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2c9249afc2058763bc4f302526fd797b0c55dc47 | wikidoc | Parotid duct | Parotid duct
# Overview
The parotid duct is also known as koslo's duct. Saliva from the parotid gland passes through it to the mouth.
It pierces the buccal fat, buccopharyngeal fascia and buccinator muscle then opens into the vestibule of the mouth opposite the upper 2nd molar tooth. The buccinator acts as a valve which prevents inflation of the duct during blowing. Running along with the duct superiorly is the transverse facial artery and upper buccal nerve, inferiorly is the lower buccal nerve.
# Pathology
Blockage, whether caused by salivary duct stones or external compression, may cause pain and swelling of the parotid gland (parotitis)
# Eponym
It is named after Niels Stensen (1638-1686), a Danish anatomist credited with its discovery.
# Additional images
- Outline of side of face, showing chief surface markings.
- interlobular duct.
- striated duct. | Parotid duct
Template:Infobox Anatomy
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
The parotid duct is also known as koslo's duct. Saliva from the parotid gland passes through it to the mouth.
It pierces the buccal fat, buccopharyngeal fascia and buccinator muscle then opens into the vestibule of the mouth opposite the upper 2nd molar tooth. The buccinator acts as a valve which prevents inflation of the duct during blowing. Running along with the duct superiorly is the transverse facial artery and upper buccal nerve, inferiorly is the lower buccal nerve.
# Pathology
Blockage, whether caused by salivary duct stones or external compression, may cause pain and swelling of the parotid gland (parotitis)
# Eponym
It is named after Niels Stensen (1638-1686), a Danish anatomist credited with its discovery.
# Additional images
- Outline of side of face, showing chief surface markings.
- interlobular duct.
- striated duct.
# External links
- Diagram at MSU
- ent/178 at eMedicine - Parotid duct injuries
- Template:WhoNamedIt
Template:Digestive-stub
Template:Head and neck general
Template:WikiDoc Sources | https://www.wikidoc.org/index.php/Ductus_parotideus | |
5eb04b66963a3cbf9b336a2d07f4f825d5cb318c | wikidoc | Dystroglycan | Dystroglycan
Dystroglycan is a protein that in humans is encoded by the DAG1 gene.
Dystroglycan is one of the dystrophin-associated glycoproteins, which is encoded by a 5.5 kb transcript in Homo sapiens on chromosome 3. There are two exons that are separated by a large intron. The spliced exons code for a protein product that is finally cleaved into two non-covalently associated subunits, (N-terminal) and (C-terminal).
# Function
In skeletal muscle the dystroglycan complex works as a transmembrane linkage between the extracellular matrix and the cytoskeleton. -dystroglycan is extracellular and binds to merosin -2 laminin in the basement membrane, while -dystroglycan is a transmembrane protein and binds to dystrophin, which is a large rod-like cytoskeletal protein, absent in Duchenne muscular dystrophy patients. Dystrophin binds to intracellular actin cables. In this way, the dystroglycan complex, which links the extracellular matrix to the intracellular actin cables, is thought to provide structural integrity in muscle tissues. The dystroglycan complex is also known to serve as an agrin receptor in muscle, where it may regulate agrin-induced acetylcholine receptor clustering at the neuromuscular junction. There is also evidence which suggests the function of dystroglycan as a part of the signal transduction pathway because it is shown that Grb2, a mediator of the Ras-related signal pathway, can interact with the cytoplasmic domain of dystroglycan.
# Expression
Dystroglycan is widely distributed in non-muscle tissues as well as in muscle tissues. During epithelial morphogenesis of kidney, the dystroglycan complex is shown to act as a receptor for the basement membrane. Dystroglycan expression in Mus musculus brain and neural retina has also been reported. However, the physiological role of dystroglycan in non-muscle tissues has remained unclear
# Interactions
Dystroglycan has been shown to interact with FYN, C-src tyrosine kinase, Src, NCK1, Grb2, Caveolin 3 and SHC1. | Dystroglycan
Dystroglycan is a protein that in humans is encoded by the DAG1 gene.[1][2][3]
Dystroglycan is one of the dystrophin-associated glycoproteins, which is encoded by a 5.5 kb transcript in Homo sapiens on chromosome 3.[4] There are two exons that are separated by a large intron. The spliced exons code for a protein product that is finally cleaved into two non-covalently associated subunits, [alpha] (N-terminal) and [beta] (C-terminal).
# Function
In skeletal muscle the dystroglycan complex works as a transmembrane linkage between the extracellular matrix and the cytoskeleton. [alpha]-dystroglycan is extracellular and binds to merosin [alpha]-2 laminin in the basement membrane, while [beta]-dystroglycan is a transmembrane protein and binds to dystrophin, which is a large rod-like cytoskeletal protein, absent in Duchenne muscular dystrophy patients. Dystrophin binds to intracellular actin cables. In this way, the dystroglycan complex, which links the extracellular matrix to the intracellular actin cables, is thought to provide structural integrity in muscle tissues. The dystroglycan complex is also known to serve as an agrin receptor in muscle, where it may regulate agrin-induced acetylcholine receptor clustering at the neuromuscular junction. There is also evidence which suggests the function of dystroglycan as a part of the signal transduction pathway because it is shown that Grb2, a mediator of the Ras-related signal pathway, can interact with the cytoplasmic domain of dystroglycan.
# Expression
Dystroglycan is widely distributed in non-muscle tissues as well as in muscle tissues. During epithelial morphogenesis of kidney, the dystroglycan complex is shown to act as a receptor for the basement membrane. Dystroglycan expression in Mus musculus brain and neural retina has also been reported. However, the physiological role of dystroglycan in non-muscle tissues has remained unclear
# Interactions
Dystroglycan has been shown to interact with FYN,[5] C-src tyrosine kinase,[5] Src,[5] NCK1,[5] Grb2,[6] Caveolin 3[7] and SHC1.[5] | https://www.wikidoc.org/index.php/Dystroglycan | |
6e01bcd97e67b49d9da37055c00add5bd62b7664 | wikidoc | ECG Criteria | ECG Criteria
# Left Axis Deviation
## Criteria
- QRS axis between -30º and -90º
- Dominant S wave (S > R) in lead II and aVF
## Causes
- Left bundle branch block
- Left anterior fascicular block
- Left ventricular hypertrophy
- Inferior myocardial infarction
- Ostium primum atrial septal defect
- Tricuspid atresia
- WPW syndrome with right-sided accessory pathway
- Ventricular pacing
- Ventricular ectopy
- Hyperkalemia
- Mechanical shifts, such as expiration, high diaphragm (pregnancy, ascites, abdominal tumor)
- Normal variation
# Right Axis Deviation
## Criteria
- QRS axis between +90º and +180º
- Dominant S wave (S > R) in lead I and aVL
## Causes
- Right ventricular strain
- Cor pulmonale as in COPD
- Pulmonary Embolism
- Right ventricular hypertrophy
- Secundum ASD
- Lateral wall myocardial infarction
- Left posterior fascicular block
- Ventricular ectopy
- WPW syndrome with left-sided accessory pathway
- Mechanical shifts, such as inspiration and emphysema
- Normal variation in children or thin adults with a horizontally oriented heart
- Dextrocardia
- Pectus excavatum
- Reversed arm leads
# Northwest Axis (No Man's Land)
## Criteria
- QRS axis between -90º and -180º
## Causes
- Lead misplacement
- Severe right ventricular hypertrophy
- Artificial pacemaker
- Ventricular tachycardia
- Ventricular ectopy
- Accelerated idioventricular rhythm
- Hyperkalemia
- Emphysema
# Left Anterior Fascicular Block
## Criteria
- Frontal plane axis between -45° and -90°.
- qR pattern in lead aVL.
- R peak time ≥ 45 ms in lead aVL.
- QRS duration < 120 ms.
# Left Posterior Fascicular Block
## Criteria
- Frontal plane axis between +90° and +180°.
- Owing to the more rightward axis in children up to 16 years of age, this criterion should only be applied to them when a distinct rightward change in axis is documented.
- rS pattern in leads I and aVL.
- qR pattern in leads III and aVF.
- QRS duration < 120 ms.
# Left Bundle Branch Block
## Complete LBBB Criteria
- QRS duration ≥ 120 ms (≥ 100 ms in children 4 to 16 years of age; ≥ 90 ms in children < 4 years of age).
- Broad notched or slurred R wave in leads I, aVL, V5, and V6 and an occasional RS pattern in V5 and V6 attributed to displaced transition of QRS complex.
- Absence of q waves in leads I, V5, and V6 (or a narrow q wave in aVL in the absence of myocardial pathology).
- R peak time ≥ 60 ms in leads V5 and V6 but normal in leads V1, V2, and V3 (when small initial r waves can be discerned).
- ST and T waves opposite in direction of QRS deflections.
## Incomplete LBBB Criteria
- QRS duration 110 - 120 ms (90 - 100 ms in children 4 to 16 years of age; 80 - 90 ms in children < 4 years of age).
- Presence of left ventricular hypertrophy pattern.
- R peak time ≥ 60 ms in leads V4, V5, and V6.
- Absence of q wave in leads I, V5, and V6.
# Right Bundle Branch Block
## Complete RBBB Criteria
- QRS duration ≥ 120 ms (≥ 100 ms in children 4 to 16 years of age; ≥ 90 ms in children < 4 years of age).
- rsr', rsR', or rSR' in leads V1 or V2.
- The R' or r' deflection is usually wider than the initial R wave.
- In a minority of patients, a wide and often notched R wave pattern may be seen in lead V1 and/or V2.
- S wave of greater duration than R wave or ≥ 40 ms in leads I and V6.
- R peak time ≥ 50 ms in lead V1 but normal in leads V5 and V6.
## Incomplete RBBB Criteria
- QRS duration 110 - 120 ms (90 - 100 ms in children 4 to 16 years of age; 80 - 90 ms in children < 4 years of age).
- rsr', rsR', or rSR' in leads V1 or V2.
- S wave of greater duration than R wave or ≥ 40 ms in leads I and V6.
- R peak time ≥ 50 ms in lead V1 but normal in leads V5 and V6.
# Nonspecific or Unspecified Intraventricular Conduction Disturbance
## Criteria
- QRS duration ≥ 110 ms (≥ 90 ms in children 8 to 16 years of age; ≥ 80 ms in children < 8 years of age).
- Absence of criteria for LBBB or BBBB.
# Ventricular Preexcitation of Wolff-Parkinson-White Type
## Criteria
- PR interval < 120 ms during sinus rhythm assuming no intra-atrial or interatrial conduction block (or < 90 ms in children).
- Delta wave: slurring of initial portion of the QRS complex, which either interrupts the P wave or arises immediately after its termination.
- QRS duration > 120 ms (or > 90 ms in children).
- Secondary ST and T wave changes.
# Left Atrial Enlargement
## Criteria
- P wave duration ≥ 110 ms (sensitivity 62%; specificity 86%)
- Negative phase of P wave in V1 ≥ 40 ms (sensitivity 20%; specificity 98%)
- P terminal force in V1 ≥ 40 msec-mm (sensitivity 56%; specificity 95%)
- Negative phase of P wave in V1 > 1 mm
- Notched P wave with interpeak interval > 40 ms
- P wave/PR duration > 1.6
# Right Atrial Enlargement
## Criteria
- A tall upright P wave in lead II (> 2.5 mm), often with a peaked or pointed appearance.
- Prominent initial positivity of the P wave in V1 or V2 (≥ 1.5 mm).
# Left Ventricular Hypertrophy
## Criteria
- Romhilt-Estes criteria (4 points = probable, 5 points = definite):
- Largest R or S in limb leads ≥ 20 mm or S in V1 or V2 ≥ 30 mm or R in V5 or V6 ≥ 30 mm (3 points)
- ST displacement opposite to QRS deflection: without digoxin (3 points); with digoxin (1 point)
- LAA (3 points)
- LAD (2 points)
- QRS duration ≥ 90 ms (1 point)
- Intrinsicoid deflection (QRS onset to peak of R) in V5 or V6 ≥ 50 ms (1 point)
- Sokolow-Lyon criteria:
- S in V1 + R in V5 or V6 ≥35 mm
- R in aVL ≥11 mm
- Cornell criteria:
- R in aVL + S in V3 >28 mm in men or >20 mm in women
- If LAD or LAFB, S in lead III + max (R+S) in precordial leads ≥ 30 mm
# Right Ventricular Hypertrophy
## Criteria
- Increased R/S ratio in V1 (> 1)
- Tall R wave in V1 (> 6 mm)
- Deep S wave in V5 (> 10 mm) or V6 (> 3 mm)
- Drop in R/S ratio across precordium (R/S ratio in V1 > R/S ratio in V3 or V4)
# Biventricular Hypertrophy
## Criteria
- ECG criteria for LVH plus the presence of:
- Prominent S waves in V5 or V6
- Right axis deviation
- Tall biphasic R/S complexes
- Right atrial enlargement
# Pathologic Q Wave
# QT Prolongation
## Criteria
- QTc > 450 ms in males or > 460 ms in females.
## Causes
- Congenital
- Congenital long QT syndromes (K, Na, Ca channelopathies)
- Medications
- Antiarrhythmics (amiodarone, disopyramide, dronedarone, flecainide, sotalol)
- Antibiotics such as macrolides (erythromycin, clarithromycin, azithromycin) and quinolones (levofloxacin, moxifloxacin)
- Antifungals (fluconazole, ketoconazole)
- Antimotility and antiemetic agents (domperidone, granisetron, ondansetron)
- Antimalarials (quinine, chloroquine)
- Antihistamines (hydroxyzine)
- Antipsychotics (chlorpromazine, clozapine, droperidol, fluphenazine, haloperidol, olanzapine, pimozide, paliperidone, quetiapine, risperidone)
- Antidepressants (amitriptyline, citalopram, escitalopram, dosulepin, doxepin, fluoxetine, imipramine, lofepramine)
- Miscellaneous (methadone, foscarnet, sorafenib, sunitinib)
- Autonomic dysfunction
- Intracerebral hemorrhage
- Stroke
- Carotid endarterectomy
- Electrolyte imbalances
- Hypocalcemia
- Hypokalemia
- Hypomagnesemia
- Miscellaneous
- Myocardial ischemia
- Cardiomyopathy
- Bradycardia
- High-grade AVB
- Hypothyroidism
- Hypothermia
- Bundle branch block
# Poor R Wave Progression
## Criteria
- Loss of anterior forces without frank Q waves in precordial leads (decrease in R wave amplitude from V1 to V2, or V2 to V3, or V3 to V4)
- R wave in V3 ≤ 3 mm
## Causes
- Prior anterior myocardial infarction
- Ventricular hypertrophy
- Left bundle branch block
- WPW syndrome
- Cardiomyopathy
- Emphysema
- Pneumothorax
- Clockwise rotation of the heart
- Lead misplacement in a cranial direction
- Normal variant
# ST Elevation
# ST Depression
# T Wave Inversion
# Low Voltage | ECG Criteria
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Left Axis Deviation
## Criteria
- QRS axis between -30º and -90º
- Dominant S wave (S > R) in lead II and aVF
## Causes
- Left bundle branch block
- Left anterior fascicular block
- Left ventricular hypertrophy
- Inferior myocardial infarction
- Ostium primum atrial septal defect
- Tricuspid atresia
- WPW syndrome with right-sided accessory pathway
- Ventricular pacing
- Ventricular ectopy
- Hyperkalemia
- Mechanical shifts, such as expiration, high diaphragm (pregnancy, ascites, abdominal tumor)
- Normal variation
# Right Axis Deviation
## Criteria
- QRS axis between +90º and +180º
- Dominant S wave (S > R) in lead I and aVL
## Causes
- Right ventricular strain
- Cor pulmonale as in COPD
- Pulmonary Embolism
- Right ventricular hypertrophy
- Secundum ASD
- Lateral wall myocardial infarction
- Left posterior fascicular block
- Ventricular ectopy
- WPW syndrome with left-sided accessory pathway
- Mechanical shifts, such as inspiration and emphysema
- Normal variation in children or thin adults with a horizontally oriented heart
- Dextrocardia
- Pectus excavatum
- Reversed arm leads
# Northwest Axis (No Man's Land)
## Criteria
- QRS axis between -90º and -180º
## Causes
- Lead misplacement
- Severe right ventricular hypertrophy
- Artificial pacemaker
- Ventricular tachycardia
- Ventricular ectopy
- Accelerated idioventricular rhythm
- Hyperkalemia
- Emphysema
# Left Anterior Fascicular Block
## Criteria
- Frontal plane axis between -45° and -90°.
- qR pattern in lead aVL.
- R peak time ≥ 45 ms in lead aVL.
- QRS duration < 120 ms.[1]
# Left Posterior Fascicular Block
## Criteria
- Frontal plane axis between +90° and +180°.
- Owing to the more rightward axis in children up to 16 years of age, this criterion should only be applied to them when a distinct rightward change in axis is documented.
- rS pattern in leads I and aVL.
- qR pattern in leads III and aVF.
- QRS duration < 120 ms.[2]
# Left Bundle Branch Block
## Complete LBBB Criteria
- QRS duration ≥ 120 ms (≥ 100 ms in children 4 to 16 years of age; ≥ 90 ms in children < 4 years of age).
- Broad notched or slurred R wave in leads I, aVL, V5, and V6 and an occasional RS pattern in V5 and V6 attributed to displaced transition of QRS complex.
- Absence of q waves in leads I, V5, and V6 (or a narrow q wave in aVL in the absence of myocardial pathology).
- R peak time ≥ 60 ms in leads V5 and V6 but normal in leads V1, V2, and V3 (when small initial r waves can be discerned).
- ST and T waves opposite in direction of QRS deflections.[3]
## Incomplete LBBB Criteria
- QRS duration 110 - 120 ms (90 - 100 ms in children 4 to 16 years of age; 80 - 90 ms in children < 4 years of age).
- Presence of left ventricular hypertrophy pattern.
- R peak time ≥ 60 ms in leads V4, V5, and V6.
- Absence of q wave in leads I, V5, and V6.[4]
# Right Bundle Branch Block
## Complete RBBB Criteria
- QRS duration ≥ 120 ms (≥ 100 ms in children 4 to 16 years of age; ≥ 90 ms in children < 4 years of age).
- rsr', rsR', or rSR' in leads V1 or V2.
- The R' or r' deflection is usually wider than the initial R wave.
- In a minority of patients, a wide and often notched R wave pattern may be seen in lead V1 and/or V2.
- S wave of greater duration than R wave or ≥ 40 ms in leads I and V6.
- R peak time ≥ 50 ms in lead V1 but normal in leads V5 and V6.[5]
## Incomplete RBBB Criteria
- QRS duration 110 - 120 ms (90 - 100 ms in children 4 to 16 years of age; 80 - 90 ms in children < 4 years of age).
- rsr', rsR', or rSR' in leads V1 or V2.
- S wave of greater duration than R wave or ≥ 40 ms in leads I and V6.
- R peak time ≥ 50 ms in lead V1 but normal in leads V5 and V6.[6]
# Nonspecific or Unspecified Intraventricular Conduction Disturbance
## Criteria
- QRS duration ≥ 110 ms (≥ 90 ms in children 8 to 16 years of age; ≥ 80 ms in children < 8 years of age).
- Absence of criteria for LBBB or BBBB.[7]
# Ventricular Preexcitation of Wolff-Parkinson-White Type
## Criteria
- PR interval < 120 ms during sinus rhythm assuming no intra-atrial or interatrial conduction block (or < 90 ms in children).
- Delta wave: slurring of initial portion of the QRS complex, which either interrupts the P wave or arises immediately after its termination.
- QRS duration > 120 ms (or > 90 ms in children).
- Secondary ST and T wave changes.[8]
# Left Atrial Enlargement
## Criteria
- P wave duration ≥ 110 ms (sensitivity 62%; specificity 86%)[9]
- Negative phase of P wave in V1 ≥ 40 ms (sensitivity 20%; specificity 98%)
- P terminal force in V1 ≥ 40 msec-mm (sensitivity 56%; specificity 95%)
- Negative phase of P wave in V1 > 1 mm
- Notched P wave with interpeak interval > 40 ms
- P wave/PR duration > 1.6
# Right Atrial Enlargement
## Criteria
- A tall upright P wave in lead II (> 2.5 mm), often with a peaked or pointed appearance.
- Prominent initial positivity of the P wave in V1 or V2 (≥ 1.5 mm).
# Left Ventricular Hypertrophy
## Criteria
- Romhilt-Estes criteria (4 points = probable, 5 points = definite):
- Largest R or S in limb leads ≥ 20 mm or S in V1 or V2 ≥ 30 mm or R in V5 or V6 ≥ 30 mm (3 points)
- ST displacement opposite to QRS deflection: without digoxin (3 points); with digoxin (1 point)
- LAA (3 points)
- LAD (2 points)
- QRS duration ≥ 90 ms (1 point)
- Intrinsicoid deflection (QRS onset to peak of R) in V5 or V6 ≥ 50 ms (1 point)
- Sokolow-Lyon criteria:
- S in V1 + R in V5 or V6 ≥35 mm
- R in aVL ≥11 mm
- Cornell criteria:
- R in aVL + S in V3 >28 mm in men or >20 mm in women
- If LAD or LAFB, S in lead III + max (R+S) in precordial leads ≥ 30 mm
# Right Ventricular Hypertrophy
## Criteria
- Increased R/S ratio in V1 (> 1)
- Tall R wave in V1 (> 6 mm)
- Deep S wave in V5 (> 10 mm) or V6 (> 3 mm)
- Drop in R/S ratio across precordium (R/S ratio in V1 > R/S ratio in V3 or V4)
# Biventricular Hypertrophy
## Criteria
- ECG criteria for LVH plus the presence of:
- Prominent S waves in V5 or V6
- Right axis deviation
- Tall biphasic R/S complexes
- Right atrial enlargement
# Pathologic Q Wave
# QT Prolongation
## Criteria
- QTc > 450 ms in males or > 460 ms in females.[10][11]
## Causes
- Congenital
- Congenital long QT syndromes (K, Na, Ca channelopathies)
- Medications
- Antiarrhythmics (amiodarone, disopyramide, dronedarone, flecainide, sotalol)
- Antibiotics such as macrolides (erythromycin, clarithromycin, azithromycin) and quinolones (levofloxacin, moxifloxacin)
- Antifungals (fluconazole, ketoconazole)
- Antimotility and antiemetic agents (domperidone, granisetron, ondansetron)
- Antimalarials (quinine, chloroquine)
- Antihistamines (hydroxyzine)
- Antipsychotics (chlorpromazine, clozapine, droperidol, fluphenazine, haloperidol, olanzapine, pimozide, paliperidone, quetiapine, risperidone)
- Antidepressants (amitriptyline, citalopram, escitalopram, dosulepin, doxepin, fluoxetine, imipramine, lofepramine)
- Miscellaneous (methadone, foscarnet, sorafenib, sunitinib)
- Autonomic dysfunction
- Intracerebral hemorrhage
- Stroke
- Carotid endarterectomy
- Electrolyte imbalances
- Hypocalcemia
- Hypokalemia
- Hypomagnesemia
- Miscellaneous
- Myocardial ischemia
- Cardiomyopathy
- Bradycardia
- High-grade AVB
- Hypothyroidism
- Hypothermia
- Bundle branch block
# Poor R Wave Progression
## Criteria
- Loss of anterior forces without frank Q waves in precordial leads (decrease in R wave amplitude from V1 to V2, or V2 to V3, or V3 to V4)
- R wave in V3 ≤ 3 mm
## Causes
- Prior anterior myocardial infarction
- Ventricular hypertrophy
- Left bundle branch block
- WPW syndrome
- Cardiomyopathy
- Emphysema
- Pneumothorax
- Clockwise rotation of the heart
- Lead misplacement in a cranial direction
- Normal variant
# ST Elevation
# ST Depression
# T Wave Inversion
# Low Voltage | https://www.wikidoc.org/index.php/ECG_Criteria | |
37fd796c446b8b4e692f727c524302d594dc2bc1 | wikidoc | Endothelin 1 | Endothelin 1
Endothelin 1, also known as EDN1, is a human gene and the corresponding peptide, one of three isoforms of human endothelin.
# Further reading
- Bruno CM, Neri S, Di Prima P, Sciacca C (2003). "Pathophysiology of endothelin and medical emergencies". Panminerva medica. 45 (2): 151–4. PMID 12855940.CS1 maint: Multiple names: authors list (link) .mw-parser-output cite.citation{font-style:inherit}.mw-parser-output q{quotes:"\"""\"""'""'"}.mw-parser-output code.cs1-code{color:inherit;background:inherit;border:inherit;padding:inherit}.mw-parser-output .cs1-lock-free a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-limited a,.mw-parser-output .cs1-lock-registration a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-subscription a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration{color:#555}.mw-parser-output .cs1-subscription span,.mw-parser-output .cs1-registration span{border-bottom:1px dotted;cursor:help}.mw-parser-output .cs1-hidden-error{display:none;font-size:100%}.mw-parser-output .cs1-visible-error{display:none;font-size:100%}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration,.mw-parser-output .cs1-format{font-size:95%}.mw-parser-output .cs1-kern-left,.mw-parser-output .cs1-kern-wl-left{padding-left:0.2em}.mw-parser-output .cs1-kern-right,.mw-parser-output .cs1-kern-wl-right{padding-right:0.2em}
- Doggrell SA (2006). "The endothelin system and its role in acute myocardial infarction". Expert Opin. Ther. Targets. 8 (3): 191–201. doi:10.1517/14728222.8.3.191. PMID 15161426.
- Beghetti M, Black SM, Fineman JR (2005). "Endothelin-1 in congenital heart disease". Pediatr. Res. 57 (5 Pt 2): 16R–20R. doi:10.1203/01.PDR.0000160447.83332.13. PMID 15817494.CS1 maint: Multiple names: authors list (link)
- Cazaubon S, Deshayes F, Couraud PO, Nahmias C (2006). "". Med Sci (Paris). 22 (4): 416–22. PMID 16597412.CS1 maint: Multiple names: authors list (link)
- Ariza AC, Bobadilla NA, Halhali A (2007). "". Rev. Invest. Clin. 59 (1): 48–56. PMID 17569300.CS1 maint: Multiple names: authors list (link) | Endothelin 1
Endothelin 1, also known as EDN1, is a human gene and the corresponding peptide, one of three isoforms of human endothelin.
# Further reading
- Bruno CM, Neri S, Di Prima P, Sciacca C (2003). "Pathophysiology of endothelin and medical emergencies". Panminerva medica. 45 (2): 151–4. PMID 12855940.CS1 maint: Multiple names: authors list (link) .mw-parser-output cite.citation{font-style:inherit}.mw-parser-output q{quotes:"\"""\"""'""'"}.mw-parser-output code.cs1-code{color:inherit;background:inherit;border:inherit;padding:inherit}.mw-parser-output .cs1-lock-free a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/6/65/Lock-green.svg/9px-Lock-green.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-limited a,.mw-parser-output .cs1-lock-registration a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/d/d6/Lock-gray-alt-2.svg/9px-Lock-gray-alt-2.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-subscription a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/a/aa/Lock-red-alt-2.svg/9px-Lock-red-alt-2.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration{color:#555}.mw-parser-output .cs1-subscription span,.mw-parser-output .cs1-registration span{border-bottom:1px dotted;cursor:help}.mw-parser-output .cs1-hidden-error{display:none;font-size:100%}.mw-parser-output .cs1-visible-error{display:none;font-size:100%}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration,.mw-parser-output .cs1-format{font-size:95%}.mw-parser-output .cs1-kern-left,.mw-parser-output .cs1-kern-wl-left{padding-left:0.2em}.mw-parser-output .cs1-kern-right,.mw-parser-output .cs1-kern-wl-right{padding-right:0.2em}
- Doggrell SA (2006). "The endothelin system and its role in acute myocardial infarction". Expert Opin. Ther. Targets. 8 (3): 191–201. doi:10.1517/14728222.8.3.191. PMID 15161426.
- Beghetti M, Black SM, Fineman JR (2005). "Endothelin-1 in congenital heart disease". Pediatr. Res. 57 (5 Pt 2): 16R–20R. doi:10.1203/01.PDR.0000160447.83332.13. PMID 15817494.CS1 maint: Multiple names: authors list (link)
- Cazaubon S, Deshayes F, Couraud PO, Nahmias C (2006). "[Endothelin-1, angiotensin II and cancer]". Med Sci (Paris). 22 (4): 416–22. PMID 16597412.CS1 maint: Multiple names: authors list (link)
- Ariza AC, Bobadilla NA, Halhali A (2007). "[Endothelin 1 and angiotensin II in preeeclampsia]". Rev. Invest. Clin. 59 (1): 48–56. PMID 17569300.CS1 maint: Multiple names: authors list (link)
Template:WH
Template:WS | https://www.wikidoc.org/index.php/EDN1 | |
75cfa467277c3f5dc7b85119be2335f476cbc364 | wikidoc | EEM syndrome | EEM syndrome
EEM syndrome (or Ectodermal dysplasia, Ectrodactyly and Macular dystrophy syndrome) is an autosomal recessive congenital malformation disorder affecting tissues associated with the ectoderm (skin, hair, nails, teeth), and also the hands, feet and eyes.
# Presentation
EEM syndrome presents a combination of prominent symptoms and features. These include: ectodermal dysplasia (systemic malformations of ectodermal tissues), ectrodactyly ("lobster claw" deformity in the hands and feet), macular dystrophy (a progressive eye disease), syndactyly (webbed fingers or toes), hypotrichosis (a type of hair-loss), and dental abnormalities (hypodontia).
# Pathophysiology
EEM syndrome is caused by mutations in the P-cadherin gene (CDH3). Distinct mutations in CDH3 (located on human chromosome 16) are responsible for the macular dystrophy and spectrum of malformations found in EEM syndrome, due in part to developmental errors caused by the resulting inability of CDH3 to respond correctly to the P-cadherin transcription factor p63.
The gene for p63 (TP73L, found on human chromosome 3) may also play a role in EEM syndrome. Mutations in this gene are associated with the symptoms of EEM and similar disorders, particularly ectrodactyly.
EEM syndrome is an autosomal recessive disorder, which means the defective gene is located on an autosome, and two copies of the defective gene - one from each parent - are required to inherit the disorder. The parents of an individual with an autosomal recessive disorder both carry one copy of the defective gene, but usually do not experience any signs or symptoms of the disorder. | EEM syndrome
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
EEM syndrome (or Ectodermal dysplasia, Ectrodactyly and Macular dystrophy syndrome)[1] is an autosomal recessive[2] congenital malformation disorder affecting tissues associated with the ectoderm (skin, hair, nails, teeth), and also the hands, feet and eyes.[1][3]
# Presentation
EEM syndrome presents a combination of prominent symptoms and features. These include: ectodermal dysplasia (systemic malformations of ectodermal tissues),[1] ectrodactyly ("lobster claw" deformity in the hands and feet),[3] macular dystrophy (a progressive eye disease),[3][2] syndactyly (webbed fingers or toes),[3] hypotrichosis (a type of hair-loss),[4] and dental abnormalities (hypodontia).[2]
# Pathophysiology
EEM syndrome is caused by mutations in the P-cadherin gene (CDH3).[5] Distinct mutations in CDH3 (located on human chromosome 16) are responsible for the macular dystrophy and spectrum of malformations found in EEM syndrome,[5] due in part to developmental errors caused by the resulting inability of CDH3 to respond correctly to the P-cadherin transcription factor p63.[6]
The gene for p63 (TP73L, found on human chromosome 3) may also play a role in EEM syndrome.[6] Mutations in this gene are associated with the symptoms of EEM and similar disorders, particularly ectrodactyly.[7]
EEM syndrome is an autosomal recessive disorder,[2] which means the defective gene is located on an autosome, and two copies of the defective gene - one from each parent - are required to inherit the disorder. The parents of an individual with an autosomal recessive disorder both carry one copy of the defective gene, but usually do not experience any signs or symptoms of the disorder. | https://www.wikidoc.org/index.php/EEM_syndrome | |
97877907a45999af3c1820ad88f2e2e0de7366d4 | wikidoc | ERCC8 (gene) | ERCC8 (gene)
DNA excision repair protein ERCC-8 is a protein that in humans is encoded by the ERCC8 gene.
This gene encodes a WD repeat protein, which interacts with the Cockayne syndrome type B (CSB) and p44 proteins, the latter being a subunit of the RNA polymerase II transcription factor II H. Mutations in this gene have been identified in patients with the hereditary disease Cockayne syndrome (CS). CS is an accelerated aging disorder characterized by photosensitivity, impaired development and multi-system progressive degeneration. The CS cells are abnormally sensitive to ultraviolet radiation and are defective in the repair of transcriptionally active genes. Multiple alternatively spliced transcript variants encoding different isoforms have been found for this gene.
CS arises from germline mutations in either of two genes CSA(ERCC8) or CSB(ERCC6). CSA mutations generally give rise to a more moderate form of CS than CSB mutations. Mutations in the CSA gene account for about 20% of CS cases.
# Function
CSA and CSB proteins are thought to function in transcription and DNA repair, most notably in transcription-coupled nucleotide excision repair. CSA and CSB-deficient cells exhibit a lack of preferential repair of UV-induced cyclobutane pyrimidine dimers in actively transcribed genes, consistent with a failed transcription coupled nucleotide excision repair response. Within the cell, the CSA protein localizes to sites of DNA damage, particularly inter-strand cross-links, double-strand breaks and some mono-adducts.
# Interactions
ERCC8 (gene) has been shown to interact with XAB2. | ERCC8 (gene)
DNA excision repair protein ERCC-8 is a protein that in humans is encoded by the ERCC8 gene.[1][2]
This gene encodes a WD repeat protein, which interacts with the Cockayne syndrome type B (CSB) and p44 proteins, the latter being a subunit of the RNA polymerase II transcription factor II H. Mutations in this gene have been identified in patients with the hereditary disease Cockayne syndrome (CS). CS is an accelerated aging disorder characterized by photosensitivity, impaired development and multi-system progressive degeneration. The CS cells are abnormally sensitive to ultraviolet radiation and are defective in the repair of transcriptionally active genes. Multiple alternatively spliced transcript variants encoding different isoforms have been found for this gene.[2]
CS arises from germline mutations in either of two genes CSA(ERCC8) or CSB(ERCC6). CSA mutations generally give rise to a more moderate form of CS than CSB mutations.[3] Mutations in the CSA gene account for about 20% of CS cases.[4]
# Function
CSA and CSB proteins are thought to function in transcription and DNA repair, most notably in transcription-coupled nucleotide excision repair. CSA and CSB-deficient cells exhibit a lack of preferential repair of UV-induced cyclobutane pyrimidine dimers in actively transcribed genes, consistent with a failed transcription coupled nucleotide excision repair response.[5] Within the cell, the CSA protein localizes to sites of DNA damage, particularly inter-strand cross-links, double-strand breaks and some mono-adducts.[3]
# Interactions
ERCC8 (gene) has been shown to interact with XAB2.[6] | https://www.wikidoc.org/index.php/ERCC8_(gene) | |
7f94ffc07b6c1b007ae9ffc1aae2c0ddcceee535 | wikidoc | ESPA College | ESPA College
ESPA College is part of European Services for People with Autism, which provides various services for people on the autistic spectrum. However, the college management team is based in a separate building to that of the company, clearly established that they are in many ways a differing service. It educates young people aged 16-18. It was recognised in a 2002 OFSTED report as providing a "good, targeted curriculum for the autistic".
# The College
Opened in 1992, the college has provided a unique educational experience for learners. All learners follow a tailor made curriculum, which is a programme of study and support specifically designed to meet the social, educational and emotional needs of the young adults that study there. Every learner has an Individual Learning Plan specific to their needs, which includes targets that learners refer to during their Record Of Achievement and Development (ROAD) target system; this is used twice per week, once to set the target, and once to review.
ESPA aims to provide learners with Asperger's Syndrome and other related disorders with an inclusive education free from the bullying and nastiness that can surround learners with AS in a mainstream environment.
The college is managed by a lead team of three people: Chris Pickup is the Principal, Sara Everett is the Deputy Principal, and Pauline Shannon is the College Manager. In addition to those, the Deputy Chief Executive of ESPA, Steve Levy, also stays very involved with the goings-on of the college.
Each site has its own management structure which will include a site co-ordinator & duty management team.
## One College, Multiple Sites
ESPA College is split into five sites, named Ashleigh (a Hall of Residence), North Rye, South Hill, Tasker & Westfield (a Hall of Residence). South Hill is located close to Grangetown, whilst Westfield & Tasker are located just outside of Sunderland City Centre. North Rye is located in Kenton, with Ashleigh being near to Fawdon. | ESPA College
Template:High School Infobox
ESPA College is part of European Services for People with Autism, which provides various services for people on the autistic spectrum. However, the college management team is based in a separate building to that of the company, clearly established that they are in many ways a differing service. It educates young people aged 16-18. It was recognised in a 2002 OFSTED report as providing a "good, targeted curriculum for the autistic".[1]
# The College
Opened in 1992, the college has provided a unique educational experience for learners. All learners follow a tailor made curriculum, which is a programme of study and support specifically designed to meet the social, educational and emotional needs of the young adults that study there. Every learner has an Individual Learning Plan specific to their needs, which includes targets that learners refer to during their Record Of Achievement and Development (ROAD) target system; this is used twice per week, once to set the target, and once to review.
ESPA aims to provide learners with Asperger's Syndrome and other related disorders with an inclusive education free from the bullying and nastiness that can surround learners with AS in a mainstream environment.
The college is managed by a lead team of three people: Chris Pickup is the Principal, Sara Everett is the Deputy Principal, and Pauline Shannon is the College Manager. In addition to those, the Deputy Chief Executive of ESPA, Steve Levy, also stays very involved with the goings-on of the college.
Each site has its own management structure which will include a site co-ordinator & duty management team.
## One College, Multiple Sites
ESPA College is split into five sites, named Ashleigh (a Hall of Residence), North Rye, South Hill, Tasker & Westfield (a Hall of Residence). South Hill is located close to Grangetown, whilst Westfield & Tasker are located just outside of Sunderland City Centre. North Rye is located in Kenton, with Ashleigh being near to Fawdon. | https://www.wikidoc.org/index.php/ESPA_College | |
cbf7e6fd3002c87e17ae00eee3f3f6ea37d2fb51 | wikidoc | Ear clearing | Ear clearing
# Overview
Ear clearing or clearing the ears is any of various maneuvers used to make the pressure in the middle ear become the same as the outside pressure, by letting air enter along the Eustachian tubes, as this does not always happen automatically when the pressure in the middle ear is lower. This need usually arises in scuba diving, but can arise in fast descent in an aircraft or a mine cage, on being put into pressure in a caisson or similar.
# Methods include:
- Yawning.
- Swallowing.
- Pinching the nose and closing the mouth and trying to breathe out through the nose. This is called the valsalva maneuver. If the hand cannot reach the nose, it is possible to learn to pinch the nose shut by the action of two small face muscles called compressor naris.
This pressure difference, if not released, can cause:
- Burst eardrum. This damages hearing, and cold water in the middle ear chills the inner ear, causing vertigo.
- Damage to other body air spaces, such as the paranasal sinuses. This can also be caused by damaged sinus ducts.
Do not dive if a eustachian tube is congested or blocked, e.g. with the common cold.
Divers should get proper diver training in clearing the ears.
# Precautions:
- Make sure that the diving suit hood does not make an airtight seal over the outside ear hole.
- Never wear earplugs. | Ear clearing
# Overview
Ear clearing or clearing the ears is any of various maneuvers used to make the pressure in the middle ear become the same as the outside pressure, by letting air enter along the Eustachian tubes, as this does not always happen automatically when the pressure in the middle ear is lower. This need usually arises in scuba diving, but can arise in fast descent in an aircraft or a mine cage, on being put into pressure in a caisson or similar.
# Methods include:
- Yawning.
- Swallowing.
- Pinching the nose and closing the mouth and trying to breathe out through the nose. This is called the valsalva maneuver. If the hand cannot reach the nose, it is possible to learn to pinch the nose shut by the action of two small face muscles called compressor naris.
This pressure difference, if not released, can cause:
- Burst eardrum. This damages hearing, and cold water in the middle ear chills the inner ear, causing vertigo.
- Damage to other body air spaces, such as the paranasal sinuses. This can also be caused by damaged sinus ducts.
Do not dive if a eustachian tube is congested or blocked, e.g. with the common cold.
Divers should get proper diver training in clearing the ears.
# Precautions:
- Make sure that the diving suit hood does not make an airtight seal over the outside ear hole.
- Never wear earplugs.
Template:WikiDoc Sources | https://www.wikidoc.org/index.php/Ear_clearing | |
93b399faec3a778cac8bb798d2e3b6249b74d32b | wikidoc | Ed Rosenthal | Ed Rosenthal
Ed Rosenthal (born Bronx, New York, 1944) is a California horticulturist, author, publisher, and Cannabis grower known for his advocacy for the legalization of marijuana (cannabis as a drug) use. He served as a columnist for High Times Magazine during the 80's and 90's. He was arrested in 2002 for cultivation of cannabis by federal authorities, who do not recognize the authority of states to regulate the use of medical marijuana. He was convicted in Federal Court, but the conviction was overturned on appeal. Rosenthal was subsequently convicted again, but was not re-sentenced, since his original sentence had been completed. Rosenthal briefly attended Youngstown State University in Youngstown, Ohio. He has two children, Nick and Justine.
Rosenthal has been active in promoting and developing policies of civil regulation for medicinal marijuana. With the passage of California's pioneering Proposition 215 in 1996, which authorizes medicinal use of marijuana, he worked with the state and local governments to implement the delivery of pharmaceutical grade cannabis to patients with a doctor's prescription to use marijuana.
# Legal battles
In 2002, federal agents arrested Rosenthal, who previously had been deputized by the City of Oakland to grow marijuana for medical use. He was convicted, and in a surprise setback for the federal government, was sentenced by U.S. District Court Judge Charles Breyer to only one day in prison; time already served. In 2006 the 9th Circuit Appeals Court subsequently overturned Rosenthal's conviction. Months later the U.S. Attorney's office re-indicted him. Although, the judge has promised to sentence Rosenthal to no additional prison time, a new trial commenced on 14 May 2007.
On May 31 2007, it was announced that Rosenthal had been convicted again on three of the five charges against him: one conspiracy count; one count of cultivation, intending to distribute and distributing marijuana; and one count of using a commercial building as a site for growing and distributing marijuana. He was acquitted of growing and distributing marijuana at the Harm Reduction Center medical-marijuana club in San Francisco. The jury deadlocked on whether he had conspired to grow and distribute marijuana at the Harm Reduction Center. Judge Breyer once again prohibited Rosenthal's lawyers from arguing before the jury that his work was sanctioned by Oakland government officials, a main point of contention for the jurors of the previous trial. Ed Rosenthal did not receive any additional jail time and planned to appeal.
See also: U.S. vs. Ed Rosenthal 2.0, The re-trial of the Ganja Guru by Vanessa Nelson
# Advocacy
Rosenthal's public battles in the court have focused attention on the question of whether marijuana laws have become more harmful to society than the behavior they were intended to regulate. Recent polls show that as many as 80% of Americans support legal access to medical marijuana. The Federal Government does not recognize the legitimacy of medical marijuana initiatives passed by individual states. | Ed Rosenthal
Ed Rosenthal (born Bronx, New York, 1944) is a California horticulturist, author, publisher, and Cannabis grower known for his advocacy for the legalization of marijuana (cannabis as a drug) use. He served as a columnist for High Times Magazine during the 80's and 90's.[1] He was arrested in 2002 for cultivation of cannabis by federal authorities, who do not recognize the authority of states to regulate the use of medical marijuana. He was convicted in Federal Court, but the conviction was overturned on appeal. Rosenthal was subsequently convicted again, but was not re-sentenced, since his original sentence had been completed. Rosenthal briefly attended Youngstown State University in Youngstown, Ohio. He has two children, Nick and Justine.
Rosenthal has been active in promoting and developing policies of civil regulation for medicinal marijuana. With the passage of California's pioneering Proposition 215 in 1996, which authorizes medicinal use of marijuana, he worked with the state and local governments to implement the delivery of pharmaceutical grade cannabis to patients with a doctor's prescription to use marijuana.
# Legal battles
In 2002, federal agents arrested Rosenthal, who previously had been deputized by the City of Oakland to grow marijuana for medical use. He was convicted, and in a surprise setback for the federal government, was sentenced by U.S. District Court Judge Charles Breyer to only one day in prison; time already served. In 2006 the 9th Circuit Appeals Court subsequently overturned Rosenthal's conviction. Months later the U.S. Attorney's office re-indicted him. Although, the judge has promised to sentence Rosenthal to no additional prison time, a new trial commenced on 14 May 2007.
On May 31 2007, it was announced that Rosenthal had been convicted again on three of the five charges against him: one conspiracy count; one count of cultivation, intending to distribute and distributing marijuana; and one count of using a commercial building as a site for growing and distributing marijuana. He was acquitted of growing and distributing marijuana at the Harm Reduction Center medical-marijuana club in San Francisco. The jury deadlocked on whether he had conspired to grow and distribute marijuana at the Harm Reduction Center. Judge Breyer once again prohibited Rosenthal's lawyers from arguing before the jury that his work was sanctioned by Oakland government officials, a main point of contention for the jurors of the previous trial. Ed Rosenthal did not receive any additional jail time and planned to appeal.[2][3]
See also: U.S. vs. Ed Rosenthal 2.0, The re-trial of the Ganja Guru by Vanessa Nelson
# Advocacy
Rosenthal's public battles in the court have focused attention on the question of whether marijuana laws have become more harmful to society than the behavior they were intended to regulate. Recent polls show that as many as 80% of Americans support legal access to medical marijuana.[4] The Federal Government does not recognize the legitimacy of medical marijuana initiatives passed by individual states. | https://www.wikidoc.org/index.php/Ed_Rosenthal | |
32aac4d775f44668ecd759b4708f5d031ca4ffae | wikidoc | Edit summary | Edit summary
# Overview
It is good practice and highly recommended to fill in the Edit Summary field, or add to it in the case of section editing, as it helps you and your fellow contributors to understand what is changed, such as when perusing the history of the page. It's a good idea to set your user preferences (under Edit) to "Prompt me when entering a blank edit summary".
# Writing edit summaries
Always fill in the summary field. This is considered an important guideline. Even a short summary is better than no summary. An edit summary is even more important if you delete any text; otherwise, people may think you're being sneaky. Also, mentioning one change but not another one can be misleading to someone who finds the other one more important; add "and misc." to cover the other change(s).
Accurate summaries help people decide whether it is worthwhile for them to check a change. We've found that summaries often pique the interest of contributors with expertise in the area. This may not be as necessary for "minor changes", but "fixed spelling" would be nice even then.
The edit summary box can hold 1 line of 200 characters. If you attempt to paste more than this only the first 200 characters will be displayed - the rest will be disregarded. For example, typing 10 new characters into a summary that already has 195 characters will result in the first 5 new characters being inserted and the second 5 being disregarded.
In the case of a small addition to an article, it is highly recommended to copy the full text of this addition to the summary field, giving a maximum of information with a minimum of effort. Put ft in front, as an abbreviation of "full text" (see the Abbreviations section for other abbreviations). This way, readers of the summary will be unlikely to check the page itself as they already know the extent of the edit. These kinds of edits allow users to check Recent changes, Page history and User contributions (see below) very efficiently - this also reduces the load on the servers.
If the addition is more than 200 characters, so it does not fit fully in the edit summary box, you should write a short summary of the changes you have introduced into the article. For an addition of, say, 400 characters you can also save time by simply copying that into the summary field. The excess will fall off, and the first 200 characters will usually be acceptable as a crude "summary".
Unfortunately you can copy only one line of text from the edit box into the edit summary box. The contents of further lines can be pasted at the end of the line. Thus, for example, a bulleted "see also" list is cumbersome to put in the edit summary box. One possible workaround for a new list is putting the list on one line, separated by the asterisks for the bullets, copying it to the edit summary box, and then, in the main edit box, putting the new lines before the asterisks.
In addition to a summary of the change itself, the summary field may also contain an explanation of the change; note that if the reason for an edit is not clear, it is more likely to be reverted, especially in the case that some text is deleted. To give a longer explanation, use the Talk page and put in the edit summary "see Talk".
After saving the page, the summary can not be edited--another reason to avoid spelling errors. In the case of important omissions or errors in the edit summary, you can make a dummy edit just to put the correction in the edit summary.
In the case of important omissions or errors in the edit summary, you can make a dummy edit just to put the correction in the edit summary.
# Places where the edit summary appears
The edit summary appears in black italics. All information on this page is attributed to Wikipedia and its contributors.
# Properties
The edit summary box can hold one line of 200 characters. If you attempt to type or paste more, only the first 200 characters will be displayed - the rest will be disregarded. Also, for example attempting to add 10 new characters (at the end or in between) to a summary already containing 195 characters will result in the first 5 new characters being inserted and the second 5 being disregarded.
The "Show preview" button also provides a preview of the edit summary to facilitate checking links.
# Places where the edit summary appears
The edit summary appears in black italics in the following places:
- Page history - list of changes to the page you edited
- User contributions - list of all your edits
- Watchlist- - list of recent changes to watched pages (logged-in users only)
- diff page - shows the difference between two edits
- Recent changes - list of all recent edits
- Wikipedia IRC channels - real time list of all edits
- Related changes - list of recent changes to pages linked to the page you edited
- List of new pages: shows the edit summary of the creation.
- Use the enhanced watchlist to see all recent changes in the watched pages, not just the last change in each page.
# Abbreviations
Experienced users, especially those with many edits to make, will often use abbreviations in edit summaries (as well as log entries), in order to save time; for example, "rv" for "revert". These should be used with care, as they can be confusing for inexperienced users, but they are generally fine for small edits such as formatting and grammar changes. See Edit summary legend for a list of commonly used abbreviations in edit summaries.
# Searching
The Wikimedia search function can not search edit summaries, and they are not indexed by external search engines.
# File upload summary
When uploading an image one can supply an upload summary. This serves multiple purposes:
- as second part of the automatically created edit summary of the upload log (the first part giving the file name)
- as text in the entry of the image history
- in the case that the file name of the image is new:
as edit summary for the creation of the image page
as wikitext for the editable part of the image page, which includes the following possibilities:
briefly describe the image
provide internal or external links
call templates
specify one or more categories the image is in
- as edit summary for the creation of the image page
- as wikitext for the editable part of the image page, which includes the following possibilities:
briefly describe the image
provide internal or external links
call templates
specify one or more categories the image is in
- briefly describe the image
- provide internal or external links
- call templates
- specify one or more categories the image is in
The capacity of the upload summary is one line of 250 characters; in the upload log the last part may fall off, because this can contain 255 characters, including "uploaded "filename"".
Note that there is no preview function to check the code for the links, template calls and category tags, but of course, if needed one can edit the image page after uploading, to correct errors and also to extend the text.
# Section editing
When adding a new section to a discussion page with the "+" button, the section title is used as the edit summary. When editing an existing section, the section title is inserted at the beginning of the edit summary, enclosed with /- and */ marks, for example /- External links */. Details of the edit should be added after this text. In the case that you provide a long summary yourself you can delete the section title in order to stay within the limit of 200 characters.
When viewing such an edit summary, the section name will appear in grey, with a small link next to it: → External links. Clicking the link to view the section (if the section no longer exists, the link will just take you to the page).
If you create a new section before or after an existing section by clicking a section "edit" link, delete the text between /- and */ marks to avoid confusion. It is possible to manually include links to multiple sections using the /- */ syntax – this may be useful when editing several sections at once.
For example, the edit summary:
is rendered as:
→Foo test →Bar test
# "Post a comment" feature
When starting a new thread on a Talk page, the "Post a comment" feature can be used. Click the plus sign next to the Edit link. A box labelled "Subject/headline" appears before the main editing box. Text typed into the subject field becomes both the edit summary and a new heading (which is added to the end of the page), and text entered into the main edit box is inserted below this heading.
# Automatic summaries
In certain circumstances, an automatic summary is generated when an edit is saved without one. This is slightly different to the summary added when editing a section, as that can be modified by the user before saving.
With the exception of the automatic summary when creating a redirect, which usually says all that needs to be said, these are not a substitute for a proper edit summary – you should always leave a meaningful summary, even in the above cases. They are, however, useful in providing some context for edits made by inexperienced users who are not aware of the importance of edit summaries, and for spotting vandalism.
# Rendering of wikitext; URLs
Text in edit summaries renders internal links, including piped links, and interwiki links, even when enclosed within and . Therefore, copying wikitext in the edit summary box may be preferable to copying text from the preview, except when one wants to save space.
Other wikitext coding is not interpreted.
When copying an external link from the preview into the edit summary box then, depending on the operating system, the
"printable version" is copied, i.e. how it is normally rendered, and in addition, between parentheses, the URL; hence the same information as in the wikitext, but in a different format, as well as a possible sequential number. | Edit summary
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
It is good practice and highly recommended to fill in the Edit Summary field, or add to it in the case of section editing, as it helps you and your fellow contributors to understand what is changed, such as when perusing the history of the page. It's a good idea to set your user preferences (under Edit) to "Prompt me when entering a blank edit summary".
# Writing edit summaries
Always fill in the summary field. This is considered an important guideline. Even a short summary is better than no summary. An edit summary is even more important if you delete any text; otherwise, people may think you're being sneaky. Also, mentioning one change but not another one can be misleading to someone who finds the other one more important; add "and misc." to cover the other change(s).
Accurate summaries help people decide whether it is worthwhile for them to check a change. We've found that summaries often pique the interest of contributors with expertise in the area. This may not be as necessary for "minor changes", but "fixed spelling" would be nice even then.
The edit summary box can hold 1 line of 200 characters. If you attempt to paste more than this only the first 200 characters will be displayed - the rest will be disregarded. For example, typing 10 new characters into a summary that already has 195 characters will result in the first 5 new characters being inserted and the second 5 being disregarded.
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Unfortunately you can copy only one line of text from the edit box into the edit summary box. The contents of further lines can be pasted at the end of the line. Thus, for example, a bulleted "see also" list is cumbersome to put in the edit summary box. One possible workaround for a new list is putting the list on one line, separated by the asterisks for the bullets, copying it to the edit summary box, and then, in the main edit box, putting the new lines before the asterisks.
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After saving the page, the summary can not be edited--another reason to avoid spelling errors. In the case of important omissions or errors in the edit summary, you can make a dummy edit just to put the correction in the edit summary.
In the case of important omissions or errors in the edit summary, you can make a dummy edit just to put the correction in the edit summary.
# Places where the edit summary appears
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# Properties
The edit summary box can hold one line of 200 characters. If you attempt to type or paste more, only the first 200 characters will be displayed - the rest will be disregarded. Also, for example attempting to add 10 new characters (at the end or in between) to a summary already containing 195 characters will result in the first 5 new characters being inserted and the second 5 being disregarded.
The "Show preview" button also provides a preview of the edit summary to facilitate checking links.
# Places where the edit summary appears
The edit summary appears in black italics in the following places:
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* Use the enhanced watchlist to see all recent changes in the watched pages, not just the last change in each page.
# Abbreviations
Experienced users, especially those with many edits to make, will often use abbreviations in edit summaries (as well as log entries), in order to save time; for example, "rv" for "revert". These should be used with care, as they can be confusing for inexperienced users, but they are generally fine for small edits such as formatting and grammar changes. See Edit summary legend for a list of commonly used abbreviations in edit summaries.
# Searching
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# File upload summary
When uploading an image one can supply an upload summary. This serves multiple purposes:
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- in the case that the file name of the image is new:
as edit summary for the creation of the image page
as wikitext for the editable part of the image page, which includes the following possibilities:
briefly describe the image
provide internal or external links
call templates
specify one or more categories the image is in
- as edit summary for the creation of the image page
- as wikitext for the editable part of the image page, which includes the following possibilities:
briefly describe the image
provide internal or external links
call templates
specify one or more categories the image is in
- briefly describe the image
- provide internal or external links
- call templates
- specify one or more categories the image is in
The capacity of the upload summary is one line of 250 characters; in the upload log the last part may fall off, because this can contain 255 characters, including "uploaded "filename"".
Note that there is no preview function to check the code for the links, template calls and category tags, but of course, if needed one can edit the image page after uploading, to correct errors and also to extend the text.
# Section editing
When adding a new section to a discussion page with the "+" button, the section title is used as the edit summary. When editing an existing section, the section title is inserted at the beginning of the edit summary, enclosed with /* and */ marks, for example /* External links */. Details of the edit should be added after this text. In the case that you provide a long summary yourself you can delete the section title in order to stay within the limit of 200 characters.
When viewing such an edit summary, the section name will appear in grey, with a small link next to it: → External links. Clicking the link to view the section (if the section no longer exists, the link will just take you to the page).
If you create a new section before or after an existing section by clicking a section "edit" link, delete the text between /* and */ marks to avoid confusion. It is possible to manually include links to multiple sections using the /* */ syntax – this may be useful when editing several sections at once.
For example, the edit summary:
is rendered as:
→Foo test →Bar test
# "Post a comment" feature
When starting a new thread on a Talk page, the "Post a comment" feature can be used. Click the plus sign next to the Edit link. A box labelled "Subject/headline" appears before the main editing box. Text typed into the subject field becomes both the edit summary and a new heading (which is added to the end of the page), and text entered into the main edit box is inserted below this heading.
# Automatic summaries
In certain circumstances, an automatic summary is generated when an edit is saved without one. This is slightly different to the summary added when editing a section, as that can be modified by the user before saving.
With the exception of the automatic summary when creating a redirect, which usually says all that needs to be said, these are not a substitute for a proper edit summary – you should always leave a meaningful summary, even in the above cases. They are, however, useful in providing some context for edits made by inexperienced users who are not aware of the importance of edit summaries, and for spotting vandalism.
# Rendering of wikitext; URLs
Text in edit summaries renders internal links, including piped links, and interwiki links, even when enclosed within <nowiki> and </nowiki>. Therefore, copying wikitext in the edit summary box may be preferable to copying text from the preview, except when one wants to save space.
Other wikitext coding is not interpreted.
When copying an external link from the preview into the edit summary box then, depending on the operating system, the
"printable version" is copied, i.e. how it is normally rendered, and in addition, between parentheses, the URL; hence the same information as in the wikitext, but in a different format, as well as a possible sequential number.
Template:WikiDoc Sources | https://www.wikidoc.org/index.php/Edit_summary | |
037072d270912c79947fa6b2a2af919ee7551162 | wikidoc | Edzard Ernst | Edzard Ernst
Edzard Ernst is notable for being the first Professor of Complementary Medicine in the United Kingdom.
He was attracted from his chair in Physical Medicine and Rehabilitation (PMR) at the University of Vienna to set up the department of Complementary Medicine at the University of Exeter in 1993 and became director of complementary medicine of the Peninsula Medical School (PMS) in 2002. He is the first occupant of the Laing chair in Complementary Medicine. He was born and trained in Germany and since 1999 has been a British citizen.
He is the editor in chief of two medical journals, Perfusion and Focus on Alternative and Complementary Therapies (FACT).
# Interests
His research relates to all areas of complementary medicine with an emphasis on efficacy and safety. His research mainly involves clinical trials, surveys and systematic reviews/meta-analyses.
The Department use a specific definition of CAM:
"Complementary medicine is diagnosis, treatment and/or prevention which complements mainstream medicine by contributing to a common whole, by satisfying a demand not met by orthodoxy or by diversifying the conceptual frameworks of medicine."
# Applying science to CAM
Prof Ernst describes his approach as applying science and not politics.
Some complementary practitioners have been uncomplimentary about him, as an initial expectation of an enthusiast for publicising unevaluated claims succumbed to a demonstration of critical appraisal and the application of the scientific method and the techniques of analysis of evidence-based healthcare to them. The few complementary therapy claims and techniques which survive this competent academic and scientific evaluation are left on a sound basis for adoption into the existing corpus of techniques of medicine.
He notes that in mainland Europe complementary techniques are largely practiced by qualified physicians, whereas in the UK they are mainly practiced by others, and also that CAM is an umbrella term, and since the various techniques and activities are so different from each other, each must be considered separately.
For some years Ernst contributed a regular column in the Guardian newspaper, frequently reviewing news stories about complementary medicine from an evidence-based perspective.
# Other significant posts
Professor Ernst is a member of the 'Medicines Commission' of the British Medicines Control Agency(MCA) which determines what substances may be introduced and promoted as medicine. It is the current version of the Committee on Safety of Medicines (CSM). He also sit on the 'Scientific Committee on Herbal Medicinal Products' of the 'Irish Medicines Board'. He is an external examiner for several university medical schools in several countries.
# Notes
- ↑ Maurice Laing (director of Laing Construction established the Laing Chair of Complementary Medicine at the University of Exeter in 2002 with a large donation
- ↑ Ernst et al British General Practitioner 1995; 45:506
- ↑ Interview: Harcourt International | Edzard Ernst
Edzard Ernst is notable for being the first Professor of Complementary Medicine in the United Kingdom.
He was attracted from his chair in Physical Medicine and Rehabilitation (PMR) at the University of Vienna to set up the department of Complementary Medicine at the University of Exeter in 1993 and became director of complementary medicine of the Peninsula Medical School (PMS) in 2002. He is the first occupant of the Laing[1] chair in Complementary Medicine. He was born and trained in Germany and since 1999 has been a British citizen.
He is the editor in chief of two medical journals, Perfusion and Focus on Alternative and Complementary Therapies (FACT).
# Interests
His research relates to all areas of complementary medicine with an emphasis on efficacy and safety. His research mainly involves clinical trials, surveys and systematic reviews/meta-analyses.
The Department use a specific definition of CAM:
"Complementary medicine is diagnosis, treatment and/or prevention which complements mainstream medicine by contributing to a common whole, by satisfying a demand not met by orthodoxy or by diversifying the conceptual frameworks of medicine."[2]
# Applying science to CAM
Prof Ernst describes his approach[1] as applying science and not politics.
Some complementary practitioners have been uncomplimentary about him, as an initial expectation of an enthusiast for publicising unevaluated claims succumbed to a demonstration of critical appraisal and the application of the scientific method and the techniques of analysis of evidence-based healthcare to them. The few complementary therapy claims and techniques which survive this competent academic and scientific evaluation are left on a sound basis for adoption into the existing corpus of techniques of medicine.
He notes that in mainland Europe complementary techniques are largely practiced by qualified physicians, whereas in the UK they are mainly practiced by others, and also that CAM is an umbrella term, and since the various techniques and activities are so different from each other, each must be considered separately[3].
For some years Ernst contributed a regular column in the Guardian newspaper, frequently reviewing news stories about complementary medicine from an evidence-based perspective.
# Other significant posts
Professor Ernst is a member of the 'Medicines Commission' of the British Medicines Control Agency(MCA) which determines what substances may be introduced and promoted as medicine. It is the current version of the Committee on Safety of Medicines (CSM). He also sit on the 'Scientific Committee on Herbal Medicinal Products' of the 'Irish Medicines Board'. He is an external examiner for several university medical schools in several countries.
# Notes
- ↑ Maurice Laing (director of Laing Construction established the Laing Chair of Complementary Medicine at the University of Exeter in 2002 with a large donation
- ↑ Ernst et al British General Practitioner 1995; 45:506
- ↑ Interview: Harcourt International | https://www.wikidoc.org/index.php/Edzard_Ernst | |
e5746f1174e10ad09c140091a09ec26327798b3c | wikidoc | Eflornithine | Eflornithine
# 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
Eflornithine is a hair growth retardant, ornithine decarboxylase inhibitor that is FDA approved for the treatment of reduction of unwanted facial hair in women. Common adverse reactions include acne and stinging of skin.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Apply a thin layer of Eflornithine cream, 13.9% to affected areas of the face and adjacent involved areas under the chin and rub in thoroughly. Do not wash treated area for at least 4 hours. Use twice daily at least 8 hours apart or as directed by a physician. The patient should continue to use hair removal techniques as needed in conjunction with Eflornithine (Eflornithine should be applied at least 5 minutes after hair removal.) Cosmetics or sunscreens may be applied over treated areas after cream has dried.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Eflornithine in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Eflornithine in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
- Apply a thin layer of Eflornithine cream, 13.9% to affected areas of the face and adjacent involved areas under the chin and rub in thoroughly. Do not wash treated area for at least 4 hours. Use twice daily at least 8 hours apart or as directed by a physician. The patient should continue to use hair removal techniques as needed in conjunction with Eflornithine (Eflornithine should be applied at least 5 minutes after hair removal.) Cosmetics or sunscreens may be applied over treated areas after cream has dried.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Eflornithine in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Eflornithine in pediatric patients.
# Contraindications
- Contraindicated in patients with a history of hypersensitivity to any components of the preparation.
# Warnings
Discontinue use if hypersensitivity occurs.
### Precautions
- For external use only.
- Transient stinging or burning sensation may occur when applied to abraded or broken skin.
Patients using Eflornithine should receive the following information and instructions:
- This medication is not a depilatory, but rather appears to retard hair growth to improve the condition and the patient's appearance. Patients will likely need to continue using a hair removal method (e.g., shaving, plucking, etc.) in conjunction with Eflornithine cream, 13.9%.
- Onset of improvement was seen after as little as 4-8 weeks of treatment in the 24-week clinical trials. The condition may return to pretreatment levels 8 weeks after discontinuing treatment.
- If skin irritation or intolerance develops, direct the patient to temporarily reduce the frequency of application (e.g., once a day). If irritation continues, the patient should discontinue use of the product.
- Refer to the Patient Information Leaflet for additional important information and instructions.
# Adverse Reactions
## Clinical Trials Experience
- Adverse events reported for most body systems occurred at similar frequencies in Eflornithine cream, 13.9% and vehicle control groups. The most frequent adverse events related to treatment with Eflornithine were skin-related. The following table notes the percentage of adverse events associated with the use of Eflornithine or its vehicle that occurred at greater than 1% in both the vehicle-controlled studies and the open-label safety studies up to 1 year of continuous use.
- Treatment-related skin adverse events that occurred in less than 1% of the subjects treated with Eflornithine are: bleeding skin, cheilitis, contact dermatitis, swelling of lips, herpes simplex, numbness, and rosacea.
- Adverse events were primarily mild in intensity and generally resolved without medical treatment or discontinuation of Eflornithine Only 2% of subjects discontinued studies due to an adverse event related to use of Eflornithine.
- No laboratory test abnormalities have been consistently found to be associated with Eflornithine. In an open-label study, some patients showed an increase in their transaminases; however, the clinical significance of these findings is not known.
## Postmarketing Experience
There is limited information regarding Eflornithine Postmarketing Experience in the drug label.
# Drug Interactions
- It is not known if Eflornithine has any interaction with other topically applied drug products.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): C
- In the first dermal embryo-fetal development study in rats treated with eflornithine hydrochloride cream, 13.9% (in which no precautions were taken to prevent ingestion of drug from application sites), maternal toxicity and fetal effects including reduced numbers of live fetuses, decreased fetal weights, and delayed ossification and development of the viscera were observed at doses of 225 and 450 mg/kg (15X and 29X the MRHD based on BSA, respectively). When the study was repeated under conditions that avoided ingestion from application sites, no maternal, fetal or teratogenic effects were observed at doses up to 450 mg/kg (29X the MRHD based on BSA). In the first study in which no precautions were taken to prevent ingestion, circulating plasma levels were 11- to 14-fold higher than in the second study in which ingestion was prevented. In a dermal embryo-fetal development study in rabbits treated with Eflornithine cream, 13.9% no adverse maternal or fetal effects occurred at doses up to 90 mg/kg (11X the MRHD based on BSA). Significant dermal irritation, as well as possible ingestion of Eflornithine occurred at 300 mg/kg/day (36X the MRHD based on BSA) and was associated with maternal deaths, abortions, increased fetal resorptions, and reduced fetal weights. Fetotoxicity in the absence of maternal toxicity has been reported in oral studies with eflornithine with fetal no-effect doses of 80 mg/kg in rats and 45 mg/kg in rabbits. In these studies, no evidence of teratogenicity was observed in rats given up to 200 mg/kg or in rabbits given up to 135 mg/kg.
- Although Eflornithine was not formally studied in pregnant patients, 22 pregnancies occurred during the trials. Nineteen of these pregnancies occurred while patients were using Eflornithine Of the 19 pregnancies, there were 9 healthy infants, 4 spontaneous abortions, 5 induced/elective abortions, and 1 birth defect (Down's Syndrome to a 35-year-old). *Because there are no adequate and well-controlled studies in pregnant women, the risk/benefit ratio of using Eflornithine in women with unwanted facial hair who are pregnant should be weighed carefully with serious consideration for either not implementing or discontinuing use of Eflornithine.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Eflornithine in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Eflornithine during labor and delivery.
### Nursing Mothers
- It is not known whether or not eflornithine hydrochloride is excreted in human milk. Caution should be exercised when Eflornithine is administered to a nursing woman.
### Pediatric Use
- The safety and effectiveness of this product have not been established in pediatric patients less than 12 years of age
### Geriatic Use
- Of the 1373 patients on active treatment in clinical studies of Eflornithine approximately 7% were 65 years or older and approximately 1% were 75 or older. No apparent differences in safety were observed between older patients and younger patients.
### Gender
There is no FDA guidance on the use of Eflornithine with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Eflornithine with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Eflornithine in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Eflornithine in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Eflornithine in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Eflornithine in patients who are immunocompromised.
# Administration and Monitoring
### Administration
There is limited information regarding Eflornithine Administration in the drug label.
### Monitoring
There is limited information regarding Eflornithine Monitoring in the drug label.
# IV Compatibility
There is limited information regarding the compatibility of Eflornithine and IV administrations.
# Overdosage
- Overdosage information with Eflornithine is unavailable. Given the low percutaneous penetration of this drug, overdosage via the topical route is not expected. However, should very high topical doses (e.g., multiple tubes per day) or oral ingestion be encountered (a 30 g tube contains 4.2 g of eflornithine hydrochloride), the patient should be monitored, and appropriate supportive measures administered as necessary.
(Note: Use of an intravenous formulation of eflornithine hydrochloride at high doses (400 mg/kg/day or approximately 24 g/day) for the treatment of Trypanosoma brucei gambiense infection (African sleeping sickness) has been associated with adverse events and laboratory abnormalities. Adverse events in this setting have included hair loss, facial swelling, seizures, hearing impairment, stomach upset, loss of appetite, headache, weakness and dizziness. A variety of hematological toxicities, including anemia, thrombocytopenia and leukopenia have also been observed, but these were usually reversible upon discontinuation of treatment.)
# Pharmacology
## Mechanism of Action
There is limited information regarding Eflornithine Mechanism of Action in the drug label.
## Structure
- Chemically, eflornithine hydrochloride is (±) -2-(difluoromethyl) ornithine monohydrochloride monohydrate, with the empirical formula C6H12F2N2O2- HClH2O, a molecular weight of 236.65 and the following structural formula:
- Anhydrous eflornithine hydrochloride has an empirical formula C6H12F2N2O2- HCl and a molecular weight of 218.65.
## Pharmacodynamics
- There are no studies examining the inhibition of the enzyme ornithine decarboxylase (]) in human skin following the application of topical eflornithine. However, there are studies in the literature that report the inhibition of ODC activity in skin following oral eflornithine. It is postulated that topical eflornithine hydrochloride irreversibly inhibits skin ODC activity. This enzyme is necessary in the synthesis of polyamines. Animal data indicate that inhibition of ornithine decarboxylase inhibits cell division and synthetic functions, which affect the rate of hair growth. Eflornithine cream, 13.9% has been shown to retard the rate of hair growth in non-clinical and clinical studies.
## Pharmacokinetics
- The mean percutaneous absorption of eflornithine in women with unwanted facial hair, from a 13.9% w/w cream formulation, is less than 1% of the radioactive dose, following either single or multiple doses under conditions of clinical use, that included shaving within 2 hours before radiolabeled dose application in addition to other forms of cutting or plucking, and tweezing to remove facial hair. Steady state was reached within four days of twice-daily application. The apparent steady-state plasma t1/2 of eflornithine was approximately 8 hours. Following twice-daily application of 0.5 g of the cream (total dose 1 g/day; 139 mg as anhydrous eflornithine hydrochloride), under conditions of clinical use in women with unwanted facial hair (n=10), the steady-state Cmax, Ctrough and AUC12hr were approximately 10 ng/mL, 5 ng/mL, and 92 nghr/mL, respectively, expressed in terms of the anhydrous free base of eflornithine hydrochloride. At steady state, the dose-normalized peak concentrations (Cmax) and the extent of daily systemic exposure (AUC) of eflornithine following twice-daily application of 0.5 g of the cream (total dose 1 g/day) is estimated to be approximately 100- and 60-fold lower, when compared to 370 mg/day once-daily oral doses. This compound is not known to be metabolized and is primarily excreted unchanged in the urine.
## Nonclinical Toxicology
- In a 12-month photocarcinogenicity study in hairless albino mice, animals treated with the vehicle alone showed an increased incidence of skin tumors induced by exposure to ultraviolet (UVA/UVB) light, whereas mice treated topically with Eflornithine at doses up to 600 mg/kg showed an incidence of skin tumors equivalent to untreated-control animals.
- A 2-year dermal carcinogenicity study in CD-1 mice treated with Eflornithine revealed no evidence of carcinogenicity at daily doses up to 600 mg/kg (950X the MRHD based on AUC comparisons).
- Eflornithine did not elicit mutagenic effects in an Ames reverse-mutation assay or clastogenicity in primary human lymphocytes, with and without metabolic activation. In a dermal micronucleus assay, eflornithine hydrochloride cream, 13.9%, at doses up to 900 mg/kg (58X the MRHD based on BSA) in rats yielded no evidence of genotoxicity.
- In a dermal fertility and early embryonic development study in rats treated with Eflornithine, there were no adverse reproductive effects at doses up to 450 mg/kg (29X the MRHD based on BSA). In a peri- and postnatal study in rats, eflornithine administered in the drinking water was associated with maternal toxicity and reduced pup weights at doses of at least 625 mg/kg (40X the MRHD based on BSA) and a slightly reduced fertility index, which was considered to be of questionable biological significance, at 1698 mg/kg (110X the MRHD based on BSA). No effects were seen with an oral dose of 223 mg/kg (14X the MRHD based on BSA). In the latter study, the multiples of the human exposure are likely much higher, since eflornithine is well absorbed orally in rats, whereas minimal absorption occurs in humans treated topically.
# Clinical Studies
- Results of topical dermal studies for contact sensitization, photocontact sensitization, and photocontact irritation reveal that under conditions of clinical use, Eflornithine is not expected to cause contact sensitization, phototoxic, or photosensitization reactions. Results of the topical dermal study for contact irritation did reveal that Eflornithine could cause irritation reactions in clinical use in susceptible individuals or under conditions of exaggerated use.
- Two randomized double-blind studies involving 594 female patients (393 treated with Eflornithine 201 with vehicle) treated twice daily for up to 24 weeks evaluated the efficacy of Eflornithine in the reduction of unwanted facial hair in women. Women in the trial had a customary frequency of removal of facial hair two or more times per week. Women with facial conditions such as severe inflammatory acne, women who were pregnant, and nursing mothers were excluded from the studies. Physicians assessed the improvement or worsening from the baseline condition (Physician's Global Assessment ), 48 hours after shaving, of all treated areas. Statistically significant improvement for Eflornithine cream, 13.9% versus vehicle was seen in each of these studies for "marked improvement" or greater response (24-week time point; p≤ 0.001). Marked improvement was seen consistently at 8 weeks after initiation of treatment and continued throughout the 24 weeks of treatment. Hair growth approached pretreatment levels within 8 weeks of treatment withdrawal. The success rate over time is graphically presented below for each pivotal trial.
- Approximately 32% of patients showed marked improvement or greater (protocol definition of clinical success) after 24 weeks of treatment with Eflornithine (eflornithine hydrochloride) cream, 13.9%, compared to 8% with the vehicle. Combined results of these two trials through 24 weeks are presented below.
- Subgroup analyses appeared to suggest greater benefit for Whites than non-Whites (37% versus 22% success, respectively; p=0.017). However, non-Whites, mostly Black subjects, did have significant treatment benefit with 22% graded as success on Eflornithine compared to 5% on vehicle.
- About 12% of women in the clinical trials were postmenopausal. Significant improvement in PGA outcome versus vehicle was seen in postmenopausal women (38% compared to 0%, p≤ 0.001).
- Eflornithine statistically significantly reduced how bothered patients felt by their facial hair and by the time spent removing, treating, or concealing facial hair. These patient-observable differences were seen as early as 8 weeks after initiating treatment. Hair growth approached pretreatment levels within 8 weeks of treatment withdrawal.
- Clinical trials with Eflornithine involved over 1370 women with unwanted facial hair of skin types I-VI, of whom 68% were White, 17% Black, 11% Hispanic-Latino, 2% Asian-Pacific Islander, 0.6% American Native, and 1.3% other.
# How Supplied
- Eflornithine hydrochloride cream, 13.9% is available as:
45 gram tube (NDC 0023-4857-45)
- 45 gram tube (NDC 0023-4857-45)
## Storage
- Store at 25°C (77°F); excursions permitted to 15°-30°C (59°-86°F)
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
There is limited information regarding Eflornithine Patient Counseling Information in the drug label.
# Precautions with Alcohol
- Alcohol-Eflornithine interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Vaniqa
# Look-Alike Drug Names
There is limited information regarding Eflornithine Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | Eflornithine
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Alberto Plate [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
Eflornithine is a hair growth retardant, ornithine decarboxylase inhibitor that is FDA approved for the treatment of reduction of unwanted facial hair in women. Common adverse reactions include acne and stinging of skin.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Apply a thin layer of Eflornithine cream, 13.9% to affected areas of the face and adjacent involved areas under the chin and rub in thoroughly. Do not wash treated area for at least 4 hours. Use twice daily at least 8 hours apart or as directed by a physician. The patient should continue to use hair removal techniques as needed in conjunction with Eflornithine (Eflornithine should be applied at least 5 minutes after hair removal.) Cosmetics or sunscreens may be applied over treated areas after cream has dried.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Eflornithine in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Eflornithine in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
- Apply a thin layer of Eflornithine cream, 13.9% to affected areas of the face and adjacent involved areas under the chin and rub in thoroughly. Do not wash treated area for at least 4 hours. Use twice daily at least 8 hours apart or as directed by a physician. The patient should continue to use hair removal techniques as needed in conjunction with Eflornithine (Eflornithine should be applied at least 5 minutes after hair removal.) Cosmetics or sunscreens may be applied over treated areas after cream has dried.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Eflornithine in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Eflornithine in pediatric patients.
# Contraindications
- Contraindicated in patients with a history of hypersensitivity to any components of the preparation.
# Warnings
Discontinue use if hypersensitivity occurs.
### Precautions
- For external use only.
- Transient stinging or burning sensation may occur when applied to abraded or broken skin.
Patients using Eflornithine should receive the following information and instructions:
- This medication is not a depilatory, but rather appears to retard hair growth to improve the condition and the patient's appearance. Patients will likely need to continue using a hair removal method (e.g., shaving, plucking, etc.) in conjunction with Eflornithine cream, 13.9%.
- Onset of improvement was seen after as little as 4-8 weeks of treatment in the 24-week clinical trials. The condition may return to pretreatment levels 8 weeks after discontinuing treatment.
- If skin irritation or intolerance develops, direct the patient to temporarily reduce the frequency of application (e.g., once a day). If irritation continues, the patient should discontinue use of the product.
- Refer to the Patient Information Leaflet for additional important information and instructions.
# Adverse Reactions
## Clinical Trials Experience
- Adverse events reported for most body systems occurred at similar frequencies in Eflornithine cream, 13.9% and vehicle control groups. The most frequent adverse events related to treatment with Eflornithine were skin-related. The following table notes the percentage of adverse events associated with the use of Eflornithine or its vehicle that occurred at greater than 1% in both the vehicle-controlled studies and the open-label safety studies up to 1 year of continuous use.
- Treatment-related skin adverse events that occurred in less than 1% of the subjects treated with Eflornithine are: bleeding skin, cheilitis, contact dermatitis, swelling of lips, herpes simplex, numbness, and rosacea.
- Adverse events were primarily mild in intensity and generally resolved without medical treatment or discontinuation of Eflornithine Only 2% of subjects discontinued studies due to an adverse event related to use of Eflornithine.
- No laboratory test abnormalities have been consistently found to be associated with Eflornithine. In an open-label study, some patients showed an increase in their transaminases; however, the clinical significance of these findings is not known.
## Postmarketing Experience
There is limited information regarding Eflornithine Postmarketing Experience in the drug label.
# Drug Interactions
- It is not known if Eflornithine has any interaction with other topically applied drug products.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): C
- In the first dermal embryo-fetal development study in rats treated with eflornithine hydrochloride cream, 13.9% (in which no precautions were taken to prevent ingestion of drug from application sites), maternal toxicity and fetal effects including reduced numbers of live fetuses, decreased fetal weights, and delayed ossification and development of the viscera were observed at doses of 225 and 450 mg/kg (15X and 29X the MRHD based on BSA, respectively). When the study was repeated under conditions that avoided ingestion from application sites, no maternal, fetal or teratogenic effects were observed at doses up to 450 mg/kg (29X the MRHD based on BSA). In the first study in which no precautions were taken to prevent ingestion, circulating plasma levels were 11- to 14-fold higher than in the second study in which ingestion was prevented. In a dermal embryo-fetal development study in rabbits treated with Eflornithine cream, 13.9% no adverse maternal or fetal effects occurred at doses up to 90 mg/kg (11X the MRHD based on BSA). Significant dermal irritation, as well as possible ingestion of Eflornithine occurred at 300 mg/kg/day (36X the MRHD based on BSA) and was associated with maternal deaths, abortions, increased fetal resorptions, and reduced fetal weights. Fetotoxicity in the absence of maternal toxicity has been reported in oral studies with eflornithine with fetal no-effect doses of 80 mg/kg in rats and 45 mg/kg in rabbits. In these studies, no evidence of teratogenicity was observed in rats given up to 200 mg/kg or in rabbits given up to 135 mg/kg.
- Although Eflornithine was not formally studied in pregnant patients, 22 pregnancies occurred during the trials. Nineteen of these pregnancies occurred while patients were using Eflornithine Of the 19 pregnancies, there were 9 healthy infants, 4 spontaneous abortions, 5 induced/elective abortions, and 1 birth defect (Down's Syndrome to a 35-year-old). *Because there are no adequate and well-controlled studies in pregnant women, the risk/benefit ratio of using Eflornithine in women with unwanted facial hair who are pregnant should be weighed carefully with serious consideration for either not implementing or discontinuing use of Eflornithine.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Eflornithine in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Eflornithine during labor and delivery.
### Nursing Mothers
- It is not known whether or not eflornithine hydrochloride is excreted in human milk. Caution should be exercised when Eflornithine is administered to a nursing woman.
### Pediatric Use
- The safety and effectiveness of this product have not been established in pediatric patients less than 12 years of age
### Geriatic Use
- Of the 1373 patients on active treatment in clinical studies of Eflornithine approximately 7% were 65 years or older and approximately 1% were 75 or older. No apparent differences in safety were observed between older patients and younger patients.
### Gender
There is no FDA guidance on the use of Eflornithine with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Eflornithine with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Eflornithine in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Eflornithine in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Eflornithine in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Eflornithine in patients who are immunocompromised.
# Administration and Monitoring
### Administration
There is limited information regarding Eflornithine Administration in the drug label.
### Monitoring
There is limited information regarding Eflornithine Monitoring in the drug label.
# IV Compatibility
There is limited information regarding the compatibility of Eflornithine and IV administrations.
# Overdosage
- Overdosage information with Eflornithine is unavailable. Given the low percutaneous penetration of this drug, overdosage via the topical route is not expected. However, should very high topical doses (e.g., multiple tubes per day) or oral ingestion be encountered (a 30 g tube contains 4.2 g of eflornithine hydrochloride), the patient should be monitored, and appropriate supportive measures administered as necessary.
(Note: Use of an intravenous formulation of eflornithine hydrochloride at high doses (400 mg/kg/day or approximately 24 g/day) for the treatment of Trypanosoma brucei gambiense infection (African sleeping sickness) has been associated with adverse events and laboratory abnormalities. Adverse events in this setting have included hair loss, facial swelling, seizures, hearing impairment, stomach upset, loss of appetite, headache, weakness and dizziness. A variety of hematological toxicities, including anemia, thrombocytopenia and leukopenia have also been observed, but these were usually reversible upon discontinuation of treatment.)
# Pharmacology
## Mechanism of Action
There is limited information regarding Eflornithine Mechanism of Action in the drug label.
## Structure
- Chemically, eflornithine hydrochloride is (±) -2-(difluoromethyl) ornithine monohydrochloride monohydrate, with the empirical formula C6H12F2N2O2• HCl•H2O, a molecular weight of 236.65 and the following structural formula:
- Anhydrous eflornithine hydrochloride has an empirical formula C6H12F2N2O2• HCl and a molecular weight of 218.65.
## Pharmacodynamics
- There are no studies examining the inhibition of the enzyme ornithine decarboxylase ([ODC]]) in human skin following the application of topical eflornithine. However, there are studies in the literature that report the inhibition of ODC activity in skin following oral eflornithine. It is postulated that topical eflornithine hydrochloride irreversibly inhibits skin ODC activity. This enzyme is necessary in the synthesis of polyamines. Animal data indicate that inhibition of ornithine decarboxylase inhibits cell division and synthetic functions, which affect the rate of hair growth. Eflornithine cream, 13.9% has been shown to retard the rate of hair growth in non-clinical and clinical studies.
## Pharmacokinetics
- The mean percutaneous absorption of eflornithine in women with unwanted facial hair, from a 13.9% w/w cream formulation, is less than 1% of the radioactive dose, following either single or multiple doses under conditions of clinical use, that included shaving within 2 hours before radiolabeled dose application in addition to other forms of cutting or plucking, and tweezing to remove facial hair. Steady state was reached within four days of twice-daily application. The apparent steady-state plasma t1/2 of eflornithine was approximately 8 hours. Following twice-daily application of 0.5 g of the cream (total dose 1 g/day; 139 mg as anhydrous eflornithine hydrochloride), under conditions of clinical use in women with unwanted facial hair (n=10), the steady-state Cmax, Ctrough and AUC12hr were approximately 10 ng/mL, 5 ng/mL, and 92 ng•hr/mL, respectively, expressed in terms of the anhydrous free base of eflornithine hydrochloride. At steady state, the dose-normalized peak concentrations (Cmax) and the extent of daily systemic exposure (AUC) of eflornithine following twice-daily application of 0.5 g of the cream (total dose 1 g/day) is estimated to be approximately 100- and 60-fold lower, when compared to 370 mg/day once-daily oral doses. This compound is not known to be metabolized and is primarily excreted unchanged in the urine.
## Nonclinical Toxicology
- In a 12-month photocarcinogenicity study in hairless albino mice, animals treated with the vehicle alone showed an increased incidence of skin tumors induced by exposure to ultraviolet (UVA/UVB) light, whereas mice treated topically with Eflornithine at doses up to 600 mg/kg [19X the Maximum Recommended Human Dose (MRHD) based on body surface area (BSA)] showed an incidence of skin tumors equivalent to untreated-control animals.
- A 2-year dermal carcinogenicity study in CD-1 mice treated with Eflornithine revealed no evidence of carcinogenicity at daily doses up to 600 mg/kg (950X the MRHD based on AUC comparisons).
- Eflornithine did not elicit mutagenic effects in an Ames reverse-mutation assay or clastogenicity in primary human lymphocytes, with and without metabolic activation. In a dermal micronucleus assay, eflornithine hydrochloride cream, 13.9%, at doses up to 900 mg/kg (58X the MRHD based on BSA) in rats yielded no evidence of genotoxicity.
- In a dermal fertility and early embryonic development study in rats treated with Eflornithine, there were no adverse reproductive effects at doses up to 450 mg/kg (29X the MRHD based on BSA). In a peri- and postnatal study in rats, eflornithine administered in the drinking water was associated with maternal toxicity and reduced pup weights at doses of at least 625 mg/kg (40X the MRHD based on BSA) and a slightly reduced fertility index, which was considered to be of questionable biological significance, at 1698 mg/kg (110X the MRHD based on BSA). No effects were seen with an oral dose of 223 mg/kg (14X the MRHD based on BSA). In the latter study, the multiples of the human exposure are likely much higher, since eflornithine is well absorbed orally in rats, whereas minimal absorption occurs in humans treated topically.
# Clinical Studies
- Results of topical dermal studies for contact sensitization, photocontact sensitization, and photocontact irritation reveal that under conditions of clinical use, Eflornithine is not expected to cause contact sensitization, phototoxic, or photosensitization reactions. Results of the topical dermal study for contact irritation did reveal that Eflornithine could cause irritation reactions in clinical use in susceptible individuals or under conditions of exaggerated use.
- Two randomized double-blind studies involving 594 female patients (393 treated with Eflornithine 201 with vehicle) treated twice daily for up to 24 weeks evaluated the efficacy of Eflornithine in the reduction of unwanted facial hair in women. Women in the trial had a customary frequency of removal of facial hair two or more times per week. Women with facial conditions such as severe inflammatory acne, women who were pregnant, and nursing mothers were excluded from the studies. Physicians assessed the improvement or worsening from the baseline condition (Physician's Global Assessment [PGA]), 48 hours after shaving, of all treated areas. Statistically significant improvement for Eflornithine cream, 13.9% versus vehicle was seen in each of these studies for "marked improvement" or greater response (24-week time point; p≤ 0.001). Marked improvement was seen consistently at 8 weeks after initiation of treatment and continued throughout the 24 weeks of treatment. Hair growth approached pretreatment levels within 8 weeks of treatment withdrawal. The success rate over time is graphically presented below for each pivotal trial.
- Approximately 32% of patients showed marked improvement or greater (protocol definition of clinical success) after 24 weeks of treatment with Eflornithine (eflornithine hydrochloride) cream, 13.9%, compared to 8% with the vehicle. Combined results of these two trials through 24 weeks are presented below.
- Subgroup analyses appeared to suggest greater benefit for Whites than non-Whites (37% versus 22% success, respectively; p=0.017). However, non-Whites, mostly Black subjects, did have significant treatment benefit with 22% graded as success on Eflornithine compared to 5% on vehicle.
- About 12% of women in the clinical trials were postmenopausal. Significant improvement in PGA outcome versus vehicle was seen in postmenopausal women (38% compared to 0%, p≤ 0.001).
- Eflornithine statistically significantly reduced how bothered patients felt by their facial hair and by the time spent removing, treating, or concealing facial hair. These patient-observable differences were seen as early as 8 weeks after initiating treatment. Hair growth approached pretreatment levels within 8 weeks of treatment withdrawal.
- Clinical trials with Eflornithine involved over 1370 women with unwanted facial hair of skin types I-VI, of whom 68% were White, 17% Black, 11% Hispanic-Latino, 2% Asian-Pacific Islander, 0.6% American Native, and 1.3% other.
# How Supplied
- Eflornithine hydrochloride cream, 13.9% is available as:
45 gram tube (NDC 0023-4857-45)
- 45 gram tube (NDC 0023-4857-45)
## Storage
- Store at 25°C (77°F); excursions permitted to 15°-30°C (59°-86°F)
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
There is limited information regarding Eflornithine Patient Counseling Information in the drug label.
# Precautions with Alcohol
- Alcohol-Eflornithine interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Vaniqa
# Look-Alike Drug Names
There is limited information regarding Eflornithine Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Eflornithine | |
93ccb6689e85ffb65de2c61636d5048258ff956f | wikidoc | Egg donation | Egg donation
Egg donation is the process by which a woman provides several eggs (ova, oocytes) for another person or couple who want to have a child. Egg donation involves the process of in vitro fertilization as the eggs are fertilized in the laboratory. After the eggs have been obtained, the role of the egg donor is complete. Egg donation is part of the process of third party reproduction.
# Indication
The need for egg donation may arise for a number of reasons. Infertile couples may resort to acquiring eggs through egg donation when the female partner cannot have genetic children because she may not have eggs that can be successfully fertilized. This situation is often based on advanced reproductive age. Early onset of menopause which can occur in women as early as their 20’s can require a woman to use donor eggs to grow her family. Some women are born without ovaries or other reproductive organs. Sometimes a woman's reproductive organs have been damaged due to disease or have been forced to have them surgically removed. Another indication would be a genetic disorder on part of the woman that can be circumvented by using eggs from another person. The couple can personally get acquainted with the egg donor, her children and family members. Or a couple can request an anonymous egg donor. Egg donation is also required for gay couples using surrogacy (see LGBT parenting).
- Congenital absence of eggs
Turner syndrome
Gonadal dysgenesis/agenesis
- Turner syndrome
- Gonadal dysgenesis/agenesis
- Acquired reduced egg quantity / quality
Oophorectomy
Premature menopause
Chemotherapy
Radiation therapy
Autoimmunity
Advanced maternal age
Compromised ovarian reserve
- Oophorectomy
- Premature menopause
- Chemotherapy
- Radiation therapy
- Autoimmunity
- Advanced maternal age
- Compromised ovarian reserve
- Other
Diseases of X-Sex linkage
Repetitive fertilization or pregnancy failure
Ovaries inaccessible for egg retrieval
- Diseases of X-Sex linkage
- Repetitive fertilization or pregnancy failure
- Ovaries inaccessible for egg retrieval
# Procedure
Egg donors are recruited, screened, and give consent prior to participation in the IVF process. Some patients bring their own, designated donors, while other patients rely on the services of often anonymous donors typically recruited by egg donor agencies or, sometimes, IVF programs.
Once the egg donor is recruited, she undergoes the IVF stimulation therapy, followed by the egg retrieval procedure. After retrieval, the ova are handed over to the recipient couple, fertilized by the sperm of the male partner in the laboratory, and after several days, the resulting embryo(s) is placed in the uterus of the recipient. For the embryo transfer the lining of the recipient has been appropriately prepared in a synchronous fashion. The recipient is usually the person who requested the service and then will carry and deliver the pregnancy and keep the baby.
# Results
Results in treatments with the use of egg from donors often have a better than 50% chance of success. With egg donation, women who are past their reproductive years or menopause can become pregnant. The oldest woman thus to give birth is Adriana Iliescu, age 66.
Babies born after egg donation are not genetically related to the recipient.
# Donor motivation
An egg donor may be motivated by a number of reasons to provide eggs. Some egg donors may be altruistic and feel that participation in the reproductive process provides a benefit for another person, sometimes a person they know or are related to. Others may be attracted to the monetary compensation.
# Risks
## Egg donor
Egg donation carries risks for both donor and recipient. The egg donor may suffer complications from IVF, such as bleeding from the oocyte recovery procedure (ovarian hyperstimulation syndrome) and, rarely, liver failure. The long-term impact of egg donation on donors has not been well studied
## Recipient
The recipient has the risk of contracting a transmittable disease. While the donor may test negative for HIV, such testing does not exclude the possibility that the donor has contracted HIV very recently, so the recipient faces a residual risk of exposure.
The recipient also trusts that the genetic and medical history of the donor is accurate. This factor of trust should not be underestimated in importance. Donors are paid thousands of dollars; monetary compensation may attract unscrupulous individuals inclined to conceal their true motivations. Moreover, recipients will have a de facto relationship to the biological parent of their offspring for life. Half of the child's genetic makeup, and related traits, capabilities, tendencies, etc. will come from the donor.
Multiple birth is a common complication if the physician transfers too many embryos. Incidence of twin births is very high.
## Custody
Generally legal documents are signed to hand oocytes over to the recipient and renounce rights of ownership and custody on part of the donor, so that there will be no claims on part of the donor concerning the offspring.
# Legality
Egg donation is regulated and /or prohibited in many countries. In the United States, having an attorney draft your contract is often necessary to establish and confirm your parental rights over any child.
# Donor registries
A donor sibling registry is a registry to facilitate donor conceived people, sperm donors and egg donors to establish contact with genetic kindred. They are mostly used by donor conceived people to find genetic half-siblings from the same egg- or sperm donor.
Some donors are non-anonymous, but most are anonymous, i.e. the donor conceived person doesn't know the true identity of the donor. Still, he/she may get the donor number from the fertility clinic. If that donor had donated before, then other donor conceived people with the same donor number are thus genetic half-siblings. In short, donor sibling registries matches people who type in the same donor number.
Alternatively, if the donor number isn't available, then known donor characteristics, e.g. hair, eye and skin color may be used in matching siblings.
Donors may also register, and therefore, donor sibling registries may also match donors with their genetic children. | Egg donation
Egg donation is the process by which a woman provides several eggs (ova, oocytes) for another person or couple who want to have a child. Egg donation involves the process of in vitro fertilization as the eggs are fertilized in the laboratory. After the eggs have been obtained, the role of the egg donor is complete. Egg donation is part of the process of third party reproduction.
# Indication
The need for egg donation may arise for a number of reasons. Infertile couples may resort to acquiring eggs through egg donation when the female partner cannot have genetic children because she may not have eggs that can be successfully fertilized. This situation is often based on advanced reproductive age. Early onset of menopause which can occur in women as early as their 20’s can require a woman to use donor eggs to grow her family. Some women are born without ovaries or other reproductive organs. Sometimes a woman's reproductive organs have been damaged due to disease or have been forced to have them surgically removed. Another indication would be a genetic disorder on part of the woman that can be circumvented by using eggs from another person. The couple can personally get acquainted with the egg donor, her children and family members. Or a couple can request an anonymous egg donor. Egg donation is also required for gay couples using surrogacy (see LGBT parenting).
- Congenital absence of eggs
Turner syndrome [1]
Gonadal dysgenesis/agenesis [1]
- Turner syndrome [1]
- Gonadal dysgenesis/agenesis [1]
- Acquired reduced egg quantity / quality
Oophorectomy[1]
Premature menopause[1]
Chemotherapy [1]
Radiation therapy[1]
Autoimmunity[1]
Advanced maternal age [1]
Compromised ovarian reserve [1]
- Oophorectomy[1]
- Premature menopause[1]
- Chemotherapy [1]
- Radiation therapy[1]
- Autoimmunity[1]
- Advanced maternal age [1]
- Compromised ovarian reserve [1]
- Other
Diseases of X-Sex linkage[1]
Repetitive fertilization or pregnancy failure [1]
Ovaries inaccessible for egg retrieval [1]
- Diseases of X-Sex linkage[1]
- Repetitive fertilization or pregnancy failure [1]
- Ovaries inaccessible for egg retrieval [1]
# Procedure
Template:Expert-portal
Egg donors are recruited, screened, and give consent prior to participation in the IVF process. Some patients bring their own, designated donors, while other patients rely on the services of often anonymous donors typically recruited by egg donor agencies or, sometimes, IVF programs.
Once the egg donor is recruited, she undergoes the IVF stimulation therapy, followed by the egg retrieval procedure. After retrieval, the ova are handed over to the recipient couple, fertilized by the sperm of the male partner in the laboratory, and after several days, the resulting embryo(s) is placed in the uterus of the recipient. For the embryo transfer the lining of the recipient has been appropriately prepared in a synchronous fashion. The recipient is usually the person who requested the service and then will carry and deliver the pregnancy and keep the baby.
# Results
Results in treatments with the use of egg from donors often have a better than 50% chance of success. With egg donation, women who are past their reproductive years or menopause can become pregnant. The oldest woman thus to give birth is Adriana Iliescu, age 66.
Babies born after egg donation are not genetically related to the recipient.
# Donor motivation
An egg donor may be motivated by a number of reasons to provide eggs. Some egg donors may be altruistic and feel that participation in the reproductive process provides a benefit for another person, sometimes a person they know or are related to. Others may be attracted to the monetary compensation.
# Risks
## Egg donor
Egg donation carries risks for both donor and recipient. The egg donor may suffer complications from IVF, such as bleeding from the oocyte recovery procedure (ovarian hyperstimulation syndrome) and, rarely, liver failure[citation needed]. The long-term impact of egg donation on donors has not been well studied
## Recipient
The recipient has the risk of contracting a transmittable disease. While the donor may test negative for HIV, such testing does not exclude the possibility that the donor has contracted HIV very recently, so the recipient faces a residual risk of exposure.
The recipient also trusts that the genetic and medical history of the donor is accurate. This factor of trust should not be underestimated in importance. Donors are paid thousands of dollars; monetary compensation may attract unscrupulous individuals inclined to conceal their true motivations. Moreover, recipients will have a de facto relationship to the biological parent of their offspring for life. Half of the child's genetic makeup, and related traits, capabilities, tendencies, etc. will come from the donor.
Multiple birth is a common complication if the physician transfers too many embryos. Incidence of twin births is very high.
## Custody
Generally legal documents are signed to hand oocytes over to the recipient and renounce rights of ownership and custody on part of the donor, so that there will be no claims on part of the donor concerning the offspring.
# Legality
Egg donation is regulated and /or prohibited in many countries. In the United States, having an attorney draft your contract is often necessary to establish and confirm your parental rights over any child.
# Donor registries
A donor sibling registry is a registry to facilitate donor conceived people, sperm donors and egg donors to establish contact with genetic kindred. They are mostly used by donor conceived people to find genetic half-siblings from the same egg- or sperm donor.
Some donors are non-anonymous, but most are anonymous, i.e. the donor conceived person doesn't know the true identity of the donor. Still, he/she may get the donor number from the fertility clinic. If that donor had donated before, then other donor conceived people with the same donor number are thus genetic half-siblings. In short, donor sibling registries matches people who type in the same donor number.
Alternatively, if the donor number isn't available, then known donor characteristics, e.g. hair, eye and skin color may be used in matching siblings.
Donors may also register, and therefore, donor sibling registries may also match donors with their genetic children. | https://www.wikidoc.org/index.php/Egg_donation | |
fb848442b5e640633a8321f55ce24f5f6ed71a09 | wikidoc | Ego-syntonic | Ego-syntonic
Egosyntonic is a medical term referring to behaviors, values,
feelings, which are in harmony with or acceptable to the needs and
goals of the ego, or consistent with one's ideal self-image. It is studied in detail in abnormal psychology. Many personality disorders are considered egosyntonic and are therefore nearly impossible to treat. Anorexia Nervosa, a hard-to-treat Type I disorder, is also considered egosyntonic because many of its sufferers deny that they have a problem.
It is the opposite of egodystonic. Obsessive compulsive disorder is considered to be an egodystonic disorder, as the thoughts and compulsions experienced or expressed are not consistent with the individual's self-perception.
de:Ich-Syntonie
nl:Egosyntonie | Ego-syntonic
Egosyntonic is a medical term referring to behaviors, values,
feelings, which are in harmony with or acceptable to the needs and
goals of the ego, or consistent with one's ideal self-image. It is studied in detail in abnormal psychology. Many personality disorders are considered egosyntonic and are therefore nearly impossible to treat. Anorexia Nervosa, a hard-to-treat Type I disorder, is also considered egosyntonic because many of its sufferers deny that they have a problem.
It is the opposite of egodystonic. Obsessive compulsive disorder is considered to be an egodystonic disorder, as the thoughts and compulsions experienced or expressed are not consistent with the individual's self-perception.
de:Ich-Syntonie
nl:Egosyntonie
Template:WH
Template:WS | https://www.wikidoc.org/index.php/Ego-syntonic | |
218ff70a8e6f5b5900a03a0073a277b07a70ad56 | wikidoc | Electric eel | Electric eel
The electric eel, Electrophorus electricus, is a species of fish. It is capable of generating powerful electric shocks, which it uses for both hunting and self-defense. It is an apex predator in its South American range. Despite its name it is not an eel at all but rather a knifefish.
# Anatomy
A typical electric eel has an elongated square body, a flattened head, and an overall dark grayish green color shifting to yellowish on the bottom. They have almost no scales. The mouth is square, placed right at the end of the snout. The anal fin continues down the length of the body to the tip of their tail. It can grow up to 2.5 m (about 8.2 feet) in length and 20 kg (about 44 pounds) in weight, making them the largest Gymnotiform. 1 m specimens are more common.
They have a vascularized respiratory organ in their oral cavity. These fish are obligate air-breathers; rising to the surface every 10 minutes or so, the animal will gulp air before returning to the bottom. Nearly 80% of the oxygen used by the fish is taken in this way.. Despite its name, the electric eel is not related to eels but is more closely related to catfish.
Scientists have been able to determine through experimental information that E. electricus has a well developed sense of hearing. They have a Weberian apparatus that connects the ear to the swim bladder which greatly enhances their hearing capability.
# Physiology
The electric eel has three abdominal pairs of organs that produce electricity. They are the main organ, the hunter's organ, and the sachs’ organ. These organs take up 4/5 of its body. Only the front 1/5 contains the vital organs. These organs are made of electrocytes lined up in series. The electrocytes are lined up so the current flows through them and produces an electrical charge. When the eel locates its prey, the brain sends a signal through the nervous system to the electric cells. This opens the ion channel, allowing positively-charged sodium to flow through, reversing the charges momentarily. By causing a sudden difference in voltage, it generates a current. The electric eel generates its characteristic electrical pulse in a manner similar to a battery, in which stacked plates produce an electrical charge. In the electric eel, some 5,000 to 6,000 stacked electroplaques are capable of producing a shock at up to 500 volts and 1 ampere of current (500 watts). The organs give the electric eel the ability to generate two types of electric organ discharges (EODs), low voltage and high voltage. The shock could be harmful for an adult human.
The Sachs organ is associated with electrolocation. Inside the organ are many muscle-like cells, called electrocytes. Each cell can only produce 0.15V, though working together the organ transmits a signal of about 10V in amplitude at around 25 Hz. These signals are what is thought to be used for communication as well as orientation; useful not only for finding prey, but also in finding and choosing a mate.
High-voltage EODs are emitted by the main organ and the Hunter's organ that can be emitted at rates of several hundred Hz. These high voltage EODs may reach up to 650 volts. The electric eel is unique among the gymnotiforms in having large electric organs capable of producing lethal discharges that allows them to stun prey. There are reports of animals producing larger voltages, but the typical output is sufficient to stun or deter virtually any other animal. Juveniles produce smaller voltages (about 100 volts). Electric eels are capable of varying the intensity of the electrical discharge, using lower discharges for "hunting" and higher intensities for stunning prey, or defending themselves. When agitated, it is capable of producing these intermittent electrical shocks over a period of at least an hour without signs of tiring. The species is of some interest to researchers, who make use of its acetylcholinesterase and ATP.
The electric eel also possesses high-frequency sensitive tuberous receptors patchily distributed over the body that seem useful for hunting other Gymnotiformes.
# Ecology and life history
## Habitat
They tend to live on muddy bottoms in calm water. They are also found in swamps, coastal plains, and creeks.
It can be found in South American rivers and in the ocean.
## Feeding ecology
Electric eels feed on invertebrates, while adult eels feed on fish and small mammals. First-born hatchlings will even prey on other eggs and embryos from later batches..
# Taxonomic history
The species is so unusual that it has been reclassified several times. Originally it was given its own family Electrophoridae, and then placed in a genus of Gymnotidae alongside Gymnotus. | Electric eel
Template:Otheruses4
The electric eel, Electrophorus electricus, is a species of fish. It is capable of generating powerful electric shocks, which it uses for both hunting and self-defense. It is an apex predator in its South American range. Despite its name it is not an eel at all but rather a knifefish.
# Anatomy
A typical electric eel has an elongated square body, a flattened head, and an overall dark grayish green color shifting to yellowish on the bottom.[1] They have almost no scales. The mouth is square, placed right at the end of the snout. The anal fin continues down the length of the body to the tip of their tail.[2] It can grow up to 2.5 m (about 8.2 feet) in length and 20 kg (about 44 pounds) in weight, making them the largest Gymnotiform.[1][2] 1 m specimens are more common.[citation needed]
They have a vascularized respiratory organ in their oral cavity.[2] These fish are obligate air-breathers; rising to the surface every 10 minutes or so, the animal will gulp air before returning to the bottom. Nearly 80% of the oxygen used by the fish is taken in this way.[citation needed]. Despite its name, the electric eel is not related to eels but is more closely related to catfish.
Scientists have been able to determine through experimental information that E. electricus has a well developed sense of hearing. They have a Weberian apparatus that connects the ear to the swim bladder which greatly enhances their hearing capability.[citation needed]
# Physiology
The electric eel has three abdominal pairs of organs that produce electricity. They are the main organ, the hunter's organ, and the sachs’ organ. These organs take up 4/5 of its body. Only the front 1/5 contains the vital organs.[1] These organs are made of electrocytes lined up in series. The electrocytes are lined up so the current flows through them and produces an electrical charge. When the eel locates its prey, the brain sends a signal through the nervous system to the electric cells. This opens the ion channel, allowing positively-charged sodium to flow through, reversing the charges momentarily. By causing a sudden difference in voltage, it generates a current. The electric eel generates its characteristic electrical pulse in a manner similar to a battery, in which stacked plates produce an electrical charge. In the electric eel, some 5,000 to 6,000 stacked electroplaques are capable of producing a shock at up to 500 volts and 1 ampere of current (500 watts). The organs give the electric eel the ability to generate two types of electric organ discharges (EODs), low voltage and high voltage. The shock could be harmful for an adult human.
The Sachs organ is associated with electrolocation.[1] Inside the organ are many muscle-like cells, called electrocytes. Each cell can only produce 0.15V, though working together the organ transmits a signal of about 10V in amplitude at around 25 Hz. These signals are what is thought to be used for communication as well as orientation; useful not only for finding prey, but also in finding and choosing a mate.
High-voltage EODs are emitted by the main organ and the Hunter's organ that can be emitted at rates of several hundred Hz. [1] These high voltage EODs may reach up to 650 volts. The electric eel is unique among the gymnotiforms in having large electric organs capable of producing lethal discharges that allows them to stun prey.[2] There are reports of animals producing larger voltages, but the typical output is sufficient to stun or deter virtually any other animal. Juveniles produce smaller voltages (about 100 volts). Electric eels are capable of varying the intensity of the electrical discharge, using lower discharges for "hunting" and higher intensities for stunning prey, or defending themselves. When agitated, it is capable of producing these intermittent electrical shocks over a period of at least an hour without signs of tiring. The species is of some interest to researchers, who make use of its acetylcholinesterase and ATP.[3][4]
The electric eel also possesses high-frequency sensitive tuberous receptors patchily distributed over the body that seem useful for hunting other Gymnotiformes.[1]
# Ecology and life history
## Habitat
They tend to live on muddy bottoms in calm water. They are also found in swamps, coastal plains, and creeks.[1]
It can be found in South American rivers and in the ocean.
## Feeding ecology
Electric eels feed on invertebrates, while adult eels feed on fish and small mammals. First-born hatchlings will even prey on other eggs and embryos from later batches..[1]
# Taxonomic history
The species is so unusual that it has been reclassified several times. Originally it was given its own family Electrophoridae, and then placed in a genus of Gymnotidae alongside Gymnotus.[2] | https://www.wikidoc.org/index.php/Electric_eel | |
dd96fb9eab6a8767fa065e64c34946ba77924ee8 | wikidoc | Electrolysis | Electrolysis
In chemistry and manufacturing, electrolysis is a method of separating chemically bonded elements and compounds by passing an electric current through them.
# Overview
Electrolysis involves the passage of an electric current through, in general, an ionic substance that is either molten or dissolved in an aqueous solution resulting in chemical reactions at the electrodes. The negative electrode is called the cathode, and the positive electrode is the anode.
An ionic compound is dissolved with an appropriate solvent, or melted by heat, so that its ions are available in the liquid. An electrical current is applied between a pair of inert electrodes immersed in the liquid.
Each electrode attracts ions that are of the opposite charge. Therefore, positively-charged ions (called cations) move towards the cathode, whereas negatively-charged ions (termed anions) move toward the anode. The energy required to separate the ions, and cause them to gather at the respective electrodes, is provided by an electrical power supply. At the probes, electrons are absorbed or released by the ions, forming a collection of the desired element or compound.
Oxidation of anions can take place at the anode, and the reduction of cations at the cathode. For example, it is possible to oxidize cations at the anode:
It is also possible to reduce anions at the cathode:
Neutral molecules can also react at either electrode. For example:
File:P-Benzoquinone.svg \mathrm{+ \ 2 e^- + \ 2 H^+ \longrightarrow \ }
The following technologies are related to electrolysis:
- Electrochemical cells, including the hydrogen fuel cell, use the reverse of this process.
- Gel electrophoresis is an electrolysis wherein the solvent is a gel: It is used to separate substances, such as DNA strands, based on their electrical charge.
# Electrolysis of water
One important use of electrolysis of water is to produce hydrogen.
This has been suggested as a way of shifting society toward using hydrogen as an energy carrier for powering electric motors and internal combustion engines. (See hydrogen economy.)
Electrolysis of water can be observed by passing direct current from a battery or other DC power supply through a cup of water (in practice a saltwater solution increases the reaction intensity making it easier to observe). Using platinum electrodes, hydrogen gas will be seen to bubble up at the cathode, and oxygen will bubble at the anode. If other metals are used as the anode, there is a chance that the oxygen will react with the anode instead of being released as a gas. For example, using iron electrodes in a sodium chloride solution electrolyte, iron oxide will be produced at the anode, which will react to form iron hydroxide. When producing large quantities of hydrogen, this can significantly contaminate the electrolytic cell - which is why iron is not used for commercial electrolysis.
The energy efficiency of water electrolysis varies widely. The efficiency is a measure of what fraction of electrical energy used is actually contained within the hydrogen. Some of the electrical energy is converted to heat, a useless by-product. Some reports quote efficiencies between 50% and 70% This efficiency is based on the Lower Heating Value of Hydrogen. The Lower Heating Value of Hydrogen is thermal energy released when Hydrogen is combusted. This does not represent the total amount of energy within the Hydrogen, hence the efficiency is lower than a more strict definition. Other reports quote the theoretical maximum efficiency of electrolysis. The theoretical maximum efficiency is between 80% and 94%.. The theoretical maximum considers the total amount of energy absorbed by both the hydrogen and oxygen. These values refer only to the efficiency of converting electrical energy into hydrogen's chemical energy. The energy lost in generating the electricity is not included. For instance, when considering a power plant that converts the heat of nuclear reactions into hydrogen via electrolysis, the total efficiency is more like 25%–40%.
About four percent of hydrogen gas produced worldwide is created by electrolysis, and normally used onsite. Hydrogen is used for the creation of ammonia for fertilizer via the Haber process, and converting heavy petroleum sources to lighter fractions via hydrocracking. There is some speculation about future development of hydrogen as an energy carrier.
# Experimenters
Scientific pioneers of electrolysis included:
- Humphry Davy
- Michael Faraday
- Paul Héroult
- Svante Arrhenius
- Adolph Wilhelm Hermann Kolbe
- William Nicholson
- Joseph Louis Gay-Lussac
- Alexander von Humboldt
More recently, electrolysis of heavy water was performed by Fleischmann and Pons in their famous experiment, allegedly resulting in anomalous heat generation and the controversial claim of cold fusion.
# Faraday's laws of electrolysis
## First law of electrolysis
In 1832, Michael Faraday reported that the quantity of elements separated by passing an electrical current through a molten or dissolved salt is proportional to the quantity of electric charge passed through the circuit. This became the basis of the first law of electrolysis:
m = k \cdot q
## Second law of electrolysis
Faraday also discovered that the mass of the resulting separated elements is directly proportional to the atomic masses of the elements when an appropriate integral divisor is applied. This provided strong evidence that discrete particles of matter exist as parts of the atoms of elements.
# Industrial uses
- Production of aluminium, lithium, sodium, potassium
- Production of hydrogen for hydrogen cars and fuel cells; high-temperature electrolysis is also used for this
- Coulometric techniques can be used to determine the amount of matter transformed during electrolysis by measuring the amount of electricity required to perform the electrolysis
- Production of chlorine and sodium hydroxide
- Production of sodium and potassium chlorate
- Production of perfluorinated organic compounds such as trifluoroacetic acid
Electrolysis has many other uses:
- Electrometallurgy is the process of reduction of metals from metallic compounds to obtain the pure form of metal using electrolysis. For example, sodium hydroxide in its molten form is separated by electrolysis into sodium and oxygen, both of which have important chemical uses. (Water is produced at the same time.)
- Anodization is an electrolytic process that makes the surface of metals resistant to corrosion. For example, ships are saved from being corroded by oxygen in the water by this process. The process is also used to decorate surfaces.
- A battery works by the reverse process to electrolysis. Humphry Davy found that lithium acts as an electrolyte and provides electrical energy.
- Production of oxygen for spacecraft and nuclear submarines.
- Electroplating is used in layering metals to fortify them. Electroplating is used in many industries for functional or decorative purposes, as in vehicle bodies and nickel coins.
- Production of hydrogen for fuel, using a cheap source of electrical energy.
- Electrolytic Etching of metal surfaces like tools or knives with a permanent mark or logo. | Electrolysis
In chemistry and manufacturing, electrolysis is a method of separating chemically bonded elements and compounds by passing an electric current through them.
# Overview
Electrolysis involves the passage of an electric current through, in general, an ionic substance that is either molten or dissolved in an aqueous solution resulting in chemical reactions at the electrodes. The negative electrode is called the cathode, and the positive electrode is the anode. [1]
An ionic compound is dissolved with an appropriate solvent, or melted by heat, so that its ions are available in the liquid. An electrical current is applied between a pair of inert electrodes immersed in the liquid.
Each electrode attracts ions that are of the opposite charge. Therefore, positively-charged ions (called cations) move towards the cathode, whereas negatively-charged ions (termed anions) move toward the anode. The energy required to separate the ions, and cause them to gather at the respective electrodes, is provided by an electrical power supply. At the probes, electrons are absorbed or released by the ions, forming a collection of the desired element or compound.
Oxidation of anions can take place at the anode, and the reduction of cations at the cathode. For example, it is possible to oxidize cations at the anode:
It is also possible to reduce anions at the cathode:
Neutral molecules can also react at either electrode. For example:
File:P-Benzoquinone.svg <math>\mathrm{+ \ 2 e^- + \ 2 H^+ \longrightarrow \ }</math>
The following technologies are related to electrolysis:
- Electrochemical cells, including the hydrogen fuel cell, use the reverse of this process.
- Gel electrophoresis is an electrolysis wherein the solvent is a gel: It is used to separate substances, such as DNA strands, based on their electrical charge.
# Electrolysis of water
One important use of electrolysis of water is to produce hydrogen.
This has been suggested as a way of shifting society toward using hydrogen as an energy carrier for powering electric motors and internal combustion engines. (See hydrogen economy.)
Electrolysis of water can be observed by passing direct current from a battery or other DC power supply through a cup of water (in practice a saltwater solution increases the reaction intensity making it easier to observe). Using platinum electrodes, hydrogen gas will be seen to bubble up at the cathode, and oxygen will bubble at the anode. If other metals are used as the anode, there is a chance that the oxygen will react with the anode instead of being released as a gas. For example, using iron electrodes in a sodium chloride solution electrolyte, iron oxide will be produced at the anode, which will react to form iron hydroxide. When producing large quantities of hydrogen, this can significantly contaminate the electrolytic cell - which is why iron is not used for commercial electrolysis.
The energy efficiency of water electrolysis varies widely. The efficiency is a measure of what fraction of electrical energy used is actually contained within the hydrogen. Some of the electrical energy is converted to heat, a useless by-product. Some reports quote efficiencies between 50% and 70%[1] This efficiency is based on the Lower Heating Value of Hydrogen. The Lower Heating Value of Hydrogen is thermal energy released when Hydrogen is combusted. This does not represent the total amount of energy within the Hydrogen, hence the efficiency is lower than a more strict definition. Other reports quote the theoretical maximum efficiency of electrolysis. The theoretical maximum efficiency is between 80% and 94%.[2]. The theoretical maximum considers the total amount of energy absorbed by both the hydrogen and oxygen. These values refer only to the efficiency of converting electrical energy into hydrogen's chemical energy. The energy lost in generating the electricity is not included. For instance, when considering a power plant that converts the heat of nuclear reactions into hydrogen via electrolysis, the total efficiency is more like 25%–40%.[3]
About four percent of hydrogen gas produced worldwide is created by electrolysis, and normally used onsite. Hydrogen is used for the creation of ammonia for fertilizer via the Haber process, and converting heavy petroleum sources to lighter fractions via hydrocracking. There is some speculation about future development of hydrogen as an energy carrier.
# Experimenters
Scientific pioneers of electrolysis included:
- Humphry Davy
- Michael Faraday
- Paul Héroult
- Svante Arrhenius
- Adolph Wilhelm Hermann Kolbe
- William Nicholson
- Joseph Louis Gay-Lussac
- Alexander von Humboldt
More recently, electrolysis of heavy water was performed by Fleischmann and Pons in their famous experiment, allegedly resulting in anomalous heat generation and the controversial claim of cold fusion.
# Faraday's laws of electrolysis
## First law of electrolysis
In 1832, Michael Faraday reported that the quantity of elements separated by passing an electrical current through a molten or dissolved salt is proportional to the quantity of electric charge passed through the circuit. This became the basis of the first law of electrolysis:
<math>m = k \cdot q</math>
## Second law of electrolysis
Faraday also discovered that the mass of the resulting separated elements is directly proportional to the atomic masses of the elements when an appropriate integral divisor is applied. This provided strong evidence that discrete particles of matter exist as parts of the atoms of elements.
# Industrial uses
- Production of aluminium, lithium, sodium, potassium
- Production of hydrogen for hydrogen cars and fuel cells; high-temperature electrolysis is also used for this
- Coulometric techniques can be used to determine the amount of matter transformed during electrolysis by measuring the amount of electricity required to perform the electrolysis
- Production of chlorine and sodium hydroxide
- Production of sodium and potassium chlorate
- Production of perfluorinated organic compounds such as trifluoroacetic acid
Electrolysis has many other uses:
- Electrometallurgy is the process of reduction of metals from metallic compounds to obtain the pure form of metal using electrolysis. For example, sodium hydroxide in its molten form is separated by electrolysis into sodium and oxygen, both of which have important chemical uses. (Water is produced at the same time.)
- Anodization is an electrolytic process that makes the surface of metals resistant to corrosion. For example, ships are saved from being corroded by oxygen in the water by this process. The process is also used to decorate surfaces.
- A battery works by the reverse process to electrolysis. Humphry Davy found that lithium acts as an electrolyte and provides electrical energy.
- Production of oxygen for spacecraft and nuclear submarines.
- Electroplating is used in layering metals to fortify them. Electroplating is used in many industries for functional or decorative purposes, as in vehicle bodies and nickel coins.
- Production of hydrogen for fuel, using a cheap source of electrical energy.
- Electrolytic Etching of metal surfaces like tools or knives with a permanent mark or logo. | https://www.wikidoc.org/index.php/Electrolysis | |
13e89c0e6086c6654ab1eff6ecae7460309e1f10 | wikidoc | Polar effect | Polar effect
Please Take Over This Page and Apply to be Editor-In-Chief for this topic:
There can be one or more than one Editor-In-Chief. You may also apply to be an Associate Editor-In-Chief of one of the subtopics below. Please mail us to indicate your interest in serving either as an Editor-In-Chief of the entire topic or as an Associate Editor-In-Chief for a subtopic. Please be sure to attach your CV and or biographical sketch.
# Overview
The Polar effect or electronic effect in chemistry is the effect exerted by a substituent on modifying electrostatic forces operating on a nearby reaction center. The main contributors to the polar effect are the inductive effect, mesomeric effect and the through-space electronic field effect.
An electron withdrawing group or EWG draws electrons away from a reaction center. When this center is an electron rich carbanion or an alkoxide anion the presence of the substituent has a stabilizing effect.
Examples of electron withdrawing groups are:
- halogens (F, Cl),
- nitriles CN,
- carboxylic acids COOH
- carbonyls CO
An electron releasing group or ERG (otherwise called electron donating groups or EDG) releases electrons into a reaction center and as such stabilizes electron deficient carbocations.
Examples of electron releasing groups are:
- alkyl groups
- alcohol groups
- amino groups
The total substituent effect is the combination of the polar effect and the combined steric effects.
In electrophilic aromatic substitution and nucleophilic aromatic substitution substituents are divided into activating groups and deactivating groups where the direction of activation or deactivation is also taken into account. | Polar effect
Please Take Over This Page and Apply to be Editor-In-Chief for this topic:
There can be one or more than one Editor-In-Chief. You may also apply to be an Associate Editor-In-Chief of one of the subtopics below. Please mail us [1] to indicate your interest in serving either as an Editor-In-Chief of the entire topic or as an Associate Editor-In-Chief for a subtopic. Please be sure to attach your CV and or biographical sketch.
# Overview
The Polar effect or electronic effect in chemistry is the effect exerted by a substituent on modifying electrostatic forces operating on a nearby reaction center. The main contributors to the polar effect are the inductive effect, mesomeric effect and the through-space electronic field effect.
An electron withdrawing group or EWG draws electrons away from a reaction center. When this center is an electron rich carbanion or an alkoxide anion the presence of the substituent has a stabilizing effect.
Examples of electron withdrawing groups are:
- halogens (F, Cl),
- nitriles CN,
- carboxylic acids COOH
- carbonyls CO
An electron releasing group or ERG (otherwise called electron donating groups or EDG) releases electrons into a reaction center and as such stabilizes electron deficient carbocations.
Examples of electron releasing groups are:
- alkyl groups
- alcohol groups
- amino groups
The total substituent effect is the combination of the polar effect and the combined steric effects.
In electrophilic aromatic substitution and nucleophilic aromatic substitution substituents are divided into activating groups and deactivating groups where the direction of activation or deactivation is also taken into account.
# External links
- Polar effect definition by the IUPAC Gold Book Link
Template:SIB | https://www.wikidoc.org/index.php/Electron-donating_group | |
276551bfc4a1b345dee1c3ef27cb5746d807b8e2 | wikidoc | Electronvolt | Electronvolt
# Overview
The electronvolt (symbol eV) is a unit of energy. It is the amount of energy equivalent to that gained by a single unbound electron when it is accelerated through an electrostatic potential difference of one volt, in vacuo. In other words, it is equal to one volt (1 volt = 1 joule per coulomb) times the (unsigned) charge of a single electron. The one-word spelling is the modern recommendation, although the use of the earlier electron volt still exists.
One electronvolt is a very small amount of energy:
The unit electronvolt is accepted (but not encouraged) for use with SI. It is widely used in solid state, atomic, nuclear, and particle physics, often with prefixes m, k, M, G or T. In a recorded lecture from 1961 Richard Feynman apologized to his students for this failure by atomic physicists to use the appropriate SI unit (which would be the attojoule):
In chemistry, it is often useful to have the molar equivalent, that is the kinetic energy that would be gained by a mole of electrons passing through a potential difference of one volt. This quantity is equal to 96.48538(2) kJ/mol. Ionization energies and other atomic properties are often quoted in electronvolts, especially in older texts.
# As a measurement of mass
Albert Einstein reasoned that energy is equivalent to mass, as famously expressed in the mass-energy equivalence formula E = mc² (1.0000 kg = 89.876 PJ). It is thus common in particle physics, where mass and energy are often interchanged, to use eV/c² or even simply eV as a unit of mass.
For example, an electron and a positron, each with a mass of 0.511 MeV/c², can annihilate to yield 1.022 MeV of energy. The proton has a mass of 0.938 GeV/c², making GeV (gigaelectronvolt) a very convenient unit of mass for particle physics.
See: Orders of magnitude (mass)
In some older documents, and in the name Bevatron, the symbol "BeV" is used, which stands for "billion-electron-volt"; it is equivalent to the GeV.
Since MeV as a unit often are used in nuclear energy equations, for example as in the stellar nuclear fusion process of carbon burning, among others the equation
conversion of atomic mass unit u to MeV is often performed by the formula:
and inversely
# Energy
For comparison:
- 3.2Template:E joule or 200 MeV - total energy released in nuclear fission of one U-235 atom (on average; depends on the precise break up); this is 82 TJ/kg = 20 kt TNT / kg
- 3.5Template:E joule or 210 MeV - total energy released in fission of one Pu-239 atom (also on average)
- Molecular bond energies are on the order of an electronvolt per molecule.
- The typical atmospheric molecule has a kinetic energy of about 1/40 eV. This corresponds to room temperature.
Conversion factor:
- 1 eV per amu is 96.5 MJ/kg
# Photon properties
The energy E, frequency f, and wavelength λ of a photon are related by
where h is Planck's constant and c is the speed of light. For example, the spectrum of visible light consists of wavelengths ranging from 400 nm to 700 nm. Photons of visible light therefore have energies ranging from
to
An electronvolt is also the energy of an infrared photon with a wavelength of approximately 1240 nm. Similarly, 10eV would correspond to ultraviolet of wavelength 124 nm, and so on.
# As a measurement for time and distance
In particle physics, distances and times are sometimes expressed in inverse electronvolts via the conversion factors
- \hbar = 6.582 118 89(26) x 10-16 eV s
- \hbar c = 197.326 960 2(77) eV nm
In these units, the mean lifetime \tau of an unstable particle can be reexpressed in terms of its decay width \Gamma (in eV) via \Gamma = \hbar/\tau. For example, the B0 meson has a mean lifetime of 1.542(16) picoseconds, or a decay width of 4.269(44) x 10-4 eV, and its mean decay length is c\tau = 462 \mum.
# Temperature
In certain fields, such as plasma physics, it is convenient to use the electronvolt as a unit of temperature. The conversion to kelvins (symbol: uppercase K) is defined by using kB, the Boltzmann constant:
For example, a typical magnetic confinement fusion plasma is 15 keV, or 174 megakelvins. | Electronvolt
# Overview
The electronvolt (symbol eV) is a unit of energy. It is the amount of energy equivalent to that gained by a single unbound electron when it is accelerated through an electrostatic potential difference of one volt, in vacuo. In other words, it is equal to one volt (1 volt = 1 joule per coulomb) times the (unsigned) charge of a single electron. The one-word spelling is the modern recommendation[1], although the use of the earlier electron volt still exists.
One electronvolt is a very small amount of energy:
The unit electronvolt is accepted (but not encouraged) for use with SI. It is widely used in solid state, atomic, nuclear, and particle physics, often with prefixes m, k, M, G or T. In a recorded lecture from 1961 Richard Feynman apologized to his students for this failure by atomic physicists to use the appropriate SI unit (which would be the attojoule):
In chemistry, it is often useful to have the molar equivalent, that is the kinetic energy that would be gained by a mole of electrons passing through a potential difference of one volt. This quantity is equal to 96.48538(2) kJ/mol. Ionization energies and other atomic properties are often quoted in electronvolts, especially in older texts.
# As a measurement of mass
Albert Einstein reasoned that energy is equivalent to mass, as famously expressed in the mass-energy equivalence formula E = mc² (1.0000 kg = 89.876 PJ). It is thus common in particle physics, where mass and energy are often interchanged, to use eV/c² or even simply eV as a unit of mass.
For example, an electron and a positron, each with a mass of 0.511 MeV/c², can annihilate to yield 1.022 MeV of energy. The proton has a mass of 0.938 GeV/c², making GeV (gigaelectronvolt) a very convenient unit of mass for particle physics.
See: Orders of magnitude (mass)
In some older documents, and in the name Bevatron, the symbol "BeV" is used, which stands for "billion-electron-volt"; it is equivalent to the GeV.
Since MeV as a unit often are used in nuclear energy equations, for example as in the stellar nuclear fusion process of carbon burning, among others the equation
conversion of atomic mass unit u to MeV is often performed by the formula:
and inversely
# Energy
For comparison:
- 3.2Template:E joule or 200 MeV - total energy released in nuclear fission of one U-235 atom (on average; depends on the precise break up); this is 82 TJ/kg = 20 kt TNT / kg
- 3.5Template:E joule or 210 MeV - total energy released in fission of one Pu-239 atom (also on average)
- Molecular bond energies are on the order of an electronvolt per molecule.
- The typical atmospheric molecule has a kinetic energy of about 1/40 eV. This corresponds to room temperature.
Conversion factor:
- 1 eV per amu is 96.5 MJ/kg
# Photon properties
The energy E, frequency f, and wavelength λ of a photon are related by
where h is Planck's constant and c is the speed of light. For example, the spectrum of visible light consists of wavelengths ranging from 400 nm to 700 nm. Photons of visible light therefore have energies ranging from
to
An electronvolt is also the energy of an infrared photon with a wavelength of approximately 1240 nm. Similarly, 10eV would correspond to ultraviolet of wavelength 124 nm, and so on.
# As a measurement for time and distance
In particle physics, distances and times are sometimes expressed in inverse electronvolts via the conversion factors[4]
- <math>\hbar</math> = 6.582 118 89(26) x 10-16 eV s
- <math>\hbar c</math> = 197.326 960 2(77) eV nm
In these units, the mean lifetime <math>\tau</math> of an unstable particle can be reexpressed in terms of its decay width <math>\Gamma</math> (in eV) via <math>\Gamma = \hbar/\tau</math>. For example, the B0 meson has a mean lifetime of 1.542(16) picoseconds, or a decay width of 4.269(44) x 10-4 eV, and its mean decay length is <math>c\tau</math> = 462 <math>\mu</math>m.
# Temperature
In certain fields, such as plasma physics, it is convenient to use the electronvolt as a unit of temperature. The conversion to kelvins (symbol: uppercase K) is defined by using kB, the Boltzmann constant:
For example, a typical magnetic confinement fusion plasma is 15 keV, or 174 megakelvins. | https://www.wikidoc.org/index.php/Electron_volt | |
9d13c1bda61c7bebc6eb7237baa300f0a749d340 | wikidoc | Electrophile | Electrophile
In chemistry, an electrophile (literally electron-lover) is a reagent attracted to electrons that participates in a chemical reaction by accepting an electron pair in order to bond to a nucleophile. Because electrophiles accept electrons, they are Lewis acids (see acid-base reaction theories). Most electrophiles are positively charged, have an atom which carries a partial positive charge, or have an atom which does not have an octet of electrons.
The electrophiles attack the most electron-populated part of a nucleophile. The electrophiles frequently seen in the organic syntheses are cations such as H+ and NO+, polarlized neutral molecules such as HCl, alkyl halides, acyl halides, and carbonyl compounds, polarlizable neutral molecules such as Cl2 and Br2, oxidizing agents such as organic peracids, chemical species that do not satisfy the octet rule such as carbenes and radicals, and some of lewis acids such as BH3 and DIBAL.
# Electrophiles in organic chemistry
## Alkenes
Electrophilic addition is one of the three main forms of reaction concerning alkenes. They consist of:
- Hydrogenation by the addition of hydrogen over the double bond.
- Electrophilic addition reactions with halogens and sulfuric acid.
- Hydration to form alcohols.
## Addition of halogens
These occur between alkenes and electrophiles, often halogens as in halogen addition reactions. Common reactions include use of bromine water to titrate against a sample to deduce the number of double bonds present. For example, ethylene + bromine → 1,2-dibromoethane:
This takes the form of 3 main steps shown below;
- Forming of a π-complex
The electrophilic Br-Br molecule interacts with electron-rich alkene molecure to form a π-complex 1.
- Forming of a three-membered bromonium ion
The alkene is working as an electron donor and bromine as an electrophile. The three-membered bromonium ion 2 consisted with two carbon atoms and a bromine atom forms with a release of Br−.
- Attacking of bromide ion
The bromonium ion is opened by the attack of Br− from the back side. This yields the vicinal dibromide with an antiperiplanar configuration. When other nucleophiles such as water or alcohol are existing, these may attack 2 to give an alcohol or an ether.
This process is called AdE2 mechanism. Iodine (I2), chlorine (Cl2), sulfenyl ion (RS+), mercury cation (Hg2+), and dichlorocarbene (:CCl2) also react through similar pathways. The direct conversion of 1 to 3 will appear when the Br− is large excess in the reaction medium. A β-bromo carbenium ion intermediate may be predominant instead of 3 if the alkene has a cation-stabilizing substituent like phenyl group. There is an example of the isolation of the bromonium ion 2.
## Addition of hydrogen halides
Hydrogen halides such as hydrogen chloride (HCl) adds to alkenes to give alkyl halide in hydrohalogenation. For example, the reaction of HCl with ethylene furnishes chloroethane. The reaction proceeds with a cation intermediate, being different from the above halogen addition. An example shown below:
- Proton (H+) adds (by working as an electrophile) to one of the carbon atoms on the alkene to form cation 1.
- Chloride ion (Cl−) combines with the cation 1 to form the adducts 2 and 3.
In this manner, the stereoselectivity of the product, that is, from which side Cl− will attack relies on the types of alkenes applied and conditions of the reaction. At least, which of the two carbon atoms will be attacked by H+ is usually decided by Markovnikov's rule. Thus, H+ attacks the carbon atom which carries the less number of substituents so as to the more stabilized carbocation (with the more stabilizing substituents) will form.
This process is called A-SE2 mechanism. Hydrogen fluoride (HF) and hydrogen iodide (HI) react with alkenes similarly and Markovnikov-type products will be given. Hydrogen bromide (HBr) also takes this pathway, but sometimes a radical process competes and a mixture of isomers may form.
## Hydration
One of the more complex hydration reactions utilises sulfuric acid as a catalyst. This reaction occurs in a similar way to the addition reaction but has an extra step in which the OSO3H group is replaced by an OH group, forming an alcohol:
As you can see the H2SO4 does not take part in the overall reaction, however it does take part but remains unchanged so is classified as a catalyst.
This is the reaction in more detail:
- The H-OSO3H molecule has a δ+ charge on the initial H atom, this is attracted to and reacts with the double bond in the same way as before.
- The remaining (negatively charged) −OSO3H ion then attaches to the carbocation. Forming ethyl hydrogensulphate (upper way on the above scheme).
- When water (H2O) is added and the mixture headed ethanol (C2H5OH) is produced, the "spare" hydrogen atom from the water goes into "replacing" the "lost" hydrogen and thus reproduces sulfuric acid. Another pathway in which water molecule combines directly to the intermediate carbocation (lower way) is also possible. This pathway become predominant when aqueous sulfuric acid is used.
Overall this process adds a molecule of water to a molecule of ethene.
This is an important reaction in industry as it produces ethanol, which is the alcohol having various purposes including fuels and starting material for other chemicals.
# Electrophilicity scale
Several methods exist to rank electrophiles in order of reactivity and one of them is devised by Robert Parr with the electrophilicity index ω given as:
with \chi\, the electronegativity and \eta\, chemical hardness. This equation is related to classical equation for electrical power:
where R\, is the resistance (Ohm or Ω) and V\, is voltage. In this sense the electrophilicity index is a kind of electrophilic power. Correlations have been found between electrophilicity of various chemical compounds and reaction rates in biochemical systems and such phenomena as allergic contact dermititis.
A electrophilicity index also exists for free radicals . Strongly electrophilic radicals such as the halogens react with electron-rich reaction sites and strongly nucleophilic radicals such as the 2-hydroxypropyl-2-yl and tert-butyl radical react with a preference for electron-poor reaction sites. | Electrophile
In chemistry, an electrophile (literally electron-lover) is a reagent attracted to electrons that participates in a chemical reaction by accepting an electron pair in order to bond to a nucleophile. Because electrophiles accept electrons, they are Lewis acids (see acid-base reaction theories). Most electrophiles are positively charged, have an atom which carries a partial positive charge, or have an atom which does not have an octet of electrons.
The electrophiles attack the most electron-populated part of a nucleophile. The electrophiles frequently seen in the organic syntheses are cations such as H+ and NO+, polarlized neutral molecules such as HCl, alkyl halides, acyl halides, and carbonyl compounds, polarlizable neutral molecules such as Cl2 and Br2, oxidizing agents such as organic peracids, chemical species that do not satisfy the octet rule such as carbenes and radicals, and some of lewis acids such as BH3 and DIBAL.
# Electrophiles in organic chemistry
## Alkenes
Electrophilic addition is one of the three main forms of reaction concerning alkenes. They consist of:
- Hydrogenation by the addition of hydrogen over the double bond.
- Electrophilic addition reactions with halogens and sulfuric acid.
- Hydration to form alcohols.
## Addition of halogens
These occur between alkenes and electrophiles, often halogens as in halogen addition reactions. Common reactions include use of bromine water to titrate against a sample to deduce the number of double bonds present. For example, ethylene + bromine → 1,2-dibromoethane:
This takes the form of 3 main steps shown below[1];
- Forming of a π-complex
The electrophilic Br-Br molecule interacts with electron-rich alkene molecure to form a π-complex 1.
- Forming of a three-membered bromonium ion
The alkene is working as an electron donor and bromine as an electrophile. The three-membered bromonium ion 2 consisted with two carbon atoms and a bromine atom forms with a release of Br−.
- Attacking of bromide ion
The bromonium ion is opened by the attack of Br− from the back side. This yields the vicinal dibromide with an antiperiplanar configuration. When other nucleophiles such as water or alcohol are existing, these may attack 2 to give an alcohol or an ether.
This process is called AdE2 mechanism. Iodine (I2), chlorine (Cl2), sulfenyl ion (RS+), mercury cation (Hg2+), and dichlorocarbene (:CCl2) also react through similar pathways. The direct conversion of 1 to 3 will appear when the Br− is large excess in the reaction medium. A β-bromo carbenium ion intermediate may be predominant instead of 3 if the alkene has a cation-stabilizing substituent like phenyl group. There is an example of the isolation of the bromonium ion 2.[2]
## Addition of hydrogen halides
Hydrogen halides such as hydrogen chloride (HCl) adds to alkenes to give alkyl halide in hydrohalogenation. For example, the reaction of HCl with ethylene furnishes chloroethane. The reaction proceeds with a cation intermediate, being different from the above halogen addition. An example shown below:
- Proton (H+) adds (by working as an electrophile) to one of the carbon atoms on the alkene to form cation 1.
- Chloride ion (Cl−) combines with the cation 1 to form the adducts 2 and 3.
In this manner, the stereoselectivity of the product, that is, from which side Cl− will attack relies on the types of alkenes applied and conditions of the reaction. At least, which of the two carbon atoms will be attacked by H+ is usually decided by Markovnikov's rule. Thus, H+ attacks the carbon atom which carries the less number of substituents so as to the more stabilized carbocation (with the more stabilizing substituents) will form.
This process is called A-SE2 mechanism. Hydrogen fluoride (HF) and hydrogen iodide (HI) react with alkenes similarly and Markovnikov-type products will be given. Hydrogen bromide (HBr) also takes this pathway, but sometimes a radical process competes and a mixture of isomers may form.
## Hydration
One of the more complex hydration reactions utilises sulfuric acid as a catalyst. This reaction occurs in a similar way to the addition reaction but has an extra step in which the OSO3H group is replaced by an OH group, forming an alcohol:
As you can see the H2SO4 does not take part in the overall reaction, however it does take part but remains unchanged so is classified as a catalyst.
This is the reaction in more detail:
- The H-OSO3H molecule has a δ+ charge on the initial H atom, this is attracted to and reacts with the double bond in the same way as before.
- The remaining (negatively charged) −OSO3H ion then attaches to the carbocation. Forming ethyl hydrogensulphate (upper way on the above scheme).
- When water (H2O) is added and the mixture headed ethanol (C2H5OH) is produced, the "spare" hydrogen atom from the water goes into "replacing" the "lost" hydrogen and thus reproduces sulfuric acid. Another pathway in which water molecule combines directly to the intermediate carbocation (lower way) is also possible. This pathway become predominant when aqueous sulfuric acid is used.
Overall this process adds a molecule of water to a molecule of ethene.
This is an important reaction in industry as it produces ethanol, which is the alcohol having various purposes including fuels and starting material for other chemicals.
# Electrophilicity scale
Several methods exist to rank electrophiles in order of reactivity [4] and one of them is devised by Robert Parr [3] with the electrophilicity index ω given as:
with <math>\chi\,</math> the electronegativity and <math>\eta\,</math> chemical hardness. This equation is related to classical equation for electrical power:
where <math>R\,</math> is the resistance (Ohm or Ω) and <math>V\,</math> is voltage. In this sense the electrophilicity index is a kind of electrophilic power. Correlations have been found between electrophilicity of various chemical compounds and reaction rates in biochemical systems and such phenomena as allergic contact dermititis.
A electrophilicity index also exists for free radicals [5]. Strongly electrophilic radicals such as the halogens react with electron-rich reaction sites and strongly nucleophilic radicals such as the 2-hydroxypropyl-2-yl and tert-butyl radical react with a preference for electron-poor reaction sites. | https://www.wikidoc.org/index.php/Electrophile | |
0c06914c2c636538594d1acc41b4f6e58464771e | wikidoc | Pimecrolimus | Pimecrolimus
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# Black Box Warning
# Overview
Pimecrolimus is an analgesic that is FDA approved for the treatment of atopic dermatitis. There is a Black Box Warning for this drug as shown here. Common adverse reactions include sensation of burning of skin, risk for viral infection, headache, fever.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- ELIDEL® (pimecrolimus) Cream, 1% is indicated as second-line therapy for the short-term and non-continuous chronic treatment of mild to moderate atopic dermatitis in non-immunocompromised adults, who have failed to respond adequately to other topical prescription treatments, or when those treatments are not advisable.
- Dosing Information
- Apply a thin layer of ELIDEL (pimecrolimus) Cream, 1% to the affected skin twice daily. The patient should stop using ELIDEL Cream, 1% when signs and symptoms (e.g., itch, rash and redness) resolve and should be instructed on what actions to take if symptoms recur.
- If signs and symptoms persist beyond 6 weeks, patients should be re-examined by their health care provider to confirm the diagnosis of atopic dermatitis.
- Continuous long-term use of ELIDEL Cream, 1% should be avoided, and application should be limited to areas of involvement with atopic dermatitis.
- The safety of ELIDEL Cream, 1% under occlusion, which may promote systemic exposure, has not been evaluated. Avoid use of ELIDEL Cream, 1% with occlusive dressings.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Pimecrolimus in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Pimecrolimus in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
- ELIDEL® (pimecrolimus) Cream, 1% is indicated as second-line therapy for the short-term and non-continuous chronic treatment of mild to moderate atopic dermatitis in non-immunocompromised children 2 years of age and older, who have failed to respond adequately to other topical prescription treatments, or when those treatments are not advisable.
- ELIDEL Cream, 1% is not indicated for use in children less than 2 years of age.
- Dosing Information
- Apply a thin layer of ELIDEL (pimecrolimus) Cream, 1% to the affected skin twice daily. The patient should stop using ELIDEL Cream, 1% when signs and symptoms (e.g., itch, rash and redness) resolve and should be instructed on what actions to take if symptoms recur.
