14 days should be allowed after stopping mirtazapine orally disintegrating tablets before starting an MAOI intended to treat psychiatric disorders. - Use of Mirtazapine Orally Disintegrating Tablets With Other MAOIs, Such as Linezolid or Methylene Blue - Do not start mirtazapine orally disintegrating tablets in a patient who is being treated with linezolid or intravenous methylene blue because there is an increased risk of serotonin syndrome. In a patient who requires more urgent treatment of a psychiatric condition, other interventions, including hospitalization, should be considered. - In some cases, a patient already receiving therapy with mirtazapine orally disintegrating tablets may require urgent treatment with linezolid or intravenous methylene blue. If acceptable alternatives to linezolid or intravenous methylene blue treatment are not available and the potential benefits of linezolid or intravenous methylene blue treatment are judged to outweigh the risks of serotonin syndrome in a particular patient, mirtazapine orally disintegrating tablets should be stopped promptly, and linezolid or intravenous methylene blue can be administered. The patient should be monitored for symptoms of serotonin syndrome for 2 weeks or until 24 hours after the last dose of linezolid or intravenous methylene blue, whichever comes first. Therapy with mirtazapine orally disintegrating tablets may be resumed 24 hours after the last dose of linezolid or intravenous methylene blue. - The risk of administering methylene blue by non-intravenous routes (such as oral tablets or by local injection) or in intravenous doses much lower than 1 mg/kg with mirtazapine orally disintegrating tablets is unclear. The clinician should, nevertheless, be aware of the possibility of emergent symptoms of serotonin syndrome with such use. - Discontinuation of Mirtazapine Treatment - Symptoms associated with the discontinuation or dose reduction of mirtazapine orally disintegrating tablets have been reported. Patients should be monitored for these and other symptoms when discontinuing treatment or during dosage reduction. A gradual reduction in the dose over several weeks, rather than abrupt cessation, is recommended whenever possible. If intolerable symptoms occur following a decrease in the dose or upon discontinuation of treatment, dose titration should be managed on the basis of the patient’s clinical response # IV Compatibility There is limited information regarding the compatibility of Mirtazapine and IV administrations. # Overdosage - Controlled Substance Class - Mirtazapine orally disintegrating tablets are not a controlled substance. - Physical and Psychologic Dependence - Mirtazapine orally disintegrating tablets have not been systematically studied in animals or humans for its potential for abuse, tolerance, or physical dependence. While the clinical trials did not reveal any tendency for any drug-seeking behavior, these observations were not systematic and it is not possible to predict on the basis of this limited experience the extent to which a CNS-active drug will be misused, diverted and/or abused once marketed. Consequently, patients should be evaluated carefully for history of drug abuse, and such patients should be observed closely for signs of mirtazapine orally disintegrating tablet misuse or abuse (e.g., development of tolerance, incrementations of dose, drug-seeking behavior). - Human Experience - There is very limited experience with mirtazapine orally disintegrating tablets overdose. In premarketing clinical studies, there were 8 reports of mirtazapine overdose alone or in combination with other pharmacological agents. The only drug overdose death reported while taking mirtazapine was in combination with amitriptyline and chlorprothixene in a non-US clinical study. Based on plasma levels, the mirtazapine dose taken was 30 to 45 mg, while plasma levels of amitriptyline and chlorprothixene were found to be at toxic levels. All other premarketing overdose cases resulted in full recovery. Signs and symptoms reported in association with overdose included disorientation, drowsiness, impaired memory, and tachycardia. There were no reports of ECG abnormalities, coma, or convulsions following overdose with mirtazapine alone. - Overdose Management - Treatment should consist of those general measures employed in the management of overdose with any drug effective in the treatment of major depressive disorder. Ensure an adequate airway, oxygenation, and ventilation. Monitor cardiac rhythm and vital signs. General supportive and symptomatic measures are also recommended. Induction of emesis is not recommended. Gastric lavage with a large-bore orogastric tube with appropriate airway protection, if needed, may be indicated if performed soon after ingestion, or in symptomatic patients. Because of the rapid disintegration of mirtazapine orally disintegrating tablets, pill fragments may not appear in gastric contents obtained with lavage. Activated charcoal should be administered. There is no experience with the use of forced diuresis, dialysis, hemoperfusion, or exchange transfusion in the treatment of mirtazapine overdosage. No specific antidotes for mirtazapine are known. - In managing overdosage, consider the possibility of multiple-drug involvement. The physician should consider contacting a poison control center for additional information on the treatment of any overdose. Telephone numbers for certified poison control centers are listed in the Physicians’ Desk Reference (PDR). # Pharmacology ## Mechanism of Action There is limited information regarding Mirtazapine Mechanism of Action in the drug label. ## Structure Mirtazapine orally disintegrating tablets USP are an orally administered drug. Mirtazapine has a tetracyclic chemical structure and belongs to the piperazino-azepine group of compounds. It is designated 1,2,3,4,10,14b-hexahydro-2-methylpyrazino pyrido benzazepine and has the empirical formula of C17H19N3. Its molecular weight is 265.36. The structural formula is the following and it is the racemic mixture: Mirtazapine is a white to creamy white crystalline powder which is slightly soluble in water. Mirtazapine orally disintegrating tablets are available for oral administration as an orally disintegrating tablet containing 15 or 30 mg of mirtazapine. It disintegrates in the mouth within seconds after placement on the tongue, allowing its contents to be subsequently swallowed with or without water. Mirtazapine orally disintegrating tablets also contain the following inactive ingredients: aspartame powder, colloidal silicon dioxide, crospovidone, magnesium stearate, mannitol, microcrystalline cellulose, natural and artificial orange flavor, sodium stearyl fumarate and xylitol. ## Pharmacodynamics - The mechanism of action of mirtazapine orally disintegrating tablets, as with other drugs effective in the treatment of major depressive disorder, is unknown. - Evidence gathered in preclinical studies suggests that mirtazapine enhances central noradrenergic and serotonergic activity. These studies have shown that mirtazapine acts as an antagonist at central presynaptic α2-adrenergic inhibitory autoreceptors and heteroreceptors, an action that is postulated to result in an increase in central noradrenergic and serotonergic activity. - Mirtazapine is a potent antagonist of 5-HT2 and 5-HT3 receptors. Mirtazapine has no significant affinity for the 5-HT1A and 5-HT1B receptors. - Mirtazapine is a potent antagonist of histamine (H1) receptors, a property that may explain its prominent sedative effects. - Mirtazapine is a moderate peripheral α1-adrenergic antagonist, a property that may explain the occasional orthostatic hypotension reported in association with its use. - Mirtazapine is a moderate antagonist at muscarinic receptors, a property that may explain the relatively low incidence of anticholinergic side effects associated with its use. ## Pharmacokinetics - Mirtazapine orally disintegrating tablets are rapidly and completely absorbed following oral administration and have a half-life of about 20 to 40 hours. Peak plasma concentrations are reached within about 2 hours following an oral dose. The presence of food in the stomach has a minimal effect on both the rate and extent of absorption and does not require a dosage adjustment. Mirtazapine orally disintegrating tablets are bioequivalent to mirtazapine tablets. - Mirtazapine is extensively metabolized after oral administration. Major pathways of biotransformation are demethylation and hydroxylation followed by glucuronide conjugation. In vitro data from human liver microsomes indicate that cytochrome 2D6 and 1A2 are involved in the formation of the 8-hydroxy metabolite of mirtazapine, whereas cytochrome 3A is considered to be responsible for the formation of the N-desmethyl and N-oxide metabolite. Mirtazapine has an absolute bioavailability of about 50%. It is eliminated predominantly via urine (75%) with 15% in feces. Several unconjugated metabolites possess pharmacological activity but are present in the plasma at very low levels. The (–) enantiomer has an elimination half-life that is approximately twice as long as the (+) enantiomer and therefore achieves plasma levels that are about 3 times as high as that of the (+) enantiomer. - Plasma levels are linearly related to dose over a dose range of 15 to 80 mg. The mean elimination half-life of mirtazapine after oral administration ranges from approximately 20 to 40 hours across age and gender subgroups, with females of all ages exhibiting significantly longer elimination half-lives than males (mean half-life of 37 hours for females vs. 26 hours for males). Steady state plasma levels of mirtazapine are attained within 5 days, with about 50% accumulation (accumulation ratio = 1.5). - Mirtazapine is approximately 85% bound to plasma proteins over a concentration range of 0.01 to 10 mcg/mL. ## Nonclinical Toxicology There is limited information regarding Mirtazapine Nonclinical Toxicology in the drug label. # Clinical Studies The efficacy of mirtazapine tablets as a treatment for major depressive disorder was established in 4 placebo-controlled, 6-week trials in adult outpatients meeting DSM-III criteria for major depressive disorder. Patients were titrated with mirtazapine from a dose range of 5 mg up to 35 mg/day. Overall, these studies demonstrated mirtazapine to be superior to placebo on at least 3 of the following 4 measures: 21-Item Hamilton Depression Rating Scale (HDRS) total score; HDRS Depressed Mood Item; CGI Severity score; and Montgomery and Asberg Depression Rating Scale (MADRS). Superiority of mirtazapine over placebo was also found for certain factors of the HDRS, including anxiety/somatization factor and sleep disturbance factor. The mean mirtazapine dose for patients who completed these 4 studies ranged from 21 to 32 mg/day. A fifth study of similar design utilized a higher dose (up to 50 mg) per day and also showed effectiveness. Examination of age and gender subsets of the population did not reveal any differential responsiveness on the basis of these subgroupings. In a longer-term study, patients meeting (DSM-IV) criteria for major depressive disorder who had responded during an initial 8 to 12 weeks of acute treatment on mirtazapine were randomized to continuation of mirtazapine or placebo for up to 40 weeks of observation for relapse. Response during the open phase was defined as having achieved a HAM-D 17 total score of ≤8 and a CGI-Improvement score of 1 or 2 at 2 consecutive visits beginning with week 6 of the 8 to 12 weeks in the open-label phase of the study. Relapse during the double-blind phase was determined by the individual investigators. Patients receiving continued mirtazapine treatment experienced significantly lower relapse rates over the subsequent 40 weeks compared to those receiving placebo. This pattern was demonstrated in both male and female patients. # How Supplied Mirtazapine orally disintegrating tablets USP are supplied as: 15 mg: White to off-white, round, flat-faced, beveled-edge, unscored tablet. Debossed with 2469 on one side and WPI on the other side. Blister package of 30 tablets NDC 0591-2469-15 30 mg: White to off-white, round, flat-faced, beveled-edge, unscored tablet. Debossed with 2470 on one side and WPI on the other side. Blister package of 30 tablets NDC 0591-2470-15 ## Storage Store at 20° to 25°C (68° to 77°F) . Protect from light and moisture. Use immediately upon opening individual tablet blister. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information - Prescribers or other health professionals should inform patients, their families, and their caregivers about the benefits and risks associated with treatment with mirtazapine orally disintegrating tablets and should counsel them in its appropriate use. A patient Medication Guide about “Antidepressant Medicines, Depression and other Serious Mental Illnesses, and Suicidal Thoughts or Actions” is available for mirtazapine orally disintegrating tablets. The prescriber or health professional should instruct patients, their families, and their caregivers to read the Medication Guide and should assist them in understanding its contents. Patients should be given the opportunity to discuss the contents of the Medication Guide and to obtain answers to any questions they may have. The complete text of the Medication Guide is reprinted at the end of this document. - Patients should be advised of the following issues and asked to alert their prescriber if these occur while taking mirtazapine orally disintegrating tablets. - Clinical Worsening and Suicide Risk - Patients, their families, and their caregivers should be encouraged to be alert to the emergence of anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, mania, other unusual changes in behavior, worsening of depression, and suicidal ideation, especially early during antidepressant treatment and when the dose is adjusted up or down. Families and caregivers of patients should be advised to look for the emergence of such symptoms on a day-to-day basis, since changes may be abrupt. Such symptoms should be reported to the patient’s prescriber or health professional, especially if they are severe, abrupt in onset, or were not part of the patient’s presenting symptoms. Symptoms such as these may be associated with an increased risk for suicidal thinking and behavior and indicate a need for very close monitoring and possibly changes in the medication. - Agranulocytosis - Patients who are to receive mirtazapine orally disintegrating tablets should be warned about the risk of developing agranulocytosis. Patients should be advised to contact their physician if they experience any indication of infection such as fever, chills, sore throat, mucous membrane ulceration, or other possible signs of infection. Particular attention should be paid to any flu-like complaints or other symptoms that might suggest infection. - Interference with Cognitive and Motor Performance Mirtazapine orally disintegrating tablets may impair judgment, thinking, and particularly, motor skills, because of its prominent sedative effect. The drowsiness associated with mirtazapine use may impair a patient’s ability to drive, use machines, or perform tasks that require alertness. Thus, patients should be cautioned about engaging in hazardous activities until they are reasonably certain that mirtazapine orally disintegrating tablets therapy does not adversely affect their ability to engage in such activities. - Completing Course of Therapy - While patients may notice improvement with mirtazapine orally disintegrating tablets therapy in 1 to 4 weeks, they should be advised to continue therapy as directed. - Concomitant Medication - Patients should be advised to inform their physician if they are taking, or intend to take, any prescription or over-the-counter drugs, since there is a potential for mirtazapine orally disintegrating tablets to interact with other drugs. - Patients should be made aware of a potential increased risk for serotonin syndrome if concomitant use of mirtazapine orally disintegrating tablets with other serotonergic drugs, including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, buspirone, tryptophan, and St. John's wort, is clinically warranted, particularly during treatment initiation and dose increases. - Phenylalanine - Phenylketonuric patients should be informed that mirtazapine orally disintegrating tablets contain phenylalanine 3.36 mg per 15-mg tablet and 6.72 mg per 30-mg tablet. - Pregnancy - Patients should be advised to notify their physician if they become pregnant or intend to become pregnant during mirtazapine orally disintegrating tablets therapy. - Nursing - Patients should be advised to notify their physician if they are breastfeeding an infant. - Laboratory Tests - There are no routine laboratory tests recommended. Mirtazapine Orally Disintegrating Tablets USP - Read the Medication Guide that comes with mirtazapine orally disintegrating tablets before you start taking it and each time you get a refill. There may be new information. This Medication Guide does not take the place of talking to your healthcare provider about your medical condition or treatment. If you have any questions about mirtazapine orally disintegrating tablets, talk to your healthcare provider. - What is the most important information I should know about mirtazapine orally disintegrating tablets? - Mirtazapine orally disintegrating tablets and other antidepressant medicines may cause serious side effects, including: - Suicidal thoughts or actions, Mirtazapine orally disintegrating tablets and other antidepressant medicines may increase suicidal thoughts or actions in some children, teenagers, or young adults within the first few months of treatment or when the dose is changed. Depression or other serious mental illnesses are the most important causes of suicidal thoughts or actions. Watch for these changes and call your healthcare provider right away if you notice, new or sudden changes in mood, behavior, actions, thoughts, or feelings, especially if severe. Pay particular attention to such changes when mirtazapine orally disintegrating tablets is started or when the dose is changed. Keep all follow-up visits with your healthcare provider and call between visits if you are worried about symptoms. - Call your healthcare provider right away if you have any of the following symptoms, or call 911 if an emergency, especially if they are new, worse, or worry you, attempts to commit suicide, acting on dangerous impulses, acting aggressive or violent, thoughts about suicide or dying, new or worse depression, new or worse anxiety or panic attacks, feeling agitated, restless, angry or irritable, trouble sleeping, an increase in activity or talking more than what is normal for you, other unusual changes in behavior or mood Call your healthcare provider right away if you have any of the following symptoms, or call 911 if an emergency. Mirtazapine orally disintegrating tablets may be associated with these serious side effects: - Manic episodes, greatly increased energy, severe trouble sleeping, racing thoughts, reckless behavior, unusually grand ideas, excessive happiness or irritability, talking more or faster than usual - Decreased White Blood Cells called neutrophils, which are needed to fight infections. Tell your doctor if you have any indication of infection such as fever, chills, sore throat, or mouth or nose sores, especially symptoms which are flu-like. - Serotonin Syndrome. This condition can be life-threatening and may include: agitation, hallucinations, coma or other changes in mental status, coordination problems or muscle twitching (overactive reflexes), racing heartbeat, high or low blood pressure, sweating or fever, nausea, vomiting, or diarrhea, muscle rigidity - Seizures - Low salt (sodium) levels in the blood. Elderly people may be at greater risk for this. Symptoms may include headache, weakness or feeling unsteady, confusion, problems concentrating or thinking or memory problems - Sleepiness. It is best to take mirtazapine orally disintegrating tablets close to bedtime. - Severe skin reactions: Call your doctor right away if you have any or all of the following symptoms: Severe rash with skin swelling (including on the palms of the hands and soles of the feet). Painful reddening of the skin and/or blisters/ulcers on the body or in the mouth - Severe allergic reactions: trouble breathing, swelling of the face, tongue, eyes or mouth rash, itchy welts (hives) or blisters, alone or with fever or joint pain - Increases in appetite or weight. Children and adolescents should have height and weight monitored during treatment. Increased cholesterol and triglyceride levels in your blood - Do not stop mirtazapine orally disintegrating tablets without first talking to your healthcare provider. Stopping mirtazapine orally disintegrating tablets too quickly may Cause potentially serious symptoms including: - Dizziness - Abnormal dreams - Agitation - Anxiety - Fatigue - Confusion - Headache - Shaking - Tingling sensation - Nausea, vomiting - Sweating - What are mirtazapine orally disintegrating tablets? Mirtazapine orally disintegrating tablets is a prescription medicine used to treat depression. It is important to talk with your healthcare provider about the risks of treating depression and also the risks of not treating it. You should discuss all treatment choices with your healthcare provider. - Talk to your healthcare provider if you do not think that your condition is getting better with mirtazapine orally disintegrating tablets treatment. - Who should not take mirtazapine orally disintegrating tablets? - Do not take mirtazapine orally disintegrating tablets if you: - Are allergic to mirtazapine or any of the ingredients in mirtazapine orally disintegrating tablets. See the end of this Medication Guide for a complete list of ingredients in mirtazapine orally disintegrating tablets. - Take a monoamine oxidase inhibitor (MAOI). Ask your healthcare provider or pharmacist if you are not sure if you take a MAOI, including the antibiotic linezolid. - Do not take a MAOI within 2 weeks of stopping mirtazapine orally disintegrating tablets unless directed to do so by your physician. - Do not start mirtazapine orally disintegrating tablets if you stopped taking a MAOI in the last 2 weeks unless directed to do so by your physician. - People who take mirtazapine orally disintegrating tabletsclose in time to an MAOI may have serious or even life-threatening side effects. Get medical help right away if you have any of these symptoms: - High fever - Uncontrolled muscle spasms - Stiff muscles - Rapid changes in heart rate or blood pressure - Confusion - Loss of consciousness (pass out) - What should I tell my healthcare provider before taking mirtazapine orally disintegrating tablets? Ask if you are not sure. - Before starting mirtazapine orally disintegrating tablets, tell your healthcare provider if you: - Are taking certain drugs such as: - Triptans used to treat migraine headache - Medicines used to treat mood, anxiety, psychotic or thought disorders, including tricyclics, lithium, SSRIs, SNRIs, or antipsychotics - Tramadol used to treat pain - Over-the-counter supplements such as tryptophan or St. John’s wort - Phenytoin, carbamazepine, or rifampicin (these drugs can decrease your blood level of mirtazapine) - Cimetidine or ketoconazole (these drugs can increase your blood level of mirtazapine) - Have or had: - Liver problems - Kidney problems - Heart problems - Seizures or convulsions - Bipolar disorder or mania - A tendency to get dizzy or faint - Are pregnant or plan to become pregnant. It is not known if mirtazapine orally disintegrating tablets will harm your unborn baby. Talk to your healthcare provider about the benefits and risks of treating depression during pregnancy - Are breastfeeding or plan to breastfeed. Some mirtazapine may pass into your breast milk. Talk to your healthcare provider about the best way to feed your baby while taking mirtazapine orally disintegrating tablets - Tell your healthcare provider about all the medicines that you take, including prescription and non-prescription medicines, vitamins, and herbal supplements. Mirtazapine orally disintegrating tablets and some medicines may interact with each other, may not work as well, or may cause serious side effects. Your healthcare provider or pharmacist can tell you if it is safe to take mirtazapine orally disintegrating tablets with your other medicines. Do not start or stop any medicine while taking mirtazapine orally disintegrating tablets without talking to your healthcare provider first. - If you take mirtazapine orally disintegrating tablets, you should not take any other medicines that contain mirtazapine including mirtazapine tablets. - How should I take mirtazapine orally disintegrating tablets? - Take mirtazapine orally disintegrating tablets exactly as prescribed. Your healthcare provider may need to change the dose of mirtazapine orally disintegrating tablets until it is the right dose for you. - Take mirtazapine orally disintegrating tablets at the same time each day, preferably in the evening at bedtime. - Open the tablet blister pack with dry hands and place the tablet whole on the tongue, immediately after removal from the blister pack. - Mirtazapine orally disintegrating tablets will disintegrate rapidly on the tongue and can be swallowed with saliva. No water is needed for taking it. - Do not attempt to split the mirtazapine orally disintegrating tablets. - It is common for antidepressant medicines such as mirtazapine orally disintegrating tablets to take up to a few weeks before you start to feel better. Do not stop taking mirtazapine orally disintegrating tablets if you do not feel results right away. - Do not stop taking or change the dose of mirtazapine orally disintegrating tablets without first talking to your doctor, even if you feel better. - Mirtazapine orally disintegrating tablets may be taken with or without food. - If you miss a dose of mirtazapine orally disintegrating tablets, take the missed dose as soon as you remember. If it is almost time for the next dose, skip the missed dose and take your next dose at the regular time. Do not take two doses of mirtazapine orally disintegrating tablets at the same time. - If you take too much mirtazapine orally disintegrating tablets, call your healthcare provider or poison control center right away, or get emergency treatment. - What should I avoid while taking mirtazapine orally disintegrating tablets? - Mirtazapine orally disintegrating tablets can cause sleepiness or may affect your ability to make decisions, think clearly, or react quickly. You should not drive, operate heavy machinery, or do other dangerous activities until you know how mirtazapine orally disintegrating tablets affect you. - Avoid drinking alcohol or taking diazepam (a medicine used for anxiety, insomnia and seizures, for example) or similar medicines while taking mirtazapine orally disintegrating tablets. If you are uncertain about whether certain medication can be taken with mirtazapine orally disintegrating tablets, please discuss with your doctor. - What are the possible side effects of mirtazapine orally disintegrating tablets? Mirtazapine orally disintegrating tablets may cause serious side effects, including all of those described in the section entitled “What is the most important information I should know about mirtazapine orally disintegrating tablets?" - Common possible side effects in people who take mirtazapine orally disintegrating tablets include: - Sleepiness - Increased appetite, weight gain - Dry mouth - Constipation - Dizziness - Abnormal dreams - Tell your healthcare provider if you have any side effect that bothers you or that does not go away. These are not all the possible side effects of mirtazapine orally disintegrating tablets. For more information, ask your healthcare provider or pharmacist. - CALL YOUR DOCTOR FOR MEDICAL ADVICE ABOUT SIDE EFFECTS. YOU MAY REPORT SIDE EFFECTS TO THE FDA AT 1-800-FDA-1088. How should I store mirtazapine orally disintegrating tablets? - Store mirtazapine orally disintegrating tablets at room temperature 68° to 77°F (20° to 25°C). - Keep mirtazapine orally disintegrating tablets away from light and moisture. - Use immediately upon opening individual tablet blister. - Keep mirtazapine orally disintegrating tablets and all medicines out of the reach of children. - General information about mirtazapine orally disintegrating tablets - Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use mirtazapine orally disintegrating tablets for a condition for which it was not prescribed. Do not give mirtazapine orally disintegrating tablets to other people, even if they have the same condition. It may harm them. - This Medication Guide summarizes the most important information about mirtazapine orally disintegrating tablets. If you would like more information, talk with your healthcare provider. You may ask your healthcare provider or pharmacist for information about mirtazapine orally disintegrating tablets that is written for healthcare professionals. - For more information about mirtazapine orally disintegrating tablets call 1-800-272-5525 or go to www.watson.com. - What are the ingredients in mirtazapine orally disintegrating tablets? Active ingredient: mirtazapine - Inactive ingredients 15 mg and 30 mg tablets: aspartame powder, colloidal silicon dioxide, crospovidone, magnesium stearate, mannitol, microcrystalline cellulose, natural and artificial orange flavor, sodium stearyl fumarate and xylitol. - This Medication Guide has been approved by the U.S. Food and Drug Administration. Manufactured by: Watson Laboratories, Inc. Corona, CA 92880 USA Distributed by: Watson Pharma, Inc. Parsippany, NJ 07054 USA Revised: October 2013 196669-2 # Precautions with Alcohol - The impairment of cognitive and motor skills produced by mirtazapine has been shown to be additive with those produced by alcohol. Accordingly, patients should be advised to avoid alcohol while taking any dosage form of mirtazapine. - Concomitant administration of alcohol (equivalent to 60 g) had a minimal effect on plasma levels of mirtazapine (15 mg) in 6 healthy male subjects. However, the impairment of cognitive and motor skills produced by mirtazapine were shown to be additive with those produced by alcohol. Accordingly, patients should be advised to avoid alcohol while taking mirtazapine orally disintegrating tablets. # Brand Names There is limited information regarding Mirtazapine Brand Names in the drug label. # Look-Alike Drug Names There is limited information regarding Mirtazapine Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	Mirtazapine Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Pratik Bahekar, MBBS [2] # Disclaimer WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here. # Black Box Warning # Overview Mirtazapine is a noradrenergic and specific serotonergic antidepressant that is FDA approved for the {{{indicationType}}} of major depressive disorder. There is a Black Box Warning for this drug as shown here. Common adverse reactions include increased appetite, serum triglycerides raised, weight gain, constipation, xerostomia, ALT/SGPT level raised, asthenia, dizziness, somnolence, disturbance in thinking. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - Major depression - 15 mg/day PO at bedtime, increase every 1-2 weeks to a max dose of 45 mg/day. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information about Off-Label Guideline-Supported Use of Mirtazapine in adult patients. ### Non–Guideline-Supported Use - Anxiety - Cancer - Dysthymia - Obsessive-compulsive disorder - Panic disorder There is limited information about Off-Label Non–Guideline-Supported Use of Mirtazapine in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) Safety in pediatric patient has not been established. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information about Off-Label Guideline-Supported Use of Mirtazapine in pediatric patients. ### Non–Guideline-Supported Use There is limited information about Off-Label Non–Guideline-Supported Use of Mirtazapine in pediatric patients. # Contraindications - Hypersensitivity - Mirtazapine orally disintegrating tablets are contraindicated in patients with a known hypersensitivity to mirtazapine or to any of the excipients. - Monoamine Oxidase Inhibitors - The use of monoamine oxidase inhibitors (MAOIs) intended to treat psychiatric disorders with mirtazapine orally disintegrating tablets or within 14 days of stopping treatment with mirtazapine orally disintegrating tablets is contraindicated because of an increased risk of serotonin syndrome. The use of mirtazapine orally disintegrating tablets within 14 days of stopping an MAOI intended to treat psychiatric disorders is also contraindicated. - Starting mirtazapine orally disintegrating tablets in a patient who is being treated with MAOIs such as linezolid or intravenous methylene blue is also contraindicated because of an increased risk of serotonin syndrome # Warnings - Clinical Worsening and Suicide Risk - Patients with major depressive disorder (MDD), both adult and pediatric, may experience worsening of their depression and/or the emergence of suicidal ideation and behavior (suicidality) or unusual changes in behavior, whether or not they are taking antidepressant medications, and this risk may persist until significant remission occurs. Suicide is a known risk of depression and certain other psychiatric disorders, and these disorders themselves are the strongest predictors of suicide. There has been a long-standing concern, however, that antidepressants may have a role in inducing worsening of depression and the emergence of suicidality in certain patients during the early phases of treatment. Pooled analyses of short-term placebo-controlled trials of antidepressant drugs (SSRIs and others) showed that these drugs increase the risk of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults (ages 18–24) with major depressive disorder (MDD) and other psychiatric disorders. Short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24; there was a reduction in risk with antidepressants compared to placebo in adults aged 65 and older. - The pooled analyses of placebo-controlled trials in children and adolescents with MDD, obsessive compulsive disorder (OCD), or other psychiatric disorders included a total of 24 short-term trials of 9 antidepressant drugs in over 4400 patients. The pooled analyses of placebo-controlled trials in adults with MDD or other psychiatric disorders included a total of 295 short-term trials (median duration of 2 months) of 11 antidepressant drugs in over 77,000 patients. There was considerable variation in risk of suicidality among drugs, but a tendency toward an increase in the younger patients for almost all drugs studied. There were differences in absolute risk of suicidality across different indications, with the highest incidence in MDD. The risk differences (drug vs. placebo), however, were relatively stable within age strata and across indications. These risk differences (drug-placebo difference in the number of cases of suicidality per 1000 patients treated) are provided in Table 1. - No suicides occurred in any of the pediatric trials. There were suicides in the adult trials, but the number was not sufficient to reach any conclusion about drug effect on suicide. - It is unknown whether the suicidality risk extends to longer-term use, i.e., beyond several months. However, there is substantial evidence from placebo-controlled maintenance trials in adults with depression that the use of antidepressants can delay the recurrence of depression. - All patients being treated with antidepressants for any indication should be monitored appropriately and observed closely for clinical worsening, suicidality, and unusual changes in behavior, especially during the initial few months of a course of drug therapy, or at times of dose changes, either increases or decreases. - The following symptoms, anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, and mania, have been reported in adult and pediatric patients being treated with antidepressants for major depressive disorder as well as for other indications, both psychiatric and nonpsychiatric. Although a causal link between the emergence of such symptoms and either the worsening of depression and/or the emergence of suicidal impulses has not been established, there is concern that such symptoms may represent precursors to emerging suicidality. - Consideration should be given to changing the therapeutic regimen, including possibly discontinuing the medication, in patients whose depression is persistently worse, or who are experiencing emergent suicidality or symptoms that might be precursors to worsening depression or suicidality, especially if these symptoms are severe, abrupt in onset, or were not part of the patient’s presenting symptoms. - Families and caregivers of patients being treated with antidepressants for major depressive disorder or other indications, both psychiatric and nonpsychiatric, should be alerted about the need to monitor patients for the emergence of agitation, irritability, unusual changes in behavior, and the other symptoms described above, as well as the emergence of suicidality, and to report such symptoms immediately to health care providers. Such monitoring should include daily observation by families and caregivers. Prescriptions for mirtazapine orally disintegrating tablets should be written for the smallest quantity of tablets consistent with good patient management, in order to reduce the risk of overdose. - Screening Patients for Bipolar Disorder: - A major depressive episode may be the initial presentation of bipolar disorder. It is generally believed (though not established in controlled trials) that treating such an episode with an antidepressant alone may increase the likelihood of precipitation of a mixed/manic episode in patients at risk for bipolar disorder. Whether any of the symptoms described above represent such a conversion is unknown. However, prior to initiating treatment with an antidepressant, patients with depressive symptoms should be adequately screened to determine if they are at risk for bipolar disorder; such screening should include a detailed psychiatric history, including a family history of suicide, bipolar disorder, and depression. It should be noted that mirtazapine orally disintegrating tablets are not approved for use in treating bipolar depression. - Agranulocytosis - In premarketing clinical trials, 2 (1 with Sjögren’s Syndrome) out of 2796 patients treated with mirtazapine tablets developed agranulocytosis [absolute neutrophil count (ANC) <500/mm3 with associated signs and symptoms, e.g., fever, infection, etc.] and a third patient developed severe neutropenia (ANC <500/mm3 without any associated symptoms). For these 3 patients, onset of severe neutropenia was detected on days 61, 9, and 14 of treatment, respectively. All 3 patients recovered after mirtazapine was stopped. These 3 cases yield a crude incidence of severe neutropenia (with or without associated infection) of approximately 1.1 per thousand patients exposed, with a very wide 95% confidence interval, i.e., 2.2 cases per 10,000 to 3.1 cases per 1000. If a patient develops a sore throat, fever, stomatitis, or other signs of infection, along with a low WBC count, treatment with mirtazapine orally disintegrating tablets should be discontinued and the patient should be closely monitored. - Serotonin Syndrome - The development of a potentially life-threatening serotonin syndrome has been reported with SNRIs and SSRIs, including mirtazapine orally disintegrating tablets, alone but particularly with concomitant use of serotonergic drugs (including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, and St. John"s wort) and with drugs that impair metabolism of serotonin (in particular, MAOIs, both those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue). - Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, delirium, and coma), autonomic instability (e.g., tachycardia, labile blood pressure, dizziness, diaphoresis, flusing, hyperthermia), neuromuscular symptoms (e.g., tremor, rigidity, myoclonus, hyperreflexia, incoordination), seizures, and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). Patients should be monitored for the emergence of serotonin syndrome. - The concomitant use of mirtazapine orally disintegrating tablets with MAOIs intended to treat psychiatric disorders is contraindicated. Mirtazapine orally disintegrating tablets should also not be started in a patient who is being treated with MAOIs such as linezolid or intravenous methylene blue. All reports with methylene blue that provided information on the route of administration involved intravenous administration in the dose range of 1 mg/kg to 8 mg/kg. No reports involved the administration of methylene blue by other routes (such as oral tablets or local tissue injection) or at lower doses. There may be circumstances when it is necessary to initiate treatment with an MAOI such as linezolid or intravenous methylene blue in a patient taking mirtazapine orally disintegrating tablets. Mirtazapine orally disintegrating tablets should be discontinued before initiating treatment with the MAOI (see CONTRAINDICATIONS and DOSAGE AND ADMINISTRATION). - If concomitant use of mirtazapine orally disintegrating tablets with other serotonergic drugs, including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, buspirone, tryptophan, and St. John"s wort, is clinically warranted, be aware of a potential increased risk for serotonin syndrome, particularly during treatment initiation and dose increases. - Treatment with mirtazapine orally disintegrating tablets and any concomitant serotonergic agents should be discontinued immediately if the above events occur and supportive symptomatic treatment should be initiated. - General - Discontinuation Symptoms There have been reports of adverse reactions upon the discontinuation of mirtazapine/mirtazapine orally disintegrating tablets (particularly when abrupt), including but not limited to the following: dizziness, abnormal dreams, sensory disturbances (including paresthesia and electric shock sensations), agitation, anxiety, fatigue, confusion, headache, tremor, nausea, vomiting, and sweating, or other symptoms which may be of clinical significance. The majority of the reported cases are mild and self-limiting. Even though these have been reported as adverse reactions, it should be realized that these symptoms may be related to underlying disease. - Patients currently taking mirtazapine should NOT discontinue treatment abruptly, due to risk of discontinuation symptoms. At the time that a medical decision is made to discontinue treatment with mirtazapine, a gradual reduction in the dose, rather than an abrupt cessation, is recommended. - Akathisia/Psychomotor Restlessness - The use of antidepressants has been associated with the development of akathisia, characterized by a subjectively unpleasant or distressing restlessness and need to move often accompanied by an inability to sit or stand still. This is most likely to occur within the first few weeks of treatment. In patients who develop these symptoms, increasing the dose may be detrimental. - Hyponatremia - Hyponatremia has been reported very rarely with the use of mirtazapine. Caution should be exercised in patients at risk, such as elderly patients or patients concomitantly treated with medications known to cause hyponatremia. - Somnolence - In US controlled studies, somnolence was reported in 54% of patients treated with mirtazapine tablets, compared to 18% for placebo and 60% for amitriptyline. In these studies, somnolence resulted in discontinuation for 10.4% of mirtazapine-treated patients, compared to 2.2% for placebo. It is unclear whether or not tolerance develops to the somnolent effects of mirtazapine. Because of the potentially significant effects of mirtazapine on impairment of performance, patients should be cautioned about engaging in activities requiring alertness until they have been able to assess the drug’s effect on their own psychomotor performance. - Dizziness - In US controlled studies, dizziness was reported in 7% of patients treated with mirtazapine, compared to 3% for placebo and 14% for amitriptyline. It is unclear whether or not tolerance develops to the dizziness observed in association with the use of mirtazapine. - Increased Appetite/Weight Gain - In US controlled studies, appetite increase was reported in 17% of patients treated with mirtazapine, compared to 2% for placebo and 6% for amitriptyline. In these same trials, weight gain of ≥7% of body weight was reported in 7.5% of patients treated with mirtazapine, compared to 0% for placebo and 5.9% for amitriptyline. In a pool of premarketing US studies, including many patients for long-term, open-label treatment, 8% of patients receiving mirtazapine discontinued for weight gain. In an 8-week-long pediatric clinical trial of doses between 15 to 45 mg/day, 49% of mirtazapine-treated patients had a weight gain of at least 7%, compared to 5.7% of placebo-treated patients (see PRECAUTIONS: Pediatric Use). - Cholesterol/Triglycerides - In US controlled studies, nonfasting cholesterol increases to ≥20% above the upper limits normal were observed in 15% of patients treated with mirtazapine, compared to 7% for placebo and 8% for amitriptyline. In these same studies, nonfasting triglyceride increases to ≥500 mg/dL were observed in 6% of patients treated with mirtazapine, compared to 3% for placebo and 3% for amitriptyline. - Transaminase Elevations - Clinically significant ALT (SGPT) elevations (≥3 times the upper limit of the normal range) were observed in 2.0% (8/424) of patients exposed to mirtazapine in a pool of short-term US controlled trials, compared to 0.3% (1/328) of placebo patients and 2.0% (3/181) of amitriptyline patients. Most of these patients with ALT increases did not develop signs or symptoms associated with compromised liver function. While some patients were discontinued for the ALT increases, in other cases, the enzyme levels returned to normal despite continued mirtazapine treatment. Mirtazapine orally disintegrating tablets should be used with caution in patients with impaired hepatic function. - Activation of Mania/Hypomania - Mania/hypomania occurred in approximately 0.2% (3/1299 patients) of mirtazapine-treated patients in US studies. Although the incidence of mania/hypomania was very low during treatment with mirtazapine, it should be used carefully in patients with a history of mania/hypomania. - Seizure - In premarketing clinical trials, only 1 seizure was reported among the 2796 US and non-US patients treated with mirtazapine. However, no controlled studies have been carried out in patients with a history of seizures. Therefore, care should be exercised when mirtazapine is used in these patients. - Use in Patients with Concomitant Illness - Clinical experience with mirtazapine orally disintegrating tablets in patients with concomitant systemic illness is limited. Accordingly, care is advisable in prescribing mirtazapine for patients with diseases or conditions that affect metabolism or hemodynamic responses. Mirtazapine orally disintegrating tablets have not been systematically evaluated or used to any appreciable extent in patients with a recent history of myocardial infarction or other significant heart disease. Mirtazapine was associated with significant orthostatic hypotension in early clinical pharmacology trials with normal volunteers. Orthostatic hypotension was infrequently observed in clinical trials with depressed patients. Mirtazapine orally disintegrating tablets should be used with caution in patients with known cardiovascular or cerebrovascular disease that could be exacerbated by hypotension (history of myocardial infarction, angina, or ischemic stroke) and conditions that would predispose patients to hypotension (dehydration, hypovolemia, and treatment with antihypertensive medication). - Mirtazapine clearance is decreased in patients with moderate [glomerular filtration rate (GFR) = 11–39 mL/min/1.73 m2] and severe [GFR <10 mL/min/1.73 m2] renal impairment, and also in patients with hepatic impairment. Caution is indicated in administering mirtazapine orally disintegrating tablets to such patients # Adverse Reactions ## Clinical Trials Experience - Associated with Discontinuation of Treatment - Approximately 16% of the 453 patients who received mirtazapine tablets in US 6-week controlled clinical trials discontinued treatment due to an adverse experience, compared to 7% of the 361 placebo-treated patients in those studies. The most common events (≥1%) associated with discontinuation and considered to be drug related (i.e., those events associated with dropout at a rate at least twice that of placebo) are included in Table 2. - Commonly Observed Adverse Events in US Controlled Clinical Trials The most commonly observed adverse events associated with the use of mirtazapine tablets (incidence of 5% or greater) and not observed at an equivalent incidence among placebo-treated patients (mirtazapine incidence at least twice that for placebo) are listed in Table 3. - Adverse Events Occurring at an Incidence of 1% or More Among Mirtazapine *Tablets-Treated Patients - Table 4 enumerates adverse events that occurred at an incidence of 1% or more, and were more frequent than in the placebo group, among mirtazapine tablets-treated patients who participated in short-term US placebo-controlled trials in which patients were dosed in a range of 5 to 60 mg/day. This table shows the percentage of patients in each group who had at least 1 episode of an event at some time during their treatment. Reported adverse events were classified using a standard COSTART-based dictionary terminology. - The prescriber should be aware that these figures cannot be used to predict the incidence of side effects in the course of usual medical practice where patient characteristics and other factors differ from those which prevailed in the clinical trials. Similarly, the cited frequencies cannot be compared with figures obtained from other investigations involving different treatments, uses, and investigators. The cited figures, however, do provide the prescribing physician with some basis for estimating the relative contribution of drug and nondrug factors to the side-effect incidence rate in the population studied. - ECG Changes - The electrocardiograms for 338 patients who received mirtazapine tablets and 261 patients who received placebo in 6-week, placebo-controlled trials were analyzed. Prolongation in QTc ≥500 msec was not observed among mirtazapine-treated patients; mean change in QTc was +1.6 msec for mirtazapine and –3.1 msec for placebo. Mirtazapine was associated with a mean increase in heart rate of 3.4 bpm, compared to 0.8 bpm for placebo. The clinical significance of these changes is unknown. - Other Adverse Events Observed During the Premarketing Evaluation of Mirtazapine - During its premarketing assessment, multiple doses of mirtazapine tablets were administered to 2796 patients in clinical studies. The conditions and duration of exposure to mirtazapine varied greatly, and included (in overlapping categories) open and double-blind studies, uncontrolled and controlled studies, inpatient and outpatient studies, fixed-dose and titration studies. Untoward events associated with this exposure were recorded by clinical investigators using terminology of their own choosing. Consequently, it is not possible to provide a meaningful estimate of the proportion of individuals experiencing adverse events without first grouping similar types of untoward events into a smaller number of standardized event categories. - In the tabulations that follow, reported adverse events were classified using a standard COSTART-based dictionary terminology. The frequencies presented, therefore, represent the proportion of the 2796 patients exposed to multiple doses of mirtazapine who experienced an event of the type cited on at least 1 occasion while receiving mirtazapine. All reported events are included except those already listed in Table 4, those adverse experiences subsumed under COSTART terms that are either overly general or excessively specific so as to be uninformative, and those events for which a drug cause was very remote. - It is important to emphasize that, although the events reported occurred during treatment with mirtazapine, they were not necessarily caused by it. - Events are further categorized by body system and listed in order of decreasing frequency according to the following definitions: frequent adverse events are those occurring on 1 or more occasions in at least 1/100 patients; infrequent adverse events are those occurring in 1/100 to 1/1000 patients; rare events are those occurring in fewer than 1/1000 patients. Only those events not already listed in Table 4 appear in this listing. Events of major clinical importance are also described in the WARNINGS and PRECAUTIONS sections. - Body as a Whole - Frequent: malaise, abdominal pain, abdominal syndrome acute; infrequent: chills, fever, face edema, ulcer, photosensitivity reaction, neck rigidity, neck pain, abdomen enlarged; rare: cellulitis, chest pain substernal. - Cardiovascular System - Frequent: hypertension, vasodilatation; infrequent: angina pectoris, myocardial infarction, bradycardia, ventricular extrasystoles, syncope, migraine, hypotension; rare: atrial arrhythmia, bigeminy, vascular headache, pulmonary embolus, cerebral ischemia, cardiomegaly, phlebitis, left heart failure. - Digestive System - Frequent: vomiting, anorexia; infrequent: eructation, glossitis, cholecystitis, nausea and vomiting, gum hemorrhage, stomatitis, colitis, liver function tests abnormal; rare: tongue discoloration, ulcerative stomatitis, salivary gland enlargement, increased salivation, intestinal obstruction, pancreatitis, aphthous stomatitis, cirrhosis of liver, gastritis, gastroenteritis, oral moniliasis, tongue edema. - Endocrine System - Rare: goiter, hypothyroidism. - Hemic and Lymphatic System: rare: lymphadenopathy, leukopenia, petechia, anemia, thrombocytopenia, lymphocytosis, pancytopenia. - Metabolic and Nutritional Disorders: frequent: thirst; infrequent: dehydration, weight loss; rare: gout, SGOT increased, healing abnormal, acid phosphatase increased, SGPT increased, diabetes mellitus, hyponatremia. - Musculoskeletal System: frequent: myasthenia, arthralgia; infrequent: arthritis, tenosynovitis; rare: pathologic fracture, osteoporosis fracture, bone pain, myositis, tendon rupture, arthrosis, bursitis. - Nervous System: frequent - Hypesthesia, apathy, depression, hypokinesia, vertigo, twitching, agitation, anxiety, amnesia, hyperkinesia, paresthesia; infrequent: ataxia, delirium, delusions, depersonalization, dyskinesia, extrapyramidal syndrome, libido increased, coordination abnormal, dysarthria, hallucinations, manic reaction, neurosis, dystonia, hostility, reflexes increased, emotional lability, euphoria, paranoid reaction; rare: aphasia, nystagmus, akathisia (psychomotor restlessness), stupor, dementia, diplopia, drug dependence, paralysis, grand mal convulsion, hypotonia, myoclonus, psychotic depression, withdrawal syndrome, serotonin syndrome. - Respiratory System - Frequent: cough increased, sinusitis; infrequent: epistaxis, bronchitis, asthma, pneumonia; rare: asphyxia, laryngitis, pneumothorax, hiccup. - Skin and Appendages: frequent: pruritus, rash; infrequent: acne, exfoliative dermatitis, dry skin, herpes simplex, alopecia; rare: urticaria, herpes zoster, skin hypertrophy, seborrhea, skin ulcer. - Special Senses: infrequent: eye pain, abnormality of accommodation, conjunctivitis, deafness, keratoconjunctivitis, lacrimation disorder, glaucoma, hyperacusis, ear pain; rare: blepharitis, partial transitory deafness, otitis media, taste loss, parosmia. - Urogenital System: frequent: urinary tract infection; infrequent: kidney calculus, cystitis, dysuria, urinary incontinence, urinary retention, vaginitis, hematuria, breast pain, amenorrhea, dysmenorrhea, leukorrhea, impotence; rare: polyuria, urethritis, metrorrhagia, menorrhagia, abnormal ejaculation, breast engorgement, breast enlargement, urinary urgency. - Other Adverse Events Observed During Postmarketing Evaluation of Mirtazapine - Adverse events reported since market introduction, which were temporally (but not necessarily causally) related to mirtazapine therapy, include 4 cases of the ventricular arrhythmia torsades de pointes. In 3 of the 4 cases, however, concomitant drugs were implicated. All patients recovered. - Cases of severe skin reactions, including Stevens-Johnson syndrome, bullous dermatitis, erythema multiforme and toxic epidermal necrolysis have also been reported. ## Postmarketing Experience There is limited information regarding Mirtazapine Postmarketing Experience in the drug label. # Drug Interactions - As with other drugs, the potential for interaction by a variety of mechanisms (e.g., pharmacodynamic, pharmacokinetic inhibition or enhancement, etc.) is a possibility. - Monoamine Oxidase Inhibitors - Serotonergic Drugs - Drugs Affecting Hepatic Metabolism The metabolism and pharmacokinetics of mirtazapine orally disintegrating tablets may be affected by the induction or inhibition of drug-metabolizing enzymes. ### Drugs that are Metabolized by and/or Inhibit Cytochrome P450 Enzymes CYP Enzyme Inducers (these studies used both drugs at steady state) - Phenytoin - In healthy male patients (n=18), phenytoin (200 mg daily) increased mirtazapine (30 mg daily) clearance about 2-fold, resulting in a decrease in average plasma mirtazapine concentrations of 45%. Mirtazapine did not significantly affect the pharmacokinetics of phenytoin. - Carbamazepine - In healthy male patients (n=24), carbamazepine (400 mg b.i.d.) increased mirtazapine (15 mg b.i.d.) clearance about 2-fold, resulting in a decrease in average plasma mirtazapine concentrations of 60%. - When phenytoin, carbamazepine, or another inducer of hepatic metabolism (such as rifampicin) is added to mirtazapine therapy, the mirtazapine dose may have to be increased. If treatment with such a medicinal product is discontinued, it may be necessary to reduce the mirtazapine dose. ### CYP Enzyme Inhibitors - Cimetidine - In healthy male patients (n=12), when cimetidine, a weak inhibitor of CYP1A2, CYP2D6, and CYP3A4, given at 800 mg b.i.d. at steady state was coadministered with mirtazapine (30 mg daily) at steady state, the Area Under the Curve (AUC) of mirtazapine increased more than 50%. Mirtazapine did not cause relevant changes in the pharmacokinetics of cimetidine. The mirtazapine dose may have to be decreased when concomitant treatment with cimetidine is started, or increased when cimetidine treatment is discontinued. - Ketoconazole - In healthy, male, Caucasian patients (n=24), coadministration of the potent CYP3A4 inhibitor ketoconazole (200 mg b.i.d. for 6.5 days) increased the peak plasma levels and the AUC of a single 30-mg dose of mirtazapine by approximately 40% and 50%, respectively. - Caution should be exercised when coadministering mirtazapine with potent CYP3A4 inhibitors, HIV protease inhibitors, azole antifungals, erythromycin, or nefazodone. - Paroxetine - In an in vivo interaction study in healthy, CYP2D6 extensive metabolizer patients (n=24), mirtazapine (30 mg/day), at steady state, did not cause relevant changes in the pharmacokinetics of steady state paroxetine (40 mg/day), a CYP2D6 inhibitor. - Amitriptyline - In healthy, CYP2D6 extensive metabolizer patients (n=32), amitriptyline (75 mg daily), at steady state, did not cause relevant changes to the pharmacokinetics of steady state mirtazapine (30 mg daily); mirtazapine also did not cause relevant changes to the pharmacokinetics of amitriptyline. - Warfarin - In healthy male subjects (n=16), mirtazapine (30 mg daily), at steady state, caused a small (0.2) but statistically significant increase in the International Normalized Ratio (INR) in subjects treated with warfarin. As at a higher dose of mirtazapine, a more pronounced effect can not be excluded, it is advisable to monitor the INR in case of concomitant treatment of warfarin with mirtazapine. - Lithium - No relevant clinical effects or significant changes in pharmacokinetics have been observed in healthy male subjects on concurrent treatment with subtherapeutic levels of lithium (600 mg/day for 10 days) at steady state and a single 30 mg dose of mirtazapine. The effects of higher doses of lithium on the pharmacokinetics of mirtazapine are unknown. - Risperidone - In an in vivo, nonrandomized, interaction study, subjects (n=6) in need of treatment with an antipsychotic and antidepressant drug, showed that mirtazapine (30 mg daily) at steady state did not influence the pharmacokinetics of risperidone (up to 3 mg b.i.d.). - Alcohol - Concomitant administration of alcohol (equivalent to 60 g) had a minimal effect on plasma levels of mirtazapine (15 mg) in 6 healthy male subjects. However, the impairment of cognitive and motor skills produced by mirtazapine were shown to be additive with those produced by alcohol. Accordingly, patients should be advised to avoid alcohol while taking mirtazapine orally disintegrating tablets. - Diazepam - Concomitant administration of diazepam (15 mg) had a minimal effect on plasma levels of mirtazapine (15 mg) in 12 healthy subjects. However, the impairment of motor skills produced by mirtazapine has been shown to be additive with those caused by diazepam. Accordingly, patients should be advised to avoid diazepam and other similar drugs while taking mirtazapine orally disintegrating tablets. - Carcinogenesis - Carcinogenicity studies were conducted with mirtazapine given in the diet at doses of 2, 20, and 200 mg/kg/day to mice and 2, 20, and 60 mg/kg/day to rats. The highest doses used are approximately 20 and 12 times the maximum recommended human dose (MRHD) of 45 mg/day on an mg/m2 basis in mice and rats, respectively. There was an increased incidence of hepatocellular adenoma and carcinoma in male mice at the high dose. In rats, there was an increase in hepatocellular adenoma in females at the mid and high doses and in hepatocellular tumors and thyroid follicular adenoma/cystadenoma and carcinoma in males at the high dose. The data suggest that the above effects could possibly be mediated by non-genotoxic mechanisms, the relevance of which to humans is not known. - The doses used in the mouse study may not have been high enough to fully characterize the carcinogenic potential of mirtazapine tablets. - Mutagenesis - Mirtazapine was not mutagenic or clastogenic and did not induce general DNA damage as determined in several genotoxicity tests: Ames test, in vitro gene mutation assay in Chinese hamster V 79 cells, in vitro sister chromatid exchange assay in cultured rabbit lymphocytes, in vivo bone marrow micronucleus test in rats, and unscheduled DNA synthesis assay in HeLa cells. - Impairment of Fertility - In a fertility study in rats, mirtazapine was given at doses up to 100 mg/kg [20 times the maximum recommended human dose (MRHD) on an mg/m2 basis]. Mating and conception were not affected by the drug, but estrous cycling was disrupted at doses that were 3 or more times the MRHD, and pre-implantation losses occurred at 20 times the MRHD. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): C Reproduction studies in pregnant rats and rabbits at doses up to 100 mg/kg and 40 mg/kg, respectively [20 and 17 times the maximum recommended human dose (MRHD) on an mg/m2 basis, respectively], have revealed no evidence of teratogenic effects. However, in rats, there was an increase in postimplantation losses in dams treated with mirtazapine. There was an increase in pup deaths during the first 3 days of lactation and a decrease in pup birth weights. The cause of these deaths is not known. The effects occurred at doses that were 20 times the MRHD, but not at 3 times the MRHD, on an mg/m2 basis. There are no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed. Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Mirtazapine in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Mirtazapine during labor and delivery. ### Nursing Mothers Because some mirtazapine may be excreted in breast milk, caution should be exercised when mirtazapine orally disintegrating tablets are administered to nursing women. ### Pediatric Use - Safety and effectiveness in the pediatric population have not been established. Two placebo-controlled trials in 258 pediatric patients with MDD have been conducted with mirtazapine tablets, and the data were not sufficient to support a claim for use in pediatric patients. Anyone considering the use of mirtazapine orally disintegrating tablets in a child or adolescent must balance the potential risks with the clinical need. - In an 8-week-long pediatric clinical trial of doses between 15 to 45 mg/day, 49% of mirtazapine-treated patients had a weight gain of at least 7%, compared to 5.7% of placebo-treated patients. The mean increase in weight was 4 kg (2 kg SD) for mirtazapine-treated patients versus 1 kg (2 kg SD) for placebo-treated patients. ### Geriatic Use - Following oral administration of mirtazapine tablets 20 mg/day for 7 days to subjects of varying ages (range, 25–74), oral clearance of mirtazapine was reduced in the elderly compared to the younger subjects. The differences were most striking in males, with a 40% lower clearance in elderly males compared to younger males, while the clearance in elderly females was only 10% lower compared to younger females. Caution is indicated in administering mirtazapine orally disintegrating tablets to elderly patients. - Approximately 190 elderly individuals (≥65 years of age) participated in clinical studies with mirtazapine tablets. This drug is known to be substantially excreted by the kidney (75%), and the risk of decreased clearance of this drug is greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection. Sedating drugs may cause confusion and over-sedation in the elderly. No unusual adverse age-related phenomena were identified in this group. Pharmacokinetic studies revealed a decreased clearance in the elderly. Caution is indicated in administering mirtazapine orally disintegrating tablets to elderly patients ### Gender The mean elimination half-life of mirtazapine after oral administration ranges from approximately 20 to 40 hours across age and gender subgroups, with females of all ages exhibiting significantly longer elimination half-lives than males (mean half-life of 37 hours for females vs. 26 hours for males) ### Race There have been no clinical studies to evaluate the effect of race on the pharmacokinetics of mirtazapine orally disintegrating tablets. ### Renal Impairment The disposition of mirtazapine was studied in patients with varying degrees of renal function. Elimination of mirtazapine is correlated with creatinine clearance. Total body clearance of mirtazapine was reduced approximately 30% in patients with moderate (Clcr = 11–39 mL/min/1.73 m2) and approximately 50% in patients with severe (Clcr = <10 mL/min/1.73 m2) renal impairment when compared to normal subjects. Caution is indicated in administering mirtazapine orally disintegrating tablets to patients with compromised renal function. ### Hepatic Impairment Following a single 15-mg oral dose of mirtazapine, the oral clearance of mirtazapine was decreased by approximately 30% in hepatically impaired patients compared to subjects with normal hepatic function. Caution is indicated in administering mirtazapine orally disintegrating tablets to patients with compromised hepatic function. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Mirtazapine in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Mirtazapine in patients who are immunocompromised. # Administration and Monitoring ### Administration - Initial Treatment - The recommended starting dose for mirtazapine orally disintegrating tablets is 15 mg/day, administered in a single dose, preferably in the evening prior to sleep. In the controlled clinical trials establishing the efficacy of mirtazapine in the treatment of major depressive disorder, the effective dose range was generally 15 to 45 mg/day. While the relationship between dose and satisfactory response in the treatment of major depressive disorder for mirtazapine has not been adequately explored, patients not responding to the initial 15-mg dose may benefit from dose increases up to a maximum of 45 mg/day. Mirtazapine has an elimination half-life of approximately 20 to 40 hours; therefore, dose changes should not be made at intervals of less than 1 to 2 weeks in order to allow sufficient time for evaluation of the therapeutic response to a given dose. - Administration of Mirtazapine Orally Disintegrating Tablets - Patients should be instructed to open tablet blister pack with dry hands and place the tablet on the tongue. The tablet should be used immediately after removal from its blister; once removed, it cannot be stored. Mirtazapine orally disintegrating tablets will disintegrate rapidly on the tongue and can be swallowed with saliva. No water is needed for taking the tablet. Patients should not attempt to split the tablet. - Elderly and Patients with Renal or Hepatic Impairment - The clearance of mirtazapine is reduced in elderly patients and in patients with moderate to severe renal or hepatic impairment. Consequently, the prescriber should be aware that plasma mirtazapine levels may be increased in these patient groups, compared to levels observed in younger adults without renal or hepatic impairment. ### Monitoring - Maintenance/Extended Treatment - It is generally agreed that acute episodes of depression require several months or longer of sustained pharmacological therapy beyond response to the acute episode. Systematic evaluation of mirtazapine tablets has demonstrated that its efficacy in major depressive disorder is maintained for periods of up to 40 weeks following 8 to 12 weeks of initial treatment at a dose of 15 to 45 mg/day. Based on these limited data, it is unknown whether or not the dose of mirtazapine needed for maintenance treatment is identical to the dose needed to achieve an initial response. Patients should be periodically reassessed to determine the need for maintenance treatment and the appropriate dose for such treatment. - Switching Patients To or From a Monoamine Oxidase Inhibitor (MAOI) Intended to Treat Psychiatric Disorders - At least 14 days should elapse between discontinuation of an MAOI intended to treat psychiatric disorders and initiation of therapy with mirtazapine orally disintegrating tablets. Conversely, at least 14 days should be allowed after stopping mirtazapine orally disintegrating tablets before starting an MAOI intended to treat psychiatric disorders. - Use of Mirtazapine Orally Disintegrating Tablets With Other MAOIs, Such as Linezolid or Methylene Blue - Do not start mirtazapine orally disintegrating tablets in a patient who is being treated with linezolid or intravenous methylene blue because there is an increased risk of serotonin syndrome. In a patient who requires more urgent treatment of a psychiatric condition, other interventions, including hospitalization, should be considered. - In some cases, a patient already receiving therapy with mirtazapine orally disintegrating tablets may require urgent treatment with linezolid or intravenous methylene blue. If acceptable alternatives to linezolid or intravenous methylene blue treatment are not available and the potential benefits of linezolid or intravenous methylene blue treatment are judged to outweigh the risks of serotonin syndrome in a particular patient, mirtazapine orally disintegrating tablets should be stopped promptly, and linezolid or intravenous methylene blue can be administered. The patient should be monitored for symptoms of serotonin syndrome for 2 weeks or until 24 hours after the last dose of linezolid or intravenous methylene blue, whichever comes first. Therapy with mirtazapine orally disintegrating tablets may be resumed 24 hours after the last dose of linezolid or intravenous methylene blue. - The risk of administering methylene blue by non-intravenous routes (such as oral tablets or by local injection) or in intravenous doses much lower than 1 mg/kg with mirtazapine orally disintegrating tablets is unclear. The clinician should, nevertheless, be aware of the possibility of emergent symptoms of serotonin syndrome with such use. - Discontinuation of Mirtazapine Treatment - Symptoms associated with the discontinuation or dose reduction of mirtazapine orally disintegrating tablets have been reported. Patients should be monitored for these and other symptoms when discontinuing treatment or during dosage reduction. A gradual reduction in the dose over several weeks, rather than abrupt cessation, is recommended whenever possible. If intolerable symptoms occur following a decrease in the dose or upon discontinuation of treatment, dose titration should be managed on the basis of the patient’s clinical response # IV Compatibility There is limited information regarding the compatibility of Mirtazapine and IV administrations. # Overdosage - Controlled Substance Class - Mirtazapine orally disintegrating tablets are not a controlled substance. - Physical and Psychologic Dependence - Mirtazapine orally disintegrating tablets have not been systematically studied in animals or humans for its potential for abuse, tolerance, or physical dependence. While the clinical trials did not reveal any tendency for any drug-seeking behavior, these observations were not systematic and it is not possible to predict on the basis of this limited experience the extent to which a CNS-active drug will be misused, diverted and/or abused once marketed. Consequently, patients should be evaluated carefully for history of drug abuse, and such patients should be observed closely for signs of mirtazapine orally disintegrating tablet misuse or abuse (e.g., development of tolerance, incrementations of dose, drug-seeking behavior). - Human Experience - There is very limited experience with mirtazapine orally disintegrating tablets overdose. In premarketing clinical studies, there were 8 reports of mirtazapine overdose alone or in combination with other pharmacological agents. The only drug overdose death reported while taking mirtazapine was in combination with amitriptyline and chlorprothixene in a non-US clinical study. Based on plasma levels, the mirtazapine dose taken was 30 to 45 mg, while plasma levels of amitriptyline and chlorprothixene were found to be at toxic levels. All other premarketing overdose cases resulted in full recovery. Signs and symptoms reported in association with overdose included disorientation, drowsiness, impaired memory, and tachycardia. There were no reports of ECG abnormalities, coma, or convulsions following overdose with mirtazapine alone. - Overdose Management - Treatment should consist of those general measures employed in the management of overdose with any drug effective in the treatment of major depressive disorder. Ensure an adequate airway, oxygenation, and ventilation. Monitor cardiac rhythm and vital signs. General supportive and symptomatic measures are also recommended. Induction of emesis is not recommended. Gastric lavage with a large-bore orogastric tube with appropriate airway protection, if needed, may be indicated if performed soon after ingestion, or in symptomatic patients. Because of the rapid disintegration of mirtazapine orally disintegrating tablets, pill fragments may not appear in gastric contents obtained with lavage. Activated charcoal should be administered. There is no experience with the use of forced diuresis, dialysis, hemoperfusion, or exchange transfusion in the treatment of mirtazapine overdosage. No specific antidotes for mirtazapine are known. - In managing overdosage, consider the possibility of multiple-drug involvement. The physician should consider contacting a poison control center for additional information on the treatment of any overdose. Telephone numbers for certified poison control centers are listed in the Physicians’ Desk Reference (PDR). # Pharmacology ## Mechanism of Action There is limited information regarding Mirtazapine Mechanism of Action in the drug label. ## Structure Mirtazapine orally disintegrating tablets USP are an orally administered drug. Mirtazapine has a tetracyclic chemical structure and belongs to the piperazino-azepine group of compounds. It is designated 1,2,3,4,10,14b-hexahydro-2-methylpyrazino [2,1-a] pyrido [2,3-c] benzazepine and has the empirical formula of C17H19N3. Its molecular weight is 265.36. The structural formula is the following and it is the racemic mixture: Mirtazapine is a white to creamy white crystalline powder which is slightly soluble in water. Mirtazapine orally disintegrating tablets are available for oral administration as an orally disintegrating tablet containing 15 or 30 mg of mirtazapine. It disintegrates in the mouth within seconds after placement on the tongue, allowing its contents to be subsequently swallowed with or without water. Mirtazapine orally disintegrating tablets also contain the following inactive ingredients: aspartame powder, colloidal silicon dioxide, crospovidone, magnesium stearate, mannitol, microcrystalline cellulose, natural and artificial orange flavor, sodium stearyl fumarate and xylitol. ## Pharmacodynamics - The mechanism of action of mirtazapine orally disintegrating tablets, as with other drugs effective in the treatment of major depressive disorder, is unknown. - Evidence gathered in preclinical studies suggests that mirtazapine enhances central noradrenergic and serotonergic activity. These studies have shown that mirtazapine acts as an antagonist at central presynaptic α2-adrenergic inhibitory autoreceptors and heteroreceptors, an action that is postulated to result in an increase in central noradrenergic and serotonergic activity. - Mirtazapine is a potent antagonist of 5-HT2 and 5-HT3 receptors. Mirtazapine has no significant affinity for the 5-HT1A and 5-HT1B receptors. - Mirtazapine is a potent antagonist of histamine (H1) receptors, a property that may explain its prominent sedative effects. - Mirtazapine is a moderate peripheral α1-adrenergic antagonist, a property that may explain the occasional orthostatic hypotension reported in association with its use. - Mirtazapine is a moderate antagonist at muscarinic receptors, a property that may explain the relatively low incidence of anticholinergic side effects associated with its use. ## Pharmacokinetics - Mirtazapine orally disintegrating tablets are rapidly and completely absorbed following oral administration and have a half-life of about 20 to 40 hours. Peak plasma concentrations are reached within about 2 hours following an oral dose. The presence of food in the stomach has a minimal effect on both the rate and extent of absorption and does not require a dosage adjustment. Mirtazapine orally disintegrating tablets are bioequivalent to mirtazapine tablets. - Mirtazapine is extensively metabolized after oral administration. Major pathways of biotransformation are demethylation and hydroxylation followed by glucuronide conjugation. In vitro data from human liver microsomes indicate that cytochrome 2D6 and 1A2 are involved in the formation of the 8-hydroxy metabolite of mirtazapine, whereas cytochrome 3A is considered to be responsible for the formation of the N-desmethyl and N-oxide metabolite. Mirtazapine has an absolute bioavailability of about 50%. It is eliminated predominantly via urine (75%) with 15% in feces. Several unconjugated metabolites possess pharmacological activity but are present in the plasma at very low levels. The (–) enantiomer has an elimination half-life that is approximately twice as long as the (+) enantiomer and therefore achieves plasma levels that are about 3 times as high as that of the (+) enantiomer. - Plasma levels are linearly related to dose over a dose range of 15 to 80 mg. The mean elimination half-life of mirtazapine after oral administration ranges from approximately 20 to 40 hours across age and gender subgroups, with females of all ages exhibiting significantly longer elimination half-lives than males (mean half-life of 37 hours for females vs. 26 hours for males). Steady state plasma levels of mirtazapine are attained within 5 days, with about 50% accumulation (accumulation ratio = 1.5). - Mirtazapine is approximately 85% bound to plasma proteins over a concentration range of 0.01 to 10 mcg/mL. ## Nonclinical Toxicology There is limited information regarding Mirtazapine Nonclinical Toxicology in the drug label. # Clinical Studies The efficacy of mirtazapine tablets as a treatment for major depressive disorder was established in 4 placebo-controlled, 6-week trials in adult outpatients meeting DSM-III criteria for major depressive disorder. Patients were titrated with mirtazapine from a dose range of 5 mg up to 35 mg/day. Overall, these studies demonstrated mirtazapine to be superior to placebo on at least 3 of the following 4 measures: 21-Item Hamilton Depression Rating Scale (HDRS) total score; HDRS Depressed Mood Item; CGI Severity score; and Montgomery and Asberg Depression Rating Scale (MADRS). Superiority of mirtazapine over placebo was also found for certain factors of the HDRS, including anxiety/somatization factor and sleep disturbance factor. The mean mirtazapine dose for patients who completed these 4 studies ranged from 21 to 32 mg/day. A fifth study of similar design utilized a higher dose (up to 50 mg) per day and also showed effectiveness. Examination of age and gender subsets of the population did not reveal any differential responsiveness on the basis of these subgroupings. In a longer-term study, patients meeting (DSM-IV) criteria for major depressive disorder who had responded during an initial 8 to 12 weeks of acute treatment on mirtazapine were randomized to continuation of mirtazapine or placebo for up to 40 weeks of observation for relapse. Response during the open phase was defined as having achieved a HAM-D 17 total score of ≤8 and a CGI-Improvement score of 1 or 2 at 2 consecutive visits beginning with week 6 of the 8 to 12 weeks in the open-label phase of the study. Relapse during the double-blind phase was determined by the individual investigators. Patients receiving continued mirtazapine treatment experienced significantly lower relapse rates over the subsequent 40 weeks compared to those receiving placebo. This pattern was demonstrated in both male and female patients. # How Supplied Mirtazapine orally disintegrating tablets USP are supplied as: 15 mg: White to off-white, round, flat-faced, beveled-edge, unscored tablet. Debossed with 2469 on one side and WPI on the other side. Blister package of 30 tablets NDC 0591-2469-15 30 mg: White to off-white, round, flat-faced, beveled-edge, unscored tablet. Debossed with 2470 on one side and WPI on the other side. Blister package of 30 tablets NDC 0591-2470-15 ## Storage Store at 20° to 25°C (68° to 77°F) [See USP Controlled Room Temperature]. Protect from light and moisture. Use immediately upon opening individual tablet blister. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information - Prescribers or other health professionals should inform patients, their families, and their caregivers about the benefits and risks associated with treatment with mirtazapine orally disintegrating tablets and should counsel them in its appropriate use. A patient Medication Guide about “Antidepressant Medicines, Depression and other Serious Mental Illnesses, and Suicidal Thoughts or Actions” is available for mirtazapine orally disintegrating tablets. The prescriber or health professional should instruct patients, their families, and their caregivers to read the Medication Guide and should assist them in understanding its contents. Patients should be given the opportunity to discuss the contents of the Medication Guide and to obtain answers to any questions they may have. The complete text of the Medication Guide is reprinted at the end of this document. - Patients should be advised of the following issues and asked to alert their prescriber if these occur while taking mirtazapine orally disintegrating tablets. - Clinical Worsening and Suicide Risk - Patients, their families, and their caregivers should be encouraged to be alert to the emergence of anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, mania, other unusual changes in behavior, worsening of depression, and suicidal ideation, especially early during antidepressant treatment and when the dose is adjusted up or down. Families and caregivers of patients should be advised to look for the emergence of such symptoms on a day-to-day basis, since changes may be abrupt. Such symptoms should be reported to the patient’s prescriber or health professional, especially if they are severe, abrupt in onset, or were not part of the patient’s presenting symptoms. Symptoms such as these may be associated with an increased risk for suicidal thinking and behavior and indicate a need for very close monitoring and possibly changes in the medication. - Agranulocytosis - Patients who are to receive mirtazapine orally disintegrating tablets should be warned about the risk of developing agranulocytosis. Patients should be advised to contact their physician if they experience any indication of infection such as fever, chills, sore throat, mucous membrane ulceration, or other possible signs of infection. Particular attention should be paid to any flu-like complaints or other symptoms that might suggest infection. - Interference with Cognitive and Motor Performance Mirtazapine orally disintegrating tablets may impair judgment, thinking, and particularly, motor skills, because of its prominent sedative effect. The drowsiness associated with mirtazapine use may impair a patient’s ability to drive, use machines, or perform tasks that require alertness. Thus, patients should be cautioned about engaging in hazardous activities until they are reasonably certain that mirtazapine orally disintegrating tablets therapy does not adversely affect their ability to engage in such activities. - Completing Course of Therapy - While patients may notice improvement with mirtazapine orally disintegrating tablets therapy in 1 to 4 weeks, they should be advised to continue therapy as directed. - Concomitant Medication - Patients should be advised to inform their physician if they are taking, or intend to take, any prescription or over-the-counter drugs, since there is a potential for mirtazapine orally disintegrating tablets to interact with other drugs. - Patients should be made aware of a potential increased risk for serotonin syndrome if concomitant use of mirtazapine orally disintegrating tablets with other serotonergic drugs, including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, buspirone, tryptophan, and St. John's wort, is clinically warranted, particularly during treatment initiation and dose increases. - Phenylalanine - Phenylketonuric patients should be informed that mirtazapine orally disintegrating tablets contain phenylalanine 3.36 mg per 15-mg tablet and 6.72 mg per 30-mg tablet. - Pregnancy - Patients should be advised to notify their physician if they become pregnant or intend to become pregnant during mirtazapine orally disintegrating tablets therapy. - Nursing - Patients should be advised to notify their physician if they are breastfeeding an infant. - Laboratory Tests - There are no routine laboratory tests recommended. Mirtazapine Orally Disintegrating Tablets USP - Read the Medication Guide that comes with mirtazapine orally disintegrating tablets before you start taking it and each time you get a refill. There may be new information. This Medication Guide does not take the place of talking to your healthcare provider about your medical condition or treatment. If you have any questions about mirtazapine orally disintegrating tablets, talk to your healthcare provider. - What is the most important information I should know about mirtazapine orally disintegrating tablets? - Mirtazapine orally disintegrating tablets and other antidepressant medicines may cause serious side effects, including: - Suicidal thoughts or actions, Mirtazapine orally disintegrating tablets and other antidepressant medicines may increase suicidal thoughts or actions in some children, teenagers, or young adults within the first few months of treatment or when the dose is changed. Depression or other serious mental illnesses are the most important causes of suicidal thoughts or actions. Watch for these changes and call your healthcare provider right away if you notice, new or sudden changes in mood, behavior, actions, thoughts, or feelings, especially if severe. Pay particular attention to such changes when mirtazapine orally disintegrating tablets is started or when the dose is changed. Keep all follow-up visits with your healthcare provider and call between visits if you are worried about symptoms. - Call your healthcare provider right away if you have any of the following symptoms, or call 911 if an emergency, especially if they are new, worse, or worry you, attempts to commit suicide, acting on dangerous impulses, acting aggressive or violent, thoughts about suicide or dying, new or worse depression, new or worse anxiety or panic attacks, feeling agitated, restless, angry or irritable, trouble sleeping, an increase in activity or talking more than what is normal for you, other unusual changes in behavior or mood Call your healthcare provider right away if you have any of the following symptoms, or call 911 if an emergency. Mirtazapine orally disintegrating tablets may be associated with these serious side effects: - Manic episodes, greatly increased energy, severe trouble sleeping, racing thoughts, reckless behavior, unusually grand ideas, excessive happiness or irritability, talking more or faster than usual - Decreased White Blood Cells called neutrophils, which are needed to fight infections. Tell your doctor if you have any indication of infection such as fever, chills, sore throat, or mouth or nose sores, especially symptoms which are flu-like. - Serotonin Syndrome. This condition can be life-threatening and may include: agitation, hallucinations, coma or other changes in mental status, coordination problems or muscle twitching (overactive reflexes), racing heartbeat, high or low blood pressure, sweating or fever, nausea, vomiting, or diarrhea, muscle rigidity - Seizures - Low salt (sodium) levels in the blood. Elderly people may be at greater risk for this. Symptoms may include headache, weakness or feeling unsteady, confusion, problems concentrating or thinking or memory problems - Sleepiness. It is best to take mirtazapine orally disintegrating tablets close to bedtime. - Severe skin reactions: Call your doctor right away if you have any or all of the following symptoms: Severe rash with skin swelling (including on the palms of the hands and soles of the feet). Painful reddening of the skin and/or blisters/ulcers on the body or in the mouth - Severe allergic reactions: trouble breathing, swelling of the face, tongue, eyes or mouth rash, itchy welts (hives) or blisters, alone or with fever or joint pain - Increases in appetite or weight. Children and adolescents should have height and weight monitored during treatment. Increased cholesterol and triglyceride levels in your blood - Do not stop mirtazapine orally disintegrating tablets without first talking to your healthcare provider. Stopping mirtazapine orally disintegrating tablets too quickly may Cause potentially serious symptoms including: - Dizziness - Abnormal dreams - Agitation - Anxiety - Fatigue - Confusion - Headache - Shaking - Tingling sensation - Nausea, vomiting - Sweating - What are mirtazapine orally disintegrating tablets? Mirtazapine orally disintegrating tablets is a prescription medicine used to treat depression. It is important to talk with your healthcare provider about the risks of treating depression and also the risks of not treating it. You should discuss all treatment choices with your healthcare provider. - Talk to your healthcare provider if you do not think that your condition is getting better with mirtazapine orally disintegrating tablets treatment. - Who should not take mirtazapine orally disintegrating tablets? - Do not take mirtazapine orally disintegrating tablets if you: - Are allergic to mirtazapine or any of the ingredients in mirtazapine orally disintegrating tablets. See the end of this Medication Guide for a complete list of ingredients in mirtazapine orally disintegrating tablets. - Take a monoamine oxidase inhibitor (MAOI). Ask your healthcare provider or pharmacist if you are not sure if you take a MAOI, including the antibiotic linezolid. - Do not take a MAOI within 2 weeks of stopping mirtazapine orally disintegrating tablets unless directed to do so by your physician. - Do not start mirtazapine orally disintegrating tablets if you stopped taking a MAOI in the last 2 weeks unless directed to do so by your physician. - People who take mirtazapine orally disintegrating tabletsclose in time to an MAOI may have serious or even life-threatening side effects. Get medical help right away if you have any of these symptoms: - High fever - Uncontrolled muscle spasms - Stiff muscles - Rapid changes in heart rate or blood pressure - Confusion - Loss of consciousness (pass out) - What should I tell my healthcare provider before taking mirtazapine orally disintegrating tablets? Ask if you are not sure. - Before starting mirtazapine orally disintegrating tablets, tell your healthcare provider if you: - Are taking certain drugs such as: - Triptans used to treat migraine headache - Medicines used to treat mood, anxiety, psychotic or thought disorders, including tricyclics, lithium, SSRIs, SNRIs, or antipsychotics - Tramadol used to treat pain - Over-the-counter supplements such as tryptophan or St. John’s wort - Phenytoin, carbamazepine, or rifampicin (these drugs can decrease your blood level of mirtazapine) - Cimetidine or ketoconazole (these drugs can increase your blood level of mirtazapine) - Have or had: - Liver problems - Kidney problems - Heart problems - Seizures or convulsions - Bipolar disorder or mania - A tendency to get dizzy or faint - Are pregnant or plan to become pregnant. It is not known if mirtazapine orally disintegrating tablets will harm your unborn baby. Talk to your healthcare provider about the benefits and risks of treating depression during pregnancy - Are breastfeeding or plan to breastfeed. Some mirtazapine may pass into your breast milk. Talk to your healthcare provider about the best way to feed your baby while taking mirtazapine orally disintegrating tablets - Tell your healthcare provider about all the medicines that you take, including prescription and non-prescription medicines, vitamins, and herbal supplements. Mirtazapine orally disintegrating tablets and some medicines may interact with each other, may not work as well, or may cause serious side effects. Your healthcare provider or pharmacist can tell you if it is safe to take mirtazapine orally disintegrating tablets with your other medicines. Do not start or stop any medicine while taking mirtazapine orally disintegrating tablets without talking to your healthcare provider first. - If you take mirtazapine orally disintegrating tablets, you should not take any other medicines that contain mirtazapine including mirtazapine tablets. - How should I take mirtazapine orally disintegrating tablets? - Take mirtazapine orally disintegrating tablets exactly as prescribed. Your healthcare provider may need to change the dose of mirtazapine orally disintegrating tablets until it is the right dose for you. - Take mirtazapine orally disintegrating tablets at the same time each day, preferably in the evening at bedtime. - Open the tablet blister pack with dry hands and place the tablet whole on the tongue, immediately after removal from the blister pack. - Mirtazapine orally disintegrating tablets will disintegrate rapidly on the tongue and can be swallowed with saliva. No water is needed for taking it. - Do not attempt to split the mirtazapine orally disintegrating tablets. - It is common for antidepressant medicines such as mirtazapine orally disintegrating tablets to take up to a few weeks before you start to feel better. Do not stop taking mirtazapine orally disintegrating tablets if you do not feel results right away. - Do not stop taking or change the dose of mirtazapine orally disintegrating tablets without first talking to your doctor, even if you feel better. - Mirtazapine orally disintegrating tablets may be taken with or without food. - If you miss a dose of mirtazapine orally disintegrating tablets, take the missed dose as soon as you remember. If it is almost time for the next dose, skip the missed dose and take your next dose at the regular time. Do not take two doses of mirtazapine orally disintegrating tablets at the same time. - If you take too much mirtazapine orally disintegrating tablets, call your healthcare provider or poison control center right away, or get emergency treatment. - What should I avoid while taking mirtazapine orally disintegrating tablets? - Mirtazapine orally disintegrating tablets can cause sleepiness or may affect your ability to make decisions, think clearly, or react quickly. You should not drive, operate heavy machinery, or do other dangerous activities until you know how mirtazapine orally disintegrating tablets affect you. - Avoid drinking alcohol or taking diazepam (a medicine used for anxiety, insomnia and seizures, for example) or similar medicines while taking mirtazapine orally disintegrating tablets. If you are uncertain about whether certain medication can be taken with mirtazapine orally disintegrating tablets, please discuss with your doctor. - What are the possible side effects of mirtazapine orally disintegrating tablets? Mirtazapine orally disintegrating tablets may cause serious side effects, including all of those described in the section entitled “What is the most important information I should know about mirtazapine orally disintegrating tablets?" - Common possible side effects in people who take mirtazapine orally disintegrating tablets include: - Sleepiness - Increased appetite, weight gain - Dry mouth - Constipation - Dizziness - Abnormal dreams - Tell your healthcare provider if you have any side effect that bothers you or that does not go away. These are not all the possible side effects of mirtazapine orally disintegrating tablets. For more information, ask your healthcare provider or pharmacist. - CALL YOUR DOCTOR FOR MEDICAL ADVICE ABOUT SIDE EFFECTS. YOU MAY REPORT SIDE EFFECTS TO THE FDA AT 1-800-FDA-1088. How should I store mirtazapine orally disintegrating tablets? - Store mirtazapine orally disintegrating tablets at room temperature 68° to 77°F (20° to 25°C). - Keep mirtazapine orally disintegrating tablets away from light and moisture. - Use immediately upon opening individual tablet blister. - Keep mirtazapine orally disintegrating tablets and all medicines out of the reach of children. - General information about mirtazapine orally disintegrating tablets - Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use mirtazapine orally disintegrating tablets for a condition for which it was not prescribed. Do not give mirtazapine orally disintegrating tablets to other people, even if they have the same condition. It may harm them. - This Medication Guide summarizes the most important information about mirtazapine orally disintegrating tablets. If you would like more information, talk with your healthcare provider. You may ask your healthcare provider or pharmacist for information about mirtazapine orally disintegrating tablets that is written for healthcare professionals. - For more information about mirtazapine orally disintegrating tablets call 1-800-272-5525 or go to www.watson.com. - What are the ingredients in mirtazapine orally disintegrating tablets? Active ingredient: mirtazapine - Inactive ingredients 15 mg and 30 mg tablets: aspartame powder, colloidal silicon dioxide, crospovidone, magnesium stearate, mannitol, microcrystalline cellulose, natural and artificial orange flavor, sodium stearyl fumarate and xylitol. - This Medication Guide has been approved by the U.S. Food and Drug Administration. Manufactured by: Watson Laboratories, Inc. Corona, CA 92880 USA Distributed by: Watson Pharma, Inc. Parsippany, NJ 07054 USA Revised: October 2013 196669-2 # Precautions with Alcohol - The impairment of cognitive and motor skills produced by mirtazapine has been shown to be additive with those produced by alcohol. Accordingly, patients should be advised to avoid alcohol while taking any dosage form of mirtazapine. - Concomitant administration of alcohol (equivalent to 60 g) had a minimal effect on plasma levels of mirtazapine (15 mg) in 6 healthy male subjects. However, the impairment of cognitive and motor skills produced by mirtazapine were shown to be additive with those produced by alcohol. Accordingly, patients should be advised to avoid alcohol while taking mirtazapine orally disintegrating tablets. # Brand Names There is limited information regarding Mirtazapine Brand Names in the drug label. # Look-Alike Drug Names There is limited information regarding Mirtazapine Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	https://www.wikidoc.org/index.php/Avanza
57cb9002c741264d92019f6bfa5b9254753960de	wikidoc	Bevacizumab	Bevacizumab # Disclaimer WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here. # Black Box Warning # Overview Bevacizumab is an antineoplastic agent that is FDA approved for the treatment of metastatic colorectal cancer (mcrc)，non-squamous non–small cell lung cancer (nsclc),glioblastoma, metastatic renal cell carcinoma (mrcc). There is a Black Box Warning for this drug as shown here. Common adverse reactions include hypertension, any grade, alopecia, hand-foot syndrome due to cytotoxic therapy abdominal pain, any grade, constipation, any grade, diarrhea, loss of appetite, stomatitis, taste sense altered, hemorrhage, any grade, asthenia, dizziness, headache, any grade proteinuria, any grade, dyspnea, epistaxis, upper respiratory infection. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) ### Metastatic Colorectal Cancer (mCRC) - Dosing information - Patients should continue treatment until disease progression or unacceptable toxicity. - 5 mg/kg or 10 mg/kg every 2 weeks when used in combination with intravenous 5-FU-based chemotherapy. - Administer 5 mg/kg when used in combination with bolus-IFL. - Administer 10 mg/kg when used in combination with FOLFOX4. - Administer 5 mg/kg every 2 weeks or 7.5 mg/kg every 3 weeks when used in combination with a fluoropyrimidine-irinotecan or fluoropyrimidine-oxaliplatin based chemotherapy regimen in patients who have progressed on a first-line Bevacizumab-containing regimen. ### Non-Squamous Non-Small Cell Lung Cancer (NSCLC) - Dosing information - 15 mg/kg every 3 weeks in combination with carboplatin and paclitaxel. ### Glioblastoma - Dosing information - Recommended dosage: 10 mg/kg every 2 weeks. ### Metastatic Renal Cell Carcinoma (mRCC) - Dosing information - Recommended dosage: 10 mg/kg every 2 weeks in combination with interferon alfa. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Bevacizumab in adult patients. ### Non–Guideline-Supported Use ### Age related macular degeneration, Secondary to choroidal neovascularization - Dosing information - Administration of intravitreal bevacizumab has been associated with improved visual acuity, decreased retinal thickness ### Angioid streaks of choroid - Dosing information - 1.25 mg intravitreally and assessed every 4 to 6 weeks - 1.25 mg intravitreally and examined at 2 month intervals ### Branch retinal vein occlusion with macular edema - Dosing information - Not applicable ### Central retinal vein occlusion with macular edema - Dosing information - 1.25 mg/0.05 mL via intravitreal injection ### Cervical cancer, Recurrent, persistent, or metastatic - Dosing information - 1.25 mg/0.05 mL ### Diabetic macular edema - Dosing information - Not applicable ### Diabetic retinopathy - Dosing information - Not applicable ### Epistaxis - Osler hemorrhagic telangiectasia syndrome - Dosing information - 100 mg nasal spray via a metered dose atomizer ### Gastric cancer - Dosing information - 7.5 mg/kg ### Liver carcinoma - Dosing information ### Metastatic breast cancer - Dosing information - 15 mg/kg IV every 3 weeks - 7.5 mg/kg or 15 mg/kg ### Neovascular glaucoma - Dosing information - 1.25 mg18463512 - 1.25 mg every 4 weeks for 3 doses ### Ovarian cancer - Dosing information - 15 mg/kg for cycles 2 through 6 - 7.5 mg/kg was administered every 3 weeks ### Recurrent Ovarian cancer - Dosing information - Not applicable , , ### Retinopathy of prematurity - Dosing information - Not applicable , # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) The safety, effectiveness and pharmacokinetic profile of Bevacizumab in pediatric patients have not been established. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Bevacizumab in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Bevacizumab in pediatric patients. # Contraindications None. # Warnings ## Gastrointestinal perforations Serious and sometimes fatal gastrointestinal perforation occurs at a higher incidence in Bevacizumab treated patients compared to controls. The incidence of gastrointestinal perforation ranged from 0.3 to 2.4% across clinical studies. The typical presentation may include abdominal pain, nausea, emesis, constipation, and fever. Perforation can be complicated by intra-abdominal abscess and fistula formation. The majority of cases occurred within the first 50 days of initiation of Bevacizumab. Discontinue Bevacizumab in patients with gastrointestinal perforation. ## Surgery and Wound Healing Complications Bevacizumab impairs wound healing in animal models. In clinical trials, administration of Bevacizumab was not allowed until at least 28 days after surgery. In a controlled clinical trial, the incidence of wound healing complications, including serious and fatal complications, in patients with mCRC who underwent surgery during the course of Bevacizumab treatment was 15% and in patients who did not receive Bevacizumab, was 4%. Bevacizumab should not be initiated for at least 28 days following surgery and until the surgical wound is fully healed. Discontinue Bevacizumab in patients with wound healing complications requiring medical intervention. The appropriate interval between the last dose of Bevacizumab and elective surgery is unknown; however, the half-life of Bevacizumab is estimated to be 20 days. Suspend Bevacizumab for at least 28 days prior to elective surgery. Do not administer Bevacizumab until the wound is fully healed. Necrotizing fasciitis including fatal cases, has been reported in patients treated with Bevacizumab; usually secondary to wound healing complications, gastrointestinal perforation or fistula formation. Discontinue Bevacizumab therapy in patients who develop necrotizing fasciitis. ## Hemorrhage Bevacizumab can result in two distinct patterns of bleeding: minor hemorrhage, most commonly Grade 1 epistaxis; and serious, and in some cases fatal, hemorrhagic events. Severe or fatal hemorrhage, including hemoptysis, gastrointestinal bleeding, hematemesis, CNS hemorrhage, epistaxis, and vaginal bleeding occurred up to five-fold more frequently in patients receiving Bevacizumab compared to patients receiving only chemotherapy. Across indications, the incidence of Grade ≥ 3 hemorrhagic events among patients receiving Bevacizumab ranged from 1.2 to 4.6%. Serious or fatal pulmonary hemorrhage occurred in four of 13 (31%) patients with squamous cell histology and two of 53 (4%) patients with non-squamous non-small cell lung cancer receiving Bevacizumab and chemotherapy compared to none of the 32 (0%) patients receiving chemotherapy alone. In clinical studies in non–small cell lung cancer where patients with CNS metastases who completed radiation and surgery more than 4 weeks prior to the start of Bevacizumab were evaluated with serial CNS imaging, symptomatic Grade 2 CNS hemorrhage was documented in one of 83 Bevacizumab-treated patients (rate 1.2%, 95% CI 0.06%–5.93%). Intracranial hemorrhage occurred in 8 of 163 patients with previously treated glioblastoma; two patients had Grade 3–4 hemorrhage. Do not administer Bevacizumab to patients with recent history of hemoptysis of ≥ 1/2 teaspoon of red blood. Discontinue Bevacizumab in patients with hemorrhage. ## Non-Gastrointestinal Fistula Formation Serious and sometimes fatal non-gastrointestinal fistula formation involving tracheo-esophageal, bronchopleural, biliary, vaginal, renal and bladder sites occurs at a higher incidence in Bevacizumab-treated patients compared to controls. The incidence of non-gastrointestinal perforation was ≤ 0.3% in clinical studies. Most events occurred within the first 6 months of Bevacizumab therapy. Discontinue Bevacizumab in patients with fistula formation involving an internal organ. ## Arterial Thromboembolic Events Serious, sometimes fatal, arterial thromboembolic events (ATE)including cerebral infarction, transient ischemic attacks, myocardial infarction, angina, and a variety of other ATE occurred at a higher incidence in patients receiving Bevacizumab compared to those in the control arm. Across indications, the incidence of Grade ≥ 3 ATE in the Bevacizumab containing arms was 2.6% compared to 0.8% in the control arms. Among patients receiving Bevacizumab in combination with chemotherapy, the risk of developing ATE during therapy was increased in patients with a history of arterial thromboembolism, diabetes, or age greater than 65 years. The safety of resumption of Bevacizumab therapy after resolution of an ATE has not been studied. Discontinue Bevacizumab in patients who experience a severe ATE. ## Hypertension The incidence of severe hypertension is increased in patients receiving Bevacizumab as compared to controls. Across clinical studies the incidence of Grade 3 or 4 hypertension ranged from 5-18%. Monitor blood pressure every two to three weeks during treatment with Bevacizumab. Treat with appropriate anti-hypertensive therapy and monitor blood pressure regularly. Continue to monitor blood pressure at regular intervals in patients with Bevacizumab-induced or -exacerbated hypertension after discontinuation of Bevacizumab. Temporarily suspend Bevacizumab in patients with severe hypertension that is not controlled with medical management. Discontinue Bevacizumab in patients with hypertensive crisis or hypertensive encephalopathy. ## Reversible Posterior Leukoencephalopathy Syndrome (RPLS) RPLS has been reported with an incidence of < 0.1% in clinical studies. The onset of symptoms occurred from 16 hours to 1 year after initiation of Bevacizumab. RPLS is a neurological disorder which can present with headache, seizure, lethargy, confusion, blindness and other visual and neurologic disturbances. Mild to severe hypertension may be present. Magnetic resonance imaging (MRI) is necessary to confirm the diagnosis of RPLS. Discontinue Bevacizumab in patients developing RPLS. Symptoms usually resolve or improve within days, although some patients have experienced ongoing neurologic sequelae. The safety of reinitiating Bevacizumab therapy in patients previously experiencing RPLS is not known. ## Proteinuria The incidence and severity of proteinuria is increased in patients receiving Bevacizumab as compared to controls. Nephrotic syndrome occurred in < 1% of patients receiving Bevacizumab in clinical trials, in some instances with fatal outcome. In a published case series, kidney biopsy of six patients with proteinuria showed findings consistent with thrombotic microangiopathy. Monitor proteinuria by dipstick urine analysis for the development or worsening of proteinuria with serial urinalyses during Bevacizumab therapy. Patients with a 2 + or greater urine dipstick reading should undergo further assessment with a 24-hour urine collection. Suspend Bevacizumab administration for ≥ 2 grams of proteinuria/24 hours and resume when proteinuria is < 2 gm/24 hours. Discontinue Bevacizumab in patients with nephrotic syndrome. Data from a postmarketing safety study showed poor correlation between UPCR (Urine Protein/Creatinine Ratio) and 24 hour urine protein (Pearson Correlation 0.39 (95% CI 0.17, 0.57). ## Infusion Reactions Infusion reactions reported in the clinical trials and post-marketing experience include hypertension, hypertensive crises associated with neurologic signs and symptoms, wheezing, oxygen desaturation, Grade 3 hypersensitivity, chest pain, headaches, rigors, and diaphoresis. In clinical studies, infusion reactions with the first dose of Bevacizumab were uncommon ( < 3%) and severe reactions occurred in 0.2% of patients. Stop infusion if a severe infusion reaction occurs and administer appropriate medical therapy. ## Ovarian Failure The incidence of ovarian failure was higher (34% vs. 2%) in premenopausal women receiving Bevacizumab in combination with mFOLFOX chemotherapy as compared to those receiving mFOLFOX chemotherapy alone for adjuvant treatment for colorectal cancer, a use for which Bevacizumab is not approved. Inform females of reproductive potential of the risk of ovarian failure prior to starting treatment with Bevacizumab. # Adverse Reactions ## Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The data below reflect exposure to Bevacizumab in 4599 patients with CRC, non-squamous NSCLC, glioblastoma, or mRCC trials including controlled (Studies 1, 2, 4, 5 and 8) or uncontrolled, single arm (Study 6) treated at the recommended dose and schedule for a median of 8 to 23 doses of Bevacizumab. The population was aged 18-89 years (median 60 years), 45.4% male and 85.8% (3729/4345) White. The population included 2184 first- and second-line mCRC patients who received a median of 10 doses of Bevacizumab, 480 first-line metastatic NSCLC patients who received a median of 8 doses of Bevacizumab, 163 glioblastoma patients who received a median of 9 doses of Bevacizumab, and 337 mRCC patients who received a median of 16 doses of Bevacizumab. These data also reflect exposure to Bevacizumab in 363 patients with metastatic breast cancer (MBC) who received a median of 9.5 doses of Bevacizumab, 669 female adjuvant CRC patients who received a median of 23 doses of Bevacizumab and exposure to Bevacizumab in 403 previously untreated patients with diffuse large B-cell lymphoma (DLBCL) who received a median of 8 doses of Bevacizumab. Bevacizumab is not approved for use in MBC, adjuvant CRC, or DLBCL. Surgery and Wound Healing Complications The incidence of post-operative wound healing and/or bleeding complications was increased in patients with mCRC receiving Bevacizumab as compared to patients receiving only chemotherapy. Among patients requiring surgery on or within 60 days of receiving study treatment, wound healing and/or bleeding complications occurred in 15% (6/39) of patients receiving bolus-IFL plus Bevacizumab as compared to 4% (1/25) of patients who received bolus-IFL alone. In Study 6, events of post-operative wound healing complications (craniotomy site wound dehiscence and cerebrospinal fluid leak) occurred in patients with previously treated glioblastoma: 3/84 patients in the Bevacizumab alone arm and 1/79 patients in the Bevacizumab plus irinotecan arm. Hemorrhage The incidence of epistaxis was higher (35% vs. 10%) in patients with mCRC receiving bolus-IFL plus Bevacizumab compared with patients receiving bolus-IFL plus placebo. All but one of these events were Grade 1 in severity and resolved without medical intervention. Grade 1 or 2 hemorrhagic events were more frequent in patients receiving bolus-IFL plus Bevacizumab when compared to those receiving bolus-IFL plus placebo and included gastrointestinal hemorrhage (24% vs. 6%), minor gum bleeding (2% vs. 0), and vaginal hemorrhage (4% vs. 2%). Venous Thromboembolic Events The overall incidence of venous thromboembolic events in Study 1 was 15.1% in patients receiving bolus-IFL plus Bevacizumab and 13.6% in patients receiving bolus-IFL plus placebo. In Study 1, more patients in the Bevacizumab containing arm experienced deep venous thrombosis (34 vs. 19 patients ) and intra-abdominal venous thrombosis (10 vs. 5 patients). The risk of developing a second thromboembolic event while on Bevacizumab and oral anticoagulants was evaluated in two randomized studies. In Study 1, 53 patients (14%) on the bolus-IFL plus Bevacizumab arm and 30 patients (8%) on the bolus-IFL plus placebo arm received full dose warfarin following a venous thromboembolic event (VTE). Among these patients, an additional thromboembolic event occurred in 21% (11/53) of patients receiving bolus-IFL plus Bevacizumab and 3% (1/30) of patients receiving bolus-IFL alone. In a second, randomized, 4-arm study in 1401 patients with mCRC, prospectively evaluating the incidence of VTE (all grades), the overall incidence of first VTE was higher in the Bevacizumab containing arms (13.5%) than the chemotherapy alone arms (9.6%). Among the 116 patients treated with anticoagulants following an initial VTE event (73 in the Bevacizumab plus chemotherapy arms and 43 in the chemotherapy alone arms), the overall incidence of subsequent VTEs was also higher among the Bevacizumab treated patients (31.5% vs. 25.6%). In this subgroup of patients treated with anticoagulants, the overall incidence of bleeding, the majority of which were Grade 1, was higher in the Bevacizumab treated arms than the chemotherapy arms (27.4% vs. 20.9%). Neutropenia and Infection The incidences of neutropenia and febrile neutropenia are increased in patients receiving Bevacizumab plus chemotherapy compared to chemotherapy alone. In Study 1, the incidence of Grade 3 or 4 neutropenia was increased in mCRC patients receiving IFL plus Bevacizumab (21%) compared to patients receiving IFL alone (14%). In Study 5, the incidence of Grade 4 neutropenia was increased in NSCLC patients receiving paclitaxel/carboplatin (PC) plus Bevacizumab (26.2%) compared with patients receiving PC alone (17.2%). Febrile neutropenia was also increased (5.4% for PC plus Bevacizumab vs. 1.8% for PC alone). There were 19 (4.5%) infections with Grade 3 or 4 neutropenia in the PC plus Bevacizumab arm of which 3 were fatal compared to 9 (2%) neutropenic infections in patients receiving PC alone, of which none were fatal. During the first 6 cycles of treatment, the incidence of serious infections including pneumonia, febrile neutropenia, catheter infections and wound infections was increased in the PC plus Bevacizumab arm compared to the PC alone arm . In Study 6, one fatal event of neutropenic infection occurred in a patient with previously treated glioblastoma receiving Bevacizumab alone. The incidence of any grade of infection in patients receiving Bevacizumab alone was 55% and the incidence of Grade 3–5 infection was 10%. Proteinuria Grade 3–4 proteinuria ranged from 0.7 to 7.4% in Studies 1, 2, 4, 5 and 8. The overall incidence of proteinuria (all grades) was only adequately assessed in Study 8, in which the incidence was 20%. Median onset of proteinuria was 5.6 months (range 15 days to 37 months) after initiation of Bevacizumab. Median time to resolution was 6.1 months (95% CI 2.8 months, 11.3 months). Proteinuria did not resolve in 40% of patients after median follow up of 11.2 months and required permanent discontinuation of Bevacizumab in 30% of the patients who developed proteinuria (Study 8). In an exploratory, pooled analysis of 8,273 patients treated in 7 randomized clinical trials, 5.4% (271 of 5037) of patients receiving Bevacizumab in combination with chemotherapy experienced Grade ≥ 2 proteinuria. The Grade ≥ 2 proteinuria resolved in 74.2% (201 of 271) of patients. Bevacizumab was re-initiated in 41.7% (113 of 271) of patients. Of the 113 patients who re-initiated Bevacizumab, 47.8% (54 of 113) experienced a second episode of Grade ≥ 2 proteinuria. Congestive Heart Failure (CHF) The incidence of Grade ≥ 3 left ventricular dysfunction was 1.0% in patients receiving Bevacizumab compared to 0.6% in the control arm across indications. In patients with metastatic breast cancer (MBC), an indication for which Bevacizumab is not approved, the incidence of Grade 3–4 CHF was increased in patients in the Bevacizumab plus paclitaxel arm (2.2%) as compared to the control arm (0.3%). Among patients receiving prior anthracyclines for MBC, the rate of CHF was 3.8% for patients receiving Bevacizumab as compared to 0.6% for patients receiving paclitaxel alone. The safety of continuation or resumption of Bevacizumab in patients with cardiac dysfunction has not been studied. In previously untreated patients with diffuse large B-cell lymphoma (DLBCL), an indication for which Bevacizumab is not approved, the incidence of CHF and decline in left-ventricular ejection fraction (LVEF) were signficantly increased in the Bevacizumab plus R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) arm (n=403) compared to the placebo plus R-CHOP arm (n=379); both regimens were given for 6 to 8 cycles. At the completion of R-CHOP therapy, the incidence of CHF was 10.9% in the Bevacizumab plus R-CHOP arm compared to 5.0% in the R-CHOP alone arm . The incidence of a LVEF event, defined as a decline from baseline of 20% or more in LVEF or a decline from baseline of 10% or more to a LVEF value of less than 50%, was also increased in the Bevacizumab plus R-CHOP arm (10.4%) compared to the R-CHOP alone arm (5.0%). Time to onset of left-ventricular dysfunction or CHF was 1-6 months after initiation of therapy in at least 85% of the patients and was resolved in 62% of the patients experiencing CHF in the Bevacizumab arm compared to 82% in the control arm. Ovarian Failure The incidence of new cases of ovarian failure (defined as amenorrhoea lasting 3 or more months, FSH level ≥ 30 mIU/mL and a negative serum β-HCG pregnancy test) was prospectively evaluated in a subset of 179 women receiving mFOLFOX chemotherapy alone (n = 84) or with Bevacizumab (n = 95). New cases of ovarian failure were identified in 34% (32/95) of women receiving Bevacizumab in combination with chemotherapy compared with 2% (2/84) of women receiving chemotherapy alone . After discontinuation of Bevacizumab treatment, recovery of ovarian function at all time points during the post-treatment period was demonstrated in 22% (7/32) of the Bevacizumab-treated women. Recovery of ovarian function is defined as resumption of menses, a positive serum β-HCG pregnancy test, or a FSH level < 30 mIU/mL during the post-treatment period. Long term effects of Bevacizumab exposure on fertility are unknown. Metastatic Colorectal Cancer (mCRC) The data in Table 1 and Table 2 were obtained in Study 1, a randomized, double-blind, controlled trial comparing chemotherapy plus Bevacizumab with chemotherapy plus placebo. Bevacizumab was administered at 5 mg/kg every 2 weeks. All Grade 3–4 adverse events and selected Grade 1–2 adverse events (hypertension, proteinuria, thromboembolic events) were collected in the entire study population. Severe and life-threatening (Grade 3–4) adverse events, which occurred at a higher incidence ( ≥ 2%) in patients receiving bolus-IFL plus Bevacizumab as compared to bolus-IFL plus placebo, are presented in Table 1. Grade 1–4 adverse events which occurred at a higher incidence ( ≥ 5%) in patients receiving bolus-IFL plus Bevacizumab as compared to the bolus-IFL plus placebo arm are presented in Table 2. Grade 1–4 adverse events were collected for the first approximately 100 patients in each of the three treatment arms who were enrolled until enrollment in Arm 3 (5-FU/LV + Bevacizumab) was discontinued. Bevacizumab in Combination with FOLFOX4 in Second-line mCRC Only Grade 3-5 non-hematologic and Grade 4–5 hematologic adverse events related to treatment were collected in Study 2. The most frequent adverse events (selected Grade 3–5 non-hematologic and Grade 4–5 hematologic adverse events) occurring at a higher incidence ( ≥ 2%) in 287 patients receiving FOLFOX4 plus Bevacizumab compared to 285 patients receiving FOLFOX4 alone were fatigue (19% vs. 13%), diarrhea (18% vs. 13%), sensory neuropathy (17% vs. 9%), nausea (12% vs. 5%), vomiting (11% vs. 4%), dehydration (10% vs. 5%), hypertension (9% vs. 2%), abdominal pain (8% vs. 5%), hemorrhage (5% vs. 1%), other neurological (5% vs. 3%), ileus (4% vs. 1%) and headache (3% vs. 0%). These data are likely to under-estimate the true adverse event rates due to the reporting mechanisms used in Study 2. Bevacizumab in Combination with Fluoropyrimidine-Irinotecan or Fluoropyrimidine-Oxaliplatin Based Chemotherapy in Second-line mCRC Patients who have Progressed on an Bevacizumab Containing Regimen in First-line mCRC: No new safety signals were observed in Study 4 when Bevacizumab was administered in second line mCRC patients who progressed on an Bevacizumab containing regimen in first line mCRC. The safety data was consistent with the known safety profile established in first and second line mCRC. Unresectable Non-Squamous Non-Small Cell Lung Cancer (NSCLC) Only Grade 3-5 non-hematologic and Grade 4-5 hematologic adverse events were collected in Study 5. Grade 3–5 non-hematologic and Grade 4–5 hematologic adverse events (occurring at a higher incidence (≥ 2%) in 427 patients receiving PC plus Bevacizumab compared with 441 patients receiving PC alone were neutropenia (27% vs. 17%), fatigue (16% vs. 13%), hypertension (8% vs. 0.7%), infection without neutropenia (7% vs. 3%), venous thrombus/embolism (5% vs. 3%), febrile neutropenia (5% vs. 2%), pneumonitis/pulmonary infiltrates (5% vs. 3%), infection with Grade 3 or 4 neutropenia (4% vs. 2%), hyponatremia (4% vs. 1%), headache (3% vs. 1%) and proteinuria (3% vs. 0%). Glioblastoma All adverse events were collected in 163 patients enrolled in Study 6 who either received Bevacizumab alone or Bevacizumab plus irinotecan. All patients received prior radiotherapy and temozolomide. Bevacizumab was administered at 10 mg/kg every 2 weeks alone or in combination with irinotecan. Bevacizumab was discontinued due to adverse events in 4.8% of patients treated with Bevacizumab alone. In patients receiving Bevacizumab alone (N = 84), the most frequently reported adverse events of any grade were infection (55%), fatigue (45%), headache (37%), hypertension (30%), epistaxis (19%) and diarrhea (21%). Of these, the incidence of Grade ≥ 3 adverse events was infection (10%), fatigue (4%), headache (4%), hypertension (8%) and diarrhea (1%). Two deaths on study were possibly related to Bevacizumab: one retroperitoneal hemorrhage and one neutropenic infection. In patients receiving Bevacizumab alone or Bevacizumab plus irinotecan (N = 163), the incidence of Bevacizumab-related adverse events (Grade 1–4) were bleeding/hemorrhage (40%), epistaxis (26%), CNS hemorrhage (5%), hypertension (32%), venous thromboembolic event (8%), arterial thromboembolic event (6%), wound-healing complications (6%), proteinuria (4%), gastrointestinal perforation (2%), and RPLS (1%). The incidence of Grade 3–5 events in these 163 patients were bleeding/hemorrhage (2%), CNS hemorrhage (1%), hypertension (5%), venous thromboembolic event (7%), arterial thromboembolic event (3%), wound-healing complications (3%), proteinuria (1%), and gastrointestinal perforation (2%). Metastatic Renal Cell Carcinoma (mRCC) All grade adverse events were collected in Study 8. Grade 3–5 adverse events occurring at a higher incidence ( ≥ 2%) in 337 patients receiving interferon alfa (IFN-α) plus Bevacizumab compared to 304 patients receiving IFN-α plus placebo arm were fatigue (13% vs. 8%), asthenia (10% vs. 7%), proteinuria (7% vs. 0%), hypertension (6% vs. 1%; including hypertension and hypertensive crisis), and hemorrhage (3% vs. 0.3%; including epistaxis, small intestinal hemorrhage, aneurysm ruptured, gastric ulcer hemorrhage, gingival bleeding, haemoptysis, hemorrhage intracranial, large intestinal hemorrhage, respiratory tract hemorrhage, and traumatic hematoma). Grade 1–5 adverse events occurring at a higher incidence ( ≥ 5%) in patients receiving IFN-α plus Bevacizumab compared to the IFN-α plus placebo arm are presented in Table 3. The following adverse events were reported at a 5-fold greater incidence in the IFN-α plus Bevacizumab arm compared to IFN-α alone and not represented in Table 3: gingival bleeding (13 patients vs. 1 patient); rhinitis (9 vs.0 ); blurred vision (8 vs. 0); gingivitis (8 vs. 1); gastroesophageal reflux disease (8 vs.1 ); tinnitus (7 vs. 1); tooth abscess (7 vs.0); mouth ulceration (6 vs. 0); acne (5 vs. 0); deafness (5 vs. 0); gastritis (5 vs. 0); gingival pain (5 vs. 0) and pulmonary embolism (5 vs. 1). ## Immunogenicity As with all therapeutic proteins, there is a potential for an immune response to Bevacizumab. In clinical trials of adjuvant colon carcinoma, 14 of 2233 evaluable patients (0.63%) tested positive for treatment-emergent anti-bevacizumab antibodies detected by an electrochemiluminescent (ECL) based assay. Among these 14 patients, three tested positive for neutralizing antibodies against bevacizumab using an enzyme-linked immunosorbent assay (ELISA). The clinical significance of these anti-product antibody responses to bevacizumab is unknown. Immunogenicity assay results are highly dependent on the sensitivity and specificity of the test method and may be influenced by several factors, including sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to Bevacizumab with the incidence of antibodies to other products may be misleading. ## Postmarketing Experience The following adverse reactions have been identified during post-approval use of Bevacizumab. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Body as a Whole: Polyserositis Cardiovascular: Pulmonary hypertension, RPLS, Mesenteric venous occlusion Eye disorders (from unapproved intravitreal use for treatment of various ocular disorders): Permanent loss of vision; Endophthalmitis (infectious and sterile); Intraocular inflammation; Retinal detachment; Increased intraocular pressure; Hemorrhage including conjunctival, vitreous hemorrhage or retinal hemorrhage; Vitreous floaters; Ocular hyperemia; Ocular pain or discomfort Gastrointestinal: Gastrointestinal ulcer, Intestinal necrosis, Anastomotic ulceration Hemic and lymphatic: Pancytopenia Hepatobiliary disorders: Gallbladder perforation Infections and infestations: Necrotizing fasciitis, usually secondary to wound healing complications, gastrointestinal perforation or fistula formation Musculoskeletal: Osteonecrosis of the jaw Renal: Renal thrombotic microangiopathy (manifested as severe proteinuria) Respiratory: Nasal septum perforation, dysphonia Systemic Events (from unapproved intravitreal use for treatment of various ocular disorders): Arterial thromboembolic events, Hypertension, Gastrointestinal perforation, Hemorrhage # Drug Interactions A drug interaction study was performed in which irinotecan was administered as part of the FOLFIRI regimen with or without Bevacizumab. The results demonstrated no significant effect of bevacizumab on the pharmacokinetics of irinotecan or its active metabolite SN38. In a randomized study in 99 patients with NSCLC, based on limited data, there did not appear to be a difference in the mean exposure of either carboplatin or paclitaxel when each was administered alone or in combination with Bevacizumab. However, 3 of the 8 patients receiving Bevacizumab plus paclitaxel/carboplatin had substantially lower paclitaxel exposure after four cycles of treatment (at Day 63) than those at Day 0, while patients receiving paclitaxel/carboplatin without Bevacizumab had a greater paclitaxel exposure at Day 63 than at Day 0. In Study 8, there was no difference in the mean exposure of interferon alfa administered in combination with Bevacizumab when compared to interferon alfa alone. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): C There are no adequate or well controlled studies of bevacizumab in pregnant women. While it is not known if bevacizumab crosses the placenta, human IgG is known to cross the placenta Reproduction studies in rabbits treated with approximately 1 to 12 times the recommended human dose of bevacizumab demonstrated teratogenicity, including an increased incidence of specific gross and skeletal fetal alterations. Adverse fetal outcomes were observed at all doses tested. Other observed effects included decreases in maternal and fetal body weights and an increased number of fetal resorptions. Because of the observed teratogenic effects of bevacizumab in animals and of other inhibitors of angiogenesis in humans, bevacizumab should be used during pregnancy only if the potential benefit to the pregnant woman justifies the potential risk to the fetus. Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Bevacizumab in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Bevacizumab during labor and delivery. ### Nursing Mothers It is not known whether Bevacizumab is secreted in human milk. Human IgG is excreted in human milk, but published data suggest that breast milk antibodies do not enter the neonatal and infant circulation in substantial amounts. Because many drugs are secreted in human milk and because of the potential for serious adverse reactions in nursing infants from bevacizumab, a decision should be made whether to discontinue nursing or discontinue drug, taking into account the half-life of the bevacizumab (approximately 20 days ) and the importance of the drug to the mother. ### Pediatric Use The safety, effectiveness and pharmacokinetic profile of Bevacizumab in pediatric patients have not been established. Antitumor activity was not observed among eight children with relapsed glioblastoma treated with bevacizumab and irinotecan. There is insufficient information to determine the safety and efficacy of Bevacizumab in children with glioblastoma. Juvenile cynomolgus monkeys with open growth plates exhibited physeal dysplasia following 4 to 26 weeks exposure at 0.4 to 20 times the recommended human dose (based on mg/kg and exposure). The incidence and severity of physeal dysplasia were dose-related and were partially reversible upon cessation of treatment. ### Geriatic Use In Study 1, severe adverse events that occurred at a higher incidence ( ≥ 2%) in patients aged ≥ 65 years as compared to younger patients were asthenia, sepsis, deep thrombophlebitis, hypertension, hypotension, myocardial infarction, congestive heart failure, diarrhea, constipation, anorexia, leukopenia, anemia, dehydration, hypokalemia, and hyponatremia. The effect of Bevacizumab on overall survival was similar in elderly patients as compared to younger patients. In Study 2, patients aged ≥ 65 years receiving Bevacizumab plus FOLFOX4 had a greater relative risk as compared to younger patients for the following adverse events: nausea, emesis, ileus, and fatigue. In Study 5, patients aged ≥ 65 years receiving carboplatin, paclitaxel, and Bevacizumab had a greater relative risk for proteinuria as compared to younger patients Of the 742 patients enrolled in Genentech-sponsored clinical studies in which all adverse events were captured, 212 (29%) were age 65 or older and 43 (6%) were age 75 or older. Adverse events of any severity that occurred at a higher incidence in the elderly as compared to younger patients, in addition to those described above, were dyspepsia, gastrointestinal hemorrhage, edema, epistaxis, increased cough, and voice alteration. In an exploratory, pooled analysis of 1745 patients treated in five randomized, controlled studies, there were 618 (35%) patients aged ≥ 65 years and 1127 patients < 65 years of age. The overall incidence of arterial thromboembolic events was increased in all patients receiving Bevacizumab with chemotherapy as compared to those receiving chemotherapy alone, regardless of age. However, the increase in arterial thromboembolic events incidence was greater in patients aged ≥ 65 years (8.5% vs. 2.9%) as compared to those < 65 years (2.1% vs. 1.4%) ### Gender There is no FDA guidance on the use of Bevacizumab with respect to specific gender populations. ### Race There is no FDA guidance on the use of Bevacizumab with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Bevacizumab in patients with renal impairment. ### Hepatic Impairment There is no FDA guidance on the use of Bevacizumab in patients with hepatic impairment. ### Females of Reproductive Potential and Males Bevacizumab increases the risk of ovarian failure and may impair fertility. Inform females of reproductive potential of the risk of ovarian failure prior to starting treatment with Bevacizumab. Long term effects of Bevacizumab exposure on fertility are unknown. In a prospectively designed substudy of 179 premenopausal women randomized to receive chemotherapy with or without Bevacizumab, the incidence of ovarian failure was higher in the Bevacizumab arm (34%) compared to the control arm (2%). After discontinuation of Bevacizumab and chemotherapy, recovery of ovarian function occurred in 22% (7/32) of these Bevacizumab-treated patients. ### Immunocompromised Patients There is no FDA guidance one the use of Bevacizumab in patients who are immunocompromised. # Administration and Monitoring ### Administration - Administration - Do not administer as an intravenous push or bolus. Administer only as an intravenous (IV) infusion. - Do not initiate Bevacizumab until at least 28 days following major surgery. Administer Bevacizumab after the surgical incision has fully healed. - First infusion: Administer infusion over 90 minutes. - Subsequent infusions: Administer second infusion over 60 minutes if first infusion is tolerated; administer all subsequent infusions over 30 minutes if infusion over 60 minutes is tolerated. - Preparation for Administration - Use appropriate aseptic technique. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Withdraw necessary amount of Bevacizumab and dilute in a total volume of 100 mL of 0.9% Sodium Chloride Injection, USP. Discard any unused portion left in a vial, as the product contains no preservatives. - DO NOT ADMINISTER OR MIX WITH DEXTROSE SOLUTION. ### Monitoring FDA Package Insert for Bevacizumab contains no information regarding drug monitoring. # IV Compatibility There is limited information about the IV Compatibility. # Overdosage The highest dose tested in humans (20 mg/kg IV) was associated with headache in nine of 16 patients and with severe headache in three of 16 patients. # Pharmacology ## Mechanism of Action Bevacizumab binds VEGF and prevents the interaction of VEGF to its receptors (Flt-1 and KDR) on the surface of endothelial cells. The interaction of VEGF with its receptors leads to endothelial cell proliferation and new blood vessel formation in in vitro models of angiogenesis. Administration of bevacizumab to xenotransplant models of colon cancer in nude (athymic) mice caused reduction of microvascular growth and inhibition of metastatic disease progression. ## Structure Bevacizumab (bevacizumab) is a recombinant humanized monoclonal IgG1 antibody that binds to and inhibits the biologic activity of human vascular endothelial growth factor (VEGF) in in vitro and in vivo assay systems. Bevacizumab contains human framework regions and the complementarity-determining regions of a murine antibody that binds to VEGF. Bevacizumab has an approximate molecular weight of 149 kD. Bevacizumab is produced in a mammalian cell (Chinese Hamster Ovary) expression system in a nutrient medium containing the antibiotic gentamicin. Gentamicin is not detectable in the final product. Bevacizumab is a clear to slightly opalescent, colorless to pale brown, sterile, pH 6.2 solution for intravenous infusion. Bevacizumab is supplied in 100 mg and 400 mg preservative-free, single-use vials to deliver 4 mL or 16 mL of Bevacizumab (25 mg/mL). The 100 mg product is formulated in 240 mg α,α-trehalose dihydrate, 23.2 mg sodium phosphate (monobasic, monohydrate), 4.8 mg sodium phosphate (dibasic, anhydrous), 1.6 mg polysorbate 20, and Water for Injection, USP. The 400 mg product is formulated in 960 mg α,α-trehalose dihydrate, 92.8 mg sodium phosphate (monobasic, monohydrate), 19.2 mg sodium phosphate (dibasic, anhydrous), 6.4 mg polysorbate 20, and Water for Injection, USP. ## Pharmacodynamics FDA Package Insert for Bevacizumab contains no information regarding pharmacodynamics. ## Pharmacokinetics The pharmacokinetic profile of bevacizumab was assessed using an assay that measures total serum bevacizumab concentrations (i.e., the assay did not distinguish between free bevacizumab and bevacizumab bound to VEGF ligand). Based on a population pharmacokinetic analysis of 491 patients who received 1 to 20 mg/kg of Bevacizumab weekly, every 2 weeks, or every 3 weeks, the estimated half-life of bevacizumab was approximately 20 days (range 11–50 days). The predicted time to reach steady state was 100 days. The accumulation ratio following a dose of 10 mg/kg of bevacizumab every 2 weeks was 2.8. The clearance of bevacizumab varied by body weight, gender, and tumor burden. After correcting for body weight, males had a higher bevacizumab clearance (0.262 L/day vs. 0.207 L/day) and a larger Vc (3.25 L vs. 2.66 L) than females. Patients with higher tumor burden (at or above median value of tumor surface area) had a higher bevacizumab clearance (0.249 L/day vs. 0.199 L/day) than patients with tumor burdens below the median. In Study 1, there was no evidence of lesser efficacy (hazard ratio for overall survival) in males or patients with higher tumor burden treated with Bevacizumab as compared to females and patients with low tumor burden. The relationship between bevacizumab exposure and clinical outcomes has not been explored. ## Nonclinical Toxicology ## Carcinogenesis, Mutagenesis, Impairment of Fertility No carcinogenicity or mutagenicity studies of bevacizumab have been conducted. Bevacizumab may impair fertility. Female cynomolgus monkeys treated with 0.4 to 20 times the recommended human dose of bevacizumab exhibited arrested follicular development or absent corpora lutea as well as dose-related decreases in ovarian and uterine weights, endometrial proliferation, and the number of menstrual cycles. Following a 4- or 12-week recovery period, there was a trend suggestive of reversibility. After the 12-week recovery period, follicular maturation arrest was no longer observed, but ovarian weights were still moderately decreased. Reduced endometrial proliferation was no longer observed at the 12-week recovery time point; however, decreased uterine weight, absent corpora lutea, and reduced number of menstrual cycles remained evident. ## Animal Toxicology and/or Pharmacology In cynomolgus monkeys, when bevacizumab was administered at doses of 0.4 to 20 times the weekly human exposure, anatomical pathology revealed several adverse effects on general growth and skeletal development, fertility and wound healing capacity. Severe physeal dysplasia was consistently reported in juvenile monkeys with open growth plates receiving 0.4 to 20 times the human dose. The physeal dysplasia was characterized by a linear cessation of growth line and chondrocyte hyperplasia which did not completely resolve after the 4 to 12 weeks recovery period without drug exposure. Rabbits dosed with bevacizumab exhibited reduced wound healing capacity. Using full-thickness skin incision and partial thickness circular dermal wound models, bevacizumab dosing resulted in reductions in wound tensile strength, decreased granulation and re-epithelialization, and delayed time to wound closure. ## Reproductive and Developmental Toxicology Pregnant rabbits dosed with 1 to 12 times the human dose of bevacizumab every three days during the period of organogenesis (gestation day 6–18) exhibited teratogenic effects, decreases in maternal and fetal body weights, and increased number of fetal resorptions. Teratogenic effects included: reduced or irregular ossification in the skull, jaw, spine, ribs, tibia and bones of the paws; meningocele; fontanel, rib and hindlimb deformities; corneal opacity; and absent hindlimb phalanges. There are no data available regarding the level of bevacizumab exposure in the offspring. # Clinical Studies ## Metastatic Colorectal Cancer (mCRC) Study 1 In this double-blind, active-controlled study, patients were randomized (1:1:1) to IV bolus-IFL (irinotecan 125 mg/m2, 5-FU 500 mg/m2, and leucovorin (LV) 20 mg/m2 given once weekly for 4 weeks every 6 weeks) plus placebo (Arm 1), bolus-IFL plus Bevacizumab (5 mg/kg every 2 weeks) (Arm 2), or 5-FU/LV plus Bevacizumab (5 mg/kg every 2 weeks) (Arm 3). Enrollment in Arm 3 was discontinued, as pre-specified, when the toxicity of Bevacizumab in combination with the bolus-IFL regimen was deemed acceptable. The main outcome measure was overall survival (OS). Of the 813 patients randomized to Arms 1 and 2, the median age was 60, 40% were female, 79% were Caucasian, 57% had an ECOG performance status of 0, 21% had a rectal primary and 28% received prior adjuvant chemotherapy. In 56% of the patients, the dominant site of disease was extra-abdominal, while the liver was the dominant site in 38% of patients. The addition of Bevacizumab resulted in an improvement in survival across subgroups defined by age ( < 65 yrs, ≥ 65 yrs) and gender. Results are presented in Table 4 and Figure 1. Among the 110 patients enrolled in Arm 3, median OS was 18.3 months, median progression-free survival (PFS) was 8.8 months, objective response rate (ORR) was 39%, and median duration of response was 8.5 months. Study 2 Study 2 was a randomized, open-label, active-controlled trial in patients who were previously treated with irinotecan ± 5-FU for initial therapy for metastatic disease or as adjuvant therapy. Patients were randomized (1:1:1) to IV FOLFOX4 (Day 1: oxaliplatin 85 mg/m2 and LV 200 mg/m2 concurrently, then 5-FU 400 mg/m2 bolus followed by 600 mg/m2 continuously; Day 2: LV 200 mg/m2, then 5-FU 400 mg/m2 bolus followed by 600 mg/m2 continuously; repeated every 2 weeks), FOLFOX4 plus Bevacizumab (10 mg/kg every 2 weeks prior to FOLFOX4 on Day 1), or Bevacizumab monotherapy(10 mg/kg every 2 weeks). The main outcome measure was OS. The Bevacizumab monotherapy arm was closed to accrual after enrollment of 244 of the planned 290 patients following a planned interim analysis by the data monitoring committee based on evidence of decreased survival compared to FOLFOX4 alone. Of the 829 patients randomized to the three arms, the median age was 61 years, 40% were female, 87% were Caucasian, 49% had an ECOG performance status of 0, 26% received prior radiation therapy, and 80% received prior adjuvant chemotherapy, 99% received prior irinotecan, with or without 5-FU as therapy for metastatic disease, and 1% received prior irinotecan and 5-FU as adjuvant therapy. The addition of Bevacizumab to FOLFOX4 resulted in significantly longer survival as compared to FOLFOX4 alone (median OS 13.0 months vs. 10.8 months; hazard ratio 0.75 , p = 0.001 stratified log rank test) with clinical benefit seen in subgroups defined by age (< 65 yrs, ≥ 65 yrs) and gender. PFS and ORR based on investigator assessment were higher in the Bevacizumab plus FOLFOX4 arm. Study 3 The activity of Bevacizumab in combination with bolus or infusional 5-FU/LV was evaluated in a single arm study enrolling 339 patients with mCRC with disease progression following both irinotecan- and oxaliplatin-containing chemotherapy regimens. Seventy-three percent of patients received concurrent bolus 5-FU/LV. One objective partial response was verified in the first 100 evaluable patients for an overall response rate of 1% (95% CI 0–5.5%). Study 4 Study 4 was a prospective, randomized, open-label, multinational, controlled trial in patients with histologically confirmed metastatic colorectal cancer who had progressed on a first-line Bevacizumab containing regimen. Patients were excluded if they progressed within 3 months of initiating first-line chemotherapy and if they received Bevacizumab for less than 3 consecutive months in the first-line setting. Patients were randomized (1:1) within 3 months after discontinuation of Bevacizumab as first-line therapy to receive fluoropyrimidine/oxaliplatin- or fluoropyrimidine/irinotecan-based chemotherapy with or without Bevacizumab administered at 5 mg/kg every 2 weeks or 7.5 mg/kg every 3 weeks. The choice of second line therapy was contingent upon first-line chemotherapy treatment. Second-line treatment was administered until progressive disease or unacceptable toxicity. The main outcome measure was OS defined as the time from randomization until death from any cause. Of the 820 patients randomized, the majority of patients were male (64%) and the median age was 63.0 years (range 21 to 84 years). At baseline, 52% of patients were ECOG performance status (PS) 1, 44% were ECOG PS 0, 58% received irinotecan-based therapy as first-line treatment, 55% progressed on first-line treatment within 9 months, and 77% received their last dose of Bevacizumab as first-line treatment within 42 days of being randomized. Second-line chemotherapy regimens were generally balanced between each treatment arm. The addition of Bevacizumab to fluoropyrimidine-based chemotherapy resulted in a statistically significant prolongation of survival and PFS; there was no significant difference in overall response rate, a key secondary outcome measure. Results are presented in Table 5 and Figure 2. ## Lack of Efficacy in Adjuvant Treatment of Colon Cancer Lack of efficacy of Bevacizumab as an adjunct to standard chemotherapy for the adjuvant treatment of colon cancer was determined in two randomized, open-label, multicenter clinical trials. The first study conducted in 3451 patients with high risk stage II and III colon cancer, who had undergone surgery for colon cancer with curative intent, was a 3-arm study of Bevacizumab administered at a dose equivalent to 2.5 mg/kg/week on either a 2-weekly schedule in combination with FOLFOX4, or on a 3-weekly schedule in combination with XELOX and FOLFOX4 alone. Patients were randomized as follows: 1151 patients to FOLFOX4 arm, 1155 to FOLFOX4 plus Bevacizumab arm, and 1145 to XELOX plus Bevacizumab arm. The median age was 58 years, 54% were male, 84% were Caucasian and 29% were ≥ age 65. Eighty-three percent had stage III disease. The main efficacy outcome of the study was disease free survival (DFS) in patients with stage III colon cancer. Addition of Bevacizumab to chemotherapy did not improve DFS. As compared to the control arm, the proportion of stage III patients with disease recurrence or with death due to disease progression were numerically higher in the FOLFOX4 plus Bevacizumab and in the XELOX plus Bevacizumab arms. The hazard ratios for DFS were 1.17 (95% CI: 0.98–1.39) for the FOLFOX4 plus Bevacizumab versus FOLFOX4 and 1.07 (95% CI: 0.90–1.28) for the XELOX plus Bevacizumab versus FOLFOX4. The hazard ratios for overall survival were 1.31 (95% CI=1.03, 1.67) and 1.27 (95% CI=1.00, 1.62) for the comparison of Bevacizumab plus FOLFOX4 versus FOLFOX4 and Bevacizumab plus XELOX versus FOLFOX4, respectively. Similar lack of efficacy for DFS were observed in the Bevacizumab-containing arms compared to control in the high-risk stage II cohort. In a second study, 2710 patients with stage II and III colon cancer who had undergone surgery with curative intent, were randomized to receive either Bevacizumab administered at a dose equivalent to 2.5 mg/kg/week in combination with mFOLFOX6 (N=1354) or mFOLFOX6 alone (N=1356). The median age was 57 years, 50% were male and 87% Caucasian. Seventy-five percent had stage III disease. The main efficacy outcome was DFS among stage III patients. The hazard ratio for DFS was 0.92 (95% CI: 0.77, 1.10). Overall survival, an additional efficacy outcome, was not significantly improved with the addition of Bevacizumab to mFOLFOX6 (HR=0.96, 95% CI=. ## Unresectable Non–Squamous Non–Small Cell Lung Cancer (NSCLC) Study 5 The safety and efficacy of Bevacizumab as first-line treatment of patients with locally advanced, metastatic, or recurrent non–squamous NSCLC was studied in a single, large, randomized, active-controlled, open-label, multicenter study. Chemotherapy-naïve patients with locally advanced, metastatic or recurrent non–squamous NSCLC were randomized (1:1) to receive six 21-day cycles of paclitaxel 200 mg/m2 and carboplatin AUC = 6.0, by IV on day 1 (PC) or PC in combination with Bevacizumab 15 mg/kg by IV on day 1 (PC plus Bevacizumab). After completion or upon discontinuation of chemotherapy, patients in the PC plus Bevacizumab arm continued to receive Bevacizumab alone until disease progression or until unacceptable toxicity. Patients with predominant squamous histology (mixed cell type tumors only), central nervous system (CNS) metastasis, gross hemoptysis ( ≥ 1/2 tsp of red blood), unstable angina, or receiving therapeutic anticoagulation were excluded. The main outcome measure was duration of survival. Of the 878 patients randomized, the median age was 63, 46% were female, 43% were ≥ age 65, and 28% had ≥ 5% weight loss at study entry. Eleven percent had recurrent disease and of the 89% with newly diagnosed NSCLC, 12% had Stage IIIB with malignant pleural effusion and 76% had Stage IV disease. The results are presented in Figure 3. OS was statistically significantly higher among patients receiving PC plus Bevacizumab compared with those receiving PC alone; median OS was 12.3 months vs. 10.3 months . Based on investigator assessment which was not independently verified, patients were reported to have longer PFS with Bevacizumab in combination with PC compared to PC alone. In an exploratory analyses across patient subgroups, the impact of Bevacizumab on OS was less robust in the following: women , age ≥ 65 years and patients with ≥ 5% weight loss at study entry . The safety and efficacy of Bevacizumab in patients with locally advanced, metastatic or recurrent non-squamous NSCLC, who had not received prior chemotherapy was studied in another randomized, double-blind, placebo controlled, three-arm study of Bevacizumab in combination with cisplatin and gemcitabine (CG) versus placebo and CG. A total of 1043 patients were randomized 1:1:1 to receive placebo plus CG, Bevacizumab 7.5 mg/kg plus CG or Bevacizumab 15.0 mg/kg plus CG. The median age was 58 years, 36% were female, and 29% were ≥ age 65. Eight percent had recurrent disease and 77% had Stage IV disease. Progression-free survival, the main efficacy outcome measure, was significantly higher in both Bevacizumab containing arms compared to the placebo arm . The addition of Bevacizumab to CG chemotherapy failed to demonstrate an improvement in the duration of overall survival, an additional efficacy outcome measure, . ## Glioblastoma Study 6 The efficacy and safety of Bevacizumab was evaluated in Study 6, an open-label, multicenter, randomized, non-comparative study of patients with previously treated glioblastoma. Patients received Bevacizumab (10 mg/kg IV) alone or Bevacizumab plus irinotecan every 2 weeks until disease progression or until unacceptable toxicity. All patients received prior radiotherapy (completed at least 8 weeks prior to receiving Bevacizumab) and temozolomide. Patients with active brain hemorrhage were excluded. Of the 85 patients randomized to the Bevacizumab arm, the median age was 54 years, 32% were female, 81% were in first relapse, Karnofsky performance status was 90–100 for 45% and 70–80 for 55%. The efficacy of Bevacizumab was demonstrated using response assessment based on both WHO radiographic criteria and by stable or decreasing corticosteroid use, which occurred in 25.9% (95% CI 17.0%, 36.1%) of the patients. Median duration of response was 4.2 months (95% CI 3.0, 5.7). Radiologic assessment was based on MRI imaging (using T1 and T2/FLAIR). MRI does not necessarily distinguish between tumor, edema, and radiation necrosis. Study 7 Study 7, was a single-arm, single institution trial with 56 patients with glioblastoma. All patients had documented disease progression after receiving temozolomide and radiation therapy. Patients received Bevacizumab 10 mg/kg IV every 2 weeks until disease progression or unacceptable toxicity. The median age was 54, 54% were male, 98% Caucasian, and 68% had a Karnofsky Performance Status of 90–100. The efficacy of Bevacizumab was supported by an objective response rate of 19.6% (95% CI 10.9%, 31.3%) using the same response criteria as in Study 6. Median duration of response was 3.9 months (95% CI 2.4, 17.4). ## Metastatic Renal Cell Carcinoma (mRCC) Study 8 Patients with treatment-naïve mRCC were evaluated in a multicenter, randomized, double-blind, international study comparing Bevacizumab plus interferon alfa 2a (IFN-α2a) versus placebo plus IFN-α2a. A total of 649 patients who had undergone a nephrectomy were randomized (1:1) to receive either Bevacizumab (10 mg/kg IV infusion every 2 weeks; n = 327) or placebo (IV every 2 weeks; n = 322) in combination with IFN-α2a (9 MIU subcutaneously three times weekly, for a maximum of 52 weeks). Patients were treated until disease progression or unacceptable toxicity. The main outcome measure of the study was investigator-assessed PFS. Secondary outcome measures were ORR and OS. The median age was 60 years (range 18–82), 96% were white, and 70% were male. The study population was characterized by Motzer scores as follows: 28% favorable (0), 56% intermediate (1-2), 8% poor (3–5), and 7% missing. The results are presented in Figure 4. PFS was statistically significantly prolonged among patients receiving Bevacizumab plus IFN-α2a compared to those receiving IFN-α2a alone; median PFS was 10.2 months vs. 5.4 months . Among the 595 patients with measurable disease, ORR was also significantly higher (30% vs. 12%, p < 0.0001, stratified CMH test). There was no improvement in OS based on the final analysis conducted after 444 deaths, with a median OS of 23 months in the Bevacizumab plus IFN-α2a arm and 21 months in the IFN-α2a plus placebo arm . # How Supplied Bevacizumab vials are stable at 2–8°C (36–46°F). Bevacizumab vials should be protected from light. Do not freeze or shake. ## Storage Diluted Bevacizumab solutions may be stored at 2–8°C (36–46°F) for up to 8 hours. Store in the original carton until time of use. No incompatibilities between Bevacizumab and polyvinylchloride or polyolefin bags have been observed. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information Advise patients: - To undergo routine blood pressure monitoring and to contact their health care provider if blood pressure is elevated. - To immediately contact their health care provider for unusual bleeding, high fever, rigors, sudden onset of worsening neurological function, or persistent or severe abdominal pain, severe constipation, or vomiting. - Of increased risk of wound healing complications during and following Bevacizumab. - Of increased risk of an arterial thromboembolic event. - Of the potential risk to the fetus during and following Bevacizumab and the need to continue adequate contraception for at least 6 months following last dose of Bevacizumab. - Of the increased risk for ovarian failure following Bevacizumab treatment. # Precautions with Alcohol Alcohol-Bevacizumab interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names Avastin # Look-Alike Drug Names Avastin - Astelin # Drug Shortage Status # Price	Bevacizumab Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Sheng Shi, M.D. [2]; Sree Teja Yelamanchili, MBBS [3] # Disclaimer WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here. # Black Box Warning # Overview Bevacizumab is an antineoplastic agent that is FDA approved for the treatment of metastatic colorectal cancer (mcrc)，non-squamous non–small cell lung cancer (nsclc),glioblastoma, metastatic renal cell carcinoma (mrcc). There is a Black Box Warning for this drug as shown here. Common adverse reactions include hypertension, any grade, alopecia, hand-foot syndrome due to cytotoxic therapy abdominal pain, any grade, constipation, any grade, diarrhea, loss of appetite, stomatitis, taste sense altered, hemorrhage, any grade, asthenia, dizziness, headache, any grade proteinuria, any grade, dyspnea, epistaxis, upper respiratory infection. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) ### Metastatic Colorectal Cancer (mCRC) - Dosing information - Patients should continue treatment until disease progression or unacceptable toxicity. - 5 mg/kg or 10 mg/kg every 2 weeks when used in combination with intravenous 5-FU-based chemotherapy. - Administer 5 mg/kg when used in combination with bolus-IFL. - Administer 10 mg/kg when used in combination with FOLFOX4. - Administer 5 mg/kg every 2 weeks or 7.5 mg/kg every 3 weeks when used in combination with a fluoropyrimidine-irinotecan or fluoropyrimidine-oxaliplatin based chemotherapy regimen in patients who have progressed on a first-line Bevacizumab-containing regimen. ### Non-Squamous Non-Small Cell Lung Cancer (NSCLC) - Dosing information - 15 mg/kg every 3 weeks in combination with carboplatin and paclitaxel. ### Glioblastoma - Dosing information - Recommended dosage: 10 mg/kg every 2 weeks. ### Metastatic Renal Cell Carcinoma (mRCC) - Dosing information - Recommended dosage: 10 mg/kg every 2 weeks in combination with interferon alfa. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Bevacizumab in adult patients. ### Non–Guideline-Supported Use ### Age related macular degeneration, Secondary to choroidal neovascularization - Dosing information - Administration of intravitreal bevacizumab has been associated with improved visual acuity, decreased retinal thickness ### Angioid streaks of choroid - Dosing information - 1.25 mg intravitreally and assessed every 4 to 6 weeks[1] - 1.25 mg intravitreally and examined at 2 month intervals [2] ### Branch retinal vein occlusion with macular edema - Dosing information - Not applicable [3] ### Central retinal vein occlusion with macular edema - Dosing information - 1.25 mg/0.05 mL via intravitreal injection[4] ### Cervical cancer, Recurrent, persistent, or metastatic - Dosing information - 1.25 mg/0.05 mL [5] ### Diabetic macular edema - Dosing information - Not applicable [6] ### Diabetic retinopathy - Dosing information - Not applicable [7] ### Epistaxis - Osler hemorrhagic telangiectasia syndrome - Dosing information - 100 mg nasal spray via a metered dose atomizer [8] ### Gastric cancer - Dosing information - 7.5 mg/kg [9] ### Liver carcinoma - Dosing information ### Metastatic breast cancer - Dosing information - 15 mg/kg IV every 3 weeks [10] - 7.5 mg/kg or 15 mg/kg[11] ### Neovascular glaucoma - Dosing information - 1.25 mg18463512 - 1.25 mg every 4 weeks for 3 doses [12] ### Ovarian cancer - Dosing information - 15 mg/kg for cycles 2 through 6[13] - 7.5 mg/kg was administered every 3 weeks[14] ### Recurrent Ovarian cancer - Dosing information - Not applicable [15], [16], [17] ### Retinopathy of prematurity - Dosing information - Not applicable [18], [19] # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) The safety, effectiveness and pharmacokinetic profile of Bevacizumab in pediatric patients have not been established. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Bevacizumab in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Bevacizumab in pediatric patients. # Contraindications None. # Warnings ## Gastrointestinal perforations Serious and sometimes fatal gastrointestinal perforation occurs at a higher incidence in Bevacizumab treated patients compared to controls. The incidence of gastrointestinal perforation ranged from 0.3 to 2.4% across clinical studies. The typical presentation may include abdominal pain, nausea, emesis, constipation, and fever. Perforation can be complicated by intra-abdominal abscess and fistula formation. The majority of cases occurred within the first 50 days of initiation of Bevacizumab. Discontinue Bevacizumab in patients with gastrointestinal perforation. ## Surgery and Wound Healing Complications Bevacizumab impairs wound healing in animal models. In clinical trials, administration of Bevacizumab was not allowed until at least 28 days after surgery. In a controlled clinical trial, the incidence of wound healing complications, including serious and fatal complications, in patients with mCRC who underwent surgery during the course of Bevacizumab treatment was 15% and in patients who did not receive Bevacizumab, was 4%. Bevacizumab should not be initiated for at least 28 days following surgery and until the surgical wound is fully healed. Discontinue Bevacizumab in patients with wound healing complications requiring medical intervention. The appropriate interval between the last dose of Bevacizumab and elective surgery is unknown; however, the half-life of Bevacizumab is estimated to be 20 days. Suspend Bevacizumab for at least 28 days prior to elective surgery. Do not administer Bevacizumab until the wound is fully healed. Necrotizing fasciitis including fatal cases, has been reported in patients treated with Bevacizumab; usually secondary to wound healing complications, gastrointestinal perforation or fistula formation. Discontinue Bevacizumab therapy in patients who develop necrotizing fasciitis. ## Hemorrhage Bevacizumab can result in two distinct patterns of bleeding: minor hemorrhage, most commonly Grade 1 epistaxis; and serious, and in some cases fatal, hemorrhagic events. Severe or fatal hemorrhage, including hemoptysis, gastrointestinal bleeding, hematemesis, CNS hemorrhage, epistaxis, and vaginal bleeding occurred up to five-fold more frequently in patients receiving Bevacizumab compared to patients receiving only chemotherapy. Across indications, the incidence of Grade ≥ 3 hemorrhagic events among patients receiving Bevacizumab ranged from 1.2 to 4.6%. Serious or fatal pulmonary hemorrhage occurred in four of 13 (31%) patients with squamous cell histology and two of 53 (4%) patients with non-squamous non-small cell lung cancer receiving Bevacizumab and chemotherapy compared to none of the 32 (0%) patients receiving chemotherapy alone. In clinical studies in non–small cell lung cancer where patients with CNS metastases who completed radiation and surgery more than 4 weeks prior to the start of Bevacizumab were evaluated with serial CNS imaging, symptomatic Grade 2 CNS hemorrhage was documented in one of 83 Bevacizumab-treated patients (rate 1.2%, 95% CI 0.06%–5.93%). Intracranial hemorrhage occurred in 8 of 163 patients with previously treated glioblastoma; two patients had Grade 3–4 hemorrhage. Do not administer Bevacizumab to patients with recent history of hemoptysis of ≥ 1/2 teaspoon of red blood. Discontinue Bevacizumab in patients with hemorrhage. [See Boxed Warning, Dosage and Administration (2.4).] ## Non-Gastrointestinal Fistula Formation Serious and sometimes fatal non-gastrointestinal fistula formation involving tracheo-esophageal, bronchopleural, biliary, vaginal, renal and bladder sites occurs at a higher incidence in Bevacizumab-treated patients compared to controls. The incidence of non-gastrointestinal perforation was ≤ 0.3% in clinical studies. Most events occurred within the first 6 months of Bevacizumab therapy. Discontinue Bevacizumab in patients with fistula formation involving an internal organ. ## Arterial Thromboembolic Events Serious, sometimes fatal, arterial thromboembolic events (ATE)including cerebral infarction, transient ischemic attacks, myocardial infarction, angina, and a variety of other ATE occurred at a higher incidence in patients receiving Bevacizumab compared to those in the control arm. Across indications, the incidence of Grade ≥ 3 ATE in the Bevacizumab containing arms was 2.6% compared to 0.8% in the control arms. Among patients receiving Bevacizumab in combination with chemotherapy, the risk of developing ATE during therapy was increased in patients with a history of arterial thromboembolism, diabetes, or age greater than 65 years. The safety of resumption of Bevacizumab therapy after resolution of an ATE has not been studied. Discontinue Bevacizumab in patients who experience a severe ATE. ## Hypertension The incidence of severe hypertension is increased in patients receiving Bevacizumab as compared to controls. Across clinical studies the incidence of Grade 3 or 4 hypertension ranged from 5-18%. Monitor blood pressure every two to three weeks during treatment with Bevacizumab. Treat with appropriate anti-hypertensive therapy and monitor blood pressure regularly. Continue to monitor blood pressure at regular intervals in patients with Bevacizumab-induced or -exacerbated hypertension after discontinuation of Bevacizumab. Temporarily suspend Bevacizumab in patients with severe hypertension that is not controlled with medical management. Discontinue Bevacizumab in patients with hypertensive crisis or hypertensive encephalopathy. ## Reversible Posterior Leukoencephalopathy Syndrome (RPLS) RPLS has been reported with an incidence of < 0.1% in clinical studies. The onset of symptoms occurred from 16 hours to 1 year after initiation of Bevacizumab. RPLS is a neurological disorder which can present with headache, seizure, lethargy, confusion, blindness and other visual and neurologic disturbances. Mild to severe hypertension may be present. Magnetic resonance imaging (MRI) is necessary to confirm the diagnosis of RPLS. Discontinue Bevacizumab in patients developing RPLS. Symptoms usually resolve or improve within days, although some patients have experienced ongoing neurologic sequelae. The safety of reinitiating Bevacizumab therapy in patients previously experiencing RPLS is not known. ## Proteinuria The incidence and severity of proteinuria is increased in patients receiving Bevacizumab as compared to controls. Nephrotic syndrome occurred in < 1% of patients receiving Bevacizumab in clinical trials, in some instances with fatal outcome. [See Adverse Reactions (6.1).] In a published case series, kidney biopsy of six patients with proteinuria showed findings consistent with thrombotic microangiopathy. Monitor proteinuria by dipstick urine analysis for the development or worsening of proteinuria with serial urinalyses during Bevacizumab therapy. Patients with a 2 + or greater urine dipstick reading should undergo further assessment with a 24-hour urine collection. Suspend Bevacizumab administration for ≥ 2 grams of proteinuria/24 hours and resume when proteinuria is < 2 gm/24 hours. Discontinue Bevacizumab in patients with nephrotic syndrome. Data from a postmarketing safety study showed poor correlation between UPCR (Urine Protein/Creatinine Ratio) and 24 hour urine protein (Pearson Correlation 0.39 (95% CI 0.17, 0.57). ## Infusion Reactions Infusion reactions reported in the clinical trials and post-marketing experience include hypertension, hypertensive crises associated with neurologic signs and symptoms, wheezing, oxygen desaturation, Grade 3 hypersensitivity, chest pain, headaches, rigors, and diaphoresis. In clinical studies, infusion reactions with the first dose of Bevacizumab were uncommon ( < 3%) and severe reactions occurred in 0.2% of patients. Stop infusion if a severe infusion reaction occurs and administer appropriate medical therapy. ## Ovarian Failure The incidence of ovarian failure was higher (34% vs. 2%) in premenopausal women receiving Bevacizumab in combination with mFOLFOX chemotherapy as compared to those receiving mFOLFOX chemotherapy alone for adjuvant treatment for colorectal cancer, a use for which Bevacizumab is not approved. Inform females of reproductive potential of the risk of ovarian failure prior to starting treatment with Bevacizumab. # Adverse Reactions ## Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The data below reflect exposure to Bevacizumab in 4599 patients with CRC, non-squamous NSCLC, glioblastoma, or mRCC trials including controlled (Studies 1, 2, 4, 5 and 8) or uncontrolled, single arm (Study 6) treated at the recommended dose and schedule for a median of 8 to 23 doses of Bevacizumab. [See Clinical Studies (14).] The population was aged 18-89 years (median 60 years), 45.4% male and 85.8% (3729/4345) White. The population included 2184 first- and second-line mCRC patients who received a median of 10 doses of Bevacizumab, 480 first-line metastatic NSCLC patients who received a median of 8 doses of Bevacizumab, 163 glioblastoma patients who received a median of 9 doses of Bevacizumab, and 337 mRCC patients who received a median of 16 doses of Bevacizumab. These data also reflect exposure to Bevacizumab in 363 patients with metastatic breast cancer (MBC) who received a median of 9.5 doses of Bevacizumab, 669 female adjuvant CRC patients who received a median of 23 doses of Bevacizumab and exposure to Bevacizumab in 403 previously untreated patients with diffuse large B-cell lymphoma (DLBCL) who received a median of 8 doses of Bevacizumab. Bevacizumab is not approved for use in MBC, adjuvant CRC, or DLBCL. Surgery and Wound Healing Complications The incidence of post-operative wound healing and/or bleeding complications was increased in patients with mCRC receiving Bevacizumab as compared to patients receiving only chemotherapy. Among patients requiring surgery on or within 60 days of receiving study treatment, wound healing and/or bleeding complications occurred in 15% (6/39) of patients receiving bolus-IFL plus Bevacizumab as compared to 4% (1/25) of patients who received bolus-IFL alone. In Study 6, events of post-operative wound healing complications (craniotomy site wound dehiscence and cerebrospinal fluid leak) occurred in patients with previously treated glioblastoma: 3/84 patients in the Bevacizumab alone arm and 1/79 patients in the Bevacizumab plus irinotecan arm. Hemorrhage The incidence of epistaxis was higher (35% vs. 10%) in patients with mCRC receiving bolus-IFL plus Bevacizumab compared with patients receiving bolus-IFL plus placebo. All but one of these events were Grade 1 in severity and resolved without medical intervention. Grade 1 or 2 hemorrhagic events were more frequent in patients receiving bolus-IFL plus Bevacizumab when compared to those receiving bolus-IFL plus placebo and included gastrointestinal hemorrhage (24% vs. 6%), minor gum bleeding (2% vs. 0), and vaginal hemorrhage (4% vs. 2%). Venous Thromboembolic Events The overall incidence of venous thromboembolic events in Study 1 was 15.1% in patients receiving bolus-IFL plus Bevacizumab and 13.6% in patients receiving bolus-IFL plus placebo. In Study 1, more patients in the Bevacizumab containing arm experienced deep venous thrombosis (34 vs. 19 patients ) and intra-abdominal venous thrombosis (10 vs. 5 patients). The risk of developing a second thromboembolic event while on Bevacizumab and oral anticoagulants was evaluated in two randomized studies. In Study 1, 53 patients (14%) on the bolus-IFL plus Bevacizumab arm and 30 patients (8%) on the bolus-IFL plus placebo arm received full dose warfarin following a venous thromboembolic event (VTE). Among these patients, an additional thromboembolic event occurred in 21% (11/53) of patients receiving bolus-IFL plus Bevacizumab and 3% (1/30) of patients receiving bolus-IFL alone. In a second, randomized, 4-arm study in 1401 patients with mCRC, prospectively evaluating the incidence of VTE (all grades), the overall incidence of first VTE was higher in the Bevacizumab containing arms (13.5%) than the chemotherapy alone arms (9.6%). Among the 116 patients treated with anticoagulants following an initial VTE event (73 in the Bevacizumab plus chemotherapy arms and 43 in the chemotherapy alone arms), the overall incidence of subsequent VTEs was also higher among the Bevacizumab treated patients (31.5% vs. 25.6%). In this subgroup of patients treated with anticoagulants, the overall incidence of bleeding, the majority of which were Grade 1, was higher in the Bevacizumab treated arms than the chemotherapy arms (27.4% vs. 20.9%). Neutropenia and Infection The incidences of neutropenia and febrile neutropenia are increased in patients receiving Bevacizumab plus chemotherapy compared to chemotherapy alone. In Study 1, the incidence of Grade 3 or 4 neutropenia was increased in mCRC patients receiving IFL plus Bevacizumab (21%) compared to patients receiving IFL alone (14%). In Study 5, the incidence of Grade 4 neutropenia was increased in NSCLC patients receiving paclitaxel/carboplatin (PC) plus Bevacizumab (26.2%) compared with patients receiving PC alone (17.2%). Febrile neutropenia was also increased (5.4% for PC plus Bevacizumab vs. 1.8% for PC alone). There were 19 (4.5%) infections with Grade 3 or 4 neutropenia in the PC plus Bevacizumab arm of which 3 were fatal compared to 9 (2%) neutropenic infections in patients receiving PC alone, of which none were fatal. During the first 6 cycles of treatment, the incidence of serious infections including pneumonia, febrile neutropenia, catheter infections and wound infections was increased in the PC plus Bevacizumab arm [58 patients (13.6%)] compared to the PC alone arm [29 patients (6.6%)]. In Study 6, one fatal event of neutropenic infection occurred in a patient with previously treated glioblastoma receiving Bevacizumab alone. The incidence of any grade of infection in patients receiving Bevacizumab alone was 55% and the incidence of Grade 3–5 infection was 10%. Proteinuria Grade 3–4 proteinuria ranged from 0.7 to 7.4% in Studies 1, 2, 4, 5 and 8. The overall incidence of proteinuria (all grades) was only adequately assessed in Study 8, in which the incidence was 20%. Median onset of proteinuria was 5.6 months (range 15 days to 37 months) after initiation of Bevacizumab. Median time to resolution was 6.1 months (95% CI 2.8 months, 11.3 months). Proteinuria did not resolve in 40% of patients after median follow up of 11.2 months and required permanent discontinuation of Bevacizumab in 30% of the patients who developed proteinuria (Study 8). In an exploratory, pooled analysis of 8,273 patients treated in 7 randomized clinical trials, 5.4% (271 of 5037) of patients receiving Bevacizumab in combination with chemotherapy experienced Grade ≥ 2 proteinuria. The Grade ≥ 2 proteinuria resolved in 74.2% (201 of 271) of patients. Bevacizumab was re-initiated in 41.7% (113 of 271) of patients. Of the 113 patients who re-initiated Bevacizumab, 47.8% (54 of 113) experienced a second episode of Grade ≥ 2 proteinuria. [See Warnings and Precautions (5.8).] Congestive Heart Failure (CHF) The incidence of Grade ≥ 3 left ventricular dysfunction was 1.0% in patients receiving Bevacizumab compared to 0.6% in the control arm across indications. In patients with metastatic breast cancer (MBC), an indication for which Bevacizumab is not approved, the incidence of Grade 3–4 CHF was increased in patients in the Bevacizumab plus paclitaxel arm (2.2%) as compared to the control arm (0.3%). Among patients receiving prior anthracyclines for MBC, the rate of CHF was 3.8% for patients receiving Bevacizumab as compared to 0.6% for patients receiving paclitaxel alone. The safety of continuation or resumption of Bevacizumab in patients with cardiac dysfunction has not been studied. In previously untreated patients with diffuse large B-cell lymphoma (DLBCL), an indication for which Bevacizumab is not approved, the incidence of CHF and decline in left-ventricular ejection fraction (LVEF) were signficantly increased in the Bevacizumab plus R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) arm (n=403) compared to the placebo plus R-CHOP arm (n=379); both regimens were given for 6 to 8 cycles. At the completion of R-CHOP therapy, the incidence of CHF was 10.9% in the Bevacizumab plus R-CHOP arm compared to 5.0% in the R-CHOP alone arm [relative risk (95% CI) of 2.2 (1.3, 3.7)]. The incidence of a LVEF event, defined as a decline from baseline of 20% or more in LVEF or a decline from baseline of 10% or more to a LVEF value of less than 50%, was also increased in the Bevacizumab plus R-CHOP arm (10.4%) compared to the R-CHOP alone arm (5.0%). Time to onset of left-ventricular dysfunction or CHF was 1-6 months after initiation of therapy in at least 85% of the patients and was resolved in 62% of the patients experiencing CHF in the Bevacizumab arm compared to 82% in the control arm. Ovarian Failure The incidence of new cases of ovarian failure (defined as amenorrhoea lasting 3 or more months, FSH level ≥ 30 mIU/mL and a negative serum β-HCG pregnancy test) was prospectively evaluated in a subset of 179 women receiving mFOLFOX chemotherapy alone (n = 84) or with Bevacizumab (n = 95). New cases of ovarian failure were identified in 34% (32/95) of women receiving Bevacizumab in combination with chemotherapy compared with 2% (2/84) of women receiving chemotherapy alone [relative risk of 14 (95% CI 4, 53)]. After discontinuation of Bevacizumab treatment, recovery of ovarian function at all time points during the post-treatment period was demonstrated in 22% (7/32) of the Bevacizumab-treated women. Recovery of ovarian function is defined as resumption of menses, a positive serum β-HCG pregnancy test, or a FSH level < 30 mIU/mL during the post-treatment period. Long term effects of Bevacizumab exposure on fertility are unknown. [See Warnings and Precautions (5.10), Use in Specific Populations (8.6).] Metastatic Colorectal Cancer (mCRC) The data in Table 1 and Table 2 were obtained in Study 1, a randomized, double-blind, controlled trial comparing chemotherapy plus Bevacizumab with chemotherapy plus placebo. Bevacizumab was administered at 5 mg/kg every 2 weeks. All Grade 3–4 adverse events and selected Grade 1–2 adverse events (hypertension, proteinuria, thromboembolic events) were collected in the entire study population. Severe and life-threatening (Grade 3–4) adverse events, which occurred at a higher incidence ( ≥ 2%) in patients receiving bolus-IFL plus Bevacizumab as compared to bolus-IFL plus placebo, are presented in Table 1. Grade 1–4 adverse events which occurred at a higher incidence ( ≥ 5%) in patients receiving bolus-IFL plus Bevacizumab as compared to the bolus-IFL plus placebo arm are presented in Table 2. Grade 1–4 adverse events were collected for the first approximately 100 patients in each of the three treatment arms who were enrolled until enrollment in Arm 3 (5-FU/LV + Bevacizumab) was discontinued. Bevacizumab in Combination with FOLFOX4 in Second-line mCRC Only Grade 3-5 non-hematologic and Grade 4–5 hematologic adverse events related to treatment were collected in Study 2. The most frequent adverse events (selected Grade 3–5 non-hematologic and Grade 4–5 hematologic adverse events) occurring at a higher incidence ( ≥ 2%) in 287 patients receiving FOLFOX4 plus Bevacizumab compared to 285 patients receiving FOLFOX4 alone were fatigue (19% vs. 13%), diarrhea (18% vs. 13%), sensory neuropathy (17% vs. 9%), nausea (12% vs. 5%), vomiting (11% vs. 4%), dehydration (10% vs. 5%), hypertension (9% vs. 2%), abdominal pain (8% vs. 5%), hemorrhage (5% vs. 1%), other neurological (5% vs. 3%), ileus (4% vs. 1%) and headache (3% vs. 0%). These data are likely to under-estimate the true adverse event rates due to the reporting mechanisms used in Study 2. Bevacizumab in Combination with Fluoropyrimidine-Irinotecan or Fluoropyrimidine-Oxaliplatin Based Chemotherapy in Second-line mCRC Patients who have Progressed on an Bevacizumab Containing Regimen in First-line mCRC: No new safety signals were observed in Study 4 when Bevacizumab was administered in second line mCRC patients who progressed on an Bevacizumab containing regimen in first line mCRC. The safety data was consistent with the known safety profile established in first and second line mCRC. Unresectable Non-Squamous Non-Small Cell Lung Cancer (NSCLC) Only Grade 3-5 non-hematologic and Grade 4-5 hematologic adverse events were collected in Study 5. Grade 3–5 non-hematologic and Grade 4–5 hematologic adverse events (occurring at a higher incidence (≥ 2%) in 427 patients receiving PC plus Bevacizumab compared with 441 patients receiving PC alone were neutropenia (27% vs. 17%), fatigue (16% vs. 13%), hypertension (8% vs. 0.7%), infection without neutropenia (7% vs. 3%), venous thrombus/embolism (5% vs. 3%), febrile neutropenia (5% vs. 2%), pneumonitis/pulmonary infiltrates (5% vs. 3%), infection with Grade 3 or 4 neutropenia (4% vs. 2%), hyponatremia (4% vs. 1%), headache (3% vs. 1%) and proteinuria (3% vs. 0%). Glioblastoma All adverse events were collected in 163 patients enrolled in Study 6 who either received Bevacizumab alone or Bevacizumab plus irinotecan. All patients received prior radiotherapy and temozolomide. Bevacizumab was administered at 10 mg/kg every 2 weeks alone or in combination with irinotecan. Bevacizumab was discontinued due to adverse events in 4.8% of patients treated with Bevacizumab alone. In patients receiving Bevacizumab alone (N = 84), the most frequently reported adverse events of any grade were infection (55%), fatigue (45%), headache (37%), hypertension (30%), epistaxis (19%) and diarrhea (21%). Of these, the incidence of Grade ≥ 3 adverse events was infection (10%), fatigue (4%), headache (4%), hypertension (8%) and diarrhea (1%). Two deaths on study were possibly related to Bevacizumab: one retroperitoneal hemorrhage and one neutropenic infection. In patients receiving Bevacizumab alone or Bevacizumab plus irinotecan (N = 163), the incidence of Bevacizumab-related adverse events (Grade 1–4) were bleeding/hemorrhage (40%), epistaxis (26%), CNS hemorrhage (5%), hypertension (32%), venous thromboembolic event (8%), arterial thromboembolic event (6%), wound-healing complications (6%), proteinuria (4%), gastrointestinal perforation (2%), and RPLS (1%). The incidence of Grade 3–5 events in these 163 patients were bleeding/hemorrhage (2%), CNS hemorrhage (1%), hypertension (5%), venous thromboembolic event (7%), arterial thromboembolic event (3%), wound-healing complications (3%), proteinuria (1%), and gastrointestinal perforation (2%). Metastatic Renal Cell Carcinoma (mRCC) All grade adverse events were collected in Study 8. Grade 3–5 adverse events occurring at a higher incidence ( ≥ 2%) in 337 patients receiving interferon alfa (IFN-α) plus Bevacizumab compared to 304 patients receiving IFN-α plus placebo arm were fatigue (13% vs. 8%), asthenia (10% vs. 7%), proteinuria (7% vs. 0%), hypertension (6% vs. 1%; including hypertension and hypertensive crisis), and hemorrhage (3% vs. 0.3%; including epistaxis, small intestinal hemorrhage, aneurysm ruptured, gastric ulcer hemorrhage, gingival bleeding, haemoptysis, hemorrhage intracranial, large intestinal hemorrhage, respiratory tract hemorrhage, and traumatic hematoma). Grade 1–5 adverse events occurring at a higher incidence ( ≥ 5%) in patients receiving IFN-α plus Bevacizumab compared to the IFN-α plus placebo arm are presented in Table 3. The following adverse events were reported at a 5-fold greater incidence in the IFN-α plus Bevacizumab arm compared to IFN-α alone and not represented in Table 3: gingival bleeding (13 patients vs. 1 patient); rhinitis (9 vs.0 ); blurred vision (8 vs. 0); gingivitis (8 vs. 1); gastroesophageal reflux disease (8 vs.1 ); tinnitus (7 vs. 1); tooth abscess (7 vs.0); mouth ulceration (6 vs. 0); acne (5 vs. 0); deafness (5 vs. 0); gastritis (5 vs. 0); gingival pain (5 vs. 0) and pulmonary embolism (5 vs. 1). ## Immunogenicity As with all therapeutic proteins, there is a potential for an immune response to Bevacizumab. In clinical trials of adjuvant colon carcinoma, 14 of 2233 evaluable patients (0.63%) tested positive for treatment-emergent anti-bevacizumab antibodies detected by an electrochemiluminescent (ECL) based assay. Among these 14 patients, three tested positive for neutralizing antibodies against bevacizumab using an enzyme-linked immunosorbent assay (ELISA). The clinical significance of these anti-product antibody responses to bevacizumab is unknown. Immunogenicity assay results are highly dependent on the sensitivity and specificity of the test method and may be influenced by several factors, including sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to Bevacizumab with the incidence of antibodies to other products may be misleading. ## Postmarketing Experience The following adverse reactions have been identified during post-approval use of Bevacizumab. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Body as a Whole: Polyserositis Cardiovascular: Pulmonary hypertension, RPLS, Mesenteric venous occlusion Eye disorders (from unapproved intravitreal use for treatment of various ocular disorders): Permanent loss of vision; Endophthalmitis (infectious and sterile); Intraocular inflammation; Retinal detachment; Increased intraocular pressure; Hemorrhage including conjunctival, vitreous hemorrhage or retinal hemorrhage; Vitreous floaters; Ocular hyperemia; Ocular pain or discomfort Gastrointestinal: Gastrointestinal ulcer, Intestinal necrosis, Anastomotic ulceration Hemic and lymphatic: Pancytopenia Hepatobiliary disorders: Gallbladder perforation Infections and infestations: Necrotizing fasciitis, usually secondary to wound healing complications, gastrointestinal perforation or fistula formation Musculoskeletal: Osteonecrosis of the jaw Renal: Renal thrombotic microangiopathy (manifested as severe proteinuria) Respiratory: Nasal septum perforation, dysphonia Systemic Events (from unapproved intravitreal use for treatment of various ocular disorders): Arterial thromboembolic events, Hypertension, Gastrointestinal perforation, Hemorrhage # Drug Interactions A drug interaction study was performed in which irinotecan was administered as part of the FOLFIRI regimen with or without Bevacizumab. The results demonstrated no significant effect of bevacizumab on the pharmacokinetics of irinotecan or its active metabolite SN38. In a randomized study in 99 patients with NSCLC, based on limited data, there did not appear to be a difference in the mean exposure of either carboplatin or paclitaxel when each was administered alone or in combination with Bevacizumab. However, 3 of the 8 patients receiving Bevacizumab plus paclitaxel/carboplatin had substantially lower paclitaxel exposure after four cycles of treatment (at Day 63) than those at Day 0, while patients receiving paclitaxel/carboplatin without Bevacizumab had a greater paclitaxel exposure at Day 63 than at Day 0. In Study 8, there was no difference in the mean exposure of interferon alfa administered in combination with Bevacizumab when compared to interferon alfa alone. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): C There are no adequate or well controlled studies of bevacizumab in pregnant women. While it is not known if bevacizumab crosses the placenta, human IgG is known to cross the placenta Reproduction studies in rabbits treated with approximately 1 to 12 times the recommended human dose of bevacizumab demonstrated teratogenicity, including an increased incidence of specific gross and skeletal fetal alterations. Adverse fetal outcomes were observed at all doses tested. Other observed effects included decreases in maternal and fetal body weights and an increased number of fetal resorptions. Because of the observed teratogenic effects of bevacizumab in animals and of other inhibitors of angiogenesis in humans, bevacizumab should be used during pregnancy only if the potential benefit to the pregnant woman justifies the potential risk to the fetus. Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Bevacizumab in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Bevacizumab during labor and delivery. ### Nursing Mothers It is not known whether Bevacizumab is secreted in human milk. Human IgG is excreted in human milk, but published data suggest that breast milk antibodies do not enter the neonatal and infant circulation in substantial amounts. Because many drugs are secreted in human milk and because of the potential for serious adverse reactions in nursing infants from bevacizumab, a decision should be made whether to discontinue nursing or discontinue drug, taking into account the half-life of the bevacizumab (approximately 20 days [range 11–50 days]) and the importance of the drug to the mother. ### Pediatric Use The safety, effectiveness and pharmacokinetic profile of Bevacizumab in pediatric patients have not been established. Antitumor activity was not observed among eight children with relapsed glioblastoma treated with bevacizumab and irinotecan. There is insufficient information to determine the safety and efficacy of Bevacizumab in children with glioblastoma. Juvenile cynomolgus monkeys with open growth plates exhibited physeal dysplasia following 4 to 26 weeks exposure at 0.4 to 20 times the recommended human dose (based on mg/kg and exposure). The incidence and severity of physeal dysplasia were dose-related and were partially reversible upon cessation of treatment. ### Geriatic Use In Study 1, severe adverse events that occurred at a higher incidence ( ≥ 2%) in patients aged ≥ 65 years as compared to younger patients were asthenia, sepsis, deep thrombophlebitis, hypertension, hypotension, myocardial infarction, congestive heart failure, diarrhea, constipation, anorexia, leukopenia, anemia, dehydration, hypokalemia, and hyponatremia. The effect of Bevacizumab on overall survival was similar in elderly patients as compared to younger patients. In Study 2, patients aged ≥ 65 years receiving Bevacizumab plus FOLFOX4 had a greater relative risk as compared to younger patients for the following adverse events: nausea, emesis, ileus, and fatigue. In Study 5, patients aged ≥ 65 years receiving carboplatin, paclitaxel, and Bevacizumab had a greater relative risk for proteinuria as compared to younger patients Of the 742 patients enrolled in Genentech-sponsored clinical studies in which all adverse events were captured, 212 (29%) were age 65 or older and 43 (6%) were age 75 or older. Adverse events of any severity that occurred at a higher incidence in the elderly as compared to younger patients, in addition to those described above, were dyspepsia, gastrointestinal hemorrhage, edema, epistaxis, increased cough, and voice alteration. In an exploratory, pooled analysis of 1745 patients treated in five randomized, controlled studies, there were 618 (35%) patients aged ≥ 65 years and 1127 patients < 65 years of age. The overall incidence of arterial thromboembolic events was increased in all patients receiving Bevacizumab with chemotherapy as compared to those receiving chemotherapy alone, regardless of age. However, the increase in arterial thromboembolic events incidence was greater in patients aged ≥ 65 years (8.5% vs. 2.9%) as compared to those < 65 years (2.1% vs. 1.4%) ### Gender There is no FDA guidance on the use of Bevacizumab with respect to specific gender populations. ### Race There is no FDA guidance on the use of Bevacizumab with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Bevacizumab in patients with renal impairment. ### Hepatic Impairment There is no FDA guidance on the use of Bevacizumab in patients with hepatic impairment. ### Females of Reproductive Potential and Males Bevacizumab increases the risk of ovarian failure and may impair fertility. Inform females of reproductive potential of the risk of ovarian failure prior to starting treatment with Bevacizumab. Long term effects of Bevacizumab exposure on fertility are unknown. In a prospectively designed substudy of 179 premenopausal women randomized to receive chemotherapy with or without Bevacizumab, the incidence of ovarian failure was higher in the Bevacizumab arm (34%) compared to the control arm (2%). After discontinuation of Bevacizumab and chemotherapy, recovery of ovarian function occurred in 22% (7/32) of these Bevacizumab-treated patients. ### Immunocompromised Patients There is no FDA guidance one the use of Bevacizumab in patients who are immunocompromised. # Administration and Monitoring ### Administration - Administration - Do not administer as an intravenous push or bolus. Administer only as an intravenous (IV) infusion. - Do not initiate Bevacizumab until at least 28 days following major surgery. Administer Bevacizumab after the surgical incision has fully healed. - First infusion: Administer infusion over 90 minutes. - Subsequent infusions: Administer second infusion over 60 minutes if first infusion is tolerated; administer all subsequent infusions over 30 minutes if infusion over 60 minutes is tolerated. - Preparation for Administration - Use appropriate aseptic technique. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Withdraw necessary amount of Bevacizumab and dilute in a total volume of 100 mL of 0.9% Sodium Chloride Injection, USP. Discard any unused portion left in a vial, as the product contains no preservatives. - DO NOT ADMINISTER OR MIX WITH DEXTROSE SOLUTION. ### Monitoring FDA Package Insert for Bevacizumab contains no information regarding drug monitoring. # IV Compatibility There is limited information about the IV Compatibility. # Overdosage The highest dose tested in humans (20 mg/kg IV) was associated with headache in nine of 16 patients and with severe headache in three of 16 patients. # Pharmacology ## Mechanism of Action Bevacizumab binds VEGF and prevents the interaction of VEGF to its receptors (Flt-1 and KDR) on the surface of endothelial cells. The interaction of VEGF with its receptors leads to endothelial cell proliferation and new blood vessel formation in in vitro models of angiogenesis. Administration of bevacizumab to xenotransplant models of colon cancer in nude (athymic) mice caused reduction of microvascular growth and inhibition of metastatic disease progression. ## Structure Bevacizumab (bevacizumab) is a recombinant humanized monoclonal IgG1 antibody that binds to and inhibits the biologic activity of human vascular endothelial growth factor (VEGF) in in vitro and in vivo assay systems. Bevacizumab contains human framework regions and the complementarity-determining regions of a murine antibody that binds to VEGF. Bevacizumab has an approximate molecular weight of 149 kD. Bevacizumab is produced in a mammalian cell (Chinese Hamster Ovary) expression system in a nutrient medium containing the antibiotic gentamicin. Gentamicin is not detectable in the final product. Bevacizumab is a clear to slightly opalescent, colorless to pale brown, sterile, pH 6.2 solution for intravenous infusion. Bevacizumab is supplied in 100 mg and 400 mg preservative-free, single-use vials to deliver 4 mL or 16 mL of Bevacizumab (25 mg/mL). The 100 mg product is formulated in 240 mg α,α-trehalose dihydrate, 23.2 mg sodium phosphate (monobasic, monohydrate), 4.8 mg sodium phosphate (dibasic, anhydrous), 1.6 mg polysorbate 20, and Water for Injection, USP. The 400 mg product is formulated in 960 mg α,α-trehalose dihydrate, 92.8 mg sodium phosphate (monobasic, monohydrate), 19.2 mg sodium phosphate (dibasic, anhydrous), 6.4 mg polysorbate 20, and Water for Injection, USP. ## Pharmacodynamics FDA Package Insert for Bevacizumab contains no information regarding pharmacodynamics. ## Pharmacokinetics The pharmacokinetic profile of bevacizumab was assessed using an assay that measures total serum bevacizumab concentrations (i.e., the assay did not distinguish between free bevacizumab and bevacizumab bound to VEGF ligand). Based on a population pharmacokinetic analysis of 491 patients who received 1 to 20 mg/kg of Bevacizumab weekly, every 2 weeks, or every 3 weeks, the estimated half-life of bevacizumab was approximately 20 days (range 11–50 days). The predicted time to reach steady state was 100 days. The accumulation ratio following a dose of 10 mg/kg of bevacizumab every 2 weeks was 2.8. The clearance of bevacizumab varied by body weight, gender, and tumor burden. After correcting for body weight, males had a higher bevacizumab clearance (0.262 L/day vs. 0.207 L/day) and a larger Vc (3.25 L vs. 2.66 L) than females. Patients with higher tumor burden (at or above median value of tumor surface area) had a higher bevacizumab clearance (0.249 L/day vs. 0.199 L/day) than patients with tumor burdens below the median. In Study 1, there was no evidence of lesser efficacy (hazard ratio for overall survival) in males or patients with higher tumor burden treated with Bevacizumab as compared to females and patients with low tumor burden. The relationship between bevacizumab exposure and clinical outcomes has not been explored. ## Nonclinical Toxicology ## Carcinogenesis, Mutagenesis, Impairment of Fertility No carcinogenicity or mutagenicity studies of bevacizumab have been conducted. Bevacizumab may impair fertility. Female cynomolgus monkeys treated with 0.4 to 20 times the recommended human dose of bevacizumab exhibited arrested follicular development or absent corpora lutea as well as dose-related decreases in ovarian and uterine weights, endometrial proliferation, and the number of menstrual cycles. Following a 4- or 12-week recovery period, there was a trend suggestive of reversibility. After the 12-week recovery period, follicular maturation arrest was no longer observed, but ovarian weights were still moderately decreased. Reduced endometrial proliferation was no longer observed at the 12-week recovery time point; however, decreased uterine weight, absent corpora lutea, and reduced number of menstrual cycles remained evident. ## Animal Toxicology and/or Pharmacology In cynomolgus monkeys, when bevacizumab was administered at doses of 0.4 to 20 times the weekly human exposure, anatomical pathology revealed several adverse effects on general growth and skeletal development, fertility and wound healing capacity. Severe physeal dysplasia was consistently reported in juvenile monkeys with open growth plates receiving 0.4 to 20 times the human dose. The physeal dysplasia was characterized by a linear cessation of growth line and chondrocyte hyperplasia which did not completely resolve after the 4 to 12 weeks recovery period without drug exposure. Rabbits dosed with bevacizumab exhibited reduced wound healing capacity. Using full-thickness skin incision and partial thickness circular dermal wound models, bevacizumab dosing resulted in reductions in wound tensile strength, decreased granulation and re-epithelialization, and delayed time to wound closure. ## Reproductive and Developmental Toxicology Pregnant rabbits dosed with 1 to 12 times the human dose of bevacizumab every three days during the period of organogenesis (gestation day 6–18) exhibited teratogenic effects, decreases in maternal and fetal body weights, and increased number of fetal resorptions. Teratogenic effects included: reduced or irregular ossification in the skull, jaw, spine, ribs, tibia and bones of the paws; meningocele; fontanel, rib and hindlimb deformities; corneal opacity; and absent hindlimb phalanges. There are no data available regarding the level of bevacizumab exposure in the offspring. # Clinical Studies ## Metastatic Colorectal Cancer (mCRC) Study 1 In this double-blind, active-controlled study, patients were randomized (1:1:1) to IV bolus-IFL (irinotecan 125 mg/m2, 5-FU 500 mg/m2, and leucovorin (LV) 20 mg/m2 given once weekly for 4 weeks every 6 weeks) plus placebo (Arm 1), bolus-IFL plus Bevacizumab (5 mg/kg every 2 weeks) (Arm 2), or 5-FU/LV plus Bevacizumab (5 mg/kg every 2 weeks) (Arm 3). Enrollment in Arm 3 was discontinued, as pre-specified, when the toxicity of Bevacizumab in combination with the bolus-IFL regimen was deemed acceptable. The main outcome measure was overall survival (OS). Of the 813 patients randomized to Arms 1 and 2, the median age was 60, 40% were female, 79% were Caucasian, 57% had an ECOG performance status of 0, 21% had a rectal primary and 28% received prior adjuvant chemotherapy. In 56% of the patients, the dominant site of disease was extra-abdominal, while the liver was the dominant site in 38% of patients. The addition of Bevacizumab resulted in an improvement in survival across subgroups defined by age ( < 65 yrs, ≥ 65 yrs) and gender. Results are presented in Table 4 and Figure 1. Among the 110 patients enrolled in Arm 3, median OS was 18.3 months, median progression-free survival (PFS) was 8.8 months, objective response rate (ORR) was 39%, and median duration of response was 8.5 months. Study 2 Study 2 was a randomized, open-label, active-controlled trial in patients who were previously treated with irinotecan ± 5-FU for initial therapy for metastatic disease or as adjuvant therapy. Patients were randomized (1:1:1) to IV FOLFOX4 (Day 1: oxaliplatin 85 mg/m2 and LV 200 mg/m2 concurrently, then 5-FU 400 mg/m2 bolus followed by 600 mg/m2 continuously; Day 2: LV 200 mg/m2, then 5-FU 400 mg/m2 bolus followed by 600 mg/m2 continuously; repeated every 2 weeks), FOLFOX4 plus Bevacizumab (10 mg/kg every 2 weeks prior to FOLFOX4 on Day 1), or Bevacizumab monotherapy(10 mg/kg every 2 weeks). The main outcome measure was OS. The Bevacizumab monotherapy arm was closed to accrual after enrollment of 244 of the planned 290 patients following a planned interim analysis by the data monitoring committee based on evidence of decreased survival compared to FOLFOX4 alone. Of the 829 patients randomized to the three arms, the median age was 61 years, 40% were female, 87% were Caucasian, 49% had an ECOG performance status of 0, 26% received prior radiation therapy, and 80% received prior adjuvant chemotherapy, 99% received prior irinotecan, with or without 5-FU as therapy for metastatic disease, and 1% received prior irinotecan and 5-FU as adjuvant therapy. The addition of Bevacizumab to FOLFOX4 resulted in significantly longer survival as compared to FOLFOX4 alone (median OS 13.0 months vs. 10.8 months; hazard ratio 0.75 [95% CI 0.63, 0.89], p = 0.001 stratified log rank test) with clinical benefit seen in subgroups defined by age (< 65 yrs, ≥ 65 yrs) and gender. PFS and ORR based on investigator assessment were higher in the Bevacizumab plus FOLFOX4 arm. Study 3 The activity of Bevacizumab in combination with bolus or infusional 5-FU/LV was evaluated in a single arm study enrolling 339 patients with mCRC with disease progression following both irinotecan- and oxaliplatin-containing chemotherapy regimens. Seventy-three percent of patients received concurrent bolus 5-FU/LV. One objective partial response was verified in the first 100 evaluable patients for an overall response rate of 1% (95% CI 0–5.5%). Study 4 Study 4 was a prospective, randomized, open-label, multinational, controlled trial in patients with histologically confirmed metastatic colorectal cancer who had progressed on a first-line Bevacizumab containing regimen. Patients were excluded if they progressed within 3 months of initiating first-line chemotherapy and if they received Bevacizumab for less than 3 consecutive months in the first-line setting. Patients were randomized (1:1) within 3 months after discontinuation of Bevacizumab as first-line therapy to receive fluoropyrimidine/oxaliplatin- or fluoropyrimidine/irinotecan-based chemotherapy with or without Bevacizumab administered at 5 mg/kg every 2 weeks or 7.5 mg/kg every 3 weeks. The choice of second line therapy was contingent upon first-line chemotherapy treatment. Second-line treatment was administered until progressive disease or unacceptable toxicity. The main outcome measure was OS defined as the time from randomization until death from any cause. Of the 820 patients randomized, the majority of patients were male (64%) and the median age was 63.0 years (range 21 to 84 years). At baseline, 52% of patients were ECOG performance status (PS) 1, 44% were ECOG PS 0, 58% received irinotecan-based therapy as first-line treatment, 55% progressed on first-line treatment within 9 months, and 77% received their last dose of Bevacizumab as first-line treatment within 42 days of being randomized. Second-line chemotherapy regimens were generally balanced between each treatment arm. The addition of Bevacizumab to fluoropyrimidine-based chemotherapy resulted in a statistically significant prolongation of survival and PFS; there was no significant difference in overall response rate, a key secondary outcome measure. Results are presented in Table 5 and Figure 2. ## Lack of Efficacy in Adjuvant Treatment of Colon Cancer Lack of efficacy of Bevacizumab as an adjunct to standard chemotherapy for the adjuvant treatment of colon cancer was determined in two randomized, open-label, multicenter clinical trials. The first study conducted in 3451 patients with high risk stage II and III colon cancer, who had undergone surgery for colon cancer with curative intent, was a 3-arm study of Bevacizumab administered at a dose equivalent to 2.5 mg/kg/week on either a 2-weekly schedule in combination with FOLFOX4, or on a 3-weekly schedule in combination with XELOX and FOLFOX4 alone. Patients were randomized as follows: 1151 patients to FOLFOX4 arm, 1155 to FOLFOX4 plus Bevacizumab arm, and 1145 to XELOX plus Bevacizumab arm. The median age was 58 years, 54% were male, 84% were Caucasian and 29% were ≥ age 65. Eighty-three percent had stage III disease. The main efficacy outcome of the study was disease free survival (DFS) in patients with stage III colon cancer. Addition of Bevacizumab to chemotherapy did not improve DFS. As compared to the control arm, the proportion of stage III patients with disease recurrence or with death due to disease progression were numerically higher in the FOLFOX4 plus Bevacizumab and in the XELOX plus Bevacizumab arms. The hazard ratios for DFS were 1.17 (95% CI: 0.98–1.39) for the FOLFOX4 plus Bevacizumab versus FOLFOX4 and 1.07 (95% CI: 0.90–1.28) for the XELOX plus Bevacizumab versus FOLFOX4. The hazard ratios for overall survival were 1.31 (95% CI=1.03, 1.67) and 1.27 (95% CI=1.00, 1.62) for the comparison of Bevacizumab plus FOLFOX4 versus FOLFOX4 and Bevacizumab plus XELOX versus FOLFOX4, respectively. Similar lack of efficacy for DFS were observed in the Bevacizumab-containing arms compared to control in the high-risk stage II cohort. In a second study, 2710 patients with stage II and III colon cancer who had undergone surgery with curative intent, were randomized to receive either Bevacizumab administered at a dose equivalent to 2.5 mg/kg/week in combination with mFOLFOX6 (N=1354) or mFOLFOX6 alone (N=1356). The median age was 57 years, 50% were male and 87% Caucasian. Seventy-five percent had stage III disease. The main efficacy outcome was DFS among stage III patients. The hazard ratio for DFS was 0.92 (95% CI: 0.77, 1.10). Overall survival, an additional efficacy outcome, was not significantly improved with the addition of Bevacizumab to mFOLFOX6 (HR=0.96, 95% CI=[0.75,1.22]. ## Unresectable Non–Squamous Non–Small Cell Lung Cancer (NSCLC) Study 5 The safety and efficacy of Bevacizumab as first-line treatment of patients with locally advanced, metastatic, or recurrent non–squamous NSCLC was studied in a single, large, randomized, active-controlled, open-label, multicenter study. Chemotherapy-naïve patients with locally advanced, metastatic or recurrent non–squamous NSCLC were randomized (1:1) to receive six 21-day cycles of paclitaxel 200 mg/m2 and carboplatin AUC = 6.0, by IV on day 1 (PC) or PC in combination with Bevacizumab 15 mg/kg by IV on day 1 (PC plus Bevacizumab). After completion or upon discontinuation of chemotherapy, patients in the PC plus Bevacizumab arm continued to receive Bevacizumab alone until disease progression or until unacceptable toxicity. Patients with predominant squamous histology (mixed cell type tumors only), central nervous system (CNS) metastasis, gross hemoptysis ( ≥ 1/2 tsp of red blood), unstable angina, or receiving therapeutic anticoagulation were excluded. The main outcome measure was duration of survival. Of the 878 patients randomized, the median age was 63, 46% were female, 43% were ≥ age 65, and 28% had ≥ 5% weight loss at study entry. Eleven percent had recurrent disease and of the 89% with newly diagnosed NSCLC, 12% had Stage IIIB with malignant pleural effusion and 76% had Stage IV disease. The results are presented in Figure 3. OS was statistically significantly higher among patients receiving PC plus Bevacizumab compared with those receiving PC alone; median OS was 12.3 months vs. 10.3 months [hazard ratio 0.80 (repeated 95% CI 0.68, 0.94), final p- value 0.013, stratified log-rank test]. Based on investigator assessment which was not independently verified, patients were reported to have longer PFS with Bevacizumab in combination with PC compared to PC alone. In an exploratory analyses across patient subgroups, the impact of Bevacizumab on OS was less robust in the following: women [HR = 0.99 (95% CI: 0.79, 1.25)], age ≥ 65 years [HR = 0.91 (95% CI: 0.72, 1.14)] and patients with ≥ 5% weight loss at study entry [HR = 0.96 (95% CI: 0.73, 1.26)]. The safety and efficacy of Bevacizumab in patients with locally advanced, metastatic or recurrent non-squamous NSCLC, who had not received prior chemotherapy was studied in another randomized, double-blind, placebo controlled, three-arm study of Bevacizumab in combination with cisplatin and gemcitabine (CG) versus placebo and CG. A total of 1043 patients were randomized 1:1:1 to receive placebo plus CG, Bevacizumab 7.5 mg/kg plus CG or Bevacizumab 15.0 mg/kg plus CG. The median age was 58 years, 36% were female, and 29% were ≥ age 65. Eight percent had recurrent disease and 77% had Stage IV disease. Progression-free survival, the main efficacy outcome measure, was significantly higher in both Bevacizumab containing arms compared to the placebo arm [HR 0.75 (95% CI 0.62, 0.91), p = 0.0026 for the Bevacizumab 7.5 mg/kg plus CG arm and HR 0.82 (95% CI 0.68; 0.98), p = 0.0301 for the Bevacizumab 15.0 mg/kg plus CG arm]. The addition of Bevacizumab to CG chemotherapy failed to demonstrate an improvement in the duration of overall survival, an additional efficacy outcome measure, [HR 0.93 (95% CI 0.78; 1.11), p = 0.4203 for the Bevacizumab 7.5 mg/kg plus CG arm and HR 1.03 (95% CI 0.86; 1.23), p = 0.7613 for the Bevacizumab 15.0 mg/kg plus CG arm]. ## Glioblastoma Study 6 The efficacy and safety of Bevacizumab was evaluated in Study 6, an open-label, multicenter, randomized, non-comparative study of patients with previously treated glioblastoma. Patients received Bevacizumab (10 mg/kg IV) alone or Bevacizumab plus irinotecan every 2 weeks until disease progression or until unacceptable toxicity. All patients received prior radiotherapy (completed at least 8 weeks prior to receiving Bevacizumab) and temozolomide. Patients with active brain hemorrhage were excluded. Of the 85 patients randomized to the Bevacizumab arm, the median age was 54 years, 32% were female, 81% were in first relapse, Karnofsky performance status was 90–100 for 45% and 70–80 for 55%. The efficacy of Bevacizumab was demonstrated using response assessment based on both WHO radiographic criteria and by stable or decreasing corticosteroid use, which occurred in 25.9% (95% CI 17.0%, 36.1%) of the patients. Median duration of response was 4.2 months (95% CI 3.0, 5.7). Radiologic assessment was based on MRI imaging (using T1 and T2/FLAIR). MRI does not necessarily distinguish between tumor, edema, and radiation necrosis. Study 7 Study 7, was a single-arm, single institution trial with 56 patients with glioblastoma. All patients had documented disease progression after receiving temozolomide and radiation therapy. Patients received Bevacizumab 10 mg/kg IV every 2 weeks until disease progression or unacceptable toxicity. The median age was 54, 54% were male, 98% Caucasian, and 68% had a Karnofsky Performance Status of 90–100. The efficacy of Bevacizumab was supported by an objective response rate of 19.6% (95% CI 10.9%, 31.3%) using the same response criteria as in Study 6. Median duration of response was 3.9 months (95% CI 2.4, 17.4). ## Metastatic Renal Cell Carcinoma (mRCC) Study 8 Patients with treatment-naïve mRCC were evaluated in a multicenter, randomized, double-blind, international study comparing Bevacizumab plus interferon alfa 2a (IFN-α2a) versus placebo plus IFN-α2a. A total of 649 patients who had undergone a nephrectomy were randomized (1:1) to receive either Bevacizumab (10 mg/kg IV infusion every 2 weeks; n = 327) or placebo (IV every 2 weeks; n = 322) in combination with IFN-α2a (9 MIU subcutaneously three times weekly, for a maximum of 52 weeks). Patients were treated until disease progression or unacceptable toxicity. The main outcome measure of the study was investigator-assessed PFS. Secondary outcome measures were ORR and OS. The median age was 60 years (range 18–82), 96% were white, and 70% were male. The study population was characterized by Motzer scores as follows: 28% favorable (0), 56% intermediate (1-2), 8% poor (3–5), and 7% missing. The results are presented in Figure 4. PFS was statistically significantly prolonged among patients receiving Bevacizumab plus IFN-α2a compared to those receiving IFN-α2a alone; median PFS was 10.2 months vs. 5.4 months [HR 0.60 (95% CI 0.49, 0.72), p-value < 0.0001, stratified log-rank test]. Among the 595 patients with measurable disease, ORR was also significantly higher (30% vs. 12%, p < 0.0001, stratified CMH test). There was no improvement in OS based on the final analysis conducted after 444 deaths, with a median OS of 23 months in the Bevacizumab plus IFN-α2a arm and 21 months in the IFN-α2a plus placebo arm [HR 0.86, (95% CI 0.72, 1.04)]. # How Supplied Bevacizumab vials [100 mg (NDC 50242-060-01) and 400 mg (NDC 50242-061-01)] are stable at 2–8°C (36–46°F). Bevacizumab vials should be protected from light. Do not freeze or shake. ## Storage Diluted Bevacizumab solutions may be stored at 2–8°C (36–46°F) for up to 8 hours. Store in the original carton until time of use. No incompatibilities between Bevacizumab and polyvinylchloride or polyolefin bags have been observed. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information Advise patients: - To undergo routine blood pressure monitoring and to contact their health care provider if blood pressure is elevated. - To immediately contact their health care provider for unusual bleeding, high fever, rigors, sudden onset of worsening neurological function, or persistent or severe abdominal pain, severe constipation, or vomiting. - Of increased risk of wound healing complications during and following Bevacizumab. - Of increased risk of an arterial thromboembolic event. - Of the potential risk to the fetus during and following Bevacizumab and the need to continue adequate contraception for at least 6 months following last dose of Bevacizumab. - Of the increased risk for ovarian failure following Bevacizumab treatment. # Precautions with Alcohol Alcohol-Bevacizumab interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names Avastin # Look-Alike Drug Names Avastin - Astelin[20] # Drug Shortage Status # Price	https://www.wikidoc.org/index.php/Avastin
f53e648ed8a5e5e9e6fa734d31a058fe5829520d	wikidoc	Dutasteride	Dutasteride # Disclaimer WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here. # Overview Dutasteride is a 5-alpha reductase inhibitor that is FDA approved for the treatment of benign prostatic hyperplasia (BPH). Common adverse reactions include disorder of breast, prostate specific antigen abnormal, ejaculation disorder, impotence, reduced libido. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) ### Symptomatic Benign Prostatic Hyperplasia - Monotherapy Dosing Information - Recommended dose: 0.5 mg PO qd. - Combination with Alpha Adrenergic Antagonist - Recommended dose: 0.5 PO qd and tamsulosin 0.4 mg PO qd - Dutasteride® (dutasteride) Soft Gelatin Capsules are indicated for the treatment of symptomatic benign prostatic hyperplasia (BPH) in men with an enlarged prostate to: - Improve symptoms, - Reduce the risk of acute urinary retention (AUR), and - Reduce the risk of the need for BPH-related surgery. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of dutasteride in adult patients. ### Non–Guideline-Supported Use ### Male Pattern Alopecia - Dosing information :- Not applicable # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) AVODART is contraindicated for use in pediatric patients. Safety and effectiveness in pediatric patients have not been established. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of dutasteride in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of dutasteride in pediatric patients. # Contraindications - Dutasteride is Contraindicated for use in: - Pregnancy. In animal reproduction and developmental toxicity studies, dutasteride inhibited development of male fetus external genitalia. Therefore, dutasteride may cause fetal harm when administered to a pregnant woman. If dutasteride is used during pregnancy or if the patient becomes pregnant while taking dutasteride, the patient should be apprised of the potential hazard to the fetus. - Women of childbearing potential. - Pediatric patients. - Patients with previously demonstrated, clinically significant hypersensitivity (e.g., serious skin reactions, angioedema) to dutasteride or other 5 alpha-reductase inhibitors. # Warnings ### Effects on Prostate Specific Antigen (PSA) and the use of PSA in Prostate Cancer Detection - In clinical trials, dutasteride reduced serum PSA concentration by approximately 50% within 3 to 6 months of treatment. This decrease was predictable over the entire range of PSA values in subjects with symptomatic BPH, although it may vary in individuals. Dutasteride may also cause decreases in serum PSA in the presence of prostate cancer. To interpret serial PSAs in men taking dutasteride, a new PSA baseline should be established at least 3 months after starting treatment and PSA monitored periodically thereafter. Any confirmed increase from the lowest PSA value while on dutasteride may signal the presence of prostate cancer and should be evaluated, even if PSA levels are still within the normal range for men not taking a 5 alpha-reductase inhibitor. Noncompliance with dutasteride may also affect PSA test results. - To interpret an isolated PSA value in a man treated with dutasteride for 3 months or more, the PSA value should be doubled for comparison with normal values in untreated men.The free-to-total PSA ratio (percent free PSA) remains constant, even under the influence of dutasteride. If clinicians elect to use percent free PSA as an aid in the detection of prostate cancer in men receiving dutasteride, no adjustment to its value appears necessary. - Co administration of dutasteride and tamsulosin resulted in similar changes to serum PSA as dutasteride monotherapy. ### Increased Risk of High-Grade Prostate Cancer - In men aged 50 to 75 years with a prior negative biopsy for prostate cancer and a baseline PSA between 2.5 ng/mL and 10.0 ng/mL taking dutasteride in the 4-year reduction by dutasteride of prostate cancer events (REDUCE) trial, there was an increased incidence of Gleason score 8-10 prostate cancer compared with men taking placebo (dutasteride 1.0% versus placebo 0.5%). In a 7-year placebo-controlled clinical trial with another 5 alpha-reductase inhibitor (finasteride 5 mg, PROSCAR), similar results for Gleason score 8-10 prostate cancer were observed (finasteride 1.8% versus placebo 1.1%). - 5 Alpha-reductase inhibitors may increase the risk of development of high-grade prostate cancer. Whether the effect of 5 alpha-reductase inhibitors to reduce prostate volume, or trial-related factors, impacted the results of these trials has not been established. ### Evaluation for Other Urological Diseases - Prior to initiating treatment with dutasteride, consideration should be given to other urological conditions that may cause similar symptoms. In addition, BPH and prostate cancer may coexist. ### Exposure of Women—Risk to Male Fetus - Dutasteride capsules should not be handled by a woman who is pregnant or who could become pregnant. Dutasteride is absorbed through the skin and could result in unintended fetal exposure. If a woman who is pregnant or who could become pregnant comes in contact with leaking dutasteride capsules, the contact area should be washed immediately with soap and water. ### Blood Donation - Men being treated with dutasteride should not donate blood until at least 6 months have passed following their last dose. The purpose of this deferred period is to prevent administration of dutasteride to a pregnant female transfusion recipient. ### Effect on Semen Characteristics - The effects of dutasteride 0.5 mg/day on semen characteristics were evaluated in normal volunteers aged 18 to 52 (n = 27 dutasteride, n = 23 placebo) throughout 52 weeks of treatment and 24 weeks of post-treatment follow-up. At 52 weeks, the mean percent reductions from baseline in total sperm count, semen volume, and sperm motility were 23%, 26%, and 18%, respectively, in the dutasteride group when adjusted for changes from baseline in the placebo group. Sperm concentration and sperm morphology were unaffected. After 24 weeks of follow-up, the mean percent change in total sperm count in the dutasteride group remained 23% lower than baseline. While mean values for all semen parameters at all time-points remained within the normal ranges and did not meet predefined criteria for a clinically significant change (30%), 2 subjects in the dutasteride group had decreases in sperm count of greater than 90% from baseline at 52 weeks, with partial recovery at the 24-week follow-up. The clinical significance of dutasteride’s effect on semen characteristics for an individual patient’s fertility is not known. # Adverse Reactions ## Clinical Trials Experience - Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trial of another drug and may not reflect the rates observed in practice. - From clinical trials with dutasteride as monotherapy or in combination with tamsulosin: - The most common adverse reactions reported in subjects receiving dutasteride were impotence, decreased libido, breast disorders (including breast enlargement and tenderness), and ejaculation disorders. The most common adverse reactions reported in subjects receiving combination therapy (dutasteride plus tamsulosin) were impotence, decreased libido, breast disorders (including breast enlargement and tenderness), ejaculation disorders, and dizziness. Ejaculation disorders occurred significantly more in subjects receiving combination therapy (11%) compared with those receiving dutasteride (2%) or tamsulosin (4%) as monotherapy. Trial withdrawal due to adverse reactions occurred in 4% of subjects receiving dutasteride, and 3% of subjects receiving placebo in placebo-controlled trials with dutasteride. The most common adverse reaction leading to trial withdrawal was impotence (1%). In the clinical trial evaluating the combination therapy, trial withdrawal due to adverse reactions occurred in 6% of subjects receiving combination therapy (dutasteride plus tamsulosin) and 4% of subjects receiving dutasteride or tamsulosin as monotherapy. The most common adverse reaction in all treatment arms leading to trial withdrawal was erectile dysfunction (1% to 1.5%). - Trial withdrawal due to adverse reactions occurred in 4% of subjects receiving dutasteride, and 3% of subjects receiving placebo in placebo-controlled trials with dutasteride. The most common adverse reaction leading to trial withdrawal was impotence (1%). - In the clinical trial evaluating the combination therapy, trial withdrawal due to adverse reactions occurred in 6% of subjects receiving combination therapy (dutasteride plus tamsulosin) and 4% of subjects receiving dutasteride or tamsulosin as monotherapy. The most common adverse reaction in all treatment arms leading to trial withdrawal was erectile dysfunction (1% to 1.5%). - Monotherapy: Over 4,300 male subjects with BPH were randomly assigned to receive placebo or 0.5-mg daily doses of dutasteride in 3 identical 2-year, placebo-controlled, double-blind, Phase 3 treatment trials, each followed by a 2-year open-label extension. During the double-blind treatment period, 2,167 male subjects were exposed to dutasteride, including 1,772 exposed for 1 year and 1,510 exposed for 2 years. When including the open-label extensions, 1,009 male subjects were exposed to dutasteride for 3 years and 812 were exposed for 4 years. The population was aged 47 to 94 years (mean age: 66 years) and greater than 90% were Caucasian. Table 1 summarizes clinical adverse reactions reported in at least 1% of subjects receiving dutasteride and at a higher incidence than subjects receiving placebo. - Long-Term Treatment (Up to 4 Years): High-Grade prostate cancer: The REDUCE trial was a randomized, double-blind, placebo-controlled trial that enrolled 8,231 men aged 50 to 75 years with a serum PSA of 2.5 ng/mL to 10 ng/mL and a negative prostate biopsy within the previous 6 months. Subjects were randomized to receive placebo (N = 4,126) or 0.5-mg daily doses of dutasteride (N = 4,105) for up to 4 years. The mean age was 63 years and 91% were Caucasian. Subjects underwent protocol-mandated scheduled prostate biopsies at 2 and 4 years of treatment or had “for-cause biopsies” at non-scheduled times if clinically indicated. There was a higher incidence of Gleason score 8-10 prostate cancer in men receiving dutasteride (1.0%) compared with men on placebo (0.5%). In a 7-year placebo-controlled clinical trial with another 5 alpha-reductase inhibitor (finasteride 5 mg, PROSCAR), similar results for Gleason score 8-10 prostate cancer were observed (finasteride 1.8% versus placebo 1.1%). - No clinical benefit has been demonstrated in patients with prostate cancer treated with dutasteride. - Reproductive and Breast Disorders: In the 3 pivotal placebo-controlled BPH trials with dutasteride, each 4 years in duration, there was no evidence of increased sexual adverse reactions (impotence, decreased libido, and ejaculation disorder) or breast disorders with increased duration of treatment. Among these 3 trials, there was 1 case of breast cancer in the dutasteride group and 1 case in the placebo group. No cases of breast cancer were reported in any treatment group in the 4-year CombAT trial or the 4-year REDUCE trial. - The relationship between long-term use of dutasteride and male breast neoplasia is currently unknown. - Combination With Alpha-Blocker Therapy (CombAT): Over 4,800 male subjects with BPH were randomly assigned to receive 0.5-mg dutasteride, 0.4-mg tamsulosin, or combination therapy (0.5-mg dutasteride plus 0.4-mg tamsulosin) administered once daily in a 4-year double-blind trial. Overall, 1,623 subjects received monotherapy with dutasteride; 1,611 subjects received monotherapy with tamsulosin; and 1,610 subjects received combination therapy. The population was aged 49 to 88 years (mean age: 66 years) and 88% were Caucasian. Table 2 summarizes adverse reactions reported in at least 1% of subjects in the combination group and at a higher incidence than subjects receiving monotherapy with dutasteride or tamsulosin. - Cardiac Failure: In CombAT, after 4 years of treatment, the incidence of the composite term cardiac failure in the combination therapy group (12/1,610; 0.7%) was higher than in either monotherapy group: dutasteride, 2/1,623 (0.1%) and tamsulosin, 9/1,611 (0.6%). Composite cardiac failure was also examined in a separate 4-year placebo-controlled trial evaluating dutasteride in men at risk for development of prostate cancer. The incidence of cardiac failure in subjects taking dutasteride was 0.6% (26/4,105) compared with 0.4% (15/4,126) in subjects on placebo. A majority of subjects with cardiac failure in both trials had comorbidities associated with an increased risk of cardiac failure. Therefore, the clinical significance of the numerical imbalances in cardiac failure is unknown. No causal relationship between dutasteride, alone or in combination with tamsulosin, and cardiac failure has been established. No imbalance was observed in the incidence of overall cardiovascular adverse events in either trial. ## Postmarketing Experience - The following adverse reactions have been identified during post-approval use of dutasteride. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. These reactions have been chosen for inclusion due to a combination of their seriousness, frequency of reporting, or potential causal connection to dutasteride. Immune System Disorders: Hypersensitivity reactions, including rash, pruritus, urticaria, localized edema, serious skin reactions, and angioedema. Neoplasms: Male breast cancer. Psychiatric Disorders: Depressed mood. Reproductive System and Breast Disorders: Testicular pain and testicular swelling. # Drug Interactions ### Cytochrome P450 3A Inhibitors - Dutasteride is extensively metabolized in humans by the CYP3A4 and CYP3A5 isoenzymes. The effect of potent CYP3A4 inhibitors on dutasteride has not been studied. Because of the potential for drug-drug interactions, use caution when prescribing dutasteride to patients taking potent, chronic CYP3A4 enzyme inhibitors (e.g., ritonavir). ### Alpha Adrenergic Antagonists - The administration of dutasteride in combination with tamsulosin or terazosin has no effect on the steady-state pharmacokinetics of either alpha adrenergic antagonist. The effect of administration of tamsulosin or terazosin on dutasteride pharmacokinetic parameters has not been evaluated. ### Calcium Channel Antagonists - Co administration of verapamil or diltiazem decreases dutasteride clearance and leads to increased exposure to dutasteride. The change in dutasteride exposure is not considered to be clinically significant. No dose adjustment is recommended . ### Cholestyramine - Administration of a single 5-mg dose of dutasteride followed 1 hour later by 12 g of cholestyramine does not affect the relative bioavailability of dutasteride . ### Digoxin - Dutasteride does not alter the steady-state pharmacokinetics of digoxin when administered concomitantly at a dose of 0.5 mg/day for 3 weeks . ### Warfarin - Concomitant administration of dutasteride 0.5 mg/day for 3 weeks with warfarin does not alter the steady-state pharmacokinetics of the S- or R-warfarin isomers or alter the effect of warfarin on prothrombin time. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): X Pregnancy Category X. - Dutasteride is contraindicated for use in women of childbearing potential and during pregnancy. Dutasteride is a 5 alpha-reductase inhibitor that prevents conversion of testosterone to dihydrotestosterone (DHT), a hormone necessary for normal development of male genitalia. In animal reproduction and developmental toxicity studies, dutasteride inhibited normal development of external genitalia in male fetuses. Therefore, dutasteride may cause fetal harm when administered to a pregnant woman. If dutasteride is used during pregnancy or if the patient becomes pregnant while taking dutasteride, the patient should be apprised of the potential hazard to the fetus. - Abnormalities in the genitalia of male fetuses is an expected physiological consequence of inhibition of the conversion of testosterone to DHT by 5 alpha-reductase inhibitors. These results are similar to observations in male infants with genetic 5 alpha-reductase deficiency. Dutasteride is absorbed through the skin. To avoid potential fetal exposure, women who are pregnant or could become pregnant should not handle dutasteride Soft Gelatin Capsules. If contact is made with leaking capsules, the contact area should be washed immediately with soap and water. Dutasteride is secreted into semen. The highest measured semen concentration of dutasteride in treated men was 14 ng/mL. Assuming exposure of a 50-kg woman to 5 mL of semen and 100% absorption, the woman’s dutasteride concentration would be about 0.0175 ng/mL. This concentration is more than 100 times less than concentrations producing abnormalities of male genitalia in animal studies. Dutasteride is highly protein bound in human semen (greater than 96%), which may reduce the amount of dutasteride available for vaginal absorption. - In an embryo-fetal development study in female rats, oral administration of dutasteride at doses 10 times less than the maximum recommended human dose (MRHD) of 0.5 mg daily resulted in abnormalities of male genitalia in the fetus (decreased anogenital distance at 0.05 mg/kg/day), nipple development, hypospadias, and distended preputial glands in male offspring (at all doses of 0.05, 2.5, 12.5, and 30 mg/kg/day). An increase in stillborn pups was observed at 111 times the MRHD, and reduced fetal body weight was observed at doses of about 15 times the MRHD (animal dose of 2.5 mg/kg/day). Increased incidences of skeletal variations considered to be delays in ossification associated with reduced body weight were observed at doses about 56 times the MRHD (animal dose of 12.5 mg/kg/day). - In a rabbit embryo-fetal study, doses 28- to 93-fold the MRHD (animal doses of 30, 100, and 200 mg/kg/day) were administered orally during the period of major organogenesis (gestation days 7 to 29) to encompass the late period of external genitalia development. Histological evaluation of the genital papilla of fetuses revealed evidence of feminization of the male fetus at all doses. A second embryo-fetal study in rabbits at 0.3- to 53-fold the expected clinical exposure (animal doses of 0.05, 0.4, 3.0, and 30 mg/kg/day) also produced evidence of feminization of the genitalia in male fetuses at all doses. - In an oral pre- and post-natal development study in rats, dutasteride doses of 0.05, 2.5, 12.5, or 30 mg/kg/day were administered. Unequivocal evidence of feminization of the genitalia (i.e., decreased anogenital distance, increased incidence of hypospadias, nipple development) of male offspring occurred at 14- to 90-fold the MRHD (animal doses of 2.5 mg/kg/day or greater). At 0.05-fold the expected clinical exposure (animal dose of 0.05 mg/kg/day), evidence of feminization was limited to a small, but statistically significant, decrease in anogenital distance. Animal doses of 2.5 to 30 mg/kg/day resulted in prolonged gestation in the parental females and a decrease in time to vaginal patency for female offspring and a decrease in prostate and seminal vesicle weights in male offspring. Effects on newborn startle response were noted at doses greater than or equal to 12.5 mg/kg/day. Increased stillbirths were noted at 30 mg/kg/day. - In an embryo-fetal development study, pregnant rhesus monkeys were exposed intravenously to a dutasteride blood level comparable to the dutasteride concentration found in human semen. Dutasteride was administered on gestation days 20 to 100 at doses of 400, 780, 1,325, or 2,010 ng/day (12 monkeys/group). The development of male external genitalia of monkey offspring was not adversely affected. Reduction of fetal adrenal weights, reduction in fetal prostate weights, and increases in fetal ovarian and testis weights were observed at the highest dose tested in monkeys. Based on the highest measured semen concentration of dutasteride in treated men (14 ng/mL), these doses represent 0.8 to 16 times the potential maximum exposure of a 50-kg human female to 5 mL semen daily from a dutasteride-treated man, assuming 100% absorption. (These calculations are based on blood levels of parent drug which are achieved at 32 to 186 times the daily doses administered to pregnant monkeys on a ng/kg basis). Dutasteride is highly bound to proteins in human semen (greater than 96%), potentially reducing the amount of dutasteride available for vaginal absorption. It is not known whether rabbits or rhesus monkeys produce any of the major human metabolites. - Estimates of exposure multiples comparing animal studies to the MRHD for dutasteride are based on clinical serum concentration at steady state. Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Dutasteride in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Dutasteride during labor and delivery. ### Nursing Mothers - Dutasteride is contraindicated for use in women of childbearing potential, including nursing women. It is not known whether dutasteride is excreted in human milk. ### Pediatric Use - Dutasteride is contraindicated for use in pediatric patients. Safety and effectiveness in pediatric patients have not been established. ### Geriatic Use - Of 2,167 male subjects treated with dutasteride in 3 clinical trials, 60% were aged 65 years and older and 15% were aged 75 years and older. No overall differences in safety or efficacy were observed between these subjects and younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out . ### Gender There is no FDA guidance on the use of Dutasteride with respect to specific gender populations. ### Race There is no FDA guidance on the use of Dutasteride with respect to specific racial populations. ### Renal Impairment - No dose adjustment is necessary for dutasteride in patients with renal impairment . ### Hepatic Impairment - The effect of hepatic impairment on dutasteride pharmacokinetics has not been studied. Because dutasteride is extensively metabolized, exposure could be higher in hepatically impaired patients. However, in a clinical trial where 60 subjects received 5 mg (10 times the therapeutic dose) daily for 24 weeks, no additional adverse events were observed compared with those observed at the therapeutic dose of 0.5 mg . ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Dutasteride in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Dutasteride in patients who are immunocompromised. # Administration and Monitoring ### Administration Oral ### Monitoring FDA package insert for dutasteride contains no information regarding drug monitoring. # IV Compatibility There is limited information about the IV Compatibility. # Overdosage - In volunteer trials, single doses of dutasteride up to 40 mg (80 times the therapeutic dose) for 7 days have been administered without significant safety concerns. In a clinical trial, daily doses of 5 mg (10 times the therapeutic dose) were administered to 60 subjects for 6 months with no additional adverse effects to those seen at therapeutic doses of 0.5 mg. - There is no specific antidote for dutasteride. Therefore, in cases of suspected overdosage symptomatic and supportive treatment should be given as appropriate, taking the long half-life of dutasteride into consideration. # Pharmacology ## Mechanism of Action - Dutasteride inhibits the conversion of testosterone to dihydrotestosterone (DHT). DHT is the androgen primarily responsible for the initial development and subsequent enlargement of the prostate gland. Testosterone is converted to DHT by the enzyme 5 alpha-reductase, which exists as 2 isoforms, type 1 and type 2. The type 2 isoenzyme is primarily active in the reproductive tissues, while the type 1 isoenzyme is also responsible for testosterone conversion in the skin and liver. - Dutasteride is a competitive and specific inhibitor of both type 1 and type 2 5 alpha-reductase isoenzymes, with which it forms a stable enzyme complex. Dissociation from this complex has been evaluated under in vitro and in vivo conditions and is extremely slow. Dutasteride does not bind to the human androgen receptor. ## Structure - Dutasteride is a synthetic 4-azasteroid compound that is a selective inhibitor of both the type 1 and type 2 isoforms of steroid 5 alpha-reductase, an intracellular enzyme that converts testosterone to DHT. - Dutasteride is chemically designated as (5α,17β)-N-{2,5 bis(trifluoromethyl)phenyl}-3-oxo-4-azaandrost-1-ene-17-carboxamide. The empirical formula of dutasteride is C27H30F6N2O2, representing a molecular weight of 528.5 with the following structural formula: - Dutasteride is a white to pale yellow powder with a melting point of 242° to 250°C. It is soluble in ethanol (44 mg/mL), methanol (64 mg/mL), and polyethylene glycol 400 (3 mg/mL), but it is insoluble in water. - Each dutasteride soft gelatin capsule, administered orally, contains 0.5 mg of dutasteride dissolved in a mixture of mono-di-glycerides of caprylic/capric acid and butylated hydroxytoluene. The inactive excipients in the capsule shell are ferric oxide (yellow), gelatin (from certified BSE-free bovine sources), glycerin, and titanium dioxide. The soft gelatin capsules are printed with edible red ink. ## Pharmacodynamics - Effect on 5 Alpha-Dihydrotestosterone and Testosterone: The maximum effect of daily doses of dutasteride on the reduction of DHT is dose dependent and is observed within 1 to 2 weeks. After 1 and 2 weeks of daily dosing with dutasteride 0.5 mg, median serum DHT concentrations were reduced by 85% and 90%, respectively. In patients with BPH treated with dutasteride 0.5 mg/day for 4 years, the median decrease in serum DHT was 94% at 1 year, 93% at 2 years, and 95% at both 3 and 4 years. The median increase in serum testosterone was 19% at both 1 and 2 years, 26% at 3 years, and 22% at 4 years, but the mean and median levels remained within the physiologic range. - In patients with BPH treated with 5 mg/day of dutasteride or placebo for up to 12 weeks prior to transurethral resection of the prostate, mean DHT concentrations in prostatic tissue were significantly lower in the dutasteride group compared with placebo (784 and 5,793 pg/g, respectively, P<0.001). Mean prostatic tissue concentrations of testosterone were significantly higher in the dutasteride group compared with placebo (2,073 and 93 pg/g, respectively, P<0.001). - Adult males with genetically inherited type 2 5 alpha-reductase deficiency also have decreased DHT levels. These 5 alpha-reductase deficient males have a small prostate gland throughout life and do not develop BPH. Except for the associated urogenital defects present at birth, no other clinical abnormalities related to 5 alpha-reductase-deficiency have been observed in these individuals. - Effects on Other Hormones: In healthy volunteers, 52 weeks of treatment with dutasteride 0.5 mg/day (n = 26) resulted in no clinically significant change compared with placebo (n = 23) in sex hormone-binding globulin, estradiol, luteinizing hormone, follicle-stimulating hormone, thyroxine (free T4), and dehydroepiandrosterone. Statistically significant, baseline-adjusted mean increases compared with placebo were observed for total testosterone at 8 weeks (97.1 ng/dL, P<0.003) and thyroid-stimulating hormone at 52 weeks (0.4 mcIU/mL, P<0.05). The median percentage changes from baseline within the dutasteride group were 17.9% for testosterone at 8 weeks and 12.4% for thyroid-stimulating hormone at 52 weeks. After stopping dutasteride for 24 weeks, the mean levels of testosterone and thyroid-stimulating hormone had returned to baseline in the group of subjects with available data at the visit. In subjects with BPH treated with dutasteride in a large randomized, double-blind, placebo-controlled trial, there was a median percent increase in luteinizing hormone of 12% at 6 months and 19% at both 12 and 24 months. - Other Effects: Plasma lipid panel and bone mineral density were evaluated following 52 weeks of dutasteride 0.5 mg once daily in healthy volunteers. There was no change in bone mineral density as measured by dual energy x-ray absorptiometry compared with either placebo or baseline. In addition, the plasma lipid profile (i.e., total cholesterol, low density lipoproteins, high density lipoproteins, and triglycerides) was unaffected by dutasteride. No clinically significant changes in adrenal hormone responses to adrenocorticotropic hormone (ACTH) stimulation were observed in a subset population (n = 13) of the 1-year healthy volunteer trial. ## Pharmacokinetics - Absorption: Following administration of a single 0.5-mg dose of a soft gelatin capsule, time to peak serum concentrations (Tmax) of dutasteride occurs within 2 to 3 hours. *Absolute bioavailability in 5 healthy subjects is approximately 60% (range: 40% to 94%). When the drug is administered with food, the maximum serum concentrations were reduced by 10% to 15%. This reduction is of no clinical significance. - Distribution: Pharmacokinetic data following single and repeat oral doses show that dutasteride has a large volume of distribution (300 to 500 L). Dutasteride is highly bound to plasma albumin (99.0%) and alpha-1 acid glycoprotein (96.6%). - In a trial of healthy subjects (n = 26) receiving dutasteride 0.5 mg/day for 12 months, semen dutasteride concentrations averaged 3.4 ng/mL (range: 0.4 to 14 ng/mL) at 12 months and, similar to serum, achieved steady-state concentrations at 6 months. On average, at 12 months 11.5% of serum dutasteride concentrations partitioned into semen. - Metabolism and Elimination: Dutasteride is extensively metabolized in humans. In vitro studies showed that dutasteride is metabolized by the CYP3A4 and CYP3A5 isoenzymes. Both of these isoenzymes produced the 4′-hydroxydutasteride, 6-hydroxydutasteride, and the 6,4′-dihydroxydutasteride metabolites. In addition, the 15-hydroxydutasteride metabolite was formed by CYP3A4. Dutasteride is not metabolized in vitro by human cytochrome P450 isoenzymes CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP2E1. In human serum following dosing to steady state, unchanged dutasteride, 3 major metabolites (4′-hydroxydutasteride, 1,2-dihydrodutasteride, and 6-hydroxydutasteride), and 2 minor metabolites (6,4′-dihydroxydutasteride and 15-hydroxydutasteride), as assessed by mass spectrometric response, have been detected. The absolute stereochemistry of the hydroxyl additions in the 6 and 15 positions is not known. In vitro, the 4′-hydroxydutasteride and 1,2-dihydrodutasteride metabolites are much less potent than dutasteride against both isoforms of human 5 alpha-reductase. The activity of 6β-hydroxydutasteride is comparable to that of dutasteride. - Dutasteride and its metabolites were excreted mainly in feces. As a percent of dose, there was approximately 5% unchanged dutasteride (~1% to ~15%) and 40% as dutasteride-related metabolites (~2% to ~90%). Only trace amounts of unchanged dutasteride were found in urine (<1%). Therefore, on average, the dose unaccounted for approximated 55% (range, 5% to 97%). - The terminal elimination half-life of dutasteride is approximately 5 weeks at steady state. The average steady-state serum dutasteride concentration was 40 ng/mL following 0.5 mg/day for 1 year. Following daily dosing, dutasteride serum concentrations achieve 65% of steady-state concentration after 1 month and approximately 90% after 3 months. Due to the long half-life of dutasteride, serum concentrations remain detectable (greater than 0.1 ng/mL) for up to 4 to 6 months after discontinuation of treatment. - Specific Populations: Pediatric: Dutasteride pharmacokinetics have not been investigated in subjects younger than 18 years. - Geriatric: No dose adjustment is necessary in the elderly. The pharmacokinetics and pharmacodynamics of dutasteride were evaluated in 36 healthy male subjects aged between 24 and 87 years following administration of a single 5-mg dose of dutasteride. In this single-dose trial, dutasteride half-life increased with age (approximately 170 hours in men aged 20 to 49 years, approximately 260 hours in men aged 50 to 69 years, and approximately 300 hours in men older than 70 years). Of 2,167 men treated with dutasteride in the 3 pivotal trials, 60% were age 65 and over and 15% were age 75 and over. No overall differences in safety or efficacy were observed between these patients and younger patients. - Gender: Dutasteride is contraindicated in pregnancy and women of childbearing potential and is not indicated for use in other women. The pharmacokinetics of dutasteride in women have not been studied. - Race: The effect of race on dutasteride pharmacokinetics has not been studied. - Renal Impairment: The effect of renal impairment on dutasteride pharmacokinetics has not been studied. However, less than 0.1% of a steady-state 0.5-mg dose of dutasteride is recovered in human urine, so no adjustment in dosage is anticipated for patients with renal impairment. - Hepatic Impairment: The effect of hepatic impairment on dutasteride pharmacokinetics has not been studied. Because dutasteride is extensively metabolized, exposure could be higher in hepatically impaired patients. ## Nonclinical Toxicology ### Carcinogenesis, Mutagenesis, Impairment of Fertility - Carcinogenesis: A 2-year carcinogenicity study was conducted in B6C3F1 mice at doses of 3, 35, 250, and 500 mg/kg/day for males and 3, 35, and 250 mg/kg/day for females; an increased incidence of benign hepatocellular adenomas was noted at 250 mg/kg/day (290-fold the MRHD of a 0.5-mg daily dose) in female mice only. Two of the 3 major human metabolites have been detected in mice. The exposure to these metabolites in mice is either lower than in humans or is not known. - In a 2-year carcinogenicity study in Han Wistar rats, at doses of 1.5, 7.5, and 53 mg/kg/day in males and 0.8, 6.3, and 15 mg/kg/day in females, there was an increase in Leydig cell adenomas in the testes at 135-fold the MRHD (53 mg/kg/day and greater). An increased incidence of Leydig cell hyperplasia was present at 52-fold the MRHD (male rat doses of 7.5 mg/kg/day and greater). A positive correlation between proliferative changes in the Leydig cells and an increase in circulating luteinizing hormone levels has been demonstrated with 5 alpha-reductase inhibitors and is consistent with an effect on the hypothalamic-pituitary-testicular axis following 5 alpha-reductase inhibition. At tumorigenic doses, luteinizing hormone levels in rats were increased by 167%. In this study, the major human metabolites were tested for carcinogenicity at approximately 1 to 3 times the expected clinical exposure. - Mutagenesis: Dutasteride was tested for genotoxicity in a bacterial mutagenesis assay (Ames test), a chromosomal aberration assay in CHO cells, and a micronucleus assay in rats. The results did not indicate any genotoxic potential of the parent drug. Two major human metabolites were also negative in either the Ames test or an abbreviated Ames test. - Impairment of Fertility: Treatment of sexually mature male rats with dutasteride at 0.1- to 110-fold the MRHD (animal doses of 0.05, 10, 50, and 500 mg/kg/day for up to 31 weeks) resulted in dose- and time-dependent decreases in fertility; reduced cauda epididymal (absolute) sperm counts but not sperm concentration (at 50 and 500 mg/kg/day); reduced weights of the epididymis, prostate, and seminal vesicles; and microscopic changes in the male reproductive organs. The fertility effects were reversed by recovery week 6 at all doses, and sperm counts were normal at the end of a 14-week recovery period. The 5 alpha-reductase–related changes consisted of cytoplasmic vacuolation of tubular epithelium in the epididymides and decreased cytoplasmic content of epithelium, consistent with decreased secretory activity in the prostate and seminal vesicles. The microscopic changes were no longer present at recovery week 14 in the low-dose group and were partly recovered in the remaining treatment groups. Low levels of dutasteride (0.6 to 17 ng/mL) were detected in the serum of untreated female rats mated to males dosed at 10, 50, or 500 mg/kg/day for 29 to 30 weeks. In a fertility study in female rats, oral administration of dutasteride at doses of 0.05, 2.5, 12.5, and 30 mg/kg/day resulted in reduced litter size, increased embryo resorption, and feminization of male fetuses (decreased anogenital distance) at 2- to 10-fold the MRHD (animal doses of 2.5 mg/kg/day or greater). Fetal body weights were also reduced at less than 0.02-fold the MRHD in rats (0.5 mg/kg/day). ### Animal Toxicology and/or Pharmacology - Central Nervous System Toxicology Studies: In rats and dogs, repeated oral administration of dutasteride resulted in some animals showing signs of non-specific, reversible, centrally-mediated toxicity without associated histopathological changes at exposures 425- and 315-fold the expected clinical exposure (of parent drug), respectively. # Clinical Studies ### Monotherapy - Dutasteride 0.5 mg/day (n = 2,167) or placebo (n = 2,158) was evaluated in male subjects with BPH in three 2-year multicenter, placebo-controlled, double-blind trials, each with 2-year open-label extensions (n = 2,340). More than 90% of the trial population was Caucasian. Subjects were at least 50 years of age with a serum PSA ≥1.5 ng/mL and <10 ng/mL and BPH diagnosed by medical history and physical examination, including enlarged prostate (≥30 cc) and BPH symptoms that were moderate to severe according to the American Urological Association Symptom Index (AUA-SI). Most of the 4,325 subjects randomly assigned to receive either dutasteride or placebo completed 2 years of double-blind treatment (70% and 67%, respectively). Most of the 2,340 subjects in the trial extensions completed 2 additional years of open-label treatment (71%). - Effect on Symptom Scores: Symptoms were quantified using the AUA-SI, a questionnaire that evaluates urinary symptoms (incomplete emptying, frequency, intermittency, urgency, weak stream, straining, and nocturia) by rating on a 0 to 5 scale for a total possible score of 35, with higher numerical total symptom scores representing greater severity of symptoms. The baseline AUA-SI score across the 3 trials was approximately 17 units in both treatment groups. Subjects receiving dutasteride achieved statistically significant improvement in symptoms versus placebo by Month 3 in 1 trial and by Month 12 in the other 2 pivotal trials. At Month 12, the mean decrease from baseline in AUA-SI total symptom scores across the 3 trials pooled was -3.3 units for dutasteride and -2.0 units for placebo with a mean difference between the 2 treatment groups of -1.3 (range: -1.1 to -1.5 units in each of the 3 trials, P<0.001) and was consistent across the 3 trials. At Month 24, the mean decrease from baseline was -3.8 units for dutasteride and -1.7 units for placebo with a mean difference of -2.1 (range: -1.9 to -2.2 units in each of the 3 trials, P<0.001). See Figure 1. The improvement in BPH symptoms seen during the first 2 years of double-blind treatment was maintained throughout an additional 2 years of open-label extension trials. - These trials were prospectively designed to evaluate effects on symptoms based on prostate size at baseline. In men with prostate volumes ≥40 cc, the mean decrease was -3.8 units for dutasteride and -1.6 units for placebo, with a mean difference between the 2 treatment groups of -2.2 at Month 24. In men with prostate volumes <40 cc, the mean decrease was -3.7 units for dutasteride and -2.2 units for placebo, with a mean difference between the 2 treatment groups of -1.5 at Month 24. - Effect on Acute Urinary Retention and the Need for BPH-Related Surgery: Efficacy was also assessed after 2 years of treatment by the incidence of AUR requiring catheterization and BPH-related urological surgical intervention. Compared with placebo, dutasteride was associated with a statistically significantly lower incidence of AUR (1.8% for dutasteride versus 4.2% for placebo, P<0.001; 57% reduction in risk, ) and with a statistically significantly lower incidence of surgery (2.2% for dutasteride versus 4.1% for placebo, P<0.001; 48% reduction in risk, ). See Figures 2 and 3. - Effect on Prostate Volume: A prostate volume of at least 30 cc measured by transrectal ultrasound was required for trial entry. The mean prostate volume at trial entry was approximately 54 cc. - Statistically significant differences (dutasteride versus placebo) were noted at the earliest post-treatment prostate volume measurement in each trial (Month 1, Month 3, or Month 6) and continued through Month 24. At Month 12, the mean percent change in prostate volume across the 3 trials pooled was -24.7% for dutasteride and -3.4% for placebo; the mean difference (dutasteride minus placebo) was -21.3% (range: -21.0% to -21.6% in each of the 3 trials, P<0.001). At Month 24, the mean percent change in prostate volume across the 3 trials pooled was -26.7% for dutasteride and -2.2% for placebo with a mean difference of -24.5% (range: -24.0% to -25.1% in each of the 3 trials, P<0.001). See Figure 4. The reduction in prostate volume seen during the first 2 years of double-blind treatment was maintained throughout an additional 2 years of open-label extension trials. - Effect on Maximum Urine Flow Rate: A mean peak urine flow rate (Qmax) of ≤15 mL/sec was required for trial entry. Qmax was approximately 10 mL/sec at baseline across the 3 pivotal trials. - Differences between the 2 groups were statistically significant from baseline at Month 3 in all 3 trials and were maintained through Month 12. At Month 12, the mean increase in Qmax across the 3 trials pooled was 1.6 mL/sec for dutasteride and 0.7 mL/sec for placebo; the mean difference (dutasteride minus placebo) was 0.8 mL/sec (range: 0.7 to 1.0 mL/sec in each of the 3 trials, P<0.001). At Month 24, the mean increase in Qmax was 1.8 mL/sec for dutasteride and 0.7 mL/sec for placebo, with a mean difference of 1.1 mL/sec (range: 1.0 to 1.2 mL/sec in each of the 3 trials P<0.001). See Figure 5. The increase in maximum urine flow rate seen during the first 2 years of double-blind treatment was maintained throughout an additional 2 years of open-label extension trials. - Summary of Clinical Trials: Data from 3 large, well-controlled efficacy trials demonstrate that treatment with dutasteride (0.5 mg once daily) reduces the risk of both AUR and BPH-related surgical intervention relative to placebo, improves BPH-related symptoms, decreases prostate volume, and increases maximum urinary flow rates. These data suggest that dutasteride arrests the disease process of BPH in men with an enlarged prostate. ### Combination With Alpha-Blocker Therapy (CombAT) - The efficacy of combination therapy (dutasteride 0.5 mg/day plus tamsulosin 0.4 mg/day, n = 1,610) was compared with dutasteride alone (n = 1,623) or tamsulosin alone (n = 1,611) in a 4-year multicenter, randomized, double-blind trial. Trial entry criteria were similar to the double-blind, placebo-controlled monotherapy efficacy trials described above in section 14.1. Eighty-eight percent (88%) of the enrolled trial population was Caucasian. Approximately 52% of subjects had previous exposure to 5 alpha-reductase inhibitor or alpha adrenergic antagonist treatment. Of the 4,844 subjects randomly assigned to receive treatment, 69% of subjects in the combination group, 67% in the group receiving dutasteride, and 61% in the tamsulosin group completed 4 years of double-blind treatment. - Effect on Symptom Score: Symptoms were quantified using the first 7 questions of the International Prostate Symptom Score (IPSS) (identical to the AUA-SI). The baseline score was approximately 16.4 units for each treatment group. Combination therapy was statistically superior to each of the monotherapy treatments in decreasing symptom score at Month 24, the primary time point for this endpoint. At Month 24 the mean changes from baseline (±SD) in IPSS total symptom scores were -6.2 (±7.14) for combination, -4.9 (±6.81) for dutasteride, and -4.3 (±7.01) for tamsulosin, with a mean difference between combination and dutasteride of -1.3 units (P<0.001; ), and between combination and tamsulosin of -1.8 units (P<0.001; ). A significant difference was seen by Month 9 and continued through Month 48. At Month 48 the mean changes from baseline (±SD) in IPSS total symptom scores were -6.3 (±7.40) for combination, -5.3 (±7.14) for dutasteride, and -3.8 (±7.74) for tamsulosin, with a mean difference between combination and dutasteride of -0.96 units (P<0.001; ), and between combination and tamsulosin of -2.5 units (P<0.001; ). See Figure 6. - Effect on Acute Urinary Retention or the Need for BPH-Related Surgery: After 4 years of treatment, combination therapy with dutasteride and tamsulosin did not provide benefit over monotherapy with dutasteride in reducing the incidence of AUR or BPH-related surgery. - Effect on Maximum Urine Flow Rate: The baseline Qmax was approximately 10.7 mL/sec for each treatment group. Combination therapy was statistically superior to each of the monotherapy treatments in increasing Qmax at Month 24, the primary time point for this endpoint. At Month 24, the mean increases from baseline (±SD) in Qmax were 2.4 (±5.26) mL/sec for combination, 1.9 (±5.10) mL/sec for dutasteride, and 0.9 (±4.57) mL/sec for tamsulosin, with a mean difference between combination and Dutasteride of 0.5 mL/sec (P = 0.003; ), and between combination and tamsulosin of 1.5 mL/sec (P<0.001; ). This difference was seen by Month 6 and continued through Month 24. See Figure 7. - The additional improvement in Qmax of combination therapy over monotherapy with dutasteride was no longer statistically significant at Month 48. - Effect on Prostate Volume: The mean prostate volume at trial entry was approximately 55 cc. At Month 24, the primary time point for this endpoint, the mean percent changes from baseline (±SD) in prostate volume were -26.9% (±22.57) for combination therapy, -28.0% (±24.88) for dutasteride, and 0% (±31.14) for tamsulosin, with a mean difference between combination and dutasteride of 1.1% (P = NS; ), and between combination and tamsulosin of -26.9% (P<0.001; ). Similar changes were seen at Month 48: -27.3% (±24.91) for combination therapy, -28.0% (±25.74) for dutasteride, and +4.6% (±35.45) for tamsulosin. # How Supplied - Dutasteride Soft Gelatin Capsules 0.5 mg are oblong, opaque, dull yellow, gelatin capsules imprinted with “GX CE2” with red edible ink on one side packaged in bottles of 30 (NDC 0173-0712-15) and 90 (NDC 0173-0712-04) with child-resistant closures. ## Storage - Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F). - Dutasteride is absorbed through the skin. Dutasteride Capsules should not be handled by women who are pregnant or who could become pregnant because of the potential for absorption of dutasteride and the subsequent potential risk to a developing male fetus. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information # Precautions with Alcohol Alcohol-dutasteride interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names AVODART # Look-Alike Drug Names There is limited information about the look-alike drug names. # Drug Shortage Status # Price	Dutasteride Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Sheng Shi, M.D. [2] # Disclaimer WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here. # Overview Dutasteride is a 5-alpha reductase inhibitor that is FDA approved for the treatment of benign prostatic hyperplasia (BPH). Common adverse reactions include disorder of breast, prostate specific antigen abnormal, ejaculation disorder, impotence, reduced libido. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) ### Symptomatic Benign Prostatic Hyperplasia - Monotherapy Dosing Information - Recommended dose: 0.5 mg PO qd. - Combination with Alpha Adrenergic Antagonist - Recommended dose: 0.5 PO qd and tamsulosin 0.4 mg PO qd - Dutasteride® (dutasteride) Soft Gelatin Capsules are indicated for the treatment of symptomatic benign prostatic hyperplasia (BPH) in men with an enlarged prostate to: - Improve symptoms, - Reduce the risk of acute urinary retention (AUR), and - Reduce the risk of the need for BPH-related surgery. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of dutasteride in adult patients. ### Non–Guideline-Supported Use ### Male Pattern Alopecia * Dosing information :* Not applicable [1] # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) AVODART is contraindicated for use in pediatric patients. Safety and effectiveness in pediatric patients have not been established. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of dutasteride in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of dutasteride in pediatric patients. # Contraindications - Dutasteride is Contraindicated for use in: - Pregnancy. In animal reproduction and developmental toxicity studies, dutasteride inhibited development of male fetus external genitalia. Therefore, dutasteride may cause fetal harm when administered to a pregnant woman. If dutasteride is used during pregnancy or if the patient becomes pregnant while taking dutasteride, the patient should be apprised of the potential hazard to the fetus. - Women of childbearing potential. - Pediatric patients. - Patients with previously demonstrated, clinically significant hypersensitivity (e.g., serious skin reactions, angioedema) to dutasteride or other 5 alpha-reductase inhibitors. # Warnings ### Effects on Prostate Specific Antigen (PSA) and the use of PSA in Prostate Cancer Detection - In clinical trials, dutasteride reduced serum PSA concentration by approximately 50% within 3 to 6 months of treatment. This decrease was predictable over the entire range of PSA values in subjects with symptomatic BPH, although it may vary in individuals. Dutasteride may also cause decreases in serum PSA in the presence of prostate cancer. To interpret serial PSAs in men taking dutasteride, a new PSA baseline should be established at least 3 months after starting treatment and PSA monitored periodically thereafter. Any confirmed increase from the lowest PSA value while on dutasteride may signal the presence of prostate cancer and should be evaluated, even if PSA levels are still within the normal range for men not taking a 5 alpha-reductase inhibitor. Noncompliance with dutasteride may also affect PSA test results. - To interpret an isolated PSA value in a man treated with dutasteride for 3 months or more, the PSA value should be doubled for comparison with normal values in untreated men.The free-to-total PSA ratio (percent free PSA) remains constant, even under the influence of dutasteride. If clinicians elect to use percent free PSA as an aid in the detection of prostate cancer in men receiving dutasteride, no adjustment to its value appears necessary. - Co administration of dutasteride and tamsulosin resulted in similar changes to serum PSA as dutasteride monotherapy. ### Increased Risk of High-Grade Prostate Cancer - In men aged 50 to 75 years with a prior negative biopsy for prostate cancer and a baseline PSA between 2.5 ng/mL and 10.0 ng/mL taking dutasteride in the 4-year reduction by dutasteride of prostate cancer events (REDUCE) trial, there was an increased incidence of Gleason score 8-10 prostate cancer compared with men taking placebo (dutasteride 1.0% versus placebo 0.5%). In a 7-year placebo-controlled clinical trial with another 5 alpha-reductase inhibitor (finasteride 5 mg, PROSCAR), similar results for Gleason score 8-10 prostate cancer were observed (finasteride 1.8% versus placebo 1.1%). - 5 Alpha-reductase inhibitors may increase the risk of development of high-grade prostate cancer. Whether the effect of 5 alpha-reductase inhibitors to reduce prostate volume, or trial-related factors, impacted the results of these trials has not been established. ### Evaluation for Other Urological Diseases - Prior to initiating treatment with dutasteride, consideration should be given to other urological conditions that may cause similar symptoms. In addition, BPH and prostate cancer may coexist. ### Exposure of Women—Risk to Male Fetus - Dutasteride capsules should not be handled by a woman who is pregnant or who could become pregnant. Dutasteride is absorbed through the skin and could result in unintended fetal exposure. If a woman who is pregnant or who could become pregnant comes in contact with leaking dutasteride capsules, the contact area should be washed immediately with soap and water. ### Blood Donation - Men being treated with dutasteride should not donate blood until at least 6 months have passed following their last dose. The purpose of this deferred period is to prevent administration of dutasteride to a pregnant female transfusion recipient. ### Effect on Semen Characteristics - The effects of dutasteride 0.5 mg/day on semen characteristics were evaluated in normal volunteers aged 18 to 52 (n = 27 dutasteride, n = 23 placebo) throughout 52 weeks of treatment and 24 weeks of post-treatment follow-up. At 52 weeks, the mean percent reductions from baseline in total sperm count, semen volume, and sperm motility were 23%, 26%, and 18%, respectively, in the dutasteride group when adjusted for changes from baseline in the placebo group. Sperm concentration and sperm morphology were unaffected. After 24 weeks of follow-up, the mean percent change in total sperm count in the dutasteride group remained 23% lower than baseline. While mean values for all semen parameters at all time-points remained within the normal ranges and did not meet predefined criteria for a clinically significant change (30%), 2 subjects in the dutasteride group had decreases in sperm count of greater than 90% from baseline at 52 weeks, with partial recovery at the 24-week follow-up. The clinical significance of dutasteride’s effect on semen characteristics for an individual patient’s fertility is not known. # Adverse Reactions ## Clinical Trials Experience - Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trial of another drug and may not reflect the rates observed in practice. - From clinical trials with dutasteride as monotherapy or in combination with tamsulosin: - The most common adverse reactions reported in subjects receiving dutasteride were impotence, decreased libido, breast disorders (including breast enlargement and tenderness), and ejaculation disorders. The most common adverse reactions reported in subjects receiving combination therapy (dutasteride plus tamsulosin) were impotence, decreased libido, breast disorders (including breast enlargement and tenderness), ejaculation disorders, and dizziness. Ejaculation disorders occurred significantly more in subjects receiving combination therapy (11%) compared with those receiving dutasteride (2%) or tamsulosin (4%) as monotherapy. Trial withdrawal due to adverse reactions occurred in 4% of subjects receiving dutasteride, and 3% of subjects receiving placebo in placebo-controlled trials with dutasteride. The most common adverse reaction leading to trial withdrawal was impotence (1%). In the clinical trial evaluating the combination therapy, trial withdrawal due to adverse reactions occurred in 6% of subjects receiving combination therapy (dutasteride plus tamsulosin) and 4% of subjects receiving dutasteride or tamsulosin as monotherapy. The most common adverse reaction in all treatment arms leading to trial withdrawal was erectile dysfunction (1% to 1.5%). - Trial withdrawal due to adverse reactions occurred in 4% of subjects receiving dutasteride, and 3% of subjects receiving placebo in placebo-controlled trials with dutasteride. The most common adverse reaction leading to trial withdrawal was impotence (1%). - In the clinical trial evaluating the combination therapy, trial withdrawal due to adverse reactions occurred in 6% of subjects receiving combination therapy (dutasteride plus tamsulosin) and 4% of subjects receiving dutasteride or tamsulosin as monotherapy. The most common adverse reaction in all treatment arms leading to trial withdrawal was erectile dysfunction (1% to 1.5%). - Monotherapy: Over 4,300 male subjects with BPH were randomly assigned to receive placebo or 0.5-mg daily doses of dutasteride in 3 identical 2-year, placebo-controlled, double-blind, Phase 3 treatment trials, each followed by a 2-year open-label extension. During the double-blind treatment period, 2,167 male subjects were exposed to dutasteride, including 1,772 exposed for 1 year and 1,510 exposed for 2 years. When including the open-label extensions, 1,009 male subjects were exposed to dutasteride for 3 years and 812 were exposed for 4 years. The population was aged 47 to 94 years (mean age: 66 years) and greater than 90% were Caucasian. Table 1 summarizes clinical adverse reactions reported in at least 1% of subjects receiving dutasteride and at a higher incidence than subjects receiving placebo. - Long-Term Treatment (Up to 4 Years): High-Grade prostate cancer: The REDUCE trial was a randomized, double-blind, placebo-controlled trial that enrolled 8,231 men aged 50 to 75 years with a serum PSA of 2.5 ng/mL to 10 ng/mL and a negative prostate biopsy within the previous 6 months. Subjects were randomized to receive placebo (N = 4,126) or 0.5-mg daily doses of dutasteride (N = 4,105) for up to 4 years. The mean age was 63 years and 91% were Caucasian. Subjects underwent protocol-mandated scheduled prostate biopsies at 2 and 4 years of treatment or had “for-cause biopsies” at non-scheduled times if clinically indicated. There was a higher incidence of Gleason score 8-10 prostate cancer in men receiving dutasteride (1.0%) compared with men on placebo (0.5%). In a 7-year placebo-controlled clinical trial with another 5 alpha-reductase inhibitor (finasteride 5 mg, PROSCAR), similar results for Gleason score 8-10 prostate cancer were observed (finasteride 1.8% versus placebo 1.1%). - No clinical benefit has been demonstrated in patients with prostate cancer treated with dutasteride. - Reproductive and Breast Disorders: In the 3 pivotal placebo-controlled BPH trials with dutasteride, each 4 years in duration, there was no evidence of increased sexual adverse reactions (impotence, decreased libido, and ejaculation disorder) or breast disorders with increased duration of treatment. Among these 3 trials, there was 1 case of breast cancer in the dutasteride group and 1 case in the placebo group. No cases of breast cancer were reported in any treatment group in the 4-year CombAT trial or the 4-year REDUCE trial. - The relationship between long-term use of dutasteride and male breast neoplasia is currently unknown. - Combination With Alpha-Blocker Therapy (CombAT): Over 4,800 male subjects with BPH were randomly assigned to receive 0.5-mg dutasteride, 0.4-mg tamsulosin, or combination therapy (0.5-mg dutasteride plus 0.4-mg tamsulosin) administered once daily in a 4-year double-blind trial. Overall, 1,623 subjects received monotherapy with dutasteride; 1,611 subjects received monotherapy with tamsulosin; and 1,610 subjects received combination therapy. The population was aged 49 to 88 years (mean age: 66 years) and 88% were Caucasian. Table 2 summarizes adverse reactions reported in at least 1% of subjects in the combination group and at a higher incidence than subjects receiving monotherapy with dutasteride or tamsulosin. - Cardiac Failure: In CombAT, after 4 years of treatment, the incidence of the composite term cardiac failure in the combination therapy group (12/1,610; 0.7%) was higher than in either monotherapy group: dutasteride, 2/1,623 (0.1%) and tamsulosin, 9/1,611 (0.6%). Composite cardiac failure was also examined in a separate 4-year placebo-controlled trial evaluating dutasteride in men at risk for development of prostate cancer. The incidence of cardiac failure in subjects taking dutasteride was 0.6% (26/4,105) compared with 0.4% (15/4,126) in subjects on placebo. A majority of subjects with cardiac failure in both trials had comorbidities associated with an increased risk of cardiac failure. Therefore, the clinical significance of the numerical imbalances in cardiac failure is unknown. No causal relationship between dutasteride, alone or in combination with tamsulosin, and cardiac failure has been established. No imbalance was observed in the incidence of overall cardiovascular adverse events in either trial. ## Postmarketing Experience - The following adverse reactions have been identified during post-approval use of dutasteride. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. These reactions have been chosen for inclusion due to a combination of their seriousness, frequency of reporting, or potential causal connection to dutasteride. Immune System Disorders: Hypersensitivity reactions, including rash, pruritus, urticaria, localized edema, serious skin reactions, and angioedema. Neoplasms: Male breast cancer. Psychiatric Disorders: Depressed mood. Reproductive System and Breast Disorders: Testicular pain and testicular swelling. # Drug Interactions ### Cytochrome P450 3A Inhibitors - Dutasteride is extensively metabolized in humans by the CYP3A4 and CYP3A5 isoenzymes. The effect of potent CYP3A4 inhibitors on dutasteride has not been studied. Because of the potential for drug-drug interactions, use caution when prescribing dutasteride to patients taking potent, chronic CYP3A4 enzyme inhibitors (e.g., ritonavir). ### Alpha Adrenergic Antagonists - The administration of dutasteride in combination with tamsulosin or terazosin has no effect on the steady-state pharmacokinetics of either alpha adrenergic antagonist. The effect of administration of tamsulosin or terazosin on dutasteride pharmacokinetic parameters has not been evaluated. ### Calcium Channel Antagonists - Co administration of verapamil or diltiazem decreases dutasteride clearance and leads to increased exposure to dutasteride. The change in dutasteride exposure is not considered to be clinically significant. No dose adjustment is recommended . ### Cholestyramine - Administration of a single 5-mg dose of dutasteride followed 1 hour later by 12 g of cholestyramine does not affect the relative bioavailability of dutasteride . ### Digoxin - Dutasteride does not alter the steady-state pharmacokinetics of digoxin when administered concomitantly at a dose of 0.5 mg/day for 3 weeks . ### Warfarin - Concomitant administration of dutasteride 0.5 mg/day for 3 weeks with warfarin does not alter the steady-state pharmacokinetics of the S- or R-warfarin isomers or alter the effect of warfarin on prothrombin time. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): X Pregnancy Category X. - Dutasteride is contraindicated for use in women of childbearing potential and during pregnancy. Dutasteride is a 5 alpha-reductase inhibitor that prevents conversion of testosterone to dihydrotestosterone (DHT), a hormone necessary for normal development of male genitalia. In animal reproduction and developmental toxicity studies, dutasteride inhibited normal development of external genitalia in male fetuses. Therefore, dutasteride may cause fetal harm when administered to a pregnant woman. If dutasteride is used during pregnancy or if the patient becomes pregnant while taking dutasteride, the patient should be apprised of the potential hazard to the fetus. - Abnormalities in the genitalia of male fetuses is an expected physiological consequence of inhibition of the conversion of testosterone to DHT by 5 alpha-reductase inhibitors. These results are similar to observations in male infants with genetic 5 alpha-reductase deficiency. Dutasteride is absorbed through the skin. To avoid potential fetal exposure, women who are pregnant or could become pregnant should not handle dutasteride Soft Gelatin Capsules. If contact is made with leaking capsules, the contact area should be washed immediately with soap and water. Dutasteride is secreted into semen. The highest measured semen concentration of dutasteride in treated men was 14 ng/mL. Assuming exposure of a 50-kg woman to 5 mL of semen and 100% absorption, the woman’s dutasteride concentration would be about 0.0175 ng/mL. This concentration is more than 100 times less than concentrations producing abnormalities of male genitalia in animal studies. Dutasteride is highly protein bound in human semen (greater than 96%), which may reduce the amount of dutasteride available for vaginal absorption. - In an embryo-fetal development study in female rats, oral administration of dutasteride at doses 10 times less than the maximum recommended human dose (MRHD) of 0.5 mg daily resulted in abnormalities of male genitalia in the fetus (decreased anogenital distance at 0.05 mg/kg/day), nipple development, hypospadias, and distended preputial glands in male offspring (at all doses of 0.05, 2.5, 12.5, and 30 mg/kg/day). An increase in stillborn pups was observed at 111 times the MRHD, and reduced fetal body weight was observed at doses of about 15 times the MRHD (animal dose of 2.5 mg/kg/day). Increased incidences of skeletal variations considered to be delays in ossification associated with reduced body weight were observed at doses about 56 times the MRHD (animal dose of 12.5 mg/kg/day). - In a rabbit embryo-fetal study, doses 28- to 93-fold the MRHD (animal doses of 30, 100, and 200 mg/kg/day) were administered orally during the period of major organogenesis (gestation days 7 to 29) to encompass the late period of external genitalia development. Histological evaluation of the genital papilla of fetuses revealed evidence of feminization of the male fetus at all doses. A second embryo-fetal study in rabbits at 0.3- to 53-fold the expected clinical exposure (animal doses of 0.05, 0.4, 3.0, and 30 mg/kg/day) also produced evidence of feminization of the genitalia in male fetuses at all doses. - In an oral pre- and post-natal development study in rats, dutasteride doses of 0.05, 2.5, 12.5, or 30 mg/kg/day were administered. Unequivocal evidence of feminization of the genitalia (i.e., decreased anogenital distance, increased incidence of hypospadias, nipple development) of male offspring occurred at 14- to 90-fold the MRHD (animal doses of 2.5 mg/kg/day or greater). At 0.05-fold the expected clinical exposure (animal dose of 0.05 mg/kg/day), evidence of feminization was limited to a small, but statistically significant, decrease in anogenital distance. Animal doses of 2.5 to 30 mg/kg/day resulted in prolonged gestation in the parental females and a decrease in time to vaginal patency for female offspring and a decrease in prostate and seminal vesicle weights in male offspring. Effects on newborn startle response were noted at doses greater than or equal to 12.5 mg/kg/day. Increased stillbirths were noted at 30 mg/kg/day. - In an embryo-fetal development study, pregnant rhesus monkeys were exposed intravenously to a dutasteride blood level comparable to the dutasteride concentration found in human semen. Dutasteride was administered on gestation days 20 to 100 at doses of 400, 780, 1,325, or 2,010 ng/day (12 monkeys/group). The development of male external genitalia of monkey offspring was not adversely affected. Reduction of fetal adrenal weights, reduction in fetal prostate weights, and increases in fetal ovarian and testis weights were observed at the highest dose tested in monkeys. Based on the highest measured semen concentration of dutasteride in treated men (14 ng/mL), these doses represent 0.8 to 16 times the potential maximum exposure of a 50-kg human female to 5 mL semen daily from a dutasteride-treated man, assuming 100% absorption. (These calculations are based on blood levels of parent drug which are achieved at 32 to 186 times the daily doses administered to pregnant monkeys on a ng/kg basis). Dutasteride is highly bound to proteins in human semen (greater than 96%), potentially reducing the amount of dutasteride available for vaginal absorption. It is not known whether rabbits or rhesus monkeys produce any of the major human metabolites. - Estimates of exposure multiples comparing animal studies to the MRHD for dutasteride are based on clinical serum concentration at steady state. Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Dutasteride in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Dutasteride during labor and delivery. ### Nursing Mothers - Dutasteride is contraindicated for use in women of childbearing potential, including nursing women. It is not known whether dutasteride is excreted in human milk. ### Pediatric Use - Dutasteride is contraindicated for use in pediatric patients. Safety and effectiveness in pediatric patients have not been established. ### Geriatic Use - Of 2,167 male subjects treated with dutasteride in 3 clinical trials, 60% were aged 65 years and older and 15% were aged 75 years and older. No overall differences in safety or efficacy were observed between these subjects and younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out . ### Gender There is no FDA guidance on the use of Dutasteride with respect to specific gender populations. ### Race There is no FDA guidance on the use of Dutasteride with respect to specific racial populations. ### Renal Impairment - No dose adjustment is necessary for dutasteride in patients with renal impairment . ### Hepatic Impairment - The effect of hepatic impairment on dutasteride pharmacokinetics has not been studied. Because dutasteride is extensively metabolized, exposure could be higher in hepatically impaired patients. However, in a clinical trial where 60 subjects received 5 mg (10 times the therapeutic dose) daily for 24 weeks, no additional adverse events were observed compared with those observed at the therapeutic dose of 0.5 mg . ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Dutasteride in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Dutasteride in patients who are immunocompromised. # Administration and Monitoring ### Administration Oral ### Monitoring FDA package insert for dutasteride contains no information regarding drug monitoring. # IV Compatibility There is limited information about the IV Compatibility. # Overdosage - In volunteer trials, single doses of dutasteride up to 40 mg (80 times the therapeutic dose) for 7 days have been administered without significant safety concerns. In a clinical trial, daily doses of 5 mg (10 times the therapeutic dose) were administered to 60 subjects for 6 months with no additional adverse effects to those seen at therapeutic doses of 0.5 mg. - There is no specific antidote for dutasteride. Therefore, in cases of suspected overdosage symptomatic and supportive treatment should be given as appropriate, taking the long half-life of dutasteride into consideration. # Pharmacology ## Mechanism of Action - Dutasteride inhibits the conversion of testosterone to dihydrotestosterone (DHT). DHT is the androgen primarily responsible for the initial development and subsequent enlargement of the prostate gland. Testosterone is converted to DHT by the enzyme 5 alpha-reductase, which exists as 2 isoforms, type 1 and type 2. The type 2 isoenzyme is primarily active in the reproductive tissues, while the type 1 isoenzyme is also responsible for testosterone conversion in the skin and liver. - Dutasteride is a competitive and specific inhibitor of both type 1 and type 2 5 alpha-reductase isoenzymes, with which it forms a stable enzyme complex. Dissociation from this complex has been evaluated under in vitro and in vivo conditions and is extremely slow. Dutasteride does not bind to the human androgen receptor. ## Structure - Dutasteride is a synthetic 4-azasteroid compound that is a selective inhibitor of both the type 1 and type 2 isoforms of steroid 5 alpha-reductase, an intracellular enzyme that converts testosterone to DHT. - Dutasteride is chemically designated as (5α,17β)-N-{2,5 bis(trifluoromethyl)phenyl}-3-oxo-4-azaandrost-1-ene-17-carboxamide. The empirical formula of dutasteride is C27H30F6N2O2, representing a molecular weight of 528.5 with the following structural formula: - Dutasteride is a white to pale yellow powder with a melting point of 242° to 250°C. It is soluble in ethanol (44 mg/mL), methanol (64 mg/mL), and polyethylene glycol 400 (3 mg/mL), but it is insoluble in water. - Each dutasteride soft gelatin capsule, administered orally, contains 0.5 mg of dutasteride dissolved in a mixture of mono-di-glycerides of caprylic/capric acid and butylated hydroxytoluene. The inactive excipients in the capsule shell are ferric oxide (yellow), gelatin (from certified BSE-free bovine sources), glycerin, and titanium dioxide. The soft gelatin capsules are printed with edible red ink. ## Pharmacodynamics - Effect on 5 Alpha-Dihydrotestosterone and Testosterone: The maximum effect of daily doses of dutasteride on the reduction of DHT is dose dependent and is observed within 1 to 2 weeks. After 1 and 2 weeks of daily dosing with dutasteride 0.5 mg, median serum DHT concentrations were reduced by 85% and 90%, respectively. In patients with BPH treated with dutasteride 0.5 mg/day for 4 years, the median decrease in serum DHT was 94% at 1 year, 93% at 2 years, and 95% at both 3 and 4 years. The median increase in serum testosterone was 19% at both 1 and 2 years, 26% at 3 years, and 22% at 4 years, but the mean and median levels remained within the physiologic range. - In patients with BPH treated with 5 mg/day of dutasteride or placebo for up to 12 weeks prior to transurethral resection of the prostate, mean DHT concentrations in prostatic tissue were significantly lower in the dutasteride group compared with placebo (784 and 5,793 pg/g, respectively, P<0.001). Mean prostatic tissue concentrations of testosterone were significantly higher in the dutasteride group compared with placebo (2,073 and 93 pg/g, respectively, P<0.001). - Adult males with genetically inherited type 2 5 alpha-reductase deficiency also have decreased DHT levels. These 5 alpha-reductase deficient males have a small prostate gland throughout life and do not develop BPH. Except for the associated urogenital defects present at birth, no other clinical abnormalities related to 5 alpha-reductase-deficiency have been observed in these individuals. - Effects on Other Hormones: In healthy volunteers, 52 weeks of treatment with dutasteride 0.5 mg/day (n = 26) resulted in no clinically significant change compared with placebo (n = 23) in sex hormone-binding globulin, estradiol, luteinizing hormone, follicle-stimulating hormone, thyroxine (free T4), and dehydroepiandrosterone. Statistically significant, baseline-adjusted mean increases compared with placebo were observed for total testosterone at 8 weeks (97.1 ng/dL, P<0.003) and thyroid-stimulating hormone at 52 weeks (0.4 mcIU/mL, P<0.05). The median percentage changes from baseline within the dutasteride group were 17.9% for testosterone at 8 weeks and 12.4% for thyroid-stimulating hormone at 52 weeks. After stopping dutasteride for 24 weeks, the mean levels of testosterone and thyroid-stimulating hormone had returned to baseline in the group of subjects with available data at the visit. In subjects with BPH treated with dutasteride in a large randomized, double-blind, placebo-controlled trial, there was a median percent increase in luteinizing hormone of 12% at 6 months and 19% at both 12 and 24 months. - Other Effects: Plasma lipid panel and bone mineral density were evaluated following 52 weeks of dutasteride 0.5 mg once daily in healthy volunteers. There was no change in bone mineral density as measured by dual energy x-ray absorptiometry compared with either placebo or baseline. In addition, the plasma lipid profile (i.e., total cholesterol, low density lipoproteins, high density lipoproteins, and triglycerides) was unaffected by dutasteride. No clinically significant changes in adrenal hormone responses to adrenocorticotropic hormone (ACTH) stimulation were observed in a subset population (n = 13) of the 1-year healthy volunteer trial. ## Pharmacokinetics - Absorption: Following administration of a single 0.5-mg dose of a soft gelatin capsule, time to peak serum concentrations (Tmax) of dutasteride occurs within 2 to 3 hours. *Absolute bioavailability in 5 healthy subjects is approximately 60% (range: 40% to 94%). When the drug is administered with food, the maximum serum concentrations were reduced by 10% to 15%. This reduction is of no clinical significance. - Distribution: Pharmacokinetic data following single and repeat oral doses show that dutasteride has a large volume of distribution (300 to 500 L). Dutasteride is highly bound to plasma albumin (99.0%) and alpha-1 acid glycoprotein (96.6%). - In a trial of healthy subjects (n = 26) receiving dutasteride 0.5 mg/day for 12 months, semen dutasteride concentrations averaged 3.4 ng/mL (range: 0.4 to 14 ng/mL) at 12 months and, similar to serum, achieved steady-state concentrations at 6 months. On average, at 12 months 11.5% of serum dutasteride concentrations partitioned into semen. - Metabolism and Elimination: Dutasteride is extensively metabolized in humans. In vitro studies showed that dutasteride is metabolized by the CYP3A4 and CYP3A5 isoenzymes. Both of these isoenzymes produced the 4′-hydroxydutasteride, 6-hydroxydutasteride, and the 6,4′-dihydroxydutasteride metabolites. In addition, the 15-hydroxydutasteride metabolite was formed by CYP3A4. Dutasteride is not metabolized in vitro by human cytochrome P450 isoenzymes CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP2E1. In human serum following dosing to steady state, unchanged dutasteride, 3 major metabolites (4′-hydroxydutasteride, 1,2-dihydrodutasteride, and 6-hydroxydutasteride), and 2 minor metabolites (6,4′-dihydroxydutasteride and 15-hydroxydutasteride), as assessed by mass spectrometric response, have been detected. The absolute stereochemistry of the hydroxyl additions in the 6 and 15 positions is not known. In vitro, the 4′-hydroxydutasteride and 1,2-dihydrodutasteride metabolites are much less potent than dutasteride against both isoforms of human 5 alpha-reductase. The activity of 6β-hydroxydutasteride is comparable to that of dutasteride. - Dutasteride and its metabolites were excreted mainly in feces. As a percent of dose, there was approximately 5% unchanged dutasteride (~1% to ~15%) and 40% as dutasteride-related metabolites (~2% to ~90%). Only trace amounts of unchanged dutasteride were found in urine (<1%). Therefore, on average, the dose unaccounted for approximated 55% (range, 5% to 97%). - The terminal elimination half-life of dutasteride is approximately 5 weeks at steady state. The average steady-state serum dutasteride concentration was 40 ng/mL following 0.5 mg/day for 1 year. Following daily dosing, dutasteride serum concentrations achieve 65% of steady-state concentration after 1 month and approximately 90% after 3 months. Due to the long half-life of dutasteride, serum concentrations remain detectable (greater than 0.1 ng/mL) for up to 4 to 6 months after discontinuation of treatment. - Specific Populations: Pediatric: Dutasteride pharmacokinetics have not been investigated in subjects younger than 18 years. - Geriatric: No dose adjustment is necessary in the elderly. The pharmacokinetics and pharmacodynamics of dutasteride were evaluated in 36 healthy male subjects aged between 24 and 87 years following administration of a single 5-mg dose of dutasteride. In this single-dose trial, dutasteride half-life increased with age (approximately 170 hours in men aged 20 to 49 years, approximately 260 hours in men aged 50 to 69 years, and approximately 300 hours in men older than 70 years). Of 2,167 men treated with dutasteride in the 3 pivotal trials, 60% were age 65 and over and 15% were age 75 and over. No overall differences in safety or efficacy were observed between these patients and younger patients. - Gender: Dutasteride is contraindicated in pregnancy and women of childbearing potential and is not indicated for use in other women. The pharmacokinetics of dutasteride in women have not been studied. - Race: The effect of race on dutasteride pharmacokinetics has not been studied. - Renal Impairment: The effect of renal impairment on dutasteride pharmacokinetics has not been studied. However, less than 0.1% of a steady-state 0.5-mg dose of dutasteride is recovered in human urine, so no adjustment in dosage is anticipated for patients with renal impairment. - Hepatic Impairment: The effect of hepatic impairment on dutasteride pharmacokinetics has not been studied. Because dutasteride is extensively metabolized, exposure could be higher in hepatically impaired patients. ## Nonclinical Toxicology ### Carcinogenesis, Mutagenesis, Impairment of Fertility - Carcinogenesis: A 2-year carcinogenicity study was conducted in B6C3F1 mice at doses of 3, 35, 250, and 500 mg/kg/day for males and 3, 35, and 250 mg/kg/day for females; an increased incidence of benign hepatocellular adenomas was noted at 250 mg/kg/day (290-fold the MRHD of a 0.5-mg daily dose) in female mice only. Two of the 3 major human metabolites have been detected in mice. The exposure to these metabolites in mice is either lower than in humans or is not known. - In a 2-year carcinogenicity study in Han Wistar rats, at doses of 1.5, 7.5, and 53 mg/kg/day in males and 0.8, 6.3, and 15 mg/kg/day in females, there was an increase in Leydig cell adenomas in the testes at 135-fold the MRHD (53 mg/kg/day and greater). An increased incidence of Leydig cell hyperplasia was present at 52-fold the MRHD (male rat doses of 7.5 mg/kg/day and greater). A positive correlation between proliferative changes in the Leydig cells and an increase in circulating luteinizing hormone levels has been demonstrated with 5 alpha-reductase inhibitors and is consistent with an effect on the hypothalamic-pituitary-testicular axis following 5 alpha-reductase inhibition. At tumorigenic doses, luteinizing hormone levels in rats were increased by 167%. In this study, the major human metabolites were tested for carcinogenicity at approximately 1 to 3 times the expected clinical exposure. - Mutagenesis: Dutasteride was tested for genotoxicity in a bacterial mutagenesis assay (Ames test), a chromosomal aberration assay in CHO cells, and a micronucleus assay in rats. The results did not indicate any genotoxic potential of the parent drug. Two major human metabolites were also negative in either the Ames test or an abbreviated Ames test. - Impairment of Fertility: Treatment of sexually mature male rats with dutasteride at 0.1- to 110-fold the MRHD (animal doses of 0.05, 10, 50, and 500 mg/kg/day for up to 31 weeks) resulted in dose- and time-dependent decreases in fertility; reduced cauda epididymal (absolute) sperm counts but not sperm concentration (at 50 and 500 mg/kg/day); reduced weights of the epididymis, prostate, and seminal vesicles; and microscopic changes in the male reproductive organs. The fertility effects were reversed by recovery week 6 at all doses, and sperm counts were normal at the end of a 14-week recovery period. The 5 alpha-reductase–related changes consisted of cytoplasmic vacuolation of tubular epithelium in the epididymides and decreased cytoplasmic content of epithelium, consistent with decreased secretory activity in the prostate and seminal vesicles. The microscopic changes were no longer present at recovery week 14 in the low-dose group and were partly recovered in the remaining treatment groups. Low levels of dutasteride (0.6 to 17 ng/mL) were detected in the serum of untreated female rats mated to males dosed at 10, 50, or 500 mg/kg/day for 29 to 30 weeks. In a fertility study in female rats, oral administration of dutasteride at doses of 0.05, 2.5, 12.5, and 30 mg/kg/day resulted in reduced litter size, increased embryo resorption, and feminization of male fetuses (decreased anogenital distance) at 2- to 10-fold the MRHD (animal doses of 2.5 mg/kg/day or greater). Fetal body weights were also reduced at less than 0.02-fold the MRHD in rats (0.5 mg/kg/day). ### Animal Toxicology and/or Pharmacology - Central Nervous System Toxicology Studies: In rats and dogs, repeated oral administration of dutasteride resulted in some animals showing signs of non-specific, reversible, centrally-mediated toxicity without associated histopathological changes at exposures 425- and 315-fold the expected clinical exposure (of parent drug), respectively. # Clinical Studies ### Monotherapy - Dutasteride 0.5 mg/day (n = 2,167) or placebo (n = 2,158) was evaluated in male subjects with BPH in three 2-year multicenter, placebo-controlled, double-blind trials, each with 2-year open-label extensions (n = 2,340). More than 90% of the trial population was Caucasian. Subjects were at least 50 years of age with a serum PSA ≥1.5 ng/mL and <10 ng/mL and BPH diagnosed by medical history and physical examination, including enlarged prostate (≥30 cc) and BPH symptoms that were moderate to severe according to the American Urological Association Symptom Index (AUA-SI). Most of the 4,325 subjects randomly assigned to receive either dutasteride or placebo completed 2 years of double-blind treatment (70% and 67%, respectively). Most of the 2,340 subjects in the trial extensions completed 2 additional years of open-label treatment (71%). - Effect on Symptom Scores: Symptoms were quantified using the AUA-SI, a questionnaire that evaluates urinary symptoms (incomplete emptying, frequency, intermittency, urgency, weak stream, straining, and nocturia) by rating on a 0 to 5 scale for a total possible score of 35, with higher numerical total symptom scores representing greater severity of symptoms. The baseline AUA-SI score across the 3 trials was approximately 17 units in both treatment groups. Subjects receiving dutasteride achieved statistically significant improvement in symptoms versus placebo by Month 3 in 1 trial and by Month 12 in the other 2 pivotal trials. At Month 12, the mean decrease from baseline in AUA-SI total symptom scores across the 3 trials pooled was -3.3 units for dutasteride and -2.0 units for placebo with a mean difference between the 2 treatment groups of -1.3 (range: -1.1 to -1.5 units in each of the 3 trials, P<0.001) and was consistent across the 3 trials. At Month 24, the mean decrease from baseline was -3.8 units for dutasteride and -1.7 units for placebo with a mean difference of -2.1 (range: -1.9 to -2.2 units in each of the 3 trials, P<0.001). See Figure 1. The improvement in BPH symptoms seen during the first 2 years of double-blind treatment was maintained throughout an additional 2 years of open-label extension trials. - These trials were prospectively designed to evaluate effects on symptoms based on prostate size at baseline. In men with prostate volumes ≥40 cc, the mean decrease was -3.8 units for dutasteride and -1.6 units for placebo, with a mean difference between the 2 treatment groups of -2.2 at Month 24. In men with prostate volumes <40 cc, the mean decrease was -3.7 units for dutasteride and -2.2 units for placebo, with a mean difference between the 2 treatment groups of -1.5 at Month 24. - Effect on Acute Urinary Retention and the Need for BPH-Related Surgery: Efficacy was also assessed after 2 years of treatment by the incidence of AUR requiring catheterization and BPH-related urological surgical intervention. Compared with placebo, dutasteride was associated with a statistically significantly lower incidence of AUR (1.8% for dutasteride versus 4.2% for placebo, P<0.001; 57% reduction in risk, [95% CI: 38% to 71%]) and with a statistically significantly lower incidence of surgery (2.2% for dutasteride versus 4.1% for placebo, P<0.001; 48% reduction in risk, [95% CI: 26% to 63%]). See Figures 2 and 3. - Effect on Prostate Volume: A prostate volume of at least 30 cc measured by transrectal ultrasound was required for trial entry. The mean prostate volume at trial entry was approximately 54 cc. - Statistically significant differences (dutasteride versus placebo) were noted at the earliest post-treatment prostate volume measurement in each trial (Month 1, Month 3, or Month 6) and continued through Month 24. At Month 12, the mean percent change in prostate volume across the 3 trials pooled was -24.7% for dutasteride and -3.4% for placebo; the mean difference (dutasteride minus placebo) was -21.3% (range: -21.0% to -21.6% in each of the 3 trials, P<0.001). At Month 24, the mean percent change in prostate volume across the 3 trials pooled was -26.7% for dutasteride and -2.2% for placebo with a mean difference of -24.5% (range: -24.0% to -25.1% in each of the 3 trials, P<0.001). See Figure 4. The reduction in prostate volume seen during the first 2 years of double-blind treatment was maintained throughout an additional 2 years of open-label extension trials. - Effect on Maximum Urine Flow Rate: A mean peak urine flow rate (Qmax) of ≤15 mL/sec was required for trial entry. Qmax was approximately 10 mL/sec at baseline across the 3 pivotal trials. - Differences between the 2 groups were statistically significant from baseline at Month 3 in all 3 trials and were maintained through Month 12. At Month 12, the mean increase in Qmax across the 3 trials pooled was 1.6 mL/sec for dutasteride and 0.7 mL/sec for placebo; the mean difference (dutasteride minus placebo) was 0.8 mL/sec (range: 0.7 to 1.0 mL/sec in each of the 3 trials, P<0.001). At Month 24, the mean increase in Qmax was 1.8 mL/sec for dutasteride and 0.7 mL/sec for placebo, with a mean difference of 1.1 mL/sec (range: 1.0 to 1.2 mL/sec in each of the 3 trials P<0.001). See Figure 5. The increase in maximum urine flow rate seen during the first 2 years of double-blind treatment was maintained throughout an additional 2 years of open-label extension trials. - Summary of Clinical Trials: Data from 3 large, well-controlled efficacy trials demonstrate that treatment with dutasteride (0.5 mg once daily) reduces the risk of both AUR and BPH-related surgical intervention relative to placebo, improves BPH-related symptoms, decreases prostate volume, and increases maximum urinary flow rates. These data suggest that dutasteride arrests the disease process of BPH in men with an enlarged prostate. ### Combination With Alpha-Blocker Therapy (CombAT) - The efficacy of combination therapy (dutasteride 0.5 mg/day plus tamsulosin 0.4 mg/day, n = 1,610) was compared with dutasteride alone (n = 1,623) or tamsulosin alone (n = 1,611) in a 4-year multicenter, randomized, double-blind trial. Trial entry criteria were similar to the double-blind, placebo-controlled monotherapy efficacy trials described above in section 14.1. Eighty-eight percent (88%) of the enrolled trial population was Caucasian. Approximately 52% of subjects had previous exposure to 5 alpha-reductase inhibitor or alpha adrenergic antagonist treatment. Of the 4,844 subjects randomly assigned to receive treatment, 69% of subjects in the combination group, 67% in the group receiving dutasteride, and 61% in the tamsulosin group completed 4 years of double-blind treatment. - Effect on Symptom Score: Symptoms were quantified using the first 7 questions of the International Prostate Symptom Score (IPSS) (identical to the AUA-SI). The baseline score was approximately 16.4 units for each treatment group. Combination therapy was statistically superior to each of the monotherapy treatments in decreasing symptom score at Month 24, the primary time point for this endpoint. At Month 24 the mean changes from baseline (±SD) in IPSS total symptom scores were -6.2 (±7.14) for combination, -4.9 (±6.81) for dutasteride, and -4.3 (±7.01) for tamsulosin, with a mean difference between combination and dutasteride of -1.3 units (P<0.001; [95% CI: -1.69, -0.86]), and between combination and tamsulosin of -1.8 units (P<0.001; [95% CI: -2.23, -1.40]). A significant difference was seen by Month 9 and continued through Month 48. At Month 48 the mean changes from baseline (±SD) in IPSS total symptom scores were -6.3 (±7.40) for combination, -5.3 (±7.14) for dutasteride, and -3.8 (±7.74) for tamsulosin, with a mean difference between combination and dutasteride of -0.96 units (P<0.001; [95% CI: -1.40, -0.52]), and between combination and tamsulosin of -2.5 units (P<0.001; [95% CI: -2.96, -2.07]). See Figure 6. - Effect on Acute Urinary Retention or the Need for BPH-Related Surgery: After 4 years of treatment, combination therapy with dutasteride and tamsulosin did not provide benefit over monotherapy with dutasteride in reducing the incidence of AUR or BPH-related surgery. - Effect on Maximum Urine Flow Rate: The baseline Qmax was approximately 10.7 mL/sec for each treatment group. Combination therapy was statistically superior to each of the monotherapy treatments in increasing Qmax at Month 24, the primary time point for this endpoint. At Month 24, the mean increases from baseline (±SD) in Qmax were 2.4 (±5.26) mL/sec for combination, 1.9 (±5.10) mL/sec for dutasteride, and 0.9 (±4.57) mL/sec for tamsulosin, with a mean difference between combination and Dutasteride of 0.5 mL/sec (P = 0.003; [95% CI: 0.17, 0.84]), and between combination and tamsulosin of 1.5 mL/sec (P<0.001; [95% CI: 1.19, 1.86]). This difference was seen by Month 6 and continued through Month 24. See Figure 7. - The additional improvement in Qmax of combination therapy over monotherapy with dutasteride was no longer statistically significant at Month 48. - Effect on Prostate Volume: The mean prostate volume at trial entry was approximately 55 cc. At Month 24, the primary time point for this endpoint, the mean percent changes from baseline (±SD) in prostate volume were -26.9% (±22.57) for combination therapy, -28.0% (±24.88) for dutasteride, and 0% (±31.14) for tamsulosin, with a mean difference between combination and dutasteride of 1.1% (P = NS; [95% CI: -0.6, 2.8]), and between combination and tamsulosin of -26.9% (P<0.001; [95% CI: -28.9, -24.9]). Similar changes were seen at Month 48: -27.3% (±24.91) for combination therapy, -28.0% (±25.74) for dutasteride, and +4.6% (±35.45) for tamsulosin. # How Supplied - Dutasteride Soft Gelatin Capsules 0.5 mg are oblong, opaque, dull yellow, gelatin capsules imprinted with “GX CE2” with red edible ink on one side packaged in bottles of 30 (NDC 0173-0712-15) and 90 (NDC 0173-0712-04) with child-resistant closures. ## Storage - Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F). - Dutasteride is absorbed through the skin. Dutasteride Capsules should not be handled by women who are pregnant or who could become pregnant because of the potential for absorption of dutasteride and the subsequent potential risk to a developing male fetus. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information # Precautions with Alcohol Alcohol-dutasteride interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names AVODART # Look-Alike Drug Names There is limited information about the look-alike drug names. # Drug Shortage Status # Price	https://www.wikidoc.org/index.php/Avodart
193e876c9a8988a43a82d829874db110d5e11e7f	wikidoc	Avoirdupois	Avoirdupois The avoirdupois (Template:IPAEng; French Template:IPA2) system is a system of weights (or, properly, mass) based on a pound of sixteen ounces. It is the everyday system of weight used in the United States. It is still widely used by many people in Canada and the United Kingdom despite the official adoption of the metric system, including the compulsory introduction of metric units in shops. It is considered more modern than the alternative troy or apothecary or the medieval English mercantile and Tower systems. # History of the term The word avoirdupois is from French and Middle English (Anglo-French) avoir de pois, "goods of weight" or "goods sold by weight", from Old French aveir de peis, literally "goods of weight" (Old French aveir, "property, goods", also "to have", comes from the Latin habere, "to have, to hold, to possess property"; de = "from", cf. Latin; peis = "weight", from Latin pensum). This term originally referred to a class of merchandise: aveir de peis, "goods of weight", things that were sold in bulk and were weighed on large steelyards or balances. Only later did it become identified with a particular system of units used to weigh such merchandise. The imaginative orthography of the day and the passage of the term through a series of languages (Latin, Anglo-French and English) has left many variants of the term, such as haberty-poie and haber de peyse. (The Norman peis became the Parisian pois. In the 17th century de was replaced with du.) # Original forms These are the units in their original French forms: Note: The plural of quintal is quintaux. # British adaptation When people in Britain began to use this system they included the stone, which was eventually defined as fourteen avoirdupois pounds. The quarter, hundredweight, and ton were altered, respectively, to 28 lb, 112 lb, and 2,240 lb in order for masses to be easily converted between them and stones. The following are the units in the British or imperial adaptation of the avoirdupois system: Note: The plural form of stone is conventionally written the same as the singular when used after a number. # American customary system The thirteen British colonies in North America (not including those that formed Canada), however, adopted the French system as it was. In the United States, quarters, hundredweights, and tons remain defined as 25, 100, and 2,000 lb respectively. The quarter is now virtually unused, as is the hundredweight outside of agriculture and commodities. If disambiguation is required then they are referred to as the "short" units, as opposed to the British "long" units. # Internationalization In the avoirdupois system, all units are multiples or fractions of the pound, which is now defined as 0.45359237 kg in most of the English-speaking world since 1959. (See the Mendenhall Order for references.) Due to the ambiguous meanings of "weight" as referring to both mass and force, it is sometimes erroneously asserted that the pound is only a unit of force. However, as defined above the pound is a unit of mass, which agrees with common usage. Also see pound-force and pound-mass.	Avoirdupois The avoirdupois (Template:IPAEng; French Template:IPA2) system is a system of weights (or, properly, mass) based on a pound of sixteen ounces. It is the everyday system of weight used in the United States. It is still widely used by many people in Canada and the United Kingdom despite the official adoption of the metric system, including the compulsory introduction of metric units in shops. It is considered[citation needed] more modern than the alternative troy or apothecary or the medieval English mercantile and Tower systems. # History of the term The word avoirdupois is from French and Middle English (Anglo-French) avoir de pois, "goods of weight" or "goods sold by weight", from Old French aveir de peis, literally "goods of weight" (Old French aveir, "property, goods", also "to have", comes from the Latin habere, "to have, to hold, to possess property"; de = "from", cf. Latin; peis = "weight", from Latin pensum). This term originally referred to a class of merchandise: aveir de peis, "goods of weight", things that were sold in bulk and were weighed on large steelyards or balances. Only later did it become identified with a particular system of units used to weigh such merchandise. The imaginative orthography of the day and the passage of the term through a series of languages (Latin, Anglo-French and English) has left many variants of the term, such as haberty-poie and haber de peyse. (The Norman peis became the Parisian pois. In the 17th century de was replaced with du.) # Original forms These are the units in their original French forms: Note: The plural of quintal is quintaux. # British adaptation When people in Britain began to use this system they included the stone, which was eventually defined as fourteen avoirdupois pounds. The quarter, hundredweight, and ton were altered, respectively, to 28 lb, 112 lb, and 2,240 lb in order for masses to be easily converted between them and stones. The following are the units in the British or imperial adaptation of the avoirdupois system: Note: The plural form of stone is conventionally written the same as the singular when used after a number. # American customary system The thirteen British colonies in North America (not including those that formed Canada), however, adopted the French system as it was. In the United States, quarters, hundredweights, and tons remain defined as 25, 100, and 2,000 lb respectively. The quarter is now virtually unused, as is the hundredweight outside of agriculture and commodities. If disambiguation is required then they are referred to as the "short" units, as opposed to the British "long" units. # Internationalization In the avoirdupois system, all units are multiples or fractions of the pound, which is now defined as 0.45359237 kg in most of the English-speaking world since 1959. (See the Mendenhall Order for references.) Due to the ambiguous meanings of "weight" as referring to both mass and force, it is sometimes erroneously asserted that the pound is only a unit of force. However, as defined above the pound is a unit of mass, which agrees with common usage. Also see pound-force and pound-mass.	https://www.wikidoc.org/index.php/Avoirdupois
176230239886e4004f36a95645836c7c1156f096	wikidoc	Azoospermia	Azoospermia Steven C. Campbell, M.D., Ph.D. # Overview Azoospermia is the medical condition of a male not having any measurable level of sperm in his semen. It is associated with very low levels of fertility. Azoospermia has two forms: - obstructive azoospermia, where sperm are created, but cannot be mixed with the rest of the ejaculatory fluid due to a physical obstruction, and; - non-obstructive azoospermia, where there is a problem with spermatogenesis, as in the condition of hyperprolactinemia. - congenital azoospermia, where azoospermia is a manifestation of cystic fibrosis due to agenesis of vas deferens. Azoospermia is a reported side effect of androgen drugs and corticosteroids because they suppress the hypothalamus release of GnRH and therefore FSH. This causes azoospermia in males and amenorrhea in females. Compare with aspermia. # Differential Diagnosis - 5-alpha reductase deficiency - Anabolic steroid hormone abuse - Androgen resistance syndromes - Congenital anorchism - Cryptorchidism - Drugs - Ejaculatory duct obstructive lesion - Epididymis obstructive lesion - Gonadotoxins - Hemochromatosis - Hypogonadotropic hypogonadism - Hypothyroidism - Impaired nerve function (retrograde ejaculation) - Mumps - Neurologic disease - Other bacterial infections - Postoperative conditions (retrograde ejaculation) - Prior urologic surgery - Psychosexual dysfunction - Sertoli only syndrome - Syphilis - Testicular Tuberculosis - Testicular tumor - Torsion - Traumatic damage - Varicocele - Vas deferens obstructive lesion - Vasectomy	Azoospermia Template:DiseaseDisorder infobox Steven C. Campbell, M.D., Ph.D. # Overview Azoospermia is the medical condition of a male not having any measurable level of sperm in his semen. It is associated with very low levels of fertility. Azoospermia has two forms: - obstructive azoospermia, where sperm are created, but cannot be mixed with the rest of the ejaculatory fluid due to a physical obstruction, and; - non-obstructive azoospermia, where there is a problem with spermatogenesis, as in the condition of hyperprolactinemia. - congenital azoospermia, where azoospermia is a manifestation of cystic fibrosis due to agenesis of vas deferens. Azoospermia is a reported side effect of androgen drugs and corticosteroids because they suppress the hypothalamus release of GnRH and therefore FSH. This causes azoospermia in males and amenorrhea in females. Compare with aspermia. # Differential Diagnosis - 5-alpha reductase deficiency - Anabolic steroid hormone abuse - Androgen resistance syndromes - Congenital anorchism - Cryptorchidism - Drugs - Ejaculatory duct obstructive lesion - Epididymis obstructive lesion - Gonadotoxins - Hemochromatosis - Hypogonadotropic hypogonadism - Hypothyroidism - Impaired nerve function (retrograde ejaculation) - Mumps - Neurologic disease - Other bacterial infections - Postoperative conditions (retrograde ejaculation) - Prior urologic surgery - Psychosexual dysfunction - Sertoli only syndrome - Syphilis - Testicular Tuberculosis - Testicular tumor - Torsion - Traumatic damage - Varicocele - Vas deferens obstructive lesion - Vasectomy [1] [2]	https://www.wikidoc.org/index.php/Azoospermia
2f387ef9ae6f15030442a3bb259f57768e5eb3ae	wikidoc	Azygos vein	Azygos vein # Overview The azygos vein is a vein running up the right side of the thoracic vertebral column. # Structure The azygos vein transports deoxygenated blood from the posterior walls of the thorax and abdomen into the superior vena cava vein. The anatomy of this blood vessel can be quite variable. In some rare variations for example, it also drains thoracic veins, bronchial veins and even gonadal veins. The vein is so named because it has no symmetrically equivalent vein on the left side of the body. It is formed by the union of the ascending lumbar veins with the right subcostal veins at the level of the 12th thoracic vertebra, ascending in the posterior mediastinum, and arching over the root of the right lung to join the superior vena cava. This "arch of the azygos vein" (arcus venae azygou) is an important anatomic landmark. Its tributaries, apart from its main tributary, the hemiazygos vein, are the bronchial veins, pericardial veins, and posterior right intercostal veins. It communicates with the vertebral venous plexuses. # Azygos venous system The azygos system of veins is considered to be the azygos vein, along with its left-sided counterparts, the hemiazygos vein and the accessory hemiazygos vein. Together, they form an anastomosis between the superior vena cava to the inferior vena cava. It can be noted that the azygos system of veins exists because the superior vena cava and the inferior vena cava are not continuous. While the aorta travels downward (continuously) through the mediastinum, supplying blood to the intercostal spaces, the vena cava does not exist at the level of the heart. Thus, the azygos venous system makes up for this deficiency of the venae cavae. # Etymology The Greek root zyg refers to a pair. 'A-' means not. Thus, azygos means unpaired. The azygos vein is unpaired in that there is only one in the body, mostly on the right side. While there is the hemiazygos vein and its accessory on the left side of the body, they are considered tributaries of the azygos vein rather than its left-side equivalent. # Additional images - Diagram showing completion of development of the parietal veins. - Transverse section of thorax, showing relations of pulmonary artery. - Base and diaphragmatic surface of heart. - The venæ cavæ and azygos veins, with their tributaries. - The thoracic and right lymphatic ducts. - Mediastinal surface of right lung. - A young patient was involved in a trauma. A supine thoracic spine film demonstrates a rounded opacity in the right mediastinum, just superior to the right main bronchus (arrow). This opacity is a distended azygous vein, and it collapses when the patient is erect (erect chest xray). The azygous vein is a normal structure which may be distended in the supine position, right heart failure, inferior vena cava obstruction, and portosystemic shunting.	Azygos vein Template:Infobox Vein Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview The azygos vein is a vein running up the right side of the thoracic vertebral column. # Structure The azygos vein transports deoxygenated blood from the posterior walls of the thorax and abdomen into the superior vena cava vein. The anatomy of this blood vessel can be quite variable. In some rare variations for example, it also drains thoracic veins, bronchial veins and even gonadal veins. The vein is so named because it has no symmetrically equivalent vein on the left side of the body. It is formed by the union of the ascending lumbar veins with the right subcostal veins at the level of the 12th thoracic vertebra, ascending in the posterior mediastinum, and arching over the root of the right lung to join the superior vena cava. This "arch of the azygos vein" (arcus venae azygou) is an important anatomic landmark. Its tributaries, apart from its main tributary, the hemiazygos vein, are the bronchial veins, pericardial veins, and posterior right intercostal veins. It communicates with the vertebral venous plexuses. # Azygos venous system The azygos system of veins is considered to be the azygos vein, along with its left-sided counterparts, the hemiazygos vein and the accessory hemiazygos vein. Together, they form an anastomosis between the superior vena cava to the inferior vena cava. It can be noted that the azygos system of veins exists because the superior vena cava and the inferior vena cava are not continuous. While the aorta travels downward (continuously) through the mediastinum, supplying blood to the intercostal spaces, the vena cava does not exist at the level of the heart. Thus, the azygos venous system makes up for this deficiency of the venae cavae. # Etymology The Greek root zyg refers to a pair. 'A-' means not. Thus, azygos means unpaired. The azygos vein is unpaired in that there is only one in the body, mostly on the right side. While there is the hemiazygos vein and its accessory on the left side of the body, they are considered tributaries of the azygos vein rather than its left-side equivalent. # Additional images - Diagram showing completion of development of the parietal veins. - Transverse section of thorax, showing relations of pulmonary artery. - Base and diaphragmatic surface of heart. - The venæ cavæ and azygos veins, with their tributaries. - The thoracic and right lymphatic ducts. - Mediastinal surface of right lung. - A young patient was involved in a trauma. A supine thoracic spine film demonstrates a rounded opacity in the right mediastinum, just superior to the right main bronchus (arrow). This opacity is a distended azygous vein, and it collapses when the patient is erect (erect chest xray). The azygous vein is a normal structure which may be distended in the supine position, right heart failure, inferior vena cava obstruction, and portosystemic shunting.	https://www.wikidoc.org/index.php/Azygos_vein
88a65ca53a8b8fe506f3309892fa329dad0f137a	wikidoc	B.J. Palmer	B.J. Palmer Bartlett Joshua (B.J.) Palmer (September 10, 1881-May 21, 1961) was a pioneer of Chiropractic. # Early life B.J. was son of Daniel David Palmer (or "D.D."), the "Founder" of chiropractic. The Palmer family of six resided in the back of a grocery store that D.D. operated. In 1885 D.D.'s wife became sick and died, after which D.D. remarried numerous times. When D.D. had settled with a new wife, he moved the family to Letts, Iowa, and he worked as a schoolteacher and a magnetic healer, developing chiropractic. B.J. developed an interest in chiropractic, and eventually assumed control of the school that his father had founded in Davenport, Iowa. As a result of his development and promotion of the profession, he became known as the "Developer" of chiropractic. # Life On May 30, 1904, Palmer married Mabel Heath, and they both worked as chiropractors and instructors at Palmer College. B.J. Palmer ran his research clinics in Davenport, IA. for 16 years and eventually became convinced that upper cervical spine was the key to health. He coined the new method Hole-In-One (HIO) as known as Upper Cervical via Toggle Recoid application. Subsequently, he modified the PSC's curriculum to reflect his new ideas. Palmer advocated the use of Neurocalometer and x-ray machine. On December 12, 1906 David Daniel Palmer was born, and would be the couple's only child. In keeping with his educational efforts for the profession, he became known as "The Educator." They had an estranged relationship for a number of years when David decide to attended University of Pennsylvania and later its Wharton School of Business. Palmer also became involved in a number of technological advances in his region of Iowa. He owned the first automobile in the area, and he would use it when he made house calls. In 1922, Palmer purchased a local radio station, WOC (whose call letters stood for "Wonders Of Chiropractic"), and began using it to market chiropractic, as well as to broadcast farm, sports and weather reports. Ronald Reagan, future President of the United States and actor, was given his first broadcast job by Dr. Palmer to broadcast sports for WOC. A second station in Des Moines, WHO, ("With Hands Only") was purchased in 1930. Television stations were later added under the same call letters.	B.J. Palmer Bartlett Joshua (B.J.) Palmer (September 10, 1881-May 21, 1961) was a pioneer of Chiropractic. # Early life B.J. was son of Daniel David Palmer (or "D.D."), the "Founder" of chiropractic. The Palmer family of six resided in the back of a grocery store that D.D. operated. In 1885 D.D.'s wife became sick and died, after which D.D. remarried numerous times. When D.D. had settled with a new wife, he moved the family to Letts, Iowa, and he worked as a schoolteacher and a magnetic healer, developing chiropractic. B.J. developed an interest in chiropractic, and eventually assumed control of the school that his father had founded in Davenport, Iowa. As a result of his development and promotion of the profession, he became known as the "Developer" of chiropractic. # Life On May 30, 1904, Palmer married Mabel Heath, and they both worked as chiropractors and instructors at Palmer College. B.J. Palmer ran his research clinics in Davenport, IA. for 16 years and eventually became convinced that upper cervical spine was the key to health. He coined the new method Hole-In-One (HIO) as known as Upper Cervical via Toggle Recoid application. Subsequently, he modified the PSC's curriculum to reflect his new ideas. Palmer advocated the use of Neurocalometer and x-ray machine. On December 12, 1906 David Daniel Palmer was born, and would be the couple's only child. In keeping with his educational efforts for the profession, he became known as "The Educator."[1] They had an estranged relationship for a number of years when David decide to attended University of Pennsylvania and later its Wharton School of Business. Palmer also became involved in a number of technological advances in his region of Iowa. He owned the first automobile in the area, and he would use it when he made house calls. In 1922, Palmer purchased a local radio station, WOC (whose call letters stood for "Wonders Of Chiropractic"),[1] and began using it to market chiropractic, as well as to broadcast farm, sports and weather reports. Ronald Reagan, future President of the United States and actor, was given his first broadcast job by Dr. Palmer to broadcast sports for WOC. A second station in Des Moines, WHO, ("With Hands Only") was purchased in 1930. Television stations were later added under the same call letters.	https://www.wikidoc.org/index.php/B.J._Palmer
2a78649a2cd4b3286689ae6c906e022ad3221415	wikidoc	Vitamin B12	Vitamin B12 Vitamin B-12 is a vitamin which is important for the normal functioning of the brain and nervous system, and for the formation of blood. It is normally involved in the metabolism of every cell of the body, especially affecting DNA synthesis and regulation, but also fatty acid synthesis and energy production. Vitamin B-12 is the name for a class of chemically-related compounds, all of which have vitamin activity. It is structurally the most complicated vitamin. Biosynthesis of the basic structure of the vitamin can only be accomplished by bacteria, but conversion between different forms of the vitamin can be accomplished in the human body. A common form of the vitamin, cyanocobalamin, does not occur in nature, but is used as a supplement and food additive, due to its stability. It is converted to other forms of the vitamin which are actually used in chemical reactions in the body. Historically, vitamin B-12 was discovered from its relationship to the disease pernicious anemia, which was eventually discovered to result from an effective lack of this vitamin due to problems with the mechanisms in the body which normally absorb it. Many other more subtle kinds of biochemical B-12 deficiencies, and biochemical effects from them, have since been elucidated. A B12 deficiency causes: - distinctive dyserythropoietic abnormalities in the bone marrow - megaloblastic erythropoiesis which is associated with abnormally large red cells in the peripheral cells, for example macrocytosis. A severe deficiency in B12 can cause pernicious anemia and funicular myelosis. # Terminology The name vitamin B-12, known also as vitamin BTemplate:Ssub (or commonly BTemplate:Ssub or B-12 for short) generally refers to all forms of the vitamin. Some medical practitioners have suggested that its use be split into two different categories, however. - In a broad sense B-12 still refers to a group of cobalt-containing vitamer compounds known as cobalamins: these include cyanocobalamin (an artifact formed as a result of the use of cyanide in the purification procedures), hydroxocobalamin (another medicinal form), and finally, the two naturally occurring cofactor forms of B-12: 5-deoxyadenosylcobalamin (adenosylcobalamin—AdoB-12), the cofactor of Methylmalonyl Coenzyme A mutase (MUT), and methylcobalamin (MeB-12), the cofactor of 5-methyltetrahydrofolate-homocysteine methyltransferase (MTR). - The term B-12 may be properly used to refer to cyanocobalamin, the principal B-12 form used for foods and in nutritional supplements. This ordinarily creates no problem, except perhaps in rare cases of eye nerve damage, where the body is only marginally able to use this form due to high cyanide levels in the blood due to cigarette smoking, and thus requires cessation of smoking, or else B-12 given in another form, for the optic symptoms to abate. However, tobacco amblyopia is a rare enough condition that debate continues about whether or not it represents a peculiar B-12 deficiency which is resistant to treatment with cyanocobalamin. Finally, so-called Pseudo-B-12 refers to B-12-like substances which are found in certain organisms, including spirulina (a cyanobacterium) and some algae. These substances are active in tests of B-12 activity by highly sensitive antibody-binding serum assay tests, which measure levels of B-12 and B-12 like compounds in blood. However, these substances do not have B-12 biological activity for humans, a fact which may pose a theoretical danger to vegans and others on limited diets who do not ingest B-12 producing bacteria, but who nevertheless may show normal "B-12" levels in the standard immunoassay which has become the normal medical method for testing for B-12 deficiency. # Structure Vitamin B-12 is a collection of cobalt and corrin ring molecules which are defined by their particular vitamin function in the body. All of the substrate cobalt-corrin molecules from which B-12 is made must be synthesized by bacteria. However, after this synthesis is complete, the body has a limited power to convert any form of B-12 to another, by means of enzymatically removing certain prosthetic chemical groups from the cobalt atom. Cyanocobalamin is one such compound that is a vitamin in this B complex, because it can be metabolized in the body to an active co-enzyme form. However, the cyanocobalamin form of B-12 does not occur in nature normally, but is a byproduct of the fact that other forms of B-12 are avid binders of cyanide (-CN) which they pick up in the process of activated charcoal purification of the vitamin after it is made by bacteria in the commercial process. Since the cyanocobalamin form of B-12 is deeply red colored, easy to crystallize, and is not sensitive to air-oxidation, it is typically used as a form of B-12 for food additives and in many common multivitamins. However, this form is not perfectly synonymous with B-12, inasmuch as a number of substances (vitamers) have B-12 vitamin activity and can properly be labeled vitamin B-12, and cyanocobalamin is but one of them. (Thus, all cyanocobalamin is vitamin B-12, but not all vitamin B-12 is cyanocobalamin). B-12 is the most chemically complex of all the vitamins. The structure of B-12 is based on a corrin ring, which is similar to the porphyrin ring found in heme, chlorophyll, and cytochrome. The central metal ion is Co (cobalt). Four of the six coordination sites are provided by the corrin ring, and a fifth by a dimethylbenzimidazole group. The sixth coordination site, the center of reactivity, is variable, being a cyano group (-CN), a hydroxyl group (-OH), a methyl group (-CH3) or a 5'-deoxyadenosyl group (here the C5' atom of the deoxyribose forms the covalent bond with Co), respectively, to yield the four B-12 forms mentioned above. The covalent C-Co bond is one of first examples of carbon-metal bonds in biology. The hydrogenases and, by necessity, enzymes associated with cobalt utilization, involve metal-carbon bonds. # Synthesis Vitamin B-12 cannot be made by plants or animals as only bacteria have the enzymes required for its synthesis. The total synthesis of B-12 was reported by Robert Burns Woodward and Albert Eschenmoser, and remains one of the classic feats of organic synthesis. Species from the following genera are known to synthesize B-12: Aerobacter, Agrobacterium, Alcaligenes, Azotobacter, Bacillus, Clostridium, Corynebacterium, Flavobacterium, Micromonospora, Mycobacterium, Nocardia, Propionibacterium, Protaminobacter, Proteus, Pseudomonas, Rhizobium, Salmonella, Serratia, Streptomyces, Streptococcus and Xanthomonas. Industrial production of B-12 is through fermentation of selected microorganisms. The species most often used, Pseudomonas denitrificans and Propionibacterium shermanii, are frequently genetically engineered and grown under special conditions to enhance yield. # Functions Vitamin B-12 is normally involved in the metabolism of every cell of the body, especially affecting the DNA synthesis and regulation but also fatty acid synthesis and energy production. However, many (though not all) of the effects of functions of B-12 can be replaced by sufficient quantities of folic acid (another B vitamin), since B-12 is used to regenerate folate in the body. Most "B-12 deficient symptoms" are actually folate deficient symptoms, since they include all the effects of pernicious anemia and megaloblastosis, which are due to poor synthesis of DNA when the body does not have a proper supply of folic acid for the production of thymine. When sufficient folic acid is available, all known B-12 related deficiency syndromes normalize, save those narrowly connected with the B-12 dependent enzymes Methylmalonyl Coenzyme A mutase (MUT), and 5-methyltetrahydrofolate-homocysteine methyltransferase (MTR), also known as methionine synthase; and the buildup of their respective substrates (methylmalonic acid, MMA) and homocysteine. Coenzyme B-12's reactive C-Co bond participates in two types of enzyme-catalyzed reactions. - Rearrangements in which a hydrogen atom is directly transferred between two adjacent atoms with concomitant exchange of the second substituent, X, which may be a carbon atom with substituents, an oxygen atom of an alcohol, or an amine. - Methyl (-CH3) group transfers between two molecules. In humans, only two corresponding coenzyme B-12-dependent enzymes are known: - Methylmalonyl Coenzyme A mutase (MUT) which uses the AdoB-12 form and reaction type 1 to catalyze a carbon skeleton rearrangement (the X group is -COSCoA). MUT's reaction converts MMl-CoA to Su-CoA, an important step in the extraction of energy from proteins and fats (for more see MUT's reaction mechanism). This functionality is lost in vitamin B-12 deficiency, and can be measured clinically as an increased methylmalonic acid (MMA) level. Unfortunately, an elevated MMA, though sensitive to B-12 deficiency, is probably overly sensitive, and not all who have it actually have B-12 deficiency. For example, MMA is elevated in 90-98% of patients with B-12 deficiency; however 25-20% of patients over the age of 70 have elevated levels of MMA, yet 25-33% of them do not have B-12 deficiency. For this reason, MMA is not routinely recommended in the elderly. The "gold standard" test for B-12 deficiency continues to be low blood levels of the vitamin. The MUT function cannot be affected by folate supplementation, and which is necessary for myelin synthesis (see mechanism below) and certain other functions of the central nervous system. Other functions of B-12 related to DNA synthesis related to MTR dysfunction (see below) can often be corrected with supplementation with the vitamin folic acid, but not the elevated levels of homocysteine, which is normally converted to methionine by MTR. - 5-methyltetrahydrofolate-homocysteine methyltransferase (MTR), also known as methionine synthase. This is a methyl transfer enzyme, which uses the MeB-12 and reaction type 2 to catalyze the conversion of the amino acid Hcy back into Met (for more see MTR's reaction mechanism). This functionality is lost in vitamin B-12 deficiency, and can be measured clinically as an increased homocysteine level in vitro. Increased homocysteine can also be caused by a folic acid deficiency, since B-12 helps to regenerate the tetrahydrofolate (THF) active form of folic acid. Without B-12, folate is trapped as 5-methyl-folate, from which THF cannot be recovered unless a MTR process reacts the 5-methyl-folate with homocysteine to produce methionine and THF, thus decreasing the need for fresh sources of THF from the diet. THF may be produced in the conversion of homocysteine to methionine, or may be obtained in the diet. It is converted by a non-B-12-dependent process to 5,10-methylene-THF, which is involved in the synthesis of thymine. Reduced availability of 5,10-methylene-THF results in problems with DNA synthesis, and ultimately in ineffective production cells with rapid turnover, in particular blood cells, and also intestinal wall cells which are responsible for absorption. The failure of blood cell production results in the once-dreaded and fatal disease, pernicious anemia. All of the DNA synthetic effects, including the megaloblastic anemia of pernicious anemia, resolve if sufficient folate is present (since levels of 5,10-methylene-THF still remain adequate with enough dietary folate). Thus the best known function of B-12 (that which is indirectly involved with DNA synthesis and restoration of cell-division and anemia) is actually a facultative function which is mediated by B-12 conservation of active folate which can be used for DNA production. If folate is present in quantity, then of the two absolutely B-12 dependent reactions, the MUT reaction shows the most direct and characteristic secondary effects, focusing on the nervous system. Since the late 1990s folic acid has begun to be added to fortify flour in many countries, so that folate deficiency is now more rare. At the same time, since DNA synthetic-sensitive tests for anemia and erythrocyte size are routinely done in even simple medical test clinics (so that these folate mediated-biochemical effects are more often directly detected), the MTR dependent effects of B-12 deficiency are becoming apparent not as anemia (as they were classically), but now mainly as an elevation of homocysteine in the blood and urine (homocysteinuria). This condition may result in long term damage to arteries and in clotting (stroke and heart attack), but is difficult to separate from other processes associated with atherosclerosis and aging. The B-12 dependent MTR reactions may have neurological effects through an indirect mechanism. Adequate methionine (which must otherwise be obtained in the diet) is needed to make S-adenosyl-methionine, which is in turn necessary for methylation of myelin sheath phospholipids. In addition, SAMe is involved in the manufacture of certain neurotransmitters, catecholamines and in brain metabolism. These neurotransmitters are important for maintaining mood, possibly explaining why depression is associated with B-12 deficiency. Methylation of the myelin sheath phospholipids may also depend on adequate folate, which in turn is dependent on MTR recycling, unless ingested in relatively high amounts. The specific myelin damage resulting from from B-12 deficiency has also been connected to B-12 reactions related to MUT, which is needed to convert methylmalonyl coenzyme A into succinyl coenzyme A. Failure of this second reaction to occur results in elevated levels of methylmalonic acid (MMA), a myelin destabilizer. Excessive MAA will prevent normal fatty acid synthesis, or it will be incorporated into fatty acid itself rather than normal malonic acid. If this abnormal fatty acid subsequently is incorporated into myelin, the resulting myelin will be too fragile, and demyelination will occur. Although the precise methanism(s) are not known with certainty, the result is subacute combined degeneration of central nervous system and spinal cord. Whatever the cause, it is known that B-12 deficiency causes neuropathies, even if folic acid is present in good supply, and therefore anemia is not present. # Human absorption and distribution The human physiology of vitamin B-12 is complex, and therefore is prone to mishaps leading to vitamin B-12 deficiency. The vitamin as it occurs in foods enters the digestive tract bound to proteins, known as salivary R-binders. Stomach proteolysis of these proteins requires an acid pH, and also requires proper pancreatic release of proteolytic enzymes. (Even small amounts of B-12 taken in supplements bypasses these steps and thus any need for gastric acid, which may be blocked by antacid drugs). The free B-12 then attaches to gastric intrinsic factor, which is generated by the gastric parietal cells. If this step fails due to gastric parietal cell atrophy (the problem in pernicious anemia), sufficient B-12 is not absorbed later on, unless administered orally in relatively massive doses (500 to 1000 mcg/day). The conjugated vitamin B-12-intrinsic factor complex (IF/B-12) is then normally absorbed by the terminal ileum of the small bowel. Absorption of food vitamin B-12 therefore requires an intact and functioning stomach, exocrine pancreas, intrinsic factor, and small bowel. Problems with any one of these organs makes a vitamin B-12 deficiency possible. Once the IF/B-12 complex is recognized by specialized ileal receptors, it is transported into the portal circulation. The vitamin is then transferred to transcobalamin II (TC-II/B-12), which serves as the plasma transporter of the vitamin. Genetic deficiencies of this protein are known, also leading to functional B-12 deficiency. For the vitamin to serve inside cells, the TC-II/B-12 complex must bind to a cell receptor, and be endocytosed. The transcobalamin-II is degraded within a lysozyme, and the B-12 is finally released into the cytoplasm, where it may be transformed into the proper coenzyme, by certain cellular enzymes (see above). Hereditary defects in production of the transcobalamins and their receptors may produce functional deficiencies in B-12 and infantile megaloblastic anemia, and abnormal B-12 related biochemistry, even in some cases with normal blood B-12 levels. The total amount of vitamin B-12 stored in body is about 2,000-5,000 mcg in adults. Around 80% of this is stored in the liver. 0.1 % of this is lost per day by secretions into the gut as not all these secretions are reabsorbed. How fast B-12 levels change depends on the balance between how much B-12 is obtained from the diet, how much is secreted and how much is absorbed. B-12 deficiency may arise in a year if initial stores are low and genetic factors unfavourable or may not appear for decades. In infants, B-12 deficiency can appear much more quickly. # History of B-12 as a treatment for pernicious anemia B-12 deficiency is the cause of pernicious anemia, a usually-fatal disease of unknown etiology when it was first described in medicine. The cure was discovered by accident. George Whipple had been inducing anemia in dogs by bleeding them, and then conducting experiments in which he fed them various foods to observe which diets allowed them fastest recovery from the anemia produced. In the process, he discovered that ingesting large amounts of liver seemed to most-rapidly cure the anemia of blood loss, and hypothesized that therefore liver ingestion be tried for pernicious anemia, an anemic disease of the time with no known cause or cure. He tried this and reported some signs of success in 1920. After a series of careful clinical studies George Minot and William Murphy set out to partly isolate the substance in liver which cured anemia in dogs, and found that it was iron. They found further that the partly isolated water-soluble liver-substance which cured pernicious anemia in humans, was something else entirely different -- and which had no effect at all on canines under the conditions used. The specific factor treatment for pernicious anemia, found in liver juice, had been found by this coincidence. These experiments were reported by Minot and Murphy in 1926, marking the date of the first real progress with this disease, though for several years, patients were still required to eat large amounts of raw liver or to drink considerable amounts of liver juice. In 1928, the chemist Edwin Cohn prepared a liver extract that was 50 to 100 times more potent than the natural liver products. The extract was the first workable treatment for the disease. For their initial work in pointing the way to a working treatment, Whipple, Minot, and Murphy shared the 1934 Nobel Prize in Physiology or Medicine. The active ingredient in liver was not isolated until 1948 by the chemists Karl A. Folkers of the United States and Alexander R. Todd of Great Britain. The substance was a cobalamin called vitamin B-12. It could also be injected directly into muscle, making it possible to treat pernicious anemia more easily. The chemical structure of the molecule was determined by Dorothy Crowfoot Hodgkin and her team in 1956, based on crystallographic data. Eventually, methods of producing the vitamin in large quantities from bacteria cultures were developed in the 1950s, and these led to the modern form of treatment for the disease. # Symptoms and damage from deficiency Vitamin B-12 deficiency can potentially cause severe and irreversible damage, especially to the brain and nervous system. At levels only slightly lower than normal, a range of symptoms such as fatigue, depression, and poor memory may be experienced. However, these symptoms by themselves are too nonspecific to diagnose deficiency of the vitamin. Vitamin B-12 deficiency has the following pathomorphology and symptoms: Pathomorphology includes: A spongiform state of neural tissue along with edema of fibers and deficiency of tissue. The myelin decays, along with axial fiber. In later phases, fibric sclerosis of nervous tissues occurs. Those changes apply to dorsal parts of the spinal cord, and to pyramidal tracts in lateral cords. In the brain itself, changes are less severe: they occur as small sources of nervous fibers decay and accumulation of astrocytes, usually subcortically located, an also round hemorrhages with a torus of glial cells. Pathological changes can be noticed as well in the posterior roots of the cord and, to lesser extent, in peripheral nerves. Clinical symptoms : The main syndrome of vitamin B-12 deficiency is Addison's disease and Biermer's disease (pernicious anemia). It is characterized by a triad of symptoms: 1) Anemia with bone marrow promegaloblastosis (Megaloblastic anemia) 2) Gastrointestinal symptoms; 3) Neurological symptoms. Each of those symptoms can occur either alone or along with others. The neurological complex, defined as myelosis funicularis, consists of the following symptoms: 1) Impaired perception of deep touch, pressure and vibration, abolishment of sense of touch, very annoying and persistent paresthesias; 2) Ataxia of dorsal cord type; 3) Decrease or abolishment of deep muscle-tendon reflexes; 4) Pathological reflexes - Babinski, Rossolimo and others, also severe paresis. During the course of disease, mental disorders can occur: irritablity, focus/concentration problems, depressive state with suicidal tendencies, paraphrenia complex. These symptoms may not reverse after correction of hematological abnormalities, and the chance of complete reversal decreases with the length of time the neurological symptoms have been present. # Differential Diagnosis of Causes of Vitamin B12 Deficiency In alphabetical order. - Acute Hepatitis - Bacterial colonization of the small intestine - Caustic burn of the stomach mucosa - Chronic Atrophic Gastritis - Chronic hepatitis - Chronic Kidney Disease - Chronic Liver Disease - Diseases of the terminal ileum - Fish tapeworm - Genuine pernicious anemia - Hepatic tumor - Leukemia - Malnutrition - Polycythemia - Pregnancy - Stomach polyposis - Stomach resection - Strict vegetarian diet - Transcobalamin 2 deficiency # Sources Vitamin B-12 is naturally found in foods of animal origin including meat (especially liver and shellfish) and milk products. Animals, in turn, must obtain it directly or indirectly from bacteria, and these bacteria may inhabit a section of the gut which is posterior to the section where B-12 is absorbed. Thus, herbivorous animals must either obtain B-12 from bacteria in their rumens, or (if fermenting plant material in the hindgut) by reingestion of cecotrope feces. Eggs are often mentioned as a good B-12 source, but they also contain a factor that blocks absorption. Certain insects such as termites contain B-12 produced by their gut bacteria, in a manner analogous to ruminant animals. An NIH Fact Sheet lists a variety of food sources of vitamin B-12. Plants only supply B-12 to humans when the soil containing B-12-producing microorganisms has not been washed from them. Vegan humans who eat only washed vegetables must take special care to supplement their diets accordingly. According to the U.K. Vegan Society, the only reliable vegan sources of B-12 are foods fortified with B-12 (including some plant milks, some soy products and some breakfast cereals), and B-12 supplements. Fortified breakfast cereals are a particularly valuable source of vitamin B-12 for vegetarians and vegans. While lacto-ovo vegetarians usually get enough B-12 through consuming dairy products, vitamin B-12 may be found to be lacking in those practicing vegan diets who do not use multivitamin supplements or eat B-12 fortified foods, such as fortified breakfast cereals, fortified soy-based products, and fortified energy bars. Claimed sources of B-12 that have been shown through direct studies of vegans to be inadequate or unreliable include, laver (a seaweed), barley grass, and human gut bacteria. People on a vegan raw food diet are also susceptible to B-12 deficiency if no supplementation is used. The Vegan Society, the Vegetarian Resource Group, and the Physicians Committee for Responsible Medicine, among others, recommend that vegans either consistently eat foods fortified with B-12 or take a daily or weekly B-12 supplement. Cyanocobalamin is converted to its active forms, first hydroxocobalamin and then methylcobalamin and adenosylcobalamin in the liver. The sublingual route, in which B-12 is presumably or supposedly absorbed more directly under the tongue, has not proven to be necessary or helpful. A 2003 study found no significant difference in absorption for serum levels from oral vs. sublingual delivery of 500 micrograms of cobalamin. However, if patient has inborn errors in the methyltransfer pathway (cobalamin C disease, combined methylmalonic aciduria and homocystinuria), treating with intravenous or intramuscular hydroxocobalamin is needed. Vitamin B-12 can be supplemented in healthy subjects also by liquid, strip, nasal spray, or injection. B-12 is available singly or in combination with other supplements. Injection is sometimes used in cases where digestive absorption is impaired, but there is some evidence that this course of action may not be necessary with modern high potency oral supplements (such as 500 to 1000 mcg or more). These supplements carry such large doses of the vitamin that the many different components of the B-12 absorption system are not required, and enough of the vitamin (only a few mcg a day) is obtained simply by mass-action transport across the gut. Even pernicious anemia can be treated entirely by the oral route. For the much lower amounts of B-12 found in food sources, however, oral absorption is complex and requires stomach acid, and also specific intestinal transport proteins (intrinsic factor) produced in the stomach. Lack of function in these systems is the causes of much of the increased risk in many elderly persons who develop B-12 deficiency later in life. However, it can be treated with a simple high dose oral B-12 supplement. Cyanocobalamin is also sometimes added to beverages including Diet Coke Plus and many energy drinks, in some cases with over 80 times the recommended intake. However, 500 mcg would be needed to reverse biochemical signs of vitamin B-12 deficiency in older adults. # Allergies Vitamin B-12 supplements in theory should be avoided in people sensitive or allergic to cobalamin, cobalt, or any other product ingredients. However, direct allergy to a vitamin or nutrient is extremely rare, and if reported, other causes should be sought. # Side effects, contraindications, and warnings - Dermatologic: Itching, rash, transitory exanthema, and urticaria have been reported. Vitamin B-12 (20 micrograms/day) and pyridoxine (80mg/day) has been associated with cases of rosacea fulminans, characterized by intense erythema with nodules, papules, and pustules. Symptoms may persist for up to 4 months after the supplement is stopped, and may require treatment with systemic corticosteroids and topical therapy. - Gastrointestinal: Diarrhea has been reported. - Hematologic: Peripheral vascular thrombosis has been reported. Treatment of vitamin B-12 deficiency can unmask polycythemia vera, which is characterized by an increase in blood volume and the number of red blood cells. The correction of megaloblastic anemia with vitamin B-12 can result in fatal hypokalemia and gout in susceptible individuals, and it can obscure folate deficiency in megaloblastic anemia. Caution is warranted. - Leber's disease: Vitamin B-12 in the form of cyanocobalamin is contraindicated in early Leber's disease, which is hereditary optic nerve atrophy. Cyanocobalamin can cause severe and swift optic atrophy, but other forms of vitamin B-12 are available. However, the sources of this statement are not clear, while an opposing view concludes: "The clinical picture of optic neuropathy associated with vitamin B-12 deficiency shows similarity to that of Leber's disease optic neuropathy. Both involve the nerve fibres of the papillomacular bundle. The present case reports suggest that optic neuropathy in patients carrying a primary LHON mtDNA mutation may be precipitated by vitamin B-12 deficiency. Therefore, known carriers should take care to have an adequate dietary intake of vitamin B-12 and malabsorption syndromes like those occurring in familial pernicious anaemia or after gastric surgery should be excluded." # Normal requirement, and in pregnancy and breastfeeding The Dietary Reference Intake for an adult ranges from 2 to 3 µg (micrograms). The recommended optimal daily intake (ODI) is 10 to 15 µg. Vitamin B-12 is believed to be safe when used orally in amounts that do not exceed the recommended dietary allowance (RDA). The RDA for vitamin B-12 in pregnant women is 2.6 µg per day and 2.8 µg during lactation periods. There is insufficient reliable information available about the safety of consuming greater amounts of Vitamin B-12 during pregnancy. # Other medical uses Hydroxycobalamin, or hydoxocobalamin, also known as Vitamin B-12a, is used in Europe both for vitamin B-12 deficiency and as a treatment for cyanide poisoning, sometimes with a large amount (5-10 g) given intravenously, and sometimes in combination with sodium thiosulfate. The mechanism of action is straightforward: the hydroxycobalamin hydroxide ligand is displaced by the toxic cyanide ion, and the resulting harmless B-12 complex is excreted in urine. In the United States, the FDA has approved in 2006 the use of hydroxocobalamin for acute treatment of cyanide poisoning. # Interactions ## Interactions with drugs - Alcohol (ethanol): Excessive alcohol intake lasting longer than two weeks can decrease vitamin B-12 absorption from the gastrointestinal tract, leading to Korsakoff's Syndrome. - Aminosalicylic acid (para-aminosalicylic acid, PAS, Paser): Aminosalicylic acid can reduce oral vitamin B-12 absorption, possibly by as much as 55%, as part of a general malabsorption syndrome. Megaloblastic changes, and occasional cases of symptomatic anemia have occurred, usually after doses of 8 to 12 grams/day for several months. Vitamin B-12 levels should be monitored in people taking aminosalicylic acid for more than one month. - Antibiotics: An increased bacterial load can bind significant amounts of vitamin B-12 in the gut, preventing its absorption. In people with bacterial overgrowth of the small bowel, antibiotics such as metronidazole (Flagyl®) can actually improve vitamin B-12 status. The effects of most antibiotics on gastrointestinal bacteria are unlikely to have clinically significant effects on vitamin B-12 levels. - Hormonal contraception: The data regarding the effects of oral contraceptives on vitamin B-12 serum levels are conflicting. Some studies have found reduced serum levels in oral contraceptive users, but others have found no effect despite use of oral contraceptives for up to 6 months. When oral contraceptive use is stopped, normalization of vitamin B-12 levels usually occurs. Lower vitamin B-12 serum levels seen with oral contraceptives probably are not clinically significant. - Chloramphenicol (Chloromycetin®): Limited case reports suggest that chloramphenicol can delay or interrupt the reticulocyte response to supplemental vitamin B-12 in some patients. Blood counts should be monitored closely if this combination cannot be avoided. - Cobalt irradiation: Cobalt irradiation of the small bowel can decrease gastrointestinal (GI) absorption of vitamin B-12. - Colchicine: Colchicine in doses of 1.9 to 3.9mg/day can disrupt normal intestinal mucosal function, leading to malabsorption of several nutrients, including vitamin B-12. Lower doses do not seem to have a significant effect on vitamin B-12 absorption after 3 years of colchicine therapy. The significance of this interaction is unclear. Vitamin B-12 levels should be monitored in people taking large doses of colchicine for prolonged periods. - Colestipol (Colestid®), Cholestyramine (Questran®): These resins used for sequestering bile acids in order to decrease cholesterol, can decrease gastrointestinal (GI) absorption of vitamin B-12. It is unlikely that this interaction will deplete body stores of vitamin B-12 unless there are other factors contributing to deficiency. In a group of children treated with cholestyramine for up to 2.5 years there was not any change in serum vitamin B-12 levels. Routine supplements are not necessary. - H2-receptor antagonists: include cimetidine (Tagamet®), famotidine (Pepcid®), nizatidine (Axid®), and ranitidine (Zantac®). Reduced secretion of gastric acid and pepsin produced by H2 blockers can reduce absorption of protein-bound (dietary) vitamin B-12, but not of supplemental vitamin B-12. Gastric acid is needed to release vitamin B-12 from protein for absorption. Clinically significant vitamin B-12 deficiency and megaloblastic anemia are unlikely, unless H2 blocker therapy is prolonged (2 years or more), or the person's diet is poor. It is also more likely if the person is rendered achlorhydric (with complete absence of gastric acid secretion), which occurs more frequently with proton pump inhibitors than H2 blockers. Vitamin B-12 levels should be monitored in people taking high doses of H2 blockers for prolonged periods. - Metformin (Glucophage®): Metformin may reduce serum folic acid and vitamin B-12 levels. These changes can lead to hyperhomocysteinemia, adding to the risk of cardiovascular disease in people with diabetes. There are also rare reports of megaloblastic anemia in people who have taken metformin for 5 years or more. Reduced serum levels of vitamin B-12 occur in up to 30% of people taking metformin chronically. However, clinically significant deficiency is not likely to develop if dietary intake of vitamin B-12 is adequate. Deficiency can be corrected with vitamin B-12 supplements even if metformin is continued. The metformin-induced malabsorption of vitamin B-12 is reversible by oral calcium supplementation. The general clinical significance of metformin upon B-12 levels is as yet unknown. - Neomycin: Absorption of vitamin B-12 can be reduced by neomycin, but prolonged use of large doses is needed to induce pernicious anemia. Supplements are not usually needed with normal doses. - Nicotine: Nicotine can reduce serum vitamin B-12 levels. The need for vitamin B-12 supplementation in smokers has not been adequately studied. - Nitrous oxide: Nitrous oxide inactivates the cobalamin form of vitamin B-12 by oxidation. Symptoms of vitamin B-12 deficiency, including sensory neuropathy, myelopathy, and encephalopathy, can occur within days or weeks of exposure to nitrous oxide anesthesia in people with subclinical vitamin B-12 deficiency. Symptoms are treated with high doses of vitamin B-12, but recovery can be slow and incomplete. People with normal vitamin B-12 levels have sufficient vitamin B-12 stores to make the effects of nitrous oxide insignificant, unless exposure is repeated and prolonged (such as recreational use). Vitamin B-12 levels should be checked in people with risk factors for vitamin B-12 deficiency prior to using nitrous oxide anesthesia. Chronic nitrous oxide B-12 poisoning (usually from use of nitrous oxide as a recreational drug), however, may result in B-12 functional deficiency even with normal measured blood levels of B-12 - Phenytoin (Dilantin®), phenobarbital, primidone (Mysoline®): These anticonvulsants have been associated with reduced vitamin B-12 absorption, and reduced serum and cerebrospinal fluid levels in some patients. This may contribute to the megaloblastic anemia, primarily caused by folate deficiency, associated with these drugs. It's also suggested that reduced vitamin B-12 levels may contribute to the neuropsychiatric side effects of these drugs. Patients should be encouraged to maintain adequate dietary vitamin B-12 intake. Folate and vitamin B-12 status should be checked if symptoms of anemia develop. - Proton pump inhibitors (PPIs): The PPIs include omeprazole (Prilosec®, Losec®), lansoprazole (Prevacid®), rabeprazole (Aciphex®), pantoprazole (Protonix®, Pantoloc®), and esomeprazole (Nexium®). The reduced secretion of gastric acid and pepsin produced by PPIs can reduce absorption of protein-bound (dietary) vitamin B-12, but not supplemental vitamin B-12. Gastric acid is needed to release vitamin B-12 from protein for absorption. Reduced vitamin B-12 levels may be more common with PPIs than with H2-blockers, because they are more likely to produce achlorhydria (complete absence of gastric acid secretion). However, clinically significant vitamin B-12 deficiency is unlikely, unless PPI therapy is prolonged (2 years or more) or dietary vitamin intake is low. Vitamin B-12 levels should be monitored in people taking high doses of PPIs for prolonged periods. - Zidovudine (AZT, Combivir®, Retrovir®): Reduced serum vitamin B-12 levels may occur when zidovudine therapy is started. This adds to other factors that cause low vitamin B-12 levels in people with HIV, and might contribute to the hematological toxicity associated with zidovudine. However, data suggests vitamin B-12 supplements are not helpful for people taking zidovudine. ## Interactions with herbs and dietary supplements - Folic acid: Folic acid, particularly in large doses, can mask vitamin B-12 deficiency by completely correcting hematological abnormalities. In vitamin B-12 deficiency, folic acid can produce complete resolution of the characteristic megaloblastic anemia, while allowing potentially irreversible neurological damage (from continued inactivity of methylmalonyl mutase) to progress. Thus, vitamin B-12 status should be determined before folic acid is given as monotherapy. - Potassium: Potassium supplements can reduce absorption of vitamin B-12 in some people. This effect has been reported with potassium chloride and, to a lesser extent, with potassium citrate. Potassium might contribute to vitamin B-12 deficiency in some people with other risk factors, but routine supplements are not necessary.	Vitamin B12 Editor-In-Chief: C. Michael Gibson, M.S., M.D. [2] Associate Editor-In-Chief: Cafer Zorkun, M.D., Ph.D. [3] Vitamin B-12 is a vitamin which is important for the normal functioning of the brain and nervous system, and for the formation of blood. It is normally involved in the metabolism of every cell of the body, especially affecting DNA synthesis and regulation, but also fatty acid synthesis and energy production. Vitamin B-12 is the name for a class of chemically-related compounds, all of which have vitamin activity. It is structurally the most complicated vitamin. Biosynthesis of the basic structure of the vitamin can only be accomplished by bacteria, but conversion between different forms of the vitamin can be accomplished in the human body. A common form of the vitamin, cyanocobalamin, does not occur in nature, but is used as a supplement and food additive, due to its stability. It is converted to other forms of the vitamin which are actually used in chemical reactions in the body. Historically, vitamin B-12 was discovered from its relationship to the disease pernicious anemia, which was eventually discovered to result from an effective lack of this vitamin due to problems with the mechanisms in the body which normally absorb it. Many other more subtle kinds of biochemical B-12 deficiencies, and biochemical effects from them, have since been elucidated. A B12 deficiency causes: - distinctive dyserythropoietic abnormalities in the bone marrow - megaloblastic erythropoiesis which is associated with abnormally large red cells in the peripheral cells, for example macrocytosis. A severe deficiency in B12 can cause pernicious anemia and funicular myelosis. # Terminology The name vitamin B-12, known also as vitamin BTemplate:Ssub (or commonly BTemplate:Ssub or B-12 for short) generally refers to all forms of the vitamin. Some medical practitioners have suggested that its use be split into two different categories, however. - In a broad sense B-12 still refers to a group of cobalt-containing vitamer compounds known as cobalamins: these include cyanocobalamin (an artifact formed as a result of the use of cyanide in the purification procedures), hydroxocobalamin (another medicinal form), and finally, the two naturally occurring cofactor forms of B-12: 5-deoxyadenosylcobalamin (adenosylcobalamin—AdoB-12), the cofactor of Methylmalonyl Coenzyme A mutase (MUT), and methylcobalamin (MeB-12), the cofactor of 5-methyltetrahydrofolate-homocysteine methyltransferase (MTR). - The term B-12 may be properly used to refer to cyanocobalamin, the principal B-12 form used for foods and in nutritional supplements. This ordinarily creates no problem, except perhaps in rare cases of eye nerve damage, where the body is only marginally able to use this form due to high cyanide levels in the blood due to cigarette smoking, and thus requires cessation of smoking, or else B-12 given in another form, for the optic symptoms to abate.[1] However, tobacco amblyopia is a rare enough condition that debate continues about whether or not it represents a peculiar B-12 deficiency which is resistant to treatment with cyanocobalamin. Finally, so-called Pseudo-B-12 refers to B-12-like substances which are found in certain organisms, including spirulina (a cyanobacterium) and some algae. These substances are active in tests of B-12 activity by highly sensitive antibody-binding serum assay tests, which measure levels of B-12 and B-12 like compounds in blood. However, these substances do not have B-12 biological activity for humans, a fact which may pose a theoretical danger to vegans and others on limited diets who do not ingest B-12 producing bacteria, but who nevertheless may show normal "B-12" levels in the standard immunoassay which has become the normal medical method for testing for B-12 deficiency.[2] # Structure Vitamin B-12 is a collection of cobalt and corrin ring molecules which are defined by their particular vitamin function in the body. All of the substrate cobalt-corrin molecules from which B-12 is made must be synthesized by bacteria. However, after this synthesis is complete, the body has a limited power to convert any form of B-12 to another, by means of enzymatically removing certain prosthetic chemical groups from the cobalt atom. Cyanocobalamin is one such compound that is a vitamin in this B complex, because it can be metabolized in the body to an active co-enzyme form. However, the cyanocobalamin form of B-12 does not occur in nature normally, but is a byproduct of the fact that other forms of B-12 are avid binders of cyanide (-CN) which they pick up in the process of activated charcoal purification of the vitamin after it is made by bacteria in the commercial process. Since the cyanocobalamin form of B-12 is deeply red colored, easy to crystallize, and is not sensitive to air-oxidation, it is typically used as a form of B-12 for food additives and in many common multivitamins. However, this form is not perfectly synonymous with B-12, inasmuch as a number of substances (vitamers) have B-12 vitamin activity and can properly be labeled vitamin B-12, and cyanocobalamin is but one of them. (Thus, all cyanocobalamin is vitamin B-12, but not all vitamin B-12 is cyanocobalamin).[3] B-12 is the most chemically complex of all the vitamins. The structure of B-12 is based on a corrin ring, which is similar to the porphyrin ring found in heme, chlorophyll, and cytochrome. The central metal ion is Co (cobalt). Four of the six coordination sites are provided by the corrin ring, and a fifth by a dimethylbenzimidazole group. The sixth coordination site, the center of reactivity, is variable, being a cyano group (-CN), a hydroxyl group (-OH), a methyl group (-CH3) or a 5'-deoxyadenosyl group (here the C5' atom of the deoxyribose forms the covalent bond with Co), respectively, to yield the four B-12 forms mentioned above. The covalent C-Co bond is one of first examples of carbon-metal bonds in biology. The hydrogenases and, by necessity, enzymes associated with cobalt utilization, involve metal-carbon bonds.[4] # Synthesis Vitamin B-12 cannot be made by plants or animals[5] as only bacteria have the enzymes required for its synthesis. The total synthesis of B-12 was reported by Robert Burns Woodward[6][7] and Albert Eschenmoser,[8][9] and remains one of the classic feats of organic synthesis. Species from the following genera are known to synthesize B-12: Aerobacter, Agrobacterium, Alcaligenes, Azotobacter, Bacillus, Clostridium, Corynebacterium, Flavobacterium, Micromonospora, Mycobacterium, Nocardia, Propionibacterium, Protaminobacter, Proteus, Pseudomonas, Rhizobium, Salmonella, Serratia, Streptomyces, Streptococcus and Xanthomonas. Industrial production of B-12 is through fermentation of selected microorganisms.[10] The species most often used, Pseudomonas denitrificans and Propionibacterium shermanii, are frequently genetically engineered and grown under special conditions to enhance yield. # Functions Vitamin B-12 is normally involved in the metabolism of every cell of the body, especially affecting the DNA synthesis and regulation but also fatty acid synthesis and energy production. However, many (though not all) of the effects of functions of B-12 can be replaced by sufficient quantities of folic acid (another B vitamin), since B-12 is used to regenerate folate in the body. Most "B-12 deficient symptoms" are actually folate deficient symptoms, since they include all the effects of pernicious anemia and megaloblastosis, which are due to poor synthesis of DNA when the body does not have a proper supply of folic acid for the production of thymine. When sufficient folic acid is available, all known B-12 related deficiency syndromes normalize, save those narrowly connected with the B-12 dependent enzymes Methylmalonyl Coenzyme A mutase (MUT), and 5-methyltetrahydrofolate-homocysteine methyltransferase (MTR), also known as methionine synthase; and the buildup of their respective substrates (methylmalonic acid, MMA) and homocysteine. Coenzyme B-12's reactive C-Co bond participates in two types of enzyme-catalyzed reactions.[11] - Rearrangements in which a hydrogen atom is directly transferred between two adjacent atoms with concomitant exchange of the second substituent, X, which may be a carbon atom with substituents, an oxygen atom of an alcohol, or an amine. - Methyl (-CH3) group transfers between two molecules. In humans, only two corresponding coenzyme B-12-dependent enzymes are known: - Methylmalonyl Coenzyme A mutase (MUT) which uses the AdoB-12 form and reaction type 1 to catalyze a carbon skeleton rearrangement (the X group is -COSCoA). MUT's reaction converts MMl-CoA to Su-CoA, an important step in the extraction of energy from proteins and fats (for more see MUT's reaction mechanism). This functionality is lost in vitamin B-12 deficiency, and can be measured clinically as an increased methylmalonic acid (MMA) level. Unfortunately, an elevated MMA, though sensitive to B-12 deficiency, is probably overly sensitive, and not all who have it actually have B-12 deficiency. For example, MMA is elevated in 90-98% of patients with B-12 deficiency; however 25-20% of patients over the age of 70 have elevated levels of MMA, yet 25-33% of them do not have B-12 deficiency. For this reason, MMA is not routinely recommended in the elderly.[12] The "gold standard" test for B-12 deficiency continues to be low blood levels of the vitamin. The MUT function cannot be affected by folate supplementation, and which is necessary for myelin synthesis (see mechanism below) and certain other functions of the central nervous system. Other functions of B-12 related to DNA synthesis related to MTR dysfunction (see below) can often be corrected with supplementation with the vitamin folic acid, but not the elevated levels of homocysteine, which is normally converted to methionine by MTR. - 5-methyltetrahydrofolate-homocysteine methyltransferase (MTR), also known as methionine synthase. This is a methyl transfer enzyme, which uses the MeB-12 and reaction type 2 to catalyze the conversion of the amino acid Hcy back into Met (for more see MTR's reaction mechanism).[13] This functionality is lost in vitamin B-12 deficiency, and can be measured clinically as an increased homocysteine level in vitro. Increased homocysteine can also be caused by a folic acid deficiency, since B-12 helps to regenerate the tetrahydrofolate (THF) active form of folic acid. Without B-12, folate is trapped as 5-methyl-folate, from which THF cannot be recovered unless a MTR process reacts the 5-methyl-folate with homocysteine to produce methionine and THF, thus decreasing the need for fresh sources of THF from the diet. THF may be produced in the conversion of homocysteine to methionine, or may be obtained in the diet. It is converted by a non-B-12-dependent process to 5,10-methylene-THF, which is involved in the synthesis of thymine. Reduced availability of 5,10-methylene-THF results in problems with DNA synthesis, and ultimately in ineffective production cells with rapid turnover, in particular blood cells, and also intestinal wall cells which are responsible for absorption. The failure of blood cell production results in the once-dreaded and fatal disease, pernicious anemia. All of the DNA synthetic effects, including the megaloblastic anemia of pernicious anemia, resolve if sufficient folate is present (since levels of 5,10-methylene-THF still remain adequate with enough dietary folate). Thus the best known function of B-12 (that which is indirectly involved with DNA synthesis and restoration of cell-division and anemia) is actually a facultative function which is mediated by B-12 conservation of active folate which can be used for DNA production.[14] If folate is present in quantity, then of the two absolutely B-12 dependent reactions, the MUT reaction shows the most direct and characteristic secondary effects, focusing on the nervous system. Since the late 1990s folic acid has begun to be added to fortify flour in many countries, so that folate deficiency is now more rare. At the same time, since DNA synthetic-sensitive tests for anemia and erythrocyte size are routinely done in even simple medical test clinics (so that these folate mediated-biochemical effects are more often directly detected), the MTR dependent effects of B-12 deficiency are becoming apparent not as anemia (as they were classically), but now mainly as an elevation of homocysteine in the blood and urine (homocysteinuria). This condition may result in long term damage to arteries and in clotting (stroke and heart attack), but is difficult to separate from other processes associated with atherosclerosis and aging. The B-12 dependent MTR reactions may have neurological effects through an indirect mechanism. Adequate methionine (which must otherwise be obtained in the diet) is needed to make S-adenosyl-methionine, which is in turn necessary for methylation of myelin sheath phospholipids. In addition, SAMe is involved in the manufacture of certain neurotransmitters, catecholamines and in brain metabolism. These neurotransmitters are important for maintaining mood, possibly explaining why depression is associated with B-12 deficiency. Methylation of the myelin sheath phospholipids may also depend on adequate folate, which in turn is dependent on MTR recycling, unless ingested in relatively high amounts. The specific myelin damage resulting from from B-12 deficiency has also been connected to B-12 reactions related to MUT, which is needed to convert methylmalonyl coenzyme A into succinyl coenzyme A. Failure of this second reaction to occur results in elevated levels of methylmalonic acid (MMA), a myelin destabilizer. Excessive MAA will prevent normal fatty acid synthesis, or it will be incorporated into fatty acid itself rather than normal malonic acid. If this abnormal fatty acid subsequently is incorporated into myelin, the resulting myelin will be too fragile, and demyelination will occur. Although the precise methanism(s) are not known with certainty, the result is subacute combined degeneration of central nervous system and spinal cord. [15] Whatever the cause, it is known that B-12 deficiency causes neuropathies, even if folic acid is present in good supply, and therefore anemia is not present. # Human absorption and distribution The human physiology of vitamin B-12 is complex, and therefore is prone to mishaps leading to vitamin B-12 deficiency. The vitamin as it occurs in foods enters the digestive tract bound to proteins, known as salivary R-binders. Stomach proteolysis of these proteins requires an acid pH, and also requires proper pancreatic release of proteolytic enzymes. (Even small amounts of B-12 taken in supplements bypasses these steps and thus any need for gastric acid, which may be blocked by antacid drugs). The free B-12 then attaches to gastric intrinsic factor, which is generated by the gastric parietal cells. If this step fails due to gastric parietal cell atrophy (the problem in pernicious anemia), sufficient B-12 is not absorbed later on, unless administered orally in relatively massive doses (500 to 1000 mcg/day). The conjugated vitamin B-12-intrinsic factor complex (IF/B-12) is then normally absorbed by the terminal ileum of the small bowel. Absorption of food vitamin B-12 therefore requires an intact and functioning stomach, exocrine pancreas, intrinsic factor, and small bowel. Problems with any one of these organs makes a vitamin B-12 deficiency possible. Once the IF/B-12 complex is recognized by specialized ileal receptors, it is transported into the portal circulation. The vitamin is then transferred to transcobalamin II (TC-II/B-12), which serves as the plasma transporter of the vitamin. Genetic deficiencies of this protein are known, also leading to functional B-12 deficiency. For the vitamin to serve inside cells, the TC-II/B-12 complex must bind to a cell receptor, and be endocytosed. The transcobalamin-II is degraded within a lysozyme, and the B-12 is finally released into the cytoplasm, where it may be transformed into the proper coenzyme, by certain cellular enzymes (see above). Hereditary defects in production of the transcobalamins and their receptors may produce functional deficiencies in B-12 and infantile megaloblastic anemia, and abnormal B-12 related biochemistry, even in some cases with normal blood B-12 levels.[16] The total amount of vitamin B-12 stored in body is about 2,000-5,000 mcg in adults. Around 80% of this is stored in the liver[4]. 0.1 % of this is lost per day by secretions into the gut as not all these secretions are reabsorbed. How fast B-12 levels change depends on the balance between how much B-12 is obtained from the diet, how much is secreted and how much is absorbed. B-12 deficiency may arise in a year if initial stores are low and genetic factors unfavourable or may not appear for decades. In infants, B-12 deficiency can appear much more quickly[5]. # History of B-12 as a treatment for pernicious anemia B-12 deficiency is the cause of pernicious anemia, a usually-fatal disease of unknown etiology when it was first described in medicine. The cure was discovered by accident. George Whipple had been inducing anemia in dogs by bleeding them, and then conducting experiments in which he fed them various foods to observe which diets allowed them fastest recovery from the anemia produced. In the process, he discovered that ingesting large amounts of liver seemed to most-rapidly cure the anemia of blood loss, and hypothesized that therefore liver ingestion be tried for pernicious anemia, an anemic disease of the time with no known cause or cure. He tried this and reported some signs of success in 1920. After a series of careful clinical studies George Minot and William Murphy set out to partly isolate the substance in liver which cured anemia in dogs, and found that it was iron. They found further that the partly isolated water-soluble liver-substance which cured pernicious anemia in humans, was something else entirely different -- and which had no effect at all on canines under the conditions used. The specific factor treatment for pernicious anemia, found in liver juice, had been found by this coincidence. These experiments were reported by Minot and Murphy in 1926, marking the date of the first real progress with this disease, though for several years, patients were still required to eat large amounts of raw liver or to drink considerable amounts of liver juice. In 1928, the chemist Edwin Cohn prepared a liver extract that was 50 to 100 times more potent than the natural liver products. The extract was the first workable treatment for the disease. For their initial work in pointing the way to a working treatment, Whipple, Minot, and Murphy shared the 1934 Nobel Prize in Physiology or Medicine. The active ingredient in liver was not isolated until 1948 by the chemists Karl A. Folkers of the United States and Alexander R. Todd of Great Britain. The substance was a cobalamin called vitamin B-12. It could also be injected directly into muscle, making it possible to treat pernicious anemia more easily.[17] The chemical structure of the molecule was determined by Dorothy Crowfoot Hodgkin and her team in 1956, based on crystallographic data. Eventually, methods of producing the vitamin in large quantities from bacteria cultures were developed in the 1950s, and these led to the modern form of treatment for the disease. # Symptoms and damage from deficiency Vitamin B-12 deficiency can potentially cause severe and irreversible damage, especially to the brain and nervous system. At levels only slightly lower than normal, a range of symptoms such as fatigue, depression, and poor memory may be experienced.[18] However, these symptoms by themselves are too nonspecific to diagnose deficiency of the vitamin. Vitamin B-12 deficiency has the following pathomorphology and symptoms:[19] Pathomorphology includes: A spongiform state of neural tissue along with edema of fibers and deficiency of tissue. The myelin decays, along with axial fiber. In later phases, fibric sclerosis of nervous tissues occurs. Those changes apply to dorsal parts of the spinal cord, and to pyramidal tracts in lateral cords. In the brain itself, changes are less severe: they occur as small sources of nervous fibers decay and accumulation of astrocytes, usually subcortically located, an also round hemorrhages with a torus of glial cells. Pathological changes can be noticed as well in the posterior roots of the cord and, to lesser extent, in peripheral nerves. Clinical symptoms : The main syndrome of vitamin B-12 deficiency is Addison's disease and Biermer's disease (pernicious anemia). It is characterized by a triad of symptoms: 1) Anemia with bone marrow promegaloblastosis (Megaloblastic anemia) 2) Gastrointestinal symptoms; 3) Neurological symptoms. Each of those symptoms can occur either alone or along with others. The neurological complex, defined as myelosis funicularis, consists of the following symptoms: 1) Impaired perception of deep touch, pressure and vibration, abolishment of sense of touch, very annoying and persistent paresthesias; 2) Ataxia of dorsal cord type; 3) Decrease or abolishment of deep muscle-tendon reflexes; 4) Pathological reflexes - Babinski, Rossolimo and others, also severe paresis. During the course of disease, mental disorders can occur: irritablity, focus/concentration problems, depressive state with suicidal tendencies, paraphrenia complex. These symptoms may not reverse after correction of hematological abnormalities, and the chance of complete reversal decreases with the length of time the neurological symptoms have been present. # Differential Diagnosis of Causes of Vitamin B12 Deficiency In alphabetical order. [20] [21] - Acute Hepatitis - Bacterial colonization of the small intestine - Caustic burn of the stomach mucosa - Chronic Atrophic Gastritis - Chronic hepatitis - Chronic Kidney Disease - Chronic Liver Disease - Diseases of the terminal ileum - Fish tapeworm - Genuine pernicious anemia - Hepatic tumor - Leukemia - Malnutrition - Polycythemia - Pregnancy - Stomach polyposis - Stomach resection - Strict vegetarian diet - Transcobalamin 2 deficiency # Sources Vitamin B-12 is naturally found in foods of animal origin including meat (especially liver and shellfish) and milk products. Animals, in turn, must obtain it directly or indirectly from bacteria, and these bacteria may inhabit a section of the gut which is posterior to the section where B-12 is absorbed. Thus, herbivorous animals must either obtain B-12 from bacteria in their rumens, or (if fermenting plant material in the hindgut) by reingestion of cecotrope feces. Eggs are often mentioned as a good B-12 source, but they also contain a factor that blocks absorption.[22] Certain insects such as termites contain B-12 produced by their gut bacteria, in a manner analogous to ruminant animals.[23] An NIH Fact Sheet lists a variety of food sources of vitamin B-12. Plants only supply B-12 to humans when the soil containing B-12-producing microorganisms has not been washed from them. Vegan humans who eat only washed vegetables must take special care to supplement their diets accordingly. According to the U.K. Vegan Society, the only reliable vegan sources of B-12 are foods fortified with B-12 (including some plant milks, some soy products and some breakfast cereals), and B-12 supplements.[24] Fortified breakfast cereals are a particularly valuable source of vitamin B-12 for vegetarians and vegans. While lacto-ovo vegetarians usually get enough B-12 through consuming dairy products, vitamin B-12 may be found to be lacking in those practicing vegan diets who do not use multivitamin supplements or eat B-12 fortified foods, such as fortified breakfast cereals, fortified soy-based products, and fortified energy bars. Claimed sources of B-12 that have been shown through direct studies[25] of vegans to be inadequate or unreliable include, laver (a seaweed), barley grass, and human gut bacteria. People on a vegan raw food diet are also susceptible to B-12 deficiency if no supplementation is used[26]. The Vegan Society, the Vegetarian Resource Group, and the Physicians Committee for Responsible Medicine, among others, recommend that vegans either consistently eat foods fortified with B-12 or take a daily or weekly B-12 supplement.[24][27][28] Cyanocobalamin is converted to its active forms, first hydroxocobalamin and then methylcobalamin and adenosylcobalamin in the liver. The sublingual route, in which B-12 is presumably or supposedly absorbed more directly under the tongue, has not proven to be necessary or helpful. A 2003 study found no significant difference in absorption for serum levels from oral vs. sublingual delivery of 500 micrograms of cobalamin.[29] However, if patient has inborn errors in the methyltransfer pathway (cobalamin C disease, combined methylmalonic aciduria and homocystinuria), treating with intravenous or intramuscular hydroxocobalamin is needed.[30][31][32][33][34] Vitamin B-12 can be supplemented in healthy subjects also by liquid, strip, nasal spray, or injection. B-12 is available singly or in combination with other supplements. Injection is sometimes used in cases where digestive absorption is impaired, but there is some evidence that this course of action may not be necessary with modern high potency oral supplements (such as 500 to 1000 mcg or more). [35][36][37] These supplements carry such large doses of the vitamin that the many different components of the B-12 absorption system are not required, and enough of the vitamin (only a few mcg a day) is obtained simply by mass-action transport across the gut. Even pernicious anemia can be treated entirely by the oral route. For the much lower amounts of B-12 found in food sources, however, oral absorption is complex and requires stomach acid, and also specific intestinal transport proteins (intrinsic factor) produced in the stomach. Lack of function in these systems is the causes of much of the increased risk in many elderly persons who develop B-12 deficiency later in life. However, it can be treated with a simple high dose oral B-12 supplement. Cyanocobalamin is also sometimes added to beverages including Diet Coke Plus and many energy drinks, in some cases with over 80 times the recommended intake. However, 500 mcg would be needed to reverse biochemical signs of vitamin B-12 deficiency in older adults.[38] # Allergies Vitamin B-12 supplements in theory should be avoided in people sensitive or allergic to cobalamin, cobalt, or any other product ingredients. However, direct allergy to a vitamin or nutrient is extremely rare, and if reported, other causes should be sought. # Side effects, contraindications, and warnings - Dermatologic: Itching, rash, transitory exanthema, and urticaria have been reported. Vitamin B-12 (20 micrograms/day) and pyridoxine (80mg/day) has been associated with cases of rosacea fulminans, characterized by intense erythema with nodules, papules, and pustules. Symptoms may persist for up to 4 months after the supplement is stopped, and may require treatment with systemic corticosteroids and topical therapy. - Gastrointestinal: Diarrhea has been reported. - Hematologic: Peripheral vascular thrombosis has been reported. Treatment of vitamin B-12 deficiency can unmask polycythemia vera, which is characterized by an increase in blood volume and the number of red blood cells. The correction of megaloblastic anemia with vitamin B-12 can result in fatal hypokalemia and gout in susceptible individuals, and it can obscure folate deficiency in megaloblastic anemia. Caution is warranted. - Leber's disease: Vitamin B-12 in the form of cyanocobalamin is contraindicated in early Leber's disease, which is hereditary optic nerve atrophy. Cyanocobalamin can cause severe and swift optic atrophy, but other forms of vitamin B-12 are available. However, the sources of this statement are not clear, while an opposing view[39] concludes: "The clinical picture of optic neuropathy associated with vitamin B-12 deficiency shows similarity to that of Leber's disease optic neuropathy. Both involve the nerve fibres of the papillomacular bundle. The present case reports suggest that optic neuropathy in patients carrying a primary LHON mtDNA mutation may be precipitated by vitamin B-12 deficiency. Therefore, known carriers should take care to have an adequate dietary intake of vitamin B-12 and malabsorption syndromes like those occurring in familial pernicious anaemia or after gastric surgery should be excluded." # Normal requirement, and in pregnancy and breastfeeding The Dietary Reference Intake for an adult ranges from 2 to 3 µg (micrograms). The recommended optimal daily intake (ODI) is 10 to 15 µg. Vitamin B-12 is believed to be safe when used orally in amounts that do not exceed the recommended dietary allowance (RDA). The RDA for vitamin B-12 in pregnant women is 2.6 µg per day and 2.8 µg during lactation periods. There is insufficient reliable information available about the safety of consuming greater amounts of Vitamin B-12 during pregnancy. # Other medical uses Hydroxycobalamin, or hydoxocobalamin, also known as Vitamin B-12a, is used in Europe both for vitamin B-12 deficiency and as a treatment for cyanide poisoning, sometimes with a large amount (5-10 g) given intravenously, and sometimes in combination with sodium thiosulfate.[40] The mechanism of action is straightforward: the hydroxycobalamin hydroxide ligand is displaced by the toxic cyanide ion, and the resulting harmless B-12 complex is excreted in urine. In the United States, the FDA has approved in 2006 the use of hydroxocobalamin for acute treatment of cyanide poisoning. # Interactions ## Interactions with drugs - Alcohol (ethanol): Excessive alcohol intake lasting longer than two weeks can decrease vitamin B-12 absorption from the gastrointestinal tract, leading to Korsakoff's Syndrome. - Aminosalicylic acid (para-aminosalicylic acid, PAS, Paser): Aminosalicylic acid can reduce oral vitamin B-12 absorption, possibly by as much as 55%, as part of a general malabsorption syndrome. Megaloblastic changes, and occasional cases of symptomatic anemia have occurred, usually after doses of 8 to 12 grams/day for several months. Vitamin B-12 levels should be monitored in people taking aminosalicylic acid for more than one month. - Antibiotics: An increased bacterial load can bind significant amounts of vitamin B-12 in the gut, preventing its absorption. In people with bacterial overgrowth of the small bowel, antibiotics such as metronidazole (Flagyl®) can actually improve vitamin B-12 status. The effects of most antibiotics on gastrointestinal bacteria are unlikely to have clinically significant effects on vitamin B-12 levels. - Hormonal contraception: The data regarding the effects of oral contraceptives on vitamin B-12 serum levels are conflicting. Some studies have found reduced serum levels in oral contraceptive users, but others have found no effect despite use of oral contraceptives for up to 6 months. When oral contraceptive use is stopped, normalization of vitamin B-12 levels usually occurs. Lower vitamin B-12 serum levels seen with oral contraceptives probably are not clinically significant. - Chloramphenicol (Chloromycetin®): Limited case reports suggest that chloramphenicol can delay or interrupt the reticulocyte response to supplemental vitamin B-12 in some patients. Blood counts should be monitored closely if this combination cannot be avoided. - Cobalt irradiation: Cobalt irradiation of the small bowel can decrease gastrointestinal (GI) absorption of vitamin B-12. - Colchicine: Colchicine in doses of 1.9 to 3.9mg/day can disrupt normal intestinal mucosal function, leading to malabsorption of several nutrients, including vitamin B-12. Lower doses do not seem to have a significant effect on vitamin B-12 absorption after 3 years of colchicine therapy. The significance of this interaction is unclear. Vitamin B-12 levels should be monitored in people taking large doses of colchicine for prolonged periods. - Colestipol (Colestid®), Cholestyramine (Questran®): These resins used for sequestering bile acids in order to decrease cholesterol, can decrease gastrointestinal (GI) absorption of vitamin B-12. It is unlikely that this interaction will deplete body stores of vitamin B-12 unless there are other factors contributing to deficiency. In a group of children treated with cholestyramine for up to 2.5 years there was not any change in serum vitamin B-12 levels. Routine supplements are not necessary. - H2-receptor antagonists: include cimetidine (Tagamet®), famotidine (Pepcid®), nizatidine (Axid®), and ranitidine (Zantac®). Reduced secretion of gastric acid and pepsin produced by H2 blockers can reduce absorption of protein-bound (dietary) vitamin B-12, but not of supplemental vitamin B-12. Gastric acid is needed to release vitamin B-12 from protein for absorption. Clinically significant vitamin B-12 deficiency and megaloblastic anemia are unlikely, unless H2 blocker therapy is prolonged (2 years or more), or the person's diet is poor. It is also more likely if the person is rendered achlorhydric (with complete absence of gastric acid secretion), which occurs more frequently with proton pump inhibitors than H2 blockers. Vitamin B-12 levels should be monitored in people taking high doses of H2 blockers for prolonged periods. - Metformin (Glucophage®): Metformin may reduce serum folic acid and vitamin B-12 levels. These changes can lead to hyperhomocysteinemia, adding to the risk of cardiovascular disease in people with diabetes. There are also rare reports of megaloblastic anemia in people who have taken metformin for 5 years or more. Reduced serum levels of vitamin B-12 occur in up to 30% of people taking metformin chronically.[41][42] However, clinically significant deficiency is not likely to develop if dietary intake of vitamin B-12 is adequate. Deficiency can be corrected with vitamin B-12 supplements even if metformin is continued. The metformin-induced malabsorption of vitamin B-12 is reversible by oral calcium supplementation.[43] The general clinical significance of metformin upon B-12 levels is as yet unknown.[44] - Neomycin: Absorption of vitamin B-12 can be reduced by neomycin, but prolonged use of large doses is needed to induce pernicious anemia. Supplements are not usually needed with normal doses. - Nicotine: Nicotine can reduce serum vitamin B-12 levels. The need for vitamin B-12 supplementation in smokers has not been adequately studied. - Nitrous oxide: Nitrous oxide inactivates the cobalamin form of vitamin B-12 by oxidation. Symptoms of vitamin B-12 deficiency, including sensory neuropathy, myelopathy, and encephalopathy, can occur within days or weeks of exposure to nitrous oxide anesthesia in people with subclinical vitamin B-12 deficiency. Symptoms are treated with high doses of vitamin B-12, but recovery can be slow and incomplete. People with normal vitamin B-12 levels have sufficient vitamin B-12 stores to make the effects of nitrous oxide insignificant, unless exposure is repeated and prolonged (such as recreational use). Vitamin B-12 levels should be checked in people with risk factors for vitamin B-12 deficiency prior to using nitrous oxide anesthesia. Chronic nitrous oxide B-12 poisoning (usually from use of nitrous oxide as a recreational drug), however, may result in B-12 functional deficiency even with normal measured blood levels of B-12 [45] - Phenytoin (Dilantin®), phenobarbital, primidone (Mysoline®): These anticonvulsants have been associated with reduced vitamin B-12 absorption, and reduced serum and cerebrospinal fluid levels in some patients. This may contribute to the megaloblastic anemia, primarily caused by folate deficiency, associated with these drugs. It's also suggested that reduced vitamin B-12 levels may contribute to the neuropsychiatric side effects of these drugs. Patients should be encouraged to maintain adequate dietary vitamin B-12 intake. Folate and vitamin B-12 status should be checked if symptoms of anemia develop. - Proton pump inhibitors (PPIs): The PPIs include omeprazole (Prilosec®, Losec®), lansoprazole (Prevacid®), rabeprazole (Aciphex®), pantoprazole (Protonix®, Pantoloc®), and esomeprazole (Nexium®). The reduced secretion of gastric acid and pepsin produced by PPIs can reduce absorption of protein-bound (dietary) vitamin B-12, but not supplemental vitamin B-12. Gastric acid is needed to release vitamin B-12 from protein for absorption. Reduced vitamin B-12 levels may be more common with PPIs than with H2-blockers, because they are more likely to produce achlorhydria (complete absence of gastric acid secretion). However, clinically significant vitamin B-12 deficiency is unlikely, unless PPI therapy is prolonged (2 years or more) or dietary vitamin intake is low. Vitamin B-12 levels should be monitored in people taking high doses of PPIs for prolonged periods. - Zidovudine (AZT, Combivir®, Retrovir®): Reduced serum vitamin B-12 levels may occur when zidovudine therapy is started. This adds to other factors that cause low vitamin B-12 levels in people with HIV, and might contribute to the hematological toxicity associated with zidovudine. However, data suggests vitamin B-12 supplements are not helpful for people taking zidovudine. ## Interactions with herbs and dietary supplements - Folic acid: Folic acid, particularly in large doses, can mask vitamin B-12 deficiency by completely correcting hematological abnormalities. In vitamin B-12 deficiency, folic acid can produce complete resolution of the characteristic megaloblastic anemia, while allowing potentially irreversible neurological damage (from continued inactivity of methylmalonyl mutase) to progress. Thus, vitamin B-12 status should be determined before folic acid is given as monotherapy. - Potassium: Potassium supplements can reduce absorption of vitamin B-12 in some people. This effect has been reported with potassium chloride and, to a lesser extent, with potassium citrate. Potassium might contribute to vitamin B-12 deficiency in some people with other risk factors, but routine supplements are not necessary.[46] # External links - Template:Pauling - fact sheet at NIH - Vitamin B-12. Medline Plus (National Library of Medicine). Part of it was used for this article (US Government public domain), specially for drug and other interactions. - Vitamin B12 Deficiency - Vitamin B-12 deficiency article in American Family Physician journal - Vitamin B-12: Vital Nutrient for Good Health at the Weston A. Price Foundation - Cyanocobalamin at the US National Library of Medicine Medical Subject Headings (MeSH)	https://www.wikidoc.org/index.php/B12
5ea5ecce260050211e68abde7c61d26be62caf8d	wikidoc	BATF (gene)	BATF (gene) Basic leucine zipper transcription factor, ATF-like, also known as BATF, is a protein which in humans is encoded by the BATF gene. # Function The protein encoded by this gene is a nuclear basic leucine zipper (bZIP) protein that belongs to the AP-1/ATF superfamily of transcription factors. The leucine zipper of this protein mediates dimerization with members of the Jun family of proteins. This protein is thought to be a negative regulator of AP-1/ATF transcriptional events. Mice without the BATF gene (BATF knockout mice) lacked a type of inflammatory immune cell (Th17) and were resistant to conditions that normally induces an autoimmune condition similar to multiple sclerosis. # Interactions BATF (gene) has been shown to interact with IFI35.	BATF (gene) Basic leucine zipper transcription factor, ATF-like, also known as BATF, is a protein which in humans is encoded by the BATF gene.[1][2][3] # Function The protein encoded by this gene is a nuclear basic leucine zipper (bZIP) protein that belongs to the AP-1/ATF superfamily of transcription factors. The leucine zipper of this protein mediates dimerization with members of the Jun family of proteins. This protein is thought to be a negative regulator of AP-1/ATF transcriptional events.[3] Mice without the BATF gene (BATF knockout mice) lacked a type of inflammatory immune cell (Th17) and were resistant to conditions that normally induces an autoimmune condition similar to multiple sclerosis.[4] # Interactions BATF (gene) has been shown to interact with IFI35.[5]	https://www.wikidoc.org/index.php/BATF_(gene)