- If signs and symptoms persist beyond 6 weeks, patients should be re-examined by their health care provider to confirm the diagnosis of atopic dermatitis.
- Continuous long-term use of ELIDEL Cream, 1% should be avoided, and application should be limited to areas of involvement with atopic dermatitis.
- The safety of ELIDEL Cream, 1% under occlusion, which may promote systemic exposure, has not been evaluated. Avoid use of ELIDEL Cream, 1% with occlusive dressings.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Pimecrolimus in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Pimecrolimus in pediatric patients.
# Contraindications
- ELIDEL® (pimecrolimus) Cream, 1% is contraindicated in individuals with a history of hypersensitivity to pimecrolimus or any of the components of the cream.
# Warnings
Risk of Immunosuppression
- Prolonged systemic use of calcineurin inhibitors for sustained immunosuppression in animal studies and transplant patients following systemic administration has been associated with an increased risk of infections, lymphomas, and skin malignancies. These risks are associated with the intensity and duration of immunosuppression.
- Based on this information and the mechanism of action, there is a concern about a potential risk with the use of topical calcineurin inhibitors, including ELIDEL Cream, 1%. While a causal relationship has not been established, rare cases of skin malignancy and lymphoma have been reported in patients treated with topical calcineurin inhibitors, including ELIDEL Cream, 1%. Therefore:
- Continuous long-term use of topical calcineurin inhibitors, including ELIDEL Cream, 1%, in any age group should be avoided, and application limited to areas of involvement with atopic dermatitis
- ELIDEL Cream, 1% is not indicated for use in children less than 2 years of age
- ELIDEL Cream, 1% should not be used in immunocompromised adults and children, including patients on systemic immunosuppressive medications.
- If signs and symptoms of atopic dermatitis do not improve within 6 weeks, patients should be re-examined by their healthcare provider and their diagnosis be confirmed.
- The safety of ELIDEL Cream, 1% has not been established beyond one year of non-continuous use.
Application to Malignant or Pre-malignant Skin Conditions
- The use of ELIDEL Cream, 1% should be avoided on malignant or pre-malignant skin conditions. Malignant or pre-malignant skin conditions, such as cutaneous T-cell lymphoma (CTCL), can present as dermatitis.
- ELIDEL Cream, 1% should not be used in patients with Netherton’s Syndrome or other skin diseases where there is the potential for increased systemic absorption of pimecrolimus. The safety of ELIDEL Cream, 1% has not been established in patients with generalized erythroderma.
- The use of ELIDEL Cream, 1% may cause local symptoms such as skin burning (burning sensation, stinging, soreness) or pruritus. Localized symptoms are most common during the first few days of ELIDEL Cream, 1% application and typically improve as the lesions of atopic dermatitis resolve.
Bacterial and Viral Skin Infections
- Before commencing treatment with ELIDEL Cream, 1%, bacterial or viral infections at treatment sites should be resolved. Trials have not evaluated the safety and efficacy of ELIDEL Cream, 1% in the treatment of clinically infected atopic dermatitis.
- While patients with atopic dermatitis are predisposed to superficial skin infections including eczema herpeticum (Kaposi’s varicelliform eruption), treatment with ELIDEL Cream, 1% may be independently associated with an increased risk of varicella zoster virus infection (chicken pox or shingles), herpes simplex virus infection, or eczema herpeticum.
- In clinical trials, 15/1,544 (1%) cases of skin papilloma (warts) were observed in subjects using ELIDEL Cream, 1%. The youngest subject was age 2 and the oldest was age 12. In cases where there is worsening of skin papillomas or they do not respond to conventional therapy, discontinuation of ELIDEL Cream, 1% should be considered until complete resolution of the warts is achieved.
Patients with Lymphadenopathy
- In clinical trials, 14/1,544 (0.9%) cases of lymphadenopathy were reported while using ELIDEL Cream, 1%. These cases of lymphadenopathy were usually related to infections and noted to resolve upon appropriate antibiotic therapy. Of these 14 cases, the majority had either a clear etiology or were known to resolve. Patients who receive ELIDEL Cream, 1% and who develop lymphadenopathy should have the etiology of their lymphadenopathy investigated. In the absence of a clear etiology for the lymphadenopathy, or in the presence of acute infectious mononucleosis, ELIDEL Cream, 1% should be discontinued. Patients who develop lymphadenopathy should be monitored to ensure that the lymphadenopathy resolves.
Sun Exposure
- During the course of treatment, it is prudent for patients to minimize or avoid natural or artificial sunlight exposure, even while ELIDEL Cream, 1% is not on the skin. The potential effects of ELIDEL Cream, 1% on skin response to ultraviolet damage are not known.
Immunocompromised Patients
- The safety and efficacy of ELIDEL Cream, 1% in immunocompromised patients have not been studied.
# Adverse Reactions
## Clinical Trials Experience
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.
- No phototoxicity and no photoallergenicity were detected in clinical trials with 24 and 33 normal volunteers, respectively. In human dermal safety trials, ELIDEL (pimecrolimus) Cream, 1% did not induce contact sensitization or cumulative irritation.
- In a one-year safety trial in pediatric subjects age 2-17 years old involving sequential use of ELIDEL Cream, 1% and a topical corticosteroid, 43% of ELIDEL Cream, 1% treated subjects and 68% of vehicle-treated subjects used corticosteroids during the trial. Corticosteroids were used for more than 7 days by 34% of ELIDEL Cream, 1% treated subjects and 54% of vehicle-treated subjects. An increased incidence of impetigo, skin infection, superinfection (infected atopic dermatitis), rhinitis, and urticaria were found in the subjects that had used ELIDEL Cream, 1% and topical corticosteroid sequentially as compared to ELIDEL Cream, 1% alone.
- In 3 randomized, double-blind vehicle-controlled pediatric trials and one active-controlled adult trial, 843 and 328 subjects respectively, were treated with ELIDEL Cream, 1%. In these clinical trials, 48 (4%) of the 1,171 ELIDEL treated subjects and 13 (3%) of 408 vehicle-treated subjects discontinued therapy due to adverse events. Discontinuations for AEs were primarily due to application site reactions, and cutaneous infections. The most common application site reaction was application site burning, which occurred in 8%-26% of subjects treated with ELIDEL Cream, 1%.
- Table 1 depicts the incidence of adverse events pooled across the 2 identically designed 6-week trials with their open label extensions and the 1-year safety trial for pediatric subjects ages 2-17. Data from the adult active-controlled trial is also included in Table 1. Adverse events are listed regardless of relationship to trial drug.
- Two cases of septic arthritis have been reported in infants less than one year of age in clinical trials conducted with ELIDEL Cream, 1% (n = 2,443). Causality has not been established.
## Postmarketing Experience
- The following adverse reactions have been identified during post-approval use of ELIDEL Cream, 1%. 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.
- General: Anaphylactic reactions, ocular irritation after application of the cream to the eye lids or near the eyes, angioneurotic edema, facial edema, skin flushing associated with alcohol use, skin discoloration.
- Hematology/Oncology: Lymphomas, basal cell carcinoma, malignant melanoma, squamous cell carcinoma.
# Drug Interactions
- Potential interactions between ELIDEL Cream, 1% and other drugs, including immunizations, have not been systematically evaluated. Due to low blood levels of pimecrolimus detected in some patients after topical application, systemic drug interactions are not expected, but cannot be ruled out. The concomitant administration of known CYP3A family of inhibitors in patients with widespread and/or erythrodermic disease should be done with caution. Some examples of such drugs are erythromycin, itraconazole, ketoconazole, fluconazole, calcium channel blockers and cimetidine.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): C
Pregnancy Category C
- There are no adequate and well-controlled studies with ELIDEL Cream, 1% in pregnant women. Therefore, ELIDEL Cream, 1% should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
- In dermal embryofetal developmental studies, no maternal or fetal toxicity was observed up to the highest practicable doses tested, 10 mg/kg/day (1% pimecrolimus cream) in rats (0.14× MRHD based on body surface area) and 10 mg/kg/day (1% pimecrolimus cream) in rabbits (0.65× MRHD based on AUC comparisons). The 1% pimecrolimus cream was administered topically for 6 hours/day during the period of organogenesis in rats and rabbits (gestational days 6-21 in rats and gestational days 6-20 in rabbits).
- A second dermal embryofetal development study was conducted in rats using pimecrolimus cream applied dermally to pregnant rats (1 g cream/kg body weight of 0.2%, 0.6% and 1.0% pimecrolimus cream) from gestation day 6 to 17 at doses of 2, 6, and 10 mg/kg/day with daily exposure of approximately 22 hours. No maternal, reproductive, or embryo-fetal toxicity attributable to pimecrolimus was noted at 10 mg/kg/day (0.66× MRHD based on AUC comparisons), the highest dose evaluated in this study. No teratogenicity was noted in this study at any dose.
- A combined oral fertility and embryofetal developmental study was conducted in rats and an oral embryofetal developmental study was conducted in rabbits. Pimecrolimus was administered during the period of organogenesis (2 weeks prior to mating until gestational day 16 in rats, gestational days 6-18 in rabbits) up to dose levels of 45 mg/kg/day in rats and 20 mg/kg/day in rabbits. In the absence of maternal toxicity, indicators of embryofetal toxicity (post-implantation loss and reduction in litter size) were noted at 45 mg/kg/day (38× MRHD based on AUC comparisons) in the oral fertility and embryofetal developmental study conducted in rats. No malformations in the fetuses were noted at 45 mg/kg/day (38× MRHD based on AUC comparisons) in this study. No maternal toxicity, embryotoxicity or teratogenicity were noted in the oral rabbit embryofetal developmental toxicity study at 20 mg/kg/day (3.9× MRHD based on AUC comparisons), which was the highest dose tested in this study.
- A second oral embryofetal development study was conducted in rats. Pimecrolimus was administered during the period of organogenesis (gestational days 6 – 17) at doses of 2, 10 and 45 mg/kg/day. Maternal toxicity, embryolethality and fetotoxicity were noted at 45 mg/kg/day (271× MRHD based on AUC comparisons). A slight increase in skeletal variations that were indicative of delayed skeletal ossification was also noted at this dose. No maternal toxicity, embryolethality or fetotoxicity were noted at 10 mg/kg/day (16× MRHD based on AUC comparisons). No teratogenicity was noted in this study at any dose.
- A second oral embryofetal development study was conducted in rabbits. Pimecrolimus was administered during the period of organogenesis (gestational days 7 – 20) at doses of 2, 6 and 20 mg/kg/day. Maternal toxicity, embryotoxicity and fetotoxicity were noted at 20 mg/kg/day (12× MRHD based on AUC comparisons). A slight increase in skeletal variations that were indicative of delayed skeletal ossification was also noted at this dose. No maternal toxicity, embryotoxicity or fetotoxicity were noted at 6 mg/kg/day (5× MRHD based on AUC comparisons). No teratogenicity was noted in this study at any dose.
- An oral peri- and post-natal developmental study was conducted in rats. Pimecrolimus was administered from gestational day 6 through lactational day 21 up to a dose level of 40 mg/kg/day. Only 2 of 22 females delivered live pups at the highest dose of 40 mg/kg/day. Postnatal survival, development of the F1 generation, their subsequent maturation and fertility were not affected at 10 mg/kg/day (12× MRHD based on AUC comparisons), the highest dose evaluated in this study.
- Pimecrolimus was transferred across the placenta in oral rat and rabbit embryofetal developmental studies.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Pimecrolimus in women who are pregnant.
### Labor and Delivery
- There is no FDA guidance on use of Pimecrolimus during labor and delivery.
### Nursing Mothers
- It is not known whether this drug is excreted in human milk. Because of the potential for serious adverse reactions in nursing infants from pimecrolimus, 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
- ELIDEL Cream, 1% is not indicated for use in children less than 2 years of age.
- The long-term safety and effects of ELIDEL Cream, 1% on the developing immune system are unknown.
- Three Phase 3 pediatric trials were conducted involving 1,114 subjects 2-17 years of age. Two trials were 6-week randomized vehicle-controlled trials with a 20-week open-label phase and one was a vehicle-controlled (up to 1 year) safety trial with the option for sequential topical corticosteroid use. Of these subjects 542 (49%) were 2-6 years of age. In the short-term trials, 11% of ELIDEL subjects did not complete these trials and 1.5% of ELIDEL subjects discontinued due to adverse events. In the one-year trial, 32% of ELIDEL subjects did not complete this trial and 3% of ELIDEL subjects discontinued due to adverse events. Most discontinuations were due to unsatisfactory therapeutic effect.
- The most common local adverse event in the short-term trials of ELIDEL Cream, 1% in pediatric subjects ages 2-17 was application site burning (10% vs. 13% vehicle); the incidence in the long-term trial was 9% ELIDEL vs. 7% vehicle . Adverse events that were more frequent (>5%) in subjects treated with ELIDEL Cream, 1% compared to vehicle were headache (14% vs. 9%) in the short-term trial. Nasopharyngitis (26% vs. 21%), influenza (13% vs. 4%), pharyngitis (8% vs. 3%), viral infection (7% vs. 1%), pyrexia (13% vs. 5%), cough (16% vs. 11%), and headache (25% vs. 16%) were increased over vehicle in the 1-year safety trial . In 843 subjects ages 2-17 years treated with ELIDEL Cream, 1%, 9 (0.8%) developed eczema herpeticum (5 on ELIDEL Cream, 1% alone and 4 on ELIDEL Cream, 1% used in sequence with corticosteroids). In 211 subjects on vehicle alone, there were no cases of eczema herpeticum. The majority of adverse events were mild to moderate in severity.
- Two Phase 3 trials were conducted involving 436 infants age 3 months-23 months. One 6-week randomized vehicle-controlled trial with a 20-week open-label phase and one safety trial, up to one year, were conducted. In the 6-week trial, 11% of ELIDEL and 48% of vehicle subjects did not complete this trial; no subject in either group discontinued due to adverse events. Infants on ELIDEL Cream, 1% had an increased incidence of some adverse events compared to vehicle. In the 6-week vehicle-controlled trial these adverse events included pyrexia (32% vs. 13% vehicle), URI (24% vs. 14%), nasopharyngitis (15% vs. 8%), gastroenteritis (7% vs. 3%), otitis media (4% vs. 0%), and diarrhea (8% vs. 0%). In the open-label phase of the trial, for infants who switched to ELIDEL Cream, 1% from vehicle, the incidence of the above-cited adverse events approached or equaled the incidence of those subjects who remained on ELIDEL Cream, 1%. In the 6 month safety data, 16% of ELIDEL and 35% of vehicle subjects discontinued early and 1.5% of ELIDEL and 0% of vehicle subjects discontinued due to adverse events. Infants on ELIDEL Cream, 1% had a greater incidence of some adverse events as compared to vehicle. These included pyrexia (30% vs. 20%), URI (21% vs. 17%), cough (15% vs. 9%), hypersensitivity (8% vs. 2%), teething (27% vs. 22%), vomiting (9% vs. 4%), rhinitis (13% vs. 9%), viral rash (4% vs. 0%), rhinorrhea (4% vs. 0%), and wheezing (4% vs. 0%).
- The systemic exposure to pimecrolimus from ELIDEL (pimecrolimus) Cream, 1% was investigated in 28 pediatric subjects with atopic dermatitis (20%-80% BSA involvement) between the ages of 8 months-14 yrs. Following twice daily application for three weeks, blood concentrations of pimecrolimus were <2 ng/mL with 60% (96/161) of the blood samples having blood concentration below the limit of quantification (0.5 ng/mL). However, more children (23 children out of the total 28 children investigated) had at least one detectable blood level as compared to the adults (12 adults out of the total 52 adults investigated) over a 3-week treatment period. Due to the erratic nature of the blood levels observed, no correlation could be made between amount of cream, degree of BSA involvement, and blood concentrations. In general, the blood concentrations measured in adult atopic dermatitis subjects were comparable to those seen in the pediatric population.
- In a second group of 30 pediatric subjects aged 3-23 months with 10%-92% BSA involvement, following twice daily application for three weeks, blood concentrations of pimecrolimus were <2.6 ng/mL with 65% (75/116) of the blood samples having blood concentration below 0.5 ng/mL, and 27% (31/116) below the limit of quantification (0.1 ng/mL) for these trials.
- Overall, a higher proportion of detectable blood levels was seen in the pediatric subject population as compared to adult population. This increase in the absolute number of positive blood levels may be due to the larger surface area to body mass ratio seen in these younger subjects. In addition, a higher incidence of upper respiratory symptoms/infections was also seen relative to the older age group in the PK trials. At this time, a causal relationship between these findings and ELIDEL use cannot be ruled out.
### Geriatic Use
- Nine (9) subjects ≥65 years old received ELIDEL Cream, 1% in Phase 3 trials. Clinical trials of ELIDEL Cream, 1% did not include sufficient numbers of subjects aged 65 and over to assess efficacy and safety.
### Gender
- There is no FDA guidance on the use of Pimecrolimus with respect to specific gender populations.
### Race
- There is no FDA guidance on the use of Pimecrolimus with respect to specific racial populations.
### Renal Impairment
- There is no FDA guidance on the use of Pimecrolimus in patients with renal impairment.
### Hepatic Impairment
- There is no FDA guidance on the use of Pimecrolimus in patients with hepatic impairment.
### Females of Reproductive Potential and Males
- There is no FDA guidance on the use of Pimecrolimus in women of reproductive potentials and males.
### Immunocompromised Patients
- There is no FDA guidance one the use of Pimecrolimus in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Apply a thin layer of ELIDEL (pimecrolimus) Cream, 1% to the affected skin twice daily. The patient should stop using ELIDEL Cream, 1% when signs and symptoms (e.g., itch, rash and redness) resolve and should be instructed on what actions to take if symptoms recur.
- If signs and symptoms persist beyond 6 weeks, patients should be re-examined by their health care provider to confirm the diagnosis of atopic dermatitis.
- Continuous long-term use of ELIDEL Cream, 1% should be avoided, and application should be limited to areas of involvement with atopic dermatitis.
(The safety of ELIDEL Cream, 1% under occlusion, which may promote systemic exposure, has not been evaluated. Avoid use of ELIDEL Cream, 1% with occlusive dressings.
DOSAGE FORMS AND STRENGTHS
- Cream, 1%.
- Each gram of ELIDEL Cream, 1% contains 10 mg of pimecrolimus in a whitish cream base.
### Monitoring
- Patients who develop lymphadenopathy should be monitored to ensure that the lymphadenopathy resolves.
# IV Compatibility
There is limited information regarding IV Compatibility of Pimecrolimus in the drug label.
# Overdosage
There is limited information regarding Pimecrolimus overdosage. If you suspect drug poisoning or overdose, please contact the National Poison Help hotline (1-800-222-1222) immediately.
# Pharmacology
There is limited information regarding Pimecrolimus Pharmacology in the drug label.
## Mechanism of Action
- The mechanism of action of pimecrolimus in atopic dermatitis is not known. While the following have been observed, the clinical significance of these observations in atopic dermatitis is not known. It has been demonstrated that pimecrolimus binds with high affinity to macrophilin-12 (FKBP-12) and inhibits the calcium-dependent phosphatase, calcineurin. As a consequence, it inhibits T cell activation by blocking the transcription of early cytokines. In particular, pimecrolimus inhibits at nanomolar concentrations Interleukin-2 and interferon gamma (Th1-type) and Interleukin-4 and Interleukin-10 (Th2-type) cytokine synthesis in human T-cells. In addition, pimecrolimus prevents the release of inflammatory cytokines and mediators from mast cells in vitro after stimulation by antigen/IgE.
## Structure
- ELIDEL® (pimecrolimus) Cream, 1%, for topical use, contains the compound pimecrolimus, the immunosuppressant 33-epi-chloro-derivative of the macrolactam ascomycin.
- Chemically, pimecrolimus is (1R,9S,12S,13R,14S,17R,18E,21S,23S,24R,25S,27R)-12--17-ethyl-1, 14-dihydroxy-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclooctacos-18-ene-2,3,10,16-tetraone. The compound has the empirical formula C43H68ClNO11 and the molecular weight of 810.47. The structural formula is
- Pimecrolimus is a white to off-white fine crystalline powder. It is soluble in methanol and ethanol and insoluble in water.
- Each gram of ELIDEL Cream, 1% contains 10 mg of pimecrolimus in a whitish cream base of benzyl alcohol, cetyl alcohol, citric acid anhydrous, mono- and di-glycerides, oleyl alcohol, propylene glycol, sodium cetostearyl sulphate, sodium hydroxide, stearyl alcohol, triglycerides, and water.
## Pharmacodynamics
There is limited information regarding Pimecrolimus Pharmacodynamics in the drug label.
## Pharmacokinetics
Absorption
- In adult subjects (n=52) being treated for atopic dermatitis for periods up to a year, a maximum pimecrolimus concentration of 1.4 ng/mL was observed among those subjects with detectable blood levels. In the majority of samples in adult (91%; 1,244/1,362) subjects, blood concentrations of pimecrolimus were below 0.5 ng/mL. Data on blood levels of pimecrolimus measured in pediatric subjects are described in Use in Specific Populations (8.4).
Distribution
- Laboratory in vitro plasma protein binding studies using equilibrium gel filtration have shown that 99.5% of pimecrolimus in plasma is bound to proteins over the pimecrolimus concentration range of 2-100 ng/mL tested. The major fraction of pimecrolimus in plasma appears to be bound to various lipoproteins. As with other topical calcineurin inhibitors, it is not known whether pimecrolimus is absorbed into cutaneous lymphatic vessels or in regional lymph nodes.
Metabolism
- Following the administration of a single oral radiolabeled dose of pimecrolimus numerous circulating O-demethylation metabolites were seen. Studies with human liver microsomes indicate that pimecrolimus is metabolized in vitro by the CYP3A sub-family of metabolizing enzymes. No evidence of skin mediated drug metabolism was identified in vivo using the minipig or in vitro using stripped human skin.
Elimination
- Based on the results of the aforementioned radiolabeled study, following a single oral dose of pimecrolimus ~81% of the administered radioactivity was recovered, primarily in the feces (78.4%) as metabolites. Less than 1% of the radioactivity found in the feces was due to unchanged pimecrolimus.
## Nonclinical Toxicology
Carcinogenesis, Mutagenesis, Impairment of Fertility
- In a 2-year rat dermal carcinogenicity study using ELIDEL Cream, 1%, a statistically significant increase in the incidence of follicular cell adenoma of the thyroid was noted in low, mid and high dose male animals compared to vehicle and saline control male animals. Follicular cell adenoma of the thyroid was noted in the dermal rat carcinogenicity study at the lowest dose of 2 mg/kg/day . No increase in the incidence of follicular cell adenoma of the thyroid was noted in the oral carcinogenicity study in male rats up to 10 mg/kg/day (66× MRHD based on AUC comparisons). However, oral studies may not reflect continuous exposure or the same metabolic profile as by the dermal route. In a mouse dermal carcinogenicity study using pimecrolimus in an ethanolic solution, no increase in incidence of neoplasms was observed in the skin or other organs up to the highest dose of 4 mg/kg/day (0.32% pimecrolimus in ethanol) 27× MRHD based on AUC comparisons. However, lymphoproliferative changes (including lymphoma) were noted in a 13 week repeat dose dermal toxicity study conducted in mice using pimecrolimus in an ethanolic solution at a dose of 25 mg/kg/day (47× MRHD based on AUC comparisons). No lymphoproliferative changes were noted in this study at a dose of 10 mg/kg/day (17× MRHD based on AUC comparison). However, the latency time to lymphoma formation was shortened to 8 weeks after dermal administration of pimecrolimus dissolved in ethanol at a dose of 100 mg/kg/day (179-217× MRHD based on AUC comparisons).
- In a mouse oral (gavage) carcinogenicity study, a statistically significant increase in the incidence of lymphoma was noted in high dose male and female animals compared to vehicle control male and female animals. Lymphomas were noted in the oral mouse carcinogenicity study at a dose of 45 mg/kg/day (258-340× MRHD based on AUC comparisons). No drug-related tumors were noted in the mouse oral carcinogenicity study at a dose of 15 mg/kg/day (60-133× MRHD based on AUC comparisons).
- In an oral (gavage) rat carcinogenicity study, a statistically significant increase in the incidence of benign thymoma was noted in 10 mg/kg/day pimecrolimus treated male and female animals compared to vehicle control treated male and female animals. In addition, a significant increase in the incidence of benign thymoma was noted in another oral (gavage) rat carcinogenicity study in 5 mg/kg/day pimecrolimus treated male animals compared to vehicle control treated male animals. No drug-related tumors were noted in the rat oral carcinogenicity study at a dose of 1 mg/kg/day male animals (1.1× MRHD based on AUC comparisons) and at a dose of 5 mg/kg/day for female animals (21× MRHD based on AUC comparisons).
- In a 52-week dermal photo-carcinogenicity study, the median time to onset of skin tumor formation was decreased in hairless mice following chronic topical dosing with concurrent exposure to UV radiation (40 weeks of treatment followed by 12 weeks of observation) with the ELIDEL Cream, 1% vehicle alone. No additional effect on tumor development beyond the vehicle effect was noted with the addition of the active ingredient, pimecrolimus, to the vehicle cream.
- A 39-week oral monkey toxicology study was conducted with pimecrolimus doses of 15, 45 and 120 mg/kg/day. A dose dependent increase in expression of immunosuppressive-related lymphoproliferative disorder (IRLD) associated with lymphocryptovirus (a monkey strain of virus related to human Epstein Barr virus) was observed. IRLD in monkeys mirrors what has been noted in human transplant patients after chronic systemic immunosuppressive therapy, post transplantation lymphoproliferative disease (PTLD), after treatment with chronic systemic immunosuppressive therapy. Both IRLD and PTLD can progress to lymphoma, which is dependent on the dose and duration of systemic immunosuppressive therapy. A dose dependent increase in opportunistic infections (a signal of systemic immunosuppression) was also noted in this monkey study. A no observed adverse effect level (NOAEL) for IRLD and opportunistic infections was not established in this study. IRLD occurred at the lowest dose of 15 mg/kg/day for 39 weeks in this study. A partial recovery from IRLD was noted upon cessation of dosing in this study.
- A battery of in vitro genotoxicity tests, including Ames assay, mouse lymphoma L5178Y assay, and chromosome aberration test in V79 Chinese hamster cells and an in vivo mouse micronucleus test revealed no evidence for a mutagenic or clastogenic potential for the drug.
- An oral fertility and embryofetal developmental study in rats revealed estrus cycle disturbances, post-implantation loss and reduction in litter size at the 45 mg/kg/day dose (38× MRHD based on AUC comparisons). No effect on fertility in female rats was noted at 10 mg/kg/day (12× MRHD based on AUC comparisons). No effect on fertility in male rats was noted at 45 mg/kg/day (23× MRHD based on AUC comparisons), which was the highest dose tested in this study.
- A second oral fertility and embryofetal developmental study in rats revealed reduced testicular and epididymal weights, reduced testicular sperm counts and motile sperm for males and estrus cycle disturbances, decreased corpora lutea, decreased implantations and viable fetuses for females at 45 mg/kg/day dose (123× MRHD for males and 192× MRHD for females based on AUC comparisons). No effect on fertility in female rats was noted at 10 mg/kg/day (5× MRHD based on AUC comparisons). No effect on fertility in male rats was noted at 2 mg/kg/day (0.7× MRHD based on AUC comparisons).
# Clinical Studies
- Three randomized, double-blind, vehicle-controlled, multi-center, Phase 3 trials were conducted in 589 pediatric subjects ages 3 months-17 years old to evaluate ELIDEL (pimecrolimus) Cream, 1% for the treatment of mild to moderate atopic dermatitis. Two of the three trials support the use of ELIDEL Cream, 1% in subjects 2 years and older with mild to moderate atopic dermatitis. Three other trials in 1,619 pediatric and adult subjects provided additional data regarding the safety of ELIDEL Cream, 1% in the treatment of atopic dermatitis. Two of these other trials were vehicle-controlled with optional sequential use of a medium potency topical corticosteroid in pediatric subjects and one trial was an active comparator trial in adult subjects with atopic dermatitis.
- Two identical 6-week, randomized, vehicle-controlled, multi-center, Phase 3 trials were conducted to evaluate ELIDEL Cream, 1% for the treatment of mild to moderate atopic dermatitis. A total of 403 pediatric subjects 2-17 years old were included in the trials. The male/female ratio was approximately 50% and 29% of the subjects were African American. At trial entry, 59% of subjects had moderate disease and the mean body surface area (BSA) affected was 26%. About 75% of subjects had atopic dermatitis affecting the face and/or neck region. In these trials, subjects applied either ELIDEL Cream, 1% or vehicle cream twice daily to 5% to 96% of their BSA for up to 6 weeks. At endpoint, based on the physician’s global evaluation of clinical response, 35% of subjects treated with ELIDEL Cream, 1% were clear or almost clear of signs of atopic dermatitis compared to only 18% of vehicle-treated subjects. More ELIDEL subjects (57%) had mild or no pruritus at 6 weeks compared to vehicle subjects (34%). The improvement in pruritus occurred in conjunction with the improvement of the subjects’ atopic dermatitis.
In these two 6-week studies of ELIDEL, the combined efficacy results at endpoint are presented in Table 2 as follows:
- In the two pediatric trials that independently support the use of ELIDEL Cream, 1% in mild to moderate atopic dermatitis, a significant treatment effect was seen by day 15. Of the key signs of atopic dermatitis, erythema, infiltration/papulation, lichenification, and excoriations were reduced at day 8 when compared to vehicle.
- Figure 1 depicts the time course of improvement in the percent body surface area affected as a result of treatment with ELIDEL Cream, 1% in 2-17 year olds.
# How Supplied
- ELIDEL (pimecrolimus) Cream, 1% is a whitish cream available in tubes of 30 grams, 60 grams, and 100 grams.
## Storage
- Store at 25°C (77°F); excursions permitted to 15°C-30°C (59°F-86°F) . Do not freeze.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
See FDA-approved patient labeling (Medication Guide)
Patients using ELIDEL Cream, 1% should receive the following information and instructions:
- ELIDEL Cream, 1% may cause serious side effects. It is not known if ELIDEL Cream, 1% is safe to use for a long period of time. A very small number of people who have used ELIDEL Cream, 1% have had cancer (for example, skin or lymphoma). However, a link with ELIDEL Cream, 1% use has not been shown. Because of this concern:
- A patient should not use ELIDEL Cream, 1% continuously for a long time.
- ELIDEL Cream, 1% should be used only on areas of skin that have eczema.
- ELIDEL Cream, 1% is not for use on a child under 2 years old.
- A patient should not use sun lamps, tanning beds, or get treatment with ultraviolet light therapy during treatment with ELIDEL Cream, 1%.
- A patient should limit sun exposure during treatment with ELIDEL Cream, 1% even when the medicine is not on the skin. If a patient needs to be outdoors after applying ELIDEL Cream, 1%, the patient should wear loose fitting clothing that protects the treated area from the sun. The physician should advise the patient about other types of protection from the sun.
- A patient should not cover the skin being treated with bandages, dressings or wraps. A patient can wear normal clothing.
- ELIDEL Cream, 1% is for use on the skin only. Do not get ELIDEL Cream, 1% in your eyes, nose, mouth, vagina, or rectum (mucous membranes). If you get ELIDEL Cream, 1% in any of these areas, burning or irritation can happen. Wipe off any ELIDEL Cream, 1% from the affected area and then rinse the area well with cold water. ELIDEL Cream, 1% is for external use only.
- A patient should use ELIDEL Cream, 1% for short periods, and if needed, treatment may be repeated with breaks in between.
- Wash hands before using ELIDEL Cream, 1%. When applying ELIDEL Cream, 1% after a bath or shower, the skin should be dry.
- Apply a thin layer of ELIDEL Cream, 1% only to the affected skin areas, twice a day, as directed by the physician.
- Use the smallest amount of ELIDEL Cream, 1% needed to control the signs and symptoms of eczema.
- A patient should not bathe, shower or swim right after applying ELIDEL Cream, 1%. This could wash off the cream.
- A patient can use moisturizers with ELIDEL Cream, 1%. They should be sure to check with the physician first about the products that are right for them. Because the skin of patients with eczema can be very dry, it is important they keep up good skin care practices. If a patient uses moisturizers, he or she should apply them after ELIDEL Cream, 1%.
# Precautions with Alcohol
- Alcohol-Pimecrolimus interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
Elidel
# Look-Alike Drug Names
- A® — B®
# Drug Shortage Status
# Price | Pimecrolimus
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Deepika Beereddy, MBBS [2]
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# Black Box Warning
# Overview
Pimecrolimus is an analgesic that is FDA approved for the treatment of atopic dermatitis. There is a Black Box Warning for this drug as shown here. Common adverse reactions include sensation of burning of skin, risk for viral infection, headache, fever.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- ELIDEL® (pimecrolimus) Cream, 1% is indicated as second-line therapy for the short-term and non-continuous chronic treatment of mild to moderate atopic dermatitis in non-immunocompromised adults, who have failed to respond adequately to other topical prescription treatments, or when those treatments are not advisable.
- Dosing Information
- Apply a thin layer of ELIDEL (pimecrolimus) Cream, 1% to the affected skin twice daily. The patient should stop using ELIDEL Cream, 1% when signs and symptoms (e.g., itch, rash and redness) resolve and should be instructed on what actions to take if symptoms recur.
- If signs and symptoms persist beyond 6 weeks, patients should be re-examined by their health care provider to confirm the diagnosis of atopic dermatitis.
- Continuous long-term use of ELIDEL Cream, 1% should be avoided, and application should be limited to areas of involvement with atopic dermatitis.
- The safety of ELIDEL Cream, 1% under occlusion, which may promote systemic exposure, has not been evaluated. Avoid use of ELIDEL Cream, 1% with occlusive dressings.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Pimecrolimus in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Pimecrolimus in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
- ELIDEL® (pimecrolimus) Cream, 1% is indicated as second-line therapy for the short-term and non-continuous chronic treatment of mild to moderate atopic dermatitis in non-immunocompromised children 2 years of age and older, who have failed to respond adequately to other topical prescription treatments, or when those treatments are not advisable.
- ELIDEL Cream, 1% is not indicated for use in children less than 2 years of age.
- Dosing Information
- Apply a thin layer of ELIDEL (pimecrolimus) Cream, 1% to the affected skin twice daily. The patient should stop using ELIDEL Cream, 1% when signs and symptoms (e.g., itch, rash and redness) resolve and should be instructed on what actions to take if symptoms recur.
- If signs and symptoms persist beyond 6 weeks, patients should be re-examined by their health care provider to confirm the diagnosis of atopic dermatitis.
- Continuous long-term use of ELIDEL Cream, 1% should be avoided, and application should be limited to areas of involvement with atopic dermatitis.
- The safety of ELIDEL Cream, 1% under occlusion, which may promote systemic exposure, has not been evaluated. Avoid use of ELIDEL Cream, 1% with occlusive dressings.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Pimecrolimus in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Pimecrolimus in pediatric patients.
# Contraindications
- ELIDEL® (pimecrolimus) Cream, 1% is contraindicated in individuals with a history of hypersensitivity to pimecrolimus or any of the components of the cream.
# Warnings
Risk of Immunosuppression
- Prolonged systemic use of calcineurin inhibitors for sustained immunosuppression in animal studies and transplant patients following systemic administration has been associated with an increased risk of infections, lymphomas, and skin malignancies. These risks are associated with the intensity and duration of immunosuppression.
- Based on this information and the mechanism of action, there is a concern about a potential risk with the use of topical calcineurin inhibitors, including ELIDEL Cream, 1%. While a causal relationship has not been established, rare cases of skin malignancy and lymphoma have been reported in patients treated with topical calcineurin inhibitors, including ELIDEL Cream, 1%. Therefore:
- Continuous long-term use of topical calcineurin inhibitors, including ELIDEL Cream, 1%, in any age group should be avoided, and application limited to areas of involvement with atopic dermatitis
- ELIDEL Cream, 1% is not indicated for use in children less than 2 years of age
- ELIDEL Cream, 1% should not be used in immunocompromised adults and children, including patients on systemic immunosuppressive medications.
- If signs and symptoms of atopic dermatitis do not improve within 6 weeks, patients should be re-examined by their healthcare provider and their diagnosis be confirmed.
- The safety of ELIDEL Cream, 1% has not been established beyond one year of non-continuous use.
Application to Malignant or Pre-malignant Skin Conditions
- The use of ELIDEL Cream, 1% should be avoided on malignant or pre-malignant skin conditions. Malignant or pre-malignant skin conditions, such as cutaneous T-cell lymphoma (CTCL), can present as dermatitis.
- ELIDEL Cream, 1% should not be used in patients with Netherton’s Syndrome or other skin diseases where there is the potential for increased systemic absorption of pimecrolimus. The safety of ELIDEL Cream, 1% has not been established in patients with generalized erythroderma.
- The use of ELIDEL Cream, 1% may cause local symptoms such as skin burning (burning sensation, stinging, soreness) or pruritus. Localized symptoms are most common during the first few days of ELIDEL Cream, 1% application and typically improve as the lesions of atopic dermatitis resolve.
Bacterial and Viral Skin Infections
- Before commencing treatment with ELIDEL Cream, 1%, bacterial or viral infections at treatment sites should be resolved. Trials have not evaluated the safety and efficacy of ELIDEL Cream, 1% in the treatment of clinically infected atopic dermatitis.
- While patients with atopic dermatitis are predisposed to superficial skin infections including eczema herpeticum (Kaposi’s varicelliform eruption), treatment with ELIDEL Cream, 1% may be independently associated with an increased risk of varicella zoster virus infection (chicken pox or shingles), herpes simplex virus infection, or eczema herpeticum.
- In clinical trials, 15/1,544 (1%) cases of skin papilloma (warts) were observed in subjects using ELIDEL Cream, 1%. The youngest subject was age 2 and the oldest was age 12. In cases where there is worsening of skin papillomas or they do not respond to conventional therapy, discontinuation of ELIDEL Cream, 1% should be considered until complete resolution of the warts is achieved.
Patients with Lymphadenopathy
- In clinical trials, 14/1,544 (0.9%) cases of lymphadenopathy were reported while using ELIDEL Cream, 1%. These cases of lymphadenopathy were usually related to infections and noted to resolve upon appropriate antibiotic therapy. Of these 14 cases, the majority had either a clear etiology or were known to resolve. Patients who receive ELIDEL Cream, 1% and who develop lymphadenopathy should have the etiology of their lymphadenopathy investigated. In the absence of a clear etiology for the lymphadenopathy, or in the presence of acute infectious mononucleosis, ELIDEL Cream, 1% should be discontinued. Patients who develop lymphadenopathy should be monitored to ensure that the lymphadenopathy resolves.
Sun Exposure
- During the course of treatment, it is prudent for patients to minimize or avoid natural or artificial sunlight exposure, even while ELIDEL Cream, 1% is not on the skin. The potential effects of ELIDEL Cream, 1% on skin response to ultraviolet damage are not known.
Immunocompromised Patients
- The safety and efficacy of ELIDEL Cream, 1% in immunocompromised patients have not been studied.
# Adverse Reactions
## Clinical Trials Experience
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.
- No phototoxicity and no photoallergenicity were detected in clinical trials with 24 and 33 normal volunteers, respectively. In human dermal safety trials, ELIDEL (pimecrolimus) Cream, 1% did not induce contact sensitization or cumulative irritation.
- In a one-year safety trial in pediatric subjects age 2-17 years old involving sequential use of ELIDEL Cream, 1% and a topical corticosteroid, 43% of ELIDEL Cream, 1% treated subjects and 68% of vehicle-treated subjects used corticosteroids during the trial. Corticosteroids were used for more than 7 days by 34% of ELIDEL Cream, 1% treated subjects and 54% of vehicle-treated subjects. An increased incidence of impetigo, skin infection, superinfection (infected atopic dermatitis), rhinitis, and urticaria were found in the subjects that had used ELIDEL Cream, 1% and topical corticosteroid sequentially as compared to ELIDEL Cream, 1% alone.
- In 3 randomized, double-blind vehicle-controlled pediatric trials and one active-controlled adult trial, 843 and 328 subjects respectively, were treated with ELIDEL Cream, 1%. In these clinical trials, 48 (4%) of the 1,171 ELIDEL treated subjects and 13 (3%) of 408 vehicle-treated subjects discontinued therapy due to adverse events. Discontinuations for AEs were primarily due to application site reactions, and cutaneous infections. The most common application site reaction was application site burning, which occurred in 8%-26% of subjects treated with ELIDEL Cream, 1%.
- Table 1 depicts the incidence of adverse events pooled across the 2 identically designed 6-week trials with their open label extensions and the 1-year safety trial for pediatric subjects ages 2-17. Data from the adult active-controlled trial is also included in Table 1. Adverse events are listed regardless of relationship to trial drug.
- Two cases of septic arthritis have been reported in infants less than one year of age in clinical trials conducted with ELIDEL Cream, 1% (n = 2,443). Causality has not been established.
## Postmarketing Experience
- The following adverse reactions have been identified during post-approval use of ELIDEL Cream, 1%. 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.
- General: Anaphylactic reactions, ocular irritation after application of the cream to the eye lids or near the eyes, angioneurotic edema, facial edema, skin flushing associated with alcohol use, skin discoloration.
- Hematology/Oncology: Lymphomas, basal cell carcinoma, malignant melanoma, squamous cell carcinoma.
# Drug Interactions
- Potential interactions between ELIDEL Cream, 1% and other drugs, including immunizations, have not been systematically evaluated. Due to low blood levels of pimecrolimus detected in some patients after topical application, systemic drug interactions are not expected, but cannot be ruled out. The concomitant administration of known CYP3A family of inhibitors in patients with widespread and/or erythrodermic disease should be done with caution. Some examples of such drugs are erythromycin, itraconazole, ketoconazole, fluconazole, calcium channel blockers and cimetidine.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): C
Pregnancy Category C
- There are no adequate and well-controlled studies with ELIDEL Cream, 1% in pregnant women. Therefore, ELIDEL Cream, 1% should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
- In dermal embryofetal developmental studies, no maternal or fetal toxicity was observed up to the highest practicable doses tested, 10 mg/kg/day (1% pimecrolimus cream) in rats (0.14× MRHD based on body surface area) and 10 mg/kg/day (1% pimecrolimus cream) in rabbits (0.65× MRHD based on AUC comparisons). The 1% pimecrolimus cream was administered topically for 6 hours/day during the period of organogenesis in rats and rabbits (gestational days 6-21 in rats and gestational days 6-20 in rabbits).
- A second dermal embryofetal development study was conducted in rats using pimecrolimus cream applied dermally to pregnant rats (1 g cream/kg body weight of 0.2%, 0.6% and 1.0% pimecrolimus cream) from gestation day 6 to 17 at doses of 2, 6, and 10 mg/kg/day with daily exposure of approximately 22 hours. No maternal, reproductive, or embryo-fetal toxicity attributable to pimecrolimus was noted at 10 mg/kg/day (0.66× MRHD based on AUC comparisons), the highest dose evaluated in this study. No teratogenicity was noted in this study at any dose.
- A combined oral fertility and embryofetal developmental study was conducted in rats and an oral embryofetal developmental study was conducted in rabbits. Pimecrolimus was administered during the period of organogenesis (2 weeks prior to mating until gestational day 16 in rats, gestational days 6-18 in rabbits) up to dose levels of 45 mg/kg/day in rats and 20 mg/kg/day in rabbits. In the absence of maternal toxicity, indicators of embryofetal toxicity (post-implantation loss and reduction in litter size) were noted at 45 mg/kg/day (38× MRHD based on AUC comparisons) in the oral fertility and embryofetal developmental study conducted in rats. No malformations in the fetuses were noted at 45 mg/kg/day (38× MRHD based on AUC comparisons) in this study. No maternal toxicity, embryotoxicity or teratogenicity were noted in the oral rabbit embryofetal developmental toxicity study at 20 mg/kg/day (3.9× MRHD based on AUC comparisons), which was the highest dose tested in this study.
- A second oral embryofetal development study was conducted in rats. Pimecrolimus was administered during the period of organogenesis (gestational days 6 – 17) at doses of 2, 10 and 45 mg/kg/day. Maternal toxicity, embryolethality and fetotoxicity were noted at 45 mg/kg/day (271× MRHD based on AUC comparisons). A slight increase in skeletal variations that were indicative of delayed skeletal ossification was also noted at this dose. No maternal toxicity, embryolethality or fetotoxicity were noted at 10 mg/kg/day (16× MRHD based on AUC comparisons). No teratogenicity was noted in this study at any dose.
- A second oral embryofetal development study was conducted in rabbits. Pimecrolimus was administered during the period of organogenesis (gestational days 7 – 20) at doses of 2, 6 and 20 mg/kg/day. Maternal toxicity, embryotoxicity and fetotoxicity were noted at 20 mg/kg/day (12× MRHD based on AUC comparisons). A slight increase in skeletal variations that were indicative of delayed skeletal ossification was also noted at this dose. No maternal toxicity, embryotoxicity or fetotoxicity were noted at 6 mg/kg/day (5× MRHD based on AUC comparisons). No teratogenicity was noted in this study at any dose.
- An oral peri- and post-natal developmental study was conducted in rats. Pimecrolimus was administered from gestational day 6 through lactational day 21 up to a dose level of 40 mg/kg/day. Only 2 of 22 females delivered live pups at the highest dose of 40 mg/kg/day. Postnatal survival, development of the F1 generation, their subsequent maturation and fertility were not affected at 10 mg/kg/day (12× MRHD based on AUC comparisons), the highest dose evaluated in this study.
- Pimecrolimus was transferred across the placenta in oral rat and rabbit embryofetal developmental studies.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Pimecrolimus in women who are pregnant.
### Labor and Delivery
- There is no FDA guidance on use of Pimecrolimus during labor and delivery.
### Nursing Mothers
- It is not known whether this drug is excreted in human milk. Because of the potential for serious adverse reactions in nursing infants from pimecrolimus, 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
- ELIDEL Cream, 1% is not indicated for use in children less than 2 years of age.
- The long-term safety and effects of ELIDEL Cream, 1% on the developing immune system are unknown.
- Three Phase 3 pediatric trials were conducted involving 1,114 subjects 2-17 years of age. Two trials were 6-week randomized vehicle-controlled trials with a 20-week open-label phase and one was a vehicle-controlled (up to 1 year) safety trial with the option for sequential topical corticosteroid use. Of these subjects 542 (49%) were 2-6 years of age. In the short-term trials, 11% of ELIDEL subjects did not complete these trials and 1.5% of ELIDEL subjects discontinued due to adverse events. In the one-year trial, 32% of ELIDEL subjects did not complete this trial and 3% of ELIDEL subjects discontinued due to adverse events. Most discontinuations were due to unsatisfactory therapeutic effect.
- The most common local adverse event in the short-term trials of ELIDEL Cream, 1% in pediatric subjects ages 2-17 was application site burning (10% vs. 13% vehicle); the incidence in the long-term trial was 9% ELIDEL vs. 7% vehicle [see Adverse Reactions (6.1)]. Adverse events that were more frequent (>5%) in subjects treated with ELIDEL Cream, 1% compared to vehicle were headache (14% vs. 9%) in the short-term trial. Nasopharyngitis (26% vs. 21%), influenza (13% vs. 4%), pharyngitis (8% vs. 3%), viral infection (7% vs. 1%), pyrexia (13% vs. 5%), cough (16% vs. 11%), and headache (25% vs. 16%) were increased over vehicle in the 1-year safety trial [see Adverse Reactions (6.1)]. In 843 subjects ages 2-17 years treated with ELIDEL Cream, 1%, 9 (0.8%) developed eczema herpeticum (5 on ELIDEL Cream, 1% alone and 4 on ELIDEL Cream, 1% used in sequence with corticosteroids). In 211 subjects on vehicle alone, there were no cases of eczema herpeticum. The majority of adverse events were mild to moderate in severity.
- Two Phase 3 trials were conducted involving 436 infants age 3 months-23 months. One 6-week randomized vehicle-controlled trial with a 20-week open-label phase and one safety trial, up to one year, were conducted. In the 6-week trial, 11% of ELIDEL and 48% of vehicle subjects did not complete this trial; no subject in either group discontinued due to adverse events. Infants on ELIDEL Cream, 1% had an increased incidence of some adverse events compared to vehicle. In the 6-week vehicle-controlled trial these adverse events included pyrexia (32% vs. 13% vehicle), URI (24% vs. 14%), nasopharyngitis (15% vs. 8%), gastroenteritis (7% vs. 3%), otitis media (4% vs. 0%), and diarrhea (8% vs. 0%). In the open-label phase of the trial, for infants who switched to ELIDEL Cream, 1% from vehicle, the incidence of the above-cited adverse events approached or equaled the incidence of those subjects who remained on ELIDEL Cream, 1%. In the 6 month safety data, 16% of ELIDEL and 35% of vehicle subjects discontinued early and 1.5% of ELIDEL and 0% of vehicle subjects discontinued due to adverse events. Infants on ELIDEL Cream, 1% had a greater incidence of some adverse events as compared to vehicle. These included pyrexia (30% vs. 20%), URI (21% vs. 17%), cough (15% vs. 9%), hypersensitivity (8% vs. 2%), teething (27% vs. 22%), vomiting (9% vs. 4%), rhinitis (13% vs. 9%), viral rash (4% vs. 0%), rhinorrhea (4% vs. 0%), and wheezing (4% vs. 0%).
- The systemic exposure to pimecrolimus from ELIDEL (pimecrolimus) Cream, 1% was investigated in 28 pediatric subjects with atopic dermatitis (20%-80% BSA involvement) between the ages of 8 months-14 yrs. Following twice daily application for three weeks, blood concentrations of pimecrolimus were <2 ng/mL with 60% (96/161) of the blood samples having blood concentration below the limit of quantification (0.5 ng/mL). However, more children (23 children out of the total 28 children investigated) had at least one detectable blood level as compared to the adults (12 adults out of the total 52 adults investigated) over a 3-week treatment period. Due to the erratic nature of the blood levels observed, no correlation could be made between amount of cream, degree of BSA involvement, and blood concentrations. In general, the blood concentrations measured in adult atopic dermatitis subjects were comparable to those seen in the pediatric population.
- In a second group of 30 pediatric subjects aged 3-23 months with 10%-92% BSA involvement, following twice daily application for three weeks, blood concentrations of pimecrolimus were <2.6 ng/mL with 65% (75/116) of the blood samples having blood concentration below 0.5 ng/mL, and 27% (31/116) below the limit of quantification (0.1 ng/mL) for these trials.
- Overall, a higher proportion of detectable blood levels was seen in the pediatric subject population as compared to adult population. This increase in the absolute number of positive blood levels may be due to the larger surface area to body mass ratio seen in these younger subjects. In addition, a higher incidence of upper respiratory symptoms/infections was also seen relative to the older age group in the PK trials. At this time, a causal relationship between these findings and ELIDEL use cannot be ruled out.
### Geriatic Use
- Nine (9) subjects ≥65 years old received ELIDEL Cream, 1% in Phase 3 trials. Clinical trials of ELIDEL Cream, 1% did not include sufficient numbers of subjects aged 65 and over to assess efficacy and safety.
### Gender
- There is no FDA guidance on the use of Pimecrolimus with respect to specific gender populations.
### Race
- There is no FDA guidance on the use of Pimecrolimus with respect to specific racial populations.
### Renal Impairment
- There is no FDA guidance on the use of Pimecrolimus in patients with renal impairment.
### Hepatic Impairment
- There is no FDA guidance on the use of Pimecrolimus in patients with hepatic impairment.
### Females of Reproductive Potential and Males
- There is no FDA guidance on the use of Pimecrolimus in women of reproductive potentials and males.
### Immunocompromised Patients
- There is no FDA guidance one the use of Pimecrolimus in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Apply a thin layer of ELIDEL (pimecrolimus) Cream, 1% to the affected skin twice daily. The patient should stop using ELIDEL Cream, 1% when signs and symptoms (e.g., itch, rash and redness) resolve and should be instructed on what actions to take if symptoms recur.
- If signs and symptoms persist beyond 6 weeks, patients should be re-examined by their health care provider to confirm the diagnosis of atopic dermatitis.
- Continuous long-term use of ELIDEL Cream, 1% should be avoided, and application should be limited to areas of involvement with atopic dermatitis.
(The safety of ELIDEL Cream, 1% under occlusion, which may promote systemic exposure, has not been evaluated. Avoid use of ELIDEL Cream, 1% with occlusive dressings.
DOSAGE FORMS AND STRENGTHS
- Cream, 1%.
- Each gram of ELIDEL Cream, 1% contains 10 mg of pimecrolimus in a whitish cream base.
### Monitoring
- Patients who develop lymphadenopathy should be monitored to ensure that the lymphadenopathy resolves.
# IV Compatibility
There is limited information regarding IV Compatibility of Pimecrolimus in the drug label.
# Overdosage
There is limited information regarding Pimecrolimus overdosage. If you suspect drug poisoning or overdose, please contact the National Poison Help hotline (1-800-222-1222) immediately.
# Pharmacology
There is limited information regarding Pimecrolimus Pharmacology in the drug label.
## Mechanism of Action
- The mechanism of action of pimecrolimus in atopic dermatitis is not known. While the following have been observed, the clinical significance of these observations in atopic dermatitis is not known. It has been demonstrated that pimecrolimus binds with high affinity to macrophilin-12 (FKBP-12) and inhibits the calcium-dependent phosphatase, calcineurin. As a consequence, it inhibits T cell activation by blocking the transcription of early cytokines. In particular, pimecrolimus inhibits at nanomolar concentrations Interleukin-2 and interferon gamma (Th1-type) and Interleukin-4 and Interleukin-10 (Th2-type) cytokine synthesis in human T-cells. In addition, pimecrolimus prevents the release of inflammatory cytokines and mediators from mast cells in vitro after stimulation by antigen/IgE.
## Structure
- ELIDEL® (pimecrolimus) Cream, 1%, for topical use, contains the compound pimecrolimus, the immunosuppressant 33-epi-chloro-derivative of the macrolactam ascomycin.
- Chemically, pimecrolimus is (1R,9S,12S,13R,14S,17R,18E,21S,23S,24R,25S,27R)-12-[(1E)-2-{(1R,3R,4S)-4-chloro-3-methoxycyclohexyl}-1-methylvinyl]-17-ethyl-1, 14-dihydroxy-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo[22.3.1.0 4,9]octacos-18-ene-2,3,10,16-tetraone. The compound has the empirical formula C43H68ClNO11 and the molecular weight of 810.47. The structural formula is
- Pimecrolimus is a white to off-white fine crystalline powder. It is soluble in methanol and ethanol and insoluble in water.
- Each gram of ELIDEL Cream, 1% contains 10 mg of pimecrolimus in a whitish cream base of benzyl alcohol, cetyl alcohol, citric acid anhydrous, mono- and di-glycerides, oleyl alcohol, propylene glycol, sodium cetostearyl sulphate, sodium hydroxide, stearyl alcohol, triglycerides, and water.
## Pharmacodynamics
There is limited information regarding Pimecrolimus Pharmacodynamics in the drug label.
## Pharmacokinetics
Absorption
- In adult subjects (n=52) being treated for atopic dermatitis [13%-62% Body Surface Area (BSA) involvement] for periods up to a year, a maximum pimecrolimus concentration of 1.4 ng/mL was observed among those subjects with detectable blood levels. In the majority of samples in adult (91%; 1,244/1,362) subjects, blood concentrations of pimecrolimus were below 0.5 ng/mL. Data on blood levels of pimecrolimus measured in pediatric subjects are described in Use in Specific Populations (8.4).
Distribution
- Laboratory in vitro plasma protein binding studies using equilibrium gel filtration have shown that 99.5% of pimecrolimus in plasma is bound to proteins over the pimecrolimus concentration range of 2-100 ng/mL tested. The major fraction of pimecrolimus in plasma appears to be bound to various lipoproteins. As with other topical calcineurin inhibitors, it is not known whether pimecrolimus is absorbed into cutaneous lymphatic vessels or in regional lymph nodes.
Metabolism
- Following the administration of a single oral radiolabeled dose of pimecrolimus numerous circulating O-demethylation metabolites were seen. Studies with human liver microsomes indicate that pimecrolimus is metabolized in vitro by the CYP3A sub-family of metabolizing enzymes. No evidence of skin mediated drug metabolism was identified in vivo using the minipig or in vitro using stripped human skin.
Elimination
- Based on the results of the aforementioned radiolabeled study, following a single oral dose of pimecrolimus ~81% of the administered radioactivity was recovered, primarily in the feces (78.4%) as metabolites. Less than 1% of the radioactivity found in the feces was due to unchanged pimecrolimus.
## Nonclinical Toxicology
Carcinogenesis, Mutagenesis, Impairment of Fertility
- In a 2-year rat dermal carcinogenicity study using ELIDEL Cream, 1%, a statistically significant increase in the incidence of follicular cell adenoma of the thyroid was noted in low, mid and high dose male animals compared to vehicle and saline control male animals. Follicular cell adenoma of the thyroid was noted in the dermal rat carcinogenicity study at the lowest dose of 2 mg/kg/day [0.2% pimecrolimus cream; 1.5× the Maximum Recommended Human Dose (MRHD) based on AUC comparisons]. No increase in the incidence of follicular cell adenoma of the thyroid was noted in the oral carcinogenicity study in male rats up to 10 mg/kg/day (66× MRHD based on AUC comparisons). However, oral studies may not reflect continuous exposure or the same metabolic profile as by the dermal route. In a mouse dermal carcinogenicity study using pimecrolimus in an ethanolic solution, no increase in incidence of neoplasms was observed in the skin or other organs up to the highest dose of 4 mg/kg/day (0.32% pimecrolimus in ethanol) 27× MRHD based on AUC comparisons. However, lymphoproliferative changes (including lymphoma) were noted in a 13 week repeat dose dermal toxicity study conducted in mice using pimecrolimus in an ethanolic solution at a dose of 25 mg/kg/day (47× MRHD based on AUC comparisons). No lymphoproliferative changes were noted in this study at a dose of 10 mg/kg/day (17× MRHD based on AUC comparison). However, the latency time to lymphoma formation was shortened to 8 weeks after dermal administration of pimecrolimus dissolved in ethanol at a dose of 100 mg/kg/day (179-217× MRHD based on AUC comparisons).
- In a mouse oral (gavage) carcinogenicity study, a statistically significant increase in the incidence of lymphoma was noted in high dose male and female animals compared to vehicle control male and female animals. Lymphomas were noted in the oral mouse carcinogenicity study at a dose of 45 mg/kg/day (258-340× MRHD based on AUC comparisons). No drug-related tumors were noted in the mouse oral carcinogenicity study at a dose of 15 mg/kg/day (60-133× MRHD based on AUC comparisons).
- In an oral (gavage) rat carcinogenicity study, a statistically significant increase in the incidence of benign thymoma was noted in 10 mg/kg/day pimecrolimus treated male and female animals compared to vehicle control treated male and female animals. In addition, a significant increase in the incidence of benign thymoma was noted in another oral (gavage) rat carcinogenicity study in 5 mg/kg/day pimecrolimus treated male animals compared to vehicle control treated male animals. No drug-related tumors were noted in the rat oral carcinogenicity study at a dose of 1 mg/kg/day male animals (1.1× MRHD based on AUC comparisons) and at a dose of 5 mg/kg/day for female animals (21× MRHD based on AUC comparisons).
- In a 52-week dermal photo-carcinogenicity study, the median time to onset of skin tumor formation was decreased in hairless mice following chronic topical dosing with concurrent exposure to UV radiation (40 weeks of treatment followed by 12 weeks of observation) with the ELIDEL Cream, 1% vehicle alone. No additional effect on tumor development beyond the vehicle effect was noted with the addition of the active ingredient, pimecrolimus, to the vehicle cream.
- A 39-week oral monkey toxicology study was conducted with pimecrolimus doses of 15, 45 and 120 mg/kg/day. A dose dependent increase in expression of immunosuppressive-related lymphoproliferative disorder (IRLD) associated with lymphocryptovirus (a monkey strain of virus related to human Epstein Barr virus) was observed. IRLD in monkeys mirrors what has been noted in human transplant patients after chronic systemic immunosuppressive therapy, post transplantation lymphoproliferative disease (PTLD), after treatment with chronic systemic immunosuppressive therapy. Both IRLD and PTLD can progress to lymphoma, which is dependent on the dose and duration of systemic immunosuppressive therapy. A dose dependent increase in opportunistic infections (a signal of systemic immunosuppression) was also noted in this monkey study. A no observed adverse effect level (NOAEL) for IRLD and opportunistic infections was not established in this study. IRLD occurred at the lowest dose of 15 mg/kg/day for 39 weeks [31× the Maximum Recommended Human Dose (MRHD) of ELIDEL Cream, 1% based on AUC comparisons] in this study. A partial recovery from IRLD was noted upon cessation of dosing in this study.
- A battery of in vitro genotoxicity tests, including Ames assay, mouse lymphoma L5178Y assay, and chromosome aberration test in V79 Chinese hamster cells and an in vivo mouse micronucleus test revealed no evidence for a mutagenic or clastogenic potential for the drug.
- An oral fertility and embryofetal developmental study in rats revealed estrus cycle disturbances, post-implantation loss and reduction in litter size at the 45 mg/kg/day dose (38× MRHD based on AUC comparisons). No effect on fertility in female rats was noted at 10 mg/kg/day (12× MRHD based on AUC comparisons). No effect on fertility in male rats was noted at 45 mg/kg/day (23× MRHD based on AUC comparisons), which was the highest dose tested in this study.
- A second oral fertility and embryofetal developmental study in rats revealed reduced testicular and epididymal weights, reduced testicular sperm counts and motile sperm for males and estrus cycle disturbances, decreased corpora lutea, decreased implantations and viable fetuses for females at 45 mg/kg/day dose (123× MRHD for males and 192× MRHD for females based on AUC comparisons). No effect on fertility in female rats was noted at 10 mg/kg/day (5× MRHD based on AUC comparisons). No effect on fertility in male rats was noted at 2 mg/kg/day (0.7× MRHD based on AUC comparisons).
# Clinical Studies
- Three randomized, double-blind, vehicle-controlled, multi-center, Phase 3 trials were conducted in 589 pediatric subjects ages 3 months-17 years old to evaluate ELIDEL (pimecrolimus) Cream, 1% for the treatment of mild to moderate atopic dermatitis. Two of the three trials support the use of ELIDEL Cream, 1% in subjects 2 years and older with mild to moderate atopic dermatitis. Three other trials in 1,619 pediatric and adult subjects provided additional data regarding the safety of ELIDEL Cream, 1% in the treatment of atopic dermatitis. Two of these other trials were vehicle-controlled with optional sequential use of a medium potency topical corticosteroid in pediatric subjects and one trial was an active comparator trial in adult subjects with atopic dermatitis.
- Two identical 6-week, randomized, vehicle-controlled, multi-center, Phase 3 trials were conducted to evaluate ELIDEL Cream, 1% for the treatment of mild to moderate atopic dermatitis. A total of 403 pediatric subjects 2-17 years old were included in the trials. The male/female ratio was approximately 50% and 29% of the subjects were African American. At trial entry, 59% of subjects had moderate disease and the mean body surface area (BSA) affected was 26%. About 75% of subjects had atopic dermatitis affecting the face and/or neck region. In these trials, subjects applied either ELIDEL Cream, 1% or vehicle cream twice daily to 5% to 96% of their BSA for up to 6 weeks. At endpoint, based on the physician’s global evaluation of clinical response, 35% of subjects treated with ELIDEL Cream, 1% were clear or almost clear of signs of atopic dermatitis compared to only 18% of vehicle-treated subjects. More ELIDEL subjects (57%) had mild or no pruritus at 6 weeks compared to vehicle subjects (34%). The improvement in pruritus occurred in conjunction with the improvement of the subjects’ atopic dermatitis.
In these two 6-week studies of ELIDEL, the combined efficacy results at endpoint are presented in Table 2 as follows:
- In the two pediatric trials that independently support the use of ELIDEL Cream, 1% in mild to moderate atopic dermatitis, a significant treatment effect was seen by day 15. Of the key signs of atopic dermatitis, erythema, infiltration/papulation, lichenification, and excoriations were reduced at day 8 when compared to vehicle.
- Figure 1 depicts the time course of improvement in the percent body surface area affected as a result of treatment with ELIDEL Cream, 1% in 2-17 year olds.
# How Supplied
- ELIDEL (pimecrolimus) Cream, 1% is a whitish cream available in tubes of 30 grams, 60 grams, and 100 grams.
## Storage
- Store at 25°C (77°F); excursions permitted to 15°C-30°C (59°F-86°F) [USP Controlled Room Temperature]. Do not freeze.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
See FDA-approved patient labeling (Medication Guide)
Patients using ELIDEL Cream, 1% should receive the following information and instructions:
- ELIDEL Cream, 1% may cause serious side effects. It is not known if ELIDEL Cream, 1% is safe to use for a long period of time. A very small number of people who have used ELIDEL Cream, 1% have had cancer (for example, skin or lymphoma). However, a link with ELIDEL Cream, 1% use has not been shown. Because of this concern:
- A patient should not use ELIDEL Cream, 1% continuously for a long time.
- ELIDEL Cream, 1% should be used only on areas of skin that have eczema.
- ELIDEL Cream, 1% is not for use on a child under 2 years old.
- A patient should not use sun lamps, tanning beds, or get treatment with ultraviolet light therapy during treatment with ELIDEL Cream, 1%.
- A patient should limit sun exposure during treatment with ELIDEL Cream, 1% even when the medicine is not on the skin. If a patient needs to be outdoors after applying ELIDEL Cream, 1%, the patient should wear loose fitting clothing that protects the treated area from the sun. The physician should advise the patient about other types of protection from the sun.
- A patient should not cover the skin being treated with bandages, dressings or wraps. A patient can wear normal clothing.
- ELIDEL Cream, 1% is for use on the skin only. Do not get ELIDEL Cream, 1% in your eyes, nose, mouth, vagina, or rectum (mucous membranes). If you get ELIDEL Cream, 1% in any of these areas, burning or irritation can happen. Wipe off any ELIDEL Cream, 1% from the affected area and then rinse the area well with cold water. ELIDEL Cream, 1% is for external use only.
- A patient should use ELIDEL Cream, 1% for short periods, and if needed, treatment may be repeated with breaks in between.
- Wash hands before using ELIDEL Cream, 1%. When applying ELIDEL Cream, 1% after a bath or shower, the skin should be dry.
- Apply a thin layer of ELIDEL Cream, 1% only to the affected skin areas, twice a day, as directed by the physician.
- Use the smallest amount of ELIDEL Cream, 1% needed to control the signs and symptoms of eczema.
- A patient should not bathe, shower or swim right after applying ELIDEL Cream, 1%. This could wash off the cream.
- A patient can use moisturizers with ELIDEL Cream, 1%. They should be sure to check with the physician first about the products that are right for them. Because the skin of patients with eczema can be very dry, it is important they keep up good skin care practices. If a patient uses moisturizers, he or she should apply them after ELIDEL Cream, 1%.
# Precautions with Alcohol
- Alcohol-Pimecrolimus interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
Elidel
# Look-Alike Drug Names
- A® — B®[1]
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Elidel | |
687931e3b24dfc4e82c1cef6a84dd4f3ca12c28b | wikidoc | Elvitegravir | Elvitegravir
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# Overview
Elvitegravir is an antiretroviral agent and integrase inhibitor that is FDA approved for the treatment of HIV-1 infection in antiretroviral treatment-experienced adults. Common adverse reactions include diarrhea, hyperglycemia, hypercholesterolemia and nausea.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Elvitegravir must be administered once daily with food in combination with a protease inhibitor coadministered with ritonavir and another antiretroviral drug. The protease inhibitor and ritonavir dosing regimens presented in Table 1 are the recommended regimens for use with Elvitegravir. For additional dosing instructions for these protease inhibitors and other concomitant antiretroviral drugs, refer to their respective prescribing information.
- Treatment history and, when available, resistance testing should guide the use of Elvitegravir-containing regimens.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Elvitegravir in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Elvitegravir in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding Elvitegravir 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 Elvitegravir in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Elvitegravir in pediatric patients.
# Contraindications
- There are no contraindications to Elvitegravir. Due to the need to use Elvitegravir with a protease inhibitor coadministered with ritonavir, prescribers should consult the complete prescribing information of the coadministered protease inhibitor and ritonavir for a description of contraindications.
# Warnings
### Risk of Adverse Reactions or Loss of Virologic Response Due to Drug Interactions
The concomitant use of Elvitegravir and other drugs may result in known or potentially significant drug interactions, some of which may lead to:
- Loss of therapeutic effect of Elvitegravir and possible development of resistance
- Possible clinically significant adverse reactions from greater exposures of concomitant drugs or elvitegravir.
See the Drug Interactions table for steps to prevent or manage these possible and known significant drug interactions, including dosing recommendations. Consider the potential for drug interactions prior to and during Elvitegravir therapy; review concomitant medications during Elvitegravir therapy; and monitor for the adverse reactions associated with the concomitant drugs.
### Use with Other Antiretroviral Agents
- Use of Elvitegravir in combination with the fixed dose combination STRIBILD is not recommended, because elvitegravir is a component of STRIBILD.
- Elvitegravir is indicated for use in combination with a protease inhibitor coadministered with ritonavir and with other antiretroviral drug(s). Elvitegravir in combination with a protease inhibitor and cobicistat is not recommended because dosing recommendations for such combinations have not been established and may result in suboptimal plasma concentrations of Elvitegravir and/or the protease inhibitor, leading to loss of therapeutic effect and development of resistance.
### Immune Reconstitution Syndrome
- Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy. During the initial phase of combination antiretroviral treatment, patients whose immune systems respond may develop an inflammatory response to indolent or residual opportunistic infections (such as Mycobacterium avium infection, cytomegalovirus, Pneumocystis jirovecii pneumonia PCP, or tuberculosis), which may necessitate further evaluation and treatment.
- Autoimmune disorders (such as Graves' disease, polymyositis, and Guillain-Barré syndrome) have also been reported to occur in the setting of immune reconstitution syndrome; however, the time to onset is more variable, and can occur many months after initiation of treatment.
# 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 assessment of Elvitegravir is primarily based on data from a controlled clinical trial, Study 145, in which 712 HIV-1 infected, antiretroviral treatment-experienced adults received Elvitegravir (N=354) or raltegravir (N=358), each administered with a background regimen consisting of a fully active protease inhibitor coadministered with ritonavir and with other antiretroviral drug(s) for at least 96 weeks.
- The proportion of subjects who discontinued study treatment due to adverse events, regardless of severity, was 3% in the Elvitegravir group and 4% in the raltegravir group. The most common adverse reaction (all Grades, incidence greater than or equal to 5%) in subjects receiving Elvitegravir in Study 145 was diarrhea. See also TABLE 2 for the frequency of adverse reactions occurring in at least 2% of subjects in any treatment group in Study 145.
- Less Common Adverse Reactions Observed in Treatment-Experienced Studies: The following adverse reactions occurred in <2% of subjects receiving Elvitegravir combined with a protease inhibitor and ritonavir. These reactions have been included because of their seriousness, increased frequency on Elvitegravir compared with raltegravir, or investigator's assessment of potential causal relationship.
- Gastrointestinal Disorders: abdominal pain, dyspepsia, vomiting
- General Disorders and Administration Site Conditions: fatigue
- Psychiatric Disorders: depression, insomnia, suicidal ideation and suicide attempt (<1%, most in subjects with a pre-existing history of depression or psychiatric illness)
- Skin and Subcutaneous Tissue Disorders: rash
- Laboratory Abnormalities: The frequency of laboratory abnormalities (Grades 3–4), occurring in at least 2% of subjects in either treatment group in Study 145, is presented in Table 3.
## Postmarketing Experience
# Drug Interactions
### Effect of Concomitant Drugs on the Pharmacokinetics of Elvitegravir
- Elvitegravir is metabolized by CYP3A. Drugs that induce CYP3A activity are expected to increase the clearance of elvitegravir, as well as ritonavir. This may result in decreased plasma concentrations of elvitegravir and/or a concomitantly administered protease inhibitor and lead to loss of therapeutic effect and to possible resistance.
### Established and Other Potentially Significant Interactions
- Table 4 provides dosing recommendations as a result of potentially clinically significant drug interactions with Elvitegravir. These recommendations are based on either drug-drug interaction studies or predicted interactions due to the expected magnitude of interaction and potential for serious adverse events or loss of therapeutic effect.
- For additional drug-drug interactions related to protease inhibitors coadministered with ritonavir, consult the prescribing information of the coadministered protease inhibitor and ritonavir.
The table is not all-inclusive
### Drugs without Clinically Significant Interactions with Elvitegravir
- Based on drug interaction studies conducted with elvitegravir, no clinically significant drug interactions have been either observed or expected when elvitegravir is combined with the following drugs: abacavir, darunavir, emtricitabine, etravirine, fosamprenavir, maraviroc, stavudine, tipranavir, tenofovir disoproxil fumarate, zidovudine; H2-receptor antagonists such as famotidine; proton-pump inhibitors such as omeprazole; and the HMG-CoA reductase inhibitors atorvastatin, pravastatin, and rosuvastatin.
- When any of the above drugs are used concomitantly with Elvitegravir in combination with a protease inhibitor coadministered with ritonavir, consult the prescribing information of the protease inhibitor for dosing recommendation for these drugs.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): B
- There are no adequate and well-controlled studies of Elvitegravir in pregnant women. Because animal reproduction studies are not always predictive of human response, Elvitegravir should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
- Antiretroviral Pregnancy Registry: To monitor fetal outcomes of pregnant women exposed to Elvitegravir, an Antiretroviral Pregnancy Registry has been established. Healthcare providers are encouraged to register patients by calling 1-800-258-4263.
- Animal Data: Elvitegravir studies in animals have shown no evidence of teratogenicity or an effect on reproductive function. In offspring from rat and rabbit dams treated with Elvitegravir during pregnancy, there were no toxicologically significant effects on developmental endpoints. The exposures (AUC) at the embryo-fetal No Observed Adverse Effects Levels (NOAELs) in rats and rabbits were respectively 23 and 0.2 times higher than the exposure in humans at the recommended daily dose of 150 mg.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Elvitegravir in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Elvitegravir during labor and delivery.
### Nursing Mothers
The Centers for Disease Control and Prevention recommend that HIV-infected mothers not breastfeed their infants, to avoid risking postnatal transmission of HIV. Studies in rats have demonstrated that elvitegravir is secreted in milk. It is not known whether elvitegravir is excreted in human milk. Because of both the potential for HIV transmission and the potential for serious adverse reactions in nursing infants, mothers should be instructed not to breastfeed if they are receiving Elvitegravir.
### Pediatric Use
## Safety and efficacy in pediatric patients have not been established
### Adolescents (12 through 17 Years Old)
- Study 152 was an open-label, multicenter trial of Elvitegravir in HIV-1 infected, antiretroviral treatment-experienced adolescent subjects 12 through 17 years of age. The trial included a 10-day pharmacokinetic evaluation phase of Elvitegravir followed by an optional extended treatment phase. Dosage regimens were similar to those evaluated in adults, either Elvitegravir 150 mg plus darunavir/ritonavir, fosamprenavir/ritonavir, or tipranavir/ritonavir (n=11) or Elvitegravir 85 mg plus lopinavir/ritonavir or atazanavir/ritonavir (n=14).
- Twenty-five subjects were enrolled and 23 completed the pharmacokinetic phase . Nine subjects with baseline HIV-1 RNA greater than 1,000 copies/mL who completed the 10-day pharmacokinetic evaluation phase enrolled in the optional 48 week treatment phase. All nine completed treatment through 48 weeks; 2/9 subjects (22%) achieved HIV-1 RNA less than 50 copies/mL at Week 48, and 4/9 (44%) achieved HIV-1 RNA less than 400 copies/mL. During the treatment phase of the trial, 8/9 subjects (89%) were found to have undetectable elvitegravir levels during treatment, suggesting that adherence to the regimen was poor and may have contributed to the low response rate in this trial. Although adolescents achieved acceptable Elvitegravir plasma levels in the pharmacokinetic phase, the 48-week treatment phase data were insufficient to establish safety and effectiveness in this age group.
## Pediatric Patients Less Than 12 Years Old
- Pharmacokinetics, safety and effectiveness of Elvitegravir in the treatment of HIV-1 infection in pediatric patients less than 12 years of age have not been evaluated in clinical trials.
### Geriatic Use
- Clinical trials of Elvitegravir did not include sufficient numbers of subjects aged 65 and older, to determine whether they respond differently from younger subjects. In general, dose selection for elderly patients should be cautious, keeping in mind the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.
### Gender
There is no FDA guidance on the use of Elvitegravir with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Elvitegravir with respect to specific racial populations.
### Renal Impairment
- No clinically relevant differences in elvitegravir pharmacokinetics were observed between subjects with severe renal impairment and healthy subjects. No dose adjustment of Elvitegravir is required for patients with renal impairment
### Hepatic Impairment
- No clinically relevant differences in elvitegravir pharmacokinetics were observed between subjects with moderate hepatic impairment (Child-Pugh Class B) and healthy subjects. No dose adjustment of Elvitegravir is required in patients with mild (Child-Pugh Class A) or moderate hepatic impairment. Elvitegravir has not been studied in patients with severe hepatic impairment (Child-Pugh Class C). Therefore, Elvitegravir is not recommended for use in patients with severe hepatic impairment
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Elvitegravir in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Elvitegravir in patients who are immunocompromised.
# Administration and Monitoring
### Administration
There is limited information regarding Elvitegravir Administration in the drug label.
### Monitoring
There is limited information regarding Elvitegravir Monitoring in the drug label.
# IV Compatibility
There is limited information regarding the compatibility of Elvitegravir and IV administrations.
# Overdosage
- If overdose occurs the patient must be monitored for evidence of toxicity. Treatment of overdose with Elvitegravir consists of general supportive measures including monitoring of vital signs, as well as observation of the clinical status of the patient.
- Limited clinical experience is available at doses higher than the therapeutic dose of elvitegravir. The effects of higher doses are not known. As elvitegravir is highly bound to plasma proteins, it is unlikely that it will be significantly removed by hemodialysis or peritoneal dialysis.
# Pharmacology
## Mechanism of Action
- Elvitegravir is an HIV-1 integrase strand transfer inhibitor (INSTI). Integrase is an HIV-1 encoded enzyme that is required for viral replication. Inhibition of integrase prevents the integration of HIV-1 DNA into host genomic DNA, blocking the formation of the HIV-1 provirus and propagation of the viral infection. Elvitegravir does not inhibit human topoisomerases I or II.
## Structure
- It has a molecular formula of C23H23ClFNO5 and a molecular weight of 447.9. It has the following structural formula:
## Pharmacodynamics
### Cardiac Electrophysiology
- The effect of multiple doses of elvitegravir 125 mg (1.5 times the lowest recommended dosage) and 250 mg (1.7 times the maximum recommended dosage) (coadministered with 100 mg ritonavir) on QT interval was evaluated in a randomized, placebo- and active-controlled (moxifloxacin 400 mg) parallel group thorough QT study in 126 healthy subjects. No clinically meaningful changes in QTc interval were observed with either 125 mg dose or the 250 mg dose. The dose of 250 mg elvitegravir (with 100 mg ritonavir) is expected to cover the high exposure clinical scenario.
## Pharmacokinetics
### Absorption
- Following oral administration of Elvitegravir and ritonavir with food, in HIV-1 infected subjects, peak elvitegravir plasma concentrations were observed approximately 4 hours post-dose. The steady-state mean elvitegravir pharmacokinetic parameters are presented in Table 5. Elvitegravir plasma exposures increased in a less than dose proportional manner, likely due to solubility-limited absorption.
Elvitegravir must be taken with food.
### Distribution
- Elvitegravir is 98–99% bound to human plasma proteins and the binding is independent of drug concentration over the range of 1 ng/mL to 1.6 µg/mL. The mean plasma-to-blood drug concentration ratio is 1.37.
### Metabolism and Elimination
- Elvitegravir undergoes primarily oxidative metabolism via CYP3A, and is secondarily glucuronidated via UGT1A1/3 enzymes. Following oral administration of elvitegravir/ritonavir, elvitegravir was the predominant species in plasma, representing ~94% of the circulating radioactivity. Aromatic and aliphatic hydroxylation or glucuronidation metabolites were present in very low levels, displayed considerably lower anti-HIV activity and did not contribute to the overall antiviral activity of elvitegravir.
- Following oral administration of elvitegravir/ritonavir, 94.8% of the dose was recovered in feces, consistent with the hepatobiliary excretion of elvitegravir; 6.7% of the administered dose was recovered in urine as metabolites. The median terminal plasma half-life of elvitegravir following administration of Elvitegravir and ritonavir was approximately 8.7 hours.
## Nonclinical Toxicology
### Carcinogenesis
- Long-term carcinogenicity studies of elvitegravir were carried out in mice (104 weeks) and in rats (up to 88 weeks in males and 90 weeks in females). No drug-related increases in tumor incidence were found in mice at doses up to 2000 mg per kg per day alone or in combination with 25 mg per kg per day ritonavir at exposures 3- and 14-fold, respectively, the human systemic exposure at the recommended daily dose of 150 mg. No drug-related increases in tumor incidence were found in rats at doses up to 2000 mg per kg per day at exposures 12- to 27-fold, respectively, in male and female, the human systemic exposure.
- Elvitegravir was not genotoxic in the reverse mutation bacterial test (Ames test) and the rat micronucleus assay. In an in vitro chromosomal aberration test, elvitegravir was negative with metabolic activation; however, an equivocal response was observed without activation.
### Fertility
- Elvitegravir did not affect fertility in male and female rats at approximately 16- and 30-fold higher exposures (AUC), respectively, than in humans at the therapeutic 150 mg daily dose.
- Fertility was normal in the offspring of rats exposed daily from before birth (in utero) through sexual maturity at daily exposures (AUC) of approximately 18-fold higher than human exposures at the recommended 150 mg daily dose.
# Clinical Studies
### Treatment-Experienced Adults with HIV-1 Infection
- The efficacy of Elvitegravir in treatment-experienced adult patients with HIV-1 infection is based on the analyses through 96 weeks from one randomized, double-blind, active-controlled trial, Study 145, in treatment-experienced, HIV-1 infected subjects (N=702). In Study 145, subjects were randomized in a 1:1 ratio to receive either Elvitegravir (150 mg or 85 mg) once daily or raltegravir 400 mg twice daily, each administered with a background regimen (BR) containing a fully active protease inhibitor coadministered with ritonavir and a second antiretroviral drug. The BR was selected by the investigator based on genotypic/phenotypic resistance testing and prior antiretroviral treatment history.
- The mean age of subjects was 45 years (range 19–78); 82% were male, 62% were White, and 34% were Black. The mean baseline plasma HIV-1 RNA was 4.3 log10 copies/mL (range 1.7–6.6) and 26% of subjects had baseline viral loads greater than 100,000 copies/mL. The mean duration of prior HIV-1 treatment was 9.4 years. The mean baseline CD4+ cell count was 262 cells/mm3 (range 1–1497), 45% had CD4+ cell counts ≤ 200 cells/mm3, and 85% had a baseline genotypic sensitivity score ≥ 2.
- Virologic outcomes were similar across the treatment arms through 96 weeks as presented in Table 8. The mean increase from baseline in CD4+ cell count at Week 96 was 205 cells/mm3 in Elvitegravir-treated subjects and 198 cells/mm3 in raltegravir-treated subjects.
# How Supplied
VITEKTA tablets are available in bottles containing 30 tablets with a child-resistant closure as follows:
- 85 mg tablets are green, pentagon-shaped, film-coated, debossed with "GSI" on one side and "85" on the other side: NDC 61958-1301-1
- 150 mg tablets are green, triangle-shaped, film-coated, debossed with "GSI" on one side and "150" on the other side: NDC 61958-1302-1
## Storage
- Store at room temperature below 30 °C (86 °F).
- Dispense only in original container.
- Do not use if seal over bottle opening is broken or missing.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
There is limited information regarding Elvitegravir Patient Counseling Information in the drug label.
# Precautions with Alcohol
- Alcohol-Elvitegravir interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Vitekta
# Look-Alike Drug Names
There is limited information regarding Elvitegravir Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | Elvitegravir
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Alberto Plate [2]
# Disclaimer
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# Overview
Elvitegravir is an antiretroviral agent and integrase inhibitor that is FDA approved for the treatment of HIV-1 infection in antiretroviral treatment-experienced adults. Common adverse reactions include diarrhea, hyperglycemia, hypercholesterolemia and nausea.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Elvitegravir must be administered once daily with food in combination with a protease inhibitor coadministered with ritonavir and another antiretroviral drug. The protease inhibitor and ritonavir dosing regimens presented in Table 1 are the recommended regimens for use with Elvitegravir. For additional dosing instructions for these protease inhibitors and other concomitant antiretroviral drugs, refer to their respective prescribing information.
- Treatment history and, when available, resistance testing should guide the use of Elvitegravir-containing regimens.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Elvitegravir in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Elvitegravir in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding Elvitegravir 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 Elvitegravir in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Elvitegravir in pediatric patients.
# Contraindications
- There are no contraindications to Elvitegravir. Due to the need to use Elvitegravir with a protease inhibitor coadministered with ritonavir, prescribers should consult the complete prescribing information of the coadministered protease inhibitor and ritonavir for a description of contraindications.
# Warnings
### Risk of Adverse Reactions or Loss of Virologic Response Due to Drug Interactions
The concomitant use of Elvitegravir and other drugs may result in known or potentially significant drug interactions, some of which may lead to:
- Loss of therapeutic effect of Elvitegravir and possible development of resistance
- Possible clinically significant adverse reactions from greater exposures of concomitant drugs or elvitegravir.
See the Drug Interactions table for steps to prevent or manage these possible and known significant drug interactions, including dosing recommendations. Consider the potential for drug interactions prior to and during Elvitegravir therapy; review concomitant medications during Elvitegravir therapy; and monitor for the adverse reactions associated with the concomitant drugs.
### Use with Other Antiretroviral Agents
- Use of Elvitegravir in combination with the fixed dose combination STRIBILD is not recommended, because elvitegravir is a component of STRIBILD.
- Elvitegravir is indicated for use in combination with a protease inhibitor coadministered with ritonavir and with other antiretroviral drug(s). Elvitegravir in combination with a protease inhibitor and cobicistat is not recommended because dosing recommendations for such combinations have not been established and may result in suboptimal plasma concentrations of Elvitegravir and/or the protease inhibitor, leading to loss of therapeutic effect and development of resistance.
### Immune Reconstitution Syndrome
- Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy. During the initial phase of combination antiretroviral treatment, patients whose immune systems respond may develop an inflammatory response to indolent or residual opportunistic infections (such as Mycobacterium avium infection, cytomegalovirus, Pneumocystis jirovecii pneumonia PCP, or tuberculosis), which may necessitate further evaluation and treatment.
- Autoimmune disorders (such as Graves' disease, polymyositis, and Guillain-Barré syndrome) have also been reported to occur in the setting of immune reconstitution syndrome; however, the time to onset is more variable, and can occur many months after initiation of treatment.
# 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 assessment of Elvitegravir is primarily based on data from a controlled clinical trial, Study 145, in which 712 HIV-1 infected, antiretroviral treatment-experienced adults received Elvitegravir (N=354) or raltegravir (N=358), each administered with a background regimen consisting of a fully active protease inhibitor coadministered with ritonavir and with other antiretroviral drug(s) for at least 96 weeks.
- The proportion of subjects who discontinued study treatment due to adverse events, regardless of severity, was 3% in the Elvitegravir group and 4% in the raltegravir group. The most common adverse reaction (all Grades, incidence greater than or equal to 5%) in subjects receiving Elvitegravir in Study 145 was diarrhea. See also TABLE 2 for the frequency of adverse reactions occurring in at least 2% of subjects in any treatment group in Study 145.
- Less Common Adverse Reactions Observed in Treatment-Experienced Studies: The following adverse reactions occurred in <2% of subjects receiving Elvitegravir combined with a protease inhibitor and ritonavir. These reactions have been included because of their seriousness, increased frequency on Elvitegravir compared with raltegravir, or investigator's assessment of potential causal relationship.
- Gastrointestinal Disorders: abdominal pain, dyspepsia, vomiting
- General Disorders and Administration Site Conditions: fatigue
- Psychiatric Disorders: depression, insomnia, suicidal ideation and suicide attempt (<1%, most in subjects with a pre-existing history of depression or psychiatric illness)
- Skin and Subcutaneous Tissue Disorders: rash
- Laboratory Abnormalities: The frequency of laboratory abnormalities (Grades 3–4), occurring in at least 2% of subjects in either treatment group in Study 145, is presented in Table 3.
## Postmarketing Experience
# Drug Interactions
### Effect of Concomitant Drugs on the Pharmacokinetics of Elvitegravir
- Elvitegravir is metabolized by CYP3A. Drugs that induce CYP3A activity are expected to increase the clearance of elvitegravir, as well as ritonavir. This may result in decreased plasma concentrations of elvitegravir and/or a concomitantly administered protease inhibitor and lead to loss of therapeutic effect and to possible resistance.
### Established and Other Potentially Significant Interactions
- Table 4 provides dosing recommendations as a result of potentially clinically significant drug interactions with Elvitegravir. These recommendations are based on either drug-drug interaction studies or predicted interactions due to the expected magnitude of interaction and potential for serious adverse events or loss of therapeutic effect.
- For additional drug-drug interactions related to protease inhibitors coadministered with ritonavir, consult the prescribing information of the coadministered protease inhibitor and ritonavir.
The table is not all-inclusive
### Drugs without Clinically Significant Interactions with Elvitegravir
- Based on drug interaction studies conducted with elvitegravir, no clinically significant drug interactions have been either observed or expected when elvitegravir is combined with the following drugs: abacavir, darunavir, emtricitabine, etravirine, fosamprenavir, maraviroc, stavudine, tipranavir, tenofovir disoproxil fumarate, zidovudine; H2-receptor antagonists such as famotidine; proton-pump inhibitors such as omeprazole; and the HMG-CoA reductase inhibitors atorvastatin, pravastatin, and rosuvastatin.
- When any of the above drugs are used concomitantly with Elvitegravir in combination with a protease inhibitor coadministered with ritonavir, consult the prescribing information of the protease inhibitor for dosing recommendation for these drugs.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): B
- There are no adequate and well-controlled studies of Elvitegravir in pregnant women. Because animal reproduction studies are not always predictive of human response, Elvitegravir should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
- Antiretroviral Pregnancy Registry: To monitor fetal outcomes of pregnant women exposed to Elvitegravir, an Antiretroviral Pregnancy Registry has been established. Healthcare providers are encouraged to register patients by calling 1-800-258-4263.
- Animal Data: Elvitegravir studies in animals have shown no evidence of teratogenicity or an effect on reproductive function. In offspring from rat and rabbit dams treated with Elvitegravir during pregnancy, there were no toxicologically significant effects on developmental endpoints. The exposures (AUC) at the embryo-fetal No Observed Adverse Effects Levels (NOAELs) in rats and rabbits were respectively 23 and 0.2 times higher than the exposure in humans at the recommended daily dose of 150 mg.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Elvitegravir in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Elvitegravir during labor and delivery.
### Nursing Mothers
The Centers for Disease Control and Prevention recommend that HIV-infected mothers not breastfeed their infants, to avoid risking postnatal transmission of HIV. Studies in rats have demonstrated that elvitegravir is secreted in milk. It is not known whether elvitegravir is excreted in human milk. Because of both the potential for HIV transmission and the potential for serious adverse reactions in nursing infants, mothers should be instructed not to breastfeed if they are receiving Elvitegravir.
### Pediatric Use
## Safety and efficacy in pediatric patients have not been established
### Adolescents (12 through 17 Years Old)
- Study 152 was an open-label, multicenter trial of Elvitegravir in HIV-1 infected, antiretroviral treatment-experienced adolescent subjects 12 through 17 years of age. The trial included a 10-day pharmacokinetic evaluation phase of Elvitegravir followed by an optional extended treatment phase. Dosage regimens were similar to those evaluated in adults, either Elvitegravir 150 mg plus darunavir/ritonavir, fosamprenavir/ritonavir, or tipranavir/ritonavir (n=11) or Elvitegravir 85 mg plus lopinavir/ritonavir or atazanavir/ritonavir (n=14).
- Twenty-five subjects were enrolled and 23 completed the pharmacokinetic phase [see Clinical Pharmacology (12.3)]. Nine subjects with baseline HIV-1 RNA greater than 1,000 copies/mL who completed the 10-day pharmacokinetic evaluation phase enrolled in the optional 48 week treatment phase. All nine completed treatment through 48 weeks; 2/9 subjects (22%) achieved HIV-1 RNA less than 50 copies/mL at Week 48, and 4/9 (44%) achieved HIV-1 RNA less than 400 copies/mL. During the treatment phase of the trial, 8/9 subjects (89%) were found to have undetectable elvitegravir levels during treatment, suggesting that adherence to the regimen was poor and may have contributed to the low response rate in this trial. Although adolescents achieved acceptable Elvitegravir plasma levels in the pharmacokinetic phase, the 48-week treatment phase data were insufficient to establish safety and effectiveness in this age group.
## Pediatric Patients Less Than 12 Years Old
- Pharmacokinetics, safety and effectiveness of Elvitegravir in the treatment of HIV-1 infection in pediatric patients less than 12 years of age have not been evaluated in clinical trials.
### Geriatic Use
- Clinical trials of Elvitegravir did not include sufficient numbers of subjects aged 65 and older, to determine whether they respond differently from younger subjects. In general, dose selection for elderly patients should be cautious, keeping in mind the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.
### Gender
There is no FDA guidance on the use of Elvitegravir with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Elvitegravir with respect to specific racial populations.
### Renal Impairment
- No clinically relevant differences in elvitegravir pharmacokinetics were observed between subjects with severe renal impairment and healthy subjects. No dose adjustment of Elvitegravir is required for patients with renal impairment
### Hepatic Impairment
- No clinically relevant differences in elvitegravir pharmacokinetics were observed between subjects with moderate hepatic impairment (Child-Pugh Class B) and healthy subjects. No dose adjustment of Elvitegravir is required in patients with mild (Child-Pugh Class A) or moderate hepatic impairment. Elvitegravir has not been studied in patients with severe hepatic impairment (Child-Pugh Class C). Therefore, Elvitegravir is not recommended for use in patients with severe hepatic impairment
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Elvitegravir in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Elvitegravir in patients who are immunocompromised.
# Administration and Monitoring
### Administration
There is limited information regarding Elvitegravir Administration in the drug label.
### Monitoring
There is limited information regarding Elvitegravir Monitoring in the drug label.
# IV Compatibility
There is limited information regarding the compatibility of Elvitegravir and IV administrations.
# Overdosage
- If overdose occurs the patient must be monitored for evidence of toxicity. Treatment of overdose with Elvitegravir consists of general supportive measures including monitoring of vital signs, as well as observation of the clinical status of the patient.
- Limited clinical experience is available at doses higher than the therapeutic dose of elvitegravir. The effects of higher doses are not known. As elvitegravir is highly bound to plasma proteins, it is unlikely that it will be significantly removed by hemodialysis or peritoneal dialysis.
# Pharmacology
## Mechanism of Action
- Elvitegravir is an HIV-1 integrase strand transfer inhibitor (INSTI). Integrase is an HIV-1 encoded enzyme that is required for viral replication. Inhibition of integrase prevents the integration of HIV-1 DNA into host genomic DNA, blocking the formation of the HIV-1 provirus and propagation of the viral infection. Elvitegravir does not inhibit human topoisomerases I or II.
## Structure
- It has a molecular formula of C23H23ClFNO5 and a molecular weight of 447.9. It has the following structural formula:
## Pharmacodynamics
### Cardiac Electrophysiology
- The effect of multiple doses of elvitegravir 125 mg (1.5 times the lowest recommended dosage) and 250 mg (1.7 times the maximum recommended dosage) (coadministered with 100 mg ritonavir) on QT interval was evaluated in a randomized, placebo- and active-controlled (moxifloxacin 400 mg) parallel group thorough QT study in 126 healthy subjects. No clinically meaningful changes in QTc interval were observed with either 125 mg dose or the 250 mg dose. The dose of 250 mg elvitegravir (with 100 mg ritonavir) is expected to cover the high exposure clinical scenario.
## Pharmacokinetics
### Absorption
- Following oral administration of Elvitegravir and ritonavir with food, in HIV-1 infected subjects, peak elvitegravir plasma concentrations were observed approximately 4 hours post-dose. The steady-state mean elvitegravir pharmacokinetic parameters are presented in Table 5. Elvitegravir plasma exposures increased in a less than dose proportional manner, likely due to solubility-limited absorption.
Elvitegravir must be taken with food.
### Distribution
- Elvitegravir is 98–99% bound to human plasma proteins and the binding is independent of drug concentration over the range of 1 ng/mL to 1.6 µg/mL. The mean plasma-to-blood drug concentration ratio is 1.37.
### Metabolism and Elimination
- Elvitegravir undergoes primarily oxidative metabolism via CYP3A, and is secondarily glucuronidated via UGT1A1/3 enzymes. Following oral administration of [14C]elvitegravir/ritonavir, elvitegravir was the predominant species in plasma, representing ~94% of the circulating radioactivity. Aromatic and aliphatic hydroxylation or glucuronidation metabolites were present in very low levels, displayed considerably lower anti-HIV activity and did not contribute to the overall antiviral activity of elvitegravir.
- Following oral administration of [14C]elvitegravir/ritonavir, 94.8% of the dose was recovered in feces, consistent with the hepatobiliary excretion of elvitegravir; 6.7% of the administered dose was recovered in urine as metabolites. The median terminal plasma half-life of elvitegravir following administration of Elvitegravir and ritonavir was approximately 8.7 hours.
## Nonclinical Toxicology
### Carcinogenesis
- Long-term carcinogenicity studies of elvitegravir were carried out in mice (104 weeks) and in rats (up to 88 weeks in males and 90 weeks in females). No drug-related increases in tumor incidence were found in mice at doses up to 2000 mg per kg per day alone or in combination with 25 mg per kg per day ritonavir at exposures 3- and 14-fold, respectively, the human systemic exposure at the recommended daily dose of 150 mg. No drug-related increases in tumor incidence were found in rats at doses up to 2000 mg per kg per day at exposures 12- to 27-fold, respectively, in male and female, the human systemic exposure.
- Elvitegravir was not genotoxic in the reverse mutation bacterial test (Ames test) and the rat micronucleus assay. In an in vitro chromosomal aberration test, elvitegravir was negative with metabolic activation; however, an equivocal response was observed without activation.
### Fertility
- Elvitegravir did not affect fertility in male and female rats at approximately 16- and 30-fold higher exposures (AUC), respectively, than in humans at the therapeutic 150 mg daily dose.
- Fertility was normal in the offspring of rats exposed daily from before birth (in utero) through sexual maturity at daily exposures (AUC) of approximately 18-fold higher than human exposures at the recommended 150 mg daily dose.
# Clinical Studies
### Treatment-Experienced Adults with HIV-1 Infection
- The efficacy of Elvitegravir in treatment-experienced adult patients with HIV-1 infection is based on the analyses through 96 weeks from one randomized, double-blind, active-controlled trial, Study 145, in treatment-experienced, HIV-1 infected subjects (N=702). In Study 145, subjects were randomized in a 1:1 ratio to receive either Elvitegravir (150 mg or 85 mg) once daily or raltegravir 400 mg twice daily, each administered with a background regimen (BR) containing a fully active protease inhibitor coadministered with ritonavir and a second antiretroviral drug. The BR was selected by the investigator based on genotypic/phenotypic resistance testing and prior antiretroviral treatment history.
- The mean age of subjects was 45 years (range 19–78); 82% were male, 62% were White, and 34% were Black. The mean baseline plasma HIV-1 RNA was 4.3 log10 copies/mL (range 1.7–6.6) and 26% of subjects had baseline viral loads greater than 100,000 copies/mL. The mean duration of prior HIV-1 treatment was 9.4 years. The mean baseline CD4+ cell count was 262 cells/mm3 (range 1–1497), 45% had CD4+ cell counts ≤ 200 cells/mm3, and 85% had a baseline genotypic sensitivity score ≥ 2.
- Virologic outcomes were similar across the treatment arms through 96 weeks as presented in Table 8. The mean increase from baseline in CD4+ cell count at Week 96 was 205 cells/mm3 in Elvitegravir-treated subjects and 198 cells/mm3 in raltegravir-treated subjects.
# How Supplied
VITEKTA tablets are available in bottles containing 30 tablets with a child-resistant closure as follows:
- 85 mg tablets are green, pentagon-shaped, film-coated, debossed with "GSI" on one side and "85" on the other side: NDC 61958-1301-1
- 150 mg tablets are green, triangle-shaped, film-coated, debossed with "GSI" on one side and "150" on the other side: NDC 61958-1302-1
## Storage
- Store at room temperature below 30 °C (86 °F).
- Dispense only in original container.
- Do not use if seal over bottle opening is broken or missing.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
There is limited information regarding Elvitegravir Patient Counseling Information in the drug label.
# Precautions with Alcohol
- Alcohol-Elvitegravir interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Vitekta
# Look-Alike Drug Names
There is limited information regarding Elvitegravir Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Elvitegravir | |
0d2f127cd877dcffce24d32499e3622053e84b04 | wikidoc | Emil Fischer | Emil Fischer
Hermann Emil Fischer (October 9, 1852 - July 15, 1919) was a German chemist and recipient of the Nobel Prize for Chemistry in 1902.
# Childhood and education
Emil Fischer was born in Euskirchen, near Cologne, the son of a businessman. After graduating he wished to study natural sciences, but his father compelled him to work in the family business until determining that his son was unsuitable.
Fischer then attended the University of Bonn in 1872, but switched to the University of Strasbourg in 1872. He earned his doctorate in 1874 with his study of phthalein and was appointed to a position at the university.
# Academic career
In 1875 von Baeyer was asked to succeed Liebig at the University of Munich and Fischer went there with him to become an assistant in organic chemistry.
In 1878 Fischer qualified as a Privatdozent at Munich, where he was appointed Associate Professor of Analytical Chemistry in 1879. In the same year he was offered, but refused, the Chair of Chemistry at Aix-la-Chapelle.
In 1881 he was appointed Professor of Chemistry at the University of Erlangen and in 1883 he was asked by the Badische Anilin- und Soda-Fabrik to direct its scientific laboratory. Fischer, however, whose father had now made him financially independent, preferred academic work.
In 1888 he was asked to become Professor of Chemistry at the University of Würzburg and here he remained until 1892, when he was asked to succeed A. W. Hofmann in the Chair of Chemistry at the University of Berlin. Here he remained until his death in 1919.
# Significant work
Fischer's early discovery of phenylhydrazine and its influence on his later work have already been mentioned. While he was at Munich, Fisher continued to work on the hydrazines and, working there with his cousin Otto Fischer, who had followed him to Munich, he and Otto worked out a new theory of the constitution of the dyes derived from triphenylmethane, proving this by experimental work to be correct.
At Erlangen Fischer studied the active principles of tea, coffee and cocoa, namely, caffeine and theobromine, and established the constitution of a series of compounds in this field, eventually synthesizing them.
The work, however, on which Fischer's fame chiefly rests, was his studies of the purines and the sugars. This work, carried out between 1882 and 1906 showed that various substances, little known at that time, such as adenine, xanthine, in vegetable substances, caffeine and, in animal excrement, uric acid and guanine, all belonged to one homogeneous family and could be derived from one another and that they corresponded to different hydroxyl and amino derivatives of the same fundamental system formed by a bicyclic nitrogenous structure into which the characteristic urea group entered. This parent substance, which at first he regarded as being hypothetical, he called purine in 1884, and he synthesized it in 1898. Numerous artificial derivatives, more or less analogous to the naturally-occurring substances, came from his laboratory between 1882 and 1896.
In 1884 Fischer began his great work on the sugars, which transformed the knowledge of these compounds and welded the new knowledge obtained into a coherent whole. Even before 1880 the aldehyde formula of glucose had been indicated, but Fischer established it by a series of transformations such as oxidation into aldonic acid and the action of phenylhydrazine which he had discovered and which made possible the formation of the phenylhydrazones and the osazones. By passage to a common osazone, he established the relation between glucose, fructose and mannose, which he discovered in 1888. In 1890, by epimerization between gluconic and mannonic acids, he established the stereochemical and isomeric nature of the sugars, and between 1891 and 1894 he established the stereochemical configuration of all the known sugars and exactly foretold the possible isomers, by an ingenious application of the theory of the asymmetrical carbon atom of Van't Hoff and Le Bel, published in 1874. Reciprocal syntheses between different hexoses by isomerization and then between pentoses, hexoses, and heptoses by reaction of degradation and synthesis proved the value of the systematics he had established. His greatest success was his synthesis of glucose, fructose and mannose in 1890, starting from glycerol.
This monumental work on the sugars, carried out between 1884 and 1894, was extended by other work, the most important being his studies of the glucosides.
Between 1899 and 1908 Fischer made his great contributions to knowledge of the proteins. He sought effective analytical methods of separating and identifying the individual amino acids, discovering a new type, the cyclic amino acids: proline and oxyproline. He also studied the synthesis of proteins by obtaining the various amino acids in an optically active form in order to unite them. He was able to establish the type of bond that would connect them together in chains, namely, the peptide bond, and by means of this he obtained the dipeptides and later the tripeptides and polypeptides. In 1901 he discovered, in collaboration with Fourneau, the synthesis of the dipeptide, glycyl-glycine and in that year he also published his work on the hydrolysis of casein. Amino acids occurring in nature were prepared in the laboratory and new ones were discovered. His synthesis of the oligopeptides culminated in an octodecapeptide, which had many characteristics of natural proteins. This and his subsequent work led to a better understanding of the proteins and laid the foundations for later studies of them.
In addition to his work in the fields already mentioned, Fischer also studied the enzymes and the chemical substances in the lichens which he found during his frequent holidays in the Black Forest, and also substances used in tanning and, during the final years of his life, the fats. In 1890, he also proposed a "Lock and Key Model" to visualize the substrate and enzyme interaction. Though, later studies did not support this model in all enzymatic reactions.
Fischer is noted for his work on sugars among other work the organic synthesis of (+) glucose and purines (including the first synthesis of caffeine).
# Awards and honours
Fischer was made a Prussian Geheimrat (Excellenz), and held honorary doctorates of the Universities of Christiania, Cambridge (England), Manchester and Brussels. He was also awarded the Prussian Order of Merit and the Maximilian Order for Arts and Sciences. In 1902 he was awarded the Nobel Prize in Chemistry for his work on sugar and purine syntheses.
# Personal life
At the age of 18, before he went to the University of Bonn, Fischer suffered from gastritis, which attacked him again towards the end of his tenure of the Chair at Erlangen and caused him to refuse a tempting offer to follow Victor Meyer at the Federal Technical University at Zurich and to take a year's leave of absence before he went, in 1888, to Würzburg. Possibly this affliction was the forerunner of the cancer from which he died.
Throughout his life he was well served by his excellent memory, which enabled him, although he was not a naturally good speaker, to memorize manuscripts of lectures that he had written.
He was particularly happy at Würzburg where he enjoyed walks among the hills and he also made frequent visits to the Black Forest. His administrative work, especially when he went to Berlin, revealed him as a tenacious campaigner for the establishment of scientific foundations, not only in chemistry, but in other fields of work as well. His keen understanding of scientific problems, his intuition and love of truth and his insistence on experimental proof of hypotheses, marked him as one of the truly great scientists of all time.
In 1888 Fischer married Agnes Gerlach, daughter of Joseph von Gerlach, Professor of Anatomy at Erlangen. Unhappily his wife died seven years after their marriage. They had three sons, one of whom was killed in the First World War; another took his own life at the age of 25 as a result of compulsory military training. The third son, Hermann Otto Laurenz Fischer, who died in 1960, was Professor of Biochemistry in the University of California at Berkeley.
# Legacy
Many consider Fischer to be the most brilliant chemist who ever lived, as his numerous contributions to science, especially chemistry and biochemistry. Many names of chemical reactions and concepts are named after him:
- Fischer indole synthesis
- Fischer projection
- Fischer oxazole synthesis
- Fischer peptide synthesis
- Fischer phenylhydrazine and oxazone reaction
- Fischer reduction
- Fischer-Speier esterification
- Fischer glycosidation
When Fischer died in 1919, the Emil Fischer Memorial Medal was instituted by the German Chemical Society. | Emil Fischer
Template:Infobox Scientist
Hermann Emil Fischer (October 9, 1852 - July 15, 1919) was a German chemist and recipient of the Nobel Prize for Chemistry in 1902.
# Childhood and education
Emil Fischer was born in Euskirchen, near Cologne, the son of a businessman. After graduating he wished to study natural sciences, but his father compelled him to work in the family business until determining that his son was unsuitable.
Fischer then attended the University of Bonn in 1872, but switched to the University of Strasbourg in 1872. He earned his doctorate in 1874 with his study of phthalein and was appointed to a position at the university.
# Academic career
In 1875 von Baeyer was asked to succeed Liebig at the University of Munich and Fischer went there with him to become an assistant in organic chemistry.
In 1878 Fischer qualified as a Privatdozent at Munich, where he was appointed Associate Professor of Analytical Chemistry in 1879. In the same year he was offered, but refused, the Chair of Chemistry at Aix-la-Chapelle.
In 1881 he was appointed Professor of Chemistry at the University of Erlangen and in 1883 he was asked by the Badische Anilin- und Soda-Fabrik to direct its scientific laboratory. Fischer, however, whose father had now made him financially independent, preferred academic work.
In 1888 he was asked to become Professor of Chemistry at the University of Würzburg and here he remained until 1892, when he was asked to succeed A. W. Hofmann in the Chair of Chemistry at the University of Berlin. Here he remained until his death in 1919.
# Significant work
Fischer's early discovery of phenylhydrazine and its influence on his later work have already been mentioned. While he was at Munich, Fisher continued to work on the hydrazines and, working there with his cousin Otto Fischer, who had followed him to Munich, he and Otto worked out a new theory of the constitution of the dyes derived from triphenylmethane, proving this by experimental work to be correct.
At Erlangen Fischer studied the active principles of tea, coffee and cocoa, namely, caffeine and theobromine, and established the constitution of a series of compounds in this field, eventually synthesizing them.
The work, however, on which Fischer's fame chiefly rests, was his studies of the purines and the sugars. This work, carried out between 1882 and 1906 showed that various substances, little known at that time, such as adenine, xanthine, in vegetable substances, caffeine and, in animal excrement, uric acid and guanine, all belonged to one homogeneous family and could be derived from one another and that they corresponded to different hydroxyl and amino derivatives of the same fundamental system formed by a bicyclic nitrogenous structure into which the characteristic urea group entered. This parent substance, which at first he regarded as being hypothetical, he called purine in 1884, and he synthesized it in 1898. Numerous artificial derivatives, more or less analogous to the naturally-occurring substances, came from his laboratory between 1882 and 1896.
In 1884 Fischer began his great work on the sugars, which transformed the knowledge of these compounds and welded the new knowledge obtained into a coherent whole. Even before 1880 the aldehyde formula of glucose had been indicated, but Fischer established it by a series of transformations such as oxidation into aldonic acid and the action of phenylhydrazine which he had discovered and which made possible the formation of the phenylhydrazones and the osazones. By passage to a common osazone, he established the relation between glucose, fructose and mannose, which he discovered in 1888. In 1890, by epimerization between gluconic and mannonic acids, he established the stereochemical and isomeric nature of the sugars, and between 1891 and 1894 he established the stereochemical configuration of all the known sugars and exactly foretold the possible isomers, by an ingenious application of the theory of the asymmetrical carbon atom of Van't Hoff and Le Bel, published in 1874. Reciprocal syntheses between different hexoses by isomerization and then between pentoses, hexoses, and heptoses by reaction of degradation and synthesis proved the value of the systematics he had established. His greatest success was his synthesis of glucose, fructose and mannose in 1890, starting from glycerol.
This monumental work on the sugars, carried out between 1884 and 1894, was extended by other work, the most important being his studies of the glucosides.
Between 1899 and 1908 Fischer made his great contributions to knowledge of the proteins. He sought effective analytical methods of separating and identifying the individual amino acids, discovering a new type, the cyclic amino acids: proline and oxyproline. He also studied the synthesis of proteins by obtaining the various amino acids in an optically active form in order to unite them. He was able to establish the type of bond that would connect them together in chains, namely, the peptide bond, and by means of this he obtained the dipeptides and later the tripeptides and polypeptides. In 1901 he discovered, in collaboration with Fourneau, the synthesis of the dipeptide, glycyl-glycine and in that year he also published his work on the hydrolysis of casein. Amino acids occurring in nature were prepared in the laboratory and new ones were discovered. His synthesis of the oligopeptides culminated in an octodecapeptide, which had many characteristics of natural proteins. This and his subsequent work led to a better understanding of the proteins and laid the foundations for later studies of them.
In addition to his work in the fields already mentioned, Fischer also studied the enzymes and the chemical substances in the lichens which he found during his frequent holidays in the Black Forest, and also substances used in tanning and, during the final years of his life, the fats. In 1890, he also proposed a "Lock and Key Model" to visualize the substrate and enzyme interaction. Though, later studies did not support this model in all enzymatic reactions.
Fischer is noted for his work on sugars among other work the organic synthesis of (+) glucose[1] and purines (including the first synthesis of caffeine).
# Awards and honours
Fischer was made a Prussian Geheimrat (Excellenz), and held honorary doctorates of the Universities of Christiania, Cambridge (England), Manchester and Brussels. He was also awarded the Prussian Order of Merit and the Maximilian Order for Arts and Sciences. In 1902 he was awarded the Nobel Prize in Chemistry for his work on sugar and purine syntheses.
# Personal life
At the age of 18, before he went to the University of Bonn, Fischer suffered from gastritis, which attacked him again towards the end of his tenure of the Chair at Erlangen and caused him to refuse a tempting offer to follow Victor Meyer at the Federal Technical University at Zurich and to take a year's leave of absence before he went, in 1888, to Würzburg. Possibly this affliction was the forerunner of the cancer from which he died.
Throughout his life he was well served by his excellent memory, which enabled him, although he was not a naturally good speaker, to memorize manuscripts of lectures that he had written.
He was particularly happy at Würzburg where he enjoyed walks among the hills and he also made frequent visits to the Black Forest. His administrative work, especially when he went to Berlin, revealed him as a tenacious campaigner for the establishment of scientific foundations, not only in chemistry, but in other fields of work as well. His keen understanding of scientific problems, his intuition and love of truth and his insistence on experimental proof of hypotheses, marked him as one of the truly great scientists of all time.
In 1888 Fischer married Agnes Gerlach, daughter of Joseph von Gerlach, Professor of Anatomy at Erlangen. Unhappily his wife died seven years after their marriage. They had three sons, one of whom was killed in the First World War; another took his own life at the age of 25 as a result of compulsory military training. The third son, Hermann Otto Laurenz Fischer, who died in 1960, was Professor of Biochemistry in the University of California at Berkeley.
# Legacy
Many consider Fischer to be the most brilliant chemist who ever lived, as his numerous contributions to science, especially chemistry and biochemistry. Many names of chemical reactions and concepts are named after him:
- Fischer indole synthesis
- Fischer projection
- Fischer oxazole synthesis
- Fischer peptide synthesis
- Fischer phenylhydrazine and oxazone reaction
- Fischer reduction
- Fischer-Speier esterification
- Fischer glycosidation
When Fischer died in 1919, the Emil Fischer Memorial Medal was instituted by the German Chemical Society. | https://www.wikidoc.org/index.php/Emil_Fischer | |
3850a8dd31eda41d6def586af4098c551da17b90 | wikidoc | Endosymbiont | Endosymbiont
An endosymbiont is any organism that lives within the body or cells of another organism, i.e. forming an endosymbiosis (Greek: endo = inner, sym = together and biosis = living). Examples are nitrogen-fixing bacteria (called rhizobia) which live in root nodules on legume roots, single-celled algae inside reef-building corals, and bacterial endosymbionts that provide essential nutrients to about 10%–15% of insects.
Many instances of endosymbiosis are obligate, that is neither the endosymbiont nor the host can survive without the other, such as the gutless marine worms of the genus Riftia, which get nutrition from their endosymbiotic bacteria. However, not all endosymbioses are obligate. Also, some endosymbioses can be harmful to either of the organisms involved. See symbiosis for further discussion of this issue.
It is generally agreed that certain organelles of the eukaryotic cell, especially mitochondria and plastids such as chloroplasts, originated as bacterial endosymbionts. This theory is called the endosymbiotic theory, confirmed and popularized by Lynn Margulis.
# The endosymbiont theory and mitochondria and chloroplasts
Is a close association between different types of organisms over an extended time. However, more specifically, the relationship was endosymbiotic, meaning that one of the organisms (the bacteria) lived within the other (the prokaryotic cells).
According to the endosymbiont theory, an anaerobic cell probably ingested an aerobic bacterium but failed to digest it. The aerobic bacterium flourished within the cell because the cell’s cytoplasm was abundant in half-digested food molecules. The bacterium digested these molecules with oxygen and gained great amounts of energy. Because the bacterium had so much energy, it probably leaked some of it as ATP into the cell’s cytoplasm. This benefited the anaerobic cell because it enabled it to digest food aerobically. Eventually, the aerobic bacterium could no longer live independently from the cell, and it therefore became a mitochondrion. The origin of the chloroplast is very similar to that of the mitochondrion. A cell must have captured a photosynthetic cyanobacterium and failed to digest it. The cyanobacterium thrived in the cell and eventually evolved into the first chloroplast. Other eukaryotic organelles may have also evolved through endosymbiosis. Scientists believe that cilia, flagella, centrioles, and microtubules may have come from a symbiosis between a spirilla-like bacterium and an early eukaryotic cell.
There are several examples of evidence that support the endosymbiont theory. Mitochondria and chloroplasts contain their own small supply of DNA, which may be remnants of the genome the organelles had when they were independent aerobic bacteria. The single most convincing evidence of the descent of organelles from bacteria is the position of mitochondria and plastid DNA sequences in phylogenetic trees of bacteria. Mitochondria have sequences that clearly indicate origin from a group of bacteria called the alpha-Proteobacteria. Plastids have DNA sequences that indicate origin from the cyanobacteria (blue-green algae). In addition, there are organisms alive today, called living intermediates, that are in a similar endosymbiotic condition to the prokaryotic cells and the aerobic bacteria. Living intermediates show that the evolution proposed by the endosymbiont theory is possible. For example, the giant amoeba Pelomyxa lacks mitochondria but has aerobic bacteria that carry out a similar role. A variety of corals, clams, snails, and one species of Paramecium permanently host algae in their cells. Many of the insect endosymbionts have been shown to have ancient associations with their hosts, involving strictly vertical inheritance. In addition, these insect symbionts have similar patterns of genome evolution to those found in true organelles: genome reduction, rapid rates of gene evolution, and bias in nucleotide base composition favoring adenine and thymine, at the expense of guanine and cytosine.
Further evidence of endosymbiosis are the prokaryotic ribosomes found within chloroplasts and mitochondria as well as the double membrane enclosing them. The inner membrane is thought to be the original membrane of the once independent prokaryote, while the outer one is thought to be the food vacuole it was enclosed in initially. Triple or quadruple membranes are found among certain algae, probably resulting from repeated endosymbiosis (although little else was retained of the engulfed cell).
These modern organisms with endosymbiotic relationships with aerobic bacteria have verified the endosymbiotic theory, which explains the origin of mitochondria and chloroplasts from bacteria. Researchers in molecular and evolutionary biology no longer question this theory, although some of the details, such as the mechanisms for loss of genes from organelles to host nuclear genomes, are still being worked out.
# Bacterial endosymbionts in marine oligochaetes
Some marine oligochaeta (e.g Olavius or Inanidrillus) have obligate extracellular endosymbionts that fill the entire body of their host. These marine worms are nutritionally dependent on their symbiotic chemoautotrophic bacteria lacking any digestive or excretory system (no gut, mouth or nephridia).
# Bacterial endosymbionts in other marine invertebrates
Extracellular endosymbionts are also represented in all 5 extant classes of Echinodermata (Crinoidea, Ophiuroidea, Asteroidea, Echinoidea, and Holothuroidea). Little is known of the nature of the association (mode of infection, transmission, metabolic requirements, etc.) but phylogenetic analysis indicates that these symbionts belong to the alpha group of the class Proteobacteria, relating them to Rhizobium and Thiobacillus. Other studies indicate that these subcuticular bacteria may be both abundant within their hosts and widely distributed among the Echinoderms in general.
# Symbiodinium dinoflagellate endosymbionts in marine metazoa and protists
Dinoflagellate endosymbionts of the genus Symbiodinium, commonly known as zooxanthellae, are found in corals, mollusks (esp. giant clams, the Tridacna), sponges, and foraminifera. These endosymbionts drive the amazing formation of coral reefs by capturing sunlight and providing their hosts with energy for carbonate deposition.
Previously thought to be a single species, molecular phylogenetic evidence over the past couple decades has shown there to be great diversity in Symbiodinium. In some cases there is specificity between host and Symbiodinium clade. More often, however, there is an ecological distribution of Symbiodinium, the symbionts switching between hosts with apparent ease. When reefs become environmentally stressed, this distribution of symbionts is related to the observed pattern of coral bleaching and recovery. Thus the distribution of Symbiodinium on coral reefs and its role in coral bleaching presents one of the most complex and interesting current problems in reef ecology.
# Endosymbionts in protists
Mixotricha paradoxa is a protozoan that lacks mitochondria, however, spherical bacteria live inside the cell and serve the function of the mitochondria. Mixotricha also has three other species of symbionts that live on the surface of the cell.
Paramecium bursaria, a species of ciliate, has a mutualistic symbiotic relationship with green alga called Zoochlorella. The algae live inside the cell, in the cytoplasm.
# Bacterial obligate endosymbionts in insects
Scientists classify insect endosymbionts in two broad categories, 'Primary' and 'Secondary'. Primary endosymbionts (sometimes referred to as P-endosymbionts) have been associated with their insect hosts for many millions of years (from 10 to several hundred million years in some cases), they form obligate associations (see below), and display cospeciation with their insect hosts. Secondary endosymbionts exhibit a more recently developed association, are sometimes horizontally transferred between hosts, live in the haemolymph of the insects (not specialized bacteriocytes, see below), and are not obligate.
Among primary endosymbionts of insects, the best studied are the pea aphid (Acyrthosiphon pisum) and its endosymbiont Buchnera sp. APS, the tsetse fly Glossina morsitans morsitans and its endosymbiont Wigglesworthia glossinidia brevipalpis and the endosymbiotic protists in lower termites. As with endosymbiosis in other insects, the symbiosis is obligate in that neither the bacteria nor the insect is viable without the other. Scientists have been unable to cultivate the bacteria in lab conditions outside of the insect. With special nutritionally-enhanced diets, the insects can survive, but are unhealthy, and at best survive only a few generations.
In some insect groups, these endosymbionts live in specialized insect cells called bacteriocytes (also called mycetocytes), and are maternally-transmitted, i.e. the mother transmits her endosymbionts to her offspring. In some cases, the bacteria are transmitted in the egg, as in Buchnera; in others like Wigglesworthia, they are transmitted via milk to the developing insect embryo. In termites, the endosymbionts reside within the hindguts and are transmitted through trophallaxis among colony members.
The primary endosymbionts are thought to help the host either by providing nutrients that the host cannot obtain itself, or by metabolizing insect waste products into safer forms. For example, the putative primary role of Buchnera is to synthesize essential amino acids that the aphid cannot acquire from its natural diet of plant sap. Similarly, the primary role of Wigglesworthia is probably to synthesize vitamins that the tsetse fly does not get from the blood that it eats. In lower termites, the endosymbiotic protists play a major role in the digestion of lignocellulosic materials which constitutes a bulk of the termites' diet.
Bacteria benefit from the reduced exposure to predators, the ample supply of nutrients and relative environmental stability inside the host.
Genome sequencing reveals that obligate bacterial endosymbionts of insects have among the smallest of known bacterial genomes and have lost many genes that are commonly found in closely related bacteria. Several theories have been put forth to explain the loss of genes. Presumably some of these genes are not needed in the environment of the host insect cell. A complementary theory suggests that the relatively small numbers of bacteria inside each insect decrease the efficiency of natural selection in 'purging' deleterious mutations and small mutations from the population, resulting in a loss of genes over many millions of years. Research in which a parallel phylogeny of bacteria and insects was inferred supports the belief that the primary endosymbionts are transferred only vertically (i.e. from the mother), and not horizontally (i.e. by escaping the host and entering a new host).
Attacking obligate bacterial endosymbionts may present a way to control their insect hosts, many of which are pests or carriers of human disease. For example aphids are crop pests and the tsetse fly carries the organism Trypanosoma brucei that causes African sleeping sickness. Other motivations for their study is to understand symbiosis, and to understand how bacteria with severely depleted genomes are able to survive, thus improving our knowledge of genetics and molecular biology.
Less is known about secondary endosymbionts. The pea aphid (Acyrthosiphon pisum) is known to contain at least three secondary endosymbionts, Hamiltonella defensa, Regiella insecticola, and Serratia symbiotica. H. defensa aids in defending the insect from parasitoids. Sodalis glossinidius is a secondary endosymbiont tsetse flies that lives inter- and intracellularly in various host tissues, including the midgut and hemolymph. Phylogenetic studies have not indicated a correlation between evolution of Sodalis and tsetse. Unlike tsetse's P-symbiont Wigglesworthia, though, Sodalis has been cultured in vitro.
# Viral endosymbionts, endogenous retrovirus(or ERV)
During pregnancy in vivipary mammals(only exception the Monotremes), a ERVs are activated and produced in high quantities during the implantation of the embryo.In one hand they act as immunodepressors,and protect the embryo from the immune system of the mother and in the other hand viral fusion proteins cause the formation of the placental syncytium in order to limit the exchange of migratory cells between the developing embryo and the body of the mother,an epithelium wont do because certain blood cells are specialized to be able to insert themselves between adjacent epithelial cells. The ERV is a similar type of virus as HIV (causing AIDS in humans), the immunodepressive action was the initial normal behavior of the virus,in a similar way as HIV,the fusion proteins was a way to spread the infection to other cells by simply merging them with the infected one(HIV does this too). It is beleaved that the ancestors of modern vivipary mammals evolved after an accidental infection to an ancestor to this virus, that permitted to the fetus to survive the immune system of the mother.
The human genome project found several thousand ERVs comprise by 24 families.
# Notes
- ↑ Douglas, A E (1998). "Nutritional interactions in insect-microbial symbioses: Aphids and their symbiotic bacteria Buchnera". Annual Review of Entomology. 43: 17–38. ISSN 00664170. |access-date= requires |url= (help).mw-parser-output cite.citation{font-style:inherit}.mw-parser-output q{quotes:"\"""\"""'""'"}.mw-parser-output code.cs1-code{color:inherit;background:inherit;border:inherit;padding:inherit}.mw-parser-output .cs1-lock-free a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-limited a,.mw-parser-output .cs1-lock-registration a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-subscription a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration{color:#555}.mw-parser-output .cs1-subscription span,.mw-parser-output .cs1-registration span{border-bottom:1px dotted;cursor:help}.mw-parser-output .cs1-hidden-error{display:none;font-size:100%}.mw-parser-output .cs1-visible-error{display:none;font-size:100%}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration,.mw-parser-output .cs1-format{font-size:95%}.mw-parser-output .cs1-kern-left,.mw-parser-output .cs1-kern-wl-left{padding-left:0.2em}.mw-parser-output .cs1-kern-right,.mw-parser-output .cs1-kern-wl-right{padding-right:0.2em}
- ↑ Aksoy, S., Pourhosseini, A. & Chow, A. 1995. Mycetome endosymbionts of tsetse flies constitute a distinct lineage related to Enterobacteriaceae. Insect Mol Biol. 4, 15-22.
- ↑ Welburn, S.C., Maudlin, I. & Ellis, D.S. 1987. In vitro cultivation of rickettsia-like-organisms from Glossina spp. Ann. Trop. Med. Parasitol. 81, 331-335.
- ↑ The Viruses That Make Us: A Role For Endogenous Retrovirus In The Evolution Of Placental Species (by Luis P. Villarreal)
- ↑ Persisting Viruses Could Play Role in Driving Host Evolution
# References and external links
### Obligate bacterial endosymbiosis in marine oligochaetes:
- Endosymbiotic sulphate-reducing and sulphide-oxidizing bacteria in an oligochaete worm. Dubilier N., Mülders C.,Ferdelman T., De Beer D.,Pernthaler A.,Klein M., Wagner M., Erseus C., Thiermann F., Krieger J., Giere O & Amann R.
### Bacterial endosymbionts in echinoderms:
- Subcuticular bacteria from the brittle star Ophiactis balli (Echinodermata: Ophiuroidea) represent a new lineage of extracellular marine symbionts in the alpha subdivision of the class Proteobacteria. Burnett, W J and J D McKenzie
### Symbiodinium dinoflagellate endosymbionts in marine metazoa and protists
- Excellent review paper covering the role of Symbiodinium in reef ecology and the current state of research: FLEXIBILITY AND SPECIFICITY IN CORAL-ALGAL SYMBIOSIS: Diversity, Ecology, and Biogeography of Symbiodinium. Andrew C. Baker, Annual Review of Ecology, Evolution, and Systematics 2003 34, 661-689
### Obligate bacterial endosymbionts in insects:
- PLOS Biology Primer- Endosymbiosis: lessons in conflict resolution
- A general review of bacterial endosymbionts in insects. P. Baumann, N. A. Moran and L. Baumann, Bacteriocyte-associated endosymbionts of insects in M. Dworkin, ed., The prokaryotes, Springer, New York, 2000. /
- An excellent review of insect endosymbionts that focuses on genetic issues. Jennifer J. Wernegreen (2002), Genome evolution in bacterial endosymbionts of insects, Nature Reviews Genetics, 3, pp. 850-861.
- A review article on aphids and their bacterial endosymbionts. A. E. Douglas (1998), Nutritional interactions in insect-microbial symbioses: Aphids and Their Symbiotic Bacteria Buchnera, Annual Reviews of Entomology, 43, pp. 17-37.
- Describes possible methods to control the human pathogen causing African sleeping sickness, which is transmitted by tsetse flies. Focuses on methods using the primary and secondary endosymbionts of the tsetse fly. Serap Aksoy, Ian Maudlin, Colin Dale, Alan S. Robinsonand and Scott L. O’Neill (2001), Prospects for control of African trypanosomiasis by tsetse vector, TRENDS in Parasitology, 17 (1), pp. 29-35.
- Announces and analyzes the full genome sequence of Buchnera sp. APS, the endosymbiont of the pea aphid, and the first endosymbiont to have its genome sequenced. S. Shigenobu, H. Watanabe, M. Hattori, Y. Sakaki and H. Ishikawa (2000), Genome sequence of the endocellular bacterial symbiont of aphids Buchnera sp. APS, Nature, 407, pp. 81-86.
- An article that presents for the first time a theory on how obligate endosymbionts may have their genomes degraded, in a freely-available journal. Nancy A. Moran (1996), Accelerated evolution and Muller’s ratchet in endosymbiotic bacteria, Proceedings of the National Academy of Sciences of the USA, 93, pp. 2873-2878. | Endosymbiont
An endosymbiont is any organism that lives within the body or cells of another organism, i.e. forming an endosymbiosis (Greek: endo = inner, sym = together and biosis = living). Examples are nitrogen-fixing bacteria (called rhizobia) which live in root nodules on legume roots, single-celled algae inside reef-building corals, and bacterial endosymbionts that provide essential nutrients to about 10%–15% of insects.
Many instances of endosymbiosis are obligate, that is neither the endosymbiont nor the host can survive without the other, such as the gutless marine worms of the genus Riftia, which get nutrition from their endosymbiotic bacteria. However, not all endosymbioses are obligate. Also, some endosymbioses can be harmful to either of the organisms involved. See symbiosis for further discussion of this issue.
It is generally agreed that certain organelles of the eukaryotic cell, especially mitochondria and plastids such as chloroplasts, originated as bacterial endosymbionts. This theory is called the endosymbiotic theory, confirmed and popularized by Lynn Margulis.
# The endosymbiont theory and mitochondria and chloroplasts
Is a close association between different types of organisms over an extended time. However, more specifically, the relationship was endosymbiotic, meaning that one of the organisms (the bacteria) lived within the other (the prokaryotic cells).
According to the endosymbiont theory, an anaerobic cell probably ingested an aerobic bacterium but failed to digest it. The aerobic bacterium flourished within the cell because the cell’s cytoplasm was abundant in half-digested food molecules. The bacterium digested these molecules with oxygen and gained great amounts of energy. Because the bacterium had so much energy, it probably leaked some of it as ATP into the cell’s cytoplasm. This benefited the anaerobic cell because it enabled it to digest food aerobically. Eventually, the aerobic bacterium could no longer live independently from the cell, and it therefore became a mitochondrion. The origin of the chloroplast is very similar to that of the mitochondrion. A cell must have captured a photosynthetic cyanobacterium and failed to digest it. The cyanobacterium thrived in the cell and eventually evolved into the first chloroplast. Other eukaryotic organelles may have also evolved through endosymbiosis. Scientists believe that cilia, flagella, centrioles, and microtubules may have come from a symbiosis between a spirilla-like bacterium and an early eukaryotic cell.
There are several examples of evidence that support the endosymbiont theory. Mitochondria and chloroplasts contain their own small supply of DNA, which may be remnants of the genome the organelles had when they were independent aerobic bacteria. The single most convincing evidence of the descent of organelles from bacteria is the position of mitochondria and plastid DNA sequences in phylogenetic trees of bacteria. Mitochondria have sequences that clearly indicate origin from a group of bacteria called the alpha-Proteobacteria. Plastids have DNA sequences that indicate origin from the cyanobacteria (blue-green algae). In addition, there are organisms alive today, called living intermediates, that are in a similar endosymbiotic condition to the prokaryotic cells and the aerobic bacteria. Living intermediates show that the evolution proposed by the endosymbiont theory is possible. For example, the giant amoeba Pelomyxa lacks mitochondria but has aerobic bacteria that carry out a similar role. A variety of corals, clams, snails, and one species of Paramecium permanently host algae in their cells. Many of the insect endosymbionts have been shown to have ancient associations with their hosts, involving strictly vertical inheritance. In addition, these insect symbionts have similar patterns of genome evolution to those found in true organelles: genome reduction, rapid rates of gene evolution, and bias in nucleotide base composition favoring adenine and thymine, at the expense of guanine and cytosine.
Further evidence of endosymbiosis are the prokaryotic ribosomes found within chloroplasts and mitochondria as well as the double membrane enclosing them. The inner membrane is thought to be the original membrane of the once independent prokaryote, while the outer one is thought to be the food vacuole it was enclosed in initially. Triple or quadruple membranes are found among certain algae, probably resulting from repeated endosymbiosis (although little else was retained of the engulfed cell).
These modern organisms with endosymbiotic relationships with aerobic bacteria have verified the endosymbiotic theory, which explains the origin of mitochondria and chloroplasts from bacteria. Researchers in molecular and evolutionary biology no longer question this theory, although some of the details, such as the mechanisms for loss of genes from organelles to host nuclear genomes, are still being worked out.
# Bacterial endosymbionts in marine oligochaetes
Some marine oligochaeta (e.g Olavius or Inanidrillus) have obligate extracellular endosymbionts that fill the entire body of their host. These marine worms are nutritionally dependent on their symbiotic chemoautotrophic bacteria lacking any digestive or excretory system (no gut, mouth or nephridia).
# Bacterial endosymbionts in other marine invertebrates
Extracellular endosymbionts are also represented in all 5 extant classes of Echinodermata (Crinoidea, Ophiuroidea, Asteroidea, Echinoidea, and Holothuroidea). Little is known of the nature of the association (mode of infection, transmission, metabolic requirements, etc.) but phylogenetic analysis indicates that these symbionts belong to the alpha group of the class Proteobacteria, relating them to Rhizobium and Thiobacillus. Other studies indicate that these subcuticular bacteria may be both abundant within their hosts and widely distributed among the Echinoderms in general.
# Symbiodinium dinoflagellate endosymbionts in marine metazoa and protists
Dinoflagellate endosymbionts of the genus Symbiodinium, commonly known as zooxanthellae, are found in corals, mollusks (esp. giant clams, the Tridacna), sponges, and foraminifera. These endosymbionts drive the amazing formation of coral reefs by capturing sunlight and providing their hosts with energy for carbonate deposition.
Previously thought to be a single species, molecular phylogenetic evidence over the past couple decades has shown there to be great diversity in Symbiodinium. In some cases there is specificity between host and Symbiodinium clade. More often, however, there is an ecological distribution of Symbiodinium, the symbionts switching between hosts with apparent ease. When reefs become environmentally stressed, this distribution of symbionts is related to the observed pattern of coral bleaching and recovery. Thus the distribution of Symbiodinium on coral reefs and its role in coral bleaching presents one of the most complex and interesting current problems in reef ecology.
# Endosymbionts in protists
Mixotricha paradoxa is a protozoan that lacks mitochondria, however, spherical bacteria live inside the cell and serve the function of the mitochondria. Mixotricha also has three other species of symbionts that live on the surface of the cell.
Paramecium bursaria, a species of ciliate, has a mutualistic symbiotic relationship with green alga called Zoochlorella. The algae live inside the cell, in the cytoplasm.
# Bacterial obligate endosymbionts in insects
Scientists classify insect endosymbionts in two broad categories, 'Primary' and 'Secondary'. Primary endosymbionts (sometimes referred to as P-endosymbionts) have been associated with their insect hosts for many millions of years (from 10 to several hundred million years in some cases), they form obligate associations (see below), and display cospeciation with their insect hosts. Secondary endosymbionts exhibit a more recently developed association, are sometimes horizontally transferred between hosts, live in the haemolymph of the insects (not specialized bacteriocytes, see below), and are not obligate.
Among primary endosymbionts of insects, the best studied are the pea aphid (Acyrthosiphon pisum) and its endosymbiont Buchnera sp. APS[1], the tsetse fly Glossina morsitans morsitans and its endosymbiont Wigglesworthia glossinidia brevipalpis and the endosymbiotic protists in lower termites. As with endosymbiosis in other insects, the symbiosis is obligate in that neither the bacteria nor the insect is viable without the other. Scientists have been unable to cultivate the bacteria in lab conditions outside of the insect. With special nutritionally-enhanced diets, the insects can survive, but are unhealthy, and at best survive only a few generations.
In some insect groups, these endosymbionts live in specialized insect cells called bacteriocytes (also called mycetocytes), and are maternally-transmitted, i.e. the mother transmits her endosymbionts to her offspring. In some cases, the bacteria are transmitted in the egg, as in Buchnera; in others like Wigglesworthia, they are transmitted via milk to the developing insect embryo. In termites, the endosymbionts reside within the hindguts and are transmitted through trophallaxis among colony members.
The primary endosymbionts are thought to help the host either by providing nutrients that the host cannot obtain itself, or by metabolizing insect waste products into safer forms. For example, the putative primary role of Buchnera is to synthesize essential amino acids that the aphid cannot acquire from its natural diet of plant sap. Similarly, the primary role of Wigglesworthia is probably to synthesize vitamins that the tsetse fly does not get from the blood that it eats. In lower termites, the endosymbiotic protists play a major role in the digestion of lignocellulosic materials which constitutes a bulk of the termites' diet.
Bacteria benefit from the reduced exposure to predators, the ample supply of nutrients and relative environmental stability inside the host.
Genome sequencing reveals that obligate bacterial endosymbionts of insects have among the smallest of known bacterial genomes and have lost many genes that are commonly found in closely related bacteria. Several theories have been put forth to explain the loss of genes. Presumably some of these genes are not needed in the environment of the host insect cell. A complementary theory suggests that the relatively small numbers of bacteria inside each insect decrease the efficiency of natural selection in 'purging' deleterious mutations and small mutations from the population, resulting in a loss of genes over many millions of years. Research in which a parallel phylogeny of bacteria and insects was inferred supports the belief that the primary endosymbionts are transferred only vertically (i.e. from the mother), and not horizontally (i.e. by escaping the host and entering a new host).
Attacking obligate bacterial endosymbionts may present a way to control their insect hosts, many of which are pests or carriers of human disease. For example aphids are crop pests and the tsetse fly carries the organism Trypanosoma brucei that causes African sleeping sickness. Other motivations for their study is to understand symbiosis, and to understand how bacteria with severely depleted genomes are able to survive, thus improving our knowledge of genetics and molecular biology.
Less is known about secondary endosymbionts. The pea aphid (Acyrthosiphon pisum) is known to contain at least three secondary endosymbionts, Hamiltonella defensa, Regiella insecticola, and Serratia symbiotica. H. defensa aids in defending the insect from parasitoids. Sodalis glossinidius is a secondary endosymbiont tsetse flies that lives inter- and intracellularly in various host tissues, including the midgut and hemolymph. Phylogenetic studies have not indicated a correlation between evolution of Sodalis and tsetse.[2] Unlike tsetse's P-symbiont Wigglesworthia, though, Sodalis has been cultured in vitro.[3]
# Viral endosymbionts, endogenous retrovirus(or ERV)
During pregnancy in vivipary mammals(only exception the Monotremes), a ERVs are activated and produced in high quantities during the implantation of the embryo.In one hand they act as immunodepressors,and protect the embryo from the immune system of the mother and in the other hand viral fusion proteins cause the formation of the placental syncytium in order to limit the exchange of migratory cells between the developing embryo and the body of the mother,an epithelium wont do because certain blood cells are specialized to be able to insert themselves between adjacent epithelial cells. The ERV is a similar type of virus as HIV (causing AIDS in humans), the immunodepressive action was the initial normal behavior of the virus,in a similar way as HIV,the fusion proteins was a way to spread the infection to other cells by simply merging them with the infected one(HIV does this too). It is beleaved that the ancestors of modern vivipary mammals evolved after an accidental infection to an ancestor to this virus, that permitted to the fetus to survive the immune system of the mother. [4]
The human genome project found several thousand ERVs comprise by 24 families.[5]
# Notes
- ↑ Douglas, A E (1998). "Nutritional interactions in insect-microbial symbioses: Aphids and their symbiotic bacteria Buchnera". Annual Review of Entomology. 43: 17–38. ISSN 00664170. |access-date= requires |url= (help).mw-parser-output cite.citation{font-style:inherit}.mw-parser-output q{quotes:"\"""\"""'""'"}.mw-parser-output code.cs1-code{color:inherit;background:inherit;border:inherit;padding:inherit}.mw-parser-output .cs1-lock-free a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/6/65/Lock-green.svg/9px-Lock-green.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-limited a,.mw-parser-output .cs1-lock-registration a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/d/d6/Lock-gray-alt-2.svg/9px-Lock-gray-alt-2.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-subscription a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/a/aa/Lock-red-alt-2.svg/9px-Lock-red-alt-2.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration{color:#555}.mw-parser-output .cs1-subscription span,.mw-parser-output .cs1-registration span{border-bottom:1px dotted;cursor:help}.mw-parser-output .cs1-hidden-error{display:none;font-size:100%}.mw-parser-output .cs1-visible-error{display:none;font-size:100%}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration,.mw-parser-output .cs1-format{font-size:95%}.mw-parser-output .cs1-kern-left,.mw-parser-output .cs1-kern-wl-left{padding-left:0.2em}.mw-parser-output .cs1-kern-right,.mw-parser-output .cs1-kern-wl-right{padding-right:0.2em}
- ↑ Aksoy, S., Pourhosseini, A. & Chow, A. 1995. Mycetome endosymbionts of tsetse flies constitute a distinct lineage related to Enterobacteriaceae. Insect Mol Biol. 4, 15-22.
- ↑ Welburn, S.C., Maudlin, I. & Ellis, D.S. 1987. In vitro cultivation of rickettsia-like-organisms from Glossina spp. Ann. Trop. Med. Parasitol. 81, 331-335.
- ↑ [1] The Viruses That Make Us: A Role For Endogenous Retrovirus In The Evolution Of Placental Species (by Luis P. Villarreal)
- ↑ [2] Persisting Viruses Could Play Role in Driving Host Evolution
# References and external links
### Obligate bacterial endosymbiosis in marine oligochaetes:
- Endosymbiotic sulphate-reducing and sulphide-oxidizing bacteria in an oligochaete worm. Dubilier N., Mülders C.,Ferdelman T., De Beer D.,Pernthaler A.,Klein M., Wagner M., Erseus C., Thiermann F., Krieger J., Giere O & Amann R. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=11357130
### Bacterial endosymbionts in echinoderms:
- Subcuticular bacteria from the brittle star Ophiactis balli (Echinodermata: Ophiuroidea) represent a new lineage of extracellular marine symbionts in the alpha subdivision of the class Proteobacteria. Burnett, W J and J D McKenzie http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=168468&rendertype=abstract
### Symbiodinium dinoflagellate endosymbionts in marine metazoa and protists
- Excellent review paper covering the role of Symbiodinium in reef ecology and the current state of research: FLEXIBILITY AND SPECIFICITY IN CORAL-ALGAL SYMBIOSIS: Diversity, Ecology, and Biogeography of Symbiodinium. Andrew C. Baker, Annual Review of Ecology, Evolution, and Systematics 2003 34, 661-689
### Obligate bacterial endosymbionts in insects:
- PLOS Biology Primer- Endosymbiosis: lessons in conflict resolution http://www.plosbiology.org/plosonline/?request=get-document&doi=10.1371/journal.pbio.0020068
- A general review of bacterial endosymbionts in insects. P. Baumann, N. A. Moran and L. Baumann, Bacteriocyte-associated endosymbionts of insects in M. Dworkin, ed., The prokaryotes, Springer, New York, 2000. http://link.springer.de/link/service/books/10125/
- An excellent review of insect endosymbionts that focuses on genetic issues. Jennifer J. Wernegreen (2002), Genome evolution in bacterial endosymbionts of insects, Nature Reviews Genetics, 3, pp. 850-861. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12415315&dopt=Abstract
- A review article on aphids and their bacterial endosymbionts. A. E. Douglas (1998), Nutritional interactions in insect-microbial symbioses: Aphids and Their Symbiotic Bacteria Buchnera, Annual Reviews of Entomology, 43, pp. 17-37.