503c974154e8bedde24fb9a54f59a82614e048dc	wikidoc	BCG vaccine	BCG vaccine # Disclaimer WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here. # Overview BCG vaccine is an immunologic adjuvant that is FDA approved for the prophylaxis of tuberculosis in persons not previously infected with M. tuberculosis who are at high risk for exposure. Common adverse reactions include percutaneous injection site reaction, nausea, axillary or cervical lymphadenopathy, , induration, cystitis, dysuria, hematuria, increased frequency of urination, urgent desire to urinate, influenza-like illness, malaise, shivering. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - BCG VACCINE (TICE® strain) is indicated for the prevention of tuberculosis in persons not previously infected with M. tuberculosis who are at high risk for exposure. As with any vaccine, immunization with BCG VACCINE may not protect 100% of susceptible individuals. - The Advisory Committee on Immunization Practices (ACIP) and the Advisory Committee for the Elimination of Tuberculosis has recommended that BCG vaccination be considered in the following circumstances. - TB Exposed Tuberculin Skin Test-Negative Infants and Children - BCG vaccination is recommended for infants and children with negative tuberculin skin tests who are (a) at high risk of intimate and prolonged exposure to persistently untreated or ineffectively treated patients with infectious pulmonary tuberculosis and who cannot be removed from the source of exposure and cannot be placed on long-term primary preventive therapy, or (b) continuously exposed to persons with infectious pulmonary tuberculosis who have bacilli resistant to isoniazid and rifampin, and the child cannot be separated from the presence of the infectious patient. - TB Exposed Health Care Workers (HCW) in High Risk Settings - BCG vaccination of HCWs should be considered on an individual basis in settings where (a) a high percentage of TB patients are infected with M. tuberculosis strains resistant to both isoniazid and rifampin, (b) transmission of such drug resistant M. tuberculosis strains to HCWs and subsequent infection are likely, and (c) comprehensive TB infection control precautions have been implemented and have not been successful. Vaccination should not be required for employment or for assignment of HCWs in specific work areas. HCWs considered for BCG vaccination should be counseled regarding the risks and benefits associated with both BCG vaccinations and TB preventive therapy. - Exposed Health Care Workers in Low Risk Settings - BCG vaccination is not recommended for HCWs in settings in which the risk for M. tuberculosis transmission is low. - Dosing Information - Preparation of Agent: - The preparation of the BCG VACCINE suspension should be done using aseptic technique. To avoid cross-contamination, parenteral drugs should not be prepared in areas where BCG VACCINE has been prepared. A separate area for the preparation of the BCG VACCINE suspension is recommended. All equipment, supplies and receptacles in contact with BCG VACCINE should be handled and disposed of as biohazardous. The pharmacist or individual responsible for mixing the agent should wear gloves, and take precautions to avoid contact of BCG with broken skin. If preparation cannot be performed in a biocontainment hood, then a mask and gown should be worn to avoid inhalation of BCG organisms and inadvertent exposure to broken skin. - Using aseptic methods, 1 mL of Sterile Water for Injection, USP at 4-25°C (39-77°F), is added to one vial of vaccine (see Pediatric Dose below for pediatric use). Gently swirl the vial until a homogenous suspension is obtained. Avoid forceful agitation which may cause clumping of the mycobacteria. - Persons administering vaccines should take necessary precautions to minimize risk for spreading disease. Hands should be washed before each new patient is seen. Syringes and needles used for applications must be sterile and preferably disposable to minimize the risk of contamination. A separate needle and syringe should be used for each application. Disposable needles and the multiple puncture device should be discarded as biohazardous waste in labeled, puncture-proof containers to prevent inadvertent needlestick injury or reuse. After use, any unused vaccine and all materials exposed to the product should be immediately placed in a biohazard container and disposed of in an appropriate manner. - Reconstituted vaccine should be kept refrigerated, protected from exposure to direct sunlight, and used within 2 hours. Freezing of the reconstituted product is not recommended. - Note: DO NOT filter the contents of the BCG VACCINE vial. Precautions should be taken to avoid exposing the BCG VACCINE to direct sunlight. Bacteriostatic solutions must be avoided. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Reconstitution should result in a uniform suspension of the bacilli. - Treatment and Schedule: - BCG vaccination is reserved for persons who have a reaction of less than 5mm induration after skin testing with 5 TU of PPD tuberculin. The preferred method of skin testing is the Mantoux tuberculin skin-test using 0.1 mL of 5 tuberculin units (TU) of PPD. It is recommended that a Mantoux skin-test be performed prior to BCG vaccination to demonstrate the absence of tuberculous infection. - The vaccine is to be administered after fully explaining the risks and benefits to the vaccinee, parent, or guardian. BCG vaccination should not be given to individuals previously infected with M. tuberculosis. The vaccine is administered percutaneously utilizing a sterile multiple puncture device. The multiple puncture device consists of a plastic holder for a thin, wafer-like stainless steel plate 7/8" by 1 1/8", from which 36 points protrude. After the vaccine is prepared, the skin site is cleansed with an alcohol or acetone sponge and allowed to dry thoroughly. ### Carcinoma in situ of bladder; Treatment and Prophylaxis - Dosing Information - TheraCys(R) BCG Live (Connaught Strain): - Wait a minimum of 14 days following bladder biopsy or transurethral resection before initiating TheraCys(R) BCG Live. Administration of TheraCys(R) BCG Live consists of 1 vial (81 mg) of TheraCys(R) BCG (Connaught strain) reconstituted with accompanying diluent (3 mL) and further diluted in sterile, preservative-free 0.9% sodium chloride to a final volume of 50 mL. Instill suspension into the bladder slowly by gravity flow via urethral catheter (total instillation volume is 50 mL). The suspension should be retained as long as possible for up to 2 hours with the patient lying in the prone position for the first 15 minutes, after which time allow the patient to be in an upright position. After 2 hours, the patient should void in a seated position. Repeat instillation once weekly for 6 weeks (induction therapy), followed by maintenance therapy of 1 dose at 3, 6, 12, 18, and 24 months after the initial dose. - Duration of treatment can be variable. The initial 6 weeks of induction may not be sufficient in some cases to achieve an adequate inflammatory response, while other patients may respond with as few as 3 treatments. BCG variability and host immune status play a role in individual patient outcomes. Prophylaxis against recurrence may be beneficial in patients with multiple, high-grade, stage Ta or T1 tumors. - TICE(R) BCG Live (TICE(R) Strain): - Wait 7 to 14 days after bladder biopsy or transurethral resection before administering TICE(R) BCG Live. Administration of TICE(R) BCG Live consists of 1 vial (50 mg) of TICE(R) BCG in 50 mL of preservative-free saline per intravesical instillation. The dose is repeated weekly for 6 weeks followed by a monthly instillation for 6 to 12 months. If tumor remission is not achieved following the first 6 weeks, the initial once weekly 6 week regimen may be repeated prior to initiating the monthly maintenance regimen depending on the clinical status of the patient. Patients should not drink fluids for 4 hours prior to treatment and they should empty their bladder before treatment. The suspension should be retained as long as possible for up to 2 hours with the patient being repositioned every 15 minutes (left side to right side, back, and abdomen) to maximize bladder surface exposure. - Duration of treatment can be variable. The initial 6 weeks of induction may not be sufficient in some cases to achieve an adequate inflammatory response, while other patients may respond with as few as 3 treatments. BCG variability and host immune status play a role in individual patient outcomes. Prophylaxis against recurrence may be beneficial in patients with multiple, high-grade, stage Ta or T1 tumors. ### Malignant tumor of urinary bladder, Stage Ta and/or T1 papillary tumors following transurethral resection; Prophylaxis - Dosing Information - TheraCys(R) BCG Live (Connaught Strain): - Wait a minimum of 14 days following bladder biopsy or transurethral resection before initiating TheraCys(R) BCG Live. Administration of TheraCys(R) BCG Live consists of 1 vial (81 mg) of TheraCys(R) BCG (Connaught strain) reconstituted with accompanying diluent (3 mL) and further diluted in sterile, preservative-free 0.9% sodium chloride to a final volume of 50 mL. Instill suspension into the bladder slowly by gravity flow via urethral catheter (total instillation volume is 50 mL). The suspension should be retained as long as possible for up to 2 hours with the patient lying in the prone position for the first 15 minutes, after which time allow the patient to be in an upright position. After 2 hours, the patient should void in a seated position. Repeat instillation once weekly for 6 weeks (induction therapy), followed by maintenance therapy of 1 dose at 3, 6, 12, 18, and 24 months after the initial dose. - Duration of treatment can be variable. The initial 6 weeks of induction may not be sufficient in some cases to achieve an adequate inflammatory response, while other patients may respond with as few as 3 treatments. BCG variability and host immune status play a role in individual patient outcomes. Prophylaxis against recurrence may be beneficial in patients with multiple, high-grade, stage Ta or T1 tumors. - TICE(R) BCG Live (TICE(R) Strain): - Wait 7 to 14 days after bladder biopsy or transurethral resection before administering TICE(R) BCG Live. Administration of TICE(R) BCG Live consists of 1 vial (50 mg) of TICE(R) BCG in 50 mL of preservative-free saline per intravesical instillation. The dose is repeated weekly for 6 weeks followed by a monthly instillation for 6 to 12 months. If tumor remission is not achieved following the first 6 weeks, the initial once weekly 6 week regimen may be repeated prior to initiating the monthly maintenance regimen depending on the clinical status of the patient. Patients should not drink fluids for 4 hours prior to treatment and they should empty their bladder before treatment. The suspension should be retained as long as possible for up to 2 hours with the patient being repositioned every 15 minutes (left side to right side, back, and abdomen) to maximize bladder surface exposure. - Duration of treatment can be variable. The initial 6 weeks of induction may not be sufficient in some cases to achieve an adequate inflammatory response, while other patients may respond with as few as 3 treatments. BCG variability and host immune status play a role in individual patient outcomes. Prophylaxis against recurrence may be beneficial in patients with multiple, high-grade, stage Ta or T1 tumors. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use - There is limited information regarding Off-Label Guideline-Supported Use of BCG vaccine in adult patients. ### Non–Guideline-Supported Use - There is limited information regarding Off-Label Non–Guideline-Supported Use of BCG vaccine in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) - Dosing Information - Do not administer INTRAVENOUSLY, SUBCUTANEOUSLY, INTRAMUSCULARLY, OR INTRADERMALLY. Administer the vaccine in the deltoid region. - In infants less than 1 month old, the dosage of BCG VACCINE should be reduced by one-half, by using 2 mL of Sterile Water for Injection, USP at 4-25°C (39-77°F) when reconstituting. If a vaccinated infant remains tuberculin negative to 5 TU on skin testing, and if indications for vaccination persist, the infant should receive a full dose after 1 year of age. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use - There is limited information regarding Off-Label Guideline-Supported Use of BCG vaccine in pediatric patients. ### Non–Guideline-Supported Use - There is limited information regarding Off-Label Non–Guideline-Supported Use of BCG vaccine in pediatric patients. # Contraindications - BCG VACCINE for prevention of tuberculosis should not be given to persons (a) whose immunologic responses are impaired because of HIV infections, congenital immunodeficiency such as chronic granulomatous disease or interferon gamma receptor deficiency, leukemia, lymphoma, or generalized malignancy or (b) whose immunologic responses have been suppressed by steroids, alkylating agents, antimetabolites, or radiation. BCG VACCINE should not be administered to HIV-infected or immunocompromised infants, children, or adults. - Prior to administration, the possibility of allergic reactions should be assessed. Allergy to any component of BCG VACCINE or an anaphylactic or allergic reaction to a previous dose of BCG VACCINE are contraindications for vaccination. - BCG VACCINE is not a vaccine for the treatment of active tuberculosis. - BCG VACCINE should not be used in infants, children, or adults with severe immune deficiency syndromes. Children with a family history of immune deficiency disease should not be vaccinated; if they are, an infectious disease specialist should be consulted and anti-tuberculous therapy administered if clinically indicated. # Warnings - Administration should be by the percutaneous route with the multiple puncture device as described below. DO NOT INJECT INTRAVENOUSLY, SUBCUTANEOUSLY, INTRAMUSCULARLY, OR INTRADERMALLY. - Although BCG vaccination often results in local adverse effects, serious or long-term complications are rare. Reactions that can be expected after vaccination include moderate axillary or cervical lymphadenopathy and induration and subsequent pustule formation at the injection site; these reactions can persist for as long as 3 months after vaccination. More severe local reactions include ulceration at the vaccination site, regional suppurative lymphadenitis with draining sinuses, and caseous lesions or purulent drainage at the puncture site; these manifestations might occur within the 5 months after vaccination and could persist for several weeks. - Acute, localized irritative toxicities of BCG may be accompanied by systemic manifestations, consistent with a "flu-like" syndrome. Systemic adverse effects of 1–2 days' duration such as fever, anorexia, myalgia, and neuralgia, often reflect hypersensitivity reactions. However, symptoms such as fever of 103°F or greater, or acute localized inflammation persisting longer than 2–3 days suggest active infections, and evaluation for serious infectious complication should be considered. If a BCG infection is suspected, the physician should consult with an infectious disease expert before therapy is initiated. Treatment should be started without delay. In patients who develop persistent fever or experience an acute febrile illness consistent with BCG infection, two or more antimycobacterial agents should be administered while diagnostic evaluation, including cultures, is conducted. Negative cultures do not necessarily rule out infection. Physicians or persons caring for patients that use this product should be familiar with the literature on prevention, diagnosis, and treatment of BCG-related complications and, when appropriate, should consult an infectious disease specialist or other physician with experience in the diagnosis and treatment of mycobacterial infections. - The most serious complication of BCG vaccination is disseminated BCG infection. BCG osteitis affecting the epiphyses of the long bones, particularly the epiphyses of the leg, can occur from 4 months to 2 years after vaccination. Fatal disseminated BCG disease has occurred at a rate of 0.06–1.56 cases per million doses of vaccine administered; these deaths occurred primarily among immunocompromised persons. The appropriate therapy for systemic BCG infections is discussed in the ADVERSE REACTIONS section. ### Precautions General - BCG VACCINE contains live bacteria and should be used with aseptic technique. To avoid cross-contamination, parenteral drugs should not be prepared in areas where BCG VACCINE has been in use. A separate sterile multiple puncture device must be used for each patient and appropriately discarded after use. All equipment, supplies and receptacles in contact with BCG VACCINE should be handled and disposed of as biohazardous. - BCG VACCINE administration should not be attempted in individuals with severe immune deficiency disease. BCG VACCINE should be administered with caution to persons in groups at high risk for HIV infection. - A review of each patient's immunization records to include history on reactions to immunizations should be completed prior to vaccination. All precautions should be taken for the prevention of allergic or any other side reactions, including understanding the use of the biological and the nature of the adverse reactions that may follow its use. Epinephrine injection (1:1000) for the control of immediate allergic reactions must be available should an acute anaphylactic reaction occur. - Vaccination is recommended only for those who are tuberculin negative to a recent skin test with 5 TU. - After BCG vaccination, it is usually not possible to clearly distinguish between a tuberculin reaction caused by persistent post-vaccination sensitivity and one caused by a virulent suprainfection. Caution is advised in attributing a positive skin test to BCG vaccination. A sharp rise in the tuberculin reaction since the latest test should be further investigated (except in the immediate post-vaccination period). Laboratory Tests - BCG vaccination results in tuberculin skin test reactivity. Tuberculin skin test reactivity as a result of BCG vaccination cannot be readily differentiated from reactivity following exposure to tuberculosis. BCG vaccination should not be administered to individuals with a positive tuberculin skin test. - Prior administration of BCG vaccine has not been associated with a positive interferon gamma release assay (IGRA) test, which are indirect tests for M. tuberculosis infection (including disease) and are intended for use in conjunction with risk assessment, radiography and other medical and diagnostic evaluations. # Adverse Reactions ## Clinical Trials Experience - Although BCG vaccination often causes local reactions, serious or long-term complications are rare. Reactions that can be expected after vaccination include moderate axillary or cervical lymphadenopathy and induration and subsequent pustule formation at the injection site; these reactions can persist for as long as 3 months after vaccination. More serious local reactions include ulceration at the vaccination site, regional suppurative lymphadenitis with draining sinuses, and caseous lesions or purulent draining at the puncture site. These manifestations might occur up to 5 months after vaccination and could persist for several weeks. The intensity and duration of the local reaction depends on the depth of penetration of the multiple puncture device and individual variations in patients' tissue reactions. Slight tenderness at the puncture site may be encountered as well as some itching. The initial skin lesions usually appear within 10–14 days and consist of small red papules at the site. The papules reach maximum diameter (about 3 mm) after 4 to 6 weeks, after which they may scale and then slowly subside. - The most serious complication of BCG vaccination is disseminated BCG infection. The most frequent disseminated infection is BCG osteomyelitis (0.01 to 43 cases per million doses of vaccine administered) which usually occurs 4 months to 2 years after vaccination. Fatal disseminated BCG infection has occurred at a rate of 0.06–1.56 cases per million doses; these deaths occurred primarily among immunocompromised persons. BCG Vaccination of Individuals Infected with HIV - The safety of BCG vaccination in HIV-infected adults and children, including infants, has not been determined by controlled or large studies. This is a concern because of the association between disseminated BCG infection and underlying immunosuppression. Individuals with HIV infection should not receive the BCG VACCINE. Treatment of Adverse Reactions - If a systemic BCG infection occurs, an infectious disease expert should be consulted and anti-tuberculosis therapy should be initiated. Since BCG strains are resistant to pyrazinamide, this antibiotic should not be used. Reporting of Adverse Reactions - All suspected adverse reactions to BCG vaccination should be reported to Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., at 1-877-888-4231 and to the Vaccine Adverse Event Reporting System (VAERS); telephone 1-800-822-7967. These reactions occasionally could occur more than 1 year after vaccination. ## Postmarketing Experience - There is limited information regarding Postmarketing Experience of BCG vaccine in the drug label. # Drug Interactions - Antimicrobial or immunosuppressive agents may interfere with the development of the immune response and should be used only under medical supervision. - Since BCG is a live vaccine, the immune response to the vaccine might be impaired if administered within 30 days of another live vaccine. However, no evidence exists for currently available vaccines to support this concern. Whenever possible, live vaccines administered on different days should be administered at least 30 days apart. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): C - Animal reproduction studies have not been conducted with BCG VACCINE. It is also not known whether BCG VACCINE can cause fetal harm when administered to a pregnant woman or can affect reproductive capacity. Although no harmful effects to the fetus have been associated with BCG VACCINE, its use is not recommended during pregnancy. Pregnancy Category (AUS): - Australian Drug Evaluation Committee (ADEC) Pregnancy Category - There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of BCG vaccine in women who are pregnant. ### Labor and Delivery - There is no FDA guidance on use of BCG vaccine during labor and delivery. ### Nursing Mothers - It is not known whether BCG is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions from BCG in nursing infants, a decision should be made whether to discontinue nursing or not to vaccinate, taking into account the importance of tuberculosis vaccination to the mother. ### Pediatric Use - See Treatment and Schedule under DOSAGE AND ADMINISTRATION section. Precautions should be taken with respect to infants vaccinated with BCG and exposed to persons with active tuberculosis. ### Geriatic Use - Clinical studies of BCG VACCINE did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in response between elderly and younger patients. An intact immune system is a prerequisite for BCG vaccination. If the immune status of an elderly patient, or any patient, is in question, the BCG vaccination should be held until the immune status of the patient has been evaluated. ### Gender - There is no FDA guidance on the use of BCG vaccine with respect to specific gender populations. ### Race - There is no FDA guidance on the use of BCG vaccine with respect to specific racial populations. ### Renal Impairment - There is no FDA guidance on the use of BCG vaccine in patients with renal impairment. ### Hepatic Impairment - There is no FDA guidance on the use of BCG vaccine in patients with hepatic impairment. ### Females of Reproductive Potential and Males - There is no FDA guidance on the use of BCG vaccine in women of reproductive potentials and males. ### Immunocompromised Patients - There is no FDA guidance one the use of BCG vaccine in patients who are immunocompromised. # Administration and Monitoring ### Administration Preparation of Agent - The preparation of the BCG VACCINE suspension should be done using aseptic technique. To avoid cross-contamination, parenteral drugs should not be prepared in areas where BCG VACCINE has been prepared. A separate area for the preparation of the BCG VACCINE suspension is recommended. All equipment, supplies and receptacles in contact with BCG VACCINE should be handled and disposed of as biohazardous. The pharmacist or individual responsible for mixing the agent should wear gloves, and take precautions to avoid contact of BCG with broken skin. If preparation cannot be performed in a biocontainment hood, then a mask and gown should be worn to avoid inhalation of BCG organisms and inadvertent exposure to broken skin. - Using aseptic methods, 1 mL of Sterile Water for Injection, USP at 4-25°C (39-77°F), is added to one vial of vaccine (see Pediatric Dose below for pediatric use). Gently swirl the vial until a homogenous suspension is obtained. Avoid forceful agitation which may cause clumping of the mycobacteria. - Persons administering vaccines should take necessary precautions to minimize risk for spreading disease. Hands should be washed before each new patient is seen. Syringes and needles used for applications must be sterile and preferably disposable to minimize the risk of contamination. A separate needle and syringe should be used for each application. Disposable needles and the multiple puncture device should be discarded as biohazardous waste in labeled, puncture-proof containers to prevent inadvertent needlestick injury or reuse. After use, any unused vaccine and all materials exposed to the product should be immediately placed in a biohazard container and disposed of in an appropriate manner. - Reconstituted vaccine should be kept refrigerated, protected from exposure to direct sunlight, and used within 2 hours. Freezing of the reconstituted product is not recommended. - Note: DO NOT filter the contents of the BCG VACCINE vial. Precautions should be taken to avoid exposing the BCG VACCINE to direct sunlight. Bacteriostatic solutions must be avoided. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Reconstitution should result in a uniform suspension of the bacilli. - Treatment and Schedule: - BCG vaccination is reserved for persons who have a reaction of less than 5mm induration after skin testing with 5 TU of PPD tuberculin. The preferred method of skin testing is the Mantoux tuberculin skin-test using 0.1 mL of 5 tuberculin units (TU) of PPD. It is recommended that a Mantoux skin-test be performed prior to BCG vaccination to demonstrate the absence of tuberculous infection. - The vaccine is to be administered after fully explaining the risks and benefits to the vaccinee, parent, or guardian. BCG vaccination should not be given to individuals previously infected with M. tuberculosis. The vaccine is administered percutaneously utilizing a sterile multiple puncture device. The multiple puncture device consists of a plastic holder for a thin, wafer-like stainless steel plate 7/8" by 1 1/8", from which 36 points protrude. After the vaccine is prepared, the skin site is cleansed with an alcohol or acetone sponge and allowed to dry thoroughly. ### Monitoring - There is limited information regarding Monitoring of BCG vaccine in the drug label. - Description # IV Compatibility - There is limited information regarding IV Compatibility of BCG vaccine in the drug label. # Overdosage - Accidental overdosages if treated immediately with anti-tuberculous drugs have not led to complications. If the vaccination response is allowed to progress it can still be treated successfully with anti-tuberculous drugs but complications can include regional adenitis, lupus vulgaris, subcutaneous cold abscesses, ocular lesions, and others. # Pharmacology ## Mechanism of Action ## Structure - BCG VACCINE for percutaneous use is an attenuated, live culture preparation of the Bacillus of Calmette and Guerin (BCG) strain of Mycobacterium bovis. The TICE® strain used in this BCG VACCINE preparation was developed at the University of Illinois from a strain originated at the Pasteur Institute. - The medium in which the TICE® BCG organism is grown for preparation of the freeze-dried cake is composed of the following ingredients: glycerin, asparagine, citric acid, potassium phosphate, magnesium sulfate, and iron ammonium citrate. The final preparation prior to freeze drying also contains lactose. The freeze-dried BCG preparation is delivered in vials, each containing 1 to 8 × 108 colony forming units (CFU) of BCG which is equivalent to approximately 50 mg wet weight. Determination of in-vitro potency is achieved through colony counts derived from a serial dilution assay. Intradermal guinea pig testing is also used as an indirect measure of potency. - Reconstitution requires addition of Sterile Water for Injection, USP at 4-25°C (39-77°F). For an adult dosage, 1 mL of Sterile Water for Injection, USP, should be added to one vial of vaccine. For a pediatric dosage, 2 mL of Sterile Water for Injection, USP, should be added to one vial of vaccine (see DOSAGE AND ADMINISTRATION). - No preservatives have been added. ## Pharmacodynamics - There is limited information regarding Pharmacodynamics of BCG vaccine in the drug label. ## Pharmacokinetics - Tuberculosis (TB) is primarily an airborne communicable disease caused by the bacterium, Mycobacterium tuberculosis. - Tuberculosis is an important global public health problem with an estimated 8–10 million cases and 2–3 million deaths occurring each year. The control of TB in the United States has been a constant challenge particularly with the resurgence in TB in the late 1980s and the early 1990s. In the United States, TB had declined approximately 6% per year since nationwide reporting began in 1953. However, in 1985 there was a 1.1% increase over the previous year. This upward trend continued through 1992, when the incidence was 10.5 cases per 100,000 population. In 1993, there was a 5.2% decrease over 1992 with a rate of 9.8 cases per 100,000 population. In 1997, the total TB cases reported was 19,855 or 7.4 cases per 100,000 people. This incidence rate represented the fifth consecutive year that number of reported TB cases had declined and a 26% decrease since the peak in 1992. - In the 1990s, drug-resistant TB also became a significant public health concern. During the period of 1993–1996, in the United States, 13.1% of TB patients were infected with TB strains that were resistant to at least one drug used as first-line treatment for TB (isoniazid, rifampin, pyrazinamide, ethambutol, and streptomycin) and 2.2% of TB patients were infected with TB strains that were multiple drug resistant (MDR as defined by resistance to both isoniazid and rifampin). Cases of MDR-TB were reported from 42 states and Washington D.C. during this time period. - Most persons infected with M. tuberculosis remain infected for many years by developing latent infections. Active TB will reactivate during the lifetime of 5–15% of infected patients who are immunocompetent. In general, active TB is fatal for about 50% of persons who have not been treated. The greatest known risk factor for developing active TB disease is immunodeficiency, particularly if caused by coinfection with HIV. Persons infected with HIV are estimated to be over one hundred times as likely as uninfected persons to develop TB, primarily as a result of reactivation of a latent TB infection. Other groups at high risk for developing TB include foreign-born individuals and persons in institutional settings such as correctional facilities, shelters for the homeless, and nursing homes. - Although over 2 billion people have been immunized with BCG, and it is currently an officially recommended vaccine in more than 180 countries, excluding the U.S., the efficacy of BCG as a vaccine against tuberculosis remains controversial. Prospective vaccine efficacy trials have shown that the protective benefit of BCG (various strains from different manufacturers) against clinical TB was variable, ranging from 0–80%. A recent meta-analysis of data from 14 prospective trials and 12 case control studies concluded that the overall protective effect of BCG against tuberculosis infection was 50%. The reasons for the wide range of effectiveness seen in these studies are unknown but may be attributed to the following: vaccination was not allocated randomly in observational studies; there were differences in BCG strains, methods, and routes of administration; and there were differences in the characteristics of the populations and environments in which the vaccines were studied. Despite the conflicting results concerning prevention of pulmonary tuberculosis, it is widely acknowledged that immunization of infants with BCG lowers the risk of disseminated complications of this disease. Estimates in areas where BCG vaccination is performed at birth indicate that the effectiveness of BCG in preventing childhood TB meningitis or miliary TB exceeds 70%. - In a prospective trial using the TICE® strain of BCG VACCINE, Rosenthal, et al., studied 1,716 vaccinated and 1,665 non-vaccinated infants, all born at the Cook County Hospital in Chicago and followed for 12–23 years. The diagnosis of tuberculosis was made following a review of chest X-ray results and clinical findings. There were 17 cases of tuberculosis among the vaccinated (0.43/1,000/yr) and 65 cases in the nonvaccinated (1.7/1,000/yr); this is a reduction of 75% (p<0.001) in cases of tuberculosis. One death was attributed to tuberculosis in the vaccinated group with 6 deaths in the controls, or a reduction of 83%. There were 639 families in which there was a sibling in both the control and vaccination groups. Eight of the 790 vaccinated subjects developed tuberculosis as compared with 30 of the 945 controls (p<0.001). Thirteen cases of nonfatal tuberculosis developed in the control group that were 2 years of age and under, with none in the vaccinated group. - There were 3 deaths from tuberculosis in the control group that were less than 2.5 years of age (all had miliary tuberculosis with meningitis), with one death in the vaccinated group (meningitis). The infant who died in the vaccinated group had not converted to a positive purified protein derivative (PPD) skin test at 6 months of age and was never subsequently revaccinated. Following a single vaccination, 99.3% of all infants studied became PPD positive, with 84.2% still being positive after 8 years. - In a 1995 study of vaccine potency, 26 tuberculin negative subjects were vaccinated with BCG VACCINE (TICE® strain) and subsequent tuberculin conversion was monitored. Conversion from a negative to a positive skin test may be considered a surrogate indicator of potency and immunization efficacy of BCG Vaccines; however, the correlation between PPD conversion and vaccine effectiveness has not been established. Twenty-four (24) subjects returned for follow-up testing with PPD 10 tuberculin units (10 TU) 8 weeks after vaccination. Twenty-two (22) of the 24 subjects converted to positive (skin test reading >5mm induration at 48 hours) and 2 remained negative. The conversion rate was 92% and the average positive skin test reading was 15.5mm in induration. - In a second study, 22 volunteers between the ages of 18 and 40 who were not health care workers, were not foreign born, were HIV negative, and were negative responders to a 10 TU PPD skin test were vaccinated with the standard dose of BCG VACCINE (TICE® strain). Eight weeks after vaccination the subjects returned for a 10 TU skin test. Twenty-one (21) out of 22 converted to PPD positive at a level greater than 5mm for a skin test conversion rate of 95%. ## Nonclinical Toxicology Carcinogenesis, Mutagenesis, Impairment of Fertility - BCG VACCINE has not been evaluated for carcinogenic, mutagenic potentials or impairment of fertility. # Clinical Studies - There is limited information regarding Clinical Studies of BCG vaccine in the drug label. # How Supplied - BCG VACCINE is supplied in a box of one vial of BCG. Each vial contains 1 to 8 × 108 CFU, which is equivalent to approximately 50 mg (wet weight), as lyophilized (freeze-dried) powder, NDC 0052-0603-02. - Multiple puncture devices may be obtained separately from the Merck Order Management Center, 351 North Sumneytown Pike, North Wales, PA 19454-2505, Telephone number: 800-MERCKRX (800-637-2579). ## Storage - The intact vials of BCG VACCINE should be stored refrigerated at 2-8°C (36-46°F). - This agent contains live bacteria and should be protected from direct sunlight. The product should not be used after the expiration date printed on the label. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information Information for Patients - Before administration of BCG VACCINE, health care personnel should inform patients or guardians of the benefits and risks of immunization and inquire about the health status of the patient. Health care workers considering BCG vaccination should be counseled regarding the risks and benefits associated with both BCG vaccination and TB preventive therapy. They should be informed about (a) the variable data concerning the efficacy of BCG vaccination, (b) the interference with the diagnosis of newly acquired M. tuberculosis infections in BCG-vaccinated persons, and (c) the potential serious complications associated with BCG vaccination of immunocompromised individuals. Health care workers should be informed about (a) the lack of data regarding the efficacy of preventive therapy for MDR-TB infections and (b) the risks of drug toxicity associated with multi-drug preventive therapy regimens. - Following BCG vaccination, no dressing is required; however, it is recommended that the site be loosely covered and kept dry for 24 hours. The vaccination site should be kept clean until the local reaction has disappeared. The patient should be advised that the vaccine contains live organisms. Although the vaccine will not survive in a dry state for long, infection of others is possible. Following vaccination with BCG, initial skin lesions usually appear within 10–14 days and consist of small red papules at the vaccination site. The papules reach a maximum diameter (about 3 mm) after 4 to 6 weeks, after which they may scale and slowly subside. Six months afterwards there is usually no visible sign of the vaccination, though on occasion, a faintly discernable pattern of the points from the multiple puncture device may be visible. On individuals whose skin tends to form keloids, there may be slightly more visible evidence of the vaccination. Any unusual adverse reactions should be reported to the health care provider. - Patients may experience "flu-like" symptoms for 24–48 hours following BCG vaccination. However, the patient should consult with their physician immediately if they experience fever of 103°F or greater, or acute local reactions persisting longer than 2–3 days. # Precautions with Alcohol - Alcohol-BCG vaccine interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names BCG Vaccine, Theracys, Tice BCG. # Look-Alike Drug Names - A® — B® # Drug Shortage Status # Price	BCG vaccine Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Deepika Beereddy, MBBS [2] # Disclaimer WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here. # Overview BCG vaccine is an immunologic adjuvant that is FDA approved for the prophylaxis of tuberculosis in persons not previously infected with M. tuberculosis who are at high risk for exposure. Common adverse reactions include percutaneous injection site reaction, nausea, axillary or cervical lymphadenopathy, , induration, cystitis, dysuria, hematuria, increased frequency of urination, urgent desire to urinate, influenza-like illness, malaise, shivering. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - BCG VACCINE (TICE® strain) is indicated for the prevention of tuberculosis in persons not previously infected with M. tuberculosis who are at high risk for exposure. As with any vaccine, immunization with BCG VACCINE may not protect 100% of susceptible individuals. - The Advisory Committee on Immunization Practices (ACIP) and the Advisory Committee for the Elimination of Tuberculosis has recommended that BCG vaccination be considered in the following circumstances. - TB Exposed Tuberculin Skin Test-Negative Infants and Children - BCG vaccination is recommended for infants and children with negative tuberculin skin tests who are (a) at high risk of intimate and prolonged exposure to persistently untreated or ineffectively treated patients with infectious pulmonary tuberculosis and who cannot be removed from the source of exposure and cannot be placed on long-term primary preventive therapy, or (b) continuously exposed to persons with infectious pulmonary tuberculosis who have bacilli resistant to isoniazid and rifampin, and the child cannot be separated from the presence of the infectious patient. - TB Exposed Health Care Workers (HCW) in High Risk Settings - BCG vaccination of HCWs should be considered on an individual basis in settings where (a) a high percentage of TB patients are infected with M. tuberculosis strains resistant to both isoniazid and rifampin, (b) transmission of such drug resistant M. tuberculosis strains to HCWs and subsequent infection are likely, and (c) comprehensive TB infection control precautions have been implemented and have not been successful. Vaccination should not be required for employment or for assignment of HCWs in specific work areas. HCWs considered for BCG vaccination should be counseled regarding the risks and benefits associated with both BCG vaccinations and TB preventive therapy. - Exposed Health Care Workers in Low Risk Settings - BCG vaccination is not recommended for HCWs in settings in which the risk for M. tuberculosis transmission is low. - Dosing Information - Preparation of Agent: - The preparation of the BCG VACCINE suspension should be done using aseptic technique. To avoid cross-contamination, parenteral drugs should not be prepared in areas where BCG VACCINE has been prepared. A separate area for the preparation of the BCG VACCINE suspension is recommended. All equipment, supplies and receptacles in contact with BCG VACCINE should be handled and disposed of as biohazardous. The pharmacist or individual responsible for mixing the agent should wear gloves, and take precautions to avoid contact of BCG with broken skin. If preparation cannot be performed in a biocontainment hood, then a mask and gown should be worn to avoid inhalation of BCG organisms and inadvertent exposure to broken skin. - Using aseptic methods, 1 mL of Sterile Water for Injection, USP at 4-25°C (39-77°F), is added to one vial of vaccine (see Pediatric Dose below for pediatric use). Gently swirl the vial until a homogenous suspension is obtained. Avoid forceful agitation which may cause clumping of the mycobacteria. - Persons administering vaccines should take necessary precautions to minimize risk for spreading disease. Hands should be washed before each new patient is seen. Syringes and needles used for applications must be sterile and preferably disposable to minimize the risk of contamination. A separate needle and syringe should be used for each application. Disposable needles and the multiple puncture device should be discarded as biohazardous waste in labeled, puncture-proof containers to prevent inadvertent needlestick injury or reuse. After use, any unused vaccine and all materials exposed to the product should be immediately placed in a biohazard container and disposed of in an appropriate manner. - Reconstituted vaccine should be kept refrigerated, protected from exposure to direct sunlight, and used within 2 hours. Freezing of the reconstituted product is not recommended. - Note: DO NOT filter the contents of the BCG VACCINE vial. Precautions should be taken to avoid exposing the BCG VACCINE to direct sunlight. Bacteriostatic solutions must be avoided. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Reconstitution should result in a uniform suspension of the bacilli. - Treatment and Schedule: - BCG vaccination is reserved for persons who have a reaction of less than 5mm induration after skin testing with 5 TU of PPD tuberculin. The preferred method of skin testing is the Mantoux tuberculin skin-test using 0.1 mL of 5 tuberculin units (TU) of PPD. It is recommended that a Mantoux skin-test be performed prior to BCG vaccination to demonstrate the absence of tuberculous infection. - The vaccine is to be administered after fully explaining the risks and benefits to the vaccinee, parent, or guardian. BCG vaccination should not be given to individuals previously infected with M. tuberculosis. The vaccine is administered percutaneously utilizing a sterile multiple puncture device. The multiple puncture device consists of a plastic holder for a thin, wafer-like stainless steel plate 7/8" by 1 1/8", from which 36 points protrude. After the vaccine is prepared, the skin site is cleansed with an alcohol or acetone sponge and allowed to dry thoroughly. ### Carcinoma in situ of bladder; Treatment and Prophylaxis - Dosing Information - TheraCys(R) BCG Live (Connaught Strain): - Wait a minimum of 14 days following bladder biopsy or transurethral resection before initiating TheraCys(R) BCG Live. Administration of TheraCys(R) BCG Live consists of 1 vial (81 mg) of TheraCys(R) BCG (Connaught strain) reconstituted with accompanying diluent (3 mL) and further diluted in sterile, preservative-free 0.9% sodium chloride to a final volume of 50 mL. Instill suspension into the bladder slowly by gravity flow via urethral catheter (total instillation volume is 50 mL). The suspension should be retained as long as possible for up to 2 hours with the patient lying in the prone position for the first 15 minutes, after which time allow the patient to be in an upright position. After 2 hours, the patient should void in a seated position. Repeat instillation once weekly for 6 weeks (induction therapy), followed by maintenance therapy of 1 dose at 3, 6, 12, 18, and 24 months after the initial dose. - Duration of treatment can be variable. The initial 6 weeks of induction may not be sufficient in some cases to achieve an adequate inflammatory response, while other patients may respond with as few as 3 treatments. BCG variability and host immune status play a role in individual patient outcomes. Prophylaxis against recurrence may be beneficial in patients with multiple, high-grade, stage Ta or T1 tumors. - TICE(R) BCG Live (TICE(R) Strain): - Wait 7 to 14 days after bladder biopsy or transurethral resection before administering TICE(R) BCG Live. Administration of TICE(R) BCG Live consists of 1 vial (50 mg) of TICE(R) BCG in 50 mL of preservative-free saline per intravesical instillation. The dose is repeated weekly for 6 weeks followed by a monthly instillation for 6 to 12 months. If tumor remission is not achieved following the first 6 weeks, the initial once weekly 6 week regimen may be repeated prior to initiating the monthly maintenance regimen depending on the clinical status of the patient. Patients should not drink fluids for 4 hours prior to treatment and they should empty their bladder before treatment. The suspension should be retained as long as possible for up to 2 hours with the patient being repositioned every 15 minutes (left side to right side, back, and abdomen) to maximize bladder surface exposure. - Duration of treatment can be variable. The initial 6 weeks of induction may not be sufficient in some cases to achieve an adequate inflammatory response, while other patients may respond with as few as 3 treatments. BCG variability and host immune status play a role in individual patient outcomes. Prophylaxis against recurrence may be beneficial in patients with multiple, high-grade, stage Ta or T1 tumors. ### Malignant tumor of urinary bladder, Stage Ta and/or T1 papillary tumors following transurethral resection; Prophylaxis - Dosing Information - TheraCys(R) BCG Live (Connaught Strain): - Wait a minimum of 14 days following bladder biopsy or transurethral resection before initiating TheraCys(R) BCG Live. Administration of TheraCys(R) BCG Live consists of 1 vial (81 mg) of TheraCys(R) BCG (Connaught strain) reconstituted with accompanying diluent (3 mL) and further diluted in sterile, preservative-free 0.9% sodium chloride to a final volume of 50 mL. Instill suspension into the bladder slowly by gravity flow via urethral catheter (total instillation volume is 50 mL). The suspension should be retained as long as possible for up to 2 hours with the patient lying in the prone position for the first 15 minutes, after which time allow the patient to be in an upright position. After 2 hours, the patient should void in a seated position. Repeat instillation once weekly for 6 weeks (induction therapy), followed by maintenance therapy of 1 dose at 3, 6, 12, 18, and 24 months after the initial dose. - Duration of treatment can be variable. The initial 6 weeks of induction may not be sufficient in some cases to achieve an adequate inflammatory response, while other patients may respond with as few as 3 treatments. BCG variability and host immune status play a role in individual patient outcomes. Prophylaxis against recurrence may be beneficial in patients with multiple, high-grade, stage Ta or T1 tumors. - TICE(R) BCG Live (TICE(R) Strain): - Wait 7 to 14 days after bladder biopsy or transurethral resection before administering TICE(R) BCG Live. Administration of TICE(R) BCG Live consists of 1 vial (50 mg) of TICE(R) BCG in 50 mL of preservative-free saline per intravesical instillation. The dose is repeated weekly for 6 weeks followed by a monthly instillation for 6 to 12 months. If tumor remission is not achieved following the first 6 weeks, the initial once weekly 6 week regimen may be repeated prior to initiating the monthly maintenance regimen depending on the clinical status of the patient. Patients should not drink fluids for 4 hours prior to treatment and they should empty their bladder before treatment. The suspension should be retained as long as possible for up to 2 hours with the patient being repositioned every 15 minutes (left side to right side, back, and abdomen) to maximize bladder surface exposure. - Duration of treatment can be variable. The initial 6 weeks of induction may not be sufficient in some cases to achieve an adequate inflammatory response, while other patients may respond with as few as 3 treatments. BCG variability and host immune status play a role in individual patient outcomes. Prophylaxis against recurrence may be beneficial in patients with multiple, high-grade, stage Ta or T1 tumors. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use - There is limited information regarding Off-Label Guideline-Supported Use of BCG vaccine in adult patients. ### Non–Guideline-Supported Use - There is limited information regarding Off-Label Non–Guideline-Supported Use of BCG vaccine in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) - Dosing Information - Do not administer INTRAVENOUSLY, SUBCUTANEOUSLY, INTRAMUSCULARLY, OR INTRADERMALLY. Administer the vaccine in the deltoid region. - In infants less than 1 month old, the dosage of BCG VACCINE should be reduced by one-half, by using 2 mL of Sterile Water for Injection, USP at 4-25°C (39-77°F) when reconstituting. If a vaccinated infant remains tuberculin negative to 5 TU on skin testing, and if indications for vaccination persist, the infant should receive a full dose after 1 year of age. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use - There is limited information regarding Off-Label Guideline-Supported Use of BCG vaccine in pediatric patients. ### Non–Guideline-Supported Use - There is limited information regarding Off-Label Non–Guideline-Supported Use of BCG vaccine in pediatric patients. # Contraindications - BCG VACCINE for prevention of tuberculosis should not be given to persons (a) whose immunologic responses are impaired because of HIV infections, congenital immunodeficiency such as chronic granulomatous disease or interferon gamma receptor deficiency, leukemia, lymphoma, or generalized malignancy or (b) whose immunologic responses have been suppressed by steroids, alkylating agents, antimetabolites, or radiation. BCG VACCINE should not be administered to HIV-infected or immunocompromised infants, children, or adults. - Prior to administration, the possibility of allergic reactions should be assessed. Allergy to any component of BCG VACCINE or an anaphylactic or allergic reaction to a previous dose of BCG VACCINE are contraindications for vaccination. - BCG VACCINE is not a vaccine for the treatment of active tuberculosis. - BCG VACCINE should not be used in infants, children, or adults with severe immune deficiency syndromes. Children with a family history of immune deficiency disease should not be vaccinated; if they are, an infectious disease specialist should be consulted and anti-tuberculous therapy administered if clinically indicated. # Warnings - Administration should be by the percutaneous route with the multiple puncture device as described below. DO NOT INJECT INTRAVENOUSLY, SUBCUTANEOUSLY, INTRAMUSCULARLY, OR INTRADERMALLY. - Although BCG vaccination often results in local adverse effects, serious or long-term complications are rare. Reactions that can be expected after vaccination include moderate axillary or cervical lymphadenopathy and induration and subsequent pustule formation at the injection site; these reactions can persist for as long as 3 months after vaccination. More severe local reactions include ulceration at the vaccination site, regional suppurative lymphadenitis with draining sinuses, and caseous lesions or purulent drainage at the puncture site; these manifestations might occur within the 5 months after vaccination and could persist for several weeks. - Acute, localized irritative toxicities of BCG may be accompanied by systemic manifestations, consistent with a "flu-like" syndrome. Systemic adverse effects of 1–2 days' duration such as fever, anorexia, myalgia, and neuralgia, often reflect hypersensitivity reactions. However, symptoms such as fever of 103°F or greater, or acute localized inflammation persisting longer than 2–3 days suggest active infections, and evaluation for serious infectious complication should be considered. If a BCG infection is suspected, the physician should consult with an infectious disease expert before therapy is initiated. Treatment should be started without delay. In patients who develop persistent fever or experience an acute febrile illness consistent with BCG infection, two or more antimycobacterial agents should be administered while diagnostic evaluation, including cultures, is conducted. Negative cultures do not necessarily rule out infection. Physicians or persons caring for patients that use this product should be familiar with the literature on prevention, diagnosis, and treatment of BCG-related complications and, when appropriate, should consult an infectious disease specialist or other physician with experience in the diagnosis and treatment of mycobacterial infections. - The most serious complication of BCG vaccination is disseminated BCG infection. BCG osteitis affecting the epiphyses of the long bones, particularly the epiphyses of the leg, can occur from 4 months to 2 years after vaccination. Fatal disseminated BCG disease has occurred at a rate of 0.06–1.56 cases per million doses of vaccine administered; these deaths occurred primarily among immunocompromised persons. The appropriate therapy for systemic BCG infections is discussed in the ADVERSE REACTIONS section. ### Precautions General - BCG VACCINE contains live bacteria and should be used with aseptic technique. To avoid cross-contamination, parenteral drugs should not be prepared in areas where BCG VACCINE has been in use. A separate sterile multiple puncture device must be used for each patient and appropriately discarded after use. All equipment, supplies and receptacles in contact with BCG VACCINE should be handled and disposed of as biohazardous. - BCG VACCINE administration should not be attempted in individuals with severe immune deficiency disease. BCG VACCINE should be administered with caution to persons in groups at high risk for HIV infection. - A review of each patient's immunization records to include history on reactions to immunizations should be completed prior to vaccination. All precautions should be taken for the prevention of allergic or any other side reactions, including understanding the use of the biological and the nature of the adverse reactions that may follow its use. Epinephrine injection (1:1000) for the control of immediate allergic reactions must be available should an acute anaphylactic reaction occur. - Vaccination is recommended only for those who are tuberculin negative to a recent skin test with 5 TU. - After BCG vaccination, it is usually not possible to clearly distinguish between a tuberculin reaction caused by persistent post-vaccination sensitivity and one caused by a virulent suprainfection. Caution is advised in attributing a positive skin test to BCG vaccination. A sharp rise in the tuberculin reaction since the latest test should be further investigated (except in the immediate post-vaccination period). Laboratory Tests - BCG vaccination results in tuberculin skin test reactivity. Tuberculin skin test reactivity as a result of BCG vaccination cannot be readily differentiated from reactivity following exposure to tuberculosis. BCG vaccination should not be administered to individuals with a positive tuberculin skin test. - Prior administration of BCG vaccine has not been associated with a positive interferon gamma release assay (IGRA) test, which are indirect tests for M. tuberculosis infection (including disease) and are intended for use in conjunction with risk assessment, radiography and other medical and diagnostic evaluations. # Adverse Reactions ## Clinical Trials Experience - Although BCG vaccination often causes local reactions, serious or long-term complications are rare. Reactions that can be expected after vaccination include moderate axillary or cervical lymphadenopathy and induration and subsequent pustule formation at the injection site; these reactions can persist for as long as 3 months after vaccination. More serious local reactions include ulceration at the vaccination site, regional suppurative lymphadenitis with draining sinuses, and caseous lesions or purulent draining at the puncture site. These manifestations might occur up to 5 months after vaccination and could persist for several weeks. The intensity and duration of the local reaction depends on the depth of penetration of the multiple puncture device and individual variations in patients' tissue reactions. Slight tenderness at the puncture site may be encountered as well as some itching. The initial skin lesions usually appear within 10–14 days and consist of small red papules at the site. The papules reach maximum diameter (about 3 mm) after 4 to 6 weeks, after which they may scale and then slowly subside. - The most serious complication of BCG vaccination is disseminated BCG infection. The most frequent disseminated infection is BCG osteomyelitis (0.01 to 43 cases per million doses of vaccine administered) which usually occurs 4 months to 2 years after vaccination. Fatal disseminated BCG infection has occurred at a rate of 0.06–1.56 cases per million doses; these deaths occurred primarily among immunocompromised persons. BCG Vaccination of Individuals Infected with HIV - The safety of BCG vaccination in HIV-infected adults and children, including infants, has not been determined by controlled or large studies. This is a concern because of the association between disseminated BCG infection and underlying immunosuppression. Individuals with HIV infection should not receive the BCG VACCINE. Treatment of Adverse Reactions - If a systemic BCG infection occurs, an infectious disease expert should be consulted and anti-tuberculosis therapy should be initiated. Since BCG strains are resistant to pyrazinamide, this antibiotic should not be used. Reporting of Adverse Reactions - All suspected adverse reactions to BCG vaccination should be reported to Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., at 1-877-888-4231 and to the Vaccine Adverse Event Reporting System (VAERS); telephone 1-800-822-7967. These reactions occasionally could occur more than 1 year after vaccination. ## Postmarketing Experience - There is limited information regarding Postmarketing Experience of BCG vaccine in the drug label. # Drug Interactions - Antimicrobial or immunosuppressive agents may interfere with the development of the immune response and should be used only under medical supervision. - Since BCG is a live vaccine, the immune response to the vaccine might be impaired if administered within 30 days of another live vaccine. However, no evidence exists for currently available vaccines to support this concern. Whenever possible, live vaccines administered on different days should be administered at least 30 days apart. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): C - Animal reproduction studies have not been conducted with BCG VACCINE. It is also not known whether BCG VACCINE can cause fetal harm when administered to a pregnant woman or can affect reproductive capacity. Although no harmful effects to the fetus have been associated with BCG VACCINE, its use is not recommended during pregnancy. Pregnancy Category (AUS): - Australian Drug Evaluation Committee (ADEC) Pregnancy Category - There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of BCG vaccine in women who are pregnant. ### Labor and Delivery - There is no FDA guidance on use of BCG vaccine during labor and delivery. ### Nursing Mothers - It is not known whether BCG is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions from BCG in nursing infants, a decision should be made whether to discontinue nursing or not to vaccinate, taking into account the importance of tuberculosis vaccination to the mother. ### Pediatric Use - See Treatment and Schedule under DOSAGE AND ADMINISTRATION section. Precautions should be taken with respect to infants vaccinated with BCG and exposed to persons with active tuberculosis. ### Geriatic Use - Clinical studies of BCG VACCINE did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in response between elderly and younger patients. An intact immune system is a prerequisite for BCG vaccination. If the immune status of an elderly patient, or any patient, is in question, the BCG vaccination should be held until the immune status of the patient has been evaluated. ### Gender - There is no FDA guidance on the use of BCG vaccine with respect to specific gender populations. ### Race - There is no FDA guidance on the use of BCG vaccine with respect to specific racial populations. ### Renal Impairment - There is no FDA guidance on the use of BCG vaccine in patients with renal impairment. ### Hepatic Impairment - There is no FDA guidance on the use of BCG vaccine in patients with hepatic impairment. ### Females of Reproductive Potential and Males - There is no FDA guidance on the use of BCG vaccine in women of reproductive potentials and males. ### Immunocompromised Patients - There is no FDA guidance one the use of BCG vaccine in patients who are immunocompromised. # Administration and Monitoring ### Administration Preparation of Agent - The preparation of the BCG VACCINE suspension should be done using aseptic technique. To avoid cross-contamination, parenteral drugs should not be prepared in areas where BCG VACCINE has been prepared. A separate area for the preparation of the BCG VACCINE suspension is recommended. All equipment, supplies and receptacles in contact with BCG VACCINE should be handled and disposed of as biohazardous. The pharmacist or individual responsible for mixing the agent should wear gloves, and take precautions to avoid contact of BCG with broken skin. If preparation cannot be performed in a biocontainment hood, then a mask and gown should be worn to avoid inhalation of BCG organisms and inadvertent exposure to broken skin. - Using aseptic methods, 1 mL of Sterile Water for Injection, USP at 4-25°C (39-77°F), is added to one vial of vaccine (see Pediatric Dose below for pediatric use). Gently swirl the vial until a homogenous suspension is obtained. Avoid forceful agitation which may cause clumping of the mycobacteria. - Persons administering vaccines should take necessary precautions to minimize risk for spreading disease. Hands should be washed before each new patient is seen. Syringes and needles used for applications must be sterile and preferably disposable to minimize the risk of contamination. A separate needle and syringe should be used for each application. Disposable needles and the multiple puncture device should be discarded as biohazardous waste in labeled, puncture-proof containers to prevent inadvertent needlestick injury or reuse. After use, any unused vaccine and all materials exposed to the product should be immediately placed in a biohazard container and disposed of in an appropriate manner. - Reconstituted vaccine should be kept refrigerated, protected from exposure to direct sunlight, and used within 2 hours. Freezing of the reconstituted product is not recommended. - Note: DO NOT filter the contents of the BCG VACCINE vial. Precautions should be taken to avoid exposing the BCG VACCINE to direct sunlight. Bacteriostatic solutions must be avoided. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Reconstitution should result in a uniform suspension of the bacilli. - Treatment and Schedule: - BCG vaccination is reserved for persons who have a reaction of less than 5mm induration after skin testing with 5 TU of PPD tuberculin. The preferred method of skin testing is the Mantoux tuberculin skin-test using 0.1 mL of 5 tuberculin units (TU) of PPD. It is recommended that a Mantoux skin-test be performed prior to BCG vaccination to demonstrate the absence of tuberculous infection. - The vaccine is to be administered after fully explaining the risks and benefits to the vaccinee, parent, or guardian. BCG vaccination should not be given to individuals previously infected with M. tuberculosis. The vaccine is administered percutaneously utilizing a sterile multiple puncture device. The multiple puncture device consists of a plastic holder for a thin, wafer-like stainless steel plate 7/8" by 1 1/8", from which 36 points protrude. After the vaccine is prepared, the skin site is cleansed with an alcohol or acetone sponge and allowed to dry thoroughly. ### Monitoring - There is limited information regarding Monitoring of BCG vaccine in the drug label. - Description # IV Compatibility - There is limited information regarding IV Compatibility of BCG vaccine in the drug label. # Overdosage - Accidental overdosages if treated immediately with anti-tuberculous drugs have not led to complications. If the vaccination response is allowed to progress it can still be treated successfully with anti-tuberculous drugs but complications can include regional adenitis, lupus vulgaris, subcutaneous cold abscesses, ocular lesions, and others. # Pharmacology ## Mechanism of Action - ## Structure - BCG VACCINE for percutaneous use is an attenuated, live culture preparation of the Bacillus of Calmette and Guerin (BCG) strain of Mycobacterium bovis. The TICE® strain used in this BCG VACCINE preparation was developed at the University of Illinois from a strain originated at the Pasteur Institute. - The medium in which the TICE® BCG organism is grown for preparation of the freeze-dried cake is composed of the following ingredients: glycerin, asparagine, citric acid, potassium phosphate, magnesium sulfate, and iron ammonium citrate. The final preparation prior to freeze drying also contains lactose. The freeze-dried BCG preparation is delivered in vials, each containing 1 to 8 × 108 colony forming units (CFU) of BCG which is equivalent to approximately 50 mg wet weight. Determination of in-vitro potency is achieved through colony counts derived from a serial dilution assay. Intradermal guinea pig testing is also used as an indirect measure of potency. - Reconstitution requires addition of Sterile Water for Injection, USP at 4-25°C (39-77°F). For an adult dosage, 1 mL of Sterile Water for Injection, USP, should be added to one vial of vaccine. For a pediatric dosage, 2 mL of Sterile Water for Injection, USP, should be added to one vial of vaccine (see DOSAGE AND ADMINISTRATION). - No preservatives have been added. ## Pharmacodynamics - There is limited information regarding Pharmacodynamics of BCG vaccine in the drug label. ## Pharmacokinetics - Tuberculosis (TB) is primarily an airborne communicable disease caused by the bacterium, Mycobacterium tuberculosis. - Tuberculosis is an important global public health problem with an estimated 8–10 million cases and 2–3 million deaths occurring each year. The control of TB in the United States has been a constant challenge particularly with the resurgence in TB in the late 1980s and the early 1990s. In the United States, TB had declined approximately 6% per year since nationwide reporting began in 1953. However, in 1985 there was a 1.1% increase over the previous year. This upward trend continued through 1992, when the incidence was 10.5 cases per 100,000 population. In 1993, there was a 5.2% decrease over 1992 with a rate of 9.8 cases per 100,000 population. In 1997, the total TB cases reported was 19,855 or 7.4 cases per 100,000 people. This incidence rate represented the fifth consecutive year that number of reported TB cases had declined and a 26% decrease since the peak in 1992. - In the 1990s, drug-resistant TB also became a significant public health concern. During the period of 1993–1996, in the United States, 13.1% of TB patients were infected with TB strains that were resistant to at least one drug used as first-line treatment for TB (isoniazid, rifampin, pyrazinamide, ethambutol, and streptomycin) and 2.2% of TB patients were infected with TB strains that were multiple drug resistant (MDR as defined by resistance to both isoniazid and rifampin). Cases of MDR-TB were reported from 42 states and Washington D.C. during this time period. - Most persons infected with M. tuberculosis remain infected for many years by developing latent infections. Active TB will reactivate during the lifetime of 5–15% of infected patients who are immunocompetent. In general, active TB is fatal for about 50% of persons who have not been treated. The greatest known risk factor for developing active TB disease is immunodeficiency, particularly if caused by coinfection with HIV. Persons infected with HIV are estimated to be over one hundred times as likely as uninfected persons to develop TB, primarily as a result of reactivation of a latent TB infection. Other groups at high risk for developing TB include foreign-born individuals and persons in institutional settings such as correctional facilities, shelters for the homeless, and nursing homes. - Although over 2 billion people have been immunized with BCG, and it is currently an officially recommended vaccine in more than 180 countries, excluding the U.S., the efficacy of BCG as a vaccine against tuberculosis remains controversial. Prospective vaccine efficacy trials have shown that the protective benefit of BCG (various strains from different manufacturers) against clinical TB was variable, ranging from 0–80%. A recent meta-analysis of data from 14 prospective trials and 12 case control studies concluded that the overall protective effect of BCG against tuberculosis infection was 50%. The reasons for the wide range of effectiveness seen in these studies are unknown but may be attributed to the following: vaccination was not allocated randomly in observational studies; there were differences in BCG strains, methods, and routes of administration; and there were differences in the characteristics of the populations and environments in which the vaccines were studied. Despite the conflicting results concerning prevention of pulmonary tuberculosis, it is widely acknowledged that immunization of infants with BCG lowers the risk of disseminated complications of this disease. Estimates in areas where BCG vaccination is performed at birth indicate that the effectiveness of BCG in preventing childhood TB meningitis or miliary TB exceeds 70%. - In a prospective trial using the TICE® strain of BCG VACCINE, Rosenthal, et al., studied 1,716 vaccinated and 1,665 non-vaccinated infants, all born at the Cook County Hospital in Chicago and followed for 12–23 years. The diagnosis of tuberculosis was made following a review of chest X-ray results and clinical findings. There were 17 cases of tuberculosis among the vaccinated (0.43/1,000/yr) and 65 cases in the nonvaccinated (1.7/1,000/yr); this is a reduction of 75% (p<0.001) in cases of tuberculosis. One death was attributed to tuberculosis in the vaccinated group with 6 deaths in the controls, or a reduction of 83%. There were 639 families in which there was a sibling in both the control and vaccination groups. Eight of the 790 vaccinated subjects developed tuberculosis as compared with 30 of the 945 controls (p<0.001). Thirteen cases of nonfatal tuberculosis developed in the control group that were 2 years of age and under, with none in the vaccinated group. - There were 3 deaths from tuberculosis in the control group that were less than 2.5 years of age (all had miliary tuberculosis with meningitis), with one death in the vaccinated group (meningitis). The infant who died in the vaccinated group had not converted to a positive purified protein derivative (PPD) skin test at 6 months of age and was never subsequently revaccinated. Following a single vaccination, 99.3% of all infants studied became PPD positive, with 84.2% still being positive after 8 years. - In a 1995 study of vaccine potency, 26 tuberculin negative subjects were vaccinated with BCG VACCINE (TICE® strain) and subsequent tuberculin conversion was monitored. Conversion from a negative to a positive skin test may be considered a surrogate indicator of potency and immunization efficacy of BCG Vaccines; however, the correlation between PPD conversion and vaccine effectiveness has not been established. Twenty-four (24) subjects returned for follow-up testing with PPD 10 tuberculin units (10 TU) 8 weeks after vaccination. Twenty-two (22) of the 24 subjects converted to positive (skin test reading >5mm induration at 48 hours) and 2 remained negative. The conversion rate was 92% and the average positive skin test reading was 15.5mm in induration. - In a second study, 22 volunteers between the ages of 18 and 40 who were not health care workers, were not foreign born, were HIV negative, and were negative responders to a 10 TU PPD skin test were vaccinated with the standard dose of BCG VACCINE (TICE® strain). Eight weeks after vaccination the subjects returned for a 10 TU skin test. Twenty-one (21) out of 22 converted to PPD positive at a level greater than 5mm for a skin test conversion rate of 95%. ## Nonclinical Toxicology Carcinogenesis, Mutagenesis, Impairment of Fertility - BCG VACCINE has not been evaluated for carcinogenic, mutagenic potentials or impairment of fertility. # Clinical Studies - There is limited information regarding Clinical Studies of BCG vaccine in the drug label. # How Supplied - BCG VACCINE is supplied in a box of one vial of BCG. Each vial contains 1 to 8 × 108 CFU, which is equivalent to approximately 50 mg (wet weight), as lyophilized (freeze-dried) powder, NDC 0052-0603-02. - Multiple puncture devices may be obtained separately from the Merck Order Management Center, 351 North Sumneytown Pike, North Wales, PA 19454-2505, Telephone number: 800-MERCKRX (800-637-2579). ## Storage - The intact vials of BCG VACCINE should be stored refrigerated at 2-8°C (36-46°F). - This agent contains live bacteria and should be protected from direct sunlight. The product should not be used after the expiration date printed on the label. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information Information for Patients - Before administration of BCG VACCINE, health care personnel should inform patients or guardians of the benefits and risks of immunization and inquire about the health status of the patient. Health care workers considering BCG vaccination should be counseled regarding the risks and benefits associated with both BCG vaccination and TB preventive therapy. They should be informed about (a) the variable data concerning the efficacy of BCG vaccination, (b) the interference with the diagnosis of newly acquired M. tuberculosis infections in BCG-vaccinated persons, and (c) the potential serious complications associated with BCG vaccination of immunocompromised individuals. Health care workers should be informed about (a) the lack of data regarding the efficacy of preventive therapy for MDR-TB infections and (b) the risks of drug toxicity associated with multi-drug preventive therapy regimens. - Following BCG vaccination, no dressing is required; however, it is recommended that the site be loosely covered and kept dry for 24 hours. The vaccination site should be kept clean until the local reaction has disappeared. The patient should be advised that the vaccine contains live organisms. Although the vaccine will not survive in a dry state for long, infection of others is possible. Following vaccination with BCG, initial skin lesions usually appear within 10–14 days and consist of small red papules at the vaccination site. The papules reach a maximum diameter (about 3 mm) after 4 to 6 weeks, after which they may scale and slowly subside. Six months afterwards there is usually no visible sign of the vaccination, though on occasion, a faintly discernable pattern of the points from the multiple puncture device may be visible. On individuals whose skin tends to form keloids, there may be slightly more visible evidence of the vaccination. Any unusual adverse reactions should be reported to the health care provider. - Patients may experience "flu-like" symptoms for 24–48 hours following BCG vaccination. However, the patient should consult with their physician immediately if they experience fever of 103°F or greater, or acute local reactions persisting longer than 2–3 days. # Precautions with Alcohol - Alcohol-BCG vaccine interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names BCG Vaccine, Theracys, Tice BCG. # Look-Alike Drug Names - A® — B®[1] # Drug Shortage Status # Price	https://www.wikidoc.org/index.php/BCG_vaccine
a574dfdf022405ae1c32d98bb88d430b234eaee6	wikidoc	Native PAGE	Native PAGE # Overview Native polyacrylamide gel electrophoresis is an electrophoretic separation method typically used in proteomics. Native PAGE should not be confused with SDS-PAGE. SDS-PAGE uses a detergent, sodium dodecyl sulfate, to denature proteins. The primary effect is that proteins in protein complexes are separated, reducing the dependence of protein mobility on folding. In contrast, native PAGE separations are run in non-denaturing conditions. Detergents are used only to the extent that they are necessary to lyse lipid membranes in the cell. Complexes remain--for the most part--associated and folded as they would be in the cell. One downside, however, is that complexes may not separate cleanly or predictably, since they cannot move through the polyacrylamide gel as quickly as individual, denatured proteins. There are three popular methods of native PAGE, clear native (CN-PAGE), blue native (BN-PAGE), and quantitative preparative native continuous (QPNC-PAGE). # Blue Native PAGE BN-PAGE is more widely used than CN-PAGE, since the use of Coomassie blue dye enables the separations to be examined with the naked eye. The disadvantage of using dye is that in binding to proteins it causes complexes to dissociate. # Clear Native PAGE CN-PAGE uses no dye, which makes it difficult to examine separations of proteins. However, this method is arguably the most useful for examining protein-protein interactions, particularly in conjunction with mass spectrometry (MS). In a typical CN-PAGE experimental procedure, the complexes will be separated with CN-PAGE. An additional separation method may then be used, such as isoelectric focusing. The gel will then be physically cut, and the protein complexes extracted from each portion separately. Each extract may then be sequenced, such as by peptide mass fingerprinting. This can provide a great deal of information about the identifies of the proteins in a complex.	Native PAGE # Overview Native polyacrylamide gel electrophoresis is an electrophoretic separation method typically used in proteomics. Native PAGE should not be confused with SDS-PAGE. SDS-PAGE uses a detergent, sodium dodecyl sulfate, to denature proteins. The primary effect is that proteins in protein complexes are separated, reducing the dependence of protein mobility on folding. In contrast, native PAGE separations are run in non-denaturing conditions. Detergents are used only to the extent that they are necessary to lyse lipid membranes in the cell. Complexes remain--for the most part--associated and folded as they would be in the cell. One downside, however, is that complexes may not separate cleanly or predictably, since they cannot move through the polyacrylamide gel as quickly as individual, denatured proteins. There are three popular methods of native PAGE, clear native (CN-PAGE), blue native (BN-PAGE), and quantitative preparative native continuous (QPNC-PAGE). # Blue Native PAGE BN-PAGE is more widely used than CN-PAGE, since the use of Coomassie blue dye enables the separations to be examined with the naked eye. The disadvantage of using dye is that in binding to proteins it causes complexes to dissociate. # Clear Native PAGE CN-PAGE uses no dye, which makes it difficult to examine separations of proteins. However, this method is arguably the most useful for examining protein-protein interactions, particularly in conjunction with mass spectrometry (MS). In a typical CN-PAGE experimental procedure, the complexes will be separated with CN-PAGE. An additional separation method may then be used, such as isoelectric focusing. The gel will then be physically cut, and the protein complexes extracted from each portion separately. Each extract may then be sequenced, such as by peptide mass fingerprinting. This can provide a great deal of information about the identifies of the proteins in a complex.	https://www.wikidoc.org/index.php/BN-PAGE
ae14e4ff9bfd51a9b4b38bce0bbf37597068bb81	wikidoc	BRAF (gene)	BRAF (gene) BRAF is a human gene that encodes a protein called B-Raf. The gene is also referred to as proto-oncogene B-Raf and v-Raf murine sarcoma viral oncogene homolog B, while the protein is more formally known as serine/threonine-protein kinase B-Raf. The B-Raf protein is involved in sending signals inside cells which are involved in directing cell growth. In 2002, it was shown to be faulty (mutated) in some human cancers. Certain other inherited BRAF mutations cause birth defects. Drugs that treat cancers driven by BRAF mutations have been developed. Two of these drugs, vemurafenib and dabrafenib are approved by FDA for treatment of late-stage melanoma. Vemurafenib was the first drug to come out of fragment-based drug discovery. # Function B-Raf is a member of the Raf kinase family of growth signal transduction protein kinases. This protein plays a role in regulating the MAP kinase/ERKs signaling pathway, which affects cell division, differentiation, and secretion. # Structure B-Raf is a 766-amino acid, regulated signal transduction serine/threonine-specific protein kinase. Broadly speaking, it is composed of three conserved domains characteristic of the Raf kinase family: conserved region 1 (CR1), a Ras-GTP-binding self-regulatory domain, conserved region 2 (CR2), a serine-rich hinge region, and conserved region 3 (CR3), a catalytic protein kinase domain that phosphorylates a consensus sequence on protein substrates. In its active conformation, B-Raf forms dimers via hydrogen-bonding and electrostatic interactions of its kinase domains. ## CR1 Conserved region 1 autoinhibits B-Raf's kinase domain (CR3) so that B-Raf signaling is regulated rather than constitutive. Residues 155–227 make up the Ras-binding domain (RBD), which binds to Ras-GTP's effector domain to release CR1 and halt kinase inhibition. Residues 234–280 comprise a phorbol ester/DAG-binding zinc finger motif that participates in B-Raf membrane docking after Ras-binding. ## CR2 Conserved Region 2 (CR2) provides a flexible linker that connects CR1 and CR3 and acts as a hinge. ## CR3 Conserved Region 3 (CR3), residues 457–717, makes up B-Raf's enzymatic kinase domain. This largely conserved structure is bi-lobal, connected by a short hinge region. The smaller N-lobe (residues 457–530) is primarily responsible for ATP binding while the larger C-lobe (residues 535–717) binds substrate proteins. The active site is the cleft between the two lobes, and the catalytic Asp576 residue is located on the C-lobe, facing the inside of this cleft. ### Subregions P-Loop The P-loop of B-Raf (residues 464–471) stabilizes the non-transferable phosphate groups of ATP during enzyme ATP-binding. Specifically, S467, F468, and G469 backbone amides hydrogen-bond to the β-phosphate of ATP to anchor the molecule. B-Raf functional motifs have been determined by analyzing the homology of PKA analyzed by Hanks and Hunter to the B-Raf kinase domain. Nucleotide-Binding Pocket V471, C532, W531, T529, L514, and A481 form a hydrophobic pocket within which the adenine of ATP is anchored through Van der Waals attractions upon ATP binding. Catalytic Loop Residues 574–581 compose a section of the kinase domain responsible for supporting the transfer of the γ-phosphate of ATP to B-Raf's protein substrate. In particular, D576 acts as a proton acceptor to activate the nucleophilic hydroxyl oxygen on substrate serine or threonine residues, allowing the phosphate transfer reaction to occur mediated by base-catalysis. DFG Motif D594, F595, and G596 compose a motif central to B-Raf's function in both its inactive and active state. In the inactive state, F595 occupies the nucleotide-binding pocket, prohibiting ATP from entering and decreasing the likelihood of enzyme catalysis. In the active state, D594 chelates the divalent magnesium cation that stabilizes the β- and γ-phosphate groups of ATP, orienting the γ-phosphate for transfer. Activation Loop Residues 596–600 form strong hydrophobic interactions with the P-loop in the inactive conformation of the kinase, locking the kinase in its inactive state until the activation loop is phosphorylated, destabilizing these interactions with the presence of negative charge. This triggers the shift to the active state of the kinase. Specifically, L597 and V600 of the activation loop interact with G466, F468, and V471 of the P-loop to keep the kinase domain inactive until it is phosphorylated. # Enzymology B-Raf is a serine/threonine-specific protein kinase. As such, it catalyzes the phosphorylation of serine and threonine residues in a consensus sequence on target proteins by ATP, yielding ADP and a phosphorylated protein as products. Since it is a highly regulated signal transduction kinase, B-Raf must first bind Ras-GTP before becoming active as an enzyme. Once B-Raf is activated, a conserved protein kinase catalytic core phosphorylates protein substrates by promoting the nucleophilic attack of the activated substrate serine or threonine hydroxyl oxygen atom on the γ-phosphate group of ATP through bimolecular nucleophilic substitution. ## Activation ### Relieving CR1 autoinhibition The kinase (CR3) domain of human Raf kinases is inhibited by two mechanisms: autoinhibition by its own regulatory Ras-GTP-binding CR1 domain and a lack of post-translational phosphorylation of key serine and tyrosine residues (S338 and Y341 for c-Raf) in the CR2 hinge region. During B-Raf activation, the protein's autoinhibitory CR1 domain first binds Ras-GTP's effector domain to the CR1 Ras-binding domain (RBD) to release the kinase CR3 domain like other members of the human Raf kinase family. The CR1-Ras interaction is later strengthened through the binding of the cysteine-rich subdomain (CRD) of CR1 to Ras and membrane phospholipids. Unlike A-Raf and C-Raf, which must be phosphorylated on hydroxyl-containing CR2 residues before fully releasing CR1 to become active, B-Raf is constituitively phosphorylated on CR2 S445. This allows the negatively charged phosphoserine to immediately repel CR1 through steric and electrostatic interactions once the regulatory domain is unbound, freeing the CR3 kinase domain to interact with substrate proteins. ### CR3 domain activation After the autoinhibitory CR1 regulatory domain is released, B-Raf's CR3 kinase domain must change to its ATP-binding active conformer before it can catalyze protein phosphorylation. In the inactive conformation, F595 of the DFG motif blocks the hydrophobic adenine binding pocket while activation loop residues form hydrophobic interactions with the P-loop, stopping ATP from accessing its binding site. When the activation loop is phosphorylated, the negative charge of the phosphate is unstable in the hydrophobic environment of the P-loop. As a result, the activation loop changes conformation, stretching out across the C-lobe of the kinase domain. In this process, it forms stabilizing β-sheet interactions with the β6 strand. Meanwhile, the phosphorylated residue approaches K507, forming a stabilizing salt bridge to lock the activation loop into place. The DFG motif changes conformation with the activation loop, causing F595 to move out of the adenine nucleotide binding site and into a hydrophobic pocket bordered by the αC and αE helices. Together, DFG and activation loop movement upon phosphorylation open the ATP binding site. Since all other substrate-binding and catalytic domains are already in place, phosphorylation of the activation loop alone activates B-Raf's kinase domain through a chain reaction that essentially removes a lid from an otherwise-prepared active site. ## Mechanism of catalysis To effectively catalyze protein phosphorylation via the bimolecular substitution of serine and threonine residues with ADP as a leaving group, B-Raf must first bind ATP and then stabilize the transition state as the γ-phosphate of ATP is transferred. ### ATP binding B-Raf binds ATP by anchoring the adenine nucleotide in a nonpolar pocket (yellow, Figure 1) and orienting the molecule through hydrogen-bonding and electrostatic interactions with phosphate groups. In addition to the P-loop and DFG motif phosphate binding described above, K483 and E501 play key roles in stabilizing non-transferable phosphate groups. The positive charge on the primary amine of K483 allows it to stabilize the negative charge on ATP α- and β-phosphate groups when ATP binds. When ATP is not present, the negative charge of the E501 carboxyl group balances this charge. ### Phosphorylation Once ATP is bound to the B-Raf kinase domain, D576 of the catalytic loop activates a substrate hydroxyl group, increasing its nucleophilicity to kinetically drive the phosphorylation reaction while other catalytic loop residues stabilize the transition state.(Figure 2). N581 chelates the divalent magnesium cation associated with ATP to help orient the molecule for optimal substitution. K578 neutralizes the negative charge on the γ-phosphate group of ATP so that the activated ser/thr substrate residue won't experience as much electron-electron repulsion when attacking the phosphate. After the phosphate group is transferred, ADP and the new phosphoprotein are released. ## Inhibitors Since constitutively active B-Raf mutants commonly cause cancer (see Clinical Significance) by excessively signaling cells to grow, inhibitors of B-Raf have been developed for both the inactive and active conformations of the kinase domain as cancer therapeutic candidates. ### Sorafenib BAY43-9006 (Sorafenib, Nexavar) is a V600E mutant B-Raf and C-Raf inhibitor approved by the FDA for the treatment of primary liver and kidney cancer. Bay43-9006 disables the B-Raf kinase domain by locking the enzyme in its inactive form. The inhibitor accomplishes this by blocking the ATP binding pocket through high-affinity for the kinase domain. It then binds key activation loop and DFG motif residues to stop the movement of the activation loop and DFG motif to the active conformation. Finally, a trifluoromethyl phenyl moiety sterically blocks the DFG motif and activation loop active conformation site, making it impossible for the kinase domain to shift conformation to become active. The distal pyridyl ring of BAY43-9006 anchors in the hydrophobic nucleotide-binding pocket of the kinase N-lobe, interacting with W531, F583, and F595. The hydrophobic interactions with catalytic loop F583 and DFG motif F595 stabilize the inactive conformation of these structures, decreasing the likelihood of enzyme activation. Further hydrophobic interaction of K483, L514, and T529 with the center phenyl ring increase the affinity of the kinase domain for the inhibitor. Hydrophobic interaction of F595 with the center ring as well decreases the energetic favorability of a DFG conformation switch further. Finally, polar interactions of BAY43-9006 with the kinase domain continue this trend of increasing enzyme affinity for the inhibitor and stabilizing DFG residues in the inactive conformation. E501 and C532 hydrogen bond the urea and pyridyl groups of the inhibitor respectively while the urea carbonyl accepts a hydrogen bond from D594's backbone amide nitrogen to lock the DFG motif in place. The trifluoromethyl phenyl moiety cements the thermodynamic favorability of the inactive conformation when the kinase domain is bound to BAY43-9006 by sterically blocking the hydrophobic pocket between the αC and αE helices that the DFG motif and activation loop would inhabit upon shifting to their locations in the active conformation of the protein. ### Vemurafenib PLX4032 (Vemurafenib) is a V600 mutant B-Raf inhibitor approved by the FDA for the treatment of late-stage melanoma. Unlike BAY43-9006, which inhibits the inactive form of the kinase domain, Vemurafenib inhibits the active "DFG-in" form of the kinase, firmly anchoring itself in the ATP-binding site. By inhibiting only the active form of the kinase, Vemurafenib selectively inhibits the proliferation of cells with unregulated B-Raf, normally those that cause cancer. Since Vemurafenib only differs from its precursor, PLX4720, in a phenyl ring added for pharmacokinetic reasons, PLX4720's mode of action is equivalent to Vemurafenib's. PLX4720 has good affinity for the ATP binding site partially because its anchor region, a 7-azaindole bicyclic, only differs from the natural adenine that occupies the site in two places where nitrogen atoms have been replaced by carbon. This enables strong intermolecular interactions like N7 hydrogen bonding to C532 and N1 hydrogen bonding to Q530 to be preserved. Excellent fit within the ATP-binding hydrophobic pocket (C532, W531, T529, L514, A481) increases binding affinity as well. Ketone linker hydrogen bonding to water and difluoro-phenyl fit in a second hydrophobic pocket (A481, V482, K483, V471, I527, T529, L514, and F583) contribute to the exceptionally high binding affinity overall. Selective binding to active Raf is accomplished by the terminal propyl group that binds to a Raf-selective pocket created by a shift of the αC helix. Selectivity for the active conformation of the kinase is further increased by a pH-sensitive deprotonated sulfonamide group that is stabilized by hydrogen bonding with the backbone peptide NH of D594 in the active state. In the inactive state, the inhibitor's sulfonamide group interacts with the backbone carbonyl of that residue instead, creating repulsion. Thus, Vemurafenib binds preferentially to the active state of B-Raf's kinase domain. # Clinical significance Mutations in the BRAF gene can cause disease in two ways. First, mutations can be inherited and cause birth defects. Second, mutations can appear later in life and cause cancer, as an oncogene. Inherited mutations in this gene cause cardiofaciocutaneous syndrome, a disease characterized by heart defects, mental retardation and a distinctive facial appearance. Mutations in this gene have been found in cancers, including non-Hodgkin lymphoma, colorectal cancer, malignant melanoma, papillary thyroid carcinoma, non-small-cell lung carcinoma, adenocarcinoma of the lung, brain tumors including glioblastoma and pilocytic astrocytomas as well as inflammatory diseases like erdheim-chester disease. The V600E mutation of the BRAF gene has been associated with hairy cell leukemia in numerous studies and has been suggested for use in screening for Lynch syndrome to reduce the number of patients undergoing unnecessary MLH1 sequencing. ## Mutants More than 30 mutations of the BRAF gene associated with human cancers have been identified. The frequency of BRAF mutations varies widely in human cancers, from more than 80% in melanomas and nevi, to as little as 0–18% in other tumors, such as 1–3% in lung cancers and 5% in colorectal cancer. In 90% of the cases, thymine is substituted with adenine at nucleotide 1799. This leads to valine (V) being substituted for by glutamate (E) at codon 600 (now referred to as V600E) in the activation segment that has been found in human cancers. This mutation has been widely observed in papillary thyroid carcinoma, colorectal cancer, melanoma and non-small-cell lung cancer. BRAF-V600E mutation are present in 57% of Langerhans cell histiocytosis patients. The V600E mutation is a likely driver mutation in 100% of cases of hairy cell leukaemia. High frequency of BRAF V600E mutations have been detected in ameloblastoma, a benign but locally infiltrative odontogenic neoplasm. The V600E mutation may also be linked, as a single-driver mutation (a genetic 'smoking gun') to certain cases of papillary craniopharyngioma development. Other mutations which have been found are R461I, I462S, G463E, G463V, G465A, G465E, G465V, G468A, G468E, N580S, E585K, D593V, F594L, G595R, L596V, T598I, V599D, V599E, V599K, V599R, V600K, A727V, etc. and most of these mutations are clustered to two regions: the glycine-rich P loop of the N lobe and the activation segment and flanking regions. These mutations change the activation segment from inactive state to active state, for example in the previous cited paper it has been reported that the aliphatic side chain of Val599 interacts with the phenyl ring of Phe467 in the P loop. Replacing the medium-sized hydrophobic Val side chain with a larger and charged residue as found in human cancer(Glu, Asp, Lys, or Arg) would be expected to destabilize the interactions that maintain the DFG motif in an inactive conformation, so flipping the activation segment into the active position. Depending on the type of mutation the kinase activity towards MEK may also vary. Most of the mutants stimulate enhanced B-Raf kinase activity toward MEK. However, a few mutants act through a different mechanism because although their activity toward MEK is reduced, they adopt a conformation that activates wild-type C-RAF, which then signals to ERK. ### BRAF-V600E - BRAF V600E is a determinant of sensitivity to proteasome inhibitors. Vulnerability to proteasome inhibitors is dependent on persistent BRAF signaling, because BRAF-V600E blockade by PLX4720 reversed sensitivity to carfilzomib in BRAF-mutant colorectal cancer cells. Proteasome inhibition might represent a valuable targeting strategy in BRAF V600E-mutant colorectal tumors. ## BRAF inhibitors As mentioned above, some pharmaceutical firms are developing specific inhibitors of mutated B-raf protein for anticancer use because BRAF is a well-understood, high yield target. Vemurafenib (RG7204 or PLX4032) was licensed by the US Food and Drug Administration as Zelboraf for the treatment of metastatic melanoma in August 2011 based on Phase III clinical data. Improved survival was seen, as well as a response rate to treatment of 53%, compared to from 7-12% with the former best chemotherapeutic treatment, dacarbazine. In clinical trials, B-Raf increased metastatic melanoma patient chance of survival. In spite of the drug's high efficacy, 20% of tumors still develop resistance to the treatment. In mice, 20% of tumors become resistant after 56 days. While the mechanisms of this resistance are still disputed, some hypotheses include the overexpression of B-Raf to compensate for high concentrations of Vemurafenib and upstream upregulation of growth signaling. More general B-Raf inhibitors include GDC-0879, PLX-4720, Sorafenib, dabrafenib and LGX818 # Interactions BRAF (gene) has been shown to interact with: - AKT1, - C-Raf, - HRAS, and - YWHAB.	BRAF (gene) BRAF is a human gene that encodes a protein called B-Raf. The gene is also referred to as proto-oncogene B-Raf and v-Raf murine sarcoma viral oncogene homolog B, while the protein is more formally known as serine/threonine-protein kinase B-Raf.[1][2] The B-Raf protein is involved in sending signals inside cells which are involved in directing cell growth. In 2002, it was shown to be faulty (mutated) in some human cancers.[3] Certain other inherited BRAF mutations cause birth defects. Drugs that treat cancers driven by BRAF mutations have been developed. Two of these drugs, vemurafenib[4] and dabrafenib are approved by FDA for treatment of late-stage melanoma. Vemurafenib was the first drug to come out of fragment-based drug discovery. # Function B-Raf is a member of the Raf kinase family of growth signal transduction protein kinases. This protein plays a role in regulating the MAP kinase/ERKs signaling pathway, which affects cell division, differentiation, and secretion.[5] # Structure B-Raf is a 766-amino acid, regulated signal transduction serine/threonine-specific protein kinase. Broadly speaking, it is composed of three conserved domains characteristic of the Raf kinase family: conserved region 1 (CR1), a Ras-GTP-binding[6] self-regulatory domain, conserved region 2 (CR2), a serine-rich hinge region, and conserved region 3 (CR3), a catalytic protein kinase domain that phosphorylates a consensus sequence on protein substrates.[7] In its active conformation, B-Raf forms dimers via hydrogen-bonding and electrostatic interactions of its kinase domains.[8] ## CR1 Conserved region 1 autoinhibits B-Raf's kinase domain (CR3) so that B-Raf signaling is regulated rather than constitutive.[7] Residues 155–227[9] make up the Ras-binding domain (RBD), which binds to Ras-GTP's effector domain to release CR1 and halt kinase inhibition. Residues 234–280 comprise a phorbol ester/DAG-binding zinc finger motif that participates in B-Raf membrane docking after Ras-binding.[9][10] ## CR2 Conserved Region 2 (CR2) provides a flexible linker that connects CR1 and CR3 and acts as a hinge. ## CR3 Conserved Region 3 (CR3), residues 457–717,[9] makes up B-Raf's enzymatic kinase domain. This largely conserved structure[11] is bi-lobal, connected by a short hinge region.[12] The smaller N-lobe (residues 457–530) is primarily responsible for ATP binding while the larger C-lobe (residues 535–717) binds substrate proteins.[11] The active site is the cleft between the two lobes, and the catalytic Asp576 residue is located on the C-lobe, facing the inside of this cleft.[9][11] ### Subregions P-Loop The P-loop of B-Raf (residues 464–471) stabilizes the non-transferable phosphate groups of ATP during enzyme ATP-binding. Specifically, S467, F468, and G469 backbone amides hydrogen-bond to the β-phosphate of ATP to anchor the molecule. B-Raf functional motifs have been determined by analyzing the homology of PKA analyzed by Hanks and Hunter to the B-Raf kinase domain.[11] Nucleotide-Binding Pocket V471, C532, W531, T529, L514, and A481 form a hydrophobic pocket within which the adenine of ATP is anchored through Van der Waals attractions upon ATP binding.[11][13] Catalytic Loop Residues 574–581 compose a section of the kinase domain responsible for supporting the transfer of the γ-phosphate of ATP to B-Raf's protein substrate. In particular, D576 acts as a proton acceptor to activate the nucleophilic hydroxyl oxygen on substrate serine or threonine residues, allowing the phosphate transfer reaction to occur mediated by base-catalysis.[11] DFG Motif D594, F595, and G596 compose a motif central to B-Raf's function in both its inactive and active state. In the inactive state, F595 occupies the nucleotide-binding pocket, prohibiting ATP from entering and decreasing the likelihood of enzyme catalysis.[8][13][14] In the active state, D594 chelates the divalent magnesium cation that stabilizes the β- and γ-phosphate groups of ATP, orienting the γ-phosphate for transfer.[11] Activation Loop Residues 596–600 form strong hydrophobic interactions with the P-loop in the inactive conformation of the kinase, locking the kinase in its inactive state until the activation loop is phosphorylated, destabilizing these interactions with the presence of negative charge. This triggers the shift to the active state of the kinase. Specifically, L597 and V600 of the activation loop interact with G466, F468, and V471 of the P-loop to keep the kinase domain inactive until it is phosphorylated.[12] # Enzymology B-Raf is a serine/threonine-specific protein kinase. As such, it catalyzes the phosphorylation of serine and threonine residues in a consensus sequence on target proteins by ATP, yielding ADP and a phosphorylated protein as products.[11] Since it is a highly regulated signal transduction kinase, B-Raf must first bind Ras-GTP before becoming active as an enzyme.[10] Once B-Raf is activated, a conserved protein kinase catalytic core phosphorylates protein substrates by promoting the nucleophilic attack of the activated substrate serine or threonine hydroxyl oxygen atom on the γ-phosphate group of ATP through bimolecular nucleophilic substitution.[11][15][16][17] ## Activation ### Relieving CR1 autoinhibition The kinase (CR3) domain of human Raf kinases is inhibited by two mechanisms: autoinhibition by its own regulatory Ras-GTP-binding CR1 domain and a lack of post-translational phosphorylation of key serine and tyrosine residues (S338 and Y341 for c-Raf) in the CR2 hinge region. During B-Raf activation, the protein's autoinhibitory CR1 domain first binds Ras-GTP's effector domain to the CR1 Ras-binding domain (RBD) to release the kinase CR3 domain like other members of the human Raf kinase family. The CR1-Ras interaction is later strengthened through the binding of the cysteine-rich subdomain (CRD) of CR1 to Ras and membrane phospholipids.[7] Unlike A-Raf and C-Raf, which must be phosphorylated on hydroxyl-containing CR2 residues before fully releasing CR1 to become active, B-Raf is constituitively phosphorylated on CR2 S445.[18] This allows the negatively charged phosphoserine to immediately repel CR1 through steric and electrostatic interactions once the regulatory domain is unbound, freeing the CR3 kinase domain to interact with substrate proteins. ### CR3 domain activation After the autoinhibitory CR1 regulatory domain is released, B-Raf's CR3 kinase domain must change to its ATP-binding active conformer before it can catalyze protein phosphorylation. In the inactive conformation, F595 of the DFG motif blocks the hydrophobic adenine binding pocket while activation loop residues form hydrophobic interactions with the P-loop, stopping ATP from accessing its binding site. When the activation loop is phosphorylated, the negative charge of the phosphate is unstable in the hydrophobic environment of the P-loop. As a result, the activation loop changes conformation, stretching out across the C-lobe of the kinase domain. In this process, it forms stabilizing β-sheet interactions with the β6 strand. Meanwhile, the phosphorylated residue approaches K507, forming a stabilizing salt bridge to lock the activation loop into place. The DFG motif changes conformation with the activation loop, causing F595 to move out of the adenine nucleotide binding site and into a hydrophobic pocket bordered by the αC and αE helices. Together, DFG and activation loop movement upon phosphorylation open the ATP binding site. Since all other substrate-binding and catalytic domains are already in place, phosphorylation of the activation loop alone activates B-Raf's kinase domain through a chain reaction that essentially removes a lid from an otherwise-prepared active site.[12] ## Mechanism of catalysis To effectively catalyze protein phosphorylation via the bimolecular substitution of serine and threonine residues with ADP as a leaving group, B-Raf must first bind ATP and then stabilize the transition state as the γ-phosphate of ATP is transferred.[11] ### ATP binding B-Raf binds ATP by anchoring the adenine nucleotide in a nonpolar pocket (yellow, Figure 1) and orienting the molecule through hydrogen-bonding and electrostatic interactions with phosphate groups. In addition to the P-loop and DFG motif phosphate binding described above, K483 and E501 play key roles in stabilizing non-transferable phosphate groups. The positive charge on the primary amine of K483 allows it to stabilize the negative charge on ATP α- and β-phosphate groups when ATP binds. When ATP is not present, the negative charge of the E501 carboxyl group balances this charge.[11][12] ### Phosphorylation Once ATP is bound to the B-Raf kinase domain, D576 of the catalytic loop activates a substrate hydroxyl group, increasing its nucleophilicity to kinetically drive the phosphorylation reaction while other catalytic loop residues stabilize the transition state.(Figure 2). N581 chelates the divalent magnesium cation associated with ATP to help orient the molecule for optimal substitution. K578 neutralizes the negative charge on the γ-phosphate group of ATP so that the activated ser/thr substrate residue won't experience as much electron-electron repulsion when attacking the phosphate. After the phosphate group is transferred, ADP and the new phosphoprotein are released.[11] ## Inhibitors Since constitutively active B-Raf mutants commonly cause cancer (see Clinical Significance) by excessively signaling cells to grow, inhibitors of B-Raf have been developed for both the inactive and active conformations of the kinase domain as cancer therapeutic candidates.[12][13][14] ### Sorafenib BAY43-9006 (Sorafenib, Nexavar) is a V600E mutant B-Raf and C-Raf inhibitor approved by the FDA for the treatment of primary liver and kidney cancer. Bay43-9006 disables the B-Raf kinase domain by locking the enzyme in its inactive form. The inhibitor accomplishes this by blocking the ATP binding pocket through high-affinity for the kinase domain. It then binds key activation loop and DFG motif residues to stop the movement of the activation loop and DFG motif to the active conformation. Finally, a trifluoromethyl phenyl moiety sterically blocks the DFG motif and activation loop active conformation site, making it impossible for the kinase domain to shift conformation to become active.[12] The distal pyridyl ring of BAY43-9006 anchors in the hydrophobic nucleotide-binding pocket of the kinase N-lobe, interacting with W531, F583, and F595. The hydrophobic interactions with catalytic loop F583 and DFG motif F595 stabilize the inactive conformation of these structures, decreasing the likelihood of enzyme activation. Further hydrophobic interaction of K483, L514, and T529 with the center phenyl ring increase the affinity of the kinase domain for the inhibitor. Hydrophobic interaction of F595 with the center ring as well decreases the energetic favorability of a DFG conformation switch further. Finally, polar interactions of BAY43-9006 with the kinase domain continue this trend of increasing enzyme affinity for the inhibitor and stabilizing DFG residues in the inactive conformation. E501 and C532 hydrogen bond the urea and pyridyl groups of the inhibitor respectively while the urea carbonyl accepts a hydrogen bond from D594's backbone amide nitrogen to lock the DFG motif in place.[12] The trifluoromethyl phenyl moiety cements the thermodynamic favorability of the inactive conformation when the kinase domain is bound to BAY43-9006 by sterically blocking the hydrophobic pocket between the αC and αE helices that the DFG motif and activation loop would inhabit upon shifting to their locations in the active conformation of the protein.[12] ### Vemurafenib PLX4032 (Vemurafenib) is a V600 mutant B-Raf inhibitor approved by the FDA for the treatment of late-stage melanoma.[8] Unlike BAY43-9006, which inhibits the inactive form of the kinase domain, Vemurafenib inhibits the active "DFG-in" form of the kinase,[13][14] firmly anchoring itself in the ATP-binding site. By inhibiting only the active form of the kinase, Vemurafenib selectively inhibits the proliferation of cells with unregulated B-Raf, normally those that cause cancer. Since Vemurafenib only differs from its precursor, PLX4720, in a phenyl ring added for pharmacokinetic reasons,[14] PLX4720's mode of action is equivalent to Vemurafenib's. PLX4720 has good affinity for the ATP binding site partially because its anchor region, a 7-azaindole bicyclic, only differs from the natural adenine that occupies the site in two places where nitrogen atoms have been replaced by carbon. This enables strong intermolecular interactions like N7 hydrogen bonding to C532 and N1 hydrogen bonding to Q530 to be preserved. Excellent fit within the ATP-binding hydrophobic pocket (C532, W531, T529, L514, A481) increases binding affinity as well. Ketone linker hydrogen bonding to water and difluoro-phenyl fit in a second hydrophobic pocket (A481, V482, K483, V471, I527, T529, L514, and F583) contribute to the exceptionally high binding affinity overall. Selective binding to active Raf is accomplished by the terminal propyl group that binds to a Raf-selective pocket created by a shift of the αC helix. Selectivity for the active conformation of the kinase is further increased by a pH-sensitive deprotonated sulfonamide group that is stabilized by hydrogen bonding with the backbone peptide NH of D594 in the active state. In the inactive state, the inhibitor's sulfonamide group interacts with the backbone carbonyl of that residue instead, creating repulsion. Thus, Vemurafenib binds preferentially to the active state of B-Raf's kinase domain.[13][14] # Clinical significance Mutations in the BRAF gene can cause disease in two ways. First, mutations can be inherited and cause birth defects. Second, mutations can appear later in life and cause cancer, as an oncogene. Inherited mutations in this gene cause cardiofaciocutaneous syndrome, a disease characterized by heart defects, mental retardation and a distinctive facial appearance.[19] Mutations in this gene have been found in cancers, including non-Hodgkin lymphoma, colorectal cancer, malignant melanoma, papillary thyroid carcinoma, non-small-cell lung carcinoma, adenocarcinoma of the lung, brain tumors including glioblastoma and pilocytic astrocytomas as well as inflammatory diseases like erdheim-chester disease.[5] The V600E mutation of the BRAF gene has been associated with hairy cell leukemia in numerous studies and has been suggested for use in screening for Lynch syndrome to reduce the number of patients undergoing unnecessary MLH1 sequencing.[20][21] ## Mutants More than 30 mutations of the BRAF gene associated with human cancers have been identified. The frequency of BRAF mutations varies widely in human cancers, from more than 80% in melanomas and nevi, to as little as 0–18% in other tumors, such as 1–3% in lung cancers and 5% in colorectal cancer.[22] In 90% of the cases, thymine is substituted with adenine at nucleotide 1799. This leads to valine (V) being substituted for by glutamate (E) at codon 600 (now referred to as V600E) in the activation segment that has been found in human cancers.[23] This mutation has been widely observed in papillary thyroid carcinoma, colorectal cancer, melanoma and non-small-cell lung cancer.[24][25][26][27][28][29][30] BRAF-V600E mutation are present in 57% of Langerhans cell histiocytosis patients.[31] The V600E mutation is a likely driver mutation in 100% of cases of hairy cell leukaemia.[32] High frequency of BRAF V600E mutations have been detected in ameloblastoma, a benign but locally infiltrative odontogenic neoplasm.[33] The V600E mutation may also be linked, as a single-driver mutation (a genetic 'smoking gun') to certain cases of papillary craniopharyngioma development.[34] Other mutations which have been found are R461I, I462S, G463E, G463V, G465A, G465E, G465V, G468A, G468E, N580S, E585K, D593V, F594L, G595R, L596V, T598I, V599D, V599E, V599K, V599R, V600K, A727V, etc. and most of these mutations are clustered to two regions: the glycine-rich P loop of the N lobe and the activation segment and flanking regions.[12] These mutations change the activation segment from inactive state to active state, for example in the previous cited paper it has been reported that the aliphatic side chain of Val599 interacts with the phenyl ring of Phe467 in the P loop. Replacing the medium-sized hydrophobic Val side chain with a larger and charged residue as found in human cancer(Glu, Asp, Lys, or Arg) would be expected to destabilize the interactions that maintain the DFG motif in an inactive conformation, so flipping the activation segment into the active position. Depending on the type of mutation the kinase activity towards MEK may also vary. Most of the mutants stimulate enhanced B-Raf kinase activity toward MEK. However, a few mutants act through a different mechanism because although their activity toward MEK is reduced, they adopt a conformation that activates wild-type C-RAF, which then signals to ERK. ### BRAF-V600E - BRAF V600E is a determinant of sensitivity to proteasome inhibitors. Vulnerability to proteasome inhibitors is dependent on persistent BRAF signaling, because BRAF-V600E blockade by PLX4720 reversed sensitivity to carfilzomib in BRAF-mutant colorectal cancer cells. Proteasome inhibition might represent a valuable targeting strategy in BRAF V600E-mutant colorectal tumors.[35] ## BRAF inhibitors As mentioned above, some pharmaceutical firms are developing specific inhibitors of mutated B-raf protein for anticancer use because BRAF is a well-understood, high yield target.[13][36] Vemurafenib (RG7204 or PLX4032) was licensed by the US Food and Drug Administration as Zelboraf for the treatment of metastatic melanoma in August 2011 based on Phase III clinical data. Improved survival was seen, as well as a response rate to treatment of 53%, compared to from 7-12% with the former best chemotherapeutic treatment, dacarbazine.[37] In clinical trials, B-Raf increased metastatic melanoma patient chance of survival. In spite of the drug's high efficacy, 20% of tumors still develop resistance to the treatment. In mice, 20% of tumors become resistant after 56 days.[38] While the mechanisms of this resistance are still disputed, some hypotheses include the overexpression of B-Raf to compensate for high concentrations of Vemurafenib[38] and upstream upregulation of growth signaling.[39] More general B-Raf inhibitors include GDC-0879, PLX-4720, Sorafenib, dabrafenib and LGX818 # Interactions BRAF (gene) has been shown to interact with: - AKT1,[40] - C-Raf,[41] - HRAS,[42][43] and - YWHAB.[44][45]	https://www.wikidoc.org/index.php/BRAF_(gene)
58dafdc899db8f633c3d25f57a4665b2a706cdab	wikidoc	Blood sugar	Blood sugar Synonyms and keywords: Blood glucose, fasting blood glucose, fasting blood sugar, FBG, FBS # Overview Blood sugar is a term used to refer to the amount of glucose in the blood. Glucose, transported via the bloodstream, is the primary source of energy for the body's cells. Blood sugar concentration, or glucose level, is tightly regulated in the human body. Normally, the blood glucose level is maintained between about 4 and 8 mmol/L (70 to 150 mg/dL). The total amount of glucose in the circulating blood is therefore about 3.3 to 7g (assuming an ordinary adult blood volume of 5 liters). Glucose levels rise after meals and are usually lowest in the morning, before the first meal of the day. Failure to maintain blood glucose in the normal range leads to conditions of persistently high (hyperglycemia) or low (hypoglycemia) blood sugar. Diabetes mellitus, characterized by persistent hyperglycemia of several causes, is the most prominent disease related to failure of blood sugar regulation. Though it is called "blood sugar" and sugars besides glucose are found in the blood, like fructose and galactose, only glucose levels are regulated via insulin and glucagon. # Glucose Measurement ## Sample Type Glucose can be measured in whole blood, serum, or plasma. Historically, blood glucose values were given in terms of whole blood, but most laboratories now measure and report the serum glucose levels. Because RBC (erythrocytes) have a higher concentration of protein (i.e. hemoglobin) than serum, serum has a higher water content and consequently more dissolved glucose than does whole blood. To convert from whole-blood glucose, multiply the value by 1.15 to give the serum/plasma level. Collection of blood in clot (red-top) tubes for serum chemistry analysis permits the metabolism of glucose in the sample by blood cells until separated by centrifugation. Higher than normal amounts of white or red blood cell counts can lead to excessive glycolysis in the sample with substantial reduction of glucose level if the sample is not processed quickly. Ambient temperature at which the blood sample is kept prior to centrifugation and separation of Plasma/Serum also affects glucose levels. At refrigerator temperatures, glucose remains relatively stable for several hours in the blood sample. At room temperature (25°C), a loss of 1 to 2% of glucose per hour should be expected. The loss of glucose levels in aforementioned conditions can be prevented by using Fluoride top (gray-top) as the anticoagulant of choice upon blood collection, as Fluoride inhibits glycolysis. However, this should only be used when blood will be transported from one hospital laboratory to another for glucose measurement. Red-top serum separator tubes also preserve glucose in samples once they have been centrifugated to isolate the serum from cells, this tube would be the most efficient. Particular care should be given to drawing blood samples from the arm opposite the one in which an intravenous line is inserted, to prevent contamination of the sample with intravenous fluids (IV). Alternatively, blood can be drawn from the same arm with an IV line after the IV was turned off for at least 5 minutes and the arm is elevated to drain the infused fluids away from the vein. As little as 10% contamination with 5% dextrose (D5W) will elevate glucose in a sample by 500mg/dl or more. Arterial, capillary and venous blood have comparable glucose levels in a fasting individual, whereas after meals venous levels are lower than capillary or arterial blood. ## Methodology There are two different major methods that have been used to measure glucose. The older one is a chemical method that exploits the nonspecific reducing property of glucose in a reaction with an indicator substance that acquires or changes color on its reduction. Since other blood compounds also have reducing properties (e.g., urea, which can build up in uremic patients), this method can have erroneous measurements up to 5 to 15 mg/dl. This is solved by the Enzymatic methods that are highly specific for glucose. The two most common employed enzymes are glucose oxidase and hexokinase. ## Laboratory Tests Commonly Employed - Fasting Blood Sugar or Glucose test (FBS) - Urine Glucose test - Two-hr Postprandial Blood Sugar Test (2-h PPBS) - Oral Glucose Tolerance test (OGTT) - Intravenous Glucose Tolerance test (IVGTT) - Glycosylated Hemoglobin (HbA1C) - Self-monitoring of Glucose level via Home Kits ## Clinical Correlation The fasting blood glucose (FBG) level is the most commonly used indication of overall glucose homeostasis. Conditions that affect glucose levels are shown in the table below. They reflect abnormalities in the multiple control mechanism of glucose regulation. The metabolic response to a carbohydrate challenge is conveniently assessed by the postprandial glucose level drawn 2 hours after a meal or a glucose load. In addition, the glucose tolerance test, consisting of serial timed measurements after a standardized amount of oral glucose intake, is used to aid in the diagnosis of Diabetes. # Health Effects If blood sugar levels drop too low, a potentially fatal condition called hypoglycemia develops. Symptoms may include lethargy, impaired mental functioning, irritability, and loss of consciousness. If levels remain too high, appetite is suppressed over the short term. Long-term hyperglycemia causes many of the long-term health problems associated with diabetes, including eye, kidney, and nerve damage. # Low Blood Sugar Some people report drowsiness or impaired cognitive function several hours after meals, which they believe is related to a drop in blood sugar, or "low blood sugar". For more information, see: - idiopathic postprandial syndrome - hypoglycemia # Converting Glucose Units Countries that use the metric system use mmol/L. The U.S. uses mg/dL. To convert Blood Glucose readings: - Divide the mg/dL by 18 to get mmol/L (or multiply by 0.055). - Multiply the mmol/L by 18 to get mg/dL (or divide with 0.055). # 2013 American Diabetes Association Standards of Medical Care in Diabetes (DO NOT EDIT) ## Glucose Monitoring ## Glycemic Goals in Adults # Sources - John Bernard Henry, M.D.: Clinical diagnosis and Management by Laboratory Methods 20th edition, Saunders, Philadelphia, PA, 2001. - Ronald A. Sacher and Richard A. McPherson: Widmann's Clinical Interpretation of Laboratory Tests 11th edition, F.A. Davis Company, 2001.	Blood sugar Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Karol Gema Hernandez, M.D. [2] Synonyms and keywords: Blood glucose, fasting blood glucose, fasting blood sugar, FBG, FBS # Overview Blood sugar is a term used to refer to the amount of glucose in the blood. Glucose, transported via the bloodstream, is the primary source of energy for the body's cells. Blood sugar concentration, or glucose level, is tightly regulated in the human body. Normally, the blood glucose level is maintained between about 4 and 8 mmol/L (70 to 150 mg/dL). The total amount of glucose in the circulating blood is therefore about 3.3 to 7g (assuming an ordinary adult blood volume of 5 liters). Glucose levels rise after meals and are usually lowest in the morning, before the first meal of the day. Failure to maintain blood glucose in the normal range leads to conditions of persistently high (hyperglycemia) or low (hypoglycemia) blood sugar. Diabetes mellitus, characterized by persistent hyperglycemia of several causes, is the most prominent disease related to failure of blood sugar regulation. Though it is called "blood sugar" and sugars besides glucose are found in the blood, like fructose and galactose, only glucose levels are regulated via insulin and glucagon. # Glucose Measurement ## Sample Type Glucose can be measured in whole blood, serum, or plasma. Historically, blood glucose values were given in terms of whole blood, but most laboratories now measure and report the serum glucose levels. Because RBC (erythrocytes) have a higher concentration of protein (i.e. hemoglobin) than serum, serum has a higher water content and consequently more dissolved glucose than does whole blood. To convert from whole-blood glucose, multiply the value by 1.15 to give the serum/plasma level. Collection of blood in clot (red-top) tubes for serum chemistry analysis permits the metabolism of glucose in the sample by blood cells until separated by centrifugation. Higher than normal amounts of white or red blood cell counts can lead to excessive glycolysis in the sample with substantial reduction of glucose level if the sample is not processed quickly. Ambient temperature at which the blood sample is kept prior to centrifugation and separation of Plasma/Serum also affects glucose levels. At refrigerator temperatures, glucose remains relatively stable for several hours in the blood sample. At room temperature (25°C), a loss of 1 to 2% of glucose per hour should be expected. The loss of glucose levels in aforementioned conditions can be prevented by using Fluoride top (gray-top) as the anticoagulant of choice upon blood collection, as Fluoride inhibits glycolysis. However, this should only be used when blood will be transported from one hospital laboratory to another for glucose measurement. Red-top serum separator tubes also preserve glucose in samples once they have been centrifugated to isolate the serum from cells, this tube would be the most efficient. Particular care should be given to drawing blood samples from the arm opposite the one in which an intravenous line is inserted, to prevent contamination of the sample with intravenous fluids (IV). Alternatively, blood can be drawn from the same arm with an IV line after the IV was turned off for at least 5 minutes and the arm is elevated to drain the infused fluids away from the vein. As little as 10% contamination with 5% dextrose (D5W) will elevate glucose in a sample by 500mg/dl or more. Arterial, capillary and venous blood have comparable glucose levels in a fasting individual, whereas after meals venous levels are lower than capillary or arterial blood. ## Methodology There are two different major methods that have been used to measure glucose. The older one is a chemical method that exploits the nonspecific reducing property of glucose in a reaction with an indicator substance that acquires or changes color on its reduction. Since other blood compounds also have reducing properties (e.g., urea, which can build up in uremic patients), this method can have erroneous measurements up to 5 to 15 mg/dl. This is solved by the Enzymatic methods that are highly specific for glucose. The two most common employed enzymes are glucose oxidase and hexokinase. ## Laboratory Tests Commonly Employed - Fasting Blood Sugar or Glucose test (FBS) - Urine Glucose test - Two-hr Postprandial Blood Sugar Test (2-h PPBS) - Oral Glucose Tolerance test (OGTT) - Intravenous Glucose Tolerance test (IVGTT) - Glycosylated Hemoglobin (HbA1C) - Self-monitoring of Glucose level via Home Kits ## Clinical Correlation The fasting blood glucose (FBG) level is the most commonly used indication of overall glucose homeostasis. Conditions that affect glucose levels are shown in the table below. They reflect abnormalities in the multiple control mechanism of glucose regulation. The metabolic response to a carbohydrate challenge is conveniently assessed by the postprandial glucose level drawn 2 hours after a meal or a glucose load. In addition, the glucose tolerance test, consisting of serial timed measurements after a standardized amount of oral glucose intake, is used to aid in the diagnosis of Diabetes. # Health Effects If blood sugar levels drop too low, a potentially fatal condition called hypoglycemia develops. Symptoms may include lethargy, impaired mental functioning, irritability, and loss of consciousness. If levels remain too high, appetite is suppressed over the short term. Long-term hyperglycemia causes many of the long-term health problems associated with diabetes, including eye, kidney, and nerve damage. # Low Blood Sugar Some people report drowsiness or impaired cognitive function several hours after meals, which they believe is related to a drop in blood sugar, or "low blood sugar". For more information, see: - idiopathic postprandial syndrome - hypoglycemia # Converting Glucose Units Countries that use the metric system use mmol/L. The U.S. uses mg/dL. To convert Blood Glucose readings: - Divide the mg/dL by 18 to get mmol/L (or multiply by 0.055). - Multiply the mmol/L by 18 to get mg/dL (or divide with 0.055). # 2013 American Diabetes Association Standards of Medical Care in Diabetes (DO NOT EDIT)[1] ## Glucose Monitoring ## Glycemic Goals in Adults # Sources - John Bernard Henry, M.D.: Clinical diagnosis and Management by Laboratory Methods 20th edition, Saunders, Philadelphia, PA, 2001. - Ronald A. Sacher and Richard A. McPherson: Widmann's Clinical Interpretation of Laboratory Tests 11th edition, F.A. Davis Company, 2001. # External links - Other medical conversions (Albumin, Protein, Creatinine, Creatinine clearance, Cholesterol, Lipid profile, Insulin, Etc..) - Lab Tests Online: Glucose - Alcohol and Blood Sugar	https://www.wikidoc.org/index.php/BSL
dbb1a8d3cc620ccef0d48b7e9534123b89b9799b	wikidoc	Biotinidase	Biotinidase Biotinidase (EC 3.5.1.12, amidohydrolase biotinidase, BTD) is an enzyme that in humans is encoded by the BTD gene. # Function This enzyme allows the body to use and to recycle the B vitamin biotin, sometimes called vitamin H. Biotinidase extracts biotin from food because the body needs biotin in its free, unattached form. This enzyme also recycles biotin from enzymes in the body that use it as a helper component in order to function. These enzymes, known as carboxylases, are important in the processing of fats, carbohydrates, and proteins. Biotin is attached to these carboxylase enzymes through an amino acid (the building material of proteins) called lysine, forming a complex called biocytin. Biotinidase removes biotin from biocytin and makes it available to be reused by other enzymes. # Clinical significance Biotin, sometimes called vitamin H, is an important water-soluble vitamin that aids in the metabolism of fats, carbohydrates and proteins. The human body cannot produce biotin, but it can obtain it from the diet, internal recycling and at some extent from intestinal bacteria. Biotin deficiency can result in behavioral disorders, lack of coordination, learning disabilities and seizure. Unlike most vitamins, which are noncovalently bound to enzymes, biotin is chemically linked (covalently bound), and therefore cannot be easily removed from the enzyme denaturation. Without biotinidase activity, the vitamin biotin cannot be separated from foods and therefore cannot be used by the body. Biotinidase deficiency is an inherited disorder caused by mutations in the BTD gene. When biotinidase activity is deficient, biotin can be neither recycled within the body nor removed from ingested food. Nor can biotin be recycled from enzymes to which it is bound. Deficient biotinidase activity causes specific metabolic enzymes, called carboxylases, to be nonfunctional, inhibiting the proper processing of proteins, fats, and carbohydrates. Individuals lacking biotinidase activity can still have normal carboxylases if they ingest small amounts of biotin. Approximately 1 in 60,000 newborns are affected by profound (less than 10 percent of normal enzyme activity) or partial (10-30 percent of normal enzyme activity) biotinidase deficiency. # Genetics The BTD gene is located on the short (p) arm of chromosome 3 at position 25, from base pair 15,618,326 to base pair 15,662,328. Mutations in the BTD gene cause biotinidase deficiency. Approximately 100 mutations in the BTD gene that lead to biotinidase deficiency have been discovered. These mutations either prevent the enzyme from being made or cause the enzyme that is produced to be nonfunctional. This condition is inherited in an autosomal recessive pattern, which means two copies of the gene in each cell must be altered for a person to be affected by the disorder. Most often, the parents of a child with an autosomal recessive disorder are not affected but are carriers of one copy of the altered gene. # Disease Database BTD gene variant database	Biotinidase Biotinidase (EC 3.5.1.12, amidohydrolase biotinidase, BTD) is an enzyme that in humans is encoded by the BTD gene. # Function This enzyme allows the body to use and to recycle the B vitamin biotin, sometimes called vitamin H. Biotinidase extracts biotin from food because the body needs biotin in its free, unattached form. This enzyme also recycles biotin from enzymes in the body that use it as a helper component in order to function. These enzymes, known as carboxylases, are important in the processing of fats, carbohydrates, and proteins. Biotin is attached to these carboxylase enzymes through an amino acid (the building material of proteins) called lysine, forming a complex called biocytin. Biotinidase removes biotin from biocytin and makes it available to be reused by other enzymes. # Clinical significance Biotin, sometimes called vitamin H, is an important water-soluble vitamin that aids in the metabolism of fats, carbohydrates and proteins. The human body cannot produce biotin, but it can obtain it from the diet, internal recycling and at some extent from intestinal bacteria. Biotin deficiency can result in behavioral disorders, lack of coordination, learning disabilities and seizure. Unlike most vitamins, which are noncovalently bound to enzymes, biotin is chemically linked (covalently bound), and therefore cannot be easily removed from the enzyme denaturation. Without biotinidase activity, the vitamin biotin cannot be separated from foods and therefore cannot be used by the body. Biotinidase deficiency is an inherited disorder caused by mutations in the BTD gene. When biotinidase activity is deficient, biotin can be neither recycled within the body nor removed from ingested food. Nor can biotin be recycled from enzymes to which it is bound. Deficient biotinidase activity causes specific metabolic enzymes, called carboxylases, to be nonfunctional, inhibiting the proper processing of proteins, fats, and carbohydrates. Individuals lacking biotinidase activity can still have normal carboxylases if they ingest small amounts of biotin. Approximately 1 in 60,000 newborns are affected by profound (less than 10 percent of normal enzyme activity) or partial (10-30 percent of normal enzyme activity) biotinidase deficiency. # Genetics The BTD gene is located on the short (p) arm of chromosome 3 at position 25, from base pair 15,618,326 to base pair 15,662,328. Mutations in the BTD gene cause biotinidase deficiency. Approximately 100 mutations in the BTD gene that lead to biotinidase deficiency have been discovered. These mutations either prevent the enzyme from being made or cause the enzyme that is produced to be nonfunctional. This condition is inherited in an autosomal recessive pattern, which means two copies of the gene in each cell must be altered for a person to be affected by the disorder. Most often, the parents of a child with an autosomal recessive disorder are not affected but are carriers of one copy of the altered gene.[1] # Disease Database BTD gene variant database	https://www.wikidoc.org/index.php/BTD
ceaada58e24b8de251ff91554638940f48b44542	wikidoc	BTRC (gene)	BTRC (gene) F-box/WD repeat-containing protein 1A (FBXW1A) also known as βTrCP1 or Fbxw1 or hsSlimb or pIkappaBalpha-E3 receptor subunit is a protein that in humans is encoded by the BTRC (beta-transducin repeat containing) gene. This gene encodes a member of the F-box protein family which is characterized by an approximately 40 residue structural motif, the F-box. The F-box proteins constitute one of the four subunits of ubiquitin protein ligase complex called SCFs (Skp1-Cul1-F-box protein), which often, but not always, recognize substrates in a phosphorylation-dependent manner. F-box proteins are divided into 3 classes: - Fbxws containing WD40 repeats, - Fbxls containing leucine-rich repeats, - and Fbxos containing either "other" protein–protein interaction modules or no recognizable motifs. The protein encoded by this gene belongs to the Fbxw class as, in addition to an F-box, this protein contains multiple WD40 repeats. This protein is homologous to Xenopus βTrCP, yeast Met30, Neurospora Scon2 and Drosophila Slimb. In mammals, in addition to βTrCP1, a paralog protein (called βTrCP2 or FBXW11) also exists, but, so far, their functions appear redundant and indistinguishable. # Discovery Human βTrCP (referred to both βTrCP1 and βTrCP2) was originally identified as a cellular ubiquitin ligase that is bound by the HIV-1 Vpu viral protein to eliminate cellular CD4 by connecting it to the proteolytic machinery. Subsequently, βTrCP was shown to regulate multiple cellular processes by mediating the degradation of various targets. Cell cycle regulators constitute a major group of βTrCP substrates. During S phase, βTrCP keeps CDK1 in check by promoting the degradation of the phosphatase CDC25A, whereas in G2, βTrCP contributes to CDK1 activation by targeting the kinase WEE1 for degradation. In early mitosis, βTrCP mediates the degradation of EMI1, an inhibitor of the APC/C ubiquitin ligase complex, which is responsible for the anaphase-metaphase transition (by inducing the proteolysis of Securin) and mitotic exit (by driving the degradation of mitotic CDK1 activating cyclin subunits). Furthermore, βTrCP controls APC/C by targeting REST, thereby removing its transcriptional repression on MAD2, an essential component of the spindle assembly checkpoint that keeps APC/C inactive until all chromatids are attached to the spindle microtubles. # Function βTrCP plays important roles in regulating cell cycle checkpoints. In response to genotoxic stress, it contributes to turn off CDK1 activity by mediating the degradation of CDC25A in collaboration with Chk1, thereby preventing cell cycle progression before the completion of DNA repair. During recovery from DNA replication and DNA damage, βTrCP instead targets Claspin in a Plk1-dependent manner. βTrCP has also emerged as an important player in protein translation, cell growth and survival. In response to mitogens, PDCD4, an inhibitor of the translation initiation factor eIF4A, is rapidly degraded in a βTrCP- and S6K1-dependent manner, allowing efficient protein translation and cell growth. Another target of βTrCP that is involved in protein translation is eEF2K, which inhibits translation elongation by phosphorylating eukaryotic Elongation Factor 2 (eEF2) and decreasing its affinity for the ribosome. βTrCP also cooperates with mTOR and CK1α to induce the degradation of DEPTOR (an mTOR inhibitor), thereby generating an auto-amplification loop to promote the full activation of mTOR. At the same time, βTrCP mediates the degradation of the pro-apoptotic protein BimEL to promote cell survival. βTrCP also associates with phosphorylated IkappaBalpha and beta-catenin destruction motifs, probably functioning in multiple transcriptional programs by regulating the NF-kappaB and the WNT pathways. βTrCP has also been shown to regulate centriole disengagement and licensing. βTrCP target the intercentrosomal linker protein Cep68 in prometaphase, which contributes to centriole disengagement and subsequent centriole separation. # Interactions BTRC (gene) has been shown to interact with: - β-catenin, - BimEL1 - Cdc25A, - CDC34, - Claspin, - CUL1, - DEPTOR, - DLG1, - EMI1, - FBXW11, - IκBα, - NFKB2, - PDCD4, - RELA, - REST, - SKP1A, and - WEE1. - C22orf25 # Clinical Significance βTrCP behaves as an oncoprotein in some tissues. Elevated levels of βTrCP expression have been found in colorectal, pancreatic, hapatoblastoma, and breast cancers.	BTRC (gene) F-box/WD repeat-containing protein 1A (FBXW1A) also known as βTrCP1 or Fbxw1 or hsSlimb or pIkappaBalpha-E3 receptor subunit is a protein that in humans is encoded by the BTRC (beta-transducin repeat containing) gene.[1][2] This gene encodes a member of the F-box protein family which is characterized by an approximately 40 residue structural motif, the F-box. The F-box proteins constitute one of the four subunits of ubiquitin protein ligase complex called SCFs (Skp1-Cul1-F-box protein), which often, but not always, recognize substrates in a phosphorylation-dependent manner. F-box proteins are divided into 3 classes: - Fbxws containing WD40 repeats, - Fbxls containing leucine-rich repeats, - and Fbxos containing either "other" protein–protein interaction modules or no recognizable motifs. The protein encoded by this gene belongs to the Fbxw class as, in addition to an F-box, this protein contains multiple WD40 repeats. This protein is homologous to Xenopus βTrCP, yeast Met30, Neurospora Scon2 and Drosophila Slimb. In mammals, in addition to βTrCP1, a paralog protein (called βTrCP2 or FBXW11) also exists, but, so far, their functions appear redundant and indistinguishable. # Discovery Human βTrCP (referred to both βTrCP1 and βTrCP2) was originally identified as a cellular ubiquitin ligase that is bound by the HIV-1 Vpu viral protein to eliminate cellular CD4 by connecting it to the proteolytic machinery.[3] Subsequently, βTrCP was shown to regulate multiple cellular processes by mediating the degradation of various targets.[4] Cell cycle regulators constitute a major group of βTrCP substrates. During S phase, βTrCP keeps CDK1 in check by promoting the degradation of the phosphatase CDC25A,[5] whereas in G2, βTrCP contributes to CDK1 activation by targeting the kinase WEE1 for degradation.[6] In early mitosis, βTrCP mediates the degradation of EMI1,[7][8] an inhibitor of the APC/C ubiquitin ligase complex, which is responsible for the anaphase-metaphase transition (by inducing the proteolysis of Securin) and mitotic exit (by driving the degradation of mitotic CDK1 activating cyclin subunits). Furthermore, βTrCP controls APC/C by targeting REST, thereby removing its transcriptional repression on MAD2, an essential component of the spindle assembly checkpoint that keeps APC/C inactive until all chromatids are attached to the spindle microtubles.[9] # Function βTrCP plays important roles in regulating cell cycle checkpoints. In response to genotoxic stress, it contributes to turn off CDK1 activity by mediating the degradation of CDC25A in collaboration with Chk1,[5][10] thereby preventing cell cycle progression before the completion of DNA repair. During recovery from DNA replication and DNA damage, βTrCP instead targets Claspin in a Plk1-dependent manner.[11][12][13] βTrCP has also emerged as an important player in protein translation, cell growth and survival. In response to mitogens, PDCD4, an inhibitor of the translation initiation factor eIF4A, is rapidly degraded in a βTrCP- and S6K1-dependent manner, allowing efficient protein translation and cell growth.[14] Another target of βTrCP that is involved in protein translation is eEF2K, which inhibits translation elongation by phosphorylating eukaryotic Elongation Factor 2 (eEF2) and decreasing its affinity for the ribosome.[15] βTrCP also cooperates with mTOR and CK1α to induce the degradation of DEPTOR (an mTOR inhibitor), thereby generating an auto-amplification loop to promote the full activation of mTOR.[16][17][18] At the same time, βTrCP mediates the degradation of the pro-apoptotic protein BimEL to promote cell survival.[19] βTrCP also associates with phosphorylated IkappaBalpha and beta-catenin destruction motifs, probably functioning in multiple transcriptional programs by regulating the NF-kappaB and the WNT pathways.[20][21] βTrCP has also been shown to regulate centriole disengagement and licensing. βTrCP target the intercentrosomal linker protein Cep68 in prometaphase, which contributes to centriole disengagement and subsequent centriole separation.[22] # Interactions BTRC (gene) has been shown to interact with: - β-catenin,[21][23] - BimEL1[19] - Cdc25A,[5][10] - CDC34,[24][25] - Claspin,[11][12][13] - CUL1,[24][26][27] - DEPTOR,[16][17][18] - DLG1,[28] - EMI1,[7][8] - FBXW11,[26] - IκBα,[26][29] - NFKB2,[30][31] - PDCD4,[14] - RELA,[29] - REST,[7][32] - SKP1A,[3][24][26][27][33] and - WEE1.[6] - C22orf25[34] # Clinical Significance βTrCP behaves as an oncoprotein in some tissues. Elevated levels of βTrCP expression have been found in colorectal,[35] pancreatic,[36] hapatoblastoma,[37] and breast cancers.[38]	https://www.wikidoc.org/index.php/BTRC_(gene)
3c96d2b8d45a15065f2260917f6fade55f80864f	wikidoc	bZIP domain	bZIP domain The Basic Leucine Zipper Domain (bZIP domain) is found in many DNA binding eukaryotic proteins. One part of the domain contains a region that mediates sequence specific DNA binding properties and the leucine zipper that is required for the dimerization of two DNA binding regions. The DNA binding region comprises a number of basic aminoacids such as arginine and lysine. # bZIP domain containing proteins - AP-1 fos/jun heterodimer that forms a transcription factor - Jun-B transcription factor - CREB cAMP response element transcription factor - OPAQUE2 (O2) transcription factor of the 22-kD zein gene that encodes a class of storage proteins in the endosperm of maize (Zea Mays) kernels # Human proteins containing this domain ATF1; ATF2; ATF4; ATF5; ATF6; ATF7; BACH1; BACH2; BATF; BATF2; CREB1; CREB3; CREB3L1; CREB3L2; CREB3L3; CREB3L4; CREB5; CREBL1; CREM; E4BP4; FOSL1; FOSL2; JUN; JUNB; JUND; NFE2; NFE2L2; NFE2L3; SNFT; CREM	bZIP domain Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] The Basic Leucine Zipper Domain (bZIP domain) is found in many DNA binding eukaryotic proteins. One part of the domain contains a region that mediates sequence specific DNA binding properties and the leucine zipper that is required for the dimerization of two DNA binding regions. The DNA binding region comprises a number of basic aminoacids such as arginine and lysine. # bZIP domain containing proteins - AP-1 fos/jun heterodimer that forms a transcription factor - Jun-B transcription factor - CREB cAMP response element transcription factor - OPAQUE2 (O2) transcription factor of the 22-kD zein gene that encodes a class of storage proteins in the endosperm of maize (Zea Mays) kernels # Human proteins containing this domain ATF1; ATF2; ATF4; ATF5; ATF6; ATF7; BACH1; BACH2; BATF; BATF2; CREB1; CREB3; CREB3L1; CREB3L2; CREB3L3; CREB3L4; CREB5; CREBL1; CREM; E4BP4; FOSL1; FOSL2; JUN; JUNB; JUND; NFE2; NFE2L2; NFE2L3; SNFT; CREM # External links - bZIP domain entry in the SMART database de:BZIP-Domäne Template:WH Template:WS	https://www.wikidoc.org/index.php/BZIP
26912167cdf04682c3539cac93e79ecfa7f63552	wikidoc	Baby dearth	Baby dearth The baby dearth refers to the birth dearth in the statistical birthrate between 1954 and 1976. Persons born during the various years in this period have been regarded as being members of the Babyboom generation, Generation Jones, Baby Busters, Generation X, MTV Generation or even Generation Y. However, it most closely corresponds to Generation Jones and the Baby Bust, beginning at the same time as both but ending later than either. Starting in 1977, the birth rate started to dramatically rise, hence signaling the end of the baby dearth, and also perhaps that of bona fide Generation X. # Sources - ^ CDC report- Table 1-1. Live Births, Birth Rates, and Fertility Rates, by Race: United States, - Klauke, A. (2000) Coping with Changing Demographics An analysis of the effect of changing demographic patterns on school enrollments and education. - Meredith, G., Schewe, C., and Haim, A. (2002), Managing by defining moments: Innovative strategies for motivating 5 very different generational cohorts, Hungry Minds Inc., New York, 2002, ISBN 0-7645-5412-3	Baby dearth The baby dearth refers to the birth dearth in the statistical birthrate between 1954 and 1976. Persons born during the various years in this period have been regarded as being members of the Babyboom generation, Generation Jones, Baby Busters, Generation X, MTV Generation or even Generation Y. However, it most closely corresponds to Generation Jones and the Baby Bust, beginning at the same time as both but ending later than either. Starting in 1977, the birth rate started to dramatically rise, hence signaling the end of the baby dearth, and also perhaps that of bona fide Generation X. # Sources - ^ CDC report- Table 1-1. Live Births, Birth Rates, and Fertility Rates, by Race: United States, - Klauke, A. (2000) Coping with Changing Demographics An analysis of the effect of changing demographic patterns on school enrollments and education. - Meredith, G., Schewe, C., and Haim, A. (2002), Managing by defining moments: Innovative strategies for motivating 5 very different generational cohorts, Hungry Minds Inc., New York, 2002, ISBN 0-7645-5412-3 Template:WikiDoc Sources	https://www.wikidoc.org/index.php/Baby_dearth