- Describes possible methods to control the human pathogen causing African sleeping sickness, which is transmitted by tsetse flies. Focuses on methods using the primary and secondary endosymbionts of the tsetse fly. Serap Aksoy, Ian Maudlin, Colin Dale, Alan S. Robinsonand and Scott L. O’Neill (2001), Prospects for control of African trypanosomiasis by tsetse vector, TRENDS in Parasitology, 17 (1), pp. 29-35. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11137738&dopt=Abstract
- Announces and analyzes the full genome sequence of Buchnera sp. APS, the endosymbiont of the pea aphid, and the first endosymbiont to have its genome sequenced. S. Shigenobu, H. Watanabe, M. Hattori, Y. Sakaki and H. Ishikawa (2000), Genome sequence of the endocellular bacterial symbiont of aphids Buchnera sp. APS, Nature, 407, pp. 81-86. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10993077&dopt=Abstract
- An article that presents for the first time a theory on how obligate endosymbionts may have their genomes degraded, in a freely-available journal. Nancy A. Moran (1996), Accelerated evolution and Muller’s ratchet in endosymbiotic bacteria, Proceedings of the National Academy of Sciences of the USA, 93, pp. 2873-2878. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8610134&dopt=Abstract | https://www.wikidoc.org/index.php/Endosymbiont | |
d66ad0d26250d04647a665ae086582ac417c07d5 | wikidoc | Endothelin 2 | Endothelin 2
Endothelin 2, also known as ET-2, is a protein that in humans is encoded by the EDN2 gene.
# Function
Endothelin 2 is a member of the endothelin protein family of secretory vasoconstrictive peptides. The preproprotein is processed to a short mature form which functions as a ligand for the endothelin receptors that initiate intracellular signaling events. This gene product is involved in a wide range of biological processes, such as hypertension and ovulation.
Endothelin 2 (ET-2) expression is mainly localized to the granulosa cells within the follicle, as observed in bovine, murine, and human ovarian tissue. Endothelin 2 has functions within the ovarian follicle related to ovulation. ET-2 causes strong contractions in smooth muscle cells of ovarian tissue, and ET-2 production is highest just before ovulation. | Endothelin 2
Endothelin 2, also known as ET-2, is a protein that in humans is encoded by the EDN2 gene.[1]
# Function
Endothelin 2 is a member of the endothelin protein family of secretory vasoconstrictive peptides. The preproprotein is processed to a short mature form which functions as a ligand for the endothelin receptors that initiate intracellular signaling events. This gene product is involved in a wide range of biological processes, such as hypertension and ovulation.[1]
Endothelin 2 (ET-2) expression is mainly localized to the granulosa cells within the follicle, as observed in bovine, murine, and human ovarian tissue. Endothelin 2 has functions within the ovarian follicle related to ovulation. ET-2 causes strong contractions in smooth muscle cells of ovarian tissue, and ET-2 production is highest just before ovulation.[2][3][4][5] | https://www.wikidoc.org/index.php/Endothelin_2 | |
11f2ad11c2000c69b93aae0de134faebae646190 | wikidoc | Warm-blooded | Warm-blooded
Warm-blooded animals maintain thermal homeostasis; that is, they keep their body temperature at a constant level. This involves the ability to cool down or produce more body heat. Warm-blooded animals mainly control their body temperature by regulating their metabolic rates (e.g. increasing their metabolic rate as the surrounding temperature begins to decrease).
Both the terms "warm-blooded" and "cold-blooded" have fallen out of favor with scientists, because of the vagueness of the terms, and due to an increased understanding in this field. Body temperature types do not fall into simple either/or categories. Each term may be replaced with one or more variants (see: Definitions of warm-bloodedness). Body temperature maintenance incorporates a wide range of different techniques that result in a body temperature continuum, with the traditional ideals of warm-blooded and cold-blooded being at opposite ends of the spectrum.
# Definitions of warm-bloodedness
Warm-bloodedness generally refers to three separate aspects of thermoregulation.
- Endothermy is the ability of some creatures to control their body temperatures through internal means such as muscle shivering, fat burning, and panting (Greek: endo = "within," therm = "heat"). Some writers restrict the meaning of "endothermy" to mechanisms which directly raise the animal's metabolic rate in order to produce heat. The opposite of endothermy is ectothermy.
- Homoiothermy is thermoregulation that maintains a stable internal body temperature regardless of external influence. This temperature is often higher than the immediate environment (Greek: homoios = "similar," therm = "heat"). The opposite is poikilothermy.
- Tachymetabolism is the kind of thermoregulation used by creatures that maintain a high resting metabolism (Greek: tachy = "fast, swift," metabol = "to change"). Tachymetabolic creatures are, essentially, "on" all the time. Though their resting metabolism is still many times slower than their active metabolism, the difference is often not as large as that seen in bradymetabolic creatures. Tachymetabolic creatures have greater difficulty dealing with a scarcity of food.
A large proportion of the creatures traditionally called "warm-blooded" (mammals and birds) fit all three of these categories. However, over the past 30 years, studies in the field of animal thermophysiology have revealed many species belonging to these two groups that don't fit all these criteria. For example, many bats and small birds are poikilothermic and bradymetabolic when they sleep for the night, or day. For these creatures, another term was coined: heterothermy.
Further studies on animals that were traditionally assumed to be cold-blooded have shown that most creatures incorporate different variations of the three terms defined above, along with their counterparts (ectothermy, poikilothermy and bradymetabolism), thus creating a broad spectrum of body temperature types (see temperature control in cold-blooded animals).
# Mechanisms
## Generating and conserving heat
The creatures traditionally regarded as warm-blooded have a larger number of mitochondria per cell which enables them to generate heat by increasing the rate at which they "burn" fats and sugars. This requires a much greater quantity of food than is needed by cold-blooded animals in order to replace the fat and sugar reserves.
Many endothermic animals supplement these reserves by shivering in cold conditions, since muscular activity also converts fats and sugars into heat. In winter, there may not be enough food to enable an endotherm to keep its metabolic rate stable all day, so some organisms go into a controlled state of hypothermia called hibernation, or torpor. This conserves energy by lowering the body temperature. Many birds and small mammals (e.g. tenrecs) also allow their body temperatures to drop at night to reduce the energy cost of maintaining body temperature. Humans also slow down their metabolism slightly during sleep.
Heat loss is a major threat to smaller creatures as they have a larger ratio of surface area to volume. Most small warm-blooded animals have insulation in the form of fur or feathers. Aquatic warm-blooded animals generally use deep layers of fat under the skin for insulation, since fur or feathers would spoil their streamlining. Penguins use both feathers and fat, since their need for streamlining limits the degree of insulation which feathers alone can give them. Birds, especially waders, have blood-vessels in their lower legs which act as heat exchangers - veins are right next to arteries and thus extract heat from the arteries and carry it back into the trunk. Many warm-blooded animals blanche (become paler) to reduce heat loss by reducing the blood flow to the skin.
## Avoiding over-heating
In equatorial climates and during temperate summers over-heating is as great a threat as cold. In hot conditions many warm-blooded animals increase heat loss by panting and or flushing (increasing the blood flow to the skin). Hairless and short-haired mammals also sweat, since the evaporation of sweat uses a lot of heat. Elephants keep cool by using their huge ears rather like the radiators in automobiles: they flap their ears to increase the airflow over them.
# Warm-blooded vs.Cold blooded
## Advantages of a fast metabolism
The overall speed of an animal's metabolism increases by a factor of about 2 for every 10 C° rise in temperature (limited by the need to avoid hyperthermia). Warm-bloodedness does not provide greater speed than cold-bloodedness - cold-blooded animals can move as fast as warm-blooded animals of the same size and build. But warm-blooded animals have much greater stamina than cold-blooded creatures of the same size and build, because their faster metabolisms quickly regenerate energy supplies (especially ATP) and break down muscular waste products (especially lactate). This enables warm-blooded predators to run down prey, warm-blooded prey to outrun cold-blooded predators (provided they avoid the initial charge or ambush) and warm-blooded animals to be much more successful foragers.
## Advantages of homeothermy
Enzymes have strong temperature preferences and their efficiency is much reduced outside their preferred ranges. A creature with a fairly constant body temperature can therefore use enzymes which are efficient at that temperature. Another advantage of a homeothermic animal would be its ability to maintain its constant body temperature even in freezing cold weather. A poikilotherm must either operate well below optimum efficiency most of the time or spend extra resources making a wider range of enzymes to cover the wider range of body temperatures.
## Disadvantages of warm-bloodedness
Because warm-blooded animals use enzymes which are specialised for a narrow range of body temperatures over-cooling rapidly leads to torpor and then death. Also, the energy required to maintain the homeothermic temperature comes from food - this results in homeothermic animals needing to eat much more food than poikilothermic animals.
Shivering and fat-burning to maintain temperature are very energy-intensive, for example:
- in winter many small birds lose one third of their body weight overnight.
- in general a warm-blooded animal requires 5 to 10 times as much food as a cold-blooded animal of the same size and build, so cold-blooded animals are better at surviving famines and barren environments.
# Temperature control in cold-blooded animals
Scientific understanding of thermal regulation regimes has advanced greatly since the original distinction was made between warm- and cold-blooded animals, and the issue has been studied much more extensively.
Many "cold-blooded" animals use behavioral means to adjust their internal temperatures:
- lizards and snakes bask in the sun in the early morning and late evening, and seek shelter around noon.
- many species of bees and moths flap their wings vigorously to raise the temperature of their flight muscles before taking off.
- bees in large hives will cool the hive in hot periods by going to its entrances and using their wings as fans to draw cooling air through the hive. They will warm the hive in cool periods by gathering in the middle and shivering to produce heat.
- termite mounds are usually oriented in a north-south direction so that they absorb as much heat as possible around dawn and dusk and minimise heat absorption around noon.
Some other "cold-blooded" creatures use internal mechanisms to maintain body temperatures significantly above the ambient level:
- Tuna and Swordfish. Fish have long been thought to be cold blooded. Tuna and swordfish dive deep into the ocean where the water is very cold. Swordfish are able to raise the temperature of their brains and eyes, which allows faster eye movements when hunting. Tuna are able to warm their entire bodies through a heat exchange mechanism called the rete mirabile, which helps keep heat inside the body, and minimizes the loss of heat through the gills. They also have their swimming muscles near the center of their bodies instead of near the surface, which minimises heat loss.
- "Warm-blooded" sharks (e.g. mako and white sharks) minimize heat loss by using their gills as heat exchangers - veins are right next to arteries and thus extract heat from the arteries and carry it back into the body.
- Large sea turtles exhibit inertial homeothermy (Gigantothermy) - their low ratio of surface area to volume minimises heat loss. | Warm-blooded
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Warm-blooded animals maintain thermal homeostasis; that is, they keep their body temperature at a constant level. This involves the ability to cool down or produce more body heat. Warm-blooded animals mainly control their body temperature by regulating their metabolic rates (e.g. increasing their metabolic rate as the surrounding temperature begins to decrease).
Both the terms "warm-blooded" and "cold-blooded" have fallen out of favor with scientists, because of the vagueness of the terms, and due to an increased understanding in this field. Body temperature types do not fall into simple either/or categories. Each term may be replaced with one or more variants (see: Definitions of warm-bloodedness). Body temperature maintenance incorporates a wide range of different techniques that result in a body temperature continuum, with the traditional ideals of warm-blooded and cold-blooded being at opposite ends of the spectrum.
# Definitions of warm-bloodedness
Warm-bloodedness generally refers to three separate aspects of thermoregulation.
- Endothermy is the ability of some creatures to control their body temperatures through internal means such as muscle shivering, fat burning, and panting (Greek: endo = "within," therm = "heat"). Some writers restrict the meaning of "endothermy" to mechanisms which directly raise the animal's metabolic rate in order to produce heat. The opposite of endothermy is ectothermy.
- Homoiothermy is thermoregulation that maintains a stable internal body temperature regardless of external influence. This temperature is often higher than the immediate environment (Greek: homoios = "similar," therm = "heat"). The opposite is poikilothermy.
- Tachymetabolism is the kind of thermoregulation used by creatures that maintain a high resting metabolism (Greek: tachy = "fast, swift," metabol = "to change"). Tachymetabolic creatures are, essentially, "on" all the time. Though their resting metabolism is still many times slower than their active metabolism, the difference is often not as large as that seen in bradymetabolic creatures. Tachymetabolic creatures have greater difficulty dealing with a scarcity of food.
A large proportion of the creatures traditionally called "warm-blooded" (mammals and birds) fit all three of these categories. However, over the past 30 years, studies in the field of animal thermophysiology have revealed many species belonging to these two groups that don't fit all these criteria. For example, many bats and small birds are poikilothermic and bradymetabolic when they sleep for the night, or day. For these creatures, another term was coined: heterothermy.
Further studies on animals that were traditionally assumed to be cold-blooded have shown that most creatures incorporate different variations of the three terms defined above, along with their counterparts (ectothermy, poikilothermy and bradymetabolism), thus creating a broad spectrum of body temperature types (see temperature control in cold-blooded animals).
# Mechanisms
## Generating and conserving heat
The creatures traditionally regarded as warm-blooded have a larger number of mitochondria per cell which enables them to generate heat by increasing the rate at which they "burn" fats and sugars. This requires a much greater quantity of food than is needed by cold-blooded animals in order to replace the fat and sugar reserves.
Many endothermic animals supplement these reserves by shivering in cold conditions, since muscular activity also converts fats and sugars into heat. In winter, there may not be enough food to enable an endotherm to keep its metabolic rate stable all day, so some organisms go into a controlled state of hypothermia called hibernation, or torpor. This conserves energy by lowering the body temperature. Many birds and small mammals (e.g. tenrecs) also allow their body temperatures to drop at night to reduce the energy cost of maintaining body temperature. Humans also slow down their metabolism slightly during sleep.
Heat loss is a major threat to smaller creatures as they have a larger ratio of surface area to volume. Most small warm-blooded animals have insulation in the form of fur or feathers. Aquatic warm-blooded animals generally use deep layers of fat under the skin for insulation, since fur or feathers would spoil their streamlining. Penguins use both feathers and fat, since their need for streamlining limits the degree of insulation which feathers alone can give them. Birds, especially waders, have blood-vessels in their lower legs which act as heat exchangers - veins are right next to arteries and thus extract heat from the arteries and carry it back into the trunk. Many warm-blooded animals blanche (become paler) to reduce heat loss by reducing the blood flow to the skin.
## Avoiding over-heating
In equatorial climates and during temperate summers over-heating is as great a threat as cold. In hot conditions many warm-blooded animals increase heat loss by panting and or flushing (increasing the blood flow to the skin). Hairless and short-haired mammals also sweat, since the evaporation of sweat uses a lot of heat. Elephants keep cool by using their huge ears rather like the radiators in automobiles: they flap their ears to increase the airflow over them.
# Warm-blooded vs.Cold blooded
## Advantages of a fast metabolism
The overall speed of an animal's metabolism increases by a factor of about 2 for every 10 C° rise in temperature (limited by the need to avoid hyperthermia). Warm-bloodedness does not provide greater speed than cold-bloodedness - cold-blooded animals can move as fast as warm-blooded animals of the same size and build. But warm-blooded animals have much greater stamina than cold-blooded creatures of the same size and build, because their faster metabolisms quickly regenerate energy supplies (especially ATP) and break down muscular waste products (especially lactate). This enables warm-blooded predators to run down prey, warm-blooded prey to outrun cold-blooded predators (provided they avoid the initial charge or ambush) and warm-blooded animals to be much more successful foragers.
## Advantages of homeothermy
Enzymes have strong temperature preferences and their efficiency is much reduced outside their preferred ranges. A creature with a fairly constant body temperature can therefore use enzymes which are efficient at that temperature. Another advantage of a homeothermic animal would be its ability to maintain its constant body temperature even in freezing cold weather. A poikilotherm must either operate well below optimum efficiency most of the time or spend extra resources making a wider range of enzymes to cover the wider range of body temperatures.
## Disadvantages of warm-bloodedness
Because warm-blooded animals use enzymes which are specialised for a narrow range of body temperatures over-cooling rapidly leads to torpor and then death. Also, the energy required to maintain the homeothermic temperature comes from food - this results in homeothermic animals needing to eat much more food than poikilothermic animals.
Shivering and fat-burning to maintain temperature are very energy-intensive, for example:
- in winter many small birds lose one third of their body weight overnight.
- in general a warm-blooded animal requires 5 to 10 times as much food as a cold-blooded animal of the same size and build, so cold-blooded animals are better at surviving famines and barren environments.
# Temperature control in cold-blooded animals
Scientific understanding of thermal regulation regimes has advanced greatly since the original distinction was made between warm- and cold-blooded animals, and the issue has been studied much more extensively.
Many "cold-blooded" animals use behavioral means to adjust their internal temperatures:
- lizards and snakes bask in the sun in the early morning and late evening, and seek shelter around noon.
- many species of bees and moths flap their wings vigorously to raise the temperature of their flight muscles before taking off.
- bees in large hives will cool the hive in hot periods by going to its entrances and using their wings as fans to draw cooling air through the hive. They will warm the hive in cool periods by gathering in the middle and shivering to produce heat.
- termite mounds are usually oriented in a north-south direction so that they absorb as much heat as possible around dawn and dusk and minimise heat absorption around noon.
Some other "cold-blooded" creatures use internal mechanisms to maintain body temperatures significantly above the ambient level:
- Tuna and Swordfish. Fish have long been thought to be cold blooded. Tuna and swordfish dive deep into the ocean where the water is very cold. Swordfish are able to raise the temperature of their brains and eyes, which allows faster eye movements when hunting. Tuna are able to warm their entire bodies through a heat exchange mechanism called the rete mirabile, which helps keep heat inside the body, and minimizes the loss of heat through the gills. They also have their swimming muscles near the center of their bodies instead of near the surface, which minimises heat loss.
- "Warm-blooded" sharks (e.g. mako and white sharks) minimize heat loss by using their gills as heat exchangers - veins are right next to arteries and thus extract heat from the arteries and carry it back into the body.
- Large sea turtles exhibit inertial homeothermy (Gigantothermy) - their low ratio of surface area to volume minimises heat loss. | https://www.wikidoc.org/index.php/Endothermy | |
1b550e27f4d826dd157724101870f9ca9ef7c9af | wikidoc | Enilconazole | Enilconazole
# Overview
Enilconazole (synonyms imazalil, chloramizole) is a fungicide widely used in agriculture, particularly in the growing of citrus fruits. Trade names include Freshgard, Fungaflor, and Nuzone.
Enilconazole is also used in veterinary medicine as a topical antimycotic.
# History
In 1983, enilconazole was first introduced by Janssen Pharmaceutica and it has since consistently been registered as an antifungal postharvest agent. Shortly after its introduction, enilconazole was used for seed treatment in 1984 and later used in chicken hatcheries in 1990. Like any fungicide, it was used to protect crops from becoming diseased and unable to yield a profitable harvest. Today, it continues to be utilized as an agricultural aid for its contribution to maintaining crop integrity and production output.
# Use on crops
Enilconazole is found on a wide variety of fruits and vegetables, but it is primarily used on tubers for storage. Common fungi that are attracted to tubers are Fusarium spp, Phoma spp, and Helminthosporum solani which depreciate the crop quality. In 1984, when enilconazole was initially used for seed treatment, barley was a main target to mitigate crop loss due to disease.
In addition, the antifungal agent is commonly used on citrus fruits.
# Hazards
In 1999, based on studies in rodents, enilconazole was identified as "likely to be carcinogenic in humans" under The Environmental Protection Agency's Draft Guidelines for Carcinogenic Assessment. However, because pesticide residues are well below the concentrations associated with risk, the lifetime cancer risk estimate associated with citrus fruit contamination was valued as insignificant.
The EPA has established an equivalent toxicity level for human exposure at 6.1 x 10−2 mg/kg/day. This level placed it in Category I, II, and IV for oral, dermal, and inhalation toxicity. Category I is classified as highly irritating to the eyes, but not to the skin. As for oral toxicity, when the fungicide is transferred via food into the body, it must be metabolized before it can do any damage.
Under California's Proposition 65, enilconazole is listed as "known to the State to cause cancer".
The EPA determined there is no substantial risk to toxic levels when considering food and water exposure. Enilconazole has a very minute degree of mobility, so its level of drinking water contamination is quite low. The estimated environmental concentration (EEC) found the levels to be 0.072 ppb for surface water and 500 ppb for drinking water. These values are quite negligible, which is why the Agency does not see them as a concern. | Enilconazole
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Enilconazole (synonyms imazalil, chloramizole) is a fungicide widely used in agriculture, particularly in the growing of citrus fruits.[1] Trade names include Freshgard, Fungaflor, and Nuzone.
Enilconazole is also used in veterinary medicine as a topical antimycotic.[2]
# History
In 1983, enilconazole was first introduced by Janssen Pharmaceutica and it has since consistently been registered as an antifungal postharvest agent.[3] Shortly after its introduction, enilconazole was used for seed treatment in 1984 and later used in chicken hatcheries in 1990. Like any fungicide, it was used to protect crops from becoming diseased and unable to yield a profitable harvest. Today, it continues to be utilized as an agricultural aid for its contribution to maintaining crop integrity and production output.
# Use on crops
Enilconazole is found on a wide variety of fruits and vegetables, but it is primarily used on tubers for storage.[4] Common fungi that are attracted to tubers are Fusarium spp, Phoma spp, and Helminthosporum solani which depreciate the crop quality.[4] In 1984, when enilconazole was initially used for seed treatment, barley was a main target to mitigate crop loss due to disease.[4]
In addition, the antifungal agent is commonly used on citrus fruits.[1]
# Hazards
In 1999, based on studies in rodents, enilconazole was identified as "likely to be carcinogenic in humans" under The Environmental Protection Agency's Draft Guidelines for Carcinogenic Assessment.[3] However, because pesticide residues are well below the concentrations associated with risk, the lifetime cancer risk estimate associated with citrus fruit contamination was valued as insignificant.[3]
The EPA has established an equivalent toxicity level for human exposure at 6.1 x 10−2 mg/kg/day. This level placed it in Category I, II, and IV for oral, dermal, and inhalation toxicity.[3] Category I is classified as highly irritating to the eyes, but not to the skin. As for oral toxicity, when the fungicide is transferred via food into the body, it must be metabolized before it can do any damage.
Under California's Proposition 65, enilconazole is listed as "known to the State to cause cancer".[5]
The EPA determined there is no substantial risk to toxic levels when considering food and water exposure. Enilconazole has a very minute degree of mobility, so its level of drinking water contamination is quite low. The estimated environmental concentration (EEC) found the levels to be 0.072 ppb for surface water and 500 ppb for drinking water.[3] These values are quite negligible, which is why the Agency does not see them as a concern. | https://www.wikidoc.org/index.php/Enilconazole | |
250add6799607d22627049c79acf7a3507f301e1 | wikidoc | Enrico Fermi | Enrico Fermi
Enrico Fermi (September 29, 1901 – November 28, 1954) was an Italian physicist most noted for his work on the development of the first nuclear reactor, and for his contributions to the development of quantum theory, nuclear and particle physics, and statistical mechanics. Fermi was awarded the Nobel Prize in Physics in 1938 for his work on induced radioactivity and is today regarded as one of the top scientists of the 20th century. Fermium, a synthetic element created in 1952 is named after him.
# Biography
## Physics in Rome
Enrico Fermi was born in Rome, Italy. His father was Alberto Fermi, a Chief Inspector of the Ministry of Communications, and his mother was Ida de Gattis, an elementary school teacher. As a young boy he enjoyed learning physics and mathematics and shared his interests with his older brother, Giulio. When Giulio died unexpectedly of a throat abscess in 1915, Enrico was distraught, and immersed himself into scientific study to distract himself. According to his own account, each day he would walk in front of the hospital where Giulio died until he became inured to the pain. Later, Enrico befriended another scientifically inclined student named Enrico Persico, and the two together engaged in scientific projects such as building gyroscopes, and measuring the magnetic field of the earth. Fermi's interest in physics was further encouraged when a friend of his father's gave him several books on physics and mathematics, which he read and assimilated.
Fermi received his undergraduate and doctoral degree from the Scuola Normale Superiore in Pisa. There was an entrance exam which candidates had to take in order to enter the prestigious institute, which included an essay. For his essay on the given theme Characteristics of Sound, 17-year-old Fermi chose to derive and solve the Fourier analysis based partial differential equation for waves on a string. The examiner interviewed Fermi and concluded that his essay would have been commendable even for a doctoral degree. At the Scuola Normale Superiore, Fermi teamed up with a fellow student named Franco Rasetti with whom he used to indulge in light hearted pranks. Later, Rasetti became Fermi's close friend and collaborator.
Fermi's Ph.D advisor was Luigi Puccianti. In 1924 Fermi spent a semester in Göttingen, and then stayed for a few months in Leiden with Paul Ehrenfest.
From January 1925 to the autumn of 1926 he stayed at the University of Florence. In this period he wrote his work on the Fermi-Dirac statistics. When he was only 24 years old, Fermi took a professorship in Rome (the first for atomic physics in Italy, which he won in a competition created by professor Orso Mario Corbino, director of the Institute of Physics). Corbino helped Fermi in selecting his team, which soon was joined by notable minds like Edoardo Amaldi, Bruno Pontecorvo, Franco Rasetti and Emilio Segrè. For the theoretical studies only, Ettore Majorana also took part in what was soon nicknamed "the Via Panisperna boys" (after the name of the road in which the Institute had its labs).
The group went on with its now famous experiments, but in 1933 Rasetti left Italy for Canada and the United States, Pontecorvo went to France and Segrè left to teach in Palermo.
During their time in Rome, Fermi and his group made important contributions to many practical and theoretical aspects of physics. Some of these include the theory of beta decay, and the discovery of slow neutrons, which was to prove pivotal for the working of nuclear reactors. His group also systematically bombarded elements with slow neutrons, and during their experiments with uranium, narrowly missed observing nuclear fission. At that time, fission was thought to be improbable, if not impossible, mostly on theoretical grounds. While people expected elements with higher atomic number to form from neutron bombardment of lighter elements, nobody expected neutrons to have enough energy to actually split a heavier atom into two light element fragments. However, the chemist Ida Noddack had criticised Fermi's work and had suggested that some of his experiments could have produced lighter elements. At the time, Fermi dismissed this possibility on the basis of calculations.
Fermi was well-known for his simplicity in solving problems. He began his inquiries with the simplest lines of mathematical reasoning, then later produced complete solutions to the problems he deemed worth pursuing. His abilities as the greatest combined theoretical and applied nuclear physicist of all time were acknowledged by and influenced many physicists who worked with him, such as Hans Bethe, who spent two semesters working with Fermi in the early 1930s. From the time he was a boy, Fermi meticulously recorded his calculations in notebooks, and later used to solve many new problems that he encountered based on these earlier known problems.
When Fermi submitted his famous paper on beta decay to the prestigious journal Nature, the journal's editor turned it down because "it contained speculations which were too remote from reality". Thus, Fermi saw the theory published in Italian and in German before it was published in English. Nature eventually did publish Fermi's report on beta decay on January 16, 1939.
# The Manhattan Project
Fermi remained in Rome until 1938.
In 1938, Fermi won the Nobel Prize in Physics for his "demonstrations of the existence of new radioactive elements produced by neutron irradiation, and for his related discovery of nuclear reactions brought about by slow neutrons".
After Fermi received the Nobel Prize in Stockholm, he, his wife Laura, and their children emigrated to New York. This was mainly because of the anti-Semitic laws promulgated by the fascist regime of Benito Mussolini which threatened Laura, who was Jewish. Also, the new laws put most of Fermi's research assistants out of work.
Soon after his arrival in New York, Fermi began working at Columbia University.
In December 1938, the German chemists Otto Hahn and Fritz Strassmann sent a manuscript to Naturwissenschaften reporting they had detected the element barium after bombarding uranium with neutrons; simultaneously, they communicated these results to Lise Meitner. Meitner, and her nephew Otto Robert Frisch, correctly interpreted these results as being nuclear fission. Frisch confirmed this experimentally on 13 January 1939. In 1944, Hahn received the Nobel Prize for Chemistry for the discovery of nuclear fission. Some historians have documented the history of the discovery of nuclear fission and believe Meitner should have been awarded the Nobel Prize with Hahn.
Meitner’s and Frisch’s interpretation of the work of Hahn and Strassmann crossed the Atlantic Ocean with Niels Bohr, who was to lecture at Princeton University. Isidor Isaac Rabi and Willis Lamb, two Columbia University physicists working at Princeton, heard the news and carried it back to Columbia. Rabi said he told Enrico Fermi; Fermi gave credit to Lamb. Bohr soon thereafter went from Princeton to Columbia to see Fermi. Not finding Fermi in his office, Bohr went down to the cyclotron area and found Herbert L. Anderson. Bohr grabbed him by the shoulder and said: “Young man, let me explain to you about something new and exciting in physics.” It was clear to a number of scientists at Columbia that they should try to detect the energy released in the nuclear fission of uranium from neutron bombardment. On 25 January 1939, a Columbia University team conducted the first nuclear fission experiment in the United States, which was done in the basement of Pupin Hall; the members of the team were Herbert L. Anderson, Eugene T. Booth, John R. Dunning, Enrico Fermi, G. Norris Glasoe, and Francis G. Slack. The next day, at the Fifth Washington Conference on Theoretical Physics began in Washington, D.C. under the joint auspices of The George Washington University and the Carnegie Institution of Washington. There, the news on nuclear fusion was spread even further, which fostered many more experimental demonstrations.
Fermi then went to the University of Chicago and began studies that led to the construction of the first nuclear pile Chicago Pile-1.
Fermi recalled the beginning of the project in a speech given in 1954 when he retired as President of the American Physical Society:
In August of 1939 Leó Szilárd prepared and Albert Einstein signed the famous letter warning President Franklin D. Roosevelt of the probability that the Nazis were planning to build an atomic bomb. Because of Hitler's September 1 invasion of Poland, it was October before they could arrange for the letter to be personally delivered. Roosevelt was concerned enough that the Uranium Committee was assembled and awarded Columbia University the first atomic energy funding of US$ 6,000. However, due to bureaucratic fears of foreigners doing secret research, the money was not actually issued until Szilárd implored Einstein to send a second letter to the president in the spring of 1940. The money was used in studies which led to the first nuclear reactor — Chicago Pile-1, a massive "atomic pile" of graphite bricks and uranium fuel which went critical on December 2, 1942, built in a hard racquets court under Stagg Field, the football stadium at the University of Chicago. Due to a mistranslation, Soviet reports on Enrico Fermi claimed that his work was performed in a converted "pumpkin field" instead of a "squash court", squash being an offshoot of hard racquets . This experiment was a landmark in the quest for energy, and it was typical of Fermi's brilliance. Every step had been carefully planned, every calculation meticulously done by him. When the first self sustained nuclear chain reaction was achieved, a coded phone call was made by one of the physicists, Arthur Compton to James Conant, chairman of the National Defense Research Committee. The conversation was in impromptu code:
This successful initiation of a chain-reacting pile was important not only for its help in assessing the properties of fission — needed for understanding the internal workings of an atomic bomb — but because it would serve as a pilot plant for the massive reactors which would be created in Hanford, Washington, which would then be used to produce the plutonium needed for the bombs used at the Trinity site and Nagasaki. Eventually Fermi and Szilárd's reactor work was folded into the Manhattan Project.
Fermi moved to Los Alamos in the later stages of the Manhattan Project to serve as a general consultant. He was sitting in the control room of the Hanford B Reactor when it first went critical in 1944. His broad knowledge of many fields of physics was useful in solving problems that were of an interdisciplinary nature.
He became a naturalized citizen of the United States of America in 1944.
Fermi was present as an observer of the Trinity test on July 16, 1945. Engineer Jack Aeby saw Fermi at work:
Fermi's strips-of paper estimate was ten kilotons of TNT ; the actual yield was about 19 kilotons .
# Post-War work
In Fermi's 1954 address to the APS he also said, "Well, this brings us to Pearl Harbor. That is the time when I left Columbia University, and after a few months of commuting between Chicago and New York, eventually moved to Chicago to keep up the work there, and from then on, with a few notable exceptions, the work at Columbia was concentrated on the isotope separation phase of the atomic energy project, initiated by Booth, Dunning and Urey about 1940".
Fermi was widely regarded as the only physicist of the twentieth century who excelled both theoretically and experimentally (Snow, 1981) (see link below in 'References'). The well-known historian of physics, C. P. Snow, says about him, "If Fermi had been born a few years earlier, one could well imagine him discovering Rutherford's atomic nucleus, and then developing Bohr's theory of the hydrogen atom. If this sounds like hyperbole, anything about Fermi is likely to sound like hyperbole". Fermi's ability and success stemmed as much from his appraisal of the art of the possible, as from his innate skill and intelligence. He disliked complicated theories, and while he had great mathematical ability, he would never use it when the job could be done much more simply. He was famous for getting quick and accurate answers to problems which would stump other people. An instance of this was seen during the first atomic bomb test in New Mexico on July 16 1945. As the blast wave reached him, Fermi dropped bits of paper. By measuring the distance they were blown, he could compare to a previously computed table and thus estimate the bomb energy yield. He estimated that the blast was greater than 10 kilotons of TNT, the measured result was 18.6. (Rhodes, page 674). Later on, this method of getting approximate and quick answers through back of the envelope calculations became informally known as the 'Fermi method'.
Fermi's most disarming trait was his great modesty, and his ability to do any kind of work, whether creative or routine. It was this quality that made him popular and liked among people of all strata, from other Nobel Laureates to technicians. Henry DeWolf Smyth, who was Chairman of the Princeton Physics department, had once invited Fermi over to do some experiments with the Princeton cyclotron. Walking into the lab one day, Smyth saw the distinguished scientist helping a graduate student move a table, under another student's directions. Another time, a Du Pont executive made a visit to see him at Columbia. Not finding him either in his lab or his office, the executive was surprised to find the Nobel Laureate in the machine shop, cutting sheets of tin with a big pair of shears.
After the war, Fermi served for a short time on the General Advisory Committee of the Atomic Energy Commission, a scientific committee chaired by Robert Oppenheimer which advised the commission on nuclear matters and policy. After the detonation of the first Soviet fission bomb in August 1949, he, along with Isidor Rabi, wrote a strongly worded report for the committee which opposed the development of a hydrogen bomb on moral and technical grounds. But Fermi also participated in preliminary work on the hydrogen bomb at Los Alamos as a consultant, and along with Stanislaw Ulam, calculated that the amount of tritium needed for Edward Teller's model of a thermonuclear weapon would be prohibitive, and a fusion reaction could not be assured to propagate even with this large quantity of tritium.
In his later years, Fermi did important work in particle physics, especially related to pions and muons. He was also known to be an inspiring teacher at the University of Chicago, and was known for his attention to detail, simplicity, and careful preparation for a lecture. Later, his lecture notes, especially those for quantum mechanics, nuclear physics, and thermodynamics, were transcribed into books which are still in print.
Also in these later years he mused about a proposition which is now referred to as the "Fermi Paradox". This absurd contradiction or proposition is this: that with the billions and billions of star systems in the universe, one would think that intelligent life would have contacted our civilization by now; yet this has not happened since it takes only about 600 years for a civilization to reach potential for annihilating itself with weapons of mass-destruction as it grows in knowledge exponentially.
Fermi died at age 53 of stomach cancer and was interred at Oak Woods Cemetery in Chicago, Illinois. Two of his graduate students who assisted him in working on or near the nuclear pile also died of cancer. Fermi and his team knew that such work carried considerable risk but they considered the outcome so vital that they forged ahead with little regard for their own personal safety.
As Eugene Wigner wrote: "Ten days before Fermi had died he told me, 'I hope it won't take long.' He had reconciled himself perfectly to his fate".
A recent poll by Time magazine listed Fermi among the top twenty scientists of the century.
The Fermilab particle accelerator and physics lab in Batavia, Illinois, is named after him in loving memory from the physics community.
Fermi 1 & Fermi 2 nuclear power plants in Newport, Michigan are also named after him, as are many schools such as Enrico Fermi High School in Enfield, Connecticut.
Fermi Court in Deep River, Ontario is named in his honour.
In 1952, element 100 on the periodic table of elements was isolated from the debris of a nuclear test. In honor of Fermi's contributions to the scientific community, it was named fermium after him.
Since the 1950s, the United States Atomic Energy Commission has named its highest honour, the Fermi Award, after him. Recipients of the award include well-known scientists like Otto Hahn, Robert Oppenheimer, Freeman Dyson, John Wheeler and Hans Bethe.
# Laura and Enrico Fermi Family Legacy
Enrico Fermi's mother built her own pressure cooker ("Enrico Fermi, Physicist", Segre, University of Chicago Press, 1970) and perhaps this inspired Enrico to build the first nuclear reactor in 1942. A pressure cooker is metal containing steam pressure. Enrico's pile was graphite containing uranium from exploding (copyright Olivia Fermi 2001-2008, unpublished manuscript). In 1928, Fermi married Laura Capon. They had two children while living in Rome, Italy: a daughter Nella Fermi Weiner, PhD (1931–1995), artist and feminist; and a son Giulio ("Judd") Fermi, PhD (1936–1997). Laura and Enrico's son Giulio worked with the Nobel laureate Max Perutz on the structure of hemoglobin.
Toward the end of his life, Enrico realized his faith in society at large to make wise choices about nuclear technology was questionable ("Fermi Remembered", Cronin, ed., University of Chicago Press, 2004). Enrico Fermi said:
"Some of you may ask, what is the good of working so hard merely to collect a few facts which will bring no pleasure except to a few long-haired professors who love to collect such things and will be of no use to anybody because only few specialists at best will be able to understand them? In answer to such question I may venture a fairly safe prediction.
History of science and technology has consistently taught us that scientific advances in basic understanding have sooner or later led to technical and industrial applications that have revolutionized our way of life. It seems to me improbable that this effort to get at the structure of matter should be an exception to this rule. What is less certain, and what we all fervently hope, is that man will soon grow sufficiently adult to make good use of the powers that he acquires over nature."
(Enrico Fermi, The Future of Nuclear Physics, unpublished address, Rochester, NY, January 10, 1953, EFP, box 53.)
His wife, Laura Fermi (1907–1977), early environmentalist, systems thinker, prolific writer and New York Times bestselling author of "Atoms in the Family: Life with Enrico Fermi, Architect of the Atomic Age" (University of Chicago Press, 1954) said, of our nuclear dilemma:
"But above all, there were the moral questions. I knew scientists had hoped that the bomb would not be possible, but there it was and it had already killed and destroyed so much. Was war or was science to be blamed? Should the scientists have stopped the work once they realized that a bomb was feasible? Would there always be war in the future? To these kinds of questions there is no simple answer." (Laura Fermi, "Reminiscences of Los Alamos", edited by Lawrence Badash)
Rachel Fermi (1964–), photographer and teacher, Laura and Enrico Fermi's 3rd grandchild, continued to question the sanity of nuclear weapons in her book, published with Rachel Samra, introduction by Richard Rhodes: "Picturing the Bomb", Abrams pub, 1995). The authors juxtapose photos from the top secret world of the Manhattan Project with family photos from Los Alamos and Hanford.
Olivia Fermi (1957–), formerly Alice Caton, M.A. A.B.S. - Leadership in Human Systems, ConRes Cert, photoartist, writer and business consultant, Laura and Enrico's first grandchild, is currently researching the legacy of her grandparents for a series of books she plans to publish. On September 29, 2001, shortly after the destruction of the World Trade Center in New York City, Olivia flew to Rome, Italy to deliver a speech to the International Conference: Enrico Fermi and the Universe of Physics. She had been invited to speak to this gathering of physicists as a representative of the Laura and Enrico Fermi family. Olivia said:
"All of us alive today, and all who will come after us, are heirs to Enrico Fermi’s scientific legacy. We all have a stake in it. Since the end of World War II, humanity has had knowledge of nuclear energy and its incredible potential for benefit as well as harm.
"Enrico Fermi gave us a lot. And there is more to be done. Enrico Fermi’s work, and the work of other scientists, exists in a world full of people who, in a certain way, are like Enrico... ... He, like all of us, was both brilliant and fallible.
"We have a collective, developmental task. We must learn to integrate our scientific knowledge and our human experience to find the answers to the nuclear dilemma, and to the many other dilemmas facing us today. ... Our world has yet to find the right nuclear recipe – how to harness nuclear power for the benefit of all living things.
"We will need all of our human gifts to survive and flourish on this planet. From here, it looks to me like Enrico contributed all of his gifts. Now it’s up to us to contribute ours. We can look back to Enrico for inspiration, if we look to ourselves for the future."
(Olivia Fermi (formerly Alice Caton), "Enrico Fermi in the Family", Speech presented at: Proceedings of the International 'Enrico Fermi and the Universe of Physics' Rome, Sept 29 - Oct 2, 2001" Accademia Nazionale dei Lincei Istitutio Nazionale di Fisica Nucleare, 2003). Her speech was translated into Italian and published by Promoteo, the Italian journal of arts and letters in the December 2001 issue. ("Fermi in Famiglia", Alice Caton (now Olivia Fermi), Promoteo Anno 19, Numero 76, Arnoldo Mondadori Editore, Dicembre 2001)
The two male grandchildren of Laura and Enrico are Olivia's brother: Paul Weiner, PhD (1959–), mathemetician and professor; and Rachel's brother: Daniel Fermi (1971–). Between Paul and Rachel, there are four great-grandchildren of Laura and Enrico Fermi. These two children, four grandchildren and four great-grandchildren are all the direct descendents of Laura and Enrico Fermi.
# Patents
- U.S. Patent 2,206,634 — Process for the Production of Radioactive Substances, filed October, 1935, issued July, 1940
- U.S. Patent 2,524,379 — Neutron Velocity Selector, filed September, 1945, issued October, 1950
- U.S. Patent 2,708,656 — Neutronic reactor, with Leo Szilard, filed December, 1944, issued May, 1955
- U.S. Patent 2,768,134 — Testing Material in a Neutronic Reactor, filed August, 1945, issued October, 1956
- U.S. Patent 2,780,595 — Test Exponential Pile, filed May, 1944, issued February 1957
- U.S. Patent 2,798,847 — Method of Operating a Neutronic Reactor, filed December 1944, issued July, 1957
- U.S. Patent 2,807,581 — Neutronic Reactor, filed October 1945, issued September, 1957
- U.S. Patent 2,807,727 — Neutronic Reactor Shield, filed January 1946, issued September, 1957
- U.S. Patent 2,813,070 — Method of Sustaining a Neutronic Chain Reacting System, filed November, 1945, issued November, 1957
- U.S. Patent 2,836,554 — Air Cooled Neutronic Reactor
- U.S. Patent 2,837,477 — Chain Reacting System
- U.S. Patent 2,852,461 — Neutronic Reactor
- U.S. Patent 2,931,762 — Neutronic Reactor
- U.S. Patent 2,969,307 — Method of Testing Thermal Neutron Fissionable Material for Purity, filed November 1945, issued January 1961 | Enrico Fermi
Template:Infobox Scientist
Enrico Fermi (September 29, 1901 – November 28, 1954) was an Italian physicist most noted for his work on the development of the first nuclear reactor, and for his contributions to the development of quantum theory, nuclear and particle physics, and statistical mechanics. Fermi was awarded the Nobel Prize in Physics in 1938 for his work on induced radioactivity and is today regarded as one of the top scientists of the 20th century. Fermium, a synthetic element created in 1952 is named after him.
# Biography
## Physics in Rome
Enrico Fermi was born in Rome, Italy. His father was Alberto Fermi, a Chief Inspector of the Ministry of Communications, and his mother was Ida de Gattis, an elementary school teacher. As a young boy he enjoyed learning physics and mathematics and shared his interests with his older brother, Giulio. When Giulio died unexpectedly of a throat abscess in 1915, Enrico was distraught, and immersed himself into scientific study to distract himself. According to his own account, each day he would walk in front of the hospital where Giulio died until he became inured to the pain. Later, Enrico befriended another scientifically inclined student named Enrico Persico, and the two together engaged in scientific projects such as building gyroscopes, and measuring the magnetic field of the earth. Fermi's interest in physics was further encouraged when a friend of his father's gave him several books on physics and mathematics, which he read and assimilated.
Fermi received his undergraduate and doctoral degree from the Scuola Normale Superiore in Pisa. There was an entrance exam which candidates had to take in order to enter the prestigious institute, which included an essay. For his essay on the given theme Characteristics of Sound, 17-year-old Fermi chose to derive and solve the Fourier analysis based partial differential equation for waves on a string. The examiner interviewed Fermi and concluded that his essay would have been commendable even for a doctoral degree. At the Scuola Normale Superiore, Fermi teamed up with a fellow student named Franco Rasetti with whom he used to indulge in light hearted pranks. Later, Rasetti became Fermi's close friend and collaborator.
Fermi's Ph.D advisor was Luigi Puccianti. In 1924 Fermi spent a semester in Göttingen, and then stayed for a few months in Leiden with Paul Ehrenfest.
From January 1925 to the autumn of 1926 he stayed at the University of Florence. In this period he wrote his work on the Fermi-Dirac statistics. When he was only 24 years old, Fermi took a professorship in Rome (the first for atomic physics in Italy, which he won in a competition created by professor Orso Mario Corbino, director of the Institute of Physics). Corbino helped Fermi in selecting his team, which soon was joined by notable minds like Edoardo Amaldi, Bruno Pontecorvo, Franco Rasetti and Emilio Segrè. For the theoretical studies only, Ettore Majorana also took part in what was soon nicknamed "the Via Panisperna boys" (after the name of the road in which the Institute had its labs).
The group went on with its now famous experiments, but in 1933 Rasetti left Italy for Canada and the United States, Pontecorvo went to France and Segrè left to teach in Palermo.
During their time in Rome, Fermi and his group made important contributions to many practical and theoretical aspects of physics. Some of these include the theory of beta decay, and the discovery of slow neutrons, which was to prove pivotal for the working of nuclear reactors. His group also systematically bombarded elements with slow neutrons, and during their experiments with uranium, narrowly missed observing nuclear fission. At that time, fission was thought to be improbable, if not impossible, mostly on theoretical grounds. While people expected elements with higher atomic number to form from neutron bombardment of lighter elements, nobody expected neutrons to have enough energy to actually split a heavier atom into two light element fragments. However, the chemist Ida Noddack had criticised Fermi's work and had suggested that some of his experiments could have produced lighter elements. At the time, Fermi dismissed this possibility on the basis of calculations.
Fermi was well-known for his simplicity in solving problems[1]. He began his inquiries with the simplest lines of mathematical reasoning, then later produced complete solutions to the problems he deemed worth pursuing. His abilities as the greatest combined theoretical and applied nuclear physicist of all time were acknowledged by and influenced many physicists who worked with him, such as Hans Bethe, who spent two semesters working with Fermi in the early 1930s. From the time he was a boy, Fermi meticulously recorded his calculations in notebooks, and later used to solve many new problems that he encountered based on these earlier known problems.
When Fermi submitted his famous paper on beta decay to the prestigious journal Nature, the journal's editor turned it down because "it contained speculations which were too remote from reality". Thus, Fermi saw the theory published in Italian and in German before it was published in English. Nature eventually did publish Fermi's report on beta decay on January 16, 1939.
# The Manhattan Project
Fermi remained in Rome until 1938.
In 1938, Fermi won the Nobel Prize in Physics for his "demonstrations of the existence of new radioactive elements produced by neutron irradiation, and for his related discovery of nuclear reactions brought about by slow neutrons".
After Fermi received the Nobel Prize in Stockholm, he, his wife Laura, and their children emigrated to New York. This was mainly because of the anti-Semitic laws promulgated by the fascist regime of Benito Mussolini which threatened Laura, who was Jewish. Also, the new laws put most of Fermi's research assistants out of work.
Soon after his arrival in New York, Fermi began working at Columbia University.
In December 1938, the German chemists Otto Hahn and Fritz Strassmann sent a manuscript to Naturwissenschaften reporting they had detected the element barium after bombarding uranium with neutrons;[2] simultaneously, they communicated these results to Lise Meitner. Meitner, and her nephew Otto Robert Frisch, correctly interpreted these results as being nuclear fission.[3] Frisch confirmed this experimentally on 13 January 1939.[4] In 1944, Hahn received the Nobel Prize for Chemistry for the discovery of nuclear fission. Some historians have documented the history of the discovery of nuclear fission and believe Meitner should have been awarded the Nobel Prize with Hahn.[5] [6] [7]
Meitner’s and Frisch’s interpretation of the work of Hahn and Strassmann crossed the Atlantic Ocean with Niels Bohr, who was to lecture at Princeton University. Isidor Isaac Rabi and Willis Lamb, two Columbia University physicists working at Princeton, heard the news and carried it back to Columbia. Rabi said he told Enrico Fermi; Fermi gave credit to Lamb. Bohr soon thereafter went from Princeton to Columbia to see Fermi. Not finding Fermi in his office, Bohr went down to the cyclotron area and found Herbert L. Anderson. Bohr grabbed him by the shoulder and said: “Young man, let me explain to you about something new and exciting in physics.”[8] It was clear to a number of scientists at Columbia that they should try to detect the energy released in the nuclear fission of uranium from neutron bombardment. On 25 January 1939, a Columbia University team conducted the first nuclear fission experiment in the United States,[9] which was done in the basement of Pupin Hall; the members of the team were Herbert L. Anderson, Eugene T. Booth, John R. Dunning, Enrico Fermi, G. Norris Glasoe, and Francis G. Slack. The next day, at the Fifth Washington Conference on Theoretical Physics began in Washington, D.C. under the joint auspices of The George Washington University and the Carnegie Institution of Washington. There, the news on nuclear fusion was spread even further, which fostered many more experimental demonstrations.[10]
Fermi then went to the University of Chicago and began studies that led to the construction of the first nuclear pile Chicago Pile-1.
Fermi recalled the beginning of the project in a speech given in 1954 when he retired as President of the American Physical Society:
In August of 1939 Leó Szilárd prepared and Albert Einstein signed the famous letter warning President Franklin D. Roosevelt of the probability that the Nazis were planning to build an atomic bomb. Because of Hitler's September 1 invasion of Poland, it was October before they could arrange for the letter to be personally delivered. Roosevelt was concerned enough that the Uranium Committee was assembled and awarded Columbia University the first atomic energy funding of US$ 6,000. However, due to bureaucratic fears of foreigners doing secret research, the money was not actually issued until Szilárd implored Einstein to send a second letter to the president in the spring of 1940. The money was used in studies which led to the first nuclear reactor — Chicago Pile-1, a massive "atomic pile" of graphite bricks and uranium fuel which went critical on December 2, 1942, built in a hard racquets court under Stagg Field, the football stadium at the University of Chicago. Due to a mistranslation, Soviet reports on Enrico Fermi claimed that his work was performed in a converted "pumpkin field" instead of a "squash court", squash being an offshoot of hard racquets [1]. This experiment was a landmark in the quest for energy, and it was typical of Fermi's brilliance. Every step had been carefully planned, every calculation meticulously done by him. When the first self sustained nuclear chain reaction was achieved, a coded phone call was made by one of the physicists, Arthur Compton to James Conant, chairman of the National Defense Research Committee. The conversation was in impromptu code:
This successful initiation of a chain-reacting pile was important not only for its help in assessing the properties of fission — needed for understanding the internal workings of an atomic bomb — but because it would serve as a pilot plant for the massive reactors which would be created in Hanford, Washington, which would then be used to produce the plutonium needed for the bombs used at the Trinity site and Nagasaki. Eventually Fermi and Szilárd's reactor work was folded into the Manhattan Project.
Fermi moved to Los Alamos in the later stages of the Manhattan Project to serve as a general consultant. He was sitting in the control room of the Hanford B Reactor when it first went critical in 1944. His broad knowledge of many fields of physics was useful in solving problems that were of an interdisciplinary nature.
He became a naturalized citizen of the United States of America in 1944.
Fermi was present as an observer of the Trinity test on July 16, 1945. Engineer Jack Aeby saw Fermi at work:
Fermi's strips-of paper estimate was ten kilotons of TNT [12]; the actual yield was about 19 kilotons [13].
# Post-War work
In Fermi's 1954 address to the APS he also said, "Well, this brings us to Pearl Harbor. That is the time when I left Columbia University, and after a few months of commuting between Chicago and New York, eventually moved to Chicago to keep up the work there, and from then on, with a few notable exceptions, the work at Columbia was concentrated on the isotope separation phase of the atomic energy project, initiated by Booth, Dunning and Urey about 1940".
Fermi was widely regarded as the only physicist of the twentieth century who excelled both theoretically and experimentally (Snow, 1981) (see link below in 'References'). The well-known historian of physics, C. P. Snow, says about him, "If Fermi had been born a few years earlier, one could well imagine him discovering Rutherford's atomic nucleus, and then developing Bohr's theory of the hydrogen atom. If this sounds like hyperbole, anything about Fermi is likely to sound like hyperbole". Fermi's ability and success stemmed as much from his appraisal of the art of the possible, as from his innate skill and intelligence. He disliked complicated theories, and while he had great mathematical ability, he would never use it when the job could be done much more simply. He was famous for getting quick and accurate answers to problems which would stump other people. An instance of this was seen during the first atomic bomb test in New Mexico on July 16 1945. As the blast wave reached him, Fermi dropped bits of paper. By measuring the distance they were blown, he could compare to a previously computed table and thus estimate the bomb energy yield. He estimated that the blast was greater than 10 kilotons of TNT, the measured result was 18.6. (Rhodes, page 674). Later on, this method of getting approximate and quick answers through back of the envelope calculations became informally known as the 'Fermi method'.
Fermi's most disarming trait was his great modesty, and his ability to do any kind of work, whether creative or routine. It was this quality that made him popular and liked among people of all strata, from other Nobel Laureates to technicians. Henry DeWolf Smyth, who was Chairman of the Princeton Physics department, had once invited Fermi over to do some experiments with the Princeton cyclotron. Walking into the lab one day, Smyth saw the distinguished scientist helping a graduate student move a table, under another student's directions. Another time, a Du Pont executive made a visit to see him at Columbia. Not finding him either in his lab or his office, the executive was surprised to find the Nobel Laureate in the machine shop, cutting sheets of tin with a big pair of shears.
After the war, Fermi served for a short time on the General Advisory Committee of the Atomic Energy Commission, a scientific committee chaired by Robert Oppenheimer which advised the commission on nuclear matters and policy. After the detonation of the first Soviet fission bomb in August 1949, he, along with Isidor Rabi, wrote a strongly worded report for the committee which opposed the development of a hydrogen bomb on moral and technical grounds. But Fermi also participated in preliminary work on the hydrogen bomb at Los Alamos as a consultant, and along with Stanislaw Ulam, calculated that the amount of tritium needed for Edward Teller's model of a thermonuclear weapon would be prohibitive, and a fusion reaction could not be assured to propagate even with this large quantity of tritium.
In his later years, Fermi did important work in particle physics, especially related to pions and muons. He was also known to be an inspiring teacher at the University of Chicago, and was known for his attention to detail, simplicity, and careful preparation for a lecture. Later, his lecture notes, especially those for quantum mechanics, nuclear physics, and thermodynamics, were transcribed into books which are still in print.
Also in these later years he mused about a proposition which is now referred to as the "Fermi Paradox". This absurd contradiction or proposition is this: that with the billions and billions of star systems in the universe, one would think that intelligent life would have contacted our civilization by now; yet this has not happened since it takes only about 600 years for a civilization to reach potential for annihilating itself with weapons of mass-destruction as it grows in knowledge exponentially.
Fermi died at age 53 of stomach cancer and was interred at Oak Woods Cemetery in Chicago, Illinois. Two of his graduate students who assisted him in working on or near the nuclear pile also died of cancer. Fermi and his team knew that such work carried considerable risk but they considered the outcome so vital that they forged ahead with little regard for their own personal safety.[14]
As Eugene Wigner wrote: "Ten days before Fermi had died he told me, 'I hope it won't take long.' He had reconciled himself perfectly to his fate".
A recent poll by Time magazine listed Fermi among the top twenty scientists of the century.
The Fermilab particle accelerator and physics lab in Batavia, Illinois, is named after him in loving memory from the physics community.
Fermi 1 & Fermi 2 nuclear power plants in Newport, Michigan are also named after him, as are many schools such as Enrico Fermi High School in Enfield, Connecticut.
Fermi Court in Deep River, Ontario is named in his honour.
In 1952, element 100 on the periodic table of elements was isolated from the debris of a nuclear test. In honor of Fermi's contributions to the scientific community, it was named fermium after him.
Since the 1950s, the United States Atomic Energy Commission has named its highest honour, the Fermi Award, after him. Recipients of the award include well-known scientists like Otto Hahn, Robert Oppenheimer, Freeman Dyson, John Wheeler and Hans Bethe.
# Laura and Enrico Fermi Family Legacy
Enrico Fermi's mother built her own pressure cooker ("Enrico Fermi, Physicist", Segre, University of Chicago Press, 1970) and perhaps this inspired Enrico to build the first nuclear reactor in 1942. A pressure cooker is metal containing steam pressure. Enrico's pile was graphite containing uranium from exploding (copyright Olivia Fermi 2001-2008, unpublished manuscript). In 1928, Fermi married Laura Capon. They had two children while living in Rome, Italy: a daughter Nella Fermi Weiner, PhD (1931–1995), artist and feminist; and a son Giulio ("Judd") Fermi, PhD (1936–1997). Laura and Enrico's son Giulio worked with the Nobel laureate Max Perutz on the structure of hemoglobin.
Toward the end of his life, Enrico realized his faith in society at large to make wise choices about nuclear technology was questionable ("Fermi Remembered", Cronin, ed., University of Chicago Press, 2004). Enrico Fermi said:
"Some of you may ask, what is the good of working so hard merely to collect a few facts which will bring no pleasure except to a few long-haired professors who love to collect such things and will be of no use to anybody because only few specialists at best will be able to understand them? In answer to such question[s] I may venture a fairly safe prediction.
History of science and technology has consistently taught us that scientific advances in basic understanding have sooner or later led to technical and industrial applications that have revolutionized our way of life. It seems to me improbable that this effort to get at the structure of matter should be an exception to this rule. What is less certain, and what we all fervently hope, is that man will soon grow sufficiently adult to make good use of the powers that he acquires over nature."
(Enrico Fermi, The Future of Nuclear Physics, unpublished address, Rochester, NY, January 10, 1953, EFP, box 53.)
His wife, Laura Fermi (1907–1977), early environmentalist, systems thinker, prolific writer and New York Times bestselling author of "Atoms in the Family: Life with Enrico Fermi, Architect of the Atomic Age" (University of Chicago Press, 1954) said, of our nuclear dilemma:
"But above all, there were the moral questions. I knew scientists had hoped that the bomb would not be possible, but there it was and it had already killed and destroyed so much. Was war or was science to be blamed? Should the scientists have stopped the work once they realized that a bomb was feasible? Would there always be war in the future? To these kinds of questions there is no simple answer." (Laura Fermi, "Reminiscences of Los Alamos", edited by Lawrence Badash)
Rachel Fermi (1964–), photographer and teacher, Laura and Enrico Fermi's 3rd grandchild, continued to question the sanity of nuclear weapons in her book, published with Rachel Samra, introduction by Richard Rhodes: "Picturing the Bomb", Abrams pub, 1995). The authors juxtapose photos from the top secret world of the Manhattan Project with family photos from Los Alamos and Hanford.
Olivia Fermi (1957–), formerly Alice Caton, M.A. A.B.S. - Leadership in Human Systems, ConRes Cert, photoartist, writer and business consultant, Laura and Enrico's first grandchild, is currently researching the legacy of her grandparents for a series of books she plans to publish. http://fermieffect.com On September 29, 2001, shortly after the destruction of the World Trade Center in New York City, Olivia flew to Rome, Italy to deliver a speech to the International Conference: Enrico Fermi and the Universe of Physics. She had been invited to speak to this gathering of physicists as a representative of the Laura and Enrico Fermi family. Olivia said:
"All of us alive today, and all who will come after us, are heirs to Enrico Fermi’s scientific legacy. We all have a stake in it. Since the end of World War II, humanity has had knowledge of nuclear energy and its incredible potential for benefit as well as harm.
"Enrico Fermi gave us a lot. And there is more to be done. Enrico Fermi’s work, and the work of other scientists, exists in a world full of people who, in a certain way, are like Enrico... [funny anecdotes about occasional Enrico errors]... He, like all of us, was both brilliant and fallible.
"We have a collective, developmental task. We must learn to integrate our scientific knowledge and our human experience to find the answers to the nuclear dilemma, and to the many other dilemmas facing us today. ... Our world has yet to find the right nuclear recipe – how to harness nuclear power for the benefit of all living things.
"We will need all of our human gifts to survive and flourish on this planet. From here, it looks to me like Enrico contributed all of his gifts. Now it’s up to us to contribute ours. We can look back to Enrico for inspiration, if we look to ourselves for the future."
(Olivia Fermi (formerly Alice Caton), "Enrico Fermi in the Family", Speech presented at: Proceedings of the International 'Enrico Fermi and the Universe of Physics' Rome, Sept 29 - Oct 2, 2001" Accademia Nazionale dei Lincei Istitutio Nazionale di Fisica Nucleare, 2003). Her speech was translated into Italian and published by Promoteo, the Italian journal of arts and letters in the December 2001 issue. ("Fermi in Famiglia", Alice Caton (now Olivia Fermi), Promoteo Anno 19, Numero 76, Arnoldo Mondadori Editore, Dicembre 2001)
The two male grandchildren of Laura and Enrico are Olivia's brother: Paul Weiner, PhD (1959–), mathemetician and professor; and Rachel's brother: Daniel Fermi (1971–). Between Paul and Rachel, there are four great-grandchildren of Laura and Enrico Fermi. These two children, four grandchildren and four great-grandchildren are all the direct descendents of Laura and Enrico Fermi.
# Patents
- U.S. Patent 2,206,634 — Process for the Production of Radioactive Substances, filed October, 1935, issued July, 1940
- U.S. Patent 2,524,379 — Neutron Velocity Selector, filed September, 1945, issued October, 1950
- U.S. Patent 2,708,656 — Neutronic reactor, with Leo Szilard, filed December, 1944, issued May, 1955
- U.S. Patent 2,768,134 — Testing Material in a Neutronic Reactor, filed August, 1945, issued October, 1956
- U.S. Patent 2,780,595 — Test Exponential Pile, filed May, 1944, issued February 1957
- U.S. Patent 2,798,847 — Method of Operating a Neutronic Reactor, filed December 1944, issued July, 1957
- U.S. Patent 2,807,581 — Neutronic Reactor, filed October 1945, issued September, 1957
- U.S. Patent 2,807,727 — Neutronic Reactor Shield, filed January 1946, issued September, 1957
- U.S. Patent 2,813,070 — Method of Sustaining a Neutronic Chain Reacting System, filed November, 1945, issued November, 1957
- U.S. Patent 2,836,554 — Air Cooled Neutronic Reactor
- U.S. Patent 2,837,477 — Chain Reacting System
- U.S. Patent 2,852,461 — Neutronic Reactor
- U.S. Patent 2,931,762 — Neutronic Reactor
- U.S. Patent 2,969,307 — Method of Testing Thermal Neutron Fissionable Material for Purity, filed November 1945, issued January 1961 | https://www.wikidoc.org/index.php/Enrico_Fermi | |
6c15535fa9e3c87da5af89f949ef32153e1e8874 | wikidoc | Enrofloxacin | Enrofloxacin
Enrofloxacin is a fluoroquinolone antibiotic sold by the Bayer Corporation under the trade name Baytril. Enrofloxacin is currently approved by the FDA for the treatment of individual pets and domestic animals in the United States. In September 2005, the FDA withdrew approval of Baytril for use in water to treat flocks of poultry, as this practice was noted to promote the evolution of fluoroquinolone-resistant strains of the bacterium Campylobacter, a human pathogen.
It is a bactericidal agent. The bactericidal activity of enrofloxacin is concentration-dependent, with susceptible bacteria cell death occurring within 20–30 minutes of exposure. Enrofloxacin has demonstrated a significant post-antibiotic effect for both Gram-negative and Gram-positive bacteria and is active in both stationary and growth phases of bacterial replication.
# Activity and susceptibility data
Enrofloxacin is a synthetic antibacterial agent from the class of the fluoroquinolone carboxylic acid derivatives. It has antibacterial activity against a broad spectrum of Gram-negative and Gram-positive bacteria. Its mechanism of action is not thoroughly understood, but it is believed to act by inhibiting bacterial DNA gyrase (a type-II topoisomerase), thereby preventing DNA supercoiling and DNA synthesis. It is effective against:
- Pseudomonas aeruginosa
- Klebsiella
- Escherichia coli
- Enterobacter
- Campylobacter
- Shigella
- Salmonella
- Aeromonas
- Haemophilus
- Proteus
- Yersinia
- Serratia
- Vibrio
- Brucella
- Chlamydia trachomatis
- Staphylococcus (including penicillinase-producing and methicillin-resistant strains)
- Mycoplasma
- Mycobacterium
Variable activity against:
- Streptococcus
Ineffective against:
- Anaerobes
The following data represent minimum inhibitory concentration ranges for a few medically significant bacterial pathogens:
- Escherichia coli - 0.004 - 512 µg/ml
- Staphylococcus aureus - 0.0925 - 64 µg/ml
- Pseudomonas aeruginosa - 0.05 µg/ml
# Contraindications/precautions
Usage in poultry.
# Adverse effects/warnings
Enrofloxacin was banned for poultry use in 2005. Baytril should not be used in rapidly growing animals (for example dogs under 12 months - 18 months in large breeds, or kittens under 8 weeks) as it causes abnormalities in the development of articular cartilage.
# Overdosage/acute toxicity
It is unlikely that an acute overdose of either compound would result in symptoms more serious than either anorexia or vomiting, but the adverse effects noted above could occur. Dogs receiving 10 times the labeled dosage rate of enrofloxacin for at least 14 days developed only vomiting and anorexia. Death did occur in some dogs when fed 25 times the labeled rate for 11 days, however.
- Oral Template:LD50: greater than 5000 mg/kg
- Dermal LD50: greater than 2000 mg/kg
- Inhalation LD50: greater than 3547 mg/m3 (4-hour exposure)
- Eye effects: irritant; reversible in less than 7 days. In cats, it can produce sudden onset blindness when administered by injection, as
# Degradation
The brown rot fungus Gloeophyllum striatum can degrade the fluoroquinolone enrofloxacin using hydroxyl radicals. | Enrofloxacin
Enrofloxacin is a fluoroquinolone antibiotic sold by the Bayer Corporation under the trade name Baytril. Enrofloxacin is currently approved by the FDA for the treatment of individual pets and domestic animals in the United States. In September 2005, the FDA withdrew approval of Baytril for use in water to treat flocks of poultry, as this practice was noted to promote the evolution of fluoroquinolone-resistant strains of the bacterium Campylobacter, a human pathogen.[4]
It is a bactericidal agent. The bactericidal activity of enrofloxacin is concentration-dependent, with susceptible bacteria cell death occurring within 20–30 minutes of exposure. Enrofloxacin has demonstrated a significant post-antibiotic effect for both Gram-negative and Gram-positive bacteria and is active in both stationary and growth phases of bacterial replication.
# Activity and susceptibility data
Enrofloxacin is a synthetic antibacterial agent from the class of the fluoroquinolone carboxylic acid derivatives. It has antibacterial activity against a broad spectrum of Gram-negative and Gram-positive bacteria. Its mechanism of action is not thoroughly understood, but it is believed to act by inhibiting bacterial DNA gyrase (a type-II topoisomerase), thereby preventing DNA supercoiling and DNA synthesis. It is effective against:
- Pseudomonas aeruginosa
- Klebsiella
- Escherichia coli
- Enterobacter
- Campylobacter
- Shigella
- Salmonella
- Aeromonas
- Haemophilus
- Proteus
- Yersinia
- Serratia
- Vibrio
- Brucella
- Chlamydia trachomatis
- Staphylococcus (including penicillinase-producing and methicillin-resistant strains)
- Mycoplasma
- Mycobacterium
Variable activity against:
- Streptococcus
Ineffective against:
- Anaerobes
The following data represent minimum inhibitory concentration ranges for a few medically significant bacterial pathogens:
- Escherichia coli - 0.004 - 512 µg/ml
- Staphylococcus aureus - 0.0925 - 64 µg/ml
- Pseudomonas aeruginosa - 0.05 µg/ml [5]
# Contraindications/precautions
Usage in poultry.
# Adverse effects/warnings
Enrofloxacin was banned for poultry use in 2005.[6] Baytril should not be used in rapidly growing animals (for example dogs under 12 months - 18 months in large breeds, or kittens under 8 weeks) as it causes abnormalities in the development of articular cartilage.[citation needed]
# Overdosage/acute toxicity
It is unlikely that an acute overdose of either compound would result in symptoms more serious than either anorexia or vomiting, but the adverse effects noted above could occur. Dogs receiving 10 times the labeled dosage rate of enrofloxacin for at least 14 days developed only vomiting and anorexia. Death did occur in some dogs when fed 25 times the labeled rate for 11 days, however.
- Oral Template:LD50: greater than 5000 mg/kg
- Dermal LD50: greater than 2000 mg/kg
- Inhalation LD50: greater than 3547 mg/m3 (4-hour exposure)
- Eye effects: irritant; reversible in less than 7 days. In cats, it can produce sudden onset blindness when administered by injection, as
# Degradation
The brown rot fungus Gloeophyllum striatum can degrade the fluoroquinolone enrofloxacin using hydroxyl radicals. [7] | https://www.wikidoc.org/index.php/Enrofloxacin | |
6e4e25808126b7cf172067811e1c8ad3a56d92b1 | wikidoc | Feeding tube | Feeding tube
# Overview
A feeding tube is a medical device used to provide nutrition to patients who cannot or refuse to (q.v. hunger strike) obtain nutrition by swallowing. The state of being fed by a feeding tube is called enteral feeding or tube feeding. Placement may be temporary for the treatment of acute conditions or lifelong in the case of chronic disabilities. Many patients treated using a feeding tube lack the ability to survive on their own without such technology.
A variety of feeding tubes are used in medical practice. They are usually made of polyurethane or silicone. The diameter of a feeding tube is measured in French units (each French unit equals 0.33 millimeters). They are classified by site of insertion and intended use.
Feeding tubes can be used for the force-feeding of prisoners on hunger strike, a controversial use. The World Medical Association prohibits the involuntary force-feeding of hunger strikers (except in cases of coma or mental impairment) through the Declaration of Tokyo (1975) and the Declaration on Hunger Strikers (1991). Feeding tubes are sometimes used on prisoners in a manner which can be categorized as torture, as allegedly at Guantanamo Bay detention camp (using nasogastric tubes).
Feeding tubes are also used for the force-feeding of animals, such as the ducks and geese used to produce foie gras.
# Types of feeding tubes
## Nasogastric
A nasogastric feeding tube, or "NG-tube", is passed through the nares, down the esophagus and into the stomach.
## Gastric feeding tube
A gastric feeding tube, or "G-tube", is a tube inserted through a small incision in the abdomen into the stomach and is used for long-term enteral nutrition. The most common type is the percutaneous endoscopic gastrostomy (PEG) tube. It is placed endoscopically: the patient is sedated, and an endoscope is passed through the mouth and esophagus into the stomach. The position of the endoscope can be visualized on the outside of the patient's abdomen because it contains a powerful light source. A needle is inserted through the abdomen, visualized within the stomach by the endoscope, and a suture passed through the needle is grasped by the endoscope and pulled up through the esophagus. The suture is then tied to the end PEG tube that will be external, and pulled back down through the esophagus, stomach, and out through abdominal wall. The insertion takes about 20 minutes. The tube is kept within the stomach either by a balloon on its tip (which can be deflated) or by a retention dome which is wider than the tract of the tube.
Gastrostomy tubes can also be placed in "open" procedures through an incision with direct visualization of the stomach, as well as via laparoscope. Gastric tubes are suitable for long-term use: they last about six months, and can be replaced through an existing passage without an additional endoscopic procedure. The G-tube is useful where there is difficulty with swallowing because of neurologic or anatomic disorders (stroke, esophageal atresia, tracheoesophageal fistula), and to avoid the risk of aspiration pneumonia. It is also used when patients are malnourished and cannot take enough food by mouth to maintain their weight. They also can be used in "reverse" to drain stomach contents.
## Jejunostomy tube
A jejunostomy tube is similar to a gastric tube, though generally has a finer bore and smaller diameter, and is surgically inserted into the jejunum rather than the stomach. They are used when the upper gastrointestinal tract must be bypassed completely, and can be used as soon as 12 hours after surgery. This type of tube is usually used for people who are at high risk for aspiration.
These small bore tubes are prone to clogging, particularly with some medications and if not flushed as directed. Feeding through these tubes are generally commercially prepared to provide adequate nutrition and to not result in clogging when used with a pump or with drip feedings.
## Gastrojejunostomy tube
Dual-lumen feeding tubes are available. Typically, the gastric lumen is used for decompression. The jejunal lumen is used to administer feedings. Either a percutaneous or open technique can be used. The jejunal portion of the tube can occasionally migrate back into the stomach, often requiring endoscopic repositioning.
# Effectiveness
The ASPEN Enteral Nutrition Committee recommended in 2022:
- "Initiate EN within 24–48 h of admission to the hospital, including the intensive care unit (ICU), in the patient who is at high risk for malnutrition or who is malnourished."
- "A delay in initiation of EN can be considered in hospitalized patients who are low risk, well nourished, and expected to resume volitional oral intake within 5–7 days of admission."
- "Advance EN cautiously in patients at risk for refeeding and in Advance EN cautiously in patients at risk for refeeding and in patients with symptoms of gastrointestinal (GI) intolerance."
ASPEN made additional recommendations for specific patient groups.
More recently, a large cohort study found increased mortality from early feeding.
Earlier, in 2019, a systematic review by the Cochrane Collaboration concluded:
- "we are uncertain whether early enteral nutrition , compared with delayed enteral nutrition, affects the risk of mortality within 30 days, feed intolerance or gastrointestinal complications, or pneumonia"
Earlier randomized controlled trials have reported:
- Nutritional supplementation is not necessary if the patient is not eating for four days or less and maybe also if duration is seven days or less.
- A randomized controlled trial found no difference between the NG tube and PEG tube in stroke patients.
The NRS 2002 may help identify patients who will benefit from early tube feeding.
# Complications
Damage to nearby structures, most commonly the colon, can occur with percutaneous techniques. Dislodgement of the tube can occur, leading to peritonitis in certain circumstances. Feeding tubes can become occluded or inadvertently pulled out. The tube can migrate distally and obstruct the pylorus, leading to gastric outlet obstruction. Abdominal fascial dehiscence can occur with an open technique. After removal of the feeding tube, a gastrocutaneous fistula can result if the tract does not close.
# Withdrawal
Tube feeding, like all medical treatments, can be declined or withdrawn, especially in the setting of a terminal illness where its use would not alter the ultimate outcome. Actively withdrawing an existing feeding tube is considered by some to be a form of active euthanasia, while deciding not to place one could be considered passive euthanasia. | Feeding tube
# Overview
A feeding tube is a medical device used to provide nutrition to patients who cannot or refuse to (q.v. hunger strike) obtain nutrition by swallowing. The state of being fed by a feeding tube is called enteral feeding or tube feeding. Placement may be temporary for the treatment of acute conditions or lifelong in the case of chronic disabilities. Many patients treated using a feeding tube lack the ability to survive on their own without such technology.
A variety of feeding tubes are used in medical practice. They are usually made of polyurethane or silicone. The diameter of a feeding tube is measured in French units (each French unit equals 0.33 millimeters). They are classified by site of insertion and intended use.
Feeding tubes can be used for the force-feeding of prisoners on hunger strike, a controversial use. The World Medical Association prohibits the involuntary force-feeding of hunger strikers (except in cases of coma or mental impairment) through the Declaration of Tokyo (1975) and the Declaration on Hunger Strikers (1991). Feeding tubes are sometimes used on prisoners in a manner which can be categorized as torture, as allegedly at Guantanamo Bay detention camp (using nasogastric tubes). [1]
Feeding tubes are also used for the force-feeding of animals, such as the ducks and geese used to produce foie gras.
# Types of feeding tubes
## Nasogastric
A nasogastric feeding tube, or "NG-tube", is passed through the nares, down the esophagus and into the stomach.
## Gastric feeding tube
A gastric feeding tube, or "G-tube", is a tube inserted through a small incision in the abdomen into the stomach and is used for long-term enteral nutrition. The most common type is the percutaneous endoscopic gastrostomy (PEG) tube. It is placed endoscopically: the patient is sedated, and an endoscope is passed through the mouth and esophagus into the stomach. The position of the endoscope can be visualized on the outside of the patient's abdomen because it contains a powerful light source. A needle is inserted through the abdomen, visualized within the stomach by the endoscope, and a suture passed through the needle is grasped by the endoscope and pulled up through the esophagus. The suture is then tied to the end PEG tube that will be external, and pulled back down through the esophagus, stomach, and out through abdominal wall. The insertion takes about 20 minutes. The tube is kept within the stomach either by a balloon on its tip (which can be deflated) or by a retention dome which is wider than the tract of the tube.
Gastrostomy tubes can also be placed in "open" procedures through an incision with direct visualization of the stomach, as well as via laparoscope. Gastric tubes are suitable for long-term use: they last about six months, and can be replaced through an existing passage without an additional endoscopic procedure. The G-tube is useful where there is difficulty with swallowing because of neurologic or anatomic disorders (stroke, esophageal atresia, tracheoesophageal fistula), and to avoid the risk of aspiration pneumonia. It is also used when patients are malnourished and cannot take enough food by mouth to maintain their weight. They also can be used in "reverse" to drain stomach contents.
## Jejunostomy tube
A jejunostomy tube is similar to a gastric tube, though generally has a finer bore and smaller diameter, and is surgically inserted into the jejunum rather than the stomach. They are used when the upper gastrointestinal tract must be bypassed completely, and can be used as soon as 12 hours after surgery. This type of tube is usually used for people who are at high risk for aspiration.
These small bore tubes are prone to clogging, particularly with some medications and if not flushed as directed. Feeding through these tubes are generally commercially prepared to provide adequate nutrition and to not result in clogging when used with a pump or with drip feedings.
## Gastrojejunostomy tube
Dual-lumen feeding tubes are available. Typically, the gastric lumen is used for decompression. The jejunal lumen is used to administer feedings. Either a percutaneous or open technique can be used. The jejunal portion of the tube can occasionally migrate back into the stomach, often requiring endoscopic repositioning.
# Effectiveness
The ASPEN Enteral Nutrition Committee recommended in 2022[1]:
- "Initiate EN within 24–48 h of admission to the hospital, including the intensive care unit (ICU), in the patient who is at high risk for malnutrition or who is malnourished."
- "A delay in initiation of EN can be considered in hospitalized patients who are low risk, well nourished, and expected to resume volitional oral intake within 5–7 days of admission."
- "Advance EN cautiously in patients at risk for refeeding and in Advance EN cautiously in patients at risk for refeeding and in patients with symptoms of gastrointestinal (GI) intolerance."
ASPEN made additional recommendations for specific patient groups.
More recently, a large cohort study found increased mortality from early feeding[2].
Earlier, in 2019, a systematic review by the Cochrane Collaboration concluded[3]:
- "we are uncertain whether early enteral nutrition [within 48 hours], compared with delayed enteral nutrition, affects the risk of mortality within 30 days, feed intolerance or gastrointestinal complications, or pneumonia"
Earlier randomized controlled trials have reported:
- Nutritional supplementation is not necessary if the patient is not eating for four days or less[4] and maybe also if duration is seven days or less.[5]
- A randomized controlled trial found no difference between the NG tube and PEG tube in stroke patients.[5]
The NRS 2002 may help identify patients who will benefit from early tube feeding[6][7].
# Complications
Damage to nearby structures, most commonly the colon, can occur with percutaneous techniques. Dislodgement of the tube can occur, leading to peritonitis in certain circumstances. Feeding tubes can become occluded or inadvertently pulled out. The tube can migrate distally and obstruct the pylorus, leading to gastric outlet obstruction. Abdominal fascial dehiscence can occur with an open technique. After removal of the feeding tube, a gastrocutaneous fistula can result if the tract does not close.
# Withdrawal
Tube feeding, like all medical treatments, can be declined or withdrawn, especially in the setting of a terminal illness where its use would not alter the ultimate outcome. Actively withdrawing an existing feeding tube is considered by some to be a form of active euthanasia, while deciding not to place one could be considered passive euthanasia. | https://www.wikidoc.org/index.php/Enteral_feeding | |
dd37f92d3d2d3cb082725aee12e0bb0d046754a1 | wikidoc | Enterobacter | Enterobacter
Enterobacter is a genus of common Gram-negative, facultatively-anaerobic, rod-shaped bacteria of the family Enterobacteriaceae. Several strains of the these bacteria are pathogenic and cause opportunistic infections in immunocompromised (usually hospitalized) hosts. The urinary and respiratory tract are the most common sites of infection. Enterobacter can be distinguished from other GNR by virtue of being a 'fast fermenter' of lactose (as are Escherichia coli and Klebsiella).
Two clinically-important species from this genus are E. aerogenes and E. cloacae.
# Antimicrobial therapy
- Enterobacter species including E. aerogenes and E. cloacae
- 1. Empiric antimicrobial therapy pending in vitro susceptibility
- 1.1 Non–life-threatening infections or MDR-GNB prevalence < 20%
- Preferred regimen: Piperacillin-Tazobactam 3.375 g IV q6h ± Aminoglycosides
- Alternative regimen: Ciprofloxacin 400 mg IV q8–12h
- 1.2 Life-threatening infections or MDR-GNB prevalence > 20%
- Preferred regimen: Meropenem 0.5–1 g IV q8h
- Alternative regimen (1): Colistin AND Meropenem 0.5–1 g IV q8h
- Alternative regimen (2): Colistin AND Imipenem 500 mg IV q6h
- Alternative regimen (3): Colistin AND Doripenem 500 mg IV q8h
- Alternative regimen (4): Colistin AND Ertapenem 1 g IV q24h
- Alternative regimen (5): Colistin AND Fosfomycin 6 g IV q6h
- 2. In vitro susceptibility available
- 2.1 Susceptible to all tested agents
- Preferred regimen: Piperacillin-Tazobactam 3.375 g IV q6h
- Alternative regimen (1): Ciprofloxacin 400 mg IV q8–12h
- Alternative regimen (2): Cefepime 2 g IV q8h (if MIC ≤ 1 μg/mL)
- 2.2 Extended spectrum beta-lactamase (ESBL)-producing Enterobacter spp.
- Preferred regimen: Meropenem 0.5–1 g IV q8h
- Alternative regimen (1): Imipenem 500 mg IV q6h
- Alternative regimen (2): Doripenem 500 mg IV q8h
- Alternative regimen (3): Ertapenem 1 g IV q24h
- Alternative regimen (4): Cefepime 2 g IV q8h (if MIC ≤ 1 μg/mL)
- 2.3 Resistant to all tested agents
- Preferred regimen: Colistin AND Meropenem 0.5–1 g IV q8h
- Alternative regimen (1): Colistin AND Imipenem 500 mg IV q6h
- Alternative regimen (2): Colistin AND Doripenem 500 mg IV q8h
- Alternative regimen (3): Colistin AND Ertapenem 1 g IV q24h
- Alternative regimen (4): Colistin AND Minocycline 100 mg IV q12h | Enterobacter
Enterobacter is a genus of common Gram-negative, facultatively-anaerobic, rod-shaped bacteria of the family Enterobacteriaceae. Several strains of the these bacteria are pathogenic and cause opportunistic infections in immunocompromised (usually hospitalized) hosts. The urinary and respiratory tract are the most common sites of infection. Enterobacter can be distinguished from other GNR by virtue of being a 'fast fermenter' of lactose (as are Escherichia coli and Klebsiella).
Two clinically-important species from this genus are E. aerogenes and E. cloacae.
# Antimicrobial therapy
- Enterobacter species including E. aerogenes and E. cloacae[1][2][3][4][5]
- 1. Empiric antimicrobial therapy pending in vitro susceptibility
- 1.1 Non–life-threatening infections or MDR-GNB prevalence < 20%
- Preferred regimen: Piperacillin-Tazobactam 3.375 g IV q6h ± Aminoglycosides
- Alternative regimen: Ciprofloxacin 400 mg IV q8–12h
- 1.2 Life-threatening infections or MDR-GNB prevalence > 20%
- Preferred regimen: Meropenem 0.5–1 g IV q8h
- Alternative regimen (1): Colistin AND Meropenem 0.5–1 g IV q8h
- Alternative regimen (2): Colistin AND Imipenem 500 mg IV q6h
- Alternative regimen (3): Colistin AND Doripenem 500 mg IV q8h
- Alternative regimen (4): Colistin AND Ertapenem 1 g IV q24h
- Alternative regimen (5): Colistin AND Fosfomycin 6 g IV q6h
- 2. In vitro susceptibility available
- 2.1 Susceptible to all tested agents
- Preferred regimen: Piperacillin-Tazobactam 3.375 g IV q6h
- Alternative regimen (1): Ciprofloxacin 400 mg IV q8–12h
- Alternative regimen (2): Cefepime 2 g IV q8h (if MIC ≤ 1 μg/mL)
- 2.2 Extended spectrum beta-lactamase (ESBL)-producing Enterobacter spp.
- Preferred regimen: Meropenem 0.5–1 g IV q8h
- Alternative regimen (1): Imipenem 500 mg IV q6h
- Alternative regimen (2): Doripenem 500 mg IV q8h
- Alternative regimen (3): Ertapenem 1 g IV q24h
- Alternative regimen (4): Cefepime 2 g IV q8h (if MIC ≤ 1 μg/mL)
- 2.3 Resistant to all tested agents
- Preferred regimen: Colistin AND Meropenem 0.5–1 g IV q8h
- Alternative regimen (1): Colistin AND Imipenem 500 mg IV q6h
- Alternative regimen (2): Colistin AND Doripenem 500 mg IV q8h
- Alternative regimen (3): Colistin AND Ertapenem 1 g IV q24h
- Alternative regimen (4): Colistin AND Minocycline 100 mg IV q12h | https://www.wikidoc.org/index.php/Enterobacter | |
fe387c47d5676bf785dd71b283170f379d4f3be5 | wikidoc | Enterococcus | Enterococcus
# Overview
Enterococcus is a genus of lactic acid bacteria of the phylum Firmicutes. Members of this genus were classified as Group D Streptococcus until 1984 when genomic DNA analysis indicated that a separate genus classification was appropriate. Important clinical infections caused by Enterococcus include urinary tract infections, bacteremia, bacterial endocarditis, diverticulitis, and meningitis. Sensitive strains of these bacteria can be treated with ampicillin and vancomycin. However, the most important feature of this genus is their high level of endemic antibiotic resistance.
# Microbiology
Enterococcus is a genus of lactic acid bacteria of the phylum Firmicutes. Members of this genus were classified as Group D Streptococcus until 1984 when genomic DNA analysis indicated that a separate genus classification was appropriate. Enterococci are Gram-positive cocci which often occur in pairs (diplococci) and are difficult to distinguish from Streptococci on physical characteristics alone. Two species are common commensal organisms in the intestines of humans: E. faecalis (90-95%) and E. faecium (5-10%). Enterococci are facultative anaerobic organisms, i.e. they prefer the use of oxygen, but they can survive in the absence of oxygen. They typically exhibit gamma-hemolysis on sheep's blood agar.
# Clinical Infections
- Bacteremia
- Bacterial endocarditis
- Diverticulitis
- Meningitis
Enterococcal meningitis is a rare complication of neurosurgery. It often requires treatment with intravenous vancomycin; intrathecal vancomycin is often used and it is debatable whether this has any impact on outcome. The removal of any neurological devices is a crucial part of the management of these infections.
- Enterococcal meningitis is a rare complication of neurosurgery. It often requires treatment with intravenous vancomycin; intrathecal vancomycin is often used and it is debatable whether this has any impact on outcome. The removal of any neurological devices is a crucial part of the management of these infections.
- Urinary tract infection
# Treatment
- Sensitive strains of these bacteria can be treated with ampicillin and vancomycin.
- From a medical standpoint, the most important feature of this genus is their high level of endemic antibiotic resistance. Some Enterococci are intrinsically resistant to β-lactam-based antibiotics (some penicillins and virtually all cephalosporins) as well as many aminoglycosides. In the last two decades, particularly virulent strains of Enterococcus which are resistant to vancomycin (Vancomycin-resistant enterococcus, or VRE) have emerged in nosocomial infections of hospitalized patients especially in the US. Other developed countries such as the UK have been spared this epidemic, and in 2005, Singapore managed to halt an epidemic of VRE. VRE may be treated with Quinupristin/dalfopristin (Synercid) with response rates of approximately 70%.
# Prevention
## Water Quality
- The acceptable level of water contamination is very low, for example in the state of Hawaii, with among the strictest tolerances in the United States, the limit for water off its beaches is 7 colony forming units per 100 ml of water, above which the state may post warnings to stay out of the ocean.
- In 2004, Enterococcus spp. took the place of fecal coliform as the new federal standard for water quality at public beaches. It is believed to provide a higher correlation than fecal coliform with many of the human pathogens often found in sewage.
# Gallery
- Scanning Electron Micrograph of Enterococcus species. From Public Health Image Library (PHIL).
- SEM depicts Gram-positiveEnterococcus sp. bacteria From Public Health Image Library (PHIL).
- SEM of Enterococcus species. From Public Health Image Library (PHIL).
- Enterococcus species From Public Health Image Library (PHIL).
- Enterococcus sp. bacteria. From Public Health Image Library (PHIL).
- Photomicrograph reveals cocci-shaped Enterococcus sp. bacteria taken from a pneumonia patient. From Public Health Image Library (PHIL).
- SEM depicts Gram-positive Enterococcus sp. bacteria. From Public Health Image Library (PHIL).
- 3D computer-generated image of a cluster of paired, or diplococcal vancomycin-resistant Enterococcus (VRE) bacteria. From Public Health Image Library (PHIL). | Enterococcus
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Enterococcus is a genus of lactic acid bacteria of the phylum Firmicutes. Members of this genus were classified as Group D Streptococcus until 1984 when genomic DNA analysis indicated that a separate genus classification was appropriate.[1] Important clinical infections caused by Enterococcus include urinary tract infections, bacteremia, bacterial endocarditis, diverticulitis, and meningitis.[2] Sensitive strains of these bacteria can be treated with ampicillin and vancomycin.[3] However, the most important feature of this genus is their high level of endemic antibiotic resistance.
# Microbiology
Enterococcus is a genus of lactic acid bacteria of the phylum Firmicutes. Members of this genus were classified as Group D Streptococcus until 1984 when genomic DNA analysis indicated that a separate genus classification was appropriate.[4] Enterococci are Gram-positive cocci which often occur in pairs (diplococci) and are difficult to distinguish from Streptococci on physical characteristics alone. Two species are common commensal organisms in the intestines of humans: E. faecalis (90-95%) and E. faecium (5-10%). Enterococci are facultative anaerobic organisms, i.e. they prefer the use of oxygen, but they can survive in the absence of oxygen.[5] They typically exhibit gamma-hemolysis on sheep's blood agar.
# Clinical Infections
- Bacteremia
- Bacterial endocarditis
- Diverticulitis
- Meningitis[2]
Enterococcal meningitis is a rare complication of neurosurgery. It often requires treatment with intravenous vancomycin; intrathecal vancomycin is often used and it is debatable whether this has any impact on outcome. The removal of any neurological devices is a crucial part of the management of these infections.[6]
- Enterococcal meningitis is a rare complication of neurosurgery. It often requires treatment with intravenous vancomycin; intrathecal vancomycin is often used and it is debatable whether this has any impact on outcome. The removal of any neurological devices is a crucial part of the management of these infections.[6]
- Urinary tract infection
# Treatment
- Sensitive strains of these bacteria can be treated with ampicillin and vancomycin.[3]
- From a medical standpoint, the most important feature of this genus is their high level of endemic antibiotic resistance. Some Enterococci are intrinsically resistant to β-lactam-based antibiotics (some penicillins and virtually all cephalosporins) as well as many aminoglycosides.[2] In the last two decades, particularly virulent strains of Enterococcus which are resistant to vancomycin (Vancomycin-resistant enterococcus, or VRE) have emerged in nosocomial infections of hospitalized patients especially in the US. Other developed countries such as the UK have been spared this epidemic, and in 2005, Singapore managed to halt an epidemic of VRE. VRE may be treated with Quinupristin/dalfopristin (Synercid) with response rates of approximately 70%.[7]
# Prevention
## Water Quality
- The acceptable level of water contamination is very low, for example in the state of Hawaii, with among the strictest tolerances in the United States, the limit for water off its beaches is 7 colony forming units per 100 ml of water, above which the state may post warnings to stay out of the ocean.[8]
- In 2004, Enterococcus spp. took the place of fecal coliform as the new federal standard for water quality at public beaches. It is believed to provide a higher correlation than fecal coliform with many of the human pathogens often found in sewage.[9]
# Gallery
- Scanning Electron Micrograph of Enterococcus species. From Public Health Image Library (PHIL). [10]
- SEM depicts Gram-positiveEnterococcus sp. bacteria From Public Health Image Library (PHIL). [10]
- SEM of Enterococcus species. From Public Health Image Library (PHIL). [10]
- Enterococcus species From Public Health Image Library (PHIL). [10]
- Enterococcus sp. bacteria. From Public Health Image Library (PHIL). [10]
- Photomicrograph reveals cocci-shaped Enterococcus sp. bacteria taken from a pneumonia patient. From Public Health Image Library (PHIL). [10]
- SEM depicts Gram-positive Enterococcus sp. bacteria. From Public Health Image Library (PHIL). [10]
- 3D computer-generated image of a cluster of paired, or diplococcal vancomycin-resistant Enterococcus (VRE) bacteria. From Public Health Image Library (PHIL). [10] | https://www.wikidoc.org/index.php/Enterococcal_Infection | |
f4af6b19d7122364207309677baf7d84c7f630a5 | wikidoc | Enzalutamide | Enzalutamide
# 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
Enzalutamide is an antineoplastic agent that is FDA approved for the treatment of patients with metastatic castration-resistant prostate cancer (CRPC). Common adverse reactions include asthenia/fatigue, back pain, decreased appetite, constipation, arthralgia, diarrhea, hot flush, upper respiratory tract infection, peripheral edema, dyspnea, musculoskeletal pain, weight decreased(Weight Loss), headache, hypertension, and dizziness/vertigo..
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
Enzalutamide is indicated for the treatment of patients with metastatic castration-resistant prostate cancer (CRPC)
- The recommended dose of Enzalutamide is 160 mg (four 40 mg capsules) administered orally once daily. Enzalutamide can be taken with or without food. Swallow capsules whole. Do not chew, dissolve, or open the capsules.
- If a patient experiences a ≥ Grade 3 toxicity or an intolerable side effect, withhold dosing for one week or until symptoms improve to ≤ Grade 2, then resume at the same or a reduced dose (120 mg or 80 mg), if warranted.
- The concomitant use of strong CYP2C8 inhibitors should be avoided if possible. If patients must be co-administered a strong CYP2C8 inhibitor, reduce the Enzalutamide dose to 80 mg once daily. If co-administration of the strong inhibitor is discontinued, the Enzalutamide dose should be returned to the dose used prior to initiation of the strong CYP2C8 inhibitor
## Off-Label Use and Dosage (Adult)
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
Safety and effectiveness of Enzalutamide in pediatric patients have not been established.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
Safety and effectiveness of Enzalutamide in pediatric patients have not been established.
### Non–Guideline-Supported Use
Safety and effectiveness of Enzalutamide in pediatric patients have not been established.
# Contraindications
- Enzalutamide can cause fetal harm when administered to a pregnant woman based on its mechanism of action and findings in animals. Enzalutamide is not indicated for use in women. Enzalutamide is contraindicated in women who are or may become pregnant. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to the fetus and the potential risk for pregnancy loss
# Warnings
- In Study 1, which enrolled patients who previously received docetaxel, 7 of 800 (0.9%) patients treated with Enzalutamide experienced a seizure and no patients treated with placebo experienced a seizure. Seizure occurred from 31 to 603 days after initiation of Enzalutamide . In Study 2, 1 of 871 (0.1%) chemotherapy-naive patients treated with Enzalutamide and 1 of 844 (0.1%) patients treated with placebo experienced a seizure. Patients experiencing seizure were permanently discontinued from therapy and all seizure events resolved. There is no clinical trial experience re-administering Enzalutamide to patients who experienced seizure.
- Limited safety data are available in patients with predisposing factors for seizure because these patients were generally excluded from the trials. These exclusion criteria included a history of seizure, underlying brain injury with loss of consciousness, transient ischemic attack within the past 12 months, cerebral vascular accident, brain metastases, and brain arteriovenous malformation. Study 1 excluded the use of concomitant medications that may lower the seizure threshold, whereas Study 2 permitted the use of these medications.
- Because of the risk of seizure associated with Enzalutamide use, patients should be advised of the risk of engaging in any activity where sudden loss of consciousness could cause serious harm to themselves or others. Permanently discontinue Enzalutamide in patients who develop a seizure during treatment.
# 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.
- Two randomized clinical trials enrolled patients with metastatic prostate cancer that has progressed on androgen deprivation therapy (GnRH therapy or bilateral orchiectomy), a disease setting that is also defined as metastatic CRPC. In both studies, patients received Enzalutamide 160 mg orally once daily in the active treatment arm or placebo in the control arm. All patients continued androgen deprivation therapy. Patients were allowed, but not required, to take glucocorticoids.
- The most common adverse reactions (≥ 10%) that occurred more commonly (≥ 2% over placebo) in the Enzalutamide -treated patients from the two randomized clinical trials were asthenia/fatigue, back pain, decreased appetite, constipation, arthralgia, diarrhea, hot flush, upper respiratory tract infection, peripheral edema, dyspnea, musculoskeletal pain, weight decreased(Weight Loss), headache, hypertension, and dizziness/vertigo.
- Study 1 enrolled 1199 patients with metastatic CRPC who had previously received docetaxel. The median duration of treatment was 8.3 months with Enzalutamide and 3.0 months with placebo. During the trial, 48% of patients on the Enzalutamide arm and 46% of patients on the placebo arm received glucocorticoids.
- Grade 3 and higher adverse reactions were reported among 47% of Enzalutamide -treated patients and 53% of placebo-treated patients. Discontinuations due to adverse events were reported for 16% of Enzalutamide -treated patients and 18% of placebo-treated patients. The most common adverse reaction leading to treatment discontinuation was seizure, which occurred in 0.9% of the Enzalutamide -treated patients compared to none (0%) of the placebo-treated patients. TABLE 1 shows adverse reactions reported in Study 1 that occurred at a ≥ 2% higher frequency in the Enzalutamide arm compared to the placebo arm.
- Study 2 enrolled 1717 patients with metastatic CRPC who had not received prior cytotoxic chemotherapy, of whom 1715 received at least one dose of study drug. The median duration of treatment was 17.5 months with Enzalutamide and 4.6 months with placebo. Grade 3-4 adverse reactions were reported in 44% of Enzalutamide -treated patients and 37% of placebo-treated patients. Discontinuations due to adverse events were reported for 6% of Enzalutamide -treated patients and 6% of placebo-treated patients. The most common adverse reaction leading to treatment discontinuation was fatigue/asthenia, which occurred in 1% of patients on each treatment arm. TABLE 2 includes adverse reactions reported in Study 2 that occurred at a ≥ 2% higher frequency in the Enzalutamide arm compared to the placebo arm.
- In the two randomized clinical trials, Grade 1-4 neutropenia occurred in 15% of patients treated with Enzalutamide (1% Grade 3-4) and in 6% of patients treated with placebo (0.5% Grade 3-4). The incidence of Grade 1-4 thrombocytopenia was 6% of patients treated with Enzalutamide (0.3% Grade 3-4) and 5% of patients treated with placebo (0.5% Grade 3-4). Grade 1-4 elevations in ALT occurred in 10% of patients treated with Enzalutamide (0.2% Grade 3-4) and 16% of patients treated with placebo (0.2% Grade 3-4). Grade 1-4 elevations in bilirubin occurred in 3% of patients treated with Enzalutamide (0.1% Grade 3-4) and 2% of patients treated with placebo (no Grade 3-4).
- In Study 1, 1% of patients treated with Enzalutamide compared to 0.3% of patients treated with placebo died from infections or sepsis. In Study 2, 1 patient in each treatment group (0.1%) had an infection resulting in death.
- In the two randomized clinical trials, falls including fall-related injuries, occurred in 9% of patients treated with Enzalutamide compared to 4% of patients treated with placebo. Falls were not associated with loss of consciousness or seizure. Fall-related injuries were more severe in patients treated with Enzalutamide and included non-pathologic fractures, joint injuries, and hematomas.
- In the two randomized trials, hypertension was reported in 11% of patients receiving Enzalutamide and 4% of patients receiving placebo. No patients experienced hypertensive crisis. Medical history of hypertension was balanced between arms. Hypertension led to study discontinuation in < 1% of patients in each arm.
## Postmarketing Experience
There is limited information regarding Postmarketing Experience of Enzalutamide in the drug label.
# Drug Interactions
- Co-administration of a strong CYP2C8 inhibitor (gemfibrozil) increased the composite area under the plasma concentration-time curve (AUC) of enzalutamide plus N-desmethyl enzalutamide by 2.2-fold in healthy volunteers. Co‑administration of Enzalutamide with strong CYP2C8 inhibitors should be avoided if possible. If co-administration of Enzalutamide with a strong CYP2C8 inhibitor cannot be avoided, reduce the dose of Enzalutamide
- The effects of CYP2C8 inducers on the pharmacokinetics of enzalutamide have not been evaluated in vivo. Co-administration of Enzalutamide with strong or moderate CYP2C8 inducers (e.g., rifampin) may alter the plasma exposure of Enzalutamide and should be avoided if possible. Selection of a concomitant medication with no or minimal CYP2C8 induction potential is recommended .
- Co-administration of a strong CYP3A4 inhibitor (itraconazole) increased the composite AUC of enzalutamide plus N-desmethyl enzalutamide by 1.3-fold in healthy volunteers.
- The effects of CYP3A4 inducers on the pharmacokinetics of enzalutamide have not been evaluated in vivo. Co-administration of Enzalutamide with strong CYP3A4 inducers (e.g., carbamazepine, phenobarbital, phenytoin, rifabutin, rifampin, rifapentine) may decrease the plasma exposure of Enzalutamide and should be avoided if possible. Selection of a concomitant medication with no or minimal CYP3A4 induction potential is recommended. Moderate CYP3A4 inducers (e.g., bosentan, efavirenz, etravirine, modafinil, nafcillin) and St. John’s Wort may also reduce the plasma exposure of Enzalutamide and should be avoided if possible .
- Enzalutamide is a strong CYP3A4 inducer and a moderate CYP2C9 and CYP2C19 inducer in humans. At steady state, Enzalutamide reduced the plasma exposure to midazolam (CYP3A4 substrate), warfarin (CYP2C9 substrate), and omeprazole (CYP2C19 substrate). Concomitant use of Enzalutamide with narrow therapeutic index drugs that are metabolized by CYP3A4 (e.g., alfentanil, cyclosporine, dihydroergotamine, ergotamine, fentanyl, pimozide, quinidine, sirolimus and tacrolimus), CYP2C9 (e.g., phenytoin, warfarin) and CYP2C19 (e.g., S-mephenytoin) should be avoided, as enzalutamide may decrease their exposure. If co-administration with warfarin cannot be avoided, conduct additional INR monitoring Effect of Enzalutamide on Drug Metabolizing Enzymes
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): X
- Enzalutamide can cause fetal harm when administered to a pregnant woman based on its mechanism of action and findings in animals. While there are no human data on the use of Enzalutamide in pregnancy and Enzalutamide is not indicated for use in women, it is important to know that maternal use of an androgen receptor inhibitor could affect development of the fetus. Enzalutamide caused embryo-fetal toxicity in mice at exposures that were lower than in patients receiving the recommended dose. Enzalutamide is contraindicated in women who are or may become pregnant while receiving the drug. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to the fetus and the potential risk for pregnancy loss. Advise females of reproductive potential to avoid becoming pregnant during treatment with Enzalutamide .
- In an embryo-fetal developmental toxicity study in mice, enzalutamide caused developmental toxicity when administered at oral doses of 10 or 30 mg/kg/day throughout the period of organogenesis (gestational days 6-15). Findings included embryo-fetal lethality (increased post-implantation loss and resorptions) and decreased anogenital distance at ≥ 10 mg/kg/day, and cleft palate and absent palatine bone at 30 mg/kg/day. Doses of 30 mg/kg/day caused maternal toxicity. The doses tested in mice (1, 10 and 30 mg/kg/day) resulted in systemic exposures (AUC) approximately 0.04, 0.4 and 1.1 times, respectively, the exposures in patients. Enzalutamide did not cause developmental toxicity in rabbits when administered throughout the period of organogenesis (gestational days 6-18) at dose levels up to 10 mg/kg/day (approximately 0.4 times the exposures in patients based on AUC).
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Enzalutamide in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Enzalutamide during labor and delivery.
### Nursing Mothers
- Enzalutamide is not indicated for use in women. It is not known if enzalutamide is excreted in human milk. Because many drugs are excreted in human milk, and because of the potential for serious adverse reactions in nursing infants from Enzalutamide , a decision should be made to either discontinue nursing, or discontinue the drug taking into account the importance of the drug to the mother.
### Pediatric Use
- Safety and effectiveness of Enzalutamide in pediatric patients have not been established.
### Geriatic Use
- Of 1671 patients who received Enzalutamide in the two randomized clinical trials, 75% were 65 and over, while 31% were 75 and over. No overall differences in safety or effectiveness were observed between these patients and younger patients. 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 Enzalutamide with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Enzalutamide with respect to specific racial populations.
### Renal Impairment
- A dedicated renal impairment trial for Enzalutamide has not been conducted. Based on the population pharmacokinetic analysis using data from clinical trials in patients with metastatic CRPC and healthy volunteers, no significant difference in enzalutamide clearance was observed in patients with pre-existing mild to moderate renal impairment (30 mL/min ≤ creatinine clearance ≤ 89 mL/min) compared to patients and volunteers with baseline normal renal function (CrCL ≥ 90 mL/min). No initial dosage adjustment is necessary for patients with mild to moderate renal impairment. Severe renal impairment (CrCL < 30 mL/min) and end-stage renal disease have not been assessed
### Hepatic Impairment
- A dedicated hepatic impairment trial compared the composite systemic exposure of enzalutamide plus N-desmethyl enzalutamide in volunteers with baseline mild or moderate hepatic impairment (Child-Pugh Class A and B, respectively) versus healthy controls with normal hepatic function. The composite AUC of enzalutamide plus N-desmethyl enzalutamide was similar in volunteers with mild or moderate baseline hepatic impairment compared to volunteers with normal hepatic function. No initial dosage adjustment is necessary for patients with baseline mild or moderate hepatic impairment. Baseline severe hepatic impairment (Child-Pugh Class C) has not been assessed
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Enzalutamide in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Enzalutamide in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Oral
### Monitoring
- If co-administration with warfarin cannot be avoided, conduct additional INR monitoring
# IV Compatibility
There is limited information regarding IV Compatibility of Enzalutamide in the drug label.
# Overdosage
- In the event of an overdose, stop treatment with Enzalutamide and initiate general supportive measures taking into consideration the half-life of 5.8 days. In a dose escalation study, no seizures were reported at < 240 mg daily, whereas 3 seizures were reported, 1 each at 360 mg, 480 mg, and 600 mg daily. Patients may be at increased risk of seizure following an overdose.
# Pharmacology
## Mechanism of Action
- Enzalutamide is an androgen receptor inhibitor that acts on different steps in the androgen receptor signaling pathway. Enzalutamide has been shown to competitively inhibit androgen binding to androgen receptors and inhibit androgen receptor nuclear translocation and interaction with DNA. A major metabolite, N-desmethyl enzalutamide, exhibited similar in vitro activity to enzalutamide. Enzalutamide decreased proliferation and induced cell death of prostate cancer cells in vitro, and decreased tumor volume in a mouse prostate cancer xenograft model.
## Structure
- Enzalutamide is an androgen receptor inhibitor. The chemical name is 4-{3--5,5-dimethyl-4-oxo-2-sulfanylideneimidazolidin-1-yl}-2-fluoro-N-methylbenzamide.
- The molecular weight is 464.44 and molecular formula is C21H16F4N4O2S. The structural formula is:
- Enzalutamide is a white crystalline non-hygroscopic solid. It is practically insoluble in water.
- Enzalutamide is provided as liquid-filled soft gelatin capsules for oral administration. Each capsule contains 40 mg of enzalutamide as a solution in caprylocaproyl polyoxylglycerides. The inactive ingredients are caprylocaproyl polyoxylglycerides, butylated hydroxyanisole, butylated hydroxytoluene, gelatin, sorbitol sorbitan solution, glycerin, purified water, titanium dioxide, and black iron oxide.
## Pharmacodynamics
There is limited information regarding Pharmacodynamics of Enzalutamide in the drug label.
## Pharmacokinetics
- The pharmacokinetics of enzalutamide and its major active metabolite (N-desmethyl enzalutamide) were evaluated in patients with metastatic CRPC and healthy male volunteers. The plasma enzalutamide pharmacokinetics are adequately described by a linear two-compartment model with first-order absorption.
- Following oral administration (Enzalutamide 160 mg daily) in patients with metastatic castration-resistant prostate cancer, the median time to reach maximum plasma enzalutamide concentrations (Cmax) is 1 hour (range 0.5 to 3 hours). At steady state, the plasma mean Cmax values for enzalutamide and N-desmethyl enzalutamide are 16.6 μg/mL (23% CV) and 12.7 μg/mL (30% CV), respectively, and the plasma mean predose trough values are 11.4 μg/mL (26% CV) and 13.0 μg/mL (30% CV), respectively.
- With the daily dosing regimen, enzalutamide steady state is achieved by Day 28, and enzalutamide accumulates approximately 8.3-fold relative to a single dose. Daily fluctuations in enzalutamide plasma concentrations are low (mean peak-to-trough ratio of 1.25). At steady state, enzalutamide showed approximately dose proportional pharmacokinetics over the daily dose range of 30 to 360 mg.
- A single 160 mg oral dose of Enzalutamide was administered to healthy volunteers with a high-fat meal or in the fasted condition. A high-fat meal did not alter the AUC to enzalutamide or N-desmethyl enzalutamide. The results are summarized in Figure 1.
- The mean apparent volume of distribution (V/F) of enzalutamide in patients after a single oral dose is 110 L (29% CV).
- Enzalutamide is 97% to 98% bound to plasma proteins, primarily albumin. N-desmethyl enzalutamide is 95% bound to plasma proteins. In vitro, there was no protein binding displacement between enzalutamide and other highly protein bound drugs (warfarin, ibuprofen, and salicylic acid) at clinically relevant concentrations.
- Following single oral administration of 14C-enzalutamide 160 mg, plasma samples were analyzed for enzalutamide and its metabolites up to 77 days post dose. Enzalutamide, N-desmethyl enzalutamide, and a major inactive carboxylic acid metabolite accounted for 88% of the 14C-radioactivity in plasma, representing 30%, 49%, and 10%, respectively, of the total 14C-AUC0-inf.
- In vitro, human CYP2C8 and CYP3A4 are responsible for the metabolism of enzalutamide. Based on in vivo and in vitro data, CYP2C8 is primarily responsible for the formation of the active metabolite (N-desmethyl enzalutamide).
- In vitro, N-desmethyl enzalutamide is not a substrate of human CYP1A1, CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C18, CYP2C19, CYP2D6, CYP2E1 and CYP3A4/5.
- Enzalutamide is primarily eliminated by hepatic metabolism. Following single oral administration of14C-enzalutamide 160 mg, 85% of the radioactivity is recovered by 77 days post dose: 71% is recovered in urine (including only trace amounts of enzalutamide and N-desmethyl enzalutamide), and 14% is recovered in feces (0.4% of dose as unchanged enzalutamide and 1% as N-desmethyl enzalutamide).
- The mean apparent clearance (CL/F) of enzalutamide in patients after a single oral dose is 0.56 L/h (range 0.33 to 1.02 L/h).
- The mean terminal half-life (t1/2) for enzalutamide in patients after a single oral dose is 5.8 days (range 2.8 to 10.2 days). Following a single 160 mg oral dose of enzalutamide in healthy volunteers, the mean terminal t1/2 for N-desmethyl enzalutamide is approximately 7.8 to 8.6 days.
### Pharmacokinetics in Special Populations
- A population pharmacokinetic analysis (based on pre-existing renal function) was carried out with data from 59 healthy male volunteers and 926 patients with metastatic CRPC enrolled in clinical trials, including 512 with normal renal function (CrCL ≥ 90 mL/min), 332 with mild renal impairment (CrCL 60 to < 90 mL/min), 88 with moderate renal impairment (CrCL 30 to < 60 mL/min), and 1 with severe renal impairment (CrCL < 30 mL/min). The apparent clearance of enzalutamide was similar in patients with pre-existing mild and moderate renal impairment (CrCL 30 to < 90 mL/min) compared to patients and volunteers with normal renal function. The potential effect of severe renal impairment or end stage renal disease on enzalutamide pharmacokinetics cannot be determined as clinical and pharmacokinetic data are available from only one patient
- The plasma pharmacokinetics of enzalutamide and N-desmethyl enzalutamide were examined in volunteers with normal hepatic function (N = 16) and with pre-existing mild (N = 8, Child-Pugh Class A) or moderate (N = 8, Child-Pugh B) hepatic impairment. Enzalutamide was administered as a single 160 mg dose. The composite AUC of enzalutamide plus N-desmethyl enzalutamide was similar in volunteers with mild or moderate baseline hepatic impairment compared to volunteers with normal hepatic function. The results are summarized in Figure 1. Clinical and pharmacokinetic data are not available for patients with severe hepatic impairment (Child-Pugh Class
## Nonclinical Toxicology
- Long-term animal studies have not been conducted to evaluate the carcinogenic potential of enzalutamide.
- Enzalutamide did not induce mutations in the bacterial reverse mutation (Ames) assay and was not genotoxic in either the in vitro mouse lymphoma thymidine kinase (Tk) gene mutation assay or the in vivo mouse micronucleus assay.
- Based on nonclinical findings in repeat-dose toxicology studies, which were consistent with the pharmacological activity of enzalutamide, male fertility may be impaired by treatment with Enzalutamide . In a 26-week study in rats, atrophy of the prostate and seminal vesicles was observed at ≥ 30 mg/kg/day (equal to the human exposure based on AUC). In 4-, 13-, and 39-week studies in dogs, hypospermatogenesis and atrophy of the prostate and epididymides were observed at ≥ 4 mg/kg/day (0.3 times the human exposure based on AUC).
# Clinical Studies
- The efficacy and safety of Enzalutamide in patients with metastatic CRPC were demonstrated in two randomized, placebo-controlled, multicenter phase 3 clinical trials. All patients continued on GnRH therapy or had prior bilateral orchitectomy. Patients were allowed, but not required, to continue or initiate glucocorticoids.
- A total of 1199 patients who had received prior docetaxel-based chemotherapy were randomized 2:1 to receive either Enzalutamide orally at a dose of 160 mg once daily (N=800) or placebo orally once daily (N=399). Study treatment continued until disease progression (evidence of radiographic progression, a skeletal-related event, or clinical progression), initiation of new systemic antineoplastic treatment, unacceptable toxicity, or withdrawal. Patients with a previous history of seizure, taking medicines known to decrease the seizure threshold, or with other risk factors for seizure were not eligible.
- The following patient demographics and baseline disease characteristics were balanced between the treatment arms. The median age was 69 years (range 41-92) and the racial distribution was 92.7% Caucasian, 3.9% Black, 1.1% Asian, and 2.1% Other. Ninety-two percent of patients had an ECOG performance status score of 0-1 and 28% had a mean Brief Pain Inventory score of ≥ 4. Ninety-one percent of patients had metastases in bone and 23% had visceral involvement in the lung and/or liver. Fifty-nine percent of patients had radiographic evidence of disease progression and 41% had PSA-only progression on study entry. All patients had received prior docetaxel-based therapy and 24% had received two cytotoxic chemotherapy regimens. During the trial, 48% of patients on the Enzalutamide arm and 46% of patients on the placebo arm received glucocorticoids.
- A statistically significant improvement in overall survival was demonstrated at the pre-specified interim analysis at the time of 520 deaths in patients on the Enzalutamide arm compared to patients on the placebo arm (TABLE 3 and Figure 3).
- In Study 2, 1717 chemotherapy-naive patients were randomized 1:1 to receive either Enzalutamide orally at a dose of 160 mg once daily (N=872) or placebo orally once daily (N=845). Patients with visceral metastases, patients with a history of mild to moderate heart failure (NYHA class I or II), and patients taking medications associated with lowering the seizure threshold were allowed. Patients with a previous history of seizure or a condition that might predispose to seizure and patients with moderate or severe pain from prostate cancer were excluded. Study treatment continued until disease progression (evidence of radiographic progression, a skeletal-related event, or clinical progression) and the initiation of a cytotoxic chemotherapy or an investigational agent, unacceptable toxicity, or withdrawal. Overall survival and radiographic progression-free survival (rPFS) were assessed. Radiographic progression was assessed with the use of sequential imaging and was defined by bone scan identification of 2 or more new bone lesions with confirmation (Prostate Cancer Clinical Trials Working Group 2 criteria) and/or Response Evaluation Criteria in Solid Tumors (RECIST v 1.1) criteria for progression of soft tissue lesions. The primary analysis of rPFS utilized centrally reviewed radiographic assessment of progression.
- Patient demographics and baseline disease characteristics were balanced between the treatment arms at entry. The median age was 71 years (range 42-93) and the racial distribution was 77% Caucasian, 10% Asian, 2% Black and 11% Other. The ECOG performance status score was 0 for 68% of patients, and 1 for 32% of patients. Baseline pain assessment was 0-1 (asymptomatic) in 67% of patients, and 2-3 (mildly symptomatic) in 32% of patients as defined by the Brief Pain Inventory Short Form (worst pain over past 24 hours at study entry). Fifty-four percent of patients had radiographic evidence of disease progression and 43% had PSA-only progression. Twelve percent of patients had visceral (lung and/or liver) disease involvement. During the study, 27% of patients on the Enzalutamide arm and 30% of patients on the placebo arm received glucocorticoids for varying reasons.
- A statistically significant improvement in overall survival was demonstrated at the pre-specified interim analysis, conducted after 540 deaths in patients treated with Enzalutamide compared to those treated with placebo (TABLE 4, Figure 4). Forty percent of Enzalutamide -treated and 70% of placebo-treated patients received subsequent therapies for metastatic CRPC that may prolong overall survival.
- Time to initiation of cytotoxic chemotherapy was prolonged after Enzalutamide treatment, with a median of 28.0 months for patients on the Enzalutamide arm versus a median of 10.8 months for patients on the placebo arm .
- The median time to first skeletal‑related event was 31.1 months for patients on the Enzalutamide arm versus 31.3 months for patients on the placebo arm . A skeletal‑related event was defined as radiation therapy or surgery to bone for prostate cancer, pathologic bone fracture, spinal cord compression, or change of antineoplastic therapy to treat bone pain.
There is limited information regarding Clinical Studies of Enzalutamide in the drug label.
# How Supplied
- Enzalutamide (enzalutamide) 40 mg capsules are supplied as white to off-white oblong soft gelatin capsules imprinted in black ink with ENZ. Enzalutamide capsules are available in the following package sizes:
- Bottles of 120 capsules (NDC 0469-0125-99)
## Storage
- Recommended storage: Store Enzalutamide capsules at 20°C to 25°C (68°F to 77°F) in a dry place and keep the container tightly closed. Excursions permitted from 15°C to 30°C (59°F to 86°F).
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- Instruct patients to take their dose at the same time each day (once daily). Enzalutamide can be taken with or without food. Each capsule should be swallowed whole. Do not chew, dissolve, or open the capsules.*Inform patients receiving GnRH therapy that they need to maintain this treatment during the course of treatment with Enzalutamide .
- Inform patients that Enzalutamide 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 physician right away if they have loss of consciousness or seizure.
- Inform patients that they should not interrupt, modify the dose, or stop Enzalutamide without first consulting their physician. Inform patients that if they miss a dose, then they should take it as soon as they remember. If they forget to take the dose for the whole day, then they should take their normal dose the next day. They should not take more than their prescribed dose per day.
- Apprise patients of the most common side effects associated with Enzalutamide : asthenia/fatigue, back pain, decreased appetite, constipation, arthralgia, diarrhea, hot flush, upper respiratory tract infection, peripheral edema, dyspnea, musculoskeletal pain, weight decreased, headache, hypertension, and dizziness/vertigo. Direct the patient to a complete list of adverse drug reactions.
- Inform patients that Enzalutamide may cause infections, falls and fall-related injuries, and hypertension.
- Inform patients that Enzalutamide can be harmful to a developing fetus. Patients should also be informed that they should use a condom if having sex with a pregnant woman. A condom and another effective method of birth control should be used if the patient is having sex with a woman of child-bearing potential. These measures are required during and for three months after treatment with Enzalutamide .
# Precautions with Alcohol
- Alcohol-Enzalutamide interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Xtandi®
# Look-Alike Drug Names
- A® — B®
# Drug Shortage Status
# Price | Enzalutamide
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Aparna Vuppala, M.B.B.S. [2]
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# Overview
Enzalutamide is an antineoplastic agent that is FDA approved for the treatment of patients with metastatic castration-resistant prostate cancer (CRPC). Common adverse reactions include asthenia/fatigue, back pain, decreased appetite, constipation, arthralgia, diarrhea, hot flush, upper respiratory tract infection, peripheral edema, dyspnea, musculoskeletal pain, weight decreased(Weight Loss), headache, hypertension, and dizziness/vertigo..
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
Enzalutamide is indicated for the treatment of patients with metastatic castration-resistant prostate cancer (CRPC)
- The recommended dose of Enzalutamide is 160 mg (four 40 mg capsules) administered orally once daily. Enzalutamide can be taken with or without food. Swallow capsules whole. Do not chew, dissolve, or open the capsules.
- If a patient experiences a ≥ Grade 3 toxicity or an intolerable side effect, withhold dosing for one week or until symptoms improve to ≤ Grade 2, then resume at the same or a reduced dose (120 mg or 80 mg), if warranted.
- The concomitant use of strong CYP2C8 inhibitors should be avoided if possible. If patients must be co-administered a strong CYP2C8 inhibitor, reduce the Enzalutamide dose to 80 mg once daily. If co-administration of the strong inhibitor is discontinued, the Enzalutamide dose should be returned to the dose used prior to initiation of the strong CYP2C8 inhibitor
## Off-Label Use and Dosage (Adult)
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
Safety and effectiveness of Enzalutamide in pediatric patients have not been established.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
Safety and effectiveness of Enzalutamide in pediatric patients have not been established.
### Non–Guideline-Supported Use
Safety and effectiveness of Enzalutamide in pediatric patients have not been established.
# Contraindications
- Enzalutamide can cause fetal harm when administered to a pregnant woman based on its mechanism of action and findings in animals. Enzalutamide is not indicated for use in women. Enzalutamide is contraindicated in women who are or may become pregnant. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to the fetus and the potential risk for pregnancy loss
# Warnings
- In Study 1, which enrolled patients who previously received docetaxel, 7 of 800 (0.9%) patients treated with Enzalutamide experienced a seizure and no patients treated with placebo experienced a seizure. Seizure occurred from 31 to 603 days after initiation of Enzalutamide . In Study 2, 1 of 871 (0.1%) chemotherapy-naive patients treated with Enzalutamide and 1 of 844 (0.1%) patients treated with placebo experienced a seizure. Patients experiencing seizure were permanently discontinued from therapy and all seizure events resolved. There is no clinical trial experience re-administering Enzalutamide to patients who experienced seizure.
- Limited safety data are available in patients with predisposing factors for seizure because these patients were generally excluded from the trials. These exclusion criteria included a history of seizure, underlying brain injury with loss of consciousness, transient ischemic attack within the past 12 months, cerebral vascular accident, brain metastases, and brain arteriovenous malformation. Study 1 excluded the use of concomitant medications that may lower the seizure threshold, whereas Study 2 permitted the use of these medications.
- Because of the risk of seizure associated with Enzalutamide use, patients should be advised of the risk of engaging in any activity where sudden loss of consciousness could cause serious harm to themselves or others. Permanently discontinue Enzalutamide in patients who develop a seizure during treatment.
# 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.
- Two randomized clinical trials enrolled patients with metastatic prostate cancer that has progressed on androgen deprivation therapy (GnRH therapy or bilateral orchiectomy), a disease setting that is also defined as metastatic CRPC. In both studies, patients received Enzalutamide 160 mg orally once daily in the active treatment arm or placebo in the control arm. All patients continued androgen deprivation therapy. Patients were allowed, but not required, to take glucocorticoids.
- The most common adverse reactions (≥ 10%) that occurred more commonly (≥ 2% over placebo) in the Enzalutamide -treated patients from the two randomized clinical trials were asthenia/fatigue, back pain, decreased appetite, constipation, arthralgia, diarrhea, hot flush, upper respiratory tract infection, peripheral edema, dyspnea, musculoskeletal pain, weight decreased(Weight Loss), headache, hypertension, and dizziness/vertigo.
- Study 1 enrolled 1199 patients with metastatic CRPC who had previously received docetaxel. The median duration of treatment was 8.3 months with Enzalutamide and 3.0 months with placebo. During the trial, 48% of patients on the Enzalutamide arm and 46% of patients on the placebo arm received glucocorticoids.
- Grade 3 and higher adverse reactions were reported among 47% of Enzalutamide -treated patients and 53% of placebo-treated patients. Discontinuations due to adverse events were reported for 16% of Enzalutamide -treated patients and 18% of placebo-treated patients. The most common adverse reaction leading to treatment discontinuation was seizure, which occurred in 0.9% of the Enzalutamide -treated patients compared to none (0%) of the placebo-treated patients. TABLE 1 shows adverse reactions reported in Study 1 that occurred at a ≥ 2% higher frequency in the Enzalutamide arm compared to the placebo arm.
- Study 2 enrolled 1717 patients with metastatic CRPC who had not received prior cytotoxic chemotherapy, of whom 1715 received at least one dose of study drug. The median duration of treatment was 17.5 months with Enzalutamide and 4.6 months with placebo. Grade 3-4 adverse reactions were reported in 44% of Enzalutamide -treated patients and 37% of placebo-treated patients. Discontinuations due to adverse events were reported for 6% of Enzalutamide -treated patients and 6% of placebo-treated patients. The most common adverse reaction leading to treatment discontinuation was fatigue/asthenia, which occurred in 1% of patients on each treatment arm. TABLE 2 includes adverse reactions reported in Study 2 that occurred at a ≥ 2% higher frequency in the Enzalutamide arm compared to the placebo arm.
- In the two randomized clinical trials, Grade 1-4 neutropenia occurred in 15% of patients treated with Enzalutamide (1% Grade 3-4) and in 6% of patients treated with placebo (0.5% Grade 3-4). The incidence of Grade 1-4 thrombocytopenia was 6% of patients treated with Enzalutamide (0.3% Grade 3-4) and 5% of patients treated with placebo (0.5% Grade 3-4). Grade 1-4 elevations in ALT occurred in 10% of patients treated with Enzalutamide (0.2% Grade 3-4) and 16% of patients treated with placebo (0.2% Grade 3-4). Grade 1-4 elevations in bilirubin occurred in 3% of patients treated with Enzalutamide (0.1% Grade 3-4) and 2% of patients treated with placebo (no Grade 3-4).
- In Study 1, 1% of patients treated with Enzalutamide compared to 0.3% of patients treated with placebo died from infections or sepsis. In Study 2, 1 patient in each treatment group (0.1%) had an infection resulting in death.
- In the two randomized clinical trials, falls including fall-related injuries, occurred in 9% of patients treated with Enzalutamide compared to 4% of patients treated with placebo. Falls were not associated with loss of consciousness or seizure. Fall-related injuries were more severe in patients treated with Enzalutamide and included non-pathologic fractures, joint injuries, and hematomas.
- In the two randomized trials, hypertension was reported in 11% of patients receiving Enzalutamide and 4% of patients receiving placebo. No patients experienced hypertensive crisis. Medical history of hypertension was balanced between arms. Hypertension led to study discontinuation in < 1% of patients in each arm.
## Postmarketing Experience
There is limited information regarding Postmarketing Experience of Enzalutamide in the drug label.
# Drug Interactions
- Co-administration of a strong CYP2C8 inhibitor (gemfibrozil) increased the composite area under the plasma concentration-time curve (AUC) of enzalutamide plus N-desmethyl enzalutamide by 2.2-fold in healthy volunteers. Co‑administration of Enzalutamide with strong CYP2C8 inhibitors should be avoided if possible. If co-administration of Enzalutamide with a strong CYP2C8 inhibitor cannot be avoided, reduce the dose of Enzalutamide
- The effects of CYP2C8 inducers on the pharmacokinetics of enzalutamide have not been evaluated in vivo. Co-administration of Enzalutamide with strong or moderate CYP2C8 inducers (e.g., rifampin) may alter the plasma exposure of Enzalutamide and should be avoided if possible. Selection of a concomitant medication with no or minimal CYP2C8 induction potential is recommended .
- Co-administration of a strong CYP3A4 inhibitor (itraconazole) increased the composite AUC of enzalutamide plus N-desmethyl enzalutamide by 1.3-fold in healthy volunteers.
- The effects of CYP3A4 inducers on the pharmacokinetics of enzalutamide have not been evaluated in vivo. Co-administration of Enzalutamide with strong CYP3A4 inducers (e.g., carbamazepine, phenobarbital, phenytoin, rifabutin, rifampin, rifapentine) may decrease the plasma exposure of Enzalutamide and should be avoided if possible. Selection of a concomitant medication with no or minimal CYP3A4 induction potential is recommended. Moderate CYP3A4 inducers (e.g., bosentan, efavirenz, etravirine, modafinil, nafcillin) and St. John’s Wort may also reduce the plasma exposure of Enzalutamide and should be avoided if possible .
- Enzalutamide is a strong CYP3A4 inducer and a moderate CYP2C9 and CYP2C19 inducer in humans. At steady state, Enzalutamide reduced the plasma exposure to midazolam (CYP3A4 substrate), warfarin (CYP2C9 substrate), and omeprazole (CYP2C19 substrate). Concomitant use of Enzalutamide with narrow therapeutic index drugs that are metabolized by CYP3A4 (e.g., alfentanil, cyclosporine, dihydroergotamine, ergotamine, fentanyl, pimozide, quinidine, sirolimus and tacrolimus), CYP2C9 (e.g., phenytoin, warfarin) and CYP2C19 (e.g., S-mephenytoin) should be avoided, as enzalutamide may decrease their exposure. If co-administration with warfarin cannot be avoided, conduct additional INR monitoring Effect of Enzalutamide on Drug Metabolizing Enzymes
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): X
- Enzalutamide can cause fetal harm when administered to a pregnant woman based on its mechanism of action and findings in animals. While there are no human data on the use of Enzalutamide in pregnancy and Enzalutamide is not indicated for use in women, it is important to know that maternal use of an androgen receptor inhibitor could affect development of the fetus. Enzalutamide caused embryo-fetal toxicity in mice at exposures that were lower than in patients receiving the recommended dose. Enzalutamide is contraindicated in women who are or may become pregnant while receiving the drug. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to the fetus and the potential risk for pregnancy loss. Advise females of reproductive potential to avoid becoming pregnant during treatment with Enzalutamide .
- In an embryo-fetal developmental toxicity study in mice, enzalutamide caused developmental toxicity when administered at oral doses of 10 or 30 mg/kg/day throughout the period of organogenesis (gestational days 6-15). Findings included embryo-fetal lethality (increased post-implantation loss and resorptions) and decreased anogenital distance at ≥ 10 mg/kg/day, and cleft palate and absent palatine bone at 30 mg/kg/day. Doses of 30 mg/kg/day caused maternal toxicity. The doses tested in mice (1, 10 and 30 mg/kg/day) resulted in systemic exposures (AUC) approximately 0.04, 0.4 and 1.1 times, respectively, the exposures in patients. Enzalutamide did not cause developmental toxicity in rabbits when administered throughout the period of organogenesis (gestational days 6-18) at dose levels up to 10 mg/kg/day (approximately 0.4 times the exposures in patients based on AUC).
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Enzalutamide in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Enzalutamide during labor and delivery.
### Nursing Mothers
- Enzalutamide is not indicated for use in women. It is not known if enzalutamide is excreted in human milk. Because many drugs are excreted in human milk, and because of the potential for serious adverse reactions in nursing infants from Enzalutamide , a decision should be made to either discontinue nursing, or discontinue the drug taking into account the importance of the drug to the mother.
### Pediatric Use
- Safety and effectiveness of Enzalutamide in pediatric patients have not been established.
### Geriatic Use
- Of 1671 patients who received Enzalutamide in the two randomized clinical trials, 75% were 65 and over, while 31% were 75 and over. No overall differences in safety or effectiveness were observed between these patients and younger patients. 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 Enzalutamide with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Enzalutamide with respect to specific racial populations.
### Renal Impairment
- A dedicated renal impairment trial for Enzalutamide has not been conducted. Based on the population pharmacokinetic analysis using data from clinical trials in patients with metastatic CRPC and healthy volunteers, no significant difference in enzalutamide clearance was observed in patients with pre-existing mild to moderate renal impairment (30 mL/min ≤ creatinine clearance [CrCL] ≤ 89 mL/min) compared to patients and volunteers with baseline normal renal function (CrCL ≥ 90 mL/min). No initial dosage adjustment is necessary for patients with mild to moderate renal impairment. Severe renal impairment (CrCL < 30 mL/min) and end-stage renal disease have not been assessed
### Hepatic Impairment
- A dedicated hepatic impairment trial compared the composite systemic exposure of enzalutamide plus N-desmethyl enzalutamide in volunteers with baseline mild or moderate hepatic impairment (Child-Pugh Class A and B, respectively) versus healthy controls with normal hepatic function. The composite AUC of enzalutamide plus N-desmethyl enzalutamide was similar in volunteers with mild or moderate baseline hepatic impairment compared to volunteers with normal hepatic function. No initial dosage adjustment is necessary for patients with baseline mild or moderate hepatic impairment. Baseline severe hepatic impairment (Child-Pugh Class C) has not been assessed
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Enzalutamide in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Enzalutamide in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Oral
### Monitoring
- If co-administration with warfarin cannot be avoided, conduct additional INR monitoring
# IV Compatibility
There is limited information regarding IV Compatibility of Enzalutamide in the drug label.
# Overdosage
- In the event of an overdose, stop treatment with Enzalutamide and initiate general supportive measures taking into consideration the half-life of 5.8 days. In a dose escalation study, no seizures were reported at < 240 mg daily, whereas 3 seizures were reported, 1 each at 360 mg, 480 mg, and 600 mg daily. Patients may be at increased risk of seizure following an overdose.
# Pharmacology
## Mechanism of Action
- Enzalutamide is an androgen receptor inhibitor that acts on different steps in the androgen receptor signaling pathway. Enzalutamide has been shown to competitively inhibit androgen binding to androgen receptors and inhibit androgen receptor nuclear translocation and interaction with DNA. A major metabolite, N-desmethyl enzalutamide, exhibited similar in vitro activity to enzalutamide. Enzalutamide decreased proliferation and induced cell death of prostate cancer cells in vitro, and decreased tumor volume in a mouse prostate cancer xenograft model.
## Structure
- Enzalutamide is an androgen receptor inhibitor. The chemical name is 4-{3-[4-cyano-3-(trifluoromethyl)phenyl]-5,5-dimethyl-4-oxo-2-sulfanylideneimidazolidin-1-yl}-2-fluoro-N-methylbenzamide.
- The molecular weight is 464.44 and molecular formula is C21H16F4N4O2S. The structural formula is:
- Enzalutamide is a white crystalline non-hygroscopic solid. It is practically insoluble in water.
- Enzalutamide is provided as liquid-filled soft gelatin capsules for oral administration. Each capsule contains 40 mg of enzalutamide as a solution in caprylocaproyl polyoxylglycerides. The inactive ingredients are caprylocaproyl polyoxylglycerides, butylated hydroxyanisole, butylated hydroxytoluene, gelatin, sorbitol sorbitan solution, glycerin, purified water, titanium dioxide, and black iron oxide.
## Pharmacodynamics
There is limited information regarding Pharmacodynamics of Enzalutamide in the drug label.
## Pharmacokinetics
- The pharmacokinetics of enzalutamide and its major active metabolite (N-desmethyl enzalutamide) were evaluated in patients with metastatic CRPC and healthy male volunteers. The plasma enzalutamide pharmacokinetics are adequately described by a linear two-compartment model with first-order absorption.
- Following oral administration (Enzalutamide 160 mg daily) in patients with metastatic castration-resistant prostate cancer, the median time to reach maximum plasma enzalutamide concentrations (Cmax) is 1 hour (range 0.5 to 3 hours). At steady state, the plasma mean Cmax values for enzalutamide and N-desmethyl enzalutamide are 16.6 μg/mL (23% CV) and 12.7 μg/mL (30% CV), respectively, and the plasma mean predose trough values are 11.4 μg/mL (26% CV) and 13.0 μg/mL (30% CV), respectively.
- With the daily dosing regimen, enzalutamide steady state is achieved by Day 28, and enzalutamide accumulates approximately 8.3-fold relative to a single dose. Daily fluctuations in enzalutamide plasma concentrations are low (mean peak-to-trough ratio of 1.25). At steady state, enzalutamide showed approximately dose proportional pharmacokinetics over the daily dose range of 30 to 360 mg.
- A single 160 mg oral dose of Enzalutamide was administered to healthy volunteers with a high-fat meal or in the fasted condition. A high-fat meal did not alter the AUC to enzalutamide or N-desmethyl enzalutamide. The results are summarized in Figure 1.
- The mean apparent volume of distribution (V/F) of enzalutamide in patients after a single oral dose is 110 L (29% CV).
- Enzalutamide is 97% to 98% bound to plasma proteins, primarily albumin. N-desmethyl enzalutamide is 95% bound to plasma proteins. In vitro, there was no protein binding displacement between enzalutamide and other highly protein bound drugs (warfarin, ibuprofen, and salicylic acid) at clinically relevant concentrations.
- Following single oral administration of 14C-enzalutamide 160 mg, plasma samples were analyzed for enzalutamide and its metabolites up to 77 days post dose. Enzalutamide, N-desmethyl enzalutamide, and a major inactive carboxylic acid metabolite accounted for 88% of the 14C-radioactivity in plasma, representing 30%, 49%, and 10%, respectively, of the total 14C-AUC0-inf.
- In vitro, human CYP2C8 and CYP3A4 are responsible for the metabolism of enzalutamide. Based on in vivo and in vitro data, CYP2C8 is primarily responsible for the formation of the active metabolite (N-desmethyl enzalutamide).
- In vitro, N-desmethyl enzalutamide is not a substrate of human CYP1A1, CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C18, CYP2C19, CYP2D6, CYP2E1 and CYP3A4/5.
- Enzalutamide is primarily eliminated by hepatic metabolism. Following single oral administration of14C-enzalutamide 160 mg, 85% of the radioactivity is recovered by 77 days post dose: 71% is recovered in urine (including only trace amounts of enzalutamide and N-desmethyl enzalutamide), and 14% is recovered in feces (0.4% of dose as unchanged enzalutamide and 1% as N-desmethyl enzalutamide).
- The mean apparent clearance (CL/F) of enzalutamide in patients after a single oral dose is 0.56 L/h (range 0.33 to 1.02 L/h).
- The mean terminal half-life (t1/2) for enzalutamide in patients after a single oral dose is 5.8 days (range 2.8 to 10.2 days). Following a single 160 mg oral dose of enzalutamide in healthy volunteers, the mean terminal t1/2 for N-desmethyl enzalutamide is approximately 7.8 to 8.6 days.
### Pharmacokinetics in Special Populations
- A population pharmacokinetic analysis (based on pre-existing renal function) was carried out with data from 59 healthy male volunteers and 926 patients with metastatic CRPC enrolled in clinical trials, including 512 with normal renal function (CrCL ≥ 90 mL/min), 332 with mild renal impairment (CrCL 60 to < 90 mL/min), 88 with moderate renal impairment (CrCL 30 to < 60 mL/min), and 1 with severe renal impairment (CrCL < 30 mL/min). The apparent clearance of enzalutamide was similar in patients with pre-existing mild and moderate renal impairment (CrCL 30 to < 90 mL/min) compared to patients and volunteers with normal renal function. The potential effect of severe renal impairment or end stage renal disease on enzalutamide pharmacokinetics cannot be determined as clinical and pharmacokinetic data are available from only one patient
- The plasma pharmacokinetics of enzalutamide and N-desmethyl enzalutamide were examined in volunteers with normal hepatic function (N = 16) and with pre-existing mild (N = 8, Child-Pugh Class A) or moderate (N = 8, Child-Pugh B) hepatic impairment. Enzalutamide was administered as a single 160 mg dose. The composite AUC of enzalutamide plus N-desmethyl enzalutamide was similar in volunteers with mild or moderate baseline hepatic impairment compared to volunteers with normal hepatic function. The results are summarized in Figure 1. Clinical and pharmacokinetic data are not available for patients with severe hepatic impairment (Child-Pugh Class
## Nonclinical Toxicology
- Long-term animal studies have not been conducted to evaluate the carcinogenic potential of enzalutamide.
- Enzalutamide did not induce mutations in the bacterial reverse mutation (Ames) assay and was not genotoxic in either the in vitro mouse lymphoma thymidine kinase (Tk) gene mutation assay or the in vivo mouse micronucleus assay.
- Based on nonclinical findings in repeat-dose toxicology studies, which were consistent with the pharmacological activity of enzalutamide, male fertility may be impaired by treatment with Enzalutamide . In a 26-week study in rats, atrophy of the prostate and seminal vesicles was observed at ≥ 30 mg/kg/day (equal to the human exposure based on AUC). In 4-, 13-, and 39-week studies in dogs, hypospermatogenesis and atrophy of the prostate and epididymides were observed at ≥ 4 mg/kg/day (0.3 times the human exposure based on AUC).
# Clinical Studies
- The efficacy and safety of Enzalutamide in patients with metastatic CRPC were demonstrated in two randomized, placebo-controlled, multicenter phase 3 clinical trials. All patients continued on GnRH therapy or had prior bilateral orchitectomy. Patients were allowed, but not required, to continue or initiate glucocorticoids.
- A total of 1199 patients who had received prior docetaxel-based chemotherapy were randomized 2:1 to receive either Enzalutamide orally at a dose of 160 mg once daily (N=800) or placebo orally once daily (N=399). Study treatment continued until disease progression (evidence of radiographic progression, a skeletal-related event, or clinical progression), initiation of new systemic antineoplastic treatment, unacceptable toxicity, or withdrawal. Patients with a previous history of seizure, taking medicines known to decrease the seizure threshold, or with other risk factors for seizure were not eligible.
- The following patient demographics and baseline disease characteristics were balanced between the treatment arms. The median age was 69 years (range 41-92) and the racial distribution was 92.7% Caucasian, 3.9% Black, 1.1% Asian, and 2.1% Other. Ninety-two percent of patients had an ECOG performance status score of 0-1 and 28% had a mean Brief Pain Inventory score of ≥ 4. Ninety-one percent of patients had metastases in bone and 23% had visceral involvement in the lung and/or liver. Fifty-nine percent of patients had radiographic evidence of disease progression and 41% had PSA-only progression on study entry. All patients had received prior docetaxel-based therapy and 24% had received two cytotoxic chemotherapy regimens. During the trial, 48% of patients on the Enzalutamide arm and 46% of patients on the placebo arm received glucocorticoids.
- A statistically significant improvement in overall survival was demonstrated at the pre-specified interim analysis at the time of 520 deaths in patients on the Enzalutamide arm compared to patients on the placebo arm (TABLE 3 and Figure 3).
- In Study 2, 1717 chemotherapy-naive patients were randomized 1:1 to receive either Enzalutamide orally at a dose of 160 mg once daily (N=872) or placebo orally once daily (N=845). Patients with visceral metastases, patients with a history of mild to moderate heart failure (NYHA class I or II), and patients taking medications associated with lowering the seizure threshold were allowed. Patients with a previous history of seizure or a condition that might predispose to seizure and patients with moderate or severe pain from prostate cancer were excluded. Study treatment continued until disease progression (evidence of radiographic progression, a skeletal-related event, or clinical progression) and the initiation of a cytotoxic chemotherapy or an investigational agent, unacceptable toxicity, or withdrawal. Overall survival and radiographic progression-free survival (rPFS) were assessed. Radiographic progression was assessed with the use of sequential imaging and was defined by bone scan identification of 2 or more new bone lesions with confirmation (Prostate Cancer Clinical Trials Working Group 2 criteria) and/or Response Evaluation Criteria in Solid Tumors (RECIST v 1.1) criteria for progression of soft tissue lesions. The primary analysis of rPFS utilized centrally reviewed radiographic assessment of progression.
- Patient demographics and baseline disease characteristics were balanced between the treatment arms at entry. The median age was 71 years (range 42-93) and the racial distribution was 77% Caucasian, 10% Asian, 2% Black and 11% Other. The ECOG performance status score was 0 for 68% of patients, and 1 for 32% of patients. Baseline pain assessment was 0-1 (asymptomatic) in 67% of patients, and 2-3 (mildly symptomatic) in 32% of patients as defined by the Brief Pain Inventory Short Form (worst pain over past 24 hours at study entry). Fifty-four percent of patients had radiographic evidence of disease progression and 43% had PSA-only progression. Twelve percent of patients had visceral (lung and/or liver) disease involvement. During the study, 27% of patients on the Enzalutamide arm and 30% of patients on the placebo arm received glucocorticoids for varying reasons.
- A statistically significant improvement in overall survival was demonstrated at the pre-specified interim analysis, conducted after 540 deaths in patients treated with Enzalutamide compared to those treated with placebo (TABLE 4, Figure 4). Forty percent of Enzalutamide -treated and 70% of placebo-treated patients received subsequent therapies for metastatic CRPC that may prolong overall survival.
- Time to initiation of cytotoxic chemotherapy was prolonged after Enzalutamide treatment, with a median of 28.0 months for patients on the Enzalutamide arm versus a median of 10.8 months for patients on the placebo arm [HR=0.35 (95% CI: 0.30, 0.40), p < 0.0001)].
- The median time to first skeletal‑related event was 31.1 months for patients on the Enzalutamide arm versus 31.3 months for patients on the placebo arm [HR = 0.72 (95% CI: 0.61, 0.84), p < 0.0001]. A skeletal‑related event was defined as radiation therapy or surgery to bone for prostate cancer, pathologic bone fracture, spinal cord compression, or change of antineoplastic therapy to treat bone pain.
There is limited information regarding Clinical Studies of Enzalutamide in the drug label.
# How Supplied
- Enzalutamide (enzalutamide) 40 mg capsules are supplied as white to off-white oblong soft gelatin capsules imprinted in black ink with ENZ. Enzalutamide capsules are available in the following package sizes:
- Bottles of 120 capsules (NDC 0469-0125-99)
## Storage
- Recommended storage: Store Enzalutamide capsules at 20°C to 25°C (68°F to 77°F) in a dry place and keep the container tightly closed. Excursions permitted from 15°C to 30°C (59°F to 86°F).
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- Instruct patients to take their dose at the same time each day (once daily). Enzalutamide can be taken with or without food. Each capsule should be swallowed whole. Do not chew, dissolve, or open the capsules.*Inform patients receiving GnRH therapy that they need to maintain this treatment during the course of treatment with Enzalutamide .
- Inform patients that Enzalutamide 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 physician right away if they have loss of consciousness or seizure.
- Inform patients that they should not interrupt, modify the dose, or stop Enzalutamide without first consulting their physician. Inform patients that if they miss a dose, then they should take it as soon as they remember. If they forget to take the dose for the whole day, then they should take their normal dose the next day. They should not take more than their prescribed dose per day.
- Apprise patients of the most common side effects associated with Enzalutamide : asthenia/fatigue, back pain, decreased appetite, constipation, arthralgia, diarrhea, hot flush, upper respiratory tract infection, peripheral edema, dyspnea, musculoskeletal pain, weight decreased, headache, hypertension, and dizziness/vertigo. Direct the patient to a complete list of adverse drug reactions.
- Inform patients that Enzalutamide may cause infections, falls and fall-related injuries, and hypertension.
- Inform patients that Enzalutamide can be harmful to a developing fetus. Patients should also be informed that they should use a condom if having sex with a pregnant woman. A condom and another effective method of birth control should be used if the patient is having sex with a woman of child-bearing potential. These measures are required during and for three months after treatment with Enzalutamide .
# Precautions with Alcohol
- Alcohol-Enzalutamide interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Xtandi®
# Look-Alike Drug Names
- A® — B®
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Enzalutamide | |
675c461fd9c8217fcfe0abfc5690a4eb1f4d8168 | wikidoc | Enzyme assay | Enzyme assay
# Overview
Enzyme assays are laboratory methods for measuring enzymatic activity. They are vital for the study of enzyme kinetics and enzyme inhibition.
# Enzyme units
Amounts of enzymes can either be expressed as molar amounts, as with any other chemical, or measured in terms of activity.
Enzyme activity = moles of substrate converted per unit time = rate × reaction volume. Enzyme activity is a measure of the quantity of active enzyme present and is thus dependent on conditions, which should be specified. The SI unit is the katal, 1 katal = 1 mol s-1, but this is an excessively large unit. A more practical and commonly-used value is 1 enzyme unit (EU) = 1 μmol min-1 (μ = micro, x 10-6). 1 U corresponds to 16.67 nanokatals.
The specific activity of an enzyme is another common unit. This is the activity of an enzyme per milligram of total protein (expressed in μmol min-1mg-1). Specific activity gives a measurement of the purity of the enzyme.
# Types of assay
All enzyme assays measure either the consumption of substrate or production of product over time. A large number of different methods of measuring the concentrations of substrates and products exist and many enzymes can be assayed in several different ways. Biochemists usually study enzyme-catalysed reactions using four types of experiments:
(1) Initial rate experiments. When an enzyme is mixed with a large excess of the substrate, the enzyme-substrate intermediate builds up in a fast initial transient. Then the reaction achieves a steady-state kinetics in which enzyme substrate intermediates remains approximately constant over time and the reaction rate changes relatively slowly. Rates are measured for a short period after the attainment of the quasi-steady state, typically by monitoring the accumulation of product with time. Because the measurements are carried out for a very short period and because of the large excess of substrate, the approximation free substrate is approximately equal to the initial substrate can be made. The initial rate experiment is the simplest to perform and analyze, being relatively free from complications such as back-reaction and enzyme degradation. It is therefore by far the most commonly used type of experiment in enzyme kinetics.
(2) Progress curve experiments. In these experiments, the kinetic parameters are determined from expressions for the species concentrations as a function of time. The concentration of the substrate or product is recorded in time after the initial fast transient and for a sufficiently long period to allow the reaction to approach equilibrium. We note in passing that, while they are less common now, progress curve experiments were widely used in the early period of enzyme kinetics.
(3) Transient kinetics experiments. In these experiments, reaction behaviour is tracked during the initial fast transient as the intermediate reaches the steady-state kinetics period. These experiments are more difficult to perform than either of the above two classes because they require rapid mixing and observation techniques.
(4) Relaxation experiments. In these experiments, an equilibrium mixture of enzyme, substrate and product is perturbed, for instance by a temperature, pressure or pH jump, and the return to equilibrium is monitored. The analysis of these experiments requires consideration of the fully reversible reaction. Moreover, relaxation experiments are relatively insensitive to mechanistic details and are thus not typically used for mechanism identification, although they can be under appropriate conditions.
Enzyme assays can be split into two groups according to their sampling method: continuous assays, where the assay gives a continuous reading of activity, and discontinuous assays, where samples are taken, the reaction stopped and then the concentration of substrates/products determined.
# Continuous assays
Continuous assays are most convenient, with one assay giving the rate of reaction with no further work necessary. There are many different types of continuous assays.
## Spectrophotometric
In spectrophotometric assays, you follow the course of the reaction by measuring a change in how much light the assay solution absorbs. If this light is in the visible region you can actually see a change in the color of the assay, these are called colorimetric assays. The MTT assay, a redox assay using a tetrazolium dye as substrate is an example of a colorimetric assay.
UV light is often used, since the common coenzymes NADH and NADPH absorb UV light in their reduced forms, but do not in their oxidised forms. An oxidoreductase using NADH as a substrate could therefore be assayed by following the decrease in UV absorbance at 340 nm as it consumes the coenzyme.
Direct versus coupled assays
Even when the enzyme reaction does not result in a change in the absorbance of light, it can still be possible to use a spectrophotometric assay for the enzyme by using a coupled assay. Here, the product of one reaction is used as the substrate of another, easily-detectable reaction. For example, figure 1 shows the coupled assay for the enzyme hexokinase, which can be assayed by coupling its production of glucose-6-phosphate to NADPH production, using glucose-6-phosphate dehydrogenase.
## Fluorimetric
Fluorescence is when a molecule emits light of one wavelength after absorbing light of a different wavelength. Fluorometric assays use a difference in the fluorescence of substrate from product to measure the enzyme reaction. These assays are in general much more sensitive than spectrophotometric assays, but can suffer from interference caused by impurities and the instability of many fluorescent compounds when exposed to light.
An example of these assays is again the use of the nucleotide coenzymes NADH and NADPH. Here, the reduced forms are fluorescent and the oxidised forms non-fluorescent. Oxidation reactions can therefore be followed by a decrease in fluorescence and reduction reactions by an increase. Synthetic substrates that release a fluorescent dye in an enzyme-catalyzed reaction are also available, such as 4-methylumbelliferyl-β-D-glucuronide for assaying β-galactosidase.
## Calorimetric
Calorimetry is the measurement of the heat released or absorbed by chemical reactions. These assays are very general, since many reactions involve some change in heat and with use of a microcalorimeter, not much enzyme or substrate is required. These assays can be used to measure reactions that are impossible to assay in any other way.
## Chemiluminescent
Chemiluminescence is the emission of light by a chemical reaction. Some enzyme reactions produce light and this can be measured to detect product formation. These types of assay can be extremely sensitive, since the light produced can be captured by photographic film over days or weeks, but can be hard to quantify, because not all the light released by a reaction will be detected.
The detection of horseradish peroxidase by enzymatic chemiluminescence (ECL) is a common method of detecting antibodies in western blotting. Another example is the enzyme luciferase, this is found in fireflies and naturally produces light from its substrate luciferin.
# Discontinuous assays
Discontinuous assays are when samples are taken from an enzyme reaction at intervals and the amount of product production or substrate consumption is measured in these samples.
## Radiometric
Radiometric assays measure the incorporation of radioactivity into substrates or its release from substrates. The radioactive isotopes most frequently used in these assays are 14C, 32P, 35S and 125I. Since radioactive isotopes can allow the specific labelling of a single atom of a substrate, these assays are both extremely sensitive and specific. They are frequently used in biochemistry and are often the only way of measuring a specific reaction in crude extracts (the complex mixtures of enzymes produced when you lyse cells).
Radioactivity is usually measured in these procedures using a scintillation counter.
## Chromatographic
Chromatographic assays measure product formation by separating the reaction mixture into its components by chromatography. This is usually done by high-performance liquid chromatography (HPLC). Although this approach can need a lot of material, its sensitivity can be increased by labelling the substrates/products with a radioactive or fluorescent tag.
# Factors to control in assays
- Salt Concentration: Most enzymes can not tolerate extremely high salt concentrations. The ions interfere with the weak ionic bonds of proteins. Typical enzymes are active in salt concentrations of 1-500 mM. As usual there are exceptions such as the halophilic (salt loving) algae and bacteria.
- Effects of Temperature: All enzymes work within a range of temperature specific to the organism. Increases in temperature generally lead to increases in reaction rates. There is a limit to the increase because higher temperatures lead to a sharp decrease in reaction rates. This is due to the denaturating (alteration) of protein structure resulting from the breakdown of the weak ionic and hydrogen bonding that stabilize the three dimensional structure of the enzyme. The "optimum" temperature for human enzymes is usually between 35 and 40 °C. The average temperature for humans is 37 °C. Human enzymes start to denature quickly at temperatures above 40 °C. Enzymes from thermophilic archaea found in the hot springs are stable up to 100 °C. However, the idea of an "optimum" rate of an enzyme reaction is misleading, as the rate observed at any temperature is the product of two rates, the reaction rate and the denaturation rate. If you were to use an assay measuring activity for one second, it would give high activity at high temperatures, however if you were to use an assay measuring product formation over an hour, it would give you low activity at these temperatures.
- Effects of pH: Most enzymes are sensitive to pH and have specific ranges of activity. All have an optimum pH. The pH can stop enzyme activity by denaturating (altering) the three dimensional shape of the enzyme by breaking ionic, and hydrogen bonds. Most enzymes function between a pH of 6 and 8; however pepsin in the stomach works best at a pH of 2 and trypsin at a pH of 8.
- Substrate Saturation: Increasing the substrate concentration increases the rate of reaction (enzyme activity). However, enzyme saturation limits reaction rates. An enzyme is saturated when the active sites of all the molecules are occupied most of the time. At the saturation point, the reaction will not speed up, no matter how much additional substrate is added. The graph of the reaction rate will plateau.
# List of enzyme assays
- MTT assay
- Overlay assay
- Fluorescein diacetate hydrolysis | Enzyme assay
# Overview
Enzyme assays are laboratory methods for measuring enzymatic activity. They are vital for the study of enzyme kinetics and enzyme inhibition.
# Enzyme units
Amounts of enzymes can either be expressed as molar amounts, as with any other chemical, or measured in terms of activity.
Enzyme activity = moles of substrate converted per unit time = rate × reaction volume. Enzyme activity is a measure of the quantity of active enzyme present and is thus dependent on conditions, which should be specified. The SI unit is the katal, 1 katal = 1 mol s-1, but this is an excessively large unit. A more practical and commonly-used value is 1 enzyme unit (EU) = 1 μmol min-1 (μ = micro, x 10-6). 1 U corresponds to 16.67 nanokatals.
The specific activity of an enzyme is another common unit. This is the activity of an enzyme per milligram of total protein (expressed in μmol min-1mg-1). Specific activity gives a measurement of the purity of the enzyme.
# Types of assay
All enzyme assays measure either the consumption of substrate or production of product over time. A large number of different methods of measuring the concentrations of substrates and products exist and many enzymes can be assayed in several different ways. Biochemists usually study enzyme-catalysed reactions using four types of experiments:[1]
(1) Initial rate experiments. When an enzyme is mixed with a large excess of the substrate, the enzyme-substrate intermediate builds up in a fast initial transient. Then the reaction achieves a steady-state kinetics in which enzyme substrate intermediates remains approximately constant over time and the reaction rate changes relatively slowly. Rates are measured for a short period after the attainment of the quasi-steady state, typically by monitoring the accumulation of product with time. Because the measurements are carried out for a very short period and because of the large excess of substrate, the approximation free substrate is approximately equal to the initial substrate can be made. The initial rate experiment is the simplest to perform and analyze, being relatively free from complications such as back-reaction and enzyme degradation. It is therefore by far the most commonly used type of experiment in enzyme kinetics.
(2) Progress curve experiments. In these experiments, the kinetic parameters are determined from expressions for the species concentrations as a function of time. The concentration of the substrate or product is recorded in time after the initial fast transient and for a sufficiently long period to allow the reaction to approach equilibrium. We note in passing that, while they are less common now, progress curve experiments were widely used in the early period of enzyme kinetics.
(3) Transient kinetics experiments. In these experiments, reaction behaviour is tracked during the initial fast transient as the intermediate reaches the steady-state kinetics period. These experiments are more difficult to perform than either of the above two classes because they require rapid mixing and observation techniques.
(4) Relaxation experiments. In these experiments, an equilibrium mixture of enzyme, substrate and product is perturbed, for instance by a temperature, pressure or pH jump, and the return to equilibrium is monitored. The analysis of these experiments requires consideration of the fully reversible reaction. Moreover, relaxation experiments are relatively insensitive to mechanistic details and are thus not typically used for mechanism identification, although they can be under appropriate conditions.
Enzyme assays can be split into two groups according to their sampling method: continuous assays, where the assay gives a continuous reading of activity, and discontinuous assays, where samples are taken, the reaction stopped and then the concentration of substrates/products determined.
# Continuous assays
Continuous assays are most convenient, with one assay giving the rate of reaction with no further work necessary. There are many different types of continuous assays.
## Spectrophotometric
In spectrophotometric assays, you follow the course of the reaction by measuring a change in how much light the assay solution absorbs. If this light is in the visible region you can actually see a change in the color of the assay, these are called colorimetric assays. The MTT assay, a redox assay using a tetrazolium dye as substrate is an example of a colorimetric assay.
UV light is often used, since the common coenzymes NADH and NADPH absorb UV light in their reduced forms, but do not in their oxidised forms. An oxidoreductase using NADH as a substrate could therefore be assayed by following the decrease in UV absorbance at 340 nm as it consumes the coenzyme.[2]
Direct versus coupled assays
Even when the enzyme reaction does not result in a change in the absorbance of light, it can still be possible to use a spectrophotometric assay for the enzyme by using a coupled assay. Here, the product of one reaction is used as the substrate of another, easily-detectable reaction. For example, figure 1 shows the coupled assay for the enzyme hexokinase, which can be assayed by coupling its production of glucose-6-phosphate to NADPH production, using glucose-6-phosphate dehydrogenase.
## Fluorimetric
Fluorescence is when a molecule emits light of one wavelength after absorbing light of a different wavelength. Fluorometric assays use a difference in the fluorescence of substrate from product to measure the enzyme reaction. These assays are in general much more sensitive than spectrophotometric assays, but can suffer from interference caused by impurities and the instability of many fluorescent compounds when exposed to light.
An example of these assays is again the use of the nucleotide coenzymes NADH and NADPH. Here, the reduced forms are fluorescent and the oxidised forms non-fluorescent. Oxidation reactions can therefore be followed by a decrease in fluorescence and reduction reactions by an increase.[3] Synthetic substrates that release a fluorescent dye in an enzyme-catalyzed reaction are also available, such as 4-methylumbelliferyl-β-D-glucuronide for assaying β-galactosidase.
## Calorimetric
Calorimetry is the measurement of the heat released or absorbed by chemical reactions. These assays are very general, since many reactions involve some change in heat and with use of a microcalorimeter, not much enzyme or substrate is required. These assays can be used to measure reactions that are impossible to assay in any other way.[4]
## Chemiluminescent
Chemiluminescence is the emission of light by a chemical reaction. Some enzyme reactions produce light and this can be measured to detect product formation. These types of assay can be extremely sensitive, since the light produced can be captured by photographic film over days or weeks, but can be hard to quantify, because not all the light released by a reaction will be detected.
The detection of horseradish peroxidase by enzymatic chemiluminescence (ECL) is a common method of detecting antibodies in western blotting. Another example is the enzyme luciferase, this is found in fireflies and naturally produces light from its substrate luciferin.
# Discontinuous assays
Discontinuous assays are when samples are taken from an enzyme reaction at intervals and the amount of product production or substrate consumption is measured in these samples.
## Radiometric
Radiometric assays measure the incorporation of radioactivity into substrates or its release from substrates. The radioactive isotopes most frequently used in these assays are 14C, 32P, 35S and 125I. Since radioactive isotopes can allow the specific labelling of a single atom of a substrate, these assays are both extremely sensitive and specific. They are frequently used in biochemistry and are often the only way of measuring a specific reaction in crude extracts (the complex mixtures of enzymes produced when you lyse cells).
Radioactivity is usually measured in these procedures using a scintillation counter.
## Chromatographic
Chromatographic assays measure product formation by separating the reaction mixture into its components by chromatography. This is usually done by high-performance liquid chromatography (HPLC). Although this approach can need a lot of material, its sensitivity can be increased by labelling the substrates/products with a radioactive or fluorescent tag.
# Factors to control in assays
- Salt Concentration: Most enzymes can not tolerate extremely high salt concentrations. The ions interfere with the weak ionic bonds of proteins. Typical enzymes are active in salt concentrations of 1-500 mM. As usual there are exceptions such as the halophilic (salt loving) algae and bacteria.
- Effects of Temperature: All enzymes work within a range of temperature specific to the organism. Increases in temperature generally lead to increases in reaction rates. There is a limit to the increase because higher temperatures lead to a sharp decrease in reaction rates. This is due to the denaturating (alteration) of protein structure resulting from the breakdown of the weak ionic and hydrogen bonding that stabilize the three dimensional structure of the enzyme. The "optimum" temperature for human enzymes is usually between 35 and 40 °C. The average temperature for humans is 37 °C. Human enzymes start to denature quickly at temperatures above 40 °C. Enzymes from thermophilic archaea found in the hot springs are stable up to 100 °C.[5] However, the idea of an "optimum" rate of an enzyme reaction is misleading, as the rate observed at any temperature is the product of two rates, the reaction rate and the denaturation rate. If you were to use an assay measuring activity for one second, it would give high activity at high temperatures, however if you were to use an assay measuring product formation over an hour, it would give you low activity at these temperatures.
- Effects of pH: Most enzymes are sensitive to pH and have specific ranges of activity. All have an optimum pH. The pH can stop enzyme activity by denaturating (altering) the three dimensional shape of the enzyme by breaking ionic, and hydrogen bonds. Most enzymes function between a pH of 6 and 8; however pepsin in the stomach works best at a pH of 2 and trypsin at a pH of 8.
- Substrate Saturation: Increasing the substrate concentration increases the rate of reaction (enzyme activity). However, enzyme saturation limits reaction rates. An enzyme is saturated when the active sites of all the molecules are occupied most of the time. At the saturation point, the reaction will not speed up, no matter how much additional substrate is added. The graph of the reaction rate will plateau.
# List of enzyme assays
- MTT assay
- Overlay assay
- Fluorescein diacetate hydrolysis | https://www.wikidoc.org/index.php/Enzyme_activity | |
673e9edaaab6584f1ecbfc4de5b32a947034f342 | wikidoc | Eomesodermin | Eomesodermin
Eomesodermin also known as T-box brain protein 2 (Tbr2) is a protein that in humans is encoded by the EOMES gene.
The Eomesodermin/Tbr2 gene, EOMES, encodes a member of a conserved protein family that shares a common DNA-binding domain, the T-box. T-box genes encode transcription factors, which control gene expression, involved in the regulation of developmental processes. Eomesodermin/Tbr2 itself controls regulation of radial glia, as well as other related cells. Eomesodermin/Tbr2 has also been found to have a role in immune response, and there exists some loose evidence for its connections in other systems.
# Development
Eomesodermin/Tbr2 is expressed highly in the intermediate progenitor stage of the developing neuron. Neurons, the primary functional cells of the brain, are developed from radial glia cells. This process of cells developing into other types of cells is called differentiation. Radial glia are present in the ventricular zone of the brain, which are on the lateral walls of the lateral ventricles. Radial glia divide and migrate towards the surface of the brain, the cerebral cortex. During this migration, there are three stages of cellular development: radial glia, intermediate progenitors, and postmitotic projection neurons. Radial glia express Pax6, while intermediate progenitor cells express Eomesodermin/Tbr2, and postmitotic projection neurons express Tbr1. This process, known as neurogenesis, occurs mainly in the developing cortex before the organism has fully developed, and thus Eomesodermin/Tbr2 has been implicated in neurodevelopment. However, neurogenesis has been found to occur to some extent in the ventricular zone in fully developed organisms.
It has been found experimentally through knock out studies, that mice lacking Eomesodermin/Tbr2 during early development have a reduced number of actively dividing cells, called proliferating cells, in the subventricular zone, a key area of neurogenesis in the brain. This, may lead to the microcephaly (small head size due to improper brain development) seen in Eomesodermin/Tbr2 deficient mice. Eomesodermin/Tbr2 lacking mice have smaller upper cortical layers and a smaller sub ventricular zone in the brain, and have an absence of a mitral cell (neurons involved in the olfactory pathway) layer, with mitral cells instead being scattered about. On the behavioral side, Eomesodermin/Tbr2 lacking mice show high anger levels and perform infanticide. Eomesodermin/Tbr2 lacking mice also seem to have problems with long axon connections. Axons are projections from neurons that connect with other cells in what is called a synapse and send neurotransmitters. In this way, they can communicate with other cells, and form the processing that allows are brains to function. Eomesodermin/Tbr2 lacking mice seem to lack fully formed commissural fibers, which connect the two hemispheres of the brain, and lack the corpus callosum, another region of the brain involved in hemisphere connections.
Eomesodermin/Tbr2 has also been implicated in other key development systems. It was found
that early in development, Eomesodermin/Tbr2 controls early differentiation of the cardiac mesoderm. In fact, lack of Eomesodermin/Tbr2 seems to cause cells to fail to differentiate into cardiomyocytes, which are heart muscle cells. Eomesodermin/Tbr2 controls the expression of cardiac specific genes Mesp1, Myl7, Myl2, Myocardin,Nkx2.5 and Mef2c.
Additionally, although neurogenesis occurs primarily in the early stages of development, there are locations within the brain that have been discovered to perform neurogenesis into adulthood. One of these areas, the hippocampus, which is involved in memory formation, shows decreased neurogenesis when Eomesodermin/Tbr2 is removed. It was also found that Eomesodermin/Tbr2 functions by reducing amounts of Sox2, which is associated with radial glia. Another study found that mice without Eomesodermin/Tbr2 lacked long term memory formation, which may relate to Eomesodermin/Tbr2's effects on the hippocampus.
# Immune response
Eomesodermin/Tbr2 is highly expressed in CD8+ T cells, but not CD4+ T cells. CD4+ T cells are the helper T cells which detect foreign particles in the body, and call CD8+ T cells to facilitate death of the foreign particles. Eomesodermin/Tbr2 was found to play a role in the anti cancer properties of CD8+ T cells. Lack of Eomesodermin/Tbr2, alongside T bet another T box protein caused CD8+ T cells to not penetrate tumors so they could perform their anti cancer duties. Eomesodermin/Tbr2 prevents CD8+ cells from differentiating into other types of T cells, but does not play a role in the production of CD8+ T cells itself. Despite Eomesodermin/Tbr2 playing a role in the ability of CD8+ T cells to penetrate tumors, it only plays a small role in production of Interferon-gamma, which is a molecule that communicates to other immune cells during an immune response. | Eomesodermin
Eomesodermin also known as T-box brain protein 2 (Tbr2) is a protein that in humans is encoded by the EOMES gene.[1]
The Eomesodermin/Tbr2 gene, EOMES, encodes a member of a conserved protein family that shares a common DNA-binding domain, the T-box.[2] T-box genes encode transcription factors, which control gene expression, involved in the regulation of developmental processes. Eomesodermin/Tbr2 itself controls regulation of radial glia, as well as other related cells.[2] Eomesodermin/Tbr2 has also been found to have a role in immune response, and there exists some loose evidence for its connections in other systems.[3]
# Development
Eomesodermin/Tbr2 is expressed highly in the intermediate progenitor stage of the developing neuron.[4] Neurons, the primary functional cells of the brain, are developed from radial glia cells. This process of cells developing into other types of cells is called differentiation. Radial glia are present in the ventricular zone of the brain, which are on the lateral walls of the lateral ventricles.[5] Radial glia divide and migrate towards the surface of the brain, the cerebral cortex. During this migration, there are three stages of cellular development: radial glia, intermediate progenitors, and postmitotic projection neurons.[4] Radial glia express Pax6, while intermediate progenitor cells express Eomesodermin/Tbr2, and postmitotic projection neurons express Tbr1.[4] This process, known as neurogenesis, occurs mainly in the developing cortex before the organism has fully developed, and thus Eomesodermin/Tbr2 has been implicated in neurodevelopment.[4] However, neurogenesis has been found to occur to some extent in the ventricular zone in fully developed organisms.[6]
It has been found experimentally through knock out studies, that mice lacking Eomesodermin/Tbr2 during early development have a reduced number of actively dividing cells, called proliferating cells, in the subventricular zone, a key area of neurogenesis in the brain.[7] This, may lead to the microcephaly (small head size due to improper brain development) seen in Eomesodermin/Tbr2 deficient mice.[7] Eomesodermin/Tbr2 lacking mice have smaller upper cortical layers and a smaller sub ventricular zone in the brain, and have an absence of a mitral cell (neurons involved in the olfactory pathway) layer, with mitral cells instead being scattered about.[7] On the behavioral side, Eomesodermin/Tbr2 lacking mice show high anger levels and perform infanticide.[2] Eomesodermin/Tbr2 lacking mice also seem to have problems with long axon connections.[7] Axons are projections from neurons that connect with other cells in what is called a synapse and send neurotransmitters. In this way, they can communicate with other cells, and form the processing that allows are brains to function. Eomesodermin/Tbr2 lacking mice seem to lack fully formed commissural fibers, which connect the two hemispheres of the brain, and lack the corpus callosum, another region of the brain involved in hemisphere connections.[7]
Eomesodermin/Tbr2 has also been implicated in other key development systems. It was found
that early in development, Eomesodermin/Tbr2 controls early differentiation of the cardiac mesoderm.[8] In fact, lack of Eomesodermin/Tbr2 seems to cause cells to fail to differentiate into cardiomyocytes, which are heart muscle cells. Eomesodermin/Tbr2 controls the expression of cardiac specific genes Mesp1, Myl7, Myl2, Myocardin,Nkx2.5 and Mef2c.[8]
Additionally, although neurogenesis occurs primarily in the early stages of development, there are locations within the brain that have been discovered to perform neurogenesis into adulthood.[3] One of these areas, the hippocampus, which is involved in memory formation, shows decreased neurogenesis when Eomesodermin/Tbr2 is removed.[9] It was also found that Eomesodermin/Tbr2 functions by reducing amounts of Sox2, which is associated with radial glia.[9] Another study found that mice without Eomesodermin/Tbr2 lacked long term memory formation, which may relate to Eomesodermin/Tbr2's effects on the hippocampus.
[10]
# Immune response
Eomesodermin/Tbr2 is highly expressed in CD8+ T cells, but not CD4+ T cells.[3] CD4+ T cells are the helper T cells which detect foreign particles in the body, and call CD8+ T cells to facilitate death of the foreign particles. Eomesodermin/Tbr2 was found to play a role in the anti cancer properties of CD8+ T cells.[3] Lack of Eomesodermin/Tbr2, alongside T bet another T box protein caused CD8+ T cells to not penetrate tumors so they could perform their anti cancer duties.[3] Eomesodermin/Tbr2 prevents CD8+ cells from differentiating into other types of T cells, but does not play a role in the production of CD8+ T cells itself.[3] Despite Eomesodermin/Tbr2 playing a role in the ability of CD8+ T cells to penetrate tumors, it only plays a small role in production of Interferon-gamma, which is a molecule that communicates to other immune cells during an immune response.[3] | https://www.wikidoc.org/index.php/Eomesodermin | |
48c0746cb734fa1b1811dfae19df2e1bbb440882 | wikidoc | Eosinophilic | Eosinophilic
# Overview
Eosinophilic means "loves eosin", and refers to the staining of certain tissues, cells, or organelles after they been washed with eosin, a dye.
Eosin is an acidic dye, thus the structure being stained is basic.
Eosinophilic describes the appearance of cells and structures seen in histological sections which take up the staining dye, eosin. This is a bright pink dye that stains the cytoplasm of cells as well as extracellular proteins such as collagen.
Such eosinophilic structures are generally composed of protein.
The stain eosin is usually combined with a stain called haematoxylin to produce a haematoxylin and eosin stained section (also called an H&E, HE or H+E section). This is the most widely used histological stain in medical diagnosis - for example when a pathologist looks at a biopsy of a suspected cancer they will have the section stained with H&E.
Some structures seen inside cells are described as being eosinophilic, for example Lewy bodies, Mallory bodies.
# Related Chapters
- basophilic (affinity to hematoxylln)
- Eosinophilia | Eosinophilic
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Eosinophilic means "loves eosin", and refers to the staining of certain tissues, cells, or organelles after they been washed with eosin, a dye.
Eosin is an acidic dye, thus the structure being stained is basic.
Eosinophilic describes the appearance of cells and structures seen in histological sections which take up the staining dye, eosin. This is a bright pink dye that stains the cytoplasm of cells as well as extracellular proteins such as collagen.
Such eosinophilic structures are generally composed of protein.
The stain eosin is usually combined with a stain called haematoxylin to produce a haematoxylin and eosin stained section (also called an H&E, HE or H+E section). This is the most widely used histological stain in medical diagnosis - for example when a pathologist looks at a biopsy of a suspected cancer they will have the section stained with H&E.
Some structures seen inside cells are described as being eosinophilic, for example Lewy bodies, Mallory bodies.
# Related Chapters
- basophilic (affinity to hematoxylln)
- Eosinophilia
Template:WH
Template:WikiDoc Sources | https://www.wikidoc.org/index.php/Eosinophilic | |
a5823e97f93999dfc8794f4faf4e995ea4ab14d8 | wikidoc | Eph receptor | Eph receptor
# Overview
In molecular biology, ephrins and Eph receptors are components of cell signaling pathways involved in animal development, and implicated in some cancers. Eph receptors are classified as receptor tyrosine kinases (RTKs), and form the largest sub-family of RTKs.
# Receptors and ligands
There are 16 known receptors (14 found in mammals):
- EPHA1, EPHA2, EPHA3, EPHA4, EPHA5, EPHA6, EPHA7, EPHA8, EPHA9, EPHA10
- EPHB1, EPHB2, EPHB3, EPHB4, EPHB5, EPHB6
There are 9 known ephrin ligands (8 found in mammals):
- EFNA1, EFNA2, EFNA3, EFNA4, EFNA5
- EFNB1, EFNB2, EFNB3
# Discovery and history
The Eph receptors were initially identified in 1987 following a search for tyrosine kinases with possible roles in cancer, earning their name from the erythropoietin-producing hepatocellular carcinoma cell line from which their cDNA was obtained. These transmembranous receptors were initially classed as orphan receptors with no known ligands or functions and it was some time before possible functions of the receptors were known.
When it was shown that almost all Eph receptors were expressed during various well defined stages of development in assorted locations and concentrations, a role in cell positioning was proposed, initiating research that revealed the Eph/ephrin families as a principle cell guidance system during vertebrate and invertebrate development.
# Applications of the Eph guidance system
The ability of the Eph receptor and ephrin ligand guidance system to position cells and modulate cell morphology reflects their various roles in development.
## Segmentation
Segmentation is a basic process of embryogenesis occurring in most invertebrates and all vertebrates by which the body is initially divided into functional units. In the segmented regions of the embryo, cells begin to present biochemical and morphological boundaries at which cell behavior is drastically different – vital for future differentiation and function. In the hindbrain segmentation is a precisely defined process, contrasted to the paraxial mesoderm, which is a dynamic and adaptive process that adjusts according to posterior body growth. Various Eph receptors and ephrins are expressed in these regions and through functional analysis it has been determined that Eph signaling is crucial for the proper development and maintenance of these segment boundaries. Similar studies conducted in zebrafish have shown similar segmenting processes within the somites containing a striped expression pattern of Eph receptors and their ligands which is vital to proper segmentation - the disruption of expression resulting in misplaced or even absent boundaries.
## Axon guidance and fasciculation
As the nervous system develops, the predefined patterning of neuronal connections is established by molecular guides that direct axons along pathways by target and pathway derived signals. Initial evidence arose via the receptor EphB2, expressed in several regions of the chick and mouse brain – having been immunolocalised to the surface of growth cones for spinal motor and occulomotor neurons from their origin toward their targets. Further evidence came with the role of Eph in topographic mapping in the visual system, with graded expression levels of both Eph receptors and ephrin ligands leading to the development of a resolved neuronal map. Further studies then showed the role of Eph’s in topographic mapping in other regions of the central nervous system, such as learning and memory via the formation of projections between the septum and hippocampus.
## Cell Migration
More than just axonal guidance, Eph’s have been implicated in the migration of neural crest cells during gastrulation. In the chick and rat embryo trunk, the migration of crest cells is partially mediated by EphB receptors. Similar mechanisms have been shown to control crest movement in the hindbrain within rhombomeres 4, 5 and 7 which distribute crest cells to brachial arches 2, 3 and 4 respectively. In C. elegans a knockout of locus VAB-1, known to encode an Eph receptor, results in two cell migratory processes being affected.
## Angiogenesis
The construction of blood vessels requires the coordination of endothelial and supportive mesenchymal cells through multiple phases to develop the intricate networks required for a fully functional circulatory system. The dynamic nature and expression patterns of the Eph’s make them therefore ideal for roles in angiogenesis. Mouse embryonic models show expression of EphA1 in mesoderm and pre-endocardial cells, later spreading up into the dorsal aorta then primary head vein, intersomitic vessels and limb bud vasculature as would be consistent with a role in angiogenesis. Different class A Eph receptors have also been detected in the lining of the aorta, brachial arch arteries, umbilical vein and endocardium. Complementary expression of EphB2/ephrin-B4 was detected in developing arterial endothelial cells and EphB4 in venous endothelial cells. Expression of EphB2 and ephrin-B2 was also detected on supportive mesenchymal cells, suggesting a role in wall development through mediation of endothelial-mesenchymal interactions. Blood vessel formation during embryogenesis consists of vasculogenesis, the formation of a primary capillary network followed by a second remodeling and restructuring into a finer tertiary network - studies utilizing ephrin-B2 deficient mice showed a disruption of the embryonic vasculature as a result of a deficiency in the restructuring of the primary network. Functional analysis of other mutant mice have led to the development of a hypothesis by which Eph’s and ephrins contribute to vascular development by restricting arterial and venous endothelial mixing, thus stimulating the production of capillary sprouts as well as in the differentiation of mesenchyme into perivascular support cells, an ongoing area of research.
## Limb Development
While there is currently little evidence to support this (and mounting evidence to refute it), some early studies implicated the Eph’s to play a part in the signaling of limb development. In chicks, EphA4 is expressed in the developing wing and leg buds, as well as in the feather and scale primordia. This expression is seen in the distal end of the limb buds, where cells are still undifferentiated and dividing, and appears to be under the regulation of retinoic acid, FGF2, FGF4 and BMP-2 – known to regulate limb patterning. EphA4 defective mice don’t present abnormalities in limb morphogenesis (personal communication between Andrew Boyd and Nigel Holder), so it is possible that these expression patterns are related to neuronal guidance or vascularisation of the limb with further studies being required to confirm or deny a potential role of Eph in limb development.
## Cancer
As a member of the RTK family and with responsibilities as diverse as Eph’s, it is not surprising to learn that the Eph’s have been implicated in several aspects of cancer. While used extensively throughout development, Eph’s are rarely detected in adult tissues. Elevated levels of expression and activity have been correlated with the growth of solid tumors, with Eph receptors of both classes A and B being over expressed in a wide range of cancers including melanoma, breast, prostate, pancreatic, gastric, esophageal and colon cancer as well as hematopoietic tumors. Increased expression was also correlated with more malignant and metastatic tumors, consistent with the role of Eph’s governing cell movement.
It is possible that the increased expression of Eph in cancer plays several roles, firstly by acting as survival factors or as a promoter of abnormal growth. The angiogenic properties of the Eph system may increase vascularisation of and thus growth capacity of tumors. Secondly, elevated Eph levels may disrupt cell-cell adhesion via cadherin, known to alter expression and localisation of Eph receptors and ephrins which is known to further disrupt cellular adhesion, a key feature of metastatic cancers. Thirdly, Eph activity may alter cell matrix interactions via integrins by the sequestering of signaling molecules following Eph receptor activation, as well as providing potential adherence via ephrin ligand binding following metastasis. | Eph receptor
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
In molecular biology, ephrins and Eph receptors are components of cell signaling pathways involved in animal development, and implicated in some cancers. Eph receptors are classified as receptor tyrosine kinases (RTKs), and form the largest sub-family of RTKs.
# Receptors and ligands
There are 16 known receptors (14 found in mammals):
- EPHA1, EPHA2, EPHA3, EPHA4, EPHA5, EPHA6, EPHA7, EPHA8, EPHA9, EPHA10
- EPHB1, EPHB2, EPHB3, EPHB4, EPHB5, EPHB6
There are 9 known ephrin ligands (8 found in mammals):
- EFNA1, EFNA2, EFNA3, EFNA4, EFNA5
- EFNB1, EFNB2, EFNB3
# Discovery and history
The Eph receptors were initially identified in 1987 following a search for tyrosine kinases with possible roles in cancer, earning their name from the erythropoietin-producing hepatocellular carcinoma cell line from which their cDNA was obtained.[1] These transmembranous receptors were initially classed as orphan receptors with no known ligands or functions and it was some time before possible functions of the receptors were known.[2]
When it was shown that almost all Eph receptors were expressed during various well defined stages of development in assorted locations and concentrations, a role in cell positioning was proposed, initiating research that revealed the Eph/ephrin families as a principle cell guidance system during vertebrate and invertebrate development.[3]
# Applications of the Eph guidance system
The ability of the Eph receptor and ephrin ligand guidance system to position cells and modulate cell morphology reflects their various roles in development.
## Segmentation
Segmentation is a basic process of embryogenesis occurring in most invertebrates and all vertebrates by which the body is initially divided into functional units. In the segmented regions of the embryo, cells begin to present biochemical and morphological boundaries at which cell behavior is drastically different – vital for future differentiation and function.[4] In the hindbrain segmentation is a precisely defined process, contrasted to the paraxial mesoderm, which is a dynamic and adaptive process that adjusts according to posterior body growth. Various Eph receptors and ephrins are expressed in these regions and through functional analysis it has been determined that Eph signaling is crucial for the proper development and maintenance of these segment boundaries.[4] Similar studies conducted in zebrafish have shown similar segmenting processes within the somites containing a striped expression pattern of Eph receptors and their ligands which is vital to proper segmentation - the disruption of expression resulting in misplaced or even absent boundaries.[5]
## Axon guidance and fasciculation
As the nervous system develops, the predefined patterning of neuronal connections is established by molecular guides that direct axons along pathways by target and pathway derived signals.[2] Initial evidence arose via the receptor EphB2, expressed in several regions of the chick and mouse brain – having been immunolocalised to the surface of growth cones for spinal motor and occulomotor neurons from their origin toward their targets.[6] Further evidence came with the role of Eph in topographic mapping in the visual system, with graded expression levels of both Eph receptors and ephrin ligands leading to the development of a resolved neuronal map.[7] Further studies then showed the role of Eph’s in topographic mapping in other regions of the central nervous system, such as learning and memory via the formation of projections between the septum and hippocampus.[8]
## Cell Migration
More than just axonal guidance, Eph’s have been implicated in the migration of neural crest cells during gastrulation.[9] In the chick and rat embryo trunk, the migration of crest cells is partially mediated by EphB receptors. Similar mechanisms have been shown to control crest movement in the hindbrain within rhombomeres 4, 5 and 7 which distribute crest cells to brachial arches 2, 3 and 4 respectively. In C. elegans a knockout of locus VAB-1, known to encode an Eph receptor, results in two cell migratory processes being affected.[4]
## Angiogenesis
The construction of blood vessels requires the coordination of endothelial and supportive mesenchymal cells through multiple phases to develop the intricate networks required for a fully functional circulatory system.[10] The dynamic nature and expression patterns of the Eph’s make them therefore ideal for roles in angiogenesis. Mouse embryonic models show expression of EphA1 in mesoderm and pre-endocardial cells, later spreading up into the dorsal aorta then primary head vein, intersomitic vessels and limb bud vasculature as would be consistent with a role in angiogenesis. Different class A Eph receptors have also been detected in the lining of the aorta, brachial arch arteries, umbilical vein and endocardium.[10] Complementary expression of EphB2/ephrin-B4 was detected in developing arterial endothelial cells and EphB4 in venous endothelial cells.[11] Expression of EphB2 and ephrin-B2 was also detected on supportive mesenchymal cells, suggesting a role in wall development through mediation of endothelial-mesenchymal interactions.[12] Blood vessel formation during embryogenesis consists of vasculogenesis, the formation of a primary capillary network followed by a second remodeling and restructuring into a finer tertiary network - studies utilizing ephrin-B2 deficient mice showed a disruption of the embryonic vasculature as a result of a deficiency in the restructuring of the primary network.[4] Functional analysis of other mutant mice have led to the development of a hypothesis by which Eph’s and ephrins contribute to vascular development by restricting arterial and venous endothelial mixing, thus stimulating the production of capillary sprouts as well as in the differentiation of mesenchyme into perivascular support cells, an ongoing area of research.[10]
## Limb Development
While there is currently little evidence to support this (and mounting evidence to refute it), some early studies implicated the Eph’s to play a part in the signaling of limb development.[4] In chicks, EphA4 is expressed in the developing wing and leg buds, as well as in the feather and scale primordia.[13] This expression is seen in the distal end of the limb buds, where cells are still undifferentiated and dividing, and appears to be under the regulation of retinoic acid, FGF2, FGF4 and BMP-2 – known to regulate limb patterning. EphA4 defective mice don’t present abnormalities in limb morphogenesis (personal communication between Andrew Boyd and Nigel Holder), so it is possible that these expression patterns are related to neuronal guidance or vascularisation of the limb with further studies being required to confirm or deny a potential role of Eph in limb development.
## Cancer
As a member of the RTK family and with responsibilities as diverse as Eph’s, it is not surprising to learn that the Eph’s have been implicated in several aspects of cancer. While used extensively throughout development, Eph’s are rarely detected in adult tissues. Elevated levels of expression and activity have been correlated with the growth of solid tumors, with Eph receptors of both classes A and B being over expressed in a wide range of cancers including melanoma, breast, prostate, pancreatic, gastric, esophageal and colon cancer as well as hematopoietic tumors.[14][15][16] Increased expression was also correlated with more malignant and metastatic tumors, consistent with the role of Eph’s governing cell movement.[10]
It is possible that the increased expression of Eph in cancer plays several roles, firstly by acting as survival factors or as a promoter of abnormal growth.[17] The angiogenic properties of the Eph system may increase vascularisation of and thus growth capacity of tumors.[10] Secondly, elevated Eph levels may disrupt cell-cell adhesion via cadherin, known to alter expression and localisation of Eph receptors and ephrins which is known to further disrupt cellular adhesion, a key feature of metastatic cancers.[17] Thirdly, Eph activity may alter cell matrix interactions via integrins by the sequestering of signaling molecules following Eph receptor activation, as well as providing potential adherence via ephrin ligand binding following metastasis.[16] [17] | https://www.wikidoc.org/index.php/Eph_receptor | |
ca47d1dc0437befe36b2b497d7db568b8f3f5bec | wikidoc | Gastrulation | Gastrulation
Gastrulation is a phase early in the development of animal embryos, during which the morphology of the embryo is dramatically restructured by cell migration. Gastrulation varies in different phyla. Gastrulation is followed by organogenesis, when individual organs develop within the newly formed germ layers.
# Mammals
## Preparation
In mammals, gastrulation occurs after implantation, around day 16 after fertilization in human embryogenesis. As the outer cell mass invades the endometrium, the inner cell mass divides into two layers: the epiblast and hypoblast. The hypoblast spreads out and covers the blastocoel to form the yolk sac. The yolk sac is an extraembryonic tissue that produces blood cells similar to the structure that surrounds the yolk in birds. The epiblast further divides into two more layers. The amnion layer forms the fluid filled cavity to surround and protect the embryo during pregnancy. The embryonic epiblast undergoes gastrulation.
## Gastrulation itself
Gastrulation in mammals is similar to that in birds with the formation of the primitive streak and Hensen's node and the ingression of cells through the primitive groove to form the endoderm and the mesoderm. Thus, gastrulation creates all three germ layers of the embryo: ectoderm, mesoderm, and endoderm
During gastrulation, extraembryonic mesoderm forms within the hypoblast or embryonic mesoderm and migrates out to form the blood vessels of the chorion and connect the chorion to the embryo through the umbilical cord.
# Sea urchins
The following description concerns gastrulation in echinoderms, representative of the triploblasts, or animals with three embryonic germ layers. The illustration, however, depicts the gastrulation of a diploblast, animals with two germ layers.
Sea urchins deviate from simple cleavage at the fourth cleavage. The four vegetal blastomeres divide unequally to produce four micromeres at the vegetal pole and four macromeres in the middle of the embryo. The animal cells divide meridionally and produce mesomeres.
At the beginning of vertebrate gastrulation, the embryo is a hollow ball of cells known as the blastula, with an animal pole and a vegetal pole. The vegetal pole begins to flatten to form the vegetal plate. Some of the cells of the vegetal pole detach and through ingression become primary mesenchyme cells. The mesenchyme cells divide rapidly and migrate along the extracellular matrix (basal lamina) to different parts of the blastocoel. The migration is believed to be dependent upon sulfated proteoglycans on the surface of the cells and molecules on the basal lamina such as fibronectin. The cells move by forming filopodia that identify the specific target location. These filopodia then organize into syncytial cables that deposit the calcium carbonate that makes up the spicules (the skeleton of the pluteus larva).
During the second phase of gastrulation, the vegetal plate invaginates into the interior, replacing the blastocoelic cavity and thereby forming a new cavity, the archenteron (literally: primitive gut), the opening into which is the blastopore. The arechenteron is elongated by three mechanisms.
First, the initial invagination is caused by a differential expansion of the inner layer made of fibropellins and outer layer made of hyalin to cause the layers to bend inward.
Second, the archenteron is formed through convergent extension. Convergent extension results when cells intercalate to narrow the tissue and move it forward.
Third, secondary mesenchyme pull the tip of the archenteron towards the animal pole. Secondary mesenchyme are formed from cells that ingress from, but remain attached to, the roof of the archenteron. These cells extend filopodia that use guidance cues to find the future mouth region. Upon reaching the target site, the cells contract to pull the archenteron to fuse with the ectoderm. Once the archenteron reaches the animal pole, a perforation forms, and the archenteron becomes a digestive tract passing all the way through the embryo.
The three embryonic germ layers have now formed. The endoderm, consisting of the archenteron, will develop into the digestive tract. The ectoderm, consisting of the cells on the outside of the gastrula that played little part in gastrulation, will develop into the skin and the central nervous system. The mesoderm, consisting of the mesenchyme cells that have proliferated in the blastocoel, will become all the other internal organs.
# Amphibians
During cleavage in amphibians, a higher density of yolk in the vegetal half of the embryo results in the blastocoel cavity being placed asymmetrically in the animal half of the embryo. Unlike in sea urchins, the cells surrounding the blastocoel are thicker than a monolayer. The blastocoel cavity prevents signaling between the animal cap and provides a space for involuting cells during gastrulation.
There are four kinds of cell movements that drive gastrulation in Xenopus: invagination, involution, convergent extension and epiboly. At the dorsal marginal zone, cells change from a columnar shape to become a bottle cell and form an invagination. At this invagination, cells begin to involute into the embryo. This site of involution is called the dorsal lip. The involuting cells migrate along the inside of the blastocoel toward the animal cap. This migration is mediated by fibronectin of the extracellular matrix (ECM) secreted by the blastocoel roof. Eventually, cells from the lateral and ventral sides begin to involute to form a ring of involuting cells surrounding the yolk plug. These involuting cells will eventually form the archenteron which displaces and eventually replaces the blastocoel. Cells from the lateral marginal zone migrate toward the dorsal midline and intercalate with the cells there. This causes the dorsal involuting cells to undergo convergent extension. The dorsal cells become the first to migrate along the roof of the blastocoel cavity and form the anterior/posterior axis of the embryo. During the involution of cells, the cells of the animal cap undergo epiboly and spread toward the vegetal pole.
# Fish
At the time of mid-blastula transition, the zebrafish embryo is composed of three distinct cell layers: the enveloping layer (EVL), deep cells, and the yolk syncytial layer (YSL) formed from the fusion of cells adjacent to the yolk cells.
The first stage of gastrulation begins with the epiboly of the EVL and the deep cells over the YSL. This epiboly is driven by the migration of nuclei and cytoplasm in the YSL and attachments between the YSL and the EVL. Intercalation of the deep cells with the EVL help drive this movement. At about 50% of epiboly, a fate map similar to that of the Xenopus can be derived. The EVL develops into an extraembryonic membrane and does not contribute to the embryo.
The second stage of gastrulation occurs when the leading edge of the epibolizing blastoderm thickens. The dorsal side forms a larger thickening and is known as the embryonic shield. The deep cells in the embryonic shield form two layers. The epiblast forms near the surface and will give rise to the ectoderm. The hypoblast forms next to the YSL and will form a mixture of endoderm and mesoderm. The hypoblast is formed through involution and/or ingression. The movement of cells in the hypoblast are similar to the involuting mesoderm of amphibians. The end result of gastrulation is an asymmetric involution of cells that form the dorsal structures of the embryo.
# Birds
After cleavage, the blastoderm of chick embryos that sits above the yolk secretes fluid into the basally into the space between the yolk and the blastoderm called the subgerminal space. The region of the blastoderm above the subgerminal space is called the area pellucida. The region of the blastoderm above the yolk is the area opaca. The region where these two zones meet is called the marginal zone. At the posterior marginal zone (PMZ), there is a condensation of cells that is important in gastrulation. Within the PMZ, there is another thickening of cells called the Koller's sickle. Before gastrulation begins, the blastoderm forms two layers: the epiblast and the hypoblast. The epiblast gives rise to the embryo and some of the extraembryonic structures while the hypoblast contributes entirely to the extraembryonic membranes. The hypoblast comes from the primary hypoblast which delaminate out of the epiblast. This structure is equivalent to the organizer in amphibians and the embryonic shield in fish. Cells ingress through the primitive groove into the blastocoel cavity, migrate anteriorly through Hensen's node and then laterally through the rest of the groove. Cells that are fated to become the endoderm migrate to the bottom of the cavity and replace the hypoblast cells. Cells that are fated to become mesoderm remain in between the future endoderm cells and the epiblast and the epiblast cells remain to become ectodermal cells. The ectoderm, however, is undergoing epiboly to surround the yolk mass. The cells at the edge of the area opaca send out long filopida that attach to fibronectin in the vitelline membrane surrounding the embryo and yolk mass and pull the ectodermal cells toward the vegetal pole.
As gastrulation proceeds, the primitive streak regresses posteriorly with pharyngeal endoderm, the head process, and the notochord being laid down as it recedes. This results in a temporal gradient of development with the anterior forming organs while the posterior is still going through gastrulation. | Gastrulation
Gastrulation is a phase early in the development of animal embryos, during which the morphology of the embryo is dramatically restructured by cell migration. Gastrulation varies in different phyla. Gastrulation is followed by organogenesis, when individual organs develop within the newly formed germ layers.
# Mammals
## Preparation
In mammals, gastrulation occurs after implantation, around day 16 after fertilization in human embryogenesis. As the outer cell mass invades the endometrium, the inner cell mass divides into two layers: the epiblast and hypoblast. The hypoblast spreads out and covers the blastocoel to form the yolk sac. The yolk sac is an extraembryonic tissue that produces blood cells similar to the structure that surrounds the yolk in birds. The epiblast further divides into two more layers. The amnion layer forms the fluid filled cavity to surround and protect the embryo during pregnancy. The embryonic epiblast undergoes gastrulation.
## Gastrulation itself
Gastrulation in mammals is similar to that in birds with the formation of the primitive streak and Hensen's node and the ingression of cells through the primitive groove to form the endoderm and the mesoderm. Thus, gastrulation creates all three germ layers of the embryo: ectoderm, mesoderm, and endoderm
During gastrulation, extraembryonic mesoderm forms within the hypoblast or embryonic mesoderm and migrates out to form the blood vessels of the chorion and connect the chorion to the embryo through the umbilical cord.
# Sea urchins
The following description concerns gastrulation in echinoderms, representative of the triploblasts, or animals with three embryonic germ layers. The illustration, however, depicts the gastrulation of a diploblast, animals with two germ layers.
Sea urchins deviate from simple cleavage at the fourth cleavage. The four vegetal blastomeres divide unequally to produce four micromeres at the vegetal pole and four macromeres in the middle of the embryo. The animal cells divide meridionally and produce mesomeres.
At the beginning of vertebrate gastrulation, the embryo is a hollow ball of cells known as the blastula, with an animal pole and a vegetal pole. The vegetal pole begins to flatten to form the vegetal plate. Some of the cells of the vegetal pole detach and through ingression become primary mesenchyme cells. The mesenchyme cells divide rapidly and migrate along the extracellular matrix (basal lamina) to different parts of the blastocoel. The migration is believed to be dependent upon sulfated proteoglycans on the surface of the cells and molecules on the basal lamina such as fibronectin. The cells move by forming filopodia that identify the specific target location. These filopodia then organize into syncytial cables that deposit the calcium carbonate that makes up the spicules (the skeleton of the pluteus larva).
During the second phase of gastrulation, the vegetal plate invaginates into the interior, replacing the blastocoelic cavity and thereby forming a new cavity, the archenteron (literally: primitive gut), the opening into which is the blastopore. The arechenteron is elongated by three mechanisms.
First, the initial invagination is caused by a differential expansion of the inner layer made of fibropellins and outer layer made of hyalin to cause the layers to bend inward.
Second, the archenteron is formed through convergent extension. Convergent extension results when cells intercalate to narrow the tissue and move it forward.
Third, secondary mesenchyme pull the tip of the archenteron towards the animal pole. Secondary mesenchyme are formed from cells that ingress from, but remain attached to, the roof of the archenteron. These cells extend filopodia that use guidance cues to find the future mouth region. Upon reaching the target site, the cells contract to pull the archenteron to fuse with the ectoderm. Once the archenteron reaches the animal pole, a perforation forms, and the archenteron becomes a digestive tract passing all the way through the embryo.
The three embryonic germ layers have now formed. The endoderm, consisting of the archenteron, will develop into the digestive tract. The ectoderm, consisting of the cells on the outside of the gastrula that played little part in gastrulation, will develop into the skin and the central nervous system. The mesoderm, consisting of the mesenchyme cells that have proliferated in the blastocoel, will become all the other internal organs.
# Amphibians
During cleavage in amphibians, a higher density of yolk in the vegetal half of the embryo results in the blastocoel cavity being placed asymmetrically in the animal half of the embryo. Unlike in sea urchins, the cells surrounding the blastocoel are thicker than a monolayer. The blastocoel cavity prevents signaling between the animal cap and provides a space for involuting cells during gastrulation.
There are four kinds of cell movements that drive gastrulation in Xenopus: invagination, involution, convergent extension and epiboly. At the dorsal marginal zone, cells change from a columnar shape to become a bottle cell and form an invagination. At this invagination, cells begin to involute into the embryo. This site of involution is called the dorsal lip. The involuting cells migrate along the inside of the blastocoel toward the animal cap. This migration is mediated by fibronectin of the extracellular matrix (ECM) secreted by the blastocoel roof. Eventually, cells from the lateral and ventral sides begin to involute to form a ring of involuting cells surrounding the yolk plug. These involuting cells will eventually form the archenteron which displaces and eventually replaces the blastocoel. Cells from the lateral marginal zone migrate toward the dorsal midline and intercalate with the cells there. This causes the dorsal involuting cells to undergo convergent extension. The dorsal cells become the first to migrate along the roof of the blastocoel cavity and form the anterior/posterior axis of the embryo. During the involution of cells, the cells of the animal cap undergo epiboly and spread toward the vegetal pole.
# Fish
At the time of mid-blastula transition, the zebrafish embryo is composed of three distinct cell layers: the enveloping layer (EVL), deep cells, and the yolk syncytial layer (YSL) formed from the fusion of cells adjacent to the yolk cells.
The first stage of gastrulation begins with the epiboly of the EVL and the deep cells over the YSL. This epiboly is driven by the migration of nuclei and cytoplasm in the YSL and attachments between the YSL and the EVL. Intercalation of the deep cells with the EVL help drive this movement. At about 50% of epiboly, a fate map similar to that of the Xenopus can be derived. The EVL develops into an extraembryonic membrane and does not contribute to the embryo.
The second stage of gastrulation occurs when the leading edge of the epibolizing blastoderm thickens. The dorsal side forms a larger thickening and is known as the embryonic shield. The deep cells in the embryonic shield form two layers. The epiblast forms near the surface and will give rise to the ectoderm. The hypoblast forms next to the YSL and will form a mixture of endoderm and mesoderm. The hypoblast is formed through involution and/or ingression. The movement of cells in the hypoblast are similar to the involuting mesoderm of amphibians. The end result of gastrulation is an asymmetric involution of cells that form the dorsal structures of the embryo.
# Birds
After cleavage, the blastoderm of chick embryos that sits above the yolk secretes fluid into the basally into the space between the yolk and the blastoderm called the subgerminal space. The region of the blastoderm above the subgerminal space is called the area pellucida. The region of the blastoderm above the yolk is the area opaca. The region where these two zones meet is called the marginal zone. At the posterior marginal zone (PMZ), there is a condensation of cells that is important in gastrulation. Within the PMZ, there is another thickening of cells called the Koller's sickle. Before gastrulation begins, the blastoderm forms two layers: the epiblast and the hypoblast. The epiblast gives rise to the embryo and some of the extraembryonic structures while the hypoblast contributes entirely to the extraembryonic membranes. The hypoblast comes from the primary hypoblast which delaminate out of the epiblast. This structure is equivalent to the organizer in amphibians and the embryonic shield in fish. Cells ingress through the primitive groove into the blastocoel cavity, migrate anteriorly through Hensen's node and then laterally through the rest of the groove. Cells that are fated to become the endoderm migrate to the bottom of the cavity and replace the hypoblast cells. Cells that are fated to become mesoderm remain in between the future endoderm cells and the epiblast and the epiblast cells remain to become ectodermal cells. The ectoderm, however, is undergoing epiboly to surround the yolk mass. The cells at the edge of the area opaca send out long filopida that attach to fibronectin in the vitelline membrane surrounding the embryo and yolk mass and pull the ectodermal cells toward the vegetal pole.
As gastrulation proceeds, the primitive streak regresses posteriorly with pharyngeal endoderm, the head process, and the notochord being laid down as it recedes. This results in a temporal gradient of development with the anterior forming organs while the posterior is still going through gastrulation.
# External links
- Gastrulation Animations
- Human gastrulation 3D animation : [1]
Template:Developmental biology
de:Gastrulation
no:Gastrulasjon
sr:Гаструлација
fi:Gastrulaatio
Template:WH
Template:WikiDoc Sources
Template:Jb1 | https://www.wikidoc.org/index.php/Epiboly | |
66d60a2432066faef73818b90b03e8bdd733ba9f | wikidoc | Spermatocele | Spermatocele
Steven C. Campbell, M.D., Ph.D.
# Overview
Spermatocele is a retention cyst of a tubule of the rete testis or the head of the epididymis distended with a milky fluid that contains spermatozoa. Spermatoceles are the most common cystic condition encountered within the scrotum. They vary in size from several millimeters to many centimeters. Spermatoceles are generally not painful. However, some men may experience discomfort from larger spermatoceles.
# Epidemiology
- Spermatoceles can originate as diverticulum from the tubules found in the head of the epididymis. Sperm formation gradually causes the diverticulum to increase in size, causing a spermatocele. They are due to continuity between the epididymis and tunica vaginalis.
- They are also believed to result from epididymitis or physical trauma. Scarring, of any part of the epididymis, can cause it to become obstructed and may form a spermatocele.
# Diagnosis
Spermatoceles can be discovered as incidental scrotal masses found on physical examination by a physician. They may also be discovered by self-inspection of the scrotum and testicles.
Finding a painless, cystic mass at the head of the epididymis, that transilluminates and can be clearly differentiated from the testicle, is generally sufficient. If uncertainty exists, ultrasonography of the scrotum can confirm if it is spermatocele.
Consult a urologist.
# Treatment
Small cysts are best left alone, as are larger cysts that are asymptomatic. Only when the cysts are causing discomfort and are enlarging in size, or the patient wants the spermatocele removed, should a spermatocelectomy be considered. Pain may persist even after removal.
Spermatocelectomy can be performed on an outpatient basis, with the use of local or general anesthesia.
Note: A spermatocelectomy will not improve fertility. | Spermatocele
Template:DiseaseDisorder infobox
Template:Search infobox
Steven C. Campbell, M.D., Ph.D.
# Overview
Spermatocele is a retention cyst of a tubule of the rete testis or the head of the epididymis distended with a milky fluid that contains spermatozoa. Spermatoceles are the most common cystic condition encountered within the scrotum. They vary in size from several millimeters to many centimeters. Spermatoceles are generally not painful. However, some men may experience discomfort from larger spermatoceles.
# Epidemiology
- Spermatoceles can originate as diverticulum from the tubules found in the head of the epididymis. Sperm formation gradually causes the diverticulum to increase in size, causing a spermatocele. They are due to continuity between the epididymis and tunica vaginalis.
- They are also believed to result from epididymitis or physical trauma. Scarring, of any part of the epididymis, can cause it to become obstructed and may form a spermatocele.
# Diagnosis
Spermatoceles can be discovered as incidental scrotal masses found on physical examination by a physician. They may also be discovered by self-inspection of the scrotum and testicles.
Finding a painless, cystic mass at the head of the epididymis, that transilluminates and can be clearly differentiated from the testicle, is generally sufficient. If uncertainty exists, ultrasonography of the scrotum can confirm if it is spermatocele.
Consult a urologist.
# Treatment
Small cysts are best left alone, as are larger cysts that are asymptomatic. Only when the cysts are causing discomfort and are enlarging in size, or the patient wants the spermatocele removed, should a spermatocelectomy be considered. Pain may persist even after removal.
Spermatocelectomy can be performed on an outpatient basis, with the use of local or general anesthesia.
Note: A spermatocelectomy will not improve fertility. | https://www.wikidoc.org/index.php/Epididymal_Cyst | |
143071d4fb12b1fc124ee9b28b60f376ef29784a | wikidoc | Episcleritis | Episcleritis
Synonyms and keywords:
# Overview
Episcleritis is an acute, recurrent, benign inflammatory condition
-f the loose connective tissue lying superficial to the sclera and deeper to the conjunctiva.
# Classification
Inflammation of the episclera is classified by its location and severity using the system devised by Watson.
# Pathophysiology
The exact pathogenesis of Episcleritis is not fully understood.
# Causes
Episcleritis has been associated with a large number systemic morbidities. The commoner systemic conditions associated with episcleritis are atopy Rheumatoid arthritis, Spondyloarthritis, Inflammatory bowel disease, Systemic lupus erythematosus, Relapsing polychondritis, Gout. Rarely it may be associated with IgA nephropathy, Lyme disease and drug reaction to pamidronate.
Acne rosacea is the commonest ocular comorbid condition with
episcleritis and is typically seen in patients with eyelid and corneal
involvement. The ocular disease often precedes dermatological manifestations.
Episcleritis is also frequently seen as part of the spectrum of
atopic keratoconjunctivitis and dry eye syndrome.
# Epidemiology and Demographics
Episcleritis is overwhelmingly a disease of adults affecting a wide range of age groups; pediatric age group involvement is rare. The sex distribution varies between published
series but those series that describe an association with rheumatic diseases tend to have a female preponderance. Episcleritis is uncommon and the exact etiology of episcleritis is difficult to ascertain.
Diffuse episcleritis is more common than nodular episcleritis.The majority of patients with episcleritis have mild evanescent disease that usually does not require ophthalmological intervention and treatment.
# Risk Factors
There are no established risk factors for Episcleritis.
# Clinical Presentation
The onset of episcleritis is usually acute and the patient presents with discomfort rather than severe pain .The pain if present in Episcleritis is usually a mild discomfort and localized to the eye, rather than the typical boring pain associated with severe headache in scleritis.
Rarely, episcleritis may be associated foreign body sensation and epiphora. The hallmark signs of episcleritis are oedema and inflammation of the episclera and injection and dilatation of the episcleral blood vessels. The sclera and subtarsal conjunctiva are not involved but
the conjunctiva overlying the inflamed area is always affected. There is no scleral swelling or necrosis and the intraocular structures
are typically not involved. The visual acuity is normal as long as there is no co-morbidity.
In diffuse episcleritis there is diffuse swelling and
-edema of a sector of the episclera in around two-thirds of patients
-r of the whole eye in around one-third of patients. The redness varies in intensity, but is always red or pink
(rather than the bluish, brawny red colour seen in diffuse scleritis),
and the episcleral vessels, although engorged, retain their characteristic radial orientation.
The eye is generally not tender to touch. In nodular episcleritis , the oedema and infiltration is
localized to one part of the globe. A raised nodule forms within
the episcleral tissue. It is bright red to pink in colour and often has overlying or surrounding vascular irregularity. The nodule may be
tender to touch and is usually mobile. There is generally only one nodule at any one time and the nodules do not undergo necrosis.
Careful slit lamp examination of the episclera, sclera, and the blood vessels is essential to differentiate episcleritis from scleritis.
In patients with episcleritis there is oedema of the episclera and
dilatation of the conjunctival vessels. There is no oedema of the underlying sclera. The lack of scleral involvement is often easiest
to appreciate using red-free light and after blanching the superficial conjunctival vessels with phenylephrine 10%. After an attack of episcleritis the eye returns completely to normal,
but after repeated attacks over a long period of time there
may be some mild scleral thinning.
# Screening
There is insufficient evidence to recommend routine screening for Episcleritis.
# Natural History, Complications, and Prognosis
Episcleral inflammation adjacent to the cornea can lead to mild peripheral corneal infiltrate or oedema, and
the peripheral cornea can be left thinned or vascularized. Recurrent attacks of episcleritis over a long time can cause mild scleral thinning, which is of no consequence to the integrity of the eye. The most common complications seen in patients with episcleritis are related to the use of long-term topical corticosteroids.
The use of long-term topical corticosteroids can lead to Cataract, ocular hypertension, and steroid-induced glaucoma. Rarely, topical corticosteroids may also induce herpetic
keratitis. These treatment-related complications are the commonest causes of visual loss in patients with episcleritis.
# Diagnosis
When diagnosed clinically, a small number of
serological tests to ascertain associative autoimmune diseases like rheumatoid arthritis or systemic lupus
erythematosus may be useful.
Anterior segment fluorescein angiography in episcleritis reveals
a normal vascular pattern but the flow rate is generally faster than
normal and the whole transit of dye may be completed within two
to three seconds.
High definition anterior segment ultrasound helps in differentiating episcleritis from scleritis but is rarely
necessary clinically.
# Treatment
## Medical Therapy
Episcleritis is a self-limiting disease, thus it doesn't frequently require any treatment. If the symptoms are severe to require treatment, topical steroids generally
provide rapid symptomatic relief and have proven benefit over
topical non-steroidal anti-inflammatory treatment and topical
lubricants.
Systemic treatment with oral non-steroidal antiinflammatory
drugs such as cyclo-oxygenase inhibitors, may be
required for episcleritis. In general any systemic disease should be
treated on its merits and the episcleritis treated as necessary.
Any local ocular disease, such as acne rosacea, atopy, or
keratoconjunctivitis sicca that may be causing or contributing to
the episcleritis, should be treated aggressively. | Episcleritis
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1];Associate Editor(s)-in-Chief: Rohan Bir Singh, M.B.B.S.[2]
Synonyms and keywords:
# Overview
Episcleritis is an acute, recurrent, benign inflammatory condition
of the loose connective tissue lying superficial to the sclera and deeper to the conjunctiva.
# Classification
Inflammation of the episclera is classified by its location and severity using the system devised by Watson.[1]
# Pathophysiology
The exact pathogenesis of Episcleritis is not fully understood.
# Causes
Episcleritis has been associated with a large number systemic morbidities. The commoner systemic conditions associated with episcleritis are atopy Rheumatoid arthritis, Spondyloarthritis, Inflammatory bowel disease, Systemic lupus erythematosus, Relapsing polychondritis, Gout. Rarely it may be associated with IgA nephropathy, Lyme disease and drug reaction to pamidronate.
Acne rosacea is the commonest ocular comorbid condition with
episcleritis and is typically seen in patients with eyelid and corneal
involvement. The ocular disease often precedes dermatological manifestations.
Episcleritis is also frequently seen as part of the spectrum of
atopic keratoconjunctivitis and dry eye syndrome.
# Epidemiology and Demographics
Episcleritis is overwhelmingly a disease of adults affecting a wide range of age groups; pediatric age group involvement is rare.[2] The sex distribution varies between published
series but those series that describe an association with rheumatic diseases tend to have a female preponderance. Episcleritis is uncommon and the exact etiology of episcleritis is difficult to ascertain.
Diffuse episcleritis is more common than nodular episcleritis.[3]The majority of patients with episcleritis have mild evanescent disease that usually does not require ophthalmological intervention and treatment.
# Risk Factors
There are no established risk factors for Episcleritis.
# Clinical Presentation
The onset of episcleritis is usually acute and the patient presents with discomfort rather than severe pain .The pain if present in Episcleritis is usually a mild discomfort and localized to the eye, rather than the typical boring pain associated with severe headache in scleritis.
Rarely, episcleritis may be associated foreign body sensation and epiphora. The hallmark signs of episcleritis are oedema and inflammation of the episclera and injection and dilatation of the episcleral blood vessels. The sclera and subtarsal conjunctiva are not involved but
the conjunctiva overlying the inflamed area is always affected. There is no scleral swelling or necrosis and the intraocular structures
are typically not involved. The visual acuity is normal as long as there is no co-morbidity.
In diffuse episcleritis there is diffuse swelling and
oedema of a sector of the episclera in around two-thirds of patients
or of the whole eye in around one-third of patients. The redness varies in intensity, but is always red or pink
(rather than the bluish, brawny red colour seen in diffuse scleritis),
and the episcleral vessels, although engorged, retain their characteristic radial orientation.[2]
The eye is generally not tender to touch. In nodular episcleritis , the oedema and infiltration is
localized to one part of the globe. A raised nodule forms within
the episcleral tissue. It is bright red to pink in colour and often has overlying or surrounding vascular irregularity. The nodule may be
tender to touch and is usually mobile. There is generally only one nodule at any one time and the nodules do not undergo necrosis.
Careful slit lamp examination of the episclera, sclera, and the blood vessels is essential to differentiate episcleritis from scleritis.
In patients with episcleritis there is oedema of the episclera and
dilatation of the conjunctival vessels. There is no oedema of the underlying sclera. The lack of scleral involvement is often easiest
to appreciate using red-free light and after blanching the superficial conjunctival vessels with phenylephrine 10%. After an attack of episcleritis the eye returns completely to normal,
but after repeated attacks over a long period of time there
may be some mild scleral thinning.
# Screening
There is insufficient evidence to recommend routine screening for Episcleritis.
# Natural History, Complications, and Prognosis
Episcleral inflammation adjacent to the cornea can lead to mild peripheral corneal infiltrate or oedema, and
the peripheral cornea can be left thinned or vascularized. Recurrent attacks of episcleritis over a long time can cause mild scleral thinning, which is of no consequence to the integrity of the eye. The most common complications seen in patients with episcleritis are related to the use of long-term topical corticosteroids.
The use of long-term topical corticosteroids can lead to Cataract, ocular hypertension, and steroid-induced glaucoma. Rarely, topical corticosteroids may also induce herpetic
keratitis. These treatment-related complications are the commonest causes of visual loss in patients with episcleritis.
# Diagnosis
When diagnosed clinically, a small number of
serological tests to ascertain associative autoimmune diseases like rheumatoid arthritis or systemic lupus
erythematosus may be useful.
Anterior segment fluorescein angiography in episcleritis reveals
a normal vascular pattern but the flow rate is generally faster than
normal and the whole transit of dye may be completed within two
to three seconds.[4]
High definition anterior segment ultrasound helps in differentiating episcleritis from scleritis but is rarely
necessary clinically.
# Treatment
## Medical Therapy
Episcleritis is a self-limiting disease, thus it doesn't frequently require any treatment. If the symptoms are severe to require treatment, topical steroids generally
provide rapid symptomatic relief and have proven benefit over
topical non-steroidal anti-inflammatory treatment and topical
lubricants.
Systemic treatment with oral non-steroidal antiinflammatory
drugs such as cyclo-oxygenase inhibitors, may be
required for episcleritis. In general any systemic disease should be
treated on its merits and the episcleritis treated as necessary.
Any local ocular disease, such as acne rosacea, atopy, or
keratoconjunctivitis sicca that may be causing or contributing to
the episcleritis, should be treated aggressively. | https://www.wikidoc.org/index.php/Episcleritis | |
0d959611245b5b8932962a4429555542f7e5e7ff | wikidoc | Epoetin Alfa | Epoetin Alfa
# Disclaimer
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# Black Box Warning
# Overview
Epoetin Alfa is an erythropoiesis-stimulating agent that is FDA approved for the treatment of anemia due to chronic kidney disease, anemia due to zidovudine in HIV-infected patients， anemia due to chemotherapy in patients with cancer and reduction of allogeneic red blood cell transfusions in patients undergoing elective, noncardiac, nonvascular surgery. There is a Black Box Warning for this drug as shown here. Common adverse reactions include edema，injection site irritation, injection site pain, pruritus, rash，nausea, vomiting，arthralgia, myalgia, spasm, muscle，dizziness, headache, insomnia，cough, upper respiratory infection and fever.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
### Evaluation of Iron Stores and Nutritional Factors
- Evaluate the iron status in all patients before and during treatment and maintain iron repletion. Correct or exclude other causes of anemia (e.g., vitamin deficiency, metabolic or chronic inflammatory conditions, bleeding, etc.) before initiating Epogen.
### Patients with chronic kidney disease
- In controlled trials, patients experienced greater risks for death, serious adverse cardiovascular reactions, and stroke when administered erythropoiesis-stimulating agents (ESAs) to target a hemoglobin level of greater than 11 g/dL. No trial has identified a hemoglobin target level, ESA dose, or dosing strategy that does not increase these risks. Individualize dosing and use the lowest dose of Epogen sufficient to reduce the need for RBC transfusions. Physicians and patients should weigh the possible benefits of decreasing transfusions against the increased risks of death and other serious cardiovascular adverse events.
For all patients with CKD
- When initiating or adjusting therapy, monitor hemoglobin levels at least weekly until stable, then monitor at least monthly. When adjusting therapy consider hemoglobin rate of rise, rate of decline, ESA responsiveness and hemoglobin variability. A single hemoglobin excursion may not require a dosing change.
- Do not increase the dose more frequently than once every 4 weeks. Decreases in dose can occur more frequently. Avoid frequent dose adjustments.
- If the hemoglobin rises rapidly (e.g., more than 1 g/dL in any 2-week period), reduce the dose of Epogen by 25% or more as needed to reduce rapid responses.
- For patients who do not respond adequately, if the hemoglobin has not increased by more than 1 g/dL after 4 weeks of therapy, increase the dose by 25%.
- For patients who do not respond adequately over a 12-week escalation period, increasing the Epogen dose further is unlikely to improve response and may increase risks. Use the lowest dose that will maintain a hemoglobin level sufficient to reduce the need for RBC transfusions. Evaluate other causes of anemia. Discontinue Epogen if responsiveness does not improve.
For patients with CKD on dialysis
- Initiate Epogen treatment when the hemoglobin level is less than 10 g/dL.
- If the hemoglobin level approaches or exceeds 11 g/dL, reduce or interrupt the dose of Epogen.
- Recommended starting dose for adult patients : 50 to 100 Units/kg 3 times weekly intravenously or subcutaneously. For pediatric patients, a starting dose of 50 Units/kg 3 times weekly intravenously or subcutaneously is recommended. The intravenous route is recommended for patients on hemodialysis.
For patients with CKD not on dialysis
- Consider initiating Epogen treatment only when the hemoglobin level is less than 10 g/dL and the following considerations apply:
- The rate of hemoglobin decline indicates the likelihood of requiring a RBC transfusion and,
- Reducing the risk of alloimmunization and/or other RBC transfusion-related risks is a goal
- If the hemoglobin level exceeds 10 g/dL, reduce or interrupt the dose of Epogen, and use the lowest dose of Epogen sufficient to reduce the need for RBC transfusions.
- Recommended starting dose for adult patients is 50 to 100 Units/kg 3 times weekly intravenously or subcutaneously.
- When treating patients who have chronic kidney disease and cancer, physicians should refer to Warnings and Precautions.
- Refer patients who self-administer Epogen to the Instructions for Use.
### Zidovudine-treated HIV-infected Patients
Starting Dose
- The recommended starting dose in adults is 100 Units/kg as an intravenous or subcutaneous injection 3 times per week.
Dose Adjustment
- If hemoglobin does not increase after 8 weeks of therapy, increase Epogen dose by approximately
50 to 100 Units/kg at 4- to 8-week intervals until hemoglobin reaches a level needed to avoid RBC transfusions or 300 Units/kg.
- Withhold Epogen if hemoglobin exceeds 12 g/dL. Resume therapy at a dose 25% below the previous dose when hemoglobin declines to less than 11 g/dL.
- Discontinue Epogen if an increase in hemoglobin is not achieved at a dose of 300 Units/kg for 8 weeks.
### Patients on Cancer chemotherapy
- Initiate Epogen in patients on cancer chemotherapy only if the hemoglobin is less than 10 g/dL, and if there is a minimum of two additional months of planned chemotherapy.
- Use the lowest dose of Epogen necessary to avoid RBC transfusions.
Recommended Starting Dose
- Adults:
- 150 Units/kg subcutaneously 3 times per week until completion of a chemotherapy course or
- 40,000 Units subcutaneously weekly until completion of a chemotherapy course.
- Pediatric Patients (5 to 18 years):
- 600 Units/kg intravenously weekly until completion of a chemotherapy course.
Dose Reduction
- Reduce dose by 25% if:
- Hemoglobin increases greater than 1 g/dL in any 2-week period or
- Hemoglobin reaches a level needed to avoid RBC transfusion.
- Withhold dose if hemoglobin exceeds a level needed to avoid RBC transfusion. Reinitiate at a dose 25% below the previous dose when hemoglobin approaches a level where RBC transfusions may be required.
Dose Increase
- After the initial 4 weeks of Epogen therapy, if hemoglobin increases by less than 1 g/dL and remains below 10 g/dL, increase dose to:
- 300 Units/kg three times per week in adults or
- 60,000 Units weekly in adults
- 900 Units/kg (maximum 60,000 Units) weekly in children
- After 8 weeks of therapy, if there is no response as measured by hemoglobin levels or if RBC transfusions are still required, discontinue Epogen.
### Surgery Patients
- The recommended Epogen regimens are:
- 300 Units/kg per day subcutaneously for 15 days total: administered daily for 10 days before surgery, on the day of surgery, and for 4 days after surgery.
- 600 Units/kg subcutaneously in 4 doses administered 21, 14, and 7 days before surgery and on the day of surgery.
- Deep venous thrombosis prophylaxis is recommended during Epogen therapy.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
- There is limited information regarding Off-Label Guideline-Supported Use of Epoetin Alfa in adult patients.
### Non–Guideline-Supported Use
- There is limited information regarding Off-Label Non–Guideline-Supported Use of Epoetin Alfa in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
### Evaluation of Iron Stores and Nutritional Factors
- Evaluate the iron status in all patients before and during treatment and maintain iron repletion. Correct or exclude other causes of anemia (e.g., vitamin deficiency, metabolic or chronic inflammatory conditions, bleeding, etc.) before initiating Epogen.
### Patients with chronic kidney disease
- In controlled trials, patients experienced greater risks for death, serious adverse cardiovascular reactions, and stroke when administered erythropoiesis-stimulating agents (ESAs) to target a hemoglobin level of greater than 11 g/dL. No trial has identified a hemoglobin target level, ESA dose, or dosing strategy that does not increase these risks. Individualize dosing and use the lowest dose of Epogen sufficient to reduce the need for RBC transfusions. Physicians and patients should weigh the possible benefits of decreasing transfusions against the increased risks of death and other serious cardiovascular adverse events.
For all patients with CKD
- When initiating or adjusting therapy, monitor hemoglobin levels at least weekly until stable, then monitor at least monthly. When adjusting therapy consider hemoglobin rate of rise, rate of decline, ESA responsiveness and hemoglobin variability. A single hemoglobin excursion may not require a dosing change.
- Do not increase the dose more frequently than once every 4 weeks. Decreases in dose can occur more frequently. Avoid frequent dose adjustments.
- If the hemoglobin rises rapidly (e.g., more than 1 g/dL in any 2-week period), reduce the dose of Epogen by 25% or more as needed to reduce rapid responses.
- For patients who do not respond adequately, if the hemoglobin has not increased by more than 1 g/dL after 4 weeks of therapy, increase the dose by 25%.
- For patients who do not respond adequately over a 12-week escalation period, increasing the Epogen dose further is unlikely to improve response and may increase risks. Use the lowest dose that will maintain a hemoglobin level sufficient to reduce the need for RBC transfusions. Evaluate other causes of anemia. Discontinue Epogen if responsiveness does not improve.
For patients with CKD on dialysis
- Initiate Epogen treatment when the hemoglobin level is less than 10 g/dL.
- If the hemoglobin level approaches or exceeds 11 g/dL, reduce or interrupt the dose of Epogen.
- Recommended starting dose for adult patients : 50 to 100 Units/kg 3 times weekly intravenously or subcutaneously. For pediatric patients, a starting dose of 50 Units/kg 3 times weekly intravenously or subcutaneously is recommended. The intravenous route is recommended for patients on hemodialysis.
For patients with CKD not on dialysis
- Consider initiating Epogen treatment only when the hemoglobin level is less than 10 g/dL and the following considerations apply:
- The rate of hemoglobin decline indicates the likelihood of requiring a RBC transfusion and,
- Reducing the risk of alloimmunization and/or other RBC transfusion-related risks is a goal
- If the hemoglobin level exceeds 10 g/dL, reduce or interrupt the dose of Epogen, and use the lowest dose of Epogen sufficient to reduce the need for RBC transfusions.
- Recommended starting dose for adult patients is 50 to 100 Units/kg 3 times weekly intravenously or subcutaneously.
- When treating patients who have chronic kidney disease and cancer, physicians should refer to Warnings and Precautions.
- Refer patients who self-administer Epogen to the Instructions for Use.
### Zidovudine-treated HIV-infected Patients
Starting Dose
- The recommended starting dose in adults is 100 Units/kg as an intravenous or subcutaneous injection 3 times per week.
Dose Adjustment
- If hemoglobin does not increase after 8 weeks of therapy, increase Epogen dose by approximately
50 to 100 Units/kg at 4- to 8-week intervals until hemoglobin reaches a level needed to avoid RBC transfusions or 300 Units/kg.
- Withhold Epogen if hemoglobin exceeds 12 g/dL. Resume therapy at a dose 25% below the previous dose when hemoglobin declines to less than 11 g/dL.
- Discontinue Epogen if an increase in hemoglobin is not achieved at a dose of 300 Units/kg for 8 weeks.
### Patients on Cancer chemotherapy
- Initiate Epogen in patients on cancer chemotherapy only if the hemoglobin is less than 10 g/dL, and if there is a minimum of two additional months of planned chemotherapy.
- Use the lowest dose of Epogen necessary to avoid RBC transfusions.
Recommended Starting Dose
- Adults:
- 150 Units/kg subcutaneously 3 times per week until completion of a chemotherapy course or
- 40,000 Units subcutaneously weekly until completion of a chemotherapy course.
- Pediatric Patients (5 to 18 years):
- 600 Units/kg intravenously weekly until completion of a chemotherapy course.
Dose Reduction
- Reduce dose by 25% if:
- Hemoglobin increases greater than 1 g/dL in any 2-week period or
- Hemoglobin reaches a level needed to avoid RBC transfusion.
- Withhold dose if hemoglobin exceeds a level needed to avoid RBC transfusion. Reinitiate at a dose 25% below the previous dose when hemoglobin approaches a level where RBC transfusions may be required.
Dose Increase
- After the initial 4 weeks of Epogen therapy, if hemoglobin increases by less than 1 g/dL and remains below 10 g/dL, increase dose to:
- 300 Units/kg three times per week in adults or
- 60,000 Units weekly in adults
- 900 Units/kg (maximum 60,000 Units) weekly in children
- After 8 weeks of therapy, if there is no response as measured by hemoglobin levels or if RBC transfusions are still required, discontinue Epogen.
### Surgery Patients
- The recommended Epogen regimens are:
- 300 Units/kg per day subcutaneously for 15 days total: administered daily for 10 days before surgery, on the day of surgery, and for 4 days after surgery.
- 600 Units/kg subcutaneously in 4 doses administered 21, 14, and 7 days before surgery and on the day of surgery.
- Deep venous thrombosis prophylaxis is recommended during Epogen therapy.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
- There is limited information regarding Off-Label Guideline-Supported Use of Epoetin Alfa in pediatric patients.
### Non–Guideline-Supported Use
- There is limited information regarding Off-Label Non–Guideline-Supported Use of Epoetin Alfa in pediatric patients.
# Contraindications
Epogen is contraindicated in patients with:
- Uncontrolled hypertension.
- Pure red cell aplasia (PRCA) that begins after treatment with Epogen or other erythropoietin protein drugs
- Serious allergic reactions to Epogen.
Epogen from multidose vials contains benzyl alcohol and is contraindicated in:
- Neonates, infants, pregnant women, and nursing mothers. Benzyl alcohol has been associated with serious adverse events and death, particularly in pediatric patients. When therapy with Epogen is needed in neonates and infants, use single-dose vials; do not admix with bacteriostatic saline containing benzyl alcohol.
# Warnings
### Increased Mortality, Myocardial Infarction, stroke, and Thromboembolism
- In controlled clinical trials of patients with CKD comparing higher hemoglobin targets (13 - 14 g/dL) to lower targets (9 - 11.3 g/dL), Epogen and other ESAs increased the risk of death, Myocardial Infarction, stroke, congestive heart failure, thrombosis of hemodialysis vascular access, and other thromboembolic events in the higher target groups.
- Using ESAs to target a hemoglobin level of greater than 11 g/dL increases the risk of serious adverse cardiovascular reactions and has not been shown to provide additional benefit. Use caution in patients with coexistent cardiovascular disease and stroke. Patients with CKD and an insufficient hemoglobin response to ESA therapy may be at even greater risk for cardiovascular reactions and mortality than other patients. A rate of hemoglobin rise of greater than 1 g/dL over 2 weeks may contribute to these risks.
- In controlled clinical trials of patients with cancer, Epogen and other ESAs increased the risks for death and serious adverse cardiovascular reactions. These adverse reactions included myocardial infarction and stroke.
- In controlled clinical trials, ESAs increased the risk of death in patients undergoing coronary artery bypass graft surgery (CABG) and the risk of deep venous thrombosis (DVT) in patients undergoing orthopedic procedures.
- The design and overall results of the 3 large trials comparing higher and lower hemoglobin targets are shown in Table 1.
Patients with chronic kidney disease
- Normal Hematocrit Study (NHS): A prospective, randomized, open-label study of 1265 patients with chronic kidney disease on dialysis with documented evidence of congestive heart failure or ischemic heart disease was designed to test the hypothesis that a higher target hematocrit (Hct) would result in improved outcomes compared with a lower target Hct. In this study, patients were randomized to epoetin alfa treatment targeted to a maintenance hemoglobin of either 14 ± 1 g/dL or 10 ± 1 g/dL. The trial was terminated early with adverse safety findings of higher mortality in the high hematocrit target group. Higher mortality (35% vs. 29%) was observed for the patients randomized to a target hemoglobin of 14 g/dL than for the patients randomized to a target hemoglobin of 10 g/dL. For all-cause mortality, the HR=1.27; 95% CI (1.04, 1.54); p=0.018. The incidence of nonfatal Myocardial Infarction, vascular access thrombosis, and other thrombotic events was also higher in the group randomized to a target hemoglobin of 14 g/dL.
- CHOIR: A randomized, prospective trial, 1432 patients with anemia due to CKD who were not undergoing dialysis and who had not previously received epoetin alfa therapy were randomized to epoetin alfa treatment targeting a maintenance hemoglobin concentration of either 13.5 g/dL or 11.3 g/dL. The trial was terminated early with adverse safety findings. A major cardiovascular event (death, Myocardial Infarction, stroke, or hospitalization for congestive heart failure) occurred in 125 of the 715 patients (18%) in the higher hemoglobin group compared to 97 of the 717 patients (14%) in the lower hemoglobin group .
- TREAT: A randomized, double-blind, placebo-controlled, prospective trial of 4038 patients with: CKD not on dialysis (eGFR of 20 – 60 mL/min), anemia (hemoglobin levels ≤ 11 g/dL), and type 2 diabetes mellitus, patients were randomized to receive either darbepoetin alfa treatment or a matching placebo. Placebo group patients also received darbepoetin alfa when their hemoglobin levels were below 9 g/dL. The trial objectives were to demonstrate the benefit of darbepoetin alfa treatment of the anemia to a target hemoglobin level of 13 g/dL, when compared to a "placebo" group, by reducing the occurrence of either of two primary endpoints: (1) a composite cardiovascular endpoint of all-cause mortality or a specified cardiovascular event (myocardial ischemia, CHF, MI, and CVA) or (2) a composite renal endpoint of all-cause mortality or progression to end stage renal disease. The overall risks for each of the two primary endpoints (the cardiovascular composite and the renal composite) were not reduced with darbepoetin alfa treatment (see Table 1), but the risk of stroke was increased nearly two-fold in the darbepoetin alfa -treated group versus the placebo group: annualized stroke rate 2.1% vs. 1.1%, respectively, HR 1.92; 95% CI: 1.38, 2.68; p < 0.001. The relative risk of stroke was particularly high in patients with a prior stroke: annualized stroke rate 5.2% in the darbepoetin alfa- treated group and 1.9% in the placebo group, HR 3.07; 95% CI: 1.44, 6.54. Also, among darbepoetin alfa -treated subjects with a past history of cancer, there were more deaths due to all causes and more deaths adjudicated as due to cancer, in comparison with the control group.
Patients with Cancer
- An increased incidence of thromboembolic reactions, some serious and life-threatening, occurred in patients with cancer treated with ESAs.
- In a randomized, placebo-controlled study (Study 1 in Table 2) of 939 women with metastatic breast cancer receiving chemotherapy, patients received either weekly epoetin alfa or placebo for up to a year. This study was designed to show that survival was superior when epoetin alfa was administered to prevent anemia (maintain hemoglobin levels between 12 and 14 g/dL or hematocrit between 36% and 42%). This study was terminated prematurely when interim results demonstrated a higher mortality at 4 months (8.7% vs. 3.4%) and a higher rate of fatal thrombotic reactions (1.1% vs. 0.2%) in the first 4 months of the study among patients treated with epoetin alfa. Based on Kaplan-Meier estimates, at the time of study termination, the 12-month survival was lower in the epoetin alfa group than in the placebo group (70% vs. 76%; HR 1.37, 95% CI: 1.07, 1.75; p = 0.012).
Patients Having Surgery
- An increased incidence of deep venous thrombosis (DVT) in patients receiving epoetin alfa undergoing surgical orthopedic procedures was demonstrated. In a randomized, controlled study, 680 adult patients, not receiving prophylactic anticoagulation and undergoing spinal surgery, were randomized to 4 doses of 600 Units/kg epoetin alfa (7, 14, and 21 days before surgery, and the day of surgery) and standard of care (SOC) treatment (n = 340) or to SOC treatment alone (n = 340). A higher incidence of DVTs, determined by either color flow duplex imaging or by clinical symptoms, was observed in the epoetin alfa group (16 patients) compared with the SOC group (7 patients). In addition to the 23 patients with DVTs included in the primary analysis, 19 patients (n = 680) experienced 1 other thrombovascular event (TVE) each (12 in the epoetin alfa group and 7 in the SOC group). deep venous thrombosis prophylaxis is strongly recommended when ESAs are used for the reduction of allogeneic RBC transfusions in surgical patients.
- Increased mortality was observed in a randomized, placebo-controlled study of Epogen in adult patients who were undergoing CABG surgery (7 deaths in 126 patients randomized to Epogen versus no deaths among 56 patients receiving placebo). Four of these deaths occurred during the period of study drug administration and all 4 deaths were associated with thrombotic events.
### Prescribing and Distribution Program for Epogen in Patients With Cancer
- In order to prescribe and/or dispense Epogen to patients with cancer and anemia due to myelosuppressive chemotherapy, prescribers and hospitals must enroll in and comply with the ESA APPRISE Oncology Program requirements. To enroll, visit www.esa-apprise.com or call 1-866-284-8089 for further assistance. Additionally, prior to each new course of Epogen in patients with cancer, prescribers and patients must provide written acknowledgment of a discussion of the risks of Epogen.
### Increased Mortality and/or Increased Risk of Tumor Progression or Recurrence in Patients With Cancer
- ESAs resulted in decreased locoregional control/progression-free survival and/or overall survival (see Table 2). These findings were observed in studies of patients with advanced head and neck cancer receiving radiation therapy (Studies 5 and 6), in patients receiving chemotherapy for metastatic breast cancer (Study 1) or lymphoid malignancy (Study 2), and in patients with non-small cell lung cancer or various malignancies who were not receiving chemotherapy or radiotherapy.
Decreased Overall Survival
- Study 1 was described in the previous section. Mortality at 4 months (8.7% vs. 3.4%) was significantly higher in the epoetin alfa arm. The most common investigator-attributed cause of death within the first 4 months was disease progression; 28 of 41 deaths in the epoetin alfa arm and 13 of 16 deaths in the placebo arm were attributed to disease progression. Investigator-assessed time to tumor progression was not different between the 2 groups. Survival at 12 months was significantly lower in the epoetin alfa arm (70% vs. 76%; HR 1.37, 95% CI: 1.07, 1.75; p = 0.012).
- Study 2 was a randomized, double-blind study (darbepoetin alfa vs. placebo) conducted in 344 anemic patients with lymphoid malignancy receiving chemotherapy. With a median follow-up of 29 months, overall mortality rates were significantly higher among patients randomized to darbepoetin alfa as compared to placebo (HR 1.36, 95% CI: 1.02, 1.82).
- Study 7 was a multicenter, randomized, double-blind study (epoetin alfa vs. placebo) in which patients with advanced non-small cell lung cancer receiving only palliative radiotherapy or no active therapy were treated with epoetin alfa to achieve and maintain hemoglobin levels between 12 and 14 g/dL. Following an interim analysis of 70 patients (planned accrual 300 patients), a significant difference in survival in favor of the patients in the placebo arm of the study was observed (median survival 63 vs. 129 days; HR 1.84; p = 0.04).
- Study 8 was a randomized, double-blind study (darbepoetin alfa vs. placebo) in 989 anemic patients with active malignant disease, neither receiving nor planning to receive chemotherapy or radiation therapy. There was no evidence of a statistically significant reduction in proportion of patients receiving RBC transfusions. The median survival was shorter in the darbepoetin alfa treatment group than in the placebo group (8 months vs. 10.8 months; HR 1.30, 95% CI: 1.07, 1.57).
Decreased Progression-free Survival and Overall Survival
- Study 3 was a randomized, open-label, controlled, factorial design study in which darbepoetin alfa was administered to prevent anemia in 733 women receiving neo-adjuvant breast cancer treatment. A final analysis was performed after a median follow-up of approximately 3 years. The 3-year survival rate was lower (86% vs. 90%; HR 1.42, 95% CI: 0.93, 2.18) and the 3-year relapse-free survival rate was lower (72% vs. 78%; HR 1.33, 95% CI: 0.99, 1.79) in the darbepoetin alfa-treated arm compared to the control arm.
- Study 4 was a randomized, open-label, controlled study that enrolled 114 of a planned 460 cervical cancer patients receiving chemotherapy and radiotherapy. Patients were randomized to receive epoetin alfa to maintain hemoglobin between 12 and 14 g/dL or to RBC transfusion support as needed. The study was terminated prematurely due to an increase in thromboembolic adverse reactions in epoetin alfa-treated patients compared to control (19% vs. 9%). Both local recurrence (21% vs. 20%) and distant recurrence (12% vs. 7%) were more frequent in epoetin alfa-treated patients compared to control. Progression-free survival at 3 years was lower in the epoetin alfa-treated group compared to control (59% vs. 62%; HR 1.06, 95% CI: 0.58, 1.91). Overall survival at 3 years was lower in the epoetin alfa-treated group compared to control (61% vs. 71%; HR 1.28, 95% CI: 0.68, 2.42).
- Study 5 was a randomized, placebo-controlled study in 351 head and neck cancer patients where epoetin beta or placebo was administered to achieve target hemoglobins ≥ 14 and ≥ 15 g/dL for women and men, respectively. Locoregional progression-free survival was significantly shorter in patients receiving epoetin beta (HR 1.62, 95% CI: 1.22, 2.14; p = 0.0008) with medians of 406 days and 745 days in the epoetin beta and placebo arms, respectively. Overall survival was significantly shorter in patients receiving epoetin beta (HR 1.39, 95% CI: 1.05, 1.84; p = 0.02).
Decreased Locoregional Control
- Study 6 was a randomized, open-label, controlled study conducted in 522 patients with primary squamous cell carcinoma of the head and neck receiving radiation therapy alone (no chemotherapy) who were randomized to receive darbepoetin alfa to maintain hemoglobin levels of 14 to15.5 g/dL or no darbepoetin alfa. An interim analysis performed on 484 patients demonstrated that locoregional control at 5 years was significantly shorter in patients receiving darbepoetin alfa (RR 1.44, 95% CI: 1.06, 1.96; p = 0.02). Overall survival was shorter in patients receiving darbepoetin alfa (RR 1.28, 95% CI: 0.98, 1.68; p = 0.08).
### Hypertension
- Epogen is contraindicated in patients with uncontrolled hypertension. Following initiation and titration of Epogen, approximately 25% of patients on dialysis required initiation of or increases in antihypertensive therapy; hypertensive encephalopathy and seizures have been reported in patients with CKD receiving Epogen.
- Appropriately control hypertension prior to initiation of and during treatment with Epogen. Reduce or withhold Epogen if blood pressure becomes difficult to control. Advise patients of the importance of compliance with antihypertensive therapy and dietary restrictions.
### Seizures
- Epogen increases the risk of seizures in patients with CKD. During the first several months following initiation of Epogen, monitor patients closely for premonitory neurologic symptoms. Advise patients to contact their healthcare practitioner for new-onset seizures, premonitory symptoms or change in seizure frequency.
### Lack or Loss of Hemoglobin Response to Epogen
- For lack or loss of hemoglobin response to Epogen, initiate a search for causative factors (e.g., iron deficiency, infection, inflammation, bleeding). If typical causes of lack or loss of hemoglobin response are excluded, evaluate for PRCA . In the absence of PRCA, follow dosing recommendations for management of patients with an insufficient hemoglobin response to Epogen therapy.
### Pure Red Cell Aplasia
- Cases of PRCA and of severe anemia, with or without other cytopenias that arise following the development of neutralizing antibodies to erythropoietin have been reported in patients treated with Epogen. This has been reported predominantly in patients with CKD receiving ESAs by subcutaneous administration. PRCA has also been reported in patients receiving ESAs for anemia related to hepatitis C treatment (an indication for which Epogen is not approved).
- If severe anemia and low reticulocyte count develop during treatment with Epogen, withhold Epogen and evaluate patients for neutralizing antibodies to erythropoietin. Contact Amgen (1-800-77-AMGEN) to perform assays for binding and neutralizing antibodies. Permanently discontinue Epogen in patients who develop PRCA following treatment with Epogen or other erythropoietin protein drugs. Do not switch patients to other ESAs.
### Serious Allergic Reactions
- Serious allergic reactions, including anaphylactic reactions, angioedema, bronchospasm, skin rash, and urticaria may occur with Epogen. Immediately and permanently discontinue Epogen and administer appropriate therapy if a serious allergic or anaphylactic reaction occurs.
### Albumin (Human)
- Epogen contains albumin, a derivative of human blood. Based on effective donor screening and product manufacturing processes, it carries an extremely remote risk for transmission of viral diseases. A theoretical risk for transmission of Creutzfeldt-Jakob disease (CJD) also is considered extremely remote. No cases of transmission of viral diseases or CJD have ever been identified for albumin.
### Dialysis Management
- Patients may require adjustments in their dialysis prescriptions after initiation of Epogen. Patients receiving Epogen may require increased anticoagulation with heparin to prevent clotting of the extracorporeal circuit during hemodialysis.
### Laboratory Monitoring
- Evaluate transferrin saturation and serum ferritin prior to and during Epogen treatment. Administer supplemental iron therapy when serum ferritin is less than 100 mcg/L or when serum transferrin saturation is less than 20%. The majority of patients with CKD will require supplemental iron during the course of ESA therapy. Following initiation of therapy and after each dose adjustment, monitor hemoglobin weekly until the hemoglobin level is stable and sufficient to minimize the need for RBC transfusion.
# 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 other drugs and may not reflect the rates observed in practice.
Patients with chronic kidney disease
Adult Patients
- Three double-blind, placebo-controlled studies, including 244 patients with CKD on dialysis, were used to identify the adverse reactions to Epogen. In these studies, the mean age of patients was 48 years (range: 20 to 80 years). One hundred and thirty-three (55%) patients were men. The racial distribution was as follows: 177 (73%) patients were white, 48 (20%) patients were black, 4 (2%) patients were Asian, 12 (5%) patients were other, and racial information was missing for 3 (1%) patients.
- Two double-blind, placebo-controlled studies, including 210 patients with CKD not on dialysis, were used to identify the adverse reactions to Epogen. In these studies, the mean age of patients was 57 years (range: 24 to 79 years). One hundred and twenty-one (58%) patients were men. The racial distribution was as follows: 164 (78%) patients were white, 38 (18%) patients were black, 3 (1%) patients were Asian, 3 (1%) patients were other, and racial information was missing for 2 (1%) patients.
- The adverse reactions with a reported incidence of ≥ 5% in Epogen-treated patients and that occurred at a ≥ 1% higher frequency than in placebo-treated patients are shown in the table below:
- An additional serious adverse reaction that occurred in less than 5% of epoetin alfa-treated dialysis patients and greater than placebo was thrombosis (2.7% Epogen and 1% placebo).
- The adverse reactions with a reported incidence of ≥ 5% in Epogen-treated patients and that occurred at a ≥ 1% higher frequency than in placebo-treated patients are shown in the table below:
- Additional serious adverse reactions that occurred in less than 5% of epoetin alfa-treated patients not on dialysis and greater than placebo were erythema (0.8% Epogen and 0% placebo) and myocardial infarction (0.8% Epogen and 0% placebo).
Pediatric Patients
- In pediatric patients with CKD on dialysis, the pattern of adverse reactions was similar to that found in adults.
Zidovudine-treated HIV-infected Patients
- A total of 297 Zidovudine-treated HIV-infected patients were studied in 4 placebo-controlled studies. A total of 144 (48%) patients were randomly assigned to receive Epogen and 153 (52%) patients were randomly assigned to receive placebo. Epogen was administered at doses between 100 and 200 Units/kg 3 times weekly subcutaneously for up to 12 weeks.
- For the combined Epogen treatment groups, a total of 141 (98%) men and 3 (2%) women between the ages of 24 and 64 years were enrolled. The racial distribution of the combined Epogen treatment groups was as follows: 129 (90%) white, 8 (6%) black, 1 (1%) Asian, and 6 (4%) other.
- In double-blind, placebo-controlled studies of 3 months duration involving approximately 300 Zidovudine-treated HIV-infected patients, adverse reactions with an incidence of ≥ 1% in patients treated with Epogen were:
Cancer Patients on chemotherapy
- The data below were obtained in Study C1, a 16-week, double-blind, placebo-controlled study that enrolled 344 patients with anemia secondary to chemotherapy. There were 333 patients who were evaluable for safety; 168 of 174 patients (97%) randomized to Epogen received at least 1 dose of study drug, and 165 of 170 patients (97%) randomized to placebo received at least 1 placebo dose. For the once weekly Epogen-treatment group, a total of 76 men (45%) and 92 women (55%) between the ages of 20 and 88 years were treated. The racial distribution of the Epogen-treatment group was 158 white (94%) and 10 black (6%). Epogen was administered once weekly for an average of 13 weeks at a dose of 20,000 to 60,000 IU subcutaneously (mean weekly dose was 49,000 IU).
- The adverse reactions with a reported incidence of ≥ 5% in Epogen-treated patients that occurred at a higher frequency than in placebo-treated patients are shown in the table below:
Surgery Patients
- Four hundred sixty-one patients undergoing major orthopedic surgery were studied in a placebo-controlled study (S1) and a comparative dosing study (2 dosing regimens, S2). A total of 358 patients were randomly assigned to receive Epogen and 103 (22%) patients were randomly assigned to receive placebo. Epogen was administered daily at a dose of 100 to 300 IU/kg subcutaneously for 15 days or at 600 IU/kg once weekly for 4 weeks.
- For the combined Epogen treatment groups, a total of 90 (25%) and 268 (75%) women between the ages of 29 and 89 years were enrolled. The racial distribution of the combined Epogen treatment groups was as follows: 288 (80%) white, 64 (18%) black, 1 (< 1%) Asian, and 5 (1%) other.
- The adverse reactions with a reported incidence of ≥ 1% in Epogen-treated patients that occurred at a higher frequency than in placebo-treated patients are shown in the table below:
## Postmarketing Experience
- Because postmarketing reporting of adverse reactions is voluntary and from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
- The following adverse reactions have been identified during postmarketing use of Epogen:
- Seizures
- PRCA
- Serious allergic reactions
- Injection site reactions, including irritation and pain
- Porphyria
## Immunogenicity
- As with all therapeutic proteins, there is a potential for immunogenicity. Neutralizing antibodies to epoetin alfa that cross-react with endogenous erythropoietin and other ESAs can result in PRCA or severe anemia (with or without other cytopenias).
- The incidence of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors, including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to Epogen with the incidence of antibodies to other products may be misleading.
# Drug Interactions
- No formal drug interaction studies have been conducted with Epogen.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): C
- The multidose vials are formulated with benzyl alcohol. Do not administer Epogen from multidose vials, or Epogen from single-dose vials admixed with bacteriostatic saline containing benzyl alcohol, to pregnant women. When therapy with Epogen is needed during pregnancy, use a benzyl alcohol-free formulation.
Pregnancy Category C (single-dose vials only)
- There are no adequate and well-controlled studies of Epogen use during pregnancy. There are limited data on Epogen use in pregnant women. In animal reproductive and developmental toxicity studies, adverse fetal effects occurred when pregnant rats received epoetin alfa at doses approximating the clinical recommended starting doses. Single-dose formulations of Epogen should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
- There are reports of at least 33 pregnant women with anemia alone or anemia associated with severe renal disease and other hematologic disorders who received Epogen. Polyhydramnios and intrauterine growth restriction were reported in women with chronic renal disease, which is associated with an increased risk for these adverse pregnancy outcomes. There was 1 infant born with pectus excavatum and hypospadias following exposure during the first trimester. Due to the limited number of exposed pregnancies and multiple confounding factors (such as underlying maternal conditions, other maternal medications, and gestational timing of exposure), these published case reports and studies do not reliably estimate the frequency or absence of adverse outcomes.
- When healthy rats received Epogen at doses of 100 Units/kg/day during mating and through early pregnancy (dosing stopped prior to organogenesis), there were slight increases in the incidences of pre-and post-implantation loss, and a decrease in live fetuses. This animal dose level of 100 Units/kg/day may approximate the clinical recommended starting dose, depending on the treatment indication. When healthy pregnant rats and rabbits received intravenous doses of up to 500 mg/kg/day of Epogen only during organogenesis, no teratogenic effects were observed in the offspring.
- When healthy pregnant rats received Epogen at doses of 500 Units/kg/day late in pregnancy (after the period of organogenesis), offspring had decreased number of caudal vertebrae and growth delays.
- Women who become pregnant during Epogen treatment are encouraged to enroll in Amgen’s Pregnancy Surveillance Program. Patients or their physicians should call 1-800-772-6436 (1-800-77-AMGEN) to enroll.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Epoetin Alfa in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Epoetin Alfa during labor and delivery.
### Nursing Mothers
- The multidose vials of Epogen are formulated with benzyl alcohol. Do not administer Epogen from multidose vials, or Epogen from single-dose vials admixed with bacteriostatic saline containing benzyl alcohol, to a nursing woman. When therapy with Epogen is needed in nursing women, use a benzyl alcohol-free formulation.
- It is not known whether Epogen is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Epogen from single-dose vials is administered to a nursing woman.
### Pediatric Use
- The multidose vials are formulated with benzyl alcohol. Do not administer Epogen from multidose vials, or Epogen from single-dose vials admixed with bacteriostatic saline containing benzyl alcohol, to neonates or infants. When therapy with Epogen is needed in neonates and infants, use a benzyl alcohol-free formulation.
- Benzyl alcohol has been associated with serious adverse events and death, particularly in pediatric patients. The "gasping syndrome," (characterized by central nervous system depression, metabolic acidosis, gasping respirations, and high levels of benzyl alcohol and its metabolites found in the blood and urine) has been associated with benzyl alcohol dosages > 99 mg/kg/day in neonates and low-birthweight neonates. Additional symptoms may include gradual neurological deterioration, seizures, intracranial hemorrhage, hematologic abnormalities, skin breakdown, hepatic and renal failure, hypotension, bradycardia, and cardiovascular collapse.
- Although normal therapeutic doses of this product deliver amounts of benzyl alcohol that are substantially lower than those reported in association with the "gasping syndrome", the minimum amount of benzyl alcohol at which toxicity may occur is not known. Premature and low-birthweight infants, as well as patients receiving high dosages, may be more likely to develop toxicity. Practitioners administering this and other medications containing benzyl alcohol should consider the combined daily metabolic load of benzyl alcohol from all sources.
Pediatric Patients on dialysis
- Epogen is indicated in pediatric patients, ages 1 month to 16 years of age, for the treatment of anemia associated with CKD requiring dialysis. Safety and effectiveness in pediatric patients less than 1 month old have not been established.
- The safety data from these studies are similar to those obtained from the studies of Epogen in adult patients with CKD.
Pediatric Cancer Patients on chemotherapy
- Epogen is indicated in patients 5 to 18 years old for the treatment of anemia due to concomitant myelosuppressive chemotherapy. Safety and effectiveness in pediatric patients less than 5 years of age have not been established. The safety data from these studies are similar to those obtained from the studies of Epogen in adult patients with cancer.
Pediatric Patients With HIV Infection Receiving Zidovudine
- Published literature has reported the use of Epogen in 20 Zidovudine-treated, anemic, pediatric patients with HIV infection, ages 8 months to 17 years, treated with 50 to 400 Units/kg subcutaneously or intravenously 2 to 3 times per week. Increases in hemoglobin levels and in reticulocyte counts and decreases in or elimination of RBC transfusions were observed.
Pharmacokinetics in Neonates
- Limited pharmacokinetic data from a study of 7 preterm, very low birth weight neonates and 10 healthy adults given intravenous erythropoietin suggested that distribution volume was approximately 1.5 to 2 times higher in the preterm neonates than in the healthy adults, and clearance was approximately 3 times higher in the preterm neonates than in the healthy adults.
### Geriatic Use
- Of the 4553 patients who received Epogen in the 6 studies for treatment of anemia due to CKD not receiving dialysis, 2726 (60%) were age 65 years and over, while 1418 (31%) were 75 years and over. Of the 757 patients who received Epogen in the 3 studies of CKD patients on dialysis, 361 (47%) were age 65 years and over, while 100 (13%) were 75 years and over. No differences in safety or effectiveness were observed between geriatric and younger patients. Dose selection and adjustment for an elderly patient should be individualized to achieve and maintain the target hemoglobin.
- Among 778 patients enrolled in the 3 clinical studies of Epogen for the treatment of anemia due to concomitant chemotherapy, 419 received Epogen and 359 received placebo. Of the 419 who received Epogen, 247 (59%) were age 65 years and over, while 78 (19%) were 75 years and over. No overall differences in safety or effectiveness were observed between geriatric and younger patients. The dose requirements for Epogen in geriatric and younger patients within the 3 studies were similar.
- Among 1731 patients enrolled in the 6 clinical studies of Epogen for reduction of allogeneic RBC transfusions in patients undergoing elective surgery, 1085 received Epogen and 646 received placebo or standard of care treatment. Of the 1085 patients who received Epogen, 582 (54%) were age 65 years and over, while 245 (23%) were 75 years and over. No overall differences in safety or effectiveness were observed between geriatric and younger patients. The dose requirements for Epogen in geriatric and younger patients within the 4 studies using the 3 times weekly schedule and 2 studies using the weekly schedule were similar.
- Insufficient numbers of patients age 65 years or older were enrolled in clinical studies of Epogen for the treatment of Zidovudine in HIV-infected patients to determine whether they respond differently from younger patients.
### Gender
There is no FDA guidance on the use of Epoetin Alfa with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Epoetin Alfa with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Epoetin Alfa in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Epoetin Alfa in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Epoetin Alfa in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Epoetin Alfa in patients who are immunocompromised.
# Administration and Monitoring
### Administration
Preparation and Administration
- Do not shake. Do not use Epogen that has been shaken or frozen.
- Protect vials from light.
- Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration. Do not use any vials exhibiting particulate matter or discoloration.
- Discard unused portions of Epogen in preservative-free vials. Do not re-enter preservative-free vials.
- Store unused portions of Epogen in multidose vials at 36°F to 46° F (2°C to 8°C). Discard 21 days after initial entry.
- Do not dilute. Do not mix with other drug solutions except for admixing as described below:
- Preservative-free Epogen from single-use vials may be admixed in a syringe with bacteriostatic 0.9% sodium chloride injection, USP, with benzyl alcohol 0.9% (bacteriostatic saline) in a 1:1 ratio using aseptic technique at the time of administration. Risks are associated with benzyl alcohol in neonates, infants, pregnant women, and nursing mothers.
### Monitoring
- FDA Package Insert for Epoetin Alfa contains no information regarding Drug Monitoring.
# IV Compatibility
- There is limited information about the IV Compatibility.
# Overdosage
- Epogen overdosage can cause hemoglobin levels above the desired level, which should be managed with discontinuation or reduction of Epogen dosage and/or with phlebotomy as clinically indicated. Cases of severe hypertension have been observed following overdose with ESAs
# Pharmacology
## Mechanism of Action
- Epogen stimulates erythropoiesis by the same mechanism as endogenous erythropoietin.
## Structure
- Epogen (epoetin alfa) is a 165-amino acid erythropoiesis-stimulating glycoprotein manufactured by recombinant DNA technology. It has a molecular weight of approximately 30,400 daltons and is produced by mammalian cells into which the human erythropoietin gene has been introduced. The product contains the identical amino acid sequence of isolated natural erythropoietin.
- Epogen is formulated as a sterile, colorless liquid in vials in multiple formulations. Single-dose vials, formulated with an isotonic sodium chloride/sodium citrate-buffered solution, are supplied in multiple strengths. Each 1 mL vial contains 2000, 3000, 4000, or 10,000 Units of epoetin alfa, Albumin (Human) (2.5 mg), citric acid (0.06 mg), sodium chloride (5.9 mg), and sodium citrate (5.8 mg) in Water for Injection, USP (pH 6.9 ± 0.3). Single-dose 1 mL vials formulated with an isotonic sodium chloride/sodium phosphate buffer contain 40,000 Units of epoetin alfa albumin (human) (2.5 mg), citric acid (0.0068 mg), sodium chloride (5.8 mg), sodium citrate (0.7 mg), sodium phosphate dibasic anhydrate (1.8 mg), and sodium phosphate monobasic monohydrate (1.2 mg) in Water for Injection, USP (pH 6.9 ± 0.3). Multidose, 2 mL vials contain 10,000 Units epoetin alfa, albumin (human) (2.5 mg), benzyl alcohol (1%), sodium chloride (8.2 mg), and sodium citrate (1.3 mg) per 1 mL Water for Injection, USP (pH 6.1 ± 0.3). Multidose 1 mL vials contain 20,000 Units epoetin alfa, albumin (human) (2.5 mg), benzyl alcohol (1%), sodium chloride (8.2 mg), citric acid (0.11 mg), and sodium citrate (1.3 mg), per 1 mL in Water for Injection, USP (pH 6.1 ± 0.3).
## Pharmacodynamics
- Epogen increases the reticulocyte count within 10 days of initiation, followed by increases in the RBC count, hemoglobin, and hematocrit, usually within 2 to 6 weeks. The rate of hemoglobin increase varies among patients and is dependent upon the dose of Epogen administered. For correction of anemia in hemodialysis patients, a greater biologic response is not observed at doses exceeding 300 Units/kg 3 times weekly.
## Pharmacokinetics
- In adult and pediatric patients with CKD, the elimination half-life (t1/2) of plasma erythropoietin after intravenous administration of Epogen ranged from 4 to 13 hours. After subcutaneous administration, Cmax was achieved within 5 to 24 hours. The t1/2 in adult patients with serum creatinine greater than 3 mg/dL was similar between those not on dialysis and those maintained on dialysis. The pharmacokinetic data indicate no apparent difference in Epogen t1/2 among adult patients above or below 65 years of age.
- A pharmacokinetic study comparing 150 Units/kg subcutaneous 3 times weekly to 40,000 Units subcutaneous weekly dosing regimen was conducted for 4 weeks in healthy subjects (n = 12) and for 6 weeks in anemic cancer patients (n = 32) receiving cyclic chemotherapy. There was no accumulation of serum erythropoietin after the 2 dosing regimens during the study period. The 40,000 Units weekly regimen had a higher Cmax (3- to 7-fold), longer Tmax (2- to 3-fold), higher AUC0-168 h (2- to 3-fold) of erythropoietin and lower clearance (CL) (50%) than the 150 Units/kg 3 times weekly regimen. In anemic cancer patients, the average t1/2 was similar (40 hours with range of 16 to 67 hours) after both dosing regimens. After the 150 Units/kg 3 times weekly dosing, the values of Tmax and CL were similar (13.3 ± 12.4 vs. 14.2 ± 6.7 hours, and 20.2 ± 15.9 vs. 23.6 ± 9.5 mL/hr/kg) between week 1 when patients were receiving chemotherapy (n = 14) and week 3 when patients were not receiving chemotherapy (n = 4). Differences were observed after the 40,000 Units weekly dosing with longer Tmax (38 ± 18 hours) and lower CL (9.2 ± 4.7 mL/hr/kg) during week 1 when patients were receiving chemotherapy (n = 18) compared with those (22 ± 4.5 hours, 13.9 ± 7.6 mL/hr/kg, respectively) during week 3 when patients were not receiving chemotherapy (n = 7).
- The pharmacokinetic profile of Epogen in children and adolescents appeared similar to that of adults.
- The pharmacokinetics of Epogen has not been studied in patients with HIV infection.
## Nonclinical Toxicology
### Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenicity
- The carcinogenic potential of Epogen has not been evaluated.
Mutagenicity
- Epogen was not mutagenic or clastogenic under the conditions tested: Epogen was negative in the in vitro bacterial reverse mutation assay (Ames test), in the in vitro mammalian cell gene mutation assay (the hypoxanthine-guanine phosphoribosyl transferase locus), in an in vitro chromosomal aberration assay in mammalian cells, and in the in vivo mouse micronucleus assay.
Impairment of Fertility
- When administered intravenously to male and female rats prior to and during mating, and to females through the beginning of implantation (up to gestational day 7; dosing stopped prior to the beginning of organogenesis), doses of 100 and 500 Units/kg/day of Epogen caused slight increases in pre-implantation loss, post-implantation loss and decreases in the incidence of live fetuses. It is not clear whether these effects reflect a drug effect on the uterine environment or on the conceptus. This animal dose level of 100 Units/kg/day approximates the clinical recommended starting dose, depending on the patient’s treatment indication, but may be lower than the clinical dose in patients whose doses have been adjusted.
### Reproductive and Developmental Toxicology
- When pregnant rats were administered intravenous Epogen, 500 Units/kg/day, after the period of organogenesis (from day 17 of gestation through day 21 of lactation), their pups exhibited decreased number of caudal vertebrae, decreased body weight gain, and delayed appearance of abdominal hair, eyelid opening, and ossification. This animal dose level of 500 Units/kg/day is approximately 5-fold higher than the clinical recommended starting dose, depending on the patient’s treatment indication.
- When Epogen was administered intravenously during the period of organogenesis to pregnant rats (gestational days 7 to 17) and pregnant rabbits (gestational days 6 to 18), no evidence of teratogenic outcome was observed at the doses tested, up to 500 Units/kg/day. The offspring (F1 generation) of the treated rats were observed postnatally; rats from the F1 generation reached maturity and were mated; no Epogen-related effects were apparent for their offspring (F2 generation fetuses).
# Clinical Studies
### Patients With chronic kidney disease
Adult Patients on dialysis
- Patients with chronic kidney disease on dialysis: ESA effects on rates of transfusion
- In clinical studies of CKD patients on dialysis, Epogen increased hemoglobin levels and decreased the need for RBC transfusion. Overall, more than 95% of patients were RBC transfusion-independent after receiving Epogen for 3 months. In clinical studies at starting doses of 50 to 150 Units/kg 3 times weekly, adult patients responded with an average rate of hemoglobin rise as presented in Table 8.
- The safety and efficacy of Epogen were evaluated in 13 clinical studies involving intravenous administration to a total of 1010 anemic patients on dialysis. Overall, more than 90% of the patients treated with Epogen experienced improvement in hemoglobin concentrations. In the 3 largest of these clinical studies, the median maintenance dose necessary to maintain the hemoglobin between 10 to 12 g/dL was approximately 75 Units/kg 3 times weekly. More than 95% of patients were able to avoid RBC transfusions. In the largest US multicenter study, approximately 65% of the patients received doses of 100 Units/kg 3 times weekly or less to maintain their hemoglobin at approximately 11.7 g/dL. Almost 10% of patients received a dose of 25 Units/kg or less, and approximately 10% received a dose of more than 200 Units/kg 3 times weekly to maintain their hemoglobin at this level.
- In the Normal Hematocrit Study, the yearly transfusion rate was 51.5% in the lower hemoglobin group (10 g/dL) and 32.4% in the higher hemoglobin group (14 g/dL).
Other ESA trials
- In a 26-week, double-blind, placebo-controlled study, 118 patients on dialysis with an average hemoglobin of approximately 7 g/dL were randomized to either Epogen or placebo. By the end of the study, average hemoglobin increased to approximately 11 g/dL in the Epogen-treated patients and remained unchanged in patients receiving placebo. Epogen-treated patients experienced improvements in exercise tolerance and patient-reported physical functioning at month 2 that were maintained throughout the study.
- A multicenter, unit-dose study was also conducted in 119 patients receiving peritoneal dialysis who self-administered Epogen subcutaneously. Patients responded to Epogen administered subcutaneously in a manner similar to patients receiving intravenous administration.
Pediatric Patients on dialysis
- The safety and efficacy of Epogen were studied in a placebo-controlled, randomized study of 113 children with anemia (hemoglobin ≤ 9 g/dL) undergoing peritoneal dialysis or hemodialysis. The initial dose of Epogen was 50 Units/kg intravenously or subcutaneously 3 times weekly. The dose of study drug was titrated to achieve either a hemoglobin of 10 to 12 g/dL or an absolute increase in hemoglobin of 2 g/dL over baseline.
- At the end of the initial 12 weeks, a statistically significant rise in mean hemoglobin (3.1 g/dL vs. 0.3 g/dL) was observed only in the Epogen arm. The proportion of children achieving a hemoglobin of 10 g/dL, or an increase in hemoglobin of 2 g/dL over baseline, at any time during the first 12 weeks was higher in the Epogen arm (96% vs. 58%). Within 12 weeks of initiating Epogen therapy, 92.3% of the pediatric patients were RBC transfusion independent as compared to 65.4% who received placebo. Among patients who received 36 weeks of Epogen, hemodialysis patients received a higher median maintenance dose and took longer to achieve a hemoglobin of 10 to 12 g/dL (median time to response 69 days vs. 32 days) than patients undergoing peritoneal dialysis.
Adult Patients With CKD Not Requiring dialysis
- Four clinical studies were conducted in patients with CKD not on dialysis involving 181 patients treated with Epogen. These patients responded to Epogen therapy in a manner similar to that observed in patients on dialysis. Patients with CKD not on dialysis demonstrated a dose-dependent and sustained increase in hemoglobin when Epogen was administered by either an intravenous or subcutaneous route, with similar rates of rise of hemoglobin when Epogen was administered by either route.
Patients with chronic kidney disease not on dialysis: ESA effects on rates of transfusion
- In TREAT, a randomized, double-blind trial of 4038 patients with CKD and type 2 diabetes not on dialysis, a post-hoc analysis showed that the proportion of patients receiving RBC transfusions was lower in patients administered an ESA to target a hemoglobin of 13 g/dL compared to the control arm in which an ESA was administered intermittently if hemoglobin concentration decreased to less than 9 g/dL (15% versus 25%, respectively). In CHOIR, a randomized open-label study of 1432 patients with CKD not on dialysis, use of epoetin alfa to target a higher (13.5 g/dL) versus lower (11.3 g/dL) hemoglobin goal did not reduce the use of RBC transfusions. In each trial, no benefits occurred for the cardiovascular or end-stage renal disease outcomes. In each trial, the potential benefit of ESA therapy was offset by worse cardiovascular safety outcomes resulting in an unfavorable benefit-risk profile.
ESA Effects on rates of death and other serious cardiac adverse events
- Three randomized outcome trials (Normal Hematocrit Study , Correction of anemia with Epoetin Alfa in chronic kidney disease , and Trial of darbepoetin Alfa in Type 2 Diabetes and CKD ) have been conducted in patients with CKD using Epogen/PROCRIT/Aranesp to target higher vs. lower hemoglobin levels. Though these trials were designed to establish a cardiovascular or renal benefit of targeting higher hemoglobin levels, in all 3 studies, patients randomized to the higher hemoglobin target experienced worse cardiovascular outcomes and showed no reduction in progression to ESRD. In each trial, the potential benefit of ESA therapy was offset by worse cardiovascular safety outcomes resulting in an unfavorable benefit-risk profile.
### Zidovudine-treated Patients With HIV Infection
- The safety and efficacy of Epogen were evaluated in 4 placebo-controlled studies enrolling 297 anemic patients (hemoglobin < 10 g/dL) with HIV infection receiving concomitant therapy with Zidovudine. In the subgroup of patients (89/125 Epogen and 88/130 placebo) with pre study endogenous serum erythropoietin levels ≤ 500 mUnits/mL, Epogen reduced the mean cumulative number of units of blood transfused per patient by approximately 40% as compared to the placebo group. Among those patients who required RBC transfusions at baseline, 43% of patients treated with Epogen versus 18% of placebo-treated patients were RBC transfusion independent during the second and third months of therapy. Epogen therapy also resulted in significant increases in hemoglobin in comparison to placebo. When examining the results according to the weekly dose of Zidovudine received during month 3 of therapy, there was a statistically significant reduction (p < 0.003) in RBC transfusion requirements in patients treated with Epogen (n = 51) compared to placebo-treated patients (n = 54) whose mean weekly Zidovudine dose was ≤ 4200 mg/week.
- Approximately 17% of the patients with endogenous serum erythropoietin levels ≤ 500 mUnits/mL receiving Epogen in doses from 100 to 200 Units/kg 3 times weekly achieved a hemoglobin of 12.7 g/dL without administration of RBC transfusions or significant reduction in Zidovudine dose. In the subgroup of patients whose pre study endogenous serum erythropoietin levels were > 500 mUnits/mL, Epogen therapy did not reduce RBC transfusion requirements or increase hemoglobin compared to the corresponding responses in placebo-treated patients.
### Cancer Patients on chemotherapy
- The safety and effectiveness of Epogen was assessed in two multicenter, randomized (1:1), placebo-controlled, double-blind studies (Study C1 and Study C2) and a pooled analysis of six additional randomized (1:1), multicenter, placebo-controlled, double-blind studies. All studies were conducted in patients with anemia due to concomitantly administered cancer chemotherapy. Study C1 enrolled 344 adult patients, Study C2 enrolled 222 pediatric patients, and the pooled analysis contained 131 patients randomized to epoetin alfa or placebo. In Studies C1 and C2, efficacy was demonstrated by a reduction in the proportion of patients who received an RBC transfusion, from week 5 through end of the study, with the last-known RBC transfusion status carried forward for patients who discontinued treatment. In the pooled analysis, efficacy was demonstrated by a reduction in the proportion of patients who received an RBC transfusion from week 5 through end of the study in the subset of patients who were remaining on therapy for 6 or more weeks.
Study C1
- Study C1 was conducted in anemic patients (hemoglobin < 11.5 g/dL for males; < 10.5 g/dL for females) with non-myeloid malignancies receiving myelosuppressive chemotherapy. Randomization was stratified by type of malignancy (lung vs. breast vs. other), concurrent radiation therapy planned (yes or no), and baseline hemoglobin (< 9 g/dL vs. ≥ 9 g/dL); patients were randomized to epoetin alfa 40,000 Units (n = 174) or placebo (n = 170) as a weekly subcutaneous injection commencing on the first day of the chemotherapy cycle.
- Ninety-one percent of patients were white, 44% were male, and the median age of patients was 66 years (range: 20 to 88 years). The proportion of patients withdrawn from the study prior to week 5 was less than 10% for placebo-treated or epoetin-treated patients. Per protocol, the last available hemoglobin values from patients who dropped out were included in the efficacy analyses. Efficacy results are shown in Table 9.
Study C2
- Study C2 was conducted in 222 anemic patients, ages 5 to 18, receiving chemotherapy for the treatment of various childhood malignancies. Randomization was stratified by cancer type (solid tumors, Hodgkin’s disease, acute lymphocytic leukemia, vs. non-Hodgkin’s lymphoma); patients were randomized to receive epoetin alfa at 600 Units/kg maximum 40,000 Units (n = 111) or placebo (n = 111) as a weekly intravenous injection.
- Sixty-nine percent of patients were white, 55% were male, and the median age of patients was 12 years (range: 5 to 18 years). Two (2%) of placebo-treated patients and 3 (3%) of epoetin alfa-treated patients dropped out of the study prior to week 5. There were fewer RBC transfusions from week 5 through the end-of-study in epoetin-alfa treated patients compared to placebo-treated patients . There was no evidence of an improvement in health-related quality of life, including no evidence of an effect on fatigue, energy, or strength in patients receiving Epogen as compared to those receiving placebo.
Pooled Analysis (Three Times Per Week Dosing)
- The results of 6 studies of similar design and that randomized 131 patients to epoetin alfa or placebo were pooled to assess the safety and effectiveness of epoetin alfa. Patients were randomized to receive epoetin alfa at 150 Units/kg (n = 63) or placebo (n = 68), subcutaneously three times per week for 12 weeks in each study. Across all studies, 72 patients were treated with concomitant non cisplatin-containing chemotherapy regimens and 59 patients were treated with concomitant cisplatin-containing chemotherapy regimens. Twelve patients (19%) in the epoetin alfa arm and 10 patients (15%) in the placebo-arm dropped out prior to week 6 and are excluded from efficacy analyses.
### Surgery Patients
- The safety and efficacy of Epogen were evaluated in a placebo-controlled, double-blind study (S1) enrolling 316 patients scheduled for major, elective orthopedic hip or knee surgery who were expected to require ≥ 2 units of blood and who were not able or willing to participate in an autologous blood donation program. Patients were stratified into 1 of 3 groups based on their pretreatment hemoglobin and then randomly assigned to receive 300 Units/kg Epogen, 100 Units/kg Epogen, or placebo by subcutaneous injection for 10 days before surgery, on the day of surgery, and for 4 days after surgery. All patients received oral iron and a low-dose, postoperative warfarin regimen.
- Treatment with Epogen 300 Units/kg significantly (p = 0.024) reduced the risk of allogeneic RBC transfusion in patients with a pretreatment hemoglobin of > 10 to ≤ 13 g/dL; 5/31 (16%) of patients treated with Epogen 300 Units/kg, 6/26 (23%) of patients treated with Epogen 100 Units/kg, and 13/29 (45%) of placebo-treated patients were transfused. There was no significant difference in the number of patients transfused between Epogen (9% 300 Units/kg, 6% 100 Units/kg) and placebo (13%) in the > 13 to ≤ 15 g/dL hemoglobin stratum. There were too few patients in the ≤ 10 g/dL group to determine if Epogen is useful in this hemoglobin strata. In the > 10 to ≤ 13 g/dL pretreatment stratum, the mean number of units transfused per Epogen-treated patient (0.45 units blood for 300 Units/kg, 0.42 units blood for 100 Units/kg) was less than the mean transfused per placebo-treated patient (1.14 units) (overall p = 0.028). In addition, mean hemoglobin, hematocrit, and reticulocyte counts increased significantly during the presurgery period in patients treated with Epogen.
- Epogen was also evaluated in an open-label, parallel-group study (S2) enrolling 145 patients with a pretreatment hemoglobin level of ≥ 10 to ≤ 13 g/dL who were scheduled for major orthopedic hip or knee surgery and who were not participating in an autologous program. Patients were randomly assigned to receive 1 of 2 subcutaneous dosing regimens of Epogen (600 Units/kg once weekly for 3 weeks prior to surgery and on the day of surgery, or 300 Units/kg once daily for 10 days prior to surgery, on the day of surgery, and for 4 days after surgery). All patients received oral iron and appropriate pharmacologic anticoagulation therapy.
- From pretreatment to presurgery, the mean increase in hemoglobin in the 600 Units/kg weekly group (1.44 g/dL) was greater than that observed in the 300 Units/kg daily group. The mean increase in absolute reticulocyte count was smaller in the weekly group (0.11 × 106/mm3) compared to the daily group (0.17 × 106/mm3). Mean hemoglobin levels were similar for the 2 treatment groups throughout the postsurgical period.
- The erythropoietic response observed in both treatment groups resulted in similar RBC transfusion rates . The mean number of units transfused per patient was approximately 0.3 units in both treatment groups.
# How Supplied
Single-dose, Preservative-free Vial (in citrate-buffered formulation): 1 mL of solution contains 2000 (NDC 55513-126-10), 3000 (NDC 55513-267-10), 4000 (NDC 55513-148-10), or 10,000 Units (NDC 55513-144-10) of epoetin alfa. Each strength is supplied in dispensing packs containing 10 single-dose vials.
Single-dose, Preservative-free Vial (in phosphate-buffered formulation): 1 mL of solution contains 40,000 Units (NDC 55513-823-10) of epoetin alfa and is supplied in dispensing packs containing 10 single-dose vials.
Multidose, Preserved Vial: 2 mL total volume (20,000 Units total; 10,000 Units/mL). Each 1 mL of solution contains 10,000 Units (NDC 55513-283-10) of epoetin alfa, and is supplied in dispensing packs containing 10 multidose vials.
Multidose, Preserved Vial: 1 mL total volume (20,000 Units/mL). Each 1 mL of solution contains 20,000 Units (NDC 55513-478-10) of epoetin alfa and is supplied in dispensing packs containing 10 multidose vials.
## Storage
- Store at 36ºF to 46ºF (2ºC to 8ºC). Do not freeze.
- Do not shake. Protect from light; store Epogen in the carton until use.
- Do not use Epogen that has been shaken or frozen.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
# Precautions with Alcohol
- Alcohol-Epoetin Alfa interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- ARANESP
# Look-Alike Drug Names
- There is limited information about the Look-alike drug names.
# Drug Shortage Status
# Price | Epoetin Alfa
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Sheng Shi, M.D. [2]
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# Black Box Warning
# Overview
Epoetin Alfa is an erythropoiesis-stimulating agent that is FDA approved for the treatment of anemia due to chronic kidney disease, anemia due to zidovudine in HIV-infected patients， anemia due to chemotherapy in patients with cancer and reduction of allogeneic red blood cell transfusions in patients undergoing elective, noncardiac, nonvascular surgery. There is a Black Box Warning for this drug as shown here. Common adverse reactions include edema，injection site irritation, injection site pain, pruritus, rash，nausea, vomiting，arthralgia, myalgia, spasm, muscle，dizziness, headache, insomnia，cough, upper respiratory infection and fever.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
### Evaluation of Iron Stores and Nutritional Factors
- Evaluate the iron status in all patients before and during treatment and maintain iron repletion. Correct or exclude other causes of anemia (e.g., vitamin deficiency, metabolic or chronic inflammatory conditions, bleeding, etc.) before initiating Epogen.
### Patients with chronic kidney disease
- In controlled trials, patients experienced greater risks for death, serious adverse cardiovascular reactions, and stroke when administered erythropoiesis-stimulating agents (ESAs) to target a hemoglobin level of greater than 11 g/dL. No trial has identified a hemoglobin target level, ESA dose, or dosing strategy that does not increase these risks. Individualize dosing and use the lowest dose of Epogen sufficient to reduce the need for RBC transfusions. Physicians and patients should weigh the possible benefits of decreasing transfusions against the increased risks of death and other serious cardiovascular adverse events.
For all patients with CKD
- When initiating or adjusting therapy, monitor hemoglobin levels at least weekly until stable, then monitor at least monthly. When adjusting therapy consider hemoglobin rate of rise, rate of decline, ESA responsiveness and hemoglobin variability. A single hemoglobin excursion may not require a dosing change.
- Do not increase the dose more frequently than once every 4 weeks. Decreases in dose can occur more frequently. Avoid frequent dose adjustments.
- If the hemoglobin rises rapidly (e.g., more than 1 g/dL in any 2-week period), reduce the dose of Epogen by 25% or more as needed to reduce rapid responses.
- For patients who do not respond adequately, if the hemoglobin has not increased by more than 1 g/dL after 4 weeks of therapy, increase the dose by 25%.
- For patients who do not respond adequately over a 12-week escalation period, increasing the Epogen dose further is unlikely to improve response and may increase risks. Use the lowest dose that will maintain a hemoglobin level sufficient to reduce the need for RBC transfusions. Evaluate other causes of anemia. Discontinue Epogen if responsiveness does not improve.
For patients with CKD on dialysis
- Initiate Epogen treatment when the hemoglobin level is less than 10 g/dL.
- If the hemoglobin level approaches or exceeds 11 g/dL, reduce or interrupt the dose of Epogen.
- Recommended starting dose for adult patients : 50 to 100 Units/kg 3 times weekly intravenously or subcutaneously. For pediatric patients, a starting dose of 50 Units/kg 3 times weekly intravenously or subcutaneously is recommended. The intravenous route is recommended for patients on hemodialysis.
For patients with CKD not on dialysis
- Consider initiating Epogen treatment only when the hemoglobin level is less than 10 g/dL and the following considerations apply:
- The rate of hemoglobin decline indicates the likelihood of requiring a RBC transfusion and,
- Reducing the risk of alloimmunization and/or other RBC transfusion-related risks is a goal
- If the hemoglobin level exceeds 10 g/dL, reduce or interrupt the dose of Epogen, and use the lowest dose of Epogen sufficient to reduce the need for RBC transfusions.
- Recommended starting dose for adult patients is 50 to 100 Units/kg 3 times weekly intravenously or subcutaneously.
- When treating patients who have chronic kidney disease and cancer, physicians should refer to Warnings and Precautions.
- Refer patients who self-administer Epogen to the Instructions for Use.
### Zidovudine-treated HIV-infected Patients
Starting Dose
- The recommended starting dose in adults is 100 Units/kg as an intravenous or subcutaneous injection 3 times per week.
Dose Adjustment
- If hemoglobin does not increase after 8 weeks of therapy, increase Epogen dose by approximately
50 to 100 Units/kg at 4- to 8-week intervals until hemoglobin reaches a level needed to avoid RBC transfusions or 300 Units/kg.
- Withhold Epogen if hemoglobin exceeds 12 g/dL. Resume therapy at a dose 25% below the previous dose when hemoglobin declines to less than 11 g/dL.
- Discontinue Epogen if an increase in hemoglobin is not achieved at a dose of 300 Units/kg for 8 weeks.
### Patients on Cancer chemotherapy
- Initiate Epogen in patients on cancer chemotherapy only if the hemoglobin is less than 10 g/dL, and if there is a minimum of two additional months of planned chemotherapy.
- Use the lowest dose of Epogen necessary to avoid RBC transfusions.
Recommended Starting Dose
- Adults:
- 150 Units/kg subcutaneously 3 times per week until completion of a chemotherapy course or
- 40,000 Units subcutaneously weekly until completion of a chemotherapy course.
- Pediatric Patients (5 to 18 years):
- 600 Units/kg intravenously weekly until completion of a chemotherapy course.
Dose Reduction
- Reduce dose by 25% if:
- Hemoglobin increases greater than 1 g/dL in any 2-week period or
- Hemoglobin reaches a level needed to avoid RBC transfusion.
- Withhold dose if hemoglobin exceeds a level needed to avoid RBC transfusion. Reinitiate at a dose 25% below the previous dose when hemoglobin approaches a level where RBC transfusions may be required.
Dose Increase
- After the initial 4 weeks of Epogen therapy, if hemoglobin increases by less than 1 g/dL and remains below 10 g/dL, increase dose to:
- 300 Units/kg three times per week in adults or
- 60,000 Units weekly in adults
- 900 Units/kg (maximum 60,000 Units) weekly in children
- After 8 weeks of therapy, if there is no response as measured by hemoglobin levels or if RBC transfusions are still required, discontinue Epogen.
### Surgery Patients
- The recommended Epogen regimens are:
- 300 Units/kg per day subcutaneously for 15 days total: administered daily for 10 days before surgery, on the day of surgery, and for 4 days after surgery.
- 600 Units/kg subcutaneously in 4 doses administered 21, 14, and 7 days before surgery and on the day of surgery.
- Deep venous thrombosis prophylaxis is recommended during Epogen therapy.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
- There is limited information regarding Off-Label Guideline-Supported Use of Epoetin Alfa in adult patients.
### Non–Guideline-Supported Use
- There is limited information regarding Off-Label Non–Guideline-Supported Use of Epoetin Alfa in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
### Evaluation of Iron Stores and Nutritional Factors
- Evaluate the iron status in all patients before and during treatment and maintain iron repletion. Correct or exclude other causes of anemia (e.g., vitamin deficiency, metabolic or chronic inflammatory conditions, bleeding, etc.) before initiating Epogen.
### Patients with chronic kidney disease
- In controlled trials, patients experienced greater risks for death, serious adverse cardiovascular reactions, and stroke when administered erythropoiesis-stimulating agents (ESAs) to target a hemoglobin level of greater than 11 g/dL. No trial has identified a hemoglobin target level, ESA dose, or dosing strategy that does not increase these risks. Individualize dosing and use the lowest dose of Epogen sufficient to reduce the need for RBC transfusions. Physicians and patients should weigh the possible benefits of decreasing transfusions against the increased risks of death and other serious cardiovascular adverse events.
For all patients with CKD
- When initiating or adjusting therapy, monitor hemoglobin levels at least weekly until stable, then monitor at least monthly. When adjusting therapy consider hemoglobin rate of rise, rate of decline, ESA responsiveness and hemoglobin variability. A single hemoglobin excursion may not require a dosing change.
- Do not increase the dose more frequently than once every 4 weeks. Decreases in dose can occur more frequently. Avoid frequent dose adjustments.
- If the hemoglobin rises rapidly (e.g., more than 1 g/dL in any 2-week period), reduce the dose of Epogen by 25% or more as needed to reduce rapid responses.
- For patients who do not respond adequately, if the hemoglobin has not increased by more than 1 g/dL after 4 weeks of therapy, increase the dose by 25%.
- For patients who do not respond adequately over a 12-week escalation period, increasing the Epogen dose further is unlikely to improve response and may increase risks. Use the lowest dose that will maintain a hemoglobin level sufficient to reduce the need for RBC transfusions. Evaluate other causes of anemia. Discontinue Epogen if responsiveness does not improve.
For patients with CKD on dialysis
- Initiate Epogen treatment when the hemoglobin level is less than 10 g/dL.
- If the hemoglobin level approaches or exceeds 11 g/dL, reduce or interrupt the dose of Epogen.
- Recommended starting dose for adult patients : 50 to 100 Units/kg 3 times weekly intravenously or subcutaneously. For pediatric patients, a starting dose of 50 Units/kg 3 times weekly intravenously or subcutaneously is recommended. The intravenous route is recommended for patients on hemodialysis.
For patients with CKD not on dialysis
- Consider initiating Epogen treatment only when the hemoglobin level is less than 10 g/dL and the following considerations apply:
- The rate of hemoglobin decline indicates the likelihood of requiring a RBC transfusion and,
- Reducing the risk of alloimmunization and/or other RBC transfusion-related risks is a goal
- If the hemoglobin level exceeds 10 g/dL, reduce or interrupt the dose of Epogen, and use the lowest dose of Epogen sufficient to reduce the need for RBC transfusions.
- Recommended starting dose for adult patients is 50 to 100 Units/kg 3 times weekly intravenously or subcutaneously.
- When treating patients who have chronic kidney disease and cancer, physicians should refer to Warnings and Precautions.
- Refer patients who self-administer Epogen to the Instructions for Use.