fae5b7db7624507973c5354e86b0f1f6c4175718	wikidoc	Pyomyositis	Pyomyositis Synonyms and keywords: Tropical pyomyositis; Myositis tropicans; Bungpagga; Lambo lambo; Tropical skeletal muscle abscess; Myositis purulenta tropica; Bacterial myositis; Suppurative myositis; Epidemic abscess # Overview Pyomyositis, also known as tropical pyomyositis or myositis tropicans is an acute primary deep bacterial infection of the skeletal muscles that results in a single or multiple pus-filled abscesses. This condition is more common in tropical areas but may also occur in the temperate zones. The majority of pyomyositis is caused by the bacterium Staphylococcus aureus. In tropical regions, the infection often follows minor trauma, while in temperate zones the infection typically occurs in people with immune deficiencies. The abscess within the muscle is drained surgically and antibiotics are administered to fully clear the infection. The infection can affect any skeletal muscle, but most commonly infects the large muscle groups such as the quadriceps or gluteal muscles. # Historical Perspective - Traquair credited Virchow for the earliest mention of pyomyositis, however it was first described by Scriba in 1885 as a disease endemic to the tropics, hence the term tropical myositis. - Levin et al. reported the first case from a temperate region in 1971. # Classification - Pyomyositis may be classified according to the International Classification of Diseases-10 (ICD-10) into: - M60.0 Infectious myositis, Tropical pyomyositis (optionally, B95-B97 to indicate the infectious agent; B95.6 for Staphylococcus aureus) - Based on prognosis, pyomyositis is classified into three stages: - Invasive stage - Purulent or suppurative stage - Late or septic stage # Pathophysiology ## Pathogenesis - Pyomyositis is an acute primary deep bacterial infection of the skeletal muscle. - Pyomyositis may be associated with IgM antibody deficiency or with defective phagocytosis. - The exact pathogenesis of pyomyositis is not fully understood. - Under normal circumstances, the skeletal muscle tissue is intrinsically resistant to bacterial infections. It is thought that there is sequestration of iron by myoglobin, which is an essential nutritional requirement of proliferating bacteria. This results in slower growth of bacteria, allowing cell-mediated and humoral defences to enter infected zones and thereby preventing establishment of infection. - Pyomyositis results from hematogenous invasion of bacteria to damaged skeletal muscle (20% with subsequent abscess formation). - It does not include: - Intermuscular abscess - Abscesses extending into muscles from adjoining tissues such as bone and subcutaneous tissues - Abscesses secondary to previous septicemia ## Common locations Commonly involved muscles include: - Quadriceps - Glutei - Pectoralis major - Serratus anterior - Biceps - Iliopsoas - Gastrocnemius - Abdominal muscles - Spinal muscles ## Microscopic histopathological analysis On microscopic histopathological analysis, the following are characteristic findings of pyomyositis in sequence: - Edematous separation of muscle fibers - Coagulation necrosis - Patchy myocytolysis and inflammatory infiltrate - Loss of striations and granular degeneration of myofibers - Appearance of lymphocytes, plasma cells and eosinophils when myofibrils degenerate # Causes Pyomyositis is an acute bacterial infection of skeletal muscle. Bacteria Most common cause of pyomyositis includes: - Staphylococcus aureus (90% cases in tropical and 75% cases in temperate regions) Less common causes of pyomyositis include: - Group A streptococci (1%-5% of cases) - Group B,C,G streptococci - Streptococcus pneumoniae - Escherichia coli - Pseudomonas mallei - Pseudomonas pseudomallei - Pneumococcus - Neisseria - Haemophilus - Aeromonas - Serratia - Yersinia - Klebsiella Rare causes of pyomyositis include: - Salmonella - Citrobacter - Fusobacterium - Anaerobes - Mycobacterium # Differentiating Pyomyositis from Other Diseases - Pyomyositis must be differentiated from other diseases that cause muscle pain, fever, and/or leukocytosis such as: - Osteomyelitis - Pyrexia of unknown origin - Muscle contusion - Cellulitis - Muscle hematoma - Thrombophlebitis - Appendicitis - Septic arthritis - Deep venous thrombosis - Muscle rupture or muscle strain - Osteosarcoma - Rhabdomyosarcoma - Trichinosis - Leptospirosis - Polymyositis - Cysticercosis cellulosae - Trypanosomiasis or toxoplasmosis - Spontaneous gangrenous myositis - It does not include: - Intermuscular abscess - Abscesses extending into muscles from adjoining tissues such as bone and subcutaneous tissues - Abscesses secondary to previous septicemia # Epidemiology and Demographics ## Tropical countries - Majority (1,000-4,000 per 100,000 of all hospital asmissions) of pyomyositis cases are reported in some tropical countries such as Asia, tropical Africa, Oceania (islands of tropical pacific ocean), and the Caribbean islands. - Between 1980-1989, the incidence of pyomyositis was approximately 2,000 per 100,000 of surgical admissions in Ecuador. ## Temperate countries - In temperate countries, such as the United States, pyomyositis was a rare condition (accounting for 1 in 3000 pediatric admissions), but has become more common since the appearance of the USA300 strain of MRSA, especially in immunocompromised patients. ## Age - In tropical countries, pyomyositis most commonly affects children and young adults but may occur in any age group. - In temperate countries, the majority of pyomyositis cases occur in adults and elderly patients. ## Gender - In tropical countries, males are more commonly affected than females. - In temperate countries, both males and females are equally affected. # Risk Factors The common risk factors in the development of pyomyositis include: - Blunt trauma (20%-50% have history of trauma to the affected muscles) - Vigorous exercise - Intravenous drug abuse - Intramuscular injections - Nutritional deficiencies - Immunosupression - HIV - Immunosupressive drugs - Organ transplantation - Liver cirrhosis - Renal insufficiency - Corticosteroid therapy - Diabetes mellitus - Viral infections - Parasitic infections # Screening According to the U.S. Preventive Service Task Force (USPSTF), there is insufficient evidence to recommend routine screening for pyomyositis. # Natural History, Complications, and Prognosis ## Natural History If left untreated, pyomyositis is a potentially life threatening condition (mortality rate of 0.5-2%) which may progress to develop bacteremia, septicemia, metastatic abscess, acute renal failure, septic shock, and death. ## Complications Common complications of pyomyositis include: Cardiac complications - Pancarditis - Staphylococcus aureus endocarditis - Micro abscesses in myocardium - Diffuse acute myocarditis - Arrhythmias - Valve infection Other complications - Metastatic abscesses (microabscesses in liver, spleen, kidney, lung, and other organs) - Anterior uveitis - Local wasting and deformity - Interference with normal development of adjacent bones in children. - Septicemia - Uremia - Confusion and coma ## Prognosis - Based on prognosis, pyomyositis is classified into three stages: - Invasive stage - Purulent or suppurative stage - Late or septic stage - Depending on the clinical stage of pyomyositis at the time of diagnosis, the prognosis may vary. However, the prognosis is generally good when diagnosed and treated properly. # Diagnosis Early diagnosis of pyomyositis is critical for good prognosis but is often missed due to following: - Unfamiliarity with the disease - Atypical presentations - A wide range of differential diagnosis - Lack of early specific signs ## History A detailed and thorough history from the patient is necessary. Specific areas of focus when obtaining a history from the patient include: - Trauma - Intravenous drug abuse - Intramuscular injection - Vigorous exercise - Immunosupression - HIV - Diabetes mellitus - Corticosteroid therapy - Chemotherapy - Organ transplantation - Malnutrition - Other infections - Viral - Parasitic ## Symptoms The symptoms of pyomyositis are divided into three stages ### Atypical symptoms The atypical symptoms of pyomyositis include: - Toxic shock syndrome - Pyrexia of unknown origin (when invasive stage is prolonged) - Acute abdomen - Spinal cord compression - Compartment syndrome - Cervicobrachial neuralgia (when localized to neck muscles) ## Physical Examination Common physical examination findings of pyomyositis include: ### Images ## Laboratory Findings Laboratory findings consistent with pyomyositis include: - Needle aspiration (gold standard for diagnosis) - Negative for pus in invasive stage - Positive for pus in suppurative and septic stage - Aspirated pus is sent for culture (aerobic and anaerobic culture) - Biopsy (gold standard for diagnosis) - Biopsy of the abscess wall and muscle taken at the time of abscess drainage should be cultured - Blood culture and sensitivity helps to identify the following: - Septicemic process in blood - Antibiotics of choice - Hematological tests: - Complete blood count - Leukocytosis - Neutrophilia - Eosinophilia - Anemia - Raised erythrocyte sedimentation rate - Creatine phosphokinase and aldolase (markers of muscle damage are usually normal) - Raised C-reactive protein - Other laboratory tests to identify risk factors ## Imaging Findings The following non invasive imaging studies can be used in the diagnosis of pyomyositis: ### Ultrasonography - Ultrasonography is the initial imaging study of choice. - On ultrasonography, pyomyositis is characterized by the following features: - Muscle swelling - Heterogenous hypoechoic areas - Hypoechoic areas - Hyperechoic areas ### CT scan - On CT scan, pyomyositis is characterized by the following features: - The affected muscle shows areas of low attenuation with loss of muscle planes - Surrounding rim of contrast enhancement - It is also useful in differentiating tumours, hematoma and thrombophlebitis from abscess. ### MRI - On MRI, pyomyositis is characterized by the following features: - The affected muscle may appear swollen, with loss of architectural definition - Heterogenous areas of low intensity appear on T1-weighted images - In the early stage, the only finding may be edema (area of high signal intensity on fluid-sensitive sequences) ### Plain radiography - Plain radiography is used to rule out bony lesions. ## Other Diagnostic Studies ### X ray Chest - All patients should have initial radiography of chest and also repeated after an interval to detect complications of pyomyositis(like lung and cardiac complications). ### Echocardiography - Echocardiogram is used to diagnose cardiac complications of pyomyositis. ### ECG - ECG is used to diagnose cardiac complications of pyomyositis. # Treatment ## Resuscitation The following conditions require immediate resuscitation: - Anemia: Blood transfusion - Malnutrition: Nutritional support and rehabilitation - Shock ## Surgery Surgery is the mainstay treatment for pyomyositis. - Abscess drainage includes: - Incision and drainage - Percutaneous drainage (ultrasound or CT guided) ## Medical Therapy ### Analgesia Appropriate analgesics are given when the patient presents with pain. ### Antimicrobial therapy - Antimicrobial therapy is recommended for patients with pyomyocitis: - Preferred regimen (1): Nafcillin - Preferred regimen (2): Oxacillin 2 g IV q4h - Preferred regimen (3): Cefazolin 2 g IV q8h (if MSSA) - Alternate regimen: Vancomycin 1 g IV q12h (if MRSA) ## Prevention ### Primary prevention There are no primary preventive measures available for pyomyositis. ### Secondary prevention There are no secondary preventive measures available for pyomyositis.	Pyomyositis Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Yamuna Kondapally, M.B.B.S[2] Synonyms and keywords: Tropical pyomyositis; Myositis tropicans; Bungpagga; Lambo lambo; Tropical skeletal muscle abscess; Myositis purulenta tropica; Bacterial myositis; Suppurative myositis; Epidemic abscess # Overview Pyomyositis, also known as tropical pyomyositis or myositis tropicans is an acute primary deep bacterial infection of the skeletal muscles that results in a single or multiple pus-filled abscesses. This condition is more common in tropical areas but may also occur in the temperate zones. The majority of pyomyositis is caused by the bacterium Staphylococcus aureus. In tropical regions, the infection often follows minor trauma, while in temperate zones the infection typically occurs in people with immune deficiencies. The abscess within the muscle is drained surgically and antibiotics are administered to fully clear the infection. The infection can affect any skeletal muscle, but most commonly infects the large muscle groups such as the quadriceps or gluteal muscles.[1][2] # Historical Perspective - Traquair credited Virchow for the earliest mention of pyomyositis, however it was first described by Scriba in 1885 as a disease endemic to the tropics, hence the term tropical myositis.[3][4] - Levin et al. reported the first case from a temperate region in 1971. # Classification - Pyomyositis may be classified according to the International Classification of Diseases-10 (ICD-10) into:[5] - M60.0 Infectious myositis, Tropical pyomyositis (optionally, B95-B97 to indicate the infectious agent; B95.6 for Staphylococcus aureus) - Based on prognosis, pyomyositis is classified into three stages: - Invasive stage - Purulent or suppurative stage - Late or septic stage # Pathophysiology ## Pathogenesis - Pyomyositis is an acute primary deep bacterial infection of the skeletal muscle.[2] - Pyomyositis may be associated with IgM antibody deficiency or with defective phagocytosis. - The exact pathogenesis of pyomyositis is not fully understood. - Under normal circumstances, the skeletal muscle tissue is intrinsically resistant to bacterial infections. It is thought that there is sequestration of iron by myoglobin, which is an essential nutritional requirement of proliferating bacteria. This results in slower growth of bacteria, allowing cell-mediated and humoral defences to enter infected zones and thereby preventing establishment of infection. - Pyomyositis results from hematogenous invasion of bacteria to damaged skeletal muscle (20% with subsequent abscess formation). - It does not include: - Intermuscular abscess - Abscesses extending into muscles from adjoining tissues such as bone and subcutaneous tissues - Abscesses secondary to previous septicemia ## Common locations Commonly involved muscles include:[6][2][7][8] - Quadriceps - Glutei - Pectoralis major - Serratus anterior - Biceps - Iliopsoas - Gastrocnemius - Abdominal muscles - Spinal muscles ## Microscopic histopathological analysis On microscopic histopathological analysis, the following are characteristic findings of pyomyositis in sequence:[2] - Edematous separation of muscle fibers - Coagulation necrosis - Patchy myocytolysis and inflammatory infiltrate - Loss of striations and granular degeneration of myofibers - Appearance of lymphocytes, plasma cells and eosinophils when myofibrils degenerate # Causes Pyomyositis is an acute bacterial infection of skeletal muscle.[3][9] Bacteria Most common cause of pyomyositis includes: - Staphylococcus aureus (90% cases in tropical and 75% cases in temperate regions) Less common causes of pyomyositis include: - Group A streptococci (1%-5% of cases) - Group B,C,G streptococci - Streptococcus pneumoniae - Escherichia coli - Pseudomonas mallei - Pseudomonas pseudomallei - Pneumococcus - Neisseria - Haemophilus - Aeromonas - Serratia - Yersinia - Klebsiella Rare causes of pyomyositis include: - Salmonella - Citrobacter - Fusobacterium - Anaerobes - Mycobacterium # Differentiating Pyomyositis from Other Diseases - Pyomyositis must be differentiated from other diseases that cause muscle pain, fever, and/or leukocytosis such as:[10][2] - Osteomyelitis - Pyrexia of unknown origin - Muscle contusion - Cellulitis - Muscle hematoma - Thrombophlebitis - Appendicitis - Septic arthritis - Deep venous thrombosis - Muscle rupture or muscle strain - Osteosarcoma - Rhabdomyosarcoma - Trichinosis - Leptospirosis - Polymyositis - Cysticercosis cellulosae - Trypanosomiasis or toxoplasmosis - Spontaneous gangrenous myositis - It does not include: - Intermuscular abscess - Abscesses extending into muscles from adjoining tissues such as bone and subcutaneous tissues - Abscesses secondary to previous septicemia # Epidemiology and Demographics ## Tropical countries - Majority (1,000-4,000 per 100,000 of all hospital asmissions) of pyomyositis cases are reported in some tropical countries such as Asia, tropical Africa, Oceania (islands of tropical pacific ocean), and the Caribbean islands. - Between 1980-1989, the incidence of pyomyositis was approximately 2,000 per 100,000 of surgical admissions in Ecuador. [11] ## Temperate countries - In temperate countries, such as the United States, pyomyositis was a rare condition (accounting for 1 in 3000 pediatric admissions), but has become more common since the appearance of the USA300 strain of MRSA, especially in immunocompromised patients.[12][13] ## Age - In tropical countries, pyomyositis most commonly affects children and young adults but may occur in any age group.[3][14] - In temperate countries, the majority of pyomyositis cases occur in adults and elderly patients. ## Gender - In tropical countries, males are more commonly affected than females.[3][14] - In temperate countries, both males and females are equally affected. # Risk Factors The common risk factors in the development of pyomyositis include:[2][15][16][17][18] - Blunt trauma (20%-50% have history of trauma to the affected muscles) - Vigorous exercise - Intravenous drug abuse - Intramuscular injections - Nutritional deficiencies - Immunosupression - HIV - Immunosupressive drugs - Organ transplantation - Liver cirrhosis - Renal insufficiency - Corticosteroid therapy - Diabetes mellitus - Viral infections - Parasitic infections # Screening According to the U.S. Preventive Service Task Force (USPSTF), there is insufficient evidence to recommend routine screening for pyomyositis. # Natural History, Complications, and Prognosis ## Natural History If left untreated, pyomyositis is a potentially life threatening condition (mortality rate of 0.5-2%) which may progress to develop bacteremia, septicemia, metastatic abscess, acute renal failure, septic shock, and death. ## Complications Common complications of pyomyositis include:[19][2] Cardiac complications - Pancarditis - Staphylococcus aureus endocarditis - Micro abscesses in myocardium - Diffuse acute myocarditis - Arrhythmias - Valve infection Other complications - Metastatic abscesses (microabscesses in liver, spleen, kidney, lung, and other organs) - Anterior uveitis - Local wasting and deformity - Interference with normal development of adjacent bones in children. - Septicemia - Uremia - Confusion and coma ## Prognosis - Based on prognosis, pyomyositis is classified into three stages: - Invasive stage - Purulent or suppurative stage - Late or septic stage - Depending on the clinical stage of pyomyositis at the time of diagnosis, the prognosis may vary. However, the prognosis is generally good when diagnosed and treated properly.[2] # Diagnosis Early diagnosis of pyomyositis is critical for good prognosis but is often missed due to following:[2] - Unfamiliarity with the disease - Atypical presentations - A wide range of differential diagnosis - Lack of early specific signs ## History A detailed and thorough history from the patient is necessary. Specific areas of focus when obtaining a history from the patient include:[20] - Trauma - Intravenous drug abuse - Intramuscular injection - Vigorous exercise - Immunosupression - HIV - Diabetes mellitus - Corticosteroid therapy - Chemotherapy - Organ transplantation - Malnutrition - Other infections - Viral - Parasitic ## Symptoms The symptoms of pyomyositis are divided into three stages[3][20] ### Atypical symptoms The atypical symptoms of pyomyositis include:[2][21] - Toxic shock syndrome - Pyrexia of unknown origin (when invasive stage is prolonged) - Acute abdomen - Spinal cord compression - Compartment syndrome - Cervicobrachial neuralgia (when localized to neck muscles) ## Physical Examination Common physical examination findings of pyomyositis include:[3][20] ### Images ## Laboratory Findings Laboratory findings consistent with pyomyositis include:[2] - Needle aspiration (gold standard for diagnosis) - Negative for pus in invasive stage - Positive for pus in suppurative and septic stage - Aspirated pus is sent for culture (aerobic and anaerobic culture) - Biopsy (gold standard for diagnosis) - Biopsy of the abscess wall and muscle taken at the time of abscess drainage should be cultured - Blood culture and sensitivity helps to identify the following: - Septicemic process in blood - Antibiotics of choice - Hematological tests: - Complete blood count - Leukocytosis - Neutrophilia - Eosinophilia - Anemia - Raised erythrocyte sedimentation rate - Creatine phosphokinase and aldolase (markers of muscle damage are usually normal) - Raised C-reactive protein - Other laboratory tests to identify risk factors ## Imaging Findings The following non invasive imaging studies can be used in the diagnosis of pyomyositis: ### Ultrasonography - Ultrasonography is the initial imaging study of choice. - On ultrasonography, pyomyositis is characterized by the following features:[22][23] - Muscle swelling - Heterogenous hypoechoic areas - Hypoechoic areas - Hyperechoic areas ### CT scan - On CT scan, pyomyositis is characterized by the following features: - The affected muscle shows areas of low attenuation with loss of muscle planes - Surrounding rim of contrast enhancement - It is also useful in differentiating tumours, hematoma and thrombophlebitis from abscess. ### MRI - On MRI, pyomyositis is characterized by the following features:[24][25] - The affected muscle may appear swollen, with loss of architectural definition - Heterogenous areas of low intensity appear on T1-weighted images - In the early stage, the only finding may be edema (area of high signal intensity on fluid-sensitive sequences) ### Plain radiography - Plain radiography is used to rule out bony lesions. ## Other Diagnostic Studies ### X ray Chest - All patients should have initial radiography of chest and also repeated after an interval to detect complications of pyomyositis(like lung and cardiac complications). ### Echocardiography - Echocardiogram is used to diagnose cardiac complications of pyomyositis. ### ECG - ECG is used to diagnose cardiac complications of pyomyositis. # Treatment ## Resuscitation The following conditions require immediate resuscitation: - Anemia: Blood transfusion - Malnutrition: Nutritional support and rehabilitation - Shock ## Surgery Surgery is the mainstay treatment for pyomyositis. - Abscess drainage includes: - Incision and drainage - Percutaneous drainage (ultrasound or CT guided) ## Medical Therapy ### Analgesia Appropriate analgesics are given when the patient presents with pain. ### Antimicrobial therapy - Antimicrobial therapy is recommended for patients with pyomyocitis:[26] - Preferred regimen (1): Nafcillin - Preferred regimen (2): Oxacillin 2 g IV q4h - Preferred regimen (3): Cefazolin 2 g IV q8h (if MSSA) - Alternate regimen: Vancomycin 1 g IV q12h (if MRSA) ## Prevention ### Primary prevention There are no primary preventive measures available for pyomyositis. ### Secondary prevention There are no secondary preventive measures available for pyomyositis.	https://www.wikidoc.org/index.php/Bacterial_myositis
936a764a1d5f6066ecbac8dc1a38d90e67a2d1a7	wikidoc	Bactericide	Bactericide A bactericide or bacteriocide is a substance that kills bacteria and, preferably, nothing else. Bactericides are either disinfectants, antiseptics or antibiotics. # Important Functional Groups in a Bactericidal Substance The most used bactericidal disinfectants are those applying - active chlorine (i.e., hypochlorites, chloramines, dichloroisocyanurate and trichloroisocyanurate, wet chlorine, chlorine dioxide etc.), - active oxygen (peroxides, such as peracetic acid, potassium persulfate, sodium perborate, sodium percarbonate and urea perhydrate), - iodine (iodpovidone (povidone-iodine, Betadine), Lugol's solution, iodine tincture, iodinated nonionic surfactants), - concentrated alcohols (mainly ethanol, 1-propanol, called also n-propanol and 2-propanol, called isopropanol and mixtures thereof; further, 2-phenoxyethanol and 1- and 2-phenoxypropanols are used), - phenolic substances (such as phenol (also called "carbolic acid"), cresols (called "Lysole" in combination with liquid potassium soaps), halogenated (chlorinated, brominated) phenols, such as hexachlorophene, triclosan, trichlorophenol, tribromophenol, pentachlorophenol, Dibromol and salts thereof), - cationic surfactants, such as some quaternary ammonium cations (such as benzalkonium chloride, cetyl trimethylammonium bromide or chloride, didecyldimethylammonium chloride, cetylpyridinium chloride, benzethonium chloride) and others, non-quarternary compounds, such as chlorhexidine, glucoprotamine, octenidine dihydrochloride etc.), - strong oxidizers, such as ozone and permanganate solutions; - heavy metals and their salts, such as colloidal silver, silver nitrate, mercury chloride, phenylmercury salts, copper sulfate, copper oxide-chloride etc. Heavy metals and their salts are the most toxic, and environment-hazardous bactericides and therefore, their use is strongly oppressed or canceled; further, also - properly concentrated strong acids (phosphoric, nitric, sulfuric, amidosulfuric, toluenesulfonic acids) and - alkalis (sodium, potassium, calcium hydroxides),such as of pH 13, particularly under elevated temperature (above 60°C), kills bacteria. # Bacteriocidal Antiseptics As antiseptics (i.e., germicide agents that can be used on human or animal body, skin, mucoses, wounds and the like), few of the above mentioned disinfectants can be used, under proper conditions (mainly concentration, pH, temperature and toxicity toward man/animal). Among them, important are some - properly diluted chlorine preparations (f.e. Daquin's solution, 0.5% sodium or potassium hypochlorite solution, pH-adjusted to pH 7 - 8, or 0.5 - 1% solution of sodium benzenesulfochloramide (chloramine B)), some - iodine preparations, such as iodopovidone in various galenics (oinment, solutions, wound plasters), in the past also Lugol's solution, - peroxides as urea perhydrate solutions and pH-buffered 0.1 - 0.25% peracetic acid solutions, - alcohols with or without antiseptic additives, used mainly for skin antisepsis, - weak organic acids such as sorbic acid, benzoic acid, lactic acid and salicylic acid - some phenolic compounds, such as hexachlorophene, triclosan and Dibromol, and - cation-active compounds, such as 0.05 - 0.5% benzalkonium, 0.5 - 4% chlorhexidine, 0.1 - 2% octenidine solutions. Others are generally not applicable as safe antiseptics, either because of their corrosive or toxic nature. # Bacteriocidal Antibiotics Bacteriocidal antibiotics kill bacteria; bacteriostatic antibiotics only slow their growth or reproduction. Penicillin is a bactericide, as are cephalosporins. Aminoglycosidic antibiotics can act in both a bactericidic manner (by disrupting cell wall precursor leading to lysis) or bacteriostatic manner (by binding to 30s ribosomal subunit and reducing translation fidelity leading to inaccurate protein synthesis) Other bactericidal antibiotics include the fluoroquinolones, nitrofurans, vancomycin, monobactams, co-trimoxazole, and metronidazole. de:Bakterizid no:Baktericid	Bactericide A bactericide or bacteriocide is a substance that kills bacteria and, preferably, nothing else. Bactericides are either disinfectants, antiseptics or antibiotics. # Important Functional Groups in a Bactericidal Substance The most used bactericidal disinfectants are those applying - active chlorine (i.e., hypochlorites, chloramines, dichloroisocyanurate and trichloroisocyanurate, wet chlorine, chlorine dioxide etc.), - active oxygen (peroxides, such as peracetic acid, potassium persulfate, sodium perborate, sodium percarbonate and urea perhydrate), - iodine (iodpovidone (povidone-iodine, Betadine), Lugol's solution, iodine tincture, iodinated nonionic surfactants), - concentrated alcohols (mainly ethanol, 1-propanol, called also n-propanol and 2-propanol, called isopropanol and mixtures thereof; further, 2-phenoxyethanol and 1- and 2-phenoxypropanols are used), - phenolic substances (such as phenol (also called "carbolic acid"), cresols (called "Lysole" in combination with liquid potassium soaps), halogenated (chlorinated, brominated) phenols, such as hexachlorophene, triclosan, trichlorophenol, tribromophenol, pentachlorophenol, Dibromol and salts thereof), - cationic surfactants, such as some quaternary ammonium cations (such as benzalkonium chloride, cetyl trimethylammonium bromide or chloride, didecyldimethylammonium chloride, cetylpyridinium chloride, benzethonium chloride) and others, non-quarternary compounds, such as chlorhexidine, glucoprotamine, octenidine dihydrochloride etc.), - strong oxidizers, such as ozone and permanganate solutions; - heavy metals and their salts, such as colloidal silver, silver nitrate, mercury chloride, phenylmercury salts, copper sulfate, copper oxide-chloride etc. Heavy metals and their salts are the most toxic, and environment-hazardous bactericides and therefore, their use is strongly oppressed or canceled; further, also - properly concentrated strong acids (phosphoric, nitric, sulfuric, amidosulfuric, toluenesulfonic acids) and - alkalis (sodium, potassium, calcium hydroxides),such as of pH < 1 or > 13, particularly under elevated temperature (above 60°C), kills bacteria. # Bacteriocidal Antiseptics As antiseptics (i.e., germicide agents that can be used on human or animal body, skin, mucoses, wounds and the like), few of the above mentioned disinfectants can be used, under proper conditions (mainly concentration, pH, temperature and toxicity toward man/animal). Among them, important are some - properly diluted chlorine preparations (f.e. Daquin's solution, 0.5% sodium or potassium hypochlorite solution, pH-adjusted to pH 7 - 8, or 0.5 - 1% solution of sodium benzenesulfochloramide (chloramine B)), some - iodine preparations, such as iodopovidone in various galenics (oinment, solutions, wound plasters), in the past also Lugol's solution, - peroxides as urea perhydrate solutions and pH-buffered 0.1 - 0.25% peracetic acid solutions, - alcohols with or without antiseptic additives, used mainly for skin antisepsis, - weak organic acids such as sorbic acid, benzoic acid, lactic acid and salicylic acid - some phenolic compounds, such as hexachlorophene, triclosan and Dibromol, and - cation-active compounds, such as 0.05 - 0.5% benzalkonium, 0.5 - 4% chlorhexidine, 0.1 - 2% octenidine solutions. Others are generally not applicable as safe antiseptics, either because of their corrosive or toxic nature. # Bacteriocidal Antibiotics Bacteriocidal antibiotics kill bacteria; bacteriostatic antibiotics only slow their growth or reproduction. Penicillin is a bactericide, as are cephalosporins. Aminoglycosidic antibiotics can act in both a bactericidic manner (by disrupting cell wall precursor leading to lysis) or bacteriostatic manner (by binding to 30s ribosomal subunit and reducing translation fidelity leading to inaccurate protein synthesis) Other bactericidal antibiotics include the fluoroquinolones, nitrofurans, vancomycin, monobactams, co-trimoxazole, and metronidazole. de:Bakterizid no:Baktericid Template:WikiDoc Sources	https://www.wikidoc.org/index.php/Bactericidal
810be7c1432ce2981909a04980a85dbad2d4d064	wikidoc	Bacteriuria	Bacteriuria # Overview In medicine, bacteriuria denotes the presence of bacteria in urine not due to contamination from urine sample collection. Urine is normally a sterile bodily fluid when inside the bladder, but can pick up commensals and pathogens when exiting through the urethra. Bacteria in the urine, especially gram-negative rods, usually indicate a urinary tract infection (either cystitis or pyelonephritis), although bacteriuria can also occur in prostatitis. Escherichia coli is the most common bacterium isolated from urine samples. Asymptomatic bacteriuria is bacteriuria without accompanying symptoms of a urinary tract infection (such as frequent urination, painful urination or fever). It is more common in women, in the elderly, in residents of long-term care facilities, and in patients with diabetes, bladder catheters and spinal cord injuries. Patients with a long-term Foley catheter uniformly show bacteriuria. # Diagnosis Bacteria can be detected with a urine dipstick test for urinary nitrite or by urinary microscopy, although bacterial culture remains the most specific and formal test (the golden standard). Bacteriuria can be confirmed if a single bacterial species is isolated in a concentration greater than 100,000 colony forming units per millilitre of urine in clean-catch midstream urine specimens (one for men, two consecutive specimens with the same bacterium for women). For urine collected via bladder catheterisation, the threshold is 100 colony forming units of a single species per millilitre. The threshold is also 100 colony forming units of a single species per millilitre for women displaying UTI symptoms. # Treatment The presence of simultaneous pyuria does not warrant treatment by itself. - Screening for asymptomatic bacteriuria with urine culture and treatment with antibiotics is recommended during pregnancy, because it significantly reduces symptomatic urinary tract infections, low birth weight, and preterm delivery. - This has not been proven for older people or people with diabetes, bladder catheters or spinal cord injuries. - Kidney transplant recipients, children with vesicoureteral reflux or others with structural abnormalities of the urinary tract, people with infected kidney stones and those who are having urological procedures might be more likely to benefit from treatment with antibiotics for asymptomatic bacteriuria.	Bacteriuria Editor-In-Chief: C. Michael Gibson, M.S., M.D. [2]To view a comprehensive algorithm of common findings of urine composition and urine output, click here # Overview In medicine, bacteriuria denotes the presence of bacteria in urine not due to contamination from urine sample collection. Urine is normally a sterile bodily fluid when inside the bladder, but can pick up commensals and pathogens when exiting through the urethra. Bacteria in the urine, especially gram-negative rods, usually indicate a urinary tract infection (either cystitis or pyelonephritis), although bacteriuria can also occur in prostatitis. Escherichia coli is the most common bacterium isolated from urine samples. Asymptomatic bacteriuria is bacteriuria without accompanying symptoms of a urinary tract infection (such as frequent urination, painful urination or fever). It is more common in women, in the elderly, in residents of long-term care facilities, and in patients with diabetes, bladder catheters and spinal cord injuries. Patients with a long-term Foley catheter uniformly show bacteriuria. # Diagnosis Bacteria can be detected with a urine dipstick test for urinary nitrite or by urinary microscopy, although bacterial culture remains the most specific and formal test (the golden standard). Bacteriuria can be confirmed if a single bacterial species is isolated in a concentration greater than 100,000 colony forming units per millilitre of urine in clean-catch midstream urine specimens (one for men, two consecutive specimens with the same bacterium for women). For urine collected via bladder catheterisation, the threshold is 100 colony forming units of a single species per millilitre. The threshold is also 100 colony forming units of a single species per millilitre for women displaying UTI symptoms.[2] # Treatment The presence of simultaneous pyuria does not warrant treatment by itself. - Screening for asymptomatic bacteriuria with urine culture and treatment with antibiotics is recommended during pregnancy, because it significantly reduces symptomatic urinary tract infections, low birth weight, and preterm delivery.[3][4] - This has not been proven for older people or people with diabetes, bladder catheters or spinal cord injuries.[5] - Kidney transplant recipients, children with vesicoureteral reflux or others with structural abnormalities of the urinary tract, people with infected kidney stones and those who are having urological procedures might be more likely to benefit from treatment with antibiotics for asymptomatic bacteriuria.[6]	https://www.wikidoc.org/index.php/Bacteriuria
539ac21db05e494195692478a1c4857ee5dcf36c	wikidoc	Bacteroides	Bacteroides # Overview # Overview Bacteroides is a genus of Gram-negative, rod-shaped bacteria. Bacteroides species are non-endospore-forming, anaerobes, and may either be motile or non-motile, depending on the species. The DNA base composition is 40-48% GC. Unusual in bacterial organisms, Bacteroides membranes contain sphingolipids. They also contain meso-diaminopimelic acid in their peptidoglycan layer. Bacteroides are normally commensal, making up the most substantial portion of the mammalian gastrointestinal flora, where they play a fundamental role in processing of complex molecules to simpler ones in the host intestine. As many as 1010-1011 cells per gram of human feces have been reported. They can use simple sugars when available, but the main source of energy is polysaccharides from plant sources. # Pathogenesis Bacteroides species also benefit their host by excluding potential pathogens from colonizing the gut. Some species (B. fragilis, for example) are opportunistic human pathogens, causing infections of the peritoneal cavity, gastrointestinal surgery, and appendicitis via abscess formation, inhibiting phagocytosis, and inactivating beta-lactam antibiotics. Although Bacteroides species are anaerobic, they are aerotolerant and thus can survive in the abdominal cavity. Bacteroides are generally resistant to a wide variety of antibiotics — beta-lactams, aminoglycosides, and recently many species have acquired resistance to erythromycin and tetracycline. This high level of antibiotic resistance has prompted concerns that Bacteroides species may become a reservoir for resistance in other, more highly pathogenic bacterial strains. # B. fragilis Bacteroides fragilis is an obligate anaerobe of the gut. It is involved in 90% of anaerobic peritoneal infections. B. fragilis is generally susceptible to metronidazole, carbapenems, and beta-lactam/beta-lactamase inhibitor combinations (e.g., Unasyn, Zosyn). The bacteria has inherent high-level resistance to penicillin. Clindamycin is no longer recommended as the first-line agent for B. fragilis due to emerging high-level resistance (>30% in some reports). # Treatment ## Antimicrobial regimen - Bacteroides fragilis - 1. Monotherapy - Preferred regimen (1): Imipenem - Preferred regimen (2): Ertapenem - Preferred regimen (3): Meropenem - Preferred regimen (4): Doripenem 0.5-1.0 g IV q6h - Preferred regimen (5): Piperacillin-tazobactam 3.375 g IV q6h - Preferred regimen (6): Ampicillin-sulbactam 1-2 g IV q6h - Preferred regimen (7): Tigecycline 100 mg IV THEN 50 mg IV q12h - 2. Combination therapy - Preferred regimen: Metronidazole 0.75-1.0 g IV q12h AND Cefotaxime 1.5-2 g IV q6h OR Aztreonam 1-2 g IV q8h OR Ceftriaxone 1 g IV q12h # Gallery - This Petri dish culture plate contained a medium of kanamycin menadione blood agar, which had been inoculated with an inoculum from a cervical swab culture specimen. The culture had given rise to pigmented colonies of Prevotella melaninogenica. From Public Health Image Library (PHIL). - Under a low magnification of 15x, this image depicts five colonies of Bacteroides variabilis bacteria. From Public Health Image Library (PHIL). - Under a low magnification of 15x, this image depicts five colonies of Bacteroides variabilis bacteria. From Public Health Image Library (PHIL). - Under a magnification of 956X, this Gram-stained photomicrograph depicts numbers of Gram-negative Bacteroides variabilis bacteria. From Public Health Image Library (PHIL). - Under a low magnification of 15x, this image depicts a single colony of Bacteroides terebrans bacteria. From Public Health Image Library (PHIL). - This image depicts a Petri dish culture plate containing a medium of blood agar to which menadione had been added. The dish had been inoculated with Prevotella melaninogenica, formerly known as Bacteroides melaninogenicus bacteria, which was incubated at a temperature of 35°C for a five day period. From Public Health Image Library (PHIL). - This photomicrograph of an unknown sample revealed the presence of a mixed infection, which involved Gram-positive Peptostreptococcus anaerobius and P. asaccharolyticus (formerly Peptococcus asaccharolyticus), and Gram-negative Prevotella melaninogenica (formerly Bacteroides melaninogenicus), anaerobic bacteria. From Public Health Image Library (PHIL). - Under a magnification of 956X, this Gram-stained photomicrograph depicts numbers of Prevotella melaninogenica, formerly known as Bacteroides melaninogenicus, bacteria, which had been grown on thioglycollate medium for a 72 hour time period. From Public Health Image Library (PHIL). - This image depicts three Bacteroides bivius bacterial cultures, which had been grown on a blood agar plate (BAP) for a 48 hour time period. From Public Health Image Library (PHIL). - This digitally-colorized scanning electron micrograph (SEM) depicted a Gram-negative Sebaldella termitidis bacterium. From Public Health Image Library (PHIL). - This digitally-colorized scanning electron micrograph (SEM) depicted a small grouping of Gram-negative Sebaldella termitidis bacteria.From Public Health Image Library (PHIL). - This digitally-colorized scanning electron micrograph (SEM) depicted a small grouping of Gram-negative Sebaldella termitidis bacteria.From Public Health Image Library (PHIL). - This digitally-colorized scanning electron micrograph (SEM) depicted a Gram-negative Sebaldella termitidis bacteria, as it was about to enter the process of cell division. From Public Health Image Library (PHIL). - This digitally-colorized scanning electron micrograph (SEM) depicted numbers of Gram-negative Sebaldella termitidis bacteria. From Public Health Image Library (PHIL). - This digitally-colorized scanning electron micrograph (SEM) depicted two Gram-negative Sebaldella termitidis bacteria. From Public Health Image Library (PHIL). - This digitally-colorized scanning electron micrograph (SEM) depicted a small grouping of Gram-negative Sebaldella termitidis bacteria. From Public Health Image Library (PHIL). - This digitally-colorized scanning electron micrograph (SEM) depicted a Gram-negative Sebaldella termitidis bacterium, which was in the process of dividing into two separate organisms. From Public Health Image Library (PHIL). - Magnified 1000X, this photomicrograph depicted numbers of Gram-negative Bacteroides fragilis subsp. fragilis bacteria, which had been cultured on Schaedler agar medium, and processed using the Gram-stain method. From Public Health Image Library (PHIL). - his 1972 photograph revealed the morphology displayed by two colonies of Bacteroides hypermegas bacteria that had been grown on blood agar medium for 48 hours. From Public Health Image Library (PHIL). - This 1972 photograph depicts two Bacteroides fragilis subsp. fragilis bacterial cultures grown on blood agar medium for 48 hours. From Public Health Image Library (PHIL). - This micrograph depicts Bacteroides clostridiforme subsp. girans bacteria that had been cultured in thioglycollate broth medium for 48 hours. From Public Health Image Library (PHIL). - This micrograph depicts Bacteroides fragilis subsp. thetaiota bacteria that had been cultured in blood agar medium for 48 hours. From Public Health Image Library (PHIL). - This micrograph depicts Bacteroides biacutis bacteria cultured in blood agar medium for 48 hours. From Public Health Image Library (PHIL). - This micrograph depicts Bacteroides biacutis bacteria cultured in blood agar medium for 48 hours. From Public Health Image Library (PHIL). - This micrograph depicts Bacteroides fragilis ss. fragilis bacteria cultured in blood agar medium for 48 hours. From Public Health Image Library (PHIL). - This micrograph depicts Bacteroides fragilis ss. fragilis bacteria cultured in blood agar medium for 48 hours. From Public Health Image Library (PHIL). - This micrograph depicts Bacteroides fragilis subsp. distasonis bacteria cultured in blood agar medium for 48 hours. From Public Health Image Library (PHIL). - This photomicrograph shows Fusobacterium novum after being cultured in a thioglycollate medium for 48 hours. From Public Health Image Library (PHIL). - Magnified 1000X, this micrograph depicts Bacteroides fragilis subsp. fragilis bacteria that had been grown in Schaedler’s broth, and processed using the Gram-stain method. From Public Health Image Library (PHIL). - This photomicrograph shows the bacterium Bacteroides biacutus cultured in a thioglycollate medium for 48 hours. From Public Health Image Library (PHIL).	Bacteroides Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview # Overview Bacteroides is a genus of Gram-negative, rod-shaped bacteria. Bacteroides species are non-endospore-forming, anaerobes, and may either be motile or non-motile, depending on the species.[1] The DNA base composition is 40-48% GC. Unusual in bacterial organisms, Bacteroides membranes contain sphingolipids. They also contain meso-diaminopimelic acid in their peptidoglycan layer. Bacteroides are normally commensal, making up the most substantial portion of the mammalian gastrointestinal flora,[2] where they play a fundamental role in processing of complex molecules to simpler ones in the host intestine. As many as 1010-1011 cells per gram of human feces have been reported.[3] They can use simple sugars when available, but the main source of energy is polysaccharides from plant sources. # Pathogenesis Bacteroides species also benefit their host by excluding potential pathogens from colonizing the gut. Some species (B. fragilis, for example) are opportunistic human pathogens, causing infections of the peritoneal cavity, gastrointestinal surgery, and appendicitis via abscess formation, inhibiting phagocytosis, and inactivating beta-lactam antibiotics.[4] Although Bacteroides species are anaerobic, they are aerotolerant and thus can survive in the abdominal cavity. Bacteroides are generally resistant to a wide variety of antibiotics — beta-lactams, aminoglycosides, and recently many species have acquired resistance to erythromycin and tetracycline. This high level of antibiotic resistance has prompted concerns that Bacteroides species may become a reservoir for resistance in other, more highly pathogenic bacterial strains.[5] # B. fragilis Bacteroides fragilis is an obligate anaerobe of the gut. It is involved in 90% of anaerobic peritoneal infections. B. fragilis is generally susceptible to metronidazole, carbapenems, and beta-lactam/beta-lactamase inhibitor combinations (e.g., Unasyn, Zosyn). The bacteria has inherent high-level resistance to penicillin. Clindamycin is no longer recommended as the first-line agent for B. fragilis due to emerging high-level resistance (>30% in some reports).[6] # Treatment ## Antimicrobial regimen - Bacteroides fragilis [7] - 1. Monotherapy - Preferred regimen (1): Imipenem - Preferred regimen (2): Ertapenem - Preferred regimen (3): Meropenem - Preferred regimen (4): Doripenem 0.5-1.0 g IV q6h - Preferred regimen (5): Piperacillin-tazobactam 3.375 g IV q6h - Preferred regimen (6): Ampicillin-sulbactam 1-2 g IV q6h - Preferred regimen (7): Tigecycline 100 mg IV THEN 50 mg IV q12h - 2. Combination therapy - Preferred regimen: Metronidazole 0.75-1.0 g IV q12h AND Cefotaxime 1.5-2 g IV q6h OR Aztreonam 1-2 g IV q8h OR Ceftriaxone 1 g IV q12h # Gallery - This Petri dish culture plate contained a medium of kanamycin menadione blood agar, which had been inoculated with an inoculum from a cervical swab culture specimen. The culture had given rise to pigmented colonies of Prevotella melaninogenica. From Public Health Image Library (PHIL). [8] - Under a low magnification of 15x, this image depicts five colonies of Bacteroides variabilis bacteria. From Public Health Image Library (PHIL). [8] - Under a low magnification of 15x, this image depicts five colonies of Bacteroides variabilis bacteria. From Public Health Image Library (PHIL). [8] - Under a magnification of 956X, this Gram-stained photomicrograph depicts numbers of Gram-negative Bacteroides variabilis bacteria. From Public Health Image Library (PHIL). [8] - Under a low magnification of 15x, this image depicts a single colony of Bacteroides terebrans bacteria. From Public Health Image Library (PHIL). [8] - This image depicts a Petri dish culture plate containing a medium of blood agar to which menadione had been added. The dish had been inoculated with Prevotella melaninogenica, formerly known as Bacteroides melaninogenicus bacteria, which was incubated at a temperature of 35°C for a five day period. From Public Health Image Library (PHIL). [8] - This photomicrograph of an unknown sample revealed the presence of a mixed infection, which involved Gram-positive Peptostreptococcus anaerobius and P. asaccharolyticus (formerly Peptococcus asaccharolyticus), and Gram-negative Prevotella melaninogenica (formerly Bacteroides melaninogenicus), anaerobic bacteria. From Public Health Image Library (PHIL). [8] - Under a magnification of 956X, this Gram-stained photomicrograph depicts numbers of Prevotella melaninogenica, formerly known as Bacteroides melaninogenicus, bacteria, which had been grown on thioglycollate medium for a 72 hour time period. From Public Health Image Library (PHIL). [8] - This image depicts three Bacteroides bivius bacterial cultures, which had been grown on a blood agar plate (BAP) for a 48 hour time period. From Public Health Image Library (PHIL). [8] - This digitally-colorized scanning electron micrograph (SEM) depicted a Gram-negative Sebaldella termitidis bacterium. From Public Health Image Library (PHIL). [8] - This digitally-colorized scanning electron micrograph (SEM) depicted a small grouping of Gram-negative Sebaldella termitidis bacteria.From Public Health Image Library (PHIL). [8] - This digitally-colorized scanning electron micrograph (SEM) depicted a small grouping of Gram-negative Sebaldella termitidis bacteria.From Public Health Image Library (PHIL). [8] - This digitally-colorized scanning electron micrograph (SEM) depicted a Gram-negative Sebaldella termitidis bacteria, as it was about to enter the process of cell division. From Public Health Image Library (PHIL). [8] - This digitally-colorized scanning electron micrograph (SEM) depicted numbers of Gram-negative Sebaldella termitidis bacteria. From Public Health Image Library (PHIL). [8] - This digitally-colorized scanning electron micrograph (SEM) depicted two Gram-negative Sebaldella termitidis bacteria. From Public Health Image Library (PHIL). [8] - This digitally-colorized scanning electron micrograph (SEM) depicted a small grouping of Gram-negative Sebaldella termitidis bacteria. From Public Health Image Library (PHIL). [8] - This digitally-colorized scanning electron micrograph (SEM) depicted a Gram-negative Sebaldella termitidis bacterium, which was in the process of dividing into two separate organisms. From Public Health Image Library (PHIL). [8] - Magnified 1000X, this photomicrograph depicted numbers of Gram-negative Bacteroides fragilis subsp. fragilis bacteria, which had been cultured on Schaedler agar medium, and processed using the Gram-stain method. From Public Health Image Library (PHIL). [8] - his 1972 photograph revealed the morphology displayed by two colonies of Bacteroides hypermegas bacteria that had been grown on blood agar medium for 48 hours. From Public Health Image Library (PHIL). [8] - This 1972 photograph depicts two Bacteroides fragilis subsp. fragilis bacterial cultures grown on blood agar medium for 48 hours. From Public Health Image Library (PHIL). [8] - This micrograph depicts Bacteroides clostridiforme subsp. girans bacteria that had been cultured in thioglycollate broth medium for 48 hours. From Public Health Image Library (PHIL). [8] - This micrograph depicts Bacteroides fragilis subsp. thetaiota bacteria that had been cultured in blood agar medium for 48 hours. From Public Health Image Library (PHIL). [8] - This micrograph depicts Bacteroides biacutis bacteria cultured in blood agar medium for 48 hours. From Public Health Image Library (PHIL). [8] - This micrograph depicts Bacteroides biacutis bacteria cultured in blood agar medium for 48 hours. From Public Health Image Library (PHIL). [8] - This micrograph depicts Bacteroides fragilis ss. fragilis bacteria cultured in blood agar medium for 48 hours. From Public Health Image Library (PHIL). [8] - This micrograph depicts Bacteroides fragilis ss. fragilis bacteria cultured in blood agar medium for 48 hours. From Public Health Image Library (PHIL). [8] - This micrograph depicts Bacteroides fragilis subsp. distasonis bacteria cultured in blood agar medium for 48 hours. From Public Health Image Library (PHIL). [8] - This photomicrograph shows Fusobacterium novum after being cultured in a thioglycollate medium for 48 hours. From Public Health Image Library (PHIL). [8] - Magnified 1000X, this micrograph depicts Bacteroides fragilis subsp. fragilis bacteria that had been grown in Schaedler’s broth, and processed using the Gram-stain method. From Public Health Image Library (PHIL). [8] - This photomicrograph shows the bacterium Bacteroides biacutus cultured in a thioglycollate medium for 48 hours. From Public Health Image Library (PHIL). [8]	https://www.wikidoc.org/index.php/Bacteroides
003fc683d59a9af992298764b4aa232efbe26e48	wikidoc	Dimercaprol	Dimercaprol # Disclaimer WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here. # Overview Dimercaprol is a heavy metal chelator that is FDA approved for the treatment of arsenic, gold and mercury poisoning. It is indicated in acute lead poisoning when used concomitantly with Edetate Calcium Disodium Injection USP. Common adverse reactions include Blepharospasm, conjunctivitis, lacrimation, nasal discharge, tightness sensation in chest, limbs, jaw and abdomen, injection site pain, nausea, vomiting, headache, paresthesia, tremor. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) ### Mild Arsenic or Gold Poisoning - 2.5 mg/kg of body weight four times daily for two days. - Two times on the third day. - Only once daily thereafter for ten days. ### Severe Arsenic or Gold Poisoning - 3 mg/kg every four hours for two-days - Four times on the third day - Twice daily thereafter for ten days. ### Mercury poisoning - 5 mg/kg initially, followed by 2.5 mg/kg one or two times daily for ten days. ### Acute Lead Encephalopathy - 4 mg/kg body weight is given alone in the first dose - Thereafter at four-hour intervals in combination with Edetate Calcium Disodium Injection USP administered at a separate site. - For less severe poisoning the dose can be reduced to 3 mg/kg after the first dose. - Treatment is maintained for two to seven days depending on clinical response. Successful treatment depends on beginning injections at the earliest possible moment and on the use of adequate amounts at frequent intervals ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Dimercaprol in adult patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Dimercaprol in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) ### Mild Arsenic or Gold Poisoning - 2.5 mg/kg of body weight four times daily for two days. - Two times on the third day. - Only once daily thereafter for ten days. ### Severe Arsenic or Gold Poisoning - 3 mg/kg every four hours for two-days - Four times on the third day - Twice daily thereafter for ten days. ### Mercury poisoning - 5 mg/kg initially, followed by 2.5 mg/kg one or two times daily for ten days. ### Acute Lead Encephalopathy - 4 mg/kg body weight is given alone in the first dose - Thereafter at four-hour intervals in combination with Edetate Calcium Disodium Injection USP administered at a separate site. - For less severe poisoning the dose can be reduced to 3 mg/kg after the first dose. - Treatment is maintained for two to seven days depending on clinical response. Successful treatment depends on beginning injections at the earliest possible moment and on the use of adequate amounts at frequent intervals ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Dimercaprol in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Dimercaprol in pediatric patients. # Contraindications - Dimercaprol (Dimercaprol Injection USP) is contraindicated in most instances of hepatic insufficiency with the exception of postarsenical jaundice. - The drug should be discontinued or used only with extreme caution if acute renal insufficiency develops during therapy. # Warnings - There may be local pain at the site of the injection. - A reaction apparently peculiar to children is fever which may persist during therapy. - It occurs in approximately 30% of children. - A transient reduction of the percentage of polymorphonuclear leukocytes may also be observed. # Adverse Reactions ## Clinical Trials Experience ### Cardiovascular - Rise in blood pressure accompanied by tachycardia. - This rise is roughly proportional to the dose administered. Doses larger than those recommended may cause other transitory signs and symptoms in approximate order of frequency as follows: ### Gastrointestinal - Nausea - abdominal pain - in some instance, vomiting ### Nervous System - Headache - Tingling of the hands - Burning sensation in the penis ### Ophtalmology - Conjunctivitis - Lacrimation - Blepharal spasm ### Other - Rhinorrhea - Salivation - Sweating of the forehead, hands and other area - Occasional appearance of painful sterile abscesses. - Burning sensation in the lips, mouth and throat - A feeling of constriction, even pain, in the throat, chest, or hands Many of the above symptoms are accompanied by a feeling of anxiety, weakness, and unrest and often are relieved by administration of antihistamine. ## Postmarketing Experience There is limited information regarding Dimercaprol Postmarketing Experience in the drug label. # Drug Interactions There is limited information regarding Dimercaprol Drug Interactions in the drug label. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): C Animal reproduction studies have not been conducted with dimercaprol. It is also not known whether dimercaprol can cause fetal harm when administered to a pregnant woman, or can affect reproduction capacity. dimercaprol should be given to a pregnant woman only if clearly needed. It is not known whether this drug is excreted in human milk. However, because many drugs are excreted in human milk, caution should be exercised when dimercaprol is administered to a nursing woman. Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Dimercaprol in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Dimercaprol during labor and delivery. ### Nursing Mothers There is no FDA guidance on the use of Dimercaprol in women who are nursing. ### Pediatric Use There is no FDA guidance on the use of Dimercaprol in pediatric settings. ### Geriatic Use There is no FDA guidance on the use of Dimercaprol in geriatric settings. ### Gender There is no FDA guidance on the use of Dimercaprol with respect to specific gender populations. ### Race There is no FDA guidance on the use of Dimercaprol with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Dimercaprol in patients with renal impairment. ### Hepatic Impairment There is no FDA guidance on the use of Dimercaprol in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Dimercaprol in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Dimercaprol in patients who are immunocompromised. # Administration and Monitoring ### Administration - Intramuscular ### Monitoring There is limited information regarding Dimercaprol Monitoring in the drug label. # IV Compatibility There is limited information regarding the compatibility of Dimercaprol and IV administrations. # Overdosage - Dosage exceeding 5 mg/kg will usually be followed by vomiting, convulsions and stupor, beginning within 30 minutes and subsiding within 6 hours following injection. # Pharmacology ## Mechanism of Action - The sulfhydryl groups of dimercaprol form complexes with certain heavy metals thus preventing or reversing the metallic binding of sulfhydryl-containing enzymes. - The complex is excreted. - The sustained presence of dimercaprol promotes continued excretion of the metallic poisons - arsenic, gold and mercury. - It is also used in combination with Edetate Calcium Disodium Injection USP to promote the excretion of lead. ## Structure ## Pharmacodynamics There is limited information regarding Dimercaprol Pharmacodynamics in the drug label. ## Pharmacokinetics There is limited information regarding Dimercaprol Pharmacokinetics in the drug label. ## Nonclinical Toxicology There is limited information regarding Dimercaprol Nonclinical Toxicology in the drug label. # Clinical Studies There is limited information regarding Dimercaprol Clinical Studies in the drug label. # How Supplied - 3 mL (100 mg/mL) ampules, box of 10 (NDC 17478-526-03). ## Storage - Store at 20° to 25°C (68° to 77°F) # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information There is limited information regarding Dimercaprol Patient Counseling Information in the drug label. # Precautions with Alcohol Alcohol-Dimercaprol interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - Bal In Oil # Look-Alike Drug Names There is limited information regarding Dimercaprol Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	Dimercaprol Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Stefano Giannoni [2] # Disclaimer WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here. # Overview Dimercaprol is a heavy metal chelator that is FDA approved for the treatment of arsenic, gold and mercury poisoning. It is indicated in acute lead poisoning when used concomitantly with Edetate Calcium Disodium Injection USP. Common adverse reactions include Blepharospasm, conjunctivitis, lacrimation, nasal discharge, tightness sensation in chest, limbs, jaw and abdomen, injection site pain, nausea, vomiting, headache, paresthesia, tremor. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) ### Mild Arsenic or Gold Poisoning - 2.5 mg/kg of body weight four times daily for two days. - Two times on the third day. - Only once daily thereafter for ten days. ### Severe Arsenic or Gold Poisoning - 3 mg/kg every four hours for two-days - Four times on the third day - Twice daily thereafter for ten days. ### Mercury poisoning - 5 mg/kg initially, followed by 2.5 mg/kg one or two times daily for ten days. ### Acute Lead Encephalopathy - 4 mg/kg body weight is given alone in the first dose - Thereafter at four-hour intervals in combination with Edetate Calcium Disodium Injection USP administered at a separate site. - For less severe poisoning the dose can be reduced to 3 mg/kg after the first dose. - Treatment is maintained for two to seven days depending on clinical response. Successful treatment depends on beginning injections at the earliest possible moment and on the use of adequate amounts at frequent intervals ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Dimercaprol in adult patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Dimercaprol in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) ### Mild Arsenic or Gold Poisoning - 2.5 mg/kg of body weight four times daily for two days. - Two times on the third day. - Only once daily thereafter for ten days. ### Severe Arsenic or Gold Poisoning - 3 mg/kg every four hours for two-days - Four times on the third day - Twice daily thereafter for ten days. ### Mercury poisoning - 5 mg/kg initially, followed by 2.5 mg/kg one or two times daily for ten days. ### Acute Lead Encephalopathy - 4 mg/kg body weight is given alone in the first dose - Thereafter at four-hour intervals in combination with Edetate Calcium Disodium Injection USP administered at a separate site. - For less severe poisoning the dose can be reduced to 3 mg/kg after the first dose. - Treatment is maintained for two to seven days depending on clinical response. Successful treatment depends on beginning injections at the earliest possible moment and on the use of adequate amounts at frequent intervals ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Dimercaprol in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Dimercaprol in pediatric patients. # Contraindications - Dimercaprol (Dimercaprol Injection USP) is contraindicated in most instances of hepatic insufficiency with the exception of postarsenical jaundice. - The drug should be discontinued or used only with extreme caution if acute renal insufficiency develops during therapy. # Warnings - There may be local pain at the site of the injection. - A reaction apparently peculiar to children is fever which may persist during therapy. - It occurs in approximately 30% of children. - A transient reduction of the percentage of polymorphonuclear leukocytes may also be observed. # Adverse Reactions ## Clinical Trials Experience ### Cardiovascular - Rise in blood pressure accompanied by tachycardia. - This rise is roughly proportional to the dose administered. Doses larger than those recommended may cause other transitory signs and symptoms in approximate order of frequency as follows: ### Gastrointestinal - Nausea - abdominal pain - in some instance, vomiting ### Nervous System - Headache - Tingling of the hands - Burning sensation in the penis ### Ophtalmology - Conjunctivitis - Lacrimation - Blepharal spasm ### Other - Rhinorrhea - Salivation - Sweating of the forehead, hands and other area - Occasional appearance of painful sterile abscesses. - Burning sensation in the lips, mouth and throat - A feeling of constriction, even pain, in the throat, chest, or hands Many of the above symptoms are accompanied by a feeling of anxiety, weakness, and unrest and often are relieved by administration of antihistamine. ## Postmarketing Experience There is limited information regarding Dimercaprol Postmarketing Experience in the drug label. # Drug Interactions There is limited information regarding Dimercaprol Drug Interactions in the drug label. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): C Animal reproduction studies have not been conducted with dimercaprol. It is also not known whether dimercaprol can cause fetal harm when administered to a pregnant woman, or can affect reproduction capacity. dimercaprol should be given to a pregnant woman only if clearly needed. It is not known whether this drug is excreted in human milk. However, because many drugs are excreted in human milk, caution should be exercised when dimercaprol is administered to a nursing woman. Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Dimercaprol in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Dimercaprol during labor and delivery. ### Nursing Mothers There is no FDA guidance on the use of Dimercaprol in women who are nursing. ### Pediatric Use There is no FDA guidance on the use of Dimercaprol in pediatric settings. ### Geriatic Use There is no FDA guidance on the use of Dimercaprol in geriatric settings. ### Gender There is no FDA guidance on the use of Dimercaprol with respect to specific gender populations. ### Race There is no FDA guidance on the use of Dimercaprol with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Dimercaprol in patients with renal impairment. ### Hepatic Impairment There is no FDA guidance on the use of Dimercaprol in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Dimercaprol in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Dimercaprol in patients who are immunocompromised. # Administration and Monitoring ### Administration - Intramuscular ### Monitoring There is limited information regarding Dimercaprol Monitoring in the drug label. # IV Compatibility There is limited information regarding the compatibility of Dimercaprol and IV administrations. # Overdosage - Dosage exceeding 5 mg/kg will usually be followed by vomiting, convulsions and stupor, beginning within 30 minutes and subsiding within 6 hours following injection. # Pharmacology ## Mechanism of Action - The sulfhydryl groups of dimercaprol form complexes with certain heavy metals thus preventing or reversing the metallic binding of sulfhydryl-containing enzymes. - The complex is excreted. - The sustained presence of dimercaprol promotes continued excretion of the metallic poisons - arsenic, gold and mercury. - It is also used in combination with Edetate Calcium Disodium Injection USP to promote the excretion of lead. ## Structure ## Pharmacodynamics There is limited information regarding Dimercaprol Pharmacodynamics in the drug label. ## Pharmacokinetics There is limited information regarding Dimercaprol Pharmacokinetics in the drug label. ## Nonclinical Toxicology There is limited information regarding Dimercaprol Nonclinical Toxicology in the drug label. # Clinical Studies There is limited information regarding Dimercaprol Clinical Studies in the drug label. # How Supplied - 3 mL (100 mg/mL) ampules, box of 10 (NDC 17478-526-03). ## Storage - Store at 20° to 25°C (68° to 77°F) # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information There is limited information regarding Dimercaprol Patient Counseling Information in the drug label. # Precautions with Alcohol Alcohol-Dimercaprol interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - Bal In Oil[1] # Look-Alike Drug Names There is limited information regarding Dimercaprol Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	https://www.wikidoc.org/index.php/Bal_In_Oil
f6ee75e93c582952c59f6ab312be0f8dfc76ab24	wikidoc	Balsalazide	Balsalazide # Disclaimer WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here. # Overview Balsalazide is a locally acting aminosalicylate that is FDA approved for the treatment of mildly to moderately active ulcerative colitis in adults. Common adverse reactions include headache, abdominal pain, diarrhea, nausea, vomiting, respiratory infection, and arthralgia. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - For treatment of active ulcerative colitis in adult patients, the usual dose is three 750 mg balsalazide disodium capsules to be taken 3 times a day (6.75 g per day) for up to 8 weeks. Some patients in the adult clinical trials required treatment for up to 12 weeks. - Balsalazide disodium capsules may also be administered by carefully opening the capsule and sprinkling the capsule contents on applesauce. The entire drug/applesauce mixture should be swallowed immediately; the contents may be chewed, if necessary, since contents of balsalazide disodium capsules are NOT coated beads/granules. Patients should be instructed not to store any drug/applesauce mixture for future use. - If the capsules are opened for sprinkling, color variation of the powder inside the capsules ranges from orange to yellow and is expected due to color variation of the active pharmaceutical ingredient. - Teeth and/or tongue staining may occur in some patients who use balsalazide disodium capsules in sprinkle form with food. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Balsalazide in adult patients. ### Non–Guideline-Supported Use - Doses of 2 grams (g) daily to 6 g daily. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) - Pediatric use information is protected by marketing exclusivity. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Balsalazide in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Balsalazide in pediatric patients. # Contraindications - Patients with hypersensitivity to salicylates or to any of the components of balsalazide disodium capsules or balsalazide metabolites. Hypersensitivity reactions may include, but are not limited to the following: anaphylaxis, bronchospasm, and skin reaction. # Warnings ### Precautions - Exacerbations of Ulcerative Colitis - In the adult clinical trials, 3 out of 259 patients reported exacerbation of the symptoms of ulcerative colitis. - Observe patients closely for worsening of these symptoms while on treatment. - Pyloric Stenosis - Patients with pyloric stenosis may have prolonged gastric retention of balsalazide disodium capsules. - Renal - Renal toxicity has been observed in animals and patients given other mesalamine products. Therefore, caution should be exercised when administering balsalazide capsules to patients with known renal dysfunction or a history of renal disease. # Adverse Reactions ## Clinical Trials Experience - During clinical development, 259 adult patients with active ulcerative colitis were exposed to 6.75 g/day balsalazide in 4 controlled trials. - In the 4 controlled clinical trials patients receiving a balsalazide dose of 6.75 g/day most frequently reported the following adverse reactions: headache (8%), abdominal pain (6%), diarrhea (5%), nausea (5%), vomiting (4%), respiratory infection (4%), and arthralgia (4%). Withdrawal from therapy due to adverse reactions was comparable among patients on balsalazide and placebo. - Adverse reactions reported by 1% or more of patients who participated in the four well controlled, Phase 3 trials are presented by treatment group (Table 1). - The number of placebo patients (35), however, is too small for valid comparisons. Some adverse reactions, such as abdominal pain, fatigue, and nausea were reported more frequently in women than in men. Abdominal pain, rectal bleeding, and anemia can be part of the clinical presentation of ulcerative colitis. ## Postmarketing Experience - The following adverse reactions have been identified during post-approval use of balsalazide in clinical practice: - myocarditis, pericarditis, vasculitis, pruritus, pleural effusion, pneumonia (with and without eosinophilia), alveolitis, renal failure, interstitial nephritis, pancreatitis, and alopecia. - Because these reactions are reported voluntarily from a population of unknown size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. These adverse reactions have been chosen for inclusion due to a combination of seriousness, frequency of reporting, or potential causal connection to balsalazide. - Hepatic - Postmarketing adverse reactions of hepatotoxicity have been reported for products which contain (or are metabolized to) mesalamine, including elevated liver function tests (SGOT/AST, SGPT/ALT, GGT, LDH, alkaline phosphatase, bilirubin), jaundice, cholestatic jaundice, cirrhosis, hepatocellular damage including liver necrosis and liver failure. Some of these cases were fatal; however, no fatalities associated with these adverse reactions were reported in balsalazide clinical trials. One case of Kawasaki-like syndrome which included hepatic function changes was also reported, however, this adverse reaction was not reported in balsalazide clinical trials. # Drug Interactions - In an in vitro study using human liver microsomes, balsalazide and its metabolites were not shown to inhibit the major CYP enzymes evaluated (CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4/5). Therefore, balsalazide and its metabolites are not expected to inhibit the metabolism of other drugs which are substrates of CYP1A2, CYP2C9, CYP2C19, CYP2D6, or CYP3A4/5. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): - Pregnancy Category B - Reproduction studies were performed in rats and rabbits at oral doses up to 2 g/kg/day, 2.4 and 4.7 times the recommended human dose based on body surface area for the rat and rabbit, respectively, and revealed no evidence of impaired fertility or harm to the fetus due to balsalazide disodium. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed. Pregnancy Category (AUS): - Australian Drug Evaluation Committee (ADEC) Pregnancy Category There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Balsalazide in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Balsalazide during labor and delivery. ### Nursing Mothers - It is not known whether balsalazide disodium is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when balsalazide is administered to a nursing woman. ### Pediatric Use - Pediatric use information is protected by marketing exclusivity. ### Geriatic Use There is no FDA guidance on the use of Balsalazide with respect to geriatric patients. ### Gender There is no FDA guidance on the use of Balsalazide with respect to specific gender populations. ### Race There is no FDA guidance on the use of Balsalazide with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Balsalazide in patients with renal impairment. ### Hepatic Impairment There is no FDA guidance on the use of Balsalazide in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Balsalazide in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Balsalazide in patients who are immunocompromised. # Administration and Monitoring ### Administration - Oral ### Monitoring There is limited information regarding Monitoring of Balsalazide in the drug label. # IV Compatibility There is limited information regarding IV Compatibility of Balsalazide in the drug label. # Overdosage ## Acute Overdose - No case of overdose has occurred with balsalazide. A 3-year-old boy is reported to have ingested 2 g of another mesalamine product. He was treated with ipecac and activated charcoal with no adverse reactions. - If an overdose occurs with balsalazide, treatment should be supportive, with particular attention to correction of electrolyte abnormalities. ## Chronic Overdose There is limited information regarding Chronic Overdose of Balsalazide in the drug label. # Pharmacology ## Mechanism of Action - Balsalazide disodium is delivered intact to the colon where it is cleaved by bacterial azoreduction to release equimolar quantities of mesalamine, which is the therapeutically active portion of the molecule, and the 4-aminobenzoyl-β-alanine carrier moiety. The carrier moiety released when balsalazide disodium is cleaved is only minimally absorbed and is largely inert. - The mechanism of action of 5-ASA is unknown, but appears to be local to the colonic mucosa rather than systemic. Mucosal production of arachidonic acid metabolites, both through the cyclooxygenase pathways, i.e., prostanoids, and through the lipoxygenase pathways, i.e., leukotrienes and hydroxyeicosatetraenoic acids, is increased in patients with chronic inflammatory bowel disease, and it is possible that 5-ASA diminishes inflammation by blocking production of arachidonic acid metabolites in the colon. ## Structure - Each balsalazide disodium capsule, USP contains 750 mg of balsalazide disodium, a prodrug that is enzymatically cleaved in the colon to produce mesalamine (5-aminosalicylic acid or 5-ASA), an anti-inflammatory drug. Each capsule of balsalazide (750 mg) is equivalent to 267 mg of mesalamine. Balsalazide disodium has the chemical name (E)-5-carbonyl] phenyl]azo]-2-hydroxybenzoic acid, disodium salt, dihydrate. Its structural formula is: - Molecular Formula: C17H13N3O6Na22H2O - Balsalazide disodium is a stable, odorless orange to yellow microcrystalline powder. It is freely soluble in water and isotonic saline, sparingly soluble in methanol and ethanol, and practically insoluble in all other organic solvents. - Inactive Ingredients: Each hard gelatin capsule contains colloidal silicon dioxide, magnesium stearate and titanium dioxide. The capsule imprinting ink contains propylene glycol, strong ammonia solution, shellac and red iron oxide. The sodium content of each capsule is approximately 86 mg. ## Pharmacodynamics There is limited information regarding Pharmacodynamics of Balsalazide in the drug label. ## Pharmacokinetics - Balsalazide disodium capsules contain a powder of balsalazide disodium that is insoluble in acid and designed to be delivered to the colon as the intact prodrug. Upon reaching the colon, bacterial azoreductases cleave the compound to release 5-ASA, the therapeutically active portion of the molecule, and 4-aminobenzoyl-β-alanine. The 5-ASA is further metabolized to yield Nacetyl-5-aminosalicylic acid (N-Ac-5-ASA), a second key metabolite. - Absorption - The plasma pharmacokinetics of balsalazide and its key metabolites from a crossover study in healthy volunteers are summarized in Table 2. In this study, a single oral dose of balsalazide 2.25 g was administered to healthy volunteers as intact capsules (3 x 750 mg) under fasting conditions, as intact capsules (3 x 750 mg) after a high-fat meal, and unencapsulated (3 x 750 mg) as sprinkles on applesauce. - A relatively low systemic exposure was observed under all three administered conditions (fasting, fed with high-fat meal, sprinkled on applesauce), which reflects the variable, but minimal absorption of balsalazide disodium and its metabolites. The data indicate that both Cmax and AUClast were lower, while tmax was markedly prolonged, under fed (high-fat meal) compared to fasted conditions. Moreover, the data suggest that dosing balsalazide disodium as a sprinkle or as a capsule provides highly variable, but relatively similar mean pharmacokinetic parameter values. No inference can be made as to how the systemic exposure differences of balsalazide and its metabolites in this study might predict the clinical efficacy under different dosing conditions (i.e., fasted, fed with high-fat meal, or sprinkled on applesauce) since clinical efficacy after balsalazide disodium administration is presumed to be primarily due to the local effects of 5- ASA on the colonic mucosa. - In a separate study of adult patients with ulcerative colitis, who received balsalazide, 1.5 g twice daily, for over 1 year, systemic drug exposure, based on mean AUC values, was up to 60 times greater (0.008 mcghr/mL to 0.480 mcghr/mL) when compared to that obtained in healthy subjects who received the same dose. - Distribution - The binding of balsalazide to human plasma proteins was ≥99%. - Metabolism - The products of the azoreduction of this compound, 5-ASA and 4-aminobenzoyl-β-alanine, and their N-acetylated metabolites have been identified in plasma, urine and feces. - Elimination - Following single-dose administration of 2.25 g balsalazide (three 750 mg capsules) under fasting conditions in healthy subjects, mean urinary recovery of balsalazide, 5-ASA, and N-Ac-5-ASA was 0.20%, 0.22% and 10.2%, respectively. - In a multiple-dose study in healthy subjects receiving a balsalazide dose of two 750 mg capsules twice daily (3 g/day) for 10 days, mean urinary recovery of balsalazide, 5-ASA, and N-Ac-5-ASA was 0.1%, 0%, and 11.3%, respectively. During this study, subjects received their morning dose 0.5 hours after being fed a standard meal, and subjects received their evening dose 2 hours after being fed a standard meal. - In a study with 10 healthy volunteers, 65% of a single 2.25-gram dose of balsalazide was recovered as 5-ASA, 4-aminobenzoyl-β-alanine, and the N-acetylated metabolites in feces, while <1% of the dose was recovered as parent compound. - In a study that examined the disposition of balsalazide in patients who were taking 3 to 6 g of balsalazide daily for more than 1 year and who were in remission from ulcerative colitis, less than 1% of an oral dose was recovered as intact balsalazide in the urine. Less than 4% of the dose was recovered as 5-ASA, while virtually no 4-aminobenzoyl-β-alanine was detected in urine. The mean urinary recovery of N-Ac-5-ASA and N-acetyl-4-aminobenzoyl-β-alanine comprised <16% and <12% of the balsalazide dose, respectively. No fecal recovery studies were performed in this population. - All pharmacokinetic studies with balsalazide are characterized by large variability in the plasma concentration versus time profiles for balsalazide and its metabolites, thus half-life estimates of these analytes are indeterminate. ## Nonclinical Toxicology - In a 24-month rat (Sprague Dawley) carcinogenicity study, oral (dietary) balsalazide disodium at doses up to 2 g/kg/day was not tumorigenic. For a 50-kg person of average height this dose represents 2.4 times the recommended human dose on a body surface area basis. Balsalazide disodium was not genotoxic in the following in vitro or in vivo tests: Ames test, human lymphocyte chromosomal aberration test, and mouse lymphoma cell (L5178Y/TK+/-) forward mutation test, or mouse micronucleus test. However, it was genotoxic in the in vitro Chinese hamster lung cell (CH V79/HGPRT) forward mutation test. - 4-aminobenzoyl-β-alanine, a metabolite of balsalazide disodium, was not genotoxic in the Ames test and the mouse lymphoma cell (L5178Y/TK+/-) forward mutation test but was positive in the human lymphocyte chromosomal aberration test. N-acetyl-4-aminobenzoyl-β-alanine, a conjugated metabolite of balsalazide disodium, was not genotoxic in Ames test, the mouse lymphoma cell (L5178Y/TK+/-) forward mutation test, or the human lymphocyte chromosomal aberration test. Balsalazide disodium at oral doses up to 2 g/kg/day, 2.4 times the recommended human dose based on body surface area, was found to have no effect on fertility and reproductive performance in rats. - Renal Toxicity - In animal studies conducted at doses up to 2000 mg/kg (approximately 21 times the recommended 6.75 g/day dose on a mg/kg basis for a 70 kg person), balsalazide demonstrated no nephrotoxic effects in rats or dogs. - Overdosage - A single oral dose of balsalazide disodium at 5 g/kg or 4-aminobenzoyl-β-alanine, a metabolite of balsalazide disodium, at 1 g/kg was non-lethal in mice and rats. No symptoms of acute toxicity were seen at these doses. # Clinical Studies - Two randomized, double-blind studies were conducted in adults. In the first trial, 103 patients with active mild-to-moderate ulcerative colitis with sigmoidoscopy findings of friable or spontaneously bleeding mucosa were randomized and treated with balsalazide 6.75 g/day or balsalazide 2.25 g/day. The primary efficacy endpoint was reduction of rectal bleeding and improvement of at least one of the other assessed symptoms (stool frequency, patient functional assessment, abdominal pain, sigmoidoscopic grade, and physician’s global assessment ). Outcome assessment for rectal bleeding at each interim period (week 2, 4, and 8) encompassed a 4-day period (96 hours). Results demonstrated a statistically significant difference between high and low doses of balsalazide (Figure 1). # How Supplied - Balsalazide Disodium Capsules, USP are available as white, opaque capsules imprinted “APO B750” in red ink. - Balsalazide Disodium Capsules, USP are supplied as follows: - Unit dose packages of 20 (5 x 4) NDC 68084-799-32 - Storage - Store at 20º to 25ºC (68º to 77ºF); excursions permitted between 15º and 30ºC (59º and 86ºF). ## Storage There is limited information regarding Balsalazide Storage in the drug label. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information - Important Precautions Regarding Balsalazide Disodium Capsules, USP - Instruct patients not to take balsalazide if they have a hypersensitivity to salicylates (e.g., aspirin). - Patients should be instructed to contact their health care provider under the following circumstances: - - If they experience a worsening of their ulcerative colitis symptoms. - If they are diagnosed with pyloric stenosis, because balsalazide disodium capsules may be slow to pass through their digestive tract. - If they are diagnosed with renal dysfunction. Damage to the kidney has been observed in people given medications similar to balsalazide. - - If they experience a worsening of their ulcerative colitis symptoms. - - If they are diagnosed with pyloric stenosis, because balsalazide disodium capsules may be slow to pass through their digestive tract. - - If they are diagnosed with renal dysfunction. Damage to the kidney has been observed in people given medications similar to balsalazide. - What Patients Should Know About Adverse Reactions - In adult clinical trials the most common adverse reactions were headache, abdominal pain, diarrhea, nausea, vomiting, respiratory infection, and arthralgia. - Inform patients that this listing of adverse reactions is not complete and not all adverse reactions can be anticipated. If appropriate, a more comprehensive list of adverse reactions can be discussed with patients. - What Patients Should Know About Taking Balsalazide Disodium Capsules with Other Medication - Based upon limited studies conducted in a test tube, balsalazide is not believed to interfere with other drugs - by preventing how the liver functions. However, as the studies were limited in scope, you should always - consult your doctor and discuss potential interactions prior to initiating any new drug. # Precautions with Alcohol - Alcohol-Balsalazide interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - BALSALAZIDE DISODIUM® # Look-Alike Drug Names There is limited information regarding Balsalazide Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	Balsalazide Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Vignesh Ponnusamy, M.B.B.S. [2] # Disclaimer WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here. # Overview Balsalazide is a locally acting aminosalicylate that is FDA approved for the treatment of mildly to moderately active ulcerative colitis in adults. Common adverse reactions include headache, abdominal pain, diarrhea, nausea, vomiting, respiratory infection, and arthralgia. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - For treatment of active ulcerative colitis in adult patients, the usual dose is three 750 mg balsalazide disodium capsules to be taken 3 times a day (6.75 g per day) for up to 8 weeks. Some patients in the adult clinical trials required treatment for up to 12 weeks. - Balsalazide disodium capsules may also be administered by carefully opening the capsule and sprinkling the capsule contents on applesauce. The entire drug/applesauce mixture should be swallowed immediately; the contents may be chewed, if necessary, since contents of balsalazide disodium capsules are NOT coated beads/granules. Patients should be instructed not to store any drug/applesauce mixture for future use. - If the capsules are opened for sprinkling, color variation of the powder inside the capsules ranges from orange to yellow and is expected due to color variation of the active pharmaceutical ingredient. - Teeth and/or tongue staining may occur in some patients who use balsalazide disodium capsules in sprinkle form with food. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Balsalazide in adult patients. ### Non–Guideline-Supported Use - Doses of 2 grams (g) daily to 6 g daily.[1] # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) - Pediatric use information is protected by marketing exclusivity. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Balsalazide in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Balsalazide in pediatric patients. # Contraindications - Patients with hypersensitivity to salicylates or to any of the components of balsalazide disodium capsules or balsalazide metabolites. Hypersensitivity reactions may include, but are not limited to the following: anaphylaxis, bronchospasm, and skin reaction. # Warnings ### Precautions - Exacerbations of Ulcerative Colitis - In the adult clinical trials, 3 out of 259 patients reported exacerbation of the symptoms of ulcerative colitis. - Observe patients closely for worsening of these symptoms while on treatment. - Pyloric Stenosis - Patients with pyloric stenosis may have prolonged gastric retention of balsalazide disodium capsules. - Renal - Renal toxicity has been observed in animals and patients given other mesalamine products. Therefore, caution should be exercised when administering balsalazide capsules to patients with known renal dysfunction or a history of renal disease. # Adverse Reactions ## Clinical Trials Experience - During clinical development, 259 adult patients with active ulcerative colitis were exposed to 6.75 g/day balsalazide in 4 controlled trials. - In the 4 controlled clinical trials patients receiving a balsalazide dose of 6.75 g/day most frequently reported the following adverse reactions: headache (8%), abdominal pain (6%), diarrhea (5%), nausea (5%), vomiting (4%), respiratory infection (4%), and arthralgia (4%). Withdrawal from therapy due to adverse reactions was comparable among patients on balsalazide and placebo. - Adverse reactions reported by 1% or more of patients who participated in the four well controlled, Phase 3 trials are presented by treatment group (Table 1). - The number of placebo patients (35), however, is too small for valid comparisons. Some adverse reactions, such as abdominal pain, fatigue, and nausea were reported more frequently in women than in men. Abdominal pain, rectal bleeding, and anemia can be part of the clinical presentation of ulcerative colitis. ## Postmarketing Experience - The following adverse reactions have been identified during post-approval use of balsalazide in clinical practice: - myocarditis, pericarditis, vasculitis, pruritus, pleural effusion, pneumonia (with and without eosinophilia), alveolitis, renal failure, interstitial nephritis, pancreatitis, and alopecia. - Because these reactions are reported voluntarily from a population of unknown size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. These adverse reactions have been chosen for inclusion due to a combination of seriousness, frequency of reporting, or potential causal connection to balsalazide. - Hepatic - Postmarketing adverse reactions of hepatotoxicity have been reported for products which contain (or are metabolized to) mesalamine, including elevated liver function tests (SGOT/AST, SGPT/ALT, GGT, LDH, alkaline phosphatase, bilirubin), jaundice, cholestatic jaundice, cirrhosis, hepatocellular damage including liver necrosis and liver failure. Some of these cases were fatal; however, no fatalities associated with these adverse reactions were reported in balsalazide clinical trials. One case of Kawasaki-like syndrome which included hepatic function changes was also reported, however, this adverse reaction was not reported in balsalazide clinical trials. # Drug Interactions - In an in vitro study using human liver microsomes, balsalazide and its metabolites [5-aminosalicylic acid (5-ASA), N-acetyl-5-aminosalicylic acid (N-Ac-5-ASA), 4-aminobenzoyl-β-alanine (4-ABA) and N-acetyl-4-aminobenzoyl-β–alanine (N-Ac-4-ABA)] were not shown to inhibit the major CYP enzymes evaluated (CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4/5). Therefore, balsalazide and its metabolites are not expected to inhibit the metabolism of other drugs which are substrates of CYP1A2, CYP2C9, CYP2C19, CYP2D6, or CYP3A4/5. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): - Pregnancy Category B - Reproduction studies were performed in rats and rabbits at oral doses up to 2 g/kg/day, 2.4 and 4.7 times the recommended human dose based on body surface area for the rat and rabbit, respectively, and revealed no evidence of impaired fertility or harm to the fetus due to balsalazide disodium. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed. Pregnancy Category (AUS): - Australian Drug Evaluation Committee (ADEC) Pregnancy Category There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Balsalazide in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Balsalazide during labor and delivery. ### Nursing Mothers - It is not known whether balsalazide disodium is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when balsalazide is administered to a nursing woman. ### Pediatric Use - Pediatric use information is protected by marketing exclusivity. ### Geriatic Use There is no FDA guidance on the use of Balsalazide with respect to geriatric patients. ### Gender There is no FDA guidance on the use of Balsalazide with respect to specific gender populations. ### Race There is no FDA guidance on the use of Balsalazide with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Balsalazide in patients with renal impairment. ### Hepatic Impairment There is no FDA guidance on the use of Balsalazide in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Balsalazide in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Balsalazide in patients who are immunocompromised. # Administration and Monitoring ### Administration - Oral ### Monitoring There is limited information regarding Monitoring of Balsalazide in the drug label. # IV Compatibility There is limited information regarding IV Compatibility of Balsalazide in the drug label. # Overdosage ## Acute Overdose - No case of overdose has occurred with balsalazide. A 3-year-old boy is reported to have ingested 2 g of another mesalamine product. He was treated with ipecac and activated charcoal with no adverse reactions. - If an overdose occurs with balsalazide, treatment should be supportive, with particular attention to correction of electrolyte abnormalities. ## Chronic Overdose There is limited information regarding Chronic Overdose of Balsalazide in the drug label. # Pharmacology ## Mechanism of Action - Balsalazide disodium is delivered intact to the colon where it is cleaved by bacterial azoreduction to release equimolar quantities of mesalamine, which is the therapeutically active portion of the molecule, and the 4-aminobenzoyl-β-alanine carrier moiety. The carrier moiety released when balsalazide disodium is cleaved is only minimally absorbed and is largely inert. - The mechanism of action of 5-ASA is unknown, but appears to be local to the colonic mucosa rather than systemic. Mucosal production of arachidonic acid metabolites, both through the cyclooxygenase pathways, i.e., prostanoids, and through the lipoxygenase pathways, i.e., leukotrienes and hydroxyeicosatetraenoic acids, is increased in patients with chronic inflammatory bowel disease, and it is possible that 5-ASA diminishes inflammation by blocking production of arachidonic acid metabolites in the colon. ## Structure - Each balsalazide disodium capsule, USP contains 750 mg of balsalazide disodium, a prodrug that is enzymatically cleaved in the colon to produce mesalamine (5-aminosalicylic acid or 5-ASA), an anti-inflammatory drug. Each capsule of balsalazide (750 mg) is equivalent to 267 mg of mesalamine. Balsalazide disodium has the chemical name (E)-5-[-4-[(2- carboxyethyl)amino]carbonyl] phenyl]azo]-2-hydroxybenzoic acid, disodium salt, dihydrate. Its structural formula is: - Molecular Formula: C17H13N3O6Na2•2H2O - Balsalazide disodium is a stable, odorless orange to yellow microcrystalline powder. It is freely soluble in water and isotonic saline, sparingly soluble in methanol and ethanol, and practically insoluble in all other organic solvents. - Inactive Ingredients: Each hard gelatin capsule contains colloidal silicon dioxide, magnesium stearate and titanium dioxide. The capsule imprinting ink contains propylene glycol, strong ammonia solution, shellac and red iron oxide. The sodium content of each capsule is approximately 86 mg. ## Pharmacodynamics There is limited information regarding Pharmacodynamics of Balsalazide in the drug label. ## Pharmacokinetics - Balsalazide disodium capsules contain a powder of balsalazide disodium that is insoluble in acid and designed to be delivered to the colon as the intact prodrug. Upon reaching the colon, bacterial azoreductases cleave the compound to release 5-ASA, the therapeutically active portion of the molecule, and 4-aminobenzoyl-β-alanine. The 5-ASA is further metabolized to yield Nacetyl-5-aminosalicylic acid (N-Ac-5-ASA), a second key metabolite. - Absorption - The plasma pharmacokinetics of balsalazide and its key metabolites from a crossover study in healthy volunteers are summarized in Table 2. In this study, a single oral dose of balsalazide 2.25 g was administered to healthy volunteers as intact capsules (3 x 750 mg) under fasting conditions, as intact capsules (3 x 750 mg) after a high-fat meal, and unencapsulated (3 x 750 mg) as sprinkles on applesauce. - A relatively low systemic exposure was observed under all three administered conditions (fasting, fed with high-fat meal, sprinkled on applesauce), which reflects the variable, but minimal absorption of balsalazide disodium and its metabolites. The data indicate that both Cmax and AUClast were lower, while tmax was markedly prolonged, under fed (high-fat meal) compared to fasted conditions. Moreover, the data suggest that dosing balsalazide disodium as a sprinkle or as a capsule provides highly variable, but relatively similar mean pharmacokinetic parameter values. No inference can be made as to how the systemic exposure differences of balsalazide and its metabolites in this study might predict the clinical efficacy under different dosing conditions (i.e., fasted, fed with high-fat meal, or sprinkled on applesauce) since clinical efficacy after balsalazide disodium administration is presumed to be primarily due to the local effects of 5- ASA on the colonic mucosa. - In a separate study of adult patients with ulcerative colitis, who received balsalazide, 1.5 g twice daily, for over 1 year, systemic drug exposure, based on mean AUC values, was up to 60 times greater (0.008 mcg•hr/mL to 0.480 mcg•hr/mL) when compared to that obtained in healthy subjects who received the same dose. - Distribution - The binding of balsalazide to human plasma proteins was ≥99%. - Metabolism - The products of the azoreduction of this compound, 5-ASA and 4-aminobenzoyl-β-alanine, and their N-acetylated metabolites have been identified in plasma, urine and feces. - Elimination - Following single-dose administration of 2.25 g balsalazide (three 750 mg capsules) under fasting conditions in healthy subjects, mean urinary recovery of balsalazide, 5-ASA, and N-Ac-5-ASA was 0.20%, 0.22% and 10.2%, respectively. - In a multiple-dose study in healthy subjects receiving a balsalazide dose of two 750 mg capsules twice daily (3 g/day) for 10 days, mean urinary recovery of balsalazide, 5-ASA, and N-Ac-5-ASA was 0.1%, 0%, and 11.3%, respectively. During this study, subjects received their morning dose 0.5 hours after being fed a standard meal, and subjects received their evening dose 2 hours after being fed a standard meal. - In a study with 10 healthy volunteers, 65% of a single 2.25-gram dose of balsalazide was recovered as 5-ASA, 4-aminobenzoyl-β-alanine, and the N-acetylated metabolites in feces, while <1% of the dose was recovered as parent compound. - In a study that examined the disposition of balsalazide in patients who were taking 3 to 6 g of balsalazide daily for more than 1 year and who were in remission from ulcerative colitis, less than 1% of an oral dose was recovered as intact balsalazide in the urine. Less than 4% of the dose was recovered as 5-ASA, while virtually no 4-aminobenzoyl-β-alanine was detected in urine. The mean urinary recovery of N-Ac-5-ASA and N-acetyl-4-aminobenzoyl-β-alanine comprised <16% and <12% of the balsalazide dose, respectively. No fecal recovery studies were performed in this population. - All pharmacokinetic studies with balsalazide are characterized by large variability in the plasma concentration versus time profiles for balsalazide and its metabolites, thus half-life estimates of these analytes are indeterminate. ## Nonclinical Toxicology - In a 24-month rat (Sprague Dawley) carcinogenicity study, oral (dietary) balsalazide disodium at doses up to 2 g/kg/day was not tumorigenic. For a 50-kg person of average height this dose represents 2.4 times the recommended human dose on a body surface area basis. Balsalazide disodium was not genotoxic in the following in vitro or in vivo tests: Ames test, human lymphocyte chromosomal aberration test, and mouse lymphoma cell (L5178Y/TK+/-) forward mutation test, or mouse micronucleus test. However, it was genotoxic in the in vitro Chinese hamster lung cell (CH V79/HGPRT) forward mutation test. - 4-aminobenzoyl-β-alanine, a metabolite of balsalazide disodium, was not genotoxic in the Ames test and the mouse lymphoma cell (L5178Y/TK+/-) forward mutation test but was positive in the human lymphocyte chromosomal aberration test. N-acetyl-4-aminobenzoyl-β-alanine, a conjugated metabolite of balsalazide disodium, was not genotoxic in Ames test, the mouse lymphoma cell (L5178Y/TK+/-) forward mutation test, or the human lymphocyte chromosomal aberration test. Balsalazide disodium at oral doses up to 2 g/kg/day, 2.4 times the recommended human dose based on body surface area, was found to have no effect on fertility and reproductive performance in rats. - Renal Toxicity - In animal studies conducted at doses up to 2000 mg/kg (approximately 21 times the recommended 6.75 g/day dose on a mg/kg basis for a 70 kg person), balsalazide demonstrated no nephrotoxic effects in rats or dogs. - Overdosage - A single oral dose of balsalazide disodium at 5 g/kg or 4-aminobenzoyl-β-alanine, a metabolite of balsalazide disodium, at 1 g/kg was non-lethal in mice and rats. No symptoms of acute toxicity were seen at these doses. # Clinical Studies - Two randomized, double-blind studies were conducted in adults. In the first trial, 103 patients with active mild-to-moderate ulcerative colitis with sigmoidoscopy findings of friable or spontaneously bleeding mucosa were randomized and treated with balsalazide 6.75 g/day or balsalazide 2.25 g/day. The primary efficacy endpoint was reduction of rectal bleeding and improvement of at least one of the other assessed symptoms (stool frequency, patient functional assessment, abdominal pain, sigmoidoscopic grade, and physician’s global assessment [PGA]). Outcome assessment for rectal bleeding at each interim period (week 2, 4, and 8) encompassed a 4-day period (96 hours). Results demonstrated a statistically significant difference between high and low doses of balsalazide (Figure 1). # How Supplied - Balsalazide Disodium Capsules, USP are available as white, opaque capsules imprinted “APO B750” in red ink. - Balsalazide Disodium Capsules, USP are supplied as follows: - Unit dose packages of 20 (5 x 4) NDC 68084-799-32 - Storage - Store at 20º to 25ºC (68º to 77ºF); excursions permitted between 15º and 30ºC (59º and 86ºF). ## Storage There is limited information regarding Balsalazide Storage in the drug label. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information - Important Precautions Regarding Balsalazide Disodium Capsules, USP - Instruct patients not to take balsalazide if they have a hypersensitivity to salicylates (e.g., aspirin). - Patients should be instructed to contact their health care provider under the following circumstances: - - If they experience a worsening of their ulcerative colitis symptoms. - If they are diagnosed with pyloric stenosis, because balsalazide disodium capsules may be slow to pass through their digestive tract. - If they are diagnosed with renal dysfunction. Damage to the kidney has been observed in people given medications similar to balsalazide. - - If they experience a worsening of their ulcerative colitis symptoms. - - If they are diagnosed with pyloric stenosis, because balsalazide disodium capsules may be slow to pass through their digestive tract. - - If they are diagnosed with renal dysfunction. Damage to the kidney has been observed in people given medications similar to balsalazide. - What Patients Should Know About Adverse Reactions - In adult clinical trials the most common adverse reactions were headache, abdominal pain, diarrhea, nausea, vomiting, respiratory infection, and arthralgia. - Inform patients that this listing of adverse reactions is not complete and not all adverse reactions can be anticipated. If appropriate, a more comprehensive list of adverse reactions can be discussed with patients. - What Patients Should Know About Taking Balsalazide Disodium Capsules with Other Medication - Based upon limited studies conducted in a test tube, balsalazide is not believed to interfere with other drugs - by preventing how the liver functions. However, as the studies were limited in scope, you should always - consult your doctor and discuss potential interactions prior to initiating any new drug. # Precautions with Alcohol - Alcohol-Balsalazide interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - BALSALAZIDE DISODIUM®[2] # Look-Alike Drug Names There is limited information regarding Balsalazide Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	https://www.wikidoc.org/index.php/Balsalazide
d8d5fa7e20841dca36b726384c42ede87708a1ee	wikidoc	Erdafitinib	Erdafitinib # Disclaimer WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here. # Overview Erdafitinib is a kinase inhibitor that is FDA approved for the treatment of adult patients with locally advanced or metastatic urothelial carcinoma (mUC), that has susceptible FGFR3 or FGFR2 genetic alterations and progressed during or following at least one line of prior platinum-containing chemotherapy including within 12 months of neoadjuvant or adjuvant platinum-containing chemotherapy. Common adverse reactions include phosphate increased, stomatitis, fatigue, creatinine increased, diarrhea, dry mouth, onycholysis, alanine aminotransferase increased, alkaline phosphatase increased, sodium decreased, decreased appetite, albumin decreased, dysgeusia, hemoglobin decreased, dry skin, aspartate aminotransferase increased, magnesium decreased, dry eye, alopecia, palmar-plantar erythrodysesthesia syndrome, constipation, phosphate decreased, abdominal pain, calcium increased, nausea, and musculoskeletal pain. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) Indication - Erdafitinib is indicated for the treatment of adult patients with locally advanced or metastatic urothelial carcinoma that has: susceptible FGFR3 or FGFR2 genetic alterations, and progressed during or following at least one line of prior platinum-containing chemotherapy, including within 12 months of neoadjuvant or adjuvant platinum-containing chemotherapy - susceptible FGFR3 or FGFR2 genetic alterations, and - progressed during or following at least one line of prior platinum-containing chemotherapy, including within 12 months of neoadjuvant or adjuvant platinum-containing chemotherapy - Select patients for therapy based on an FDA-approved companion diagnostic for erdafitinib. - This indication is approved under accelerated approval based on tumor response rate. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials. Dosage - Recommended initial dosage: 8 mg orally once daily with a dose increase to 9 mg daily if criteria are met. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding erdafitinib Off-Label Guideline-Supported Use and Dosage (Adult) in the drug label. ### Non–Guideline-Supported Use There is limited information regarding erdafitinib Off-Label Non-Guideline-Supported Use and Dosage (Adult) in the drug label. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) Safety and effectiveness of erdafitinib in pediatric patients have not been established. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding erdafitinib Off-Label Guideline-Supported Use and Dosage (Pediatric) in the drug label. ### Non–Guideline-Supported Use There is limited information regarding erdafitinib Off-Label Non-Guideline-Supported Use and Dosage (Pediatric) in the drug label. # Contraindications None. # Warnings - Erdafitinib can cause ocular disorders, including central serous retinopathy/retinal pigment epithelial detachment (CSR/RPED) resulting in visual field defect. - CSR/RPED was reported in 25% of patients treated with erdafitinib, with a median time to first onset of 50 days. Grade 3 CSR/RPED, involving central field of vision, was reported in 3% of patients. CSR/RPED resolved in 13% of patients and was ongoing in 13% of patients at the study cutoff. CSR/RPED led to dose interruptions and reductions in 9% and 14% of patients, respectively and 3% of patients discontinued erdafitinib. - Dry eye symptoms occurred in 28% of patients during treatment with erdafitinib and were Grade 3 in 6% of patients. All patients should receive dry eye prophylaxis with ocular demulcents as needed. - Perform monthly ophthalmological examinations during the first 4 months of treatment and every 3 months afterwards, and urgently at any time for visual symptoms. Ophthalmological examination should include assessment of visual acuity, slit lamp examination, fundoscopy, and optical coherence tomography. - Withhold erdafitinib when CSR occurs and permanently discontinue if it does not resolve within 4 weeks or if Grade 4 in severity. For ocular adverse reactions, follow the dose modification guidelines. - Increases in phosphate levels are a pharmacodynamic effect of erdafitinib. Hyperphosphatemia was reported as adverse reaction in 76% of patients treated with erdafitinib. The median onset time for any grade event of hyperphosphatemia was 20 days (range: 8 –116) after initiating erdafitinib. Thirty-two percent of patients received phosphate binders during treatment with erdafitinib. - Monitor for hyperphosphatemia and follow the dose modification guidelines when required. - Based on the mechanism of action and findings in animal reproduction studies, erdafitinib can cause fetal harm when administered to a pregnant woman. In an embryo-fetal toxicity study, oral administration of erdafitinib to pregnant rats during the period of organogenesis caused malformations and embryo-fetal death at maternal exposures that were less than the human exposures at the maximum human recommended dose based on area under the curve (AUC). Advise pregnant women of the potential risk to the fetus. Advise female patients of reproductive potential to use effective contraception during treatment with erdafitinib and for one month after the last dose. Advise male patients with female partners of reproductive potential to use effective contraception during treatment with erdafitinib and for one month after the last dose. # Adverse Reactions ## Clinical Trials Experience - Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. - The safety of erdafitinib was evaluated in the BLC2001 study that included 87 patients with locally advanced or metastatic urothelial carcinoma which had susceptible FGFR3 or FGFR2 genetic alterations, and which progressed during or following at least one line of prior chemotherapy including within 12 months of neoadjuvant or adjuvant chemotherapy. Patients were treated with erdafitinib at 8 mg orally once daily; with a dose increase to 9 mg in patients with phosphate levels <5.5 mg/dL on Day 14 of Cycle 1. Median duration of treatment was 5.3 months (range: 0 to 17 months). - The most common adverse reactions (ARs) including laboratory abnormalities (≥20%) were phosphate increased, stomatitis, fatigue, creatinine increased, diarrhea, dry mouth, onycholysis, alanine aminotransferase increased, alkaline phosphatase increased, sodium decreased, decreased appetite, albumin decreased, dysgeusia, hemoglobin decreased, dry skin, aspartate aminotransferase increased, magnesium decreased, dry eye, alopecia, palmar-plantar erythrodysesthesia syndrome, constipation, phosphate decreased, abdominal pain, calcium increased, nausea, and musculoskeletal pain. The most common Grade 3 or greater ARs (>1%) were stomatitis, nail dystrophy, palmar-plantar erythrodysesthesia syndrome, paronychia, nail disorder, keratitis, onycholysis, and hyperphosphatemia. - An adverse reaction with a fatal outcome in 1% of patients was acute myocardial infarction. - Serious adverse reactions occurred in 41% of patients including eye disorders (10%). - Permanent discontinuation due to an adverse reaction occurred in 13% of patients. The most frequent reasons for permanent discontinuation included eye disorders (6%). - Dosage interruptions occurred in 68% of patients. The most frequent adverse reactions requiring dosage interruption included hyperphosphatemia (24%), stomatitis (17%), eye disorders (17%), and palmar-plantar erythro-dysaesthesia syndrome (8%). - Dose reductions occurred in 53% of patients. The most frequent adverse reactions for dose reductions included eye disorders (23%), stomatitis (15%), hyperphosphatemia (7%), palmar-plantar erythro-dysaesthesia syndrome (7%), paronychia (7%), and nail dystrophy (6%). - Table 3 presents ARs reported in ≥10% of patients treated with erdafitinib at 8 mg once daily. ## Postmarketing Experience There is limited information regarding Erdafitinib Postmarketing Experience in the drug label. # Drug Interactions - Table 5 summarizes drug interactions that affect the exposure of erdafitinib or serum phosphate level and their clinical management. - Table 6 summarizes the effect of erdafitinib on other drugs and their clinical management. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): Risk Summary - Based on the mechanism of action and findings in animal reproduction studies, erdafitinib can cause fetal harm when administered to a pregnant woman. There are no available data on erdafitinib use in pregnant women to inform a drug-associated risk. Oral administration of erdafitinib to pregnant rats during organogenesis caused malformations and embryo-fetal death at maternal exposures that were less than the human exposures at the maximum recommended human dose based on AUC. Advise pregnant women and females of reproductive potential of the potential risk to the fetus. - The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2–4% and 15–20%, respectively. Animal Data - In an embryo-fetal toxicity study, erdafitinib was orally administered to pregnant rats during the period of organogenesis. Doses ≥4mg/kg/day (at total maternal exposures <0.1% of total human exposures at the maximum recommended human dose based on AUC) produced embryo-fetal death, major blood vessel malformations and other vascular anomalies, limb malformations (ectrodactyly, absent or misshapen long bones), an increased incidence of skeletal anomalies in multiple bones (vertebrae, sternebrae, ribs), and decreased fetal weight. Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Erdafitinib in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Erdafitinib during labor and delivery. ### Nursing Mothers - There are no data on the presence of erdafitinib in human milk, or the effects of erdafitinib on the breastfed child, or on milk production. Because of the potential for serious adverse reactions from erdafitinib in a breastfed child, advise lactating women not to breastfeed during treatment with erdafitinib and for one month following the last dose. ### Pediatric Use - Safety and effectiveness of erdafitinib in pediatric patients have not been established. - In 4 and 13-week repeat-dose toxicology studies in rats and dogs, toxicities in bone and teeth were observed at an exposure less than the human exposure (AUC) at the maximum recommended human dose. Chondroid dysplasia/metaplasia were reported in multiple bones in both species, and tooth abnormalities included abnormal/irregular denting in rats and dogs and discoloration and degeneration of odontoblasts in rats. ### Geriatic Use - Of the 416 patients treated with erdafitinib in clinical studies, 45% were 65 years of age or older, and 12% were 75 years of age or older. No overall differences in safety or effectiveness were observed between these patients and younger patients ### Gender There is no FDA guidance on the use of Erdafitinib with respect to specific gender populations. ### Race There is no FDA guidance on the use of Erdafitinib with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Erdafitinib in patients with renal impairment. ### Hepatic Impairment There is no FDA guidance on the use of Erdafitinib in patients with hepatic impairment. ### Females of Reproductive Potential and Males Pregnancy Testing - Pregnancy testing is recommended for females of reproductive potential prior to initiating treatment with erdafitinib. Contraception (Females) - Erdafitinib can cause fetal harm when administered to a pregnant woman. Advise females of reproductive potential to use effective contraception during treatment with erdafitinib and for one month after the last dose. Contraception (Males) - Advise male patients with female partners of reproductive potential to use effective contraception during treatment with erdafitinib and for one month after the last dose. Infertility - Based on findings from animal studies, erdafitinib may impair fertility in females of reproductive potential. ### Immunocompromised Patients There is no FDA guidance one the use of Erdafitinib in patients who are immunocompromised. ### CYP2C9 Poor Metabolizers - CYP2C93/3 Genotype: Erdafitinib plasma concentrations were predicted to be higher in patients with the CYP2C93/3 genotype. Monitor for increased adverse reactions in patients who are known or suspected to have CYP2C93/3 genotype. # Administration and Monitoring ### Administration - Select patients for the treatment of locally advanced or metastatic urothelial carcinoma with erdafitinib based on the presence of susceptible FGFR genetic alterations in tumor specimens as detected by an FDA-approved companion diagnostic. - Information on FDA-approved tests for the detection of FGFR genetic alterations in urothelial cancer is available at: . - The recommended starting dose of erdafitinib is 8 mg (two 4 mg tablets) orally once daily, with a dose increase to 9 mg (three 3 mg tablets) once daily based on serum phosphate (PO4) levels and tolerability at 14 to 21 days. - Swallow tablets whole with or without food. If vomiting occurs any time after taking erdafitinib, the next dose should be taken the next day. Treatment should continue until disease progression or unacceptable toxicity occurs. - If a dose of erdafitinib is missed, it can be taken as soon as possible on the same day. Resume the regular daily dose schedule for erdafitinib the next day. Extra tablets should not be taken to make up for the missed dose. Dose Increase based on Serum Phosphate Levels - Assess serum phosphate levels 14 to 21 days after initiating treatment. Increase the dose of erdafitinib to 9 mg once daily if serum phosphate level is < 5.5 mg/dL and there are no ocular disorders or Grade 2 or greater adverse reactions. Monitor phosphate levels monthly for hyperphosphatemia. - The recommended dose modifications for adverse reactions are listed in Table 1. - Table 2 summarizes recommendations for dose interruption, reduction, or discontinuation of erdafitinib in the management of specific adverse reactions. ### Monitoring There is limited information regarding Erdafitinib Monitoring in the drug label. # IV Compatibility There is limited information regarding the compatibility of Erdafitinib and IV administrations. # Overdosage There is limited information regarding Erdafitinib overdosage. If you suspect drug poisoning or overdose, please contact the National Poison Help hotline (1-800-222-1222) immediately. # Pharmacology ## Mechanism of Action - Erdafitinib is a kinase inhibitor that binds to and inhibits enzymatic activity of FGFR1, FGFR2, FGFR3 and FGFR4 based on in vitro data. Erdafitinib also binds to RET, CSF1R, PDGFRA, PDGFRB, FLT4, KIT, and VEGFR2. Erdafitinib inhibited FGFR phosphorylation and signaling and decreased cell viability in cell lines expressing FGFR genetic alterations, including point mutations, amplifications, and fusions. Erdafitinib demonstrated antitumor activity in FGFR-expressing cell lines and xenograft models derived from tumor types, including bladder cancer. ## Structure ## Pharmacodynamics Cardiac Electrophysiology - Based on evaluation of QTc interval in an open-label, dose escalation and dose expansion study in 187 patients with cancer, erdafitinib had no large effect (i.e., > 20 ms) on the QTc interval. Serum Phosphate - Erdafitinib increased serum phosphate level as a consequence of FGFR inhibition. Erdafitinib should be increased to the maximum recommended dose to achieve target serum phosphate levels of 5.5–7.0 mg/dL in early cycles with continuous daily dosing. - In erdafitinib clinical trials, the use of drugs which can increase serum phosphate levels, such as potassium phosphate supplements, vitamin D supplements, antacids, phosphate-containing enemas or laxatives, and medications known to have phosphate as an excipient were prohibited unless no alternatives exist. To manage phosphate elevation, phosphate binders were permitted. Avoid concomitant use with agents that can alter serum phosphate levels before the initial dose increase period based on serum phosphate levels. ## Pharmacokinetics - Following administration of 8 mg once daily, the mean (coefficient of variation ) erdafitinib steady-state maximum observed plasma concentration (Cmax), area under the curve (AUCtau), and minimum observed plasma concentration (Cmin) were 1,399 ng/mL (51%), 29,268 ng∙h/mL (60%), and 936 ng/mL (65%), respectively. - Following single and repeat once daily dosing, erdafitinib exposure (maximum observed plasma concentration and area under the plasma concentration time curve ) increased proportionally across the dose range of 0.5 to 12 mg (0.06 to 1.3 times the maximum approved recommended dose). Steady state was achieved after 2 weeks with once daily dosing and the mean accumulation ratio was 4-fold. Absorption - Median time to achieve peak plasma concentration (tmax) was 2.5 hours (range: 2 to 6 hours). Effect of Food - No clinically meaningful differences with erdafitinib pharmacokinetics were observed following administration of a high-fat and high-calorie meal (800 calories to 1,000 calories with approximately 50% of total caloric content of the meal from fat) in healthy subjects. Distribution - The mean apparent volume of distribution of erdafitinib was 29 L in patients. - Erdafitinib protein binding was 99.8% in patients, primarily to alpha-1-acid glycoprotein. Elimination - The mean total apparent clearance (CL/F) of erdafitinib was 0.362 L/h in patients. - The mean effective half-life of erdafitinib was 59 hours in patients. Metabolism - Erdafitinib is primarily metabolized by CYP2C9 and CYP3A4. The contribution of CYP2C9 and CYP3A4 in the total clearance of erdafitinib is estimated to be 39% and 20% respectively. Unchanged erdafitinib was the major drug-related moiety in plasma, there were no circulating metabolites. Excretion - Following a single oral dose of radiolabeled erdafitinib, approximately 69% of the dose was recovered in feces (19% as unchanged) and 19% in urine (13% as unchanged). Specific Populations - No clinically meaningful trends in the pharmacokinetics of erdafitinib were observed based on age (21–88 years), sex, race, body weight (36–132 kg), mild (eGFR 60 to 89 mL/min/1.73 m2) or moderate (eGFR 30–59 mL/min/1.73 m2) renal impairment or mild hepatic impairment (total bilirubin ≤ ULN and AST > ULN, or total bilirubin > 1.0–1.5 × ULN and any AST). - The pharmacokinetics of erdafitinib in patients with severe renal impairment, renal impairment requiring dialysis, moderate or severe hepatic impairment is unknown. Drug Interaction Studies - Clinical Studies and Model-Based Approaches Strong CYP2C9 Inhibitors: Erdafitinib mean ratios (90% CI) for Cmax and AUCinf were 121% (99.9, 147) and 148% (120, 182), respectively, when co-administered with fluconazole, a strong CYP2C9 inhibitor and moderate CYP3A4 inhibitor, relative to erdafitinib alone. - Erdafitinib mean ratios (90% CI) for Cmax and AUCinf were 121% (99.9, 147) and 148% (120, 182), respectively, when co-administered with fluconazole, a strong CYP2C9 inhibitor and moderate CYP3A4 inhibitor, relative to erdafitinib alone. - Strong CYP3A4 Inhibitors: Erdafitinib mean ratios (90% CI) for Cmax and AUCinf were 105% (86.7, 127) and 134% (109, 164), respectively, when co-administered with itraconazole (a strong CYP3A4 inhibitor and P-gp inhibitor) relative to erdafitinib alone. - Erdafitinib mean ratios (90% CI) for Cmax and AUCinf were 105% (86.7, 127) and 134% (109, 164), respectively, when co-administered with itraconazole (a strong CYP3A4 inhibitor and P-gp inhibitor) relative to erdafitinib alone. - Strong CYP3A4/2C9 Inducers: Simulations suggested that rifampicin (a strong CYP3A4/2C9 inducer) may significantly decrease erdafitinib Cmax and AUC. - Simulations suggested that rifampicin (a strong CYP3A4/2C9 inducer) may significantly decrease erdafitinib Cmax and AUC. In Vitro Studies - CYP Substrates: Erdafitinib is a time dependent inhibitor and inducer of CYP3A4. The effect of erdafitinib on a sensitive CYP3A4 substrate is unknown. Erdafitinib is not an inhibitor of other major CYP isozymes at clinically relevant concentrations. - Erdafitinib is a time dependent inhibitor and inducer of CYP3A4. The effect of erdafitinib on a sensitive CYP3A4 substrate is unknown. Erdafitinib is not an inhibitor of other major CYP isozymes at clinically relevant concentrations. - Transporters: Erdafitinib is a substrate and inhibitor of P-gp. P-gp inhibitors are not expected to affect erdafitinib exposure to a clinically relevant extent. Erdafitinib is an inhibitor of OCT2. Erdafitinib does not inhibit BCRP, OATP1B, OATP1B3, OAT1, OAT3, OCT1, MATE-1, or MATE-2K at clinically relevant concentrations. - Erdafitinib is a substrate and inhibitor of P-gp. P-gp inhibitors are not expected to affect erdafitinib exposure to a clinically relevant extent. Erdafitinib is an inhibitor of OCT2. - Erdafitinib does not inhibit BCRP, OATP1B, OATP1B3, OAT1, OAT3, OCT1, MATE-1, or MATE-2K at clinically relevant concentrations. - Acid-Lowering Agents: Erdafitinib has adequate solubility across the pH range of 1 to 7.4. Acid-lowering agents (e.g., antacids, H2-antagonists, proton pump inhibitors) are not expected to affect the bioavailability of erdafitinib. - Erdafitinib has adequate solubility across the pH range of 1 to 7.4. Acid-lowering agents (e.g., antacids, H2-antagonists, proton pump inhibitors) are not expected to affect the bioavailability of erdafitinib. ## Nonclinical Toxicology - Carcinogenicity studies have not been conducted with erdafitinib. - Erdafitinib was not mutagenic in a bacterial reverse mutation (Ames) assay and was not clastogenic in an in vitro micronucleus or an in vivo rat bone marrow micronucleus assay. - Fertility studies in animals have not been conducted with erdafitinib. In the 3-month repeat-dose toxicity study, erdafitinib showed effects on female reproductive organs (necrosis of the ovarian corpora lutea) in rats at an exposure less than the human exposure (AUC) at maximum recommended human dose. # Clinical Studies - Study BLC2001 (NCT02365597) was a multicenter, open-label, single-arm study to evaluate the efficacy and safety of erdafitinib in patients with locally advanced or metastatic urothelial carcinoma(mUC). Fibroblast growth factor receptor (FGFR) mutation status for screening and enrollment of patients was determined by a clinical trial assay (CTA). The efficacy population consists of a cohort of eighty-seven patients who were enrolled in this study with disease that had progressed on or after at least one prior chemotherapy and that had at least 1 of the following genetic alterations: FGFR3 gene mutations (R248C, S249C, G370C, Y373C) or FGFR gene fusions (FGFR3-TACC3, FGFR3-BAIAP2L1, FGFR2-BICC1, FGFR2-CASP7), as determined by the CTA performed at a central laboratory. Tumor samples from 69 patients were tested retrospectively by the QIAGEN therascreen® FGFR RGQ RT-PCR Kit, which is the FDA-approved test for selection of patients with mUC for erdafitinib. - Patients received a starting dose of erdafitinib at 8 mg once daily with a dose increase to 9 mg once daily in patients whose serum phosphate levels were below the target of 5.5 mg/dL between days 14 and 17; a dose increase occurred in 41% of patients. Erdafitinib was administered until disease progression or unacceptable toxicity. The major efficacy outcome measures were objective response rate (ORR) and duration of response (DoR), as determined by blinded independent review committee (BIRC) according to RECIST v1.1. - The median age was 67 years (range: 36 to 87 years), 79% were male, and 74% were Caucasian. Most patients (92%) had a baseline Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. Sixty-six percent of patients had visceral metastases. Eighty-four (97%) patients received at least one of cisplatin or carboplatin previously. Fifty-six percent of patients only received prior cisplatin-based regimens, 29% received only prior carboplatin-based regimens, and 10% received both cisplatin and carboplatin-based regimens. Three (3%) patients had disease progression following prior platinum-containing neoadjuvant or adjuvant therapy only. Twenty-four percent of patients had been treated with prior anti PD-L1/PD-1 therapy. - Efficacy results are summarized in Table 7 and Table 8. Overall response rate was 32.2%. Responders included patients who had previously not responded to anti PD-L1/PD-1 therapy. # How Supplied - Erdafitinib tablets are available in the strengths and packages listed below: 3 mg tablets: Yellow, round biconvex, film-coated, debossed with "3" on one side and "EF" on the other side. Bottle of 56-tablets with child resistant closure Bottle of 84-tablets with child resistant closure 4 mg tablets: Orange, round biconvex, film-coated, debossed with "4" on one side and "EF" on the other side. Bottle of 28-tablets with child resistant closure Bottle of 56-tablets with child resistant closure 5 mg tablets: Brown, round biconvex, film-coated, debossed with "5" on one side and "EF" on the other side. Bottle of 28-tablets with child resistant closure - 3 mg tablets: Yellow, round biconvex, film-coated, debossed with "3" on one side and "EF" on the other side. Bottle of 56-tablets with child resistant closure Bottle of 84-tablets with child resistant closure - Bottle of 56-tablets with child resistant closure - Bottle of 84-tablets with child resistant closure - 4 mg tablets: Orange, round biconvex, film-coated, debossed with "4" on one side and "EF" on the other side. Bottle of 28-tablets with child resistant closure Bottle of 56-tablets with child resistant closure - Bottle of 28-tablets with child resistant closure - Bottle of 56-tablets with child resistant closure - 5 mg tablets: Brown, round biconvex, film-coated, debossed with "5" on one side and "EF" on the other side. Bottle of 28-tablets with child resistant closure - Bottle of 28-tablets with child resistant closure ## Storage - Store at 20°C–25°C (68°F–77°F); excursions permitted between 15°C and 30°C (59°F and 86°F). # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information - Advise the patient to read the FDA-approved patient labeling (Patient Information). - FGFR genetic alterations: Advise patients that evidence of a susceptible FGFR3 or FGFR2 mutation or gene fusion within the tumor specimen is necessary to identify patients for whom treatment is indicated - Ocular disorders: Advise patients to contact their healthcare provider if they experience any visual changes. In order to prevent or treat dry eyes, advise patients to use artificial tear substitutes, hydrating or lubricating eye gels or ointments frequently, at least every 2 hours during waking hours. - Skin, mucous or nail disorders: Advise patients to contact their healthcare provider if they experience progressive or intolerable skin, mucous or nail disorders. - Hyperphosphatemia: Advise patients that their healthcare provider will assess their serum phosphate level between 14 and 21 days of initiating treatment and will adjust the dose if needed. During this initial phosphate-assessment period, advise patients to avoid concomitant use with agents that can alter serum phosphate levels. Advise patients that, after the initial phosphate assessment period, monthly phosphate level monitoring for hyperphosphatemia should be performed during treatment with erdafitinib. - Drug Interactions: Advise patients to inform their healthcare providers of all concomitant medications, including prescription medicines, over-the-counter drugs, and herbal products. - Dosing Instructions: Instruct patients to swallow the tablets whole once daily with or without food. If vomiting occurs any time after taking erdafitinib, advise patients to take the next dose the next day. - Missed dose: If a dose is missed, advise patients to take the missed as soon as possible. Resume the regular daily dose schedule for erdafitinib the next day. Extra tablets should not be taken to make up for the missed dose. - Embryo-Fetal Toxicity: Advise pregnant women and females of reproductive potential of the potential risk to the fetus. Advise females to inform their healthcare providers of a known or suspected pregnancy. Advise female patients of reproductive potential to use effective contraception during treatment and for one month after the last dose of erdafitinib. Advise male patients with female partners of reproductive potential to use effective contraception during treatment and for one month after the last dose of erdafitinib. - Lactation: Advise females not to breastfeed during treatment with erdafitinib and for one month after the last dose. # Precautions with Alcohol Alcohol-Erdafitinib interaction has not been established. Talk to your doctor regarding the effects of taking alcohol with this medication. # Brand Names Balversa # Look-Alike Drug Names There is limited information regarding Erdafitinib Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	Erdafitinib Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Zach Leibowitz [2] # Disclaimer WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here. # Overview Erdafitinib is a kinase inhibitor that is FDA approved for the treatment of adult patients with locally advanced or metastatic urothelial carcinoma (mUC), that has susceptible FGFR3 or FGFR2 genetic alterations and progressed during or following at least one line of prior platinum-containing chemotherapy including within 12 months of neoadjuvant or adjuvant platinum-containing chemotherapy. Common adverse reactions include phosphate increased, stomatitis, fatigue, creatinine increased, diarrhea, dry mouth, onycholysis, alanine aminotransferase increased, alkaline phosphatase increased, sodium decreased, decreased appetite, albumin decreased, dysgeusia, hemoglobin decreased, dry skin, aspartate aminotransferase increased, magnesium decreased, dry eye, alopecia, palmar-plantar erythrodysesthesia syndrome, constipation, phosphate decreased, abdominal pain, calcium increased, nausea, and musculoskeletal pain. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) Indication - Erdafitinib is indicated for the treatment of adult patients with locally advanced or metastatic urothelial carcinoma that has: susceptible FGFR3 or FGFR2 genetic alterations, and progressed during or following at least one line of prior platinum-containing chemotherapy, including within 12 months of neoadjuvant or adjuvant platinum-containing chemotherapy - susceptible FGFR3 or FGFR2 genetic alterations, and - progressed during or following at least one line of prior platinum-containing chemotherapy, including within 12 months of neoadjuvant or adjuvant platinum-containing chemotherapy - Select patients for therapy based on an FDA-approved companion diagnostic for erdafitinib. - This indication is approved under accelerated approval based on tumor response rate. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials. Dosage - Recommended initial dosage: 8 mg orally once daily with a dose increase to 9 mg daily if criteria are met. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding erdafitinib Off-Label Guideline-Supported Use and Dosage (Adult) in the drug label. ### Non–Guideline-Supported Use There is limited information regarding erdafitinib Off-Label Non-Guideline-Supported Use and Dosage (Adult) in the drug label. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) Safety and effectiveness of erdafitinib in pediatric patients have not been established. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding erdafitinib Off-Label Guideline-Supported Use and Dosage (Pediatric) in the drug label. ### Non–Guideline-Supported Use There is limited information regarding erdafitinib Off-Label Non-Guideline-Supported Use and Dosage (Pediatric) in the drug label. # Contraindications None. # Warnings - Erdafitinib can cause ocular disorders, including central serous retinopathy/retinal pigment epithelial detachment (CSR/RPED) resulting in visual field defect. - CSR/RPED was reported in 25% of patients treated with erdafitinib, with a median time to first onset of 50 days. Grade 3 CSR/RPED, involving central field of vision, was reported in 3% of patients. CSR/RPED resolved in 13% of patients and was ongoing in 13% of patients at the study cutoff. CSR/RPED led to dose interruptions and reductions in 9% and 14% of patients, respectively and 3% of patients discontinued erdafitinib. - Dry eye symptoms occurred in 28% of patients during treatment with erdafitinib and were Grade 3 in 6% of patients. All patients should receive dry eye prophylaxis with ocular demulcents as needed. - Perform monthly ophthalmological examinations during the first 4 months of treatment and every 3 months afterwards, and urgently at any time for visual symptoms. Ophthalmological examination should include assessment of visual acuity, slit lamp examination, fundoscopy, and optical coherence tomography. - Withhold erdafitinib when CSR occurs and permanently discontinue if it does not resolve within 4 weeks or if Grade 4 in severity. For ocular adverse reactions, follow the dose modification guidelines. - Increases in phosphate levels are a pharmacodynamic effect of erdafitinib. Hyperphosphatemia was reported as adverse reaction in 76% of patients treated with erdafitinib. The median onset time for any grade event of hyperphosphatemia was 20 days (range: 8 –116) after initiating erdafitinib. Thirty-two percent of patients received phosphate binders during treatment with erdafitinib. - Monitor for hyperphosphatemia and follow the dose modification guidelines when required. - Based on the mechanism of action and findings in animal reproduction studies, erdafitinib can cause fetal harm when administered to a pregnant woman. In an embryo-fetal toxicity study, oral administration of erdafitinib to pregnant rats during the period of organogenesis caused malformations and embryo-fetal death at maternal exposures that were less than the human exposures at the maximum human recommended dose based on area under the curve (AUC). Advise pregnant women of the potential risk to the fetus. Advise female patients of reproductive potential to use effective contraception during treatment with erdafitinib and for one month after the last dose. Advise male patients with female partners of reproductive potential to use effective contraception during treatment with erdafitinib and for one month after the last dose. # Adverse Reactions ## Clinical Trials Experience - Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. - The safety of erdafitinib was evaluated in the BLC2001 study that included 87 patients with locally advanced or metastatic urothelial carcinoma which had susceptible FGFR3 or FGFR2 genetic alterations, and which progressed during or following at least one line of prior chemotherapy including within 12 months of neoadjuvant or adjuvant chemotherapy. Patients were treated with erdafitinib at 8 mg orally once daily; with a dose increase to 9 mg in patients with phosphate levels <5.5 mg/dL on Day 14 of Cycle 1. Median duration of treatment was 5.3 months (range: 0 to 17 months). - The most common adverse reactions (ARs) including laboratory abnormalities (≥20%) were phosphate increased, stomatitis, fatigue, creatinine increased, diarrhea, dry mouth, onycholysis, alanine aminotransferase increased, alkaline phosphatase increased, sodium decreased, decreased appetite, albumin decreased, dysgeusia, hemoglobin decreased, dry skin, aspartate aminotransferase increased, magnesium decreased, dry eye, alopecia, palmar-plantar erythrodysesthesia syndrome, constipation, phosphate decreased, abdominal pain, calcium increased, nausea, and musculoskeletal pain. The most common Grade 3 or greater ARs (>1%) were stomatitis, nail dystrophy, palmar-plantar erythrodysesthesia syndrome, paronychia, nail disorder, keratitis, onycholysis, and hyperphosphatemia. - An adverse reaction with a fatal outcome in 1% of patients was acute myocardial infarction. - Serious adverse reactions occurred in 41% of patients including eye disorders (10%). - Permanent discontinuation due to an adverse reaction occurred in 13% of patients. The most frequent reasons for permanent discontinuation included eye disorders (6%). - Dosage interruptions occurred in 68% of patients. The most frequent adverse reactions requiring dosage interruption included hyperphosphatemia (24%), stomatitis (17%), eye disorders (17%), and palmar-plantar erythro-dysaesthesia syndrome (8%). - Dose reductions occurred in 53% of patients. The most frequent adverse reactions for dose reductions included eye disorders (23%), stomatitis (15%), hyperphosphatemia (7%), palmar-plantar erythro-dysaesthesia syndrome (7%), paronychia (7%), and nail dystrophy (6%). - Table 3 presents ARs reported in ≥10% of patients treated with erdafitinib at 8 mg once daily. ## Postmarketing Experience There is limited information regarding Erdafitinib Postmarketing Experience in the drug label. # Drug Interactions - Table 5 summarizes drug interactions that affect the exposure of erdafitinib or serum phosphate level and their clinical management. - Table 6 summarizes the effect of erdafitinib on other drugs and their clinical management. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): Risk Summary - Based on the mechanism of action and findings in animal reproduction studies, erdafitinib can cause fetal harm when administered to a pregnant woman. There are no available data on erdafitinib use in pregnant women to inform a drug-associated risk. Oral administration of erdafitinib to pregnant rats during organogenesis caused malformations and embryo-fetal death at maternal exposures that were less than the human exposures at the maximum recommended human dose based on AUC. Advise pregnant women and females of reproductive potential of the potential risk to the fetus. - The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2–4% and 15–20%, respectively. Animal Data - In an embryo-fetal toxicity study, erdafitinib was orally administered to pregnant rats during the period of organogenesis. Doses ≥4mg/kg/day (at total maternal exposures <0.1% of total human exposures at the maximum recommended human dose based on AUC) produced embryo-fetal death, major blood vessel malformations and other vascular anomalies, limb malformations (ectrodactyly, absent or misshapen long bones), an increased incidence of skeletal anomalies in multiple bones (vertebrae, sternebrae, ribs), and decreased fetal weight. Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Erdafitinib in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Erdafitinib during labor and delivery. ### Nursing Mothers - There are no data on the presence of erdafitinib in human milk, or the effects of erdafitinib on the breastfed child, or on milk production. Because of the potential for serious adverse reactions from erdafitinib in a breastfed child, advise lactating women not to breastfeed during treatment with erdafitinib and for one month following the last dose. ### Pediatric Use - Safety and effectiveness of erdafitinib in pediatric patients have not been established. - In 4 and 13-week repeat-dose toxicology studies in rats and dogs, toxicities in bone and teeth were observed at an exposure less than the human exposure (AUC) at the maximum recommended human dose. Chondroid dysplasia/metaplasia were reported in multiple bones in both species, and tooth abnormalities included abnormal/irregular denting in rats and dogs and discoloration and degeneration of odontoblasts in rats. ### Geriatic Use - Of the 416 patients treated with erdafitinib in clinical studies, 45% were 65 years of age or older, and 12% were 75 years of age or older. No overall differences in safety or effectiveness were observed between these patients and younger patients ### Gender There is no FDA guidance on the use of Erdafitinib with respect to specific gender populations. ### Race There is no FDA guidance on the use of Erdafitinib with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Erdafitinib in patients with renal impairment. ### Hepatic Impairment There is no FDA guidance on the use of Erdafitinib in patients with hepatic impairment. ### Females of Reproductive Potential and Males Pregnancy Testing - Pregnancy testing is recommended for females of reproductive potential prior to initiating treatment with erdafitinib. Contraception (Females) - Erdafitinib can cause fetal harm when administered to a pregnant woman. Advise females of reproductive potential to use effective contraception during treatment with erdafitinib and for one month after the last dose. Contraception (Males) - Advise male patients with female partners of reproductive potential to use effective contraception during treatment with erdafitinib and for one month after the last dose. Infertility - Based on findings from animal studies, erdafitinib may impair fertility in females of reproductive potential. ### Immunocompromised Patients There is no FDA guidance one the use of Erdafitinib in patients who are immunocompromised. ### CYP2C9 Poor Metabolizers - CYP2C93/3 Genotype: Erdafitinib plasma concentrations were predicted to be higher in patients with the CYP2C93/3 genotype. Monitor for increased adverse reactions in patients who are known or suspected to have CYP2C93/3 genotype. # Administration and Monitoring ### Administration - Select patients for the treatment of locally advanced or metastatic urothelial carcinoma with erdafitinib based on the presence of susceptible FGFR genetic alterations in tumor specimens as detected by an FDA-approved companion diagnostic. - Information on FDA-approved tests for the detection of FGFR genetic alterations in urothelial cancer is available at: http://www.fda.gov/CompanionDiagnostics. - The recommended starting dose of erdafitinib is 8 mg (two 4 mg tablets) orally once daily, with a dose increase to 9 mg (three 3 mg tablets) once daily based on serum phosphate (PO4) levels and tolerability at 14 to 21 days. - Swallow tablets whole with or without food. If vomiting occurs any time after taking erdafitinib, the next dose should be taken the next day. Treatment should continue until disease progression or unacceptable toxicity occurs. - If a dose of erdafitinib is missed, it can be taken as soon as possible on the same day. Resume the regular daily dose schedule for erdafitinib the next day. Extra tablets should not be taken to make up for the missed dose. Dose Increase based on Serum Phosphate Levels - Assess serum phosphate levels 14 to 21 days after initiating treatment. Increase the dose of erdafitinib to 9 mg once daily if serum phosphate level is < 5.5 mg/dL and there are no ocular disorders or Grade 2 or greater adverse reactions. Monitor phosphate levels monthly for hyperphosphatemia. - The recommended dose modifications for adverse reactions are listed in Table 1. - Table 2 summarizes recommendations for dose interruption, reduction, or discontinuation of erdafitinib in the management of specific adverse reactions. ### Monitoring There is limited information regarding Erdafitinib Monitoring in the drug label. # IV Compatibility There is limited information regarding the compatibility of Erdafitinib and IV administrations. # Overdosage There is limited information regarding Erdafitinib overdosage. If you suspect drug poisoning or overdose, please contact the National Poison Help hotline (1-800-222-1222) immediately. # Pharmacology ## Mechanism of Action - Erdafitinib is a kinase inhibitor that binds to and inhibits enzymatic activity of FGFR1, FGFR2, FGFR3 and FGFR4 based on in vitro data. Erdafitinib also binds to RET, CSF1R, PDGFRA, PDGFRB, FLT4, KIT, and VEGFR2. Erdafitinib inhibited FGFR phosphorylation and signaling and decreased cell viability in cell lines expressing FGFR genetic alterations, including point mutations, amplifications, and fusions. Erdafitinib demonstrated antitumor activity in FGFR-expressing cell lines and xenograft models derived from tumor types, including bladder cancer. ## Structure ## Pharmacodynamics Cardiac Electrophysiology - Based on evaluation of QTc interval in an open-label, dose escalation and dose expansion study in 187 patients with cancer, erdafitinib had no large effect (i.e., > 20 ms) on the QTc interval. Serum Phosphate - Erdafitinib increased serum phosphate level as a consequence of FGFR inhibition. Erdafitinib should be increased to the maximum recommended dose to achieve target serum phosphate levels of 5.5–7.0 mg/dL in early cycles with continuous daily dosing. - In erdafitinib clinical trials, the use of drugs which can increase serum phosphate levels, such as potassium phosphate supplements, vitamin D supplements, antacids, phosphate-containing enemas or laxatives, and medications known to have phosphate as an excipient were prohibited unless no alternatives exist. To manage phosphate elevation, phosphate binders were permitted. Avoid concomitant use with agents that can alter serum phosphate levels before the initial dose increase period based on serum phosphate levels. ## Pharmacokinetics - Following administration of 8 mg once daily, the mean (coefficient of variation [CV%]) erdafitinib steady-state maximum observed plasma concentration (Cmax), area under the curve (AUCtau), and minimum observed plasma concentration (Cmin) were 1,399 ng/mL (51%), 29,268 ng∙h/mL (60%), and 936 ng/mL (65%), respectively. - Following single and repeat once daily dosing, erdafitinib exposure (maximum observed plasma concentration [Cmax] and area under the plasma concentration time curve [AUC]) increased proportionally across the dose range of 0.5 to 12 mg (0.06 to 1.3 times the maximum approved recommended dose). Steady state was achieved after 2 weeks with once daily dosing and the mean accumulation ratio was 4-fold. Absorption - Median time to achieve peak plasma concentration (tmax) was 2.5 hours (range: 2 to 6 hours). Effect of Food - No clinically meaningful differences with erdafitinib pharmacokinetics were observed following administration of a high-fat and high-calorie meal (800 calories to 1,000 calories with approximately 50% of total caloric content of the meal from fat) in healthy subjects. Distribution - The mean apparent volume of distribution of erdafitinib was 29 L in patients. - Erdafitinib protein binding was 99.8% in patients, primarily to alpha-1-acid glycoprotein. Elimination - The mean total apparent clearance (CL/F) of erdafitinib was 0.362 L/h in patients. - The mean effective half-life of erdafitinib was 59 hours in patients. Metabolism - Erdafitinib is primarily metabolized by CYP2C9 and CYP3A4. The contribution of CYP2C9 and CYP3A4 in the total clearance of erdafitinib is estimated to be 39% and 20% respectively. Unchanged erdafitinib was the major drug-related moiety in plasma, there were no circulating metabolites. Excretion - Following a single oral dose of radiolabeled erdafitinib, approximately 69% of the dose was recovered in feces (19% as unchanged) and 19% in urine (13% as unchanged). Specific Populations - No clinically meaningful trends in the pharmacokinetics of erdafitinib were observed based on age (21–88 years), sex, race, body weight (36–132 kg), mild (eGFR [estimated glomerular filtration rate, using modification of diet in renal disease equation] 60 to 89 mL/min/1.73 m2) or moderate (eGFR 30–59 mL/min/1.73 m2) renal impairment or mild hepatic impairment (total bilirubin ≤ ULN and AST > ULN, or total bilirubin > 1.0–1.5 × ULN and any AST). - The pharmacokinetics of erdafitinib in patients with severe renal impairment, renal impairment requiring dialysis, moderate or severe hepatic impairment is unknown. Drug Interaction Studies - Clinical Studies and Model-Based Approaches Strong CYP2C9 Inhibitors: Erdafitinib mean ratios (90% CI) for Cmax and AUCinf were 121% (99.9, 147) and 148% (120, 182), respectively, when co-administered with fluconazole, a strong CYP2C9 inhibitor and moderate CYP3A4 inhibitor, relative to erdafitinib alone. - Erdafitinib mean ratios (90% CI) for Cmax and AUCinf were 121% (99.9, 147) and 148% (120, 182), respectively, when co-administered with fluconazole, a strong CYP2C9 inhibitor and moderate CYP3A4 inhibitor, relative to erdafitinib alone. - Strong CYP3A4 Inhibitors: Erdafitinib mean ratios (90% CI) for Cmax and AUCinf were 105% (86.7, 127) and 134% (109, 164), respectively, when co-administered with itraconazole (a strong CYP3A4 inhibitor and P-gp inhibitor) relative to erdafitinib alone. - Erdafitinib mean ratios (90% CI) for Cmax and AUCinf were 105% (86.7, 127) and 134% (109, 164), respectively, when co-administered with itraconazole (a strong CYP3A4 inhibitor and P-gp inhibitor) relative to erdafitinib alone. - Strong CYP3A4/2C9 Inducers: Simulations suggested that rifampicin (a strong CYP3A4/2C9 inducer) may significantly decrease erdafitinib Cmax and AUC. - Simulations suggested that rifampicin (a strong CYP3A4/2C9 inducer) may significantly decrease erdafitinib Cmax and AUC. In Vitro Studies - CYP Substrates: Erdafitinib is a time dependent inhibitor and inducer of CYP3A4. The effect of erdafitinib on a sensitive CYP3A4 substrate is unknown. Erdafitinib is not an inhibitor of other major CYP isozymes at clinically relevant concentrations. - Erdafitinib is a time dependent inhibitor and inducer of CYP3A4. The effect of erdafitinib on a sensitive CYP3A4 substrate is unknown. Erdafitinib is not an inhibitor of other major CYP isozymes at clinically relevant concentrations. - Transporters: Erdafitinib is a substrate and inhibitor of P-gp. P-gp inhibitors are not expected to affect erdafitinib exposure to a clinically relevant extent. Erdafitinib is an inhibitor of OCT2. Erdafitinib does not inhibit BCRP, OATP1B, OATP1B3, OAT1, OAT3, OCT1, MATE-1, or MATE-2K at clinically relevant concentrations. - Erdafitinib is a substrate and inhibitor of P-gp. P-gp inhibitors are not expected to affect erdafitinib exposure to a clinically relevant extent. Erdafitinib is an inhibitor of OCT2. - Erdafitinib does not inhibit BCRP, OATP1B, OATP1B3, OAT1, OAT3, OCT1, MATE-1, or MATE-2K at clinically relevant concentrations. - Acid-Lowering Agents: Erdafitinib has adequate solubility across the pH range of 1 to 7.4. Acid-lowering agents (e.g., antacids, H2-antagonists, proton pump inhibitors) are not expected to affect the bioavailability of erdafitinib. - Erdafitinib has adequate solubility across the pH range of 1 to 7.4. Acid-lowering agents (e.g., antacids, H2-antagonists, proton pump inhibitors) are not expected to affect the bioavailability of erdafitinib. ## Nonclinical Toxicology - Carcinogenicity studies have not been conducted with erdafitinib. - Erdafitinib was not mutagenic in a bacterial reverse mutation (Ames) assay and was not clastogenic in an in vitro micronucleus or an in vivo rat bone marrow micronucleus assay. - Fertility studies in animals have not been conducted with erdafitinib. In the 3-month repeat-dose toxicity study, erdafitinib showed effects on female reproductive organs (necrosis of the ovarian corpora lutea) in rats at an exposure less than the human exposure (AUC) at maximum recommended human dose. # Clinical Studies - Study BLC2001 (NCT02365597) was a multicenter, open-label, single-arm study to evaluate the efficacy and safety of erdafitinib in patients with locally advanced or metastatic urothelial carcinoma(mUC). Fibroblast growth factor receptor (FGFR) mutation status for screening and enrollment of patients was determined by a clinical trial assay (CTA). The efficacy population consists of a cohort of eighty-seven patients who were enrolled in this study with disease that had progressed on or after at least one prior chemotherapy and that had at least 1 of the following genetic alterations: FGFR3 gene mutations (R248C, S249C, G370C, Y373C) or FGFR gene fusions (FGFR3-TACC3, FGFR3-BAIAP2L1, FGFR2-BICC1, FGFR2-CASP7), as determined by the CTA performed at a central laboratory. Tumor samples from 69 patients were tested retrospectively by the QIAGEN therascreen® FGFR RGQ RT-PCR Kit, which is the FDA-approved test for selection of patients with mUC for erdafitinib. - Patients received a starting dose of erdafitinib at 8 mg once daily with a dose increase to 9 mg once daily in patients whose serum phosphate levels were below the target of 5.5 mg/dL between days 14 and 17; a dose increase occurred in 41% of patients. Erdafitinib was administered until disease progression or unacceptable toxicity. The major efficacy outcome measures were objective response rate (ORR) and duration of response (DoR), as determined by blinded independent review committee (BIRC) according to RECIST v1.1. - The median age was 67 years (range: 36 to 87 years), 79% were male, and 74% were Caucasian. Most patients (92%) had a baseline Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. Sixty-six percent of patients had visceral metastases. Eighty-four (97%) patients received at least one of cisplatin or carboplatin previously. Fifty-six percent of patients only received prior cisplatin-based regimens, 29% received only prior carboplatin-based regimens, and 10% received both cisplatin and carboplatin-based regimens. Three (3%) patients had disease progression following prior platinum-containing neoadjuvant or adjuvant therapy only. Twenty-four percent of patients had been treated with prior anti PD-L1/PD-1 therapy. - Efficacy results are summarized in Table 7 and Table 8. Overall response rate was 32.2%. Responders included patients who had previously not responded to anti PD-L1/PD-1 therapy. # How Supplied - Erdafitinib tablets are available in the strengths and packages listed below: 3 mg tablets: Yellow, round biconvex, film-coated, debossed with "3" on one side and "EF" on the other side. Bottle of 56-tablets with child resistant closure Bottle of 84-tablets with child resistant closure 4 mg tablets: Orange, round biconvex, film-coated, debossed with "4" on one side and "EF" on the other side. Bottle of 28-tablets with child resistant closure Bottle of 56-tablets with child resistant closure 5 mg tablets: Brown, round biconvex, film-coated, debossed with "5" on one side and "EF" on the other side. Bottle of 28-tablets with child resistant closure - 3 mg tablets: Yellow, round biconvex, film-coated, debossed with "3" on one side and "EF" on the other side. Bottle of 56-tablets with child resistant closure Bottle of 84-tablets with child resistant closure - Bottle of 56-tablets with child resistant closure - Bottle of 84-tablets with child resistant closure - 4 mg tablets: Orange, round biconvex, film-coated, debossed with "4" on one side and "EF" on the other side. Bottle of 28-tablets with child resistant closure Bottle of 56-tablets with child resistant closure - Bottle of 28-tablets with child resistant closure - Bottle of 56-tablets with child resistant closure - 5 mg tablets: Brown, round biconvex, film-coated, debossed with "5" on one side and "EF" on the other side. Bottle of 28-tablets with child resistant closure - Bottle of 28-tablets with child resistant closure ## Storage - Store at 20°C–25°C (68°F–77°F); excursions permitted between 15°C and 30°C (59°F and 86°F). # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information - Advise the patient to read the FDA-approved patient labeling (Patient Information). - FGFR genetic alterations: Advise patients that evidence of a susceptible FGFR3 or FGFR2 mutation or gene fusion within the tumor specimen is necessary to identify patients for whom treatment is indicated - Ocular disorders: Advise patients to contact their healthcare provider if they experience any visual changes. In order to prevent or treat dry eyes, advise patients to use artificial tear substitutes, hydrating or lubricating eye gels or ointments frequently, at least every 2 hours during waking hours. - Skin, mucous or nail disorders: Advise patients to contact their healthcare provider if they experience progressive or intolerable skin, mucous or nail disorders. - Hyperphosphatemia: Advise patients that their healthcare provider will assess their serum phosphate level between 14 and 21 days of initiating treatment and will adjust the dose if needed. During this initial phosphate-assessment period, advise patients to avoid concomitant use with agents that can alter serum phosphate levels. Advise patients that, after the initial phosphate assessment period, monthly phosphate level monitoring for hyperphosphatemia should be performed during treatment with erdafitinib. - Drug Interactions: Advise patients to inform their healthcare providers of all concomitant medications, including prescription medicines, over-the-counter drugs, and herbal products. - Dosing Instructions: Instruct patients to swallow the tablets whole once daily with or without food. If vomiting occurs any time after taking erdafitinib, advise patients to take the next dose the next day. - Missed dose: If a dose is missed, advise patients to take the missed as soon as possible. Resume the regular daily dose schedule for erdafitinib the next day. Extra tablets should not be taken to make up for the missed dose. - Embryo-Fetal Toxicity: Advise pregnant women and females of reproductive potential of the potential risk to the fetus. Advise females to inform their healthcare providers of a known or suspected pregnancy. Advise female patients of reproductive potential to use effective contraception during treatment and for one month after the last dose of erdafitinib. Advise male patients with female partners of reproductive potential to use effective contraception during treatment and for one month after the last dose of erdafitinib. - Lactation: Advise females not to breastfeed during treatment with erdafitinib and for one month after the last dose. # Precautions with Alcohol Alcohol-Erdafitinib interaction has not been established. Talk to your doctor regarding the effects of taking alcohol with this medication. # Brand Names Balversa # Look-Alike Drug Names There is limited information regarding Erdafitinib Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	https://www.wikidoc.org/index.php/Balversa
264a84b0bfb1ec712e10af625cd1a4157e6340a1	wikidoc	Barbiturate	Barbiturate # Overview Barbiturates are drugs that act as central nervous system depressants, and by virtue of this they produce a wide spectrum of effects, from mild sedation to anesthesia. Some are also used as anticonvulsants. Barbiturates are derivatives of barbituric acid. # History Barbituric acid was first synthesised on December 4, 1864, by German researcher Adolf von Baeyer. This was done by condensing urea (an animal waste product) with diethyl malonate (an ester derived from the acid of apples). There are several stories about how the substance got its name. The most likely story is that von Baeyer and his colleagues went to celebrate their discovery in a tavern where the town's artillery garrison were also celebrating the day of Saint Barbara — the patron saint of artillerists. An artillery officer is said to have christened the new substance by amalgamating Barbara with urea. Barbituric acid itself is not pharmacologically active, but chemists immediately began making a great variety of derivatives for potential use as drugs. No substance of medical value was discovered, however, until 1903 when two German chemists working at Bayer, Emil Fischer and Joseph von Mering, discovered that barbital was very effective in putting dogs to sleep. Barbital was then marketed by Bayer under the trade name Veronal. It is said that Von Mering proposed this name because the most peaceful place he knew was the Italian city of Verona. In 1912, Bayer introduced another barbituric acid derivative, Phenobarbital, under the trade name Luminal, as a sedative-hypnotic. In the 1950s and 1960s, reports began to be published about side effects and dependence related to barbiturates. In 1970 several barbiturates were designated in the United States as controlled substances with the passage of the American Controlled Substances Act of 1970. Pentobarbital, secobarbital and amobarbital were designated schedule II drugs, butabarbital schedule III, and barbital and phenobarbital schedule IV. In 1971 the Convention on Psychotropic Substances was signed in Vienna. Designed to regulate amphetamines, barbiturates, and other synthetics, the treaty today regulates amobarbital (schedule III), butalbital (III), cyclobarbital (III), pentobarbital (III), allobarbital (IV), methylphenobarbital (IV), phenobarbital (IV), secobarbital (IV), and vinylbital (IV) as scheduled substances. # Table of Barbiturates # Mechanism of Action The principal mechanism of action of barbiturates is believed to be their affinity for the GABAA receptor. GABA is the principal inhibitory neurotransmitter in the mammalian Central Nervous System (CNS). Barbiturates bind to the GABAA receptor at a binding site distinct from GABA itself and also distinct from the benzodiazepine binding site. Like benzodiazepines, barbiturates potentiate the effect of GABA at this receptor. In addition to this GABA-ergic effect, barbiturates also block the AMPA receptor, a subtype of glutamate receptor. Glutamate is the principal excitatory neurotransmitter in the mammalian CNS. Taken together, the findings that barbiturates potentiate inhibitory GABAA receptors and inhibit excitatory AMPA receptors can explain the CNS-depressant effects of these agents. # Therapeutic use Barbiturates like pentobarbital and phenobarbital were long used as anxiolytics and hypnotics. Today benzodiazepines have largely supplanted them for these purposes, because benzodiazepines have less potential for abuse and less danger of lethal overdose. Today, fewer than 10 percent of all sedative/hypnotic prescriptions in the United States are for barbiturates. Barbiturates are still widely used in surgical anesthesia, especially to induce anesthesia. Phenobarbital is used for as an anticonvulsant for people suffering from seizure disorders such as febrile seizures, tonic-clonic seizures, status epilepticus, and eclampsia. # Potential for addiction Barbiturates are habit forming and lead to physical withdrawal symptoms. These can include tremors, anxiety, weakness, restlessness, nausea and vomiting, delirium, tonic-clonic or grand mal seizures, and cardiac arrest. Death can result from seizures or cardiac arrest. # Effects on the Body Barbiturates are classified as ultrashort-, short-, intermediate-, and long-acting, depending on how quickly they act and how long their effects last. Ultrashort barbiturates such as thiopental (Pentothal) produce unconsciousness within about a minute of intravenous (IV) injection. These drugs are used to prepare patients for surgery; other general anesthetics like nitrous oxide are then used to keep the patient from waking up before the surgery is complete. Because Pentothal and other ultrashort-acting barbiturates are typically used in hospital settings, they are not very likely to be abused, noted the DEA. Abusers tend to prefer short-acting and intermediate-acting barbiturates. The most commonly abused are amobarbital (Amytal), pentobarbital (Nembutal), and secobarbital (Seconal). A combination of amobarbital and secobarbital (called Tuinal) is also highly abused. Short-acting and intermediate-acting barbiturates are usually prescribed as sedatives and sleeping pills. These pills begin acting fifteen to forty minutes after they are swallowed, and their effects last from five to six hours. Veterinarians use pentobarbital to anesthetise animals before surgery; in large doses, it can be used to euthanise animals. Long-acting barbiturates such as phenobarbital (Luminal) and mephobarbital (Mebaral) are prescribed for two main reasons. When taken at bedtime, they help treat insomnia. When taken during the day, they have sedative effects that can aid in the treatment of tension and anxiety. These same effects have been found helpful in the treatment of convulsive conditions like epilepsy. Long-acting barbiturates take effect within one to two hours and last twelve hours or longer. # Similarity to Alcohol Recreational users report that a barbiturate high makes them feel "relaxed, sociable, and good-humored," according to an Independent article. Users typically describe feelings of decreased anxiety, a loss of inhibitions, and an increased sense of confidence. Physical effects include slowed breathing and a lowering of both blood pressure and heart rate. Like alcohol, barbiturates are intoxicating. During the stage after mild intoxication, the user's speech may be slurred and a loss of coordination may become noticeable. Stumbling and staggering are common. Other symptoms include shallow breathing, fatigue, frequent yawning, and irritability. When taken in high doses, barbiturates can cause serious side effects, including "unpredictable emotional reactions and mental confusion," noted the Independent. Judgment becomes severely impaired and the user may experience mood swings. The mental effects of barbiturates generally depend on the amount of the drug taken and the strength of the dosage. Generally, a person falls asleep when taking a prescribed dosage at bedtime. But barbiturates remain in the system for a long time. "At normal doses," explained Cynthia Kuhn and her coauthors in Buzzed: The Straight Facts about the Most Used and Abused Drugs from Alcohol to Ecstasy, "the major concern is that they can have sedative effects that outlast their sleep-inducing properties. Driving, flying an airplane, or other activities requiring muscle coordination can be impaired for up to a day after a single dose." Some barbiturates can be detected in a user's urine sample days or even weeks after the drug was consumed. # Truth Serum Thiopental is a barbiturate that is marketed under the name Sodium Pentothal, but it is probably best known as "truth serum." When dissolved in water, it can be swallowed or administered by intravenous injection. In large doses, it is one of three drugs used in the United States to execute prisoners on death row. In lower doses, it is sometimes used as a truth serum. Drug experts claim that truth serum does not force people to tell the truth. It merely decreases their inhibitions, making them more likely to be "caught off guard" when questioned by authorities. People being questioned may slip up and expose a lie or give more information on a subject or event than they intended. # Dependance, Tolerance, and Overdose Barbiturate use can lead to both psychological and physical dependence. Psychological addiction can occur quickly. Signs of drug dependence include relying on a drug regularly for a desired effect. The addicted abuser believes he or she must take a barbiturate to sleep, relax, or just get through the day. Continued use of barbiturates leads to physical dependence. As people develop a tolerance for barbiturates, they may need more of the drug or a higher dosage to get the desired effect. This can lead to an overdose, which results when a person takes a larger-than-prescribed dose of a drug. "People who get in the habit of taking sleeping pills every night to fall sleep," noted Andrew Weil and Winifred Rosen in From Chocolate to Morphine, "might start out with one a night, progress to two, then graduate to four to get the same effect. One night the dose they need to fall asleep might also be the dose that stops their breathing." Generally, barbiturate overdoses "occur because the effective dose of the drug is not too far away from the lethal dose," explained Dr. Eric H. Chudler on the Neuroscience for Kids Web site. Symptoms of an overdose typically include severe weakness, confusion, shortness of breath, extreme drowsiness, an unusually slow heartbeat, and darting eye movements. The amount of a fatal dosage of barbiturate varies from one individual to another. However, the lethal dose is usually ten to fifteen times as large as a usual dose. An overdose affects the heart and the respiratory system. The user then falls into a coma and dies. Clayton pointed out that barbiturates "can have a 'multiplying' effect when taken with other depressants. For example, if someone drinks alcohol and takes a barbiturate, the effect may be ten times stronger than either one taken separately." According to Weil, "many people have died because they were ignorant of this fact." Older adults and pregnant women should consider the risks associated with barbiturate use. When a person ages, the body becomes less able to rid itself of barbiturates. As a result, people over the age of sixty-five are at higher risk of experiencing the harmful effects of barbiturates, including drug dependence and accidental overdose. When barbiturates are taken during pregnancy, the drug passes through the mother's bloodstream to her fetus. After the baby is born, it may experience withdrawal symptoms and have trouble breathing. In addition, nursing mothers who take barbiturates may transmit the drug to their babies through breast milk. # Recreational use Barbiturates were very popular in the first half of the twentieth century. In moderate amounts, these drugs produce a state of intoxication that is remarkably similar to alcohol intoxication. Symptoms include slurred speech, loss of motor coordination, and impaired judgment. Depending on the dose, frequency, and duration of use, one can rapidly develop tolerance, physical dependence, and psychological dependence on barbiturates. With the development of tolerance, the margin of safety between the effective dose and the lethal dose becomes very narrow. That is, in order to obtain the same level of intoxication, the tolerant abuser may raise his or her dose to a level that may result in coma or death. Although many individuals have taken barbiturates therapeutically without harm, concern about the addiction potential of barbiturates and the ever-increasing number of fatalities associated with them led to the development of alternative medications, namely benzodiazepines. # Other non-therapeutical use Barbiturates in high doses are used for physician-assisted suicide (PAS), and in combination with a muscle relaxant for euthanasia and for capital punishment by lethal injection.	Barbiturate Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview Barbiturates are drugs that act as central nervous system depressants, and by virtue of this they produce a wide spectrum of effects, from mild sedation to anesthesia. Some are also used as anticonvulsants. Barbiturates are derivatives of barbituric acid. # History Barbituric acid was first synthesised on December 4, 1864, by German researcher Adolf von Baeyer. This was done by condensing urea (an animal waste product) with diethyl malonate (an ester derived from the acid of apples). There are several stories about how the substance got its name. The most likely story is that von Baeyer and his colleagues went to celebrate their discovery in a tavern where the town's artillery garrison were also celebrating the day of Saint Barbara — the patron saint of artillerists. An artillery officer is said to have christened the new substance by amalgamating Barbara with urea. [2] Barbituric acid itself is not pharmacologically active, but chemists immediately began making a great variety of derivatives for potential use as drugs. No substance of medical value was discovered, however, until 1903 when two German chemists working at Bayer, Emil Fischer and Joseph von Mering, discovered that barbital was very effective in putting dogs to sleep. Barbital was then marketed by Bayer under the trade name Veronal. It is said that Von Mering proposed this name because the most peaceful place he knew was the Italian city of Verona. [3] In 1912, Bayer introduced another barbituric acid derivative, Phenobarbital, under the trade name Luminal, as a sedative-hypnotic. In the 1950s and 1960s, reports began to be published about side effects and dependence related to barbiturates. In 1970 several barbiturates were designated in the United States as controlled substances with the passage of the American Controlled Substances Act of 1970. Pentobarbital, secobarbital and amobarbital were designated schedule II drugs, butabarbital schedule III, and barbital and phenobarbital schedule IV. In 1971 the Convention on Psychotropic Substances was signed in Vienna. Designed to regulate amphetamines, barbiturates, and other synthetics, the treaty today regulates amobarbital (schedule III), butalbital (III), cyclobarbital (III), pentobarbital (III), allobarbital (IV), methylphenobarbital (IV), phenobarbital (IV), secobarbital (IV), and vinylbital (IV) as scheduled substances. # Table of Barbiturates # Mechanism of Action The principal mechanism of action of barbiturates is believed to be their affinity for the GABAA receptor. GABA is the principal inhibitory neurotransmitter in the mammalian Central Nervous System (CNS). Barbiturates bind to the GABAA receptor at a binding site distinct from GABA itself and also distinct from the benzodiazepine binding site. Like benzodiazepines, barbiturates potentiate the effect of GABA at this receptor. In addition to this GABA-ergic effect, barbiturates also block the AMPA receptor, a subtype of glutamate receptor. Glutamate is the principal excitatory neurotransmitter in the mammalian CNS. Taken together, the findings that barbiturates potentiate inhibitory GABAA receptors and inhibit excitatory AMPA receptors can explain the CNS-depressant effects of these agents.[1] # Therapeutic use Barbiturates like pentobarbital and phenobarbital were long used as anxiolytics and hypnotics. Today benzodiazepines have largely supplanted them for these purposes, because benzodiazepines have less potential for abuse and less danger of lethal overdose. Today, fewer than 10 percent of all sedative/hypnotic prescriptions in the United States are for barbiturates. Barbiturates are still widely used in surgical anesthesia, especially to induce anesthesia. Phenobarbital is used for as an anticonvulsant for people suffering from seizure disorders such as febrile seizures, tonic-clonic seizures, status epilepticus, and eclampsia.[2] # Potential for addiction Barbiturates are habit forming and lead to physical withdrawal symptoms. These can include tremors, anxiety, weakness, restlessness, nausea and vomiting, delirium, tonic-clonic or grand mal seizures, and cardiac arrest. Death can result from seizures or cardiac arrest. # Effects on the Body Barbiturates are classified as ultrashort-, short-, intermediate-, and long-acting, depending on how quickly they act and how long their effects last. Ultrashort barbiturates such as thiopental (Pentothal) produce unconsciousness within about a minute of intravenous (IV) injection. These drugs are used to prepare patients for surgery; other general anesthetics like nitrous oxide are then used to keep the patient from waking up before the surgery is complete. Because Pentothal and other ultrashort-acting barbiturates are typically used in hospital settings, they are not very likely to be abused, noted the DEA. Abusers tend to prefer short-acting and intermediate-acting barbiturates. The most commonly abused are amobarbital (Amytal), pentobarbital (Nembutal), and secobarbital (Seconal). A combination of amobarbital and secobarbital (called Tuinal) is also highly abused. Short-acting and intermediate-acting barbiturates are usually prescribed as sedatives and sleeping pills. These pills begin acting fifteen to forty minutes after they are swallowed, and their effects last from five to six hours. Veterinarians use pentobarbital to anesthetise animals before surgery; in large doses, it can be used to euthanise animals. Long-acting barbiturates such as phenobarbital (Luminal) and mephobarbital (Mebaral) are prescribed for two main reasons. When taken at bedtime, they help treat insomnia. When taken during the day, they have sedative effects that can aid in the treatment of tension and anxiety. These same effects have been found helpful in the treatment of convulsive conditions like epilepsy. Long-acting barbiturates take effect within one to two hours and last twelve hours or longer. # Similarity to Alcohol Recreational users report that a barbiturate high makes them feel "relaxed, sociable, and good-humored," according to an Independent article. Users typically describe feelings of decreased anxiety, a loss of inhibitions, and an increased sense of confidence. Physical effects include slowed breathing and a lowering of both blood pressure and heart rate. Like alcohol, barbiturates are intoxicating. During the stage after mild intoxication, the user's speech may be slurred and a loss of coordination may become noticeable. Stumbling and staggering are common. Other symptoms include shallow breathing, fatigue, frequent yawning, and irritability. When taken in high doses, barbiturates can cause serious side effects, including "unpredictable emotional reactions and mental confusion," noted the Independent. Judgment becomes severely impaired and the user may experience mood swings. The mental effects of barbiturates generally depend on the amount of the drug taken and the strength of the dosage. Generally, a person falls asleep when taking a prescribed dosage at bedtime. But barbiturates remain in the system for a long time. "At normal doses," explained Cynthia Kuhn and her coauthors in Buzzed: The Straight Facts about the Most Used and Abused Drugs from Alcohol to Ecstasy, "the major concern is that they can have sedative effects that outlast their sleep-inducing properties. Driving, flying an airplane, or other activities requiring muscle coordination can be impaired for up to a day after a single dose." Some barbiturates can be detected in a user's urine sample days or even weeks after the drug was consumed. # Truth Serum Thiopental is a barbiturate that is marketed under the name Sodium Pentothal, but it is probably best known as "truth serum." When dissolved in water, it can be swallowed or administered by intravenous injection. In large doses, it is one of three drugs used in the United States to execute prisoners on death row. In lower doses, it is sometimes used as a truth serum. Drug experts claim that truth serum does not force people to tell the truth. It merely decreases their inhibitions, making them more likely to be "caught off guard" when questioned by authorities. People being questioned may slip up and expose a lie or give more information on a subject or event than they intended. # Dependance, Tolerance, and Overdose Barbiturate use can lead to both psychological and physical dependence. Psychological addiction can occur quickly. Signs of drug dependence include relying on a drug regularly for a desired effect. The addicted abuser believes he or she must take a barbiturate to sleep, relax, or just get through the day. Continued use of barbiturates leads to physical dependence. As people develop a tolerance for barbiturates, they may need more of the drug or a higher dosage to get the desired effect. This can lead to an overdose, which results when a person takes a larger-than-prescribed dose of a drug. "People who get in the habit of taking sleeping pills every night to fall sleep," noted Andrew Weil and Winifred Rosen in From Chocolate to Morphine, "might start out with one a night, progress to two, then graduate to four to get the same effect. One night the dose they need to fall asleep might also be the dose that stops their breathing." Generally, barbiturate overdoses "occur because the effective dose of the drug is not too far away from the lethal dose," explained Dr. Eric H. Chudler on the Neuroscience for Kids Web site. Symptoms of an overdose typically include severe weakness, confusion, shortness of breath, extreme drowsiness, an unusually slow heartbeat, and darting eye movements. The amount of a fatal dosage of barbiturate varies from one individual to another. However, the lethal dose is usually ten to fifteen times as large as a usual dose. An overdose affects the heart and the respiratory system. The user then falls into a coma and dies. Clayton pointed out that barbiturates "can have a 'multiplying' effect when taken with other depressants. For example, if someone drinks alcohol and takes a barbiturate, the effect may be ten times stronger than either one taken separately." According to Weil, "many people have died because they were ignorant of this fact." Older adults and pregnant women should consider the risks associated with barbiturate use. When a person ages, the body becomes less able to rid itself of barbiturates. As a result, people over the age of sixty-five are at higher risk of experiencing the harmful effects of barbiturates, including drug dependence and accidental overdose. When barbiturates are taken during pregnancy, the drug passes through the mother's bloodstream to her fetus. After the baby is born, it may experience withdrawal symptoms and have trouble breathing. In addition, nursing mothers who take barbiturates may transmit the drug to their babies through breast milk. # Recreational use Barbiturates were very popular in the first half of the twentieth century. In moderate amounts, these drugs produce a state of intoxication that is remarkably similar to alcohol intoxication. Symptoms include slurred speech, loss of motor coordination, and impaired judgment. Depending on the dose, frequency, and duration of use, one can rapidly develop tolerance, physical dependence, and psychological dependence on barbiturates. With the development of tolerance, the margin of safety between the effective dose and the lethal dose becomes very narrow. That is, in order to obtain the same level of intoxication, the tolerant abuser may raise his or her dose to a level that may result in coma or death. Although many individuals have taken barbiturates therapeutically without harm, concern about the addiction potential of barbiturates and the ever-increasing number of fatalities associated with them led to the development of alternative medications, namely benzodiazepines. # Other non-therapeutical use Barbiturates in high doses are used for physician-assisted suicide (PAS), and in combination with a muscle relaxant for euthanasia and for capital punishment by lethal injection.	https://www.wikidoc.org/index.php/Barbituate
11249cb738639ae6278e4803b2d29040d4be3348	wikidoc	Baricitinib	Baricitinib # Disclaimer WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here. # Black Box Warning # Overview Baricitinib is a Janus kinase (JAK) inhibitor that is FDA approved for the treatment of adult patients with moderately to severely active rheumatoid arthritis who have had an inadequate response to one or more TNF antagonist therapies. There is a Black Box Warning for this drug as shown here. Common adverse reactions include upper respiratory tract infections, nausea, herpes simplex, and herpes zoster. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) Indication - Baricitinib is indicated for the treatment of adult patients with moderately to severely active rheumatoid arthritis who have had an inadequate response to one or more tumor necrosis factor (TNF) antagonist therapies. - Limitation of Use: Use of baricitinib in combination with other JAK inhibitors, biologic disease-modifying antirheumatic drugs (DMARDs), or with potent immunosuppressants such as azathioprine and cyclosporine is not recommended. Dosage - The recommended dose of baricitinib is 2 mg once daily. - Baricitinib may be used as monotherapy or in combination with methotrexate or other DMARDs. - Baricitinib is given orally with or without food. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding baricitinib Off-Label Guideline-Supported Use and Dosage (Adult) in the drug label. ### Non–Guideline-Supported Use There is limited information regarding baricitinib Off-Label Non-Guideline-Supported Use and Dosage (Adult) in the drug label. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) The safety and effectiveness of baricitinib in pediatric patients have not been established. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding baricitinib Off-Label Guideline-Supported Use and Dosage (Pediatric) in the drug label. ### Non–Guideline-Supported Use There is limited information regarding baricitinib Off-Label Non-Guideline-Supported Use and Dosage (Pediatric) in the drug label. # Contraindications None. # Warnings - Serious and sometimes fatal infections due to bacterial, mycobacterial, invasive fungal, viral, or other opportunistic pathogens have been reported in rheumatoid arthritis patients receiving baricitinib. The most common serious infections reported with baricitinib included pneumonia, herpes zoster, and urinary tract infection. Among opportunistic infections, tuberculosis, multidermatomal herpes zoster, esophageal candidiasis, pneumocystosis, acute histoplasmosis, cryptococcosis, cytomegalovirus, and BK virus were reported with baricitinib. Some patients have presented with disseminated rather than localized disease, and were often taking concomitant immunosuppressants such as methotrexate or corticosteroids. - Avoid use of baricitinib in patients with an active, serious infection, including localized infections. Consider the risks and benefits of treatment prior to initiating baricitinib in patients: with chronic or recurrent infection who have been exposed to tuberculosis with a history of a serious or an opportunistic infection who have resided or traveled in areas of endemic tuberculosis or endemic mycoses; or with underlying conditions that may predispose them to infection. - with chronic or recurrent infection - who have been exposed to tuberculosis - with a history of a serious or an opportunistic infection - who have resided or traveled in areas of endemic tuberculosis or endemic mycoses; or - with underlying conditions that may predispose them to infection. - Closely monitor patients for the development of signs and symptoms of infection during and after treatment with baricitinib. Interrupt baricitinib if a patient develops a serious infection, an opportunistic infection, or sepsis. A patient who develops a new infection during treatment with baricitinib should undergo prompt and complete diagnostic testing appropriate for an immunocompromised patient; appropriate antimicrobial therapy should be initiated, the patient should be closely monitored, and baricitinib should be interrupted if the patient is not responding to therapy. Do not resume baricitinib until the infection is controlled. Tuberculosis - Evaluate and test patients for latent or active infection prior to administration of baricitinib. Patients with latent tuberculosis (TB) should be treated with standard antimycobacterial therapy before initiating baricitinib. - Baricitinib should not be given to patients with active TB. Consider anti-TB therapy prior to initiation of baricitinib in patients with a history of latent or active TB in whom an adequate course of treatment cannot be confirmed, and for patients with a negative test for latent TB but who have risk factors for TB infection. Consultation with a physician with expertise in the treatment of TB is recommended to aid in the decision about whether initiating anti-TB therapy is appropriate for an individual patient. - Monitor patients for the development of signs and symptoms of TB, including patients who tested negative for latent TB infection prior to initiating therapy. Viral Reactivation - Viral reactivation, including cases of herpes virus reactivation (e.g., herpes zoster), were reported in clinical studies with baricitinib. If a patient develops herpes zoster, interrupt baricitinib treatment until the episode resolves. - The impact of baricitinib on chronic viral hepatitis reactivation is unknown. Patients with evidence of active hepatitis B or C infection were excluded from clinical trials. Patients who were positive for hepatitis C antibody but negative for hepatitis C virus RNA were permitted to enroll. Patients with positive hepatitis B surface antibody and hepatitis B core antibody, without hepatitis B surface antigen, were permitted to enroll; such patients should be monitored for expression of hepatitis B virus (HBV) DNA. Should HBV DNA be detected, consult with a hepatologist. Perform screening for viral hepatitis in accordance with clinical guidelines before starting therapy with baricitinib. - Consider the risks and benefits of baricitinib treatment prior to initiating therapy in patients with a known malignancy other than a successfully treated non-melanoma skin cancer (NMSC) or when considering continuing baricitinib in patients who develop a malignancy. Malignancies were observed in clinical studies of baricitinib. Non-melanoma skin cancers - Non-melanoma skin cancers (NMSCs) have been reported in patients treated with baricitinib. Periodic skin examination is recommended for patients who are at increased risk for skin cancer. - Thrombosis, including deep venous thrombosis (DVT) and pulmonary embolism (PE), has been observed at an increased incidence in patients treated with baricitinib compared to placebo. In addition, arterial thrombosis events in the extremities have been reported in clinical studies with baricitinib. Many of these adverse events were serious and some resulted in death. There was no clear relationship between platelet count elevations and thrombotic events. Baricitinib should be used with caution in patients who may be at increased risk of thrombosis. If clinical features of DVT/PE or arterial thrombosis occur, patients should be evaluated promptly and treated appropriately. - Events of gastrointestinal perforation have been reported in clinical studies with baricitinib, although the role of JAK inhibition in these events is not known. - Baricitinib should be used with caution in patients who may be at increased risk for gastrointestinal perforation (e.g., patients with a history of diverticulitis). Patients presenting with new onset abdominal symptoms should be evaluated promptly for early identification of gastrointestinal perforation. - Neutropenia – Treatment with baricitinib was associated with an increased incidence of neutropenia (ANC less than 1000 cells/mm3) compared to placebo. Avoid initiation or interrupt baricitinib treatment in patients with an ANC less than 1000 cells/mm3. Evaluate at baseline and thereafter according to routine patient management. For recommended modifications based on ANC. - Lymphopenia – ALC less than 500 cells/mm3 were reported in baricitinib clinical trials. Lymphocyte counts less than the lower limit of normal were associated with infection in patients treated with baricitinib, but not placebo. Avoid initiation or interrupt baricitinib treatment in patients with an ALC less than 500 cells/mm3. Evaluate at baseline and thereafter according to routine patient management. For recommended modifications based on ALC results. - Avoid initiation or interrupt baricitinib treatment in patients with an ALC less than 500 cells/mm3. Evaluate at baseline and thereafter according to routine patient management. For recommended modifications based on ALC results. - Anemia – Decreases in hemoglobin levels to less than 8 g/dL were reported in baricitinib clinical trials. Avoid initiation or interrupt baricitinib treatment in patients with hemoglobin less than 8 g/dL. Evaluate at baseline and thereafter according to routine patient management. For recommended modifications based on hemoglobin results. - Liver Enzyme Elevations – Treatment with baricitinib was associated with increased incidence of liver enzyme elevation compared to placebo. Increases to greater than or equal to 5x and greater than or equal to 10x upper limit of normal (ULN) were observed for both ALT and AST in patients in baricitinib clinical trials. Evaluate at baseline and thereafter according to routine patient management. Prompt investigation of the cause of liver enzyme elevation is recommended to identify potential cases of drug-induced liver injury. If increases in ALT or AST are observed and drug-induced liver injury is suspected, interrupt baricitinib until this diagnosis is excluded. - Evaluate at baseline and thereafter according to routine patient management. Prompt investigation of the cause of liver enzyme elevation is recommended to identify potential cases of drug-induced liver injury. If increases in ALT or AST are observed and drug-induced liver injury is suspected, interrupt baricitinib until this diagnosis is excluded. - Lipid Elevations – Treatment with baricitinib was associated with increases in lipid parameters, including total cholesterol, low-density lipoprotein (LDL) cholesterol, and high-density lipoprotein (HDL) cholesterol. Assessment of lipid parameters should be performed approximately 12 weeks following baricitinib initiation. Manage patients according to clinical guidelines for the management of hyperlipidemia. - Manage patients according to clinical guidelines for the management of hyperlipidemia. - Avoid use of live vaccines with baricitinib. - Update immunizations in agreement with current immunization guidelines prior to initiating baricitinib therapy. # Adverse Reactions ## Clinical Trials Experience - Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not predict the rates observed in a broader patient population in clinical practice. - The following data include six randomized double-blind placebo-controlled studies (three Phase 2, three Phase 3) and a long-term extension study. All patients had moderately to severely active RA. Patients were randomized to placebo (1070 patients), baricitinib 2 mg (479 patients), or baricitinib 4 mg (997 patients). - Patients could be switched to baricitinib 4 mg from placebo or baricitinib 2 mg from as early as Week 12 depending on the study design. All patients initially randomized to placebo were switched to baricitinib 4 mg by Week 24. - During the 16-week treatment period, adverse events leading to discontinuation of treatment were reported by 35 patients (11.4 events per 100 patient-years) treated with placebo, 17 patients (12.1 events per 100 patient-years) with baricitinib 2 mg, and 40 patients (13.4 events per 100 patient-years) treated with baricitinib 4 mg. - During 0 to 52 week exposure, adverse events leading to discontinuation of treatment were reported by 31 patients (9.2 events per 100 patient-years) with baricitinib 2 mg, and 92 patients (10.2 events per 100 patient-years) treated with baricitinib 4 mg. - Overall Infections – During the 16-week treatment period, infections were reported by 253 patients (82.1 events per 100 patient-years) treated with placebo, 139 patients (99.1 events per 100 patient-years) treated with baricitinib 2 mg, and 298 patients (100.1 events per 100 patient-years) treated with baricitinib 4 mg. - During 0 to 52 week exposure, infections were reported by 200 patients (59.6 events per 100 patients-years) treated with baricitinib 2 mg, and 500 patients (55.3 events per 100 patient-years) treated with baricitinib 4 mg. - In the 0 to 52 week exposure population, the most commonly reported infections with baricitinib were viral upper respiratory tract infection, upper respiratory tract infection, urinary tract infection, and bronchitis. - Serious Infections – During the 16-week treatment period, serious infections were reported in 13 patients (4.2 events per 100 patient-years) treated with placebo, 5 patients (3.6 events per 100 patient-years) treated with baricitinib 2 mg, and 11 patients (3.7 events per 100 patient-years) treated with baricitinib 4 mg. - During 0 to 52 week exposure, serious infections were reported in 14 patients (4.2 events per 100 patient-years) treated with baricitinib 2 mg and 32 patients (3.5 events per 100 patient-years) treated with baricitinib 4 mg. - In the 0 to 52 week exposure population, the most commonly reported serious infections with baricitinib were pneumonia, herpes zoster, and urinary tract infection. - Tuberculosis – During the 16-week treatment period, no events of tuberculosis were reported. - During 0 to 52 week exposure, events of tuberculosis were reported in 0 patients treated with baricitinib 2 mg and 1 patient (0.1 per 100 patient-years) treated with baricitinib 4 mg. - Cases of disseminated tuberculosis were also reported. - Opportunistic Infections (excluding tuberculosis) – During the 16-week treatment period, opportunistic infections were reported in 2 patients (0.6 per 100 patient-years) treated with placebo, 0 patients treated with baricitinib 2 mg and 2 patients (0.7 per 100 patient-years) treated with baricitinib 4 mg. - During 0 to 52 week exposure, opportunistic infections were reported in 1 patient (0.3 per 100 patient-years) treated with baricitinib 2 mg and 5 patients (0.6 per 100 patient-years) treated with baricitinib 4 mg. - Malignancy – During the 16-week treatment period, malignancies excluding non-melanoma skin cancers (NMSC) were reported in 0 patients treated with placebo, 1 patient (0.7 per 100 patient-years) treated with baricitinib 2 mg, and 1 patient (0.3 per 100 patient-years) treated with baricitinib 4 mg. - During the 0 to 52 week treatment period, malignancies excluding NMSC were reported in 2 patients (0.6 per 100 patient-years) treated with baricitinib 2 mg and 6 patients (0.7 per 100 patient-years) treated with baricitinib 4 mg. - Venous Thrombosis – During the 16-week treatment period, venous thromboses (deep vein thrombosis or pulmonary embolism) were reported in 0 patients treated with placebo, 0 patients treated with baricitinib 2 mg, and 5 patients (1.7 per 100 patient-years) treated with baricitinib 4 mg. - During the 0 to 52 week treatment period, venous thromboses were reported in 2 patients (0.6 per 100 patient-years) treated with baricitinib 2 mg and 7 patients (0.8 per 100 patient-years) treated with baricitinib 4 mg. - Arterial Thrombosis – During the 16-week treatment period, arterial thromboses were reported in 1 patient treated with placebo (0.3 per 100 patient-years), 2 patients (1.4 per 100 patient-years) treated with baricitinib 2 mg, and 2 patients (0.7 per 100 patient-years) treated with baricitinib 4 mg. - During the 0 to 52 week treatment period, arterial thromboses were reported in 3 patients (0.9 per 100 patient-years) treated with baricitinib 2 mg and 3 patients (0.3 per 100 patient-years) treated with baricitinib 4 mg. Laboratory Abnormalities - Neutropenia – During the 16-week treatment period, neutrophil counts below 1000 cells/mm3 occurred in 0% of patients treated with placebo, 0.6% of patients treated with baricitinib 2 mg, and 0.3% of patients treated with baricitinib 4 mg. There were no neutrophil counts below 500 cells/mm3 observed in any treatment group. - Platelet Elevations – During the 16-week treatment period, increases in platelet counts above 600,000 cells/mm3 occurred in 1.1% of patients treated with placebo, 1.1% of patients treated with baricitinib 2 mg, and 2.0% of patients treated with baricitinib 4 mg. Mean platelet count increased by 3000 cells/mm3 at 16 weeks in patients treated with placebo, by 15,000 cells/mm3 at 16 weeks in patients treated with baricitinib 2 mg and by 23,000 cells/mm3 in patients treated with baricitinib 4 mg. - Liver Enzyme Elevations – Events of increases in liver enzymes greater than or equal to 3x ULN were observed in patients treated with baricitinib. During the 16-week treatment period, ALT elevations greater than or equal to 3x ULN occurred in 1.0% of patients treated with placebo, 1.7% of patients treated with baricitinib 2 mg, and 1.4% of patients treated with baricitinib 4 mg. During the 16-week treatment period, AST elevations greater than or equal to 3x ULN occurred in 0.8% of patients treated with placebo, 1.3% of patients treated with baricitinib 2 mg, and 0.8% of patients treated with baricitinib 4 mg. In a phase 3 study of DMARD naive patients, during the 24-week treatment period, ALT and AST elevations ≥3x ULN occurred in 1.9% and 0% of patients treated with methotrexate monotherapy, 1.9% and 1.3% of patients treated with baricitinib 4 mg monotherapy, and 4.7% and 1.9% of patients treated with baricitinib 4 mg plus methotrexate. - During the 16-week treatment period, ALT elevations greater than or equal to 3x ULN occurred in 1.0% of patients treated with placebo, 1.7% of patients treated with baricitinib 2 mg, and 1.4% of patients treated with baricitinib 4 mg. - During the 16-week treatment period, AST elevations greater than or equal to 3x ULN occurred in 0.8% of patients treated with placebo, 1.3% of patients treated with baricitinib 2 mg, and 0.8% of patients treated with baricitinib 4 mg. - In a phase 3 study of DMARD naive patients, during the 24-week treatment period, ALT and AST elevations ≥3x ULN occurred in 1.9% and 0% of patients treated with methotrexate monotherapy, 1.9% and 1.3% of patients treated with baricitinib 4 mg monotherapy, and 4.7% and 1.9% of patients treated with baricitinib 4 mg plus methotrexate. - Lipid Elevations – In controlled clinical trials, baricitinib treatment was associated with dose-related increases in lipid parameters including total cholesterol, triglycerides, LDL cholesterol, and HDL cholesterol. Elevations were observed at 12 weeks and remained stable thereafter. During the 12-week treatment period, changes in lipid parameters are summarized below: Mean LDL cholesterol increased by 8 mg/dL in patients treated with baricitinib 2 mg and by 14 mg/dL in patients treated with baricitinib 4 mg. Mean HDL cholesterol increased by 7 mg/dL in patients treated with baricitinib 2 mg and by 9 mg/dL in patients treated with baricitinib 4 mg. The mean LDL/HDL ratio remained stable. Mean triglycerides increased by 7 mg/dL in patients treated with baricitinib 2 mg and by 15 mg/dL in patients treated with baricitinib 4 mg. - Mean LDL cholesterol increased by 8 mg/dL in patients treated with baricitinib 2 mg and by 14 mg/dL in patients treated with baricitinib 4 mg. - Mean HDL cholesterol increased by 7 mg/dL in patients treated with baricitinib 2 mg and by 9 mg/dL in patients treated with baricitinib 4 mg. - The mean LDL/HDL ratio remained stable. - Mean triglycerides increased by 7 mg/dL in patients treated with baricitinib 2 mg and by 15 mg/dL in patients treated with baricitinib 4 mg. - Creatine Phosphokinase (CPK) – baricitinib treatment was associated with increases in CPK within one week of starting baricitinib and plateauing after 8 to 12 weeks. At 16 weeks, the mean change in CPK for baricitinib 2 mg and baricitinib 4 mg was 37 IU/L and 52 IU/L, respectively. - Creatinine – In controlled clinical trials, dose-related increases in serum creatinine were observed with baricitinib treatment. At 52 weeks, the mean increase in serum creatinine was less than 0.1 mg/dL with baricitinib 4 mg. The clinical significance of the observed serum creatinine increases is unknown. Other Adverse Reactions - Other adverse reactions are summarized in TABLE 4. - Additional adverse drug reactions occurring in fewer than 1% of patients: acne. ## Postmarketing Experience There is limited information regarding Baricitinib Postmarketing Experience in the drug label. # Drug Interactions - Baricitinib exposure is increased when baricitinib is co-administered with strong OAT3 inhibitors (such as probenecid). - Baricitinib has not been studied in combination with other JAK inhibitors or with biologic DMARDs. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): Risk Summary - The limited human data on use of baricitinib in pregnant women are not sufficient to inform a drug-associated risk for major birth defects or miscarriage. In animal embryo-fetal development studies, oral baricitinib administration to pregnant rats and rabbits at exposures equal to and greater than approximately 20 and 84 times the maximum recommended human dose (MRHD), respectively, resulted in reduced fetal body weights, increased embryolethality (rabbits only), and dose-related increases in skeletal malformations. No developmental toxicity was observed in pregnant rats and rabbits treated with oral baricitinib during organogenesis at approximately 5 and 13 times the exposure at the MRHD, respectively. In a pre- and post-natal development study in pregnant female rats, oral baricitinib administration at exposures approximately 43 times the MRHD resulted in reduction in pup viability (increased incidence of stillborn pups and early neonatal deaths), decreased fetal birth weight, reduced fetal body weight gain, decreased cytotoxic T cells on post-natal day (PND) 35 with evidence of recovery by PND 65, and developmental delays that might be attributable to decreased body weight gain. No developmental toxicity was observed at an exposure approximately 9 times the exposure at the MRHD. - The estimated background risk of major birth defects and miscarriage for the indicated population(s) are unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. Animal Data - In an embryofetal development study in pregnant rats, dosed orally during the period of organogenesis from gestation days 6 to 17, baricitinib was teratogenic (skeletal malformations that consisted of bent limb bones and rib anomalies) at exposures equal to or greater than approximately 20 times the MRHD (on an AUC basis at maternal oral doses of 10 mg/kg/day and higher). No developmental toxicity was observed in rats at an exposure approximately 5 times the MRHD (on an AUC basis at a maternal oral dose of 2 mg/kg/day). - In an embryofetal development study in pregnant rabbits, dosed orally during the period of organogenesis from gestation days 7 to 20, embryolethality, decreased fetal body weights, and skeletal malformations (rib anomalies) were observed in the presence of maternal toxicity at an exposure approximately 84 times the MRHD (on an AUC basis at a maternal oral dose of 30 mg/kg/day). Embryolethality consisted of increased post-implantation loss that was due to elevated incidences of both early and late resorptions. No developmental toxicity was observed in rabbits at an exposure approximately 12 times the MRHD (on an AUC basis at a maternal oral dose of 10 mg/kg/day). - In a pre- and post-natal development study in pregnant female rats dosed orally from gestation day 6 through lactation day 20, adverse findings observed in pups included decreased survival from birth to post-natal day 4 (due to increased stillbirths and early neonatal deaths), decreased birth weight, decreased body weight gain during the pre-weaning phase, increased incidence of malrotated forelimbs during the pre-weaning phase, and decreased cytotoxic T cells on PND 35 with recovery by PND 65 at exposures approximately 43 times the MRHD (on an AUC basis at a maternal oral dose of 25 mg/kg/day). Developmental delays (that may be secondary to decreased body weight gain) were observed in males and females at exposures approximately 43 times the MRHD (on an AUC basis at a maternal oral dose of 25 mg/kg/day). These findings included decreased forelimb and hindlimb grip strengths, and delayed mean age of sexual maturity. No developmental toxicity was observed in rats at an exposure approximately 9 times the MRHD (on an AUC basis at a maternal oral dose of 5 mg/kg/day). Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Baricitinib in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Baricitinib during labor and delivery. ### Nursing Mothers Risk Summary - No information is available on the presence of baricitinib in human milk, the effects of the drug on the breastfed infant, or the effects of the drug on milk production. Baricitinib is present in the milk of lactating rats. Due to species-specific differences in lactation physiology, the clinical relevance of these data are not clear. Because of the potential for serious adverse reactions in nursing infants, advise an baricitinib-treated woman not to breastfeed. Data - A single oral dose of 25 mg/kg radiolabeled baricitinib was administered to lactating female Sprague-Dawley rats on post-partum day 13. Drug exposure was approximately 45-fold greater in milk than in plasma based on AUC0-t values. ### Pediatric Use - The safety and effectiveness of baricitinib in pediatric patients have not been established. ### Geriatic Use - Of the 3100 patients treated in the four phase 3 studies, a total of 537 rheumatoid arthritis patients were 65 years of age and older, including 71 patients 75 years and older. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. - Baricitinib is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. ### Gender There is no FDA guidance on the use of Baricitinib with respect to specific gender populations. ### Race There is no FDA guidance on the use of Baricitinib with respect to specific racial populations. ### Renal Impairment - Renal function was found to significantly affect baricitinib exposure. Baricitinib is not recommended for use in patients with estimated GFR of less than 60 mL/min/1.73 m2 ### Hepatic Impairment - No dose adjustment is necessary in patients with mild or moderate hepatic impairment. The use of baricitinib has not been studied in patients with severe hepatic impairment and is therefore not recommended. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Baricitinib in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Baricitinib in patients who are immunocompromised. # Administration and Monitoring ### Administration - The recommended dose of baricitinib is 2 mg once daily. - Baricitinib may be used as monotherapy or in combination with methotrexate or other DMARDs. - Baricitinib is given orally with or without food. - Baricitinib initiation is not recommended in patients with an absolute lymphocyte count (ALC) less than 500 cells/mm3, absolute neutrophil count (ANC) less than 1000 cells/mm3, or hemoglobin level less than 8 g/dL. - Avoid use of baricitinib in patients with active, serious infection, including localized infections. - Prior to initiating baricitinib, test patients for latent tuberculosis (TB). If positive, consider treating for TB prior to baricitinib use. ### Monitoring - If a patient develops a serious infection, hold treatment with baricitinib until the infection is controlled. - Modify dosage in cases of lymphopenia, neutropenia or anemia (TABLES 1, 2, and 3). For treatment initiation criteria. - Baricitinib is not recommended for use in patients with estimated GFR of less than 60 mL/min/1.73 m2. - Baricitinib is not recommended for use in patients with severe hepatic impairment. - Baricitinib is not recommended for use in patients taking strong Organic Anion Transporter 3 (OAT3) inhibitors, such as probenecid. # IV Compatibility There is limited information regarding the compatibility of Baricitinib and IV administrations. # Overdosage - Single doses up to 40 mg and multiple doses of up to 20 mg daily for 10 days have been administered in clinical trials without dose-limiting toxicity. Pharmacokinetic data of a single dose of 40 mg in healthy volunteers indicate that more than 90% of the administered dose is expected to be eliminated within 24 hours. - In case of an overdose, it is recommended that the patient should be monitored for signs and symptoms of adverse reactions. Patients who develop adverse reactions should receive appropriate treatment. # Pharmacology ## Mechanism of Action - Baricitinib is a Janus kinase (JAK) inhibitor. JAKs are intracellular enzymes which transmit signals arising from cytokine or growth factor-receptor interactions on the cellular membrane to influence cellular processes of hematopoiesis and immune cell function. Within the signaling pathway, JAKs phosphorylate and activate Signal Transducers and Activators of Transcription (STATs) which modulate intracellular activity including gene expression. Baricitinib modulates the signaling pathway at the point of JAKs, preventing the phosphorylation and activation of STATs. - JAK enzymes transmit cytokine signaling through their pairing (e.g., JAK1/JAK2, JAK1/JAK3, JAK1/TYK2, JAK2/JAK2, JAK2/TYK2). In cell-free isolated enzyme assays, baricitinib had greater inhibitory potency at JAK1, JAK2 and TYK2 relative to JAK3. In human leukocytes, baricitinib inhibited cytokine induced STAT phosphorylation mediated by JAK1/JAK2, JAK1/JAK3, JAK1/TYK2, or JAK2/TYK2 with comparable potencies. However, the relevance of inhibition of specific JAK enzymes to therapeutic effectiveness is not currently known. ## Structure - Baricitinib has an empirical formula of C16H17N7O2S and a molecular weight of 371.42. Baricitinib has the following structural formula: ## Pharmacodynamics - Baricitinib inhibition of IL-6 induced STAT3 phosphorylation – Baricitinib administration resulted in a dose dependent inhibition of IL-6 induced STAT3 phosphorylation in whole blood from healthy subjects with maximal inhibition observed approximately 1 hour after dosing, which returned to near baseline by 24 hours. Similar levels of inhibition were observed using either IL-6 or TPO as the stimulus. - Immunoglobulins – Mean serum IgG, IgM, and IgA values decreased by 12 weeks after starting treatment with baricitinib, and remained stable through at least 52 weeks. For most patients, changes in immunoglobulins occurred within the normal reference range. - C-reactive protein – In patients with rheumatoid arthritis, decreases in serum C-reactive protein (CRP) were observed as early as one week after starting treatment with baricitinib and were maintained throughout dosing. - Cardiac Electrophysiology – At a dose 10 times the maximum recommended dose, baricitinib does not prolong the QT interval to any clinically relevant extent. ## Pharmacokinetics - Following oral administration of baricitinib, peak plasma concentrations are reached approximately at 1 hour. A dose-proportional increase in systemic exposure was observed in the therapeutic dose range. The pharmacokinetics of baricitinib do not change over time. Steady-state concentrations are achieved in 2 to 3 days with minimal accumulation after once-daily administration. - Absorption – The absolute bioavailability of baricitinib is approximately 80%. An assessment of food effects in healthy subjects showed that a high-fat meal decreased the mean AUC and Cmax of baricitinib by approximately 11% and 18%, respectively, and delayed the tmax by 0.5 hours. Administration with meals is not associated with a clinically relevant effect on exposure. In clinical studies, baricitinib was administered without regard to meals. - Distribution – After intravenous administration, the volume of distribution is 76 L, indicating distribution of baricitinib into tissues. Baricitinib is approximately 50% bound to plasma proteins and 45% bound to serum proteins. Baricitinib is a substrate of the Pgp, BCRP, OAT3 and MATE2-K transporters, which play roles in drug distribution. - Elimination – The total body clearance of baricitinib is 8.9 L/h in patients with RA. Elimination half-life in patients with rheumatoid arthritis is approximately 12 hours. - Metabolism – Approximately 6% of the orally administered baricitinib dose is identified as metabolites (three from urine and one from feces), with CYP3A4 identified as the main metabolizing enzyme. No metabolites of baricitinib were quantifiable in plasma. - Excretion – Renal elimination is the principal clearance mechanism for baricitinib through filtration and active secretion as baricitinib is identified as a substrate of OAT3, Pgp, BCRP and MATE2-K from in vitro studies. In a clinical pharmacology study, approximately 75% of the administered dose was eliminated in the urine, while about 20% of the dose was eliminated in the feces. Baricitinib was excreted predominately as unchanged drug in urine (69%) and feces (15%). Specific Populations: Effects of Body Weight, Gender, Race, and Age - Body weight, gender, race, ethnicity, and age did not have a clinically relevant effect on the PK (AUC and Cmax) of baricitinib (FIGURE 1). The mean effects of intrinsic factors on PK parameters (AUC and Cmax) were generally within the inter-subject PK variability of baricitinib. The inter-subject variabilities (% coefficients of variation) in AUC and Cmax of baricitinib are approximately 41% and 22%, respectively. Renal Impairment - Baricitinib systemic exposure in AUC was increased by 1.41-, 2.22-, 4.05- and 2.41-fold for mild, moderate, severe, and ESRD (with hemodialysis) renal impairment sub-groups, respectively, compared to subjects with normal renal function. The corresponding values for increase in Cmax were 1.16-, 1.46-, 1.40- and 0.88-fold, respectively (FIGURE 1). Hepatic Impairment - Baricitinib systemic exposure and Cmax increased by 1.19- and 1.08-fold for the moderate hepatic impairment group, respectively, compared to subjects with normal hepatic function (FIGURE 1). Drug Interactions: Potential for Baricitinib to Influence the PK of Other Drugs - In vitro, baricitinib did not significantly inhibit or induce the activity of cytochrome P450 enzymes (CYPs 3A, 1A2, 2B6, 2C8, 2C9, 2C19, and 2D6). In clinical pharmacology studies, there were no clinically meaningful changes in the pharmacokinetics (PK) of simvastatin, ethinyl estradiol, or levonorgestrel (CYP3A substrates) when co-administered with baricitinib. - In vitro studies suggest that baricitinib is not an inhibitor of the transporters, P-glycoprotein (Pgp) or Organic Anion Transporting Polypeptide (OATP) 1B1. In vitro data indicate baricitinib does inhibit organic anionic transporter (OAT) 1, OAT2, OAT3, organic cationic transporter (OCT) 1, OCT2, OATP1B3, Breast Cancer Resistance Protein (BCRP) and Multidrug and Toxic Extrusion Protein (MATE) 1 and MATE2-K, but clinically meaningful changes in the pharmacokinetics of drugs that are substrates for these transporters are unlikely. In clinical pharmacology studies there were no clinically meaningful effects on the PK of digoxin (Pgp substrate) or methotrexate (substrate of several transporters) when co-administered with baricitinib. - Exposure changes of drugs following co-administration with baricitinib are shown in FIGURE 2. Potential for Other Drugs to Influence the PK of Baricitinib - In vitro studies suggest that baricitinib is a CYP3A4 substrate. In clinical pharmacology studies there was no effect on the PK of baricitinib when co-administered with ketoconazole (CYP3A inhibitor). There were no clinically meaningful changes in the PK of baricitinib when co-administered with fluconazole (CYP3A/CYP2C19/CYP2C9 inhibitor) or rifampicin (CYP3A inducer). - In vitro studies suggest that baricitinib is a substrate for OAT3, Pgp, BCRP and MATE2-K. In a clinical study, probenecid administration (strong OAT3 inhibitor) resulted in an approximately 2-fold increase in baricitinib AUC0-∞ with no effect on Cmax and tmax. However, simulations with diclofenac and ibuprofen (OAT3 inhibitors with less inhibition potential) predicted minimal effect on the PK of baricitinib. In clinical pharmacology studies there was no clinically meaningful effect on the PK of baricitinib when co-administered with cyclosporine (Pgp and BCRP inhibitor). Co-administration with methotrexate (substrate of several transporters) did not have a clinically meaningful effect on the PK of baricitinib. - Exposure changes of baricitinib following co-administration with CYP inhibitors or inducers, transporter inhibitors, as well as methotrexate and the proton pump inhibitor, omeprazole, are shown in FIGURE 3. ## Nonclinical Toxicology - The carcinogenic potential of baricitinib was evaluated in Sprague-Dawley rats and Tg.rasH2 mice. No evidence of tumorigenicity was observed in male or female rats that received baricitinib for 91 to 94 weeks at oral doses up to 8 or 25 mg/kg/day, respectively (approximately 12 and 55 times the MRHD on an AUC basis). No evidence of tumorigenicity was observed in Tg.rasH2 mice that received baricitinib for 26 weeks at oral doses up to 300 and 150 mg/kg/day in male and female mice, respectively. - Baricitinib tested negative in the following genotoxicity assays: the in vitro bacterial mutagenicity assay (Ames assay), in vitro chromosome aberration assay in human peripheral blood lymphocytes, and in vivo rat bone marrow micronucleus assay. - Fertility (achievement of pregnancy) was reduced in male and female rats that received baricitinib at oral doses of 50 and 100 mg/kg/day respectively (approximately 113 and 169 times the MRHD in males and females, respectively, on an AUC basis) based upon findings that 7 of 19 (36.8%) drug-treated females with evidence of mating were not gravid compared to 1 of 19 (5.3%) control females. It could not be determined from the study design if these findings were attributable to toxicities in one sex or both. Fertility was unaffected in male and female rats at oral doses of 15 mg/kg and 25 mg/kg, respectively (approximately 25 and 48 times the MRHD on an AUC basis). However, maintenance of pregnancy was adversely affected at these doses based upon findings of increased post-implantation losses (early resorptions) and decreased numbers of mean viable embryos per litter. The number of viable embryos was unaffected in female rats that received baricitinib at an oral dose of 5 mg/kg/day and were mated to males that received the same dose (approximately 8 times the MRHD on an AUC basis). Reproductive performance was unaffected in male and female rats that received baricitinib at oral doses up to 50 and 100 mg/kg/day respectively (approximately 113 and 169 times the MRHD in males and females, respectively, on an AUC basis). # Clinical Studies - The baricitinib clinical development program included two dose-ranging trials and four confirmatory phase 3 trials. Although other doses have been studied, the recommended dose of baricitinib is 2 mg once daily. Dose-Ranging Studies - The dose-ranging studies I (NCT01185353) and II (NCT01469013) included a 12-week randomized comparison of baricitinib 1, 2, 4, and 8 mg versus placebo in 301 and 145 patients, respectively. - The results from the dose-ranging studies are shown in TABLE 5. In dose-ranging Study I, the observed ACR response was similar for baricitinib 1 and 2 mg daily and for baricitinib 4 and 8 mg daily, with the highest response for baricitinib 8 mg daily. In dose-ranging Study II, there was not a clear trend of dose response, with similar response rates for 1 mg and 4 mg and 2 mg and 8 mg. Confirmatory Studies - The efficacy and safety of baricitinib 2 mg once daily was assessed in two confirmatory phase 3 trials. These trials were randomized, double-blind, multicenter studies in patients with active rheumatoid arthritis diagnosed according to American College of Rheumatology (ACR)/European League Against Rheumatism 2010 criteria. Patients over 18 years of age were eligible if at least 6 tender and 6 swollen joints were present at baseline. The two studies (Studies III and IV) evaluated baricitinib 2 mg and baricitinib 4 mg. - Study III (NCT01721057) was a 24-week trial in 684 patients with moderately to severely active rheumatoid arthritis who had an inadequate response or intolerance to conventional DMARDs (cDMARDs). Patients received baricitinib 2 mg or 4 mg once daily or placebo added to existing background cDMARD treatment. From Week 16, non-responding patients could be rescued to receive baricitinib 4 mg once daily. The primary endpoint was the proportion of patients who achieved an ACR20 response at Week 12. - Study IV (NCT01721044) was a 24-week trial in 527 patients with moderately to severely active rheumatoid arthritis who had an inadequate response or intolerance to 1 or more TNF inhibitor therapies with or without other biologic DMARDs (TNFi-IR). Patients received baricitinib 2 mg or baricitinib 4 mg once daily or placebo added to background cDMARD treatment. From Week 16, non-responding patients could be rescued to receive baricitinib 4 mg once daily. The primary endpoint was the proportion of patients who achieved an ACR20 response at Week 12. Clinical Response - The percentages of baricitinib-treated patients achieving ACR20, ACR50, and ACR70 responses, and Disease Activity Score (DAS28-CRP) <2.6 in Studies III and IV are shown in TABLE 6. - Patients treated with baricitinib had higher rates of ACR response and DAS28-CRP <2.6 versus placebo-treated patients at Week 12 (Studies III and IV) (TABLE 6). - In Study IV, higher ACR20 response rates (FIGURE 4) were observed as early as 1 week with baricitinib 2 mg versus placebo. - In Study IV, the proportions of patients achieving DAS28-CRP <2.6 who had at least 3 active joints at the end of Week 24 were 18.2% and 10.5%, in the placebo and baricitinib 2 mg arms, respectively. Physical Function Response - Improvement in physical function was measured by the Health Assessment Questionnaire-Disability Index (HAQ-DI). Patients receiving baricitinib 2 mg demonstrated greater improvement from baseline in physical functioning compared to placebo at Week 24. The mean difference (95% CI) from placebo in HAQ-DI change from baseline at Week 24 was -0.24 (-0.35, -0.14) in Study III and -0.23 (-0.35, -0.12) in Study IV. Other Health Related Outcomes - General health status was assessed by the Short Form health survey (SF-36). In Studies III and IV, compared to placebo, patients treated with baricitinib 2 mg demonstrated greater improvement from baseline in the physical component summary (PCS) score and the physical function, role physical, bodily pain, vitality, and general health domains at Week 12, with no consistent improvements in the mental component summary (MCS) scores or the role emotional, mental health, and social functioning domains. # How Supplied - Baricitinib for oral administration is available as debossed, film-coated, immediate-release tablets. Each tablet contains a recessed area on each face of the tablet surface. ## Storage - Store at 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F). - Keep out of reach of children. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information - Advise the patient to read the FDA-approved patient labeling (Medication Guide). Patient Counseling - Advise patients of the potential benefits and risks of baricitinib. Infections - Inform patients that they may be more likely to develop infections when taking baricitinib. Instruct patients to tell their healthcare provider if they develop any signs or symptoms of an infection. - Advise patients that the risk of herpes zoster is increased in patients treated with baricitinib and some cases can be serious. Malignancies and Lymphoproliferative Disorders - Inform patients that baricitinib may increase their risk of certain cancers, and that lymphoma and other cancers have been observed in patients taking baricitinib. Instruct patients to inform their healthcare provider if they have ever had any type of cancer. Thrombosis - Advise patients that events of DVT and PE have been reported in clinical studies with baricitinib. Instruct patients to tell their healthcare provider if they develop any signs or symptoms of a DVT or PE. Laboratory Abnormalities - Inform patients that baricitinib may affect certain lab tests, and that blood tests are required before and during baricitinib treatment. Lactation - Advise a woman not to breastfeed during treatment with baricitinib. # Precautions with Alcohol Alcohol-Baricitinib interaction has not been established. Talk to your doctor regarding the effects of taking alcohol with this medication. # Brand Names Olumiant # Look-Alike Drug Names There is limited information regarding Baricitinib Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	Baricitinib Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Zach Leibowitz [2] # Disclaimer WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here. # Black Box Warning # Overview Baricitinib is a Janus kinase (JAK) inhibitor that is FDA approved for the treatment of adult patients with moderately to severely active rheumatoid arthritis who have had an inadequate response to one or more TNF antagonist therapies. There is a Black Box Warning for this drug as shown here. Common adverse reactions include upper respiratory tract infections, nausea, herpes simplex, and herpes zoster. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) Indication - Baricitinib is indicated for the treatment of adult patients with moderately to severely active rheumatoid arthritis who have had an inadequate response to one or more tumor necrosis factor (TNF) antagonist therapies. - Limitation of Use: Use of baricitinib in combination with other JAK inhibitors, biologic disease-modifying antirheumatic drugs (DMARDs), or with potent immunosuppressants such as azathioprine and cyclosporine is not recommended. Dosage - The recommended dose of baricitinib is 2 mg once daily. - Baricitinib may be used as monotherapy or in combination with methotrexate or other DMARDs. - Baricitinib is given orally with or without food. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding baricitinib Off-Label Guideline-Supported Use and Dosage (Adult) in the drug label. ### Non–Guideline-Supported Use There is limited information regarding baricitinib Off-Label Non-Guideline-Supported Use and Dosage (Adult) in the drug label. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) The safety and effectiveness of baricitinib in pediatric patients have not been established. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding baricitinib Off-Label Guideline-Supported Use and Dosage (Pediatric) in the drug label. ### Non–Guideline-Supported Use There is limited information regarding baricitinib Off-Label Non-Guideline-Supported Use and Dosage (Pediatric) in the drug label. # Contraindications None. # Warnings - Serious and sometimes fatal infections due to bacterial, mycobacterial, invasive fungal, viral, or other opportunistic pathogens have been reported in rheumatoid arthritis patients receiving baricitinib. The most common serious infections reported with baricitinib included pneumonia, herpes zoster, and urinary tract infection. Among opportunistic infections, tuberculosis, multidermatomal herpes zoster, esophageal candidiasis, pneumocystosis, acute histoplasmosis, cryptococcosis, cytomegalovirus, and BK virus were reported with baricitinib. Some patients have presented with disseminated rather than localized disease, and were often taking concomitant immunosuppressants such as methotrexate or corticosteroids. - Avoid use of baricitinib in patients with an active, serious infection, including localized infections. Consider the risks and benefits of treatment prior to initiating baricitinib in patients: with chronic or recurrent infection who have been exposed to tuberculosis with a history of a serious or an opportunistic infection who have resided or traveled in areas of endemic tuberculosis or endemic mycoses; or with underlying conditions that may predispose them to infection. - with chronic or recurrent infection - who have been exposed to tuberculosis - with a history of a serious or an opportunistic infection - who have resided or traveled in areas of endemic tuberculosis or endemic mycoses; or - with underlying conditions that may predispose them to infection. - Closely monitor patients for the development of signs and symptoms of infection during and after treatment with baricitinib. Interrupt baricitinib if a patient develops a serious infection, an opportunistic infection, or sepsis. A patient who develops a new infection during treatment with baricitinib should undergo prompt and complete diagnostic testing appropriate for an immunocompromised patient; appropriate antimicrobial therapy should be initiated, the patient should be closely monitored, and baricitinib should be interrupted if the patient is not responding to therapy. Do not resume baricitinib until the infection is controlled. Tuberculosis - Evaluate and test patients for latent or active infection prior to administration of baricitinib. Patients with latent tuberculosis (TB) should be treated with standard antimycobacterial therapy before initiating baricitinib. - Baricitinib should not be given to patients with active TB. Consider anti-TB therapy prior to initiation of baricitinib in patients with a history of latent or active TB in whom an adequate course of treatment cannot be confirmed, and for patients with a negative test for latent TB but who have risk factors for TB infection. Consultation with a physician with expertise in the treatment of TB is recommended to aid in the decision about whether initiating anti-TB therapy is appropriate for an individual patient. - Monitor patients for the development of signs and symptoms of TB, including patients who tested negative for latent TB infection prior to initiating therapy. Viral Reactivation - Viral reactivation, including cases of herpes virus reactivation (e.g., herpes zoster), were reported in clinical studies with baricitinib. If a patient develops herpes zoster, interrupt baricitinib treatment until the episode resolves. - The impact of baricitinib on chronic viral hepatitis reactivation is unknown. Patients with evidence of active hepatitis B or C infection were excluded from clinical trials. Patients who were positive for hepatitis C antibody but negative for hepatitis C virus RNA were permitted to enroll. Patients with positive hepatitis B surface antibody and hepatitis B core antibody, without hepatitis B surface antigen, were permitted to enroll; such patients should be monitored for expression of hepatitis B virus (HBV) DNA. Should HBV DNA be detected, consult with a hepatologist. Perform screening for viral hepatitis in accordance with clinical guidelines before starting therapy with baricitinib. - Consider the risks and benefits of baricitinib treatment prior to initiating therapy in patients with a known malignancy other than a successfully treated non-melanoma skin cancer (NMSC) or when considering continuing baricitinib in patients who develop a malignancy. Malignancies were observed in clinical studies of baricitinib. Non-melanoma skin cancers - Non-melanoma skin cancers (NMSCs) have been reported in patients treated with baricitinib. Periodic skin examination is recommended for patients who are at increased risk for skin cancer. - Thrombosis, including deep venous thrombosis (DVT) and pulmonary embolism (PE), has been observed at an increased incidence in patients treated with baricitinib compared to placebo. In addition, arterial thrombosis events in the extremities have been reported in clinical studies with baricitinib. Many of these adverse events were serious and some resulted in death. There was no clear relationship between platelet count elevations and thrombotic events. Baricitinib should be used with caution in patients who may be at increased risk of thrombosis. If clinical features of DVT/PE or arterial thrombosis occur, patients should be evaluated promptly and treated appropriately. - Events of gastrointestinal perforation have been reported in clinical studies with baricitinib, although the role of JAK inhibition in these events is not known. - Baricitinib should be used with caution in patients who may be at increased risk for gastrointestinal perforation (e.g., patients with a history of diverticulitis). Patients presenting with new onset abdominal symptoms should be evaluated promptly for early identification of gastrointestinal perforation. - Neutropenia – Treatment with baricitinib was associated with an increased incidence of neutropenia (ANC less than 1000 cells/mm3) compared to placebo. Avoid initiation or interrupt baricitinib treatment in patients with an ANC less than 1000 cells/mm3. Evaluate at baseline and thereafter according to routine patient management. For recommended modifications based on ANC. - Lymphopenia – ALC less than 500 cells/mm3 were reported in baricitinib clinical trials. Lymphocyte counts less than the lower limit of normal were associated with infection in patients treated with baricitinib, but not placebo. Avoid initiation or interrupt baricitinib treatment in patients with an ALC less than 500 cells/mm3. Evaluate at baseline and thereafter according to routine patient management. For recommended modifications based on ALC results. - Avoid initiation or interrupt baricitinib treatment in patients with an ALC less than 500 cells/mm3. Evaluate at baseline and thereafter according to routine patient management. For recommended modifications based on ALC results. - Anemia – Decreases in hemoglobin levels to less than 8 g/dL were reported in baricitinib clinical trials. Avoid initiation or interrupt baricitinib treatment in patients with hemoglobin less than 8 g/dL. Evaluate at baseline and thereafter according to routine patient management. For recommended modifications based on hemoglobin results. - Liver Enzyme Elevations – Treatment with baricitinib was associated with increased incidence of liver enzyme elevation compared to placebo. Increases to greater than or equal to 5x and greater than or equal to 10x upper limit of normal (ULN) were observed for both ALT and AST in patients in baricitinib clinical trials. Evaluate at baseline and thereafter according to routine patient management. Prompt investigation of the cause of liver enzyme elevation is recommended to identify potential cases of drug-induced liver injury. If increases in ALT or AST are observed and drug-induced liver injury is suspected, interrupt baricitinib until this diagnosis is excluded. - Evaluate at baseline and thereafter according to routine patient management. Prompt investigation of the cause of liver enzyme elevation is recommended to identify potential cases of drug-induced liver injury. If increases in ALT or AST are observed and drug-induced liver injury is suspected, interrupt baricitinib until this diagnosis is excluded. - Lipid Elevations – Treatment with baricitinib was associated with increases in lipid parameters, including total cholesterol, low-density lipoprotein (LDL) cholesterol, and high-density lipoprotein (HDL) cholesterol. Assessment of lipid parameters should be performed approximately 12 weeks following baricitinib initiation. Manage patients according to clinical guidelines for the management of hyperlipidemia. - Manage patients according to clinical guidelines for the management of hyperlipidemia. - Avoid use of live vaccines with baricitinib. - Update immunizations in agreement with current immunization guidelines prior to initiating baricitinib therapy. # Adverse Reactions ## Clinical Trials Experience - Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not predict the rates observed in a broader patient population in clinical practice. - The following data include six randomized double-blind placebo-controlled studies (three Phase 2, three Phase 3) and a long-term extension study. All patients had moderately to severely active RA. Patients were randomized to placebo (1070 patients), baricitinib 2 mg (479 patients), or baricitinib 4 mg (997 patients). - Patients could be switched to baricitinib 4 mg from placebo or baricitinib 2 mg from as early as Week 12 depending on the study design. All patients initially randomized to placebo were switched to baricitinib 4 mg by Week 24. - During the 16-week treatment period, adverse events leading to discontinuation of treatment were reported by 35 patients (11.4 events per 100 patient-years) treated with placebo, 17 patients (12.1 events per 100 patient-years) with baricitinib 2 mg, and 40 patients (13.4 events per 100 patient-years) treated with baricitinib 4 mg. - During 0 to 52 week exposure, adverse events leading to discontinuation of treatment were reported by 31 patients (9.2 events per 100 patient-years) with baricitinib 2 mg, and 92 patients (10.2 events per 100 patient-years) treated with baricitinib 4 mg. - Overall Infections – During the 16-week treatment period, infections were reported by 253 patients (82.1 events per 100 patient-years) treated with placebo, 139 patients (99.1 events per 100 patient-years) treated with baricitinib 2 mg, and 298 patients (100.1 events per 100 patient-years) treated with baricitinib 4 mg. - During 0 to 52 week exposure, infections were reported by 200 patients (59.6 events per 100 patients-years) treated with baricitinib 2 mg, and 500 patients (55.3 events per 100 patient-years) treated with baricitinib 4 mg. - In the 0 to 52 week exposure population, the most commonly reported infections with baricitinib were viral upper respiratory tract infection, upper respiratory tract infection, urinary tract infection, and bronchitis. - Serious Infections – During the 16-week treatment period, serious infections were reported in 13 patients (4.2 events per 100 patient-years) treated with placebo, 5 patients (3.6 events per 100 patient-years) treated with baricitinib 2 mg, and 11 patients (3.7 events per 100 patient-years) treated with baricitinib 4 mg. - During 0 to 52 week exposure, serious infections were reported in 14 patients (4.2 events per 100 patient-years) treated with baricitinib 2 mg and 32 patients (3.5 events per 100 patient-years) treated with baricitinib 4 mg. - In the 0 to 52 week exposure population, the most commonly reported serious infections with baricitinib were pneumonia, herpes zoster, and urinary tract infection. - Tuberculosis – During the 16-week treatment period, no events of tuberculosis were reported. - During 0 to 52 week exposure, events of tuberculosis were reported in 0 patients treated with baricitinib 2 mg and 1 patient (0.1 per 100 patient-years) treated with baricitinib 4 mg. - Cases of disseminated tuberculosis were also reported. - Opportunistic Infections (excluding tuberculosis) – During the 16-week treatment period, opportunistic infections were reported in 2 patients (0.6 per 100 patient-years) treated with placebo, 0 patients treated with baricitinib 2 mg and 2 patients (0.7 per 100 patient-years) treated with baricitinib 4 mg. - During 0 to 52 week exposure, opportunistic infections were reported in 1 patient (0.3 per 100 patient-years) treated with baricitinib 2 mg and 5 patients (0.6 per 100 patient-years) treated with baricitinib 4 mg. - Malignancy – During the 16-week treatment period, malignancies excluding non-melanoma skin cancers (NMSC) were reported in 0 patients treated with placebo, 1 patient (0.7 per 100 patient-years) treated with baricitinib 2 mg, and 1 patient (0.3 per 100 patient-years) treated with baricitinib 4 mg. - During the 0 to 52 week treatment period, malignancies excluding NMSC were reported in 2 patients (0.6 per 100 patient-years) treated with baricitinib 2 mg and 6 patients (0.7 per 100 patient-years) treated with baricitinib 4 mg. - Venous Thrombosis – During the 16-week treatment period, venous thromboses (deep vein thrombosis or pulmonary embolism) were reported in 0 patients treated with placebo, 0 patients treated with baricitinib 2 mg, and 5 patients (1.7 per 100 patient-years) treated with baricitinib 4 mg. - During the 0 to 52 week treatment period, venous thromboses were reported in 2 patients (0.6 per 100 patient-years) treated with baricitinib 2 mg and 7 patients (0.8 per 100 patient-years) treated with baricitinib 4 mg. - Arterial Thrombosis – During the 16-week treatment period, arterial thromboses were reported in 1 patient treated with placebo (0.3 per 100 patient-years), 2 patients (1.4 per 100 patient-years) treated with baricitinib 2 mg, and 2 patients (0.7 per 100 patient-years) treated with baricitinib 4 mg. - During the 0 to 52 week treatment period, arterial thromboses were reported in 3 patients (0.9 per 100 patient-years) treated with baricitinib 2 mg and 3 patients (0.3 per 100 patient-years) treated with baricitinib 4 mg. Laboratory Abnormalities - Neutropenia – During the 16-week treatment period, neutrophil counts below 1000 cells/mm3 occurred in 0% of patients treated with placebo, 0.6% of patients treated with baricitinib 2 mg, and 0.3% of patients treated with baricitinib 4 mg. There were no neutrophil counts below 500 cells/mm3 observed in any treatment group. - Platelet Elevations – During the 16-week treatment period, increases in platelet counts above 600,000 cells/mm3 occurred in 1.1% of patients treated with placebo, 1.1% of patients treated with baricitinib 2 mg, and 2.0% of patients treated with baricitinib 4 mg. Mean platelet count increased by 3000 cells/mm3 at 16 weeks in patients treated with placebo, by 15,000 cells/mm3 at 16 weeks in patients treated with baricitinib 2 mg and by 23,000 cells/mm3 in patients treated with baricitinib 4 mg. - Liver Enzyme Elevations – Events of increases in liver enzymes greater than or equal to 3x ULN were observed in patients treated with baricitinib. During the 16-week treatment period, ALT elevations greater than or equal to 3x ULN occurred in 1.0% of patients treated with placebo, 1.7% of patients treated with baricitinib 2 mg, and 1.4% of patients treated with baricitinib 4 mg. During the 16-week treatment period, AST elevations greater than or equal to 3x ULN occurred in 0.8% of patients treated with placebo, 1.3% of patients treated with baricitinib 2 mg, and 0.8% of patients treated with baricitinib 4 mg. In a phase 3 study of DMARD naive patients, during the 24-week treatment period, ALT and AST elevations ≥3x ULN occurred in 1.9% and 0% of patients treated with methotrexate monotherapy, 1.9% and 1.3% of patients treated with baricitinib 4 mg monotherapy, and 4.7% and 1.9% of patients treated with baricitinib 4 mg plus methotrexate. - During the 16-week treatment period, ALT elevations greater than or equal to 3x ULN occurred in 1.0% of patients treated with placebo, 1.7% of patients treated with baricitinib 2 mg, and 1.4% of patients treated with baricitinib 4 mg. - During the 16-week treatment period, AST elevations greater than or equal to 3x ULN occurred in 0.8% of patients treated with placebo, 1.3% of patients treated with baricitinib 2 mg, and 0.8% of patients treated with baricitinib 4 mg. - In a phase 3 study of DMARD naive patients, during the 24-week treatment period, ALT and AST elevations ≥3x ULN occurred in 1.9% and 0% of patients treated with methotrexate monotherapy, 1.9% and 1.3% of patients treated with baricitinib 4 mg monotherapy, and 4.7% and 1.9% of patients treated with baricitinib 4 mg plus methotrexate. - Lipid Elevations – In controlled clinical trials, baricitinib treatment was associated with dose-related increases in lipid parameters including total cholesterol, triglycerides, LDL cholesterol, and HDL cholesterol. Elevations were observed at 12 weeks and remained stable thereafter. During the 12-week treatment period, changes in lipid parameters are summarized below: Mean LDL cholesterol increased by 8 mg/dL in patients treated with baricitinib 2 mg and by 14 mg/dL in patients treated with baricitinib 4 mg. Mean HDL cholesterol increased by 7 mg/dL in patients treated with baricitinib 2 mg and by 9 mg/dL in patients treated with baricitinib 4 mg. The mean LDL/HDL ratio remained stable. Mean triglycerides increased by 7 mg/dL in patients treated with baricitinib 2 mg and by 15 mg/dL in patients treated with baricitinib 4 mg. - Mean LDL cholesterol increased by 8 mg/dL in patients treated with baricitinib 2 mg and by 14 mg/dL in patients treated with baricitinib 4 mg. - Mean HDL cholesterol increased by 7 mg/dL in patients treated with baricitinib 2 mg and by 9 mg/dL in patients treated with baricitinib 4 mg. - The mean LDL/HDL ratio remained stable. - Mean triglycerides increased by 7 mg/dL in patients treated with baricitinib 2 mg and by 15 mg/dL in patients treated with baricitinib 4 mg. - Creatine Phosphokinase (CPK) – baricitinib treatment was associated with increases in CPK within one week of starting baricitinib and plateauing after 8 to 12 weeks. At 16 weeks, the mean change in CPK for baricitinib 2 mg and baricitinib 4 mg was 37 IU/L and 52 IU/L, respectively. - Creatinine – In controlled clinical trials, dose-related increases in serum creatinine were observed with baricitinib treatment. At 52 weeks, the mean increase in serum creatinine was less than 0.1 mg/dL with baricitinib 4 mg. The clinical significance of the observed serum creatinine increases is unknown. Other Adverse Reactions - Other adverse reactions are summarized in TABLE 4. - Additional adverse drug reactions occurring in fewer than 1% of patients: acne. ## Postmarketing Experience There is limited information regarding Baricitinib Postmarketing Experience in the drug label. # Drug Interactions - Baricitinib exposure is increased when baricitinib is co-administered with strong OAT3 inhibitors (such as probenecid). - Baricitinib has not been studied in combination with other JAK inhibitors or with biologic DMARDs. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): Risk Summary - The limited human data on use of baricitinib in pregnant women are not sufficient to inform a drug-associated risk for major birth defects or miscarriage. In animal embryo-fetal development studies, oral baricitinib administration to pregnant rats and rabbits at exposures equal to and greater than approximately 20 and 84 times the maximum recommended human dose (MRHD), respectively, resulted in reduced fetal body weights, increased embryolethality (rabbits only), and dose-related increases in skeletal malformations. No developmental toxicity was observed in pregnant rats and rabbits treated with oral baricitinib during organogenesis at approximately 5 and 13 times the exposure at the MRHD, respectively. In a pre- and post-natal development study in pregnant female rats, oral baricitinib administration at exposures approximately 43 times the MRHD resulted in reduction in pup viability (increased incidence of stillborn pups and early neonatal deaths), decreased fetal birth weight, reduced fetal body weight gain, decreased cytotoxic T cells on post-natal day (PND) 35 with evidence of recovery by PND 65, and developmental delays that might be attributable to decreased body weight gain. No developmental toxicity was observed at an exposure approximately 9 times the exposure at the MRHD. - The estimated background risk of major birth defects and miscarriage for the indicated population(s) are unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. Animal Data - In an embryofetal development study in pregnant rats, dosed orally during the period of organogenesis from gestation days 6 to 17, baricitinib was teratogenic (skeletal malformations that consisted of bent limb bones and rib anomalies) at exposures equal to or greater than approximately 20 times the MRHD (on an AUC basis at maternal oral doses of 10 mg/kg/day and higher). No developmental toxicity was observed in rats at an exposure approximately 5 times the MRHD (on an AUC basis at a maternal oral dose of 2 mg/kg/day). - In an embryofetal development study in pregnant rabbits, dosed orally during the period of organogenesis from gestation days 7 to 20, embryolethality, decreased fetal body weights, and skeletal malformations (rib anomalies) were observed in the presence of maternal toxicity at an exposure approximately 84 times the MRHD (on an AUC basis at a maternal oral dose of 30 mg/kg/day). Embryolethality consisted of increased post-implantation loss that was due to elevated incidences of both early and late resorptions. No developmental toxicity was observed in rabbits at an exposure approximately 12 times the MRHD (on an AUC basis at a maternal oral dose of 10 mg/kg/day). - In a pre- and post-natal development study in pregnant female rats dosed orally from gestation day 6 through lactation day 20, adverse findings observed in pups included decreased survival from birth to post-natal day 4 (due to increased stillbirths and early neonatal deaths), decreased birth weight, decreased body weight gain during the pre-weaning phase, increased incidence of malrotated forelimbs during the pre-weaning phase, and decreased cytotoxic T cells on PND 35 with recovery by PND 65 at exposures approximately 43 times the MRHD (on an AUC basis at a maternal oral dose of 25 mg/kg/day). Developmental delays (that may be secondary to decreased body weight gain) were observed in males and females at exposures approximately 43 times the MRHD (on an AUC basis at a maternal oral dose of 25 mg/kg/day). These findings included decreased forelimb and hindlimb grip strengths, and delayed mean age of sexual maturity. No developmental toxicity was observed in rats at an exposure approximately 9 times the MRHD (on an AUC basis at a maternal oral dose of 5 mg/kg/day). Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Baricitinib in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Baricitinib during labor and delivery. ### Nursing Mothers Risk Summary - No information is available on the presence of baricitinib in human milk, the effects of the drug on the breastfed infant, or the effects of the drug on milk production. Baricitinib is present in the milk of lactating rats. Due to species-specific differences in lactation physiology, the clinical relevance of these data are not clear. Because of the potential for serious adverse reactions in nursing infants, advise an baricitinib-treated woman not to breastfeed. Data - A single oral dose of 25 mg/kg radiolabeled baricitinib was administered to lactating female Sprague-Dawley rats on post-partum day 13. Drug exposure was approximately 45-fold greater in milk than in plasma based on AUC0-t values. ### Pediatric Use - The safety and effectiveness of baricitinib in pediatric patients have not been established. ### Geriatic Use - Of the 3100 patients treated in the four phase 3 studies, a total of 537 rheumatoid arthritis patients were 65 years of age and older, including 71 patients 75 years and older. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. - Baricitinib is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. ### Gender There is no FDA guidance on the use of Baricitinib with respect to specific gender populations. ### Race There is no FDA guidance on the use of Baricitinib with respect to specific racial populations. ### Renal Impairment - Renal function was found to significantly affect baricitinib exposure. Baricitinib is not recommended for use in patients with estimated GFR of less than 60 mL/min/1.73 m2 ### Hepatic Impairment - No dose adjustment is necessary in patients with mild or moderate hepatic impairment. The use of baricitinib has not been studied in patients with severe hepatic impairment and is therefore not recommended. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Baricitinib in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Baricitinib in patients who are immunocompromised. # Administration and Monitoring ### Administration - The recommended dose of baricitinib is 2 mg once daily. - Baricitinib may be used as monotherapy or in combination with methotrexate or other DMARDs. - Baricitinib is given orally with or without food. - Baricitinib initiation is not recommended in patients with an absolute lymphocyte count (ALC) less than 500 cells/mm3, absolute neutrophil count (ANC) less than 1000 cells/mm3, or hemoglobin level less than 8 g/dL. - Avoid use of baricitinib in patients with active, serious infection, including localized infections. - Prior to initiating baricitinib, test patients for latent tuberculosis (TB). If positive, consider treating for TB prior to baricitinib use. ### Monitoring - If a patient develops a serious infection, hold treatment with baricitinib until the infection is controlled. - Modify dosage in cases of lymphopenia, neutropenia or anemia (TABLES 1, 2, and 3). For treatment initiation criteria. - Baricitinib is not recommended for use in patients with estimated GFR of less than 60 mL/min/1.73 m2. - Baricitinib is not recommended for use in patients with severe hepatic impairment. - Baricitinib is not recommended for use in patients taking strong Organic Anion Transporter 3 (OAT3) inhibitors, such as probenecid. # IV Compatibility There is limited information regarding the compatibility of Baricitinib and IV administrations. # Overdosage - Single doses up to 40 mg and multiple doses of up to 20 mg daily for 10 days have been administered in clinical trials without dose-limiting toxicity. Pharmacokinetic data of a single dose of 40 mg in healthy volunteers indicate that more than 90% of the administered dose is expected to be eliminated within 24 hours. - In case of an overdose, it is recommended that the patient should be monitored for signs and symptoms of adverse reactions. Patients who develop adverse reactions should receive appropriate treatment. # Pharmacology ## Mechanism of Action - Baricitinib is a Janus kinase (JAK) inhibitor. JAKs are intracellular enzymes which transmit signals arising from cytokine or growth factor-receptor interactions on the cellular membrane to influence cellular processes of hematopoiesis and immune cell function. Within the signaling pathway, JAKs phosphorylate and activate Signal Transducers and Activators of Transcription (STATs) which modulate intracellular activity including gene expression. Baricitinib modulates the signaling pathway at the point of JAKs, preventing the phosphorylation and activation of STATs. - JAK enzymes transmit cytokine signaling through their pairing (e.g., JAK1/JAK2, JAK1/JAK3, JAK1/TYK2, JAK2/JAK2, JAK2/TYK2). In cell-free isolated enzyme assays, baricitinib had greater inhibitory potency at JAK1, JAK2 and TYK2 relative to JAK3. In human leukocytes, baricitinib inhibited cytokine induced STAT phosphorylation mediated by JAK1/JAK2, JAK1/JAK3, JAK1/TYK2, or JAK2/TYK2 with comparable potencies. However, the relevance of inhibition of specific JAK enzymes to therapeutic effectiveness is not currently known. ## Structure - Baricitinib has an empirical formula of C16H17N7O2S and a molecular weight of 371.42. Baricitinib has the following structural formula: ## Pharmacodynamics - Baricitinib inhibition of IL-6 induced STAT3 phosphorylation – Baricitinib administration resulted in a dose dependent inhibition of IL-6 induced STAT3 phosphorylation in whole blood from healthy subjects with maximal inhibition observed approximately 1 hour after dosing, which returned to near baseline by 24 hours. Similar levels of inhibition were observed using either IL-6 or TPO as the stimulus. - Immunoglobulins – Mean serum IgG, IgM, and IgA values decreased by 12 weeks after starting treatment with baricitinib, and remained stable through at least 52 weeks. For most patients, changes in immunoglobulins occurred within the normal reference range. - C-reactive protein – In patients with rheumatoid arthritis, decreases in serum C-reactive protein (CRP) were observed as early as one week after starting treatment with baricitinib and were maintained throughout dosing. - Cardiac Electrophysiology – At a dose 10 times the maximum recommended dose, baricitinib does not prolong the QT interval to any clinically relevant extent. ## Pharmacokinetics - Following oral administration of baricitinib, peak plasma concentrations are reached approximately at 1 hour. A dose-proportional increase in systemic exposure was observed in the therapeutic dose range. The pharmacokinetics of baricitinib do not change over time. Steady-state concentrations are achieved in 2 to 3 days with minimal accumulation after once-daily administration. - Absorption – The absolute bioavailability of baricitinib is approximately 80%. An assessment of food effects in healthy subjects showed that a high-fat meal decreased the mean AUC and Cmax of baricitinib by approximately 11% and 18%, respectively, and delayed the tmax by 0.5 hours. Administration with meals is not associated with a clinically relevant effect on exposure. In clinical studies, baricitinib was administered without regard to meals. - Distribution – After intravenous administration, the volume of distribution is 76 L, indicating distribution of baricitinib into tissues. Baricitinib is approximately 50% bound to plasma proteins and 45% bound to serum proteins. Baricitinib is a substrate of the Pgp, BCRP, OAT3 and MATE2-K transporters, which play roles in drug distribution. - Elimination – The total body clearance of baricitinib is 8.9 L/h in patients with RA. Elimination half-life in patients with rheumatoid arthritis is approximately 12 hours. - Metabolism – Approximately 6% of the orally administered baricitinib dose is identified as metabolites (three from urine and one from feces), with CYP3A4 identified as the main metabolizing enzyme. No metabolites of baricitinib were quantifiable in plasma. - Excretion – Renal elimination is the principal clearance mechanism for baricitinib through filtration and active secretion as baricitinib is identified as a substrate of OAT3, Pgp, BCRP and MATE2-K from in vitro studies. In a clinical pharmacology study, approximately 75% of the administered dose was eliminated in the urine, while about 20% of the dose was eliminated in the feces. Baricitinib was excreted predominately as unchanged drug in urine (69%) and feces (15%). Specific Populations: Effects of Body Weight, Gender, Race, and Age - Body weight, gender, race, ethnicity, and age did not have a clinically relevant effect on the PK (AUC and Cmax) of baricitinib (FIGURE 1). The mean effects of intrinsic factors on PK parameters (AUC and Cmax) were generally within the inter-subject PK variability of baricitinib. The inter-subject variabilities (% coefficients of variation) in AUC and Cmax of baricitinib are approximately 41% and 22%, respectively. Renal Impairment - Baricitinib systemic exposure in AUC was increased by 1.41-, 2.22-, 4.05- and 2.41-fold for mild, moderate, severe, and ESRD (with hemodialysis) renal impairment sub-groups, respectively, compared to subjects with normal renal function. The corresponding values for increase in Cmax were 1.16-, 1.46-, 1.40- and 0.88-fold, respectively (FIGURE 1). Hepatic Impairment - Baricitinib systemic exposure and Cmax increased by 1.19- and 1.08-fold for the moderate hepatic impairment group, respectively, compared to subjects with normal hepatic function (FIGURE 1). Drug Interactions: Potential for Baricitinib to Influence the PK of Other Drugs - In vitro, baricitinib did not significantly inhibit or induce the activity of cytochrome P450 enzymes (CYPs 3A, 1A2, 2B6, 2C8, 2C9, 2C19, and 2D6). In clinical pharmacology studies, there were no clinically meaningful changes in the pharmacokinetics (PK) of simvastatin, ethinyl estradiol, or levonorgestrel (CYP3A substrates) when co-administered with baricitinib. - In vitro studies suggest that baricitinib is not an inhibitor of the transporters, P-glycoprotein (Pgp) or Organic Anion Transporting Polypeptide (OATP) 1B1. In vitro data indicate baricitinib does inhibit organic anionic transporter (OAT) 1, OAT2, OAT3, organic cationic transporter (OCT) 1, OCT2, OATP1B3, Breast Cancer Resistance Protein (BCRP) and Multidrug and Toxic Extrusion Protein (MATE) 1 and MATE2-K, but clinically meaningful changes in the pharmacokinetics of drugs that are substrates for these transporters are unlikely. In clinical pharmacology studies there were no clinically meaningful effects on the PK of digoxin (Pgp substrate) or methotrexate (substrate of several transporters) when co-administered with baricitinib. - Exposure changes of drugs following co-administration with baricitinib are shown in FIGURE 2. Potential for Other Drugs to Influence the PK of Baricitinib - In vitro studies suggest that baricitinib is a CYP3A4 substrate. In clinical pharmacology studies there was no effect on the PK of baricitinib when co-administered with ketoconazole (CYP3A inhibitor). There were no clinically meaningful changes in the PK of baricitinib when co-administered with fluconazole (CYP3A/CYP2C19/CYP2C9 inhibitor) or rifampicin (CYP3A inducer). - In vitro studies suggest that baricitinib is a substrate for OAT3, Pgp, BCRP and MATE2-K. In a clinical study, probenecid administration (strong OAT3 inhibitor) resulted in an approximately 2-fold increase in baricitinib AUC0-∞ with no effect on Cmax and tmax. However, simulations with diclofenac and ibuprofen (OAT3 inhibitors with less inhibition potential) predicted minimal effect on the PK of baricitinib. In clinical pharmacology studies there was no clinically meaningful effect on the PK of baricitinib when co-administered with cyclosporine (Pgp and BCRP inhibitor). Co-administration with methotrexate (substrate of several transporters) did not have a clinically meaningful effect on the PK of baricitinib. - Exposure changes of baricitinib following co-administration with CYP inhibitors or inducers, transporter inhibitors, as well as methotrexate and the proton pump inhibitor, omeprazole, are shown in FIGURE 3. ## Nonclinical Toxicology - The carcinogenic potential of baricitinib was evaluated in Sprague-Dawley rats and Tg.rasH2 mice. No evidence of tumorigenicity was observed in male or female rats that received baricitinib for 91 to 94 weeks at oral doses up to 8 or 25 mg/kg/day, respectively (approximately 12 and 55 times the MRHD on an AUC basis). No evidence of tumorigenicity was observed in Tg.rasH2 mice that received baricitinib for 26 weeks at oral doses up to 300 and 150 mg/kg/day in male and female mice, respectively. - Baricitinib tested negative in the following genotoxicity assays: the in vitro bacterial mutagenicity assay (Ames assay), in vitro chromosome aberration assay in human peripheral blood lymphocytes, and in vivo rat bone marrow micronucleus assay. - Fertility (achievement of pregnancy) was reduced in male and female rats that received baricitinib at oral doses of 50 and 100 mg/kg/day respectively (approximately 113 and 169 times the MRHD in males and females, respectively, on an AUC basis) based upon findings that 7 of 19 (36.8%) drug-treated females with evidence of mating were not gravid compared to 1 of 19 (5.3%) control females. It could not be determined from the study design if these findings were attributable to toxicities in one sex or both. Fertility was unaffected in male and female rats at oral doses of 15 mg/kg and 25 mg/kg, respectively (approximately 25 and 48 times the MRHD on an AUC basis). However, maintenance of pregnancy was adversely affected at these doses based upon findings of increased post-implantation losses (early resorptions) and decreased numbers of mean viable embryos per litter. The number of viable embryos was unaffected in female rats that received baricitinib at an oral dose of 5 mg/kg/day and were mated to males that received the same dose (approximately 8 times the MRHD on an AUC basis). Reproductive performance was unaffected in male and female rats that received baricitinib at oral doses up to 50 and 100 mg/kg/day respectively (approximately 113 and 169 times the MRHD in males and females, respectively, on an AUC basis). # Clinical Studies - The baricitinib clinical development program included two dose-ranging trials and four confirmatory phase 3 trials. Although other doses have been studied, the recommended dose of baricitinib is 2 mg once daily. Dose-Ranging Studies - The dose-ranging studies I (NCT01185353) and II (NCT01469013) included a 12-week randomized comparison of baricitinib 1, 2, 4, and 8 mg versus placebo in 301 and 145 patients, respectively. - The results from the dose-ranging studies are shown in TABLE 5. In dose-ranging Study I, the observed ACR response was similar for baricitinib 1 and 2 mg daily and for baricitinib 4 and 8 mg daily, with the highest response for baricitinib 8 mg daily. In dose-ranging Study II, there was not a clear trend of dose response, with similar response rates for 1 mg and 4 mg and 2 mg and 8 mg. Confirmatory Studies - The efficacy and safety of baricitinib 2 mg once daily was assessed in two confirmatory phase 3 trials. These trials were randomized, double-blind, multicenter studies in patients with active rheumatoid arthritis diagnosed according to American College of Rheumatology (ACR)/European League Against Rheumatism 2010 criteria. Patients over 18 years of age were eligible if at least 6 tender and 6 swollen joints were present at baseline. The two studies (Studies III and IV) evaluated baricitinib 2 mg and baricitinib 4 mg. - Study III (NCT01721057) was a 24-week trial in 684 patients with moderately to severely active rheumatoid arthritis who had an inadequate response or intolerance to conventional DMARDs (cDMARDs). Patients received baricitinib 2 mg or 4 mg once daily or placebo added to existing background cDMARD treatment. From Week 16, non-responding patients could be rescued to receive baricitinib 4 mg once daily. The primary endpoint was the proportion of patients who achieved an ACR20 response at Week 12. - Study IV (NCT01721044) was a 24-week trial in 527 patients with moderately to severely active rheumatoid arthritis who had an inadequate response or intolerance to 1 or more TNF inhibitor therapies with or without other biologic DMARDs (TNFi-IR). Patients received baricitinib 2 mg or baricitinib 4 mg once daily or placebo added to background cDMARD treatment. From Week 16, non-responding patients could be rescued to receive baricitinib 4 mg once daily. The primary endpoint was the proportion of patients who achieved an ACR20 response at Week 12. Clinical Response - The percentages of baricitinib-treated patients achieving ACR20, ACR50, and ACR70 responses, and Disease Activity Score (DAS28-CRP) <2.6 in Studies III and IV are shown in TABLE 6. - Patients treated with baricitinib had higher rates of ACR response and DAS28-CRP <2.6 versus placebo-treated patients at Week 12 (Studies III and IV) (TABLE 6). - In Study IV, higher ACR20 response rates (FIGURE 4) were observed as early as 1 week with baricitinib 2 mg versus placebo. - In Study IV, the proportions of patients achieving DAS28-CRP <2.6 who had at least 3 active joints at the end of Week 24 were 18.2% and 10.5%, in the placebo and baricitinib 2 mg arms, respectively. Physical Function Response - Improvement in physical function was measured by the Health Assessment Questionnaire-Disability Index (HAQ-DI). Patients receiving baricitinib 2 mg demonstrated greater improvement from baseline in physical functioning compared to placebo at Week 24. The mean difference (95% CI) from placebo in HAQ-DI change from baseline at Week 24 was -0.24 (-0.35, -0.14) in Study III and -0.23 (-0.35, -0.12) in Study IV. Other Health Related Outcomes - General health status was assessed by the Short Form health survey (SF-36). In Studies III and IV, compared to placebo, patients treated with baricitinib 2 mg demonstrated greater improvement from baseline in the physical component summary (PCS) score and the physical function, role physical, bodily pain, vitality, and general health domains at Week 12, with no consistent improvements in the mental component summary (MCS) scores or the role emotional, mental health, and social functioning domains. # How Supplied - Baricitinib for oral administration is available as debossed, film-coated, immediate-release tablets. Each tablet contains a recessed area on each face of the tablet surface. ## Storage - Store at 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F). - Keep out of reach of children. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information - Advise the patient to read the FDA-approved patient labeling (Medication Guide). Patient Counseling - Advise patients of the potential benefits and risks of baricitinib. Infections - Inform patients that they may be more likely to develop infections when taking baricitinib. Instruct patients to tell their healthcare provider if they develop any signs or symptoms of an infection. - Advise patients that the risk of herpes zoster is increased in patients treated with baricitinib and some cases can be serious. Malignancies and Lymphoproliferative Disorders - Inform patients that baricitinib may increase their risk of certain cancers, and that lymphoma and other cancers have been observed in patients taking baricitinib. Instruct patients to inform their healthcare provider if they have ever had any type of cancer. Thrombosis - Advise patients that events of DVT and PE have been reported in clinical studies with baricitinib. Instruct patients to tell their healthcare provider if they develop any signs or symptoms of a DVT or PE. Laboratory Abnormalities - Inform patients that baricitinib may affect certain lab tests, and that blood tests are required before and during baricitinib treatment. Lactation - Advise a woman not to breastfeed during treatment with baricitinib. # Precautions with Alcohol Alcohol-Baricitinib interaction has not been established. Talk to your doctor regarding the effects of taking alcohol with this medication. # Brand Names Olumiant # Look-Alike Drug Names There is limited information regarding Baricitinib Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	https://www.wikidoc.org/index.php/Baricitinib