### Zidovudine-treated HIV-infected Patients
Starting Dose
- The recommended starting dose in adults is 100 Units/kg as an intravenous or subcutaneous injection 3 times per week.
Dose Adjustment
- If hemoglobin does not increase after 8 weeks of therapy, increase Epogen dose by approximately
50 to 100 Units/kg at 4- to 8-week intervals until hemoglobin reaches a level needed to avoid RBC transfusions or 300 Units/kg.
- Withhold Epogen if hemoglobin exceeds 12 g/dL. Resume therapy at a dose 25% below the previous dose when hemoglobin declines to less than 11 g/dL.
- Discontinue Epogen if an increase in hemoglobin is not achieved at a dose of 300 Units/kg for 8 weeks.
### Patients on Cancer chemotherapy
- Initiate Epogen in patients on cancer chemotherapy only if the hemoglobin is less than 10 g/dL, and if there is a minimum of two additional months of planned chemotherapy.
- Use the lowest dose of Epogen necessary to avoid RBC transfusions.
Recommended Starting Dose
- Adults:
- 150 Units/kg subcutaneously 3 times per week until completion of a chemotherapy course or
- 40,000 Units subcutaneously weekly until completion of a chemotherapy course.
- Pediatric Patients (5 to 18 years):
- 600 Units/kg intravenously weekly until completion of a chemotherapy course.
Dose Reduction
- Reduce dose by 25% if:
- Hemoglobin increases greater than 1 g/dL in any 2-week period or
- Hemoglobin reaches a level needed to avoid RBC transfusion.
- Withhold dose if hemoglobin exceeds a level needed to avoid RBC transfusion. Reinitiate at a dose 25% below the previous dose when hemoglobin approaches a level where RBC transfusions may be required.
Dose Increase
- After the initial 4 weeks of Epogen therapy, if hemoglobin increases by less than 1 g/dL and remains below 10 g/dL, increase dose to:
- 300 Units/kg three times per week in adults or
- 60,000 Units weekly in adults
- 900 Units/kg (maximum 60,000 Units) weekly in children
- After 8 weeks of therapy, if there is no response as measured by hemoglobin levels or if RBC transfusions are still required, discontinue Epogen.
### Surgery Patients
- The recommended Epogen regimens are:
- 300 Units/kg per day subcutaneously for 15 days total: administered daily for 10 days before surgery, on the day of surgery, and for 4 days after surgery.
- 600 Units/kg subcutaneously in 4 doses administered 21, 14, and 7 days before surgery and on the day of surgery.
- Deep venous thrombosis prophylaxis is recommended during Epogen therapy.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
- There is limited information regarding Off-Label Guideline-Supported Use of Epoetin Alfa in pediatric patients.
### Non–Guideline-Supported Use
- There is limited information regarding Off-Label Non–Guideline-Supported Use of Epoetin Alfa in pediatric patients.
# Contraindications
Epogen is contraindicated in patients with:
- Uncontrolled hypertension.
- Pure red cell aplasia (PRCA) that begins after treatment with Epogen or other erythropoietin protein drugs
- Serious allergic reactions to Epogen.
Epogen from multidose vials contains benzyl alcohol and is contraindicated in:
- Neonates, infants, pregnant women, and nursing mothers. Benzyl alcohol has been associated with serious adverse events and death, particularly in pediatric patients. When therapy with Epogen is needed in neonates and infants, use single-dose vials; do not admix with bacteriostatic saline containing benzyl alcohol.
# Warnings
### Increased Mortality, Myocardial Infarction, stroke, and Thromboembolism
- In controlled clinical trials of patients with CKD comparing higher hemoglobin targets (13 - 14 g/dL) to lower targets (9 - 11.3 g/dL), Epogen and other ESAs increased the risk of death, Myocardial Infarction, stroke, congestive heart failure, thrombosis of hemodialysis vascular access, and other thromboembolic events in the higher target groups.
- Using ESAs to target a hemoglobin level of greater than 11 g/dL increases the risk of serious adverse cardiovascular reactions and has not been shown to provide additional benefit. Use caution in patients with coexistent cardiovascular disease and stroke. Patients with CKD and an insufficient hemoglobin response to ESA therapy may be at even greater risk for cardiovascular reactions and mortality than other patients. A rate of hemoglobin rise of greater than 1 g/dL over 2 weeks may contribute to these risks.
- In controlled clinical trials of patients with cancer, Epogen and other ESAs increased the risks for death and serious adverse cardiovascular reactions. These adverse reactions included myocardial infarction and stroke.
- In controlled clinical trials, ESAs increased the risk of death in patients undergoing coronary artery bypass graft surgery (CABG) and the risk of deep venous thrombosis (DVT) in patients undergoing orthopedic procedures.
- The design and overall results of the 3 large trials comparing higher and lower hemoglobin targets are shown in Table 1.
Patients with chronic kidney disease
- Normal Hematocrit Study (NHS): A prospective, randomized, open-label study of 1265 patients with chronic kidney disease on dialysis with documented evidence of congestive heart failure or ischemic heart disease was designed to test the hypothesis that a higher target hematocrit (Hct) would result in improved outcomes compared with a lower target Hct. In this study, patients were randomized to epoetin alfa treatment targeted to a maintenance hemoglobin of either 14 ± 1 g/dL or 10 ± 1 g/dL. The trial was terminated early with adverse safety findings of higher mortality in the high hematocrit target group. Higher mortality (35% vs. 29%) was observed for the patients randomized to a target hemoglobin of 14 g/dL than for the patients randomized to a target hemoglobin of 10 g/dL. For all-cause mortality, the HR=1.27; 95% CI (1.04, 1.54); p=0.018. The incidence of nonfatal Myocardial Infarction, vascular access thrombosis, and other thrombotic events was also higher in the group randomized to a target hemoglobin of 14 g/dL.
- CHOIR: A randomized, prospective trial, 1432 patients with anemia due to CKD who were not undergoing dialysis and who had not previously received epoetin alfa therapy were randomized to epoetin alfa treatment targeting a maintenance hemoglobin concentration of either 13.5 g/dL or 11.3 g/dL. The trial was terminated early with adverse safety findings. A major cardiovascular event (death, Myocardial Infarction, stroke, or hospitalization for congestive heart failure) occurred in 125 of the 715 patients (18%) in the higher hemoglobin group compared to 97 of the 717 patients (14%) in the lower hemoglobin group [hazard ratio (HR) 1.34, 95% CI: 1.03, 1.74; p = 0.03].
- TREAT: A randomized, double-blind, placebo-controlled, prospective trial of 4038 patients with: CKD not on dialysis (eGFR of 20 – 60 mL/min), anemia (hemoglobin levels ≤ 11 g/dL), and type 2 diabetes mellitus, patients were randomized to receive either darbepoetin alfa treatment or a matching placebo. Placebo group patients also received darbepoetin alfa when their hemoglobin levels were below 9 g/dL. The trial objectives were to demonstrate the benefit of darbepoetin alfa treatment of the anemia to a target hemoglobin level of 13 g/dL, when compared to a "placebo" group, by reducing the occurrence of either of two primary endpoints: (1) a composite cardiovascular endpoint of all-cause mortality or a specified cardiovascular event (myocardial ischemia, CHF, MI, and CVA) or (2) a composite renal endpoint of all-cause mortality or progression to end stage renal disease. The overall risks for each of the two primary endpoints (the cardiovascular composite and the renal composite) were not reduced with darbepoetin alfa treatment (see Table 1), but the risk of stroke was increased nearly two-fold in the darbepoetin alfa -treated group versus the placebo group: annualized stroke rate 2.1% vs. 1.1%, respectively, HR 1.92; 95% CI: 1.38, 2.68; p < 0.001. The relative risk of stroke was particularly high in patients with a prior stroke: annualized stroke rate 5.2% in the darbepoetin alfa- treated group and 1.9% in the placebo group, HR 3.07; 95% CI: 1.44, 6.54. Also, among darbepoetin alfa -treated subjects with a past history of cancer, there were more deaths due to all causes and more deaths adjudicated as due to cancer, in comparison with the control group.
Patients with Cancer
- An increased incidence of thromboembolic reactions, some serious and life-threatening, occurred in patients with cancer treated with ESAs.
- In a randomized, placebo-controlled study (Study 1 in Table 2) of 939 women with metastatic breast cancer receiving chemotherapy, patients received either weekly epoetin alfa or placebo for up to a year. This study was designed to show that survival was superior when epoetin alfa was administered to prevent anemia (maintain hemoglobin levels between 12 and 14 g/dL or hematocrit between 36% and 42%). This study was terminated prematurely when interim results demonstrated a higher mortality at 4 months (8.7% vs. 3.4%) and a higher rate of fatal thrombotic reactions (1.1% vs. 0.2%) in the first 4 months of the study among patients treated with epoetin alfa. Based on Kaplan-Meier estimates, at the time of study termination, the 12-month survival was lower in the epoetin alfa group than in the placebo group (70% vs. 76%; HR 1.37, 95% CI: 1.07, 1.75; p = 0.012).
Patients Having Surgery
- An increased incidence of deep venous thrombosis (DVT) in patients receiving epoetin alfa undergoing surgical orthopedic procedures was demonstrated. In a randomized, controlled study, 680 adult patients, not receiving prophylactic anticoagulation and undergoing spinal surgery, were randomized to 4 doses of 600 Units/kg epoetin alfa (7, 14, and 21 days before surgery, and the day of surgery) and standard of care (SOC) treatment (n = 340) or to SOC treatment alone (n = 340). A higher incidence of DVTs, determined by either color flow duplex imaging or by clinical symptoms, was observed in the epoetin alfa group (16 [4.7%] patients) compared with the SOC group (7 [2.1%] patients). In addition to the 23 patients with DVTs included in the primary analysis, 19 [2.8%] patients (n = 680) experienced 1 other thrombovascular event (TVE) each (12 [3.5%] in the epoetin alfa group and 7 [2.1%] in the SOC group). deep venous thrombosis prophylaxis is strongly recommended when ESAs are used for the reduction of allogeneic RBC transfusions in surgical patients.
- Increased mortality was observed in a randomized, placebo-controlled study of Epogen in adult patients who were undergoing CABG surgery (7 deaths in 126 patients randomized to Epogen versus no deaths among 56 patients receiving placebo). Four of these deaths occurred during the period of study drug administration and all 4 deaths were associated with thrombotic events.
### Prescribing and Distribution Program for Epogen in Patients With Cancer
- In order to prescribe and/or dispense Epogen to patients with cancer and anemia due to myelosuppressive chemotherapy, prescribers and hospitals must enroll in and comply with the ESA APPRISE Oncology Program requirements. To enroll, visit www.esa-apprise.com or call 1-866-284-8089 for further assistance. Additionally, prior to each new course of Epogen in patients with cancer, prescribers and patients must provide written acknowledgment of a discussion of the risks of Epogen.
### Increased Mortality and/or Increased Risk of Tumor Progression or Recurrence in Patients With Cancer
- ESAs resulted in decreased locoregional control/progression-free survival and/or overall survival (see Table 2). These findings were observed in studies of patients with advanced head and neck cancer receiving radiation therapy (Studies 5 and 6), in patients receiving chemotherapy for metastatic breast cancer (Study 1) or lymphoid malignancy (Study 2), and in patients with non-small cell lung cancer or various malignancies who were not receiving chemotherapy or radiotherapy.
Decreased Overall Survival
- Study 1 was described in the previous section. Mortality at 4 months (8.7% vs. 3.4%) was significantly higher in the epoetin alfa arm. The most common investigator-attributed cause of death within the first 4 months was disease progression; 28 of 41 deaths in the epoetin alfa arm and 13 of 16 deaths in the placebo arm were attributed to disease progression. Investigator-assessed time to tumor progression was not different between the 2 groups. Survival at 12 months was significantly lower in the epoetin alfa arm (70% vs. 76%; HR 1.37, 95% CI: 1.07, 1.75; p = 0.012).
- Study 2 was a randomized, double-blind study (darbepoetin alfa vs. placebo) conducted in 344 anemic patients with lymphoid malignancy receiving chemotherapy. With a median follow-up of 29 months, overall mortality rates were significantly higher among patients randomized to darbepoetin alfa as compared to placebo (HR 1.36, 95% CI: 1.02, 1.82).
- Study 7 was a multicenter, randomized, double-blind study (epoetin alfa vs. placebo) in which patients with advanced non-small cell lung cancer receiving only palliative radiotherapy or no active therapy were treated with epoetin alfa to achieve and maintain hemoglobin levels between 12 and 14 g/dL. Following an interim analysis of 70 patients (planned accrual 300 patients), a significant difference in survival in favor of the patients in the placebo arm of the study was observed (median survival 63 vs. 129 days; HR 1.84; p = 0.04).
- Study 8 was a randomized, double-blind study (darbepoetin alfa vs. placebo) in 989 anemic patients with active malignant disease, neither receiving nor planning to receive chemotherapy or radiation therapy. There was no evidence of a statistically significant reduction in proportion of patients receiving RBC transfusions. The median survival was shorter in the darbepoetin alfa treatment group than in the placebo group (8 months vs. 10.8 months; HR 1.30, 95% CI: 1.07, 1.57).
Decreased Progression-free Survival and Overall Survival
- Study 3 was a randomized, open-label, controlled, factorial design study in which darbepoetin alfa was administered to prevent anemia in 733 women receiving neo-adjuvant breast cancer treatment. A final analysis was performed after a median follow-up of approximately 3 years. The 3-year survival rate was lower (86% vs. 90%; HR 1.42, 95% CI: 0.93, 2.18) and the 3-year relapse-free survival rate was lower (72% vs. 78%; HR 1.33, 95% CI: 0.99, 1.79) in the darbepoetin alfa-treated arm compared to the control arm.
- Study 4 was a randomized, open-label, controlled study that enrolled 114 of a planned 460 cervical cancer patients receiving chemotherapy and radiotherapy. Patients were randomized to receive epoetin alfa to maintain hemoglobin between 12 and 14 g/dL or to RBC transfusion support as needed. The study was terminated prematurely due to an increase in thromboembolic adverse reactions in epoetin alfa-treated patients compared to control (19% vs. 9%). Both local recurrence (21% vs. 20%) and distant recurrence (12% vs. 7%) were more frequent in epoetin alfa-treated patients compared to control. Progression-free survival at 3 years was lower in the epoetin alfa-treated group compared to control (59% vs. 62%; HR 1.06, 95% CI: 0.58, 1.91). Overall survival at 3 years was lower in the epoetin alfa-treated group compared to control (61% vs. 71%; HR 1.28, 95% CI: 0.68, 2.42).
- Study 5 was a randomized, placebo-controlled study in 351 head and neck cancer patients where epoetin beta or placebo was administered to achieve target hemoglobins ≥ 14 and ≥ 15 g/dL for women and men, respectively. Locoregional progression-free survival was significantly shorter in patients receiving epoetin beta (HR 1.62, 95% CI: 1.22, 2.14; p = 0.0008) with medians of 406 days and 745 days in the epoetin beta and placebo arms, respectively. Overall survival was significantly shorter in patients receiving epoetin beta (HR 1.39, 95% CI: 1.05, 1.84; p = 0.02).
Decreased Locoregional Control
- Study 6 was a randomized, open-label, controlled study conducted in 522 patients with primary squamous cell carcinoma of the head and neck receiving radiation therapy alone (no chemotherapy) who were randomized to receive darbepoetin alfa to maintain hemoglobin levels of 14 to15.5 g/dL or no darbepoetin alfa. An interim analysis performed on 484 patients demonstrated that locoregional control at 5 years was significantly shorter in patients receiving darbepoetin alfa (RR 1.44, 95% CI: 1.06, 1.96; p = 0.02). Overall survival was shorter in patients receiving darbepoetin alfa (RR 1.28, 95% CI: 0.98, 1.68; p = 0.08).
### Hypertension
- Epogen is contraindicated in patients with uncontrolled hypertension. Following initiation and titration of Epogen, approximately 25% of patients on dialysis required initiation of or increases in antihypertensive therapy; hypertensive encephalopathy and seizures have been reported in patients with CKD receiving Epogen.
- Appropriately control hypertension prior to initiation of and during treatment with Epogen. Reduce or withhold Epogen if blood pressure becomes difficult to control. Advise patients of the importance of compliance with antihypertensive therapy and dietary restrictions.
### Seizures
- Epogen increases the risk of seizures in patients with CKD. During the first several months following initiation of Epogen, monitor patients closely for premonitory neurologic symptoms. Advise patients to contact their healthcare practitioner for new-onset seizures, premonitory symptoms or change in seizure frequency.
### Lack or Loss of Hemoglobin Response to Epogen
- For lack or loss of hemoglobin response to Epogen, initiate a search for causative factors (e.g., iron deficiency, infection, inflammation, bleeding). If typical causes of lack or loss of hemoglobin response are excluded, evaluate for PRCA . In the absence of PRCA, follow dosing recommendations for management of patients with an insufficient hemoglobin response to Epogen therapy.
### Pure Red Cell Aplasia
- Cases of PRCA and of severe anemia, with or without other cytopenias that arise following the development of neutralizing antibodies to erythropoietin have been reported in patients treated with Epogen. This has been reported predominantly in patients with CKD receiving ESAs by subcutaneous administration. PRCA has also been reported in patients receiving ESAs for anemia related to hepatitis C treatment (an indication for which Epogen is not approved).
- If severe anemia and low reticulocyte count develop during treatment with Epogen, withhold Epogen and evaluate patients for neutralizing antibodies to erythropoietin. Contact Amgen (1-800-77-AMGEN) to perform assays for binding and neutralizing antibodies. Permanently discontinue Epogen in patients who develop PRCA following treatment with Epogen or other erythropoietin protein drugs. Do not switch patients to other ESAs.
### Serious Allergic Reactions
- Serious allergic reactions, including anaphylactic reactions, angioedema, bronchospasm, skin rash, and urticaria may occur with Epogen. Immediately and permanently discontinue Epogen and administer appropriate therapy if a serious allergic or anaphylactic reaction occurs.
### Albumin (Human)
- Epogen contains albumin, a derivative of human blood. Based on effective donor screening and product manufacturing processes, it carries an extremely remote risk for transmission of viral diseases. A theoretical risk for transmission of Creutzfeldt-Jakob disease (CJD) also is considered extremely remote. No cases of transmission of viral diseases or CJD have ever been identified for albumin.
### Dialysis Management
- Patients may require adjustments in their dialysis prescriptions after initiation of Epogen. Patients receiving Epogen may require increased anticoagulation with heparin to prevent clotting of the extracorporeal circuit during hemodialysis.
### Laboratory Monitoring
- Evaluate transferrin saturation and serum ferritin prior to and during Epogen treatment. Administer supplemental iron therapy when serum ferritin is less than 100 mcg/L or when serum transferrin saturation is less than 20%. The majority of patients with CKD will require supplemental iron during the course of ESA therapy. Following initiation of therapy and after each dose adjustment, monitor hemoglobin weekly until the hemoglobin level is stable and sufficient to minimize the need for RBC transfusion.
# 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 other drugs and may not reflect the rates observed in practice.
Patients with chronic kidney disease
Adult Patients
- Three double-blind, placebo-controlled studies, including 244 patients with CKD on dialysis, were used to identify the adverse reactions to Epogen. In these studies, the mean age of patients was 48 years (range: 20 to 80 years). One hundred and thirty-three (55%) patients were men. The racial distribution was as follows: 177 (73%) patients were white, 48 (20%) patients were black, 4 (2%) patients were Asian, 12 (5%) patients were other, and racial information was missing for 3 (1%) patients.
- Two double-blind, placebo-controlled studies, including 210 patients with CKD not on dialysis, were used to identify the adverse reactions to Epogen. In these studies, the mean age of patients was 57 years (range: 24 to 79 years). One hundred and twenty-one (58%) patients were men. The racial distribution was as follows: 164 (78%) patients were white, 38 (18%) patients were black, 3 (1%) patients were Asian, 3 (1%) patients were other, and racial information was missing for 2 (1%) patients.
- The adverse reactions with a reported incidence of ≥ 5% in Epogen-treated patients and that occurred at a ≥ 1% higher frequency than in placebo-treated patients are shown in the table below:
- An additional serious adverse reaction that occurred in less than 5% of epoetin alfa-treated dialysis patients and greater than placebo was thrombosis (2.7% Epogen and 1% placebo).
- The adverse reactions with a reported incidence of ≥ 5% in Epogen-treated patients and that occurred at a ≥ 1% higher frequency than in placebo-treated patients are shown in the table below:
- Additional serious adverse reactions that occurred in less than 5% of epoetin alfa-treated patients not on dialysis and greater than placebo were erythema (0.8% Epogen and 0% placebo) and myocardial infarction (0.8% Epogen and 0% placebo).
Pediatric Patients
- In pediatric patients with CKD on dialysis, the pattern of adverse reactions was similar to that found in adults.
Zidovudine-treated HIV-infected Patients
- A total of 297 Zidovudine-treated HIV-infected patients were studied in 4 placebo-controlled studies. A total of 144 (48%) patients were randomly assigned to receive Epogen and 153 (52%) patients were randomly assigned to receive placebo. Epogen was administered at doses between 100 and 200 Units/kg 3 times weekly subcutaneously for up to 12 weeks.
- For the combined Epogen treatment groups, a total of 141 (98%) men and 3 (2%) women between the ages of 24 and 64 years were enrolled. The racial distribution of the combined Epogen treatment groups was as follows: 129 (90%) white, 8 (6%) black, 1 (1%) Asian, and 6 (4%) other.
- In double-blind, placebo-controlled studies of 3 months duration involving approximately 300 Zidovudine-treated HIV-infected patients, adverse reactions with an incidence of ≥ 1% in patients treated with Epogen were:
Cancer Patients on chemotherapy
- The data below were obtained in Study C1, a 16-week, double-blind, placebo-controlled study that enrolled 344 patients with anemia secondary to chemotherapy. There were 333 patients who were evaluable for safety; 168 of 174 patients (97%) randomized to Epogen received at least 1 dose of study drug, and 165 of 170 patients (97%) randomized to placebo received at least 1 placebo dose. For the once weekly Epogen-treatment group, a total of 76 men (45%) and 92 women (55%) between the ages of 20 and 88 years were treated. The racial distribution of the Epogen-treatment group was 158 white (94%) and 10 black (6%). Epogen was administered once weekly for an average of 13 weeks at a dose of 20,000 to 60,000 IU subcutaneously (mean weekly dose was 49,000 IU).
- The adverse reactions with a reported incidence of ≥ 5% in Epogen-treated patients that occurred at a higher frequency than in placebo-treated patients are shown in the table below:
Surgery Patients
- Four hundred sixty-one patients undergoing major orthopedic surgery were studied in a placebo-controlled study (S1) and a comparative dosing study (2 dosing regimens, S2). A total of 358 patients were randomly assigned to receive Epogen and 103 (22%) patients were randomly assigned to receive placebo. Epogen was administered daily at a dose of 100 to 300 IU/kg subcutaneously for 15 days or at 600 IU/kg once weekly for 4 weeks.
- For the combined Epogen treatment groups, a total of 90 (25%) and 268 (75%) women between the ages of 29 and 89 years were enrolled. The racial distribution of the combined Epogen treatment groups was as follows: 288 (80%) white, 64 (18%) black, 1 (< 1%) Asian, and 5 (1%) other.
- The adverse reactions with a reported incidence of ≥ 1% in Epogen-treated patients that occurred at a higher frequency than in placebo-treated patients are shown in the table below:
## Postmarketing Experience
- Because postmarketing reporting of adverse reactions is voluntary and from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
- The following adverse reactions have been identified during postmarketing use of Epogen:
- Seizures
- PRCA
- Serious allergic reactions
- Injection site reactions, including irritation and pain
- Porphyria
## Immunogenicity
- As with all therapeutic proteins, there is a potential for immunogenicity. Neutralizing antibodies to epoetin alfa that cross-react with endogenous erythropoietin and other ESAs can result in PRCA or severe anemia (with or without other cytopenias).
- The incidence of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors, including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to Epogen with the incidence of antibodies to other products may be misleading.
# Drug Interactions
- No formal drug interaction studies have been conducted with Epogen.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): C
- The multidose vials are formulated with benzyl alcohol. Do not administer Epogen from multidose vials, or Epogen from single-dose vials admixed with bacteriostatic saline containing benzyl alcohol, to pregnant women. When therapy with Epogen is needed during pregnancy, use a benzyl alcohol-free formulation.
Pregnancy Category C (single-dose vials only)
- There are no adequate and well-controlled studies of Epogen use during pregnancy. There are limited data on Epogen use in pregnant women. In animal reproductive and developmental toxicity studies, adverse fetal effects occurred when pregnant rats received epoetin alfa at doses approximating the clinical recommended starting doses. Single-dose formulations of Epogen should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
- There are reports of at least 33 pregnant women with anemia alone or anemia associated with severe renal disease and other hematologic disorders who received Epogen. Polyhydramnios and intrauterine growth restriction were reported in women with chronic renal disease, which is associated with an increased risk for these adverse pregnancy outcomes. There was 1 infant born with pectus excavatum and hypospadias following exposure during the first trimester. Due to the limited number of exposed pregnancies and multiple confounding factors (such as underlying maternal conditions, other maternal medications, and gestational timing of exposure), these published case reports and studies do not reliably estimate the frequency or absence of adverse outcomes.
- When healthy rats received Epogen at doses of 100 Units/kg/day during mating and through early pregnancy (dosing stopped prior to organogenesis), there were slight increases in the incidences of pre-and post-implantation loss, and a decrease in live fetuses. This animal dose level of 100 Units/kg/day may approximate the clinical recommended starting dose, depending on the treatment indication. When healthy pregnant rats and rabbits received intravenous doses of up to 500 mg/kg/day of Epogen only during organogenesis, no teratogenic effects were observed in the offspring.
- When healthy pregnant rats received Epogen at doses of 500 Units/kg/day late in pregnancy (after the period of organogenesis), offspring had decreased number of caudal vertebrae and growth delays.
- Women who become pregnant during Epogen treatment are encouraged to enroll in Amgen’s Pregnancy Surveillance Program. Patients or their physicians should call 1-800-772-6436 (1-800-77-AMGEN) to enroll.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Epoetin Alfa in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Epoetin Alfa during labor and delivery.
### Nursing Mothers
- The multidose vials of Epogen are formulated with benzyl alcohol. Do not administer Epogen from multidose vials, or Epogen from single-dose vials admixed with bacteriostatic saline containing benzyl alcohol, to a nursing woman. When therapy with Epogen is needed in nursing women, use a benzyl alcohol-free formulation.
- It is not known whether Epogen is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Epogen from single-dose vials is administered to a nursing woman.
### Pediatric Use
- The multidose vials are formulated with benzyl alcohol. Do not administer Epogen from multidose vials, or Epogen from single-dose vials admixed with bacteriostatic saline containing benzyl alcohol, to neonates or infants. When therapy with Epogen is needed in neonates and infants, use a benzyl alcohol-free formulation.
- Benzyl alcohol has been associated with serious adverse events and death, particularly in pediatric patients. The "gasping syndrome," (characterized by central nervous system depression, metabolic acidosis, gasping respirations, and high levels of benzyl alcohol and its metabolites found in the blood and urine) has been associated with benzyl alcohol dosages > 99 mg/kg/day in neonates and low-birthweight neonates. Additional symptoms may include gradual neurological deterioration, seizures, intracranial hemorrhage, hematologic abnormalities, skin breakdown, hepatic and renal failure, hypotension, bradycardia, and cardiovascular collapse.
- Although normal therapeutic doses of this product deliver amounts of benzyl alcohol that are substantially lower than those reported in association with the "gasping syndrome", the minimum amount of benzyl alcohol at which toxicity may occur is not known. Premature and low-birthweight infants, as well as patients receiving high dosages, may be more likely to develop toxicity. Practitioners administering this and other medications containing benzyl alcohol should consider the combined daily metabolic load of benzyl alcohol from all sources.
Pediatric Patients on dialysis
- Epogen is indicated in pediatric patients, ages 1 month to 16 years of age, for the treatment of anemia associated with CKD requiring dialysis. Safety and effectiveness in pediatric patients less than 1 month old have not been established.
- The safety data from these studies are similar to those obtained from the studies of Epogen in adult patients with CKD.
Pediatric Cancer Patients on chemotherapy
- Epogen is indicated in patients 5 to 18 years old for the treatment of anemia due to concomitant myelosuppressive chemotherapy. Safety and effectiveness in pediatric patients less than 5 years of age have not been established. The safety data from these studies are similar to those obtained from the studies of Epogen in adult patients with cancer.
Pediatric Patients With HIV Infection Receiving Zidovudine
- Published literature has reported the use of Epogen in 20 Zidovudine-treated, anemic, pediatric patients with HIV infection, ages 8 months to 17 years, treated with 50 to 400 Units/kg subcutaneously or intravenously 2 to 3 times per week. Increases in hemoglobin levels and in reticulocyte counts and decreases in or elimination of RBC transfusions were observed.
Pharmacokinetics in Neonates
- Limited pharmacokinetic data from a study of 7 preterm, very low birth weight neonates and 10 healthy adults given intravenous erythropoietin suggested that distribution volume was approximately 1.5 to 2 times higher in the preterm neonates than in the healthy adults, and clearance was approximately 3 times higher in the preterm neonates than in the healthy adults.
### Geriatic Use
- Of the 4553 patients who received Epogen in the 6 studies for treatment of anemia due to CKD not receiving dialysis, 2726 (60%) were age 65 years and over, while 1418 (31%) were 75 years and over. Of the 757 patients who received Epogen in the 3 studies of CKD patients on dialysis, 361 (47%) were age 65 years and over, while 100 (13%) were 75 years and over. No differences in safety or effectiveness were observed between geriatric and younger patients. Dose selection and adjustment for an elderly patient should be individualized to achieve and maintain the target hemoglobin.
- Among 778 patients enrolled in the 3 clinical studies of Epogen for the treatment of anemia due to concomitant chemotherapy, 419 received Epogen and 359 received placebo. Of the 419 who received Epogen, 247 (59%) were age 65 years and over, while 78 (19%) were 75 years and over. No overall differences in safety or effectiveness were observed between geriatric and younger patients. The dose requirements for Epogen in geriatric and younger patients within the 3 studies were similar.
- Among 1731 patients enrolled in the 6 clinical studies of Epogen for reduction of allogeneic RBC transfusions in patients undergoing elective surgery, 1085 received Epogen and 646 received placebo or standard of care treatment. Of the 1085 patients who received Epogen, 582 (54%) were age 65 years and over, while 245 (23%) were 75 years and over. No overall differences in safety or effectiveness were observed between geriatric and younger patients. The dose requirements for Epogen in geriatric and younger patients within the 4 studies using the 3 times weekly schedule and 2 studies using the weekly schedule were similar.
- Insufficient numbers of patients age 65 years or older were enrolled in clinical studies of Epogen for the treatment of Zidovudine in HIV-infected patients to determine whether they respond differently from younger patients.
### Gender
There is no FDA guidance on the use of Epoetin Alfa with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Epoetin Alfa with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Epoetin Alfa in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Epoetin Alfa in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Epoetin Alfa in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Epoetin Alfa in patients who are immunocompromised.
# Administration and Monitoring
### Administration
Preparation and Administration
- Do not shake. Do not use Epogen that has been shaken or frozen.
- Protect vials from light.
- Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration. Do not use any vials exhibiting particulate matter or discoloration.
- Discard unused portions of Epogen in preservative-free vials. Do not re-enter preservative-free vials.
- Store unused portions of Epogen in multidose vials at 36°F to 46° F (2°C to 8°C). Discard 21 days after initial entry.
- Do not dilute. Do not mix with other drug solutions except for admixing as described below:
- Preservative-free Epogen from single-use vials may be admixed in a syringe with bacteriostatic 0.9% sodium chloride injection, USP, with benzyl alcohol 0.9% (bacteriostatic saline) in a 1:1 ratio using aseptic technique at the time of administration. Risks are associated with benzyl alcohol in neonates, infants, pregnant women, and nursing mothers.
### Monitoring
- FDA Package Insert for Epoetin Alfa contains no information regarding Drug Monitoring.
# IV Compatibility
- There is limited information about the IV Compatibility.
# Overdosage
- Epogen overdosage can cause hemoglobin levels above the desired level, which should be managed with discontinuation or reduction of Epogen dosage and/or with phlebotomy as clinically indicated. Cases of severe hypertension have been observed following overdose with ESAs
# Pharmacology
## Mechanism of Action
- Epogen stimulates erythropoiesis by the same mechanism as endogenous erythropoietin.
## Structure
- Epogen (epoetin alfa) is a 165-amino acid erythropoiesis-stimulating glycoprotein manufactured by recombinant DNA technology. It has a molecular weight of approximately 30,400 daltons and is produced by mammalian cells into which the human erythropoietin gene has been introduced. The product contains the identical amino acid sequence of isolated natural erythropoietin.
- Epogen is formulated as a sterile, colorless liquid in vials in multiple formulations. Single-dose vials, formulated with an isotonic sodium chloride/sodium citrate-buffered solution, are supplied in multiple strengths. Each 1 mL vial contains 2000, 3000, 4000, or 10,000 Units of epoetin alfa, Albumin (Human) (2.5 mg), citric acid (0.06 mg), sodium chloride (5.9 mg), and sodium citrate (5.8 mg) in Water for Injection, USP (pH 6.9 ± 0.3). Single-dose 1 mL vials formulated with an isotonic sodium chloride/sodium phosphate buffer contain 40,000 Units of epoetin alfa albumin (human) (2.5 mg), citric acid (0.0068 mg), sodium chloride (5.8 mg), sodium citrate (0.7 mg), sodium phosphate dibasic anhydrate (1.8 mg), and sodium phosphate monobasic monohydrate (1.2 mg) in Water for Injection, USP (pH 6.9 ± 0.3). Multidose, 2 mL vials contain 10,000 Units epoetin alfa, albumin (human) (2.5 mg), benzyl alcohol (1%), sodium chloride (8.2 mg), and sodium citrate (1.3 mg) per 1 mL Water for Injection, USP (pH 6.1 ± 0.3). Multidose 1 mL vials contain 20,000 Units epoetin alfa, albumin (human) (2.5 mg), benzyl alcohol (1%), sodium chloride (8.2 mg), citric acid (0.11 mg), and sodium citrate (1.3 mg), per 1 mL in Water for Injection, USP (pH 6.1 ± 0.3).
## Pharmacodynamics
- Epogen increases the reticulocyte count within 10 days of initiation, followed by increases in the RBC count, hemoglobin, and hematocrit, usually within 2 to 6 weeks. The rate of hemoglobin increase varies among patients and is dependent upon the dose of Epogen administered. For correction of anemia in hemodialysis patients, a greater biologic response is not observed at doses exceeding 300 Units/kg 3 times weekly.
## Pharmacokinetics
- In adult and pediatric patients with CKD, the elimination half-life (t1/2) of plasma erythropoietin after intravenous administration of Epogen ranged from 4 to 13 hours. After subcutaneous administration, Cmax was achieved within 5 to 24 hours. The t1/2 in adult patients with serum creatinine greater than 3 mg/dL was similar between those not on dialysis and those maintained on dialysis. The pharmacokinetic data indicate no apparent difference in Epogen t1/2 among adult patients above or below 65 years of age.
- A pharmacokinetic study comparing 150 Units/kg subcutaneous 3 times weekly to 40,000 Units subcutaneous weekly dosing regimen was conducted for 4 weeks in healthy subjects (n = 12) and for 6 weeks in anemic cancer patients (n = 32) receiving cyclic chemotherapy. There was no accumulation of serum erythropoietin after the 2 dosing regimens during the study period. The 40,000 Units weekly regimen had a higher Cmax (3- to 7-fold), longer Tmax (2- to 3-fold), higher AUC0-168 h (2- to 3-fold) of erythropoietin and lower clearance (CL) (50%) than the 150 Units/kg 3 times weekly regimen. In anemic cancer patients, the average t1/2 was similar (40 hours with range of 16 to 67 hours) after both dosing regimens. After the 150 Units/kg 3 times weekly dosing, the values of Tmax and CL were similar (13.3 ± 12.4 vs. 14.2 ± 6.7 hours, and 20.2 ± 15.9 vs. 23.6 ± 9.5 mL/hr/kg) between week 1 when patients were receiving chemotherapy (n = 14) and week 3 when patients were not receiving chemotherapy (n = 4). Differences were observed after the 40,000 Units weekly dosing with longer Tmax (38 ± 18 hours) and lower CL (9.2 ± 4.7 mL/hr/kg) during week 1 when patients were receiving chemotherapy (n = 18) compared with those (22 ± 4.5 hours, 13.9 ± 7.6 mL/hr/kg, respectively) during week 3 when patients were not receiving chemotherapy (n = 7).
- The pharmacokinetic profile of Epogen in children and adolescents appeared similar to that of adults.
- The pharmacokinetics of Epogen has not been studied in patients with HIV infection.
## Nonclinical Toxicology
### Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenicity
- The carcinogenic potential of Epogen has not been evaluated.
Mutagenicity
- Epogen was not mutagenic or clastogenic under the conditions tested: Epogen was negative in the in vitro bacterial reverse mutation assay (Ames test), in the in vitro mammalian cell gene mutation assay (the hypoxanthine-guanine phosphoribosyl transferase [HGPRT] locus), in an in vitro chromosomal aberration assay in mammalian cells, and in the in vivo mouse micronucleus assay.
Impairment of Fertility
- When administered intravenously to male and female rats prior to and during mating, and to females through the beginning of implantation (up to gestational day 7; dosing stopped prior to the beginning of organogenesis), doses of 100 and 500 Units/kg/day of Epogen caused slight increases in pre-implantation loss, post-implantation loss and decreases in the incidence of live fetuses. It is not clear whether these effects reflect a drug effect on the uterine environment or on the conceptus. This animal dose level of 100 Units/kg/day approximates the clinical recommended starting dose, depending on the patient’s treatment indication, but may be lower than the clinical dose in patients whose doses have been adjusted.
### Reproductive and Developmental Toxicology
- When pregnant rats were administered intravenous Epogen, 500 Units/kg/day, after the period of organogenesis (from day 17 of gestation through day 21 of lactation), their pups exhibited decreased number of caudal vertebrae, decreased body weight gain, and delayed appearance of abdominal hair, eyelid opening, and ossification. This animal dose level of 500 Units/kg/day is approximately 5-fold higher than the clinical recommended starting dose, depending on the patient’s treatment indication.
- When Epogen was administered intravenously during the period of organogenesis to pregnant rats (gestational days 7 to 17) and pregnant rabbits (gestational days 6 to 18), no evidence of teratogenic outcome was observed at the doses tested, up to 500 Units/kg/day. The offspring (F1 generation) of the treated rats were observed postnatally; rats from the F1 generation reached maturity and were mated; no Epogen-related effects were apparent for their offspring (F2 generation fetuses).
# Clinical Studies
### Patients With chronic kidney disease
Adult Patients on dialysis
- Patients with chronic kidney disease on dialysis: ESA effects on rates of transfusion
- In clinical studies of CKD patients on dialysis, Epogen increased hemoglobin levels and decreased the need for RBC transfusion. Overall, more than 95% of patients were RBC transfusion-independent after receiving Epogen for 3 months. In clinical studies at starting doses of 50 to 150 Units/kg 3 times weekly, adult patients responded with an average rate of hemoglobin rise as presented in Table 8.
- The safety and efficacy of Epogen were evaluated in 13 clinical studies involving intravenous administration to a total of 1010 anemic patients on dialysis. Overall, more than 90% of the patients treated with Epogen experienced improvement in hemoglobin concentrations. In the 3 largest of these clinical studies, the median maintenance dose necessary to maintain the hemoglobin between 10 to 12 g/dL was approximately 75 Units/kg 3 times weekly. More than 95% of patients were able to avoid RBC transfusions. In the largest US multicenter study, approximately 65% of the patients received doses of 100 Units/kg 3 times weekly or less to maintain their hemoglobin at approximately 11.7 g/dL. Almost 10% of patients received a dose of 25 Units/kg or less, and approximately 10% received a dose of more than 200 Units/kg 3 times weekly to maintain their hemoglobin at this level.
- In the Normal Hematocrit Study, the yearly transfusion rate was 51.5% in the lower hemoglobin group (10 g/dL) and 32.4% in the higher hemoglobin group (14 g/dL).
Other ESA trials
- In a 26-week, double-blind, placebo-controlled study, 118 patients on dialysis with an average hemoglobin of approximately 7 g/dL were randomized to either Epogen or placebo. By the end of the study, average hemoglobin increased to approximately 11 g/dL in the Epogen-treated patients and remained unchanged in patients receiving placebo. Epogen-treated patients experienced improvements in exercise tolerance and patient-reported physical functioning at month 2 that were maintained throughout the study.
- A multicenter, unit-dose study was also conducted in 119 patients receiving peritoneal dialysis who self-administered Epogen subcutaneously. Patients responded to Epogen administered subcutaneously in a manner similar to patients receiving intravenous administration.
Pediatric Patients on dialysis
- The safety and efficacy of Epogen were studied in a placebo-controlled, randomized study of 113 children with anemia (hemoglobin ≤ 9 g/dL) undergoing peritoneal dialysis or hemodialysis. The initial dose of Epogen was 50 Units/kg intravenously or subcutaneously 3 times weekly. The dose of study drug was titrated to achieve either a hemoglobin of 10 to 12 g/dL or an absolute increase in hemoglobin of 2 g/dL over baseline.
- At the end of the initial 12 weeks, a statistically significant rise in mean hemoglobin (3.1 g/dL vs. 0.3 g/dL) was observed only in the Epogen arm. The proportion of children achieving a hemoglobin of 10 g/dL, or an increase in hemoglobin of 2 g/dL over baseline, at any time during the first 12 weeks was higher in the Epogen arm (96% vs. 58%). Within 12 weeks of initiating Epogen therapy, 92.3% of the pediatric patients were RBC transfusion independent as compared to 65.4% who received placebo. Among patients who received 36 weeks of Epogen, hemodialysis patients received a higher median maintenance dose [167 Units/kg/week (n = 28) vs. 76 Units/kg/week (n = 36)] and took longer to achieve a hemoglobin of 10 to 12 g/dL (median time to response 69 days vs. 32 days) than patients undergoing peritoneal dialysis.
Adult Patients With CKD Not Requiring dialysis
- Four clinical studies were conducted in patients with CKD not on dialysis involving 181 patients treated with Epogen. These patients responded to Epogen therapy in a manner similar to that observed in patients on dialysis. Patients with CKD not on dialysis demonstrated a dose-dependent and sustained increase in hemoglobin when Epogen was administered by either an intravenous or subcutaneous route, with similar rates of rise of hemoglobin when Epogen was administered by either route.
Patients with chronic kidney disease not on dialysis: ESA effects on rates of transfusion
- In TREAT, a randomized, double-blind trial of 4038 patients with CKD and type 2 diabetes not on dialysis, a post-hoc analysis showed that the proportion of patients receiving RBC transfusions was lower in patients administered an ESA to target a hemoglobin of 13 g/dL compared to the control arm in which an ESA was administered intermittently if hemoglobin concentration decreased to less than 9 g/dL (15% versus 25%, respectively). In CHOIR, a randomized open-label study of 1432 patients with CKD not on dialysis, use of epoetin alfa to target a higher (13.5 g/dL) versus lower (11.3 g/dL) hemoglobin goal did not reduce the use of RBC transfusions. In each trial, no benefits occurred for the cardiovascular or end-stage renal disease outcomes. In each trial, the potential benefit of ESA therapy was offset by worse cardiovascular safety outcomes resulting in an unfavorable benefit-risk profile.
ESA Effects on rates of death and other serious cardiac adverse events
- Three randomized outcome trials (Normal Hematocrit Study [NHS], Correction of anemia with Epoetin Alfa in chronic kidney disease [CHOIR], and Trial of darbepoetin Alfa in Type 2 Diabetes and CKD [TREAT]) have been conducted in patients with CKD using Epogen/PROCRIT/Aranesp to target higher vs. lower hemoglobin levels. Though these trials were designed to establish a cardiovascular or renal benefit of targeting higher hemoglobin levels, in all 3 studies, patients randomized to the higher hemoglobin target experienced worse cardiovascular outcomes and showed no reduction in progression to ESRD. In each trial, the potential benefit of ESA therapy was offset by worse cardiovascular safety outcomes resulting in an unfavorable benefit-risk profile.
### Zidovudine-treated Patients With HIV Infection
- The safety and efficacy of Epogen were evaluated in 4 placebo-controlled studies enrolling 297 anemic patients (hemoglobin < 10 g/dL) with HIV infection receiving concomitant therapy with Zidovudine. In the subgroup of patients (89/125 Epogen and 88/130 placebo) with pre study endogenous serum erythropoietin levels ≤ 500 mUnits/mL, Epogen reduced the mean cumulative number of units of blood transfused per patient by approximately 40% as compared to the placebo group. Among those patients who required RBC transfusions at baseline, 43% of patients treated with Epogen versus 18% of placebo-treated patients were RBC transfusion independent during the second and third months of therapy. Epogen therapy also resulted in significant increases in hemoglobin in comparison to placebo. When examining the results according to the weekly dose of Zidovudine received during month 3 of therapy, there was a statistically significant reduction (p < 0.003) in RBC transfusion requirements in patients treated with Epogen (n = 51) compared to placebo-treated patients (n = 54) whose mean weekly Zidovudine dose was ≤ 4200 mg/week.
- Approximately 17% of the patients with endogenous serum erythropoietin levels ≤ 500 mUnits/mL receiving Epogen in doses from 100 to 200 Units/kg 3 times weekly achieved a hemoglobin of 12.7 g/dL without administration of RBC transfusions or significant reduction in Zidovudine dose. In the subgroup of patients whose pre study endogenous serum erythropoietin levels were > 500 mUnits/mL, Epogen therapy did not reduce RBC transfusion requirements or increase hemoglobin compared to the corresponding responses in placebo-treated patients.
### Cancer Patients on chemotherapy
- The safety and effectiveness of Epogen was assessed in two multicenter, randomized (1:1), placebo-controlled, double-blind studies (Study C1 and Study C2) and a pooled analysis of six additional randomized (1:1), multicenter, placebo-controlled, double-blind studies. All studies were conducted in patients with anemia due to concomitantly administered cancer chemotherapy. Study C1 enrolled 344 adult patients, Study C2 enrolled 222 pediatric patients, and the pooled analysis contained 131 patients randomized to epoetin alfa or placebo. In Studies C1 and C2, efficacy was demonstrated by a reduction in the proportion of patients who received an RBC transfusion, from week 5 through end of the study, with the last-known RBC transfusion status carried forward for patients who discontinued treatment. In the pooled analysis, efficacy was demonstrated by a reduction in the proportion of patients who received an RBC transfusion from week 5 through end of the study in the subset of patients who were remaining on therapy for 6 or more weeks.
Study C1
- Study C1 was conducted in anemic patients (hemoglobin < 11.5 g/dL for males; < 10.5 g/dL for females) with non-myeloid malignancies receiving myelosuppressive chemotherapy. Randomization was stratified by type of malignancy (lung vs. breast vs. other), concurrent radiation therapy planned (yes or no), and baseline hemoglobin (< 9 g/dL vs. ≥ 9 g/dL); patients were randomized to epoetin alfa 40,000 Units (n = 174) or placebo (n = 170) as a weekly subcutaneous injection commencing on the first day of the chemotherapy cycle.
- Ninety-one percent of patients were white, 44% were male, and the median age of patients was 66 years (range: 20 to 88 years). The proportion of patients withdrawn from the study prior to week 5 was less than 10% for placebo-treated or epoetin-treated patients. Per protocol, the last available hemoglobin values from patients who dropped out were included in the efficacy analyses. Efficacy results are shown in Table 9.
Study C2
- Study C2 was conducted in 222 anemic patients, ages 5 to 18, receiving chemotherapy for the treatment of various childhood malignancies. Randomization was stratified by cancer type (solid tumors, Hodgkin’s disease, acute lymphocytic leukemia, vs. non-Hodgkin’s lymphoma); patients were randomized to receive epoetin alfa at 600 Units/kg maximum 40,000 Units (n = 111) or placebo (n = 111) as a weekly intravenous injection.
- Sixty-nine percent of patients were white, 55% were male, and the median age of patients was 12 years (range: 5 to 18 years). Two (2%) of placebo-treated patients and 3 (3%) of epoetin alfa-treated patients dropped out of the study prior to week 5. There were fewer RBC transfusions from week 5 through the end-of-study in epoetin-alfa treated patients [51% (57/111)] compared to placebo-treated patients [69% (77/111)]. There was no evidence of an improvement in health-related quality of life, including no evidence of an effect on fatigue, energy, or strength in patients receiving Epogen as compared to those receiving placebo.
Pooled Analysis (Three Times Per Week Dosing)
- The results of 6 studies of similar design and that randomized 131 patients to epoetin alfa or placebo were pooled to assess the safety and effectiveness of epoetin alfa. Patients were randomized to receive epoetin alfa at 150 Units/kg (n = 63) or placebo (n = 68), subcutaneously three times per week for 12 weeks in each study. Across all studies, 72 patients were treated with concomitant non cisplatin-containing chemotherapy regimens and 59 patients were treated with concomitant cisplatin-containing chemotherapy regimens. Twelve patients (19%) in the epoetin alfa arm and 10 patients (15%) in the placebo-arm dropped out prior to week 6 and are excluded from efficacy analyses.
### Surgery Patients
- The safety and efficacy of Epogen were evaluated in a placebo-controlled, double-blind study (S1) enrolling 316 patients scheduled for major, elective orthopedic hip or knee surgery who were expected to require ≥ 2 units of blood and who were not able or willing to participate in an autologous blood donation program. Patients were stratified into 1 of 3 groups based on their pretreatment hemoglobin [≤ 10 g/dL (n = 2), > 10 to ≤ 13 g/dL (n = 96), and > 13 to ≤ 15 g/dL (n = 218)] and then randomly assigned to receive 300 Units/kg Epogen, 100 Units/kg Epogen, or placebo by subcutaneous injection for 10 days before surgery, on the day of surgery, and for 4 days after surgery. All patients received oral iron and a low-dose, postoperative warfarin regimen.
- Treatment with Epogen 300 Units/kg significantly (p = 0.024) reduced the risk of allogeneic RBC transfusion in patients with a pretreatment hemoglobin of > 10 to ≤ 13 g/dL; 5/31 (16%) of patients treated with Epogen 300 Units/kg, 6/26 (23%) of patients treated with Epogen 100 Units/kg, and 13/29 (45%) of placebo-treated patients were transfused. There was no significant difference in the number of patients transfused between Epogen (9% 300 Units/kg, 6% 100 Units/kg) and placebo (13%) in the > 13 to ≤ 15 g/dL hemoglobin stratum. There were too few patients in the ≤ 10 g/dL group to determine if Epogen is useful in this hemoglobin strata. In the > 10 to ≤ 13 g/dL pretreatment stratum, the mean number of units transfused per Epogen-treated patient (0.45 units blood for 300 Units/kg, 0.42 units blood for 100 Units/kg) was less than the mean transfused per placebo-treated patient (1.14 units) (overall p = 0.028). In addition, mean hemoglobin, hematocrit, and reticulocyte counts increased significantly during the presurgery period in patients treated with Epogen.
- Epogen was also evaluated in an open-label, parallel-group study (S2) enrolling 145 patients with a pretreatment hemoglobin level of ≥ 10 to ≤ 13 g/dL who were scheduled for major orthopedic hip or knee surgery and who were not participating in an autologous program. Patients were randomly assigned to receive 1 of 2 subcutaneous dosing regimens of Epogen (600 Units/kg once weekly for 3 weeks prior to surgery and on the day of surgery, or 300 Units/kg once daily for 10 days prior to surgery, on the day of surgery, and for 4 days after surgery). All patients received oral iron and appropriate pharmacologic anticoagulation therapy.
- From pretreatment to presurgery, the mean increase in hemoglobin in the 600 Units/kg weekly group (1.44 g/dL) was greater than that observed in the 300 Units/kg daily group. The mean increase in absolute reticulocyte count was smaller in the weekly group (0.11 × 106/mm3) compared to the daily group (0.17 × 106/mm3). Mean hemoglobin levels were similar for the 2 treatment groups throughout the postsurgical period.
- The erythropoietic response observed in both treatment groups resulted in similar RBC transfusion rates [11/69 (16%) in the 600 Units/kg weekly group and 14/71 (20%) in the 300 Units/kg daily group]. The mean number of units transfused per patient was approximately 0.3 units in both treatment groups.
# How Supplied
Single-dose, Preservative-free Vial (in citrate-buffered formulation): 1 mL of solution contains 2000 (NDC 55513-126-10), 3000 (NDC 55513-267-10), 4000 (NDC 55513-148-10), or 10,000 Units (NDC 55513-144-10) of epoetin alfa. Each strength is supplied in dispensing packs containing 10 single-dose vials.
Single-dose, Preservative-free Vial (in phosphate-buffered formulation): 1 mL of solution contains 40,000 Units (NDC 55513-823-10) of epoetin alfa and is supplied in dispensing packs containing 10 single-dose vials.
Multidose, Preserved Vial: 2 mL total volume (20,000 Units total; 10,000 Units/mL). Each 1 mL of solution contains 10,000 Units (NDC 55513-283-10) of epoetin alfa, and is supplied in dispensing packs containing 10 multidose vials.
Multidose, Preserved Vial: 1 mL total volume (20,000 Units/mL). Each 1 mL of solution contains 20,000 Units (NDC 55513-478-10) of epoetin alfa and is supplied in dispensing packs containing 10 multidose vials.
## Storage
- Store at 36ºF to 46ºF (2ºC to 8ºC). Do not freeze.
- Do not shake. Protect from light; store Epogen in the carton until use.
- Do not use Epogen that has been shaken or frozen.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
# Precautions with Alcohol
- Alcohol-Epoetin Alfa interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- ARANESP
# Look-Alike Drug Names
- There is limited information about the Look-alike drug names.
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Epoetin_Alfa | |
2c4667c1c249857b92d44646ce36c80eb20c25ae | wikidoc | Epoprostenol | Epoprostenol
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# Overview
Epoprostenol is a prostaglandin that is FDA approved for the treatment of pulmonary arterial hypertension. Common adverse reactions include bradyarrhythmia, chest pain, hypotension, tachycardia, flushing, abdominal pain, diarrhea, loss of appetite, nausea, vomiting, dizziness, and headache.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Important Note: Epoprostenol sodium for injection must be reconstituted only with STERILE DILUENT for epoprostenol sodium for injection. Do not dilute reconstituted solutions of epoprostenol for injection or administer with other parenteral solutions or medications.
- Dosing Information
- Administer continuous chronic infusion of epoprostenol sodium for injection through a central venous catheter. Temporary peripheral intravenous infusion may be used until central access is established. Initiate chronic infusion of epoprostenol sodium for injection at 2 ng/kg/min and increase in increments of 2 ng/kg/min every 15 minutes or longer until dose-limiting pharmacologic effects are elicited or until a tolerance limit to the drug is established or further increases in the infusion rate are not clinically warranted. If dose-limiting pharmacologic effects occur, then decrease the infusion rate until epoprostenol sodium for injection is tolerated. In clinical trials, the most common dose-limiting adverse events were nausea, vomiting, hypotension, sepsis, headache, abdominal pain, or respiratory disorder (most treatment-limiting adverse events were not serious). If the initial infusion rate of 2 ng/kg/min is not tolerated, identify a lower dose that is tolerated by the patient.
- In the controlled 12-week trial in PAH/SSD, for example, the dose increased from a mean starting dose of 2.2 ng/kg/min. During the first 7 days of treatment, the dose was increased daily to a mean dose of 4.1 ng/kg/min on day 7 of treatment. At the end of week 12, the mean dose was 11.2 ng/kg/min. The mean incremental increase was 2 to 3 ng/kg/min every 3 weeks.
- Dosage Adjustments
- Base changes in the chronic infusion rate on persistence, recurrence, or worsening of the patient's symptoms of pulmonary hypertension and the occurrence of adverse events due to excessive doses of epoprostenol sodium for injection. In general, expect increases in dose from the initial chronic dose.
- Consider increments in dose if symptoms of PAH persist or recur. Increase the infusion by 1- to 2-ng/kg/min increments at intervals sufficient to allow assessment of clinical response; these intervals should be at least 15 minutes. In clinical trials, incremental increases in dose occurred at intervals of 24 to 48 hours or longer. Following establishment of a new chronic infusion rate, observe the patient, and monitor standing and supine blood pressure and heart rate for several hours to ensure that the new dose is tolerated.
- During chronic infusion, the occurrence of dose-limiting pharmacological events may necessitate a decrease in infusion rate, but the adverse event may occasionally resolve without dosage adjustment. Make dosage decreases gradually in 2-ng/kg/min decrements every 15 minutes or longer until the dose-limiting effects resolve. Avoid abrupt withdrawal of epoprostenol sodium for injection or sudden large reductions in infusion rates. Except in life-threatening situations (e.g., unconsciousness, collapse, etc.), adjust infusion rates of epoprostenol sodium for injection only under the direction of a physician.
- In patients receiving lung transplants, doses of epoprostenol sodium for injection were tapered after the initiation of cardiopulmonary bypass.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Epoprostenol in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Epoprostenol in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
- 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 Epoprostenol in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Epoprostenol in pediatric patients.
# Contraindications
- A large study evaluating the effect of epoprostenol on survival in NYHA Class III and IV patients with congestive heart failure due to severe left ventricular systolic dysfunction was terminated after an interim analysis of 471 patients revealed a higher mortality in patients receiving epoprostenol plus conventional therapy than in those receiving conventional therapy alone. The chronic use of epoprostenol in patients with congestive heart failure due to severe left ventricular systolic dysfunction is therefore contraindicated.
- Some patients with pulmonary hypertension have developed pulmonary edema during dose initiation, which may be associated with pulmonary veno-occlusive disease. Epoprostenol should not be used chronically in patients who develop pulmonary edema during dose initiation.
- Epoprostenol is also contraindicated in patients with known hypersensitivity to the drug or to structurally related compounds.
# Warnings
- Epoprostenol sodium for injection must be reconstituted only as directed using STERILE DILUENT for epoprostenol sodium for injection. Epoprostenol sodium for injection must not be reconstituted or mixed with any other parenteral medications or solutions prior to or during administration.
- Abrupt withdrawal (including interruptions in drug delivery) or sudden large reductions in dosage of epoprostenol may result in symptoms associated with rebound pulmonary hypertension, including dyspnea, dizziness, and asthenia. In clinical trials, one Class III patient's death was judged attributable to the interruption of epoprostenol. Avoid abrupt withdrawal.
### Precautions
- Epoprostenol should be used only by clinicians experienced in the diagnosis and treatment of pulmonary hypertension. Carefully establish the diagnosis of idiopathic or heritable PAH or PAH/CTD.
- Epoprostenol is a potent pulmonary and systemic vasodilator. Initiate epoprostenol in a setting with adequate personnel and equipment for physiologic monitoring and emergency care. Dose initiation has been performed during right heart catheterization and without cardiac catheterization. During dose initiation, asymptomatic increases in pulmonary artery pressure coincident with increases in cardiac output occurred rarely. In such cases, consider dose reduction, but such an increase does not imply that chronic treatment is contraindicated.
- Epoprostenol is a potent inhibitor of platelet aggregation. Therefore, expect an increased risk for hemorrhagic complications, particularly for patients with other risk factors for bleeding.
- During chronic use, deliver epoprostenol continuously on an ambulatory basis through a permanent indwelling central venous catheter. Unless contraindicated, administer anticoagulant therapy to patients receiving epoprostenol to reduce the risk of pulmonary thromboembolism or systemic embolism through a patent foramen ovale. To reduce the risk of infection, use aseptic technique in the reconstitution and administration of epoprostenol and in routine catheter care. Because epoprostenol is metabolized rapidly, even brief interruptions in the delivery of epoprostenol may result in symptoms associated with rebound pulmonary hypertension including dyspnea, dizziness, and asthenia. Intravenous therapy with epoprostenol will likely be needed for prolonged periods, possibly years, so consider the patient's ability to accept and care for a permanent intravenous catheter and infusion pump.
- Based on clinical trials, the acute hemodynamic response to epoprostenol did not correlate well with improvement in exercise tolerance or survival during chronic use of epoprostenol. Adjust dosage of epoprostenol during chronic use at the first sign of recurrence or worsening of symptoms attributable to pulmonary hypertension or the occurrence of adverse events associated with epoprostenol. Following dosage adjustments, monitor standing and supine blood pressure and heart rate closely for several hours.
# Adverse Reactions
## Clinical Trials Experience
- During clinical trials, adverse events were classified as follows: (1) adverse events during dose initiation and escalation, (2) adverse events during chronic dosing, and (3) adverse events associated with the drug delivery system.
- During early clinical trials, epoprostenol was increased in 2-ng/kg/min increments until the patients developed symptomatic intolerance. The most common adverse events and the adverse events that limited further increases in dose were generally related to vasodilation, the major pharmacologic effect of epoprostenol. The most common dose-limiting adverse events (occurring in ≥1% of patients) were nausea, vomiting, headache, hypotension, and flushing, but also include chest pain, anxiety, dizziness, bradycardia, dyspnea, abdominal pain, musculoskeletal pain, and tachycardia. Table 3 lists the adverse events reported during dose initiation and escalation in decreasing order of frequency.
- Interpretation of adverse events is complicated by the clinical features of PAH, which are similar to some of the pharmacologic effects of epoprostenol (e.g., dizziness, syncope). Adverse events which may be related to the underlying disease include dyspnea, fatigue, chest pain, edema, hypoxia, right ventricular failure, and pallor. Several adverse events, on the other hand, can clearly be attributed to epoprostenol. These include hypotension, bradycardia, tachycardia, pulmonary edema, bleeding at various sites, thrombocytopenia, headache, abdominal pain, pain (unspecified), sweating, rash, arthralgia, jaw pain, flushing, diarrhea, nausea and vomiting, flu-like symptoms, anxiety/nervousness, and agitation. In addition, chest pain, fatigue, and pallor have been reported during epoprostenol therapy, and a role for the drug in these events cannot be excluded.
- In an effort to separate the adverse effects of the drug from the adverse effects of the underlying disease, Table 4 lists adverse events that occurred at a rate at least 10% greater on epoprostenol in controlled trials.
- Thrombocytopenia has been reported during uncontrolled clinical trials in patients receiving epoprostenol.
- In an effort to separate the adverse effects of the drug from the adverse effects of the underlying disease, Table 5 lists adverse events that occurred at a rate at least 10% greater on epoprostenol in the controlled trial.
- Although the relationship to epoprostenol administration has not been established, pulmonary embolism has been reported in several patients taking epoprostenol and there have been reports of hepatic failure.
- Chronic infusions of epoprostenol are delivered using a small, portable infusion pump through an indwelling central venous catheter. During controlled PAH trials of up to 12 weeks’ duration, the local infection rate was about 18%, and the rate for pain was about 11%. During long-term follow-up, sepsis was reported at a rate of 0.3 infections/patient per year in patients treated with epoprostenol. This rate was higher than reported in patients using chronic indwelling central venous catheters to administer parenteral nutrition, but lower than reported in oncology patients using these catheters. Malfunctions in the delivery system resulting in an inadvertent bolus of or a reduction in epoprostenol were associated with symptoms related to excess or insufficient epoprostenol, respectively.
- In addition to adverse reactions reported from clinical trials, the following events have been identified during post-approval use of epoprostenol. Because they are reported voluntarily from a population of unknown size, estimates of frequency cannot be made. These events have been chosen for inclusion due to a combination of their seriousness, frequency of reporting, or potential causal connection to epoprostenol.
- Blood and Lymphatic: Anemia, hypersplenism, pancytopenia, splenomegaly.
- Endocrine and Metabolic: Hyperthyroidism.
## Postmarketing Experience
There is limited information regarding Postmarketing Experience of Epoprostenol in the drug label.
# Drug Interactions
- Additional reductions in blood pressure may occur when epoprostenol is administered with diuretics, antihypertensive agents, or other vasodilators. When other antiplatelet agents or anticoagulants are used concomitantly, there is the potential for epoprostenol to increase the risk of bleeding. However, patients receiving infusions of epoprostenol in clinical trials were maintained on anticoagulants without evidence of increased bleeding. In clinical trials, epoprostenol was used with digoxin, diuretics, anticoagulants, oral vasodilators, and supplemental oxygen.
- In a pharmacokinetic substudy in patients with congestive heart failure receiving furosemide or digoxin in whom therapy with epoprostenol was initiated, apparent oral clearance values for furosemide (n = 23) and digoxin (n = 30) were decreased by 13% and 15%, respectively, on the second day of therapy and had returned to baseline values by day 87. The change in furosemide clearance value is not likely to be clinically significant. However, patients on digoxin may show elevations of digoxin concentrations after initiation of therapy with epoprostenol, which may be clinically significant in patients prone to digoxin toxicity.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
- Pregnancy Category B
- Reproductive studies have been performed in pregnant rats and rabbits at doses up to 100 mcg/kg/day (600 mcg/m2/day in rats, 2.5 times the recommended human dose, and 1,180 mcg/m2/day in rabbits, 4.8 times the recommended human dose based on body surface area) and have revealed no evidence of impaired fertility or harm to the fetus due to epoprostenol. 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 Epoprostenol in women who are pregnant.
### Labor and Delivery
- The use of epoprostenol during labor, vaginal delivery, or cesarean section has not been adequately studied in humans.
### 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 epoprostenol is administered to a nursing woman.
### Pediatric Use
- Safety and effectiveness in pediatric patients have not been established.
### Geriatic Use
- Clinical studies of epoprostenol in pulmonary hypertension did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger patients. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or other drug therapy.
### Gender
There is no FDA guidance on the use of Epoprostenol with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Epoprostenol with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Epoprostenol in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Epoprostenol in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Epoprostenol in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Epoprostenol in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Intravenous
- Epoprostenol sodium for injection is administered by continuous intravenous infusion via a central venous catheter using an ambulatory infusion pump. During initiation of treatment, epoprostenol sodium for injection may be administered peripherally.
- The ambulatory infusion pump used to administer epoprostenol sodium for injection should: (1) be small and lightweight, (2) be able to adjust infusion rates in 2-ng/kg/min increments, (3) have occlusion, end-of-infusion, and low-battery alarms, (4) be accurate to ±6% of the programmed rate, and (5) be positive pressure-driven (continuous or pulsatile) with intervals between pulses not exceeding 3 minutes at infusion rates used to deliver epoprostenol sodium for injection. The reservoir should be made of polyvinyl chloride, polypropylene, or glass. The infusion pump used in the most recent clinical trials was the CADD-1 HFX 5100 (SIMS Deltec). A 60-inch microbore non-DEHP extension set with proximal antisyphon valve, low priming volume (0.9 mL), and in-line 0.22 micron filter was used during clinical trials.
- To avoid interruptions in drug delivery, the patient should have access to a backup infusion pump and intravenous infusion sets. Consider a multi-lumen catheter if other intravenous therapies are routinely administered.
- To facilitate extended use at ambient temperatures exceeding 20° to 25°C (68° to 77°F), a cold pouch with frozen gel packs was used in clinical trials. The cold pouches and gel packs used in clinical trials were obtained from Palco Labs, Palo Alto, California. Any cold pouch used must be capable of maintaining the temperature of reconstituted epoprostenol sodium for injection between 2° and 8°C for 12 hours.
- Epoprostenol sodium for injection is stable only when reconstituted with STERILE DILUENT for epoprostenol sodium for injection. Epoprostenol sodium for injection must not be reconstituted or mixed with any other parenteral medications or solutions prior to or during administration.
- Select a concentration for the solution of epoprostenol sodium for injection that is compatible with the infusion pump being used with respect to minimum and maximum flow rates, reservoir capacity, and the infusion pump criteria listed above. - When administered chronically, prepare epoprostenol sodium for injection in a drug delivery reservoir appropriate for the infusion pump with a total reservoir volume of at least 100 mL, using 2 vials of STERILE DILUENT for epoprostenol sodium for injection for use during a 24-hour period. Table 6 gives directions for preparing several different concentrations of epoprostenol sodium for injection.
- Generally, 3,000 ng/mL and 10,000 ng/mL are satisfactory concentrations to deliver between 2 to 16 ng/kg/min in adults. Infusion rates may be calculated using the following formula:
- Tables 7 through 10 provide infusion delivery rates for doses up to 16 ng/kg/min based upon patient weight, drug delivery rate, and concentration of the solution of epoprostenol sodium for injection to be used. These tables may be used to select the most appropriate concentration of epoprostenol sodium for injection that will result in an infusion rate between the minimum and maximum flow rates of the infusion pump and that will allow the desired duration of infusion from a given reservoir volume. Higher infusion rates, and therefore, more concentrated solutions may be necessary with long-term administration of epoprostenol sodium for injection.
- Use at Room Temperature
- Prior to use at room temperature, 15° to 25°C (59° to 77°F), reconstituted solutions of epoprostenol sodium for injection may be stored refrigerated at 2° to 8°C (36° to 46°F) for no longer than 40 hours. When administered at room temperature, reconstituted solutions may be used for no longer than 8 hours. This 48-hour period allows the patient to reconstitute a 2-day supply (200 mL) of epoprostenol sodium for injection. Each 100 mL daily supply may be divided into 3 equal portions. Two of the portions are stored refrigerated at 2° to 8°C (36° to 46°F) until they are used.
- Use with a Cold Pouch
- Prior to infusion with the use of a cold pouch, solutions may be stored refrigerated at 2° to 8°C (36° to 46°F) for up to 24 hours. When a cold pouch is employed during the infusion, reconstituted solutions of epoprostenol sodium for injection may be used for no longer than 24 hours. Change gel packs every 12 hours. Reconstituted solutions may be kept at 2° to 8°C (36° to 46°F), either in refrigerated storage or in a cold pouch or a combination of the two, for no more than 48 hours.
- Inspect parenteral drug products for particulate matter and discoloration prior to administration whenever solution and container permit. If either occurs, do not administer.
### Monitoring
There is limited information regarding Monitoring of Epoprostenol in the drug label.
# IV Compatibility
There is limited information regarding IV Compatibility of Epoprostenol in the drug label.
# Overdosage
## Acute Overdose
- Signs and symptoms of excessive doses of epoprostenol during clinical trials are the expected dose-limiting pharmacologic effects of epoprostenol, including flushing, headache, hypotension, tachycardia, nausea, vomiting, and diarrhea. Treatment will ordinarily require dose reduction of epoprostenol.
- One patient with PAH/CTD accidentally received 50 mL of an unspecified concentration of epoprostenol. The patient vomited and became unconscious with an initially unrecordable blood pressure. Epoprostenol was discontinued and the patient regained consciousness within seconds. In clinical practice, fatal occurrences of hypoxemia, hypotension, and respiratory arrest have been reported following overdosage of epoprostenol.
- Single intravenous doses of epoprostenol at 10 and 50 mg/kg (2,703 and 27,027 times the recommended acute phase human dose based on body surface area) were lethal to mice and rats, respectively. Symptoms of acute toxicity were hypoactivity, ataxia, loss of righting reflex, deep slow breathing, and hypothermia.
## Chronic Overdose
There is limited information regarding Chronic Overdose of Epoprostenol in the drug label.
# Pharmacology
## Mechanism of Action
- Epoprostenol has 2 major pharmacological actions: (1) direct vasodilation of pulmonary and systemic arterial vascular beds, and (2) inhibition of platelet aggregation. In animals, the vasodilatory effects reduce right- and left-ventricular afterload and increase cardiac output and stroke volume. The effect of epoprostenol on heart rate in animals varies with dose. At low doses, there is vagally mediated bradycardia, but at higher doses, epoprostenol causes reflex tachycardia in response to direct vasodilation and hypotension. No major effects on cardiac conduction have been observed. Additional pharmacologic effects of epoprostenol in animals include bronchodilation, inhibition of gastric acid secretion, and decreased gastric emptying.
## Structure
- Epoprostenol sodium for injection is a sterile sodium salt formulated for intravenous (IV) administration. Each vial of epoprostenol sodium for injection contains epoprostenol sodium equivalent to either 0.5 mg (500,000 ng) or 1.5 mg (1,500,000 ng) epoprostenol, 3.76 mg glycine, 2.93 mg sodium chloride, and 50 mg mannitol. Sodium hydroxide may have been added to adjust pH.
- Epoprostenol (PGI2, PGX, prostacyclin), a metabolite of arachidonic acid, is a naturally occurring prostaglandin with potent vasodilatory activity and inhibitory activity of platelet aggregation.
- Epoprostenol is (5Z,9α,11α,13E,15S)-6,9-epoxy-11,15-dihydroxyprosta-5,13-dien-1-oic acid.
- Epoprostenol sodium has a molecular weight of 374.45 and a molecular formula of C20H31NaO5. The structural formula is:
- Epoprostenol sodium for injection is a white to off-white powder that must be reconstituted with STERILE DILUENT for epoprostenol sodium for injection. STERILE DILUENT for epoprostenol sodium for injection is supplied in glass vials containing 50 mL of 94 mg glycine, 73.3 mg sodium chloride, sodium hydroxide (added to adjust pH), and Water for Injection, USP.
- The reconstituted solution of epoprostenol sodium for injection has a pH of 11.0 to 11.8 and is increasingly unstable at a lower pH.
## Pharmacodynamics
There is limited information regarding Pharmacodynamics of Epoprostenol in the drug label.
## Pharmacokinetics
- Epoprostenol is rapidly hydrolyzed at neutral pH in blood and is also subject to enzymatic degradation. Animal studies using tritium-labeled epoprostenol have indicated a high clearance (93 mL/kg/min), small volume of distribution (357 mL/kg), and a short half-life (2.7 minutes). During infusions in animals, steady-state plasma concentrations of tritium-labeled epoprostenol were reached within 15 minutes and were proportional to infusion rates.
- No available chemical assay is sufficiently sensitive and specific to assess the in vivo human pharmacokinetics of epoprostenol. The in vitro half-life of epoprostenol in human blood at 37°C and pH 7.4 is approximately 6 minutes; therefore, the in vivo half-life of epoprostenol in humans is expected to be no greater than 6 minutes. The in vitro pharmacologic half-life of epoprostenol in human plasma, based on inhibition of platelet aggregation, was similar for males (n = 954) and females (n = 1,024).
- Tritium-labeled epoprostenol has been administered to humans in order to identify the metabolic products of epoprostenol. Epoprostenol is metabolized to 2 primary metabolites: 6-keto-PGF1α (formed by spontaneous degradation) and 6,15-diketo-13,14-dihydro-PGF1α (enzymatically formed), both of which have pharmacological activity orders of magnitude less than epoprostenol in animal test systems. The recovery of radioactivity in urine and feces over a 1-week period was 82% and 4% of the administered dose, respectively. Fourteen additional minor metabolites have been isolated from urine, indicating that epoprostenol is extensively metabolized in humans.
## Nonclinical Toxicology
- Carcinogenesis, Mutagenesis, Impairment of Fertility
- Long-term studies in animals have not been performed to evaluate carcinogenic potential. A micronucleus test in rats revealed no evidence of mutagenicity. The Ames test and DNA elution tests were also negative, although the instability of epoprostenol makes the significance of these tests uncertain. Fertility was not impaired in rats given epoprostenol by subcutaneous injection at doses up to 100 mcg/kg/day (600 mcg/m2/day, 2.5 times the recommended human dose based on body surface area).
# Clinical Studies
- Acute Hemodynamic Effects
- Acute intravenous infusions of epoprostenol for up to 15 minutes in patients with idiopathic or heritable PAH or PAH associated with scleroderma spectrum of diseases (PAH/SSD) produce dose-related increases in cardiac index (CI) and stroke volume (SV) and dose-related decreases in pulmonary vascular resistance (PVR), total pulmonary resistance (TPR), and mean systemic arterial pressure (SAPm). The effects of epoprostenol on mean pulmonary artery pressure (PAPm) were variable and minor.
- Hemodynamic Effects
- Chronic continuous infusions of epoprostenol in patients with idiopathic or heritable PAH were studied in 2 prospective, open, randomized trials of 8 and 12 weeks’ duration comparing epoprostenol plus conventional therapy to conventional therapy alone. Dosage of epoprostenol was determined as described in DOSAGE AND ADMINISTRATION and averaged 9.2 ng/kg/min at study’s end. Conventional therapy varied among patients and included some or all of the following: anticoagulants in essentially all patients; oral vasodilators, diuretics, and digoxin in one half to two thirds of patients; and supplemental oxygen in about half the patients. Except for 2 New York Heart Association (NYHA) functional Class II patients, all patients were either functional Class III or Class IV. As results were similar in the 2 studies, the pooled results are described.
- Chronic hemodynamic effects were generally similar to acute effects. Increases in CI, SV, and arterial oxygen saturation and decreases in PAPm, mean right atrial pressure (RAPm), TPR, and systemic vascular resistance (SVR) were observed in patients who received epoprostenol chronically compared to those who did not. Table 1 illustrates the treatment-related hemodynamic changes in these patients after 8 or 12 weeks of treatment.
- These hemodynamic improvements appeared to persist when epoprostenol was administered for at least 36 months in an open, nonrandomized study.
- Clinical Effects
- Statistically significant improvement was observed in exercise capacity, as measured by the 6-minute walk test in patients receiving continuous intravenous epoprostenol plus conventional therapy (N = 52) for 8 or 12 weeks compared to those receiving conventional therapy alone (N = 54). Improvements were apparent as early as the first week of therapy. Increases in exercise capacity were accompanied by statistically significant improvement in dyspnea and fatigue, as measured by the Chronic Heart Failure Questionnaire and the Dyspnea Fatigue Index.
- Survival was improved in NYHA functional Class III and Class IV patients with idiopathic or heritable PAH treated with epoprostenol for 12 weeks in a multicenter, open, randomized, parallel study. At the end of the treatment period, 8 of 40 (20%) patients receiving conventional therapy alone died, whereas none of the 41 patients receiving epoprostenol died (p = 0.003).
- Hemodynamic Effects
- Chronic continuous infusions of epoprostenol in patients with PAH/SSD were studied in a prospective, open, randomized trial of 12 weeks’ duration comparing epoprostenol plus conventional therapy (N = 56) to conventional therapy alone (N = 55). Except for 5 NYHA functional Class II patients, all patients were either functional Class III or Class IV. Dosage of epoprostenol was determined as described in DOSAGE AND ADMINISTRATION and averaged 11.2 ng/kg/min at study’s end. Conventional therapy varied among patients and included some or all of the following: anticoagulants in essentially all patients, supplemental oxygen and diuretics in two thirds of the patients, oral vasodilators in 40% of the patients, and digoxin in a third of the patients. A statistically significant increase in CI, and statistically significant decreases in PAPm, RAPm, PVR, and SAPm after 12 weeks of treatment were observed in patients who received epoprostenol chronically compared to those who did not. Table 2 illustrates the treatment-related hemodynamic changes in these patients after 12 weeks of treatment.
- Clinical Effects
- Statistically significant improvement was observed in exercise capacity, as measured by the 6-minute walk, in patients receiving continuous intravenous epoprostenol plus conventional therapy for 12 weeks compared to those receiving conventional therapy alone. Improvements were apparent in some patients at the end of the first week of therapy. Increases in exercise capacity were accompanied by statistically significant improvements in dyspnea and fatigue, as measured by the Borg Dyspnea Index and Dyspnea Fatigue Index. At week 12, NYHA functional class improved in 21 of 51 (41%) patients treated with epoprostenol compared to none of the 48 patients treated with conventional therapy alone. However, more patients in both treatment groups (28/51 with epoprostenol and 35/48 with conventional therapy alone) showed no change in functional class, and 2/51 (4%) with epoprostenol and 13/48 (27%) with conventional therapy alone worsened. Of the patients randomized, NYHA functional class data at 12 weeks were not available for 5 patients treated with epoprostenol and 7 patients treated with conventional therapy alone.
- No statistical difference in survival over 12 weeks was observed in PAH/SSD patients treated with epoprostenol as compared to those receiving conventional therapy alone. At the end of the treatment period, 4 of 56 (7%) patients receiving epoprostenol died, whereas 5 of 55 (9%) patients receiving conventional therapy alone died.
- No controlled clinical trials with epoprostenol have been performed in patients with pulmonary hypertension associated with other diseases.
# How Supplied
- Epoprostenol sodium for injection is supplied as a sterile freeze-dried powder in 10 mL flint glass vials with gray butyl rubber closures, individually packaged in a carton.
- Store the vials of epoprostenol sodium for injection at 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F). Protect from light. Retain in carton until time of use. Discard unused portion.
- The STERILE DILUENT for Epoprostenol Sodium for Injection is supplied in flint glass vials containing 50 mL diluent with butyl rubber closures.
- Storage and Stability
- Unopened vials of epoprostenol sodium for injection are stable until the date indicated on the package when stored at 20° to 25°C (68° to 77°F) and protected from light in the carton. Unopened vials of STERILE DILUENT for epoprostenol sodium for injection are stable until the date indicated on the package when stored at 20° to 25°C (68° to 77°F).
- Prior to use, reconstituted solutions of epoprostenol sodium for injection must be protected from light and must be refrigerated at 2° to 8°C (36° to 46°F) if not used immediately. Do not freeze reconstituted solutions of epoprostenol sodium for injection. Discard any reconstituted solution that has been frozen. Discard any reconstituted solution if it has been refrigerated for more than 48 hours.
- During use, a single reservoir of reconstituted solution of epoprostenol sodium for injection can be administered at room temperature for a total duration of 8 hours, or it can be used with a cold pouch and administered up to 24 hours with the use of 2 frozen 6 oz gel packs in a cold pouch. When stored or in use, insulate reconstituted epoprostenol sodium for injection from temperatures greater than 25°C (77°F) and less than 0°C (32°F), and do not expose to direct sunlight.
## Storage
There is limited information regarding Epoprostenol Storage in the drug label.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- Patients receiving epoprostenol should receive the following information. Epoprostenol sodium for injection must be reconstituted only with STERILE DILUENT for epoprostenol sodium for injection. Epoprostenol is infused continuously through a permanent indwelling central venous catheter via a small, portable infusion pump. Thus, therapy with epoprostenol requires commitment by the patient to drug reconstitution, drug administration, and care of the permanent central venous catheter. Patients must adhere to sterile technique in preparing the drug and in the care of the catheter, and even brief interruptions in the delivery of epoprostenol may result in rapid symptomatic deterioration. A patient’s decision to receive epoprostenol should be based upon the understanding that there is a high likelihood that therapy with epoprostenol will be needed for prolonged periods, possibly years. The patient's ability to accept and care for a permanent intravenous catheter and infusion pump should also be carefully considered.
# Precautions with Alcohol
- Alcohol-Epoprostenol interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Veletri®
- Flolan®
# Look-Alike Drug Names
- N/A
# Drug Shortage Status
# Price | Epoprostenol
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Gerald Chi
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# Overview
Epoprostenol is a prostaglandin that is FDA approved for the treatment of pulmonary arterial hypertension. Common adverse reactions include bradyarrhythmia, chest pain, hypotension, tachycardia, flushing, abdominal pain, diarrhea, loss of appetite, nausea, vomiting, dizziness, and headache.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Important Note: Epoprostenol sodium for injection must be reconstituted only with STERILE DILUENT for epoprostenol sodium for injection. Do not dilute reconstituted solutions of epoprostenol for injection or administer with other parenteral solutions or medications.
- Dosing Information
- Administer continuous chronic infusion of epoprostenol sodium for injection through a central venous catheter. Temporary peripheral intravenous infusion may be used until central access is established. Initiate chronic infusion of epoprostenol sodium for injection at 2 ng/kg/min and increase in increments of 2 ng/kg/min every 15 minutes or longer until dose-limiting pharmacologic effects are elicited or until a tolerance limit to the drug is established or further increases in the infusion rate are not clinically warranted. If dose-limiting pharmacologic effects occur, then decrease the infusion rate until epoprostenol sodium for injection is tolerated. In clinical trials, the most common dose-limiting adverse events were nausea, vomiting, hypotension, sepsis, headache, abdominal pain, or respiratory disorder (most treatment-limiting adverse events were not serious). If the initial infusion rate of 2 ng/kg/min is not tolerated, identify a lower dose that is tolerated by the patient.
- In the controlled 12-week trial in PAH/SSD, for example, the dose increased from a mean starting dose of 2.2 ng/kg/min. During the first 7 days of treatment, the dose was increased daily to a mean dose of 4.1 ng/kg/min on day 7 of treatment. At the end of week 12, the mean dose was 11.2 ng/kg/min. The mean incremental increase was 2 to 3 ng/kg/min every 3 weeks.
- Dosage Adjustments
- Base changes in the chronic infusion rate on persistence, recurrence, or worsening of the patient's symptoms of pulmonary hypertension and the occurrence of adverse events due to excessive doses of epoprostenol sodium for injection. In general, expect increases in dose from the initial chronic dose.
- Consider increments in dose if symptoms of PAH persist or recur. Increase the infusion by 1- to 2-ng/kg/min increments at intervals sufficient to allow assessment of clinical response; these intervals should be at least 15 minutes. In clinical trials, incremental increases in dose occurred at intervals of 24 to 48 hours or longer. Following establishment of a new chronic infusion rate, observe the patient, and monitor standing and supine blood pressure and heart rate for several hours to ensure that the new dose is tolerated.
- During chronic infusion, the occurrence of dose-limiting pharmacological events may necessitate a decrease in infusion rate, but the adverse event may occasionally resolve without dosage adjustment. Make dosage decreases gradually in 2-ng/kg/min decrements every 15 minutes or longer until the dose-limiting effects resolve. Avoid abrupt withdrawal of epoprostenol sodium for injection or sudden large reductions in infusion rates. Except in life-threatening situations (e.g., unconsciousness, collapse, etc.), adjust infusion rates of epoprostenol sodium for injection only under the direction of a physician.
- In patients receiving lung transplants, doses of epoprostenol sodium for injection were tapered after the initiation of cardiopulmonary bypass.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Epoprostenol in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Epoprostenol in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
- 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 Epoprostenol in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Epoprostenol in pediatric patients.
# Contraindications
- A large study evaluating the effect of epoprostenol on survival in NYHA Class III and IV patients with congestive heart failure due to severe left ventricular systolic dysfunction was terminated after an interim analysis of 471 patients revealed a higher mortality in patients receiving epoprostenol plus conventional therapy than in those receiving conventional therapy alone. The chronic use of epoprostenol in patients with congestive heart failure due to severe left ventricular systolic dysfunction is therefore contraindicated.
- Some patients with pulmonary hypertension have developed pulmonary edema during dose initiation, which may be associated with pulmonary veno-occlusive disease. Epoprostenol should not be used chronically in patients who develop pulmonary edema during dose initiation.
- Epoprostenol is also contraindicated in patients with known hypersensitivity to the drug or to structurally related compounds.
# Warnings
- Epoprostenol sodium for injection must be reconstituted only as directed using STERILE DILUENT for epoprostenol sodium for injection. Epoprostenol sodium for injection must not be reconstituted or mixed with any other parenteral medications or solutions prior to or during administration.
- Abrupt withdrawal (including interruptions in drug delivery) or sudden large reductions in dosage of epoprostenol may result in symptoms associated with rebound pulmonary hypertension, including dyspnea, dizziness, and asthenia. In clinical trials, one Class III patient's death was judged attributable to the interruption of epoprostenol. Avoid abrupt withdrawal.
### Precautions
- Epoprostenol should be used only by clinicians experienced in the diagnosis and treatment of pulmonary hypertension. Carefully establish the diagnosis of idiopathic or heritable PAH or PAH/CTD.
- Epoprostenol is a potent pulmonary and systemic vasodilator. Initiate epoprostenol in a setting with adequate personnel and equipment for physiologic monitoring and emergency care. Dose initiation has been performed during right heart catheterization and without cardiac catheterization. During dose initiation, asymptomatic increases in pulmonary artery pressure coincident with increases in cardiac output occurred rarely. In such cases, consider dose reduction, but such an increase does not imply that chronic treatment is contraindicated.
- Epoprostenol is a potent inhibitor of platelet aggregation. Therefore, expect an increased risk for hemorrhagic complications, particularly for patients with other risk factors for bleeding.
- During chronic use, deliver epoprostenol continuously on an ambulatory basis through a permanent indwelling central venous catheter. Unless contraindicated, administer anticoagulant therapy to patients receiving epoprostenol to reduce the risk of pulmonary thromboembolism or systemic embolism through a patent foramen ovale. To reduce the risk of infection, use aseptic technique in the reconstitution and administration of epoprostenol and in routine catheter care. Because epoprostenol is metabolized rapidly, even brief interruptions in the delivery of epoprostenol may result in symptoms associated with rebound pulmonary hypertension including dyspnea, dizziness, and asthenia. Intravenous therapy with epoprostenol will likely be needed for prolonged periods, possibly years, so consider the patient's ability to accept and care for a permanent intravenous catheter and infusion pump.
- Based on clinical trials, the acute hemodynamic response to epoprostenol did not correlate well with improvement in exercise tolerance or survival during chronic use of epoprostenol. Adjust dosage of epoprostenol during chronic use at the first sign of recurrence or worsening of symptoms attributable to pulmonary hypertension or the occurrence of adverse events associated with epoprostenol. Following dosage adjustments, monitor standing and supine blood pressure and heart rate closely for several hours.
# Adverse Reactions
## Clinical Trials Experience
- During clinical trials, adverse events were classified as follows: (1) adverse events during dose initiation and escalation, (2) adverse events during chronic dosing, and (3) adverse events associated with the drug delivery system.
- During early clinical trials, epoprostenol was increased in 2-ng/kg/min increments until the patients developed symptomatic intolerance. The most common adverse events and the adverse events that limited further increases in dose were generally related to vasodilation, the major pharmacologic effect of epoprostenol. The most common dose-limiting adverse events (occurring in ≥1% of patients) were nausea, vomiting, headache, hypotension, and flushing, but also include chest pain, anxiety, dizziness, bradycardia, dyspnea, abdominal pain, musculoskeletal pain, and tachycardia. Table 3 lists the adverse events reported during dose initiation and escalation in decreasing order of frequency.
- Interpretation of adverse events is complicated by the clinical features of PAH, which are similar to some of the pharmacologic effects of epoprostenol (e.g., dizziness, syncope). Adverse events which may be related to the underlying disease include dyspnea, fatigue, chest pain, edema, hypoxia, right ventricular failure, and pallor. Several adverse events, on the other hand, can clearly be attributed to epoprostenol. These include hypotension, bradycardia, tachycardia, pulmonary edema, bleeding at various sites, thrombocytopenia, headache, abdominal pain, pain (unspecified), sweating, rash, arthralgia, jaw pain, flushing, diarrhea, nausea and vomiting, flu-like symptoms, anxiety/nervousness, and agitation. In addition, chest pain, fatigue, and pallor have been reported during epoprostenol therapy, and a role for the drug in these events cannot be excluded.
- In an effort to separate the adverse effects of the drug from the adverse effects of the underlying disease, Table 4 lists adverse events that occurred at a rate at least 10% greater on epoprostenol in controlled trials.
- Thrombocytopenia has been reported during uncontrolled clinical trials in patients receiving epoprostenol.
- In an effort to separate the adverse effects of the drug from the adverse effects of the underlying disease, Table 5 lists adverse events that occurred at a rate at least 10% greater on epoprostenol in the controlled trial.
- Although the relationship to epoprostenol administration has not been established, pulmonary embolism has been reported in several patients taking epoprostenol and there have been reports of hepatic failure.
- Chronic infusions of epoprostenol are delivered using a small, portable infusion pump through an indwelling central venous catheter. During controlled PAH trials of up to 12 weeks’ duration, the local infection rate was about 18%, and the rate for pain was about 11%. During long-term follow-up, sepsis was reported at a rate of 0.3 infections/patient per year in patients treated with epoprostenol. This rate was higher than reported in patients using chronic indwelling central venous catheters to administer parenteral nutrition, but lower than reported in oncology patients using these catheters. Malfunctions in the delivery system resulting in an inadvertent bolus of or a reduction in epoprostenol were associated with symptoms related to excess or insufficient epoprostenol, respectively.
- In addition to adverse reactions reported from clinical trials, the following events have been identified during post-approval use of epoprostenol. Because they are reported voluntarily from a population of unknown size, estimates of frequency cannot be made. These events have been chosen for inclusion due to a combination of their seriousness, frequency of reporting, or potential causal connection to epoprostenol.
- Blood and Lymphatic: Anemia, hypersplenism, pancytopenia, splenomegaly.
- Endocrine and Metabolic: Hyperthyroidism.
## Postmarketing Experience
There is limited information regarding Postmarketing Experience of Epoprostenol in the drug label.
# Drug Interactions
- Additional reductions in blood pressure may occur when epoprostenol is administered with diuretics, antihypertensive agents, or other vasodilators. When other antiplatelet agents or anticoagulants are used concomitantly, there is the potential for epoprostenol to increase the risk of bleeding. However, patients receiving infusions of epoprostenol in clinical trials were maintained on anticoagulants without evidence of increased bleeding. In clinical trials, epoprostenol was used with digoxin, diuretics, anticoagulants, oral vasodilators, and supplemental oxygen.
- In a pharmacokinetic substudy in patients with congestive heart failure receiving furosemide or digoxin in whom therapy with epoprostenol was initiated, apparent oral clearance values for furosemide (n = 23) and digoxin (n = 30) were decreased by 13% and 15%, respectively, on the second day of therapy and had returned to baseline values by day 87. The change in furosemide clearance value is not likely to be clinically significant. However, patients on digoxin may show elevations of digoxin concentrations after initiation of therapy with epoprostenol, which may be clinically significant in patients prone to digoxin toxicity.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
- Pregnancy Category B
- Reproductive studies have been performed in pregnant rats and rabbits at doses up to 100 mcg/kg/day (600 mcg/m2/day in rats, 2.5 times the recommended human dose, and 1,180 mcg/m2/day in rabbits, 4.8 times the recommended human dose based on body surface area) and have revealed no evidence of impaired fertility or harm to the fetus due to epoprostenol. 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 Epoprostenol in women who are pregnant.
### Labor and Delivery
- The use of epoprostenol during labor, vaginal delivery, or cesarean section has not been adequately studied in humans.
### 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 epoprostenol is administered to a nursing woman.
### Pediatric Use
- Safety and effectiveness in pediatric patients have not been established.
### Geriatic Use
- Clinical studies of epoprostenol in pulmonary hypertension did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger patients. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or other drug therapy.
### Gender
There is no FDA guidance on the use of Epoprostenol with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Epoprostenol with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Epoprostenol in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Epoprostenol in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Epoprostenol in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Epoprostenol in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Intravenous
- Epoprostenol sodium for injection is administered by continuous intravenous infusion via a central venous catheter using an ambulatory infusion pump. During initiation of treatment, epoprostenol sodium for injection may be administered peripherally.
- The ambulatory infusion pump used to administer epoprostenol sodium for injection should: (1) be small and lightweight, (2) be able to adjust infusion rates in 2-ng/kg/min increments, (3) have occlusion, end-of-infusion, and low-battery alarms, (4) be accurate to ±6% of the programmed rate, and (5) be positive pressure-driven (continuous or pulsatile) with intervals between pulses not exceeding 3 minutes at infusion rates used to deliver epoprostenol sodium for injection. The reservoir should be made of polyvinyl chloride, polypropylene, or glass. The infusion pump used in the most recent clinical trials was the CADD-1 HFX 5100 (SIMS Deltec). A 60-inch microbore non-DEHP extension set with proximal antisyphon valve, low priming volume (0.9 mL), and in-line 0.22 micron filter was used during clinical trials.
- To avoid interruptions in drug delivery, the patient should have access to a backup infusion pump and intravenous infusion sets. Consider a multi-lumen catheter if other intravenous therapies are routinely administered.
- To facilitate extended use at ambient temperatures exceeding 20° to 25°C (68° to 77°F), a cold pouch with frozen gel packs was used in clinical trials. The cold pouches and gel packs used in clinical trials were obtained from Palco Labs, Palo Alto, California. Any cold pouch used must be capable of maintaining the temperature of reconstituted epoprostenol sodium for injection between 2° and 8°C for 12 hours.
- Epoprostenol sodium for injection is stable only when reconstituted with STERILE DILUENT for epoprostenol sodium for injection. Epoprostenol sodium for injection must not be reconstituted or mixed with any other parenteral medications or solutions prior to or during administration.
- Select a concentration for the solution of epoprostenol sodium for injection that is compatible with the infusion pump being used with respect to minimum and maximum flow rates, reservoir capacity, and the infusion pump criteria listed above. * When administered chronically, prepare epoprostenol sodium for injection in a drug delivery reservoir appropriate for the infusion pump with a total reservoir volume of at least 100 mL, using 2 vials of STERILE DILUENT for epoprostenol sodium for injection for use during a 24-hour period. Table 6 gives directions for preparing several different concentrations of epoprostenol sodium for injection.
- Generally, 3,000 ng/mL and 10,000 ng/mL are satisfactory concentrations to deliver between 2 to 16 ng/kg/min in adults. Infusion rates may be calculated using the following formula:
- Tables 7 through 10 provide infusion delivery rates for doses up to 16 ng/kg/min based upon patient weight, drug delivery rate, and concentration of the solution of epoprostenol sodium for injection to be used. These tables may be used to select the most appropriate concentration of epoprostenol sodium for injection that will result in an infusion rate between the minimum and maximum flow rates of the infusion pump and that will allow the desired duration of infusion from a given reservoir volume. Higher infusion rates, and therefore, more concentrated solutions may be necessary with long-term administration of epoprostenol sodium for injection.
- Use at Room Temperature
- Prior to use at room temperature, 15° to 25°C (59° to 77°F), reconstituted solutions of epoprostenol sodium for injection may be stored refrigerated at 2° to 8°C (36° to 46°F) for no longer than 40 hours. When administered at room temperature, reconstituted solutions may be used for no longer than 8 hours. This 48-hour period allows the patient to reconstitute a 2-day supply (200 mL) of epoprostenol sodium for injection. Each 100 mL daily supply may be divided into 3 equal portions. Two of the portions are stored refrigerated at 2° to 8°C (36° to 46°F) until they are used.
- Use with a Cold Pouch
- Prior to infusion with the use of a cold pouch, solutions may be stored refrigerated at 2° to 8°C (36° to 46°F) for up to 24 hours. When a cold pouch is employed during the infusion, reconstituted solutions of epoprostenol sodium for injection may be used for no longer than 24 hours. Change gel packs every 12 hours. Reconstituted solutions may be kept at 2° to 8°C (36° to 46°F), either in refrigerated storage or in a cold pouch or a combination of the two, for no more than 48 hours.
- Inspect parenteral drug products for particulate matter and discoloration prior to administration whenever solution and container permit. If either occurs, do not administer.
### Monitoring
There is limited information regarding Monitoring of Epoprostenol in the drug label.
# IV Compatibility
There is limited information regarding IV Compatibility of Epoprostenol in the drug label.
# Overdosage
## Acute Overdose
- Signs and symptoms of excessive doses of epoprostenol during clinical trials are the expected dose-limiting pharmacologic effects of epoprostenol, including flushing, headache, hypotension, tachycardia, nausea, vomiting, and diarrhea. Treatment will ordinarily require dose reduction of epoprostenol.
- One patient with PAH/CTD accidentally received 50 mL of an unspecified concentration of epoprostenol. The patient vomited and became unconscious with an initially unrecordable blood pressure. Epoprostenol was discontinued and the patient regained consciousness within seconds. In clinical practice, fatal occurrences of hypoxemia, hypotension, and respiratory arrest have been reported following overdosage of epoprostenol.
- Single intravenous doses of epoprostenol at 10 and 50 mg/kg (2,703 and 27,027 times the recommended acute phase human dose based on body surface area) were lethal to mice and rats, respectively. Symptoms of acute toxicity were hypoactivity, ataxia, loss of righting reflex, deep slow breathing, and hypothermia.
## Chronic Overdose
There is limited information regarding Chronic Overdose of Epoprostenol in the drug label.
# Pharmacology
## Mechanism of Action
- Epoprostenol has 2 major pharmacological actions: (1) direct vasodilation of pulmonary and systemic arterial vascular beds, and (2) inhibition of platelet aggregation. In animals, the vasodilatory effects reduce right- and left-ventricular afterload and increase cardiac output and stroke volume. The effect of epoprostenol on heart rate in animals varies with dose. At low doses, there is vagally mediated bradycardia, but at higher doses, epoprostenol causes reflex tachycardia in response to direct vasodilation and hypotension. No major effects on cardiac conduction have been observed. Additional pharmacologic effects of epoprostenol in animals include bronchodilation, inhibition of gastric acid secretion, and decreased gastric emptying.
## Structure
- Epoprostenol sodium for injection is a sterile sodium salt formulated for intravenous (IV) administration. Each vial of epoprostenol sodium for injection contains epoprostenol sodium equivalent to either 0.5 mg (500,000 ng) or 1.5 mg (1,500,000 ng) epoprostenol, 3.76 mg glycine, 2.93 mg sodium chloride, and 50 mg mannitol. Sodium hydroxide may have been added to adjust pH.
- Epoprostenol (PGI2, PGX, prostacyclin), a metabolite of arachidonic acid, is a naturally occurring prostaglandin with potent vasodilatory activity and inhibitory activity of platelet aggregation.
- Epoprostenol is (5Z,9α,11α,13E,15S)-6,9-epoxy-11,15-dihydroxyprosta-5,13-dien-1-oic acid.
- Epoprostenol sodium has a molecular weight of 374.45 and a molecular formula of C20H31NaO5. The structural formula is:
- Epoprostenol sodium for injection is a white to off-white powder that must be reconstituted with STERILE DILUENT for epoprostenol sodium for injection. STERILE DILUENT for epoprostenol sodium for injection is supplied in glass vials containing 50 mL of 94 mg glycine, 73.3 mg sodium chloride, sodium hydroxide (added to adjust pH), and Water for Injection, USP.
- The reconstituted solution of epoprostenol sodium for injection has a pH of 11.0 to 11.8 and is increasingly unstable at a lower pH.
## Pharmacodynamics
There is limited information regarding Pharmacodynamics of Epoprostenol in the drug label.
## Pharmacokinetics
- Epoprostenol is rapidly hydrolyzed at neutral pH in blood and is also subject to enzymatic degradation. Animal studies using tritium-labeled epoprostenol have indicated a high clearance (93 mL/kg/min), small volume of distribution (357 mL/kg), and a short half-life (2.7 minutes). During infusions in animals, steady-state plasma concentrations of tritium-labeled epoprostenol were reached within 15 minutes and were proportional to infusion rates.
- No available chemical assay is sufficiently sensitive and specific to assess the in vivo human pharmacokinetics of epoprostenol. The in vitro half-life of epoprostenol in human blood at 37°C and pH 7.4 is approximately 6 minutes; therefore, the in vivo half-life of epoprostenol in humans is expected to be no greater than 6 minutes. The in vitro pharmacologic half-life of epoprostenol in human plasma, based on inhibition of platelet aggregation, was similar for males (n = 954) and females (n = 1,024).
- Tritium-labeled epoprostenol has been administered to humans in order to identify the metabolic products of epoprostenol. Epoprostenol is metabolized to 2 primary metabolites: 6-keto-PGF1α (formed by spontaneous degradation) and 6,15-diketo-13,14-dihydro-PGF1α (enzymatically formed), both of which have pharmacological activity orders of magnitude less than epoprostenol in animal test systems. The recovery of radioactivity in urine and feces over a 1-week period was 82% and 4% of the administered dose, respectively. Fourteen additional minor metabolites have been isolated from urine, indicating that epoprostenol is extensively metabolized in humans.
## Nonclinical Toxicology
- Carcinogenesis, Mutagenesis, Impairment of Fertility
- Long-term studies in animals have not been performed to evaluate carcinogenic potential. A micronucleus test in rats revealed no evidence of mutagenicity. The Ames test and DNA elution tests were also negative, although the instability of epoprostenol makes the significance of these tests uncertain. Fertility was not impaired in rats given epoprostenol by subcutaneous injection at doses up to 100 mcg/kg/day (600 mcg/m2/day, 2.5 times the recommended human dose [4.6 ng/kg/min or 245.1 mcg/m2/day, IV] based on body surface area).
# Clinical Studies
- Acute Hemodynamic Effects
- Acute intravenous infusions of epoprostenol for up to 15 minutes in patients with idiopathic or heritable PAH or PAH associated with scleroderma spectrum of diseases (PAH/SSD) produce dose-related increases in cardiac index (CI) and stroke volume (SV) and dose-related decreases in pulmonary vascular resistance (PVR), total pulmonary resistance (TPR), and mean systemic arterial pressure (SAPm). The effects of epoprostenol on mean pulmonary artery pressure (PAPm) were variable and minor.
- Hemodynamic Effects
- Chronic continuous infusions of epoprostenol in patients with idiopathic or heritable PAH were studied in 2 prospective, open, randomized trials of 8 and 12 weeks’ duration comparing epoprostenol plus conventional therapy to conventional therapy alone. Dosage of epoprostenol was determined as described in DOSAGE AND ADMINISTRATION and averaged 9.2 ng/kg/min at study’s end. Conventional therapy varied among patients and included some or all of the following: anticoagulants in essentially all patients; oral vasodilators, diuretics, and digoxin in one half to two thirds of patients; and supplemental oxygen in about half the patients. Except for 2 New York Heart Association (NYHA) functional Class II patients, all patients were either functional Class III or Class IV. As results were similar in the 2 studies, the pooled results are described.
- Chronic hemodynamic effects were generally similar to acute effects. Increases in CI, SV, and arterial oxygen saturation and decreases in PAPm, mean right atrial pressure (RAPm), TPR, and systemic vascular resistance (SVR) were observed in patients who received epoprostenol chronically compared to those who did not. Table 1 illustrates the treatment-related hemodynamic changes in these patients after 8 or 12 weeks of treatment.
- These hemodynamic improvements appeared to persist when epoprostenol was administered for at least 36 months in an open, nonrandomized study.
- Clinical Effects
- Statistically significant improvement was observed in exercise capacity, as measured by the 6-minute walk test in patients receiving continuous intravenous epoprostenol plus conventional therapy (N = 52) for 8 or 12 weeks compared to those receiving conventional therapy alone (N = 54). Improvements were apparent as early as the first week of therapy. Increases in exercise capacity were accompanied by statistically significant improvement in dyspnea and fatigue, as measured by the Chronic Heart Failure Questionnaire and the Dyspnea Fatigue Index.
- Survival was improved in NYHA functional Class III and Class IV patients with idiopathic or heritable PAH treated with epoprostenol for 12 weeks in a multicenter, open, randomized, parallel study. At the end of the treatment period, 8 of 40 (20%) patients receiving conventional therapy alone died, whereas none of the 41 patients receiving epoprostenol died (p = 0.003).
- Hemodynamic Effects
- Chronic continuous infusions of epoprostenol in patients with PAH/SSD were studied in a prospective, open, randomized trial of 12 weeks’ duration comparing epoprostenol plus conventional therapy (N = 56) to conventional therapy alone (N = 55). Except for 5 NYHA functional Class II patients, all patients were either functional Class III or Class IV. Dosage of epoprostenol was determined as described in DOSAGE AND ADMINISTRATION and averaged 11.2 ng/kg/min at study’s end. Conventional therapy varied among patients and included some or all of the following: anticoagulants in essentially all patients, supplemental oxygen and diuretics in two thirds of the patients, oral vasodilators in 40% of the patients, and digoxin in a third of the patients. A statistically significant increase in CI, and statistically significant decreases in PAPm, RAPm, PVR, and SAPm after 12 weeks of treatment were observed in patients who received epoprostenol chronically compared to those who did not. Table 2 illustrates the treatment-related hemodynamic changes in these patients after 12 weeks of treatment.
- Clinical Effects
- Statistically significant improvement was observed in exercise capacity, as measured by the 6-minute walk, in patients receiving continuous intravenous epoprostenol plus conventional therapy for 12 weeks compared to those receiving conventional therapy alone. Improvements were apparent in some patients at the end of the first week of therapy. Increases in exercise capacity were accompanied by statistically significant improvements in dyspnea and fatigue, as measured by the Borg Dyspnea Index and Dyspnea Fatigue Index. At week 12, NYHA functional class improved in 21 of 51 (41%) patients treated with epoprostenol compared to none of the 48 patients treated with conventional therapy alone. However, more patients in both treatment groups (28/51 [55%] with epoprostenol and 35/48 [73%] with conventional therapy alone) showed no change in functional class, and 2/51 (4%) with epoprostenol and 13/48 (27%) with conventional therapy alone worsened. Of the patients randomized, NYHA functional class data at 12 weeks were not available for 5 patients treated with epoprostenol and 7 patients treated with conventional therapy alone.
- No statistical difference in survival over 12 weeks was observed in PAH/SSD patients treated with epoprostenol as compared to those receiving conventional therapy alone. At the end of the treatment period, 4 of 56 (7%) patients receiving epoprostenol died, whereas 5 of 55 (9%) patients receiving conventional therapy alone died.
- No controlled clinical trials with epoprostenol have been performed in patients with pulmonary hypertension associated with other diseases.
# How Supplied
- Epoprostenol sodium for injection is supplied as a sterile freeze-dried powder in 10 mL flint glass vials with gray butyl rubber closures, individually packaged in a carton.
- Store the vials of epoprostenol sodium for injection at 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F). Protect from light. Retain in carton until time of use. Discard unused portion.
- The STERILE DILUENT for Epoprostenol Sodium for Injection is supplied in flint glass vials containing 50 mL diluent with butyl rubber closures.
- Storage and Stability
- Unopened vials of epoprostenol sodium for injection are stable until the date indicated on the package when stored at 20° to 25°C (68° to 77°F) and protected from light in the carton. Unopened vials of STERILE DILUENT for epoprostenol sodium for injection are stable until the date indicated on the package when stored at 20° to 25°C (68° to 77°F).
- Prior to use, reconstituted solutions of epoprostenol sodium for injection must be protected from light and must be refrigerated at 2° to 8°C (36° to 46°F) if not used immediately. Do not freeze reconstituted solutions of epoprostenol sodium for injection. Discard any reconstituted solution that has been frozen. Discard any reconstituted solution if it has been refrigerated for more than 48 hours.
- During use, a single reservoir of reconstituted solution of epoprostenol sodium for injection can be administered at room temperature for a total duration of 8 hours, or it can be used with a cold pouch and administered up to 24 hours with the use of 2 frozen 6 oz gel packs in a cold pouch. When stored or in use, insulate reconstituted epoprostenol sodium for injection from temperatures greater than 25°C (77°F) and less than 0°C (32°F), and do not expose to direct sunlight.
## Storage
There is limited information regarding Epoprostenol Storage in the drug label.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- Patients receiving epoprostenol should receive the following information. Epoprostenol sodium for injection must be reconstituted only with STERILE DILUENT for epoprostenol sodium for injection. Epoprostenol is infused continuously through a permanent indwelling central venous catheter via a small, portable infusion pump. Thus, therapy with epoprostenol requires commitment by the patient to drug reconstitution, drug administration, and care of the permanent central venous catheter. Patients must adhere to sterile technique in preparing the drug and in the care of the catheter, and even brief interruptions in the delivery of epoprostenol may result in rapid symptomatic deterioration. A patient’s decision to receive epoprostenol should be based upon the understanding that there is a high likelihood that therapy with epoprostenol will be needed for prolonged periods, possibly years. The patient's ability to accept and care for a permanent intravenous catheter and infusion pump should also be carefully considered.
# Precautions with Alcohol
- Alcohol-Epoprostenol interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Veletri®
- Flolan®[1]
# Look-Alike Drug Names
- N/A[2]
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Epoprostenol | |
faeadc7b4009e54a23feb20b4a8d67cea1501ce0 | wikidoc | Eptifibatide | Eptifibatide
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# Overview
Eptifibatide is a Platelet Aggregation Inhibitor that is FDA approved for the treatment of acute coronary syndrome (ACS), percutaneous coronary intervention (PCI). Common adverse reactions include hypotension, bleeding.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
### Acute Coronary Syndrome (ACS)
- Dosing information
- This image is provided by the National Library of Medicine.
Eptifibatide should be given concomitantly with heparin dosed to achieve the following parameters:
During Medical Management: Target aPTT 50 to 70 seconds
- If weight greater than or equal to 70 kg, 5000-unit bolus followed by infusion of 1000 units/h.
- If weight less than 70 kg, 60-units/kg bolus followed by infusion of 12 units/kg/h.
During PCI: Target ACT 200 to 300 seconds
- If heparin is initiated prior to PCI, additional boluses during PCI to maintain an ACT target of 200 to 300 seconds.
- Heparin infusion after the PCI is discouraged.
### Percutaneous Coronary Intervention (PCI)
- Dosing information
- This image is provided by the National Library of Medicine.
- Patients requiring thrombolytic therapy should discontinue Eptifibatide.
### Important Administration Instructions
- Dosing information
- 1.Inspect Eptifibatide for particulate matter and discoloration prior to administration, whenever solution and container permit.
- 2.May administer Eptifibatide in the same intravenous line as alteplase, atropine, dobutamine, heparin, lidocaine, meperidine, metoprolol, midazolam, morphine, nitroglycerin, or verapamil. Do not administer Eptifibatide through the same intravenous line as furosemide.
- 3.May administer Eptifibatide in the same IV line with 0.9% NaCl or 0.9% NaCl/5% dextrose. With either vehicle, the infusion may also contain up to 60 mEq/L of potassium chloride
- 4.Withdraw the bolus dose(s) of Eptifibatide from the 10-mL vial into a syringe. Administer the bolus dose(s) by IV push.
- 5.Immediately following the bolus dose administration, initiate a continuous infusion of Eptifibatide. When using an intravenous infusion pump, administer Eptifibatide undiluted directly from the 100-mL vial. Spike the 100-mL vial with a vented infusion set. Center the spike within the circle on the stopper top.
- 6.Discard any unused portion left in the vial.
- Administer Eptifibatide by volume according to patient weight (see Table 1).
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Eptifibatide in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Eptifibatide in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
Safety and effectiveness of Eptifibatide in pediatric patients have not been studied.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Eptifibatide in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Eptifibatide in pediatric patients.
# Contraindications
Treatment with eptifibatide is contraindicated in patients with:
- A history of bleeding diathesis, or evidence of active abnormal bleeding within the previous 30 days.
- Severe hypertension (systolic blood pressure >200 mm Hg or diastolic blood pressure >110 mm Hg) not adequately controlled on antihypertensive therapy.
- Major surgery within the preceding 6 weeks.
- History of stroke within 30 days or any history of hemorrhagic stroke.
- Current or planned administration of another parenteral GP IIb/IIIa inhibitor.
- Dependency on renal dialysis.
- Known hypersensitivity to any component of the product.
# Warnings
## Bleeding
Bleeding is the most common complication encountered during Eptifibatide therapy. Administration of Eptifibatide is associated with an increase in major and minor bleeding, as classified by the criteria of the Thrombolysis in Myocardial Infarction Study group (TIMI) . Most major bleeding associated with Eptifibatide has been at the arterial access site for cardiac catheterization or from the gastrointestinal or genitourinary tract. Minimize the use of arterial and venous punctures, intramuscular injections, and the use of urinary catheters, nasotracheal intubation, and nasogastric tubes. When obtaining intravenous access, avoid non-compressible sites (e.g., subclavian or jugular veins).
### Use of Thrombolytics, Anticoagulants, and Other Antiplatelet Agents
Risk factors for bleeding include older age, a history of bleeding disorders, and concomitant use of drugs that increase the risk of bleeding (thrombolytics, oral anticoagulants, nonsteroidal anti-inflammatory drugs, and P2Y12 inhibitors). Concomitant treatment with other inhibitors of platelet receptor glycoprotein (GP) IIb/IIIa should be avoided. In patients treated with heparin, bleeding can be minimized by close monitoring of the aPTT and ACT.
### Care of the Femoral Artery Access Site in Patients Undergoing Percutaneous Coronary Intervention (PCI)
In patients undergoing PCI, treatment with Eptifibatide is associated with an increase in major and minor bleeding at the site of arterial sheath placement. After PCI, Eptifibatide infusion should be continued until hospital discharge or up to 18 to 24 hours, whichever comes first. heparin use is discouraged after the PCI procedure. Early sheath removal is encouraged while Eptifibatide is being infused. Prior to removing the sheath, it is recommended that heparin be discontinued for 3 to 4 hours and an aPTT of <45 seconds or ACT <150 seconds be achieved. In any case, both heparin and Eptifibatide should be discontinued and sheath hemostasis should be achieved at least 2 to 4 hours before hospital discharge. If bleeding at access site cannot be controlled with pressure, infusion of Eptifibatide and heparin should be discontinued immediately.
## Thrombocytopenia
There have been reports of acute, profound thrombocytopenia (immune-mediated and non-immune mediated) with Eptifibatide. In the event of acute profound thrombocytopenia or a confirmed platelet decrease to <100,000/mm3, discontinue Eptifibatide and heparin (unfractionated or low-molecular weight). Monitor serial platelet counts, assess the presence of drug-dependent antibodies, and treat as appropriate .
There has been no clinical experience with Eptifibatide initiated in patients with a baseline platelet count <100,000/mm3. If a patient with low platelet counts is receiving Eptifibatide, their platelet count should be monitored closely.
# 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 trials of another drug and may not reflect the rates observed in clinical practice.
A total of 16,782 patients were treated in the Phase III clinical trials (PURSUIT, ESPRIT, and IMPACT II) . These 16,782 patients had a mean age of 62 years (range: 20-94 years). Eighty-nine percent of the patients were Caucasian, with the remainder being predominantly Black (5%) and Hispanic (5%). Sixty-eight percent were men. Because of the different regimens used in PURSUIT, IMPACT II, and ESPRIT, data from the 3 studies were not pooled.
Bleeding and hypotension were the most commonly reported adverse reactions (incidence ≥5% and greater than placebo) in the Eptifibatide controlled clinical trial database.
Bleeding
The incidence of bleeding and transfusions in the PURSUIT and ESPRIT studies are shown in Table 2. Bleeding was classified as major or minor by the criteria of the TIMI study group. Major bleeding consisted of intracranial hemorrhage and other bleeding that led to decreases in hemoglobin greater than 5 g/dL. Minor bleeding included spontaneous gross hematuria, spontaneous hematemesis, other observed blood loss with a hemoglobin decrease of more than 3 g/dL, and other hemoglobin decreases that were greater than 4 g/dL but less than 5 g/dL. In patients who received transfusions, the corresponding loss in hemoglobin was estimated through an adaptation of the method of Landefeld et al.
The majority of major bleeding reactions in the ESPRIT study occurred at the vascular access site (1 and 8 patients, or 0.1% and 0.8% in the placebo and Eptifibatide groups, respectively). Bleeding at "other" locations occurred in 0.2% and 0.4% of patients, respectively.
In the PURSUIT study, the greatest increase in major bleeding in Eptifibatide-treated patients compared to placebo-treated patients was also associated with bleeding at the femoral artery access site (2.8% versus 1.3%). Oropharyngeal (primarily gingival), genitourinary, gastrointestinal, and retroperitoneal bleeding were also seen more commonly in Eptifibatide-treated patients compared to placebo-treated patients.
Among patients experiencing a major bleed in the IMPACT II study, an increase in bleeding on Eptifibatide versus placebo was observed only for the femoral artery access site (3.2% versus 2.8%).
Table 3 displays the incidence of TIMI major bleeding according to the cardiac procedures carried out in the PURSUIT study. The most common bleeding complications were related to cardiac revascularization (CABG-related or femoral artery access site bleeding). A corresponding table for ESPRIT is not presented, as every patient underwent PCI in the ESPRIT study and only 11 patients underwent CABG.
In the PURSUIT and ESPRIT studies, the risk of major bleeding with Eptifibatide increased as patient weight decreased. This relationship was most apparent for patients weighing less than 70 kg.
Bleeding resulting in discontinuation of the study drug was more frequent among patients receiving Eptifibatide than placebo (4.6% versus 0.9% in ESPRIT, 8% versus 1% in PURSUIT, 3.5% versus 1.9% in IMPACT II).
### Intracranial Hemorrhage and Stroke
Intracranial hemorrhage was rare in the PURSUIT, IMPACT II, and ESPRIT clinical studies. In the PURSUIT study, 3 patients in the placebo group, 1 patient in the group treated with Eptifibatide 180/1.3, and 5 patients in the group treated with Eptifibatide 180/2 experienced a hemorrhagic stroke. The overall incidence of stroke was 0.5% in patients receiving Eptifibatide 180/1.3, 0.7% in patients receiving Eptifibatide 180/2, and 0.8% in placebo patients.
In the IMPACT II study,intracranial hemorrhage was experienced by 1 patient treated with Eptifibatide 135/0.5, 2 patients treated with Eptifibatide 135/0.75, and 2 patients in the placebo group. The overall incidence of stroke was 0.5% in patients receiving 135/0.5 Eptifibatide, 0.7% in patients receiving Eptifibatide 135/0.75, and 0.7% in the placebo group.
In the ESPRIT study, there were 3 hemorrhagic strokes, 1 in the placebo group and 2 in the Eptifibatide group. In addition there was 1 case of cerebral infarction in the Eptifibatide group.
### Immunogenicity/Thrombocytopenia
The potential for development of antibodies to eptifibatide has been studied in 433 subjects. Eptifibatide was nonantigenic in 412 patients receiving a single administration of Eptifibatide (135-mcg/kg bolus followed by a continuous infusion of either 0.5 mcg/kg/min or 0.75 mcg/kg/min), and in 21 subjects to whom Eptifibatide (135-mcg/kg bolus followed by a continuous infusion of 0.75 mcg/kg/min) was administered twice, 28 days apart. In both cases, plasma for antibody detection was collected approximately 30 days after each dose. The development of antibodies to eptifibatide at higher doses has not been evaluated.
In patients with suspected Eptifibatide-related immune-mediated thrombocytopenia, IgG antibodies that react with the GP IIb/IIIa complex were identified in the presence of eptifibatide and in Eptifibatide-naïve patients. These findings suggest acute thrombocytopenia after the administration of Eptifibatide can develop as a result of naturally occurring drug-dependent antibodies or those induced by prior exposure to Eptifibatide. Similar antibodies were identified with other GP IIb/IIIa ligand-mimetic agents. Immune-mediated thrombocytopenia with Eptifibatide may be associated with hypotension and/or other signs of hypersensitivity.
In the PURSUIT and IMPACT II studies, the incidence of thrombocytopenia (<100,000/mm3 or ≥50% reduction from baseline) and the incidence of platelet transfusions were similar between patients treated with Eptifibatide and placebo. In the ESPRIT study, the incidence was 0.6% in the placebo group and 1.2% in the Eptifibatide group.
### Other Adverse Reactions
In the PURSUIT and ESPRIT studies, the incidence of serious nonbleeding adverse reactions was similar in patients receiving placebo or Eptifibatide (19% and 19%, respectively, in PURSUIT; 6% and 7%, respectively, in ESPRIT). In PURSUIT, the only serious nonbleeding adverse reaction that occurred at a rate of at least 1% and was more common with Eptifibatide than placebo (7% versus 6%) was hypotension. Most of the serious nonbleeding adverse reactions consisted of cardiovascular reactions typical of a UA population. In the IMPACT II study, serious nonbleeding adverse reactions that occurred in greater than 1% of patients were uncommon and similar in incidence between placebo- and Eptifibatide-treated patients.
Discontinuation of study drug due to adverse reactions other than bleeding was uncommon in the PURSUIT, IMPACT II, and ESPRIT studies, with no single reaction occurring in >0.5% of the study population (except for "other" in the ESPRIT study).
## Postmarketing Experience
Because the reactions below are reported voluntarily from a population of uncertain size, it is generally not possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
The following adverse reactions have been reported in postmarketing experience, primarily with Eptifibatide in combination with heparin and aspirin: cerebral, GI, and pulmonary hemorrhage. Fatal bleeding reactions have been reported. Acute profound thrombocytopenia, as well as immune-mediated thrombocytopenia, has been reported.
# Drug Interactions
Coadministration of antiplatelet agents, thrombolytics, heparin, aspirin, and chronic NSAID use increases the risk of bleeding. Concomitant treatment with other inhibitors of platelet receptor GP IIb/IIIa should be avoided.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): B
Teratology studies have been performed by continuous intravenous infusion of eptifibatide in pregnant rats at total daily doses of up to 72 mg/kg/day (about 4 times the recommended maximum daily human dose on a body surface area basis) and in pregnant rabbits at total daily doses of up to 36 mg/kg/day (also about 4 times the recommended maximum daily human dose on a body surface area basis). These studies revealed no evidence of harm to the fetus due to eptifibatide. There are, however, no adequate and well-controlled studies in pregnant women with Eptifibatide. Because animal reproduction studies are not always predictive of human response, Eptifibatide should be used during pregnancy only if clearly needed.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Eptifibatide in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Eptifibatide during labor and delivery.
### Nursing Mothers
It is not known whether eptifibatide is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Eptifibatide is administered to a nursing mother.
### Pediatric Use
Safety and effectiveness of Eptifibatide in pediatric patients have not been studied.
### Geriatic Use
The PURSUIT and IMPACT II clinical studies enrolled patients up to the age of 94 years (45% were age 65 and over; 12% were age 75 and older). There was no apparent difference in efficacy between older and younger patients treated with Eptifibatide. The incidence of bleeding complications was higher in the elderly in both placebo and Eptifibatide groups, and the incremental risk of Eptifibatide-associated bleeding was greater in the older patients. No dose adjustment was made for elderly patients, but patients over 75 years of age had to weigh at least 50 kg to be enrolled in the PURSUIT study; no such limitation was stipulated in the ESPRIT study.
### Gender
There is no FDA guidance on the use of Eptifibatide with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Eptifibatide with respect to specific racial populations.
### Renal Impairment
Approximately 50% of eptifibatide is cleared by the kidney in patients with normal renal function. Total drug clearance is decreased by approximately 50% and steady-state plasma Eptifibatide concentrations are doubled in patients with an estimated CrCl <50 mL/min (using the Cockcroft-Gault equation). Therefore, the infusion dose should be reduced to 1 mcg/kg/min in such patients . The safety and efficacy of Eptifibatide in patients dependent on dialysis has not been established.
### Hepatic Impairment
There is no FDA guidance on the use of Eptifibatide in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Eptifibatide in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Eptifibatide in patients who are immunocompromised.
# Administration and Monitoring
### Administration
Intravenous
### Monitoring
FDA Package Insert for Eptifibatide contains no information regarding drug monitoring.
# IV Compatibility
There is limited information about the IV Compability.
# Overdosage
There has been only limited experience with overdosage of Eptifibatide. There were 8 patients in the IMPACT II study, 9 patients in the PURSUIT study, and no patients in the ESPRIT study who received bolus doses and/or infusion doses more than double those called for in the protocols. None of these patients experienced an intracranial bleed or other major bleeding.
Eptifibatide was not lethal to rats, rabbits, or monkeys when administered by continuous intravenous infusion for 90 minutes at a total dose of 45 mg/kg (about 2 to 5 times the recommended maximum daily human dose on a body surface area basis). Symptoms of acute toxicity were loss of righting reflex, dyspnea, ptosis, and decreased muscle tone in rabbits and petechial hemorrhages in the femoral and abdominal areas of monkeys.
From in vitro studies, eptifibatide is not extensively bound to plasma proteins and thus may be cleared from plasma by dialysis.
# Pharmacology
## Mechanism of Action
Eptifibatide reversibly inhibits platelet aggregation by preventing the binding of fibrinogen, von Willebrand factor, and other adhesive ligands to GP IIb/IIIa. When administered intravenously, eptifibatide inhibits ex vivo platelet aggregation in a dose- and concentration-dependent manner. Platelet aggregation inhibition is reversible following cessation of the eptifibatide infusion; this is thought to result from dissociation of eptifibatide from the platelet.
## Structure
Eptifibatide is a cyclic heptapeptide containing 6 amino acids and 1 mercaptopropionyl (des-amino cysteinyl) residue. An interchain disulfide bridge is formed between the cysteine amide and the mercaptopropionyl moieties. Chemically it is N6-(aminoiminomethyl)-N2-(3-mercapto-1-oxopropyl)-L-lysylglycyl-L-α-aspartyl-L-tryptophyl-L-prolyl-L-cysteinamide, cyclic (1→6)-disulfide. Eptifibatide binds to the platelet receptor glycoprotein (GP) IIb/IIIa of human platelets and inhibits platelet aggregation.
The eptifibatide peptide is produced by solution-phase peptide synthesis, and is purified by preparative reverse-phase liquid chromatography and lyophilized. The structural formula is:
Eptifibatide Injection is a clear, colorless, sterile, non-pyrogenic solution for intravenous (IV) use with an empirical formula of C35H49N11O9S2 and a molecular weight of 831.96. Each 10-mL vial contains 2 mg/mL of Eptifibatide and each 100-mL vial contains either 0.75 mg/mL of Eptifibatide or 2 mg/mL of Eptifibatide. Each vial of either size also contains 5.25 mg/mL citric acid and sodium hydroxide to adjust the pH to 5.35.
## Pharmacodynamics
Infusion of eptifibatide into baboons caused a dose-dependent inhibition of ex vivo platelet aggregation, with complete inhibition of aggregation achieved at infusion rates greater than 5 mcg/kg/min. In a baboon model that is refractory to aspirin and heparin, doses of eptifibatide that inhibit aggregation prevented acute thrombosis with only a modest prolongation (2- to 3-fold) of the bleeding time. Platelet aggregation in dogs was also inhibited by infusions of eptifibatide, with complete inhibition at 2 mcg/kg/min. This infusion dose completely inhibited canine coronary thrombosis induced by coronary artery injury (Folts model).
Human pharmacodynamic data were obtained in healthy subjects and in patients presenting with UA or NSTEMI and/or undergoing percutaneous coronary intervention. Studies in healthy subjects enrolled only males; patient studies enrolled approximately one-third women. In these studies, Eptifibatide inhibited ex vivo platelet aggregation induced by adenosine diphosphate (ADP) and other agonists in a dose- and concentration-dependent manner. The effect of Eptifibatide was observed immediately after administration of a 180-mcg/kg intravenous bolus. Table 4 shows the effects of dosing regimens of Eptifibatide used in the IMPACT II and PURSUIT studies on ex vivo platelet aggregation induced by 20 µM ADP in PPACK-anticoagulated platelet-rich plasma and on bleeding time. The effects of the dosing regimen used in ESPRIT on platelet aggregation have not been studied.
The Eptifibatide dosing regimen used in the ESPRIT study included two 180-mcg/kg bolus doses given 10 minutes apart combined with a continuous 2-mcg/kg/min infusion.
When administered alone, Eptifibatide has no measurable effect on PT or aPTT.
There were no important differences between men and women or between age groups in the pharmacodynamic properties of eptifibatide. Differences among ethnic groups have not been assessed.
## Pharmacokinetics
The pharmacokinetics of eptifibatide are linear and dose-proportional for bolus doses ranging from 90 to 250 mcg/kg and infusion rates from 0.5 to 3 mcg/kg/min. Plasma elimination half-life is approximately 2.5 hours. Administration of a single 180-mcg/kg bolus combined with an infusion produces an early peak level, followed by a small decline prior to attaining steady state (within 4-6 hours). This decline can be prevented by administering a second 180-mcg/kg bolus 10 minutes after the first. The extent of eptifibatide binding to human plasma protein is about 25%. Clearance in patients with coronary artery disease is about 55 mL/kg/h. In healthy subjects, renal clearance accounts for approximately 50% of total body clearance, with the majority of the drug excreted in the urine as eptifibatide, deaminated eptifibatide, and other, more polar metabolites. No major metabolites have been detected in human plasma.
## Nonclinical Toxicology
No long-term studies in animals have been performed to evaluate the carcinogenic potential of eptifibatide. Eptifibatide was not genotoxic in the Ames test, the mouse lymphoma cell (L 5178Y, TK+/-) forward mutation test, the human lymphocyte chromosome aberration test, or the mouse micronucleus test. Administered by continuous intravenous infusion at total daily doses up to 72 mg/kg/day (about 4 times the recommended maximum daily human dose on a body surface area basis), eptifibatide had no effect on fertility and reproductive performance of male and female rats.
# Clinical Studies
Eptifibatide was studied in 3 placebo-controlled, randomized studies. PURSUIT evaluated patients with acute coronary syndromes: UA or NSTEMI. Two other studies, ESPRIT and IMPACT II, evaluated patients about to undergo a PCI. Patients underwent primarily balloon angioplasty in IMPACT II and intracoronary stent placement, with or without angioplasty, in ESPRIT.
## Non-ST-Segment Elevation Acute Coronary Syndrome
Non-ST-segment elevation acute coronary syndrome is defined as prolonged (≥10 minutes) symptoms of cardiac ischemia within the previous 24 hours associated with either ST-segment changes (elevations between 0.6 mm and 1 mm or depression >0.5 mm), T-wave inversion (>1 mm), or positive CK-MB. This definition includes "unstable angina" and "NSTEMI" but excludes MI that is associated with Q waves or greater degrees of ST-segment elevation.
PURSUIT (Platelet Glycoprotein IIb/IIIa in unstable angina: Receptor Suppression Using Eptifibatide Therapy)
PURSUIT was a 726-center, 27-country, double-blind, randomized, placebo-controlled study in 10,948 patients presenting with UA or NSTEMI. Patients could be enrolled only if they had experienced cardiac ischemia at rest (≥10 minutes) within the previous 24 hours and had either ST-segment changes (elevations between 0.6 mm and 1 mm or depression >0.5 mm), T-wave inversion (>1 mm), or increased CK-MB. Important exclusion criteria included a history of bleeding diathesis, evidence of abnormal bleeding within the previous 30 days, uncontrolled hypertension, major surgery within the previous 6 weeks, stroke within the previous 30 days, any history of hemorrhagic stroke, serum creatinine >2 mg/dL, dependency on renal dialysis, or platelet count <100,000/mm3.
Patients were randomized to placebo, to Eptifibatide 180-mcg/kg bolus followed by a 2-mcg/kg/min infusion (180/2), or to Eptifibatide 180-mcg/kg bolus followed by a 1.3-mcg/kg/min infusion (180/1.3). The infusion was continued for 72 hours, until hospital discharge, or until the time of CABG, whichever occurred first, except that if PCI was performed, the Eptifibatide infusion was continued for 24 hours after the procedure, allowing for a duration of infusion up to 96 hours.
The lower-infusion-rate arm was stopped after the first interim analysis when the 2 active-treatment arms appeared to have the same incidence of bleeding.
Patient age ranged from 20 to 94 (mean 63) years, and 65% were male. The patients were 89% Caucasian, 6% Hispanic, and 5% Black, recruited in the United States and Canada (40%), Western Europe (39%), Eastern Europe (16%), and Latin America (5%).
This was a "real world" study; each patient was managed according to the usual standards of the investigational site; frequencies of angiography, PCI, and CABG therefore differed widely from site to site and from country to country. Of the patients in PURSUIT, 13% were managed with PCI during drug infusion, of whom 50% received intracoronary stents; 87% were managed medically (without PCI during drug infusion).
The majority of patients received aspirin (75-325 mg once daily). Heparin was administered intravenously or subcutaneously, at the physician's discretion, most commonly as an intravenous bolus of 5000 units followed by a continuous infusion of 1000 units/h. For patients weighing less than 70 kg, the recommended Heparin bolus dose was 60 units/kg followed by a continuous infusion of 12 units/kg/h. A target aPTT of 50 to 70 seconds was recommended. A total of 1250 patients underwent PCI within 72 hours after randomization, in which case they received intravenous Heparin to maintain an ACT of 300 to 350 seconds.
The primary endpoint of the study was the occurrence of death from any cause or new MI (evaluated by a blinded Clinical Endpoints Committee) within 30 days of randomization.
Compared to placebo, Eptifibatide administered as a 180-mcg/kg bolus followed by a 2-mcg/kg/min infusion significantly (p=0.042) reduced the incidence of endpoint events (see Table 6). The reduction in the incidence of endpoint events in patients receiving Eptifibatide was evident early during treatment, and this reduction was maintained through at least 30 days (see Figure 1). Table 5 also shows the incidence of the components of the primary endpoint, death (whether or not preceded by an MI) and new MI in surviving patients at 30 days.
Treatment with Eptifibatide prior to determination of patient management strategy reduced clinical events regardless of whether patients ultimately underwent diagnostic catheterization, revascularization (i.e., PCI or CABG surgery) or continued to receive medical management alone. Table 6 shows the incidence of death or MI within 72 hours.
All of the effect of Eptifibatide was established within 72 hours (during the period of drug infusion), regardless of management strategy. Moreover, for patients undergoing early PCI, a reduction in events was evident prior to the procedure.
An analysis of the results by sex suggests that women who would not routinely be expected to undergo PCI receive less benefit from Eptifibatide (95% confidence limits for relative risk of 0.94 - 1.28) than do men (0.72 - 0.9). This difference may be a true treatment difference, the effect of other differences in these subgroups, or a statistical anomaly. No differential outcomes were seen between male and female patients undergoing PCI (see results for ESPRIT).
Follow-up data were available through 165 days for 10,611 patients enrolled in the PURSUIT trial (96.9% of the initial enrollment). This follow-up included 4566 patients who received Eptifibatide at the 180/2 dose. As reported by the investigators, the occurrence of death from any cause or new MI for patients followed for at least 165 days was reduced from 13.6% with placebo to 12.1% with Eptifibatide 180/2.
## Percutaneous Coronary Intervention (PCI)
### IMPACT II (Eptifibatide to Minimize Platelet Aggregation and Prevent Coronary Thrombosis II)
IMPACT II was a multicenter, double-blind, randomized, placebo-controlled study conducted in the United States in 4010 patients undergoing PCI. Major exclusion criteria included a history of bleeding diathesis, major surgery within 6 weeks of treatment, gastrointestinal bleeding within 30 days, any stroke or structural CNS abnormality, uncontrolled hypertension, PT >1.2 times control, hematocrit <30%, platelet count <100,000/mm3, and pregnancy.
Patient age ranged from 24 to 89 (mean 60) years, and 75% were male. The patients were 92% Caucasian, 5% Black, and 3% Hispanic. Forty-one percent of the patients underwent PCI for ongoing ACS. Patients were randomly assigned to 1 of 3 treatment regimens, each incorporating a bolus dose initiated immediately prior to PCI followed by a continuous infusion lasting 20 to 24 hours:
1)135-mcg/kg bolus followed by a continuous infusion of 0.5 mcg/kg/min of Eptifibatide (135/0.5);
2)135-mcg/kg bolus followed by a continuous infusion of 0.75 mcg/kg/min of Eptifibatide (135/0.75); or
3)a matching placebo bolus followed by a matching placebo continuous infusion.
Each patient received aspirin and an intravenous heparin bolus of 100 units/kg, with additional bolus infusions of up to 2000 additional units of heparin every 15 minutes to maintain an ACT of 300 to 350 seconds.
The primary endpoint was the composite of death, MI, or urgent revascularization, analyzed at 30 days after randomization in all patients who received at least 1 dose of study drug.
As shown in Table 7, each Eptifibatide regimen reduced the rate of death, MI, or urgent intervention, although at 30 days, this finding was statistically significant only in the lower-dose Eptifibatide group. As in the PURSUIT study, the effects of Eptifibatide were seen early and persisted throughout the 30-day period.
### ESPRIT (Enhanced Suppression of the Platelet IIb/IIIa Receptor with Eptifibatide Therapy)
The ESPRIT study was a multicenter, double-blind, randomized, placebo-controlled study conducted in the United States and Canada that enrolled 2064 patients undergoing elective or urgent PCI with intended intracoronary stent placement. Exclusion criteria included MI within the previous 24 hours, ongoing chest pain, administration of any oral antiplatelet or oral anticoagulant other than aspirin within 30 days of PCI (although loading doses of thienopyridine on the day of PCI were encouraged), planned PCI of a saphenous vein graft or subsequent "staged" PCI, prior stent placement in the target lesion, PCI within the previous 90 days, a history of bleeding diathesis, major surgery within 6 weeks of treatment, gastrointestinal bleeding within 30 days, any stroke or structural CNS abnormality, uncontrolled hypertension, PT >1.2 times control, hematocrit <30%, platelet count <100,000/mm3, and pregnancy.
Patient age ranged from 24 to 93 (mean 62) years, and 73% of patients were male. The study enrolled 90% Caucasian, 5% African American, 2% Hispanic, and 1% Asian patients. Patients received a wide variety of stents. Patients were randomized either to placebo or Eptifibatide administered as an intravenous bolus of 180 mcg/kg followed immediately by a continuous infusion of 2 mcg/kg/min, and a second bolus of 180 mcg/kg administered 10 minutes later (180/2/180). Eptifibatide infusion was continued for 18 to 24 hours after PCI or until hospital discharge, whichever came first. Each patient received at least 1 dose of aspirin (162-325 mg) and 60 units/kg of heparin as a bolus (not to exceed 6000 units) if not already receiving a heparin infusion. Additional boluses of heparin (10-40 units/kg) could be administered in order to reach a target ACT between 200 and 300 seconds.
The primary endpoint of the ESPRIT study was the composite of death, MI, urgent target vessel revascularization (UTVR), and "bailout" to open-label Eptifibatide due to a thrombotic complication of PCI (TBO) (e.g., visible thrombus, "no reflow," or abrupt closure) at 48 hours. MI, UTVR, and TBO were evaluated by a blinded Clinical Events Committee.
As shown in Table 8, the incidence of the primary endpoint and selected secondary endpoints was significantly reduced in patients who received Eptifibatide. A treatment benefit in patients who received Eptifibatide was seen by 48 hours and at the end of the 30-day observation period.
The need for thrombotic "bailout" was significantly reduced with Eptifibatide at 48 hours (2.1% for placebo, 1% for Eptifibatide; p=0.029). Consistent with previous studies of GP IIb/IIIa inhibitors, most of the benefit achieved acutely with Eptifibatide was in the reduction of MI. Eptifibatide reduced the occurrence of MI at 48 hours from 9% for placebo to 5.4% (p=0.0015) and maintained that effect with significance at 30 days.
There was no treatment difference with respect to sex in ESPRIT. Eptifibatide reduced the incidence of the primary endpoint in both men (95% confidence limits for relative risk: 0.54, 1.07) and women (0.24, 0.72) at 48 hours.
Follow-up (12-month) mortality data were available for 2024 patients (1017 on Eptifibatide) enrolled in the ESPRIT trial (98.1% of the initial enrollment). Twelve-month clinical event data were available for 1964 patients (988 on Eptifibatide), representing 95.2% of the initial enrollment. As shown in Table 9, the treatment effect of Eptifibatide seen at 48 hours and 30 days appeared preserved at 6 months and 1 year. Most of the benefit was in reduction of MI.
## Percutaneous Coronary Intervention (PCI)
IMPACT II (Eptifibatide to Minimize Platelet Aggregation and Prevent Coronary Thrombosis II)
IMPACT II was a multicenter, double-blind, randomized, placebo-controlled study conducted in the United States in 4010 patients undergoing PCI. Major exclusion criteria included a history of bleeding diathesis, major surgery within 6 weeks of treatment, gastrointestinal bleeding within 30 days, any stroke or structural CNS abnormality, uncontrolled hypertension, PT >1.2 times control, hematocrit <30%, platelet count <100,000/mm3, and pregnancy.
Patient age ranged from 24 to 89 (mean 60) years, and 75% were male. The patients were 92% Caucasian, 5% Black, and 3% Hispanic. Forty-one percent of the patients underwent PCI for ongoing ACS. Patients were randomly assigned to 1 of 3 treatment regimens, each incorporating a bolus dose initiated immediately prior to PCI followed by a continuous infusion lasting 20 to 24 hours:
1)135-mcg/kg bolus followed by a continuous infusion of 0.5 mcg/kg/min of Eptifibatide (135/0.5);
2)135-mcg/kg bolus followed by a continuous infusion of 0.75 mcg/kg/min of Eptifibatide (135/0.75); or
3)a matching placebo bolus followed by a matching placebo continuous infusion.
Each patient received aspirin and an intravenous heparin bolus of 100 units/kg, with additional bolus infusions of up to 2000 additional units of heparin every 15 minutes to maintain an ACT of 300 to 350 seconds.
The primary endpoint was the composite of death, MI, or urgent revascularization, analyzed at 30 days after randomization in all patients who received at least 1 dose of study drug.
As shown in Table 7, each Eptifibatide regimen reduced the rate of death, MI, or urgent intervention, although at 30 days, this finding was statistically significant only in the lower-dose Eptifibatide group. As in the PURSUIT study, the effects of Eptifibatide were seen early and persisted throughout the 30-day period.
# How Supplied
Eptifibatide (eptifibatide) injection is supplied as a sterile solution in 10-mL vials containing 20 mg of Eptifibatide (NDC 0085-1177-01) and 100-mL vials containing either 75 mg of Eptifibatide (NDC 0085-1136-01) or 200 mg of Eptifibatide (NDC 0085-1177-02).
## Storage
Vials should be stored refrigerated at 2-8°C (36-46°F). Vials may be transferred to room temperature storage1 for a period not to exceed 2 months. Upon transfer, vial cartons must be marked by the dispensing pharmacist with a "DISCARD BY" date (2 months from the transfer date or the labeled expiration date, whichever comes first).
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
Instruct patients to inform the doctor or healthcare provider about any medical conditions, medications, and allergies.
# Precautions with Alcohol
Alcohol-Eptifibatide 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 Eptifibatide Brand Names in the drug label.
# Look-Alike Drug Names
There is limited information regarding Eptifibatide Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | Eptifibatide
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Sheng Shi, M.D. [2]; Aparna Vuppala, M.B.B.S. [3]
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# Overview
Eptifibatide is a Platelet Aggregation Inhibitor that is FDA approved for the treatment of acute coronary syndrome (ACS), percutaneous coronary intervention (PCI). Common adverse reactions include hypotension, bleeding.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
### Acute Coronary Syndrome (ACS)
- Dosing information
- This image is provided by the National Library of Medicine.
Eptifibatide should be given concomitantly with heparin dosed to achieve the following parameters:
During Medical Management: Target aPTT 50 to 70 seconds
- If weight greater than or equal to 70 kg, 5000-unit bolus followed by infusion of 1000 units/h.
- If weight less than 70 kg, 60-units/kg bolus followed by infusion of 12 units/kg/h.
During PCI: Target ACT 200 to 300 seconds
- If heparin is initiated prior to PCI, additional boluses during PCI to maintain an ACT target of 200 to 300 seconds.
- Heparin infusion after the PCI is discouraged.
### Percutaneous Coronary Intervention (PCI)
- Dosing information
- This image is provided by the National Library of Medicine.
- Patients requiring thrombolytic therapy should discontinue Eptifibatide.
### Important Administration Instructions
- Dosing information
- 1.Inspect Eptifibatide for particulate matter and discoloration prior to administration, whenever solution and container permit.
- 2.May administer Eptifibatide in the same intravenous line as alteplase, atropine, dobutamine, heparin, lidocaine, meperidine, metoprolol, midazolam, morphine, nitroglycerin, or verapamil. Do not administer Eptifibatide through the same intravenous line as furosemide.
- 3.May administer Eptifibatide in the same IV line with 0.9% NaCl or 0.9% NaCl/5% dextrose. With either vehicle, the infusion may also contain up to 60 mEq/L of potassium chloride
- 4.Withdraw the bolus dose(s) of Eptifibatide from the 10-mL vial into a syringe. Administer the bolus dose(s) by IV push.
- 5.Immediately following the bolus dose administration, initiate a continuous infusion of Eptifibatide. When using an intravenous infusion pump, administer Eptifibatide undiluted directly from the 100-mL vial. Spike the 100-mL vial with a vented infusion set. Center the spike within the circle on the stopper top.
- 6.Discard any unused portion left in the vial.
- Administer Eptifibatide by volume according to patient weight (see Table 1).
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Eptifibatide in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Eptifibatide in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
Safety and effectiveness of Eptifibatide in pediatric patients have not been studied.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Eptifibatide in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Eptifibatide in pediatric patients.
# Contraindications
Treatment with eptifibatide is contraindicated in patients with:
- A history of bleeding diathesis, or evidence of active abnormal bleeding within the previous 30 days.
- Severe hypertension (systolic blood pressure >200 mm Hg or diastolic blood pressure >110 mm Hg) not adequately controlled on antihypertensive therapy.
- Major surgery within the preceding 6 weeks.
- History of stroke within 30 days or any history of hemorrhagic stroke.
- Current or planned administration of another parenteral GP IIb/IIIa inhibitor.
- Dependency on renal dialysis.
- Known hypersensitivity to any component of the product.
# Warnings
## Bleeding
Bleeding is the most common complication encountered during Eptifibatide therapy. Administration of Eptifibatide is associated with an increase in major and minor bleeding, as classified by the criteria of the Thrombolysis in Myocardial Infarction Study group (TIMI) . Most major bleeding associated with Eptifibatide has been at the arterial access site for cardiac catheterization or from the gastrointestinal or genitourinary tract. Minimize the use of arterial and venous punctures, intramuscular injections, and the use of urinary catheters, nasotracheal intubation, and nasogastric tubes. When obtaining intravenous access, avoid non-compressible sites (e.g., subclavian or jugular veins).
### Use of Thrombolytics, Anticoagulants, and Other Antiplatelet Agents
Risk factors for bleeding include older age, a history of bleeding disorders, and concomitant use of drugs that increase the risk of bleeding (thrombolytics, oral anticoagulants, nonsteroidal anti-inflammatory drugs, and P2Y12 inhibitors). Concomitant treatment with other inhibitors of platelet receptor glycoprotein (GP) IIb/IIIa should be avoided. In patients treated with heparin, bleeding can be minimized by close monitoring of the aPTT and ACT.
### Care of the Femoral Artery Access Site in Patients Undergoing Percutaneous Coronary Intervention (PCI)
In patients undergoing PCI, treatment with Eptifibatide is associated with an increase in major and minor bleeding at the site of arterial sheath placement. After PCI, Eptifibatide infusion should be continued until hospital discharge or up to 18 to 24 hours, whichever comes first. heparin use is discouraged after the PCI procedure. Early sheath removal is encouraged while Eptifibatide is being infused. Prior to removing the sheath, it is recommended that heparin be discontinued for 3 to 4 hours and an aPTT of <45 seconds or ACT <150 seconds be achieved. In any case, both heparin and Eptifibatide should be discontinued and sheath hemostasis should be achieved at least 2 to 4 hours before hospital discharge. If bleeding at access site cannot be controlled with pressure, infusion of Eptifibatide and heparin should be discontinued immediately.
## Thrombocytopenia
There have been reports of acute, profound thrombocytopenia (immune-mediated and non-immune mediated) with Eptifibatide. In the event of acute profound thrombocytopenia or a confirmed platelet decrease to <100,000/mm3, discontinue Eptifibatide and heparin (unfractionated or low-molecular weight). Monitor serial platelet counts, assess the presence of drug-dependent antibodies, and treat as appropriate .
There has been no clinical experience with Eptifibatide initiated in patients with a baseline platelet count <100,000/mm3. If a patient with low platelet counts is receiving Eptifibatide, their platelet count should be monitored closely.
# 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 trials of another drug and may not reflect the rates observed in clinical practice.
A total of 16,782 patients were treated in the Phase III clinical trials (PURSUIT, ESPRIT, and IMPACT II) . These 16,782 patients had a mean age of 62 years (range: 20-94 years). Eighty-nine percent of the patients were Caucasian, with the remainder being predominantly Black (5%) and Hispanic (5%). Sixty-eight percent were men. Because of the different regimens used in PURSUIT, IMPACT II, and ESPRIT, data from the 3 studies were not pooled.
Bleeding and hypotension were the most commonly reported adverse reactions (incidence ≥5% and greater than placebo) in the Eptifibatide controlled clinical trial database.
Bleeding
The incidence of bleeding and transfusions in the PURSUIT and ESPRIT studies are shown in Table 2. Bleeding was classified as major or minor by the criteria of the TIMI study group. Major bleeding consisted of intracranial hemorrhage and other bleeding that led to decreases in hemoglobin greater than 5 g/dL. Minor bleeding included spontaneous gross hematuria, spontaneous hematemesis, other observed blood loss with a hemoglobin decrease of more than 3 g/dL, and other hemoglobin decreases that were greater than 4 g/dL but less than 5 g/dL. In patients who received transfusions, the corresponding loss in hemoglobin was estimated through an adaptation of the method of Landefeld et al.
The majority of major bleeding reactions in the ESPRIT study occurred at the vascular access site (1 and 8 patients, or 0.1% and 0.8% in the placebo and Eptifibatide groups, respectively). Bleeding at "other" locations occurred in 0.2% and 0.4% of patients, respectively.
In the PURSUIT study, the greatest increase in major bleeding in Eptifibatide-treated patients compared to placebo-treated patients was also associated with bleeding at the femoral artery access site (2.8% versus 1.3%). Oropharyngeal (primarily gingival), genitourinary, gastrointestinal, and retroperitoneal bleeding were also seen more commonly in Eptifibatide-treated patients compared to placebo-treated patients.
Among patients experiencing a major bleed in the IMPACT II study, an increase in bleeding on Eptifibatide versus placebo was observed only for the femoral artery access site (3.2% versus 2.8%).
Table 3 displays the incidence of TIMI major bleeding according to the cardiac procedures carried out in the PURSUIT study. The most common bleeding complications were related to cardiac revascularization (CABG-related or femoral artery access site bleeding). A corresponding table for ESPRIT is not presented, as every patient underwent PCI in the ESPRIT study and only 11 patients underwent CABG.
In the PURSUIT and ESPRIT studies, the risk of major bleeding with Eptifibatide increased as patient weight decreased. This relationship was most apparent for patients weighing less than 70 kg.
Bleeding resulting in discontinuation of the study drug was more frequent among patients receiving Eptifibatide than placebo (4.6% versus 0.9% in ESPRIT, 8% versus 1% in PURSUIT, 3.5% versus 1.9% in IMPACT II).
### Intracranial Hemorrhage and Stroke
Intracranial hemorrhage was rare in the PURSUIT, IMPACT II, and ESPRIT clinical studies. In the PURSUIT study, 3 patients in the placebo group, 1 patient in the group treated with Eptifibatide 180/1.3, and 5 patients in the group treated with Eptifibatide 180/2 experienced a hemorrhagic stroke. The overall incidence of stroke was 0.5% in patients receiving Eptifibatide 180/1.3, 0.7% in patients receiving Eptifibatide 180/2, and 0.8% in placebo patients.
In the IMPACT II study,intracranial hemorrhage was experienced by 1 patient treated with Eptifibatide 135/0.5, 2 patients treated with Eptifibatide 135/0.75, and 2 patients in the placebo group. The overall incidence of stroke was 0.5% in patients receiving 135/0.5 Eptifibatide, 0.7% in patients receiving Eptifibatide 135/0.75, and 0.7% in the placebo group.
In the ESPRIT study, there were 3 hemorrhagic strokes, 1 in the placebo group and 2 in the Eptifibatide group. In addition there was 1 case of cerebral infarction in the Eptifibatide group.
### Immunogenicity/Thrombocytopenia
The potential for development of antibodies to eptifibatide has been studied in 433 subjects. Eptifibatide was nonantigenic in 412 patients receiving a single administration of Eptifibatide (135-mcg/kg bolus followed by a continuous infusion of either 0.5 mcg/kg/min or 0.75 mcg/kg/min), and in 21 subjects to whom Eptifibatide (135-mcg/kg bolus followed by a continuous infusion of 0.75 mcg/kg/min) was administered twice, 28 days apart. In both cases, plasma for antibody detection was collected approximately 30 days after each dose. The development of antibodies to eptifibatide at higher doses has not been evaluated.
In patients with suspected Eptifibatide-related immune-mediated thrombocytopenia, IgG antibodies that react with the GP IIb/IIIa complex were identified in the presence of eptifibatide and in Eptifibatide-naïve patients. These findings suggest acute thrombocytopenia after the administration of Eptifibatide can develop as a result of naturally occurring drug-dependent antibodies or those induced by prior exposure to Eptifibatide. Similar antibodies were identified with other GP IIb/IIIa ligand-mimetic agents. Immune-mediated thrombocytopenia with Eptifibatide may be associated with hypotension and/or other signs of hypersensitivity.
In the PURSUIT and IMPACT II studies, the incidence of thrombocytopenia (<100,000/mm3 or ≥50% reduction from baseline) and the incidence of platelet transfusions were similar between patients treated with Eptifibatide and placebo. In the ESPRIT study, the incidence was 0.6% in the placebo group and 1.2% in the Eptifibatide group.
### Other Adverse Reactions
In the PURSUIT and ESPRIT studies, the incidence of serious nonbleeding adverse reactions was similar in patients receiving placebo or Eptifibatide (19% and 19%, respectively, in PURSUIT; 6% and 7%, respectively, in ESPRIT). In PURSUIT, the only serious nonbleeding adverse reaction that occurred at a rate of at least 1% and was more common with Eptifibatide than placebo (7% versus 6%) was hypotension. Most of the serious nonbleeding adverse reactions consisted of cardiovascular reactions typical of a UA population. In the IMPACT II study, serious nonbleeding adverse reactions that occurred in greater than 1% of patients were uncommon and similar in incidence between placebo- and Eptifibatide-treated patients.
Discontinuation of study drug due to adverse reactions other than bleeding was uncommon in the PURSUIT, IMPACT II, and ESPRIT studies, with no single reaction occurring in >0.5% of the study population (except for "other" in the ESPRIT study).
## Postmarketing Experience
Because the reactions below are reported voluntarily from a population of uncertain size, it is generally not possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
The following adverse reactions have been reported in postmarketing experience, primarily with Eptifibatide in combination with heparin and aspirin: cerebral, GI, and pulmonary hemorrhage. Fatal bleeding reactions have been reported. Acute profound thrombocytopenia, as well as immune-mediated thrombocytopenia, has been reported.
# Drug Interactions
Coadministration of antiplatelet agents, thrombolytics, heparin, aspirin, and chronic NSAID use increases the risk of bleeding. Concomitant treatment with other inhibitors of platelet receptor GP IIb/IIIa should be avoided.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): B
Teratology studies have been performed by continuous intravenous infusion of eptifibatide in pregnant rats at total daily doses of up to 72 mg/kg/day (about 4 times the recommended maximum daily human dose on a body surface area basis) and in pregnant rabbits at total daily doses of up to 36 mg/kg/day (also about 4 times the recommended maximum daily human dose on a body surface area basis). These studies revealed no evidence of harm to the fetus due to eptifibatide. There are, however, no adequate and well-controlled studies in pregnant women with Eptifibatide. Because animal reproduction studies are not always predictive of human response, Eptifibatide should be used during pregnancy only if clearly needed.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Eptifibatide in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Eptifibatide during labor and delivery.
### Nursing Mothers
It is not known whether eptifibatide is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Eptifibatide is administered to a nursing mother.
### Pediatric Use
Safety and effectiveness of Eptifibatide in pediatric patients have not been studied.
### Geriatic Use
The PURSUIT and IMPACT II clinical studies enrolled patients up to the age of 94 years (45% were age 65 and over; 12% were age 75 and older). There was no apparent difference in efficacy between older and younger patients treated with Eptifibatide. The incidence of bleeding complications was higher in the elderly in both placebo and Eptifibatide groups, and the incremental risk of Eptifibatide-associated bleeding was greater in the older patients. No dose adjustment was made for elderly patients, but patients over 75 years of age had to weigh at least 50 kg to be enrolled in the PURSUIT study; no such limitation was stipulated in the ESPRIT study.
### Gender
There is no FDA guidance on the use of Eptifibatide with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Eptifibatide with respect to specific racial populations.
### Renal Impairment
Approximately 50% of eptifibatide is cleared by the kidney in patients with normal renal function. Total drug clearance is decreased by approximately 50% and steady-state plasma Eptifibatide concentrations are doubled in patients with an estimated CrCl <50 mL/min (using the Cockcroft-Gault equation). Therefore, the infusion dose should be reduced to 1 mcg/kg/min in such patients . The safety and efficacy of Eptifibatide in patients dependent on dialysis has not been established.
### Hepatic Impairment
There is no FDA guidance on the use of Eptifibatide in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Eptifibatide in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Eptifibatide in patients who are immunocompromised.
# Administration and Monitoring
### Administration
Intravenous
### Monitoring
FDA Package Insert for Eptifibatide contains no information regarding drug monitoring.
# IV Compatibility
There is limited information about the IV Compability.
# Overdosage
There has been only limited experience with overdosage of Eptifibatide. There were 8 patients in the IMPACT II study, 9 patients in the PURSUIT study, and no patients in the ESPRIT study who received bolus doses and/or infusion doses more than double those called for in the protocols. None of these patients experienced an intracranial bleed or other major bleeding.
Eptifibatide was not lethal to rats, rabbits, or monkeys when administered by continuous intravenous infusion for 90 minutes at a total dose of 45 mg/kg (about 2 to 5 times the recommended maximum daily human dose on a body surface area basis). Symptoms of acute toxicity were loss of righting reflex, dyspnea, ptosis, and decreased muscle tone in rabbits and petechial hemorrhages in the femoral and abdominal areas of monkeys.
From in vitro studies, eptifibatide is not extensively bound to plasma proteins and thus may be cleared from plasma by dialysis.
# Pharmacology
## Mechanism of Action
Eptifibatide reversibly inhibits platelet aggregation by preventing the binding of fibrinogen, von Willebrand factor, and other adhesive ligands to GP IIb/IIIa. When administered intravenously, eptifibatide inhibits ex vivo platelet aggregation in a dose- and concentration-dependent manner. Platelet aggregation inhibition is reversible following cessation of the eptifibatide infusion; this is thought to result from dissociation of eptifibatide from the platelet.
## Structure
Eptifibatide is a cyclic heptapeptide containing 6 amino acids and 1 mercaptopropionyl (des-amino cysteinyl) residue. An interchain disulfide bridge is formed between the cysteine amide and the mercaptopropionyl moieties. Chemically it is N6-(aminoiminomethyl)-N2-(3-mercapto-1-oxopropyl)-L-lysylglycyl-L-α-aspartyl-L-tryptophyl-L-prolyl-L-cysteinamide, cyclic (1→6)-disulfide. Eptifibatide binds to the platelet receptor glycoprotein (GP) IIb/IIIa of human platelets and inhibits platelet aggregation.
The eptifibatide peptide is produced by solution-phase peptide synthesis, and is purified by preparative reverse-phase liquid chromatography and lyophilized. The structural formula is:
Eptifibatide Injection is a clear, colorless, sterile, non-pyrogenic solution for intravenous (IV) use with an empirical formula of C35H49N11O9S2 and a molecular weight of 831.96. Each 10-mL vial contains 2 mg/mL of Eptifibatide and each 100-mL vial contains either 0.75 mg/mL of Eptifibatide or 2 mg/mL of Eptifibatide. Each vial of either size also contains 5.25 mg/mL citric acid and sodium hydroxide to adjust the pH to 5.35.
## Pharmacodynamics
Infusion of eptifibatide into baboons caused a dose-dependent inhibition of ex vivo platelet aggregation, with complete inhibition of aggregation achieved at infusion rates greater than 5 mcg/kg/min. In a baboon model that is refractory to aspirin and heparin, doses of eptifibatide that inhibit aggregation prevented acute thrombosis with only a modest prolongation (2- to 3-fold) of the bleeding time. Platelet aggregation in dogs was also inhibited by infusions of eptifibatide, with complete inhibition at 2 mcg/kg/min. This infusion dose completely inhibited canine coronary thrombosis induced by coronary artery injury (Folts model).
Human pharmacodynamic data were obtained in healthy subjects and in patients presenting with UA or NSTEMI and/or undergoing percutaneous coronary intervention. Studies in healthy subjects enrolled only males; patient studies enrolled approximately one-third women. In these studies, Eptifibatide inhibited ex vivo platelet aggregation induced by adenosine diphosphate (ADP) and other agonists in a dose- and concentration-dependent manner. The effect of Eptifibatide was observed immediately after administration of a 180-mcg/kg intravenous bolus. Table 4 shows the effects of dosing regimens of Eptifibatide used in the IMPACT II and PURSUIT studies on ex vivo platelet aggregation induced by 20 µM ADP in PPACK-anticoagulated platelet-rich plasma and on bleeding time. The effects of the dosing regimen used in ESPRIT on platelet aggregation have not been studied.
The Eptifibatide dosing regimen used in the ESPRIT study included two 180-mcg/kg bolus doses given 10 minutes apart combined with a continuous 2-mcg/kg/min infusion.
When administered alone, Eptifibatide has no measurable effect on PT or aPTT.
There were no important differences between men and women or between age groups in the pharmacodynamic properties of eptifibatide. Differences among ethnic groups have not been assessed.
## Pharmacokinetics
The pharmacokinetics of eptifibatide are linear and dose-proportional for bolus doses ranging from 90 to 250 mcg/kg and infusion rates from 0.5 to 3 mcg/kg/min. Plasma elimination half-life is approximately 2.5 hours. Administration of a single 180-mcg/kg bolus combined with an infusion produces an early peak level, followed by a small decline prior to attaining steady state (within 4-6 hours). This decline can be prevented by administering a second 180-mcg/kg bolus 10 minutes after the first. The extent of eptifibatide binding to human plasma protein is about 25%. Clearance in patients with coronary artery disease is about 55 mL/kg/h. In healthy subjects, renal clearance accounts for approximately 50% of total body clearance, with the majority of the drug excreted in the urine as eptifibatide, deaminated eptifibatide, and other, more polar metabolites. No major metabolites have been detected in human plasma.
## Nonclinical Toxicology
No long-term studies in animals have been performed to evaluate the carcinogenic potential of eptifibatide. Eptifibatide was not genotoxic in the Ames test, the mouse lymphoma cell (L 5178Y, TK+/-) forward mutation test, the human lymphocyte chromosome aberration test, or the mouse micronucleus test. Administered by continuous intravenous infusion at total daily doses up to 72 mg/kg/day (about 4 times the recommended maximum daily human dose on a body surface area basis), eptifibatide had no effect on fertility and reproductive performance of male and female rats.
# Clinical Studies
Eptifibatide was studied in 3 placebo-controlled, randomized studies. PURSUIT evaluated patients with acute coronary syndromes: UA or NSTEMI. Two other studies, ESPRIT and IMPACT II, evaluated patients about to undergo a PCI. Patients underwent primarily balloon angioplasty in IMPACT II and intracoronary stent placement, with or without angioplasty, in ESPRIT.
## Non-ST-Segment Elevation Acute Coronary Syndrome
Non-ST-segment elevation acute coronary syndrome is defined as prolonged (≥10 minutes) symptoms of cardiac ischemia within the previous 24 hours associated with either ST-segment changes (elevations between 0.6 mm and 1 mm or depression >0.5 mm), T-wave inversion (>1 mm), or positive CK-MB. This definition includes "unstable angina" and "NSTEMI" but excludes MI that is associated with Q waves or greater degrees of ST-segment elevation.
PURSUIT (Platelet Glycoprotein IIb/IIIa in unstable angina: Receptor Suppression Using Eptifibatide Therapy)
PURSUIT was a 726-center, 27-country, double-blind, randomized, placebo-controlled study in 10,948 patients presenting with UA or NSTEMI. Patients could be enrolled only if they had experienced cardiac ischemia at rest (≥10 minutes) within the previous 24 hours and had either ST-segment changes (elevations between 0.6 mm and 1 mm or depression >0.5 mm), T-wave inversion (>1 mm), or increased CK-MB. Important exclusion criteria included a history of bleeding diathesis, evidence of abnormal bleeding within the previous 30 days, uncontrolled hypertension, major surgery within the previous 6 weeks, stroke within the previous 30 days, any history of hemorrhagic stroke, serum creatinine >2 mg/dL, dependency on renal dialysis, or platelet count <100,000/mm3.
Patients were randomized to placebo, to Eptifibatide 180-mcg/kg bolus followed by a 2-mcg/kg/min infusion (180/2), or to Eptifibatide 180-mcg/kg bolus followed by a 1.3-mcg/kg/min infusion (180/1.3). The infusion was continued for 72 hours, until hospital discharge, or until the time of CABG, whichever occurred first, except that if PCI was performed, the Eptifibatide infusion was continued for 24 hours after the procedure, allowing for a duration of infusion up to 96 hours.
The lower-infusion-rate arm was stopped after the first interim analysis when the 2 active-treatment arms appeared to have the same incidence of bleeding.
Patient age ranged from 20 to 94 (mean 63) years, and 65% were male. The patients were 89% Caucasian, 6% Hispanic, and 5% Black, recruited in the United States and Canada (40%), Western Europe (39%), Eastern Europe (16%), and Latin America (5%).
This was a "real world" study; each patient was managed according to the usual standards of the investigational site; frequencies of angiography, PCI, and CABG therefore differed widely from site to site and from country to country. Of the patients in PURSUIT, 13% were managed with PCI during drug infusion, of whom 50% received intracoronary stents; 87% were managed medically (without PCI during drug infusion).
The majority of patients received aspirin (75-325 mg once daily). Heparin was administered intravenously or subcutaneously, at the physician's discretion, most commonly as an intravenous bolus of 5000 units followed by a continuous infusion of 1000 units/h. For patients weighing less than 70 kg, the recommended Heparin bolus dose was 60 units/kg followed by a continuous infusion of 12 units/kg/h. A target aPTT of 50 to 70 seconds was recommended. A total of 1250 patients underwent PCI within 72 hours after randomization, in which case they received intravenous Heparin to maintain an ACT of 300 to 350 seconds.
The primary endpoint of the study was the occurrence of death from any cause or new MI (evaluated by a blinded Clinical Endpoints Committee) within 30 days of randomization.
Compared to placebo, Eptifibatide administered as a 180-mcg/kg bolus followed by a 2-mcg/kg/min infusion significantly (p=0.042) reduced the incidence of endpoint events (see Table 6). The reduction in the incidence of endpoint events in patients receiving Eptifibatide was evident early during treatment, and this reduction was maintained through at least 30 days (see Figure 1). Table 5 also shows the incidence of the components of the primary endpoint, death (whether or not preceded by an MI) and new MI in surviving patients at 30 days.
Treatment with Eptifibatide prior to determination of patient management strategy reduced clinical events regardless of whether patients ultimately underwent diagnostic catheterization, revascularization (i.e., PCI or CABG surgery) or continued to receive medical management alone. Table 6 shows the incidence of death or MI within 72 hours.
All of the effect of Eptifibatide was established within 72 hours (during the period of drug infusion), regardless of management strategy. Moreover, for patients undergoing early PCI, a reduction in events was evident prior to the procedure.
An analysis of the results by sex suggests that women who would not routinely be expected to undergo PCI receive less benefit from Eptifibatide (95% confidence limits for relative risk of 0.94 - 1.28) than do men (0.72 - 0.9). This difference may be a true treatment difference, the effect of other differences in these subgroups, or a statistical anomaly. No differential outcomes were seen between male and female patients undergoing PCI (see results for ESPRIT).
Follow-up data were available through 165 days for 10,611 patients enrolled in the PURSUIT trial (96.9% of the initial enrollment). This follow-up included 4566 patients who received Eptifibatide at the 180/2 dose. As reported by the investigators, the occurrence of death from any cause or new MI for patients followed for at least 165 days was reduced from 13.6% with placebo to 12.1% with Eptifibatide 180/2.
## Percutaneous Coronary Intervention (PCI)
### IMPACT II (Eptifibatide to Minimize Platelet Aggregation and Prevent Coronary Thrombosis II)
IMPACT II was a multicenter, double-blind, randomized, placebo-controlled study conducted in the United States in 4010 patients undergoing PCI. Major exclusion criteria included a history of bleeding diathesis, major surgery within 6 weeks of treatment, gastrointestinal bleeding within 30 days, any stroke or structural CNS abnormality, uncontrolled hypertension, PT >1.2 times control, hematocrit <30%, platelet count <100,000/mm3, and pregnancy.
Patient age ranged from 24 to 89 (mean 60) years, and 75% were male. The patients were 92% Caucasian, 5% Black, and 3% Hispanic. Forty-one percent of the patients underwent PCI for ongoing ACS. Patients were randomly assigned to 1 of 3 treatment regimens, each incorporating a bolus dose initiated immediately prior to PCI followed by a continuous infusion lasting 20 to 24 hours:
1)135-mcg/kg bolus followed by a continuous infusion of 0.5 mcg/kg/min of Eptifibatide (135/0.5);
2)135-mcg/kg bolus followed by a continuous infusion of 0.75 mcg/kg/min of Eptifibatide (135/0.75); or
3)a matching placebo bolus followed by a matching placebo continuous infusion.
Each patient received aspirin and an intravenous heparin bolus of 100 units/kg, with additional bolus infusions of up to 2000 additional units of heparin every 15 minutes to maintain an ACT of 300 to 350 seconds.
The primary endpoint was the composite of death, MI, or urgent revascularization, analyzed at 30 days after randomization in all patients who received at least 1 dose of study drug.
As shown in Table 7, each Eptifibatide regimen reduced the rate of death, MI, or urgent intervention, although at 30 days, this finding was statistically significant only in the lower-dose Eptifibatide group. As in the PURSUIT study, the effects of Eptifibatide were seen early and persisted throughout the 30-day period.
### ESPRIT (Enhanced Suppression of the Platelet IIb/IIIa Receptor with Eptifibatide Therapy)
The ESPRIT study was a multicenter, double-blind, randomized, placebo-controlled study conducted in the United States and Canada that enrolled 2064 patients undergoing elective or urgent PCI with intended intracoronary stent placement. Exclusion criteria included MI within the previous 24 hours, ongoing chest pain, administration of any oral antiplatelet or oral anticoagulant other than aspirin within 30 days of PCI (although loading doses of thienopyridine on the day of PCI were encouraged), planned PCI of a saphenous vein graft or subsequent "staged" PCI, prior stent placement in the target lesion, PCI within the previous 90 days, a history of bleeding diathesis, major surgery within 6 weeks of treatment, gastrointestinal bleeding within 30 days, any stroke or structural CNS abnormality, uncontrolled hypertension, PT >1.2 times control, hematocrit <30%, platelet count <100,000/mm3, and pregnancy.
Patient age ranged from 24 to 93 (mean 62) years, and 73% of patients were male. The study enrolled 90% Caucasian, 5% African American, 2% Hispanic, and 1% Asian patients. Patients received a wide variety of stents. Patients were randomized either to placebo or Eptifibatide administered as an intravenous bolus of 180 mcg/kg followed immediately by a continuous infusion of 2 mcg/kg/min, and a second bolus of 180 mcg/kg administered 10 minutes later (180/2/180). Eptifibatide infusion was continued for 18 to 24 hours after PCI or until hospital discharge, whichever came first. Each patient received at least 1 dose of aspirin (162-325 mg) and 60 units/kg of heparin as a bolus (not to exceed 6000 units) if not already receiving a heparin infusion. Additional boluses of heparin (10-40 units/kg) could be administered in order to reach a target ACT between 200 and 300 seconds.
The primary endpoint of the ESPRIT study was the composite of death, MI, urgent target vessel revascularization (UTVR), and "bailout" to open-label Eptifibatide due to a thrombotic complication of PCI (TBO) (e.g., visible thrombus, "no reflow," or abrupt closure) at 48 hours. MI, UTVR, and TBO were evaluated by a blinded Clinical Events Committee.
As shown in Table 8, the incidence of the primary endpoint and selected secondary endpoints was significantly reduced in patients who received Eptifibatide. A treatment benefit in patients who received Eptifibatide was seen by 48 hours and at the end of the 30-day observation period.
The need for thrombotic "bailout" was significantly reduced with Eptifibatide at 48 hours (2.1% for placebo, 1% for Eptifibatide; p=0.029). Consistent with previous studies of GP IIb/IIIa inhibitors, most of the benefit achieved acutely with Eptifibatide was in the reduction of MI. Eptifibatide reduced the occurrence of MI at 48 hours from 9% for placebo to 5.4% (p=0.0015) and maintained that effect with significance at 30 days.
There was no treatment difference with respect to sex in ESPRIT. Eptifibatide reduced the incidence of the primary endpoint in both men (95% confidence limits for relative risk: 0.54, 1.07) and women (0.24, 0.72) at 48 hours.
Follow-up (12-month) mortality data were available for 2024 patients (1017 on Eptifibatide) enrolled in the ESPRIT trial (98.1% of the initial enrollment). Twelve-month clinical event data were available for 1964 patients (988 on Eptifibatide), representing 95.2% of the initial enrollment. As shown in Table 9, the treatment effect of Eptifibatide seen at 48 hours and 30 days appeared preserved at 6 months and 1 year. Most of the benefit was in reduction of MI.
## Percutaneous Coronary Intervention (PCI)
IMPACT II (Eptifibatide to Minimize Platelet Aggregation and Prevent Coronary Thrombosis II)
IMPACT II was a multicenter, double-blind, randomized, placebo-controlled study conducted in the United States in 4010 patients undergoing PCI. Major exclusion criteria included a history of bleeding diathesis, major surgery within 6 weeks of treatment, gastrointestinal bleeding within 30 days, any stroke or structural CNS abnormality, uncontrolled hypertension, PT >1.2 times control, hematocrit <30%, platelet count <100,000/mm3, and pregnancy.
Patient age ranged from 24 to 89 (mean 60) years, and 75% were male. The patients were 92% Caucasian, 5% Black, and 3% Hispanic. Forty-one percent of the patients underwent PCI for ongoing ACS. Patients were randomly assigned to 1 of 3 treatment regimens, each incorporating a bolus dose initiated immediately prior to PCI followed by a continuous infusion lasting 20 to 24 hours:
1)135-mcg/kg bolus followed by a continuous infusion of 0.5 mcg/kg/min of Eptifibatide (135/0.5);
2)135-mcg/kg bolus followed by a continuous infusion of 0.75 mcg/kg/min of Eptifibatide (135/0.75); or
3)a matching placebo bolus followed by a matching placebo continuous infusion.
Each patient received aspirin and an intravenous heparin bolus of 100 units/kg, with additional bolus infusions of up to 2000 additional units of heparin every 15 minutes to maintain an ACT of 300 to 350 seconds.
The primary endpoint was the composite of death, MI, or urgent revascularization, analyzed at 30 days after randomization in all patients who received at least 1 dose of study drug.
As shown in Table 7, each Eptifibatide regimen reduced the rate of death, MI, or urgent intervention, although at 30 days, this finding was statistically significant only in the lower-dose Eptifibatide group. As in the PURSUIT study, the effects of Eptifibatide were seen early and persisted throughout the 30-day period.
# How Supplied
Eptifibatide (eptifibatide) injection is supplied as a sterile solution in 10-mL vials containing 20 mg of Eptifibatide (NDC 0085-1177-01) and 100-mL vials containing either 75 mg of Eptifibatide (NDC 0085-1136-01) or 200 mg of Eptifibatide (NDC 0085-1177-02).
## Storage
Vials should be stored refrigerated at 2-8°C (36-46°F). Vials may be transferred to room temperature storage1 for a period not to exceed 2 months. Upon transfer, vial cartons must be marked by the dispensing pharmacist with a "DISCARD BY" date (2 months from the transfer date or the labeled expiration date, whichever comes first).
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
Instruct patients to inform the doctor or healthcare provider about any medical conditions, medications, and allergies.
# Precautions with Alcohol
Alcohol-Eptifibatide 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 Eptifibatide Brand Names in the drug label.
# Look-Alike Drug Names
There is limited information regarding Eptifibatide Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Eptifibatide | |
1680c44e3ff0dffe720771447d66e187158f1147 | wikidoc | Equifinality | Equifinality
Equifinality is the principle that in open systems a given end state can be reached by many potential means.
In closed systems, a direct cause-and-effect relationship exists between the initial condition and the final state of the system: When a computer's 'on' switch is pushed, the system powers up. Open systems (such as biological and social systems), however, operate quite differently. The idea of equifinality suggests that similar results may be achieved with different initial conditions and in many different ways.
In psychology, equifinality refers to how different early experiences in life (e.g., parental divorce, physical abuse, parental substance abuse) can lead to similar outcomes (e.g., childhood depression). In other words, there are many different early experiences that can lead to the same psychological disorder.
In archaeology, equifinality refers to how different historical processes may lead to a similar outcome or social formation. For example, the development of agriculture or the bow and arrow occurred independently in many different areas of the world, yet for different reasons and through different historical trajectories. Highlights that generalizations based on cross-cultural comparisons cannot uncritically be made.
In geomorphology, the term equifinality indicates that similar landforms might arise as a result of quite different sets of processes.
In environmental modeling studies, and especially in hydrological modeling, two models are equifinal if they lead to an equally acceptable or behavioral representation of the observed natural processes. It is a key concept to assess how uncertain hydrological predictions are. | Equifinality
Equifinality is the principle that in open systems a given end state can be reached by many potential means.
In closed systems, a direct cause-and-effect relationship exists between the initial condition and the final state of the system: When a computer's 'on' switch is pushed, the system powers up. Open systems (such as biological and social systems), however, operate quite differently. The idea of equifinality suggests that similar results may be achieved with different initial conditions and in many different ways. [1]
In psychology, equifinality refers to how different early experiences in life (e.g., parental divorce, physical abuse, parental substance abuse) can lead to similar outcomes (e.g., childhood depression). In other words, there are many different early experiences that can lead to the same psychological disorder.
In archaeology, equifinality refers to how different historical processes may lead to a similar outcome or social formation. For example, the development of agriculture or the bow and arrow occurred independently in many different areas of the world, yet for different reasons and through different historical trajectories. Highlights that generalizations based on cross-cultural comparisons cannot uncritically be made.
In geomorphology, the term equifinality indicates that similar landforms might arise as a result of quite different sets of processes.
In environmental modeling studies, and especially in hydrological modeling, two models are equifinal if they lead to an equally acceptable or behavioral representation of the observed natural processes. It is a key concept to assess how uncertain hydrological predictions are. | https://www.wikidoc.org/index.php/Equifinality | |
908752e3c6188bbd747da639b7167af870784f13 | wikidoc | Equinophobia | Equinophobia
# Background
Equinophobia is a psychological fear of horses, derived from the Phobos for fear and Equus for horse.
Sufferers of Equinophobia usually experience an anxiety of approaching horses.
Equinophobics usually begin such feelings at a young age, either:
- Falling off a horse while riding
- Being bitten by a horse at a young age
- Meeting a horse for the first time that turns out to be aggressiveTemplate:Facts
Even in cases where horses are relatively tame, Equinophobics will avoid any form of contact with horses or stables.
Another less common word for Equinophobia is Hippophobia. | Equinophobia
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Background
Equinophobia is a psychological fear of horses, derived from the Phobos for fear and Equus for horse.
Sufferers of Equinophobia usually experience an anxiety of approaching horses.
Equinophobics usually begin such feelings at a young age, either:
- Falling off a horse while riding
- Being bitten by a horse at a young age
- Meeting a horse for the first time that turns out to be aggressiveTemplate:Facts
Even in cases where horses are relatively tame, Equinophobics will avoid any form of contact with horses or stables.
Another less common word for Equinophobia is Hippophobia.
Template:WH
Template:WS | https://www.wikidoc.org/index.php/Equinophobia | |
39ad668f06f7f309b584f0a7439c7766707d93c4 | wikidoc | Eravacycline | Eravacycline
# 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
Eravacycline is a tetracycline class antibacterial that is FDA approved for the treatment of complicated intra‑abdominal infections in patients 18 years of age and older. Common adverse reactions include infusion site reactions, nausea, and vomiting.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
Indication
- Eravacycline is indicated for the treatment of complicated intra‑abdominal infections (cIAI) caused by susceptible microorganisms: Escherichia coli, Klebsiella pneumoniae, Citrobacter freundii, Enterobacter cloacae, Klebsiella oxytoca, Enterococcus faecalis, Enterococcus faecium, Staphylococcus aureus, Streptococcus anginosus group, Clostridium perfringens, Bacteroides species, and Parabacteroides distasonis in patients 18 years or older.
Limitations of Use
- Eravacycline is not indicated for the treatment of complicated urinary tract infections (cUTI).
Dosage
- The recommended dose regimen of eravacycline is 1 mg/kg every 12 hours. Administer intravenous infusions of eravacycline over approximately 60 minutes every 12 hours.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding eravacycline Off-Label Guideline-Supported Use and Dosage (Adult) in the drug label.
### Non–Guideline-Supported Use
There is limited information regarding eravacycline 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 eravacycline in pediatric patients have not been established.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding eravacycline Off-Label Guideline-Supported Use and Dosage (Pediatric) in the drug label.
### Non–Guideline-Supported Use
There is limited information regarding eravacycline Off-Label Non-Guideline-Supported Use and Dosage (Pediatric) in the drug label.
# Contraindications
- Eravacycline is contraindicated for use in patients with known hypersensitivity to eravacycline, tetracycline-class antibacterial drugs, or to any of the excipients.
# Warnings
- Life-threatening hypersensitivity (anaphylactic) reactions have been reported with eravacycline. Eravacycline is structurally similar to other tetracycline-class antibacterial drugs and should be avoided in patients with known hypersensitivity to tetracycline-class antibacterial drugs. Discontinue eravacycline if an allergic reaction occurs.
- The use of eravacycline during tooth development (last half of pregnancy, infancy and childhood to the age of 8 years) may cause permanent discoloration of the teeth (yellow-grey-brown). This adverse reaction is more common during long-term use of the tetracycline class drugs, but it has been observed following repeated short-term courses. Enamel hypoplasia has also been reported with tetracycline class drugs. Advise the patient of the potential risk to the fetus if eravacycline is used during the second or third trimester of pregnancy.
- The use of eravacycline during the second and third trimester of pregnancy, infancy and childhood up to the age of 8 years may cause reversible inhibition of bone growth. All tetracyclines form a stable calcium complex in any bone-forming tissue. A decrease in fibula growth rate has been observed in premature infants given oral tetracycline in doses of 25 mg/kg every 6 hours. This reaction was shown to be reversible when the drug was discontinued. Advise the patient of the potential risk to the fetus if eravacycline is used during the second or third trimester of pregnancy.
- Clostridium difficile associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of C. difficile.
- C. difficile produces toxins A and B which contribute to the development of CDAD. Hypertoxin producing strains of C. difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhea following antibacterial drug use. Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents.
- If CDAD is suspected or confirmed, ongoing antibacterial drug use not directed against C. difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibacterial drug treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated.
- Eravacycline is structurally similar to tetracycline-class antibacterial drugs and may have similar adverse reactions. Adverse reactions including photosensitivity, pseudotumor cerebri, and anti‑anabolic action which has led to increased BUN, azotemia, acidosis, hyperphosphatemia, pancreatitis, and abnormal liver function tests, have been reported for other tetracycline-class antibacterial drugs, and may occur with eravacycline. Discontinue eravacycline if any of these adverse reactions are suspected.
- Eravacycline use may result in overgrowth of non-susceptible organisms, including fungi. If such infections occur, discontinue eravacycline and institute appropriate therapy.
- Prescribing eravacycline in the absence of a proven or strongly suspected bacterial infection is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria.
# 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.
- Eravacycline was evaluated in 3 active-controlled clinical trials (Trial 1, Trial 2 and Trial 3) in adults with cIAI. These trials included two Phase 3 trials (Trial 1and Trial 2) and one Phase 2 trial (Trial 3, NCT01265784). The Phase 3 trials included 520 patients treated with eravacycline and 517 patients treated with comparator antibacterial drugs (ertapenem or meropenem). The median age of patients treated with eravacycline was 56 years, ranging between 18 and 93 years old; 30% were age 65 years and older. Patients treated with eravacycline were predominantly male (57%) and Caucasian (98%). The eravacycline- treated population included 31% obese patients (BMI ≥ 30 kg/m2) and 8% with baseline moderate to severe renal impairment (calculated creatinine clearance 15 to less than 60 mL/min). Among the trials, 66 (13%) of patients had baseline moderate hepatic impairment (Child Pugh B); patients with severe hepatic impairment (Child Pugh C) were excluded from the trials.
Adverse Reactions Leading to Discontinuation
- Treatment discontinuation due to an adverse reaction occurred in 2% (11/520) of patients receiving eravacycline and 2% (11/517) of patients receiving the comparator. The most commonly reported adverse reactions leading to discontinuation of eravacycline were related to gastrointestinal disorders.
Most Common Adverse Reactions
- Adverse reactions occurring at 3% or greater in patients receiving eravacycline were infusion site reactions, nausea, and vomiting.
- Table 1 lists adverse reactions occurring in ≥ 1% of patients receiving eravacycline and with incidences greater than the comparator in the Phase 3 cIAI clinical trials. A similar adverse reaction profile was observed in the Phase 2 cIAI clinical trial (Trial 3).
Other Adverse Reactions of Eravacycline
- The following selected adverse reactions were reported in eravacycline-treated patients at a rate of less than 1% in the Phase 3 trials:
Cardiac disorders: palpitations
Gastrointestinal System: acute pancreatitis, pancreatic necrosis
General Disorders and Administrative Site Conditions: chest pain
Immune system disorders: hypersensitivity
Laboratory Investigations: increased amylase, increased lipase, increased alanine aminotransferase, prolonged activated partial thromboplastin time, decreased renal clearance of creatinine, increased gamma-glutamyltransferase, decreased white blood cell count, neutropenia
Metabolism and nutrition disorders: hypocalcemia
Nervous System: dizziness, dysgeusia
Psychiatric disorders: anxiety, insomnia, depression
Respiratory, Thoracic, and Mediastinal System: pleural effusion, dyspnea
Skin and subcutaneous tissue disorders: rash, hyperhidrosis
- Cardiac disorders: palpitations
- Gastrointestinal System: acute pancreatitis, pancreatic necrosis
- General Disorders and Administrative Site Conditions: chest pain
- Immune system disorders: hypersensitivity
- Laboratory Investigations: increased amylase, increased lipase, increased alanine aminotransferase, prolonged activated partial thromboplastin time, decreased renal clearance of creatinine, increased gamma-glutamyltransferase, decreased white blood cell count, neutropenia
- Metabolism and nutrition disorders: hypocalcemia
- Nervous System: dizziness, dysgeusia
- Psychiatric disorders: anxiety, insomnia, depression
- Respiratory, Thoracic, and Mediastinal System: pleural effusion, dyspnea
- Skin and subcutaneous tissue disorders: rash, hyperhidrosis
## Postmarketing Experience
There is limited information regarding Eravacycline Postmarketing Experience in the drug label.
# Drug Interactions
- Concomitant use of strong CYP3A inducers decreases the exposure of eravacycline, which may reduce the efficacy of eravacycline. Increase eravacycline dose in patients with concomitant use of a strong CYP3A inducer.
- Because tetracyclines have been shown to depress plasma prothrombin activity, patients who are on anticoagulant therapy may require downward adjustment of their anticoagulant dosage.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
Risk Summary
- Eravacycline, like other tetracycline-class antibacterial drugs, may cause discoloration of deciduous teeth and reversible inhibition of bone growth when administered during the second and third trimester of pregnancy. The limited available data with eravacycline use in pregnant women are insufficient to inform drug‑associated risk of major birth defects and miscarriages. Animal studies indicate that eravacycline crosses the placenta and is found in fetal plasma; doses greater than approximately 3- and 2.8- times the clinical exposure, based on AUC in rats and rabbits, respectively, administered during the period of organogenesis, were associated with decreased ossification, decreased fetal body weight, and/or increased post-implantation loss.
- 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 to 4% and 15 to 20%, respectively.
Animal Data
- Embryo-fetal development studies in rats and rabbits reported no treatment-related effects at approximately 3 and 2.8 times the clinical exposure (based on AUC). Dosing was during the period of organogenesis, i.e. gestation days 7-17 in rats and gestation days 7-19 in rabbits. Higher doses, approximately 8.6 and 6.3 times the clinical exposure (based on AUC) in rats and rabbits, respectively, were associated with fetal effects including increased post-implantation loss, reduced fetal body weights, and delays in skeletal ossification in both species, and abortion in the rabbit.
- A peri-natal and post-natal rat toxicity study demonstrated that eravacycline crosses the placenta and is found in fetal plasma following intravenous administration to the dams. This study did not demonstrate anatomical malformations, but there were early decreases in pup weight that were later comparable to controls and a non-significant trend toward increased stillbirths or dead pups during lactation. F1 males from dams treated with 10 mg/kg/day eravacycline that continued to fertility testing had decreased testis and epididymis weights at approximately Post-Natal Day 111 that may have been at least partially related to lower body weights in this group.
- tetracyclines cross the placenta, are found in fetal tissues, and can have toxic effects on the developing fetus (often related to retardation of skeletal development). Evidence of embryotoxicity also has been noted in animals treated early in pregnancy.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Eravacycline in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Eravacycline during labor and delivery.
### Nursing Mothers
Risk Summary
- It is not known whether eravacycline is excreted in human breast milk. Eravacycline (and its metabolites) is excreted in the milk of lactating rats. tetracyclines are excreted in human milk; however, the extent of absorption of tetracyclines, including eravacycline, by the breastfed infant is not known. There are no data on the effects of eravacycline on the breastfed infant, or the effects on milk production. Because there are other antibacterial drug options available to treat cIAI in lactating women and because of the potential for serious adverse reactions, including tooth discoloration and inhibition of bone growth, advise patients that breastfeeding is not recommended during treatment with eravacycline and for 4 days (based on half-life) after the last dose.
Animal Data
- Eravacycline (and its metabolites) was excreted in the milk of lactating rats on post-natal day 15 following intravenous administration of 3, 5, and 10 mg/kg/day eravacycline.
### Pediatric Use
- The safety and effectiveness of eravacycline in pediatric patients have not been established.
- Due to the adverse effects of the tetracycline-class of drugs, including eravacycline on tooth development and bone growth, use of eravacycline in pediatric patients less than 8 years of age is not recommended.
### Geriatic Use
- Of the total number of patients with cIAI who received eravacycline in Phase 3 clinical trials (n = 520), 158 subjects were ≥ 65 years of age, while 59 subjects were ≥ 75 years of age. No overall differences in safety or efficacy were observed between these subjects and younger subjects.
- No clinically relevant differences in the pharmacokinetics of eravacycline were observed with respect to age in a population pharmacokinetic analysis of eravacycline.
### Gender
There is no FDA guidance on the use of Eravacycline with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Eravacycline with respect to specific racial populations.
### Renal Impairment
- No dosage adjustment is necessary for eravacycline in patients with renal impairment.
### Hepatic Impairment
- No dosage adjustment is warranted for eravacycline in patients with mild to moderate hepatic impairment (Child Pugh A and Child Pugh B). Adjust eravacycline dosage in patients with severe hepatic impairment (Child Pugh C).
### Females of Reproductive Potential and Males
Infertility
- Based on animal studies, eravacycline can lead to impaired spermiation and sperm maturation, resulting in abnormal sperm morphology and poor motility. The effect is reversible in rats. The long-term effects of eravacycline on male fertility have not been studied.
### Immunocompromised Patients
There is no FDA guidance one the use of Eravacycline in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- The recommended dose regimen of eravacycline is 1 mg/kg every 12 hours. Administer intravenous infusions of eravacycline over approximately 60 minutes every 12 hours.
- The recommended duration of treatment with eravacycline for cIAI is 4 to 14 days. The duration of therapy should be guided by the severity and location of infection and the patient’s clinical response.
- In patients with severe hepatic impairment (Child Pugh C), administer eravacycline 1 mg/kg every 12 hours on Day 1 followed by eravacycline 1 mg/kg every 24 hours starting on Day 2 for a total duration of 4 to 14 days. No dosage adjustment is warranted in patients with mild to moderate hepatic impairment (Child Pugh A and Child Pugh B).
- With concomitant use of a strong CYP3A inducer, administer eravacycline 1.5 mg/kg every 12 hours for a total duration of 4 to 14 days. No dosage adjustment is warranted in patients with concomitant use of a weak or moderate CYP3A inducer.
- Eravacycline is for intravenous infusion only. Each vial is for a single dose only.
Preparation
- Eravacycline is supplied as a sterile yellow to orange dry powder in a single-dose vial that must be reconstituted and further diluted prior to intravenous infusion as outlined below. Eravacycline does not contain preservatives. Aseptic technique must be used for reconstitution and dilution as follows:
- Calculate the dose of eravacycline based on the patient weight; 1 mg/kg actual body weight. Prepare the required dose for intravenous infusion, by reconstituting the appropriate number of vials needed. Reconstitute each vial of eravacycline with 5 mL of Sterile Water for Injection, USP. When the eravacycline vial content is reconstituted with 5 mL sterile Water for Injection, USP it will deliver 50 mg (10 mg/mL) of eravacycline (free base equivalents).
- Swirl the vial gently until the powder has dissolved entirely. Avoid shaking or rapid movement as it may cause foaming. The reconstituted eravacycline solution should be a clear, pale yellow to orange solution. Do not use the solution if you notice any particles or the solution is cloudy. Reconstituted solution is not for direct injection.
- The reconstituted eravacycline solution is further diluted for intravenous infusion to a target concentration of 0.3 mg/mL, in a 0.9% Sodium Chloride Injection, USP infusion bag before intravenous infusion. To dilute the reconstituted solution, withdraw the full or partial reconstituted vial content from each vial and add it into the infusion bag to generate an infusion solution with a target concentration of 0.3 mg/mL (within a range of 0.2 to 0.6 mg/mL). Do not shake the bag.
- The reconstituted and diluted solutions must be infused within 6 hours if stored at room temperature (not to exceed 25°C/77°F) or within 24 hours if stored refrigerated at 2 °C to 8 °C (36 °F to 46 °F). Reconstituted eravacycline solutions and diluted eravacycline infusion solutions should not be frozen.
- Visually inspect the diluted eravacycline solution for particulate matter and discoloration prior to administration (the eravacycline infusion solution for administration is clear and ranges from light yellow to orange). Discard unused portions of the reconstituted and diluted solution.
Administration of the Intravenous Infusion
- The diluted eravacycline solution is administered as an intravenous infusion over approximately 60 minutes.
- Eravacycline may be administered intravenously through a dedicated line or through a Y-site. If the same intravenous line is used for sequential infusion of several drugs, the line should be flushed before and after infusion of eravacycline with 0.9% Sodium Chloride Injection, USP.
- Eravacycline is compatible with 0.9% Sodium Chloride Injection, USP. The compatibility of eravacycline with other drugs and infusion solutions has not been established. Eravacycline should not be mixed with other drugs or added to solutions containing other drugs.
### Monitoring
There is limited information regarding Eravacycline Monitoring in the drug label.
# IV Compatibility
- Eravacycline is indicated for intravenous use.
# Overdosage
- No reports of overdose were reported in clinical trials. In the case of suspected overdose, eravacycline should be discontinued and the patient monitored for adverse reactions. Hemodialysis is not expected to remove significant quantities of eravacycline.
# Pharmacology
## Mechanism of Action
- Eravacycline is an antibacterial drug.
## Structure
- The molecular formula for eravacycline dihydrochloride is C27H31FN4O82HCl, and its molecular weight is 631.5.
- The following represents the chemical structure of eravacycline dihydrochloride:
## Pharmacodynamics
- The AUC divided by the MIC of eravacycline has been shown to be the best predictor of activity. Based on the flat exposure-response relationship observed in clinical studies, eravacycline exposure achieved with the recommended dosage regimen appears to be on the plateau of the exposure-response curve.
Cardiac Electrophysiology
- The effect of eravacycline on the QTc interval was evaluated in a Phase 1 randomized, placebo and positive controlled, double-blind, single-dose, crossover thorough QTc study in 60 healthy adult subjects. At the 1.5 mg/kg single dose (1.5 times the maximum approved recommended dose), eravacycline did not prolong the QTc interval to any clinically relevant extent.
## Pharmacokinetics
- Following single-dose intravenous administration, eravacycline AUC and Cmax increase approximately dose-proportionally over doses from 1 mg/kg to 3 mg/kg (3 times the approved dose).
- The mean exposure of eravacycline after single and multiple intravenous infusions (approximately 60 minutes) of 1 mg/kg administered to healthy adults every 12 hours is presented in Table 2.
- There is approximately 45% accumulation following intravenous dosing of 1 mg/kg every 12 hours.
Distribution
- Protein binding of eravacycline to human plasma proteins increases with increasing plasma concentrations, with 79% to 90% (bound) at plasma concentrations ranging from 100 to 10,000 ng/mL. The volume of distribution at steady-state is approximately 321 L.
Elimination
- The mean elimination half-life is 20 hours.
Metabolism
- Eravacycline is metabolized primarily by CYP3A4- and FMO-mediated oxidation.
Excretion
- Following a single intravenous dose of radiolabeled eravacycline 60 mg, approximately 34% of the dose is excreted in urine and 47% in feces as unchanged eravacycline (20% in urine and 17% in feces) and metabolites.
Specific Populations
- No clinically significant differences in the pharmacokinetics of eravacycline were observed based on age (18-86 years), sex, and race.
Patients with Renal Impairment
- The geometric least square mean Cmax for eravacycline was increased by 8.8% for subjects with end stage renal disease (ESRD) versus healthy subjects with 90% CI -19.4, 45.2. The geometric least square mean AUC0-inf for eravacycline was decreased by 4.0% for subjects with ESRD versus healthy subjects with 90% CI -14.0, 12.3.
Patients with Hepatic Impairment
- Eravacycline Cmax was 13.9%, 16.3%, and 19.7% higher in subjects with mild (Child-Pugh Class A), moderate (Child-Pugh Class B), and severe (Child‑Pugh Class C) hepatic impairment versus healthy subjects, respectively. Eravacycline AUC0-inf was 22.9%, 37.9%, and 110.3% higher in subjects with mild, moderate, and severe hepatic impairment versus healthy subjects, respectively.
Drug Interaction Studies
Clinical Studies
- Concomitant use of rifampin (strong CYP3A4/3A5 inducer) decreased eravacycline AUC by 35% and increased eravacycline clearance by 54%.
- Concomitant use of itraconazole (strong CYP3A inhibitor) increased eravacycline Cmax by 5% and AUC by 32%, and decreased eravacycline clearance by 32%.
In Vitro Studies
- Eravacycline is not an inhibitor of CYP1A2, 2B6, 2C8, 2C9, 2C19, 2D6, or 3A4/5. Eravacycline is not an inducer of CYP1A2, 2B6, or 3A4.
- Eravacycline is not a substrate for P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), bile salt export pump (BSEP), organic anion transporter peptide (OATP)1B1, OATP1B3, organic ion transporter (OAT)1, OAT3, OCT1, OCT2, multidrug and toxin extrusion (protein) (MATE)1, or MATE2-K transporters.
- Eravacycline is not an inhibitor of BCRP, BSEP, OATP1B1, OATP1B3, OAT1, OAT3, OCT1, OCT2, MATE1, or MATE2-K transporters.
## Microbiology
Mechanism of Action
- Eravacycline is a fluorocycline antibacterial within the tetracycline class of antibacterial drugs. Eravacycline disrupts bacterial protein synthesis by binding to the 30S ribosomal subunit thus preventing the incorporation of amino acid residues into elongating peptide chains.
- In general, eravacycline is bacteriostatic against gram-positive bacteria (e.g., Staphylococcus aureus and Enterococcus faecalis); however, in vitro bactericidal activity has been demonstrated against certain strains of Escherichia coli, Klebsiella pneumoniae.
Resistance
- Eravacycline resistance in some bacteria is associated with upregulated, non-specific intrinsic multidrug-resistant (MDR) efflux, and target-site modifications such as to the 16s rRNA or certain 30S ribosomal proteins (e.g., S10).
- The C7 and C9 substitutions in eravacycline are not present in any naturally occurring or semisynthetic tetracyclines and the substitution pattern imparts microbiological activities including in vitro activity against gram-positive and gram-negative strains expressing certain tetracycline-specific resistance mechanism(s) .
- Activity of eravacycline was demonstrated in vitro against Enterobacteriaceae in the presence of certain beta-lactamases, including extended spectrum β-lactamases, and AmpC. However, some beta-lactamase-producing isolates may confer resistance to eravacycline via other resistance mechanisms.
- The overall frequency of spontaneous mutants in the gram-positive organisms tested was in the range of 10-9 to 10-10 at 4 times the eravacycline Minimum Inhibitory Concentration (MIC). Multistep selection of gram-negative strains resulted in a 16- to 32-times increase in eravacycline MIC for one isolate of Escherichia coli and Klebsiella pneumoniae, respectively. The frequency of spontaneous mutations in K. pneumoniae was 10-7 to 10‑8 at 4 times the eravacycline MIC.
Interaction with Other Antimicrobials
- In vitro studies have not demonstrated antagonism between eravacycline and other commonly used antibacterial drugs for the indicated pathogens.
Antimicrobial Activity
- Eravacycline has been shown to be active against most isolates of the following microorganisms, both in vitro and in clinical infections:
Aerobic bacteria
Gram-positive bacteria
Enterococcus faecalis
Enterococcus faecium
Staphylococcus aureus
Streptococcus anginosus group
Gram-negative bacteria
Citrobacter freundii
Enterobacter cloacae
Escherichia coli
Klebsiella oxytoca
Klebsiella pneumoniae
Anaerobic bacteria
Gram-positive bacteria
Clostridium perfringens
Gram-negative bacteria
Bacteroides caccae
Bacteroides fragilis
Bacteroides ovatus
Bacteroides thetaiotaomicron
Bacteroides uniformis
Bacteroides vulgatus
Parabacteroides distasonis
- Aerobic bacteria
Gram-positive bacteria
Enterococcus faecalis
Enterococcus faecium
Staphylococcus aureus
Streptococcus anginosus group
Gram-negative bacteria
Citrobacter freundii
Enterobacter cloacae
Escherichia coli
Klebsiella oxytoca
Klebsiella pneumoniae
- Gram-positive bacteria
Enterococcus faecalis
Enterococcus faecium
Staphylococcus aureus
Streptococcus anginosus group
- Enterococcus faecalis
- Enterococcus faecium
- Staphylococcus aureus
- Streptococcus anginosus group
- Gram-negative bacteria
Citrobacter freundii
Enterobacter cloacae
Escherichia coli
Klebsiella oxytoca
Klebsiella pneumoniae
- Citrobacter freundii
- Enterobacter cloacae
- Escherichia coli
- Klebsiella oxytoca
- Klebsiella pneumoniae
- Anaerobic bacteria
Gram-positive bacteria
Clostridium perfringens
Gram-negative bacteria
Bacteroides caccae
Bacteroides fragilis
Bacteroides ovatus
Bacteroides thetaiotaomicron
Bacteroides uniformis
Bacteroides vulgatus
Parabacteroides distasonis
- Gram-positive bacteria
Clostridium perfringens
- Clostridium perfringens
- Gram-negative bacteria
Bacteroides caccae
Bacteroides fragilis
Bacteroides ovatus
Bacteroides thetaiotaomicron
Bacteroides uniformis
Bacteroides vulgatus
Parabacteroides distasonis
- Bacteroides caccae
- Bacteroides fragilis
- Bacteroides ovatus
- Bacteroides thetaiotaomicron
- Bacteroides uniformis
- Bacteroides vulgatus
- Parabacteroides distasonis
- The following in vitro data are available, but their clinical significance is unknown. At least 90 percent of the following bacteria exhibit an in vitro minimum inhibitory concentration (MIC) less than or equal to the susceptible breakpoint for eravacycline against isolates of similar genus or organism group. However, the efficacy of eravacycline in treating clinical infections caused by these bacteria has not been established in adequate and well-controlled clinical trials.
Aerobic bacteria
Gram-positive bacteria
Streptococcus salivarius group
Gram-negative bacteria
Citrobacter koseri
Enterobacter aerogenes
- Aerobic bacteria
Gram-positive bacteria
Streptococcus salivarius group
Gram-negative bacteria
Citrobacter koseri
Enterobacter aerogenes
- Gram-positive bacteria
Streptococcus salivarius group
- Streptococcus salivarius group
- Gram-negative bacteria
Citrobacter koseri
Enterobacter aerogenes
- Citrobacter koseri
- Enterobacter aerogenes
Susceptibility Test Methods
- For specific information regarding susceptibility test interpretive criteria, and associated test methods and quality control standards recognized by FDA for this drug, please see .
## Nonclinical Toxicology
- Carcinogenicity studies with eravacycline have not been conducted. However, there has been evidence of oncogenic activity in rats in studies with the related antibacterial drugs, oxytetracycline (adrenal and pituitary tumors) and minocycline (thyroid tumors).
- Eravacycline was not genotoxic in a standard battery of assays, including an in vitro mammalian cell mutation assay, an in vitro clastogenicity assay, and an in vivo rat bone marrow micronucleus assay.
- There are no human data on the effect of eravacycline on fertility. Eravacycline did not affect mating or fertility in male rats following intravenous administration at a dose approximating a clinical dose of 0.65 mg/kg/day (approximately 1.5 times the clinical exposure, based on AUC determined in a separate study), however, eravacycline administration at higher doses was associated with adverse reactions on male fertility and spermatogenesis that were at least partially reversible after a 70-day recovery period (1 spermatogenic cycle). Decreased sperm counts, abnormal sperm morphology, and reduced sperm motility were observed with testicular effects (impaired spermiation and sperm maturation). There were no adverse reactions on mating or fertility in female rats administered intravenous eravacycline at a dose approximating a clinical dose of 3.2 mg/kg/day (approximately 18 times the clinical exposure based on AUC determined in a separate study in unmated females).
- Decreased sperm counts and eravacycline‑related lesions noted in the testes and epididymides were seen in general toxicology studies in rats and were reversible. These findings were anticipated effects for a tetracycline-class compound.
- In repeated dose toxicity studies in rats, dogs and monkeys, lymphoid depletion/atrophy of lymph nodes, spleen and thymus, decreased erythrocytes, reticulocytes, leukocytes, and platelets (dog and monkey), in association with bone marrow hypocellularity, and adverse gastrointestinal effects (dog and monkey) were observed with eravacycline. These findings were reversible or partially reversible during recovery periods of 3 to 7 weeks.
- Bone discoloration, which was not fully reversible over recovery periods of up to 7 weeks, was observed in rats and monkeys after 13 weeks of dosing and in the juvenile rat study after dosing over Post-Natal Days 21-70.
- Intravenous administration of eravacycline has been associated with a histamine response in rat and dog studies.
# Clinical Studies
- A total of 1,041 adults hospitalized with cIAI were enrolled in two Phase 3, randomized, double-blind, active-controlled, multinational, multicenter trials (Trials 1, NCT01844856, and Trial 2, NCT02784704). These studies compared eravacycline (1 mg/kg intravenous every 12 hours) with either ertapenem (1 g every 24 hours) or meropenem (1 g every 8 hours) as the active comparator for 4 to 14 days of therapy. Complicated intra-abdominal infections included appendicitis, cholecystitis, diverticulitis, gastric/duodenal perforation, intra-abdominal abscess, perforation of intestine, and peritonitis.
- The microbiologic intent-to-treat (micro-ITT) population, which included all patients who had at least one baseline intra-abdominal pathogen, consisted of 846 patients in the two trials. Populations in Trial 1 and Trial 2 were similar. The median age was 56 years and 56% were male. The majority of patients (95%) were from Europe; 5% were from the United States. The most common primary cIAI diagnosis was intra-abdominal abscess(es), occurring in 60% of patients. Bacteremia at baseline was present in 8% of patients.
- Clinical cure was defined as complete resolution or significant improvement of signs or symptoms of the index infection at the Test of Cure (TOC) visit which occurred 25 to 31 days after randomization. Selected clinical responses were reviewed by a Surgical Adjudication Committee. Table 3 presents the clinical cure rates in the micro-ITT population. Clinical cure rates at the TOC visit for selected pathogens are presented in Table 4.
- Two randomized, double-blind, active-controlled, clinical trials (Trial 4, NCT01978938, and Trial 5, NCT03032510) evaluated the efficacy and safety of once-daily intravenous eravacycline for the treatment of patients with complicated urinary tract infections (cUTI). Trial 4 included an optional switch from IV to oral therapy with eravacycline. The trials did not demonstrate the efficacy of eravacycline for the combined endpoints of clinical cure and microbiological success in the microbiological intent-to-treat (micro-ITT) population at the test-of-cure visit.
# How Supplied
- Eravacycline for injection, 50 mg/vial, is a yellow to orange, sterile, preservative-free powder for reconstitution in single-dose 10-mL clear glass vials with a rubber stopper and an aluminum overseal. Each vial contains 50 mg of eravacycline (equivalent to 63.5 mg of eravacycline dihydrochloride). Eravacycline is supplied in two packaging configurations:
Single-vial carton containing one 50 mg single-dose vial
Twelve-vial carton containing twelve 50 mg single-dose vial cartons
- Single-vial carton containing one 50 mg single-dose vial
- Twelve-vial carton containing twelve 50 mg single-dose vial cartons
## Storage
- Prior to reconstitution, eravacycline should be stored at 2°C to 8°C (36°F to 46°F). Keep vial in carton until use.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
Serious Allergic Reactions
- Advise patients that allergic reactions, including serious allergic reactions, could occur and that serious reactions require immediate treatment. Ask patient about any previous hypersensitivity reactions to antibacterial drugs including tetracycline or other allergens.
Tooth Discoloration and Inhibition of Bone Growth
- Advise patients that eravacycline, like other tetracycline-class drugs, may cause permanent tooth discoloration of deciduous teeth and reversible inhibition of bone growth when administered during the second and third trimesters of pregnancy. Tell your healthcare provider right away if you become pregnant during treatment.
Lactation
- Advise women not to breastfeed during treatment with eravacycline and for 4 days after the last dose.
Diarrhea
- Diarrhea is a common problem caused by antibacterial drugs, including eravacycline, which usually ends when the antibacterial drug is discontinued. Sometimes after starting treatment with antibacterial drug, patients can develop watery and bloody stools (with or without stomach cramps and fever) which may be a sign of a more serious intestinal infection, even as late as 2 or more months after having taken the last dose of the antibacterial drug. If this occurs, instruct patients to contact their healthcare provider as soon as possible.
Tetracycline Class Adverse Reactions
- Inform patients that eravacycline is similar to tetracycline-class antibacterial drugs and may have similar adverse reactions.
Overgrowth of Non-susceptible Microorganisms
- Inform patients that antibacterial drugs including eravacycline may promote the overgrowth of non-susceptible microorganisms, including fungi.
Antibacterial Resistance
- Inform patients that antibacterial drugs including eravacycline should only be used to treat bacterial infections. They do not treat viral infections (for example, the common cold). When eravacycline is prescribed to treat a bacterial infection, patients should be told that although it is common to feel better early in the course of therapy, the medication should be taken exactly as directed. Skipping doses or not completing the full course of therapy may (1) decrease the effectiveness of the immediate treatment and (2) increase the likelihood that bacteria will develop resistance and will not be treatable by eravacycline or other antibacterial drugs in the future.
# Precautions with Alcohol
Alcohol-Eravacycline interaction has not been established. Talk to your doctor regarding the effects of taking alcohol with this medication.
# Brand Names
Xerava
# Look-Alike Drug Names
There is limited information regarding Eravacycline Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | Eravacycline
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Zach Leibowitz [2]
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# Overview
Eravacycline is a tetracycline class antibacterial that is FDA approved for the treatment of complicated intra‑abdominal infections in patients 18 years of age and older. Common adverse reactions include infusion site reactions, nausea, and vomiting.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
Indication
- Eravacycline is indicated for the treatment of complicated intra‑abdominal infections (cIAI) caused by susceptible microorganisms: Escherichia coli, Klebsiella pneumoniae, Citrobacter freundii, Enterobacter cloacae, Klebsiella oxytoca, Enterococcus faecalis, Enterococcus faecium, Staphylococcus aureus, Streptococcus anginosus group, Clostridium perfringens, Bacteroides species, and Parabacteroides distasonis in patients 18 years or older.
Limitations of Use
- Eravacycline is not indicated for the treatment of complicated urinary tract infections (cUTI).
Dosage
- The recommended dose regimen of eravacycline is 1 mg/kg every 12 hours. Administer intravenous infusions of eravacycline over approximately 60 minutes every 12 hours.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding eravacycline Off-Label Guideline-Supported Use and Dosage (Adult) in the drug label.
### Non–Guideline-Supported Use
There is limited information regarding eravacycline 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 eravacycline in pediatric patients have not been established.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding eravacycline Off-Label Guideline-Supported Use and Dosage (Pediatric) in the drug label.
### Non–Guideline-Supported Use
There is limited information regarding eravacycline Off-Label Non-Guideline-Supported Use and Dosage (Pediatric) in the drug label.
# Contraindications
- Eravacycline is contraindicated for use in patients with known hypersensitivity to eravacycline, tetracycline-class antibacterial drugs, or to any of the excipients.
# Warnings
- Life-threatening hypersensitivity (anaphylactic) reactions have been reported with eravacycline. Eravacycline is structurally similar to other tetracycline-class antibacterial drugs and should be avoided in patients with known hypersensitivity to tetracycline-class antibacterial drugs. Discontinue eravacycline if an allergic reaction occurs.
- The use of eravacycline during tooth development (last half of pregnancy, infancy and childhood to the age of 8 years) may cause permanent discoloration of the teeth (yellow-grey-brown). This adverse reaction is more common during long-term use of the tetracycline class drugs, but it has been observed following repeated short-term courses. Enamel hypoplasia has also been reported with tetracycline class drugs. Advise the patient of the potential risk to the fetus if eravacycline is used during the second or third trimester of pregnancy.
- The use of eravacycline during the second and third trimester of pregnancy, infancy and childhood up to the age of 8 years may cause reversible inhibition of bone growth. All tetracyclines form a stable calcium complex in any bone-forming tissue. A decrease in fibula growth rate has been observed in premature infants given oral tetracycline in doses of 25 mg/kg every 6 hours. This reaction was shown to be reversible when the drug was discontinued. Advise the patient of the potential risk to the fetus if eravacycline is used during the second or third trimester of pregnancy.
- Clostridium difficile associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of C. difficile.
- C. difficile produces toxins A and B which contribute to the development of CDAD. Hypertoxin producing strains of C. difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhea following antibacterial drug use. Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents.
- If CDAD is suspected or confirmed, ongoing antibacterial drug use not directed against C. difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibacterial drug treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated.
- Eravacycline is structurally similar to tetracycline-class antibacterial drugs and may have similar adverse reactions. Adverse reactions including photosensitivity, pseudotumor cerebri, and anti‑anabolic action which has led to increased BUN, azotemia, acidosis, hyperphosphatemia, pancreatitis, and abnormal liver function tests, have been reported for other tetracycline-class antibacterial drugs, and may occur with eravacycline. Discontinue eravacycline if any of these adverse reactions are suspected.
- Eravacycline use may result in overgrowth of non-susceptible organisms, including fungi. If such infections occur, discontinue eravacycline and institute appropriate therapy.
- Prescribing eravacycline in the absence of a proven or strongly suspected bacterial infection is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria.
# 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.
- Eravacycline was evaluated in 3 active-controlled clinical trials (Trial 1, Trial 2 and Trial 3) in adults with cIAI. These trials included two Phase 3 trials (Trial 1and Trial 2) and one Phase 2 trial (Trial 3, NCT01265784). The Phase 3 trials included 520 patients treated with eravacycline and 517 patients treated with comparator antibacterial drugs (ertapenem or meropenem). The median age of patients treated with eravacycline was 56 years, ranging between 18 and 93 years old; 30% were age 65 years and older. Patients treated with eravacycline were predominantly male (57%) and Caucasian (98%). The eravacycline- treated population included 31% obese patients (BMI ≥ 30 kg/m2) and 8% with baseline moderate to severe renal impairment (calculated creatinine clearance 15 to less than 60 mL/min). Among the trials, 66 (13%) of patients had baseline moderate hepatic impairment (Child Pugh B); patients with severe hepatic impairment (Child Pugh C) were excluded from the trials.
Adverse Reactions Leading to Discontinuation
- Treatment discontinuation due to an adverse reaction occurred in 2% (11/520) of patients receiving eravacycline and 2% (11/517) of patients receiving the comparator. The most commonly reported adverse reactions leading to discontinuation of eravacycline were related to gastrointestinal disorders.
Most Common Adverse Reactions
- Adverse reactions occurring at 3% or greater in patients receiving eravacycline were infusion site reactions, nausea, and vomiting.
- Table 1 lists adverse reactions occurring in ≥ 1% of patients receiving eravacycline and with incidences greater than the comparator in the Phase 3 cIAI clinical trials. A similar adverse reaction profile was observed in the Phase 2 cIAI clinical trial (Trial 3).
Other Adverse Reactions of Eravacycline
- The following selected adverse reactions were reported in eravacycline-treated patients at a rate of less than 1% in the Phase 3 trials:
Cardiac disorders: palpitations
Gastrointestinal System: acute pancreatitis, pancreatic necrosis
General Disorders and Administrative Site Conditions: chest pain
Immune system disorders: hypersensitivity
Laboratory Investigations: increased amylase, increased lipase, increased alanine aminotransferase, prolonged activated partial thromboplastin time, decreased renal clearance of creatinine, increased gamma-glutamyltransferase, decreased white blood cell count, neutropenia
Metabolism and nutrition disorders: hypocalcemia
Nervous System: dizziness, dysgeusia
Psychiatric disorders: anxiety, insomnia, depression
Respiratory, Thoracic, and Mediastinal System: pleural effusion, dyspnea
Skin and subcutaneous tissue disorders: rash, hyperhidrosis
- Cardiac disorders: palpitations
- Gastrointestinal System: acute pancreatitis, pancreatic necrosis
- General Disorders and Administrative Site Conditions: chest pain
- Immune system disorders: hypersensitivity
- Laboratory Investigations: increased amylase, increased lipase, increased alanine aminotransferase, prolonged activated partial thromboplastin time, decreased renal clearance of creatinine, increased gamma-glutamyltransferase, decreased white blood cell count, neutropenia
- Metabolism and nutrition disorders: hypocalcemia
- Nervous System: dizziness, dysgeusia
- Psychiatric disorders: anxiety, insomnia, depression
- Respiratory, Thoracic, and Mediastinal System: pleural effusion, dyspnea
- Skin and subcutaneous tissue disorders: rash, hyperhidrosis
## Postmarketing Experience
There is limited information regarding Eravacycline Postmarketing Experience in the drug label.
# Drug Interactions
- Concomitant use of strong CYP3A inducers decreases the exposure of eravacycline, which may reduce the efficacy of eravacycline. Increase eravacycline dose in patients with concomitant use of a strong CYP3A inducer.
- Because tetracyclines have been shown to depress plasma prothrombin activity, patients who are on anticoagulant therapy may require downward adjustment of their anticoagulant dosage.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
Risk Summary
- Eravacycline, like other tetracycline-class antibacterial drugs, may cause discoloration of deciduous teeth and reversible inhibition of bone growth when administered during the second and third trimester of pregnancy. The limited available data with eravacycline use in pregnant women are insufficient to inform drug‑associated risk of major birth defects and miscarriages. Animal studies indicate that eravacycline crosses the placenta and is found in fetal plasma; doses greater than approximately 3- and 2.8- times the clinical exposure, based on AUC in rats and rabbits, respectively, administered during the period of organogenesis, were associated with decreased ossification, decreased fetal body weight, and/or increased post-implantation loss.
- 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 to 4% and 15 to 20%, respectively.
Animal Data
- Embryo-fetal development studies in rats and rabbits reported no treatment-related effects at approximately 3 and 2.8 times the clinical exposure (based on AUC). Dosing was during the period of organogenesis, i.e. gestation days 7-17 in rats and gestation days 7-19 in rabbits. Higher doses, approximately 8.6 and 6.3 times the clinical exposure (based on AUC) in rats and rabbits, respectively, were associated with fetal effects including increased post-implantation loss, reduced fetal body weights, and delays in skeletal ossification in both species, and abortion in the rabbit.
- A peri-natal and post-natal rat toxicity study demonstrated that eravacycline crosses the placenta and is found in fetal plasma following intravenous administration to the dams. This study did not demonstrate anatomical malformations, but there were early decreases in pup weight that were later comparable to controls and a non-significant trend toward increased stillbirths or dead pups during lactation. F1 males from dams treated with 10 mg/kg/day eravacycline that continued to fertility testing had decreased testis and epididymis weights at approximately Post-Natal Day 111 that may have been at least partially related to lower body weights in this group.
- tetracyclines cross the placenta, are found in fetal tissues, and can have toxic effects on the developing fetus (often related to retardation of skeletal development). Evidence of embryotoxicity also has been noted in animals treated early in pregnancy.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Eravacycline in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Eravacycline during labor and delivery.
### Nursing Mothers
Risk Summary
- It is not known whether eravacycline is excreted in human breast milk. Eravacycline (and its metabolites) is excreted in the milk of lactating rats. tetracyclines are excreted in human milk; however, the extent of absorption of tetracyclines, including eravacycline, by the breastfed infant is not known. There are no data on the effects of eravacycline on the breastfed infant, or the effects on milk production. Because there are other antibacterial drug options available to treat cIAI in lactating women and because of the potential for serious adverse reactions, including tooth discoloration and inhibition of bone growth, advise patients that breastfeeding is not recommended during treatment with eravacycline and for 4 days (based on half-life) after the last dose.
Animal Data
- Eravacycline (and its metabolites) was excreted in the milk of lactating rats on post-natal day 15 following intravenous administration of 3, 5, and 10 mg/kg/day eravacycline.
### Pediatric Use
- The safety and effectiveness of eravacycline in pediatric patients have not been established.
- Due to the adverse effects of the tetracycline-class of drugs, including eravacycline on tooth development and bone growth, use of eravacycline in pediatric patients less than 8 years of age is not recommended.
### Geriatic Use
- Of the total number of patients with cIAI who received eravacycline in Phase 3 clinical trials (n = 520), 158 subjects were ≥ 65 years of age, while 59 subjects were ≥ 75 years of age. No overall differences in safety or efficacy were observed between these subjects and younger subjects.
- No clinically relevant differences in the pharmacokinetics of eravacycline were observed with respect to age in a population pharmacokinetic analysis of eravacycline.
### Gender
There is no FDA guidance on the use of Eravacycline with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Eravacycline with respect to specific racial populations.
### Renal Impairment
- No dosage adjustment is necessary for eravacycline in patients with renal impairment.
### Hepatic Impairment
- No dosage adjustment is warranted for eravacycline in patients with mild to moderate hepatic impairment (Child Pugh A and Child Pugh B). Adjust eravacycline dosage in patients with severe hepatic impairment (Child Pugh C).
### Females of Reproductive Potential and Males
Infertility
- Based on animal studies, eravacycline can lead to impaired spermiation and sperm maturation, resulting in abnormal sperm morphology and poor motility. The effect is reversible in rats. The long-term effects of eravacycline on male fertility have not been studied.
### Immunocompromised Patients
There is no FDA guidance one the use of Eravacycline in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- The recommended dose regimen of eravacycline is 1 mg/kg every 12 hours. Administer intravenous infusions of eravacycline over approximately 60 minutes every 12 hours.
- The recommended duration of treatment with eravacycline for cIAI is 4 to 14 days. The duration of therapy should be guided by the severity and location of infection and the patient’s clinical response.
- In patients with severe hepatic impairment (Child Pugh C), administer eravacycline 1 mg/kg every 12 hours on Day 1 followed by eravacycline 1 mg/kg every 24 hours starting on Day 2 for a total duration of 4 to 14 days. No dosage adjustment is warranted in patients with mild to moderate hepatic impairment (Child Pugh A and Child Pugh B).
- With concomitant use of a strong CYP3A inducer, administer eravacycline 1.5 mg/kg every 12 hours for a total duration of 4 to 14 days. No dosage adjustment is warranted in patients with concomitant use of a weak or moderate CYP3A inducer.
- Eravacycline is for intravenous infusion only. Each vial is for a single dose only.
Preparation
- Eravacycline is supplied as a sterile yellow to orange dry powder in a single-dose vial that must be reconstituted and further diluted prior to intravenous infusion as outlined below. Eravacycline does not contain preservatives. Aseptic technique must be used for reconstitution and dilution as follows:
- Calculate the dose of eravacycline based on the patient weight; 1 mg/kg actual body weight. Prepare the required dose for intravenous infusion, by reconstituting the appropriate number of vials needed. Reconstitute each vial of eravacycline with 5 mL of Sterile Water for Injection, USP. When the eravacycline vial content is reconstituted with 5 mL sterile Water for Injection, USP it will deliver 50 mg (10 mg/mL) of eravacycline (free base equivalents).
- Swirl the vial gently until the powder has dissolved entirely. Avoid shaking or rapid movement as it may cause foaming. The reconstituted eravacycline solution should be a clear, pale yellow to orange solution. Do not use the solution if you notice any particles or the solution is cloudy. Reconstituted solution is not for direct injection.
- The reconstituted eravacycline solution is further diluted for intravenous infusion to a target concentration of 0.3 mg/mL, in a 0.9% Sodium Chloride Injection, USP infusion bag before intravenous infusion. To dilute the reconstituted solution, withdraw the full or partial reconstituted vial content from each vial and add it into the infusion bag to generate an infusion solution with a target concentration of 0.3 mg/mL (within a range of 0.2 to 0.6 mg/mL). Do not shake the bag.
- The reconstituted and diluted solutions must be infused within 6 hours if stored at room temperature (not to exceed 25°C/77°F) or within 24 hours if stored refrigerated at 2 °C to 8 °C (36 °F to 46 °F). Reconstituted eravacycline solutions and diluted eravacycline infusion solutions should not be frozen.
- Visually inspect the diluted eravacycline solution for particulate matter and discoloration prior to administration (the eravacycline infusion solution for administration is clear and ranges from light yellow to orange). Discard unused portions of the reconstituted and diluted solution.
Administration of the Intravenous Infusion
- The diluted eravacycline solution is administered as an intravenous infusion over approximately 60 minutes.
- Eravacycline may be administered intravenously through a dedicated line or through a Y-site. If the same intravenous line is used for sequential infusion of several drugs, the line should be flushed before and after infusion of eravacycline with 0.9% Sodium Chloride Injection, USP.
- Eravacycline is compatible with 0.9% Sodium Chloride Injection, USP. The compatibility of eravacycline with other drugs and infusion solutions has not been established. Eravacycline should not be mixed with other drugs or added to solutions containing other drugs.
### Monitoring
There is limited information regarding Eravacycline Monitoring in the drug label.
# IV Compatibility
- Eravacycline is indicated for intravenous use.
# Overdosage
- No reports of overdose were reported in clinical trials. In the case of suspected overdose, eravacycline should be discontinued and the patient monitored for adverse reactions. Hemodialysis is not expected to remove significant quantities of eravacycline.
# Pharmacology
## Mechanism of Action
- Eravacycline is an antibacterial drug.
## Structure
- The molecular formula for eravacycline dihydrochloride is C27H31FN4O8•2HCl, and its molecular weight is 631.5.
- The following represents the chemical structure of eravacycline dihydrochloride:
## Pharmacodynamics
- The AUC divided by the MIC of eravacycline has been shown to be the best predictor of activity. Based on the flat exposure-response relationship observed in clinical studies, eravacycline exposure achieved with the recommended dosage regimen appears to be on the plateau of the exposure-response curve.
Cardiac Electrophysiology
- The effect of eravacycline on the QTc interval was evaluated in a Phase 1 randomized, placebo and positive controlled, double-blind, single-dose, crossover thorough QTc study in 60 healthy adult subjects. At the 1.5 mg/kg single dose (1.5 times the maximum approved recommended dose), eravacycline did not prolong the QTc interval to any clinically relevant extent.
## Pharmacokinetics
- Following single-dose intravenous administration, eravacycline AUC and Cmax increase approximately dose-proportionally over doses from 1 mg/kg to 3 mg/kg (3 times the approved dose).
- The mean exposure of eravacycline after single and multiple intravenous infusions (approximately 60 minutes) of 1 mg/kg administered to healthy adults every 12 hours is presented in Table 2.
- There is approximately 45% accumulation following intravenous dosing of 1 mg/kg every 12 hours.
Distribution
- Protein binding of eravacycline to human plasma proteins increases with increasing plasma concentrations, with 79% to 90% (bound) at plasma concentrations ranging from 100 to 10,000 ng/mL. The volume of distribution at steady-state is approximately 321 L.
Elimination
- The mean elimination half-life is 20 hours.
Metabolism
- Eravacycline is metabolized primarily by CYP3A4- and FMO-mediated oxidation.
Excretion
- Following a single intravenous dose of radiolabeled eravacycline 60 mg, approximately 34% of the dose is excreted in urine and 47% in feces as unchanged eravacycline (20% in urine and 17% in feces) and metabolites.
Specific Populations
- No clinically significant differences in the pharmacokinetics of eravacycline were observed based on age (18-86 years), sex, and race.
Patients with Renal Impairment
- The geometric least square mean Cmax for eravacycline was increased by 8.8% for subjects with end stage renal disease (ESRD) versus healthy subjects with 90% CI -19.4, 45.2. The geometric least square mean AUC0-inf for eravacycline was decreased by 4.0% for subjects with ESRD versus healthy subjects with 90% CI -14.0, 12.3.
Patients with Hepatic Impairment
- Eravacycline Cmax was 13.9%, 16.3%, and 19.7% higher in subjects with mild (Child-Pugh Class A), moderate (Child-Pugh Class B), and severe (Child‑Pugh Class C) hepatic impairment versus healthy subjects, respectively. Eravacycline AUC0-inf was 22.9%, 37.9%, and 110.3% higher in subjects with mild, moderate, and severe hepatic impairment versus healthy subjects, respectively.
Drug Interaction Studies
Clinical Studies
- Concomitant use of rifampin (strong CYP3A4/3A5 inducer) decreased eravacycline AUC by 35% and increased eravacycline clearance by 54%.
- Concomitant use of itraconazole (strong CYP3A inhibitor) increased eravacycline Cmax by 5% and AUC by 32%, and decreased eravacycline clearance by 32%.
In Vitro Studies
- Eravacycline is not an inhibitor of CYP1A2, 2B6, 2C8, 2C9, 2C19, 2D6, or 3A4/5. Eravacycline is not an inducer of CYP1A2, 2B6, or 3A4.
- Eravacycline is not a substrate for P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), bile salt export pump (BSEP), organic anion transporter peptide (OATP)1B1, OATP1B3, organic ion transporter (OAT)1, OAT3, OCT1, OCT2, multidrug and toxin extrusion (protein) (MATE)1, or MATE2-K transporters.
- Eravacycline is not an inhibitor of BCRP, BSEP, OATP1B1, OATP1B3, OAT1, OAT3, OCT1, OCT2, MATE1, or MATE2-K transporters.
## Microbiology
Mechanism of Action
- Eravacycline is a fluorocycline antibacterial within the tetracycline class of antibacterial drugs. Eravacycline disrupts bacterial protein synthesis by binding to the 30S ribosomal subunit thus preventing the incorporation of amino acid residues into elongating peptide chains.
- In general, eravacycline is bacteriostatic against gram-positive bacteria (e.g., Staphylococcus aureus and Enterococcus faecalis); however, in vitro bactericidal activity has been demonstrated against certain strains of Escherichia coli, Klebsiella pneumoniae.
Resistance
- Eravacycline resistance in some bacteria is associated with upregulated, non-specific intrinsic multidrug-resistant (MDR) efflux, and target-site modifications such as to the 16s rRNA or certain 30S ribosomal proteins (e.g., S10).
- The C7 and C9 substitutions in eravacycline are not present in any naturally occurring or semisynthetic tetracyclines and the substitution pattern imparts microbiological activities including in vitro activity against gram-positive and gram-negative strains expressing certain tetracycline-specific resistance mechanism(s) [i.e., efflux mediated by tet(A), tet(B), and tet(K); ribosomal protection as encoded by tet(M) and tet(Q)].
- Activity of eravacycline was demonstrated in vitro against Enterobacteriaceae in the presence of certain beta-lactamases, including extended spectrum β-lactamases, and AmpC. However, some beta-lactamase-producing isolates may confer resistance to eravacycline via other resistance mechanisms.
- The overall frequency of spontaneous mutants in the gram-positive organisms tested was in the range of 10-9 to 10-10 at 4 times the eravacycline Minimum Inhibitory Concentration (MIC). Multistep selection of gram-negative strains resulted in a 16- to 32-times increase in eravacycline MIC for one isolate of Escherichia coli and Klebsiella pneumoniae, respectively. The frequency of spontaneous mutations in K. pneumoniae was 10-7 to 10‑8 at 4 times the eravacycline MIC.
Interaction with Other Antimicrobials
- In vitro studies have not demonstrated antagonism between eravacycline and other commonly used antibacterial drugs for the indicated pathogens.
Antimicrobial Activity
- Eravacycline has been shown to be active against most isolates of the following microorganisms, both in vitro and in clinical infections:
Aerobic bacteria
Gram-positive bacteria
Enterococcus faecalis
Enterococcus faecium
Staphylococcus aureus
Streptococcus anginosus group
Gram-negative bacteria
Citrobacter freundii
Enterobacter cloacae
Escherichia coli
Klebsiella oxytoca
Klebsiella pneumoniae
Anaerobic bacteria
Gram-positive bacteria
Clostridium perfringens
Gram-negative bacteria
Bacteroides caccae
Bacteroides fragilis
Bacteroides ovatus
Bacteroides thetaiotaomicron
Bacteroides uniformis
Bacteroides vulgatus
Parabacteroides distasonis
- Aerobic bacteria
Gram-positive bacteria
Enterococcus faecalis
Enterococcus faecium
Staphylococcus aureus
Streptococcus anginosus group
Gram-negative bacteria
Citrobacter freundii
Enterobacter cloacae
Escherichia coli
Klebsiella oxytoca
Klebsiella pneumoniae
- Gram-positive bacteria
Enterococcus faecalis
Enterococcus faecium
Staphylococcus aureus
Streptococcus anginosus group
- Enterococcus faecalis
- Enterococcus faecium
- Staphylococcus aureus
- Streptococcus anginosus group
- Gram-negative bacteria
Citrobacter freundii
Enterobacter cloacae
Escherichia coli
Klebsiella oxytoca
Klebsiella pneumoniae
- Citrobacter freundii
- Enterobacter cloacae
- Escherichia coli
- Klebsiella oxytoca
- Klebsiella pneumoniae
- Anaerobic bacteria
Gram-positive bacteria
Clostridium perfringens
Gram-negative bacteria
Bacteroides caccae
Bacteroides fragilis
Bacteroides ovatus
Bacteroides thetaiotaomicron
Bacteroides uniformis
Bacteroides vulgatus
Parabacteroides distasonis
- Gram-positive bacteria
Clostridium perfringens
- Clostridium perfringens
- Gram-negative bacteria
Bacteroides caccae
Bacteroides fragilis
Bacteroides ovatus
Bacteroides thetaiotaomicron
Bacteroides uniformis
Bacteroides vulgatus
Parabacteroides distasonis
- Bacteroides caccae
- Bacteroides fragilis
- Bacteroides ovatus
- Bacteroides thetaiotaomicron
- Bacteroides uniformis
- Bacteroides vulgatus
- Parabacteroides distasonis
- The following in vitro data are available, but their clinical significance is unknown. At least 90 percent of the following bacteria exhibit an in vitro minimum inhibitory concentration (MIC) less than or equal to the susceptible breakpoint for eravacycline against isolates of similar genus or organism group. However, the efficacy of eravacycline in treating clinical infections caused by these bacteria has not been established in adequate and well-controlled clinical trials.
Aerobic bacteria
Gram-positive bacteria
Streptococcus salivarius group
Gram-negative bacteria
Citrobacter koseri
Enterobacter aerogenes
- Aerobic bacteria
Gram-positive bacteria
Streptococcus salivarius group
Gram-negative bacteria
Citrobacter koseri
Enterobacter aerogenes
- Gram-positive bacteria
Streptococcus salivarius group
- Streptococcus salivarius group
- Gram-negative bacteria
Citrobacter koseri
Enterobacter aerogenes
- Citrobacter koseri
- Enterobacter aerogenes
Susceptibility Test Methods
- For specific information regarding susceptibility test interpretive criteria, and associated test methods and quality control standards recognized by FDA for this drug, please see https://www.fda.gov/STIC.
## Nonclinical Toxicology
- Carcinogenicity studies with eravacycline have not been conducted. However, there has been evidence of oncogenic activity in rats in studies with the related antibacterial drugs, oxytetracycline (adrenal and pituitary tumors) and minocycline (thyroid tumors).
- Eravacycline was not genotoxic in a standard battery of assays, including an in vitro mammalian cell mutation assay, an in vitro clastogenicity assay, and an in vivo rat bone marrow micronucleus assay.
- There are no human data on the effect of eravacycline on fertility. Eravacycline did not affect mating or fertility in male rats following intravenous administration at a dose approximating a clinical dose of 0.65 mg/kg/day (approximately 1.5 times the clinical exposure, based on AUC determined in a separate study), however, eravacycline administration at higher doses was associated with adverse reactions on male fertility and spermatogenesis that were at least partially reversible after a 70-day recovery period (1 spermatogenic cycle). Decreased sperm counts, abnormal sperm morphology, and reduced sperm motility were observed with testicular effects (impaired spermiation and sperm maturation). There were no adverse reactions on mating or fertility in female rats administered intravenous eravacycline at a dose approximating a clinical dose of 3.2 mg/kg/day (approximately 18 times the clinical exposure based on AUC determined in a separate study in unmated females).
- Decreased sperm counts and eravacycline‑related lesions noted in the testes and epididymides were seen in general toxicology studies in rats and were reversible. These findings were anticipated effects for a tetracycline-class compound.
- In repeated dose toxicity studies in rats, dogs and monkeys, lymphoid depletion/atrophy of lymph nodes, spleen and thymus, decreased erythrocytes, reticulocytes, leukocytes, and platelets (dog and monkey), in association with bone marrow hypocellularity, and adverse gastrointestinal effects (dog and monkey) were observed with eravacycline. These findings were reversible or partially reversible during recovery periods of 3 to 7 weeks.
- Bone discoloration, which was not fully reversible over recovery periods of up to 7 weeks, was observed in rats and monkeys after 13 weeks of dosing and in the juvenile rat study after dosing over Post-Natal Days 21-70.
- Intravenous administration of eravacycline has been associated with a histamine response in rat and dog studies.
# Clinical Studies
- A total of 1,041 adults hospitalized with cIAI were enrolled in two Phase 3, randomized, double-blind, active-controlled, multinational, multicenter trials (Trials 1, NCT01844856, and Trial 2, NCT02784704). These studies compared eravacycline (1 mg/kg intravenous every 12 hours) with either ertapenem (1 g every 24 hours) or meropenem (1 g every 8 hours) as the active comparator for 4 to 14 days of therapy. Complicated intra-abdominal infections included appendicitis, cholecystitis, diverticulitis, gastric/duodenal perforation, intra-abdominal abscess, perforation of intestine, and peritonitis.
- The microbiologic intent-to-treat (micro-ITT) population, which included all patients who had at least one baseline intra-abdominal pathogen, consisted of 846 patients in the two trials. Populations in Trial 1 and Trial 2 were similar. The median age was 56 years and 56% were male. The majority of patients (95%) were from Europe; 5% were from the United States. The most common primary cIAI diagnosis was intra-abdominal abscess(es), occurring in 60% of patients. Bacteremia at baseline was present in 8% of patients.
- Clinical cure was defined as complete resolution or significant improvement of signs or symptoms of the index infection at the Test of Cure (TOC) visit which occurred 25 to 31 days after randomization. Selected clinical responses were reviewed by a Surgical Adjudication Committee. Table 3 presents the clinical cure rates in the micro-ITT population. Clinical cure rates at the TOC visit for selected pathogens are presented in Table 4.
- Two randomized, double-blind, active-controlled, clinical trials (Trial 4, NCT01978938, and Trial 5, NCT03032510) evaluated the efficacy and safety of once-daily intravenous eravacycline for the treatment of patients with complicated urinary tract infections (cUTI). Trial 4 included an optional switch from IV to oral therapy with eravacycline. The trials did not demonstrate the efficacy of eravacycline for the combined endpoints of clinical cure and microbiological success in the microbiological intent-to-treat (micro-ITT) population at the test-of-cure visit.
# How Supplied
- Eravacycline for injection, 50 mg/vial, is a yellow to orange, sterile, preservative-free powder for reconstitution in single-dose 10-mL clear glass vials with a rubber stopper and an aluminum overseal. Each vial contains 50 mg of eravacycline (equivalent to 63.5 mg of eravacycline dihydrochloride). Eravacycline is supplied in two packaging configurations:
Single-vial carton containing one 50 mg single-dose vial
Twelve-vial carton containing twelve 50 mg single-dose vial cartons
- Single-vial carton containing one 50 mg single-dose vial
- Twelve-vial carton containing twelve 50 mg single-dose vial cartons
## Storage
- Prior to reconstitution, eravacycline should be stored at 2°C to 8°C (36°F to 46°F). Keep vial in carton until use.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
Serious Allergic Reactions
- Advise patients that allergic reactions, including serious allergic reactions, could occur and that serious reactions require immediate treatment. Ask patient about any previous hypersensitivity reactions to antibacterial drugs including tetracycline or other allergens.
Tooth Discoloration and Inhibition of Bone Growth
- Advise patients that eravacycline, like other tetracycline-class drugs, may cause permanent tooth discoloration of deciduous teeth and reversible inhibition of bone growth when administered during the second and third trimesters of pregnancy. Tell your healthcare provider right away if you become pregnant during treatment.
Lactation
- Advise women not to breastfeed during treatment with eravacycline and for 4 days after the last dose.
Diarrhea
- Diarrhea is a common problem caused by antibacterial drugs, including eravacycline, which usually ends when the antibacterial drug is discontinued. Sometimes after starting treatment with antibacterial drug, patients can develop watery and bloody stools (with or without stomach cramps and fever) which may be a sign of a more serious intestinal infection, even as late as 2 or more months after having taken the last dose of the antibacterial drug. If this occurs, instruct patients to contact their healthcare provider as soon as possible.
Tetracycline Class Adverse Reactions
- Inform patients that eravacycline is similar to tetracycline-class antibacterial drugs and may have similar adverse reactions.
Overgrowth of Non-susceptible Microorganisms
- Inform patients that antibacterial drugs including eravacycline may promote the overgrowth of non-susceptible microorganisms, including fungi.
Antibacterial Resistance
- Inform patients that antibacterial drugs including eravacycline should only be used to treat bacterial infections. They do not treat viral infections (for example, the common cold). When eravacycline is prescribed to treat a bacterial infection, patients should be told that although it is common to feel better early in the course of therapy, the medication should be taken exactly as directed. Skipping doses or not completing the full course of therapy may (1) decrease the effectiveness of the immediate treatment and (2) increase the likelihood that bacteria will develop resistance and will not be treatable by eravacycline or other antibacterial drugs in the future.
# Precautions with Alcohol
Alcohol-Eravacycline interaction has not been established. Talk to your doctor regarding the effects of taking alcohol with this medication.
# Brand Names
Xerava
# Look-Alike Drug Names
There is limited information regarding Eravacycline Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Eravacycline | |
fe8c68235bb338367a17a94f781d852961fc15c4 | wikidoc | Erythromicin | Erythromicin
Erythromycin is a macrolide antibiotic that has an antimicrobial spectrum similar to or slightly wider than that of penicillin, and is often used for people that have an allergy to penicillins. For respiratory tract infections, it has better coverage of atypical organisms, including mycoplasma and Legionellosis. It is also used to treat outbreaks of chlamydia, syphilis, acne, and gonorrhea. It is manufactured and distributed by Eli Lilly and Company.
In structure, this macrocyclic compound contains a 14-membered lactone ring with ten asymmetric centers and two sugars (L-cladinose and D-desoamine), making it a compound very difficult to produce via synthetic methods.
Erythromycin is produced from a strain of the actinomycete Saccharopolyspora erythraea, formerly known as Streptomyces erythraeus.
# History
Abelardo Aguilar, a Filipino scientist, sent some soil samples to his employer Eli Lilly in 1949. Eli Lilly’s research team, led by J. M. McGuire, managed to isolate Erythromycin from the metabolic products of a strain of Streptomyces erythreus (designation changed to "Saccharopolyspora erythraea") found in the samples.
Lilly filed for patent protection of the compound and U.S. patent 2,653,899 was granted in 1953. The product was launched commercially in 1952 under the brand name Ilosone (after the Philippine region of Iloilo where it was originally collected from). Erythromycin was formerly also called Ilotycin.
In 1981, Nobel laureate (1965 in chemistry) and Professor of Chemistry at Harvard University (Cambridge, MA) Robert B. Woodward, along with a large number of members from his research group, posthumously reported the first stereocontrolled asymmetric chemical synthesis of Erythromycin A.
The antiobiotic clarithromycin was invented by scientists at the Japanese drug company Taisho Pharmaceutical in the 1970s as a result of their efforts to overcome the acid instability of erythromycin.
# Available Forms
Erythromycin is available in enteric-coated tablets, slow-release capsules, oral suspensions, ophthalmic solutions, ointments, gels, and injections.
Brand names include Robimycin, E-Mycin, E.E.S. Granules, E.E.S.-200, E.E.S.-400, E.E.S.-400 Filmtab, Erymax, Ery-Tab, Eryc, Erypar, EryPed, Eryped 200, Eryped 400, Erythrocin Stearate Filmtab, Erythrocot, E-Base, Erythroped, Ilosone, MY-E, Pediamycin, Zineryt, Abboticin, Abboticin-ES, Erycin, PCE Dispertab, Stiemycine and Acnasol.
# Mechanism of action
Erythromycin may possess bacteriocidal activity, particularly at higher concentrations. The mechanism is not fully elucidated however. By binding to the 50S subunit of the bacterial 70S rRNA complex, protein synthesis and subsequently structure/function processes critical for life or replication are inhibited. Erythromycin interferes with aminoacyl translocation, preventing the transfer of the tRNA bound at the A site of the rRNA complex to the P site of the rRNA complex. Without this translocation, the A site remains occupied and thus the addition of an incoming tRNA and its attached amino acid to the nascent polypeptide chain is inhibited. This interferes with the production of functionally useful proteins and is therefore the basis of antimicrobial action.
# Pharmacokinetics
Erythromycin is easily inactivated by gastric acid; therefore, all orally-administered formulations are given as either enteric-coated or more-stable laxatives or esters, such as erythromycin ethylsuccinate. Erythromycin is very rapidly absorbed, and diffuses into most tissues and phagocytes. Due to the high concentration in phagocytes, erythromycin is actively transported to the site of infection, where, during active phagocytosis, large concentrations of erythromycin are released.
## Metabolism
Most of erythromycin is metabolised by demethylation in the liver. Its main elimination route is in the bile, and a small portion in the urine. Erythromycin's elimination half-life is 1.5 hours.
# Adverse effects
Erythromycin inhibits the cytochrome P450 system, particularly CYP3A4, which can cause it to affect the metabolism of many different drugs. If CYP3A4 substrates, such as simvastatin (Zocor), lovastatin (Mevacor), or atorvastatin (Lipitor), are taken concomitantly with erythromycin, levels of the substrates will increase, often causing adverse effects. A noted drug interaction involves erythromycin and simvastatin, resulting in increased simvastatin levels and the potential for rhabdomyolysis. Another group of CYP3A4 substrates are drugs used for migraine such as ergotamine and dihydroergotamine; their adverse effects may be more pronounced if erythromycin is associated.
Gastrointestinal disturbances, such as diarrhea, nausea, abdominal pain, and vomiting, are fairly common, so erythromycin tends not to be prescribed as a first-line drug. However, erythromycin may be useful in treating gastroparesis due to this pro-motility effect. Intravenous erythromycin may also be used in endoscopy as an adjunct to clear gastric contents.
More serious side-effects, such as arrhythmia and reversible deafness, are rare. Allergic reactions, while uncommon, may occur, ranging from urticaria to anaphylaxis. Cholestasis, Stevens-Johnson syndrome, and toxic epidermal necrolysis are some other rare side-effects that may occur.
Exposure to erythromycin (especially long courses at antimicrobial doses, and also through breastfeeding) has been linked to an increased probability of pyloric stenosis in young infants. Erythromycin used for feeding intolerance in young infants has not been associated with hypertrophic pyloric stenosis.
It can also affect the central nervous system, causing psychotic reactions and nightmares and night sweats.
# Contraindications
Earlier case reports on sudden death prompted a study on a large cohort that confirmed a link between erythromycin, ventricular tachycardia, and sudden cardiac death in patients also taking drugs that prolong the metabolism of erythromycin (like verapamil or diltiazem) by interfering with CYP3A4 (Ray et al 2004). Hence, erythromycin should not be administered in patients using these drugs, or drugs that also prolong the QT time. Other examples include terfenadine (Seldane, Seldane-D), astemizole (Hismanal), cisapride (Propulsid, withdrawn in many countries for prolonging the QT time) and pimozide (Orap). Theophylline (which is mostly used in asthma) is also contradicted. | Erythromicin
Erythromycin is a macrolide antibiotic that has an antimicrobial spectrum similar to or slightly wider than that of penicillin, and is often used for people that have an allergy to penicillins. For respiratory tract infections, it has better coverage of atypical organisms, including mycoplasma and Legionellosis. It is also used to treat outbreaks of chlamydia, syphilis, acne, and gonorrhea. It is manufactured and distributed by Eli Lilly and Company.
In structure, this macrocyclic compound contains a 14-membered lactone ring with ten asymmetric centers and two sugars (L-cladinose and D-desoamine), making it a compound very difficult to produce via synthetic methods.
Erythromycin is produced from a strain of the actinomycete Saccharopolyspora erythraea, formerly known as Streptomyces erythraeus.
# History
Abelardo Aguilar, a Filipino scientist, sent some soil samples to his employer Eli Lilly in 1949. Eli Lilly’s research team, led by J. M. McGuire, managed to isolate Erythromycin from the metabolic products of a strain of Streptomyces erythreus (designation changed to "Saccharopolyspora erythraea") found in the samples.
Lilly filed for patent protection of the compound and U.S. patent 2,653,899 was granted in 1953. The product was launched commercially in 1952 under the brand name Ilosone (after the Philippine region of Iloilo where it was originally collected from). Erythromycin was formerly also called Ilotycin.
In 1981, Nobel laureate (1965 in chemistry) and Professor of Chemistry at Harvard University (Cambridge, MA) Robert B. Woodward, along with a large number of members from his research group, posthumously reported the first stereocontrolled asymmetric chemical synthesis of Erythromycin A.
The antiobiotic clarithromycin was invented by scientists at the Japanese drug company Taisho Pharmaceutical in the 1970s as a result of their efforts to overcome the acid instability of erythromycin.
# Available Forms
Erythromycin is available in enteric-coated tablets, slow-release capsules, oral suspensions, ophthalmic solutions, ointments, gels, and injections.
Brand names include Robimycin, E-Mycin, E.E.S. Granules, E.E.S.-200, E.E.S.-400, E.E.S.-400 Filmtab, Erymax, Ery-Tab, Eryc, Erypar, EryPed, Eryped 200, Eryped 400, Erythrocin Stearate Filmtab, Erythrocot, E-Base, Erythroped, Ilosone, MY-E, Pediamycin, Zineryt, Abboticin, Abboticin-ES, Erycin, PCE Dispertab, Stiemycine and Acnasol.
# Mechanism of action
Erythromycin may possess bacteriocidal activity, particularly at higher concentrations[1]. The mechanism is not fully elucidated however. By binding to the 50S subunit of the bacterial 70S rRNA complex, protein synthesis and subsequently structure/function processes critical for life or replication are inhibited[2]. Erythromycin interferes with aminoacyl translocation, preventing the transfer of the tRNA bound at the A site of the rRNA complex to the P site of the rRNA complex. Without this translocation, the A site remains occupied and thus the addition of an incoming tRNA and its attached amino acid to the nascent polypeptide chain is inhibited. This interferes with the production of functionally useful proteins and is therefore the basis of antimicrobial action.
# Pharmacokinetics
Erythromycin is easily inactivated by gastric acid; therefore, all orally-administered formulations are given as either enteric-coated or more-stable laxatives or esters, such as erythromycin ethylsuccinate. Erythromycin is very rapidly absorbed, and diffuses into most tissues and phagocytes. Due to the high concentration in phagocytes, erythromycin is actively transported to the site of infection, where, during active phagocytosis, large concentrations of erythromycin are released.
## Metabolism
Most of erythromycin is metabolised by demethylation in the liver. Its main elimination route is in the bile, and a small portion in the urine. Erythromycin's elimination half-life is 1.5 hours.
# Adverse effects
Erythromycin inhibits the cytochrome P450 system, particularly CYP3A4, which can cause it to affect the metabolism of many different drugs. If CYP3A4 substrates, such as simvastatin (Zocor), lovastatin (Mevacor), or atorvastatin (Lipitor), are taken concomitantly with erythromycin, levels of the substrates will increase, often causing adverse effects. A noted drug interaction involves erythromycin and simvastatin, resulting in increased simvastatin levels and the potential for rhabdomyolysis. Another group of CYP3A4 substrates are drugs used for migraine such as ergotamine and dihydroergotamine; their adverse effects may be more pronounced if erythromycin is associated.[3]
Gastrointestinal disturbances, such as diarrhea, nausea, abdominal pain, and vomiting, are fairly common, so erythromycin tends not to be prescribed as a first-line drug. However, erythromycin may be useful in treating gastroparesis due to this pro-motility effect. Intravenous erythromycin may also be used in endoscopy as an adjunct to clear gastric contents.
More serious side-effects, such as arrhythmia and reversible deafness, are rare. Allergic reactions, while uncommon, may occur, ranging from urticaria to anaphylaxis. Cholestasis, Stevens-Johnson syndrome, and toxic epidermal necrolysis are some other rare side-effects that may occur.
Exposure to erythromycin (especially long courses at antimicrobial doses, and also through breastfeeding) has been linked to an increased probability of pyloric stenosis in young infants.[4] Erythromycin used for feeding intolerance in young infants has not been associated with hypertrophic pyloric stenosis.[4]
It can also affect the central nervous system, causing psychotic reactions and nightmares and night sweats.[3]
# Contraindications
Earlier case reports on sudden death prompted a study on a large cohort that confirmed a link between erythromycin, ventricular tachycardia, and sudden cardiac death in patients also taking drugs that prolong the metabolism of erythromycin (like verapamil or diltiazem) by interfering with CYP3A4 (Ray et al 2004). Hence, erythromycin should not be administered in patients using these drugs, or drugs that also prolong the QT time. Other examples include terfenadine (Seldane, Seldane-D), astemizole (Hismanal), cisapride (Propulsid, withdrawn in many countries for prolonging the QT time) and pimozide (Orap). Theophylline (which is mostly used in asthma) is also contradicted. | https://www.wikidoc.org/index.php/Erythromicin | |
b35adfa01a5ba34ecf85152364e40565068d02dd | wikidoc | Escitalopram | Escitalopram
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# Black Box Warning
# Overview
Escitalopram is a selective serotonin reuptake inhibitor (SSRI) that is FDA approved for the {{{indicationType}}} of acute and maintenance treatment of major depressive disorder (MDD) in adults and adolescents aged 12 to 17 years, acute treatment of generalized anxiety disorder (GAD) in adults. There is a Black Box Warning for this drug as shown here. Common adverse reactions include insomnia, ejaculation disorder (primarily ejaculatory delay), nausea, sweating increased, fatigue and somnolence, decreased libido, and anorgasmia.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Dosing Information
- The recommended dose of escitalopram tablets is 10 mg once daily. A fixed-dose trial of escitalopram tablets demonstrated the effectiveness of both 10 mg and 20 mg of escitalopram tablets, but failed to demonstrate a greater benefit of 20 mg over 10 mg. If the dose is increased to 20 mg, this should occur after a minimum of one week.
- Maintenance Treatment
- It is generally agreed that acute episodes of major depressive disorder require several months or longer of sustained pharmacological therapy beyond response to the acute episode. Systematic evaluation of continuing escitalopram tablets 10 or 20 mg/day in adults patients with major depressive disorder who responded while taking escitalopram tablets during an 8-week, acute-treatment phase demonstrated a benefit of such maintenance treatment. Nevertheless, the physician who elects to use escitalopram tablets for extended periods should periodically re-evaluate the long-term usefulness of the drug for the individual patient. Patients should be periodically reassessed to determine the need for maintenance treatment.
- Dosing Information
- The recommended starting dose of escitalopram tablets is 10 mg once daily. If the dose is increased to 20 mg, this should occur after a minimum of one week.
- Maintenance Treatment
- Generalized anxiety disorder is recognized as a chronic condition. The efficacy of escitalopram tablets in the treatment of GAD beyond 8 weeks has not been systematically studied. The physician who elects to use escitalopram tablets for extended periods should periodically re-evaluate the long-term usefulness of the drug for the individual patient.
- Discontinuation of Treatment with Escitalopram Tablets
- Symptoms associated with discontinuation of escitalopram tablets and other SSRIs and SNRIs have been reported. Patients should be monitored for these symptoms when discontinuing treatment. A gradual reduction in the dose rather than abrupt cessation is recommended whenever possible. If intolerable symptoms occur following a decrease in the dose or upon discontinuation of treatment, then resuming the previously prescribed dose may be considered. Subsequently, the physician may continue decreasing the dose but at a more gradual rate.
- Switching a Patient 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 escitalopram tablets. Conversely, at least 14 days should be allowed after stopping escitalopram tablets before starting an MAOI intended to treat psychiatric disorders.
- Use of Escitalopram Tablets with Other MAOIs such as Linezolid or Methylene Blue
- Do not start escitalopram 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 escitalopram tablets therapy 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, escitalopram 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 escitalopram 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 escitalopram tablets is unclear. The clinician should, nevertheless, be aware of the possibility of emergent symptoms of serotonin syndrome with such use.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Escitalopram in adult patients.
### Non–Guideline-Supported Use
- Dosing Information
- Prophylaxis with oral escitalopram.
- Dosing Information
- Escitalopram 10 or 20 mg/day for 16 weeks.
- Dosing Information
- Oral escitalopram 20 mg/day during the luteal phase of the menstrual cycle.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
- Dosing Information
- Adolescents
- The recommended dose of escitalopram tablets is 10 mg once daily. A flexible-dose trial of escitalopram tablets (10 to 20 mg/day) demonstrated the effectiveness of escitalopram tablets. If the dose is increased to 20 mg, this should occur after a minimum of three weeks.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Escitalopram in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Escitalopram in pediatric patients.
# Contraindications
- Monoamine Oxidase Inhibitors (MAOIs)
- The use of MAOIs intended to treat psychiatric disorders with escitalopram tablets or within 14 days of stopping treatment with escitalopram tablets are contraindicated because of an increased risk of serotonin syndrome. The use of escitalopram tablets within 14 days of stopping an MAOI intended to treat psychiatric disorders are also contraindicated.
- Starting escitalopram 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.
- Pimozide
- Concomitant use in patients taking pimozide is contraindicated.
- Hypersensitivity to Escitalopram or Citalopram
- Escitalopram tablets are contraindicated in patients with a hypersensitivity to escitalopram or citalopram or any of the inactive ingredients in escitalopram tablets.
# Warnings
### Precautions
- 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 to 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 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 the 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.
- If the decision has been made to discontinue treatment, medication should be tapered, as rapidly as is feasible, but with recognition that abrupt discontinuation can be associated with certain 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 escitalopram oxalate 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 escitalopram oxalate is not approved for use in treating bipolar depression.
- Serotonin Syndrome
- The development of a potentially life-threatening serotonin syndrome has been reported with SNRIs and SSRIs, including escitalopram oxalate, alone but particularly with concomitant use of other 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, flushing, 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 escitalopram oxalate with MAOIs intended to treat psychiatric disorders is contraindicated. Escitalopram oxalate 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 escitalopram oxalate. Escitalopram oxalate should be discontinued before initiating treatment with the MAOI.
- If concomitant use of escitalopram oxalate with other serotonergic drugs including, triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, buspirone, tryptophan and St. John’s Wort is clinically warranted, patients should be made aware of a potential increased risk for serotonin syndrome, particularly during treatment initiation and dose increases.
- Treatment with escitalopram oxalate and any concomitant serotonergic agents, should be discontinued immediately if the above events occur and supportive symptomatic treatment should be initiated.
- Discontinuation of Treatment with Escitalopram Oxalate
- During marketing of escitalopram oxalate and other SSRIs and SNRIs (serotonin and norepinephrine reuptake inhibitors), there have been spontaneous reports of adverse events occurring upon discontinuation of these drugs, particularly when abrupt, including the following: dysphoric mood, irritability, agitation, dizziness, sensory disturbances (e.g., paresthesias such as electric shock sensations), anxiety, confusion, headache, lethargy, emotional lability, insomnia, and hypomania. While these events are generally self-limiting, there have been reports of serious discontinuation symptoms.
- Patients should be monitored for these symptoms when discontinuing treatment with escitalopram oxalate. A gradual reduction in the dose rather than abrupt cessation is recommended whenever possible. If intolerable symptoms occur following a decrease in the dose or upon discontinuation of treatment, then resuming the previously prescribed dose may be considered. Subsequently, the physician may continue decreasing the dose but at a more gradual rate.
- Seizures
- Although anticonvulsant effects of racemic citalopram have been observed in animal studies, escitalopram oxalate has not been systematically evaluated in patients with a seizure disorder. These patients were excluded from clinical studies during the product's premarketing testing. In clinical trials of escitalopram oxalate, cases of convulsion have been reported in association with escitalopram oxalate treatment. Like other drugs effective in the treatment of major depressive disorder, escitalopram oxalate should be introduced with care in patients with a history of seizure disorder.
- Activation of Mania/Hypomania
- In placebo-controlled trials of escitalopram oxalate in major depressive disorder, activation of mania/hypomania was reported in one (0.1%) of 715 patients treated with escitalopram oxalate and in none of the 592 patients treated with placebo. One additional case of hypomania has been reported in association with escitalopram oxalate treatment. Activation of mania/hypomania has also been reported in a small proportion of patients with major affective disorders treated with racemic citalopram and other marketed drugs effective in the treatment of major depressive disorder. As with all drugs effective in the treatment of major depressive disorder, escitalopram oxalate should be used cautiously in patients with a history of mania.
- Hyponatremia
- Hyponatremia may occur as a result of treatment with SSRIs and SNRIs, including escitalopram oxalate. In many cases, this hyponatremia appears to be the result of the syndrome of inappropriate antidiuretic hormone secretion (SIADH), and was reversible when escitalopram oxalate was discontinued. Cases with serum sodium lower than 110 mmol/L have been reported. Elderly patients may be at greater risk of developing hyponatremia with SSRIs and SNRIs. Also, patients taking diuretics or who are otherwise volume depleted may be at greater risk. Discontinuation of escitalopram oxalate should be considered in patients with symptomatic hyponatremia and appropriate medical intervention should be instituted.
- Signs and symptoms of hyponatremia include headache, difficulty concentrating, memory impairment, confusion, weakness, and unsteadiness, which may lead to falls. Signs and symptoms associated with more severe and/or acute cases have included hallucination, syncope, seizure, coma, respiratory arrest, and death.
- Abnormal Bleeding
- SSRIs and SNRIs, including escitalopram oxalate, may increase the risk of bleeding events. Concomitant use of aspirin, nonsteroidal anti-inflammatory drugs, warfarin, and other anticoagulants may add to the risk. Case reports and epidemiological studies (case-control and cohort design) have demonstrated an association between use of drugs that interfere with serotonin reuptake and the occurrence of gastrointestinal bleeding. Bleeding events related to SSRIs and SNRIs use have ranged from ecchymoses, hematomas, epistaxis, and petechiae to life-threatening hemorrhages.
- Patients should be cautioned about the risk of bleeding associated with the concomitant use of escitalopram oxalate and NSAIDs, aspirin, or other drugs that affect coagulation.
- Interference with Cognitive and Motor Performance
- In a study in normal volunteers, escitalopram oxalate 10 mg/day did not produce impairment of intellectual function or psychomotor performance. Because any psychoactive drug may impair judgment, thinking, or motor skills, however, patients should be cautioned about operating hazardous machinery, including automobiles, until they are reasonably certain that escitalopram oxalate therapy does not affect their ability to engage in such activities.
- Angle Closure Glaucoma
- Angle-Closure Glaucoma: The pupillary dilation that occurs following use of many antidepressant drugs including escitalopram oxalate may trigger an angle closure attack in a patient with anatomically narrow angles who does not have a patent iridectomy.
- Use in Patients with Concomitant Illness
- Clinical experience with escitalopram oxalate in patients with certain concomitant systemic illnesses is limited. Caution is advisable in using escitalopram oxalate in patients with diseases or conditions that produce altered metabolism or hemodynamic responses.
- Escitalopram oxalate has not been systematically evaluated in patients with a recent history of myocardial infarction or unstable heart disease. Patients with these diagnoses were generally excluded from clinical studies during the product's premarketing testing.
- In subjects with hepatic impairment, clearance of racemic citalopram was decreased and plasma concentrations were increased. The recommended dose of escitalopram oxalate in hepatically impaired patients is 10 mg/day.
- Because escitalopram is extensively metabolized, excretion of unchanged drug in urine is a minor route of elimination. Until adequate numbers of patients with severe renal impairment have been evaluated during chronic treatment with escitalopram oxalate, however, it should be used with caution in such patients.
# 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 the rates observed in practice.
- Pediatrics (6 to 17 years)
- Adverse events were collected in 576 pediatric patients (286 escitalopram oxalate, 290 placebo) with major depressive disorder in double-blind placebo-controlled studies. Safety and effectiveness of escitalopram oxalate in pediatric patients less than 12 years of age has not been established.
- Adults
- Adverse events information for escitalopram oxalate was collected from 715 patients with major depressive disorder who were exposed to escitalopram and from 592 patients who were exposed to placebo in double-blind, placebo-controlled trials. An additional 284 patients with major depressive disorder were newly exposed to escitalopram in open-label trials. The adverse event information for escitalopram oxalate in patients with GAD was collected from 429 patients exposed to escitalopram and from 427 patients exposed to placebo in double-blind, placebo-controlled trials.
- Adverse events during exposure were obtained primarily by general inquiry and 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 events into a smaller number of standardized event categories. In the tables and tabulations that follow, standard World Health Organization (WHO) terminology has been used to classify reported adverse events.
- The stated frequencies of adverse reactions represent the proportion of individuals who experienced, at least once, a treatment-emergent adverse event of the type listed. An event was considered treatment-emergent if it occurred for the first time or worsened while receiving therapy following baseline evaluation.
- Pediatrics (6 to 17 years)
- Adverse events were associated with discontinuation of 3.5% of 286 patients receiving escitalopram oxalate and 1% of 290 patients receiving placebo. The most common adverse event (incidence at least 1% for escitalopram oxalate and greater than placebo) associated with discontinuation was insomnia (1% escitalopram oxalate, 0% placebo).
- Adults
- Among the 715 depressed patients who received escitalopram oxalate in placebo-controlled trials, 6% discontinued treatment due to an adverse event, as compared to 2% of 592 patients receiving placebo. In two fixed-dose studies, the rate of discontinuation for adverse events in patients receiving 10 mg/day escitalopram oxalate was not significantly different from the rate of discontinuation for adverse events in patients receiving placebo. The rate of discontinuation for adverse events in patients assigned to a fixed dose of 20 mg/day escitalopram oxalate was 10%, which was significantly different from the rate of discontinuation for adverse events in patients receiving 10 mg/day escitalopram oxalate (4%) and placebo (3%). Adverse events that were associated with the discontinuation of at least 1% of patients treated with escitalopram oxalate, and for which the rate was at least twice that of placebo, were nausea (2%) and ejaculation disorder (2% of male patients).
- Adults
- Among the 429 GAD patients who received escitalopram oxalate 10 to 20 mg/day in placebo-controlled trials, 8% discontinued treatment due to an adverse event, as compared to 4% of 427 patients receiving placebo. Adverse events that were associated with the discontinuation of at least 1% of patients treated with escitalopram oxalate, and for which the rate was at least twice the placebo rate, were nausea (2%), insomnia (1%), and fatigue (1%).
- Pediatrics (6 to 17 years)
- The overall profile of adverse reactions in pediatric patients was generally similar to that seen in adult studies, as shown in Table 2. However, the following adverse reactions (excluding those which appear in Table 2 and those for which the coded terms were uninformative or misleading) were reported at an incidence of at least 2% for escitalopram oxalate and greater than placebo: back pain, urinary tract infection, vomiting, and nasal congestion.
- Adults
- The most commonly observed adverse reactions in escitalopram oxalate patients (incidence of approximately 5% or greater and approximately twice the incidence in placebo patients) were insomnia, ejaculation disorder (primarily ejaculatory delay), nausea, sweating increased, fatigue, and somnolence.
- Table 2 enumerates the incidence, rounded to the nearest percent, of treatment-emergent adverse events that occurred among 715 depressed patients who received escitalopram oxalate at doses ranging from 10 to 20 mg/day in placebo-controlled trials. Events included are those occurring in 2% or more of patients treated with escitalopram oxalate and for which the incidence in patients treated with escitalopram oxalate was greater than the incidence in placebo-treated patients.
- Adults
- The most commonly observed adverse reactions in escitalopram oxalate patients (incidence of approximately 5% or greater and approximately twice the incidence in placebo patients) were nausea, ejaculation disorder (primarily ejaculatory delay), insomnia, fatigue, decreased libido, and anorgasmia.
- Table 3 enumerates the incidence, rounded to the nearest percent of treatment-emergent adverse events that occurred among 429 GAD patients who received escitalopram oxalate 10 to 20 mg/day in placebo-controlled trials. Events included are those occurring in 2% or more of patients treated with escitalopram oxalate and for which the incidence in patients treated with escitalopram oxalate was greater than the incidence in placebo-treated patients.
- The potential dose dependency of common adverse reactions (defined as an incidence rate of ≥5% in either the 10 mg or 20 mg escitalopram oxalate groups) was examined on the basis of the combined incidence of adverse reactions in two fixed-dose trials. The overall incidence rates of adverse events in 10 mg escitalopram oxalate-treated patients (66%) was similar to that of the placebo-treated patients (61%), while the incidence rate in 20 mg/day escitalopram oxalate-treated patients was greater (86%). Table 4 shows common adverse reactions that occurred in the 20 mg/day escitalopram oxalate group with an incidence that was approximately twice that of the 10 mg/day escitalopram oxalate group and approximately twice that of the placebo group.
- Although changes in sexual desire, sexual performance, and sexual satisfaction often occur as manifestations of a psychiatric disorder, they may also be a consequence of pharmacologic treatment. In particular, some evidence suggests that SSRIs can cause such untoward sexual experiences.
- Reliable estimates of the incidence and severity of untoward experiences involving sexual desire, performance, and satisfaction are difficult to obtain, however, in part 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 their actual incidence.
- There are no adequately designed studies examining sexual dysfunction with escitalopram treatment.
- Priapism has been reported with all SSRIs.
- While it is difficult to know the precise risk of sexual dysfunction associated with the use of SSRIs, physicians should routinely inquire about such possible side effects.
- Escitalopram oxalate and placebo groups were compared with respect to (1) mean change from baseline in vital signs (pulse, systolic blood pressure, and diastolic blood pressure) and (2) the incidence of patients meeting criteria for potentially clinically significant changes from baseline in these variables. These analyses did not reveal any clinically important changes in vital signs associated with escitalopram oxalate treatment. In addition, a comparison of supine and standing vital sign measures in subjects receiving escitalopram oxalate indicated that escitalopram oxalate treatment is not associated with orthostatic changes.
- Patients treated with escitalopram oxalate in controlled trials did not differ from placebo-treated patients with regard to clinically important change in body weight.
- Escitalopram oxalate and placebo groups were compared with respect to (1) mean change from baseline in various serum chemistry, hematology, and urinalysis variables, and (2) the incidence of patients meeting criteria for potentially clinically significant changes from baseline in these variables. These analyses revealed no clinically important changes in laboratory test parameters associated with escitalopram oxalate treatment.
- Electrocardiograms from escitalopram oxalate (N=625) and placebo (N=527) groups were compared with respect to outliers defined as subjects with QTc changes over 60 msec from baseline or absolute values over 500 msec post-dose, and subjects with heart rate increases to over 100 bpm or decreases to less than 50 bpm with a 25% change from baseline (tachycardic or bradycardic outliers, respectively). None of the patients in the escitalopram oxalate group had a QTcF interval >500 msec or a prolongation >60 msec compared to 0.2% of patients in the placebo group. The incidence of tachycardic outliers was 0.2% in the escitalopram oxalate and the placebo group. The incidence of bradycardic outliers was 0.5% in the escitalopram oxalate group and 0.2% in the placebo group.
- QTcF interval was evaluated in a randomized, placebo and active (moxifloxacin 400 mg) controlled cross-over, escalating multiple-dose study in 113 healthy subjects. The maximum mean (95% upper confidence bound) difference from placebo arm were 4.5 (6.4) and 10.7 (12.7) msec for 10 mg and supratherapeutic 30 mg escitalopram given once daily, respectively. Based on the established exposure-response relationship, the predicted QTcF change from placebo arm (95% confidence interval) under the Cmax for the dose of 20 mg is 6.6 (7.9) msec. Escitalopram 30 mg given once daily resulted in mean Cmax of 1.7-fold higher than the mean Cmax for the maximum recommended therapeutic dose at steady state (20 mg). The exposure under supratherapeutic 30 mg dose is similar to the steady state concentrations expected in CYP2C19 poor metabolizers following a therapeutic dose of 20 mg.
- Following is a list of treatment-emergent adverse events, as defined in the introduction to the ADVERSE REACTIONS section, reported by the 1428 patients treated with escitalopram oxalate for periods of up to one year in double-blind or open-label clinical trials during its premarketing evaluation. The listing does not include those events already listed in Tables 2 & 3, those events for which a drug cause was remote and at a rate less than 1% or lower than placebo, those events which were so general as to be uninformative, and those events reported only once which did not have a substantial probability of being acutely life threatening. Events are categorized by body system. Events of major clinical importance are described in the Warnings and Precautions section (5).
Hypertension, palpitation.
Light-Headed feeling, migraine.
Abdominal Cramp, heartburn, gastroenteritis.
Allergy, chest pain, fever, hot flushes, pain in limb.
Increased weight.
Arthralgia, myalgia, jaw stiffness.
Appetite increased, concentration impaired, irritability.
Menstrual cramps, menstrual disorder.
Bronchitis, coughing, nasal congestion, sinus congestion, sinus headache.
Rash.
Vision blurred, tinnitus.
Urinary frequency, urinary tract infection.
## Postmarketing Experience
- The following additional adverse reactions have been identified from spontaneous reports of escitalopram received worldwide. These adverse reactions have been chosen for inclusion because of a combination of seriousness, frequency of reporting, or potential causal connection to escitalopram and have not been listed elsewhere in labeling. However, because these adverse reactions were 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 events include:
Anemia, agranulocytis, aplastic anemia, hemolytic anemia, idiopathic thrombocytopenia purpura, leukopenia, thrombocytopenia.
Atrial fibrillation, bradycardia, cardiac failure, myocardial infarction, tachycardia, torsade de pointes, ventricular arrhythmia, ventricular tachycardia.
Vertigo.
Diabetes mellitus, hyperprolactinemia, SIADH.
Angle closure glaucoma, diplopia, mydriasis, visual disturbance.
Dysphagia, gastrointestinal hemorrhage, gastroesophageal reflux, pancreatitis, rectal hemorrhage.
Abnormal gait, asthenia, edema, fall, feeling abnormal, malaise.
Fulminant hepatitis, hepatic failure, hepatic necrosis, hepatitis.
Allergic reaction, anaphylaxis.
Bilirubin increased, decreased weight, electrocardiogram QT prolongation, hepatic enzymes increased, hypercholesterolemia, INR increased, prothrombin decreased.
Hyperglycemia, hypoglycemia, hypokalemia, hyponatremia.
Muscle cramp, muscle stiffness, muscle weakness, rhabdomyolysis.
Akathisia, amnesia, ataxia, choreoathetosis, cerebrovascular accident, dysarthria, dyskinesia, dystonia, extrapyramidal disorders, grand mal seizures (or convulsions), hypoaesthesia, myoclonus, nystagmus, Parkinsonism, restless legs, seizures, syncope, tardive dyskinesia, tremor.
Spontaneous abortion.
Acute psychosis, aggression, agitation, anger, anxiety, apathy, completed suicide, confusion, depersonalization, depression aggravated, delirium, delusion, disorientation, feeling unreal, hallucinations (visual and auditory), mood swings, nervousness, nightmare, panic reaction, paranoia, restlessness, self-harm or thoughts of self-harm, suicide attempt, suicidal ideation, suicidal tendency.
Acute renal failure, dysuria, urinary retention.
Menorrhagia, priapism.
Dyspnea, epistaxis, pulmonary embolism, pulmonary hypertension of the newborn.
Alopecia, angioedema, dermatitis, ecchymosis, erythema multiforme, photosensitivity reaction, Stevens Johnson Syndrome, toxic epidermal necrolysis, urticaria.
Deep vein thrombosis, flushing, hypertensive crisis, hypotension, orthostatic hypotension, phlebitis, thrombosis.
# Drug Interactions
- Monoamine Oxidase Inhibitors (MAOIs)
- Do not start escitalopram 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 escitalopram tablets therapy 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, escitalopram 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 escitalopram 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 escitalopram tablets is unclear. The clinician should, nevertheless, be aware of the possibility of emergent symptoms of serotonin syndrome with such use.
- Serotonergic Drugs
- The development of a potentially life-threatening serotonin syndrome has been reported with SNRIs and SSRIs, including escitalopram oxalate, alone but particularly with concomitant use of other 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, flushing, 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 escitalopram oxalate with MAOIs intended to treat psychiatric disorders is contraindicated. Escitalopram oxalate 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 escitalopram oxalate. Escitalopram oxalate should be discontinued before initiating treatment with the MAOI.
- If concomitant use of escitalopram oxalate with other serotonergic drugs including, triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, buspirone, tryptophan and St. John’s Wort is clinically warranted, patients should be made aware of a potential increased risk for serotonin syndrome, particularly during treatment initiation and dose increases.
- Treatment with escitalopram oxalate and any concomitant serotonergic agents, should be discontinued immediately if the above events occur and supportive symptomatic treatment should be initiated.
- Triptans
- There have been rare postmarketing reports of serotonin syndrome with use of an SSRI and a triptan. If concomitant treatment of escitalopram oxalate with a triptan is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases.
- CNS Drugs
- Given the primary CNS effects of escitalopram, caution should be used when it is taken in combination with other centrally acting drugs.
- Alcohol
- Although escitalopram oxalate did not potentiate the cognitive and motor effects of alcohol in a clinical trial, as with other psychotropic medications, the use of alcohol by patients taking escitalopram oxalate is not recommended.
- Drugs That Interfere With Hemostasis (NSAIDs, Aspirin, Warfarin, etc.)
- Serotonin release by platelets plays an important role in hemostasis. Epidemiological studies of the case-control and cohort design that have demonstrated an association between use of psychotropic drugs that interfere with serotonin reuptake and the occurrence of upper gastrointestinal bleeding have also shown that concurrent use of an NSAID or aspirin may potentiate the risk of bleeding. Altered anticoagulant effects, including increased bleeding, have been reported when SSRIs and SNRIs are coadministered with warfarin. Patients receiving warfarin therapy should be carefully monitored when escitalopram oxalate is initiated or discontinued.
- Cimetidine
- In subjects who had received 21 days of 40 mg/day racemic citalopram, combined administration of 400 mg twice a day cimetidine for 8 days resulted in an increase in citalopram AUC and Cmax of 43% and 39%, respectively. The clinical significance of these findings is unknown.
- Digoxin
- In subjects who had received 21 days of 40 mg/day racemic citalopram, combined administration of citalopram and digoxin (single dose of 1 mg) did not significantly affect the pharmacokinetics of either citalopram or digoxin.
- Lithium
- Coadministration of racemic citalopram (40 mg/day for 10 days) and lithium (30 mmol/day for 5 days) had no significant effect on the pharmacokinetics of citalopram or lithium. Nevertheless, plasma lithium levels should be monitored with appropriate adjustment to the lithium dose in accordance with standard clinical practice. Because lithium may enhance the serotonergic effects of escitalopram, caution should be exercised when escitalopram oxalate and lithium are coadministered.
- Pimozide and Celexa
- In a controlled study, a single dose of pimozide 2 mg coadministered with racemic citalopram 40 mg given once daily for 11 days was associated with a mean increase in QTc values of approximately 10 msec compared to pimozide given alone. Racemic citalopram did not alter the mean AUC or Cmax of pimozide. The mechanism of this pharmacodynamic interaction is not known.
- Sumatriptan
- There have been rare postmarketing reports describing patients with weakness, hyperreflexia, and incoordination following the use of an SSRI and sumatriptan. If concomitant treatment with sumatriptan and an SSRI (e.g., fluoxetine, fluvoxamine, paroxetine, sertraline, citalopram, escitalopram) is clinically warranted, appropriate observation of the patient is advised.
- Theophylline
- Combined administration of racemic citalopram (40 mg/day for 21 days) and the CYP1A2 substrate theophylline (single dose of 300 mg) did not affect the pharmacokinetics of theophylline. The effect of theophylline on the pharmacokinetics of citalopram was not evaluated.
- Warfarin
- Administration of 40 mg/day racemic citalopram for 21 days did not affect the pharmacokinetics of warfarin, a CYP3A4 substrate. Prothrombin time was increased by 5%, the clinical significance of which is unknown.
- Carbamazepine
- Combined administration of racemic citalopram (40 mg/day for 14 days) and carbamazepine (titrated to 400 mg/day for 35 days) did not significantly affect the pharmacokinetics of carbamazepine, a CYP3A4 substrate. Although trough citalopram plasma levels were unaffected, given the enzyme-inducing properties of carbamazepine, the possibility that carbamazepine might increase the clearance of escitalopram should be considered if the two drugs are coadministered.
- Triazolam
- Combined administration of racemic citalopram (titrated to 40 mg/day for 28 days) and the CYP3A4 substrate triazolam (single dose of 0.25 mg) did not significantly affect the pharmacokinetics of either citalopram or triazolam.
- Ketoconazole
- Combined administration of racemic citalopram (40 mg) and ketoconazole (200 mg), a potent CYP3A4 inhibitor, decreased the Cmax and AUC of ketoconazole by 21% and 10%, respectively, and did not significantly affect the pharmacokinetics of citalopram.
- Ritonavir
- Combined administration of a single dose of ritonavir (600 mg), both a CYP3A4 substrate and a potent inhibitor of CYP3A4, and escitalopram (20 mg) did not affect the pharmacokinetics of either ritonavir or escitalopram.
- CYP3A4 and -2C19 Inhibitors
- In vitro studies indicated that CYP3A4 and -2C19 are the primary enzymes involved in the metabolism of escitalopram. However, coadministration of escitalopram (20 mg) and ritonavir (600 mg), a potent inhibitor of CYP3A4, did not significantly affect the pharmacokinetics of escitalopram. Because escitalopram is metabolized by multiple enzyme systems, inhibition of a single enzyme may not appreciably decrease escitalopram clearance.
- Drugs Metabolized by Cytochrome P4502D6
- In vitro studies did not reveal an inhibitory effect of escitalopram on CYP2D6. In addition, steady state levels of racemic citalopram were not significantly different in poor metabolizers and extensive CYP2D6 metabolizers after multiple-dose administration of citalopram, suggesting that coadministration, with escitalopram, of a drug that inhibits CYP2D6, is unlikely to have clinically significant effects on escitalopram metabolism. However, there are limited in vivo data suggesting a modest CYP2D6 inhibitory effect for escitalopram, i.e., coadministration of escitalopram (20 mg/day for 21 days) with the tricyclic antidepressant desipramine (single dose of 50 mg), a substrate for CYP2D6, resulted in a 40% increase in Cmax and a 100% increase in AUC of desipramine. The clinical significance of this finding is unknown. Nevertheless, caution is indicated in the coadministration of escitalopram and drugs metabolized by CYP2D6.
- Metoprolol
- Administration of 20 mg/day escitalopram oxalate for 21 days in healthy volunteers resulted in a 50% increase in Cmax and 82% increase in AUC of the beta-adrenergic blocker metoprolol (given in a single dose of 100 mg). Increased metoprolol plasma levels have been associated with decreased cardioselectivity. Coadministration of escitalopram oxalate and metoprolol had no clinically significant effects on blood pressure or heart rate.
- Electroconvulsive Therapy (ECT)
- There are no clinical studies of the combined use of ECT and escitalopram.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
- Pregnancy Category C
- In a rat embryo/fetal development study, oral administration of escitalopram (56, 112, or 150 mg/kg/day) to pregnant animals during the period of organogenesis resulted in decreased fetal body weight and associated delays in ossification at the two higher doses (approximately ≥ 56 times the maximum recommended human dose of 20 mg/day on a body surface area basis). Maternal toxicity (clinical signs and decreased body weight gain and food consumption), mild at 56 mg/kg/day, was present at all dose levels. The developmental no-effect dose of 56 mg/kg/day is approximately 28 times the MRHD on a mg/m2 basis. No teratogenicity was observed at any of the doses tested (as high as 75 times the MRHD on a mg/m2 basis).
- When female rats were treated with escitalopram (6, 12, 24, or 48 mg/kg/day) during pregnancy and through weaning, slightly increased offspring mortality and growth retardation were noted at 48 mg/kg/day which is approximately 24 times the MRHD on a mg/m2 basis. Slight maternal toxicity (clinical signs and decreased body weight gain and food consumption) was seen at this dose. Slightly increased offspring mortality was also seen at 24 mg/kg/day. The no-effect dose was 12 mg/kg/day which is approximately 6 times the MRHD on a mg/m2 basis.
- In animal reproduction studies, racemic citalopram has been shown to have adverse effects on embryo/fetal and postnatal development, including teratogenic effects, when administered at doses greater than human therapeutic doses.
- In two rat embryo/fetal development studies, oral administration of racemic citalopram (32, 56, or 112 mg/kg/day) to pregnant animals during the period of organogenesis resulted in decreased embryo/fetal growth and survival and an increased incidence of fetal abnormalities (including cardiovascular and skeletal defects) at the high dose. This dose was also associated with maternal toxicity (clinical signs, decreased body weight gain). The developmental no-effect dose was 56 mg/kg/day. In a rabbit study, no adverse effects on embryo/fetal development were observed at doses of racemic citalopram of up to 16 mg/kg/day. Thus, teratogenic effects of racemic citalopram were observed at a maternally toxic dose in the rat and were not observed in the rabbit.
- When female rats were treated with racemic citalopram (4.8, 12.8, or 32 mg/kg/day) from late gestation through weaning, increased offspring mortality during the first 4 days after birth and persistent offspring growth retardation were observed at the highest dose. The no-effect dose was 12.8 mg/kg/day. Similar effects on offspring mortality and growth were seen when dams were treated throughout gestation and early lactation at doses ≥ 24 mg/kg/day. A no-effect dose was not determined in that study.
- There are no adequate and well-controlled studies in pregnant women; therefore, escitalopram should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
- Pregnancy-Nonteratogenic Effects
- Neonates exposed to escitalopram oxalate and other SSRIs or serotonin and norepinephrine reuptake inhibitors (SNRIs), late in the third trimester have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding. Such complications can arise immediately upon delivery. Reported clinical findings have included respiratory distress, cyanosis, apnea, seizures, temperature instability, feeding difficulty, vomiting, hypoglycemia, hypotonia, hypertonia, hyperreflexia, tremor, jitteriness, irritability, and constant crying. These features are consistent with either a direct toxic effect of SSRIs and SNRIs or, possibly, a drug discontinuation syndrome. It should be noted that, in some cases, the clinical picture is consistent with serotonin syndrome.
- Infants exposed to SSRIs in pregnancy may have an increased risk for persistent pulmonary hypertension of the newborn (PPHN). PPHN occurs in 1 to 2 per 1,000 live births in the general population and is associated with substantial neonatal morbidity and mortality. Several recent epidemiologic studies suggest a positive statistical association between SSRI use (including escitalopram oxalate) in pregnancy and PPHN. Other studies do not show a significant statistical association.
- Physicians should also note the results of a prospective longitudinal study of 201 pregnant women with a history of major depression, who were either on antidepressants or had received antidepressants less than 12 weeks prior to their last menstrual period, and were in remission. Women who discontinued antidepressant medication during pregnancy showed a significant increase in relapse of their major depression compared to those women who remained on antidepressant medication throughout pregnancy.
- When treating a pregnant woman with escitalopram oxalate, the physician should carefully consider both the potential risks of taking an SSRI, along with the established benefits of treating depression with an antidepressant. This decision can only be made on a case by case basis.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Escitalopram in women who are pregnant.