eb98917e4647a1b01b74e9a8bc0e4839ec29e2c8	wikidoc	Barium meal	Barium meal # Overview A barium meal, also known as an upper gastrointestinal series is a procedure in which radiographs of the esophagus, stomach and duodenum are taken after barium sulfate is ingested by a patient. Barium meals are useful in the diagnosis of structural and motility abnormalities of the foregut. The gastrointestinal tract, like other soft-tissue structures, does not show clearly enough for diagnostic purposes on plain radiographs. Barium salts are radioopaque: they show clearly on a radiograph. If barium is swallowed before radiographs are taken, the barium within the esophagus, stomach or duodenum shows the shape of the lumina of these organs. Liquid suspensions of barium compounds are non-toxic, apart from a small risk of producing a disturbance in bowel function for 48 hours after ingestion. They usually have a chalky taste that can be disguised by adding flavours. A barium meal usually takes less than an hour. The patient ingests gas pellets and citric acid to expand the stomach. Barium sulfate is then ingested. The patient may move or roll over to coat the stomach and esophagus in barium. A needle may also be used to relax the muscle between the stomach and the duodenum. Following these preparations, an x-ray is taken. There are two varieties of barium meal: single and double contrast meals. A single contrast meal uses only barium, a radioopaque (or positive) contrast medium, to image the upper gastrointestinal tract. A double contrast meal uses barium as well as a radiolucent (or negative) contrast medium such as air, nitrogen, or carbon dioxide. The double contrast meal is more useful as a diagnostic test, demonstrating mucosal details and allowing the detection of small mucosal lesions such as diverticula or polyps. The diagnostic usage of barium studies has declined in recent years with the increasing use of the practice of endoscopy, which allows direct visual inspection of suspicious areas within the oesophagus, stomach and duodenum.	Barium meal # Overview A barium meal, also known as an upper gastrointestinal series is a procedure in which radiographs of the esophagus, stomach and duodenum are taken after barium sulfate is ingested by a patient. Barium meals are useful in the diagnosis of structural and motility abnormalities of the foregut. The gastrointestinal tract, like other soft-tissue structures, does not show clearly enough for diagnostic purposes on plain radiographs. Barium salts are radioopaque: they show clearly on a radiograph. If barium is swallowed before radiographs are taken, the barium within the esophagus, stomach or duodenum shows the shape of the lumina of these organs. Liquid suspensions of barium compounds are non-toxic, apart from a small risk of producing a disturbance in bowel function for 48 hours after ingestion. They usually have a chalky taste that can be disguised by adding flavours.[1] A barium meal usually takes less than an hour. The patient ingests gas pellets and citric acid to expand the stomach. Barium sulfate is then ingested. The patient may move or roll over to coat the stomach and esophagus in barium. A needle may also be used to relax the muscle between the stomach and the duodenum. Following these preparations, an x-ray is taken. There are two varieties of barium meal: single and double contrast meals. A single contrast meal uses only barium, a radioopaque (or positive) contrast medium, to image the upper gastrointestinal tract. A double contrast meal uses barium as well as a radiolucent (or negative) contrast medium such as air, nitrogen, or carbon dioxide. The double contrast meal is more useful as a diagnostic test, demonstrating mucosal details and allowing the detection of small mucosal lesions such as diverticula or polyps. The diagnostic usage of barium studies has declined in recent years with the increasing use of the practice of endoscopy, which allows direct visual inspection of suspicious areas within the oesophagus, stomach and duodenum.	https://www.wikidoc.org/index.php/Barium_meal
cde29da6b7c79e17857f8717b59d1314938296c3	wikidoc	Barre lieou	Barre lieou # Overview The "Posterior Cervical Sympathetic Syndrome of Barre-Lieou consists of headache, neck pain, blurred vision, tinnitus, dysphagia and paresthesias. Common clinical presentations include mixed headaches, vasomotor headache and complicated flexion-extension (whiplash) injuries. # Historical Perspective and Etymology In 1925 Jean Alexandre Barre, M.D., a French Neurologist described a syndrome consisting cervicogenic headache in association with ringing in the ears, blurred vision, trouble swallowing and vertigo. The majority of these symptoms were thought to be due to over activity in the posterior cervical sympathetic nervous system (a group of nerves located near the vertebrae in the neck). The syndrome was again described in 1928 by Yong-Choen Lieou, a Chinese physician. In 1947 Louis Gayral published "Oto-neuro-opthalomologic Manifestations of Cervical Origin" in The Lancet. The article was subtitled the "Posterior Cervical Sympathetic Syndrome of Barre-Lieou" and the name Barre-lieou for the syndrome has been popularized ever since. # Pathophysiology It has been hypothesized to be due to a traction injury of the posterior cervical sympathetic chain in association with musculoskeletal injury of the head or neck. # Causes ## Common Causes - Traumatic flexion-extension movement ## Complete List of Causes in Alphabetical Order - Autoimmune disorders - Gunshot wounds - Head trauma - Infection - Traumatic flexion-extension movement # Epidemiology and Demographics Barre Lieou syndrome is listed as a "rare disease" by the Office of Rare Diseases (ORD) of the National Institutes of Health (NIH). This means that Barre Lieou syndrome, or a subtype of Barre Lieou syndrome, affects less than 200,000 people in the US population. # Diagnosis # Symptoms The identifying factors that distinguish Barre-Lieou from other injuries of the head and neck include involvement of the autonomic nervous system. The most commonly described symptoms include tinnitus, vertigo (dizziness, nausea, vomiting, blurred vision, tearing of the eyes and sinus congestion however other symptoms may also include swelling on one side of the face, localized cyanosis (bluish color) of the face, facial numbness, hoarseness, shoulder pain, dysesthesias (pins and needles sensations) of the hands & forearms, muscle weakness and fatigue. ## Laboratory Findings Sympathetic Skin Response studies (Thermography) are an excellent diagnostic tool for Barre- Lieou . Sympathetic Skin Response studies are a fractal measurement of galvonic impedance. Since both vasomotor and sudomotor physiology is controlled by the autonomic nervous system, assymetry patterns (reduced galvonic impedance or cold regions) in facial structures, especially when seen in association with localized hot spots in the ipsilateral omohyoid or nuchal ligament. Other diagnostic techniques are dependent upon clinical response to treatment of the underling disorder. Sphenopalatine ganglion or Superior Cervical Sympathetic ganglion blocks can provide dramatic relief. If a C23 interspinous ligament strain is the underlying generator then local injection at that local can be curative. # Treatment Many of the same injections (Sphenopalatine ganglion or Superior Cervical Sympathetic ganglion blocks) used for diagnosis are also used for treatment. Using a hit or miss approach to treatment by selecting a particular block based upon symptoms alone is far less effective then block selection based upon objective findings with Sympathetic Skin Response studies (Thermography) however. In addition to employing sympathetic block, treating the underlying source, or generator of sympathetic response, can be curative . Prolotherapy can be very effective in treating the underlying source, especially if the sympathetic response is due to underlying ligament strain (such as the nuchal ligament, C23 interspinous ligament) or tendinosis (especially at the nuchal ligament). As with all sympathetic pain syndromes, it is best to block above the sympathetic response and to do so before trying to treat the underlying source. Medications by mouth, including muscle relaxers, NSAID's, analgesics and hypnotics are often helpful, however due to the autonomic manifestations seen with Barre- Lieou vasoactive agents such as clonidine, oral magnesium supplements or Epsom salts baths can often be even more effective. Restorative therapy, including the use of physical agents such as electrical stimulation, TENS and ultrasound, are helpful adjunct treatments. Stretching what is tight and reeducating what is weak are often more helpful then exercise directed toward strengthening. # Prognosis For most cases the prognosis is good, however recalcitrant cases of Barre-lieou are common place. There is a tendency for symptoms to improve over time, but it can take years. More severe cases are disabling and less severe cases just a detractor to quality of life. With proper care and treatment symptoms do frequently respond more quickly then without treatment, so like other sympathetic pain syndromes aggressive care is recommended. # Similar disorders CRPS, RSD, Vasomotor migraine, Cluster headaches, Atypcial facial pain and certain cases of TMJ can produce similar symptoms. When they do it is essentially a result of autonomic involvement.	Barre lieou Editor-In-Chief: Robert G. Schwartz, M.D. [1], Piedmont Physical Medicine and Rehabilitation, P.A., Ross Hauser, M.D. [2], Physical Medicine and Rehabilitation Specialist, Oak Park, IL # Overview The "Posterior Cervical Sympathetic Syndrome of Barre-Lieou consists of headache, neck pain, blurred vision, tinnitus, dysphagia and paresthesias. Common clinical presentations include mixed headaches, vasomotor headache and complicated flexion-extension (whiplash) injuries. # Historical Perspective and Etymology In 1925 Jean Alexandre Barre, M.D., a French Neurologist described a syndrome consisting cervicogenic headache in association with ringing in the ears, blurred vision, trouble swallowing and vertigo. The majority of these symptoms were thought to be due to over activity in the posterior cervical sympathetic nervous system (a group of nerves located near the vertebrae in the neck). The syndrome was again described in 1928 by Yong-Choen Lieou, a Chinese physician. In 1947 Louis Gayral published "Oto-neuro-opthalomologic Manifestations of Cervical Origin" in The Lancet. The article was subtitled the "Posterior Cervical Sympathetic Syndrome of Barre-Lieou" and the name Barre-lieou for the syndrome has been popularized ever since. # Pathophysiology It has been hypothesized to be due to a traction injury of the posterior cervical sympathetic chain in association with musculoskeletal injury of the head or neck. # Causes ## Common Causes - Traumatic flexion-extension movement ## Complete List of Causes in Alphabetical Order - Autoimmune disorders - Gunshot wounds - Head trauma - Infection - Traumatic flexion-extension movement # Epidemiology and Demographics Barre Lieou syndrome is listed as a "rare disease" by the Office of Rare Diseases (ORD) of the National Institutes of Health (NIH). This means that Barre Lieou syndrome, or a subtype of Barre Lieou syndrome, affects less than 200,000 people in the US population. # Diagnosis # Symptoms The identifying factors that distinguish Barre-Lieou from other injuries of the head and neck include involvement of the autonomic nervous system. The most commonly described symptoms include tinnitus, vertigo (dizziness, nausea, vomiting, blurred vision, tearing of the eyes and sinus congestion however other symptoms may also include swelling on one side of the face, localized cyanosis (bluish color) of the face, facial numbness, hoarseness, shoulder pain, dysesthesias (pins and needles sensations) of the hands & forearms, muscle weakness and fatigue. ## Laboratory Findings Sympathetic Skin Response studies (Thermography) are an excellent diagnostic tool for Barre- Lieou [3]. Sympathetic Skin Response studies are a fractal measurement of galvonic impedance. Since both vasomotor and sudomotor physiology is controlled by the autonomic nervous system, assymetry patterns (reduced galvonic impedance or cold regions) in facial structures, especially when seen in association with localized hot spots in the ipsilateral omohyoid or nuchal ligament. Other diagnostic techniques are dependent upon clinical response to treatment of the underling disorder. Sphenopalatine ganglion or Superior Cervical Sympathetic ganglion blocks can provide dramatic relief. If a C23 interspinous ligament strain is the underlying generator then local injection at that local can be curative. # Treatment Many of the same injections (Sphenopalatine ganglion or Superior Cervical Sympathetic ganglion blocks) used for diagnosis are also used for treatment. Using a hit or miss approach to treatment by selecting a particular block based upon symptoms alone is far less effective then block selection based upon objective findings with Sympathetic Skin Response studies (Thermography) however. In addition to employing sympathetic block, treating the underlying source, or generator of sympathetic response, can be curative [4]. Prolotherapy can be very effective in treating the underlying source, especially if the sympathetic response is due to underlying ligament strain (such as the nuchal ligament, C23 interspinous ligament) or tendinosis (especially at the nuchal ligament). As with all sympathetic pain syndromes, it is best to block above the sympathetic response and to do so before trying to treat the underlying source. Medications by mouth, including muscle relaxers, NSAID's, analgesics and hypnotics are often helpful, however due to the autonomic manifestations seen with Barre- Lieou vasoactive agents such as clonidine, oral magnesium supplements or Epsom salts baths can often be even more effective. Restorative therapy, including the use of physical agents such as electrical stimulation, TENS and ultrasound, are helpful adjunct treatments. Stretching what is tight and reeducating what is weak are often more helpful then exercise directed toward strengthening. # Prognosis For most cases the prognosis is good, however recalcitrant cases of Barre-lieou are common place. There is a tendency for symptoms to improve over time, but it can take years. More severe cases are disabling and less severe cases just a detractor to quality of life. With proper care and treatment symptoms do frequently respond more quickly then without treatment, so like other sympathetic pain syndromes aggressive care is recommended. # Similar disorders CRPS, RSD, Vasomotor migraine, Cluster headaches, Atypcial facial pain and certain cases of TMJ can produce similar symptoms. When they do it is essentially a result of autonomic involvement. # External links - Piedmontpmr.com - [5] - Barre-Lieou Syndrome - NIH Template:WH Template:WS	https://www.wikidoc.org/index.php/Barre_lieou
5ce46d38c27610d9f41e3d4de508a9cff240a5fa	wikidoc	Basic oxide	Basic oxide In chemistry, a basic oxide is an oxide that either - reacts with water to have a proton transferred to it - reacts with an acid to form a salt. Examples include: - Sodium oxide which reacts with water to produce Sodium hydroxide. - Magnesium oxide which reacts with water to form Magnesium hydroxide. - Copper(II) oxide which reacts with Nitric acid to form Copper nitrate and water. - i.e. CuO + 2HNO3 → Cu(NO3)2 + H2O Basic oxides are oxides of metals.	Basic oxide In chemistry, a basic oxide is an oxide that either - reacts with water to have a proton transferred to it - reacts with an acid to form a salt. Examples include: - Sodium oxide which reacts with water to produce Sodium hydroxide. - Magnesium oxide which reacts with water to form Magnesium hydroxide. - Copper(II) oxide which reacts with Nitric acid to form Copper nitrate and water. - i.e. CuO + 2HNO3 → Cu(NO3)2 + H2O Basic oxides are oxides of metals.	https://www.wikidoc.org/index.php/Basic_oxide
bac5807bdbcc0d6c284521af748da14c73e86f10	wikidoc	Basiliximab	Basiliximab # Disclaimer WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here. # Black Box Warning # Overview Basiliximab is a monoclonal antibody that is FDA approved for the prophylaxis of acute organ rejection in patients receiving renal transplantation when used as part of an immunosuppressive regimen. There is a Black Box Warning for this drug as shown here. Common adverse reactions include Abdominal pain, Vomiting, constipation, diarrhea, dizziness. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) ### Indications - Simulect® (basiliximab) is indicated for the prophylaxis of acute organ rejection in patients receiving renal transplantation when used as part of an immunosuppressive regimen that includes cyclosporine, USP (MODIFIED) and corticosteroids. - The efficacy of Simulect for the prophylaxis of acute rejection in recipients of other solid organ allografts has not been demonstrated. ### Dosage - Simulect® (basiliximab) is used as part of an immunosuppressive regimen that includes cyclosporine, USP (MODIFIED) and corticosteroids. Simulect is for central or peripheral intravenous administration only. Reconstituted Simulect should be given either as a bolus injection or diluted to a volume of 25 mL (10-mg vial) or 50 mL (20-mg vial) with normal saline or dextrose 5% and administered as an intravenous infusion over 20 to 30 minutes. Bolus administration may be associated with nausea, vomiting and local reactions, including pain. - Simulect should only be administered once it has been determined that the patient will receive the graft and concomitant immunosuppression. Patients previously administered Simulect should only be re-exposed to a subsequent course of therapy with extreme caution due to the potential risk of hypersensitivity. - Parenteral drug products should be inspected visually for particulate matter and discoloration before administration. After reconstitution, Simulect should be a clear-to-opalescent, colorless solution. If particulate matter is present or the solution is colored, do not use. - Care must be taken to assure sterility of the prepared solution because the drug product does not contain any antimicrobial preservatives or bacteriostatic agents. - It is recommended that after reconstitution, the solution should be used immediately. If not used immediately, it can be stored at 2ºC to 8ºC for 24 hours or at room temperature for 4 hours. Discard the reconstituted solution if not used within 24 hours. - No incompatibility between Simulect and polyvinyl chloride bags or infusion sets has been observed. No data are available on the compatibility of Simulect with other intravenous substances. Other drug substances should not be added or infused simultaneously through the same intravenous line. - In adult patients, the recommended regimen is two doses of 20 mg each. The first 20-mg dose should be given within 2 hours prior to transplantation surgery. The recommended second 20-mg dose should be given 4 days after transplantation. The second dose should be withheld if complications such as severe hypersensitivity reactions to Simulect or graft loss occur. - To prepare the reconstituted solution, add 2.5 mL of Sterile Water for Injection, USP, using aseptic technique, to the vial containing the Simulect powder. Shake the vial gently to dissolve the powder. - The reconstituted solution is isotonic and may be given either as a bolus injection or diluted to a volume of 25 mL with normal saline or dextrose 5% for infusion. When mixing the solution, gently invert the bag in order to avoid foaming; DO NOT SHAKE. - To prepare the reconstituted solution, add 5 mL of Sterile Water for Injection, USP, using aseptic technique, to the vial containing the Simulect powder. Shake the vial gently to dissolve the powder. - The reconstituted solution is isotonic and may be given either as a bolus injection or diluted to a volume of 50 mL with normal saline or dextrose 5% for infusion. When mixing the solution, gently invert the bag in order to avoid foaming; DO NOT SHAKE. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Basiliximab in adult patients. ### Non–Guideline-Supported Use - Graft versus host disease - Liver transplant rejection; Prophylaxis # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) ### Pediatric dosage - In pediatric patients weighing less than 35 kg, the recommended regimen is two doses of 10 mg each. In pediatric patients weighing 35 kg or more, the recommended regimen is two doses of 20 mg each. The first dose should be given within 2 hours prior to transplantation surgery. The recommended second dose should be given 4 days after transplantation. The second dose should be withheld if complications such as severe hypersensitivity reactions to Simulect or graft loss occur. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Basiliximab in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Basiliximab in pediatric patients. # Contraindications - Simulect® (basiliximab) is contraindicated in patients with known hypersensitivity to basiliximab or any other component of the formulation. See composition of Simulect under DESCRIPTION. # Warnings - Simulect® (basiliximab) should be administered under qualified medical supervision. Patients should be informed of the potential benefits of therapy and the risks associated with administration of immunosuppressive therapy. - While neither the incidence of lymphoproliferative disorders nor opportunistic infections was higher in Simulect-treated patients than in placebo-treated patients, patients on immunosuppressive therapy are at increased risk for developing these complications and should be monitored accordingly. - Severe acute (onset within 24 hours) hypersensitivity reactions including anaphylaxis have been observed both on initial exposure to Simulect and/or following re-exposure after several months. These reactions may include hypotension, tachycardia, cardiac failure, dyspnea, wheezing, bronchospasm, pulmonary edema, respiratory failure, urticaria, rash, pruritus, and/or sneezing. Extreme caution should be exercised in all patients previously given Simulect when being administered a subsequent course of Simulect. A subgroup of patients may be particularly at risk of developing severe hypersensitivity reactions on re-administration. These are patients in whom concomitant immunosuppression was discontinued prematurely (e.g., due to abandoned transplantation or early loss of the graft) following the initial administration of Simulect. If a severe hypersensitivity reaction occurs, therapy with Simulect should be permanently discontinued. Medications for the treatment of severe hypersensitivity reactions including anaphylaxis should be available for immediate use. ### Precautions - It is not known whether Simulect® (basiliximab) use will have a long-term effect on the ability of the immune system to respond to antigens first encountered during Simulect-induced immunosuppression. - Of renal transplantation patients treated with Simulect and tested for anti-idiotype antibodies, 4/339 developed an anti-idiotype antibody response, with no deleterious clinical effect upon the patient. In none of these cases was there evidence that the presence of anti-idiotype antibody accelerated Simulect clearance or decreased the period of receptor saturation. In Study 2, the incidence of human anti-murine antibody (HAMA) in renal transplantation patients treated with Simulect was 2/138 in patients not exposed to muromonab-CD3 and 4/34 in patients who subsequently received muromonab-CD3. The available clinical data on the use of muromonab-CD3 in patients previously treated with Simulect suggest that subsequent use of muromonab-CD3 or other murine anti-lymphocytic antibody preparations is not precluded. - These data reflect the percentage of patients whose test results were considered positive for antibodies to Simulect in an ELISA assay, and are highly dependent on the sensitivity and specificity of the assay. Additionally the observed incidence of antibody positivity in an assay may be influenced by several factors including sample handling, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to Simulect with the incidence of antibodies to other products may be misleading. # Adverse Reactions ## Clinical Trials Experience - Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The adverse reaction information from clinical trials does, however, provide a basis for identifying the adverse events that appear to be related to drug use and for approximating rates. - The incidence of adverse events for Simulect® (basiliximab) was determined in four randomized, double-blind, placebo-controlled clinical trials for the prevention of renal allograft rejection. Two of the studies (Study 1 and Study 2), used a dual maintenance immunosuppressive regimen comprised of cyclosporine, USP (MODIFIED) and corticosteroids, whereas the other two studies (Study 3 and Study 4) used a triple-immunosuppressive regimen comprised of cyclosporine, USP (MODIFIED), corticosteroids, and either azathioprine or mycophenolate mofetil. - Simulect did not appear to add to the background of adverse events seen in organ transplantation patients as a consequence of their underlying disease and the concurrent administration of immunosuppressants and other medications. Adverse events were reported by 96% of the patients in the placebo-treated group and 96% of the patients in the Simulect-treated group. In the four placebo-controlled studies, the pattern of adverse events in 590 patients treated with the recommended dose of Simulect was similar to that in 594 patients treated with placebo. Simulect did not increase the incidence of serious adverse events observed compared with placebo. - The most frequently reported adverse events were gastrointestinal disorders, reported in 69% of Simulect-treated patients and 67% of placebo-treated patients. - The incidence and types of adverse events were similar in Simulect-treated and placebo-treated patients. The following adverse events occurred in ≥10% of Simulect-treated patients: Gastrointestinal System: constipation, nausea, abdominal pain, vomiting, diarrhea, dyspepsia; Body as a Whole-General: pain, peripheral edema, fever, viral infection; Metabolic and Nutritional: hyperkalemia, hypokalemia, hyperglycemia, hypercholesterolemia, hypophosphatemia, hyperuricemia; Urinary System: urinary tract infection; Respiratory System: dyspnea, upper respiratory tract infection; Skin and Appendages: surgical wound complications, acne; Cardiovascular Disorders-General: hypertension; Central and Peripheral Nervous System: headache, tremor; Psychiatric: insomnia; Red Blood Cell: anemia. - The following adverse events, not mentioned above, were reported with an incidence of ≥3% and <10% in pooled analysis of patients treated with Simulect in the four controlled clinical trials, or in an analysis of the two dual-therapy trials: Body as a Whole-General: accidental trauma, asthenia, chest pain, increased drug level, infection, face edema, fatigue, dependent edema, generalized edema, leg edema, malaise, rigors, sepsis; Cardiovascular: abnormal heart sounds, aggravated hypertension, angina pectoris, cardiac failure, chest pain, hypotension; Endocrine: increased glucocorticoids; Gastrointestinal: enlarged abdomen, esophagitis, flatulence, gastrointestinal disorder, gastroenteritis, GI hemorrhage, gum hyperplasia, melena, moniliasis, ulcerative stomatitis; Heart Rate and Rhythm: arrhythmia, atrial fibrillation, tachycardia; Metabolic and Nutritional: acidosis, dehydration, diabetes mellitus, fluid overload, hypercalcemia, hyperlipemia, hypertriglyceridemia, hypocalcemia, hypoglycemia, hypomagnesemia, hypoproteinemia, weight increase; Musculoskeletal: arthralgia, arthropathy, back pain, bone fracture, cramps, hernia, myalgia, leg pain; Nervous System: dizziness, neuropathy, paraesthesia, hypoesthesia; Platelet and Bleeding: hematoma, hemorrhage, purpura, thrombocytopenia, thrombosis; Psychiatric: agitation, anxiety, depression; Red Blood Cell: polycythemia; Reproductive Disorders, Male: genital edema, impotence; Respiratory: bronchitis, bronchospasm, abnormal chest sounds, coughing, pharyngitis, pneumonia, pulmonary disorder, pulmonary edema, rhinitis, sinusitis; Skin and Appendages: cyst, herpes simplex, herpes zoster, hypertrichosis, pruritus, rash, skin disorder, skin ulceration; Urinary: albuminuria, bladder disorder, dysuria, frequent micturition, hematuria, increased non-protein nitrogen, oliguria, abnormal renal function, renal tubular necrosis, surgery, ureteral disorder, urinary retention; Vascular Disorders: vascular disorder; Vision Disorders: cataract, conjunctivitis, abnormal vision; White Blood Cell: leucopenia. Among these events, leucopenia and hypertriglyceridemia occurred more frequently in the two triple-therapy studies using azathioprine and mycophenolate mofetil than in the dual-therapy studies. - The incidence of malignancies in the controlled clinical trials of renal transplant was not significantly different between groups at 1 year (9/590 Simulect-treated patients vs. 12/594 placebo-treated patients) or among patients with 5-year follow-up from Studies 1 and 2 (21/295 Simulect-treated patients vs. 21/291 placebo-treated patients). The incidence of lymphoproliferative disease was not significantly different between groups, and less than 1% in the Simulect-treated patients. ### Infections - The overall incidence of cytomegalovirus infection was similar in Simulect- and placebo-treated patients (15% vs. 17%) receiving a dual- or triple-immunosuppression regimen. However, in patients receiving a triple-immunosuppression regimen, the incidence of serious cytomegalovirus infection was higher in Simulect-treated patients compared to placebo-treated patients (11% vs. 5%). The rates of infections, serious infections, and infectious organisms were similar in the Simulect- and placebo-treatment groups among dual- and triple-therapy treated patients. ## Postmarketing Experience - Severe acute hypersensitivity reactions including anaphylaxis characterized by hypotension, tachycardia, cardiac failure, dyspnea, wheezing, bronchospasm, pulmonary edema, respiratory failure, urticaria, rash, pruritus, and/or sneezing, as well as capillary leak syndrome and cytokine release syndrome, have been reported during post-marketing experience with Simulect. # Drug Interactions - No dose adjustment is necessary when Simulect is added to triple-immunosuppression regimens including cyclosporine, corticosteroids, and either azathioprine or mycophenolate mofetil. Three clinical trials have investigated Simulect use in combination with triple-therapy regimens. Pharmacokinetics were assessed in two of these trials. Total body clearance of Simulect was reduced by an average 22% and 51% when azathioprine and mycophenolate mofetil, respectively, were added to a regimen consisting of cyclosporine, USP (MODIFIED) and corticosteroids. Nonetheless, the range of individual Simulect clearance values in the presence of azathioprine (12-57 mL/h) or mycophenolate mofetil (7-54 mL/h) did not extend outside the range observed with dual therapy (10-78 mL/h). The following medications have been administered in clinical trials with Simulect with no increase in adverse reactions: ATG/ALG, azathioprine, corticosteroids, cyclosporine, mycophenolate mofetil, and muromonab-CD3. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): B - There are no adequate and well-controlled studies in pregnant women. No maternal toxicity, embryotoxicity, or teratogenicity was observed in cynomolgus monkeys 100 days post coitum following dosing with basiliximab during the organogenesis period; blood levels in pregnant monkeys were 13-fold higher than those seen in human patients. Immunotoxicology studies have not been performed in the offspring. Because IgG molecules are known to cross the placental barrier, because the IL-2 receptor may play an important role in development of the immune system, and because animal reproduction studies are not always predictive of human response, Simulect should only be used in pregnant women when the potential benefit justifies the potential risk to the fetus. Women of childbearing potential should use effective contraception before beginning Simulect therapy, during therapy, and for 4 months after completion of Simulect therapy. Pregnancy Category (AUS): - Australian Drug Evaluation Committee (ADEC) Pregnancy Category There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Basiliximab in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Basiliximab during labor and delivery. ### Nursing Mothers - It is not known whether Simulect is excreted in human milk. Because many drugs including human antibodies are excreted in human milk, and because of the potential for adverse reactions, a decision should be made to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. ### Pediatric Use - No randomized, placebo-controlled studies have been completed in pediatric patients. In a safety and pharmacokinetic study, 41 pediatric patients (1-11 years of age , 12-16 years of age , median age 8.1 years) were treated with Simulect via intravenous bolus injection in addition to standard immunosuppressive agents including cyclosporine, USP (MODIFIED), corticosteroids, azathioprine, and mycophenolate mofetil. The acute rejection rate at 6 months was comparable to that in adults in the triple-therapy trials. The most frequently reported adverse events were hypertension, hypertrichosis, and rhinitis (49% each), urinary tract infections (46%), and fever (39%). Overall, the adverse event profile was consistent with general clinical experience in the pediatric renal transplantation population and with the profile in the controlled adult renal transplantation studies. The available pharmacokinetic data in children and adolescents are described in CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION. - It is not known whether the immune response to vaccines, infection, and other antigenic stimuli administered or encountered during Simulect therapy is impaired or whether such response will remain impaired after Simulect therapy. ### Geriatic Use - Controlled clinical studies of Simulect have included a small number of patients 65 years and older (Simulect 28; placebo 32). From the available data comparing Simulect and placebo-treated patients, the adverse event profile in patients ≥65 years of age is not different from patients <65 years of age and no age-related dosing adjustment is required. Caution must be used in giving immunosuppressive drugs to elderly patients. ### Gender There is no FDA guidance on the use of Basiliximab with respect to specific gender populations. ### Race There is no FDA guidance on the use of Basiliximab with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Basiliximab in patients with renal impairment. ### Hepatic Impairment There is no FDA guidance on the use of Basiliximab in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Basiliximab in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Basiliximab in patients who are immunocompromised. # Administration and Monitoring ### Administration - Intravenous ### Monitoring There is limited information regarding Monitoring of Basiliximab in the drug label. # IV Compatibility There is limited information regarding IV Compatibility of Basiliximab in the drug label. # Overdosage - A maximum tolerated dose of Simulect® (basiliximab) has not been determined in patients. During the course of clinical studies, Simulect has been administered to adult renal transplantation patients in single doses of up to 60 mg, or in divided doses over 3-5 days of up to 120 mg, without any associated serious adverse events. There has been one spontaneous report of a pediatric renal transplantation patient who received a single 20-mg dose (2.3 mg/kg) without adverse events. # Pharmacology ## Mechanism of Action - Basiliximab functions as an IL-2 receptor antagonist by binding with high affinity (Ka = 1 x 1010 M-1) to the alpha chain of the high affinity IL-2 receptor complex and inhibiting IL-2 binding. Basiliximab is specifically targeted against IL-2Rα, which is selectively expressed on the surface of activated T-lymphocytes. This specific high affinity binding of Simulect® (basiliximab) to IL-2Rα competitively inhibits IL-2-mediated activation of lymphocytes, a critical pathway in the cellular immune response involved in allograft rejection. - While in the circulation, Simulect impairs the response of the immune system to antigenic challenges. Whether the ability to respond to repeated or ongoing challenges with those antigens returns to normal after Simulect is cleared is unknown ## Structure - Simulect® (basiliximab) is a chimeric (murine/human) monoclonal antibody (IgG1к), produced by recombinant DNA technology, that functions as an immunosuppressive agent, specifically binding to and blocking the interleukin-2 receptor α-chain (IL-2Rα, also known as CD25 antigen) on the surface of activated T-lymphocytes. Based on the amino acid sequence, the calculated molecular weight of the protein is 144 kilodaltons. It is a glycoprotein obtained from fermentation of an established mouse myeloma cell line genetically engineered to express plasmids containing the human heavy and light chain constant region genes and mouse heavy and light chain variable region genes encoding the RFT5 antibody that binds selectively to the IL-2Rα. - The active ingredient, basiliximab, is water soluble. The drug product, Simulect, is a sterile lyophilisate which is available in 6 mL colorless glass vials and is available in 10 mg and 20 mg strengths. - Each 10-mg vial contains 10 mg basiliximab, 3.61 mg monobasic potassium phosphate, 0.50 mg disodium hydrogen phosphate (anhydrous), 0.80 mg sodium chloride, 10 mg sucrose, 40 mg mannitol and 20 mg glycine, to be reconstituted in 2.5 mL of Sterile Water for Injection, USP. No preservatives are added. - Each 20-mg vial contains 20 mg basiliximab, 7.21 mg monobasic potassium phosphate, 0.99 mg disodium hydrogen phosphate (anhydrous), 1.61 mg sodium chloride, 20 mg sucrose, 80 mg mannitol and 40 mg glycine, to be reconstituted in 5 mL of Sterile Water for Injection, USP. No preservatives are added. ## Pharmacodynamics - Complete and consistent binding to IL-2Rα in adults is maintained as long as serum Simulect levels exceed 0.2 µg/mL. As concentrations fall below this threshold, the IL-2Rα sites are no longer fully bound and the number of T-cells expressing unbound IL-2Rα returns to pretherapy values within 1-2 weeks. The relationship between serum concentration and receptor saturation was assessed in 13 pediatric patients and was similar to that characterized in adult renal transplantation patients. In vitro studies using human tissues indicate that Simulect binds only to lymphocytes. - The duration of clinically relevant IL-2 receptor blockade after the recommended course of Simulect is not known. When basiliximab was added to a regimen of cyclosporine, USP (MODIFIED) and corticosteroids in adult patients, the duration of IL-2Rα saturation was 36 ± 14 days (mean ± SD), similar to that observed in pediatric patients (36 ± 14 days). When basiliximab was added to a triple therapy regimen consisting of cyclosporine, USP (MODIFIED), corticosteroids, and azathioprine in adults, the duration was 50 ± 20 days and when added to cyclosporine, USP (MODIFIED), corticosteroids, and mycophenolate mofetil in adults, the duration was 59 ± 17 days. No significant changes to circulating lymphocyte numbers or cell phenotypes were observed by flow cytometry. ## Pharmacokinetics - Single-dose and multiple-dose pharmacokinetic studies have been conducted in patients undergoing first kidney transplantation. Cumulative doses ranged from 15 mg up to 150 mg. Peak mean ± SD serum concentration following intravenous infusion of 20 mg over 30 minutes is 7.1 ± 5.1 mg/L. There is a dose-proportional increase in Cmax and AUC up to the highest tested single dose of 60 mg. The volume of distribution at steady state is 8.6 ± 4.1 L. The extent and degree of distribution to various body compartments have not been fully studied. The terminal half-life is 7.2 ± 3.2 days. Total body clearance is 41 ± 19 mL/h. No clinically relevant influence of body weight or gender on distribution volume or clearance has been observed in adult patients. Elimination half-life was not influenced by age (20-69 years), gender or race . - The pharmacokinetics of Simulect have been assessed in 39 pediatric patients undergoing renal transplantation. In infants and children (1-11 years of age, n=25), the distribution volume and clearance were reduced by about 50% compared to adult renal transplantation patients. The volume of distribution at steady state was 4.8 ± 2.1 L, half-life was 9.5 ± 4.5 days and clearance was 17 ± 6 mL/h. Disposition parameters were not influenced to a clinically relevant extent by age (1-11 years of age), body weight (9-37 kg) or body surface area (0.44-1.20 m2) in this age group. In adolescents (12-16 years of age, n=14), disposition was similar to that in adult renal transplantation patients. The volume of distribution at steady state was 7.8 ± 5.1 L, half-life was 9.1 ± 3.9 days and clearance was 31 ± 19 mL/h ## Nonclinical Toxicology - No mutagenic potential of Simulect was observed in the in vitro assays with Salmonella (Ames) and V79 Chinese hamster cells. No long-term or fertility studies in laboratory animals have been performed to evaluate the potential of Simulect to produce carcinogenicity or fertility impairment, respectively. # Clinical Studies - The safety and efficacy of Simulect® (basiliximab) for the prophylaxis of acute organ rejection in adults following cadaveric- or living-donor renal transplantation were assessed in four randomized, double-blind, placebo-controlled clinical studies (1,184 patients). Of these four, two studies (Study 1 and Study 2 ) compared two 20-mg doses of Simulect with placebo, each administered intravenously as an infusion, as part of a standard immunosuppressive regimen comprised of cyclosporine, USP (MODIFIED) and corticosteroids. The other two controlled studies compared two 20-mg doses of Simulect with placebo, each administered intravenously as a bolus injection, as part of a standard triple-immunosuppressive regimen comprised of cyclosporine, USP (MODIFIED), corticosteroids and either azathioprine or mycophenolate mofetil (Study 3 and Study 4, respectively). The first dose of Simulect or placebo was administered within 2 hours prior to transplantation surgery (Day 0) and the second dose administered on Day 4 post-transplantation. The regimen of Simulect was chosen to provide 30-45 days of IL-2Rα saturation. - 729 patients were enrolled in the two studies using a dual maintenance immunosuppressive regimen comprised of cyclosporine, USP (MODIFIED) and corticosteroids, of which 363 patients were treated with Simulect and 358 patients were placebo-treated. Study 1 was conducted at 21 sites in Europe and Canada (EU/CAN Study); Study 2 was conducted at 21 sites in the USA (US Study). Patients 18-75 years of age undergoing first cadaveric- (Study 1 and Study 2) or living-donor (Study 2 only) renal transplantation, with ≥1 HLA mismatch, were enrolled.1,2 - The primary efficacy endpoint in both studies was the incidence of death, graft loss or an episode of acute rejection during the first 6 months post-transplantation. Secondary efficacy endpoints included the primary efficacy variable measured during the first 12 months post-transplantation, the incidence of biopsy-confirmed acute rejection during the first 6 and 12 months post-transplantation, and patient survival and graft survival, each measured at 12 months post-transplantation. Table 1 summarizes the results of these studies. Figure 1 displays the Kaplan-Meier estimates of the percentage of patients by treatment group experiencing the primary efficacy endpoint during the first 12 months post-transplantation for Study 2. Patients in both studies receiving Simulect experienced a significantly lower incidence of biopsy-confirmed rejection episodes at both 6 and 12 months post-transplantation. There was no difference in the rate of delayed graft function, patient survival, or graft survival between Simulect-treated patients and placebo-treated patients in either study. - There was no evidence that the clinical benefit of Simulect was limited to specific subpopulations based on age, gender, race, donor type (cadaveric or living donor allograft) or history of diabetes mellitus. - Two double-blind, randomized, placebo-controlled studies (Study 3 and Study 4) assessed the safety and efficacy of Simulect for the prophylaxis of acute renal transplant rejection in adults when used in combination with a triple immunosuppressive regimen. In Study 3, 340 patients were concomitantly treated with cyclosporine, USP (MODIFIED), corticosteroids and azathioprine (AZA), of which 168 patients were treated with Simulect and 172 patients were treated with placebo. In Study 4, 123 patients were concomitantly treated with cyclosporine, USP (MODIFIED), corticosteroids and mycophenolate mofetil (MMF), of which 59 patients were treated with Simulect and 64 patients were treated with placebo. Patients 18-70 years of age undergoing first or second cadaveric or living donor (related or unrelated) renal transplantation were enrolled in both studies. - The results of Study 3 are shown in Table 2. These results are consistent with the findings from Study 1 and Study 2. - USP (MODIFIED) - In Study 4, the percentage of patients experiencing biopsy-proven acute rejection by 6 months was 15% (9 of 59 patients) in the Simulect group and 27% (17 of 64 patients) in the placebo group. Although numerically lower, the difference in acute rejection was not significant. - In a multicenter, randomized, double-blind, placebo-controlled trial of Simulect for the prevention of allograft rejection in liver transplant recipients (n=381) receiving concomitant cyclosporine, USP (MODIFIED) and steroids, the incidence of the combined endpoint of death, graft loss, or first biopsy-confirmed rejection episode at either 6 or 12 months was similar between patients randomized to receive Simulect and those randomized to receive placebo. - The efficacy of Simulect for the prophylaxis of acute rejection in recipients of a second renal allograft has not been demonstrated. - Long Term Follow-up - Five-year patient survival and graft survival data were provided by 71% and 58% of the original subjects of Study 1 and Study 2, respectively. Subjects in both studies continued to receive a dual-therapy regimen with cyclosporine, USP (MODIFIED) and corticosteroid. No difference was observed between groups in the 5-year graft survival in either Study 1 (91% Simulect group, 92% placebo group) or Study 2 (85% Simulect group, 86% placebo group). In Study 1, patient survival was lower in the Simulect-treated patients compared to the placebo-treated patients (142/163 vs. 156/164 , respectively). The cause of this difference in survival is unknown. The data do not indicate an increase in malignancy- or infection-related mortality. In Study 2, patient survival in the placebo group (90%) was the same compared to Simulect group (90%). # How Supplied - Simulect® (basiliximab) is supplied in a single-use glass vial. - Each carton contains one of the following ## Storage - Store lyophilized Simulect under refrigerated conditions (2ºC to 8ºC; 36ºF to 46ºF). - Do not use beyond the expiration date stamped on the vial. # Images ## Drug Images ## Package and Label Display Panel ### PRINCIPAL DISPLAY PANEL Package Label – 10 mg Rx Only NDC 0078-0393-61 Simulect® (basiliximab) for injection 10 mg (single use vial) Package Label – 20 mg Rx Only NDC 0078-0331-84 Simulect® (basiliximab) for injection 20 mg (single use vial) ### Inredients and Appearance # Patient Counseling Information There is limited information regarding Patient Counseling Information of Basiliximab in the drug label. # Precautions with Alcohol - Alcohol-Basiliximab interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - SIMULECT® # Look-Alike Drug Names There is limited information regarding Basiliximab Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	Basiliximab Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Rabin Bista, M.B.B.S. [2] # Disclaimer WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here. # Black Box Warning # Overview Basiliximab is a monoclonal antibody that is FDA approved for the prophylaxis of acute organ rejection in patients receiving renal transplantation when used as part of an immunosuppressive regimen. There is a Black Box Warning for this drug as shown here. Common adverse reactions include Abdominal pain, Vomiting, constipation, diarrhea, dizziness. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) ### Indications - Simulect® (basiliximab) is indicated for the prophylaxis of acute organ rejection in patients receiving renal transplantation when used as part of an immunosuppressive regimen that includes cyclosporine, USP (MODIFIED) and corticosteroids. - The efficacy of Simulect for the prophylaxis of acute rejection in recipients of other solid organ allografts has not been demonstrated. ### Dosage - Simulect® (basiliximab) is used as part of an immunosuppressive regimen that includes cyclosporine, USP (MODIFIED) and corticosteroids. Simulect is for central or peripheral intravenous administration only. Reconstituted Simulect should be given either as a bolus injection or diluted to a volume of 25 mL (10-mg vial) or 50 mL (20-mg vial) with normal saline or dextrose 5% and administered as an intravenous infusion over 20 to 30 minutes. Bolus administration may be associated with nausea, vomiting and local reactions, including pain. - Simulect should only be administered once it has been determined that the patient will receive the graft and concomitant immunosuppression. Patients previously administered Simulect should only be re-exposed to a subsequent course of therapy with extreme caution due to the potential risk of hypersensitivity. - Parenteral drug products should be inspected visually for particulate matter and discoloration before administration. After reconstitution, Simulect should be a clear-to-opalescent, colorless solution. If particulate matter is present or the solution is colored, do not use. - Care must be taken to assure sterility of the prepared solution because the drug product does not contain any antimicrobial preservatives or bacteriostatic agents. - It is recommended that after reconstitution, the solution should be used immediately. If not used immediately, it can be stored at 2ºC to 8ºC for 24 hours or at room temperature for 4 hours. Discard the reconstituted solution if not used within 24 hours. - No incompatibility between Simulect and polyvinyl chloride bags or infusion sets has been observed. No data are available on the compatibility of Simulect with other intravenous substances. Other drug substances should not be added or infused simultaneously through the same intravenous line. - In adult patients, the recommended regimen is two doses of 20 mg each. The first 20-mg dose should be given within 2 hours prior to transplantation surgery. The recommended second 20-mg dose should be given 4 days after transplantation. The second dose should be withheld if complications such as severe hypersensitivity reactions to Simulect or graft loss occur. - To prepare the reconstituted solution, add 2.5 mL of Sterile Water for Injection, USP, using aseptic technique, to the vial containing the Simulect powder. Shake the vial gently to dissolve the powder. - The reconstituted solution is isotonic and may be given either as a bolus injection or diluted to a volume of 25 mL with normal saline or dextrose 5% for infusion. When mixing the solution, gently invert the bag in order to avoid foaming; DO NOT SHAKE. - To prepare the reconstituted solution, add 5 mL of Sterile Water for Injection, USP, using aseptic technique, to the vial containing the Simulect powder. Shake the vial gently to dissolve the powder. - The reconstituted solution is isotonic and may be given either as a bolus injection or diluted to a volume of 50 mL with normal saline or dextrose 5% for infusion. When mixing the solution, gently invert the bag in order to avoid foaming; DO NOT SHAKE. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Basiliximab in adult patients. ### Non–Guideline-Supported Use - Graft versus host disease[1] - Liver transplant rejection; Prophylaxis[2] # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) ### Pediatric dosage - In pediatric patients weighing less than 35 kg, the recommended regimen is two doses of 10 mg each. In pediatric patients weighing 35 kg or more, the recommended regimen is two doses of 20 mg each. The first dose should be given within 2 hours prior to transplantation surgery. The recommended second dose should be given 4 days after transplantation. The second dose should be withheld if complications such as severe hypersensitivity reactions to Simulect or graft loss occur. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Basiliximab in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Basiliximab in pediatric patients. # Contraindications - Simulect® (basiliximab) is contraindicated in patients with known hypersensitivity to basiliximab or any other component of the formulation. See composition of Simulect under DESCRIPTION. # Warnings - Simulect® (basiliximab) should be administered under qualified medical supervision. Patients should be informed of the potential benefits of therapy and the risks associated with administration of immunosuppressive therapy. - While neither the incidence of lymphoproliferative disorders nor opportunistic infections was higher in Simulect-treated patients than in placebo-treated patients, patients on immunosuppressive therapy are at increased risk for developing these complications and should be monitored accordingly. - Severe acute (onset within 24 hours) hypersensitivity reactions including anaphylaxis have been observed both on initial exposure to Simulect and/or following re-exposure after several months. These reactions may include hypotension, tachycardia, cardiac failure, dyspnea, wheezing, bronchospasm, pulmonary edema, respiratory failure, urticaria, rash, pruritus, and/or sneezing. Extreme caution should be exercised in all patients previously given Simulect when being administered a subsequent course of Simulect. A subgroup of patients may be particularly at risk of developing severe hypersensitivity reactions on re-administration. These are patients in whom concomitant immunosuppression was discontinued prematurely (e.g., due to abandoned transplantation or early loss of the graft) following the initial administration of Simulect. If a severe hypersensitivity reaction occurs, therapy with Simulect should be permanently discontinued. Medications for the treatment of severe hypersensitivity reactions including anaphylaxis should be available for immediate use. ### Precautions - It is not known whether Simulect® (basiliximab) use will have a long-term effect on the ability of the immune system to respond to antigens first encountered during Simulect-induced immunosuppression. - Of renal transplantation patients treated with Simulect and tested for anti-idiotype antibodies, 4/339 developed an anti-idiotype antibody response, with no deleterious clinical effect upon the patient. In none of these cases was there evidence that the presence of anti-idiotype antibody accelerated Simulect clearance or decreased the period of receptor saturation. In Study 2, the incidence of human anti-murine antibody (HAMA) in renal transplantation patients treated with Simulect was 2/138 in patients not exposed to muromonab-CD3 and 4/34 in patients who subsequently received muromonab-CD3. The available clinical data on the use of muromonab-CD3 in patients previously treated with Simulect suggest that subsequent use of muromonab-CD3 or other murine anti-lymphocytic antibody preparations is not precluded. - These data reflect the percentage of patients whose test results were considered positive for antibodies to Simulect in an ELISA assay, and are highly dependent on the sensitivity and specificity of the assay. Additionally the observed incidence of antibody positivity in an assay may be influenced by several factors including sample handling, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to Simulect with the incidence of antibodies to other products may be misleading. # Adverse Reactions ## Clinical Trials Experience - Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The adverse reaction information from clinical trials does, however, provide a basis for identifying the adverse events that appear to be related to drug use and for approximating rates. - The incidence of adverse events for Simulect® (basiliximab) was determined in four randomized, double-blind, placebo-controlled clinical trials for the prevention of renal allograft rejection. Two of the studies (Study 1 and Study 2), used a dual maintenance immunosuppressive regimen comprised of cyclosporine, USP (MODIFIED) and corticosteroids, whereas the other two studies (Study 3 and Study 4) used a triple-immunosuppressive regimen comprised of cyclosporine, USP (MODIFIED), corticosteroids, and either azathioprine or mycophenolate mofetil. - Simulect did not appear to add to the background of adverse events seen in organ transplantation patients as a consequence of their underlying disease and the concurrent administration of immunosuppressants and other medications. Adverse events were reported by 96% of the patients in the placebo-treated group and 96% of the patients in the Simulect-treated group. In the four placebo-controlled studies, the pattern of adverse events in 590 patients treated with the recommended dose of Simulect was similar to that in 594 patients treated with placebo. Simulect did not increase the incidence of serious adverse events observed compared with placebo. - The most frequently reported adverse events were gastrointestinal disorders, reported in 69% of Simulect-treated patients and 67% of placebo-treated patients. - The incidence and types of adverse events were similar in Simulect-treated and placebo-treated patients. The following adverse events occurred in ≥10% of Simulect-treated patients: Gastrointestinal System: constipation, nausea, abdominal pain, vomiting, diarrhea, dyspepsia; Body as a Whole-General: pain, peripheral edema, fever, viral infection; Metabolic and Nutritional: hyperkalemia, hypokalemia, hyperglycemia, hypercholesterolemia, hypophosphatemia, hyperuricemia; Urinary System: urinary tract infection; Respiratory System: dyspnea, upper respiratory tract infection; Skin and Appendages: surgical wound complications, acne; Cardiovascular Disorders-General: hypertension; Central and Peripheral Nervous System: headache, tremor; Psychiatric: insomnia; Red Blood Cell: anemia. - The following adverse events, not mentioned above, were reported with an incidence of ≥3% and <10% in pooled analysis of patients treated with Simulect in the four controlled clinical trials, or in an analysis of the two dual-therapy trials: Body as a Whole-General: accidental trauma, asthenia, chest pain, increased drug level, infection, face edema, fatigue, dependent edema, generalized edema, leg edema, malaise, rigors, sepsis; Cardiovascular: abnormal heart sounds, aggravated hypertension, angina pectoris, cardiac failure, chest pain, hypotension; Endocrine: increased glucocorticoids; Gastrointestinal: enlarged abdomen, esophagitis, flatulence, gastrointestinal disorder, gastroenteritis, GI hemorrhage, gum hyperplasia, melena, moniliasis, ulcerative stomatitis; Heart Rate and Rhythm: arrhythmia, atrial fibrillation, tachycardia; Metabolic and Nutritional: acidosis, dehydration, diabetes mellitus, fluid overload, hypercalcemia, hyperlipemia, hypertriglyceridemia, hypocalcemia, hypoglycemia, hypomagnesemia, hypoproteinemia, weight increase; Musculoskeletal: arthralgia, arthropathy, back pain, bone fracture, cramps, hernia, myalgia, leg pain; Nervous System: dizziness, neuropathy, paraesthesia, hypoesthesia; Platelet and Bleeding: hematoma, hemorrhage, purpura, thrombocytopenia, thrombosis; Psychiatric: agitation, anxiety, depression; Red Blood Cell: polycythemia; Reproductive Disorders, Male: genital edema, impotence; Respiratory: bronchitis, bronchospasm, abnormal chest sounds, coughing, pharyngitis, pneumonia, pulmonary disorder, pulmonary edema, rhinitis, sinusitis; Skin and Appendages: cyst, herpes simplex, herpes zoster, hypertrichosis, pruritus, rash, skin disorder, skin ulceration; Urinary: albuminuria, bladder disorder, dysuria, frequent micturition, hematuria, increased non-protein nitrogen, oliguria, abnormal renal function, renal tubular necrosis, surgery, ureteral disorder, urinary retention; Vascular Disorders: vascular disorder; Vision Disorders: cataract, conjunctivitis, abnormal vision; White Blood Cell: leucopenia. Among these events, leucopenia and hypertriglyceridemia occurred more frequently in the two triple-therapy studies using azathioprine and mycophenolate mofetil than in the dual-therapy studies. - The incidence of malignancies in the controlled clinical trials of renal transplant was not significantly different between groups at 1 year (9/590 Simulect-treated patients vs. 12/594 placebo-treated patients) or among patients with 5-year follow-up from Studies 1 and 2 (21/295 Simulect-treated patients vs. 21/291 placebo-treated patients). The incidence of lymphoproliferative disease was not significantly different between groups, and less than 1% in the Simulect-treated patients. ### Infections - The overall incidence of cytomegalovirus infection was similar in Simulect- and placebo-treated patients (15% vs. 17%) receiving a dual- or triple-immunosuppression regimen. However, in patients receiving a triple-immunosuppression regimen, the incidence of serious cytomegalovirus infection was higher in Simulect-treated patients compared to placebo-treated patients (11% vs. 5%). The rates of infections, serious infections, and infectious organisms were similar in the Simulect- and placebo-treatment groups among dual- and triple-therapy treated patients. ## Postmarketing Experience - Severe acute hypersensitivity reactions including anaphylaxis characterized by hypotension, tachycardia, cardiac failure, dyspnea, wheezing, bronchospasm, pulmonary edema, respiratory failure, urticaria, rash, pruritus, and/or sneezing, as well as capillary leak syndrome and cytokine release syndrome, have been reported during post-marketing experience with Simulect. # Drug Interactions - No dose adjustment is necessary when Simulect is added to triple-immunosuppression regimens including cyclosporine, corticosteroids, and either azathioprine or mycophenolate mofetil. Three clinical trials have investigated Simulect use in combination with triple-therapy regimens. Pharmacokinetics were assessed in two of these trials. Total body clearance of Simulect was reduced by an average 22% and 51% when azathioprine and mycophenolate mofetil, respectively, were added to a regimen consisting of cyclosporine, USP (MODIFIED) and corticosteroids. Nonetheless, the range of individual Simulect clearance values in the presence of azathioprine (12-57 mL/h) or mycophenolate mofetil (7-54 mL/h) did not extend outside the range observed with dual therapy (10-78 mL/h). The following medications have been administered in clinical trials with Simulect with no increase in adverse reactions: ATG/ALG, azathioprine, corticosteroids, cyclosporine, mycophenolate mofetil, and muromonab-CD3. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): B - There are no adequate and well-controlled studies in pregnant women. No maternal toxicity, embryotoxicity, or teratogenicity was observed in cynomolgus monkeys 100 days post coitum following dosing with basiliximab during the organogenesis period; blood levels in pregnant monkeys were 13-fold higher than those seen in human patients. Immunotoxicology studies have not been performed in the offspring. Because IgG molecules are known to cross the placental barrier, because the IL-2 receptor may play an important role in development of the immune system, and because animal reproduction studies are not always predictive of human response, Simulect should only be used in pregnant women when the potential benefit justifies the potential risk to the fetus. Women of childbearing potential should use effective contraception before beginning Simulect therapy, during therapy, and for 4 months after completion of Simulect therapy. Pregnancy Category (AUS): - Australian Drug Evaluation Committee (ADEC) Pregnancy Category There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Basiliximab in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Basiliximab during labor and delivery. ### Nursing Mothers - It is not known whether Simulect is excreted in human milk. Because many drugs including human antibodies are excreted in human milk, and because of the potential for adverse reactions, a decision should be made to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. ### Pediatric Use - No randomized, placebo-controlled studies have been completed in pediatric patients. In a safety and pharmacokinetic study, 41 pediatric patients (1-11 years of age [n=27], 12-16 years of age [n=14], median age 8.1 years) were treated with Simulect via intravenous bolus injection in addition to standard immunosuppressive agents including cyclosporine, USP (MODIFIED), corticosteroids, azathioprine, and mycophenolate mofetil. The acute rejection rate at 6 months was comparable to that in adults in the triple-therapy trials. The most frequently reported adverse events were hypertension, hypertrichosis, and rhinitis (49% each), urinary tract infections (46%), and fever (39%). Overall, the adverse event profile was consistent with general clinical experience in the pediatric renal transplantation population and with the profile in the controlled adult renal transplantation studies. The available pharmacokinetic data in children and adolescents are described in CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION. - It is not known whether the immune response to vaccines, infection, and other antigenic stimuli administered or encountered during Simulect therapy is impaired or whether such response will remain impaired after Simulect therapy. ### Geriatic Use - Controlled clinical studies of Simulect have included a small number of patients 65 years and older (Simulect 28; placebo 32). From the available data comparing Simulect and placebo-treated patients, the adverse event profile in patients ≥65 years of age is not different from patients <65 years of age and no age-related dosing adjustment is required. Caution must be used in giving immunosuppressive drugs to elderly patients. ### Gender There is no FDA guidance on the use of Basiliximab with respect to specific gender populations. ### Race There is no FDA guidance on the use of Basiliximab with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Basiliximab in patients with renal impairment. ### Hepatic Impairment There is no FDA guidance on the use of Basiliximab in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Basiliximab in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Basiliximab in patients who are immunocompromised. # Administration and Monitoring ### Administration - Intravenous ### Monitoring There is limited information regarding Monitoring of Basiliximab in the drug label. # IV Compatibility There is limited information regarding IV Compatibility of Basiliximab in the drug label. # Overdosage - A maximum tolerated dose of Simulect® (basiliximab) has not been determined in patients. During the course of clinical studies, Simulect has been administered to adult renal transplantation patients in single doses of up to 60 mg, or in divided doses over 3-5 days of up to 120 mg, without any associated serious adverse events. There has been one spontaneous report of a pediatric renal transplantation patient who received a single 20-mg dose (2.3 mg/kg) without adverse events. # Pharmacology ## Mechanism of Action - Basiliximab functions as an IL-2 receptor antagonist by binding with high affinity (Ka = 1 x 1010 M-1) to the alpha chain of the high affinity IL-2 receptor complex and inhibiting IL-2 binding. Basiliximab is specifically targeted against IL-2Rα, which is selectively expressed on the surface of activated T-lymphocytes. This specific high affinity binding of Simulect® (basiliximab) to IL-2Rα competitively inhibits IL-2-mediated activation of lymphocytes, a critical pathway in the cellular immune response involved in allograft rejection. - While in the circulation, Simulect impairs the response of the immune system to antigenic challenges. Whether the ability to respond to repeated or ongoing challenges with those antigens returns to normal after Simulect is cleared is unknown ## Structure - Simulect® (basiliximab) is a chimeric (murine/human) monoclonal antibody (IgG1к), produced by recombinant DNA technology, that functions as an immunosuppressive agent, specifically binding to and blocking the interleukin-2 receptor α-chain (IL-2Rα, also known as CD25 antigen) on the surface of activated T-lymphocytes. Based on the amino acid sequence, the calculated molecular weight of the protein is 144 kilodaltons. It is a glycoprotein obtained from fermentation of an established mouse myeloma cell line genetically engineered to express plasmids containing the human heavy and light chain constant region genes and mouse heavy and light chain variable region genes encoding the RFT5 antibody that binds selectively to the IL-2Rα. - The active ingredient, basiliximab, is water soluble. The drug product, Simulect, is a sterile lyophilisate which is available in 6 mL colorless glass vials and is available in 10 mg and 20 mg strengths. - Each 10-mg vial contains 10 mg basiliximab, 3.61 mg monobasic potassium phosphate, 0.50 mg disodium hydrogen phosphate (anhydrous), 0.80 mg sodium chloride, 10 mg sucrose, 40 mg mannitol and 20 mg glycine, to be reconstituted in 2.5 mL of Sterile Water for Injection, USP. No preservatives are added. - Each 20-mg vial contains 20 mg basiliximab, 7.21 mg monobasic potassium phosphate, 0.99 mg disodium hydrogen phosphate (anhydrous), 1.61 mg sodium chloride, 20 mg sucrose, 80 mg mannitol and 40 mg glycine, to be reconstituted in 5 mL of Sterile Water for Injection, USP. No preservatives are added. ## Pharmacodynamics - Complete and consistent binding to IL-2Rα in adults is maintained as long as serum Simulect levels exceed 0.2 µg/mL. As concentrations fall below this threshold, the IL-2Rα sites are no longer fully bound and the number of T-cells expressing unbound IL-2Rα returns to pretherapy values within 1-2 weeks. The relationship between serum concentration and receptor saturation was assessed in 13 pediatric patients and was similar to that characterized in adult renal transplantation patients. In vitro studies using human tissues indicate that Simulect binds only to lymphocytes. - The duration of clinically relevant IL-2 receptor blockade after the recommended course of Simulect is not known. When basiliximab was added to a regimen of cyclosporine, USP (MODIFIED) and corticosteroids in adult patients, the duration of IL-2Rα saturation was 36 ± 14 days (mean ± SD), similar to that observed in pediatric patients (36 ± 14 days). When basiliximab was added to a triple therapy regimen consisting of cyclosporine, USP (MODIFIED), corticosteroids, and azathioprine in adults, the duration was 50 ± 20 days and when added to cyclosporine, USP (MODIFIED), corticosteroids, and mycophenolate mofetil in adults, the duration was 59 ± 17 days. No significant changes to circulating lymphocyte numbers or cell phenotypes were observed by flow cytometry. ## Pharmacokinetics - Single-dose and multiple-dose pharmacokinetic studies have been conducted in patients undergoing first kidney transplantation. Cumulative doses ranged from 15 mg up to 150 mg. Peak mean ± SD serum concentration following intravenous infusion of 20 mg over 30 minutes is 7.1 ± 5.1 mg/L. There is a dose-proportional increase in Cmax and AUC up to the highest tested single dose of 60 mg. The volume of distribution at steady state is 8.6 ± 4.1 L. The extent and degree of distribution to various body compartments have not been fully studied. The terminal half-life is 7.2 ± 3.2 days. Total body clearance is 41 ± 19 mL/h. No clinically relevant influence of body weight or gender on distribution volume or clearance has been observed in adult patients. Elimination half-life was not influenced by age (20-69 years), gender or race . - The pharmacokinetics of Simulect have been assessed in 39 pediatric patients undergoing renal transplantation. In infants and children (1-11 years of age, n=25), the distribution volume and clearance were reduced by about 50% compared to adult renal transplantation patients. The volume of distribution at steady state was 4.8 ± 2.1 L, half-life was 9.5 ± 4.5 days and clearance was 17 ± 6 mL/h. Disposition parameters were not influenced to a clinically relevant extent by age (1-11 years of age), body weight (9-37 kg) or body surface area (0.44-1.20 m2) in this age group. In adolescents (12-16 years of age, n=14), disposition was similar to that in adult renal transplantation patients. The volume of distribution at steady state was 7.8 ± 5.1 L, half-life was 9.1 ± 3.9 days and clearance was 31 ± 19 mL/h ## Nonclinical Toxicology - No mutagenic potential of Simulect was observed in the in vitro assays with Salmonella (Ames) and V79 Chinese hamster cells. No long-term or fertility studies in laboratory animals have been performed to evaluate the potential of Simulect to produce carcinogenicity or fertility impairment, respectively. # Clinical Studies - The safety and efficacy of Simulect® (basiliximab) for the prophylaxis of acute organ rejection in adults following cadaveric- or living-donor renal transplantation were assessed in four randomized, double-blind, placebo-controlled clinical studies (1,184 patients). Of these four, two studies (Study 1 [EU/CAN] and Study 2 [US Study]) compared two 20-mg doses of Simulect with placebo, each administered intravenously as an infusion, as part of a standard immunosuppressive regimen comprised of cyclosporine, USP (MODIFIED) and corticosteroids. The other two controlled studies compared two 20-mg doses of Simulect with placebo, each administered intravenously as a bolus injection, as part of a standard triple-immunosuppressive regimen comprised of cyclosporine, USP (MODIFIED), corticosteroids and either azathioprine or mycophenolate mofetil (Study 3 and Study 4, respectively). The first dose of Simulect or placebo was administered within 2 hours prior to transplantation surgery (Day 0) and the second dose administered on Day 4 post-transplantation. The regimen of Simulect was chosen to provide 30-45 days of IL-2Rα saturation. - 729 patients were enrolled in the two studies using a dual maintenance immunosuppressive regimen comprised of cyclosporine, USP (MODIFIED) and corticosteroids, of which 363 patients were treated with Simulect and 358 patients were placebo-treated. Study 1 was conducted at 21 sites in Europe and Canada (EU/CAN Study); Study 2 was conducted at 21 sites in the USA (US Study). Patients 18-75 years of age undergoing first cadaveric- (Study 1 and Study 2) or living-donor (Study 2 only) renal transplantation, with ≥1 HLA mismatch, were enrolled.1,2 - The primary efficacy endpoint in both studies was the incidence of death, graft loss or an episode of acute rejection during the first 6 months post-transplantation. Secondary efficacy endpoints included the primary efficacy variable measured during the first 12 months post-transplantation, the incidence of biopsy-confirmed acute rejection during the first 6 and 12 months post-transplantation, and patient survival and graft survival, each measured at 12 months post-transplantation. Table 1 summarizes the results of these studies. Figure 1 displays the Kaplan-Meier estimates of the percentage of patients by treatment group experiencing the primary efficacy endpoint during the first 12 months post-transplantation for Study 2. Patients in both studies receiving Simulect experienced a significantly lower incidence of biopsy-confirmed rejection episodes at both 6 and 12 months post-transplantation. There was no difference in the rate of delayed graft function, patient survival, or graft survival between Simulect-treated patients and placebo-treated patients in either study. - There was no evidence that the clinical benefit of Simulect was limited to specific subpopulations based on age, gender, race, donor type (cadaveric or living donor allograft) or history of diabetes mellitus. - Two double-blind, randomized, placebo-controlled studies (Study 3 and Study 4) assessed the safety and efficacy of Simulect for the prophylaxis of acute renal transplant rejection in adults when used in combination with a triple immunosuppressive regimen. In Study 3, 340 patients were concomitantly treated with cyclosporine, USP (MODIFIED), corticosteroids and azathioprine (AZA), of which 168 patients were treated with Simulect and 172 patients were treated with placebo. In Study 4, 123 patients were concomitantly treated with cyclosporine, USP (MODIFIED), corticosteroids and mycophenolate mofetil (MMF), of which 59 patients were treated with Simulect and 64 patients were treated with placebo. Patients 18-70 years of age undergoing first or second cadaveric or living donor (related or unrelated) renal transplantation were enrolled in both studies. - The results of Study 3 are shown in Table 2. These results are consistent with the findings from Study 1 and Study 2. - USP (MODIFIED) - In Study 4, the percentage of patients experiencing biopsy-proven acute rejection by 6 months was 15% (9 of 59 patients) in the Simulect group and 27% (17 of 64 patients) in the placebo group. Although numerically lower, the difference in acute rejection was not significant. - In a multicenter, randomized, double-blind, placebo-controlled trial of Simulect for the prevention of allograft rejection in liver transplant recipients (n=381) receiving concomitant cyclosporine, USP (MODIFIED) and steroids, the incidence of the combined endpoint of death, graft loss, or first biopsy-confirmed rejection episode at either 6 or 12 months was similar between patients randomized to receive Simulect and those randomized to receive placebo. - The efficacy of Simulect for the prophylaxis of acute rejection in recipients of a second renal allograft has not been demonstrated. - Long Term Follow-up - Five-year patient survival and graft survival data were provided by 71% and 58% of the original subjects of Study 1 and Study 2, respectively. Subjects in both studies continued to receive a dual-therapy regimen with cyclosporine, USP (MODIFIED) and corticosteroid. No difference was observed between groups in the 5-year graft survival in either Study 1 (91% Simulect group, 92% placebo group) or Study 2 (85% Simulect group, 86% placebo group). In Study 1, patient survival was lower in the Simulect-treated patients compared to the placebo-treated patients (142/163 [87%] vs. 156/164 [95%], respectively). The cause of this difference in survival is unknown. The data do not indicate an increase in malignancy- or infection-related mortality. In Study 2, patient survival in the placebo group (90%) was the same compared to Simulect group (90%). # How Supplied - Simulect® (basiliximab) is supplied in a single-use glass vial. - Each carton contains one of the following ## Storage - Store lyophilized Simulect under refrigerated conditions (2ºC to 8ºC; 36ºF to 46ºF). - Do not use beyond the expiration date stamped on the vial. # Images ## Drug Images ## Package and Label Display Panel ### PRINCIPAL DISPLAY PANEL Package Label – 10 mg Rx Only NDC 0078-0393-61 Simulect® (basiliximab) for injection 10 mg (single use vial) Package Label – 20 mg Rx Only NDC 0078-0331-84 Simulect® (basiliximab) for injection 20 mg (single use vial) ### Inredients and Appearance # Patient Counseling Information There is limited information regarding Patient Counseling Information of Basiliximab in the drug label. # Precautions with Alcohol - Alcohol-Basiliximab interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - SIMULECT®[3] # Look-Alike Drug Names There is limited information regarding Basiliximab Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	https://www.wikidoc.org/index.php/Basiliximab
094c89be4bc994c38017d73f365b648dae024d96	wikidoc	Child abuse	Child abuse For patient information on Child physical abuse, click here For patient information on Child psychological abuse and neglect, click here # Overview Child abuse is the physical, emotional or sexual abuse or neglect of children by parents, guardians, or others. While most child abuse happens in the child's home, large numbers of cases of child abuse have been identified within some organizations involving children, such as churches, schools, child care businesses, and residential schools. It also can occur almost anywhere (eg kidnappings, random murders etc.) According to a recent UNICEF report on child well-being the United States and the United Kingdom ranked lowest among first world nations with respect to the well being of their children. This study also found that child neglect and child abuse are far more common in single-parent families than in families where both parents are present. There are many forms of abuse and neglect and many governments have developed their own legal definition of what constitutes child maltreatment for the purposes of removing a child and/or prosecuting a criminal charge. In the United States, the Federal Government puts out a full definition of child abuse and neglect and creates a summary of each State definition. # Effects of child abuse Child abuse in its various forms has numerous effects and consequences, both tangible and intangible, upon society, those mistreated, and those entrusted with the responsibility of its detection, prevention, and treatment. Child abuse can have dire consequences, during both childhood and adulthood. The effects of being abused as a child vary according to the severity of the abuse and the surrounding environment of the child. If the family or school environment is nurturing and supportive, the child will probably have a healthier outcome. The U.S. National Adoption Center found that 52% of adoptable children (meaning those children in U.S. foster care) freed for adoption had symptoms of attachment disorder. Children with histories of maltreatment, such as physical and psychological neglect and physical abuse are at risk of developing psychiatric problems., Such children are at risk of developing a disorganized attachment. Disorganized attachment is associated with a number of developmental problems, including dissociative symptoms, as well as anxiety, depressive, and acting-out symptoms. A study by Dante Cicchetti found that 80% of abused and maltreated infants exhibited symptoms of disorganized attachment., Negative Consequences of Child Abuse Emotional effects include low self-esteem, depression and anxiety, eating disorders, relationship difficulties, alienation and withdrawal, and personality disorders. Physical effects include injury, death, lifelong health problems, cognitive difficulties, and physical disabilities. Behavioral effects include problems in school and work, delinquency, teen pregnancy, suicide attempts, criminal or antisocial behavior, substance abuse, aggressive behavior, spousal and child abuse, and anger. # Causes of child abuse There are many causes of child abuse. Many child abusers were themselves victims of abuse. Mental illness is another common factor, with many abusers having personality disorders or other severe forms of mental illness. Psychosocial factors also play a role. Parental choices and other unforeseen circumstances that place families under extraordinary stress ― for instance, poverty, divorce, sickness, disability, lack of parental skills and drugs are often associated to child maltreatment. Children in families that have a parent deployed in combat are also more likely to be victims of child maltreatment. Many of these factors may contribute to family stress that can result in child abuse or neglect. Understanding the root causes of abuse can help better determine the best methods of prevention and treatment. # Prevention Given these possible causes, most professionals agree that there are three levels of prevention services; primary prevention, secondary prevention, and tertiary prevention. ## Primary prevention Primary prevention consists of activities that are targeted at the community level. These activities are meant to impact families prior to any allegations of abuse and neglect. Primary prevention services include public education activities, parent education classes that are open to anyone in the community for parents or abusers to interact with the child, and family support programs. Primary prevention can be difficult to measure because you are attempting to impact something before it happens, an unknown variable. ## Secondary prevention Secondary prevention consists of activities targeted to families that have one or more risk factors including families with substance abuse, teen parents, parents of special need children, single parents, and low income families. Secondary prevention services include parent education classes targeted for high risk parents, respite care for parents of a child with a disability, or home visiting programs for new parents. ## Tertiary prevention These families have already demonstrated the need for intervention, with or without court supervision. Prevention supporters consider 'tertiary prevention' synonymous with treatment and entirely different from prevention through family support. # Treatment Treatment for those experiencing sequelae from abuse, or Complex post-traumatic stress disorder, which may be caused by early chronic maltreatment, should address each dimension. Often treatment must be multi-modal. Children who have experienced complex trauma caused by chronic maltreatment can be treated effectively with Cognitive Behavioral Therapy interventions, other therapeutic interventions, education, EMDR and other approaches. For children with attachment difficulties or disorders there are a number of recognized interventions. # Child abuse prevention organizations ## Childhelp CEO and Co-Founder Sara O’Meara and President and Co-Founder Yvonne Fedderson started Childhelp in 1959, establishing it as a leading national non-profit organization dedicated to helping victims of child abuse and neglect and at-risk children. Childhelp focuses on advocacy, prevention, treatment and community outreach. The Childhelp National Child Abuse Hotline, 1-800-4-A-CHILD®, operates 24 hours a day, seven days a week and receives calls from throughout the United States, Canada and the U.S. Virgin Islands, Puerto Rico and Guam. Childhelp’s programs and services also include residential treatment services (villages); children’s advocacy centers; therapeutic foster care; group homes and child abuse prevention, education and training. Childhelp also created the National Day of Hope® that mobilizes people across America to join the fight against child abuse. ## Najidah The Najidah Association was originally established as a Domestic and Family Violence service. In 2003 Najidah began to advocate on behalf of the child victims of DV. Citing the Australian national practice standards for working with children exposed to DV, Najidah revised their practice to respond on the basis that (as per the Australian Standards) exposing children, and or failing to protect children from DV is a form of child abuse. Najidah also began a campaign to highlight the fact that 70% of people in DV refuges are in fact children. Further to this Najidah has developed a suite of programs that respond to the needs of abused children and the prevention of child abuse. These programs have since won national acclaim and recognition as best practice. ## C.A.S. Children's Aid Societies in Canada The children's aid society (CAS), also known as Family and Children's Services (F&CS), is a non-profit agency working in local communities to provide help and support to children and their families in Canada. ## ISPCAN (International Society for Prevention of Child Abuse and Neglect) The International Society for Prevention of Child Abuse and Neglect, founded in 1977, is the only multidisciplinary international organization that brings together a worldwide cross-section of committed professionals to work towards the prevention and treatment of child abuse, neglect and exploitation globally. Objectives - To increase awareness of the extent, the causes and possible solutions for all forms of child abuse. - To disseminate academic and clinical research to those in positions to enhance practice and improve policy. - To support international efforts to promote and protect the Rights of the Child. - To improve the quality of current efforts to detect, treat and prevent child abuse. - To facilitate the exchange of best practice standards being developed by ISPCAN members throughout the world. - To design and deliver comprehensive training programs to professionals and concerned volunteers engaged in efforts to treat and prevent child abuse. ## SPARC (Society for the Protection of the Rights of the Child) SPARC is a Pakistan-based child abuse prevention organization. In its annual report titled 'The State of Pakistan's Children-2006', SPARC stated that Pakistan had the highest maternal, which at the present-time was 70 deaths per 1,000 live births, and infant mortality rates in South Asia. The report stated around four children were abused daily, and in 2006 there were a total of 2,447 cases of abuse. # Reporting of child abuse ## Authorities Depending on the country, the agencies responsible for investigating child abuse are either managed nationally, regionally, or locally. These agencies may be called Child Protective Services (CPS), Department of Children and Family Services (DCFS), or by other similar names. In the U.S., these agencies are usually listed in the state government section of the telephone book under "Children" or "Health" or "Human Services". In a few instances in the U.S., some of the functions of these agencies are outsourced to private individuals or companies. People who investigate claims of child abuse may be called a "children's social worker" (CSW) or a case worker. ## Reporting abuse and neglect in Australia Child abuse and neglect is the subject of mandatory reporting in most Australian jurisdictions. Usually professional people such as doctors, nurses and teachers are bound to report strong evidence of abuse or neglect. State authorities, such as the Child Protection Unit of the Department of Human Services (Victoria), have statutory authority to investigate and deal with child abuse. A document from Child Protection and Family Services, in Melbourne states: "The service system is facing escalating and changing demand pressures and we are increasingly aware of growing client complexity. Too many children, young people and families are coming back into the child protection system on a repeat basis with services making little impact on their issues. The analysis confirms this and identifies the need for a strategic rethink if we are to achieve better outcomes for vulnerable children, young people and their families. " ## Reporting Abuse in the UK All professionals who work with children, such as teachers, health professionals and the like are required to report to social services (or the police as appropriate) any 'concern' amounting to possible 'significant harm' (neglect, physical, sexual or emotional abuse) regarding a child's welfare. The police and social services operate a multi-agency approach in cases of serious abuse. A system of referrals to Social Services so that one authority held all information started in the 1960s following the death of Maria Colwell, but was insufficiently effective and a number of notorious cases over the years have resulted in several major overhauls of the system, the most recent following the death of Victoria Climbie in 2000. Social Service departments, organised regionally, are required to investigate reports of abuse, keep records and take appropriate action to protect children. This can range from the provision of advice and support to families through to immediate removal under an Emergency Protection Order, and Care Proceedings which may result in permanent placement of the child outside the family. The threshold to enable a court to make an order is actual or likely significant harm. In care proceedings the welfare of the child is paramount and all information affecting the welfare of a child must be disclosed by professionals, including lawyers, regardless of their clients' interests.	Child abuse Editor-In-Chief: C. Michael Gibson, M.S., M.D. [2] For patient information on Child physical abuse, click here For patient information on Child psychological abuse and neglect, click here # Overview Child abuse is the physical, emotional or sexual abuse or neglect of children by parents, guardians, or others. While most child abuse happens in the child's home, large numbers of cases of child abuse have been identified within some organizations involving children, such as churches, schools, child care businesses, and residential schools[1][2]. It also can occur almost anywhere (eg kidnappings, random murders etc.) According to a recent UNICEF report on child well-being[3] the United States and the United Kingdom ranked lowest among first world nations with respect to the well being of their children. This study also found that child neglect and child abuse are far more common in single-parent families than in families where both parents are present. There are many forms of abuse and neglect and many governments have developed their own legal definition of what constitutes child maltreatment for the purposes of removing a child and/or prosecuting a criminal charge. In the United States, the Federal Government puts out a full definition of child abuse and neglect and creates a summary of each State definition.[4] # Effects of child abuse Template:Seealso Child abuse in its various forms has numerous effects and consequences, both tangible and intangible, upon society, those mistreated, and those entrusted with the responsibility of its detection, prevention, and treatment. Child abuse can have dire consequences, during both childhood and adulthood. The effects of being abused as a child vary according to the severity of the abuse and the surrounding environment of the child. If the family or school environment is nurturing and supportive, the child will probably have a healthier outcome. The U.S. National Adoption Center found that 52% of adoptable children (meaning those children in U.S. foster care) freed for adoption had symptoms of attachment disorder.[citation needed] Children with histories of maltreatment, such as physical and psychological neglect and physical abuse are at risk of developing psychiatric problems.[5],[6] Such children are at risk of developing a disorganized attachment.[7][8][9] Disorganized attachment is associated with a number of developmental problems, including dissociative symptoms,[10] as well as anxiety, depressive, and acting-out symptoms.[11][12] A study by Dante Cicchetti found that 80% of abused and maltreated infants exhibited symptoms of disorganized attachment.[13], [14] Negative Consequences of Child Abuse Emotional effects include low self-esteem, depression and anxiety, eating disorders, relationship difficulties, alienation and withdrawal, and personality disorders. Physical effects include injury, death, lifelong health problems, cognitive difficulties, and physical disabilities. Behavioral effects include problems in school and work, delinquency, teen pregnancy, suicide attempts, criminal or antisocial behavior, substance abuse, aggressive behavior, spousal and child abuse, and anger. # Causes of child abuse There are many causes of child abuse. Many child abusers were themselves victims of abuse. Mental illness is another common factor, with many abusers having personality disorders or other severe forms of mental illness. Psychosocial factors also play a role. Parental choices and other unforeseen circumstances that place families under extraordinary stress ― for instance, poverty, divorce, sickness, disability, lack of parental skills and drugs are often associated to child maltreatment. Children in families that have a parent deployed in combat are also more likely to be victims of child maltreatment. Many of these factors may contribute to family stress that can result in child abuse or neglect. Understanding the root causes of abuse can help better determine the best methods of prevention and treatment. # Prevention Given these possible causes, most professionals agree that there are three levels of prevention services; primary prevention, secondary prevention, and tertiary prevention. ## Primary prevention Primary prevention consists of activities that are targeted at the community level. These activities are meant to impact families prior to any allegations of abuse and neglect. Primary prevention services include public education activities, parent education classes that are open to anyone in the community for parents or abusers to interact with the child, and family support programs. Primary prevention can be difficult to measure because you are attempting to impact something before it happens, an unknown variable. ## Secondary prevention Secondary prevention consists of activities targeted to families that have one or more risk factors including families with substance abuse, teen parents, parents of special need children, single parents, and low income families. Secondary prevention services include parent education classes targeted for high risk parents, respite care for parents of a child with a disability, or home visiting programs for new parents. ## Tertiary prevention These families have already demonstrated the need for intervention, with or without court supervision. Prevention supporters consider 'tertiary prevention' synonymous with treatment and entirely different from prevention through family support. # Treatment Treatment for those experiencing sequelae from abuse, or Complex post-traumatic stress disorder, which may be caused by early chronic maltreatment, should address each dimension. Often treatment must be multi-modal. Children who have experienced complex trauma caused by chronic maltreatment can be treated effectively with Cognitive Behavioral Therapy interventions, other therapeutic interventions, education, EMDR and other approaches. For children with attachment difficulties or disorders there are a number of recognized interventions. # Child abuse prevention organizations ## Childhelp CEO and Co-Founder Sara O’Meara and President and Co-Founder Yvonne Fedderson started Childhelp in 1959, establishing it as a leading national non-profit organization dedicated to helping victims of child abuse and neglect and at-risk children. Childhelp focuses on advocacy, prevention, treatment and community outreach. The Childhelp National Child Abuse Hotline, 1-800-4-A-CHILD®, operates 24 hours a day, seven days a week and receives calls from throughout the United States, Canada and the U.S. Virgin Islands, Puerto Rico and Guam. Childhelp’s programs and services also include residential treatment services (villages); children’s advocacy centers; therapeutic foster care; group homes and child abuse prevention, education and training. Childhelp also created the National Day of Hope® that mobilizes people across America to join the fight against child abuse. ## Najidah The Najidah Association was originally established as a Domestic and Family Violence service. In 2003 Najidah began to advocate on behalf of the child victims of DV. Citing the Australian national practice standards for working with children exposed to DV, Najidah revised their practice to respond on the basis that (as per the Australian Standards) exposing children, and or failing to protect children from DV is a form of child abuse. Najidah also began a campaign to highlight the fact that 70% of people in DV refuges are in fact children. Further to this Najidah has developed a suite of programs that respond to the needs of abused children and the prevention of child abuse. These programs have since won national acclaim and recognition as best practice. ## C.A.S. Children's Aid Societies in Canada The children's aid society (CAS), also known as Family and Children's Services (F&CS), is a non-profit agency working in local communities to provide help and support to children and their families in Canada.[15] ## ISPCAN (International Society for Prevention of Child Abuse and Neglect) The International Society for Prevention of Child Abuse and Neglect, founded in 1977, is the only multidisciplinary international organization that brings together a worldwide cross-section of committed professionals to work towards the prevention and treatment of child abuse, neglect and exploitation globally. Objectives • To increase awareness of the extent, the causes and possible solutions for all forms of child abuse. • To disseminate academic and clinical research to those in positions to enhance practice and improve policy. • To support international efforts to promote and protect the Rights of the Child. • To improve the quality of current efforts to detect, treat and prevent child abuse. • To facilitate the exchange of best practice standards being developed by ISPCAN members throughout the world. • To design and deliver comprehensive training programs to professionals and concerned volunteers engaged in efforts to treat and prevent child abuse. ## SPARC (Society for the Protection of the Rights of the Child) SPARC is a Pakistan-based child abuse prevention organization.[16] In its annual report titled 'The State of Pakistan's Children-2006', SPARC stated that Pakistan had the highest maternal, which at the present-time was 70 deaths per 1,000 live births, and infant mortality rates in South Asia. The report stated around four children were abused daily, and in 2006 there were a total of 2,447 cases of abuse.[17] # Reporting of child abuse ## Authorities Depending on the country, the agencies responsible for investigating child abuse are either managed nationally, regionally, or locally. These agencies may be called Child Protective Services (CPS), Department of Children and Family Services (DCFS), or by other similar names. In the U.S., these agencies are usually listed in the state government section of the telephone book under "Children" or "Health" or "Human Services". In a few instances in the U.S., some of the functions of these agencies are outsourced to private individuals or companies. People who investigate claims of child abuse may be called a "children's social worker" (CSW) or a case worker. ## Reporting abuse and neglect in Australia Child abuse and neglect is the subject of mandatory reporting in most Australian jurisdictions. Usually professional people such as doctors, nurses and teachers are bound to report strong evidence of abuse or neglect. State authorities, such as the Child Protection Unit of the Department of Human Services (Victoria), have statutory authority to investigate and deal with child abuse. A document from Child Protection and Family Services, in Melbourne states: "The service system is facing escalating and changing demand pressures and we are increasingly aware of growing client complexity. Too many children, young people and families are coming back into the child protection system on a repeat basis with services making little impact on their issues. The analysis confirms this and identifies the need for a strategic rethink if we are to achieve better outcomes for vulnerable children, young people and their families. "[18] ## Reporting Abuse in the UK All professionals who work with children, such as teachers, health professionals and the like are required to report to social services (or the police as appropriate) any 'concern' amounting to possible 'significant harm' (neglect, physical, sexual or emotional abuse) regarding a child's welfare. The police and social services operate a multi-agency approach in cases of serious abuse. A system of referrals to Social Services so that one authority held all information started in the 1960s following the death of Maria Colwell, but was insufficiently effective and a number of notorious cases over the years have resulted in several major overhauls of the system, the most recent following the death of Victoria Climbie in 2000. Social Service departments, organised regionally, are required to investigate reports of abuse, keep records and take appropriate action to protect children. This can range from the provision of advice and support to families through to immediate removal under an Emergency Protection Order, and Care Proceedings which may result in permanent placement of the child outside the family. The threshold to enable a court to make an order is actual or likely significant harm. In care proceedings the welfare of the child is paramount and all information affecting the welfare of a child must be disclosed by professionals, including lawyers, regardless of their clients' interests.	https://www.wikidoc.org/index.php/Battered_child_syndrome
32adffd1ffd8f51ade2df416eeaeed03e34734ee	wikidoc	Bavituximab	Bavituximab # Overview Bavituximab is a chimeric Anti-PS monoclonal antibody analog which is used to potentially treat cancers and viral infections. It binds to phosphatidylserine and other exposed host cell lipids when induced by cellular stress. Additional analogs in the class include 3G4, 2aG4, 9d2 and Hu3g4. Bavituximab binds to various aminophospholipids and is dependent on interaction with plasma protein beta2-glycoprotein 1 to mediate binding. These target aminophospholipids, usually residing only on the inner leaflet of the plasma membrane of cells are purportedly only exposed in virally infected, damaged or malignant cells. The drug’s binding to phospholipids, alerts the body’s immune system to attack the tumor endothelial cells, Thrombosing the tumors vascular network and/or attacking free floating virally infected and metastatic cells while potentially minimizing side effects in healthy tissues. # Antibody-mediated targeting of "inside-out" anionic phospholipids in viral disease Melina Soares, Sameer Syed, Gustavo Barbero and Philip E Thorpe Pharmacology, University of Texas Southwestern Medical Center, 2201 Inwood Road, NC7.304, MC 9041, Dallas, TX, 75390 J. Immunol., Apr 2007; 178: 47.21. ## Abstract The anionic phospholipid phosphatidylserine (PS) is found exclusively in the inner leaflet of the plasma membrane of resting mammalian cells. We hypothesized that certain events that occur during virus replication (eg cell activation or membrane rearrangement) would trigger the exposure of anionic phospholipids on the outer surface of virus- infected cells and subsequently on the enveloped viruses that bud out of these virus- infected cells. We further hypothesized that these exposed anionic phospholipids would serve as targets for anti-viral therapy. We demonstrate here that anionic phospholipids become exposed on the enveloped Pichinde Virus (a model virus for Lassa Fever virus, a potential bioterrorism agent) and on Pichinde virus-infected cells. To detect anionic phospholipids, we used a chimeric monoclonal antibody, bavituximab, that binds anionic phospholipids in a B2-glycoprotein I dependent manner. We show that bavituximab treatment is able to cure overt disease in guinea pigs lethally infected with Pichinde virus. Bavituximab treatment reduced the amounts of virus in multiple tissues and caused direct clearance of virus from the blood. Direct clearance of free virus and antibody-dependent cellular cytotoxicity of virus-infected cells appear to be the major mechanisms that contribute to the anti-viral effect of bavituximab. Bavituximab-treated survivors were immune to reinfection. Furthermore, the murine version of bavituximab, 3G4, shows therapeutic efficacy in a lethal murine model for human cytomegalovirus. Our study demonstrates the promise of anionic phospholipids as targets for new broad-spectrum anti-viral drugs.	Bavituximab Template:Drugbox-mab # Overview Bavituximab is a chimeric Anti-PS monoclonal antibody analog which is used to potentially treat cancers and viral infections. It binds to phosphatidylserine and other exposed host cell lipids when induced by cellular stress. Additional analogs in the class include 3G4, 2aG4, 9d2 and Hu3g4. Bavituximab binds to various aminophospholipids and is dependent on interaction with plasma protein beta2-glycoprotein 1 to mediate binding. These target aminophospholipids, usually residing only on the inner leaflet of the plasma membrane of cells are purportedly only exposed in virally infected, damaged or malignant cells. The drug’s binding to phospholipids, alerts the body’s immune system to attack the tumor endothelial cells, Thrombosing the tumors vascular network and/or attacking free floating virally infected and metastatic cells while potentially minimizing side effects in healthy tissues. # Antibody-mediated targeting of "inside-out" anionic phospholipids in viral disease Melina Soares, Sameer Syed, Gustavo Barbero and Philip E Thorpe Pharmacology, University of Texas Southwestern Medical Center, 2201 Inwood Road, NC7.304, MC 9041, Dallas, TX, 75390 J. Immunol., Apr 2007; 178: 47.21. ## Abstract The anionic phospholipid phosphatidylserine (PS) is found exclusively in the inner leaflet of the plasma membrane of resting mammalian cells. We hypothesized that certain events that occur during virus replication (eg cell activation or membrane rearrangement) would trigger the exposure of anionic phospholipids on the outer surface of virus- infected cells and subsequently on the enveloped viruses that bud out of these virus- infected cells. We further hypothesized that these exposed anionic phospholipids would serve as targets for anti-viral therapy. We demonstrate here that anionic phospholipids become exposed on the enveloped Pichinde Virus (a model virus for Lassa Fever virus, a potential bioterrorism agent) and on Pichinde virus-infected cells. To detect anionic phospholipids, we used a chimeric monoclonal antibody, bavituximab, that binds anionic phospholipids in a B2-glycoprotein I dependent manner. We show that bavituximab treatment is able to cure overt disease in guinea pigs lethally infected with Pichinde virus. Bavituximab treatment reduced the amounts of virus in multiple tissues and caused direct clearance of virus from the blood. Direct clearance of free virus and antibody-dependent cellular cytotoxicity of virus-infected cells appear to be the major mechanisms that contribute to the anti-viral effect of bavituximab. Bavituximab-treated survivors were immune to reinfection. Furthermore, the murine version of bavituximab, 3G4, shows therapeutic efficacy in a lethal murine model for human cytomegalovirus. Our study demonstrates the promise of anionic phospholipids as targets for new broad-spectrum anti-viral drugs. Template:Chimericmonoclonals Template:WikiDoc Sources	https://www.wikidoc.org/index.php/Bavituximab
8cd3086b34f856e4b594ca41d18e21dd98aeb708	wikidoc	Becaplermin	Becaplermin # Disclaimer WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here. # Black Box Warning # Overview Becaplermin is a human platelet-derived growth factor that is FDA approved for the treatment of lower extremity diabetic neuropathic ulcers that extend into the subcutaneous tissue or beyond and have an adequate blood supply. There is a Black Box Warning for this drug as shown here. Common adverse reactions include erythematous rashes. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - For topical use; not for oral, ophthalmic or intravaginal use. - The amount of REGRANEX Gel to be applied will vary depending upon the size of the ulcer area. To calculate the length of gel to apply to the ulcer, measure the greatest length of the ulcer by the greatest width of the ulcer in either inches or centimeters. To calculate the length of gel in inches, use the formula shown below in Table 1, and to calculate the length of gel in centimeters, use the formula shown below in Table 2. - Using the calculation, each square inch of ulcer surface will require approximately 2/3 inch length of gel squeezed from a 15g tube, or approximately 1 1/3 inch length of the gel from a 2g tube (physician sample). For example, if the ulcer measures 1 inch by 2 inches, then a 1 1/4 inch length of gel should be used for 15g tubes (1 × 2 × 0.6 = 1 1/4) and 2 3/4 inch gel length should be used for a 2g tube (1 × 2 × 1.3 = 2 3/4). - Using the calculations for ulcer size in centimeters, each square centimeter of ulcer surface will require approximately a 0.25 centimeter length of gel squeezed from a 15g tube, or approximately a 0.5 centimeter length of gel from a 2g tube. For example, if the ulcer measures 4 cm by 2 cm, then a 2 centimeter length of gel should be used for a 15g tube and a 4 centimeter length of gel should be used for a 2g tube . ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Becaplermin in adult patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Becaplermin in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) - Safety and effectiveness of REGRANEX Gel in pediatric patients below the age of 16 years have not been established. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Becaplermin in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Becaplermin in pediatric patients. # Contraindications - REGRANEX Gel is contraindicated in patients with known neoplasm(s) at the site(s) of application. # Warnings ### Precautions - Cancer and Cancer Mortality - REGRANEX Gel contains becaplermin, a recombinant human platelet-derived growth factor, which promotes cellular proliferation and angiogenesis. The benefits and risks of becaplermin treatment should be carefully evaluated before prescribing. Becaplermin should be used with caution in patients with a known malignancy. - Malignancies distant from the site of application have occurred in becaplermin users in both a clinical study and postmarketing use, and an increased rate of death from systemic malignancies was seen in patients who have received 3 or more tubes of REGRANEX Gel. - In a follow-up study, 491 (75%) of 651 subjects from two randomized, controlled trials of becaplermin gel 0.01% were followed for a median of approximately 20 months to identify malignancies diagnosed after the end of the trials. Eight of 291 subjects (3%) from the becaplermin group and two of 200 subjects (1%) from the vehicle/standard of care group were diagnosed with cancers during the follow-up period, a relative risk of 2.7 (95% confidence interval 0.6–12.8). The types of cancers varied and all were remote from the treatment site. - In a retrospective study of a medical claims database, cancer rates and overall cancer mortality were compared between 1,622 patients who used REGRANEX Gel and 2,809 matched comparators. Estimates of the incidence rates reported below may be under-reported due to limited follow-up for each individual. - The incidence rate for all cancers was 10.2 per 1,000 person years for patients treated with REGRANEX Gel and 9.1 per 1,000 person years for the comparators. Adjusted for several possible confounders, the rate ratio was 1.2 (95% confidence interval 0.7–1.9). Types of cancers varied and were remote from the site of treatment. - The incidence rate for mortality from all cancers was 1.6 per 1,000 person years for those who received REGRANEX Gel and 0.9 per 1,000 person years for the comparators. The adjusted rate ratio was 1.8 (95% confidence interval 0.7–4.9). - The incidence rate for mortality from all cancers among patients who received 3 or more tubes of REGRANEX Gel was 3.9 per 1,000 person years and 0.9 per 1,000 person years in the comparators. The adjusted rate ratio for cancer mortality among those who received 3 or more tubes relative to those who received none was 5.2 (95% confidence interval 1.6–17.6). - Application Site Reactions - If application site reactions occur, the possibility of sensitization or irritation caused by parabens or m-cresol should be considered. Consider interruption or discontinuation and further evaluation (e.g. patch testing) as dictated by clinical circumstances. # Adverse Reactions ## Clinical Trials Experience - Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. - In a follow-up study from two randomized, controlled trials, an increased rate of cancer remote from the becaplermin treatment site was observed in subjects treated with REGRANEX Gel. - In clinical trials, erythematous rashes occurred in 2% of patients treated with REGRANEX Gel (and good ulcer care) or placebo (and good ulcer care), and none in patients receiving good ulcer care alone. Patients treated with REGRANEX Gel did not develop neutralizing antibodies against becaplermin. ## Postmarketing Experience - An increased rate of mortality secondary to malignancy was observed in patients treated with 3 or more tubes of REGRANEX Gel in a postmarketing retrospective cohort study. - Burning sensation at the site of application and erythema have been reported during post-approval use of REGRANEX Gel. Because post approval adverse reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to the drug. # Drug Interactions - It is not known if REGRANEX Gel interacts with other topical medications applied to the ulcer site. The use of REGRANEX Gel with other topical drugs has not been studied. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): - Pregnancy Category C - There are no adequate and well-controlled studies in pregnant women treated with REGRANEX Gel. REGRANEX Gel should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Animal reproduction studies have not been conducted with REGRANEX Gel. Pregnancy Category (AUS): - Australian Drug Evaluation Committee (ADEC) Pregnancy Category There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Becaplermin in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Becaplermin during labor and delivery. ### Nursing Mothers - It is not known whether becaplermin is excreted in human milk. Because many drugs are secreted in human milk, caution should be exercised when REGRANEX Gel is administered to nursing women. ### Pediatric Use - Safety and effectiveness of REGRANEX Gel in pediatric patients below the age of 16 years have not been established. ### Geriatic Use - Among patients receiving any dose of REGRANEX Gel in clinical studies of diabetic lower extremity ulcers, 150 patients were 65 years of age and older. No overall differences in safety or effectiveness were observed between patients < 65 years of age and patients ≥ 65 years of age. The number of patients aged 75 and older were insufficient (n=34) to determine whether they respond differently from younger patients. ### Gender There is no FDA guidance on the use of Becaplermin with respect to specific gender populations. ### Race There is no FDA guidance on the use of Becaplermin with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Becaplermin in patients with renal impairment. ### Hepatic Impairment There is no FDA guidance on the use of Becaplermin in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Becaplermin in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Becaplermin in patients who are immunocompromised. # Administration and Monitoring ### Administration - Topical ### Monitoring There is limited information regarding Monitoring of Becaplermin in the drug label. # IV Compatibility There is limited information regarding IV Compatibility of Becaplermin in the drug label. # Overdosage ## Chronic Overdose There is limited information regarding Chronic Overdose of Becaplermin in the drug label. # Pharmacology ## Mechanism of Action - REGRANEX Gel has biological activity similar to that of endogenous platelet-derived growth factor, which includes promoting the chemotactic recruitment and proliferation of cells involved in wound repair and enhancing the formation of granulation tissue. ## Structure - REGRANEX Gel contains becaplermin, a recombinant human platelet-derived growth factor for topical administration. Becaplermin is produced by recombinant DNA technology by insertion of the gene for the B chain of platelet-derived growth factor (PDGF) into the yeast, Saccharomyces cerevisiae. Becaplermin has a molecular weight of approximately 25 KD and is a homodimer composed of two identical polypeptide chains that are bound together by disulfide bonds. REGRANEX Gel is a non-sterile, low bioburden, preserved, sodium carboxymethylcellulose-based (CMC) topical gel, containing the active ingredient becaplermin and the following inactive ingredients: carboxymethylcellulose sodium, glacial acetic acid, l-lysine hydrochloride, m-cresol, methylparaben, propylparaben, sodium acetate trihydrate, sodium chloride, and water for injection. Each gram of REGRANEX Gel contains 100 mcg of becaplermin. ## Pharmacodynamics There is limited information regarding Pharmacodynamics of Becaplermin in the drug label. ## Pharmacokinetics - Ten patients with Stage III or IV (as defined in the International Association of Enterostomal Therapy (IAET) guide to chronic wound staging,1, 2 lower extremity diabetic ulcers received topical applications of becaplermin gel 0.01% at a dose range of 0.32–2.95 µg/kg (7µg/cm2) daily for 14 days. Six patients had non-quantifiable PDGF levels at baseline and throughout the study, two patients had PDGF levels at baseline which did not increase substantially, and two patients had PDGF levels that increased sporadically above their baseline values during the 14 day study period. ## Nonclinical Toxicology - Becaplermin was not genotoxic in a battery of in vitro assays (including those for bacterial and mammalian cell point mutation, chromosomal aberration, and DNA damage/repair). Becaplermin was also not mutagenic in an in vivo assay for the induction of micronuclei in mouse bone marrow cells. - Carcinogenesis and reproductive toxicity studies have not been conducted with REGRANEX Gel. - In nonclinical studies, rats injected at the metatarsals with 3 or 10 mcg/site (approximately 60 or 200 mcg/kg) of becaplermin every other day for 13 days displayed histological changes indicative of accelerated bone remodeling consisting of periosteal hyperplasia and subperiosteal bone resorption and exostosis. The soft tissue adjacent to the injection site had fibroplasia with accompanying mononuclear cell infiltration reflective of the ability of PDGF to stimulate connective tissue growth. # Clinical Studies - The effects of REGRANEX Gel on the incidence of and time to complete healing in lower extremity diabetic ulcers were assessed in four randomized controlled studies. Of 922 patients studied, 478 received either REGRANEX Gel 0.003% or 0.01%. All study participants had lower extremity diabetic neuropathic ulcers that extended into the subcutaneous tissue or beyond (Stages III and IV of the IAET guide to chronic wound staging). Ninety-three percent of the patients enrolled in these four trials had foot ulcers. The remaining 7% of the patients had ankle or leg ulcers. The diabetic ulcers were of at least 8 weeks duration and had an adequate blood supply (defined as TcpO2 > 30 mm Hg). In the four trials, ninety-five percent of the ulcers measured in area up to 10 cm2, and the median ulcer size at baseline ranged from 1.4 cm2 to 3.5 cm2. All treatment groups received a program of good ulcer care consisting of initial complete sharp debridement, a non-weight-bearing regimen, systemic treatment for wound-related infection if present, moist saline dressings changed twice a day, and additional debridement as necessary. REGRANEX Gel 0.003% or 0.01% or placebo gel was applied once a day and covered with a saline moistened dressing. After approximately 12 hours, the gel was gently rinsed off and a saline moistened dressing was then applied for the remainder of the day. Patients were treated until complete healing, or for a period of up to 20 weeks. Patients were considered a treatment failure if their ulcer did not show an approximately 30% reduction in initial ulcer area after eight to ten weeks of REGRANEX Gel therapy. - The primary endpoint, incidence of complete ulcer closure within 20 weeks, for all treatment arms is shown in Figure 1. In each study, REGRANEX Gel in conjunction with good ulcer care was compared to placebo gel plus good ulcer care or good ulcer care alone. - In Study 1, a multicenter, double-blind, placebo controlled trial of 118 patients, the incidence of complete ulcer closure for REGRANEX Gel 0.003% (n=61) was 48% versus 25% for placebo gel (n=57; p=0.02, logistic regression analysis). - In Study 2, a multicenter, double-blind, placebo controlled trial of 382 patients, the incidence of complete ulcer closure for REGRANEX Gel 0.01% (n=123) was 50% versus 36% for REGRANEX Gel 0.003% (n=132) and 35% for placebo gel (n=127). Only REGRANEX Gel 0.01% was significantly different from placebo gel (p=0.01, logistic regression analysis). - The primary goal of Study 3, a multicenter controlled trial of 172 patients, was to assess the safety of vehicle gel (placebo; n=70) compared to good ulcer care alone (n=68). The study included a small (n=34) REGRANEX Gel 0.01% arm. Incidences of complete ulcer closure were 44% for REGRANEX Gel, 36% for placebo gel and 22% for good ulcer care alone. - In Study 4, a multicenter, evaluator-blind, controlled trial of 250 patients, the incidences of complete ulcer closure in the REGRANEX Gel 0.01% arm (n=128) (36%) and good ulcer care alone (n=122) (32%) were not statistically different. - In general, where REGRANEX Gel was associated with higher incidences of complete ulcer closure, differences in the incidence first became apparent after approximately 10 weeks and increased with continued treatment (Table 3). - In a 3-month follow-up period where no standardized regimen of preventative care was utilized, the incidence of ulcer recurrence was approximately 30% in all treatment groups, demonstrating that the durability of ulcer closure was comparable in all treatment groups. - In a randomized, double-blind study of REGRANEX Gel (100 mcg/g once daily for 16 weeks) in patients with Stage III or IV pressure ulcers, the incidence of complete ulcer closure was 15% (28/189) in the becaplermin group and 12% (22/190) in the vehicle control group. This difference was not statistically significant. - In two small, randomized, double-blinded studies of REGRANEX Gel (100 mcg/g once daily for 16 weeks) in patients with venous stasis ulcers, the combined incidence of complete ulcer closure was 46% (30/65) in the becaplermin group and 39% (26/67) in the vehicle control group. This difference was not statistically significant. # How Supplied - REGRANEX Gel is available in multi-use tubes in the following size: - 15 g tube NDC 0064-0810-15 - REGRANEX Gel is for external use only. - Store refrigerated at 2° – 8° C (36° – 46°F). Do not freeze. Do not use the gel after the expiration date shown at the bottom of the tube. ## Storage There is limited information regarding Becaplermin Storage in the drug label. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information - Counsel patients to review and discuss any questions or concerns with their healthcare provider before starting REGRANEX and at regular intervals while receiving REGRANEX. - Patients should be advised that: - they should read the medication guide; - hands should be washed thoroughly before applying REGRANEX Gel; - the tip of the tube should not come into contact with the ulcer or any other surface; the tube should be recapped tightly after each use; - a cotton swab, tongue depressor, or other application aid should be used to apply REGRANEX Gel; - REGRANEX Gel should only be applied once a day in a carefully measured quantity. The measured quantity of gel should be spread evenly over the ulcerated area to yield a thin continuous layer of approximately 1/16 of an inch thickness. The measured length of the gel to be squeezed from the tube should be adjusted according to the size of the ulcer. The amount of REGRANEX Gel to be applied daily should be recalculated at weekly or biweekly intervals by the physician or wound care giver. - Step-by-step instructions for application of REGRANEX Gel are as follows: - Squeeze the calculated length of gel onto a clean, firm, nonabsorbable surface, e.g., wax paper. - With a clean cotton swab, tongue depressor, or similar application aid, spread the measured REGRANEX Gel over the ulcer surface to obtain an even layer. - Cover with a saline moistened gauze dressing. after approximately 12 hours, the ulcer should be gently rinsed with saline or water to remove residual gel and covered with a saline-moistened gauze dressing (without REGRANEX Gel); it is important to use REGRANEX Gel together with a good ulcer care program, including a strict non-weight-bearing program; excess application of REGRANEX Gel has not been shown to be beneficial; REGRANEX Gel should be stored in the refrigerator. Do not freeze REGRANEX Gel; REGRANEX Gel should not be used after the expiration date on the bottom, crimped end of the tube. - after approximately 12 hours, the ulcer should be gently rinsed with saline or water to remove residual gel and covered with a saline-moistened gauze dressing (without REGRANEX Gel); - it is important to use REGRANEX Gel together with a good ulcer care program, including a strict non-weight-bearing program; - excess application of REGRANEX Gel has not been shown to be beneficial; - REGRANEX Gel should be stored in the refrigerator. Do not freeze REGRANEX Gel; - REGRANEX Gel should not be used after the expiration date on the bottom, crimped end of the tube. # Precautions with Alcohol - Alcohol-Becaplermin interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - REGRANEX® # Look-Alike Drug Names - Regranex® — Granulex® # Drug Shortage Status # Price	Becaplermin Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Vignesh Ponnusamy, M.B.B.S. [2] # Disclaimer WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here. # Black Box Warning # Overview Becaplermin is a human platelet-derived growth factor that is FDA approved for the treatment of lower extremity diabetic neuropathic ulcers that extend into the subcutaneous tissue or beyond and have an adequate blood supply. There is a Black Box Warning for this drug as shown here. Common adverse reactions include erythematous rashes. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - For topical use; not for oral, ophthalmic or intravaginal use. - The amount of REGRANEX Gel to be applied will vary depending upon the size of the ulcer area. To calculate the length of gel to apply to the ulcer, measure the greatest length of the ulcer by the greatest width of the ulcer in either inches or centimeters. To calculate the length of gel in inches, use the formula shown below in Table 1, and to calculate the length of gel in centimeters, use the formula shown below in Table 2. - Using the calculation, each square inch of ulcer surface will require approximately 2/3 inch length of gel squeezed from a 15g tube, or approximately 1 1/3 inch length of the gel from a 2g tube (physician sample). For example, if the ulcer measures 1 inch by 2 inches, then a 1 1/4 inch length of gel should be used for 15g tubes (1 × 2 × 0.6 = 1 1/4) and 2 3/4 inch gel length should be used for a 2g tube (1 × 2 × 1.3 = 2 3/4). - Using the calculations for ulcer size in centimeters, each square centimeter of ulcer surface will require approximately a 0.25 centimeter length of gel squeezed from a 15g tube, or approximately a 0.5 centimeter length of gel from a 2g tube. For example, if the ulcer measures 4 cm by 2 cm, then a 2 centimeter length of gel should be used for a 15g tube [(4 × 2) ÷ 4 = 2] and a 4 centimeter length of gel should be used for a 2g tube [(4 × 2) ÷ 2 = 4]. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Becaplermin in adult patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Becaplermin in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) - Safety and effectiveness of REGRANEX Gel in pediatric patients below the age of 16 years have not been established. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Becaplermin in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Becaplermin in pediatric patients. # Contraindications - REGRANEX Gel is contraindicated in patients with known neoplasm(s) at the site(s) of application. # Warnings ### Precautions - Cancer and Cancer Mortality - REGRANEX Gel contains becaplermin, a recombinant human platelet-derived growth factor, which promotes cellular proliferation and angiogenesis. The benefits and risks of becaplermin treatment should be carefully evaluated before prescribing. Becaplermin should be used with caution in patients with a known malignancy. - Malignancies distant from the site of application have occurred in becaplermin users in both a clinical study and postmarketing use, and an increased rate of death from systemic malignancies was seen in patients who have received 3 or more tubes of REGRANEX Gel. - In a follow-up study, 491 (75%) of 651 subjects from two randomized, controlled trials of becaplermin gel 0.01% were followed for a median of approximately 20 months to identify malignancies diagnosed after the end of the trials. Eight of 291 subjects (3%) from the becaplermin group and two of 200 subjects (1%) from the vehicle/standard of care group were diagnosed with cancers during the follow-up period, a relative risk of 2.7 (95% confidence interval 0.6–12.8). The types of cancers varied and all were remote from the treatment site. - In a retrospective study of a medical claims database, cancer rates and overall cancer mortality were compared between 1,622 patients who used REGRANEX Gel and 2,809 matched comparators. Estimates of the incidence rates reported below may be under-reported due to limited follow-up for each individual. - The incidence rate for all cancers was 10.2 per 1,000 person years for patients treated with REGRANEX Gel and 9.1 per 1,000 person years for the comparators. Adjusted for several possible confounders, the rate ratio was 1.2 (95% confidence interval 0.7–1.9). Types of cancers varied and were remote from the site of treatment. - The incidence rate for mortality from all cancers was 1.6 per 1,000 person years for those who received REGRANEX Gel and 0.9 per 1,000 person years for the comparators. The adjusted rate ratio was 1.8 (95% confidence interval 0.7–4.9). - The incidence rate for mortality from all cancers among patients who received 3 or more tubes of REGRANEX Gel was 3.9 per 1,000 person years and 0.9 per 1,000 person years in the comparators. The adjusted rate ratio for cancer mortality among those who received 3 or more tubes relative to those who received none was 5.2 (95% confidence interval 1.6–17.6). - Application Site Reactions - If application site reactions occur, the possibility of sensitization or irritation caused by parabens or m-cresol should be considered. Consider interruption or discontinuation and further evaluation (e.g. patch testing) as dictated by clinical circumstances. # Adverse Reactions ## Clinical Trials Experience - Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. - In a follow-up study from two randomized, controlled trials, an increased rate of cancer remote from the becaplermin treatment site was observed in subjects treated with REGRANEX Gel. - In clinical trials, erythematous rashes occurred in 2% of patients treated with REGRANEX Gel (and good ulcer care) or placebo (and good ulcer care), and none in patients receiving good ulcer care alone. Patients treated with REGRANEX Gel did not develop neutralizing antibodies against becaplermin. ## Postmarketing Experience - An increased rate of mortality secondary to malignancy was observed in patients treated with 3 or more tubes of REGRANEX Gel in a postmarketing retrospective cohort study. - Burning sensation at the site of application and erythema have been reported during post-approval use of REGRANEX Gel. Because post approval adverse reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to the drug. # Drug Interactions - It is not known if REGRANEX Gel interacts with other topical medications applied to the ulcer site. The use of REGRANEX Gel with other topical drugs has not been studied. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): - Pregnancy Category C - There are no adequate and well-controlled studies in pregnant women treated with REGRANEX Gel. REGRANEX Gel should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Animal reproduction studies have not been conducted with REGRANEX Gel. Pregnancy Category (AUS): - Australian Drug Evaluation Committee (ADEC) Pregnancy Category There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Becaplermin in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Becaplermin during labor and delivery. ### Nursing Mothers - It is not known whether becaplermin is excreted in human milk. Because many drugs are secreted in human milk, caution should be exercised when REGRANEX Gel is administered to nursing women. ### Pediatric Use - Safety and effectiveness of REGRANEX Gel in pediatric patients below the age of 16 years have not been established. ### Geriatic Use - Among patients receiving any dose of REGRANEX Gel in clinical studies of diabetic lower extremity ulcers, 150 patients were 65 years of age and older. No overall differences in safety or effectiveness were observed between patients < 65 years of age and patients ≥ 65 years of age. The number of patients aged 75 and older were insufficient (n=34) to determine whether they respond differently from younger patients. ### Gender There is no FDA guidance on the use of Becaplermin with respect to specific gender populations. ### Race There is no FDA guidance on the use of Becaplermin with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Becaplermin in patients with renal impairment. ### Hepatic Impairment There is no FDA guidance on the use of Becaplermin in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Becaplermin in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Becaplermin in patients who are immunocompromised. # Administration and Monitoring ### Administration - Topical ### Monitoring There is limited information regarding Monitoring of Becaplermin in the drug label. # IV Compatibility There is limited information regarding IV Compatibility of Becaplermin in the drug label. # Overdosage ## Chronic Overdose There is limited information regarding Chronic Overdose of Becaplermin in the drug label. # Pharmacology ## Mechanism of Action - REGRANEX Gel has biological activity similar to that of endogenous platelet-derived growth factor, which includes promoting the chemotactic recruitment and proliferation of cells involved in wound repair and enhancing the formation of granulation tissue. ## Structure - REGRANEX Gel contains becaplermin, a recombinant human platelet-derived growth factor for topical administration. Becaplermin is produced by recombinant DNA technology by insertion of the gene for the B chain of platelet-derived growth factor (PDGF) into the yeast, Saccharomyces cerevisiae. Becaplermin has a molecular weight of approximately 25 KD and is a homodimer composed of two identical polypeptide chains that are bound together by disulfide bonds. REGRANEX Gel is a non-sterile, low bioburden, preserved, sodium carboxymethylcellulose-based (CMC) topical gel, containing the active ingredient becaplermin and the following inactive ingredients: carboxymethylcellulose sodium, glacial acetic acid, l-lysine hydrochloride, m-cresol, methylparaben, propylparaben, sodium acetate trihydrate, sodium chloride, and water for injection. Each gram of REGRANEX Gel contains 100 mcg of becaplermin. ## Pharmacodynamics There is limited information regarding Pharmacodynamics of Becaplermin in the drug label. ## Pharmacokinetics - Ten patients with Stage III or IV (as defined in the International Association of Enterostomal Therapy (IAET) guide to chronic wound staging,1, 2 lower extremity diabetic ulcers received topical applications of becaplermin gel 0.01% at a dose range of 0.32–2.95 µg/kg (7µg/cm2) daily for 14 days. Six patients had non-quantifiable PDGF levels at baseline and throughout the study, two patients had PDGF levels at baseline which did not increase substantially, and two patients had PDGF levels that increased sporadically above their baseline values during the 14 day study period. ## Nonclinical Toxicology - Becaplermin was not genotoxic in a battery of in vitro assays (including those for bacterial and mammalian cell point mutation, chromosomal aberration, and DNA damage/repair). Becaplermin was also not mutagenic in an in vivo assay for the induction of micronuclei in mouse bone marrow cells. - Carcinogenesis and reproductive toxicity studies have not been conducted with REGRANEX Gel. - In nonclinical studies, rats injected at the metatarsals with 3 or 10 mcg/site (approximately 60 or 200 mcg/kg) of becaplermin every other day for 13 days displayed histological changes indicative of accelerated bone remodeling consisting of periosteal hyperplasia and subperiosteal bone resorption and exostosis. The soft tissue adjacent to the injection site had fibroplasia with accompanying mononuclear cell infiltration reflective of the ability of PDGF to stimulate connective tissue growth. # Clinical Studies - The effects of REGRANEX Gel on the incidence of and time to complete healing in lower extremity diabetic ulcers were assessed in four randomized controlled studies. Of 922 patients studied, 478 received either REGRANEX Gel 0.003% or 0.01%. All study participants had lower extremity diabetic neuropathic ulcers that extended into the subcutaneous tissue or beyond (Stages III and IV of the IAET guide to chronic wound staging). Ninety-three percent of the patients enrolled in these four trials had foot ulcers. The remaining 7% of the patients had ankle or leg ulcers. The diabetic ulcers were of at least 8 weeks duration and had an adequate blood supply (defined as TcpO2 > 30 mm Hg). In the four trials, ninety-five percent of the ulcers measured in area up to 10 cm2, and the median ulcer size at baseline ranged from 1.4 cm2 to 3.5 cm2. All treatment groups received a program of good ulcer care consisting of initial complete sharp debridement, a non-weight-bearing regimen, systemic treatment for wound-related infection if present, moist saline dressings changed twice a day, and additional debridement as necessary. REGRANEX Gel 0.003% or 0.01% or placebo gel was applied once a day and covered with a saline moistened dressing. After approximately 12 hours, the gel was gently rinsed off and a saline moistened dressing was then applied for the remainder of the day. Patients were treated until complete healing, or for a period of up to 20 weeks. Patients were considered a treatment failure if their ulcer did not show an approximately 30% reduction in initial ulcer area after eight to ten weeks of REGRANEX Gel therapy. - The primary endpoint, incidence of complete ulcer closure within 20 weeks, for all treatment arms is shown in Figure 1. In each study, REGRANEX Gel in conjunction with good ulcer care was compared to placebo gel plus good ulcer care or good ulcer care alone. - In Study 1, a multicenter, double-blind, placebo controlled trial of 118 patients, the incidence of complete ulcer closure for REGRANEX Gel 0.003% (n=61) was 48% versus 25% for placebo gel (n=57; p=0.02, logistic regression analysis). - In Study 2, a multicenter, double-blind, placebo controlled trial of 382 patients, the incidence of complete ulcer closure for REGRANEX Gel 0.01% (n=123) was 50% versus 36% for REGRANEX Gel 0.003% (n=132) and 35% for placebo gel (n=127). Only REGRANEX Gel 0.01% was significantly different from placebo gel (p=0.01, logistic regression analysis). - The primary goal of Study 3, a multicenter controlled trial of 172 patients, was to assess the safety of vehicle gel (placebo; n=70) compared to good ulcer care alone (n=68). The study included a small (n=34) REGRANEX Gel 0.01% arm. Incidences of complete ulcer closure were 44% for REGRANEX Gel, 36% for placebo gel and 22% for good ulcer care alone. - In Study 4, a multicenter, evaluator-blind, controlled trial of 250 patients, the incidences of complete ulcer closure in the REGRANEX Gel 0.01% arm (n=128) (36%) and good ulcer care alone (n=122) (32%) were not statistically different. - In general, where REGRANEX Gel was associated with higher incidences of complete ulcer closure, differences in the incidence first became apparent after approximately 10 weeks and increased with continued treatment (Table 3). - In a 3-month follow-up period where no standardized regimen of preventative care was utilized, the incidence of ulcer recurrence was approximately 30% in all treatment groups, demonstrating that the durability of ulcer closure was comparable in all treatment groups. - In a randomized, double-blind study of REGRANEX Gel (100 mcg/g once daily for 16 weeks) in patients with Stage III or IV pressure ulcers, the incidence of complete ulcer closure was 15% (28/189) in the becaplermin group and 12% (22/190) in the vehicle control group. This difference was not statistically significant. - In two small, randomized, double-blinded studies of REGRANEX Gel (100 mcg/g once daily for 16 weeks) in patients with venous stasis ulcers, the combined incidence of complete ulcer closure was 46% (30/65) in the becaplermin group and 39% (26/67) in the vehicle control group. This difference was not statistically significant. # How Supplied - REGRANEX Gel is available in multi-use tubes in the following size: - 15 g tube NDC 0064-0810-15 - REGRANEX Gel is for external use only. - Store refrigerated at 2° – 8° C (36° – 46°F). Do not freeze. Do not use the gel after the expiration date shown at the bottom of the tube. ## Storage There is limited information regarding Becaplermin Storage in the drug label. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information - Counsel patients to review and discuss any questions or concerns with their healthcare provider before starting REGRANEX and at regular intervals while receiving REGRANEX. - Patients should be advised that: - they should read the medication guide; - hands should be washed thoroughly before applying REGRANEX Gel; - the tip of the tube should not come into contact with the ulcer or any other surface; the tube should be recapped tightly after each use; - a cotton swab, tongue depressor, or other application aid should be used to apply REGRANEX Gel; - REGRANEX Gel should only be applied once a day in a carefully measured quantity. The measured quantity of gel should be spread evenly over the ulcerated area to yield a thin continuous layer of approximately 1/16 of an inch thickness. The measured length of the gel to be squeezed from the tube should be adjusted according to the size of the ulcer. The amount of REGRANEX Gel to be applied daily should be recalculated at weekly or biweekly intervals by the physician or wound care giver. - Step-by-step instructions for application of REGRANEX Gel are as follows: - Squeeze the calculated length of gel onto a clean, firm, nonabsorbable surface, e.g., wax paper. - With a clean cotton swab, tongue depressor, or similar application aid, spread the measured REGRANEX Gel over the ulcer surface to obtain an even layer. - Cover with a saline moistened gauze dressing. after approximately 12 hours, the ulcer should be gently rinsed with saline or water to remove residual gel and covered with a saline-moistened gauze dressing (without REGRANEX Gel); it is important to use REGRANEX Gel together with a good ulcer care program, including a strict non-weight-bearing program; excess application of REGRANEX Gel has not been shown to be beneficial; REGRANEX Gel should be stored in the refrigerator. Do not freeze REGRANEX Gel; REGRANEX Gel should not be used after the expiration date on the bottom, crimped end of the tube. - after approximately 12 hours, the ulcer should be gently rinsed with saline or water to remove residual gel and covered with a saline-moistened gauze dressing (without REGRANEX Gel); - it is important to use REGRANEX Gel together with a good ulcer care program, including a strict non-weight-bearing program; - excess application of REGRANEX Gel has not been shown to be beneficial; - REGRANEX Gel should be stored in the refrigerator. Do not freeze REGRANEX Gel; - REGRANEX Gel should not be used after the expiration date on the bottom, crimped end of the tube. # Precautions with Alcohol - Alcohol-Becaplermin interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - REGRANEX®[1] # Look-Alike Drug Names - Regranex® — Granulex®[2] # Drug Shortage Status # Price	https://www.wikidoc.org/index.php/Becaplermin