### Labor and Delivery
- The effect of escitalopram oxalate on labor and delivery in humans is unknown.
### Nursing Mothers
- Escitalopram is excreted in human breast milk. Limited data from women taking 10 to 20 mg escitalopram showed that exclusively breastfed infants receive approximately 3.9% of the maternal weight-adjusted dose of escitalopram and 1.7% of the maternal weight-adjusted dose of desmethylcitalopram. There were two reports of infants experiencing excessive somnolence, decreased feeding, and weight loss in association with breastfeeding from a racemic citalopram-treated mother; in one case, the infant was reported to recover completely upon discontinuation of racemic citalopram by its mother and, in the second case, no follow-up information was available. Caution should be exercised and breastfeeding infants should be observed for adverse reactions when escitalopram oxalate is administered to a nursing woman.
### Pediatric Use
- Safety and effectiveness of escitalopram oxalate has not been established in pediatric patients (less than 12 years of age) with Major Depressive Disorder. Safety and effectiveness of escitalopram oxalate has been established in adolescents (12 to 17 years of age) for the treatment of major depressive disorder. Although maintenance efficacy in adolescent patients with Major Depressive Disorder has not been systematically evaluated, maintenance efficacy can be extrapolated from adult data along with comparisons of escitalopram pharmacokinetic parameters in adults and adolescent patients.
- Safety and effectiveness of escitalopram oxalate has not been established in pediatric patients less than 18 years of age with Generalized Anxiety Disorder.
- Decrease appetite and weight loss have been observed in association with the use of SSRIs. Consequently, regular monitoring of weight and growth should be performed in children and adolescents treated with an SSRI such as escitalopram.
### Geriatic Use
- Approximately 6% of the 1144 patients receiving escitalopram in controlled trials of escitalopram oxalate in major depressive disorder and GAD were 60 years of age or older; elderly patients in these trials received daily doses of escitalopram oxalate between 10 and 20 mg. The number of elderly patients in these trials was insufficient to adequately assess for possible differential efficacy and safety measures on the basis of age. Nevertheless, greater sensitivity of some elderly individuals to effects of escitalopram oxalate cannot be ruled out.
- SSRIs and SNRIs, including escitalopram oxalate, have been associated with cases of clinically significant hyponatremia in elderly patients, who may be at greater risk for this adverse event.
- In two pharmacokinetic studies, escitalopram half-life was increased by approximately 50% in elderly subjects as compared to young subjects and Cmax was unchanged. 10 mg/day is the recommended dose for elderly patients.
- Of 4422 patients in clinical studies of racemic citalopram, 1357 were 60 and over, 1034 were 65 and over, and 457 were 75 and over. 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 again, greater sensitivity of some elderly individuals cannot be ruled out.
### Gender
There is no FDA guidance on the use of Escitalopram with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Escitalopram with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Escitalopram in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Escitalopram in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Escitalopram in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Escitalopram in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Oral
### Monitoring
There is limited information regarding Monitoring of Escitalopram in the drug label.
# IV Compatibility
There is limited information regarding IV Compatibility of Escitalopram in the drug label.
# Overdosage
## Acute Overdose
### Signs and Symptoms
- In clinical trials of escitalopram, there were reports of escitalopram overdose, including overdoses of up to 600 mg, with no associated fatalities. During the postmarketing evaluation of escitalopram, escitalopram oxalate overdoses involving overdoses of over 1000 mg have been reported. As with other SSRIs, a fatal outcome in a patient who has taken an overdose of escitalopram has been rarely reported.
- Symptoms most often accompanying escitalopram overdose, alone or in combination with other drugs and/or alcohol, included convulsions, coma, dizziness, hypotension, insomnia, nausea, vomiting, sinus tachycardia, somnolence, and ECG changes (including QT prolongation and very rare cases of torsade de pointes). Acute renal failure has been very rarely reported accompanying overdose.
### Management
- Establish and maintain an airway to ensure adequate ventilation and oxygenation. Gastric evacuation by lavage and use of activated charcoal should be considered. Careful observation and cardiac and vital sign monitoring are recommended, along with general symptomatic and supportive care. Due to the large volume of distribution of escitalopram, forced diuresis, dialysis, hemoperfusion, and exchange transfusion are unlikely to be of benefit. There are no specific antidotes for escitalopram oxalate.
- 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.
## Chronic Overdose
There is limited information regarding Chronic Overdose of Escitalopram in the drug label.
# Pharmacology
## Mechanism of Action
- The mechanism of antidepressant action of escitalopram, the S-enantiomer of racemic citalopram, is presumed to be linked to potentiation of serotonergic activity in the central nervous system (CNS) resulting from its inhibition of CNS neuronal reuptake of serotonin (5-HT).
## Structure
- Escitalopram oxalate is an orally administered selective serotonin reuptake inhibitor (SSRI). Escitalopram is the pure S-enantiomer (single isomer) of the racemic bicyclic phthalane derivative citalopram. Escitalopram oxalate is designated S-(+)-1--1-(p-fluorophenyl)-5-phthalancarbonitrile oxalate with the following structural formula:
- The molecular formula is C20H21FN2O - C2H2O4 and the molecular weight is 414.40.
- Escitalopram oxalate USP occurs as a white to almost white, crystalline powder and is freely soluble in methanol and dimethyl sulfoxide (DMSO), soluble in isotonic saline solution, sparingly soluble in water and ethanol, slightly soluble in ethyl acetate, and insoluble in heptane.
- Escitalopram oxalate USP is available as tablets.
- Escitalopram tablets USP are film-coated, containing escitalopram oxalate USP in strengths equivalent to 5 mg, 10 mg, and 20 mg escitalopram base. The 10 and 20 mg tablets are scored. The tablets also contain the following inactive ingredients: butylated hydroxyl anisole, butylated hydroxy toluene, colloidal silicon dioxide, croscarmellose sodium, magnesium stearate, microcrystalline cellulose, silicified microcrystalline cellulose, and talc. The film coating contains hypromellose, polyethylene glycol 400, and titanium dioxide.
## Pharmacodynamics
- In vitro and in vivo studies in animals suggest that escitalopram is a highly selective serotonin reuptake inhibitor (SSRI) with minimal effects on norepinephrine and dopamine neuronal reuptake. Escitalopram is at least 100-fold more potent than the R-enantiomer with respect to inhibition of 5-HT reuptake and inhibition of 5-HT neuronal firing rate. Tolerance to a model of antidepressant effect in rats was not induced by long-term (up to 5 weeks) treatment with escitalopram. Escitalopram has no or very low affinity for serotonergic (5-HT1-7) or other receptors including alpha- and beta-adrenergic, dopamine (D1-5), histamine (H1-3), muscarinic (M1-5), and benzodiazepine receptors. Escitalopram also does not bind to, or has low affinity for, various ion channels including Na+, K+, Cl-, and Ca++ channels. Antagonism of muscarinic, histaminergic, and adrenergic receptors has been hypothesized to be associated with various anticholinergic, sedative, and cardiovascular side effects of other psychotropic drugs.
## Pharmacokinetics
- The single- and multiple-dose pharmacokinetics of escitalopram are linear and dose-proportional in a dose range of 10 to 30 mg/day. Biotransformation of escitalopram is mainly hepatic, with a mean terminal half-life of about 27 to 32 hours. With once-daily dosing, steady state plasma concentrations are achieved within approximately one week. At steady state, the extent of accumulation of escitalopram in plasma in young healthy subjects was 2.2 to 2.5 times the plasma concentrations observed after a single dose. The tablet and the oral solution dosage forms of escitalopram oxalate are bioequivalent.
- Absorption and Distribution
- Following a single oral dose (20 mg tablet or solution) of escitalopram, peak blood levels occur at about 5 hours. Absorption of escitalopram is not affected by food.
- The absolute bioavailability of citalopram is about 80% relative to an intravenous dose, and the volume of distribution of citalopram is about 12 L/kg. Data specific on escitalopram are unavailable.
- The binding of escitalopram to human plasma proteins is approximately 56%.
- Metabolism and Elimination
- Following oral administrations of escitalopram, the fraction of drug recovered in the urine as escitalopram and S-demethylcitalopram (S-DCT) is about 8% and 10%, respectively. The oral clearance of escitalopram is 600 mL/min, with approximately 7% of that due to renal clearance.
- Escitalopram is metabolized to S-DCT and S-didemethylcitalopram (S-DDCT). In humans, unchanged escitalopram is the predominant compound in plasma. At steady state, the concentration of the escitalopram metabolite S-DCT in plasma is approximately one-third that of escitalopram. The level of S-DDCT was not detectable in most subjects. In vitro studies show that escitalopram is at least 7 and 27 times more potent than S-DCT and S-DDCT, respectively, in the inhibition of serotonin reuptake, suggesting that the metabolites of escitalopram do not contribute significantly to the antidepressant actions of escitalopram. S-DCT and S-DDCT also have no or very low affinity for serotonergic (5-HT1-7) or other receptors including alpha- and beta-adrenergic, dopamine (D1-5), histamine (H1-3), muscarinic (M1-5), and benzodiazepine receptors. S-DCT and S-DDCT also do not bind to various ion channels including Na+, K+, Cl-, and Ca++ channels.
- In vitro studies using human liver microsomes indicated that CYP3A4 and CYP2C19 are the primary isozymes involved in the N-demethylation of escitalopram.
- Population Subgroups
- Age
- Adolescents - In a single dose study of 10 mg escitalopram, AUC of escitalopram decreased by 19%, and Cmax increased by 26% in healthy adolescent subjects (12 to 17 years of age) compared to adults. Following multiple dosing of 40 mg/day citalopram, escitalopram elimination half-life, steady-state Cmax and AUC were similar in patients with MDD (12 to 17 years of age) compared to adult patients. No adjustment of dosage is needed in adolescent patients.
- Elderly - Escitalopram pharmacokinetics in subjects ≥ 65 years of age were compared to younger subjects in a single-dose and a multiple-dose study. Escitalopram AUC and half-life were increased by approximately 50% in elderly subjects, and Cmax was unchanged. 10 mg is the recommended dose for elderly patients.
- Gender - Based on data from single- and multiple-dose studies measuring escitalopram in elderly, young adults, and adolescents, no dosage adjustment on the basis of gender is needed.
- Reduced Hepatic Function - Citalopram oral clearance was reduced by 37% and half-life was doubled in patients with reduced hepatic function compared to normal subjects. 10 mg is the recommended dose of escitalopram for most hepatically impaired patients.
- Reduced Renal Function - In patients with mild to moderate renal function impairment, oral clearance of citalopram was reduced by 17% compared to normal subjects. No adjustment of dosage for such patients is recommended. No information is available about the pharmacokinetics of escitalopram in patients with severely reduced renal function (creatinine clearance < 20 mL/min).
- Drug-Drug Interactions - In vitro enzyme inhibition data did not reveal an inhibitory effect of escitalopram on CYP3A4, -1A2, -2C9, -2C19, and -2E1. Based on in vitro data, escitalopram would be expected to have little inhibitory effect on in vivo metabolism mediated by these cytochromes. While in vivo data to address this question are limited, results from drug interaction studies suggest that escitalopram, at a dose of 20 mg, has no 3A4 inhibitory effect and a modest 2D6 inhibitory effect.
## Nonclinical Toxicology
- Carcinogenesis
- Racemic citalopram was administered in the diet to NMRI/BOM strain mice and COBS WI strain rats for 18 and 24 months, respectively. There was no evidence for carcinogenicity of racemic citalopram in mice receiving up to 240 mg/kg/day. There was an increased incidence of small intestine carcinoma in rats receiving 8 or 24 mg/kg/day racemic citalopram. A no-effect dose for this finding was not established. The relevance of these findings to humans is unknown.
- Mutagenesis
- Racemic citalopram was mutagenic in the in vitro bacterial reverse mutation assay (Ames test) in 2 of 5 bacterial strains (Salmonella TA98 and TA1537) in the absence of metabolic activation. It was clastogenic in the in vitro Chinese hamster lung cell assay for chromosomal aberrations in the presence and absence of metabolic activation. Racemic citalopram was not mutagenic in the in vitro mammalian forward gene mutation assay (HPRT) in mouse lymphoma cells or in a coupled in vitro/in vivo unscheduled DNA synthesis (UDS) assay in rat liver. It was not clastogenic in the in vitro chromosomal aberration assay in human lymphocytes or in two in vivo mouse micronucleus assays.
- Impairment of Fertility
- When racemic citalopram was administered orally to 16 male and 24 female rats prior to and throughout mating and gestation at doses of 32, 48, and 72 mg/kg/day, mating was decreased at all doses, and fertility was decreased at doses ≥ 32 mg/kg/day. Gestation duration was increased at 48 mg/kg/day.
- Retinal Changes in Rats
- Pathologic changes (degeneration/atrophy) were observed in the retinas of albino rats in the 2-year carcinogenicity study with racemic citalopram. There was an increase in both incidence and severity of retinal pathology in both male and female rats receiving 80 mg/kg/day. Similar findings were not present in rats receiving 24 mg/kg/day of racemic citalopram for two years, in mice receiving up to 240 mg/kg/day of racemic citalopram for 18 months, or in dogs receiving up to 20 mg/kg/day of racemic citalopram for one year.
- Additional studies to investigate the mechanism for this pathology have not been performed, and the potential significance of this effect in humans has not been established.
- Cardiovascular Changes in Dogs
- In a one-year toxicology study, 5 of 10 beagle dogs receiving oral racemic citalopram doses of 8 mg/kg/day died suddenly between weeks 17 and 31 following initiation of treatment. Sudden deaths were not observed in rats at doses of racemic citalopram up to 120 mg/kg/day, which produced plasma levels of citalopram and its metabolites demethylcitalopram and didemethylcitalopram (DDCT) similar to those observed in dogs at 8 mg/kg/day. A subsequent intravenous dosing study demonstrated that in beagle dogs, racemic DDCT caused QT prolongation, a known risk factor for the observed outcome in dogs.
# Clinical Studies
- Adolescents
- The efficacy of escitalopram oxalate as an acute treatment for major depressive disorder in adolescent patients was established in an 8-week, flexible-dose, placebo-controlled study that compared escitalopram oxalate 10 to 20 mg/day to placebo in outpatients 12 to 17 years of age inclusive who met DSM-IV criteria for major depressive disorder. The primary outcome was change from baseline to endpoint in the Children’s Depression Rating Scale - Revised (CDRS-R). In this study, escitalopram oxalate showed statistically significant greater mean improvement compared to placebo on the CDRS-R.
- The efficacy of escitalopram oxalate in the acute treatment of major depressive disorder in adolescents was established, in part, on the basis of extrapolation from the 8-week, flexible-dose, placebo-controlled study with racemic citalopram 20 to 40 mg/day. In this outpatient study in children and adolescents 7 to 17 years of age who met DSM-IV criteria for major depressive disorder, citalopram treatment showed statistically significant greater mean improvement from baseline, compared to placebo, on the CDRS-R; the positive results for this trial largely came from the adolescent subgroup.
- Two additional flexible-dose, placebo-controlled MDD studies (one escitalopram oxalate study in patients ages 7 to 17 and one citalopram study in adolescents) did not demonstrate efficacy.
- Although maintenance efficacy in adolescent patients has not been systematically evaluated, maintenance efficacy can be extrapolated from adult data along with comparisons of escitalopram pharmacokinetic parameters in adults and adolescent patients.
- Adults
- The efficacy of escitalopram oxalate as a treatment for major depressive disorder was established in three, 8-week, placebo-controlled studies conducted in outpatients between 18 and 65 years of age who met DSM-IV criteria for major depressive disorder. The primary outcome in all three studies was change from baseline to endpoint in the Montgomery Asberg Depression Rating Scale (MADRS).
- A fixed-dose study compared 10 mg/day escitalopram oxalate and 20 mg/day escitalopram oxalate to placebo and 40 mg/day citalopram. The 10 mg/day and 20 mg/day escitalopram oxalate treatment groups showed statistically significant greater mean improvement compared to placebo on the MADRS. The 10 mg and 20 mg escitalopram oxalate groups were similar on this outcome measure.
- In a second fixed-dose study of 10 mg/day escitalopram oxalate and placebo, the 10 mg/day escitalopram oxalate treatment group showed statistically significant greater mean improvement compared to placebo on the MADRS.
- In a flexible-dose study, comparing escitalopram oxalate, titrated between 10 and 20 mg/day, to placebo and citalopram, titrated between 20 and 40 mg/day, the escitalopram oxalate treatment group showed statistically significant greater mean improvement compared to placebo on the MADRS.
- Analyses of the relationship between treatment outcome and age, gender, and race did not suggest any differential responsiveness on the basis of these patient characteristics.
- In a longer-term trial, 274 patients meeting (DSM-IV) criteria for major depressive disorder, who had responded during an initial 8-week, open-label treatment phase with escitalopram oxalate 10 or 20 mg/day, were randomized to continuation of escitalopram oxalate at their same dose, or to placebo, for up to 36 weeks of observation for relapse. Response during the open-label phase was defined by having a decrease of the MADRS total score to ≤ 12. Relapse during the double-blind phase was defined as an increase of the MADRS total score to ≥ 22, or discontinuation due to insufficient clinical response. Patients receiving continued escitalopram oxalate experienced a statistically significant longer time to relapse compared to those receiving placebo.
- The efficacy of escitalopram oxalate in the acute treatment of Generalized Anxiety Disorder (GAD) was demonstrated in three, 8-week, multicenter, flexible-dose, placebo-controlled studies that compared escitalopram oxalate 10 to 20 mg/day to placebo in adult outpatients between 18 and 80 years of age who met DSM-IV criteria for GAD. In all three studies, escitalopram oxalate showed statistically significant greater mean improvement compared to placebo on the Hamilton Anxiety Scale (HAM-A).
- There were too few patients in differing ethnic and age groups to adequately assess whether or not escitalopram oxalate has differential effects in these groups. There was no difference in response to escitalopram oxalate between men and women.
# How Supplied
- Escitalopram Tablets USP, 5 mg are white to off-white, round, biconvex film-coated tablets debossed with ‘F’ on one side and ‘53’ on the other side.
- Bottles of 30 NDC 65862-373-30
- Bottles of 90 NDC 65862-373-90
- Bottles of 100 NDC 65862-373-01
- Bottles of 500 NDC 65862-373-05
- Bottles of 10,000 NDC 65862-373-19
- 10 x 10 Unit-dose Tablets NDC 65862-373-10
Escitalopram Tablets USP, 10 mg are white to off-white, oval shaped, biconvex film-coated tablets debossed with ‘F’ on one side and ‘54’ on the other side with a deep scoreline between ‘5’ and ‘4’.
- Bottles of 30 NDC 65862-374-30
- Bottles of 90 NDC 65862-374-90
- Bottles of 100 NDC 65862-374-01
- Bottles of 500 NDC 65862-374-05
- Bottles of 5,000 NDC 65862-374-59
- 10 x 10 Unit-dose Tablets NDC 65862-374-10
Escitalopram Tablets USP, 20 mg are white to off-white, oval shaped, biconvex film-coated tablets debossed with ‘F’ on one side and ‘56’ on the other side with a deep scoreline between ‘5’ and ‘6’.
- Bottles of 30 NDC 65862-375-30
- Bottles of 90 NDC 65862-375-90
- Bottles of 100 NDC 65862-375-01
- Bottles of 500 NDC 65862-375-05
- Bottles of 3,000 NDC 65862-375-39
- 10 x 10 Unit-dose Tablets NDC 65862-375-10
- Storage and Handling
- Store at 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F).
## Storage
There is limited information regarding Escitalopram Storage in the drug label.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- Physicians are advised to discuss the following issues with patients for whom they prescribe escitalopram oxalate.
- Prescribers or other health professionals should inform patients, their families, and their caregivers about the benefits and risks associated with treatment with escitalopram oxalate and should counsel them in its appropriate use. A patient Medication Guide about “Antidepressant Medicines, Depression and other Serious Mental Illness, and Suicidal Thoughts or Actions” is available for escitalopram oxalate. 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 escitalopram oxalate.
- 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.
- Patients should be cautioned about the risk of serotonin syndrome with the concomitant use of escitalopram oxalate with other 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).
- Patients should be cautioned about the concomitant use of escitalopram oxalate and NSAIDs, aspirin, warfarin, or other drugs that affect coagulation since combined use of psychotropic drugs that interfere with serotonin reuptake and these agents has been associated with an increased risk of bleeding.
- Patients should be advised that taking escitalopram oxalate can cause mild pupillary dilation, which in susceptible individuals, can lead to an episode of angle closure glaucoma. Pre-existing glaucoma is almost always open-angle glaucoma because angle closure glaucoma, when diagnosed, can be treated definitively with iridectomy. Open-angle glaucoma is not a risk factor for angle closure glaucoma. Patients may wish to be examined to determine whether they are susceptible to angle closure, and have a prophylactic procedure (e.g., iridectomy), if they are susceptible.
- Since escitalopram is the active isomer of racemic citalopram (Celexa), the two agents should not be coadministered. Patients should be advised to inform their physician if they are taking, or plan to take, any prescription or over-the-counter drugs, as there is a potential for interactions.
- While patients may notice improvement with escitalopram oxalate therapy in 1 to 4 weeks, they should be advised to continue therapy as directed.
- Because psychoactive drugs may impair judgment, thinking, or motor skills, patients should be cautioned about operating hazardous machinery, including automobiles, until they are reasonably certain that escitalopram oxalate therapy does not affect their ability to engage in such activities.
- Patients should be told that, although escitalopram oxalate has not been shown in experiments with normal subjects to increase the mental and motor skill impairments caused by alcohol, the concomitant use of escitalopram oxalate and alcohol in depressed patients is not advised.
- Patients should be advised to notify their physician if they
- become pregnant or intend to become pregnant during therapy.
- are breastfeeding an infant.
- Escitalopram oxalate is indicated as an integral part of a total treatment program for MDD that may include other measures (psychological, educational, social) for patients with this syndrome. Drug treatment may not be indicated for all adolescents with this syndrome. Safety and effectiveness of escitalopram oxalate in MDD has not been established in pediatric patients less than 12 years of age. Antidepressants are not intended for use in the adolescent who exhibits symptoms secondary to environmental factors and/or other primary psychiatric disorders. Appropriate educational placement is essential and psychosocial intervention is often helpful. When remedial measures alone are insufficient, the decision to prescribe antidepressant medication will depend upon the physician’s assessment of the chronicity and severity of the patient’s symptoms.
# Precautions with Alcohol
- Although escitalopram oxalate did not potentiate the cognitive and motor effects of alcohol in a clinical trial, as with other psychotropic medications, the use of alcohol by patients taking escitalopram oxalate is not recommended.
# Brand Names
- Escitalopram®
# Look-Alike Drug Names
There is limited information regarding Escitalopram Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | Escitalopram
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Vignesh Ponnusamy, M.B.B.S. [2]
# Disclaimer
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# Black Box Warning
# Overview
Escitalopram is a selective serotonin reuptake inhibitor (SSRI) that is FDA approved for the {{{indicationType}}} of acute and maintenance treatment of major depressive disorder (MDD) in adults and adolescents aged 12 to 17 years, acute treatment of generalized anxiety disorder (GAD) in adults. There is a Black Box Warning for this drug as shown here. Common adverse reactions include insomnia, ejaculation disorder (primarily ejaculatory delay), nausea, sweating increased, fatigue and somnolence, decreased libido, and anorgasmia.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Dosing Information
- The recommended dose of escitalopram tablets is 10 mg once daily. A fixed-dose trial of escitalopram tablets demonstrated the effectiveness of both 10 mg and 20 mg of escitalopram tablets, but failed to demonstrate a greater benefit of 20 mg over 10 mg. If the dose is increased to 20 mg, this should occur after a minimum of one week.
- Maintenance Treatment
- It is generally agreed that acute episodes of major depressive disorder require several months or longer of sustained pharmacological therapy beyond response to the acute episode. Systematic evaluation of continuing escitalopram tablets 10 or 20 mg/day in adults patients with major depressive disorder who responded while taking escitalopram tablets during an 8-week, acute-treatment phase demonstrated a benefit of such maintenance treatment. Nevertheless, the physician who elects to use escitalopram tablets for extended periods should periodically re-evaluate the long-term usefulness of the drug for the individual patient. Patients should be periodically reassessed to determine the need for maintenance treatment.
- Dosing Information
- The recommended starting dose of escitalopram tablets is 10 mg once daily. If the dose is increased to 20 mg, this should occur after a minimum of one week.
- Maintenance Treatment
- Generalized anxiety disorder is recognized as a chronic condition. The efficacy of escitalopram tablets in the treatment of GAD beyond 8 weeks has not been systematically studied. The physician who elects to use escitalopram tablets for extended periods should periodically re-evaluate the long-term usefulness of the drug for the individual patient.
- Discontinuation of Treatment with Escitalopram Tablets
- Symptoms associated with discontinuation of escitalopram tablets and other SSRIs and SNRIs have been reported. Patients should be monitored for these symptoms when discontinuing treatment. A gradual reduction in the dose rather than abrupt cessation is recommended whenever possible. If intolerable symptoms occur following a decrease in the dose or upon discontinuation of treatment, then resuming the previously prescribed dose may be considered. Subsequently, the physician may continue decreasing the dose but at a more gradual rate.
- Switching a Patient 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 escitalopram tablets. Conversely, at least 14 days should be allowed after stopping escitalopram tablets before starting an MAOI intended to treat psychiatric disorders.
- Use of Escitalopram Tablets with Other MAOIs such as Linezolid or Methylene Blue
- Do not start escitalopram 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 escitalopram tablets therapy 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, escitalopram 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 escitalopram 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 escitalopram tablets is unclear. The clinician should, nevertheless, be aware of the possibility of emergent symptoms of serotonin syndrome with such use.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Escitalopram in adult patients.
### Non–Guideline-Supported Use
- Dosing Information
- Prophylaxis with oral escitalopram.[1]
- Dosing Information
- Escitalopram 10 or 20 mg/day for 16 weeks.[2]
- Dosing Information
- Oral escitalopram 20 mg/day during the luteal phase of the menstrual cycle.[3]
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
- Dosing Information
- Adolescents
- The recommended dose of escitalopram tablets is 10 mg once daily. A flexible-dose trial of escitalopram tablets (10 to 20 mg/day) demonstrated the effectiveness of escitalopram tablets. If the dose is increased to 20 mg, this should occur after a minimum of three weeks.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Escitalopram in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Escitalopram in pediatric patients.
# Contraindications
- Monoamine Oxidase Inhibitors (MAOIs)
- The use of MAOIs intended to treat psychiatric disorders with escitalopram tablets or within 14 days of stopping treatment with escitalopram tablets are contraindicated because of an increased risk of serotonin syndrome. The use of escitalopram tablets within 14 days of stopping an MAOI intended to treat psychiatric disorders are also contraindicated.
- Starting escitalopram 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.
- Pimozide
- Concomitant use in patients taking pimozide is contraindicated.
- Hypersensitivity to Escitalopram or Citalopram
- Escitalopram tablets are contraindicated in patients with a hypersensitivity to escitalopram or citalopram or any of the inactive ingredients in escitalopram tablets.
# Warnings
### Precautions
- 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 to 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 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 the 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.
- If the decision has been made to discontinue treatment, medication should be tapered, as rapidly as is feasible, but with recognition that abrupt discontinuation can be associated with certain 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 escitalopram oxalate 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 escitalopram oxalate is not approved for use in treating bipolar depression.
- Serotonin Syndrome
- The development of a potentially life-threatening serotonin syndrome has been reported with SNRIs and SSRIs, including escitalopram oxalate, alone but particularly with concomitant use of other 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, flushing, 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 escitalopram oxalate with MAOIs intended to treat psychiatric disorders is contraindicated. Escitalopram oxalate 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 escitalopram oxalate. Escitalopram oxalate should be discontinued before initiating treatment with the MAOI.
- If concomitant use of escitalopram oxalate with other serotonergic drugs including, triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, buspirone, tryptophan and St. John’s Wort is clinically warranted, patients should be made aware of a potential increased risk for serotonin syndrome, particularly during treatment initiation and dose increases.
- Treatment with escitalopram oxalate and any concomitant serotonergic agents, should be discontinued immediately if the above events occur and supportive symptomatic treatment should be initiated.
- Discontinuation of Treatment with Escitalopram Oxalate
- During marketing of escitalopram oxalate and other SSRIs and SNRIs (serotonin and norepinephrine reuptake inhibitors), there have been spontaneous reports of adverse events occurring upon discontinuation of these drugs, particularly when abrupt, including the following: dysphoric mood, irritability, agitation, dizziness, sensory disturbances (e.g., paresthesias such as electric shock sensations), anxiety, confusion, headache, lethargy, emotional lability, insomnia, and hypomania. While these events are generally self-limiting, there have been reports of serious discontinuation symptoms.
- Patients should be monitored for these symptoms when discontinuing treatment with escitalopram oxalate. A gradual reduction in the dose rather than abrupt cessation is recommended whenever possible. If intolerable symptoms occur following a decrease in the dose or upon discontinuation of treatment, then resuming the previously prescribed dose may be considered. Subsequently, the physician may continue decreasing the dose but at a more gradual rate.
- Seizures
- Although anticonvulsant effects of racemic citalopram have been observed in animal studies, escitalopram oxalate has not been systematically evaluated in patients with a seizure disorder. These patients were excluded from clinical studies during the product's premarketing testing. In clinical trials of escitalopram oxalate, cases of convulsion have been reported in association with escitalopram oxalate treatment. Like other drugs effective in the treatment of major depressive disorder, escitalopram oxalate should be introduced with care in patients with a history of seizure disorder.
- Activation of Mania/Hypomania
- In placebo-controlled trials of escitalopram oxalate in major depressive disorder, activation of mania/hypomania was reported in one (0.1%) of 715 patients treated with escitalopram oxalate and in none of the 592 patients treated with placebo. One additional case of hypomania has been reported in association with escitalopram oxalate treatment. Activation of mania/hypomania has also been reported in a small proportion of patients with major affective disorders treated with racemic citalopram and other marketed drugs effective in the treatment of major depressive disorder. As with all drugs effective in the treatment of major depressive disorder, escitalopram oxalate should be used cautiously in patients with a history of mania.
- Hyponatremia
- Hyponatremia may occur as a result of treatment with SSRIs and SNRIs, including escitalopram oxalate. In many cases, this hyponatremia appears to be the result of the syndrome of inappropriate antidiuretic hormone secretion (SIADH), and was reversible when escitalopram oxalate was discontinued. Cases with serum sodium lower than 110 mmol/L have been reported. Elderly patients may be at greater risk of developing hyponatremia with SSRIs and SNRIs. Also, patients taking diuretics or who are otherwise volume depleted may be at greater risk. Discontinuation of escitalopram oxalate should be considered in patients with symptomatic hyponatremia and appropriate medical intervention should be instituted.
- Signs and symptoms of hyponatremia include headache, difficulty concentrating, memory impairment, confusion, weakness, and unsteadiness, which may lead to falls. Signs and symptoms associated with more severe and/or acute cases have included hallucination, syncope, seizure, coma, respiratory arrest, and death.
- Abnormal Bleeding
- SSRIs and SNRIs, including escitalopram oxalate, may increase the risk of bleeding events. Concomitant use of aspirin, nonsteroidal anti-inflammatory drugs, warfarin, and other anticoagulants may add to the risk. Case reports and epidemiological studies (case-control and cohort design) have demonstrated an association between use of drugs that interfere with serotonin reuptake and the occurrence of gastrointestinal bleeding. Bleeding events related to SSRIs and SNRIs use have ranged from ecchymoses, hematomas, epistaxis, and petechiae to life-threatening hemorrhages.
- Patients should be cautioned about the risk of bleeding associated with the concomitant use of escitalopram oxalate and NSAIDs, aspirin, or other drugs that affect coagulation.
- Interference with Cognitive and Motor Performance
- In a study in normal volunteers, escitalopram oxalate 10 mg/day did not produce impairment of intellectual function or psychomotor performance. Because any psychoactive drug may impair judgment, thinking, or motor skills, however, patients should be cautioned about operating hazardous machinery, including automobiles, until they are reasonably certain that escitalopram oxalate therapy does not affect their ability to engage in such activities.
- Angle Closure Glaucoma
- Angle-Closure Glaucoma: The pupillary dilation that occurs following use of many antidepressant drugs including escitalopram oxalate may trigger an angle closure attack in a patient with anatomically narrow angles who does not have a patent iridectomy.
- Use in Patients with Concomitant Illness
- Clinical experience with escitalopram oxalate in patients with certain concomitant systemic illnesses is limited. Caution is advisable in using escitalopram oxalate in patients with diseases or conditions that produce altered metabolism or hemodynamic responses.
- Escitalopram oxalate has not been systematically evaluated in patients with a recent history of myocardial infarction or unstable heart disease. Patients with these diagnoses were generally excluded from clinical studies during the product's premarketing testing.
- In subjects with hepatic impairment, clearance of racemic citalopram was decreased and plasma concentrations were increased. The recommended dose of escitalopram oxalate in hepatically impaired patients is 10 mg/day.
- Because escitalopram is extensively metabolized, excretion of unchanged drug in urine is a minor route of elimination. Until adequate numbers of patients with severe renal impairment have been evaluated during chronic treatment with escitalopram oxalate, however, it should be used with caution in such patients.
# 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 the rates observed in practice.
- Pediatrics (6 to 17 years)
- Adverse events were collected in 576 pediatric patients (286 escitalopram oxalate, 290 placebo) with major depressive disorder in double-blind placebo-controlled studies. Safety and effectiveness of escitalopram oxalate in pediatric patients less than 12 years of age has not been established.
- Adults
- Adverse events information for escitalopram oxalate was collected from 715 patients with major depressive disorder who were exposed to escitalopram and from 592 patients who were exposed to placebo in double-blind, placebo-controlled trials. An additional 284 patients with major depressive disorder were newly exposed to escitalopram in open-label trials. The adverse event information for escitalopram oxalate in patients with GAD was collected from 429 patients exposed to escitalopram and from 427 patients exposed to placebo in double-blind, placebo-controlled trials.
- Adverse events during exposure were obtained primarily by general inquiry and 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 events into a smaller number of standardized event categories. In the tables and tabulations that follow, standard World Health Organization (WHO) terminology has been used to classify reported adverse events.
- The stated frequencies of adverse reactions represent the proportion of individuals who experienced, at least once, a treatment-emergent adverse event of the type listed. An event was considered treatment-emergent if it occurred for the first time or worsened while receiving therapy following baseline evaluation.
- Pediatrics (6 to 17 years)
- Adverse events were associated with discontinuation of 3.5% of 286 patients receiving escitalopram oxalate and 1% of 290 patients receiving placebo. The most common adverse event (incidence at least 1% for escitalopram oxalate and greater than placebo) associated with discontinuation was insomnia (1% escitalopram oxalate, 0% placebo).
- Adults
- Among the 715 depressed patients who received escitalopram oxalate in placebo-controlled trials, 6% discontinued treatment due to an adverse event, as compared to 2% of 592 patients receiving placebo. In two fixed-dose studies, the rate of discontinuation for adverse events in patients receiving 10 mg/day escitalopram oxalate was not significantly different from the rate of discontinuation for adverse events in patients receiving placebo. The rate of discontinuation for adverse events in patients assigned to a fixed dose of 20 mg/day escitalopram oxalate was 10%, which was significantly different from the rate of discontinuation for adverse events in patients receiving 10 mg/day escitalopram oxalate (4%) and placebo (3%). Adverse events that were associated with the discontinuation of at least 1% of patients treated with escitalopram oxalate, and for which the rate was at least twice that of placebo, were nausea (2%) and ejaculation disorder (2% of male patients).
- Adults
- Among the 429 GAD patients who received escitalopram oxalate 10 to 20 mg/day in placebo-controlled trials, 8% discontinued treatment due to an adverse event, as compared to 4% of 427 patients receiving placebo. Adverse events that were associated with the discontinuation of at least 1% of patients treated with escitalopram oxalate, and for which the rate was at least twice the placebo rate, were nausea (2%), insomnia (1%), and fatigue (1%).
- Pediatrics (6 to 17 years)
- The overall profile of adverse reactions in pediatric patients was generally similar to that seen in adult studies, as shown in Table 2. However, the following adverse reactions (excluding those which appear in Table 2 and those for which the coded terms were uninformative or misleading) were reported at an incidence of at least 2% for escitalopram oxalate and greater than placebo: back pain, urinary tract infection, vomiting, and nasal congestion.
- Adults
- The most commonly observed adverse reactions in escitalopram oxalate patients (incidence of approximately 5% or greater and approximately twice the incidence in placebo patients) were insomnia, ejaculation disorder (primarily ejaculatory delay), nausea, sweating increased, fatigue, and somnolence.
- Table 2 enumerates the incidence, rounded to the nearest percent, of treatment-emergent adverse events that occurred among 715 depressed patients who received escitalopram oxalate at doses ranging from 10 to 20 mg/day in placebo-controlled trials. Events included are those occurring in 2% or more of patients treated with escitalopram oxalate and for which the incidence in patients treated with escitalopram oxalate was greater than the incidence in placebo-treated patients.
- Adults
- The most commonly observed adverse reactions in escitalopram oxalate patients (incidence of approximately 5% or greater and approximately twice the incidence in placebo patients) were nausea, ejaculation disorder (primarily ejaculatory delay), insomnia, fatigue, decreased libido, and anorgasmia.
- Table 3 enumerates the incidence, rounded to the nearest percent of treatment-emergent adverse events that occurred among 429 GAD patients who received escitalopram oxalate 10 to 20 mg/day in placebo-controlled trials. Events included are those occurring in 2% or more of patients treated with escitalopram oxalate and for which the incidence in patients treated with escitalopram oxalate was greater than the incidence in placebo-treated patients.
- The potential dose dependency of common adverse reactions (defined as an incidence rate of ≥5% in either the 10 mg or 20 mg escitalopram oxalate groups) was examined on the basis of the combined incidence of adverse reactions in two fixed-dose trials. The overall incidence rates of adverse events in 10 mg escitalopram oxalate-treated patients (66%) was similar to that of the placebo-treated patients (61%), while the incidence rate in 20 mg/day escitalopram oxalate-treated patients was greater (86%). Table 4 shows common adverse reactions that occurred in the 20 mg/day escitalopram oxalate group with an incidence that was approximately twice that of the 10 mg/day escitalopram oxalate group and approximately twice that of the placebo group.
- Although changes in sexual desire, sexual performance, and sexual satisfaction often occur as manifestations of a psychiatric disorder, they may also be a consequence of pharmacologic treatment. In particular, some evidence suggests that SSRIs can cause such untoward sexual experiences.
- Reliable estimates of the incidence and severity of untoward experiences involving sexual desire, performance, and satisfaction are difficult to obtain, however, in part 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 their actual incidence.
- There are no adequately designed studies examining sexual dysfunction with escitalopram treatment.
- Priapism has been reported with all SSRIs.
- While it is difficult to know the precise risk of sexual dysfunction associated with the use of SSRIs, physicians should routinely inquire about such possible side effects.
- Escitalopram oxalate and placebo groups were compared with respect to (1) mean change from baseline in vital signs (pulse, systolic blood pressure, and diastolic blood pressure) and (2) the incidence of patients meeting criteria for potentially clinically significant changes from baseline in these variables. These analyses did not reveal any clinically important changes in vital signs associated with escitalopram oxalate treatment. In addition, a comparison of supine and standing vital sign measures in subjects receiving escitalopram oxalate indicated that escitalopram oxalate treatment is not associated with orthostatic changes.
- Patients treated with escitalopram oxalate in controlled trials did not differ from placebo-treated patients with regard to clinically important change in body weight.
- Escitalopram oxalate and placebo groups were compared with respect to (1) mean change from baseline in various serum chemistry, hematology, and urinalysis variables, and (2) the incidence of patients meeting criteria for potentially clinically significant changes from baseline in these variables. These analyses revealed no clinically important changes in laboratory test parameters associated with escitalopram oxalate treatment.
- Electrocardiograms from escitalopram oxalate (N=625) and placebo (N=527) groups were compared with respect to outliers defined as subjects with QTc changes over 60 msec from baseline or absolute values over 500 msec post-dose, and subjects with heart rate increases to over 100 bpm or decreases to less than 50 bpm with a 25% change from baseline (tachycardic or bradycardic outliers, respectively). None of the patients in the escitalopram oxalate group had a QTcF interval >500 msec or a prolongation >60 msec compared to 0.2% of patients in the placebo group. The incidence of tachycardic outliers was 0.2% in the escitalopram oxalate and the placebo group. The incidence of bradycardic outliers was 0.5% in the escitalopram oxalate group and 0.2% in the placebo group.
- QTcF interval was evaluated in a randomized, placebo and active (moxifloxacin 400 mg) controlled cross-over, escalating multiple-dose study in 113 healthy subjects. The maximum mean (95% upper confidence bound) difference from placebo arm were 4.5 (6.4) and 10.7 (12.7) msec for 10 mg and supratherapeutic 30 mg escitalopram given once daily, respectively. Based on the established exposure-response relationship, the predicted QTcF change from placebo arm (95% confidence interval) under the Cmax for the dose of 20 mg is 6.6 (7.9) msec. Escitalopram 30 mg given once daily resulted in mean Cmax of 1.7-fold higher than the mean Cmax for the maximum recommended therapeutic dose at steady state (20 mg). The exposure under supratherapeutic 30 mg dose is similar to the steady state concentrations expected in CYP2C19 poor metabolizers following a therapeutic dose of 20 mg.
- Following is a list of treatment-emergent adverse events, as defined in the introduction to the ADVERSE REACTIONS section, reported by the 1428 patients treated with escitalopram oxalate for periods of up to one year in double-blind or open-label clinical trials during its premarketing evaluation. The listing does not include those events already listed in Tables 2 & 3, those events for which a drug cause was remote and at a rate less than 1% or lower than placebo, those events which were so general as to be uninformative, and those events reported only once which did not have a substantial probability of being acutely life threatening. Events are categorized by body system. Events of major clinical importance are described in the Warnings and Precautions section (5).
Hypertension, palpitation.
Light-Headed feeling, migraine.
Abdominal Cramp, heartburn, gastroenteritis.
Allergy, chest pain, fever, hot flushes, pain in limb.
Increased weight.
Arthralgia, myalgia, jaw stiffness.
Appetite increased, concentration impaired, irritability.
Menstrual cramps, menstrual disorder.
Bronchitis, coughing, nasal congestion, sinus congestion, sinus headache.
Rash.
Vision blurred, tinnitus.
Urinary frequency, urinary tract infection.
## Postmarketing Experience
- The following additional adverse reactions have been identified from spontaneous reports of escitalopram received worldwide. These adverse reactions have been chosen for inclusion because of a combination of seriousness, frequency of reporting, or potential causal connection to escitalopram and have not been listed elsewhere in labeling. However, because these adverse reactions were 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 events include:
Anemia, agranulocytis, aplastic anemia, hemolytic anemia, idiopathic thrombocytopenia purpura, leukopenia, thrombocytopenia.
Atrial fibrillation, bradycardia, cardiac failure, myocardial infarction, tachycardia, torsade de pointes, ventricular arrhythmia, ventricular tachycardia.
Vertigo.
Diabetes mellitus, hyperprolactinemia, SIADH.
Angle closure glaucoma, diplopia, mydriasis, visual disturbance.
Dysphagia, gastrointestinal hemorrhage, gastroesophageal reflux, pancreatitis, rectal hemorrhage.
Abnormal gait, asthenia, edema, fall, feeling abnormal, malaise.
Fulminant hepatitis, hepatic failure, hepatic necrosis, hepatitis.
Allergic reaction, anaphylaxis.
Bilirubin increased, decreased weight, electrocardiogram QT prolongation, hepatic enzymes increased, hypercholesterolemia, INR increased, prothrombin decreased.
Hyperglycemia, hypoglycemia, hypokalemia, hyponatremia.
Muscle cramp, muscle stiffness, muscle weakness, rhabdomyolysis.
Akathisia, amnesia, ataxia, choreoathetosis, cerebrovascular accident, dysarthria, dyskinesia, dystonia, extrapyramidal disorders, grand mal seizures (or convulsions), hypoaesthesia, myoclonus, nystagmus, Parkinsonism, restless legs, seizures, syncope, tardive dyskinesia, tremor.
Spontaneous abortion.
Acute psychosis, aggression, agitation, anger, anxiety, apathy, completed suicide, confusion, depersonalization, depression aggravated, delirium, delusion, disorientation, feeling unreal, hallucinations (visual and auditory), mood swings, nervousness, nightmare, panic reaction, paranoia, restlessness, self-harm or thoughts of self-harm, suicide attempt, suicidal ideation, suicidal tendency.
Acute renal failure, dysuria, urinary retention.
Menorrhagia, priapism.
Dyspnea, epistaxis, pulmonary embolism, pulmonary hypertension of the newborn.
Alopecia, angioedema, dermatitis, ecchymosis, erythema multiforme, photosensitivity reaction, Stevens Johnson Syndrome, toxic epidermal necrolysis, urticaria.
Deep vein thrombosis, flushing, hypertensive crisis, hypotension, orthostatic hypotension, phlebitis, thrombosis.
# Drug Interactions
- Monoamine Oxidase Inhibitors (MAOIs)
- Do not start escitalopram 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 escitalopram tablets therapy 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, escitalopram 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 escitalopram 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 escitalopram tablets is unclear. The clinician should, nevertheless, be aware of the possibility of emergent symptoms of serotonin syndrome with such use.
- Serotonergic Drugs
- The development of a potentially life-threatening serotonin syndrome has been reported with SNRIs and SSRIs, including escitalopram oxalate, alone but particularly with concomitant use of other 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, flushing, 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 escitalopram oxalate with MAOIs intended to treat psychiatric disorders is contraindicated. Escitalopram oxalate 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 escitalopram oxalate. Escitalopram oxalate should be discontinued before initiating treatment with the MAOI.
- If concomitant use of escitalopram oxalate with other serotonergic drugs including, triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, buspirone, tryptophan and St. John’s Wort is clinically warranted, patients should be made aware of a potential increased risk for serotonin syndrome, particularly during treatment initiation and dose increases.
- Treatment with escitalopram oxalate and any concomitant serotonergic agents, should be discontinued immediately if the above events occur and supportive symptomatic treatment should be initiated.
- Triptans
- There have been rare postmarketing reports of serotonin syndrome with use of an SSRI and a triptan. If concomitant treatment of escitalopram oxalate with a triptan is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases.
- CNS Drugs
- Given the primary CNS effects of escitalopram, caution should be used when it is taken in combination with other centrally acting drugs.
- Alcohol
- Although escitalopram oxalate did not potentiate the cognitive and motor effects of alcohol in a clinical trial, as with other psychotropic medications, the use of alcohol by patients taking escitalopram oxalate is not recommended.
- Drugs That Interfere With Hemostasis (NSAIDs, Aspirin, Warfarin, etc.)
- Serotonin release by platelets plays an important role in hemostasis. Epidemiological studies of the case-control and cohort design that have demonstrated an association between use of psychotropic drugs that interfere with serotonin reuptake and the occurrence of upper gastrointestinal bleeding have also shown that concurrent use of an NSAID or aspirin may potentiate the risk of bleeding. Altered anticoagulant effects, including increased bleeding, have been reported when SSRIs and SNRIs are coadministered with warfarin. Patients receiving warfarin therapy should be carefully monitored when escitalopram oxalate is initiated or discontinued.
- Cimetidine
- In subjects who had received 21 days of 40 mg/day racemic citalopram, combined administration of 400 mg twice a day cimetidine for 8 days resulted in an increase in citalopram AUC and Cmax of 43% and 39%, respectively. The clinical significance of these findings is unknown.
- Digoxin
- In subjects who had received 21 days of 40 mg/day racemic citalopram, combined administration of citalopram and digoxin (single dose of 1 mg) did not significantly affect the pharmacokinetics of either citalopram or digoxin.
- Lithium
- Coadministration of racemic citalopram (40 mg/day for 10 days) and lithium (30 mmol/day for 5 days) had no significant effect on the pharmacokinetics of citalopram or lithium. Nevertheless, plasma lithium levels should be monitored with appropriate adjustment to the lithium dose in accordance with standard clinical practice. Because lithium may enhance the serotonergic effects of escitalopram, caution should be exercised when escitalopram oxalate and lithium are coadministered.
- Pimozide and Celexa
- In a controlled study, a single dose of pimozide 2 mg coadministered with racemic citalopram 40 mg given once daily for 11 days was associated with a mean increase in QTc values of approximately 10 msec compared to pimozide given alone. Racemic citalopram did not alter the mean AUC or Cmax of pimozide. The mechanism of this pharmacodynamic interaction is not known.
- Sumatriptan
- There have been rare postmarketing reports describing patients with weakness, hyperreflexia, and incoordination following the use of an SSRI and sumatriptan. If concomitant treatment with sumatriptan and an SSRI (e.g., fluoxetine, fluvoxamine, paroxetine, sertraline, citalopram, escitalopram) is clinically warranted, appropriate observation of the patient is advised.
- Theophylline
- Combined administration of racemic citalopram (40 mg/day for 21 days) and the CYP1A2 substrate theophylline (single dose of 300 mg) did not affect the pharmacokinetics of theophylline. The effect of theophylline on the pharmacokinetics of citalopram was not evaluated.
- Warfarin
- Administration of 40 mg/day racemic citalopram for 21 days did not affect the pharmacokinetics of warfarin, a CYP3A4 substrate. Prothrombin time was increased by 5%, the clinical significance of which is unknown.
- Carbamazepine
- Combined administration of racemic citalopram (40 mg/day for 14 days) and carbamazepine (titrated to 400 mg/day for 35 days) did not significantly affect the pharmacokinetics of carbamazepine, a CYP3A4 substrate. Although trough citalopram plasma levels were unaffected, given the enzyme-inducing properties of carbamazepine, the possibility that carbamazepine might increase the clearance of escitalopram should be considered if the two drugs are coadministered.
- Triazolam
- Combined administration of racemic citalopram (titrated to 40 mg/day for 28 days) and the CYP3A4 substrate triazolam (single dose of 0.25 mg) did not significantly affect the pharmacokinetics of either citalopram or triazolam.
- Ketoconazole
- Combined administration of racemic citalopram (40 mg) and ketoconazole (200 mg), a potent CYP3A4 inhibitor, decreased the Cmax and AUC of ketoconazole by 21% and 10%, respectively, and did not significantly affect the pharmacokinetics of citalopram.
- Ritonavir
- Combined administration of a single dose of ritonavir (600 mg), both a CYP3A4 substrate and a potent inhibitor of CYP3A4, and escitalopram (20 mg) did not affect the pharmacokinetics of either ritonavir or escitalopram.
- CYP3A4 and -2C19 Inhibitors
- In vitro studies indicated that CYP3A4 and -2C19 are the primary enzymes involved in the metabolism of escitalopram. However, coadministration of escitalopram (20 mg) and ritonavir (600 mg), a potent inhibitor of CYP3A4, did not significantly affect the pharmacokinetics of escitalopram. Because escitalopram is metabolized by multiple enzyme systems, inhibition of a single enzyme may not appreciably decrease escitalopram clearance.
- Drugs Metabolized by Cytochrome P4502D6
- In vitro studies did not reveal an inhibitory effect of escitalopram on CYP2D6. In addition, steady state levels of racemic citalopram were not significantly different in poor metabolizers and extensive CYP2D6 metabolizers after multiple-dose administration of citalopram, suggesting that coadministration, with escitalopram, of a drug that inhibits CYP2D6, is unlikely to have clinically significant effects on escitalopram metabolism. However, there are limited in vivo data suggesting a modest CYP2D6 inhibitory effect for escitalopram, i.e., coadministration of escitalopram (20 mg/day for 21 days) with the tricyclic antidepressant desipramine (single dose of 50 mg), a substrate for CYP2D6, resulted in a 40% increase in Cmax and a 100% increase in AUC of desipramine. The clinical significance of this finding is unknown. Nevertheless, caution is indicated in the coadministration of escitalopram and drugs metabolized by CYP2D6.
- Metoprolol
- Administration of 20 mg/day escitalopram oxalate for 21 days in healthy volunteers resulted in a 50% increase in Cmax and 82% increase in AUC of the beta-adrenergic blocker metoprolol (given in a single dose of 100 mg). Increased metoprolol plasma levels have been associated with decreased cardioselectivity. Coadministration of escitalopram oxalate and metoprolol had no clinically significant effects on blood pressure or heart rate.
- Electroconvulsive Therapy (ECT)
- There are no clinical studies of the combined use of ECT and escitalopram.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
- Pregnancy Category C
- In a rat embryo/fetal development study, oral administration of escitalopram (56, 112, or 150 mg/kg/day) to pregnant animals during the period of organogenesis resulted in decreased fetal body weight and associated delays in ossification at the two higher doses (approximately ≥ 56 times the maximum recommended human dose [MRHD] of 20 mg/day on a body surface area [mg/m2] basis). Maternal toxicity (clinical signs and decreased body weight gain and food consumption), mild at 56 mg/kg/day, was present at all dose levels. The developmental no-effect dose of 56 mg/kg/day is approximately 28 times the MRHD on a mg/m2 basis. No teratogenicity was observed at any of the doses tested (as high as 75 times the MRHD on a mg/m2 basis).
- When female rats were treated with escitalopram (6, 12, 24, or 48 mg/kg/day) during pregnancy and through weaning, slightly increased offspring mortality and growth retardation were noted at 48 mg/kg/day which is approximately 24 times the MRHD on a mg/m2 basis. Slight maternal toxicity (clinical signs and decreased body weight gain and food consumption) was seen at this dose. Slightly increased offspring mortality was also seen at 24 mg/kg/day. The no-effect dose was 12 mg/kg/day which is approximately 6 times the MRHD on a mg/m2 basis.
- In animal reproduction studies, racemic citalopram has been shown to have adverse effects on embryo/fetal and postnatal development, including teratogenic effects, when administered at doses greater than human therapeutic doses.
- In two rat embryo/fetal development studies, oral administration of racemic citalopram (32, 56, or 112 mg/kg/day) to pregnant animals during the period of organogenesis resulted in decreased embryo/fetal growth and survival and an increased incidence of fetal abnormalities (including cardiovascular and skeletal defects) at the high dose. This dose was also associated with maternal toxicity (clinical signs, decreased body weight gain). The developmental no-effect dose was 56 mg/kg/day. In a rabbit study, no adverse effects on embryo/fetal development were observed at doses of racemic citalopram of up to 16 mg/kg/day. Thus, teratogenic effects of racemic citalopram were observed at a maternally toxic dose in the rat and were not observed in the rabbit.
- When female rats were treated with racemic citalopram (4.8, 12.8, or 32 mg/kg/day) from late gestation through weaning, increased offspring mortality during the first 4 days after birth and persistent offspring growth retardation were observed at the highest dose. The no-effect dose was 12.8 mg/kg/day. Similar effects on offspring mortality and growth were seen when dams were treated throughout gestation and early lactation at doses ≥ 24 mg/kg/day. A no-effect dose was not determined in that study.
- There are no adequate and well-controlled studies in pregnant women; therefore, escitalopram should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
- Pregnancy-Nonteratogenic Effects
- Neonates exposed to escitalopram oxalate and other SSRIs or serotonin and norepinephrine reuptake inhibitors (SNRIs), late in the third trimester have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding. Such complications can arise immediately upon delivery. Reported clinical findings have included respiratory distress, cyanosis, apnea, seizures, temperature instability, feeding difficulty, vomiting, hypoglycemia, hypotonia, hypertonia, hyperreflexia, tremor, jitteriness, irritability, and constant crying. These features are consistent with either a direct toxic effect of SSRIs and SNRIs or, possibly, a drug discontinuation syndrome. It should be noted that, in some cases, the clinical picture is consistent with serotonin syndrome.
- Infants exposed to SSRIs in pregnancy may have an increased risk for persistent pulmonary hypertension of the newborn (PPHN). PPHN occurs in 1 to 2 per 1,000 live births in the general population and is associated with substantial neonatal morbidity and mortality. Several recent epidemiologic studies suggest a positive statistical association between SSRI use (including escitalopram oxalate) in pregnancy and PPHN. Other studies do not show a significant statistical association.
- Physicians should also note the results of a prospective longitudinal study of 201 pregnant women with a history of major depression, who were either on antidepressants or had received antidepressants less than 12 weeks prior to their last menstrual period, and were in remission. Women who discontinued antidepressant medication during pregnancy showed a significant increase in relapse of their major depression compared to those women who remained on antidepressant medication throughout pregnancy.
- When treating a pregnant woman with escitalopram oxalate, the physician should carefully consider both the potential risks of taking an SSRI, along with the established benefits of treating depression with an antidepressant. This decision can only be made on a case by case basis.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Escitalopram in women who are pregnant.
### Labor and Delivery
- The effect of escitalopram oxalate on labor and delivery in humans is unknown.
### Nursing Mothers
- Escitalopram is excreted in human breast milk. Limited data from women taking 10 to 20 mg escitalopram showed that exclusively breastfed infants receive approximately 3.9% of the maternal weight-adjusted dose of escitalopram and 1.7% of the maternal weight-adjusted dose of desmethylcitalopram. There were two reports of infants experiencing excessive somnolence, decreased feeding, and weight loss in association with breastfeeding from a racemic citalopram-treated mother; in one case, the infant was reported to recover completely upon discontinuation of racemic citalopram by its mother and, in the second case, no follow-up information was available. Caution should be exercised and breastfeeding infants should be observed for adverse reactions when escitalopram oxalate is administered to a nursing woman.
### Pediatric Use
- Safety and effectiveness of escitalopram oxalate has not been established in pediatric patients (less than 12 years of age) with Major Depressive Disorder. Safety and effectiveness of escitalopram oxalate has been established in adolescents (12 to 17 years of age) for the treatment of major depressive disorder. Although maintenance efficacy in adolescent patients with Major Depressive Disorder has not been systematically evaluated, maintenance efficacy can be extrapolated from adult data along with comparisons of escitalopram pharmacokinetic parameters in adults and adolescent patients.
- Safety and effectiveness of escitalopram oxalate has not been established in pediatric patients less than 18 years of age with Generalized Anxiety Disorder.
- Decrease appetite and weight loss have been observed in association with the use of SSRIs. Consequently, regular monitoring of weight and growth should be performed in children and adolescents treated with an SSRI such as escitalopram.
### Geriatic Use
- Approximately 6% of the 1144 patients receiving escitalopram in controlled trials of escitalopram oxalate in major depressive disorder and GAD were 60 years of age or older; elderly patients in these trials received daily doses of escitalopram oxalate between 10 and 20 mg. The number of elderly patients in these trials was insufficient to adequately assess for possible differential efficacy and safety measures on the basis of age. Nevertheless, greater sensitivity of some elderly individuals to effects of escitalopram oxalate cannot be ruled out.
- SSRIs and SNRIs, including escitalopram oxalate, have been associated with cases of clinically significant hyponatremia in elderly patients, who may be at greater risk for this adverse event.
- In two pharmacokinetic studies, escitalopram half-life was increased by approximately 50% in elderly subjects as compared to young subjects and Cmax was unchanged. 10 mg/day is the recommended dose for elderly patients.
- Of 4422 patients in clinical studies of racemic citalopram, 1357 were 60 and over, 1034 were 65 and over, and 457 were 75 and over. 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 again, greater sensitivity of some elderly individuals cannot be ruled out.
### Gender
There is no FDA guidance on the use of Escitalopram with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Escitalopram with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Escitalopram in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Escitalopram in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Escitalopram in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Escitalopram in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Oral
### Monitoring
There is limited information regarding Monitoring of Escitalopram in the drug label.
# IV Compatibility
There is limited information regarding IV Compatibility of Escitalopram in the drug label.
# Overdosage
## Acute Overdose
### Signs and Symptoms
- In clinical trials of escitalopram, there were reports of escitalopram overdose, including overdoses of up to 600 mg, with no associated fatalities. During the postmarketing evaluation of escitalopram, escitalopram oxalate overdoses involving overdoses of over 1000 mg have been reported. As with other SSRIs, a fatal outcome in a patient who has taken an overdose of escitalopram has been rarely reported.
- Symptoms most often accompanying escitalopram overdose, alone or in combination with other drugs and/or alcohol, included convulsions, coma, dizziness, hypotension, insomnia, nausea, vomiting, sinus tachycardia, somnolence, and ECG changes (including QT prolongation and very rare cases of torsade de pointes). Acute renal failure has been very rarely reported accompanying overdose.
### Management
- Establish and maintain an airway to ensure adequate ventilation and oxygenation. Gastric evacuation by lavage and use of activated charcoal should be considered. Careful observation and cardiac and vital sign monitoring are recommended, along with general symptomatic and supportive care. Due to the large volume of distribution of escitalopram, forced diuresis, dialysis, hemoperfusion, and exchange transfusion are unlikely to be of benefit. There are no specific antidotes for escitalopram oxalate.
- 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.
## Chronic Overdose
There is limited information regarding Chronic Overdose of Escitalopram in the drug label.
# Pharmacology
## Mechanism of Action
- The mechanism of antidepressant action of escitalopram, the S-enantiomer of racemic citalopram, is presumed to be linked to potentiation of serotonergic activity in the central nervous system (CNS) resulting from its inhibition of CNS neuronal reuptake of serotonin (5-HT).
## Structure
- Escitalopram oxalate is an orally administered selective serotonin reuptake inhibitor (SSRI). Escitalopram is the pure S-enantiomer (single isomer) of the racemic bicyclic phthalane derivative citalopram. Escitalopram oxalate is designated S-(+)-1-[3-(dimethyl-amino)propyl]-1-(p-fluorophenyl)-5-phthalancarbonitrile oxalate with the following structural formula:
- The molecular formula is C20H21FN2O • C2H2O4 and the molecular weight is 414.40.
- Escitalopram oxalate USP occurs as a white to almost white, crystalline powder and is freely soluble in methanol and dimethyl sulfoxide (DMSO), soluble in isotonic saline solution, sparingly soluble in water and ethanol, slightly soluble in ethyl acetate, and insoluble in heptane.
- Escitalopram oxalate USP is available as tablets.
- Escitalopram tablets USP are film-coated, containing escitalopram oxalate USP in strengths equivalent to 5 mg, 10 mg, and 20 mg escitalopram base. The 10 and 20 mg tablets are scored. The tablets also contain the following inactive ingredients: butylated hydroxyl anisole, butylated hydroxy toluene, colloidal silicon dioxide, croscarmellose sodium, magnesium stearate, microcrystalline cellulose, silicified microcrystalline cellulose, and talc. The film coating contains hypromellose, polyethylene glycol 400, and titanium dioxide.
## Pharmacodynamics
- In vitro and in vivo studies in animals suggest that escitalopram is a highly selective serotonin reuptake inhibitor (SSRI) with minimal effects on norepinephrine and dopamine neuronal reuptake. Escitalopram is at least 100-fold more potent than the R-enantiomer with respect to inhibition of 5-HT reuptake and inhibition of 5-HT neuronal firing rate. Tolerance to a model of antidepressant effect in rats was not induced by long-term (up to 5 weeks) treatment with escitalopram. Escitalopram has no or very low affinity for serotonergic (5-HT1-7) or other receptors including alpha- and beta-adrenergic, dopamine (D1-5), histamine (H1-3), muscarinic (M1-5), and benzodiazepine receptors. Escitalopram also does not bind to, or has low affinity for, various ion channels including Na+, K+, Cl-, and Ca++ channels. Antagonism of muscarinic, histaminergic, and adrenergic receptors has been hypothesized to be associated with various anticholinergic, sedative, and cardiovascular side effects of other psychotropic drugs.
## Pharmacokinetics
- The single- and multiple-dose pharmacokinetics of escitalopram are linear and dose-proportional in a dose range of 10 to 30 mg/day. Biotransformation of escitalopram is mainly hepatic, with a mean terminal half-life of about 27 to 32 hours. With once-daily dosing, steady state plasma concentrations are achieved within approximately one week. At steady state, the extent of accumulation of escitalopram in plasma in young healthy subjects was 2.2 to 2.5 times the plasma concentrations observed after a single dose. The tablet and the oral solution dosage forms of escitalopram oxalate are bioequivalent.
- Absorption and Distribution
- Following a single oral dose (20 mg tablet or solution) of escitalopram, peak blood levels occur at about 5 hours. Absorption of escitalopram is not affected by food.
- The absolute bioavailability of citalopram is about 80% relative to an intravenous dose, and the volume of distribution of citalopram is about 12 L/kg. Data specific on escitalopram are unavailable.
- The binding of escitalopram to human plasma proteins is approximately 56%.
- Metabolism and Elimination
- Following oral administrations of escitalopram, the fraction of drug recovered in the urine as escitalopram and S-demethylcitalopram (S-DCT) is about 8% and 10%, respectively. The oral clearance of escitalopram is 600 mL/min, with approximately 7% of that due to renal clearance.
- Escitalopram is metabolized to S-DCT and S-didemethylcitalopram (S-DDCT). In humans, unchanged escitalopram is the predominant compound in plasma. At steady state, the concentration of the escitalopram metabolite S-DCT in plasma is approximately one-third that of escitalopram. The level of S-DDCT was not detectable in most subjects. In vitro studies show that escitalopram is at least 7 and 27 times more potent than S-DCT and S-DDCT, respectively, in the inhibition of serotonin reuptake, suggesting that the metabolites of escitalopram do not contribute significantly to the antidepressant actions of escitalopram. S-DCT and S-DDCT also have no or very low affinity for serotonergic (5-HT1-7) or other receptors including alpha- and beta-adrenergic, dopamine (D1-5), histamine (H1-3), muscarinic (M1-5), and benzodiazepine receptors. S-DCT and S-DDCT also do not bind to various ion channels including Na+, K+, Cl-, and Ca++ channels.
- In vitro studies using human liver microsomes indicated that CYP3A4 and CYP2C19 are the primary isozymes involved in the N-demethylation of escitalopram.
- Population Subgroups
- Age
- Adolescents - In a single dose study of 10 mg escitalopram, AUC of escitalopram decreased by 19%, and Cmax increased by 26% in healthy adolescent subjects (12 to 17 years of age) compared to adults. Following multiple dosing of 40 mg/day citalopram, escitalopram elimination half-life, steady-state Cmax and AUC were similar in patients with MDD (12 to 17 years of age) compared to adult patients. No adjustment of dosage is needed in adolescent patients.
- Elderly - Escitalopram pharmacokinetics in subjects ≥ 65 years of age were compared to younger subjects in a single-dose and a multiple-dose study. Escitalopram AUC and half-life were increased by approximately 50% in elderly subjects, and Cmax was unchanged. 10 mg is the recommended dose for elderly patients.
- Gender - Based on data from single- and multiple-dose studies measuring escitalopram in elderly, young adults, and adolescents, no dosage adjustment on the basis of gender is needed.
- Reduced Hepatic Function - Citalopram oral clearance was reduced by 37% and half-life was doubled in patients with reduced hepatic function compared to normal subjects. 10 mg is the recommended dose of escitalopram for most hepatically impaired patients.
- Reduced Renal Function - In patients with mild to moderate renal function impairment, oral clearance of citalopram was reduced by 17% compared to normal subjects. No adjustment of dosage for such patients is recommended. No information is available about the pharmacokinetics of escitalopram in patients with severely reduced renal function (creatinine clearance < 20 mL/min).
- Drug-Drug Interactions - In vitro enzyme inhibition data did not reveal an inhibitory effect of escitalopram on CYP3A4, -1A2, -2C9, -2C19, and -2E1. Based on in vitro data, escitalopram would be expected to have little inhibitory effect on in vivo metabolism mediated by these cytochromes. While in vivo data to address this question are limited, results from drug interaction studies suggest that escitalopram, at a dose of 20 mg, has no 3A4 inhibitory effect and a modest 2D6 inhibitory effect.
## Nonclinical Toxicology
- Carcinogenesis
- Racemic citalopram was administered in the diet to NMRI/BOM strain mice and COBS WI strain rats for 18 and 24 months, respectively. There was no evidence for carcinogenicity of racemic citalopram in mice receiving up to 240 mg/kg/day. There was an increased incidence of small intestine carcinoma in rats receiving 8 or 24 mg/kg/day racemic citalopram. A no-effect dose for this finding was not established. The relevance of these findings to humans is unknown.
- Mutagenesis
- Racemic citalopram was mutagenic in the in vitro bacterial reverse mutation assay (Ames test) in 2 of 5 bacterial strains (Salmonella TA98 and TA1537) in the absence of metabolic activation. It was clastogenic in the in vitro Chinese hamster lung cell assay for chromosomal aberrations in the presence and absence of metabolic activation. Racemic citalopram was not mutagenic in the in vitro mammalian forward gene mutation assay (HPRT) in mouse lymphoma cells or in a coupled in vitro/in vivo unscheduled DNA synthesis (UDS) assay in rat liver. It was not clastogenic in the in vitro chromosomal aberration assay in human lymphocytes or in two in vivo mouse micronucleus assays.
- Impairment of Fertility
- When racemic citalopram was administered orally to 16 male and 24 female rats prior to and throughout mating and gestation at doses of 32, 48, and 72 mg/kg/day, mating was decreased at all doses, and fertility was decreased at doses ≥ 32 mg/kg/day. Gestation duration was increased at 48 mg/kg/day.
- Retinal Changes in Rats
- Pathologic changes (degeneration/atrophy) were observed in the retinas of albino rats in the 2-year carcinogenicity study with racemic citalopram. There was an increase in both incidence and severity of retinal pathology in both male and female rats receiving 80 mg/kg/day. Similar findings were not present in rats receiving 24 mg/kg/day of racemic citalopram for two years, in mice receiving up to 240 mg/kg/day of racemic citalopram for 18 months, or in dogs receiving up to 20 mg/kg/day of racemic citalopram for one year.
- Additional studies to investigate the mechanism for this pathology have not been performed, and the potential significance of this effect in humans has not been established.
- Cardiovascular Changes in Dogs
- In a one-year toxicology study, 5 of 10 beagle dogs receiving oral racemic citalopram doses of 8 mg/kg/day died suddenly between weeks 17 and 31 following initiation of treatment. Sudden deaths were not observed in rats at doses of racemic citalopram up to 120 mg/kg/day, which produced plasma levels of citalopram and its metabolites demethylcitalopram and didemethylcitalopram (DDCT) similar to those observed in dogs at 8 mg/kg/day. A subsequent intravenous dosing study demonstrated that in beagle dogs, racemic DDCT caused QT prolongation, a known risk factor for the observed outcome in dogs.
# Clinical Studies
- Adolescents
- The efficacy of escitalopram oxalate as an acute treatment for major depressive disorder in adolescent patients was established in an 8-week, flexible-dose, placebo-controlled study that compared escitalopram oxalate 10 to 20 mg/day to placebo in outpatients 12 to 17 years of age inclusive who met DSM-IV criteria for major depressive disorder. The primary outcome was change from baseline to endpoint in the Children’s Depression Rating Scale - Revised (CDRS-R). In this study, escitalopram oxalate showed statistically significant greater mean improvement compared to placebo on the CDRS-R.
- The efficacy of escitalopram oxalate in the acute treatment of major depressive disorder in adolescents was established, in part, on the basis of extrapolation from the 8-week, flexible-dose, placebo-controlled study with racemic citalopram 20 to 40 mg/day. In this outpatient study in children and adolescents 7 to 17 years of age who met DSM-IV criteria for major depressive disorder, citalopram treatment showed statistically significant greater mean improvement from baseline, compared to placebo, on the CDRS-R; the positive results for this trial largely came from the adolescent subgroup.
- Two additional flexible-dose, placebo-controlled MDD studies (one escitalopram oxalate study in patients ages 7 to 17 and one citalopram study in adolescents) did not demonstrate efficacy.
- Although maintenance efficacy in adolescent patients has not been systematically evaluated, maintenance efficacy can be extrapolated from adult data along with comparisons of escitalopram pharmacokinetic parameters in adults and adolescent patients.
- Adults
- The efficacy of escitalopram oxalate as a treatment for major depressive disorder was established in three, 8-week, placebo-controlled studies conducted in outpatients between 18 and 65 years of age who met DSM-IV criteria for major depressive disorder. The primary outcome in all three studies was change from baseline to endpoint in the Montgomery Asberg Depression Rating Scale (MADRS).
- A fixed-dose study compared 10 mg/day escitalopram oxalate and 20 mg/day escitalopram oxalate to placebo and 40 mg/day citalopram. The 10 mg/day and 20 mg/day escitalopram oxalate treatment groups showed statistically significant greater mean improvement compared to placebo on the MADRS. The 10 mg and 20 mg escitalopram oxalate groups were similar on this outcome measure.
- In a second fixed-dose study of 10 mg/day escitalopram oxalate and placebo, the 10 mg/day escitalopram oxalate treatment group showed statistically significant greater mean improvement compared to placebo on the MADRS.
- In a flexible-dose study, comparing escitalopram oxalate, titrated between 10 and 20 mg/day, to placebo and citalopram, titrated between 20 and 40 mg/day, the escitalopram oxalate treatment group showed statistically significant greater mean improvement compared to placebo on the MADRS.
- Analyses of the relationship between treatment outcome and age, gender, and race did not suggest any differential responsiveness on the basis of these patient characteristics.
- In a longer-term trial, 274 patients meeting (DSM-IV) criteria for major depressive disorder, who had responded during an initial 8-week, open-label treatment phase with escitalopram oxalate 10 or 20 mg/day, were randomized to continuation of escitalopram oxalate at their same dose, or to placebo, for up to 36 weeks of observation for relapse. Response during the open-label phase was defined by having a decrease of the MADRS total score to ≤ 12. Relapse during the double-blind phase was defined as an increase of the MADRS total score to ≥ 22, or discontinuation due to insufficient clinical response. Patients receiving continued escitalopram oxalate experienced a statistically significant longer time to relapse compared to those receiving placebo.
- The efficacy of escitalopram oxalate in the acute treatment of Generalized Anxiety Disorder (GAD) was demonstrated in three, 8-week, multicenter, flexible-dose, placebo-controlled studies that compared escitalopram oxalate 10 to 20 mg/day to placebo in adult outpatients between 18 and 80 years of age who met DSM-IV criteria for GAD. In all three studies, escitalopram oxalate showed statistically significant greater mean improvement compared to placebo on the Hamilton Anxiety Scale (HAM-A).
- There were too few patients in differing ethnic and age groups to adequately assess whether or not escitalopram oxalate has differential effects in these groups. There was no difference in response to escitalopram oxalate between men and women.
# How Supplied
- Escitalopram Tablets USP, 5 mg are white to off-white, round, biconvex film-coated tablets debossed with ‘F’ on one side and ‘53’ on the other side.
- Bottles of 30 NDC 65862-373-30
- Bottles of 90 NDC 65862-373-90
- Bottles of 100 NDC 65862-373-01
- Bottles of 500 NDC 65862-373-05
- Bottles of 10,000 NDC 65862-373-19
- 10 x 10 Unit-dose Tablets NDC 65862-373-10
Escitalopram Tablets USP, 10 mg are white to off-white, oval shaped, biconvex film-coated tablets debossed with ‘F’ on one side and ‘54’ on the other side with a deep scoreline between ‘5’ and ‘4’.
- Bottles of 30 NDC 65862-374-30
- Bottles of 90 NDC 65862-374-90
- Bottles of 100 NDC 65862-374-01
- Bottles of 500 NDC 65862-374-05
- Bottles of 5,000 NDC 65862-374-59
- 10 x 10 Unit-dose Tablets NDC 65862-374-10
Escitalopram Tablets USP, 20 mg are white to off-white, oval shaped, biconvex film-coated tablets debossed with ‘F’ on one side and ‘56’ on the other side with a deep scoreline between ‘5’ and ‘6’.
- Bottles of 30 NDC 65862-375-30
- Bottles of 90 NDC 65862-375-90
- Bottles of 100 NDC 65862-375-01
- Bottles of 500 NDC 65862-375-05
- Bottles of 3,000 NDC 65862-375-39
- 10 x 10 Unit-dose Tablets NDC 65862-375-10
- Storage and Handling
- Store at 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F).
## Storage
There is limited information regarding Escitalopram Storage in the drug label.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- Physicians are advised to discuss the following issues with patients for whom they prescribe escitalopram oxalate.
- Prescribers or other health professionals should inform patients, their families, and their caregivers about the benefits and risks associated with treatment with escitalopram oxalate and should counsel them in its appropriate use. A patient Medication Guide about “Antidepressant Medicines, Depression and other Serious Mental Illness, and Suicidal Thoughts or Actions” is available for escitalopram oxalate. 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 escitalopram oxalate.
- 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.
- Patients should be cautioned about the risk of serotonin syndrome with the concomitant use of escitalopram oxalate with other 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).
- Patients should be cautioned about the concomitant use of escitalopram oxalate and NSAIDs, aspirin, warfarin, or other drugs that affect coagulation since combined use of psychotropic drugs that interfere with serotonin reuptake and these agents has been associated with an increased risk of bleeding.
- Patients should be advised that taking escitalopram oxalate can cause mild pupillary dilation, which in susceptible individuals, can lead to an episode of angle closure glaucoma. Pre-existing glaucoma is almost always open-angle glaucoma because angle closure glaucoma, when diagnosed, can be treated definitively with iridectomy. Open-angle glaucoma is not a risk factor for angle closure glaucoma. Patients may wish to be examined to determine whether they are susceptible to angle closure, and have a prophylactic procedure (e.g., iridectomy), if they are susceptible.
- Since escitalopram is the active isomer of racemic citalopram (Celexa), the two agents should not be coadministered. Patients should be advised to inform their physician if they are taking, or plan to take, any prescription or over-the-counter drugs, as there is a potential for interactions.
- While patients may notice improvement with escitalopram oxalate therapy in 1 to 4 weeks, they should be advised to continue therapy as directed.
- Because psychoactive drugs may impair judgment, thinking, or motor skills, patients should be cautioned about operating hazardous machinery, including automobiles, until they are reasonably certain that escitalopram oxalate therapy does not affect their ability to engage in such activities.
- Patients should be told that, although escitalopram oxalate has not been shown in experiments with normal subjects to increase the mental and motor skill impairments caused by alcohol, the concomitant use of escitalopram oxalate and alcohol in depressed patients is not advised.
- Patients should be advised to notify their physician if they
- become pregnant or intend to become pregnant during therapy.
- are breastfeeding an infant.
- Escitalopram oxalate is indicated as an integral part of a total treatment program for MDD that may include other measures (psychological, educational, social) for patients with this syndrome. Drug treatment may not be indicated for all adolescents with this syndrome. Safety and effectiveness of escitalopram oxalate in MDD has not been established in pediatric patients less than 12 years of age. Antidepressants are not intended for use in the adolescent who exhibits symptoms secondary to environmental factors and/or other primary psychiatric disorders. Appropriate educational placement is essential and psychosocial intervention is often helpful. When remedial measures alone are insufficient, the decision to prescribe antidepressant medication will depend upon the physician’s assessment of the chronicity and severity of the patient’s symptoms.
# Precautions with Alcohol
- Although escitalopram oxalate did not potentiate the cognitive and motor effects of alcohol in a clinical trial, as with other psychotropic medications, the use of alcohol by patients taking escitalopram oxalate is not recommended.
# Brand Names
- Escitalopram®[4]
# Look-Alike Drug Names
There is limited information regarding Escitalopram Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Escitalopram | |
6221336ea6119d232766fe8fb5fa52811e741e49 | wikidoc | Estramustine | Estramustine
# Disclaimer
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# Overview
Estramustine is an antineoplastic agent that is FDA approved for the treatment of patients with metastatic and/or progressive carcinoma of the prostate. Common adverse reactions include edema, breast tenderness, diarrhea, gastrointestinal irritation, nausea, leg cramp and dyspnea.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
Estramustine Capsules are indicated in the palliative treatment of patients with metastatic and/or progressive carcinoma of the prostate.
- The recommended daily dose is 14 mg per kg of body weight (ie, one 140 mg capsule for each 10 kg or 22 lb of body weight), given in 3 or 4 divided doses. Most patients in studies in the United States have been treated at a dosage range of 10 to 16 mg per kg per day.
- Patients should be instructed to take Estramustine Capsules at least 1 hour before or 2 hours after meals. Estramustine should be swallowed with water. Milk, milk products, and calcium-rich foods or drugs (such as calcium-containing antacids) must not be taken simultaneously with Estramustine .
- Patients should be treated for 30 to 90 days before the physician determines the possible benefits of continued therapy. Therapy should be continued as long as the favorable response lasts. Some patients have been maintained on therapy for more than 3 years at doses ranging from 10 to 16 mg per kg of body weight per day.
- Procedures for proper handling and disposal of anticancer drugs should be considered. Several guidelines on this subject have been published.1–8 There is no general agreement that all of the procedures recommended in the guidelines are necessary or appropriate.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Estramustine in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Estramustine in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding Estramustine 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 Estramustine in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Estramustine in pediatric patients.
# Contraindications
- Estramustine Capsules should not be used in patients with any of the following conditions:
- Known hypersensitivity to either estradiol or to nitrogen mustard.
- Active thrombophlebitis or thromboembolic disorders, except in those cases where the actual tumor mass is the cause of the thromboembolic phenomenon and the physician feels the benefits of therapy may outweigh the risks.
# Warnings
- It has been shown that there is an increased risk of thrombosis, including fatal and nonfatal myocardial infarction, in men receiving estrogens for prostatic cancer. Estramustine Capsules should be used with caution in patients with a history of thrombophlebitis, thrombosis, or thromboembolic disorders, especially if they were associated with estrogen therapy. Caution should also be used in patients with cerebral vascular or coronary artery disease.
- Glucose Tolerance—Because glucose tolerance may be decreased, diabetic patients should be carefully observed while receiving Estramustine .
- Elevated Blood Pressure—Because hypertension may occur, blood pressure should be monitored periodically.
### Precautions
- Fluid Retention. Exacerbation of preexisting or incipient peripheral edema or congestive heart disease has been seen in some patients receiving therapy with Estramustine Capsules. Other conditions which might be influenced by fluid retention, such as epilepsy, migraine, or renal dysfunction, require careful observation.
- Estramustine may be poorly metabolized in patients with impaired liver function and should be administered with caution in such patients.
- Because Estramustine may influence the metabolism of calcium and phosphorus, it should be used with caution in patients with metabolic bone diseases that are associated with hypercalcemia or in patients with renal insufficiency. Patients with prostate cancer and osteoblastic metastases are at risk for hypocalcemia and should have calcium levels closely monitored.
- Gynecomastia and impotence are known estrogenic effects.
- Allergic reactions and angioedema at times involving the airway have been reported.
- Because of the possibility of mutagenic effects, patients should be advised to use contraceptive measures.
- Certain endocrine and liver function tests may be affected by estrogen-containing drugs. Estramustine may depress testosterone levels. Abnormalities of hepatic enzymes and of bilirubin have occurred in patients receiving Estramustine . Such tests should be done at appropriate intervals during therapy and repeated after the drug has been withdrawn for two months.
- Milk, milk products, and calcium-rich foods or drugs may impair the absorption of Estramustine .
# Adverse Reactions
## Clinical Trials Experience
- In a randomized, double-blind trial comparing therapy with Estramustine Capsules in 93 patients (11.5 to 15.9 mg/kg/day) or diethylstilbestrol (DES) in 93 patients (3.0 mg/day), the following adverse effects were reported:
## Postmarketing Experience
There is limited information regarding Postmarketing Experience of Estramustine in the drug label.
# Drug Interactions
There is limited information regarding Estramustine Drug Interactions in the drug label.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
There is no FDA guidance on usage of Estramustine in women who are pregnant.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Estramustine in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Estramustine during labor and delivery.
### Nursing Mothers
There is no FDA guidance on the use of Estramustine with respect to nursing mothers.
### Pediatric Use
There is no FDA guidance on the use of Estramustine with respect to pediatric patients.
### Geriatic Use
There is no FDA guidance on the use of Estramustine with respect to geriatric patients.
### Gender
There is no FDA guidance on the use of Estramustine with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Estramustine with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Estramustine in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Estramustine in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Estramustine in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Estramustine in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Oral
### Monitoring
There is limited information regarding Monitoring of Estramustine in the drug label.
# IV Compatibility
There is limited information regarding IV Compatibility of Estramustine in the drug label.
# Overdosage
- Although there has been no experience with overdosage to date, it is reasonable to expect that such episodes may produce pronounced manifestations of the known adverse reactions. In the event of overdosage, the gastric contents should be evacuated by gastric lavage and symptomatic therapy should be initiated. Hematologic and hepatic parameters should be monitored for at least 6 weeks after overdosage of Estramustine Capsules
# Pharmacology
## Mechanism of Action
- Prolonged treatment with estramustine phosphate produces elevated total plasma concentrations of estradiol that fall within ranges similar to the elevated estradiol levels found in prostatic cancer patients given conventional estradiol therapy.
## Structure
- Estramustine phosphate sodium, an antineoplastic agent, is an off-white powder readily soluble in water. Estramustine Capsules are white and opaque, each containing estramustine phosphate sodium as the disodium salt monohydrate equivalent to 140 mg estramustine phosphate, for oral administration. Each capsule also contains magnesium stearate, silicon dioxide, sodium lauryl sulfate, and talc. Gelatin capsule shells contain the following pigment: titanium dioxide.
- Chemically, estramustine phosphate sodium is estra-1,3,5(10)-triene-3,17-diol(17β)-,3- 17-(dihydrogen phosphate), disodium salt, monohydrate. It is also referred to as estradiol 3- 17-(dihydrogen phosphate), disodium salt, monohydrate. Estramustine phosphate sodium has an empiric formula of C23H30Cl2NNa2O6PH2O, a calculated molecular weight of 582.4, and the following structural formula:
## Pharmacodynamics
There is limited information regarding Pharmacodynamics of Estramustine in the drug label.
## Pharmacokinetics
- Estramustine phosphate (Figure 1) is a molecule combining estradiol and nornitrogen mustard by a carbamate link. The molecule is phosphorylated to make it water soluble.There is limited information regarding Pharmacokinetics of Estramustine in the drug label.
- Estramustine phosphate taken orally is readily dephosphorylated during absorption, and the major metabolites in plasma are estramustine (Figure 2), the estrone analog (Figure 3), estradiol, and estrone.
- Estrogenic effects, as demonstrated by changes in circulating levels of steroids and pituitary hormones, are similar in patients treated with either estramustine phosphate or conventional estradiol.
- The metabolic urinary patterns of the estradiol moiety of estramustine phosphate and estradiol itself are very similar, although the metabolites derived from estramustine phosphate are excreted at a slower rate.
## Nonclinical Toxicology
- Long-term continuous administration of estrogens in certain animal species increases the frequency of carcinomas of the breast and liver. Compounds structurally similar to Estramustine are carcinogenic in mice. Carcinogenic studies of Estramustine have not been conducted in man. Although testing by the Ames method failed to demonstrate mutagenicity for estramustine phosphate sodium, it is known that both estradiol and nitrogen mustard are mutagenic. For this reason and because some patients who had been impotent while on estrogen therapy have regained potency while taking Estramustine , the patient should be advised to use contraceptive measures.
# Clinical Studies
There is limited information regarding Clinical Studies of Estramustine in the drug label.
# How Supplied
- White opaque capsules, each containing estramustine phosphate sodium as the disodium salt monohydrate equivalent to 140 mg estramustine phosphate—bottle of 100 (NDC 0013-0132-02).
## Storage
NOTE
- Estramustine Capsules should be stored in the refrigerator at 36° to 46°F (2° to 8°C).
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
There is limited information regarding Patient Counseling Information of Estramustine in the drug label.
# Precautions with Alcohol
- Alcohol-Estramustine interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Emcyt®
# Look-Alike Drug Names
There is limited information regarding Estramustine Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | Estramustine
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
Estramustine is an antineoplastic agent that is FDA approved for the treatment of patients with metastatic and/or progressive carcinoma of the prostate. Common adverse reactions include edema, breast tenderness, diarrhea, gastrointestinal irritation, nausea, leg cramp and dyspnea.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
Estramustine Capsules are indicated in the palliative treatment of patients with metastatic and/or progressive carcinoma of the prostate.
- The recommended daily dose is 14 mg per kg of body weight (ie, one 140 mg capsule for each 10 kg or 22 lb of body weight), given in 3 or 4 divided doses. Most patients in studies in the United States have been treated at a dosage range of 10 to 16 mg per kg per day.
- Patients should be instructed to take Estramustine Capsules at least 1 hour before or 2 hours after meals. Estramustine should be swallowed with water. Milk, milk products, and calcium-rich foods or drugs (such as calcium-containing antacids) must not be taken simultaneously with Estramustine .
- Patients should be treated for 30 to 90 days before the physician determines the possible benefits of continued therapy. Therapy should be continued as long as the favorable response lasts. Some patients have been maintained on therapy for more than 3 years at doses ranging from 10 to 16 mg per kg of body weight per day.
- Procedures for proper handling and disposal of anticancer drugs should be considered. Several guidelines on this subject have been published.1–8 There is no general agreement that all of the procedures recommended in the guidelines are necessary or appropriate.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Estramustine in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Estramustine in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding Estramustine 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 Estramustine in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Estramustine in pediatric patients.
# Contraindications
- Estramustine Capsules should not be used in patients with any of the following conditions:
- Known hypersensitivity to either estradiol or to nitrogen mustard.
- Active thrombophlebitis or thromboembolic disorders, except in those cases where the actual tumor mass is the cause of the thromboembolic phenomenon and the physician feels the benefits of therapy may outweigh the risks.
# Warnings
- It has been shown that there is an increased risk of thrombosis, including fatal and nonfatal myocardial infarction, in men receiving estrogens for prostatic cancer. Estramustine Capsules should be used with caution in patients with a history of thrombophlebitis, thrombosis, or thromboembolic disorders, especially if they were associated with estrogen therapy. Caution should also be used in patients with cerebral vascular or coronary artery disease.
- Glucose Tolerance—Because glucose tolerance may be decreased, diabetic patients should be carefully observed while receiving Estramustine .
- Elevated Blood Pressure—Because hypertension may occur, blood pressure should be monitored periodically.
### Precautions
- Fluid Retention. Exacerbation of preexisting or incipient peripheral edema or congestive heart disease has been seen in some patients receiving therapy with Estramustine Capsules. Other conditions which might be influenced by fluid retention, such as epilepsy, migraine, or renal dysfunction, require careful observation.
- Estramustine may be poorly metabolized in patients with impaired liver function and should be administered with caution in such patients.
- Because Estramustine may influence the metabolism of calcium and phosphorus, it should be used with caution in patients with metabolic bone diseases that are associated with hypercalcemia or in patients with renal insufficiency. Patients with prostate cancer and osteoblastic metastases are at risk for hypocalcemia and should have calcium levels closely monitored.
- Gynecomastia and impotence are known estrogenic effects.
- Allergic reactions and angioedema at times involving the airway have been reported.
- Because of the possibility of mutagenic effects, patients should be advised to use contraceptive measures.
- Certain endocrine and liver function tests may be affected by estrogen-containing drugs. Estramustine may depress testosterone levels. Abnormalities of hepatic enzymes and of bilirubin have occurred in patients receiving Estramustine . Such tests should be done at appropriate intervals during therapy and repeated after the drug has been withdrawn for two months.
- Milk, milk products, and calcium-rich foods or drugs may impair the absorption of Estramustine .
# Adverse Reactions
## Clinical Trials Experience
- In a randomized, double-blind trial comparing therapy with Estramustine Capsules in 93 patients (11.5 to 15.9 mg/kg/day) or diethylstilbestrol (DES) in 93 patients (3.0 mg/day), the following adverse effects were reported:
## Postmarketing Experience
There is limited information regarding Postmarketing Experience of Estramustine in the drug label.
# Drug Interactions
There is limited information regarding Estramustine Drug Interactions in the drug label.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
There is no FDA guidance on usage of Estramustine in women who are pregnant.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Estramustine in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Estramustine during labor and delivery.
### Nursing Mothers
There is no FDA guidance on the use of Estramustine with respect to nursing mothers.
### Pediatric Use
There is no FDA guidance on the use of Estramustine with respect to pediatric patients.
### Geriatic Use
There is no FDA guidance on the use of Estramustine with respect to geriatric patients.
### Gender
There is no FDA guidance on the use of Estramustine with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Estramustine with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Estramustine in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Estramustine in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Estramustine in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Estramustine in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Oral
### Monitoring
There is limited information regarding Monitoring of Estramustine in the drug label.
# IV Compatibility
There is limited information regarding IV Compatibility of Estramustine in the drug label.
# Overdosage
- Although there has been no experience with overdosage to date, it is reasonable to expect that such episodes may produce pronounced manifestations of the known adverse reactions. In the event of overdosage, the gastric contents should be evacuated by gastric lavage and symptomatic therapy should be initiated. Hematologic and hepatic parameters should be monitored for at least 6 weeks after overdosage of Estramustine Capsules
# Pharmacology
## Mechanism of Action
- Prolonged treatment with estramustine phosphate produces elevated total plasma concentrations of estradiol that fall within ranges similar to the elevated estradiol levels found in prostatic cancer patients given conventional estradiol therapy.
## Structure
- Estramustine phosphate sodium, an antineoplastic agent, is an off-white powder readily soluble in water. Estramustine Capsules are white and opaque, each containing estramustine phosphate sodium as the disodium salt monohydrate equivalent to 140 mg estramustine phosphate, for oral administration. Each capsule also contains magnesium stearate, silicon dioxide, sodium lauryl sulfate, and talc. Gelatin capsule shells contain the following pigment: titanium dioxide.
- Chemically, estramustine phosphate sodium is estra-1,3,5(10)-triene-3,17-diol(17β)-,3-[bis(2-chloroethyl)carbamate] 17-(dihydrogen phosphate), disodium salt, monohydrate. It is also referred to as estradiol 3-[bis(2-chloroethyl)carbamate] 17-(dihydrogen phosphate), disodium salt, monohydrate. Estramustine phosphate sodium has an empiric formula of C23H30Cl2NNa2O6P•H2O, a calculated molecular weight of 582.4, and the following structural formula:
## Pharmacodynamics
There is limited information regarding Pharmacodynamics of Estramustine in the drug label.
## Pharmacokinetics
- Estramustine phosphate (Figure 1) is a molecule combining estradiol and nornitrogen mustard by a carbamate link. The molecule is phosphorylated to make it water soluble.There is limited information regarding Pharmacokinetics of Estramustine in the drug label.
- Estramustine phosphate taken orally is readily dephosphorylated during absorption, and the major metabolites in plasma are estramustine (Figure 2), the estrone analog (Figure 3), estradiol, and estrone.
- Estrogenic effects, as demonstrated by changes in circulating levels of steroids and pituitary hormones, are similar in patients treated with either estramustine phosphate or conventional estradiol.
- The metabolic urinary patterns of the estradiol moiety of estramustine phosphate and estradiol itself are very similar, although the metabolites derived from estramustine phosphate are excreted at a slower rate.
## Nonclinical Toxicology
- Long-term continuous administration of estrogens in certain animal species increases the frequency of carcinomas of the breast and liver. Compounds structurally similar to Estramustine are carcinogenic in mice. Carcinogenic studies of Estramustine have not been conducted in man. Although testing by the Ames method failed to demonstrate mutagenicity for estramustine phosphate sodium, it is known that both estradiol and nitrogen mustard are mutagenic. For this reason and because some patients who had been impotent while on estrogen therapy have regained potency while taking Estramustine , the patient should be advised to use contraceptive measures.
# Clinical Studies
There is limited information regarding Clinical Studies of Estramustine in the drug label.
# How Supplied
- White opaque capsules, each containing estramustine phosphate sodium as the disodium salt monohydrate equivalent to 140 mg estramustine phosphate—bottle of 100 (NDC 0013-0132-02).
## Storage
NOTE
- Estramustine Capsules should be stored in the refrigerator at 36° to 46°F (2° to 8°C).
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
There is limited information regarding Patient Counseling Information of Estramustine in the drug label.
# Precautions with Alcohol
- Alcohol-Estramustine interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Emcyt®
# Look-Alike Drug Names
There is limited information regarding Estramustine Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Estramustine | |
d42514969b05a36c23cc992aab99ba79e398133b | wikidoc | Ethanolamine | Ethanolamine
# Overview
Ethanolamine, also called 2-aminoethanol or monoethanolamine (often abbreviated as MEA), is an organic chemical compound which is both a primary amine (due to an amino group in its molecule) and a primary alcohol (due to a hydroxyl group). Like other amines, monoethanolamine acts as a weak base. Ethanolamine is a toxic, flammable, corrosive, colorless, viscous liquid with an odor similar to ammonia. Refractive index of ethanolamine is 1.4539.
Ethanolamine is commonly called monoethanolamine or MEA to distinguish it from diethanolamine (DEA) and triethanolamine (TEA). Monoethanolamine is produced by reacting ethylene oxide with ammonia. Further treatment with ethylene oxide can yield DEA and/or TEA. Ethanolamine is the second most abundant head group for phospholipids, substances found in biological membranes.
Ethanolamine also refers to a class of antihistamines containing an ethyl-amine group attached to a diphenyl structure. Examples of drugs within this class include diphenhydramine (Benadryl), phenyltoloxamine (Percogesic), and doxylamine (Unisom Sleep Tablets). They are one of the oldest classes of antihistamine drugs, yet remain the most effective for treating allergy symptoms, even exceeding the effectiveness of new OTC and prescription antihistamines such as loratadine (Claritin) and Fexofenadine (Allegra). However, all ethanolamines are extremely sedating, even more so than many barbiturates. For this reason, they are not always desirable drugs for treatment, and less-effective drugs are indicated to avoid the substantial drowsiness inherent in ethanolamines. On the other hand, they are such effective sedatives that they are marketed as over-the-counter sleep-aids in addition to anti-allergy medications.
# Uses of monoethanolamine (MEA)
MEA is used in aqueous solutions for scrubbing certain acidic gases and is also used in surface active agents, emulsifiers, polishes, pharmaceuticals, corrosion inhibitors, chemical intermediates. In pharmaceutical formulations, MEA is primarily used for buffering or preparation of emulsions.
Aqueous solutions of MEA (solutions of MEA in water) are used as a gas stream scrubbing liquid in amine treaters. For example, aqueous MEA is used to remove carbon dioxide (CO2) from flue gas. Aqueous solutions can weakly dissolve certain kinds of gases from a mixed gas stream. The MEA in such solutions, acting as a weak base, then neutralizes acidic compounds dissolved in the solution to turn the molecules into an ionic form, making them polar and considerably more soluble in a cold MEA solution and thus keeping such acidic gases dissolved in this gas-scrubbing solution. Therefore, large surface area contact with such a cold scrubbing solution in a scrubber unit can selectively remove such acidic components as hydrogen sulfide (H2S) and CO2 from some mixed gas streams. For example, basic solutions such as aqueous MEA or aqueous potassium carbonate can neutralize H2S into hydrosulfide ion (HS-) or CO2 into bicarbonate ion (HCO3-).
H2S and CO2 are only weakly acidic gases. An aqueous solution of a strong base such as sodium hydroxide (NaOH) will not readily release these gases once they have dissolved. However, MEA is rather weak base and will re-release H2S or CO2 when the scrubbing solution is heated. Therefore, the MEA scrubbing solution is recycled through a regeneration unit which heats the MEA solution from the scrubber unit to release these only slightly acidic gases into a purer form and returns the regenerated MEA solution to the scrubber unit again for reuse. | Ethanolamine
Template:Chembox new
# Overview
Ethanolamine, also called 2-aminoethanol or monoethanolamine (often abbreviated as MEA), is an organic chemical compound which is both a primary amine (due to an amino group in its molecule) and a primary alcohol (due to a hydroxyl group). Like other amines, monoethanolamine acts as a weak base. Ethanolamine is a toxic, flammable, corrosive, colorless, viscous liquid with an odor similar to ammonia. Refractive index of ethanolamine is 1.4539.
Ethanolamine is commonly called monoethanolamine or MEA to distinguish it from diethanolamine (DEA) and triethanolamine (TEA). Monoethanolamine is produced by reacting ethylene oxide with ammonia. Further treatment with ethylene oxide can yield DEA and/or TEA. Ethanolamine is the second most abundant head group for phospholipids, substances found in biological membranes.
Ethanolamine also refers to a class of antihistamines containing an ethyl-amine group attached to a diphenyl structure. Examples of drugs within this class include diphenhydramine (Benadryl), phenyltoloxamine (Percogesic), and doxylamine (Unisom Sleep Tablets). They are one of the oldest classes of antihistamine drugs, yet remain the most effective for treating allergy symptoms, even exceeding the effectiveness of new OTC and prescription antihistamines such as loratadine (Claritin) and Fexofenadine (Allegra). However, all ethanolamines are extremely sedating, even more so than many barbiturates. For this reason, they are not always desirable drugs for treatment, and less-effective drugs are indicated to avoid the substantial drowsiness inherent in ethanolamines. On the other hand, they are such effective sedatives that they are marketed as over-the-counter sleep-aids in addition to anti-allergy medications.
# Uses of monoethanolamine (MEA)
MEA is used in aqueous solutions for scrubbing certain acidic gases and is also used in surface active agents, emulsifiers, polishes, pharmaceuticals, corrosion inhibitors, chemical intermediates. In pharmaceutical formulations, MEA is primarily used for buffering or preparation of emulsions.
Aqueous solutions of MEA (solutions of MEA in water) are used as a gas stream scrubbing liquid in amine treaters. For example, aqueous MEA is used to remove carbon dioxide (CO2) from flue gas. Aqueous solutions can weakly dissolve certain kinds of gases from a mixed gas stream. The MEA in such solutions, acting as a weak base, then neutralizes acidic compounds dissolved in the solution to turn the molecules into an ionic form, making them polar and considerably more soluble in a cold MEA solution and thus keeping such acidic gases dissolved in this gas-scrubbing solution. Therefore, large surface area contact with such a cold scrubbing solution in a scrubber unit can selectively remove such acidic components as hydrogen sulfide (H2S) and CO2 from some mixed gas streams. For example, basic solutions such as aqueous MEA or aqueous potassium carbonate can neutralize H2S into hydrosulfide ion (HS-) or CO2 into bicarbonate ion (HCO3-).
H2S and CO2 are only weakly acidic gases. An aqueous solution of a strong base such as sodium hydroxide (NaOH) will not readily release these gases once they have dissolved. However, MEA is rather weak base and will re-release H2S or CO2 when the scrubbing solution is heated. Therefore, the MEA scrubbing solution is recycled through a regeneration unit which heats the MEA solution from the scrubber unit to release these only slightly acidic gases into a purer form and returns the regenerated MEA solution to the scrubber unit again for reuse. | https://www.wikidoc.org/index.php/Ethanolamine | |
31cf8d8fd98c143184d9124407a47984cb9c32a2 | wikidoc | Ethmoid bone | Ethmoid bone
# Overview
The ethmoid bone (from Greek ethmos, "sieve") is a bone in the skull that separates the nasal cavity from the brain. As such, it is located at the roof of the nose, between the two orbits. The cubical bone is lightweight due to a spongy construction.
# Parts
The ethmoid bone consists of four parts:
- the horizontal Cribriform plate (lamina cribrosa), part of the cranial base
- the vertical Perpendicular plate (lamina perpendicularis), which is part of the nasal septum
- the two lateral masses or labyrinths.
# Articulations
The ethmoid articulates with fifteen bones:
- four of the cranium—the frontal, the sphenoid, and the two sphenoidal conchae
- eleven of the face—the two nasals, two maxillae, two lacrimals, two palatines, two inferior nasal conchae, and the vomer
# Injuries
The ethmoid bone is very delicate and is easily injured by a sharp upward blow to the nose, such as a person might suffer by striking an automobile dashboard in a collision. The force of a blow can drive bone fragments through the cribiform plate into the meninges or brain tissue. Such injuries are often evidenced by leakage of cerebrospinal fluid into the nasal cavity, and may be followed from the nasal cavity to the brain.
Blows to the head can also shear off the olfactory nerves that pass though the ethmoid bone and cause anosmia, an irreversible loss of the sense of smell and a great reduction in the sense of taste (most of which depends on smell). This not only deprives life of some of its pleasures, but can also be dangerous, as when a person fails to smell smoke, gas, or spoiled food.
Fracture of the lamina papyracea, the lateral plate of the ethmoid labyrinth bone, permits communication between the nasal cavity and the ipsilateral orbit through the inferomedial orbital wall, resulting in orbital emphysema. Increased pressure within the nasal cavity, as seen during sneezing, for example, leads to temporary exophthalmos.
# Role in magnetoception
Some birds and other migratory animals have deposits of biological magnetite in their ethmoid bones which allow them to sense the direction of the Earth's magnetic field. Humans have a similar magnetite deposit, but it is believed to be vestigial.
# Additional images
- Ethmoid bone from above.
- Perpendicular plate of ethmoid.
- Ethmoid bone (frontal view).
- Ethmoid bone from the right side.
- Sphenoid bone visible center right.
- Side view of the skull.
- The skull from the front.
- Medial wall of left orbit.
- Base of the skull. Upper surface.
- Medial wall of left nasal fossa.
- Roof, floor, and lateral wall of left nasal cavity.
- Lateral wall of nasal cavity, showing ethmoid bone in position. | Ethmoid bone
Template:Infobox Bone
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
The ethmoid bone (from Greek ethmos, "sieve") is a bone in the skull that separates the nasal cavity from the brain. As such, it is located at the roof of the nose, between the two orbits. The cubical bone is lightweight due to a spongy construction.
# Parts
The ethmoid bone consists of four parts:
- the horizontal Cribriform plate (lamina cribrosa), part of the cranial base
- the vertical Perpendicular plate (lamina perpendicularis), which is part of the nasal septum
- the two lateral masses or labyrinths.
# Articulations
The ethmoid articulates with fifteen bones:
- four of the cranium—the frontal, the sphenoid, and the two sphenoidal conchae
- eleven of the face—the two nasals, two maxillae, two lacrimals, two palatines, two inferior nasal conchae, and the vomer
# Injuries
The ethmoid bone is very delicate and is easily injured by a sharp upward blow to the nose, such as a person might suffer by striking an automobile dashboard in a collision. The force of a blow can drive bone fragments through the cribiform plate into the meninges or brain tissue. Such injuries are often evidenced by leakage of cerebrospinal fluid into the nasal cavity, and may be followed from the nasal cavity to the brain.
Blows to the head can also shear off the olfactory nerves that pass though the ethmoid bone and cause anosmia, an irreversible loss of the sense of smell and a great reduction in the sense of taste (most of which depends on smell). This not only deprives life of some of its pleasures, but can also be dangerous, as when a person fails to smell smoke, gas, or spoiled food.
Fracture of the lamina papyracea, the lateral plate of the ethmoid labyrinth bone, permits communication between the nasal cavity and the ipsilateral orbit through the inferomedial orbital wall, resulting in orbital emphysema. Increased pressure within the nasal cavity, as seen during sneezing, for example, leads to temporary exophthalmos.
# Role in magnetoception
Some birds and other migratory animals have deposits of biological magnetite in their ethmoid bones which allow them to sense the direction of the Earth's magnetic field. Humans have a similar magnetite deposit, but it is believed to be vestigial. [2]
# Additional images
- Ethmoid bone from above.
- Perpendicular plate of ethmoid.
- Ethmoid bone (frontal view).
- Ethmoid bone from the right side.
- Sphenoid bone visible center right.
- Side view of the skull.
- The skull from the front.
- Medial wall of left orbit.
- Base of the skull. Upper surface.
- Medial wall of left nasal fossa.
- Roof, floor, and lateral wall of left nasal cavity.
- Lateral wall of nasal cavity, showing ethmoid bone in position. | https://www.wikidoc.org/index.php/Ethmoid | |
1ee0e86c99d3d90410e4a33f838393b019b4656d | wikidoc | Ethnic group | Ethnic group
# Overview
An ethnic group (also called a people or an ethnicity) is a group of human beings whose members identify with each other, usually on the basis of a presumed common genealogy or ancestry. Ethnic identity is also marked by the recognition from others of a group's distinctiveness and by common cultural, linguistic, religious, behavioral or biological traits.
According to the international meeting on the Challenges of Measuring an Ethnic World (1992), "Ethnicity is a fundamental factor in human life: it is a phenomenon inherent in human experience" despite its often malleable definitions. Others, like anthropologists Fredrik Barth and Eric Wolf, regard ethnicity as a result of interaction, rather than essential qualities of groups.
Processes that result in the emergence of such identification are called ethnogenesis. Members of an ethnic group, on the whole, claim cultural continuities over time, although historians and cultural anthropologists have documented that many of the values, practices, and norms that imply continuity with the past are of relatively recent invention.
# Defining ethnicity
The sociologist Max Weber once remarked that "the whole conception of ethnic groups is so complex and so vague that it might be good to abandon it altogether."
In any case, Weber proposed a definition of ethnic group that became accepted by many sociologists:
hose human groups that entertain a subjective belief in their common descent because of similarities of physical type or of customs or both, or because of memories of colonization and migration; this belief must be important for group formation; furthermore it does not matter whether an objective blood relationship exists.
Anthropologist Ronald Cohen, in a review of anthropological and sociological studies of ethnic groups since Weber, claimed that the identification of "ethnic groups" by social scientists often reflected inaccurate labels more than indigenous realities:
Cohen also suggests that claims concerning "ethnic" identity (like earlier claims concerning "tribal" identity) are often colonialist practices and effects of the relations between colonized peoples and nation-states. Harold Isaacs has identified other diacritics (distinguishing markers) of ethnicity, among them physical appearance, name, language, history, and religion; this definition has entered some dictionaries. Social scientists have thus focused on how, when, and why different markers of ethnic identity become salient. Thus, anthropologist Joan Vincent observed that ethnic boundaries often have a mercurial character. Ronald Cohen concluded that ethnicity is "a series of nesting dichotomizations of inclusiveness and exclusiveness". He agrees with Joan Vincent's observation that (in Cohen's paraphrase) "Ethnicity ... can be narrowed or broadened in boundary terms in relation to the specific needs of political mobilization. This may be why descent is sometimes a marker of ethnicity, and sometimes not: which diacritic of ethnicity is salient depends on whether people are scaling ethnic boundaries up or down, and whether they are scaling them up or down depends generally on the political situation.
# Ethnicity and race
Ethnicity and race are related concepts in that both are usually defined in terms of shared genealogy. Often, ethnicity also connotes shared cultural, linguistic, behavioural or religious traits. For example, to call oneself Jewish or Arab one immediately invokes a clutch of linguistic, religious, cultural and racial features that are held to be common within each ethnic category. Such broad ethnic categories have also been termed macroethnicity to distinguish them from smaller more subjective ethnic features, often termed microethnicity. Race, by contrast, refers to "some concentrations, as relative to frequency and distribution, of hereditary particles (genes) and physical characters, which appear, fluctuate, and often disappear in the course of time by reason of geographic and or cultural isolation." In 1950, the UNESCO statement The Race Question, signed by some of the internationally renowned scholars of the time (including Ashley Montagu, Claude Lévi-Strauss, Gunnar Myrdal, Julian Huxley, etc.), suggested that: "National, religious, geographic, linguistic and cultural groups do not necessarily coincide with racial groups: and the cultural traits of such groups have no demonstrated genetic connection with racial traits. Because serious errors of this kind are habitually committed when the term 'race' is used in popular parlance, it would be better when speaking of human races to drop the term 'race' altogether and speak of 'ethnic groups'."
In 1982, American cultural anthropologist, summing up forty years of ethnographic research, argued that racial and ethnic categories are symbolic markers for different ways that people from different parts of the world have been incorporated into a global economy. According to Wolf, races were incorporated during the period of European mercantile expansion, and ethnic groups during the period of capitalist expansion:
# Ethnic stratification
In sociology and social theory, ethnicity can be viewed as a way of social stratification, meaning that ethnicity is the basis for a hierarchical arrangement of individuals. According to Donald Noel, a sociologist who developed a theory on the origin of ethnic stratification, ethnic stratification is a "system of stratification wherein some relatively fixed group membership (e.g., race, religion, or nationality) is utilized as a major criterion for assigning social positions" Ethnic stratification is one of many different types of social stratification, including stratification based on socio-economic status, race, or gender.
According to Donald Noel, ethnic stratification will emerge only when specific ethnic groups are brought into contact with one another, and only when those groups are characterized by a high degree of ethnocentrism, competition, and differential power. Ethnocentrism is the tendency to look at the world primarily from the perspective of one's own culture, and to downgrade all other groups outside one’s own culture. Some sociologists, such as Lawrence Bobo and Vincent Hutchings, say the origin of ethnic stratification lies in individual dispositions of ethnic prejudice, which relates to the theory of ethnocentrism
Continuing with Noel’s theory, some degree of differential power must also be present for the emergence of ethnic stratification. In other words, an inequality of power among ethnic groups means "they are of such unequal power that one is able to impose its will upon another". In addition to differential power, a degree of competition structured along ethnic lines is a prerequisite to ethnic stratification as well. The different ethnic groups must be competing for some common goal, such as power or influence, or a material interest such as wealth or territory. Lawrence Bobo and Vincent Hutchings propose that competition is driven by self-interest and hostility, and results in inevitable stratification and conflict.
# Ethnicity and nation
In some cases, especially involving transnational migration, or colonial expansion, ethnicity is linked to nationality. Many anthropologists and historians, following the work of Ernest Gellner and Benedict Anderson see nations and nationalism as developing with the rise of the modern state system in the seventeenth century, culminating in the rise of "nation-states" in which the presumptive boundaries of the nation coincided (or ideally coincided) with state boundaries.
Thus, in the West, the notion of ethnicity, like race and nation, developed in the context of European colonial expansion, when mercantilism and capitalism were promoting global movements of populations at the same time that state boundaries were being more clearly and rigidly defined. In the nineteenth century, modern states generally sought legitimacy through their claim to represent "nations." Nation-states, however, invariably include populations that have been excluded from national life for one reason or another. Members of excluded groups, consequently, will either demand inclusion on the basis of equality, or seek autonomy, sometimes even to the extent of complete political separation in their own nation-state. Under these conditions - when people moved from one state to another, or one state conquered or colonized peoples beyond its national boundaries - ethnic groups were formed by people who identified with one nation, but lived in another state.
# Ethno-national conflict
Sometimes ethnic groups are subject to prejudicial attitudes and actions by the state or its constituents. In the twentieth century, people began to argue that conflicts among ethnic groups or between members of an ethnic group and the state can and should be resolved in one of two ways. Some, like Jürgen Habermas and Bruce Barry, have argued that the legitimacy of modern states must be based on a notion of political rights of autonomous individual subjects. According to this view the state should not acknowledge ethnic, national or racial identity but rather instead enforce political and legal equality of all individuals. Others, like Charles Taylor and Will Kymlicka argue that the notion of the autonomous individual is itself a cultural construct. According to this view, states must recognize ethnic identity and develop processes through which the particular needs of ethnic groups can be accommodated within the boundaries of the nation-state.
The nineteenth century saw the development of the political ideology of ethnic nationalism, when the concept of race was tied to nationalism, first by German theorists including Johann Gottfried von Herder. Instances of societies focusing on ethnic ties arguably to the exclusion of history or historical context have resulted in the justification of nationalist goals. Two periods frequently cited as examples of this are the nineteenth century consolidation and expansion of the German Empire and the Third (Greater German) Reich, each promoted on the pan-ethnic idea that these governments were only acquiring lands that had always been ethnically German. The history of late-comers to the nation-state model, such as those arising in the Near East and south-eastern Europe out of the dissolution of the Ottoman and Austro-Hungarian Empires, as well as those arising out of the former USSR, is marked by inter-ethnic conflicts that usually occurs within multi-ethnic states, as opposed to between them, in other regions of the world; thus, those other conflicts are often misleadingly labelled and characterized as "civil war."
# Ethnicity in specific countries
In the United States of America, collectives of related ethnic groups are typically denoted as "ethnic." Most prominently in the U.S., the various Latin American racial and ancestral groups are typically grouped as either "Hispanics" or "Latinos" (although sometimes some white American lump black Latinos with black Americans. The many previously designated 'Oriental' ethnic groups are designated as Asian ethnic groups and similarly linked together as "Asians." The terms "Black" and "African-American," while different, usually describe the descendants whose ancestors were indigenous to Africa and generally excludes the African descendants of European colonists. Even the racial term "White American" generally describes people whose ancestry can be traced to Europe (including non-European nations such as Argentina, Australia, and Canada where European ancestry contributes to the overall populations) who now live in the United States. "Middle Easterners" are peoples from the Middle-East, i.e. Southwest Asia and North Africa. These countries include Iran, Turkey, Tunisia, Iraq, Saudi Arabia, Egypt, Libya, Algeria, and Morocco. (The U.S. Census Bureau compiled a list of ethnic groups which may be seen at Ethnicity (United States Census)).
In the United Kingdom, different classifications, both formal and informal, are used. Perhaps the most accepted is the National Statistics classification, identical to that used in the 2001 Census in England and Wales (see Ethnicity (United Kingdom)). In general popular use in the United Kingdom and Europe, the terms oriental and Asian are widespread and without negative connotation, with the latter term usually reserved in the United Kingdom for people from the Indian subcontinent (see British Oriental and British Asian for more details).
China officially recognizes 56 ethnic groups of which the majority is comprised by the Han Chinese. Many of the ethnic minorities maintain their own individual culture and language, although many are also becoming more like the Han Chinese. Han Chinese predominates most areas of China with the exception of Tibet and Xinjiang where the Han are still in the minority. The Han Chinese are the only ethnic group bound by the One-child policy. (For more details, see List of ethnic groups in China and Ethnic minorities in China.)
In France, no population census includes ethnic categories, and the government is prohibited from collecting, maintaining or using ethnic population statistics. The current French government, led by Nicolas Sarkozy and François Fillon, has begun a legislative process to repeal this prohibition. | Ethnic group
# Overview
An ethnic group (also called a people or an ethnicity) is a group of human beings whose members identify with each other, usually on the basis of a presumed common genealogy or ancestry.[1] Ethnic identity is also marked by the recognition from others of a group's distinctiveness[2] and by common cultural, linguistic, religious, behavioral or biological traits.[1][3]
According to the international meeting on the Challenges of Measuring an Ethnic World (1992), "Ethnicity is a fundamental factor in human life: it is a phenomenon inherent in human experience" despite its often malleable definitions.[3] Others, like anthropologists Fredrik Barth and Eric Wolf, regard ethnicity as a result of interaction, rather than essential qualities of groups.[4]
Processes that result in the emergence of such identification are called ethnogenesis. Members of an ethnic group, on the whole, claim cultural continuities over time, although historians and cultural anthropologists have documented that many of the values, practices, and norms that imply continuity with the past are of relatively recent invention.[5]
# Defining ethnicity
The sociologist Max Weber once remarked that "the whole conception of ethnic groups is so complex and so vague that it might be good to abandon it altogether."[6]
In any case, Weber proposed a definition of ethnic group that became accepted by many sociologists[citation needed]:
[T]hose human groups that entertain a subjective belief in their common descent because of similarities of physical type or of customs or both, or because of memories of colonization and migration; this belief must be important for group formation; furthermore it does not matter whether an objective blood relationship exists.[6]
Anthropologist Ronald Cohen, in a review of anthropological and sociological studies of ethnic groups since Weber, claimed that the identification of "ethnic groups" by social scientists often reflected inaccurate labels more than indigenous realities:
Cohen also suggests that claims concerning "ethnic" identity (like earlier claims concerning "tribal" identity) are often colonialist practices and effects of the relations between colonized peoples and nation-states.[7] Harold Isaacs has identified other diacritics (distinguishing markers) of ethnicity, among them physical appearance, name, language, history, and religion;[8] this definition has entered some dictionaries.[9] Social scientists have thus focused on how, when, and why different markers of ethnic identity become salient. Thus, anthropologist Joan Vincent observed that ethnic boundaries often have a mercurial character.[10] Ronald Cohen concluded that ethnicity is "a series of nesting dichotomizations of inclusiveness and exclusiveness".[7] He agrees with Joan Vincent's observation that (in Cohen's paraphrase) "Ethnicity ... can be narrowed or broadened in boundary terms in relation to the specific needs of political mobilization.[7] This may be why descent is sometimes a marker of ethnicity, and sometimes not: which diacritic of ethnicity is salient depends on whether people are scaling ethnic boundaries up or down, and whether they are scaling them up or down depends generally on the political situation.
# Ethnicity and race
Ethnicity and race are related concepts in that both are usually defined in terms of shared genealogy.[11] Often, ethnicity also connotes shared cultural, linguistic, behavioural or religious traits. For example, to call oneself Jewish or Arab one immediately invokes a clutch of linguistic, religious, cultural and racial features that are held to be common within each ethnic category. Such broad ethnic categories have also been termed macroethnicity[12] to distinguish them from smaller more subjective ethnic features, often termed microethnicity.[13][14] Race, by contrast, refers to "some concentrations, as relative to frequency and distribution, of hereditary particles (genes) and physical characters, which appear, fluctuate, and often disappear in the course of time by reason of geographic and or cultural isolation." In 1950, the UNESCO statement The Race Question, signed by some of the internationally renowned scholars of the time (including Ashley Montagu, Claude Lévi-Strauss, Gunnar Myrdal, Julian Huxley, etc.), suggested that: "National, religious, geographic, linguistic and cultural groups do not necessarily coincide with racial groups: and the cultural traits of such groups have no demonstrated genetic connection with racial traits. Because serious errors of this kind are habitually committed when the term 'race' is used in popular parlance, it would be better when speaking of human races to drop the term 'race' altogether and speak of 'ethnic groups'."[15]
In 1982, American cultural anthropologist, summing up forty years of ethnographic research, argued that racial and ethnic categories are symbolic markers for different ways that people from different parts of the world have been incorporated into a global economy. According to Wolf, races were incorporated during the period of European mercantile expansion, and ethnic groups during the period of capitalist expansion:
# Ethnic stratification
In sociology and social theory, ethnicity can be viewed as a way of social stratification, meaning that ethnicity is the basis for a hierarchical arrangement of individuals. According to Donald Noel, a sociologist who developed a theory on the origin of ethnic stratification, ethnic stratification is a "system of stratification wherein some relatively fixed group membership (e.g., race, religion, or nationality) is utilized as a major criterion for assigning social positions"[17] Ethnic stratification is one of many different types of social stratification, including stratification based on socio-economic status, race, or gender.
According to Donald Noel, ethnic stratification will emerge only when specific ethnic groups are brought into contact with one another, and only when those groups are characterized by a high degree of ethnocentrism, competition, and differential power. Ethnocentrism is the tendency to look at the world primarily from the perspective of one's own culture, and to downgrade all other groups outside one’s own culture. Some sociologists, such as Lawrence Bobo and Vincent Hutchings, say the origin of ethnic stratification lies in individual dispositions of ethnic prejudice, which relates to the theory of ethnocentrism[18]
Continuing with Noel’s theory, some degree of differential power must also be present for the emergence of ethnic stratification. In other words, an inequality of power among ethnic groups means "they are of such unequal power that one is able to impose its will upon another".[19] In addition to differential power, a degree of competition structured along ethnic lines is a prerequisite to ethnic stratification as well. The different ethnic groups must be competing for some common goal, such as power or influence, or a material interest such as wealth or territory. Lawrence Bobo and Vincent Hutchings propose that competition is driven by self-interest and hostility, and results in inevitable stratification and conflict.[20]
# Ethnicity and nation
In some cases, especially involving transnational migration, or colonial expansion, ethnicity is linked to nationality. Many anthropologists and historians, following the work of Ernest Gellner[21] and Benedict Anderson[22] see nations and nationalism as developing with the rise of the modern state system in the seventeenth century, culminating in the rise of "nation-states" in which the presumptive boundaries of the nation coincided (or ideally coincided) with state boundaries.
Thus, in the West, the notion of ethnicity, like race and nation, developed in the context of European colonial expansion, when mercantilism and capitalism were promoting global movements of populations at the same time that state boundaries were being more clearly and rigidly defined. In the nineteenth century, modern states generally sought legitimacy through their claim to represent "nations." Nation-states, however, invariably include populations that have been excluded from national life for one reason or another. Members of excluded groups, consequently, will either demand inclusion on the basis of equality, or seek autonomy, sometimes even to the extent of complete political separation in their own nation-state.[23] Under these conditions - when people moved from one state to another,[24] or one state conquered or colonized peoples beyond its national boundaries - ethnic groups were formed by people who identified with one nation, but lived in another state.
# Ethno-national conflict
Sometimes ethnic groups are subject to prejudicial attitudes and actions by the state or its constituents. In the twentieth century, people began to argue that conflicts among ethnic groups or between members of an ethnic group and the state can and should be resolved in one of two ways. Some, like Jürgen Habermas and Bruce Barry, have argued that the legitimacy of modern states must be based on a notion of political rights of autonomous individual subjects. According to this view the state should not acknowledge ethnic, national or racial identity but rather instead enforce political and legal equality of all individuals. Others, like Charles Taylor and Will Kymlicka argue that the notion of the autonomous individual is itself a cultural construct. According to this view, states must recognize ethnic identity and develop processes through which the particular needs of ethnic groups can be accommodated within the boundaries of the nation-state.
The nineteenth century saw the development of the political ideology of ethnic nationalism, when the concept of race was tied to nationalism, first by German theorists including Johann Gottfried von Herder. Instances of societies focusing on ethnic ties arguably to the exclusion of history or historical context have resulted in the justification of nationalist goals. Two periods frequently cited as examples of this are the nineteenth century consolidation and expansion of the German Empire and the Third (Greater German) Reich, each promoted on the pan-ethnic idea that these governments were only acquiring lands that had always been ethnically German. The history of late-comers to the nation-state model, such as those arising in the Near East and south-eastern Europe out of the dissolution of the Ottoman and Austro-Hungarian Empires, as well as those arising out of the former USSR, is marked by inter-ethnic conflicts that usually occurs within multi-ethnic states, as opposed to between them, in other regions of the world; thus, those other conflicts are often misleadingly labelled and characterized as "civil war."
# Ethnicity in specific countries
In the United States of America, collectives of related ethnic groups are typically denoted as "ethnic." Most prominently in the U.S., the various Latin American racial and ancestral groups are typically grouped as either "Hispanics" or "Latinos" (although sometimes some white American lump black Latinos with black Americans. The many previously designated 'Oriental' ethnic groups are designated as Asian ethnic groups and similarly linked together as "Asians." The terms "Black" and "African-American," while different, usually describe the descendants whose ancestors were indigenous to Africa and generally excludes the African descendants of European colonists. Even the racial term "White American" generally describes people whose ancestry can be traced to Europe (including non-European nations such as Argentina, Australia, and Canada where European ancestry contributes to the overall populations) who now live in the United States. "Middle Easterners" are peoples from the Middle-East, i.e. Southwest Asia and North Africa. These countries include Iran, Turkey, Tunisia, Iraq, Saudi Arabia, Egypt, Libya, Algeria, and Morocco. (The U.S. Census Bureau compiled a list of ethnic groups which may be seen at Ethnicity (United States Census)).
In the United Kingdom, different classifications, both formal and informal, are used. Perhaps the most accepted is the National Statistics classification, identical to that used in the 2001 Census in England and Wales (see Ethnicity (United Kingdom)). In general popular use in the United Kingdom and Europe, the terms oriental and Asian are widespread and without negative connotation, with the latter term usually reserved in the United Kingdom for people from the Indian subcontinent (see British Oriental and British Asian for more details).
China officially recognizes 56 ethnic groups of which the majority is comprised by the Han Chinese. Many of the ethnic minorities maintain their own individual culture and language, although many are also becoming more like the Han Chinese. Han Chinese predominates most areas of China with the exception of Tibet and Xinjiang where the Han are still in the minority. The Han Chinese are the only ethnic group bound by the One-child policy. (For more details, see List of ethnic groups in China and Ethnic minorities in China.)
In France, no population census includes ethnic categories, and the government is prohibited from collecting, maintaining or using ethnic population statistics.[25] The current French government, led by Nicolas Sarkozy and François Fillon, has begun a legislative process to repeal this prohibition. | https://www.wikidoc.org/index.php/Ethnic_group | |
6c25481807f09cba75b93f75b537a711720fa861 | wikidoc | Ethosuximide | Ethosuximide
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# Overview
Ethosuximide is a anticonvulsant that is FDA approved for the treatment of absence (petit mal) epilepsy. Common adverse reactions include anorexia, vague gastric upset, nausea and vomiting, ataxia, headache, dizziness, drowsiness.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
### Indications
- Ethosuximide is indicated for the control of absence (petit mal) epilepsy.
### Dosage
- Ethosuximide is administered by the oral route. The initial dose for patients 3 to 6 years of age is one teaspoonful (250 mg) per day; for patients 6 years of age and older, 2 teaspoonfuls (500 mg) per day. The dose thereafter must be individualized according to the patient’s response. Dosage should be increased by small increments. One useful method is to increase the daily dose by 250 mg every four to seven days until control is achieved with minimal side effects. Dosages exceeding 1.5 g daily, in divided doses, should be administered only under the strictest supervision of the physician. The optimal dose for most pediatric patients is 20 mg/kg/day. This dose has given average plasma levels within the accepted therapeutic range of 40 to 100 mcg/mL. Subsequent dose schedules can be based on effectiveness and plasma level determinations.
- Ethosuximide may be administered in combination with other anticonvulsants when other forms of epilepsy coexist with absence (petit mal). The optimal dose for most pediatric patients is 20 mg/kg/day.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Ethosuximide in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Ethosuximide in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
### Dosage
- The optimal dose for most pediatric patients is 20 mg/kg/day.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Ethosuximide in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Ethosuximide in pediatric patients.
# Contraindications
- Ethosuximide should not be used in patients with a history of hypersensitivity to succinimides.
# Warnings
- Blood dyscrasias, including some with fatal outcome, have been reported to be associated with the use of ethosuximide; therefore, periodic blood counts should be performed. Should signs and/or symptoms of infection (e.g., sore throat, fever) develop, blood counts should be considered at that point.
- Ethosuximide is capable of producing morphological and functional changes in the animal liver. In humans, abnormal liver and renal function studies have been reported. Ethosuximide should be administered with extreme caution to patients with known liver or renal disease. Periodic urinalysis and liver function studies are advised for all patients receiving the drug.
- Cases of systemic lupus erythematosus have been reported with the use of ethosuximide. The physician should be alert to this possibility.
- Antiepileptic drugs (AEDs), including ethosuximide, increase the risk of suicidal thoughts or behavior in patients taking these drugs for any indication. Patients treated with any AED for any indication should be monitored for the emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in mood or behavior.
- Pooled analyses of 199 placebo-controlled clinical trials (mono- and adjunctive therapy) of 11 different AEDs showed that patients randomized to one of the AEDs had approximately twice the risk (adjusted Relative Risk 1.8, 95% CI:1.2, 2.7) of suicidal thinking or behavior compared to patients randomized to placebo. In these trials, which had a median treatment duration of 12 weeks, the estimated incidence rate of suicidal behavior or ideation among 27,863 AED-treated patients was 0.43%, compared to 0.24% among 16,029 placebo-treated patients, representing an increase of approximately one case of suicidal thinking or behavior for every 530 patients treated. There were four suicides in drug-treated patients in the trials and none in placebo-treated patients, but the number is too small to allow any conclusion about drug effect on suicide.
- The increased risk of suicidal thoughts or behavior with AEDs was observed as early as one week after starting drug treatment with AEDs and persisted for the duration of treatment assessed. Because most trials included in the analysis did not extend beyond 24 weeks, the risk of suicidal thoughts or behavior beyond 24 weeks could not be assessed.
- The risk of suicidal thoughts or behavior was generally consistent among drugs in the data analyzed. The finding of increased risk with AEDs of varying mechanisms of action and across a range of indications suggests that the risk applies to all AEDs used for any indication. The risk did not vary substantially by age (5-100 years) in the clinical trials analyzed.
- Table 1 shows absolute and relative risk by indication for all evaluated AEDs.
- The relative risk for suicidal thoughts or behavior was higher in clinical trials for epilepsy than in clinical trials for psychiatric or other conditions, but the absolute risk differences were similar for the epilepsy and psychiatric indications.
- Anyone considering prescribing ethosuximide or any other AED must balance the risk of suicidal thoughts and behavior with the risk of untreated illness. Epilepsy and many other illnesses for which AEDs are prescribed are themselves associated with morbidity and mortality and an increased risk of suicidal thoughts and behavior. Should suicidal thoughts and behavior emerge during treatment, the prescriber needs to consider whether the emergence of these symptoms in any given patient may be related to the illness being treated.
- Patients, their caregivers, and families should be informed that AEDs increase the risk of suicidal thoughts and behavior and should be advised of the need to be alert for the emergence or worsening of the signs and symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts, behavior, or thoughts about self-harm. Behaviors of concern should be reported immediately to healthcare providers.
- Serious dermatologic reactions, including Stevens-Johnson syndrome (SJS), have been reported with ethosuximide treatment. SJS can be fatal. The onset of symptoms is usually within 28 days, but can occur later. Ethosuximide should be discontinued at the first sign of a rash, unless the rash is clearly not drug-related. If signs or symptoms suggest SJS, use of this drug should not be resumed and alternative therapy should be considered.
### Precautions
- Ethosuximide, when used alone in mixed types of epilepsy, may increase the frequency of grand mal seizures in some patients.
- As with other anticonvulsants, it is important to proceed slowly when increasing or decreasing dosage, as well as when adding or eliminating other medication. Abrupt withdrawal of anticonvulsant medication may precipitate absence (petit mal) status.
# Adverse Reactions
## Clinical Trials Experience
- Allergic reaction. Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS).
- Gastrointestinal symptoms occur frequently and include anorexia, vague gastric upset, nausea and vomiting, cramps, epigastric and abdominal pain, weight loss, and diarrhea. There have been reports of gum hypertrophy and swelling of the tongue.
- Hemopoietic complications associated with the administration of ethosuximide have included leukopenia, agranulocytosis, pancytopenia, with or without bone marrow suppression, and eosinophilia.
- Neurologic and sensory reactions reported during therapy with ethosuximide have included drowsiness, headache, dizziness, euphoria, hiccups, irritability, hyperactivity, lethargy, fatigue, and ataxia.
- Psychiatric or psychological aberrations associated with ethosuximide administration have included disturbances of sleep, night terrors, inability to concentrate, and aggressiveness.
- These effects may be noted particularly in patients who have previously exhibited psychological abnormalities. There have been rare reports of paranoid psychosis, increased libido, and increased state of depression with overt suicidal intentions.
- Dermatologic manifestations which have occurred with the administration of ethosuximide have included urticaria, pruritic erythematous rashes, and hirsutism.
- Myopia
- Vaginal bleeding, microscopic hematuria.
## Postmarketing Experience
There is limited information regarding Postmarketing Experience of Ethosuximide in the drug label.
# Drug Interactions
- Since ethosuximide may interact with concurrently administered antiepileptic drugs, periodic serum level determinations of these drugs may be necessary (e.g., ethosuximide may elevate phenytoin serum levels and valproic acid has been reported to both increase and decrease ethosuximide levels).
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
- Ethosuximide crosses the placenta.
- Reports suggest an association between the use of anticonvulsant drugs by women with epilepsy and an elevated incidence of birth defects in children born to these women. Data are more extensive with respect to phenytoin and phenobarbital, but these are also the most commonly prescribed anticonvulsants; less systematic or anecdotal reports suggest a possible similar association with the use of all known anticonvulsant drugs.
- Cases of birth defects have been reported with ethosuximide. The reports suggesting an elevated incidence of birth defects in children of drug-treated epileptic women cannot be regarded as adequate to prove a definite cause and effect relationship. There are intrinsic methodologic problems in obtaining adequate data on drug teratogenicity in humans; the possibility also exists that other factors, e.g., genetic factors or the epileptic condition itself, may be more important than drug therapy in leading to birth defects. The great majority of mothers on anticonvulsant medication deliver normal infants. It is important to note that anticonvulsant drugs should not be discontinued in patients in whom the drug is administered to prevent major seizures because of the strong possibility of precipitating status epilepticus with attendant hypoxia and threat to life. In individual cases where the severity and frequency of the seizure disorder are such that the removal of medication does not pose a serious threat to the patient, discontinuation of the drug may be considered prior to and during pregnancy, although it cannot be said with any confidence that even minor seizures do not pose some hazard to the developing embryo or fetus.
- The prescribing physician will wish to weigh these considerations in treating or counseling epileptic women of childbearing potential.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Ethosuximide in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Ethosuximide during labor and delivery.
### Nursing Mothers
- Ethosuximide is excreted in human breast milk. Because the effects of ethosuximide on the nursing infant are unknown, caution should be exercised when ethosuximide is administered to a nursing mother. Ethosuximide should be used in nursing mothers only if the benefits clearly outweigh the risks.
### Pediatric Use
- Safety and effectiveness in pediatric patients below the age of 3 years have not been established.
### Geriatic Use
There is no FDA guidance on the use of Ethosuximide with respect to geriatric patients.
### Gender
There is no FDA guidance on the use of Ethosuximide with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Ethosuximide with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Ethosuximide in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Ethosuximide in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Ethosuximide in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Ethosuximide in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Oral
### Monitoring
There is limited information regarding Monitoring of Ethosuximide in the drug label.
# IV Compatibility
There is limited information regarding IV Compatibility of Ethosuximide in the drug label.
# Overdosage
### Acute overdoses
- Acute overdoses may produce nausea, vomiting, and CNS depression including coma with respiratory depression. A relationship between ethosuximide toxicity and its plasma levels has not been established. The therapeutic range of serum levels is 40 mcg/mL to 100 mcg/mL, although levels as high as 150 mcg/mL have been reported without signs of toxicity.
### Treatment
- Treatment should include emesis (unless the patient is, or could rapidly become, obtunded, comatose, or convulsing) or gastric lavage, activated charcoal, cathartics, and general supportive measures. Hemodialysis may be useful to treat ethosuximide overdose. Forced diuresis and exchange transfusions are ineffective.
# Pharmacology
## Mechanism of Action
- Ethosuximide suppresses the paroxysmal three cycle per second spike and wave activity associated with lapses of consciousness which is common in absence (petit mal) seizures. The frequency of epileptiform attacks is reduced, apparently by depression of the motor cortex and elevation of the threshold of the central nervous system to convulsive stimuli.
## Structure
- Ethosuximide is an anticonvulsant succinimide, chemically designated as alpha-ethyl-alpha-methyl-succinimide, with the following structural formula:
## Pharmacodynamics
There is limited information regarding Pharmacodynamics of Ethosuximide in the drug label.
## Pharmacokinetics
There is limited information regarding Pharmacokinetics of Ethosuximide in the drug label.
## Nonclinical Toxicology
There is limited information regarding Nonclinical Toxicology of Ethosuximide in the drug label.
# Clinical Studies
There is limited information regarding Clinical Studies of Ethosuximide in the drug label.
# How Supplied
- Ethosuximide oral solution, USP 250 mg/5 mL is supplied as:
- NDC 46672-641-16 - 16 fl. oz. bottles. Each 5 mL of oral solution contains 250 mg ethosuximide in a raspberry flavored base.
## Storage
- Store at 20º to 25ºC (68º to 77ºF) . Protect from freezing and light.
- Dispense in a tight, light-resistant container with a child-resistant closure.
# Images
## Drug Images
## Package and Label Display Panel
### Ingredients and Appearance
# Patient Counseling Information
- Inform patients of the availability of a Medication Guide, and instruct them to read the Medication Guide prior to taking ethosuximide. Instruct patients to take ethosuximide only as prescribed.
- Ethosuximide may impair the mental and/or physical abilities required for the performance of potentially hazardous tasks such as driving a motor vehicle or other such activity requiring alertness; therefore, the patient should be cautioned accordingly.
- Patients taking ethosuximide should be advised of the importance of adhering strictly to the prescribed dosage regimen.
- Patients should be instructed to promptly contact their physician when they develop signs and/or symptoms suggesting an infection (e.g., sore throat, fever).
- Patients, their caregivers, and families should be counseled that AEDs, including ethosuximide, may increase the risk of suicidal thoughts and behavior and should be advised of the need to be alert for the emergence or worsening of symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts, behavior, or thoughts about self-harm. Behaviors of concern should be reported immediately to healthcare providers.
- Prior to initiation of treatment with ethosuximide, the patient should be instructed that a rash may herald a serious medical event and that the patient should report any such occurrence to a physician immediately.
- Patients should be encouraged to enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry if they become pregnant. This Registry is collecting information about the safety of antiepileptic drugs during pregnancy. To enroll, patients can call the toll free number 1-888-233-2334
### MEDICATION GUIDE
- ETHOSUXIMIDE ORAL SOLUTION USP, 250 mg/5 mL
- Read this Medication Guide before you start taking ethosuximide oral solution and each time you get a refill. There may be new information. This information does not take the place of talking to your healthcare provider about your medical condition or treatment. If you have any questions about ethosuximide oral solution, ask your healthcare provider or pharmacist.
- Stopping ethosuximide oral solution suddenly can cause serious problems.
- Rare but serious blood problems that may be life-threatening. Call your healthcare provider right away if you have:
- fever, swollen glands, or sore throat that come and go or do not go away
- frequent infections or an infection that does not go away
- easy bruising
- red or purple spots on your body
- bleeding gums or nose bleeds
- severe fatigue or weakness
- Systemic Lupus Erythematosus. Call your healthcare provider right away if you have any of these symptoms:
- joint pain and swelling
- muscle pain
- fatigue
- low-grade fever
- pain in the chest that is worse with breathing
- unexplained skin rash
- Like other antiepileptic drugs, ethosuximide oral solution may cause suicidal thoughts or actions in a very small number of people, about 1 in 500.
- Call a healthcare provider right away if you have any of these symptoms, especially if they are new, worse, or worry you:
- thoughts about suicide or dying
- attempts to commit suicide
- new or worse depression
- new or worse anxiety
- feeling agitated or restless
- panic attacks
- trouble sleeping (insomnia)
- new or worse irritability
- acting aggressive, being angry, or violent
- acting on dangerous impulses
- an extreme increase activity and talking (mania)
- other unusual changes in behavior or mood
- How can I watch for early symptoms of suicidal thoughts and actions?
- Pay attention to any changes, especially sudden changes, in mood, behaviors, thoughts, or feelings.
- Keep all follow-up visits with your healthcare provider as scheduled.
- Call your healthcare provider between visits as needed, especially if you are worried about symptoms.
- Do not stop ethosuximide oral solution without first talking to a healthcare provider.
- Stopping ethosuximide oral solution suddenly can cause serious problems.
- Stopping a seizure medicine suddenly in a patient who has epilepsy can cause seizures that will not stop (status epilepticus).
- Suicidal thoughts or actions can be caused by things other than medicines. If you have suicidal thoughts or actions, your healthcare provider may check for other causes.
- Ethosuximide oral solution is a prescription medicine used to treat absence (petit mal) seizures.
- Do not take ethosuximide oral solution if you are allergic to succinimides (methsuximide or ethosuximide), or any of the ingredients in ethosuximide oral solution. See the end of this Medication Guide for a complete list of ingredients in ethosuximide oral solution.
- Before you take ethosuximide oral solution, tell your healthcare provider if you:
- have or had liver problems
- have or have had depression, mood problems or suicidal thoughts or behavior
- have any other medical conditions
- are pregnant or plan to become pregnant. It is not known if ethosuximide oral solution can harm your unborn baby. Tell your healthcare provider right away if you become pregnant while taking ethosuximide oral solution. You and your healthcare provider should decide if you should take ethosuximide oral solution while you are pregnant.
- If you become pregnant while taking ethosuximide oral solution, talk to your healthcare provider about registering with the North American Antiepileptic Drug (NAAED) Pregnancy Registry. The purpose of this registry is to collect information about the safety of antiepileptic drugs during pregnancy. You can enroll in this registry by calling 1-888-233-2334.
- are breast-feeding or plan to breast-feed. It is not known if ethosuximide can pass into breast milk. You and your healthcare provider should decide how you will feed your baby while you take ethosuximide oral solution.
- Tell your healthcare provider about all the medicines you take, including prescription and non-prescription medicines, vitamins, and herbal supplements. Taking ethosuximide oral solution with certain other medicines can cause side effects or affect how well they work. Do not start or stop other medicines without talking to your healthcare provider.
- Know the medicines you take. Keep a list of them with you to show your healthcare provider and pharmacist when you get a new medicine.
- Take ethosuximide oral solution exactly as prescribed. Your healthcare provider will tell you how much ethosuximide oral solution to take.
- Your healthcare provider may change your dose. Do not change your dose of ethosuximide oral solution without talking to your healthcare provider.
- If you take too much ethosuximide oral solution, call your healthcare provider or your local Poison Control Center right away.
- Do not drink alcohol or take other medicines that make you sleepy or dizzy while taking ethosuximide oral solution without first talking to your healthcare provider. Ethosuximide oral solution taken with alcohol or medicines that cause sleepiness or dizziness may make your sleepiness or dizziness worse.
- Do not drive, operate heavy machinery, or do other dangerous activities until you know how ethosuximide oral solution affects you. Ethosuximide oral solution can slow your thinking and motor skills.
- See "What is the most important information I should know about ethosuximide oral solution?"
- Ethosuximide oral solution may cause other serious side effects, including:
- Serious allergic reactions. Call your healthcare provider right away if you have any of these symptoms:
- skin rash
- hives
- sores in your mouth
- blistering or peeling skin
- Changes in thinking, mood, or behavior. Some patients may get abnormally suspicious thoughts, hallucinations (seeing or hearing things that are not there), or delusions (false thoughts or beliefs).
- Grand mal seizures can happen more often or become worse
- The most common side effects of ethosuximide oral solution include
- nausea or vomiting
- indigestion, stomach pain
- diarrhea
- weight loss
- loss of appetite
- hiccups
- fatigue
- dizziness or lightheadedness
- unsteadiness when walking
- headache
- loss of concentration
- Tell your healthcare provider about any side effect that bothers you or that does not go away.
- These are not all the possible side effects with ethosuximide oral solution. For more information, ask your healthcare provider or pharmacist.
- Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.
- Store ethosuximide oral solution at 20° to 25°C (68° to 77°F). Preserve in tight containers. Protect from freezing and light.
- Keep ethosuximide oral solution and all medicines out of the reach of children.
- Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use ethosuximide oral solution for a condition for which it was not prescribed. Do not give ethosuximide oral solution to other people, even if they have the same condition. It may harm them.
- This Medication Guide summarizes the most important information about ethosuximide oral solution. If you would like more information, talk with your healthcare provider. You can ask your healthcare provider or pharmacist for information about ethosuximide oral solution that is written for healthcare professionals.