a37622372b49be007743417966f92dbc9ad57edd	wikidoc	Behaviorism	Behaviorism Behaviorism or Behaviourism, also called the learning perspective, is a philosophy of psychology based on the proposition that all things which organisms do — including acting, thinking and feeling—can and should be regarded as behaviors. The school of psychology maintains that behaviors as such can be described scientifically without recourse either to internal physiological events or to hypothetical constructs such as the mind. Behaviorism comprises the position that all theories should have observational correlates but that there are no philosophical differences between publicly observable processes (such as actions) and privately observable processes (such as thinking and feeling). From early psychology in the 19th century, the behaviorist school of thought ran concurrently and shared commonalities with the psychoanalytic and Gestalt movements in psychology into the 20th century; but also differed from the mental philosophy of the Gestalt psychologists in critical ways. Its main influences were Ivan Pavlov, who investigated classical conditioning, Edward Lee Thorndike, John B. Watson who rejected introspective methods and sought to restrict psychology to experimental methods, and B.F. Skinner who conducted research on operant conditioning. # Versions There is no classification generally agreed upon, but some titles given to the various branches of behaviorism include: - Classical: The behaviorism of Watson; the objective study of behavior; no mental life, no internal states; thought is covert speech. - Methodological: The objective study of third-person behavior; the data of psychology must be inter-subjectively verifiable; no theoretical prescriptions. It has been absorbed into general experimental and cognitive psychology. - Radical: Skinner's behaviorism; is considered radical since it expands behavioral principles to processes within the organism; in contrast to methodological behaviorism; not mechanistic or reductionist; hypothetical (mentalistic) internal states are not considered causes of behavior, phenomena must be observable at least to the individual experiencing them. Willard Van Orman Quine used many of radical behaviorism's ideas in his study of knowing and language. - Logical: Established by Oxford philosopher Gilbert Ryle in his book The Concept of Mind (1949). - Teleological: Post-Skinnerian, purposive, close to microeconomics. - Theoretical: Post-Skinnerian, accepts observable internal states ("within the skin" once meant "unobservable", but with modern technology we are not so constrained); dynamic, but eclectic in choice of theoretical structures, emphasizes parsimony. - Biological: Post-Skinnerian, centered on perceptual and motor modules of behavior, theory of behavior systems. - Inter behaviorism: Founded by J. R. Kantor before Skinner's writings and currently worked by L. Hayes; E. Ribes; and S. Bijou. centered in the inter behavior of organisms, field theory of behavior; emphasis on human behavior. Two popular subtypes are Neo: Hullian and post-Hullian, theoretical, group data, not dynamic, physiological, and Purposive: Tolman’s behavioristic anticipation of cognitive psychology. # B.F. Skinner and radical behaviorism Skinner, who carried out experimental work mainly in comparative psychology from the 1930s to the 1950s, but remained behaviorism's best known theorist and exponent virtually until his death in 1990, developed a distinct kind of behaviorist philosophy, which came to be called radical behaviorism. He is credited with having founded a new version of psychological science, which has come to be called behavior analysis or the experimental analysis of behavior after variations on the subtitle to his 1938 work The Behavior of Organisms: An Experimental Analysis Of Behavior. ## Definition B.F Skinner was influential in defining radical behaviorism, a philosophy codifying the basis of his school of research (named the Experimental Analysis of Behavior, or EAB.) While EAB differs from other approaches to behavioral research on numerous methodological and theoretical points, radical behaviorism departs from methodological behaviorism most notably in accepting treatment of feelings, states of mind and introspection as existent and scientifically treatable. This is done by identifying them as something non-dualistic, and here Skinner takes a divide-and-conquer approach, with some instances being identified with bodily conditions or behavior, and others getting a more extended 'analysis' in terms of behavior. However, radical behaviorism stops short of identifying feelings as causes of behavior. Among other points of difference were a rejection of the reflex as a model of all behavior and a defense of a science of behavior complementary to but independent of physiology. Radical behaviorism has considerable overlap with other western philosophical positions such as American pragmatism ## Experimental and conceptual innovations This essentially philosophical position gained strength from the success of Skinner's early experimental work with rats and pigeons, summarized in his books The Behavior of Organisms and Schedules of Reinforcement. Of particular importance was his concept of the operant response, of which the canonical example was the rat's lever-press. In contrast with the idea of a physiological or reflex response, an operant is a class of structurally distinct but functionally equivalent responses. For example, while a rat might press a lever with its left paw or its right paw or its tail, all of these responses operate on the world in the same way and have a common consequence. Operants are often thought of as species of responses, where the individuals differ but the class coheres in its function--shared consequences with operants and reproductive success with species. This is a clear distinction between Skinner's theory and S-R theory. Skinner's empirical work expanded on earlier research on trial-and-error learning by researchers such as Thorndike and Guthrie with both conceptual reformulations – Thorndike's notion of a stimulus-response 'association' or 'connection' was abandoned – and methodological ones – the use of the 'free operant', so called because the animal was now permitted to respond at its own rate rather than in a series of trials determined by the experimenter procedures. With this method, Skinner carried out substantial experimental work on the effects of different schedules and rates of reinforcement on the rates of operant responses made by rats and pigeons. He achieved remarkable success in training animals to perform unexpected responses, and to emit large numbers of responses, and to demonstrate many empirical regularities at the purely behavioral level. This lent some credibility to his conceptual analysis. It is largely his conceptual analysis that made his work much more rigorous than his peers, a point which can be seen clearly in his seminal work Are Theories of Learning Necessary? in which he criticizes what he viewed to be theoretical weaknesses then common in the study of psychology. An important descendant of the experimental analysis of behavior is the Society for Quantitative Analysis of Behavior. ## Relation to language As Skinner turned from experimental work to concentrate on the philosophical underpinnings of a science of behavior, his attention turned to human language with Verbal Behavior and other language-related publications; Verbal Behavior laid out a vocabulary and theory for functional analysis of verbal behavior, and was strongly criticized in a review by Noam Chomsky. Skinner did not respond in detail but claimed that Chomsky failed to understand his ideas, and the disagreements between the two and the theories involved have been further discussed. What was important for a behaviorist's analysis of human behavior was not language acquisition so much as the interaction between language and overt behavior. In an essay republished in his 1969 book Contingencies of Reinforcement, Skinner took the view that humans could construct linguistic stimuli that would then acquire control over their behavior in the same way that external stimuli could. The possibility of such "instructional control" over behavior meant that contingencies of reinforcement would not always produce the same effects on human behavior as they reliably do in other animals. The focus of a radical behaviorist analysis of human behavior therefore shifted to an attempt to understand the interaction between instructional control and contingency control, and also to understand the behavioral processes that determine what instructions are constructed and what control they acquire over behavior. # Molar versus molecular behaviorism Skinner's view of behavior is most often characterized as a "molecular" view of behavior, that is each behavior can be decomposed into atomistic parts or molecules. This view is inaccurate when one considers his complete description of behavior as delineated in the 1981 article, Selection by Consequences and many other works. Skinner claims that a complete account of behavior has involved an understanding of selection history at three levels: biology (the natural selection or phylogeny of the animal); behavior (the reinforcement history or ontogeny of the behavioral repertoire of the animal); and for some species, culture (the cultural practices of the social group to which the animal belongs). This whole organism, with all those histories, then interacts with its environment. He often described even his own behavior as a product of his phylogenetic history, his reinforcement history (which includes the learning of cultural practices) interacting with the environment at the moment. Molar behaviorists, such as Howard Rachlin argue that behavior can not be understood by focusing on events in the moment. That is, they argue that a behavior can be understood best in terms of the ultimate cause of history and that molecular behaviorist are committing a fallacy by inventing a fictitious proximal cause for behavior. Molar behaviorists argue that standard molecular constructs such as "associative strength" are such fictitious proximal causes that simply take the place of molar variables such as rate of reinforcement. Thus, a molar behaviorist would define a behavior such as loving someone as exhibiting a pattern of loving behavior over time, there is no known proximal cause of loving behavior, only a history of behaviors (of which the current behavior might be an example of) that can be summarized as love. Molectular behaviorists use notions from Melioration theory, Negative power function discounting or additive versions of negative power function discounting. # Behaviorism in philosophy Behaviorism is a psychological movement that can be compared with philosophy of mind. The basic premise of radical behaviorism is that the study of behavior should be a natural science, such as chemistry or physics, without any reference to hypothetical inner states of organisms as causes for their behavior. A modern example of such analysis would be Fantino and colleagues work on behavioral approaches to reasoning. Other varieties, such as theoretical behaviorism, permit internal states, but do not require them to be mental or have any relation to subjective experience. Behaviorism takes a functional view of behavior. There are points of view within analytic philosophy that have called themselves, or have been called by others, behaviorist. In logical behaviorism (as held, e.g., by Rudolf Carnap and Carl Hempel), the meaning of psychological statements are their verification conditions, which consist of performed overt behavior. W. V. Quine made use of a type of behaviorism, influenced by some of Skinner's ideas, in his own work on language. Gilbert Ryle defended a distinct strain of philosophical behaviorism, sketched in his book The Concept of Mind. Ryle's central claim was that instances of dualism frequently represented 'category mistakes,' and hence that they were really misunderstandings of the use of ordinary language. Daniel Dennett likewise acknowledges himself to be a type of behaviorist. It is sometimes argued that Ludwig Wittgenstein defended a behaviorist position, but while there are important relations between his thought and behaviorism, the claim that he was a behaviorist is quite controversial (e.g., the Beetle in a box argument). Mathematician Alan Turing is also sometimes considered a behaviorist, but he himself did not make this identification. # List of notable behaviorists - Albert Bandura - Edwin Ray Guthrie - Richard J. Herrnstein - Clark L. Hull - Ivan Pavlov - B. F. Skinner - Edward Lee Thorndike - Edward C. Tolman - John B. Watson	Behaviorism Template:Psychology Behaviorism or Behaviourism, also called the learning perspective, is a philosophy of psychology based on the proposition that all things which organisms do — including acting, thinking and feeling—can and should be regarded as behaviors.[1] The school of psychology maintains that behaviors as such can be described scientifically without recourse either to internal physiological events or to hypothetical constructs such as the mind.[2] Behaviorism comprises the position that all theories should have observational correlates but that there are no philosophical differences between publicly observable processes (such as actions) and privately observable processes (such as thinking and feeling).[3] From early psychology in the 19th century, the behaviorist school of thought ran concurrently and shared commonalities with the psychoanalytic and Gestalt movements in psychology into the 20th century; but also differed from the mental philosophy of the Gestalt psychologists in critical ways.[citation needed] Its main influences were Ivan Pavlov, who investigated classical conditioning, Edward Lee Thorndike, John B. Watson who rejected introspective methods and sought to restrict psychology to experimental methods, and B.F. Skinner who conducted research on operant conditioning. [3] # Versions There is no classification generally agreed upon, but some titles given to the various branches of behaviorism include: - Classical: The behaviorism of Watson; the objective study of behavior; no mental life, no internal states; thought is covert speech. - Methodological: The objective study of third-person behavior; the data of psychology must be inter-subjectively verifiable; no theoretical prescriptions. It has been absorbed into general experimental and cognitive psychology. - Radical: Skinner's behaviorism; is considered radical since it expands behavioral principles to processes within the organism; in contrast to methodological behaviorism; not mechanistic or reductionist; hypothetical (mentalistic) internal states are not considered causes of behavior, phenomena must be observable at least to the individual experiencing them. Willard Van Orman Quine used many of radical behaviorism's ideas in his study of knowing and language. - Logical: Established by Oxford philosopher Gilbert Ryle in his book The Concept of Mind (1949). - Teleological: Post-Skinnerian, purposive, close to microeconomics. - Theoretical: Post-Skinnerian, accepts observable internal states ("within the skin" once meant "unobservable", but with modern technology we are not so constrained); dynamic, but eclectic in choice of theoretical structures, emphasizes parsimony. - Biological: Post-Skinnerian, centered on perceptual and motor modules of behavior, theory of behavior systems. - Inter behaviorism: Founded by J. R. Kantor before Skinner's writings and currently worked by L. Hayes; E. Ribes; and S. Bijou. centered in the inter behavior of organisms, field theory of behavior; emphasis on human behavior. Two popular subtypes are Neo: Hullian and post-Hullian, theoretical, group data, not dynamic, physiological, and Purposive: Tolman’s behavioristic anticipation of cognitive psychology. # B.F. Skinner and radical behaviorism Skinner, who carried out experimental work mainly in comparative psychology from the 1930s to the 1950s, but remained behaviorism's best known theorist and exponent virtually until his death in 1990, developed a distinct kind of behaviorist philosophy, which came to be called radical behaviorism. He is credited with having founded a new version of psychological science, which has come to be called behavior analysis or the experimental analysis of behavior after variations on the subtitle to his 1938 work The Behavior of Organisms: An Experimental Analysis Of Behavior. ## Definition B.F Skinner was influential in defining radical behaviorism, a philosophy codifying the basis of his school of research (named the Experimental Analysis of Behavior, or EAB.) While EAB differs from other approaches to behavioral research on numerous methodological and theoretical points, radical behaviorism departs from methodological behaviorism most notably in accepting treatment of feelings, states of mind and introspection as existent and scientifically treatable. This is done by identifying them as something non-dualistic, and here Skinner takes a divide-and-conquer approach, with some instances being identified with bodily conditions or behavior, and others getting a more extended 'analysis' in terms of behavior. However, radical behaviorism stops short of identifying feelings as causes of behavior.[1] Among other points of difference were a rejection of the reflex as a model of all behavior and a defense of a science of behavior complementary to but independent of physiology. Radical behaviorism has considerable overlap with other western philosophical positions such as American pragmatism [4] ## Experimental and conceptual innovations This essentially philosophical position gained strength from the success of Skinner's early experimental work with rats and pigeons, summarized in his books The Behavior of Organisms[5] and Schedules of Reinforcement.[6] Of particular importance was his concept of the operant response, of which the canonical example was the rat's lever-press. In contrast with the idea of a physiological or reflex response, an operant is a class of structurally distinct but functionally equivalent responses. For example, while a rat might press a lever with its left paw or its right paw or its tail, all of these responses operate on the world in the same way and have a common consequence. Operants are often thought of as species of responses, where the individuals differ but the class coheres in its function--shared consequences with operants and reproductive success with species. This is a clear distinction between Skinner's theory and S-R theory. Skinner's empirical work expanded on earlier research on trial-and-error learning by researchers such as Thorndike and Guthrie with both conceptual reformulations – Thorndike's notion of a stimulus-response 'association' or 'connection' was abandoned – and methodological ones – the use of the 'free operant', so called because the animal was now permitted to respond at its own rate rather than in a series of trials determined by the experimenter procedures. With this method, Skinner carried out substantial experimental work on the effects of different schedules and rates of reinforcement on the rates of operant responses made by rats and pigeons. He achieved remarkable success in training animals to perform unexpected responses, and to emit large numbers of responses, and to demonstrate many empirical regularities at the purely behavioral level. This lent some credibility to his conceptual analysis. It is largely his conceptual analysis that made his work much more rigorous than his peers, a point which can be seen clearly in his seminal work Are Theories of Learning Necessary? in which he criticizes what he viewed to be theoretical weaknesses then common in the study of psychology. An important descendant of the experimental analysis of behavior is the Society for Quantitative Analysis of Behavior.[7] ## Relation to language As Skinner turned from experimental work to concentrate on the philosophical underpinnings of a science of behavior, his attention turned to human language with Verbal Behavior[8] and other language-related publications;[9] Verbal Behavior laid out a vocabulary and theory for functional analysis of verbal behavior, and was strongly criticized in a review by Noam Chomsky.[10] Skinner did not respond in detail but claimed that Chomsky failed to understand his ideas,[11] and the disagreements between the two and the theories involved have been further discussed.[12][13] What was important for a behaviorist's analysis of human behavior was not language acquisition so much as the interaction between language and overt behavior. In an essay republished in his 1969 book Contingencies of Reinforcement,[14] Skinner took the view that humans could construct linguistic stimuli that would then acquire control over their behavior in the same way that external stimuli could. The possibility of such "instructional control" over behavior meant that contingencies of reinforcement would not always produce the same effects on human behavior as they reliably do in other animals. The focus of a radical behaviorist analysis of human behavior therefore shifted to an attempt to understand the interaction between instructional control and contingency control, and also to understand the behavioral processes that determine what instructions are constructed and what control they acquire over behavior. # Molar versus molecular behaviorism Skinner's view of behavior is most often characterized as a "molecular" view of behavior, that is each behavior can be decomposed into atomistic parts or molecules. This view is inaccurate when one considers his complete description of behavior as delineated in the 1981 article, Selection by Consequences and many other works. Skinner claims that a complete account of behavior has involved an understanding of selection history at three levels: biology (the natural selection or phylogeny of the animal); behavior (the reinforcement history or ontogeny of the behavioral repertoire of the animal); and for some species, culture (the cultural practices of the social group to which the animal belongs). This whole organism, with all those histories, then interacts with its environment. He often described even his own behavior as a product of his phylogenetic history, his reinforcement history (which includes the learning of cultural practices) interacting with the environment at the moment. Molar behaviorists, such as Howard Rachlin argue that behavior can not be understood by focusing on events in the moment. That is, they argue that a behavior can be understood best in terms of the ultimate cause of history and that molecular behaviorist are committing a fallacy by inventing a fictitious proximal cause for behavior. Molar behaviorists argue that standard molecular constructs such as "associative strength" are such fictitious proximal causes that simply take the place of molar variables such as rate of reinforcement.[15] Thus, a molar behaviorist would define a behavior such as loving someone as exhibiting a pattern of loving behavior over time, there is no known proximal cause of loving behavior, only a history of behaviors (of which the current behavior might be an example of) that can be summarized as love. Molectular behaviorists use notions from Melioration theory, Negative power function discounting or additive versions of negative power function discounting.[16] # Behaviorism in philosophy Behaviorism is a psychological movement that can be compared with philosophy of mind. The basic premise of radical behaviorism is that the study of behavior should be a natural science, such as chemistry or physics, without any reference to hypothetical inner states of organisms as causes for their behavior. A modern example of such analysis would be Fantino and colleagues work on behavioral approaches to reasoning.[17] Other varieties, such as theoretical behaviorism, permit internal states, but do not require them to be mental or have any relation to subjective experience. Behaviorism takes a functional view of behavior. There are points of view within analytic philosophy that have called themselves, or have been called by others, behaviorist. In logical behaviorism (as held, e.g., by Rudolf Carnap and Carl Hempel), the meaning of psychological statements are their verification conditions, which consist of performed overt behavior. W. V. Quine made use of a type of behaviorism, influenced by some of Skinner's ideas, in his own work on language. Gilbert Ryle defended a distinct strain of philosophical behaviorism, sketched in his book The Concept of Mind. Ryle's central claim was that instances of dualism frequently represented 'category mistakes,' and hence that they were really misunderstandings of the use of ordinary language. Daniel Dennett likewise acknowledges himself to be a type of behaviorist.[18] It is sometimes argued that Ludwig Wittgenstein defended a behaviorist position, but while there are important relations between his thought and behaviorism, the claim that he was a behaviorist is quite controversial (e.g., the Beetle in a box argument). Mathematician Alan Turing is also sometimes considered a behaviorist,[citation needed] but he himself did not make this identification. # List of notable behaviorists - Albert Bandura - Edwin Ray Guthrie - Richard J. Herrnstein - Clark L. Hull - Ivan Pavlov - B. F. Skinner - Edward Lee Thorndike - Edward C. Tolman - John B. Watson	https://www.wikidoc.org/index.php/Behavior_analysis
43da4c3dfec5bbf9726157baed46783d6353f6e2	wikidoc	Belumosudil	Belumosudil # Disclaimer WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here. # Overview Belumosudil is a kinase inhibitor that is FDA approved for the treatment of chronic graft-versus-host disease after failure of at least two prior lines of systemic therapy. Common adverse reactions include dyspnea, asthenia, phosphate decrease, hypertension, cough, nausea, lymphocytes decreased, edema, diarrhea, glutamyl transferase increased,, hemorrhage, headache, abdominal pain, and musculoskeletal pain. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) Recommended Dosage - 200 mg given once daily is the recommended dosage of Belumosudil. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Belumosudil in adult patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Belumosudil in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) There is limited information regarding Belumosudil FDA-Labeled Indications and Dosage (Pediatric) in the drug label. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Belumosudil in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Belumosudil in pediatric patients. # Contraindications There are no contraindications associated with Belumosudil. # Warnings Embryo-Fetal Toxicity - Fetal harm may occur in pregnant women when taking Belumosudil based on animal studies. - Embryo-fetal mortality and malformations were seen in animal studies conducted on pregnant rabbits and rats when taking Belumosudil during the period organogenesis. - Advise females of reproductive potential to use effective contraception during treatment with Belumosudil and for at least 1 week after the last dose. - Advise males with female partners of reproductive potential to use effective contraception during treatment with Belumosudil and for at least 1 week after the last dose. # Adverse Reactions ## Clinical Trials Experience Clinical Trial Experience - Because clinical trials are conducted under widely varying conditions and durations of follow up, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Chronic Graft versus Host Disease - 83 adult patients with chronic GVHD were part of 2 clinical trials that looked into adverse reactions caused by Belumosudil. - 200 mg of Belumosudil was given to each patient part of the clinical trial. - 9.2 months was the median duration of Belumosudil treatment. - 1 patient in the trials reported fatal adverse reactions such as diarrhea, multi-organ failure, nausea, and vomiting. - 18% of patients had to permanently stop Belumosudil treatment as a result of adverse reactions. - 29% of patients had to interrupt Belumosudil treatment as a result of adverse reactions. - Hemorrhage, renal failure, infection, liver function test abnormal, asthenia, dyspnea, nausea, pyrexia, edema, and diarrhea were common adverse reactions reported by patients that dosage interruptions in clinical studies. Table 2 summarizes the Non-laboratory Adverse Reactions. Table 3 summarizes the Laboratory Abnormalities in Belumosudil. ## Postmarketing Experience There is limited information regarding Belumosudil Postmarketing Experience in the drug label. # Drug Interactions Strong CYP3A Inducers - Belumosudil exposure is decreased with the co-administration of strong CYP3A inducers and Belumosudil. - Advise patients that co-administration of strong CYP3A inducers and Belumosudil should result in an increase in Belumosudil dosage. Proton Pump Inhibitors - Belumosudil exposure is decreased with the co-administration of proton pump inhibitors and Belumosudil. - Advise patients that co-administration of proton pump inhibitors and Belumosudil should result in an increase in Belumosudil dosage. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): Fetal harm is associated with Belumosudil treatment in pregnant women based on animal studies. Embryo-fetal mortality, alterations to growth, and embryo-fetal malformations were seen in pregnant rabbits and rats given Belumosudil during the period of organogenesis. Pregnant rats part of embryo-fetal development studies were given oral doses of 25, 50, 150, and 300 mg/kg/day in a pilot study. Pregnant rats were also given dose of 15, 50, and 150 mg/kg/day in a pivotal study. At doses of 150 and 300 mg/kg/day, pregnant rats experienced maternal toxicity. At doses of 50 and 300 mg/kg/day, pregnant rats experienced an increase in post-implantation loss. At doses greater than 50 mg/kg/day, fetal malformations were seen in pregnant rats. Pregnant rabbits part of embryo-fetal developmental studies were given oral doses of 50, 125, and 225 mg/kg/day. At doses ≥125 mg/kg/day, pregnant rabbits experienced maternal toxicity such as body weight loss and mortality. At doses ≥50 mg/kg/day, pregnant rabbits experienced embryo-fetal effects such as increased post-implantation loss, decreased fetal body weight, spontaneous abortion, malformations, and decreased percentage of live fetuses. Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Belumosudil in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Belumosudil during labor and delivery. ### Nursing Mothers No data is present on the effects done on the breastfed child and the effects on milk production when treated with Belumosudil. Advise female patients not to nurse during treatment with Belumosudil and for at least 1 week after the last dose based on the potential for serious adverse reactions. ### Pediatric Use Pediatric patients 12 years and older were part of studies to look into the safety and effectiveness of Belumosudil. The exposure of Belumosudil between adults and pediatric patients age 12 years and older should be similar. Studies have not been conducted on pediatric patients less than 12 years of age that looks into the safety and effectiveness of Belumosudil. ### Geriatic Use Based on clinical studies, the differences in safety and effectiveness of Belumosudil is not clinically meaningful between older and younger patients. ### Gender There is no FDA guidance on the use of Belumosudil with respect to specific gender populations. ### Race There is no FDA guidance on the use of Belumosudil with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Belumosudil in patients with renal impairment. ### Hepatic Impairment There is no FDA guidance on the use of Belumosudil in patients with hepatic impairment. ### Females of Reproductive Potential and Males Fetal harm is associated with Belumosudil treatment in pregnant women. Before starting Belumosudil treatment, verify pregnancy status of females with reproductive potential. Advise females of reproductive potential to use effective contraception during treatment with Belumosudil and for at least 1 week after the last dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with Belumosudil and for at least 1 week after the last dose. Fertility may be impaired in females and males taking Belumosudil based on rat studies. Fertility effects caused by Belumosudil can be reversed in males and females. ### Immunocompromised Patients There is no FDA guidance one the use of Belumosudil in patients who are immunocompromised. # Administration and Monitoring ### Administration Administration - Advise patients to swallow Belumosudil tablets whole. - Advise patients to take Belumosudil at the same time each day with a meal. - Advise patients to not take extra doses if a dosage is missed. ### Monitoring Dose Modifications for Adverse Reactions - Monitor patients AST, ALT, and total bilirubin levels monthly.' Table 1 summarizes the Dosage Changes in Belumosudil depending on Adverse Reactions. Dosage Modification Due to Drug Interactions Strong CYP3A Inducers: - If taking a strong CYP3A inducer, increase Belumosudil dosage to 200 mg twice daily. Proton Pump Inhibitors: - If taking a proton pump inhibitor, increase Belumosudil dosage to 200 mg twice daily. # IV Compatibility There is limited information regarding the compatibility of Belumosudil and IV administrations. # Overdosage There is limited information regarding Belumosudil overdosage. If you suspect drug poisoning or overdose, please contact the National Poison Help hotline (1-800-222-1222) immediately. # Pharmacology ## Mechanism of Action - Belumosudil is an inhibitor of rho-associated, coiled-coil containing protein kinase. - STAT3/STAT5 phosphorylation and shifting Th17/Treg balance is regulated by Belumosudil. ## Structure - Belumosudil is a kinase inhibitor. It has an empirical formula of C27H28N6O5S. - The molecular weight is 548.62 g/mol. ## Pharmacodynamics - Pharmacodynamic studies on Belumosudil when looking into exposure-response relationships have not been conducted. ## Pharmacokinetics - 22,700 h∙ng/mL is the mean steady-state AUC of Belumosudil in chronic GVHD patients. - 2390 ng/mL is the Cmax of Belumosudil in chronic GVHD patients. - 1.4 is the accumulation ratio of Belumosudil. Absorption - 1.26 to 2.53 hours is the range of time for the Median T-max at steady state of Belumosudil. - 64% is the mean bioavailability of a single dose of Belumosudil. Effect of Food - When given a high-fat and high-calorie meal, a 2.2 times increase in Cmax was observed of Belumosudil in patients. - When given a high-fat and high-calorie meal, a 2 times increase in AUC was observed of Belumosudil in patients. - 0.5 hours is the time that the Median Tmax was delayed of Belumosudil after patients were given a high-fat and high-calorie meal. Distribution - 184 L is the geometric mean volume of distribution of a singe dose of Belumosudil. - In vitro, 99.9% is the binding percentage of Belumosudil to human serum albumin. - In vitro, 98.6% is the binding percentage of Belumosudil to human α1-acid glycoprotein. Elimination - 19 hours is the mean elimination half-life of Belumosudil. - 9.83 L/hours is the clearance of Belumosudil. Metabolism - In vitro, CYP3A4 is the primary metabolizer of Belumosudil. - In vitro, CYP2D6, CYP2C8, and UGT1A9 metabolizes Belumosudil to a lesser extent. Excretion - 85% of Belumosudil was recovered in feces in which 30% was found unchanged after patients were given a single oral dose of radiolabeled Belumosudil. - Less than 5% of Belumosudil was recovered in urine after patients were given a single oral dose of radiolabeled Belumosudil. Specific Populations - Weight, age, mild to moderate renal impairment, or sex had no clinically significant effects on the pharmacokinetics of Belumosudil. Drug Interaction Studies Effects of other drugs on Belumosudil: - When co-administrating Belumosudil and Itraconazole, there were no clinically meaningful effects on the exposure of Belumosudil. - A 59% decrease of Belumosudil Cmax was observed with the co-administration of Belumosudil and Rifampin. - A 72% decrease of Belumosudil AUC was observed with the co-administration of Belumosudil and Rifampin. - A 32% decrease of Belumosudil Cmax was predicted with the co-administration of Belumosudil and Efavirenz. - A 35% decrease of Belumosudil AUC was predicted with the co-administration of Belumosudil and Efavirenz. - A 87% decrease of Belumosudil Cmax was observed with the co-administration of Belumosudil and Rabeprazole. - A 80% decrease of Belumosudil AUC was observed with the co-administration of Belumosudil and Rabeprazole. - A 68% decrease of Belumosudil Cmax was observed with the co-administration of Belumosudil and Omeprazole. - A 47% decrease of Belumosudil AUC was observed with the co-administration of Belumosudil and Omeprazole. Effects of Belumosudil on other drugs: - 1.3 fold increase of Midazolam Cmax was observed with the co-administration of Belumosudil and Midazolam. - 1.5 fold increase of Midazolam AUC was observed with the co-administration of Belumosudil and Midazolam. - The exposure of CYP2C9 substrates is not effected clinically with the co-administration of Belumosudil and CYP2C9 substrates. - The exposure of CYP2C8 substrates is not effected clinically, excluding OATP1B1 substrate, with the co-administration of Belumosudil and CYP2C8 substrates. In Vitro studies - A substrate of P-gp is Belumosudil. - P-gp, BCRP, and OATP1B1 are inhibited by Belumosudil. - Belumosudil is an inhibitor of CYP2C19, CYP2D6, UGT1A1, CYP1A2, and UGT1A9. ## Nonclinical Toxicology Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis: - Studies on carcinogenicity have not been done on Belumosudil. Mutagenesis: - In human peripheral blood lymphocytes, vitro chromosome aberration assay, vivo rat bone marrow micronucleus assay, or in vitro bacterial mutagenicity assay, Belumosudil was not genotoxic. Impairment of Fertility: - 70 days prior to mating period for male rats, doses of 50, 150 or 275 mg/kg/day of Belumosudil were given to male rats. - 14 days prior to mating for female rats, doses of 50, 150 or 275 mg/kg/day of Belumosudil were given to female rats. - Decreased number of viable embryos and increased pre- or post-implantation loss was seen in female rats that were given 275 mg/kg/day of Belumosudil. - Testes/epididymis organ changes and abnormal sperm findings were seen in male rats that were given 275 mg/kg/day of Belumosudil. - When both male and female rats were given 275 mg/kg/day of Belumosudil, a reduction of fertility was seen. - In general toxicology studies, there were adverse changes in both male and female reproductive organs. # Clinical Studies Chronic Graft versus Host Disease - Study KD025-213 is a a randomized, open-label, multicenter study. - The study looked at the effects of Belumosudil on chronic GVHD patients who had received 2 to 5 prior lines of systemic therapy. - A total of 66 patients receiving 200 mg of Belumosudil once daily made up the study. Table 4 shows the Demographics and Baseline Characteristics of the Patient Pool. Table 5 shows the Overall Response Rate through Cycle 7 Day 1 for Patients with Chronic GVHD in Study KD025-213. # How Supplied - 200 mg pale yellow film-coated oblong tablets of Belumosudil in a 30 count bottle. ## Storage - Store at 20° to 25°C (68° to 77°F) . - To prevent moisture, store in original container. - Advise patients to seal cap securely each time bottle is opened. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information Embryo-fetal Toxicity - Advise patients about the harms of the fetus that may occur when taking Belumosudil. - Verify pregnancy status of females with reproductive potential. - Advise females of reproductive potential to use effective contraception during treatment with Belumosudil and for at least 1 week after the last dose. - Advise males with female partners of reproductive potential to use effective contraception during treatment with Belumosudil and for at least 1 week after the last dose. Lactation - Advise female patients not to nurse during treatment with Belumosudil and for at least 1 week after the last dose. Infertility - Advise patients that fertility may be impaired in both females and males taking Belumosudil. Administration - Advise patients to take Belumosudil orally once daily with a meal. - Advise patients to swallow tablet whole with water. - Advise patients to not crush, chew, or cut Belumosudil tablets. - Advise patients to not take extra doses if a dosage is missed. - Advise patients to take a dosage immediately the same day if missed. Drug Interactions - Advise patients about the effects of concomitant medications when taking Belumosudil. Belumosudil Package Insert: # Precautions with Alcohol Alcohol-Belumosudil interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - Rezurock # Look-Alike Drug Names There is limited information regarding Belumosudil Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	Belumosudil Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Tejasvi Aryaputra # Disclaimer WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here. # Overview Belumosudil is a kinase inhibitor that is FDA approved for the treatment of chronic graft-versus-host disease after failure of at least two prior lines of systemic therapy. Common adverse reactions include dyspnea, asthenia, phosphate decrease, hypertension, cough, nausea, lymphocytes decreased, edema, diarrhea, glutamyl transferase increased,, hemorrhage, headache, abdominal pain, and musculoskeletal pain. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) Recommended Dosage - 200 mg given once daily is the recommended dosage of Belumosudil. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Belumosudil in adult patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Belumosudil in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) There is limited information regarding Belumosudil FDA-Labeled Indications and Dosage (Pediatric) in the drug label. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Belumosudil in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Belumosudil in pediatric patients. # Contraindications There are no contraindications associated with Belumosudil. # Warnings Embryo-Fetal Toxicity - Fetal harm may occur in pregnant women when taking Belumosudil based on animal studies. - Embryo-fetal mortality and malformations were seen in animal studies conducted on pregnant rabbits and rats when taking Belumosudil during the period organogenesis. - Advise females of reproductive potential to use effective contraception during treatment with Belumosudil and for at least 1 week after the last dose. - Advise males with female partners of reproductive potential to use effective contraception during treatment with Belumosudil and for at least 1 week after the last dose. # Adverse Reactions ## Clinical Trials Experience Clinical Trial Experience - Because clinical trials are conducted under widely varying conditions and durations of follow up, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Chronic Graft versus Host Disease - 83 adult patients with chronic GVHD were part of 2 clinical trials that looked into adverse reactions caused by Belumosudil. - 200 mg of Belumosudil was given to each patient part of the clinical trial. - 9.2 months was the median duration of Belumosudil treatment. - 1 patient in the trials reported fatal adverse reactions such as diarrhea, multi-organ failure, nausea, and vomiting. - 18% of patients had to permanently stop Belumosudil treatment as a result of adverse reactions. - 29% of patients had to interrupt Belumosudil treatment as a result of adverse reactions. - Hemorrhage, renal failure, infection, liver function test abnormal, asthenia, dyspnea, nausea, pyrexia, edema, and diarrhea were common adverse reactions reported by patients that dosage interruptions in clinical studies. Table 2 summarizes the Non-laboratory Adverse Reactions. Table 3 summarizes the Laboratory Abnormalities in Belumosudil. ## Postmarketing Experience There is limited information regarding Belumosudil Postmarketing Experience in the drug label. # Drug Interactions Strong CYP3A Inducers - Belumosudil exposure is decreased with the co-administration of strong CYP3A inducers and Belumosudil. - Advise patients that co-administration of strong CYP3A inducers and Belumosudil should result in an increase in Belumosudil dosage. Proton Pump Inhibitors - Belumosudil exposure is decreased with the co-administration of proton pump inhibitors and Belumosudil. - Advise patients that co-administration of proton pump inhibitors and Belumosudil should result in an increase in Belumosudil dosage. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): Fetal harm is associated with Belumosudil treatment in pregnant women based on animal studies. Embryo-fetal mortality, alterations to growth, and embryo-fetal malformations were seen in pregnant rabbits and rats given Belumosudil during the period of organogenesis. Pregnant rats part of embryo-fetal development studies were given oral doses of 25, 50, 150, and 300 mg/kg/day in a pilot study. Pregnant rats were also given dose of 15, 50, and 150 mg/kg/day in a pivotal study. At doses of 150 and 300 mg/kg/day, pregnant rats experienced maternal toxicity. At doses of 50 and 300 mg/kg/day, pregnant rats experienced an increase in post-implantation loss. At doses greater than 50 mg/kg/day, fetal malformations were seen in pregnant rats. Pregnant rabbits part of embryo-fetal developmental studies were given oral doses of 50, 125, and 225 mg/kg/day. At doses ≥125 mg/kg/day, pregnant rabbits experienced maternal toxicity such as body weight loss and mortality. At doses ≥50 mg/kg/day, pregnant rabbits experienced embryo-fetal effects such as increased post-implantation loss, decreased fetal body weight, spontaneous abortion, malformations, and decreased percentage of live fetuses. Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Belumosudil in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Belumosudil during labor and delivery. ### Nursing Mothers No data is present on the effects done on the breastfed child and the effects on milk production when treated with Belumosudil. Advise female patients not to nurse during treatment with Belumosudil and for at least 1 week after the last dose based on the potential for serious adverse reactions. ### Pediatric Use Pediatric patients 12 years and older were part of studies to look into the safety and effectiveness of Belumosudil. The exposure of Belumosudil between adults and pediatric patients age 12 years and older should be similar. Studies have not been conducted on pediatric patients less than 12 years of age that looks into the safety and effectiveness of Belumosudil. ### Geriatic Use Based on clinical studies, the differences in safety and effectiveness of Belumosudil is not clinically meaningful between older and younger patients. ### Gender There is no FDA guidance on the use of Belumosudil with respect to specific gender populations. ### Race There is no FDA guidance on the use of Belumosudil with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Belumosudil in patients with renal impairment. ### Hepatic Impairment There is no FDA guidance on the use of Belumosudil in patients with hepatic impairment. ### Females of Reproductive Potential and Males Fetal harm is associated with Belumosudil treatment in pregnant women. Before starting Belumosudil treatment, verify pregnancy status of females with reproductive potential. Advise females of reproductive potential to use effective contraception during treatment with Belumosudil and for at least 1 week after the last dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with Belumosudil and for at least 1 week after the last dose. Fertility may be impaired in females and males taking Belumosudil based on rat studies. Fertility effects caused by Belumosudil can be reversed in males and females. ### Immunocompromised Patients There is no FDA guidance one the use of Belumosudil in patients who are immunocompromised. # Administration and Monitoring ### Administration Administration - Advise patients to swallow Belumosudil tablets whole. - Advise patients to take Belumosudil at the same time each day with a meal. - Advise patients to not take extra doses if a dosage is missed. ### Monitoring Dose Modifications for Adverse Reactions - Monitor patients AST, ALT, and total bilirubin levels monthly.' Table 1 summarizes the Dosage Changes in Belumosudil depending on Adverse Reactions. Dosage Modification Due to Drug Interactions Strong CYP3A Inducers: - If taking a strong CYP3A inducer, increase Belumosudil dosage to 200 mg twice daily. Proton Pump Inhibitors: - If taking a proton pump inhibitor, increase Belumosudil dosage to 200 mg twice daily. # IV Compatibility There is limited information regarding the compatibility of Belumosudil and IV administrations. # Overdosage There is limited information regarding Belumosudil overdosage. If you suspect drug poisoning or overdose, please contact the National Poison Help hotline (1-800-222-1222) immediately. # Pharmacology ## Mechanism of Action - Belumosudil is an inhibitor of rho-associated, coiled-coil containing protein kinase. - STAT3/STAT5 phosphorylation and shifting Th17/Treg balance is regulated by Belumosudil. ## Structure - Belumosudil is a kinase inhibitor. It has an empirical formula of C27H28N6O5S. - The molecular weight is 548.62 g/mol. ## Pharmacodynamics - Pharmacodynamic studies on Belumosudil when looking into exposure-response relationships have not been conducted. ## Pharmacokinetics - 22,700 h∙ng/mL is the mean steady-state AUC of Belumosudil in chronic GVHD patients. - 2390 ng/mL is the Cmax of Belumosudil in chronic GVHD patients. - 1.4 is the accumulation ratio of Belumosudil. Absorption - 1.26 to 2.53 hours is the range of time for the Median T-max at steady state of Belumosudil. - 64% is the mean bioavailability of a single dose of Belumosudil. Effect of Food - When given a high-fat and high-calorie meal, a 2.2 times increase in Cmax was observed of Belumosudil in patients. - When given a high-fat and high-calorie meal, a 2 times increase in AUC was observed of Belumosudil in patients. - 0.5 hours is the time that the Median Tmax was delayed of Belumosudil after patients were given a high-fat and high-calorie meal. Distribution - 184 L is the geometric mean volume of distribution of a singe dose of Belumosudil. - In vitro, 99.9% is the binding percentage of Belumosudil to human serum albumin. - In vitro, 98.6% is the binding percentage of Belumosudil to human α1-acid glycoprotein. Elimination - 19 hours is the mean elimination half-life of Belumosudil. - 9.83 L/hours is the clearance of Belumosudil. Metabolism - In vitro, CYP3A4 is the primary metabolizer of Belumosudil. - In vitro, CYP2D6, CYP2C8, and UGT1A9 metabolizes Belumosudil to a lesser extent. Excretion - 85% of Belumosudil was recovered in feces in which 30% was found unchanged after patients were given a single oral dose of radiolabeled Belumosudil. - Less than 5% of Belumosudil was recovered in urine after patients were given a single oral dose of radiolabeled Belumosudil. Specific Populations - Weight, age, mild to moderate renal impairment, or sex had no clinically significant effects on the pharmacokinetics of Belumosudil. Drug Interaction Studies Effects of other drugs on Belumosudil: - When co-administrating Belumosudil and Itraconazole, there were no clinically meaningful effects on the exposure of Belumosudil. - A 59% decrease of Belumosudil Cmax was observed with the co-administration of Belumosudil and Rifampin. - A 72% decrease of Belumosudil AUC was observed with the co-administration of Belumosudil and Rifampin. - A 32% decrease of Belumosudil Cmax was predicted with the co-administration of Belumosudil and Efavirenz. - A 35% decrease of Belumosudil AUC was predicted with the co-administration of Belumosudil and Efavirenz. - A 87% decrease of Belumosudil Cmax was observed with the co-administration of Belumosudil and Rabeprazole. - A 80% decrease of Belumosudil AUC was observed with the co-administration of Belumosudil and Rabeprazole. - A 68% decrease of Belumosudil Cmax was observed with the co-administration of Belumosudil and Omeprazole. - A 47% decrease of Belumosudil AUC was observed with the co-administration of Belumosudil and Omeprazole. Effects of Belumosudil on other drugs: - 1.3 fold increase of Midazolam Cmax was observed with the co-administration of Belumosudil and Midazolam. - 1.5 fold increase of Midazolam AUC was observed with the co-administration of Belumosudil and Midazolam. - The exposure of CYP2C9 substrates is not effected clinically with the co-administration of Belumosudil and CYP2C9 substrates. - The exposure of CYP2C8 substrates is not effected clinically, excluding OATP1B1 substrate, with the co-administration of Belumosudil and CYP2C8 substrates. In Vitro studies - A substrate of P-gp is Belumosudil. - P-gp, BCRP, and OATP1B1 are inhibited by Belumosudil. - Belumosudil is an inhibitor of CYP2C19, CYP2D6, UGT1A1, CYP1A2, and UGT1A9. ## Nonclinical Toxicology Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis: - Studies on carcinogenicity have not been done on Belumosudil. Mutagenesis: - In human peripheral blood lymphocytes, vitro chromosome aberration assay, vivo rat bone marrow micronucleus assay, or in vitro bacterial mutagenicity assay, Belumosudil was not genotoxic. Impairment of Fertility: - 70 days prior to mating period for male rats, doses of 50, 150 or 275 mg/kg/day of Belumosudil were given to male rats. - 14 days prior to mating for female rats, doses of 50, 150 or 275 mg/kg/day of Belumosudil were given to female rats. - Decreased number of viable embryos and increased pre- or post-implantation loss was seen in female rats that were given 275 mg/kg/day of Belumosudil. - Testes/epididymis organ changes and abnormal sperm findings were seen in male rats that were given 275 mg/kg/day of Belumosudil. - When both male and female rats were given 275 mg/kg/day of Belumosudil, a reduction of fertility was seen. - In general toxicology studies, there were adverse changes in both male and female reproductive organs. # Clinical Studies Chronic Graft versus Host Disease - Study KD025-213 is a a randomized, open-label, multicenter study. - The study looked at the effects of Belumosudil on chronic GVHD patients who had received 2 to 5 prior lines of systemic therapy. - A total of 66 patients receiving 200 mg of Belumosudil once daily made up the study. Table 4 shows the Demographics and Baseline Characteristics of the Patient Pool. Table 5 shows the Overall Response Rate through Cycle 7 Day 1 for Patients with Chronic GVHD in Study KD025-213. # How Supplied - 200 mg pale yellow film-coated oblong tablets of Belumosudil in a 30 count bottle. ## Storage - Store at 20° to 25°C (68° to 77°F) [See USP Controlled Room Temperature]. - To prevent moisture, store in original container. - Advise patients to seal cap securely each time bottle is opened. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information Embryo-fetal Toxicity - Advise patients about the harms of the fetus that may occur when taking Belumosudil. - Verify pregnancy status of females with reproductive potential. - Advise females of reproductive potential to use effective contraception during treatment with Belumosudil and for at least 1 week after the last dose. - Advise males with female partners of reproductive potential to use effective contraception during treatment with Belumosudil and for at least 1 week after the last dose. Lactation - Advise female patients not to nurse during treatment with Belumosudil and for at least 1 week after the last dose. Infertility - Advise patients that fertility may be impaired in both females and males taking Belumosudil. Administration - Advise patients to take Belumosudil orally once daily with a meal. - Advise patients to swallow tablet whole with water. - Advise patients to not crush, chew, or cut Belumosudil tablets. - Advise patients to not take extra doses if a dosage is missed. - Advise patients to take a dosage immediately the same day if missed. Drug Interactions - Advise patients about the effects of concomitant medications when taking Belumosudil. Belumosudil Package Insert: # Precautions with Alcohol Alcohol-Belumosudil interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - Rezurock # Look-Alike Drug Names There is limited information regarding Belumosudil Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	https://www.wikidoc.org/index.php/Belumosudil
3b68936515c519feb7c1455d6a74a8c86189ec2a	wikidoc	Bentoquatam	Bentoquatam # Disclaimer WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here. # Overview Bentoquatam is a Protectant, Dermatological that is FDA approved for the prevention of poison ivy, oak and sumac rash when applied before exposure. Common adverse reactions include erythema. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - Helps prevent poison ivy, oak and sumac rash when applied before exposure. - Shake well before use - apply 15 minutes before risk exposure - avoid intentional contact with poison ivy, oak and sumac - adults and children 6 and older: apply every 4 hours for continued protection or sooner if needed - children under 6 years: ask a doctor - remove with soap and water after risk of exposure ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Bentoquatam in adult patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Bentoquatam in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) There is limited information regarding FDA-Labeled Use of Bentoquatam in pediatric patients. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Bentoquatam in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Bentoquatam in pediatric patients. # Contraindications - Hypersensitivity to bentoquatam and any components of the products such as methylparabens # Warnings - For external use only. Flammable: keep away from fire or flame. - Do not use: if you are allergic to any ingredients, on open rash. When using this product: do not get into eyes. If contact occurs, rinse eyes thoroughly with water. - Keep out of reach of children. - If swallowed, get medical help or contact a Poison Control Center right away. # Adverse Reactions ## Clinical Trials Experience There is limited information regarding Clinical Trial Experience of Bentoquatam in the drug label. ## Postmarketing Experience There is limited information regarding Postmarketing Experience of Bentoquatam in the drug label. # Drug Interactions There is limited information regarding Bentoquatam Drug Interactions in the drug label. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): There is no FDA guidance on usage of Bentoquatam in women who are pregnant. Pregnancy Category (AUS): - Australian Drug Evaluation Committee (ADEC) Pregnancy Category There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Bentoquatam in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Bentoquatam during labor and delivery. ### Nursing Mothers There is no FDA guidance on the use of Bentoquatam with respect to nursing mothers. ### Pediatric Use There is no FDA guidance on the use of Bentoquatam with respect to pediatric patients. ### Geriatic Use There is no FDA guidance on the use of Bentoquatam with respect to geriatric patients. ### Gender There is no FDA guidance on the use of Bentoquatam with respect to specific gender populations. ### Race There is no FDA guidance on the use of Bentoquatam with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Bentoquatam in patients with renal impairment. ### Hepatic Impairment There is no FDA guidance on the use of Bentoquatam in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Bentoquatam in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Bentoquatam in patients who are immunocompromised. # Administration and Monitoring ### Administration - Topical Lotion ### Monitoring There is limited information regarding Monitoring of Bentoquatam in the drug label. # IV Compatibility There is limited information regarding IV Compatibility of Bentoquatam in the drug label. # Overdosage There is limited information regarding Chronic Overdose of Bentoquatam in the drug label. # Pharmacology There is limited information regarding Bentoquatam Pharmacology in the drug label. ## Mechanism of Action There is limited information regarding Bentoquatam Mechanism of Action in the drug label. ## Structure ## Pharmacodynamics There is limited information regarding Pharmacodynamics of Bentoquatam in the drug label. ## Pharmacokinetics There is limited information regarding Pharmacokinetics of Bentoquatam in the drug label. ## Nonclinical Toxicology There is limited information regarding Nonclinical Toxicology of Bentoquatam in the drug label. # Clinical Studies There is limited information regarding Clinical Studies of Bentoquatam in the drug label. # How Supplied There is limited information regarding Bentoquatam How Supplied in the drug label. ## Storage There is limited information regarding Bentoquatam Storage in the drug label. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information There is limited information regarding Patient Counseling Information of Bentoquatam in the drug label. # Precautions with Alcohol - Alcohol-Bentoquatam interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names There is limited information regarding Bentoquatam Brand Names in the drug label. # Look-Alike Drug Names There is limited information regarding Bentoquatam Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	Bentoquatam Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Aparna Vuppala, M.B.B.S. [2] # Disclaimer WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here. # Overview Bentoquatam is a Protectant, Dermatological that is FDA approved for the prevention of poison ivy, oak and sumac rash when applied before exposure. Common adverse reactions include erythema. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - Helps prevent poison ivy, oak and sumac rash when applied before exposure. - Shake well before use - apply 15 minutes before risk exposure - avoid intentional contact with poison ivy, oak and sumac - adults and children 6 and older: apply every 4 hours for continued protection or sooner if needed - children under 6 years: ask a doctor - remove with soap and water after risk of exposure ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Bentoquatam in adult patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Bentoquatam in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) There is limited information regarding FDA-Labeled Use of Bentoquatam in pediatric patients. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Bentoquatam in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Bentoquatam in pediatric patients. # Contraindications - Hypersensitivity to bentoquatam and any components of the products such as methylparabens # Warnings - For external use only. Flammable: keep away from fire or flame. - Do not use: if you are allergic to any ingredients, on open rash. When using this product: do not get into eyes. If contact occurs, rinse eyes thoroughly with water. - Keep out of reach of children. - If swallowed, get medical help or contact a Poison Control Center right away. # Adverse Reactions ## Clinical Trials Experience There is limited information regarding Clinical Trial Experience of Bentoquatam in the drug label. ## Postmarketing Experience There is limited information regarding Postmarketing Experience of Bentoquatam in the drug label. # Drug Interactions There is limited information regarding Bentoquatam Drug Interactions in the drug label. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): There is no FDA guidance on usage of Bentoquatam in women who are pregnant. Pregnancy Category (AUS): - Australian Drug Evaluation Committee (ADEC) Pregnancy Category There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Bentoquatam in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Bentoquatam during labor and delivery. ### Nursing Mothers There is no FDA guidance on the use of Bentoquatam with respect to nursing mothers. ### Pediatric Use There is no FDA guidance on the use of Bentoquatam with respect to pediatric patients. ### Geriatic Use There is no FDA guidance on the use of Bentoquatam with respect to geriatric patients. ### Gender There is no FDA guidance on the use of Bentoquatam with respect to specific gender populations. ### Race There is no FDA guidance on the use of Bentoquatam with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Bentoquatam in patients with renal impairment. ### Hepatic Impairment There is no FDA guidance on the use of Bentoquatam in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Bentoquatam in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Bentoquatam in patients who are immunocompromised. # Administration and Monitoring ### Administration - Topical Lotion ### Monitoring There is limited information regarding Monitoring of Bentoquatam in the drug label. # IV Compatibility There is limited information regarding IV Compatibility of Bentoquatam in the drug label. # Overdosage There is limited information regarding Chronic Overdose of Bentoquatam in the drug label. # Pharmacology There is limited information regarding Bentoquatam Pharmacology in the drug label. ## Mechanism of Action There is limited information regarding Bentoquatam Mechanism of Action in the drug label. ## Structure ## Pharmacodynamics There is limited information regarding Pharmacodynamics of Bentoquatam in the drug label. ## Pharmacokinetics There is limited information regarding Pharmacokinetics of Bentoquatam in the drug label. ## Nonclinical Toxicology There is limited information regarding Nonclinical Toxicology of Bentoquatam in the drug label. # Clinical Studies There is limited information regarding Clinical Studies of Bentoquatam in the drug label. # How Supplied There is limited information regarding Bentoquatam How Supplied in the drug label. ## Storage There is limited information regarding Bentoquatam Storage in the drug label. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information There is limited information regarding Patient Counseling Information of Bentoquatam in the drug label. # Precautions with Alcohol - Alcohol-Bentoquatam interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names There is limited information regarding Bentoquatam Brand Names in the drug label. # Look-Alike Drug Names There is limited information regarding Bentoquatam Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	https://www.wikidoc.org/index.php/Bentoquatam
280f50674252e082839e711bca0b7419e7b1a807	wikidoc	Benztropine	Benztropine # Disclaimer WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here. # Overview Benztropine is an anticholinergic that is FDA approved for the treatment of postencephalitic and idiopathic parkinsonism and drug-induced\|extrapyramidal disorders. Common adverse reactions include tachycardia, constipation, nausea, xerostomia, blurred vision, dysuria, and urinary retention. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - The usual daily dose is 1 to 2 mg, with a range of 0.5 to 6 mg orally. - As with any agent used in parkinsonism, dosage must be individualized accordingto age and weight. and the type of parkinsonism being treated. Generally, older patients, and thin patients cannot tolerate large doses. Most patients with postencephalitic parkinsonism need fairly large doses and tolerate them well. Patients with a poor mental outlook are usually poor candidates for therapy. - In idiopathic parkinsonism, therapy may be initiated with a single daily dose of 0.5 to 1 mg at bedtime. In some patients, this will be adequate; in others 4 to 6 mg a day may be required. - In postencephalitic parkinsonism, therapy may be initiated in most patients with 2 mg a day in one or more doses. In highly sensitive patients, therapy may be initiated with 0.5 mg at bedtime, and increased as necessary. - Some patients experience greatest relief by taking the entire dose at bedtime; others react more favorably to divided doses, two to four times a day. Frequently, one dose a day is sufficient, and divided doses may be unnecessary or undesirable. - The long duration of action of this drug makes it particularly suitable for bedtime medication when its effects may last throughout the night, enabling patients to turn in bed during the night more easily, and to rise in the morning. - When benztropine mesylate is started, do not terminate therapy with other antiparkinsonian agents abruptly. If the other agents are to be reduced or discontinued, it must be done gradually. Many patients obtain greatest relief with combination therapy. - Benztropine mesylate may be used concomitantly with Carbidopa-Levodopa, or with levodopa, in which case periodic dosage adjustment may be required in order to maintain optimum response. - In treating extrapyramidal disorders due to neuroleptic drugs (e.g., phenothiazines), the recommended dosage is 1 to 4 mg once or twice a day orally. Dosage must be individualized according to the need of the patient. Some patients require more than recommended; others do not need as much. - In acute dystonic reactions, 1 to 2 mL of the injection usually relieves the condition quickly. After that, the tablets 1 to 2 mg twice a day, usually prevents recurrence. - When extrapyramidal disorders develop soon after initiation of treatment with neuroleptic drugs (e.g., phenothiazines), they are likely to be transient. One to 2 mgof benztropine mesylate tablets two or three times a day usually provides relief within one or two days. After one or two weeks the drug should be withdrawn to determine the continued need for it. If such disorders recur, benztropine mesylate can be reinstituted. - Certain drug-induced extrapyramidal disorders that develop slowly may not respond to benztropine mesylate. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Benztropine in adult patients. ### Non–Guideline-Supported Use - Benztropine daily doses of 3.8 mg. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) There is limited information regarding FDA-Labeled Use of Benztropine in pediatric patients. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Benztropine in pediatric patients. ### Non–Guideline-Supported Use - Benztropine daily doses of 3.8 mg. # Contraindications - Hypersensitivity to benztropine mesylate tablets. - Because of its atropine-like side effects, this drug is contraindicated in pediatric patients under three years of age, and should be used with caution in older pediatric patients. # Warnings - Safe use in pregnancy has not been established. - Benztropine mesylate may impair mental and/or physical abilities required for performance of hazardous tasks, such as operating machinery or driving a motorvehicle. - When benztropine mesylate is given concomitantly with phenothiazines, haloperidol,or other drugs with anticholinergic or antidopaminergic activity, patients should be advised to report gastrointestinal complaints, fever or heat intolerance promptly. Paralytic ileus, hyperthermia and heat stroke, all of which have sometimes been fatal, have occurred in patients taking anticholinergic-type antiparkinsonism drugs, including benztropine mesylate, in combination with phenothiazines and/or tricyclic antidepressants. - Since benztropine mesylate contains structural features of atropine, it may produce anhidrosis. For this reason, it should be administered with caution during hot weather, especially when given concomitantly with other atropine-like drugs to thechronically ill, the alcoholic, those who have central nervous system disease, and those who do manual labor in a hot environment. Anhidrosis may occur more readily when some disturbance of sweating already exists. If there is evidence of anhidrosis, the possibility of hyperthermia should be considered.Dosage should be decreased at the discretion of the physician so that the ability to maintain body heat equilibrium by perspiration is not impaired. Severe anhidrosis and fatal hyperthermia have occurred. ### Precautions - Since benztropine mesylate has cumulative action, continued supervision is advisable. Patients with a tendency to tachycardia and patients with prostatic hypertrophy should be observed closely during treatment. - Dysuria may occur, but rarely becomes a problem. Urinary retention has been reported with benztropine mesylate. - The drug may cause complaints of weakness and inability to move particular muscle groups, especially in large doses. For example, if the neck has been rigid and suddenly relaxes, it may feel weak, causing some concern. In this event, dosage adjustment is required. - Mental confusion and excitement may occur with large doses, or in susceptible patients. Visual hallucinations have been reported occasionally. Furthermore, in the treatment of extrapyramidal disorders due to neuroleptic drugs (e.g.,phenothiazines), in patients with mental disorders, occasionally there may be intensification of mental symptoms. In such cases, antiparkinsonian drugs can precipitate a toxic psychosis. Patients with mental disorders should be kept under careful observation, especially at the beginning of treatment or if dosage is increased. - Tardive dyskinesia may appear in some patients on long-term therapy with phenothiazines and related agents, or may occur after therapy with these drugs has been discontinued. Antiparkinsonism agents do not alleviate the symptoms of tardive dyskinesia, and in some instances may aggravate them. Benztropine mesylate is not recommended for use in patients with tardive dyskinesia. - The physician should be aware of the possible occurrence of glaucoma. Although the drug does not appear to have any adverse effect on simple glaucoma, it probably should not be used in angle-closure glaucoma. # Adverse Reactions ## Clinical Trials Experience - The adverse reactions below, most of which are antichlolinergic in nature, have been reported and within each category are listed in order of decreasing severity. Tachycardia. Paralytic ileus, constipation, vomiting, nausea, dry mouth. If dry mouth is so severe that there is difficulty in swallowing or speaking, or loss of appetite and weight, reduce dosage, or discontinue the drug temporarily. Slight reduction in dosage may control nausea and still give sufficient relief of symptoms. Vomiting may be controlled by temporary discontinuation, followed by resumption at a lower dosage. Toxic psychosis, including confusion, disorientation, memory impairment, visual hallucinations; exacerbation of pre-existing psychotic symptoms; nervousness; depression; listlessness; numbness of fingers. Blurred vision, dilated pupils. Urinary retention, dysuria. Occasionally, an allergic reaction, e.g., skin rash, develops. If this cannot be controlled by dosage reduction, the medication should be discontinued. Heat stroke, hyperthermia, fever. ## Postmarketing Experience There is limited information regarding Postmarketing Experience of Benztropine in the drug label. # Drug Interactions There is limited information regarding Benztropine Drug Interactions in the drug label. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): There is no FDA guidance on use of Benztropine in women who are pregnant. Pregnancy Category (AUS): - Australian Drug Evaluation Committee (ADEC) Pregnancy Category There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Benztropine in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Benztropine during labor and delivery. ### Nursing Mothers There is no FDA guidance on the use of Benztropine with respect to nursing mothers. ### Pediatric Use - Because of the atropine-like side effects, benztropine mesylate should be used with caution in pediatric patients over three years of age. ### Geriatic Use There is no FDA guidance on the use of Benztropine with respect to geriatric patients. ### Gender There is no FDA guidance on the use of Benztropine with respect to specific gender populations. ### Race There is no FDA guidance on the use of Benztropine with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Benztropine in patients with renal impairment. ### Hepatic Impairment There is no FDA guidance on the use of Benztropine in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Benztropine in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Benztropine in patients who are immunocompromised. # Administration and Monitoring ### Administration - Oral - Intravenous ### Monitoring There is limited information regarding Monitoring of Benztropine in the drug label. # IV Compatibility There is limited information regarding IV Compatibility of Benztropine in the drug label. # Overdosage ## Acute Overdose ### Signs and Symptoms - May be any of those seen in atropine poisoning or antihistamine overdosage: CNS depression, preceded or followed by stimulation; confusion; nervousness; listlessness; intensification of mental symptoms or toxic psychosis in patients with mental illness being treated with neuroleptic drugs (e.g.,phenothiazines); hallucinations (especially visual); dizziness; muscle weakness; ataxia; dry mouth; mydriasis; blurred vision; palpitations; tachycardia; elevated blood pressure; nausea; vomiting; dysuria; numbness of fingers; dysphagia; allergic reactions, e.g., skin rash; headache; hot, dry, flushed skin; delirium; coma; shock; convulsions; respiratory arrest; anhidrosis; hyperthermia; glaucoma; constipation. ### Management - Physostigmine salicylate, 1 to 2 mg, SC or IV, reportedly will reverse symptoms of anticholinergic intoxication.- A second injection may be given after 2 hours if required. Otherwise treatment is symptomatic and supportive. Induce emesis or perform gastric lavage (contraindicated in precomatose convulsive, or psychotic states). Maintain respiration. A short-acting barbiturate may be used for CNS excitement, but with caution to avoid subsequent depression; supportive care for depression (avoid convulsant stimulants such as picrotoxin, pentylenetetrazol,or bemegride); artificial respiration for severe respiratory depression; a local miotic for mydriasis and cycloplegia; ice bags or other cold applications and alcohol sponges for hyperpyrexia, a vasopressor and fluids for circulatory collapse. Darken room for photophobia. ## Chronic Overdose There is limited information regarding Chronic Overdose of Benztropine in the drug label. # Pharmacology ## Mechanism of Action - Benztropine mesylate possesses both anticholinergic and antihistaminic effects,although only the former have been established as therapeutically significant in the management of parkinsonism. ## Structure - Benztropine Mesylate is a synthetic compound containing structural features found in atropine and diphenhydramine. - It is a crystalline white powder, very soluble in water, designated as 3α-(Diphenylmethoxy)-1αH, 5αH-tropane methanesulfonate, with the following structural formula: - Each tablet, for oral administration, contains 0.5 mg, 1 mg or 2 mg of benztropine mesylate. - Each tablet contains the following inactive ingredients: dibasic calcium phosphate lactose monohydrate, lactose anhydrous, microcrystalline cellulose, cornstarch,talc and hydrogenated vegetable oil. ## Pharmacodynamics There is limited information regarding Pharmacodynamics of Benztropine in the drug label. ## Pharmacokinetics There is limited information regarding Pharmacokinetics of Benztropine in the drug label. ## Nonclinical Toxicology There is limited information regarding Nonclinical Toxicology of Benztropine in the drug label. # Clinical Studies There is limited information regarding Clinical Studies of Benztropine in the drug label. # How Supplied - Benztropine Mesylate Tablets, USP are available as follows: - 0.5 mg white, round, bisected, compressed tablets, debossed “EP 136”, in bottles of 100 (NDC 64125-136-01) and 1000 (NDC 64125-136-10) tablets. - 1 mg white, oval, bisected, compressed tablets debossed “EP 137”, in bottles of 100 (NDC 64125-137-01) and 1000 (NDC 64125-137-10) tablets. - 2 mg white, round, bisected, compressed tablets, debossed “EP 138”, in bottles of100 (NDC 64125-138-01) and 1000 (NDC 64125-138-10) tablets. - Dispense in a well-closed container as defined in the USP, with a child-resistant closure. - Store at 20°-25°C (68°-77°F). ## Storage There is limited information regarding Benztropine Storage in the drug label. # Images ## Drug Images ## Package and Label Display Panel ### PRINCIPAL DISPLAY PANEL NDC 17478-012-02 Benztropine Mesylate Injection, USP 2 mg/2 mL (1 mg/mL) 2 mL Ampule Rx only Akorn Logo NDC 17478-012-02 Benztropine Mesylate Injection, USP 2 mg/2 mL (1 mg/mL) For Intravenous or Intramuscular Use 5 Ampules (2 mL each) Rx only Akorn Logo # Patient Counseling Information There is limited information regarding Patient Counseling Information of Benztropine in the drug label. # Precautions with Alcohol - Alcohol-Benztropine interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - BENZTROPINE MESYLATE® # Look-Alike Drug Names There is limited information regarding Benztropine Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	Benztropine Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Adeel Jamil, M.D. [2] # Disclaimer WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here. # Overview Benztropine is an anticholinergic that is FDA approved for the treatment of postencephalitic and idiopathic parkinsonism and drug-induced\|extrapyramidal disorders. Common adverse reactions include tachycardia, constipation, nausea, xerostomia, blurred vision, dysuria, and urinary retention. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - The usual daily dose is 1 to 2 mg, with a range of 0.5 to 6 mg orally. - As with any agent used in parkinsonism, dosage must be individualized accordingto age and weight. and the type of parkinsonism being treated. Generally, older patients, and thin patients cannot tolerate large doses. Most patients with postencephalitic parkinsonism need fairly large doses and tolerate them well. Patients with a poor mental outlook are usually poor candidates for therapy. - In idiopathic parkinsonism, therapy may be initiated with a single daily dose of 0.5 to 1 mg at bedtime. In some patients, this will be adequate; in others 4 to 6 mg a day may be required. - In postencephalitic parkinsonism, therapy may be initiated in most patients with 2 mg a day in one or more doses. In highly sensitive patients, therapy may be initiated with 0.5 mg at bedtime, and increased as necessary. - Some patients experience greatest relief by taking the entire dose at bedtime; others react more favorably to divided doses, two to four times a day. Frequently, one dose a day is sufficient, and divided doses may be unnecessary or undesirable. - The long duration of action of this drug makes it particularly suitable for bedtime medication when its effects may last throughout the night, enabling patients to turn in bed during the night more easily, and to rise in the morning. - When benztropine mesylate is started, do not terminate therapy with other antiparkinsonian agents abruptly. If the other agents are to be reduced or discontinued, it must be done gradually. Many patients obtain greatest relief with combination therapy. - Benztropine mesylate may be used concomitantly with Carbidopa-Levodopa, or with levodopa, in which case periodic dosage adjustment may be required in order to maintain optimum response. - In treating extrapyramidal disorders due to neuroleptic drugs (e.g., phenothiazines), the recommended dosage is 1 to 4 mg once or twice a day orally. Dosage must be individualized according to the need of the patient. Some patients require more than recommended; others do not need as much. - In acute dystonic reactions, 1 to 2 mL of the injection usually relieves the condition quickly. After that, the tablets 1 to 2 mg twice a day, usually prevents recurrence. - When extrapyramidal disorders develop soon after initiation of treatment with neuroleptic drugs (e.g., phenothiazines), they are likely to be transient. One to 2 mgof benztropine mesylate tablets two or three times a day usually provides relief within one or two days. After one or two weeks the drug should be withdrawn to determine the continued need for it. If such disorders recur, benztropine mesylate can be reinstituted. - Certain drug-induced extrapyramidal disorders that develop slowly may not respond to benztropine mesylate. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Benztropine in adult patients. ### Non–Guideline-Supported Use - Benztropine daily doses of 3.8 mg. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) There is limited information regarding FDA-Labeled Use of Benztropine in pediatric patients. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Benztropine in pediatric patients. ### Non–Guideline-Supported Use - Benztropine daily doses of 3.8 mg. # Contraindications - Hypersensitivity to benztropine mesylate tablets. - Because of its atropine-like side effects, this drug is contraindicated in pediatric patients under three years of age, and should be used with caution in older pediatric patients. # Warnings - Safe use in pregnancy has not been established. - Benztropine mesylate may impair mental and/or physical abilities required for performance of hazardous tasks, such as operating machinery or driving a motorvehicle. - When benztropine mesylate is given concomitantly with phenothiazines, haloperidol,or other drugs with anticholinergic or antidopaminergic activity, patients should be advised to report gastrointestinal complaints, fever or heat intolerance promptly. Paralytic ileus, hyperthermia and heat stroke, all of which have sometimes been fatal, have occurred in patients taking anticholinergic-type antiparkinsonism drugs, including benztropine mesylate, in combination with phenothiazines and/or tricyclic antidepressants. - Since benztropine mesylate contains structural features of atropine, it may produce anhidrosis. For this reason, it should be administered with caution during hot weather, especially when given concomitantly with other atropine-like drugs to thechronically ill, the alcoholic, those who have central nervous system disease, and those who do manual labor in a hot environment. Anhidrosis may occur more readily when some disturbance of sweating already exists. If there is evidence of anhidrosis, the possibility of hyperthermia should be considered.Dosage should be decreased at the discretion of the physician so that the ability to maintain body heat equilibrium by perspiration is not impaired. Severe anhidrosis and fatal hyperthermia have occurred. ### Precautions - Since benztropine mesylate has cumulative action, continued supervision is advisable. Patients with a tendency to tachycardia and patients with prostatic hypertrophy should be observed closely during treatment. - Dysuria may occur, but rarely becomes a problem. Urinary retention has been reported with benztropine mesylate. - The drug may cause complaints of weakness and inability to move particular muscle groups, especially in large doses. For example, if the neck has been rigid and suddenly relaxes, it may feel weak, causing some concern. In this event, dosage adjustment is required. - Mental confusion and excitement may occur with large doses, or in susceptible patients. Visual hallucinations have been reported occasionally. Furthermore, in the treatment of extrapyramidal disorders due to neuroleptic drugs (e.g.,phenothiazines), in patients with mental disorders, occasionally there may be intensification of mental symptoms. In such cases, antiparkinsonian drugs can precipitate a toxic psychosis. Patients with mental disorders should be kept under careful observation, especially at the beginning of treatment or if dosage is increased. - Tardive dyskinesia may appear in some patients on long-term therapy with phenothiazines and related agents, or may occur after therapy with these drugs has been discontinued. Antiparkinsonism agents do not alleviate the symptoms of tardive dyskinesia, and in some instances may aggravate them. Benztropine mesylate is not recommended for use in patients with tardive dyskinesia. - The physician should be aware of the possible occurrence of glaucoma. Although the drug does not appear to have any adverse effect on simple glaucoma, it probably should not be used in angle-closure glaucoma. # Adverse Reactions ## Clinical Trials Experience - The adverse reactions below, most of which are antichlolinergic in nature, have been reported and within each category are listed in order of decreasing severity. Tachycardia. Paralytic ileus, constipation, vomiting, nausea, dry mouth. If dry mouth is so severe that there is difficulty in swallowing or speaking, or loss of appetite and weight, reduce dosage, or discontinue the drug temporarily. Slight reduction in dosage may control nausea and still give sufficient relief of symptoms. Vomiting may be controlled by temporary discontinuation, followed by resumption at a lower dosage. Toxic psychosis, including confusion, disorientation, memory impairment, visual hallucinations; exacerbation of pre-existing psychotic symptoms; nervousness; depression; listlessness; numbness of fingers. Blurred vision, dilated pupils. Urinary retention, dysuria. Occasionally, an allergic reaction, e.g., skin rash, develops. If this cannot be controlled by dosage reduction, the medication should be discontinued. Heat stroke, hyperthermia, fever. ## Postmarketing Experience There is limited information regarding Postmarketing Experience of Benztropine in the drug label. # Drug Interactions There is limited information regarding Benztropine Drug Interactions in the drug label. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): There is no FDA guidance on use of Benztropine in women who are pregnant. Pregnancy Category (AUS): - Australian Drug Evaluation Committee (ADEC) Pregnancy Category There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Benztropine in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Benztropine during labor and delivery. ### Nursing Mothers There is no FDA guidance on the use of Benztropine with respect to nursing mothers. ### Pediatric Use - Because of the atropine-like side effects, benztropine mesylate should be used with caution in pediatric patients over three years of age. ### Geriatic Use There is no FDA guidance on the use of Benztropine with respect to geriatric patients. ### Gender There is no FDA guidance on the use of Benztropine with respect to specific gender populations. ### Race There is no FDA guidance on the use of Benztropine with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Benztropine in patients with renal impairment. ### Hepatic Impairment There is no FDA guidance on the use of Benztropine in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Benztropine in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Benztropine in patients who are immunocompromised. # Administration and Monitoring ### Administration - Oral - Intravenous ### Monitoring There is limited information regarding Monitoring of Benztropine in the drug label. # IV Compatibility There is limited information regarding IV Compatibility of Benztropine in the drug label. # Overdosage ## Acute Overdose ### Signs and Symptoms - May be any of those seen in atropine poisoning or antihistamine overdosage: CNS depression, preceded or followed by stimulation; confusion; nervousness; listlessness; intensification of mental symptoms or toxic psychosis in patients with mental illness being treated with neuroleptic drugs (e.g.,phenothiazines); hallucinations (especially visual); dizziness; muscle weakness; ataxia; dry mouth; mydriasis; blurred vision; palpitations; tachycardia; elevated blood pressure; nausea; vomiting; dysuria; numbness of fingers; dysphagia; allergic reactions, e.g., skin rash; headache; hot, dry, flushed skin; delirium; coma; shock; convulsions; respiratory arrest; anhidrosis; hyperthermia; glaucoma; constipation. ### Management - Physostigmine salicylate, 1 to 2 mg, SC or IV, reportedly will reverse symptoms of anticholinergic intoxication.* A second injection may be given after 2 hours if required. Otherwise treatment is symptomatic and supportive. Induce emesis or perform gastric lavage (contraindicated in precomatose convulsive, or psychotic states). Maintain respiration. A short-acting barbiturate may be used for CNS excitement, but with caution to avoid subsequent depression; supportive care for depression (avoid convulsant stimulants such as picrotoxin, pentylenetetrazol,or bemegride); artificial respiration for severe respiratory depression; a local miotic for mydriasis and cycloplegia; ice bags or other cold applications and alcohol sponges for hyperpyrexia, a vasopressor and fluids for circulatory collapse. Darken room for photophobia. ## Chronic Overdose There is limited information regarding Chronic Overdose of Benztropine in the drug label. # Pharmacology ## Mechanism of Action - Benztropine mesylate possesses both anticholinergic and antihistaminic effects,although only the former have been established as therapeutically significant in the management of parkinsonism. ## Structure - Benztropine Mesylate is a synthetic compound containing structural features found in atropine and diphenhydramine. - It is a crystalline white powder, very soluble in water, designated as 3α-(Diphenylmethoxy)-1αH, 5αH-tropane methanesulfonate, with the following structural formula: - Each tablet, for oral administration, contains 0.5 mg, 1 mg or 2 mg of benztropine mesylate. - Each tablet contains the following inactive ingredients: dibasic calcium phosphate lactose monohydrate, lactose anhydrous, microcrystalline cellulose, cornstarch,talc and hydrogenated vegetable oil. ## Pharmacodynamics There is limited information regarding Pharmacodynamics of Benztropine in the drug label. ## Pharmacokinetics There is limited information regarding Pharmacokinetics of Benztropine in the drug label. ## Nonclinical Toxicology There is limited information regarding Nonclinical Toxicology of Benztropine in the drug label. # Clinical Studies There is limited information regarding Clinical Studies of Benztropine in the drug label. # How Supplied - Benztropine Mesylate Tablets, USP are available as follows: - 0.5 mg white, round, bisected, compressed tablets, debossed “EP 136”, in bottles of 100 (NDC 64125-136-01) and 1000 (NDC 64125-136-10) tablets. - 1 mg white, oval, bisected, compressed tablets debossed “EP 137”, in bottles of 100 (NDC 64125-137-01) and 1000 (NDC 64125-137-10) tablets. - 2 mg white, round, bisected, compressed tablets, debossed “EP 138”, in bottles of100 (NDC 64125-138-01) and 1000 (NDC 64125-138-10) tablets. - Dispense in a well-closed container as defined in the USP, with a child-resistant closure. - Store at 20°-25°C (68°-77°F). ## Storage There is limited information regarding Benztropine Storage in the drug label. # Images ## Drug Images ## Package and Label Display Panel ### PRINCIPAL DISPLAY PANEL NDC 17478-012-02 Benztropine Mesylate Injection, USP 2 mg/2 mL (1 mg/mL) 2 mL Ampule Rx only Akorn Logo NDC 17478-012-02 Benztropine Mesylate Injection, USP 2 mg/2 mL (1 mg/mL) For Intravenous or Intramuscular Use 5 Ampules (2 mL each) Rx only Akorn Logo # Patient Counseling Information There is limited information regarding Patient Counseling Information of Benztropine in the drug label. # Precautions with Alcohol - Alcohol-Benztropine interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - BENZTROPINE MESYLATE®[1] # Look-Alike Drug Names There is limited information regarding Benztropine Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	https://www.wikidoc.org/index.php/Benzatropine
86ae3926929820f1780a83ea4f744f38be52163c	wikidoc	Benzonatate	Benzonatate # Disclaimer WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here. # Overview Benzonatate is an antitussive that is FDA approved for the {{{indicationType}}} of symptomatic relief of cough. Common adverse reactions include nausea, oral hypoesthesia, throat symptom, numbness, dizziness, headache, sedation, somnolence. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) ### Cough - Dosing information - Usual dose is: 100 mg or 200 mg PO tid. - If necessary to control cough, up to 600 mg PO tid divided doses may be given. - Benzonatate should be swallowed whole. Benzonatate Capsules are not to be broken, chewed, dissolved, cut or crushed. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of benzonatate in adult patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of benzonatate in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) ### Cough - Dosing information (for children over 10 years of age) - Usual dose is: 100 mg or 200 mg PO tid. - If necessary to control cough, up to 600 mg PO tid divided doses may be given. - Benzonatate should be swallowed whole. Benzonatate Capsules are not to be broken, chewed, dissolved, cut or crushed. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of benzonatate in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of benzonatate in pediatric patients. # Contraindications Hypersensitivity to benzonatate or related compounds. # Warnings ### Hypersensitivity - Severe hypersensitivity reactions (including bronchospasm, laryngospasm and cardiovascular collapse) have been reported which are possibly related to local anesthesia from sucking or chewing the capsule instead of swallowing it. Severe reactions have required intervention with vasopressor agents and supportive measures. ### Psychiatric Effects - Isolated instances of bizarre behavior, including mental confusion and visual hallucinations, have also been reported in patients taking benzonatate in combination with other prescribed drugs. ### Accidental Ingestion and Death in Children - Keep benzonatate out of reach of children. Accidental ingestion of benzonatate resulting in death has been reported in children below age 10. Signs and symptoms of overdose have been reported within 15-20 minutes and death has been reported within one hour of ingestion. If accidental ingestion occurs, seek medical attention immediately # Adverse Reactions ## Clinical Trials Experience - Potential Adverse Reactions to Benzonatate may include: - Hypersensitivity reactions including bronchospasm, laryngospasm, cardiovascular collapse possibly related to local anesthesia from chewing or sucking the capsule. - CNS: sedation; headache; dizziness; mental confusion; visual hallucinations. - GI: constipation; nausea; GI upset. - Dermatologic: pruritus; skin eruptions. - Other: nasal congestion; sensation of burning in the eyes; vague “chilly” sensation; numbness of the chest; hypersensitivity. - Deliberate or accidental overdose has resulted in death, particularly in children. ## Postmarketing Experience FDA package insert for benzonatate contains no information regarding postmarkting experience. # Drug Interactions FDA Package Insert for benzonatate contains no information regarding drug interaction. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): C Animal reproduction studies have not been conducted with benzonatate. It is also not known whether benzonatate can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Benzonatate should be given to a pregnant woman only if clearly needed. Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Benzonatate in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Benzonatate during labor and delivery. ### Nursing Mothers It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk caution should be exercised when benzonatate is administered to a nursing woman. ### Pediatric Use There is no FDA guidance on the use of Benzonatate in pediatric settings. ### Geriatic Use Safety and effectiveness in children below the age of 10 have not been established. Accidental ingestion resulting in death has been reported in children below age 10. Keep out of reach of children. ### Gender There is no FDA guidance on the use of Benzonatate with respect to specific gender populations. ### Race There is no FDA guidance on the use of Benzonatate with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Benzonatate in patients with renal impairment. ### Hepatic Impairment There is no FDA guidance on the use of Benzonatate in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Benzonatate in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Benzonatate in patients who are immunocompromised. # Administration and Monitoring ### Administration Benzonatate should be swallowed whole. Benzonatate capsules are not to be broken, chewed, dissolved, cut or crushed. ### Monitoring FDA package insert for benzonatate contains no information regarding drug monitoring. # IV Compatibility There is limited information about the IV compatibility. # Overdosage - Intentional and unintentional overdose may result in death, particularly in children. - The drug is chemically related to tetracaine and other topical anesthetics and shares various aspects of their pharmacology and toxicology. Drugs of this type are generally well absorbed after ingestion. Signs and Symptoms: - The signs and symptoms of overdose of benzonatate have been reported within 15-20 minutes. If capsules are chewed or dissolved in the mouth, oropharyngeal anesthesia will develop rapidly, which may cause choking and airway compromise. - CNS stimulation may cause restlessness and tremors which may proceed to clonic convulsions followed by profound CNS depression. Convulsions, coma, cerebral edema and cardiac arrest leading to death have been reported within 1 hour of ingestion. Treatment: - In case of overdose, seek medical attention immediately. Evacuate gastric contents and administer copious amounts of activated charcoal slurry. Even in the conscious patient, cough and gag reflexes may be so depressed as to necessitate special attention to protection against aspiration of gastric contents and orally administered materials. Convulsions should be treated with a short-acting barbiturate given intravenously and carefully titrated for the smallest effective dosage. Intensive support of respiration and cardiovascular-renal function is an essential feature of the treatment of severe intoxication from overdosage. - Do not use CNS stimulants. # Pharmacology ## Mechanism of Action - Benzonatate acts peripherally by anesthetizing the stretch receptors located in the respiratory passages, lungs, and pleura by dampening their activity and thereby reducing the cough reflex at its source. It begins to act within 15 to 20 minutes and its effect lasts for 3 to 8 hours. Benzonatate has no inhibitory effect on the respiratory center in recommended dosage. ## Structure - Benzonatate, a non-narcotic oral antitussive agent, is 2, 5, 8, 11, 14, 17, 20, 23, 26-nonaoxaoctacosan-28-yl p(butylamino) benzoate; with a molecular weight of 603.7. - Each soft gelatin capsule, for oral administration, contains 100 mg or 200 mg benzonatate USP. In addition, each capsule contains the following inactive ingredients: D&C Yellow No. 10, gelatin, glycerin, and purified water. ## Pharmacodynamics There is limited information regarding Benzonatate Pharmacodynamics in the drug label. ## Pharmacokinetics There is limited information regarding Benzonatate Pharmacokinetics in the drug label. ## Nonclinical Toxicology Carcinogenicity, mutagenicity, and reproduction studies have not been conducted with Benzonatate. # Clinical Studies There is limited information about the clinical studies. # How Supplied - Benzonatate Capsules USP, 100 mg: Yellow soft gelatin capsules, imprinted with “PA46”, available in bottles of 100’s and 500’s. - Benzonatate Capsules USP, 200 mg: Yellow soft gelatin capsules, imprinted with “PA83”, available in bottles of 100’s. ## Storage - The capsules should be protected from light, moisture and humidity, and stored at controlled room temperature 20° to 25°C (68° to 77°F) . # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information - Swallow benzonatate capsules whole. Do not break, chew, dissolve, cut, or crush benzonatate capsules. Release of benzonatate from the capsule in the mouth can produce a temporary local anesthesia of the oral mucosa and choking could occur. If numbness or tingling of the tongue, mouth, throat, or face occurs, refrain from oral ingestion of food or liquids until the numbness has resolved. If the symptoms worsen or persist, seek medical attention. - Keep benzonatate out of reach of children. Accidental ingestion resulting in death has been reported in children. Signs and symptoms of overdose have been reported within 15-20 minutes and death has been reported within one hour of ingestion. Signs and symptoms may include restlessness, tremors, convulsions, coma and cardiac arrest. If accidental ingestion occurs, seek medical attention immediately. - Overdosage resulting in death may occur in adults. - Do not exceed a single dose of 200 mg and a total daily dosage of 600 mg. If you miss a dose of benzonatate, skip that dose and take the next dose at the next scheduled time. Do not take 2 doses of benzonatate at one time. # Precautions with Alcohol Alcohol-Benzonatate interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - Tessalon Perles - Zonatuss # Look-Alike Drug Names There is limited information about the look-alike drug names. # Drug Shortage Status # Price	Benzonatate Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Sheng Shi, M.D. [2] # Disclaimer WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here. # Overview Benzonatate is an antitussive that is FDA approved for the {{{indicationType}}} of symptomatic relief of cough. Common adverse reactions include nausea, oral hypoesthesia, throat symptom, numbness, dizziness, headache, sedation, somnolence. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) ### Cough - Dosing information - Usual dose is: 100 mg or 200 mg PO tid. - If necessary to control cough, up to 600 mg PO tid divided doses may be given. - Benzonatate should be swallowed whole. Benzonatate Capsules are not to be broken, chewed, dissolved, cut or crushed. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of benzonatate in adult patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of benzonatate in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) ### Cough - Dosing information (for children over 10 years of age) - Usual dose is: 100 mg or 200 mg PO tid. - If necessary to control cough, up to 600 mg PO tid divided doses may be given. - Benzonatate should be swallowed whole. Benzonatate Capsules are not to be broken, chewed, dissolved, cut or crushed. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of benzonatate in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of benzonatate in pediatric patients. # Contraindications Hypersensitivity to benzonatate or related compounds. # Warnings ### Hypersensitivity - Severe hypersensitivity reactions (including bronchospasm, laryngospasm and cardiovascular collapse) have been reported which are possibly related to local anesthesia from sucking or chewing the capsule instead of swallowing it. Severe reactions have required intervention with vasopressor agents and supportive measures. ### Psychiatric Effects - Isolated instances of bizarre behavior, including mental confusion and visual hallucinations, have also been reported in patients taking benzonatate in combination with other prescribed drugs. ### Accidental Ingestion and Death in Children - Keep benzonatate out of reach of children. Accidental ingestion of benzonatate resulting in death has been reported in children below age 10. Signs and symptoms of overdose have been reported within 15-20 minutes and death has been reported within one hour of ingestion. If accidental ingestion occurs, seek medical attention immediately # Adverse Reactions ## Clinical Trials Experience - Potential Adverse Reactions to Benzonatate may include: - Hypersensitivity reactions including bronchospasm, laryngospasm, cardiovascular collapse possibly related to local anesthesia from chewing or sucking the capsule. - CNS: sedation; headache; dizziness; mental confusion; visual hallucinations. - GI: constipation; nausea; GI upset. - Dermatologic: pruritus; skin eruptions. - Other: nasal congestion; sensation of burning in the eyes; vague “chilly” sensation; numbness of the chest; hypersensitivity. - Deliberate or accidental overdose has resulted in death, particularly in children. ## Postmarketing Experience FDA package insert for benzonatate contains no information regarding postmarkting experience. # Drug Interactions FDA Package Insert for benzonatate contains no information regarding drug interaction. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): C Animal reproduction studies have not been conducted with benzonatate. It is also not known whether benzonatate can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Benzonatate should be given to a pregnant woman only if clearly needed. Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Benzonatate in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Benzonatate during labor and delivery. ### Nursing Mothers It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk caution should be exercised when benzonatate is administered to a nursing woman. ### Pediatric Use There is no FDA guidance on the use of Benzonatate in pediatric settings. ### Geriatic Use Safety and effectiveness in children below the age of 10 have not been established. Accidental ingestion resulting in death has been reported in children below age 10. Keep out of reach of children. ### Gender There is no FDA guidance on the use of Benzonatate with respect to specific gender populations. ### Race There is no FDA guidance on the use of Benzonatate with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Benzonatate in patients with renal impairment. ### Hepatic Impairment There is no FDA guidance on the use of Benzonatate in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Benzonatate in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Benzonatate in patients who are immunocompromised. # Administration and Monitoring ### Administration Benzonatate should be swallowed whole. Benzonatate capsules are not to be broken, chewed, dissolved, cut or crushed. ### Monitoring FDA package insert for benzonatate contains no information regarding drug monitoring. # IV Compatibility There is limited information about the IV compatibility. # Overdosage - Intentional and unintentional overdose may result in death, particularly in children. - The drug is chemically related to tetracaine and other topical anesthetics and shares various aspects of their pharmacology and toxicology. Drugs of this type are generally well absorbed after ingestion. Signs and Symptoms: - The signs and symptoms of overdose of benzonatate have been reported within 15-20 minutes. If capsules are chewed or dissolved in the mouth, oropharyngeal anesthesia will develop rapidly, which may cause choking and airway compromise. - CNS stimulation may cause restlessness and tremors which may proceed to clonic convulsions followed by profound CNS depression. Convulsions, coma, cerebral edema and cardiac arrest leading to death have been reported within 1 hour of ingestion. Treatment: - In case of overdose, seek medical attention immediately. Evacuate gastric contents and administer copious amounts of activated charcoal slurry. Even in the conscious patient, cough and gag reflexes may be so depressed as to necessitate special attention to protection against aspiration of gastric contents and orally administered materials. Convulsions should be treated with a short-acting barbiturate given intravenously and carefully titrated for the smallest effective dosage. Intensive support of respiration and cardiovascular-renal function is an essential feature of the treatment of severe intoxication from overdosage. - Do not use CNS stimulants. # Pharmacology ## Mechanism of Action - Benzonatate acts peripherally by anesthetizing the stretch receptors located in the respiratory passages, lungs, and pleura by dampening their activity and thereby reducing the cough reflex at its source. It begins to act within 15 to 20 minutes and its effect lasts for 3 to 8 hours. Benzonatate has no inhibitory effect on the respiratory center in recommended dosage. ## Structure - Benzonatate, a non-narcotic oral antitussive agent, is 2, 5, 8, 11, 14, 17, 20, 23, 26-nonaoxaoctacosan-28-yl p(butylamino) benzoate; with a molecular weight of 603.7. - Each soft gelatin capsule, for oral administration, contains 100 mg or 200 mg benzonatate USP. In addition, each capsule contains the following inactive ingredients: D&C Yellow No. 10, gelatin, glycerin, and purified water. ## Pharmacodynamics There is limited information regarding Benzonatate Pharmacodynamics in the drug label. ## Pharmacokinetics There is limited information regarding Benzonatate Pharmacokinetics in the drug label. ## Nonclinical Toxicology Carcinogenicity, mutagenicity, and reproduction studies have not been conducted with Benzonatate. # Clinical Studies There is limited information about the clinical studies. # How Supplied - Benzonatate Capsules USP, 100 mg: Yellow soft gelatin capsules, imprinted with “PA46”, available in bottles of 100’s and 500’s. - Benzonatate Capsules USP, 200 mg: Yellow soft gelatin capsules, imprinted with “PA83”, available in bottles of 100’s. ## Storage - The capsules should be protected from light, moisture and humidity, and stored at controlled room temperature 20° to 25°C (68° to 77°F) [See USP]. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information - Swallow benzonatate capsules whole. Do not break, chew, dissolve, cut, or crush benzonatate capsules. Release of benzonatate from the capsule in the mouth can produce a temporary local anesthesia of the oral mucosa and choking could occur. If numbness or tingling of the tongue, mouth, throat, or face occurs, refrain from oral ingestion of food or liquids until the numbness has resolved. If the symptoms worsen or persist, seek medical attention. - Keep benzonatate out of reach of children. Accidental ingestion resulting in death has been reported in children. Signs and symptoms of overdose have been reported within 15-20 minutes and death has been reported within one hour of ingestion. Signs and symptoms may include restlessness, tremors, convulsions, coma and cardiac arrest. If accidental ingestion occurs, seek medical attention immediately. - Overdosage resulting in death may occur in adults. - Do not exceed a single dose of 200 mg and a total daily dosage of 600 mg. If you miss a dose of benzonatate, skip that dose and take the next dose at the next scheduled time. Do not take 2 doses of benzonatate at one time. # Precautions with Alcohol Alcohol-Benzonatate interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - Tessalon Perles - Zonatuss # Look-Alike Drug Names There is limited information about the look-alike drug names. # Drug Shortage Status # Price	https://www.wikidoc.org/index.php/Benzonatate
71721f1e034ef11d5e691b4cb91396c78a698dae	wikidoc	Benzopyrene	Benzopyrene # Overview Benzopyrene, C20H12, is a five-ring polycyclic aromatic hydrocarbon that is mutagenic and highly carcinogenic. It is a crystalline yellow solid. Benzopyrene is a product of incomplete combustion at temperatures between 300 and 600 °C. Benzopyrene was determined in 1933 to be the component of coal tar responsible for the first recognized occupation-associated cancers, the sooty warts (cancers of the scrotum) suffered by chimney sweeps in 18th century England. In the 19th century, high incidences of skin cancers were noted among fuel industry workers. By the early 20th century, malignant skin tumors were produced in laboratory animals by repeatedly painting them with coal tar. # Sources of Benzopyrene Benzopyrene is found in coal tar, in automobile exhaust fumes (especially from diesel engines), tobacco smoke, wood smoke, and in charbroiled food. Recent studies have revealed that levels of benzopyrene in burnt toast are significantly higher than once thought, although it is unproven whether burnt toast is itself carcinogenic. # Toxicity of Benzopyrene A vast number of studies over the previous three decades have documented links between benzopyrene and cancers. It has been more difficult to link cancers to specific benzopyrene sources, especially in humans, and difficult to quantify risks posed by various methods of exposure (inhalation or ingestion). Researchers at Kansas State University recently discovered a link between vitamin A and emphysema in smokers. Benzopyrene was found to be the link to the deficiency, since it induces vitamin A deficiency in rats. In 1996, a study was published that provided the clear molecular evidence conclusively linking components in tobacco smoke to lung cancer. Benzopyrene, found in tobacco smoke, was shown to cause genetic damage in lung cells that was identical to the damage observed in the DNA of most malignant lung tumours. A 2001 National Cancer Institute study found levels of benzopyrene to be significantly higher in foods that were cooked well-done on the barbecue, particularly steaks, chicken with skin, and hamburgers. Japanese scientists showed that cooked beef contains mutagens, chemicals that are capable of altering the chemical structure of DNA. However, the foods themselves are not necessarily carcinogenic, even if they contain trace amounts of carcinogens, because the gastrointestinal tract protects itself against carcinomas by shedding its outer layer continuously. Furthermore, detoxification enzymes, such as cytochromes P450 have increased activities in the gut due to the normal requirement for protection from food-borne toxins. Thus in most cases small amounts of benzopyrene are metabolized by gut enzymes prior to being passed on to the blood. The lungs are not protected in either of these manners. A recent study has found that cytochrome P450 1A1 (CYP1A1) and cytochrome P450 1B1 (CYP1B1) are both protective and, confusingly, necessary for benzopyrene toxicity. Experiments with strains of mice engineered to remove (knockout) CYP1A1and CYP1B1 reveal that CYP1A1 primarily acts to protect mammals from low doses of benzopyrene, and that removing this protection causes the biological accumulation of large concentrations of benzopyrene. Unless CYP1B1 is also knocked out, benzopyrene toxicity results from the bioactivation of benzopyrene to the ultimate toxic compound, benzopyrene-7,8-dihydrodiol-9,10-epoxide (see below). # Interaction with DNA Properly speaking, benzopyrene is a procarcinogen, meaning that the mechanism of carcinogensis of benzopyrene depends on enzymatic metabolism of benzopyrene to the ultimate mutagen, benzopyrene diol epoxide, pictured at right. This molecule intercalates in DNA, covalently bonding to the nucleophilic guanine nucleobases at the N2 position. X-ray crystallographic and nuclear magnetic resonance structure studies show that this binding distorts the DNA, inducing mutations by perturbing the double-helical DNA structure. This disrupts the normal process of copying DNA and induces mutations, which explains the occurrence of cancer after exposure. This mechanism of action is similar to that of aflatoxin which binds to the N7 position of guanine. There are indications that specifically benzopyrene diol epoxide specifically targets the protective p53 gene. This gene is a transcription factor that regulates the cell cycle and hence functions as a tumor suppressor. By inducing G (guanine) to T (thymidine) transversions in transversion hotspots within p53, there is a probability that benzopyrene diol epoxide inactivates the tumor suppression ability in certain cells, leading to cancer. Benzopyrene diol epoxide is the carcinogenic product of three enzymatic reactions: Benzopyrene induces cytochrome P4501A1 (CYP1A1) by binding to the AHR (aryl hydrocarbon receptor) in the cytosol. Upon binding the transformed receptor translocates to the nucleus where it dimerises with ARNT (aryl hydrocarbon receptor nuclear translocator) and then binds xenobiotic response elements (XREs) in DNA located upstream of certain genes. This process increases transcription of certain genes, notably CYP1A1, followed by increased CYP1A1 protein production. This process is similar to induction of CYP1A1 by certain polychlorinated biphenyls and dioxins. Recently, Benzopyrene has been found to activate a transposon, LINE1, in humans	Benzopyrene Template:Chembox new # Overview Benzo[a]pyrene, C20H12, is a five-ring polycyclic aromatic hydrocarbon that is mutagenic and highly carcinogenic. It is a crystalline yellow solid. Benzo[a]pyrene is a product of incomplete combustion at temperatures between 300 and 600 °C. Benzo[a]pyrene was determined in 1933 to be the component of coal tar responsible for the first recognized occupation-associated cancers, the sooty warts (cancers of the scrotum) suffered by chimney sweeps in 18th century England. In the 19th century, high incidences of skin cancers were noted among fuel industry workers. By the early 20th century, malignant skin tumors were produced in laboratory animals by repeatedly painting them with coal tar. # Sources of Benzo[a]pyrene Benzo[a]pyrene is found in coal tar, in automobile exhaust fumes (especially from diesel engines), tobacco smoke, wood smoke, and in charbroiled food. Recent studies have revealed that levels of benzo[a]pyrene in burnt toast are significantly higher than once thought, although it is unproven whether burnt toast is itself carcinogenic. # Toxicity of Benzo[a]pyrene A vast number of studies over the previous three decades have documented links between benzo[a]pyrene and cancers. It has been more difficult to link cancers to specific benzo[a]pyrene sources, especially in humans, and difficult to quantify risks posed by various methods of exposure (inhalation or ingestion). Researchers at Kansas State University recently discovered a link between vitamin A and emphysema in smokers.[1] Benzo[a]pyrene was found to be the link to the deficiency, since it induces vitamin A deficiency in rats. In 1996, a study was published that provided the clear molecular evidence conclusively linking components in tobacco smoke to lung cancer.[2] Benzo[a]pyrene, found in tobacco smoke, was shown to cause genetic damage in lung cells that was identical to the damage observed in the DNA of most malignant lung tumours. A 2001 National Cancer Institute study found levels of benzo[a]pyrene to be significantly higher in foods that were cooked well-done on the barbecue, particularly steaks, chicken with skin, and hamburgers.[citation needed] Japanese scientists showed that cooked beef contains mutagens, chemicals that are capable of altering the chemical structure of DNA[citation needed]. However, the foods themselves are not necessarily carcinogenic, even if they contain trace amounts of carcinogens, because the gastrointestinal tract protects itself against carcinomas by shedding its outer layer continuously. Furthermore, detoxification enzymes, such as cytochromes P450 have increased activities in the gut due to the normal requirement for protection from food-borne toxins. Thus in most cases small amounts of benzo[a]pyrene are metabolized by gut enzymes prior to being passed on to the blood. The lungs are not protected in either of these manners. A recent study has found that cytochrome P450 1A1 (CYP1A1) and cytochrome P450 1B1 (CYP1B1) are both protective and, confusingly, necessary for benzo[a]pyrene toxicity. Experiments with strains of mice engineered to remove (knockout) CYP1A1and CYP1B1 reveal that CYP1A1 primarily acts to protect mammals from low doses of benzo[a]pyrene, and that removing this protection causes the biological accumulation of large concentrations of benzo[a]pyrene. Unless CYP1B1 is also knocked out, benzo[a]pyrene toxicity results from the bioactivation of benzo[a]pyrene to the ultimate toxic compound, benzo[a]pyrene-7,8-dihydrodiol-9,10-epoxide (see below).[3] # Interaction with DNA Properly speaking, benzo[a]pyrene is a procarcinogen, meaning that the mechanism of carcinogensis of benzo[a]pyrene depends on enzymatic metabolism of benzo[a]pyrene to the ultimate mutagen, benzo[a]pyrene diol epoxide, pictured at right. This molecule intercalates in DNA, covalently bonding to the nucleophilic guanine nucleobases at the N2 position. X-ray crystallographic and nuclear magnetic resonance structure studies show that this binding distorts the DNA,[5] inducing mutations by perturbing the double-helical DNA structure. This disrupts the normal process of copying DNA and induces mutations, which explains the occurrence of cancer after exposure. This mechanism of action is similar to that of aflatoxin which binds to the N7 position of guanine.[6] There are indications that specifically benzo[a]pyrene diol epoxide specifically targets the protective p53 gene.[7] This gene is a transcription factor that regulates the cell cycle and hence functions as a tumor suppressor. By inducing G (guanine) to T (thymidine) transversions in transversion hotspots within p53, there is a probability that benzo[a]pyrene diol epoxide inactivates the tumor suppression ability in certain cells, leading to cancer. Benzo[a]pyrene diol epoxide is the carcinogenic product of three enzymatic reactions: Benzo[a]pyrene induces cytochrome P4501A1 (CYP1A1) by binding to the AHR (aryl hydrocarbon receptor) in the cytosol.[9] Upon binding the transformed receptor translocates to the nucleus where it dimerises with ARNT (aryl hydrocarbon receptor nuclear translocator) and then binds xenobiotic response elements (XREs) in DNA located upstream of certain genes. This process increases transcription of certain genes, notably CYP1A1, followed by increased CYP1A1 protein production.[10] This process is similar to induction of CYP1A1 by certain polychlorinated biphenyls and dioxins. Recently, Benzo[a]pyrene has been found to activate a transposon, LINE1, in humans[11]	https://www.wikidoc.org/index.php/Benzopyrene
0f299bc9a50eb62c01a347b9c0e42d0d8486c2e8	wikidoc	Benzydamine	Benzydamine # Overview Benzydamine, available as the hydrochloride, is a locally-acting nonsteroidal anti-inflammatory drug with local anaesthetic and analgesic properties providing both rapid and extended pain relief as well as a significant anti-inflammatory treatment for the painful inflammatory conditions of the mouth and throat. It selectively binds to inflamed tissues (Prostaglandinsynthase-inhibitor) is virtually free of any adverse systemic effects. It may be used alone or as an adjunct to other therapy giving the possibility of increased therapeutic effect with little risk of interaction. # Availability It is available in a mouth wash named Tantum Verde across Europe. In the UK it is sold by 3M under the trade name Difflam, as Difflam Spray, Difflam Oral Rinse and Difflam Cream. Its high cost (about £7 a bottle) makes it less attractive than the cheaper method of gargling aspirin. In Australia it is available from 3M as Difflam-C Alcohol & Colour Free Solution, Difflam 3% Gel, Difflam Extra Strength Gel 5%, Difflam-C Solution, Difflam Solution (including Difflam Throat Spray), Difflam Cream and Difflam Lozenges. It is sold in Poland with no prescription as Tantum Rosa - a vagina cleansing powder, containing 500 mg of benzydamine mixed with salt for 1 Euro. In Brazil it is sold by prescription under the name "Benflogin", with each box containing 20 pills (50mg each). In Pakistan it is sold by prescription under the name" Tantum capsule" (50mg) # Indications Odontostomatology: gingivitis, stomatitis, glossitis, aphthous ulcers, dental surgery and oral ulceration due to radiation therapy. Otorhinolaryngology: pharyngitis, tonsillitis, post-tonsillectomy, radiation or intubation mucositis. # Contraindications There are no contraindications to the use of Benzydamine except for known hypersensitivity. # Side effects Benzydamine is well tolerated. Occasionally oral tissue numbness or stinging sensations may occur. Benzydamine may be abused recreationally. In oral dosages of 750 mg to 3000 mg it is a deliriant and CNS stimulant, popular in Poland and Brazil. In Brazil it is very popular and many people use it for recreational purposes. A person in a benzydamine trip may experience a feeling of well-being, euphoria and in higher doses will hallucinate, paranoia, dry mouth and convulsions may also be experienced. The trip can last up to 8 hours, after that the user becomes tired and quiet, but sleeping is almost impossible. Abuse can cause ulcers, liver and kidney damage. # Footnotes - ↑ Turnbull RS. Benzydamine Hydrochloride (Tantum) in the management of oral inflammatory conditions. Journal of the Canadian Dental Association. 1995 Feb;61(2):127-34. - ↑ Material Safety Data Sheets for Difflam varieties sold in Australia - ↑ Anand JS, Glebocka ML, Korolkiewicz RP. Recreational abuse with benzydamine hydrochloride (tantum rosa). Clinical Toxicology (Philadelphia, Pa). 2007;45(2):198-9.	Benzydamine Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview Benzydamine, available as the hydrochloride, is a locally-acting nonsteroidal anti-inflammatory drug with local anaesthetic and analgesic properties providing both rapid and extended pain relief as well as a significant anti-inflammatory treatment for the painful inflammatory conditions of the mouth and throat.[1] It selectively binds to inflamed tissues (Prostaglandinsynthase-inhibitor) is virtually free of any adverse systemic effects. It may be used alone or as an adjunct to other therapy giving the possibility of increased therapeutic effect with little risk of interaction. # Availability It is available in a mouth wash named Tantum Verde across Europe. In the UK it is sold by 3M under the trade name Difflam, as Difflam Spray, Difflam Oral Rinse and Difflam Cream. Its high cost (about £7 a bottle) makes it less attractive than the cheaper method of gargling aspirin. In Australia it is available from 3M as Difflam-C Alcohol & Colour Free Solution, Difflam 3% Gel, Difflam Extra Strength Gel 5%, Difflam-C Solution, Difflam Solution (including Difflam Throat Spray), Difflam Cream and Difflam Lozenges.[2] It is sold in Poland with no prescription as Tantum Rosa - a vagina cleansing powder, containing 500 mg of benzydamine mixed with salt for 1 Euro. In Brazil it is sold by prescription under the name "Benflogin", with each box containing 20 pills (50mg each). In Pakistan it is sold by prescription under the name" Tantum capsule" (50mg) # Indications Odontostomatology: gingivitis, stomatitis, glossitis, aphthous ulcers, dental surgery and oral ulceration due to radiation therapy. Otorhinolaryngology: pharyngitis, tonsillitis, post-tonsillectomy, radiation or intubation mucositis. # Contraindications There are no contraindications to the use of Benzydamine except for known hypersensitivity. # Side effects Benzydamine is well tolerated. Occasionally oral tissue numbness or stinging sensations may occur. Benzydamine may be abused recreationally.[3] In oral dosages of 750 mg to 3000 mg it is a deliriant and CNS stimulant, popular in Poland and Brazil. In Brazil it is very popular and many people use it for recreational purposes. A person in a benzydamine trip may experience a feeling of well-being, euphoria and in higher doses will hallucinate, paranoia, dry mouth and convulsions may also be experienced. The trip can last up to 8 hours, after that the user becomes tired and quiet, but sleeping is almost impossible. Abuse can cause ulcers, liver and kidney damage. # Footnotes - ↑ Turnbull RS. Benzydamine Hydrochloride (Tantum) in the management of oral inflammatory conditions. Journal of the Canadian Dental Association. 1995 Feb;61(2):127-34. - ↑ Material Safety Data Sheets for Difflam varieties sold in Australia - ↑ Anand JS, Glebocka ML, Korolkiewicz RP. Recreational abuse with benzydamine hydrochloride (tantum rosa). Clinical Toxicology (Philadelphia, Pa). 2007;45(2):198-9. # External links - Medicinenet.com - Net Doctor, UK Template:Deliriants Template:Topical products for joint and muscular pain Template:WikiDoc Sources Template:Jb1	https://www.wikidoc.org/index.php/Benzydamine

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