For more information, call 404-351-4510.
Active ingredient: ethosuximide
Inactive ingredients: artificial raspberry flavor, citric acid, ethyl maltol, FD&C Red No. 40, FD&C Yellow No. 6, glycerin, purified water, saccharin sodium, sodium benzoate, sodium citrate, and sucrose.
This Medication Guide has been approved by the U.S. Food and Drug Administration.
# Precautions with Alcohol
- Alcohol-Ethosuximide interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Zarontin®
# Look-Alike Drug Names
There is limited information regarding Ethosuximide Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | Ethosuximide
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
Ethosuximide is a anticonvulsant that is FDA approved for the treatment of absence (petit mal) epilepsy. Common adverse reactions include anorexia, vague gastric upset, nausea and vomiting, ataxia, headache, dizziness, drowsiness.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
### Indications
- Ethosuximide is indicated for the control of absence (petit mal) epilepsy.
### Dosage
- Ethosuximide is administered by the oral route. The initial dose for patients 3 to 6 years of age is one teaspoonful (250 mg) per day; for patients 6 years of age and older, 2 teaspoonfuls (500 mg) per day. The dose thereafter must be individualized according to the patient’s response. Dosage should be increased by small increments. One useful method is to increase the daily dose by 250 mg every four to seven days until control is achieved with minimal side effects. Dosages exceeding 1.5 g daily, in divided doses, should be administered only under the strictest supervision of the physician. The optimal dose for most pediatric patients is 20 mg/kg/day. This dose has given average plasma levels within the accepted therapeutic range of 40 to 100 mcg/mL. Subsequent dose schedules can be based on effectiveness and plasma level determinations.
- Ethosuximide may be administered in combination with other anticonvulsants when other forms of epilepsy coexist with absence (petit mal). The optimal dose for most pediatric patients is 20 mg/kg/day.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Ethosuximide in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Ethosuximide in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
### Dosage
- The optimal dose for most pediatric patients is 20 mg/kg/day.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Ethosuximide in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Ethosuximide in pediatric patients.
# Contraindications
- Ethosuximide should not be used in patients with a history of hypersensitivity to succinimides.
<--Warnings-->
# Warnings
- Blood dyscrasias, including some with fatal outcome, have been reported to be associated with the use of ethosuximide; therefore, periodic blood counts should be performed. Should signs and/or symptoms of infection (e.g., sore throat, fever) develop, blood counts should be considered at that point.
- Ethosuximide is capable of producing morphological and functional changes in the animal liver. In humans, abnormal liver and renal function studies have been reported. Ethosuximide should be administered with extreme caution to patients with known liver or renal disease. Periodic urinalysis and liver function studies are advised for all patients receiving the drug.
- Cases of systemic lupus erythematosus have been reported with the use of ethosuximide. The physician should be alert to this possibility.
- Antiepileptic drugs (AEDs), including ethosuximide, increase the risk of suicidal thoughts or behavior in patients taking these drugs for any indication. Patients treated with any AED for any indication should be monitored for the emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in mood or behavior.
- Pooled analyses of 199 placebo-controlled clinical trials (mono- and adjunctive therapy) of 11 different AEDs showed that patients randomized to one of the AEDs had approximately twice the risk (adjusted Relative Risk 1.8, 95% CI:1.2, 2.7) of suicidal thinking or behavior compared to patients randomized to placebo. In these trials, which had a median treatment duration of 12 weeks, the estimated incidence rate of suicidal behavior or ideation among 27,863 AED-treated patients was 0.43%, compared to 0.24% among 16,029 placebo-treated patients, representing an increase of approximately one case of suicidal thinking or behavior for every 530 patients treated. There were four suicides in drug-treated patients in the trials and none in placebo-treated patients, but the number is too small to allow any conclusion about drug effect on suicide.
- The increased risk of suicidal thoughts or behavior with AEDs was observed as early as one week after starting drug treatment with AEDs and persisted for the duration of treatment assessed. Because most trials included in the analysis did not extend beyond 24 weeks, the risk of suicidal thoughts or behavior beyond 24 weeks could not be assessed.
- The risk of suicidal thoughts or behavior was generally consistent among drugs in the data analyzed. The finding of increased risk with AEDs of varying mechanisms of action and across a range of indications suggests that the risk applies to all AEDs used for any indication. The risk did not vary substantially by age (5-100 years) in the clinical trials analyzed.
- Table 1 shows absolute and relative risk by indication for all evaluated AEDs.
- The relative risk for suicidal thoughts or behavior was higher in clinical trials for epilepsy than in clinical trials for psychiatric or other conditions, but the absolute risk differences were similar for the epilepsy and psychiatric indications.
- Anyone considering prescribing ethosuximide or any other AED must balance the risk of suicidal thoughts and behavior with the risk of untreated illness. Epilepsy and many other illnesses for which AEDs are prescribed are themselves associated with morbidity and mortality and an increased risk of suicidal thoughts and behavior. Should suicidal thoughts and behavior emerge during treatment, the prescriber needs to consider whether the emergence of these symptoms in any given patient may be related to the illness being treated.
- Patients, their caregivers, and families should be informed that AEDs increase the risk of suicidal thoughts and behavior and should be advised of the need to be alert for the emergence or worsening of the signs and symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts, behavior, or thoughts about self-harm. Behaviors of concern should be reported immediately to healthcare providers.
- Serious dermatologic reactions, including Stevens-Johnson syndrome (SJS), have been reported with ethosuximide treatment. SJS can be fatal. The onset of symptoms is usually within 28 days, but can occur later. Ethosuximide should be discontinued at the first sign of a rash, unless the rash is clearly not drug-related. If signs or symptoms suggest SJS, use of this drug should not be resumed and alternative therapy should be considered.
### Precautions
- Ethosuximide, when used alone in mixed types of epilepsy, may increase the frequency of grand mal seizures in some patients.
- As with other anticonvulsants, it is important to proceed slowly when increasing or decreasing dosage, as well as when adding or eliminating other medication. Abrupt withdrawal of anticonvulsant medication may precipitate absence (petit mal) status.
# Adverse Reactions
## Clinical Trials Experience
- Allergic reaction. Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS).
- Gastrointestinal symptoms occur frequently and include anorexia, vague gastric upset, nausea and vomiting, cramps, epigastric and abdominal pain, weight loss, and diarrhea. There have been reports of gum hypertrophy and swelling of the tongue.
- Hemopoietic complications associated with the administration of ethosuximide have included leukopenia, agranulocytosis, pancytopenia, with or without bone marrow suppression, and eosinophilia.
- Neurologic and sensory reactions reported during therapy with ethosuximide have included drowsiness, headache, dizziness, euphoria, hiccups, irritability, hyperactivity, lethargy, fatigue, and ataxia.
- Psychiatric or psychological aberrations associated with ethosuximide administration have included disturbances of sleep, night terrors, inability to concentrate, and aggressiveness.
- These effects may be noted particularly in patients who have previously exhibited psychological abnormalities. There have been rare reports of paranoid psychosis, increased libido, and increased state of depression with overt suicidal intentions.
- Dermatologic manifestations which have occurred with the administration of ethosuximide have included urticaria, pruritic erythematous rashes, and hirsutism.
- Myopia
- Vaginal bleeding, microscopic hematuria.
## Postmarketing Experience
There is limited information regarding Postmarketing Experience of Ethosuximide in the drug label.
# Drug Interactions
- Since ethosuximide may interact with concurrently administered antiepileptic drugs, periodic serum level determinations of these drugs may be necessary (e.g., ethosuximide may elevate phenytoin serum levels and valproic acid has been reported to both increase and decrease ethosuximide levels).
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
- Ethosuximide crosses the placenta.
- Reports suggest an association between the use of anticonvulsant drugs by women with epilepsy and an elevated incidence of birth defects in children born to these women. Data are more extensive with respect to phenytoin and phenobarbital, but these are also the most commonly prescribed anticonvulsants; less systematic or anecdotal reports suggest a possible similar association with the use of all known anticonvulsant drugs.
- Cases of birth defects have been reported with ethosuximide. The reports suggesting an elevated incidence of birth defects in children of drug-treated epileptic women cannot be regarded as adequate to prove a definite cause and effect relationship. There are intrinsic methodologic problems in obtaining adequate data on drug teratogenicity in humans; the possibility also exists that other factors, e.g., genetic factors or the epileptic condition itself, may be more important than drug therapy in leading to birth defects. The great majority of mothers on anticonvulsant medication deliver normal infants. It is important to note that anticonvulsant drugs should not be discontinued in patients in whom the drug is administered to prevent major seizures because of the strong possibility of precipitating status epilepticus with attendant hypoxia and threat to life. In individual cases where the severity and frequency of the seizure disorder are such that the removal of medication does not pose a serious threat to the patient, discontinuation of the drug may be considered prior to and during pregnancy, although it cannot be said with any confidence that even minor seizures do not pose some hazard to the developing embryo or fetus.
- The prescribing physician will wish to weigh these considerations in treating or counseling epileptic women of childbearing potential.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Ethosuximide in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Ethosuximide during labor and delivery.
### Nursing Mothers
- Ethosuximide is excreted in human breast milk. Because the effects of ethosuximide on the nursing infant are unknown, caution should be exercised when ethosuximide is administered to a nursing mother. Ethosuximide should be used in nursing mothers only if the benefits clearly outweigh the risks.
### Pediatric Use
- Safety and effectiveness in pediatric patients below the age of 3 years have not been established.
### Geriatic Use
There is no FDA guidance on the use of Ethosuximide with respect to geriatric patients.
### Gender
There is no FDA guidance on the use of Ethosuximide with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Ethosuximide with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Ethosuximide in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Ethosuximide in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Ethosuximide in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Ethosuximide in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Oral
### Monitoring
There is limited information regarding Monitoring of Ethosuximide in the drug label.
# IV Compatibility
There is limited information regarding IV Compatibility of Ethosuximide in the drug label.
# Overdosage
### Acute overdoses
- Acute overdoses may produce nausea, vomiting, and CNS depression including coma with respiratory depression. A relationship between ethosuximide toxicity and its plasma levels has not been established. The therapeutic range of serum levels is 40 mcg/mL to 100 mcg/mL, although levels as high as 150 mcg/mL have been reported without signs of toxicity.
### Treatment
- Treatment should include emesis (unless the patient is, or could rapidly become, obtunded, comatose, or convulsing) or gastric lavage, activated charcoal, cathartics, and general supportive measures. Hemodialysis may be useful to treat ethosuximide overdose. Forced diuresis and exchange transfusions are ineffective.
# Pharmacology
## Mechanism of Action
- Ethosuximide suppresses the paroxysmal three cycle per second spike and wave activity associated with lapses of consciousness which is common in absence (petit mal) seizures. The frequency of epileptiform attacks is reduced, apparently by depression of the motor cortex and elevation of the threshold of the central nervous system to convulsive stimuli.
## Structure
- Ethosuximide is an anticonvulsant succinimide, chemically designated as alpha-ethyl-alpha-methyl-succinimide, with the following structural formula:
## Pharmacodynamics
There is limited information regarding Pharmacodynamics of Ethosuximide in the drug label.
## Pharmacokinetics
There is limited information regarding Pharmacokinetics of Ethosuximide in the drug label.
## Nonclinical Toxicology
There is limited information regarding Nonclinical Toxicology of Ethosuximide in the drug label.
# Clinical Studies
There is limited information regarding Clinical Studies of Ethosuximide in the drug label.
# How Supplied
- Ethosuximide oral solution, USP 250 mg/5 mL is supplied as:
- NDC 46672-641-16 - 16 fl. oz. bottles. Each 5 mL of oral solution contains 250 mg ethosuximide in a raspberry flavored base.
## Storage
- Store at 20º to 25ºC (68º to 77ºF) [see USP Controlled Room Temperature]. Protect from freezing and light.
- Dispense in a tight, light-resistant container with a child-resistant closure.
# Images
## Drug Images
## Package and Label Display Panel
### Ingredients and Appearance
# Patient Counseling Information
- Inform patients of the availability of a Medication Guide, and instruct them to read the Medication Guide prior to taking ethosuximide. Instruct patients to take ethosuximide only as prescribed.
- Ethosuximide may impair the mental and/or physical abilities required for the performance of potentially hazardous tasks such as driving a motor vehicle or other such activity requiring alertness; therefore, the patient should be cautioned accordingly.
- Patients taking ethosuximide should be advised of the importance of adhering strictly to the prescribed dosage regimen.
- Patients should be instructed to promptly contact their physician when they develop signs and/or symptoms suggesting an infection (e.g., sore throat, fever).
- Patients, their caregivers, and families should be counseled that AEDs, including ethosuximide, may increase the risk of suicidal thoughts and behavior and should be advised of the need to be alert for the emergence or worsening of symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts, behavior, or thoughts about self-harm. Behaviors of concern should be reported immediately to healthcare providers.
- Prior to initiation of treatment with ethosuximide, the patient should be instructed that a rash may herald a serious medical event and that the patient should report any such occurrence to a physician immediately.
- Patients should be encouraged to enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry if they become pregnant. This Registry is collecting information about the safety of antiepileptic drugs during pregnancy. To enroll, patients can call the toll free number 1-888-233-2334
### MEDICATION GUIDE
- ETHOSUXIMIDE ORAL SOLUTION USP, 250 mg/5 mL
- Read this Medication Guide before you start taking ethosuximide oral solution and each time you get a refill. There may be new information. This information does not take the place of talking to your healthcare provider about your medical condition or treatment. If you have any questions about ethosuximide oral solution, ask your healthcare provider or pharmacist.
- Stopping ethosuximide oral solution suddenly can cause serious problems.
- Rare but serious blood problems that may be life-threatening. Call your healthcare provider right away if you have:
- fever, swollen glands, or sore throat that come and go or do not go away
- frequent infections or an infection that does not go away
- easy bruising
- red or purple spots on your body
- bleeding gums or nose bleeds
- severe fatigue or weakness
- Systemic Lupus Erythematosus. Call your healthcare provider right away if you have any of these symptoms:
- joint pain and swelling
- muscle pain
- fatigue
- low-grade fever
- pain in the chest that is worse with breathing
- unexplained skin rash
- Like other antiepileptic drugs, ethosuximide oral solution may cause suicidal thoughts or actions in a very small number of people, about 1 in 500.
- Call a healthcare provider right away if you have any of these symptoms, especially if they are new, worse, or worry you:
- thoughts about suicide or dying
- attempts to commit suicide
- new or worse depression
- new or worse anxiety
- feeling agitated or restless
- panic attacks
- trouble sleeping (insomnia)
- new or worse irritability
- acting aggressive, being angry, or violent
- acting on dangerous impulses
- an extreme increase activity and talking (mania)
- other unusual changes in behavior or mood
- How can I watch for early symptoms of suicidal thoughts and actions?
- Pay attention to any changes, especially sudden changes, in mood, behaviors, thoughts, or feelings.
- Keep all follow-up visits with your healthcare provider as scheduled.
- Call your healthcare provider between visits as needed, especially if you are worried about symptoms.
- Do not stop ethosuximide oral solution without first talking to a healthcare provider.
- Stopping ethosuximide oral solution suddenly can cause serious problems.
- Stopping a seizure medicine suddenly in a patient who has epilepsy can cause seizures that will not stop (status epilepticus).
- Suicidal thoughts or actions can be caused by things other than medicines. If you have suicidal thoughts or actions, your healthcare provider may check for other causes.
- Ethosuximide oral solution is a prescription medicine used to treat absence (petit mal) seizures.
- Do not take ethosuximide oral solution if you are allergic to succinimides (methsuximide or ethosuximide), or any of the ingredients in ethosuximide oral solution. See the end of this Medication Guide for a complete list of ingredients in ethosuximide oral solution.
- Before you take ethosuximide oral solution, tell your healthcare provider if you:
- have or had liver problems
- have or have had depression, mood problems or suicidal thoughts or behavior
- have any other medical conditions
- are pregnant or plan to become pregnant. It is not known if ethosuximide oral solution can harm your unborn baby. Tell your healthcare provider right away if you become pregnant while taking ethosuximide oral solution. You and your healthcare provider should decide if you should take ethosuximide oral solution while you are pregnant.
- If you become pregnant while taking ethosuximide oral solution, talk to your healthcare provider about registering with the North American Antiepileptic Drug (NAAED) Pregnancy Registry. The purpose of this registry is to collect information about the safety of antiepileptic drugs during pregnancy. You can enroll in this registry by calling 1-888-233-2334.
- are breast-feeding or plan to breast-feed. It is not known if ethosuximide can pass into breast milk. You and your healthcare provider should decide how you will feed your baby while you take ethosuximide oral solution.
- Tell your healthcare provider about all the medicines you take, including prescription and non-prescription medicines, vitamins, and herbal supplements. Taking ethosuximide oral solution with certain other medicines can cause side effects or affect how well they work. Do not start or stop other medicines without talking to your healthcare provider.
- Know the medicines you take. Keep a list of them with you to show your healthcare provider and pharmacist when you get a new medicine.
- Take ethosuximide oral solution exactly as prescribed. Your healthcare provider will tell you how much ethosuximide oral solution to take.
- Your healthcare provider may change your dose. Do not change your dose of ethosuximide oral solution without talking to your healthcare provider.
- If you take too much ethosuximide oral solution, call your healthcare provider or your local Poison Control Center right away.
- Do not drink alcohol or take other medicines that make you sleepy or dizzy while taking ethosuximide oral solution without first talking to your healthcare provider. Ethosuximide oral solution taken with alcohol or medicines that cause sleepiness or dizziness may make your sleepiness or dizziness worse.
- Do not drive, operate heavy machinery, or do other dangerous activities until you know how ethosuximide oral solution affects you. Ethosuximide oral solution can slow your thinking and motor skills.
- See "What is the most important information I should know about ethosuximide oral solution?"
- Ethosuximide oral solution may cause other serious side effects, including:
- Serious allergic reactions. Call your healthcare provider right away if you have any of these symptoms:
- skin rash
- hives
- sores in your mouth
- blistering or peeling skin
- Changes in thinking, mood, or behavior. Some patients may get abnormally suspicious thoughts, hallucinations (seeing or hearing things that are not there), or delusions (false thoughts or beliefs).
- Grand mal seizures can happen more often or become worse
- The most common side effects of ethosuximide oral solution include
- nausea or vomiting
- indigestion, stomach pain
- diarrhea
- weight loss
- loss of appetite
- hiccups
- fatigue
- dizziness or lightheadedness
- unsteadiness when walking
- headache
- loss of concentration
- Tell your healthcare provider about any side effect that bothers you or that does not go away.
- These are not all the possible side effects with ethosuximide oral solution. For more information, ask your healthcare provider or pharmacist.
- Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.
- Store ethosuximide oral solution at 20° to 25°C (68° to 77°F). Preserve in tight containers. Protect from freezing and light.
- Keep ethosuximide oral solution and all medicines out of the reach of children.
- Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use ethosuximide oral solution for a condition for which it was not prescribed. Do not give ethosuximide oral solution to other people, even if they have the same condition. It may harm them.
- This Medication Guide summarizes the most important information about ethosuximide oral solution. If you would like more information, talk with your healthcare provider. You can ask your healthcare provider or pharmacist for information about ethosuximide oral solution that is written for healthcare professionals.
For more information, call 404-351-4510.
Active ingredient: ethosuximide
Inactive ingredients: artificial raspberry flavor, citric acid, ethyl maltol, FD&C Red No. 40, FD&C Yellow No. 6, glycerin, purified water, saccharin sodium, sodium benzoate, sodium citrate, and sucrose.
This Medication Guide has been approved by the U.S. Food and Drug Administration.
# Precautions with Alcohol
- Alcohol-Ethosuximide interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Zarontin®[1]
# Look-Alike Drug Names
There is limited information regarding Ethosuximide Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Ethosuximide | |
3973b6ffcf4582770f4f8ca5e0d52eeed5debc7b | wikidoc | Ethoxylation | Ethoxylation
Ethoxylation is a chemical process in which ethylene oxide (IUPAC name: 1,2-epoxyethane) is added to fatty acids in order to make them more soluble in water. An example is the ethoxylation of sodium dodecyl sulfate to form sodium laureth sulfate, which is used as a foaming agent in shampoos and toothpastes, and as an industrial detergent.
In an industrial ethoxylation plant, the raw material is preheated and fed to a stainless steel chemical reactor, where it is mixed with ethylene oxide and potassium hydroxide (KOH), which acts as the catalyst. The reactor is pressurised with nitrogen to 5 bar and heated to 150°C.
Many types of "substrate" chemicals may undergo ethoxylation: for example, alcohols, fatty acids, amines and phenols.
nl:Ethoxyleren | Ethoxylation
Ethoxylation is a chemical process in which ethylene oxide (IUPAC name: 1,2-epoxyethane) is added to fatty acids in order to make them more soluble in water. An example is the ethoxylation of sodium dodecyl sulfate to form sodium laureth sulfate, which is used as a foaming agent in shampoos and toothpastes, and as an industrial detergent.
In an industrial ethoxylation plant, the raw material is preheated and fed to a stainless steel chemical reactor, where it is mixed with ethylene oxide and potassium hydroxide (KOH), which acts as the catalyst. The reactor is pressurised with nitrogen to 5 bar and heated to 150°C.
Many types of "substrate" chemicals may undergo ethoxylation: for example, alcohols, fatty acids, amines and phenols.
nl:Ethoxyleren
Template:WS | https://www.wikidoc.org/index.php/Ethoxylation | |
c83285860847ce9c9d9f155d844cd462c10df536 | wikidoc | Etonogestrel | Etonogestrel
# 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
Etonogestrel is a progestin that is FDA approved for the prophylaxis of pregnancy. Common adverse reactions include headache, weight gain and abdominal pain.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
Etonogestrel is indicated for use by women to prevent pregnancy.
- Dosage:
- Etonogestrel is insert subdermally just under the skin at the inner side of the non-dominant upper arm.
- Etonogestrel must be removed no later than by the end of the third year.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Etonogestrel in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Etonogestrel in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
- Clinical studies have not been conducted in women less than 18 years of age
- Safety and efficacy are expected to be identical for postpubertal adolescents
- Use before menarche is not indicated
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Etonogestrel in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Etonogestrel in pediatric patients.
# Contraindications
Etonogestrel should not be used in women who have
- Known or suspected pregnancy
- Current or past history of thrombosis or thromboembolic disorders
- Liver tumors, benign or malignant, or active liver disease
- Undiagnosed abnormal genital bleeding
- Known or suspected breast cancer, personal history of breast cancer, or other progestin-sensitive cancer, now or in the past
- Allergic reaction to any of the components of etonogestrel
# Warnings
Etonogestrel should be inserted subdermally so that it will be palpable after insertion, and this should be confirmed by palpation immediately after insertion. Failure to insert etonogestrel properly may go unnoticed unless it is palpated immediately after insertion. Undetected failure to insert the implant may lead to an unintended pregnancy. Complications related to insertion and removal procedures, such as pain, paresthesias, bleeding, hematoma, scarring or infection, may occur. Occasionally in post-marketing use, implant insertions have failed because the implant fell out of the needle or remained in the needle during insertion.
If etonogestrel is inserted too deeply (intramuscular or in the fascia), neural or vascular injury may occur. To reduce the risk of neural or vascular injury, etonogestrel should be inserted at the inner side of the non-dominant upper arm about 8-10 cm (3-4 inches) above the medial epicondyle of the humerus. etonogestrel should be inserted subdermally just under the skin to avoid the large blood vessels and nerves that lie deeper in the subcutaneous tissues in the sulcus between the triceps and biceps muscles. Deep insertions of etonogestrel have been associated with paraesthesia (due to neural injury) and migration of the implant (due to intramuscular or fascial insertion), and in a very few cases with intravascular insertion. If infection develops at the insertion site, start suitable treatment. If the infection persists, the implant should be removed. Incomplete insertions or infections may lead to expulsion. In postmarketing use there have been cases of failure to localize and remove the implant, probably due to deep insertion. There has been 1 case of an intravascular insertion reported post-marketing which led to inability to remove the implant.
Implant removal may be difficult or impossible if the implant is not inserted correctly, is inserted too deeply, not palpable, encased in fibrous tissue, or has migrated. Deep insertions may lead to difficult localization of the implant and may also result in the need for a surgical procedure in an operating room in order to remove the implant. Exploratory surgery without knowledge of the exact location of the implant is strongly discouraged. Removal of deeply inserted implants should be conducted with caution in order to prevent injury to deeper neural or vascular structures in the arm and be performed by healthcare providers familiar with the anatomy of the arm. Failure to remove the implant may result in continued effects of etonogestrel, such as compromised fertility, ectopic pregnancy, or persistence or occurrence of a drug-related adverse event.
After starting etonogestrel, women are likely to have a change from their normal menstrual bleeding pattern. These may include changes in bleeding frequency (absent, less, more frequent or continuous), intensity (reduced or increased) or duration. In clinical trials, bleeding patterns ranged from amenorrhea (1 in 5 women) to frequent and/or prolonged bleeding (1 in 5 women). The bleeding pattern experienced during the first three months of etonogestrel use is broadly predictive of the future bleeding pattern for many women. Women should be counseled regarding the bleeding pattern changes they may experience so that they know what to expect. Abnormal bleeding should be evaluated as needed to exclude pathologic conditions or pregnancy.
In clinical studies of etonogestrel, reports of changes in bleeding pattern were the most common reason for stopping treatment (11.1%). Irregular bleeding (10.8%) was the single most common reason women stopped treatment, while amenorrhea (0.3%) was cited less frequently. In these studies, women had an average of 17.7 days of bleeding or spotting every 90 days (based on 3,315 intervals of 90 days recorded by 780 patients). The percentages of patients having 0, 1-7, 8-21, or >21 days of spotting or bleeding over a 90-day interval while using the etonogestrel implant are shown in TABLE 1.
Bleeding patterns observed with use of etonogestrel for up to 2 years, and the proportion of 90-day intervals with these bleeding patterns, are summarized in TABLE 2.
In case of undiagnosed, persistent, or recurrent abnormal vaginal bleeding, appropriate measures should be conducted to rule out malignancy.
As with all progestin-only contraceptive products, be alert to the possibility of an ectopic pregnancy among women using etonogestrel who become pregnant or complain of lower abdominal pain. Although ectopic pregnancies are uncommon among women using etonogestrel, a pregnancy that occurs in a woman using etonogestrel may be more likely to be ectopic than a pregnancy occurring in a woman using no contraception.
The use of combination hormonal contraceptives (progestin plus estrogen) increases the risk of vascular events, including arterial events (strokes and myocardial infarctions) or deep venous thrombotic events (venous thromboembolism, deep venous thrombosis, retinal vein thrombosis, and pulmonary embolism). Etonogestrel is a progestin-only contraceptive. It is unknown whether this increased risk is applicable to etonogestrel alone. It is recommended, however, that women with risk factors known to increase the risk of venous and arterial thromboembolism be carefully assessed.
There have been postmarketing reports of serious arterial and venous thromboembolic events, including cases of pulmonary emboli (some fatal), deep vein thrombosis, myocardial infarction, and strokes, in women using etonogestrel. Etonogestrel should be removed in the event of a thrombosis.
Due to the risk of thromboembolism associated with pregnancy and immediately following delivery, etonogestrel should not be used prior to 21 days postpartum. Women with a history of thromboembolic disorders should be made aware of the possibility of a recurrence.
Evaluate for retinal vein thrombosis immediately if there is unexplained loss of vision, proptosis, diplopia, papilledema, or retinal vascular lesions.
Consider removal of the etonogestrel implant in case of long-term immobilization due to surgery or illness.
If follicular development occurs, atresia of the follicle is sometimes delayed, and the follicle may continue to grow beyond the size it would attain in a normal cycle. Generally, these enlarged follicles disappear spontaneously. On rare occasion, surgery may be required.
Women who currently have or have had breast cancer should not use hormonal contraception because breast cancer may be hormonally sensitive. Some studies suggest that the use of combination hormonal contraceptives might increase the incidence of breast cancer; however, other studies have not confirmed such findings.
Some studies suggest that the use of combination hormonal contraceptives is associated with an increase in the risk of cervical cancer or intraepithelial neoplasia. However, there is controversy about the extent to which such findings are due to differences in sexual behavior and other factors.
Women with a family history of breast cancer or who develop breast nodules should be carefully monitored.
Disturbances of liver function may necessitate the discontinuation of hormonal contraceptive use until markers of liver function return to normal. Remove etonogestrel if jaundice develops.
Hepatic adenomas are associated with combination hormonal contraceptives use. An estimate of the attributable risk is 3.3 cases per 100,000 for combination hormonal contraceptives users. It is not known whether a similar risk exists with progestin-only methods like etonogestrel.
The progestin in etonogestrel may be poorly metabolized in women with liver impairment. Use of etonogestrel in women with active liver disease or liver cancer is contraindicated.
In clinical studies, mean weight gain in US etonogestrel users was 2.8 pounds after 1 year and 3.7 pounds after 2 years. How much of the weight gain was related to the implant is unknown. In studies, 2.3% of the users reported weight gain as the reason for having the implant removed.
Women with a history of hypertension-related diseases or renal disease should be discouraged from using hormonal contraception. For women with well-controlled hypertension, use of etonogestrel can be considered. Women with hypertension using etonogestrel should be closely monitored. lf sustained hypertension develops during the use of etonogestrel, or if a significant increase in blood pressure does not respond adequately to antihypertensive therapy, etonogestrel should be removed.
Studies suggest a small increased relative risk of developing gallbladder disease among combination hormonal contraceptive users. It is not known whether a similar risk exists with progestin-only methods like etonogestrel.
Use of etonogestrel may induce mild insulin resistance and small changes in glucose concentrations of unknown clinical significance. Carefully monitor prediabetic and diabetic women using etonogestrel.
Women who are being treated for hyperlipidemia should be followed closely if they elect to use etonogestrel. Some progestins may elevate LDL levels and may render the control of hyperlipidemia more difficult.
Women with a history of depressed mood should be carefully observed. Consideration should be given to removing etonogestrel in patients who become significantly depressed.
In clinical trials with etonogestrel, the etonogestrel levels in blood decreased below sensitivity of the assay by one week after removal of the implant. In addition, pregnancies were observed to occur as early as 7 to 14 days after removal. Therefore, a woman should re-start contraception immediately after removal of the implant if continued contraceptive protection is desired.
Hormonal contraceptives may cause some degree of fluid retention. They should be prescribed with caution, and only with careful monitoring, in patients with conditions which might be aggravated by fluid retention. It is unknown if etonogestrel causes peripheral edema.
Contact lens wearers who develop visual changes or changes in lens tolerance should be assessed by an ophthalmologist.
# 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 clinical trials including 942 women who were evaluated for safety, change in menstrual bleeding patterns (irregular menses) was the most common adverse reaction causing discontinuation of use of etonogestrel (11.1% of women).
Adverse reactions that resulted in a rate of discontinuation of ≥1% are shown in TABLE 3.
Other adverse reactions that were reported by at least 5% of subjects in clinical trials of etonogestrel are listed in TABLE 4.
Implant site complications were reported by 3.6% of subjects during any of the assessments in clinical trials. Pain was the most frequent implant site complication, reported during and/or after insertion, occurring in 2.9% of subjects. Additionally, hematoma, redness, and swelling were reported by 0.1%, 0.3%, and 0.3% of patients, respectively.
## Postmarketing Experience
The following additional adverse reactions have been identified during post-approval use of etonogestrel. Because these reactions are reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
- Gastrointestinal disorders: constipation, diarrhea, flatulence, vomiting.
- General disorders and administration site conditions: edema, fatigue, implant site reaction, pyrexia.
- Immune system disorders: anaphylactic reactions
- Infections and infestations: rhinitis, urinary tract infection.
- Investigations: clinically relevant rise in blood pressure, weight decreased.
- Metabolism and nutrition disorders: increased appetite.
- Musculoskeletal and connective tissue disorders: arthralgia, musculoskeletal pain, myalgia.
- Nervous system disorders: convulsions, migraine, somnolence.
- Pregnancy, puerperium and perinatal conditions: ectopic pregnancy.
- Psychiatric disorders: anxiety, insomnia, libido decreased.
- Renal and urinary disorders: dysuria.
- Reproductive system and breast disorders: breast discharge, breast enlargement, ovarian cyst, pruritus genital, vulvovaginal discomfort.
- Skin and subcutaneous tissue disorders: angioedema, aggravation of angioedema and/or aggravation of hereditary angioedema, alopecia, chloasma, hypertrichosis, pruritus, rash, seborrhea, urticaria.
- Vascular disorders: hot flush.
Complications related to insertion or removal of the implant reported include: bruising, slight local irritation, pain or itching, fibrosis at the implant site, paresthesia or paresthesia-like events, scarring and abscess.
# Drug Interactions
Drugs or herbal products that induce enzymes, including CYP3A4, that metabolize progestins may decrease the plasma concentrations of progestins, and may decrease the effectiveness of etonogestrel. In women on long-term treatment with hepatic enzyme inducing drugs, it is recommended to remove the implant and to advise a contraceptive method that is unaffected by the interacting drug.
Some of these drugs or herbal products that induce enzymes, including CYP3A4, include:
- barbiturates
- bosentan
- carbamazepine
- felbamate
- griseofulvin
- oxcarbazepine
- phenytoin
- rifampin
- St. John's wort
- Topiramate
Significant changes (increase or decrease) in the plasma levels of progestin have been noted in some cases of co-administration with HIV protease inhibitors or with non-nucleoside reverse transcriptase inhibitors. Consult the labeling of all concurrently-used drugs to obtain further information about interactions with hormonal contraceptives or the potential for enzyme alterations.
CYP3A4 inhibitors such as itraconazole or ketoconazole may increase plasma concentrations of etonogestrel.
Hormonal contraceptives may affect the metabolism of other drugs. Consequently, plasma concentrations may either increase (for example, cyclosporin) or decrease (for example, lamotrigine). Consult the labeling of all concurrently-used drugs to obtain further information about interactions with hormonal contraceptives or the potential for enzyme alterations.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
Etonogestrel is not indicated for use during pregnancy.
Teratology studies have been performed in rats and rabbits using oral administration up to 390 and 790 times the human etonogestrel dose (based upon body surface) and revealed no evidence of fetal harm due to etonogestrel exposure.
Studies have revealed no increased risk of birth defects in women who have used combination oral contraceptives before pregnancy or during early pregnancy. There is no evidence that the risk associated with etonogestrel is different from that of combination oral contraceptives.
Etonogestrel should be removed if maintaining a pregnancy.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Etonogestrel in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Etonogestrel during labor and delivery.
### Nursing Mothers
Based on limited clinical data, etonogestrel may be used during breastfeeding after the fourth postpartum week. Use of etonogestrel before the fourth postpartum week has not been studied. Small amounts of etonogestrel are excreted in breast milk. During the first months after insertion of etonogestrel, when maternal blood levels of etonogestrel are highest, about 100 ng of etonogestrel may be ingested by the child per day based on an average daily milk ingestion of 658 mL. Based on daily milk ingestion of 150 mL/kg, the mean daily infant etonogestrel dose one month after insertion of etonogestrel is about 2.2% of the weight-adjusted maternal daily dose, or about 0.2% of the estimated absolute maternal daily dose. The health of breast-fed infants whose mothers began using etonogestrel during the fourth to eighth week postpartum (n=38) was evaluated in a comparative study with infants of mothers using a non-hormonal IUD (n=33). They were breast-fed for a mean duration of 14 months and followed up to 36 months of age. No significant effects and no differences between the groups were observed on the physical and psychomotor development of these infants. No differences between groups in the production or quality of breast milk were detected.
Healthcare providers should discuss both hormonal and non-hormonal contraceptive options, as steroids may not be the initial choice for these patients.
### Pediatric Use
Safety and efficacy of etonogestrel have been established in women of reproductive age. Safety and efficacy of etonogestrel are expected to be the same for postpubertal adolescents. However, no clinical studies have been conducted in women less than 18 years of age. Use of this product before menarche is not indicated.
### Geriatic Use
This product has not been studied in women over 65 years of age and is not indicated in this population.
### Gender
There is no FDA guidance on the use of Etonogestrel with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Etonogestrel with respect to specific racial populations.
### Renal Impairment
No studies were conducted to evaluate the effect of renal disease on the disposition of etonogestrel.
### Hepatic Impairment
No studies were conducted to evaluate the effect of hepatic disease on the disposition of etonogestrel. The use of etonogestrel in women with active liver disease is contraindicated.
### Females of Reproductive Potential and Males
Fertility returned after withdrawal from treatment.
### Immunocompromised Patients
There is no FDA guidance one the use of Etonogestrel in patients who are immunocompromised.
### Overweight Women
The effectiveness of etonogestrel in women who weighed more than 130% of their ideal body weight has not been defined because such women were not studied in clinical trials. Serum concentrations of etonogestrel are inversely related to body weight and decrease with time after implant insertion. It is therefore possible that etonogestrel may be less effective in overweight women, especially in the presence of other factors that decrease serum etonogestrel concentrations such as concomitant use of hepatic enzyme inducers.
# Administration and Monitoring
### Administration
Intradermal
### Monitoring
A woman who is using etonogestrel should have a yearly visit with her healthcare provider for a blood pressure check and for other indicated health care.
# IV Compatibility
There is limited information regarding the compatibility of Etonogestrel and IV administrations.
# Overdosage
Overdosage may result if more than 1 implant is inserted. In case of suspected overdose, the implant should be removed.
# Pharmacology
## Mechanism of Action
The contraceptive effect of etonogestrel is achieved by suppression of ovulation, increased viscosity of the cervical mucus, and alterations in the endometrium.
## Structure
Etonogestrel structurally derived from 19-nortestosterone, is the synthetic biologically active metabolite of the synthetic progestin desogestrel. It has a molecular weight of 324.46 and the following structural formula:
## Pharmacodynamics
Exposure-response relationships of etonogestrel are unknown.
## Pharmacokinetics
After subdermal insertion of the etonogestrel implant, etonogestrel is released into the circulation and is approximately 100% bioavailable.
The mean peak serum concentrations in 3 pharmacokinetic studies ranged between 781 and 894 pg/mL and were reached within the first few weeks after insertion. The mean serum etonogestrel concentration decreases gradually over time declining to 192 to 261 pg/mL at 12 months (n=41), 154 to 194 pg/mL at 24 months (n=35), and 156 to 177 pg/mL at 36 months (n=17).
The apparent volume of distribution averages about 201 L. Etonogestrel is approximately 32% bound to sex hormone binding globulin (SHBG) and 66% bound to albumin in blood.
In vitro data shows that etonogestrel is metabolized in liver microsomes by the cytochrome P450 3A4 isoenzyme. The biological activity of etonogestrel metabolites is unknown.
The elimination half-life of etonogestrel is approximately 25 hours. Excretion of etonogestrel and its metabolites, either as free steroid or as conjugates, is mainly in urine and to a lesser extent in feces. After removal of the implant, etonogestrel concentrations decreased below sensitivity of the assay by 1 week.
## Nonclinical Toxicology
In a 24-month carcinogenicity study in rats with subdermal implants releasing 10 and 20 mcg etonogestrel per day (equal to approximately 1.8-3.6 times the systemic steady state exposure in women using etonogestrel), no drug-related carcinogenic potential was observed. Etonogestrel was not genotoxic in the in vitro Ames/Salmonella reverse mutation assay, the chromosomal aberration assay in Chinese hamster ovary cells or in the in vivo mouse micronucleus test.
# Clinical Studies
### Pregnancy
In clinical trials of up to 3 years duration that involved 923 subjects, 18 - 40 years of age at entry, and 1,756 women-years of etonogestrel use, the total exposures expressed as 28-day cycle equivalents by study year were:
- Year 1: 10,866 cycles
- Year 2: 8,581 cycles
- Year 3: 3,442 cycles
The clinical trials excluded women who:
- Weighed more than 130% of their ideal body weight
- Were chronically taking medications that induce liver enzymes
In the subgroup of women 18 to 35 years of age at entry, 6 pregnancies during 20,648 cycles of use were reported. Two pregnancies occurred in each of Years 1, 2 and 3. Each conception was likely to have occurred shortly before or within 2 weeks after etonogestrel removal. With these 6 pregnancies, the cumulative Pearl Index was 0.38 pregnancies per 100 women-years of use.
### Return to Ovulation
In clinical trials with etonogestrel, the etonogestrel levels in blood decreased below sensitivity of the assay by one week after removal of the implant. In addition, pregnancies were observed to occur as early as 7 to 14 days after removal. Therefore, a woman should re-start contraception immediately after removal of the implant if continued contraceptive protection is desired.
# How Supplied
Single implant containing 68 mg etonogestrel that is 4 cm in length and 2 mm in diameter, which is pre-loaded in the needle of a disposable applicator.
- NDC 0052-0272-01
## Storage
Store at 25°C (77°F)
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- Counsel women about the insertion and removal procedure of the etonogestrel implant. Provide the woman with a copy of the Patient Labeling and ensure that she understands the information in the Patient Labeling before insertion and removal. A USER CARD and consent form are included in the packaging. Have the woman complete a consent form and retain it in your records. The USER CARD should be filled out and given to the patient after insertion of the etonogestrel implant so that she will have a record of the location of the implant in the upper arm and when it should be removed.
- Counsel women that etonogestrel does not protect against HIV infection (AIDS) or other sexually transmitted diseases.
- Counsel women that the use of etonogestrel may be associated with changes in their normal menstrual bleeding patterns so that they know what to expect.
# Precautions with Alcohol
Alcohol-Etonogestrel interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Implanon
- Nexplanon
# Look-Alike Drug Names
There is limited information regarding Etonogestrel Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | Etonogestrel
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.
# Overview
Etonogestrel is a progestin that is FDA approved for the prophylaxis of pregnancy. Common adverse reactions include headache, weight gain and abdominal pain.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
Etonogestrel is indicated for use by women to prevent pregnancy.
- Dosage:
- Etonogestrel is insert subdermally just under the skin at the inner side of the non-dominant upper arm.
- Etonogestrel must be removed no later than by the end of the third year.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Etonogestrel in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Etonogestrel in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
- Clinical studies have not been conducted in women less than 18 years of age
- Safety and efficacy are expected to be identical for postpubertal adolescents
- Use before menarche is not indicated
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Etonogestrel in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Etonogestrel in pediatric patients.
# Contraindications
Etonogestrel should not be used in women who have
- Known or suspected pregnancy
- Current or past history of thrombosis or thromboembolic disorders
- Liver tumors, benign or malignant, or active liver disease
- Undiagnosed abnormal genital bleeding
- Known or suspected breast cancer, personal history of breast cancer, or other progestin-sensitive cancer, now or in the past
- Allergic reaction to any of the components of etonogestrel
# Warnings
Etonogestrel should be inserted subdermally so that it will be palpable after insertion, and this should be confirmed by palpation immediately after insertion. Failure to insert etonogestrel properly may go unnoticed unless it is palpated immediately after insertion. Undetected failure to insert the implant may lead to an unintended pregnancy. Complications related to insertion and removal procedures, such as pain, paresthesias, bleeding, hematoma, scarring or infection, may occur. Occasionally in post-marketing use, implant insertions have failed because the implant fell out of the needle or remained in the needle during insertion.
If etonogestrel is inserted too deeply (intramuscular or in the fascia), neural or vascular injury may occur. To reduce the risk of neural or vascular injury, etonogestrel should be inserted at the inner side of the non-dominant upper arm about 8-10 cm (3-4 inches) above the medial epicondyle of the humerus. etonogestrel should be inserted subdermally just under the skin to avoid the large blood vessels and nerves that lie deeper in the subcutaneous tissues in the sulcus between the triceps and biceps muscles. Deep insertions of etonogestrel have been associated with paraesthesia (due to neural injury) and migration of the implant (due to intramuscular or fascial insertion), and in a very few cases with intravascular insertion. If infection develops at the insertion site, start suitable treatment. If the infection persists, the implant should be removed. Incomplete insertions or infections may lead to expulsion. In postmarketing use there have been cases of failure to localize and remove the implant, probably due to deep insertion. There has been 1 case of an intravascular insertion reported post-marketing which led to inability to remove the implant.
Implant removal may be difficult or impossible if the implant is not inserted correctly, is inserted too deeply, not palpable, encased in fibrous tissue, or has migrated. Deep insertions may lead to difficult localization of the implant and may also result in the need for a surgical procedure in an operating room in order to remove the implant. Exploratory surgery without knowledge of the exact location of the implant is strongly discouraged. Removal of deeply inserted implants should be conducted with caution in order to prevent injury to deeper neural or vascular structures in the arm and be performed by healthcare providers familiar with the anatomy of the arm. Failure to remove the implant may result in continued effects of etonogestrel, such as compromised fertility, ectopic pregnancy, or persistence or occurrence of a drug-related adverse event.
After starting etonogestrel, women are likely to have a change from their normal menstrual bleeding pattern. These may include changes in bleeding frequency (absent, less, more frequent or continuous), intensity (reduced or increased) or duration. In clinical trials, bleeding patterns ranged from amenorrhea (1 in 5 women) to frequent and/or prolonged bleeding (1 in 5 women). The bleeding pattern experienced during the first three months of etonogestrel use is broadly predictive of the future bleeding pattern for many women. Women should be counseled regarding the bleeding pattern changes they may experience so that they know what to expect. Abnormal bleeding should be evaluated as needed to exclude pathologic conditions or pregnancy.
In clinical studies of etonogestrel, reports of changes in bleeding pattern were the most common reason for stopping treatment (11.1%). Irregular bleeding (10.8%) was the single most common reason women stopped treatment, while amenorrhea (0.3%) was cited less frequently. In these studies, women had an average of 17.7 days of bleeding or spotting every 90 days (based on 3,315 intervals of 90 days recorded by 780 patients). The percentages of patients having 0, 1-7, 8-21, or >21 days of spotting or bleeding over a 90-day interval while using the etonogestrel implant are shown in TABLE 1.
Bleeding patterns observed with use of etonogestrel for up to 2 years, and the proportion of 90-day intervals with these bleeding patterns, are summarized in TABLE 2.
In case of undiagnosed, persistent, or recurrent abnormal vaginal bleeding, appropriate measures should be conducted to rule out malignancy.
As with all progestin-only contraceptive products, be alert to the possibility of an ectopic pregnancy among women using etonogestrel who become pregnant or complain of lower abdominal pain. Although ectopic pregnancies are uncommon among women using etonogestrel, a pregnancy that occurs in a woman using etonogestrel may be more likely to be ectopic than a pregnancy occurring in a woman using no contraception.
The use of combination hormonal contraceptives (progestin plus estrogen) increases the risk of vascular events, including arterial events (strokes and myocardial infarctions) or deep venous thrombotic events (venous thromboembolism, deep venous thrombosis, retinal vein thrombosis, and pulmonary embolism). Etonogestrel is a progestin-only contraceptive. It is unknown whether this increased risk is applicable to etonogestrel alone. It is recommended, however, that women with risk factors known to increase the risk of venous and arterial thromboembolism be carefully assessed.
There have been postmarketing reports of serious arterial and venous thromboembolic events, including cases of pulmonary emboli (some fatal), deep vein thrombosis, myocardial infarction, and strokes, in women using etonogestrel. Etonogestrel should be removed in the event of a thrombosis.
Due to the risk of thromboembolism associated with pregnancy and immediately following delivery, etonogestrel should not be used prior to 21 days postpartum. Women with a history of thromboembolic disorders should be made aware of the possibility of a recurrence.
Evaluate for retinal vein thrombosis immediately if there is unexplained loss of vision, proptosis, diplopia, papilledema, or retinal vascular lesions.
Consider removal of the etonogestrel implant in case of long-term immobilization due to surgery or illness.
If follicular development occurs, atresia of the follicle is sometimes delayed, and the follicle may continue to grow beyond the size it would attain in a normal cycle. Generally, these enlarged follicles disappear spontaneously. On rare occasion, surgery may be required.
Women who currently have or have had breast cancer should not use hormonal contraception because breast cancer may be hormonally sensitive. Some studies suggest that the use of combination hormonal contraceptives might increase the incidence of breast cancer; however, other studies have not confirmed such findings.
Some studies suggest that the use of combination hormonal contraceptives is associated with an increase in the risk of cervical cancer or intraepithelial neoplasia. However, there is controversy about the extent to which such findings are due to differences in sexual behavior and other factors.
Women with a family history of breast cancer or who develop breast nodules should be carefully monitored.
Disturbances of liver function may necessitate the discontinuation of hormonal contraceptive use until markers of liver function return to normal. Remove etonogestrel if jaundice develops.
Hepatic adenomas are associated with combination hormonal contraceptives use. An estimate of the attributable risk is 3.3 cases per 100,000 for combination hormonal contraceptives users. It is not known whether a similar risk exists with progestin-only methods like etonogestrel.
The progestin in etonogestrel may be poorly metabolized in women with liver impairment. Use of etonogestrel in women with active liver disease or liver cancer is contraindicated.
In clinical studies, mean weight gain in US etonogestrel users was 2.8 pounds after 1 year and 3.7 pounds after 2 years. How much of the weight gain was related to the implant is unknown. In studies, 2.3% of the users reported weight gain as the reason for having the implant removed.
Women with a history of hypertension-related diseases or renal disease should be discouraged from using hormonal contraception. For women with well-controlled hypertension, use of etonogestrel can be considered. Women with hypertension using etonogestrel should be closely monitored. lf sustained hypertension develops during the use of etonogestrel, or if a significant increase in blood pressure does not respond adequately to antihypertensive therapy, etonogestrel should be removed.
Studies suggest a small increased relative risk of developing gallbladder disease among combination hormonal contraceptive users. It is not known whether a similar risk exists with progestin-only methods like etonogestrel.
Use of etonogestrel may induce mild insulin resistance and small changes in glucose concentrations of unknown clinical significance. Carefully monitor prediabetic and diabetic women using etonogestrel.
Women who are being treated for hyperlipidemia should be followed closely if they elect to use etonogestrel. Some progestins may elevate LDL levels and may render the control of hyperlipidemia more difficult.
Women with a history of depressed mood should be carefully observed. Consideration should be given to removing etonogestrel in patients who become significantly depressed.
In clinical trials with etonogestrel, the etonogestrel levels in blood decreased below sensitivity of the assay by one week after removal of the implant. In addition, pregnancies were observed to occur as early as 7 to 14 days after removal. Therefore, a woman should re-start contraception immediately after removal of the implant if continued contraceptive protection is desired.
Hormonal contraceptives may cause some degree of fluid retention. They should be prescribed with caution, and only with careful monitoring, in patients with conditions which might be aggravated by fluid retention. It is unknown if etonogestrel causes peripheral edema.
Contact lens wearers who develop visual changes or changes in lens tolerance should be assessed by an ophthalmologist.
# 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 clinical trials including 942 women who were evaluated for safety, change in menstrual bleeding patterns (irregular menses) was the most common adverse reaction causing discontinuation of use of etonogestrel (11.1% of women).
Adverse reactions that resulted in a rate of discontinuation of ≥1% are shown in TABLE 3.
Other adverse reactions that were reported by at least 5% of subjects in clinical trials of etonogestrel are listed in TABLE 4.
Implant site complications were reported by 3.6% of subjects during any of the assessments in clinical trials. Pain was the most frequent implant site complication, reported during and/or after insertion, occurring in 2.9% of subjects. Additionally, hematoma, redness, and swelling were reported by 0.1%, 0.3%, and 0.3% of patients, respectively.
## Postmarketing Experience
The following additional adverse reactions have been identified during post-approval use of etonogestrel. Because these reactions are reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
- Gastrointestinal disorders: constipation, diarrhea, flatulence, vomiting.
- General disorders and administration site conditions: edema, fatigue, implant site reaction, pyrexia.
- Immune system disorders: anaphylactic reactions
- Infections and infestations: rhinitis, urinary tract infection.
- Investigations: clinically relevant rise in blood pressure, weight decreased.
- Metabolism and nutrition disorders: increased appetite.
- Musculoskeletal and connective tissue disorders: arthralgia, musculoskeletal pain, myalgia.
- Nervous system disorders: convulsions, migraine, somnolence.
- Pregnancy, puerperium and perinatal conditions: ectopic pregnancy.
- Psychiatric disorders: anxiety, insomnia, libido decreased.
- Renal and urinary disorders: dysuria.
- Reproductive system and breast disorders: breast discharge, breast enlargement, ovarian cyst, pruritus genital, vulvovaginal discomfort.
- Skin and subcutaneous tissue disorders: angioedema, aggravation of angioedema and/or aggravation of hereditary angioedema, alopecia, chloasma, hypertrichosis, pruritus, rash, seborrhea, urticaria.
- Vascular disorders: hot flush.
Complications related to insertion or removal of the implant reported include: bruising, slight local irritation, pain or itching, fibrosis at the implant site, paresthesia or paresthesia-like events, scarring and abscess.
# Drug Interactions
Drugs or herbal products that induce enzymes, including CYP3A4, that metabolize progestins may decrease the plasma concentrations of progestins, and may decrease the effectiveness of etonogestrel. In women on long-term treatment with hepatic enzyme inducing drugs, it is recommended to remove the implant and to advise a contraceptive method that is unaffected by the interacting drug.
Some of these drugs or herbal products that induce enzymes, including CYP3A4, include:
- barbiturates
- bosentan
- carbamazepine
- felbamate
- griseofulvin
- oxcarbazepine
- phenytoin
- rifampin
- St. John's wort
- Topiramate
Significant changes (increase or decrease) in the plasma levels of progestin have been noted in some cases of co-administration with HIV protease inhibitors or with non-nucleoside reverse transcriptase inhibitors. Consult the labeling of all concurrently-used drugs to obtain further information about interactions with hormonal contraceptives or the potential for enzyme alterations.
CYP3A4 inhibitors such as itraconazole or ketoconazole may increase plasma concentrations of etonogestrel.
Hormonal contraceptives may affect the metabolism of other drugs. Consequently, plasma concentrations may either increase (for example, cyclosporin) or decrease (for example, lamotrigine). Consult the labeling of all concurrently-used drugs to obtain further information about interactions with hormonal contraceptives or the potential for enzyme alterations.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
Etonogestrel is not indicated for use during pregnancy.
Teratology studies have been performed in rats and rabbits using oral administration up to 390 and 790 times the human etonogestrel dose (based upon body surface) and revealed no evidence of fetal harm due to etonogestrel exposure.
Studies have revealed no increased risk of birth defects in women who have used combination oral contraceptives before pregnancy or during early pregnancy. There is no evidence that the risk associated with etonogestrel is different from that of combination oral contraceptives.
Etonogestrel should be removed if maintaining a pregnancy.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Etonogestrel in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Etonogestrel during labor and delivery.
### Nursing Mothers
Based on limited clinical data, etonogestrel may be used during breastfeeding after the fourth postpartum week. Use of etonogestrel before the fourth postpartum week has not been studied. Small amounts of etonogestrel are excreted in breast milk. During the first months after insertion of etonogestrel, when maternal blood levels of etonogestrel are highest, about 100 ng of etonogestrel may be ingested by the child per day based on an average daily milk ingestion of 658 mL. Based on daily milk ingestion of 150 mL/kg, the mean daily infant etonogestrel dose one month after insertion of etonogestrel is about 2.2% of the weight-adjusted maternal daily dose, or about 0.2% of the estimated absolute maternal daily dose. The health of breast-fed infants whose mothers began using etonogestrel during the fourth to eighth week postpartum (n=38) was evaluated in a comparative study with infants of mothers using a non-hormonal IUD (n=33). They were breast-fed for a mean duration of 14 months and followed up to 36 months of age. No significant effects and no differences between the groups were observed on the physical and psychomotor development of these infants. No differences between groups in the production or quality of breast milk were detected.
Healthcare providers should discuss both hormonal and non-hormonal contraceptive options, as steroids may not be the initial choice for these patients.
### Pediatric Use
Safety and efficacy of etonogestrel have been established in women of reproductive age. Safety and efficacy of etonogestrel are expected to be the same for postpubertal adolescents. However, no clinical studies have been conducted in women less than 18 years of age. Use of this product before menarche is not indicated.
### Geriatic Use
This product has not been studied in women over 65 years of age and is not indicated in this population.
### Gender
There is no FDA guidance on the use of Etonogestrel with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Etonogestrel with respect to specific racial populations.
### Renal Impairment
No studies were conducted to evaluate the effect of renal disease on the disposition of etonogestrel.
### Hepatic Impairment
No studies were conducted to evaluate the effect of hepatic disease on the disposition of etonogestrel. The use of etonogestrel in women with active liver disease is contraindicated.
### Females of Reproductive Potential and Males
Fertility returned after withdrawal from treatment.
### Immunocompromised Patients
There is no FDA guidance one the use of Etonogestrel in patients who are immunocompromised.
### Overweight Women
The effectiveness of etonogestrel in women who weighed more than 130% of their ideal body weight has not been defined because such women were not studied in clinical trials. Serum concentrations of etonogestrel are inversely related to body weight and decrease with time after implant insertion. It is therefore possible that etonogestrel may be less effective in overweight women, especially in the presence of other factors that decrease serum etonogestrel concentrations such as concomitant use of hepatic enzyme inducers.
# Administration and Monitoring
### Administration
Intradermal
### Monitoring
A woman who is using etonogestrel should have a yearly visit with her healthcare provider for a blood pressure check and for other indicated health care.
# IV Compatibility
There is limited information regarding the compatibility of Etonogestrel and IV administrations.
# Overdosage
Overdosage may result if more than 1 implant is inserted. In case of suspected overdose, the implant should be removed.
# Pharmacology
## Mechanism of Action
The contraceptive effect of etonogestrel is achieved by suppression of ovulation, increased viscosity of the cervical mucus, and alterations in the endometrium.
## Structure
Etonogestrel structurally derived from 19-nortestosterone, is the synthetic biologically active metabolite of the synthetic progestin desogestrel. It has a molecular weight of 324.46 and the following structural formula:
## Pharmacodynamics
Exposure-response relationships of etonogestrel are unknown.
## Pharmacokinetics
After subdermal insertion of the etonogestrel implant, etonogestrel is released into the circulation and is approximately 100% bioavailable.
The mean peak serum concentrations in 3 pharmacokinetic studies ranged between 781 and 894 pg/mL and were reached within the first few weeks after insertion. The mean serum etonogestrel concentration decreases gradually over time declining to 192 to 261 pg/mL at 12 months (n=41), 154 to 194 pg/mL at 24 months (n=35), and 156 to 177 pg/mL at 36 months (n=17).
The apparent volume of distribution averages about 201 L. Etonogestrel is approximately 32% bound to sex hormone binding globulin (SHBG) and 66% bound to albumin in blood.
In vitro data shows that etonogestrel is metabolized in liver microsomes by the cytochrome P450 3A4 isoenzyme. The biological activity of etonogestrel metabolites is unknown.
The elimination half-life of etonogestrel is approximately 25 hours. Excretion of etonogestrel and its metabolites, either as free steroid or as conjugates, is mainly in urine and to a lesser extent in feces. After removal of the implant, etonogestrel concentrations decreased below sensitivity of the assay by 1 week.
## Nonclinical Toxicology
In a 24-month carcinogenicity study in rats with subdermal implants releasing 10 and 20 mcg etonogestrel per day (equal to approximately 1.8-3.6 times the systemic steady state exposure in women using etonogestrel), no drug-related carcinogenic potential was observed. Etonogestrel was not genotoxic in the in vitro Ames/Salmonella reverse mutation assay, the chromosomal aberration assay in Chinese hamster ovary cells or in the in vivo mouse micronucleus test.
# Clinical Studies
### Pregnancy
In clinical trials of up to 3 years duration that involved 923 subjects, 18 - 40 years of age at entry, and 1,756 women-years of etonogestrel use, the total exposures expressed as 28-day cycle equivalents by study year were:
- Year 1: 10,866 cycles
- Year 2: 8,581 cycles
- Year 3: 3,442 cycles
The clinical trials excluded women who:
- Weighed more than 130% of their ideal body weight
- Were chronically taking medications that induce liver enzymes
In the subgroup of women 18 to 35 years of age at entry, 6 pregnancies during 20,648 cycles of use were reported. Two pregnancies occurred in each of Years 1, 2 and 3. Each conception was likely to have occurred shortly before or within 2 weeks after etonogestrel removal. With these 6 pregnancies, the cumulative Pearl Index was 0.38 pregnancies per 100 women-years of use.
### Return to Ovulation
In clinical trials with etonogestrel, the etonogestrel levels in blood decreased below sensitivity of the assay by one week after removal of the implant. In addition, pregnancies were observed to occur as early as 7 to 14 days after removal. Therefore, a woman should re-start contraception immediately after removal of the implant if continued contraceptive protection is desired.
# How Supplied
Single implant containing 68 mg etonogestrel that is 4 cm in length and 2 mm in diameter, which is pre-loaded in the needle of a disposable applicator.
- NDC 0052-0272-01
## Storage
Store at 25°C (77°F)
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- Counsel women about the insertion and removal procedure of the etonogestrel implant. Provide the woman with a copy of the Patient Labeling and ensure that she understands the information in the Patient Labeling before insertion and removal. A USER CARD and consent form are included in the packaging. Have the woman complete a consent form and retain it in your records. The USER CARD should be filled out and given to the patient after insertion of the etonogestrel implant so that she will have a record of the location of the implant in the upper arm and when it should be removed.
- Counsel women that etonogestrel does not protect against HIV infection (AIDS) or other sexually transmitted diseases.
- Counsel women that the use of etonogestrel may be associated with changes in their normal menstrual bleeding patterns so that they know what to expect.
# Precautions with Alcohol
Alcohol-Etonogestrel interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Implanon [1]
- Nexplanon
# Look-Alike Drug Names
There is limited information regarding Etonogestrel Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Etonogestrel | |
d4ce533f9e86e86007c0a247824fe92c7e786616 | wikidoc | Evolutionism | Evolutionism
In the creation-evolution controversy, those who accept the scientific theory of biological evolution by natural selection or genetic drift are often called "evolutionists", and the theory of evolution itself is referred to as "evolutionism" by creationists. This label is used to suggest that evolution is an ideology such as creationism and other "-isms". In this way, creationists bolster their claim that the scientific theory of evolution is in its basics a belief, dogma, ideology or even a religion, rather than a scientific theory. The terms "evolutionism" and "evolutionist" are rarely used in the scientific community as self-descriptive terms.
"Evolutionism", is defined by the OED as "he theory of evolution, evolutionary assumptions or principles". Creationists tend to use the term evolutionism in order to suggest that evolution and creationism are equal in a philosophical debate.
# Development of usage
Anthropologists and biologists refer to "evolutionists" in the 19th century as those who believed that the cultures or life forms being studied are evolving to a particular form (see Platonic form). Very few scientists today, if any, believe that evolution in culture or biology works that way, and serious discussions generally take caution to distance themselves from that perspective.
Evolutionary biology explains biotic changes in terms of internal processes and gradual development as a natural progression of previously existing lifeforms. Evolution neither denies nor requires a role for divine intervention. Before the 19th century there were a number of hypotheses regarding the evolution of all material phenomena: suns, moons, planets, earth, life, civilization, and society. The number of hypotheses being propounded increased dramatically in the middle of the 19th century.
In modern times, the term evolution is widely used, but the terms evolutionism and evolutionist are rarely used in scientific circles to refer to the biological discipline. The term evolution was popularised during the 19th century by Herbert Spencer to mean cultural evolution; i.e. the increasing complexity of cultures (see History of the theory of cultural evolution) — it was only later that it acquired its biological meaning. Advocacy of such theory was called evolutionism.
Most scientists object to the terms evolutionism and evolutionist because the -ism and -ist suffixes accentuate belief rather than scientific study. Conversely, creationists use those same two terms partly because the terms accentuate belief, and partly perhaps because they provide a way to package their opposition into one group, seemingly atheist and materialist, designations which are considered to be irrelevant to natural science. | Evolutionism
In the creation-evolution controversy, those who accept the scientific theory of biological evolution by natural selection or genetic drift are often called "evolutionists", and the theory of evolution itself is referred to as "evolutionism" by creationists. This label is used to suggest that evolution is an ideology such as creationism and other "-isms". In this way, creationists bolster their claim that the scientific theory of evolution is in its basics a belief, dogma, ideology or even a religion, rather than a scientific theory. The terms "evolutionism" and "evolutionist" are rarely used in the scientific community as self-descriptive terms.
"Evolutionism", is defined by the OED as "[t]he theory of evolution, evolutionary assumptions or principles". Creationists tend to use the term evolutionism in order to suggest that evolution and creationism are equal in a philosophical debate.
# Development of usage
Anthropologists and biologists refer to "evolutionists" in the 19th century as those who believed that the cultures or life forms being studied are evolving to a particular form (see Platonic form). Very few scientists today, if any, believe that evolution in culture or biology works that way, and serious discussions generally take caution to distance themselves from that perspective.
Evolutionary biology explains biotic changes in terms of internal processes and gradual development as a natural progression of previously existing lifeforms. Evolution neither denies nor requires a role for divine intervention. Before the 19th century there were a number of hypotheses regarding the evolution of all material phenomena: suns, moons, planets, earth, life, civilization, and society. The number of hypotheses being propounded increased dramatically in the middle of the 19th century.
In modern times, the term evolution is widely used, but the terms evolutionism and evolutionist are rarely used in scientific circles to refer to the biological discipline. The term evolution was popularised during the 19th century by Herbert Spencer to mean cultural evolution; i.e. the increasing complexity of cultures (see History of the theory of cultural evolution) — it was only later that it acquired its biological meaning. Advocacy of such theory was called evolutionism.
Most scientists object to the terms evolutionism and evolutionist because the -ism and -ist suffixes accentuate belief rather than scientific study. Conversely, creationists use those same two terms partly because the terms accentuate belief, and partly perhaps because they provide a way to package their opposition into one group, seemingly atheist and materialist, designations which are considered to be irrelevant to natural science. | https://www.wikidoc.org/index.php/Evolutionism | |
c593376da9ee127f434c047eb1add8868a305f2d | wikidoc | Evolvability | Evolvability
Evolvability is a concept within the Darwinian understanding of biological evolution. Darwin's theory of evolution by natural selection requires that plants, animals, and other organisms be able to produce offspring that are sometimes better adapted to the circumstances of life than the parents are. It is these offspring that survive and reproduce, and the adaptive traits thus increase in number if they are passed down to the offspring. If the only changes to be found in offspring were deleterious, adaptive evolution could not occur. So, the ability to produce enough advantageous variation to allow adaptive evolution to occur is what is called "evolvability".
Wagner (2005) describes two definitions of evolvability which have two main meanings. The first one is:
A biological system is evolvable
- if its properties show heritable genetic variation,
and
- if natural selection can thus change these properties.
The second one is:
A biological system is evolvable
- if it can acquire novel functions through genetic change, functions that help the organism survive and reproduce.
These definitions can be applied on all levels of biological organisation, from macromolecules to mammals.
The two meanings are not synonymous. Not all systems that are evolvable in the first sense are evolvable in the second sense. An example is given by Wagner (2005).
# Example
Consider an enzyme-coding gene that undergoes different mutations in different individuals of a population. Because of the mutations, the activity of the enzyme fluctuates among different individuals. If this mutation is heritable and influences fitness than natural selection can act on the enzyme’s activity. The enzyme’s activity is thus evolvable in the first sense. However, after millions of years, no mutation might give this enzyme a trait which might permit survival in a new environment.
Thus, although the enzyme’s activity is evolvable in the first sense, that does not mean it is evolvable in the second sense. The opposite, does not work. Every innovative, evolvable system can evolve by natural selection.
Organisms are incredibly complex, yet also highly robust to genetic change on all levels of organization. This robustness is one of a few aspects that can affect evolvability in the first and the second sense.
# Robustness and evolvability
Robustness will not increase evolvability in the first sense. In organisms with a high level of robustness, mutations will have smaller phenotypic effects than in organisms with a low level of robustness. Thus, robustness reduces the amount of heritable genetic variation on which selection can act.
One can see this conclusion in two ways:
The first way is that robustness causes mutations to be neutral and therefore no innovation will occur.
The second way gives neutral mutations an important function in innovation. Although many neutral mutations do not change primary functions, they can change other system features for future evolution.
So, robustness can facilitate exaptation. From this point of view, robustness implies that many mutations are neutral and such neutrality promotes innovation. | Evolvability
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Evolvability is a concept within the Darwinian understanding of biological evolution. Darwin's theory of evolution by natural selection requires that plants, animals, and other organisms be able to produce offspring that are sometimes better adapted to the circumstances of life than the parents are. It is these offspring that survive and reproduce, and the adaptive traits thus increase in number if they are passed down to the offspring. If the only changes to be found in offspring were deleterious, adaptive evolution could not occur. So, the ability to produce enough advantageous variation to allow adaptive evolution to occur is what is called "evolvability".
Wagner (2005) describes two definitions of evolvability which have two main meanings. The first one is:
A biological system is evolvable
- if its properties show heritable genetic variation,
and
- if natural selection can thus change these properties.
The second one is:
A biological system is evolvable
- if it can acquire novel functions through genetic change, functions that help the organism survive and reproduce.
These definitions can be applied on all levels of biological organisation, from macromolecules to mammals.
The two meanings are not synonymous. Not all systems that are evolvable in the first sense are evolvable in the second sense. An example is given by Wagner (2005).
# Example
Consider an enzyme-coding gene that undergoes different mutations in different individuals of a population. Because of the mutations, the activity of the enzyme fluctuates among different individuals. If this mutation is heritable and influences fitness than natural selection can act on the enzyme’s activity. The enzyme’s activity is thus evolvable in the first sense. However, after millions of years, no mutation might give this enzyme a trait which might permit survival in a new environment.
Thus, although the enzyme’s activity is evolvable in the first sense, that does not mean it is evolvable in the second sense. The opposite, does not work. Every innovative, evolvable system can evolve by natural selection.
Organisms are incredibly complex, yet also highly robust to genetic change on all levels of organization. This robustness is one of a few aspects that can affect evolvability in the first and the second sense.
# Robustness and evolvability
Robustness will not increase evolvability in the first sense. In organisms with a high level of robustness, mutations will have smaller phenotypic effects than in organisms with a low level of robustness. Thus, robustness reduces the amount of heritable genetic variation on which selection can act.
One can see this conclusion in two ways:
The first way is that robustness causes mutations to be neutral and therefore no innovation will occur.
The second way gives neutral mutations an important function in innovation. Although many neutral mutations do not change primary functions, they can change other system features for future evolution.
So, robustness can facilitate exaptation. From this point of view, robustness implies that many mutations are neutral and such neutrality promotes innovation. | https://www.wikidoc.org/index.php/Evolvability | |
ae4b4582983623a7566dce0910ef4267c2834591 | wikidoc | Lung volumes | Lung volumes
Lung volumes refer to physical differences in lung volume, while lung capacities represent different combinations of lung volumes, usually in relation to respiration and exhalation.
The average pair of human lungs can hold about 6 liters of air, but only a small amount of this capacity is used during normal breathing.
Breathing mechanism in mammals is called "tidal breathing". Tidal breathing means that air goes into the lungs the same way that it comes out.
# Factors affecting lung volume
Several factors affect lung volumes, some that can be controlled and some that can not. These factors include:
A person who is born and lives at sea level will develop a slightly smaller lung capacity than a person who spends their life at a high altitude. This is because the atmosphere is less dense at higher altitude, and therefore, the same volume of air contains fewer molecules of all gases, including oxygen. In response to higher altitude, the body's diffusing capacity increases in order to be able to process more air.
When someone living at or near sea level travels to locations at high altitudes (eg. the Andes, Denver, Colorado, Tibet, the Himalayas, etc.) they can develop a condition called altitude sickness because their lungs cannot respirate sufficiently in the thinner air.
# Measurement and values
These values vary with the age and height of the person; the values that follow are for a 70 kg (154 lb), average-sized adult male :
The tidal volume, vital capacity, inspiratory capacity and expiratory reserve volume can be measured directly with a spirometer. Determination of the residual volume can be done by radiographic planemetry, body plethysmography, closed circuit dilution and nitrogen washout.
These are the basic elements of a ventilatory pulmonary function test. The results (in particular FEV1/FVC and FRC) can be used to distinguish between restrictive and obstructive pulmonary diseases:
# Other
The largest human lung capacity recorded is that of British rower Peter Reed at 11.68 litres, roughly twice that of an average person. | Lung volumes
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Lung volumes refer to physical differences in lung volume, while lung capacities represent different combinations of lung volumes, usually in relation to respiration and exhalation.
The average pair of human lungs can hold about 6 liters of air, but only a small amount of this capacity is used during normal breathing.
Breathing mechanism in mammals is called "tidal breathing". Tidal breathing means that air goes into the lungs the same way that it comes out.
# Factors affecting lung volume
Several factors affect lung volumes, some that can be controlled and some that can not. These factors include:
A person who is born and lives at sea level will develop a slightly smaller lung capacity than a person who spends their life at a high altitude. This is because the atmosphere is less dense at higher altitude, and therefore, the same volume of air contains fewer molecules of all gases, including oxygen. In response to higher altitude, the body's diffusing capacity increases in order to be able to process more air.
When someone living at or near sea level travels to locations at high altitudes (eg. the Andes, Denver, Colorado, Tibet, the Himalayas, etc.) they can develop a condition called altitude sickness because their lungs cannot respirate sufficiently in the thinner air.
# Measurement and values
These values vary with the age and height of the person; the values that follow are for a 70 kg (154 lb), average-sized adult male [1]:
The tidal volume, vital capacity, inspiratory capacity and expiratory reserve volume can be measured directly with a spirometer. Determination of the residual volume can be done by radiographic planemetry, body plethysmography, closed circuit dilution and nitrogen washout.
These are the basic elements of a ventilatory pulmonary function test. The results (in particular FEV1/FVC and FRC) can be used to distinguish between restrictive and obstructive pulmonary diseases:
# Other
The largest human lung capacity recorded is that of British rower Peter Reed at 11.68 litres, roughly twice that of an average person. | https://www.wikidoc.org/index.php/Expiratory_reserve_volume | |
b17366e74df581498635c21ada9b02be54d60597 | wikidoc | Expressivity | Expressivity
# Overview
Expressivity refers to variations of a phenotype in genetics. The term is used to qualitatively characterize the variance or extent of the phenotype. For example a quantitative trait - like body height - might have large variance and therefore can make prediction of the phenotype difficult. Like penetrance in most instances expressivity is related to an allele or a mutation or more generally a genotype. In these instances expressivity denotes how well the phenotype can be predicted, given the genotype.
# Expressivity
Expressivity is a term used in genetics to refer to variations in a phenotype among individuals carrying a particular genotype. The term can be used to characterize qualitatively or quantitatively the extent of phenotypic variation given a particular genotype. The term is analogous to the severity of a condition in clinical medicine. For example, the volume of blood ejected from the pumping heart with each contraction, relative to the total amount of blood contained in the heart's chamber can be quantified by echocardiography and is called the ejection fraction. If a specific genotype is associated with the development of congestive heart failure, the expressivity would be represented by the range of ejection fractions seen in patients that have that genotype. As a more qualitative example, the "blue" gene might have an expressivity of 25% for individuals that express the "blue" gene and appear light blue, and 75% for individuals that express the "blue" gene and appear dark blue. Expressivity is measured only when there is 100% penetrance.
This differs from penetrance, which refers to the likelihood of the gene generating its associated phenotype at all, as determined by the proportion of individuals with a given genotype who also possess the associated phenotype. In contrast, expressivity refers to the influence of an expressed gene at the level of particular individuals.
# Variable expressivity
Variable expressivity occurs when a phenotype is expressed to a different degree among individuals with the same genotype. For example, individuals with the same allele for a gene involved in a quantitative trait like body height might have large variance (some are taller than others), making prediction of the phenotype from a particular genotype alone difficult. The expression of a phenotype may be modified by the effects of aging, other genetic loci, or environmental factors. Another example is neurofibromatosis, where patients with the same genetic mutation show different signs and symptoms of the disease. | Expressivity
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Expressivity refers to variations of a phenotype in genetics. The term is used to qualitatively characterize the variance or extent of the phenotype. For example a quantitative trait - like body height - might have large variance and therefore can make prediction of the phenotype difficult. Like penetrance in most instances expressivity is related to an allele or a mutation or more generally a genotype. In these instances expressivity denotes how well the phenotype can be predicted, given the genotype.
# Expressivity
Expressivity is a term used in genetics to refer to variations in a phenotype among individuals carrying a particular genotype. The term can be used to characterize qualitatively or quantitatively the extent of phenotypic variation given a particular genotype. The term is analogous to the severity of a condition in clinical medicine. For example, the volume of blood ejected from the pumping heart with each contraction, relative to the total amount of blood contained in the heart's chamber can be quantified by echocardiography and is called the ejection fraction. If a specific genotype is associated with the development of congestive heart failure, the expressivity would be represented by the range of ejection fractions seen in patients that have that genotype. As a more qualitative example, the "blue" gene might have an expressivity of 25% for individuals that express the "blue" gene and appear light blue, and 75% for individuals that express the "blue" gene and appear dark blue. Expressivity is measured only when there is 100% penetrance.
This differs from penetrance, which refers to the likelihood of the gene generating its associated phenotype at all, as determined by the proportion of individuals with a given genotype who also possess the associated phenotype. In contrast, expressivity refers to the influence of an expressed gene at the level of particular individuals.
# Variable expressivity
Variable expressivity occurs when a phenotype is expressed to a different degree among individuals with the same genotype.[1] For example, individuals with the same allele for a gene involved in a quantitative trait like body height might have large variance (some are taller than others), making prediction of the phenotype from a particular genotype alone difficult. The expression of a phenotype may be modified by the effects of aging, other genetic loci, or environmental factors. Another example is neurofibromatosis, where patients with the same genetic mutation show different signs and symptoms of the disease.[1] | https://www.wikidoc.org/index.php/Expressivity | |
df6f8fb554a6fc12fdb9aa1befb1b1fd9e9ddd91 | wikidoc | Lithotriptor | Lithotriptor
Steven C. Campbell, M.D., Ph.D.
# Overview
A lithotriptor is a medical device used in the non-invasive treatment of kidney stones (urinary calculosis) and biliary calculi (stones in the gallbladder or in the liver). The scientific name of this procedure is Extracorporeal Shock Wave Lithotripsy (ESWL). Lithotripsy was developed in the early 1980s in Germany by Dornier Medizintechnik GmbH (now known as Dornier MedTech Systems GmbH), and came into widespread use with the introduction of the HM-3 lithotriptor in 1983. Within a few short years, ESWL revolutionized treatment of calculosis. It is estimated that more than one million patients are treated annually with ESWL in the USA alone.
## How it works
Lithotripsy attempts to break up the stone with minimal collateral damage by using an externally applied, focused, high-intensity acoustic pulse. The sedated or anesthesized patient lies down in the apparatus' bed, with his back supported by a water-filled coupling device placed at the level of kidneys, for instance. A fluoroscopic x-ray imaging system or an ultrasound imaging system is used to locate the stone and aim the treatment head so that the F1 of the shock wave is focused on the stone. The treatment usually starts at the equipment's lowest power level, with a long gap between pulses, in order to accustom the patient to the sensation. The frequency of pulses and the power level will then be gradually increased, in order to break up the stone more effectively. The final power level will usually depend on the patient's pain threshold. If the stone is positioned near a bone (usually a rib in the case of kidney stones), this treatment may be more uncomfortable because the shock waves can cause a mild resonance in the bone which can be felt by the patient. The sensation of the treatment is likened to an elastic band twanging off the skin, and the patient is shocked in time with his heartbeat (he will be hooked up to an ECG).
The successive shock wave pressure pulses result in direct shearing forces, as well as cavitation bubbles surrounding the stone, which fragment the stones into smaller pieces that then can pass easily through the ureters or the cystic duct. The process takes about an hour. A ureteral stent (a kind of expandable hollow tube) may be used at the discretion of the urologist. The stent allows for easier passage of the stone by relieving obstruction and through passive dilatation of the ureter.
Extracorporeal lithotropsy works best with stones between 4 mm and 2 cm in diameter that are still located in the kidney. It can be used to break up stones which are located in a ureter too, but with less success.
The patients undergoing this procedure can, in some cases, see for themselves the progress of their treatment. If allowed to view the ultrasound or x-ray monitor, they may be able to see their stones change from a distinct bright point to a fuzzy cloud as the stone is disintegrated into a fine powder.
ESWL is the least invasive of the commonplace modalities for definitive stone treatment, but provides a lower stone-free rate than other more invasive treatment methods, such as ureteroscopic manipulation with laser lithotripsy or percutaneous nephrolithotomy (PCNL). The passage of stone fragments may take a few days or a week and may cause mild pain. Patients may be instructed to drink as much water as is practical during this time.
A patient of the procedure has equated the the after effects to "a punch to the kidney". (pain while urinating, with blood evident)
ESWL is not without risks. The shock waves themselves, as well as cavitation bubbles formed by the agitation of the urine medium, can lead to capillary damage, renal parenchymal or subcapsular hemorrhage. This can lead to long-term consequences such as renal failure and hypertension. Overall complication rates of ESWL range from 5-20%. | Lithotriptor
Template:Search infobox
Steven C. Campbell, M.D., Ph.D.
# Overview
A lithotriptor is a medical device used in the non-invasive treatment of kidney stones (urinary calculosis) and biliary calculi (stones in the gallbladder or in the liver). The scientific name of this procedure is Extracorporeal Shock Wave Lithotripsy (ESWL). Lithotripsy was developed in the early 1980s in Germany by Dornier Medizintechnik GmbH (now known as Dornier MedTech Systems GmbH), and came into widespread use with the introduction of the HM-3 lithotriptor in 1983. Within a few short years, ESWL revolutionized treatment of calculosis. It is estimated that more than one million patients are treated annually with ESWL in the USA alone.
## How it works
Lithotripsy attempts to break up the stone with minimal collateral damage by using an externally applied, focused, high-intensity acoustic pulse. The sedated or anesthesized patient lies down in the apparatus' bed, with his back supported by a water-filled coupling device placed at the level of kidneys, for instance. A fluoroscopic x-ray imaging system or an ultrasound imaging system is used to locate the stone and aim the treatment head so that the F1 of the shock wave is focused on the stone. The treatment usually starts at the equipment's lowest power level, with a long gap between pulses, in order to accustom the patient to the sensation. The frequency of pulses and the power level will then be gradually increased, in order to break up the stone more effectively. The final power level will usually depend on the patient's pain threshold. If the stone is positioned near a bone (usually a rib in the case of kidney stones), this treatment may be more uncomfortable because the shock waves can cause a mild resonance in the bone which can be felt by the patient. The sensation of the treatment is likened to an elastic band twanging off the skin, and the patient is shocked in time with his heartbeat (he will be hooked up to an ECG).
The successive shock wave pressure pulses result in direct shearing forces, as well as cavitation bubbles surrounding the stone, which fragment the stones into smaller pieces that then can pass easily through the ureters or the cystic duct. The process takes about an hour. A ureteral stent (a kind of expandable hollow tube) may be used at the discretion of the urologist. The stent allows for easier passage of the stone by relieving obstruction and through passive dilatation of the ureter.
Extracorporeal lithotropsy works best with stones between 4 mm and 2 cm in diameter that are still located in the kidney. It can be used to break up stones which are located in a ureter too, but with less success.
The patients undergoing this procedure can, in some cases, see for themselves the progress of their treatment. If allowed to view the ultrasound or x-ray monitor, they may be able to see their stones change from a distinct bright point to a fuzzy cloud as the stone is disintegrated into a fine powder.
ESWL is the least invasive of the commonplace modalities for definitive stone treatment, but provides a lower stone-free rate than other more invasive treatment methods, such as ureteroscopic manipulation with laser lithotripsy or percutaneous nephrolithotomy (PCNL). The passage of stone fragments may take a few days or a week and may cause mild pain. Patients may be instructed to drink as much water as is practical during this time.
A patient of the procedure has equated the the after effects to "a punch to the kidney". (pain while urinating, with blood evident)
ESWL is not without risks. The shock waves themselves, as well as cavitation bubbles formed by the agitation of the urine medium, can lead to capillary damage, renal parenchymal or subcapsular hemorrhage. This can lead to long-term consequences such as renal failure and hypertension. Overall complication rates of ESWL range from 5-20%.
# External links
- Patient Guide To Kidney Stone Diagnosis, Treatment and Prevention. Written by a nephrologist at the New York University School of Medicine.
- International Kidney Stone Institute
- Lithotripsy (Stones Treatment). Center for Advanced Urology, USA.
- Electromagnetic Technology
- Spark Gap Technology
- How ESWL works
- Worldwide ESWL device manufacturer
- Mayo Clinic
- Shock wave therapy for kidney stones linked to increased risk of diabetes, hypertension | https://www.wikidoc.org/index.php/Extracorporeal_shockwave_lithotripsy | |
c25e8a5e2dad6edb3f434ec5d1475dc089d9095d | wikidoc | F11 receptor | F11 receptor
Junctional adhesion molecule A is a protein that in humans is encoded by the F11R gene. It has also been designated as CD321 (cluster of differentiation 321).
# Function
Tight junctions represent one mode of cell-to-cell adhesion in epithelial or endothelial cell sheets, forming continuous seals around cells and serving as a physical barrier to prevent solutes and water from passing freely through the paracellular space. The protein encoded by this immunoglobulin superfamily gene member is an important regulator of tight junction assembly in epithelia. In addition, the encoded protein can act as (1) a receptor for reovirus, (2) a ligand for the integrin LFA1, involved in leukocyte transmigration, and (3) a platelet receptor. Multiple transcript variants encoding two different isoforms have been found for this gene.
# Interactions
F11 receptor has been shown to interact with MLLT4, CASK and Tight junction protein 1. | F11 receptor
Junctional adhesion molecule A is a protein that in humans is encoded by the F11R gene.[1][2][3] It has also been designated as CD321 (cluster of differentiation 321).
# Function
Tight junctions represent one mode of cell-to-cell adhesion in epithelial or endothelial cell sheets, forming continuous seals around cells and serving as a physical barrier to prevent solutes and water from passing freely through the paracellular space. The protein encoded by this immunoglobulin superfamily gene member is an important regulator of tight junction assembly in epithelia. In addition, the encoded protein can act as (1) a receptor for reovirus, (2) a ligand for the integrin LFA1, involved in leukocyte transmigration, and (3) a platelet receptor. Multiple transcript variants encoding two different isoforms have been found for this gene.[3]
# Interactions
F11 receptor has been shown to interact with MLLT4,[4] CASK[4][5] and Tight junction protein 1.[4][6] | https://www.wikidoc.org/index.php/F11_receptor | |
1193c73b1bafcf97682bfe67540e62f240b29b2c | wikidoc | FSH-receptor | FSH-receptor
The follicle stimulating hormone receptor or FSH-receptor (FSHR) is a transmembrane receptor that interacts with the follicle stimulating hormone (FSH) and represents a G protein-coupled receptor (GPCR). Its activation is necessary for the hormonal functioning of FSH. FSHRs are found in the ovary, testis, and uterus.
# FSHR gene
The gene for the FSHR is found on chromosome 2 p21 in humans. The gene sequence of the FSHR consists of about 2,080 nucleotides.
# Receptor structure
The FSHR consists of 695 amino acids and has a molecular mass of about 76 kDa. Like other GPCRs, the FSH-receptor possess seven membrane-spanning domains or transmembrane helices.
- The extracellular domain of the receptor is glycosylated.
- The transmembrane domain contains two highly conserved cysteine residues which build disulfide bonds to stabilize the receptor structure. A highly conserved Asp-Arg-Tyr triplet motif is present and may be of importance to transmit the signal.
- The C-terminal domain is intracellular and brief, rich in serine and threonine residues for possible phosphorylation.
# Ligand binding and signal transduction
Upon binding FSH externally to the membrane, a transduction of the signal takes place that activates the G protein that is bound to the receptor internally. With FSH attached, the receptor shifts conformation and thus mechanically activates the G protein, which detaches from the receptor and activates the cAMP system.
It is believed that a receptor molecule exists in a conformational equilibrium between active and inactive states. The binding of FSH to the receptor shifts the equilibrium between active and inactive receptors. FSH and FSH-agonists shift the equilibrium in favor of active states; FSH antagonists shift the equilibrium in favor of inactive states. For a cell to respond to FSH only a small percentage (~1%) of receptor sites need to be activated.
## Phosphorylation by cAMP-dependent protein kinases
Cyclic AMP-dependent protein kinases (protein kinase A) are activated by the signal chain coming from the G protein (that was activated by the FSH-receptor) via adenylate cyclase and cyclic AMP (cAMP).
These protein kinases are present as tetramer with two regulatory units and two catalytic units. Upon binding of cAMP to the regulatory units, the catalytic units are released and initiate the phosphorylation of proteins leading to the physiologic action. The cyclic AMP-regulatory dimers are degraded by phosphodiesterase and release 5’AMP. DNA in the cell nucleus binds to phosphorylated proteins through the cyclic AMP response element (CRE) which results in the activation of genes.
The signal is amplified by the involvement of cAMP and the resulting phosphorylation. The process is modified by prostaglandins. Other cellular regulators are participate are the intracellular calcium concentration modified by phospholipase, nitric acid, and other growth factors.
The FSH receptor can also activate the extracellular signal-regulated kinases (ERK).
In a feedback mechanism, these activated kinases phosphorylate the receptor. The longer the receptor remains active, the more kinases are activated, the more receptors are phosphorylated.
# Action
In the ovary, the FSH receptor is necessary for follicular development and expressed on the granulosa cells.
In the male the FSH receptor has been identified on the Sertoli cells that are critical for spermatogenesis.
The FSHR is expressed during the luteal phase in the secretory endometrium of the uterus.
# Receptor regulation
## Upregulation
Upregulation refers to the increase in the number of receptor site on the membrane. Estrogen upregulates FSH receptor sites. In turn, FSH stimulates granulosa cells to produce estrogens. This synergistic activity of estrogen and FSH allows for follicle growth and development in the ovary.
## Desensitization
The FSHR become desensitized when exposed to FSH for some time. A key reaction of this downregulation is the phosphorylation of the intracellular (or cytoplasmic) receptor domain by protein kinases. This process uncouples Gs protein from the FSHR. Another way to desensitize is to uncouple the regulatory and catalytic units of the cAMP system.
## Downregulation
Downregulation refers to the decrease in the number of receptor sites. This can be accomplished by metabolizing bound FSHR sites. The bound FSH-receptor complex is brought by lateral migration to a "coated pit" where such units are concentrated and then stabilized by a framework of clathrins. A pinched-off coated pit is internalized and degraded by lysosomes. Proteins may be metabolized or the receptor can be recycled. Use of long-acting agonists will downregulate the receptor population.
## Modulators
Antibodies to FSHR can interfere with FSHR activity.
# FSHR abnormalities
Some patients with ovarian hyperstimulation syndrome may have mutations in the gene for FSHR making them more sensitive to gonadotropin stimulation.
Women with 46 XX gonadal dysgenesis experience primary amenorrhea with hypergonadotropic hypogonadism. There are forms of 46 xx gonadal dysgenesis where abnormalities in the FSH-receptor have been reported and are thought to be the cause of the hypogonadism.
Polymorphism may affect FSH receptor populations and lead to poorer responses in infertile women who receive FSH medication for IVF.
# History
Alfred G. Gilman and Martin Rodbell received the 1994 Nobel Prize in Medicine and Physiology for the discovery of the G Protein System. | FSH-receptor
The follicle stimulating hormone receptor or FSH-receptor (FSHR) is a transmembrane receptor that interacts with the follicle stimulating hormone (FSH) and represents a G protein-coupled receptor (GPCR). Its activation is necessary for the hormonal functioning of FSH. FSHRs are found in the ovary, testis, and uterus.
# FSHR gene
The gene for the FSHR is found on chromosome 2 p21 in humans. The gene sequence of the FSHR consists of about 2,080 nucleotides.[1]
# Receptor structure
The FSHR consists of 695 amino acids and has a molecular mass of about 76 kDa.[1] Like other GPCRs, the FSH-receptor possess seven membrane-spanning domains or transmembrane helices.
- The extracellular domain of the receptor is glycosylated.
- The transmembrane domain contains two highly conserved cysteine residues which build disulfide bonds to stabilize the receptor structure. A highly conserved Asp-Arg-Tyr triplet motif is present and may be of importance to transmit the signal.
- The C-terminal domain is intracellular and brief, rich in serine and threonine residues for possible phosphorylation.
# Ligand binding and signal transduction
Upon binding FSH externally to the membrane, a transduction of the signal takes place that activates the G protein that is bound to the receptor internally. With FSH attached, the receptor shifts conformation and thus mechanically activates the G protein, which detaches from the receptor and activates the cAMP system.
It is believed that a receptor molecule exists in a conformational equilibrium between active and inactive states. The binding of FSH to the receptor shifts the equilibrium between active and inactive receptors. FSH and FSH-agonists shift the equilibrium in favor of active states; FSH antagonists shift the equilibrium in favor of inactive states. For a cell to respond to FSH only a small percentage (~1%) of receptor sites need to be activated.
## Phosphorylation by cAMP-dependent protein kinases
Cyclic AMP-dependent protein kinases (protein kinase A) are activated by the signal chain coming from the G protein (that was activated by the FSH-receptor) via adenylate cyclase and cyclic AMP (cAMP).
These protein kinases are present as tetramer with two regulatory units and two catalytic units. Upon binding of cAMP to the regulatory units, the catalytic units are released and initiate the phosphorylation of proteins leading to the physiologic action. The cyclic AMP-regulatory dimers are degraded by phosphodiesterase and release 5’AMP. DNA in the cell nucleus binds to phosphorylated proteins through the cyclic AMP response element (CRE) which results in the activation of genes.[1]
The signal is amplified by the involvement of cAMP and the resulting phosphorylation. The process is modified by prostaglandins. Other cellular regulators are participate are the intracellular calcium concentration modified by phospholipase, nitric acid, and other growth factors.
The FSH receptor can also activate the extracellular signal-regulated kinases (ERK). [2]
In a feedback mechanism, these activated kinases phosphorylate the receptor. The longer the receptor remains active, the more kinases are activated, the more receptors are phosphorylated.
# Action
In the ovary, the FSH receptor is necessary for follicular development and expressed on the granulosa cells.[1]
In the male the FSH receptor has been identified on the Sertoli cells that are critical for spermatogenesis.[3]
The FSHR is expressed during the luteal phase in the secretory endometrium of the uterus.[4]
# Receptor regulation
## Upregulation
Upregulation refers to the increase in the number of receptor site on the membrane. Estrogen upregulates FSH receptor sites. In turn, FSH stimulates granulosa cells to produce estrogens. This synergistic activity of estrogen and FSH allows for follicle growth and development in the ovary.
## Desensitization
The FSHR become desensitized when exposed to FSH for some time. A key reaction of this downregulation is the phosphorylation of the intracellular (or cytoplasmic) receptor domain by protein kinases. This process uncouples Gs protein from the FSHR. Another way to desensitize is to uncouple the regulatory and catalytic units of the cAMP system.
## Downregulation
Downregulation refers to the decrease in the number of receptor sites. This can be accomplished by metabolizing bound FSHR sites. The bound FSH-receptor complex is brought by lateral migration to a "coated pit" where such units are concentrated and then stabilized by a framework of clathrins. A pinched-off coated pit is internalized and degraded by lysosomes. Proteins may be metabolized or the receptor can be recycled. Use of long-acting agonists will downregulate the receptor population.
## Modulators
Antibodies to FSHR can interfere with FSHR activity.
# FSHR abnormalities
Some patients with ovarian hyperstimulation syndrome may have mutations in the gene for FSHR making them more sensitive to gonadotropin stimulation.[5]
Women with 46 XX gonadal dysgenesis experience primary amenorrhea with hypergonadotropic hypogonadism. There are forms of 46 xx gonadal dysgenesis where abnormalities in the FSH-receptor have been reported and are thought to be the cause of the hypogonadism.[6]
Polymorphism may affect FSH receptor populations and lead to poorer responses in infertile women who receive FSH medication for IVF.[7]
# History
Alfred G. Gilman and Martin Rodbell received the 1994 Nobel Prize in Medicine and Physiology for the discovery of the G Protein System. | https://www.wikidoc.org/index.php/FSH-receptor | |
6d0c4607fe124e1da6ab548f0e659d28396d9b8e | wikidoc | Rhytidectomy | Rhytidectomy
# Overview
A facelift, technically known as a rhytidectomy (literally, surgical removal of wrinkles), is a type of cosmetic surgery procedure used to give a more youthful appearance. It usually involves the removal of excess facial skin, with or without the tightening of underlying tissues, and the redraping of the skin on the patient's face and neck. The first facelift was performed in Berlin in 1901 by Eugen Holländer. According to the most recent 2007 statistics from the American Society for Aesthetic Plastic Surgery, facelifts were the seventh most popular aesthetic surgery performed after liposuction, breast augmentation, blepharoplasty (eyelid surgery), abdominoplasty (tummy tuck), breast reduction, and rhinoplasty.
In the traditional facelift, an incision is made in front of the ear extending up into the hairline. The incision curves around the bottom of the ear and then behind it, usually ending near the hairline on the back of the neck. After the skin incision is made, the skin is separated from the deeper tissues with a scalpel or scissors (also called undermining) over the cheeks and neck. At this point, the deeper tissues (SMAS, the fascial suspension system of the face) can be tightened with sutures, with or without removing some of the excess deeper tissues. The skin is then redraped, and the amount of excess skin to be removed is determined by the surgeon's judgement and experience. The excess skin is then removed, and the skin incisions are closed with sutures and staples.
Facelifts are helpful for eliminating loose skin folds in the neck and laxity of tissues in the cheeks. The areas not well corrected by a facelift include the nasolabial folds and perioral mounds marionette lines which are more suitably treated with Botox or liposculpture, respectively. A facelift requires skin incisions; however, the incisions in front of and behind the ear are usually inconspicuous. Hair loss in the portions of the incision within the hair-bearing scalp can rarely occur. In men, the sideburns can be pulled backwards and upwards, resulting in an unnatural appearance if appropriate techniques are not employed to address this issue. Achieving a natural appearance following surgery in men can be more challenging due to their hair-bearing preauricular skin. In both men and women, one of the signs of having had a facelift can be an earlobe which is pulled forwards and/or distorted. If too much skin is removed, or a more vertical vector not employed, the face can assume a pulled-back, "windswept" appearance.
Facelifts are effectively combined with eyelid surgery (blepharoplasty) and other facial procedures and are typically performed under general anesthesia or deep twilight sleep.
The most common complication can be bleeding which usually requires a return to the operating room. Less common, but potentially serious, complications may include damage to the facial nerves and necrosis of the skin flaps, or infection.
Contraindications to facelift surgery include severe concomitant medical problems. While not absolute contraindications, the risk of postoperative complications is increased in cigarette smokers and patients with hypertension and diabetes. Patients should abstain from taking aspirin or other blood thinners for at least one week prior to surgery. Patients should consult either an otolaryngologist, maxillofacial surgeon, or a plastic surgeon for more information.
# Costs
Cost varies by country where surgery is performed (2008):
- India - US$4,800
- Malaysia - US$6,400
- Panama - US$2,500
- Singapore - US$7,500
- South Korea - US$6,650
- Taiwan - US$8,500
- Thailand - US$5,000
- United States - US$4,000-$6,000
Additional Notes on Costs in Europe (2009)
- Belgium - UK£1,650
- Italy - UK£5,000
- United Kingdom - UK£4,000-£9,000 | Rhytidectomy
Editors-In-Chief: Martin I. Newman, M.D., FACS, Cleveland Clinic Florida, [1]; Michel C. Samson, M.D., FRCSC, FACS [2], Paul C. Zwiebel, M.D., D.M.D., FACS [3]
# Overview
A facelift, technically known as a rhytidectomy (literally, surgical removal of wrinkles), is a type of cosmetic surgery procedure used to give a more youthful appearance. It usually involves the removal of excess facial skin, with or without the tightening of underlying tissues, and the redraping of the skin on the patient's face and neck. The first facelift was performed in Berlin in 1901 by Eugen Holländer. According to the most recent 2007 statistics from the American Society for Aesthetic Plastic Surgery, facelifts were the seventh most popular aesthetic surgery performed after liposuction, breast augmentation, blepharoplasty (eyelid surgery), abdominoplasty (tummy tuck), breast reduction, and rhinoplasty.
In the traditional facelift, an incision is made in front of the ear extending up into the hairline. The incision curves around the bottom of the ear and then behind it, usually ending near the hairline on the back of the neck. After the skin incision is made, the skin is separated from the deeper tissues with a scalpel or scissors (also called undermining) over the cheeks and neck. At this point, the deeper tissues (SMAS, the fascial suspension system of the face) can be tightened with sutures, with or without removing some of the excess deeper tissues. The skin is then redraped, and the amount of excess skin to be removed is determined by the surgeon's judgement and experience. The excess skin is then removed, and the skin incisions are closed with sutures and staples.
Facelifts are helpful for eliminating loose skin folds in the neck and laxity of tissues in the cheeks. The areas not well corrected by a facelift include the nasolabial folds and perioral mounds marionette lines which are more suitably treated with Botox or liposculpture, respectively. A facelift requires skin incisions; however, the incisions in front of and behind the ear are usually inconspicuous. Hair loss in the portions of the incision within the hair-bearing scalp can rarely occur. In men, the sideburns can be pulled backwards and upwards, resulting in an unnatural appearance if appropriate techniques are not employed to address this issue. Achieving a natural appearance following surgery in men can be more challenging due to their hair-bearing preauricular skin. In both men and women, one of the signs of having had a facelift can be an earlobe which is pulled forwards and/or distorted. If too much skin is removed, or a more vertical vector not employed, the face can assume a pulled-back, "windswept" appearance.
Facelifts are effectively combined with eyelid surgery (blepharoplasty) and other facial procedures and are typically performed under general anesthesia or deep twilight sleep.
The most common complication can be bleeding which usually requires a return to the operating room. Less common, but potentially serious, complications may include damage to the facial nerves and necrosis of the skin flaps, or infection.
Contraindications to facelift surgery include severe concomitant medical problems. While not absolute contraindications, the risk of postoperative complications is increased in cigarette smokers and patients with hypertension and diabetes. Patients should abstain from taking aspirin or other blood thinners for at least one week prior to surgery. Patients should consult either an otolaryngologist, maxillofacial surgeon, or a plastic surgeon for more information.
# Costs
Cost varies by country where surgery is performed (2008)[1]:
- India - US$4,800
- Malaysia - US$6,400
- Panama - US$2,500
- Singapore - US$7,500
- South Korea - US$6,650
- Taiwan - US$8,500
- Thailand - US$5,000
- United States - US$4,000-$6,000
Additional Notes on Costs in Europe (2009)
[2]:
- Belgium - UK£1,650
- Italy - UK£5,000
- United Kingdom - UK£4,000-£9,000 | https://www.wikidoc.org/index.php/Face_lift | |
77d367fe90a71ff88a01d2c565643ca1772b0622 | wikidoc | Faget's sign | Faget's sign
Synonyms and keywords: pulse-temperature deficit; relative bradycardia
# Overview
Faget's sign refers to a significant pulse-temperature deficit relative to the degree of fever.
# Historical Perspective
Feget's sign is named after Jean Charles Faget, who characterized the unusual constellation of fever and bradycardia in 1859.
# Pathophysiology
Physiologically, fever is accompanied by tachycardia rather than bradycardia. For every degree of temperature elevation in degrees Fahrenheit, there is a commensurate increase in pulse rate of 10 beats per minute. This physiologic relationship between temperature and pulse rate is known as Liebermeister's rule (Table 1). When fever is associated with bradycardia, it is referred to as Faget's sign.
# Clinical Significance
Abnormalities in the pulse-temperature relationship may be indiscernible when the body temperature falls below 102°F. Relative bradycardia should not be applied to patients with paced rhythms or advanced AV block or to those taking beta-blockers. Digoxin, angiotensin-converting enzyme inhibitors, and dihydropyridine calcium channel blockers do not affect pulse-temperature relationships as do beta-blockers.
Relative bradycardia may aid differential diagnosis in selected clinical contexts. Faget's sign may be used to discriminate Legionella pneumophila from Mycoplasma pneumoniae in community-acquired pneumonias. When relative bradycardia is associated with fever of unknown origin, certain non-infectious causes including central nervous system lesions, lymphomas, drug fever, factitious fever, and beta-blockers should be considered in addition to the infectious etiologies (Table 2).
# Causes
## Common Causes
- Brucellosis
- Chlamydia
- Colorado tick fever virus
- Coxiella burnetii
- Dengue Fever
- Drug fever
- Legionella
- Leptospirosis
- Leishmaniasis
- Mycoplasma
- Psittacosis
- Tularemia
- Typhoid fever
- Yellow Fever
## Causes by Organ System
## Causes in Alphabetical Order
- Anaphylaxis
- Atypical pneumonia
- Babesiosis
- Beta blocker
- Brucellosis
- Campylobacter fetus
- Central nervous system lesion
- Chagas disease
- Chlamydia
- Chlamydophila psittaci
- Colorado tick fever virus
- Coxiella burnetii
- Cyclic neutropenia
- Cytomegalovirus mononucleosis
- Dengue fever
- Drug fever
- Ehrlichia canis
- Enteric fever
- Factitious fever
- Francisella tularensis
- Group A streptococcus
- Guanarito virus
- Junin virus
- Legionnaires' disease
- Leishmaniasis
- Leptospirosis
- Listeria monocytogenes
- Lymphoma
- Machupo virus
- Malaria
- Murine typhus
- Mycoplasma
- Orientia tsutsugamushi
- Plasmodium vivax
- Q fever
- Rickettsia typhi
- Rickettsiosis
- Rocky mountain spotted fever
- Salmonella enterica
- Typhoid fever
- Viral hemorrhagic fever
- Yellow fever | Faget's sign
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Synonyms and keywords: pulse-temperature deficit; relative bradycardia
# Overview
Faget's sign refers to a significant pulse-temperature deficit relative to the degree of fever.
# Historical Perspective
Feget's sign is named after Jean Charles Faget, who characterized the unusual constellation of fever and bradycardia in 1859.[1]
# Pathophysiology
Physiologically, fever is accompanied by tachycardia rather than bradycardia. For every degree of temperature elevation in degrees Fahrenheit, there is a commensurate increase in pulse rate of 10 beats per minute. This physiologic relationship between temperature and pulse rate is known as Liebermeister's rule (Table 1). When fever is associated with bradycardia, it is referred to as Faget's sign.
# Clinical Significance
Abnormalities in the pulse-temperature relationship may be indiscernible when the body temperature falls below 102°F. Relative bradycardia should not be applied to patients with paced rhythms or advanced AV block or to those taking beta-blockers. Digoxin, angiotensin-converting enzyme inhibitors, and dihydropyridine calcium channel blockers do not affect pulse-temperature relationships as do beta-blockers.[2]
Relative bradycardia may aid differential diagnosis in selected clinical contexts. Faget's sign may be used to discriminate Legionella pneumophila from Mycoplasma pneumoniae in community-acquired pneumonias.[3][4] When relative bradycardia is associated with fever of unknown origin, certain non-infectious causes including central nervous system lesions, lymphomas, drug fever, factitious fever, and beta-blockers should be considered in addition to the infectious etiologies (Table 2).
# Causes
## Common Causes
- Brucellosis
- Chlamydia
- Colorado tick fever virus
- Coxiella burnetii
- Dengue Fever[5]
- Drug fever
- Legionella[3][6]
- Leptospirosis
- Leishmaniasis
- Mycoplasma[3]
- Psittacosis
- Tularemia
- Typhoid fever
- Yellow Fever[2][7]
## Causes by Organ System
## Causes in Alphabetical Order
- Anaphylaxis
- Atypical pneumonia
- Babesiosis
- Beta blocker
- Brucellosis
- Campylobacter fetus
- Central nervous system lesion
- Chagas disease
- Chlamydia
- Chlamydophila psittaci
- Colorado tick fever virus
- Coxiella burnetii
- Cyclic neutropenia
- Cytomegalovirus mononucleosis
- Dengue fever
- Drug fever
- Ehrlichia canis
- Enteric fever
- Factitious fever
- Francisella tularensis
- Group A streptococcus
- Guanarito virus
- Junin virus
- Legionnaires' disease
- Leishmaniasis
- Leptospirosis
- Listeria monocytogenes
- Lymphoma
- Machupo virus
- Malaria
- Murine typhus
- Mycoplasma
- Orientia tsutsugamushi
- Plasmodium vivax
- Q fever
- Rickettsia typhi
- Rickettsiosis
- Rocky mountain spotted fever
- Salmonella enterica
- Typhoid fever
- Viral hemorrhagic fever
- Yellow fever | https://www.wikidoc.org/index.php/Faget%27s_sign | |
fb928394af2eb74ad80d0916953ea367c7529040 | wikidoc | False memory | False memory
# Overview
A false memory is a memory of an event that did not happen or is a distortion of an event that did occur as determined by externally corroborated facts.
# Background
It is common experience that memory may be unreliable to some degree.
Our sense of identity, of who we are and what we have done, is tied to our memories, and it can be disturbing to have those challenged. Amnesia, Alzheimer's disease, and post-traumatic stress disorder (also known as “shell-shock”) provide examples of dramatic loss of memory, with devastating effects on the sufferer and those around them.
Memory is a complicated process, only partly understood, but research suggests that the qualities of a memory do not in and of themselves provide a reliable way to determine accuracy. For example, a vivid and detailed memory may be based upon inaccurate reconstruction of facts, or largely self-created impressions that appear to have actually occurred. Likewise, continuity of memory is no guarantee of truth, and disruption of memory is no guarantee of falsity. Finally, memory is a reconstructed phenomenon, and so it can often be strongly influenced by various biases, such as: subjective or social expectation, emotions, the implied beliefs of others, inappropriate interpretation, or desired outcome.
# Discussion
If a person remembers an event that lacks another witness or corroborative physical evidence, due to lack of perfect accuracy in most memories, the validity of the memory may be questioned if it would have a significant impact on others. It might be said that absence of evidence does not in fact constitute the non-existence of evidence, but validation has high priority in such situations, such as courts of law or military situations. For instance, one might say that they have witnessed scores of an enemy army over the hillside. As difficult as it may be to disprove such a statement outright, the statement cannot be validated until the enemy army is actually validated by corroborating witnesses.
Complications arise when a memory involves trauma inflicted by another. If it is in a reputedly involved third party's interest to deny an incriminating memory, the memory cannot be dismissed merely on the strength of such a denial. Likewise, the memory alone does not warrant an accusation of the third party—hence need for external corroborative evidence.
The origin of false memories is controversial. Hypnosis can be used to form false memories because this technique can lead to fantasizing and can increase the subjective certainty of fantasy. Research suggests that at least some false memories are formed through rehearsal, or repetition, of an event that has been confirmed as fantastic: after repeatedly thinking about and visualizing an event, a person may begin to “remember” it as if it had actually occurred. Upon questioning, such a person might confidently recall the event when in fact it is merely ''''previous '''visualizations''''''' that make it seem familiar. Rehearsal is the strongest mechanism of moving short-term memory into long-term memory. Naturally, the rehearsal of incorrect information leads to the formation of an incorrect long-term memory. This applies to both implanted and real memories. For example, many people have experienced the phenomenon of learning that a childhood memory actually happened to a sibling.
Research suggests that memory involves reconstruction, not just recall. For example, a child remembers standing beside a fence overlooking an eerie looking valley. As an adult, the real eerieness of the valley may be falsely remembered as containing a dead body, when in fact the child witnessed a homeless man sleeping under the trees. This particular memory would represent an inaccurate reconstruction.
Many proponents of recovered memories emphasize the importance of distinguishing between ordinary and traumatic memory. Studies show that memories can be implanted, but we lack studies on implanted traumatic memories and their related effects—such as post-traumatic stress disorder and dissociative identity disorder—because such studies would be unethical.
## False memory syndrome
False memory syndrome (FMS) is the term for the hypothesis describing a state of mind wherein sufferers have a high number of highly vivid but false memories, often of abusive events during their childhood. This condition has been studied, and sufferers have confessed to “entirely made up stories.” However, the DSM-IV does not recognize FMS, although the forgetting of traumatic events constitutes several of the manual's diagnostic criteria for PTSD. The debate over FMS centers largely around the topic of child abuse, wherein alleged victims are said to experience dissociation, which causes repression of the traumatic memory until later in life, when the memory resurfaces either naturally or with the aid of a professional. Many advocates of FMS argue against both methods of memory recovery, claiming that such professionals as therapists and psychiatrists accidentally implant false memories. Specific therapies considered by some to be pseudoscientific (such as past lives therapies) have been explained with reference to false memory syndrome. The term and concept were popularized, though not invented, by the False Memory Syndrome Foundation (FMSF).
The Courage to Heal is a book that has received much controversy over the years, as some believe it encourages the recovery of repressed memories as a healing technique. Some retractors have blamed the book for encouraging them into memory confabulation.
Ultimately, it is undeniable that true memories are often forgotten. The difficulty comes in deciding whether a memory which has been recovered or spontaneously recollected, is accurate and correctly interpreted, or not.
# Prominent examples
## Murder
In July of 1978, 44 year old Mary Bowman died in her bedroom with large quantities of alcohol and valium in her system. Her daughter, five at the time, would recall 20 years later in 1998 that her father had abused both her and her mother when she was young. She also "recovered" memories of an assault on her mother that ended with her father force-feeding her pills and booze on the night of her death.
As charges were being filed, the investigation turned up evidence that the account given by the daughter was inconsistent (both in itself and with established facts of the original autopsy and body exhumation). This case is one of many where false memories led to murder accusations or formal charges.
## Sexual abuse
False memory has figured prominently in many investigations and court cases, including cases of alleged sexual abuse. There is no scientific way to prove that any of these recollections are completely accurate.
In the 1980s, day care sexual abuse hysteria based on recovered memories resulted in the imprisonment of some of the accused parents. Most of these convictions were reversed in the 1990s, and there are cases in which recovered-memory therapists have been successfully sued by former clients for implanting false memories.
Many individuals who were led to believe in things that they later were able to show did not happen have retracted allegations of such abuse (for instance, ). Known as "retractors", they are sometimes vilified as being "in denial" about the "real abuse they suffered and want to forget about" by advocates of recovered memory therapy (see below), a suggestion which many find offensive.
## Alien abduction and past life therapy
Other reputed instances of therapist-implanted false memory involve alien abductions and past life regression. These cases are cited as proof that certain methods can induce false memories.
Psychologist Stephen Jay Lynn conducted a simulated hypnosis experiment in 1994, asking patients to imagine they had seen bright lights and experienced lost time. 91% of subjects who had been primed with questions about UFOs stated that they had interacted with aliens.
Harvard University professor Richard McNally has found that many Americans who believe they have been abducted by aliens share personality traits such as New Age beliefs and episodes of sleep paralysis accompanied by hypnopompic hallucinations. These experiences prompted the individuals to visit therapists, who would frequently suggest alien abduction as a cause. The individuals readily accepted the explanation and in laboratory experiments exhibited stress symptoms similar to those of Vietnam veterans suffering from post-traumatic stress disorder. The experiment led McNally to conclude, "Emotion does not prove the veracity of the interpretation."
In the United States, in the 1980s, a wave of false allegations erupted as a result of the use of recovered memory techniques in cases of Satanic ritual abuse. Hundreds of psychotherapists began teaching that adult stress was a sign that a person was sexually abused by their parents and neighbors. Using putative techniques to "recover" these lost memories, hundreds of people eventually were convinced by their therapists that they were abused by Satanic priests, these Satanists being their own family or kindergarten teachers. Hundreds of people were convicted of these "crimes" and put in jail. From the late 1990s onward a skeptical reappraisal of these recovered memory techniques has shown that these were not recovered memories at all, but rather created memories. Most of the people convicted on such charges have since been freed.
# Criticisms of recovered memory therapy
Although there is genuine concern that important memories may be buried and need uncovering, there is concern that the goal of neutral truth may be forgotten, compared to the belief that they must exist and be found, and that lives are therefore devastated by the pressure to find such memories when such events often may not have happened, or may be misinterpreted.
Critics, such as FMS advocates, claim that recovered memory therapists often have a non-neutral interest in proving that such experiences happened, and use techniques similar to those used by cults and interrogators which are known to produce mental confusion such as:
- keeping information from their clients that could place their recovered memories in doubt
- assuming by default that repressed memories exist in the client
- relying upon techniques based upon suggestibility rather than ones which neutrally explore the client's experience
- mentally isolating people from their previous social support (families and so on)
- viciously attacking opponents, insinuating that they are practitioners of Satanic ritual abuse or that they endorse the sexual abuse of children
Critics of recovered memory therapy, like Richard Ofshe, Ethan Watters (Making Monsters: False Memories, Psychotherapy, And Sexual Hysteria) and Elizabeth Loftus (The Myth of Repressed Memory), view the practice of "recovering" memories as fraudulent and dangerous. They base this assertion on several claims:
- Traumatic experiences which obviously have happened, such as war time experiences, are not "repressed"—they are either forgotten or remembered clearly in spite of attempts to suppress them.
- The "memories" recovered in RMT are highly detailed. According to RMT literature, the human brain stores very vivid memories which can be recalled in detail, like a video tape. This belief contradicts virtually all research on the way memories work.
- The patient is given very extensive lists of "symptoms" including sleeplessness, headaches, the feeling of being different from others etc. If several of these symptoms are found, the therapist suggests to the patient that they were probably sexually abused. If the patient denies this, they are "in denial" and require more extensive therapy. This is a form of Catch-22.
- During the questioning, patients are openly encouraged to ignore their own feelings and memories and to assume that the abuse has happened. They then explore together with this therapist, over a prolonged period of many months or even years, how the abuse happened. The possibility that the abuse has not happened at all is usually not considered.
According to these critics, RMT techniques used for "reincarnation therapy" or "alien abduction therapy" are comparable to the techniques used in Satanic ritual abuse therapy. To verify the false memory hypothesis, researchers like Elizabeth Loftus have successfully produced false memories of various childhood incidents in test subjects. This is viewed as further evidence that comprehensive false memories can be produced in therapy. The false memories in these studies, however, are ordinary memory (like convincing people they were lost in a mall as a child) and not traumatic memories. It would be highly unethical to subject people to traumatic experiences for experimental purposes when studying traumatic memory. | False memory
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
A false memory is a memory of an event that did not happen or is a distortion of an event that did occur as determined by externally corroborated facts.
# Background
It is common experience that memory may be unreliable to some degree.
Our sense of identity, of who we are and what we have done, is tied to our memories, and it can be disturbing to have those challenged. Amnesia, Alzheimer's disease, and post-traumatic stress disorder (also known as “shell-shock”) provide examples of dramatic loss of memory, with devastating effects on the sufferer and those around them.
Memory is a complicated process, only partly understood, but research suggests that the qualities of a memory do not in and of themselves provide a reliable way to determine accuracy. For example, a vivid and detailed memory may be based upon inaccurate reconstruction of facts, or largely self-created impressions that appear to have actually occurred. Likewise, continuity of memory is no guarantee of truth, and disruption of memory is no guarantee of falsity. Finally, memory is a reconstructed phenomenon, and so it can often be strongly influenced by various biases, such as: subjective or social expectation, emotions, the implied beliefs of others, inappropriate interpretation, or desired outcome.
# Discussion
If a person remembers an event that lacks another witness or corroborative physical evidence, due to lack of perfect accuracy in most memories, the validity of the memory may be questioned if it would have a significant impact on others. It might be said that absence of evidence does not in fact constitute the non-existence of evidence, but validation has high priority in such situations, such as courts of law or military situations. For instance, one might say that they have witnessed scores of an enemy army over the hillside. As difficult as it may be to disprove such a statement outright, the statement cannot be validated until the enemy army is actually validated by corroborating witnesses.
Complications arise when a memory involves trauma inflicted by another. If it is in a reputedly involved third party's interest to deny an incriminating memory, the memory cannot be dismissed merely on the strength of such a denial. Likewise, the memory alone does not warrant an accusation of the third party—hence need for external corroborative evidence.
The origin of false memories is controversial. Hypnosis can be used to form false memories because this technique can lead to fantasizing and can increase the subjective certainty of fantasy. Research suggests that at least some false memories are formed through rehearsal, or repetition, of an event that has been confirmed as fantastic: after repeatedly thinking about and visualizing an event, a person may begin to “remember” it as if it had actually occurred. Upon questioning, such a person might confidently recall the event when in fact it is merely ''''previous '''visualizations''''''' that make it seem familiar. Rehearsal is the strongest mechanism of moving short-term memory into long-term memory. Naturally, the rehearsal of incorrect information leads to the formation of an incorrect long-term memory. This applies to both implanted and real memories. For example, many people have experienced the phenomenon of learning that a childhood memory actually happened to a sibling.
Research suggests that memory involves reconstruction, not just recall. For example, a child remembers standing beside a fence overlooking an eerie looking valley. As an adult, the real eerieness of the valley may be falsely remembered as containing a dead body, when in fact the child witnessed a homeless man sleeping under the trees. This particular memory would represent an inaccurate reconstruction.
Many proponents of recovered memories emphasize the importance of distinguishing between ordinary and traumatic memory. Studies show that memories can be implanted, but we lack studies on implanted traumatic memories and their related effects—such as post-traumatic stress disorder and dissociative identity disorder—because such studies would be unethical.
## False memory syndrome
False memory syndrome (FMS) is the term for the hypothesis describing a state of mind wherein sufferers have a high number of highly vivid but false memories, often of abusive events during their childhood. This condition has been studied, and sufferers have confessed to “entirely made up stories.” However, the DSM-IV does not recognize FMS, although the forgetting of traumatic events constitutes several of the manual's diagnostic criteria for PTSD. The debate over FMS centers largely around the topic of child abuse, wherein alleged victims are said to experience dissociation, which causes repression of the traumatic memory until later in life, when the memory resurfaces either naturally or with the aid of a professional. Many advocates of FMS argue against both methods of memory recovery, claiming that such professionals as therapists and psychiatrists accidentally implant false memories. Specific therapies considered by some to be pseudoscientific (such as past lives therapies) have been explained with reference to false memory syndrome. The term and concept were popularized, though not invented, by the False Memory Syndrome Foundation (FMSF).
The Courage to Heal is a book that has received much controversy over the years, as some believe it encourages the recovery of repressed memories as a healing technique. Some retractors have blamed the book for encouraging them into memory confabulation.[2]
Ultimately, it is undeniable that true memories are often forgotten. The difficulty comes in deciding whether a memory which has been recovered or spontaneously recollected, is accurate and correctly interpreted, or not.
# Prominent examples
## Murder
In July of 1978, 44 year old Mary Bowman died in her bedroom with large quantities of alcohol and valium in her system. Her daughter, five at the time, would recall 20 years later in 1998 that her father had abused both her and her mother when she was young. She also "recovered" memories of an assault on her mother that ended with her father force-feeding her pills and booze on the night of her death.
As charges were being filed, the investigation turned up evidence that the account given by the daughter was inconsistent (both in itself and with established facts of the original autopsy and body exhumation).[1] This case is one of many [2][3] where false memories led to murder accusations or formal charges.
## Sexual abuse
False memory has figured prominently in many investigations and court cases, including cases of alleged sexual abuse. There is no scientific way to prove that any of these recollections are completely accurate.
In the 1980s, day care sexual abuse hysteria based on recovered memories resulted in the imprisonment of some of the accused parents. Most of these convictions were reversed in the 1990s, and there are cases in which recovered-memory therapists have been successfully sued by former clients for implanting false memories. [3]
Many individuals who were led to believe in things that they later were able to show did not happen have retracted allegations of such abuse (for instance, [4]). Known as "retractors", they are sometimes vilified as being "in denial" about the "real abuse they suffered and want to forget about" by advocates of recovered memory therapy (see below), a suggestion which many find offensive.[5]
## Alien abduction and past life therapy
Other reputed instances of therapist-implanted false memory involve alien abductions and past life regression. These cases are cited as proof that certain methods can induce false memories.
Psychologist Stephen Jay Lynn conducted a simulated hypnosis experiment in 1994, asking patients to imagine they had seen bright lights and experienced lost time. 91% of subjects who had been primed with questions about UFOs stated that they had interacted with aliens. [6]
Harvard University professor Richard McNally has found that many Americans who believe they have been abducted by aliens share personality traits such as New Age beliefs and episodes of sleep paralysis accompanied by hypnopompic hallucinations. These experiences prompted the individuals to visit therapists, who would frequently suggest alien abduction as a cause. The individuals readily accepted the explanation and in laboratory experiments exhibited stress symptoms similar to those of Vietnam veterans suffering from post-traumatic stress disorder.[7] The experiment led McNally to conclude, "Emotion does not prove the veracity of the interpretation."[8]
In the United States, in the 1980s, a wave of false allegations erupted as a result of the use of recovered memory techniques in cases of Satanic ritual abuse.[9] Hundreds of psychotherapists began teaching that adult stress was a sign that a person was sexually abused by their parents and neighbors. Using putative techniques to "recover" these lost memories, hundreds of people eventually were convinced by their therapists that they were abused by Satanic priests, these Satanists being their own family or kindergarten teachers. Hundreds of people were convicted of these "crimes" and put in jail. From the late 1990s onward a skeptical reappraisal of these recovered memory techniques has shown that these were not recovered memories at all, but rather created memories. Most of the people convicted on such charges have since been freed.[10]
# Criticisms of recovered memory therapy
Although there is genuine concern that important memories may be buried and need uncovering, there is concern that the goal of neutral truth may be forgotten, compared to the belief that they must exist and be found, and that lives are therefore devastated by the pressure to find such memories when such events often may not have happened, or may be misinterpreted.
Critics, such as FMS advocates, claim that recovered memory therapists often have a non-neutral interest in proving that such experiences happened, and use techniques similar to those used by cults and interrogators which are known to produce mental confusion such as:
- keeping information from their clients that could place their recovered memories in doubt
- assuming by default that repressed memories exist in the client
- relying upon techniques based upon suggestibility rather than ones which neutrally explore the client's experience
- mentally isolating people from their previous social support (families and so on)
- viciously attacking opponents, insinuating that they are practitioners of Satanic ritual abuse or that they endorse the sexual abuse of children
Critics of recovered memory therapy, like Richard Ofshe, Ethan Watters (Making Monsters: False Memories, Psychotherapy, And Sexual Hysteria) and Elizabeth Loftus (The Myth of Repressed Memory), view the practice of "recovering" memories as fraudulent and dangerous. They base this assertion on several claims:
- Traumatic experiences which obviously have happened, such as war time experiences, are not "repressed"—they are either forgotten or remembered clearly in spite of attempts to suppress them.
- The "memories" recovered in RMT are highly detailed. According to RMT literature, the human brain stores very vivid memories which can be recalled in detail, like a video tape. This belief contradicts virtually all research on the way memories work.
- The patient is given very extensive lists of "symptoms" including sleeplessness, headaches, the feeling of being different from others etc. If several of these symptoms are found, the therapist suggests to the patient that they were probably sexually abused. If the patient denies this, they are "in denial" and require more extensive therapy. This is a form of Catch-22.
- During the questioning, patients are openly encouraged to ignore their own feelings and memories and to assume that the abuse has happened. They then explore together with this therapist, over a prolonged period of many months or even years, how the abuse happened. The possibility that the abuse has not happened at all is usually not considered.
According to these critics, RMT techniques used for "reincarnation therapy" or "alien abduction therapy" are comparable to the techniques used in Satanic ritual abuse therapy. To verify the false memory hypothesis, researchers like Elizabeth Loftus have successfully produced false memories of various childhood incidents in test subjects. This is viewed as further evidence that comprehensive false memories can be produced in therapy. The false memories in these studies, however, are ordinary memory (like convincing people they were lost in a mall as a child) and not traumatic memories. It would be highly unethical to subject people to traumatic experiences for experimental purposes when studying traumatic memory. | https://www.wikidoc.org/index.php/False_memory | |
b04ac6b3d355bde774495b76b09258619410451b | wikidoc | Pseudocyesis | Pseudocyesis
# Overview
Pseudocyesis also known as false pregnancy, can cause many of the signs and symptoms associated with pregnancy, and can resemble the condition in every way except for fetal presence. Other names include - spurious pregnancy, feigned pregnancy, imaginary pregnancy, hysterical pregnancy, phantom pregnancy and grossesse nerveuse ("mental pregnancy"). John Mason Good coined the term pseudocyesis from the Greek words pseudes (false) and kyesis (pregnancy) in 1923. False pregnancy is common in many mammals and is a method of providing milk for the group's offspring, most often cats, dogs, and rabbits.
# History
Cases of pseudocyesis have been documented since antiquity. Hippocrates gives us the first written account around 300 B.C. when he recorded 12 different cases of women with the disorder. Mary Tudor (1516-1558), Queen of England, was perhaps the most famous of western historical examples, who believed on several occasions that she was pregnant, when she was in fact not. Some even attribute, mistakenly, the violence that gave her the nickname "Bloody Mary" to be a reaction to her disappointment on realising she was without child. Other medical historians believe that the queen's physicians mistook fibroid tumors in her uterus for a pregnancy.
# Signs and symptoms
The symptoms of pseudocyesis are similar to the symptoms of true pregnancy and are often hard to distinguish from it. Such natural signs as amenorrhoea, morning sickness, tender breasts, and weight gain may all be present. Many health care professionals can be deceived by the symptoms associated with pseudocyesis. Research shows that 18% of women with pseudocyesis were at one time diagnosed as pregnant by medical professionals.
The hallmark sign of pseudocyesis that is common to all cases is that the affected patient is convinced that she is pregnant. Abdominal distension is the most common physical symptom of pseudocyesis (60– 90%). The abdomen expands in the same manner as it does during pregnancy, so that the affected woman looks pregnant. This phenomenon is thought to be caused by buildup of gas, fat, feces, or urine. These symptoms often resolve under general anesthesia and the woman's abdomen returns to its normal size.
The second most common physical sign of pseudocyesis is menstrual irregularity (50–90%). Women are also reported to experience the sensation of fetal movements known as quickening, even though there is no fetus present (50%-75%). Other common signs and symptoms include: gastrointestinal symptoms, breast changes or secretions, labor pains, uterine enlargement, and softening of the cervix. One percent of women eventually experience false labor.
# Causes
There are various explanations, none of which are universally accepted. Psychodynamic theories attribute the false pregnancy to emotional conflict. It is thought that an intense desire to become pregnant, or an intense fear of becoming pregnant, can create internal conflicts and changes in the endocrine system, which may explain some of the symptoms of pseudocyesis. Another theory concerns wish-fulfillment. It holds that if a woman desires pregnancy badly enough she may interpret minor changes in her body as signs of pregnancy.
Proposed biological mechanisms include the effect of stress on the hypothalamo-pituitary-adrenal axis, constipation, weight gain and the movement of intestinal gas.
# Demographics
The rate of pseudocyesis in the United States has declined significantly in the past century. In the 1940s there was one occurrence for approximately every 250 pregnancies. This rate has since dropped to between one and six occurrences for every 22,000 births (). The average age of the affected woman is 33, though cases have been reported for women as young as 6-1/2 and as old as 79. More than two-thirds of women who experience pseudocyesis are married, and about one-third have been pregnant at least once. Women who have been victims of incest may be at greater risk for developing pseudocyesis.
# Treatment
Because pseudocyesis is not known to have a direct underlying physical cause, there are no general recommendations regarding treatment with medications. In some cases, however, the patient may be given medications for such symptoms as the cessation of menstruation. Because most patients with pseudocyesis have underlying psychological problems, they should be referred to a psychotherapist for the treatment of these problems. It is important at the same time, however, for the treating professional not to minimize the reality of the patient's physical symptoms.
The treatment that has had the most success is demonstrating to the patient that she is not really pregnant by the use of ultrasound or other imaging techniques.
# Alternative therapies
There have been reports of patients being cured of pseudocyesis by hypnosis, purgatives, massage, opioids, or after nine months of symptoms, by experiencing "hysterical childbirth," but there are few data available on the effectiveness of these or similar procedures.
# In animals
## Dogs
Bitches that are pseudopregnant will lactate and build nests for their imaginary puppies. Dalmatians and various labradors are infamous for pseudopregnancies.
## Mice
In creating transgenic mice, DNA is injected into the male pronucleus of a freshly fertilized egg. The embryos are implanted in a female mouse which has been made pseudo-pregnant by mating her with a vasectomized male mouse in order to make her uterus receptive. (RJ Reece, 2004. Analysis of Genes and Genomes.)
# In Popular Culture
-On the CBS show, "CSI: Crime Scene Investigation," a character played by Evan Rachel Wood suffered from pseudocyesis after becoming obsessed with her own father.
-In a renowned 60's movie Who's Afraid of Virginia Woolf? based on the play by Edward Albee, Nick's wife Honey, suffers from a hysterical pregnancy which inclined Nick to marry her.
de:Scheinschwangerschaft
ko:상상 임신
nl:Schijnzwangerschap
fi:Valeraskaus | Pseudocyesis
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Pseudocyesis also known as false pregnancy, can cause many of the signs and symptoms associated with pregnancy, and can resemble the condition in every way except for fetal presence. Other names include - spurious pregnancy, feigned pregnancy, imaginary pregnancy, hysterical pregnancy, phantom pregnancy and grossesse nerveuse ("mental pregnancy"). John Mason Good coined the term pseudocyesis from the Greek words pseudes (false) and kyesis (pregnancy) in 1923. False pregnancy is common in many mammals and is a method of providing milk for the group's offspring, most often cats, dogs, and rabbits.
# History
Cases of pseudocyesis have been documented since antiquity. Hippocrates gives us the first written account around 300 B.C. when he recorded 12 different cases of women with the disorder. Mary Tudor (1516-1558), Queen of England, was perhaps the most famous of western historical examples, who believed on several occasions that she was pregnant, when she was in fact not. Some even attribute, mistakenly, the violence that gave her the nickname "Bloody Mary" to be a reaction to her disappointment on realising she was without child. Other medical historians believe that the queen's physicians mistook fibroid tumors in her uterus for a pregnancy.
# Signs and symptoms
The symptoms of pseudocyesis are similar to the symptoms of true pregnancy and are often hard to distinguish from it. Such natural signs as amenorrhoea, morning sickness, tender breasts, and weight gain may all be present. Many health care professionals can be deceived by the symptoms associated with pseudocyesis. Research shows that 18% of women with pseudocyesis were at one time diagnosed as pregnant by medical professionals.
The hallmark sign of pseudocyesis that is common to all cases is that the affected patient is convinced that she is pregnant. Abdominal distension is the most common physical symptom of pseudocyesis (60– 90%). The abdomen expands in the same manner as it does during pregnancy, so that the affected woman looks pregnant. This phenomenon is thought to be caused by buildup of gas, fat, feces, or urine. These symptoms often resolve under general anesthesia and the woman's abdomen returns to its normal size.
The second most common physical sign of pseudocyesis is menstrual irregularity (50–90%). Women are also reported to experience the sensation of fetal movements known as quickening, even though there is no fetus present (50%-75%). Other common signs and symptoms include: gastrointestinal symptoms, breast changes or secretions, labor pains, uterine enlargement, and softening of the cervix. One percent of women eventually experience false labor.
# Causes
There are various explanations, none of which are universally accepted. Psychodynamic theories attribute the false pregnancy to emotional conflict. It is thought that an intense desire to become pregnant, or an intense fear of becoming pregnant, can create internal conflicts and changes in the endocrine system, which may explain some of the symptoms of pseudocyesis. Another theory concerns wish-fulfillment. It holds that if a woman desires pregnancy badly enough she may interpret minor changes in her body as signs of pregnancy.
Proposed biological mechanisms include the effect of stress on the hypothalamo-pituitary-adrenal axis, constipation, weight gain and the movement of intestinal gas.
# Demographics
The rate of pseudocyesis in the United States has declined significantly in the past century. In the 1940s there was one occurrence for approximately every 250 pregnancies. This rate has since dropped to between one and six occurrences for every 22,000 births (http://www.womens-health.co.uk/false_pregnancy.html). The average age of the affected woman is 33, though cases have been reported for women as young as 6-1/2 and as old as 79. More than two-thirds of women who experience pseudocyesis are married, and about one-third have been pregnant at least once. Women who have been victims of incest may be at greater risk for developing pseudocyesis.
# Treatment
Because pseudocyesis is not known to have a direct underlying physical cause, there are no general recommendations regarding treatment with medications. In some cases, however, the patient may be given medications for such symptoms as the cessation of menstruation. Because most patients with pseudocyesis have underlying psychological problems, they should be referred to a psychotherapist for the treatment of these problems. It is important at the same time, however, for the treating professional not to minimize the reality of the patient's physical symptoms.
The treatment that has had the most success is demonstrating to the patient that she is not really pregnant by the use of ultrasound or other imaging techniques.
# Alternative therapies
There have been reports of patients being cured of pseudocyesis by hypnosis, purgatives, massage, opioids, or after nine months of symptoms, by experiencing "hysterical childbirth," but there are few data available on the effectiveness of these or similar procedures.
# In animals
## Dogs
Bitches that are pseudopregnant will lactate and build nests for their imaginary puppies. Dalmatians and various labradors are infamous for pseudopregnancies.
## Mice
In creating transgenic mice, DNA is injected into the male pronucleus of a freshly fertilized egg. The embryos are implanted in a female mouse which has been made pseudo-pregnant by mating her with a vasectomized male mouse in order to make her uterus receptive. (RJ Reece, 2004. Analysis of Genes and Genomes.)
# In Popular Culture
-On the CBS show, "CSI: Crime Scene Investigation," a character played by Evan Rachel Wood suffered from pseudocyesis after becoming obsessed with her own father.
-In a renowned 60's movie Who's Afraid of Virginia Woolf? based on the play by Edward Albee, Nick's wife Honey, suffers from a hysterical pregnancy which inclined Nick to marry her.
Template:SIB
de:Scheinschwangerschaft
ko:상상 임신
nl:Schijnzwangerschap
fi:Valeraskaus
Template:WH
Template:WS | https://www.wikidoc.org/index.php/False_pregnancy | |
1b4b730da4a5a109302cf121309c193590a5e7ab | wikidoc | Fas receptor | Fas receptor
Fas or FasR, also known as apoptosis antigen 1 (APO-1 or APT), cluster of differentiation 95 (CD95) or tumor necrosis factor receptor superfamily member 6 (TNFRSF6) is a protein that in humans is encoded by the FAS gene.
The Fas receptor is a death receptor on the surface of cells that leads to programmed cell death (apoptosis). It is one of two apoptosis pathways, the other being the mitochondrial pathway. FasR is located on chromosome 10 in humans and 19 in mice. Similar sequences related by evolution (orthologs) are found in most mammals.
# Gene
FAS receptor is located on the long arm of chromosome 10 (10q24.1) in humans and on chromosome 19 in mice. The gene lies on the plus (Watson strand) and is 25,255 bases in length organised into nine protein encoding exons.
# Protein
Previous reports have identified as many as eight splice variants, which are translated into seven isoforms of the protein. Apoptosis-inducing Fas receptor is dubbed isoform 1 and is a type 1 transmembrane protein. Many of the other isoforms are rare haplotypes that are usually associated with a state of disease. However, two isoforms, the apoptosis-inducing membrane-bound form and the soluble form, are normal products whose production via alternative splicing is regulated by the cytotoxic RNA binding protein TIA1.
The mature Fas protein has 319 amino acids, has a predicted molecular weight of 48 kiloDaltons and is divided into 3 domains: an extracellular domain, a transmembrane domain, and a cytoplasmic domain. The extracellular domain has 157 amino acids and is rich in cysteine residues. The transmembrane and cytoplasmic domains have 17 and 145 amino acids respectively. Exons 1 through 5 encode the extracelluar region. Exon 6 encodes the transmembrane region. Exons 7-9 encode the intracellular region.
# Function
Fas forms the death-inducing signaling complex (DISC) upon ligand binding. Membrane-anchored Fas ligand trimer on the surface of an adjacent cell causes oligomerization of Fas.
Recent studies which suggested the trimerization of Fas could not be validated. Other models suggested the oligomerization up to 5-7 Fas molecules in the DISC.
This event is also mimicked by binding of an agonistic Fas antibody, though some evidence suggests that the apoptotic signal induced by the antibody is unreliable in the study of Fas signaling. To this end, several clever ways of trimerizing the antibody for in vitro research have been employed.
Upon ensuing death domain (DD) aggregation, the receptor complex is internalized via the cellular endosomal machinery. This allows the adaptor molecule FADD to bind the death domain of Fas through its own death domain.
FADD also contains a death effector domain (DED) near its amino terminus, which facilitates binding to the DED of FADD-like interleukin-1 beta-converting enzyme (FLICE), more commonly referred to as caspase-8. FLICE can then self-activate through proteolytic cleavage into p10 and p18 subunits, two each of which form the active heterotetramer enzyme. Active caspase-8 is then released from the DISC into the cytosol, where it cleaves other effector caspases, eventually leading to DNA degradation, membrane blebbing, and other hallmarks of apoptosis.
Recently, Fas has also been shown to promote tumor growth, since during tumor progression, it is frequently downregulated or cells are rendered apoptosis resistant. Cancer cells in general, regardless of their Fas apoptosis sensitivity, depend on constitutive activity of Fas. This is stimulated by cancer-produced Fas ligand for optimal growth.
Although Fas has been shown to promote tumor growth in the above mouse models, analysis of the human cancer genomics database revealed that FAS is not significantly focally amplified across a dataset of 3131 tumors (FAS is not an oncogene), but is significantly focally deleted across the entire dataset of these 3131 tumors, suggesting that FAS functions as a tumor suppressor in humans.
In cultured cells, FasL induces various types of cancer cell apoptosis through the Fas receptor. In AOM-DSS-induced colon carcinoma and MCA-induced sarcoma mouse models, it has been shown that Fas acts as a tumor suppressor. Furthermore, the Fas receptor also mediates tumor-specific cytotoxic T lymphocyte (CTL) anti-tumor cytotoxicity.
# Role in apoptosis
Some reports have suggested that the extrinsic Fas pathway is sufficient to induce complete apoptosis in certain cell types through DISC assembly and subsequent caspase-8 activation.
These cells are dubbed Type 1 cells and are characterized by the inability of anti-apoptotic members of the Bcl-2 family (namely Bcl-2 and Bcl-xL) to protect from Fas-mediated apoptosis.
Characterized Type 1 cells include H9, CH1, SKW6.4 and SW480, all of which are lymphocyte lineages except the latter, which is a colon adenocarcinoma lineage.
However, evidence for crosstalk between the extrinsic and intrinsic pathways exists in the Fas signal cascade.
In most cell types, caspase-8 catalyzes the cleavage of the pro-apoptotic BH3-only protein Bid into its truncated form, tBid. BH-3 only members of the Bcl-2 family exclusively engage anti-apoptotic members of the family (Bcl-2, Bcl-xL), allowing Bak and Bax to translocate to the outer mitochondrial membrane, thus permeabilizing it and facilitating release of pro-apoptotic proteins such as cytochrome c and Smac/DIABLO, an antagonist of inhibitors of apoptosis proteins (IAPs).
# Interactions
Fas receptor has been shown to interact with:
- Caspase 8,
- Caspase 10,
- CFLAR,
- FADD,
- Fas ligand,
- PDCD6, and
- Small ubiquitin-related modifier 1. | Fas receptor
Fas or FasR, also known as apoptosis antigen 1 (APO-1 or APT), cluster of differentiation 95 (CD95) or tumor necrosis factor receptor superfamily member 6 (TNFRSF6) is a protein that in humans is encoded by the FAS gene.[1][2]
The Fas receptor is a death receptor on the surface of cells that leads to programmed cell death (apoptosis). It is one of two apoptosis pathways, the other being the mitochondrial pathway.[3] FasR is located on chromosome 10 in humans and 19 in mice. Similar sequences related by evolution (orthologs)[4] are found in most mammals.
# Gene
FAS receptor is located on the long arm of chromosome 10 (10q24.1) in humans and on chromosome 19 in mice. The gene lies on the plus (Watson strand) and is 25,255 bases in length organised into nine protein encoding exons.
# Protein
Previous reports have identified as many as eight splice variants, which are translated into seven isoforms of the protein. Apoptosis-inducing Fas receptor is dubbed isoform 1 and is a type 1 transmembrane protein. Many of the other isoforms are rare haplotypes that are usually associated with a state of disease. However, two isoforms, the apoptosis-inducing membrane-bound form and the soluble form, are normal products whose production via alternative splicing is regulated by the cytotoxic RNA binding protein TIA1.[5]
The mature Fas protein has 319 amino acids, has a predicted molecular weight of 48 kiloDaltons and is divided into 3 domains: an extracellular domain, a transmembrane domain, and a cytoplasmic domain. The extracellular domain has 157 amino acids and is rich in cysteine residues. The transmembrane and cytoplasmic domains have 17 and 145 amino acids respectively. Exons 1 through 5 encode the extracelluar region. Exon 6 encodes the transmembrane region. Exons 7-9 encode the intracellular region.
# Function
Fas forms the death-inducing signaling complex (DISC) upon ligand binding. Membrane-anchored Fas ligand trimer on the surface of an adjacent cell causes oligomerization of Fas.
Recent studies which suggested the trimerization of Fas could not be validated. Other models suggested the oligomerization up to 5-7 Fas molecules in the DISC.[6]
This event is also mimicked by binding of an agonistic Fas antibody, though some evidence suggests that the apoptotic signal induced by the antibody is unreliable in the study of Fas signaling. To this end, several clever ways of trimerizing the antibody for in vitro research have been employed.
Upon ensuing death domain (DD) aggregation, the receptor complex is internalized via the cellular endosomal machinery. This allows the adaptor molecule FADD to bind the death domain of Fas through its own death domain.[7]
FADD also contains a death effector domain (DED) near its amino terminus,[8] which facilitates binding to the DED of FADD-like interleukin-1 beta-converting enzyme (FLICE), more commonly referred to as caspase-8. FLICE can then self-activate through proteolytic cleavage into p10 and p18 subunits, two each of which form the active heterotetramer enzyme. Active caspase-8 is then released from the DISC into the cytosol, where it cleaves other effector caspases, eventually leading to DNA degradation, membrane blebbing, and other hallmarks of apoptosis.
Recently, Fas has also been shown to promote tumor growth, since during tumor progression, it is frequently downregulated or cells are rendered apoptosis resistant. Cancer cells in general, regardless of their Fas apoptosis sensitivity, depend on constitutive activity of Fas. This is stimulated by cancer-produced Fas ligand for optimal growth.[9]
Although Fas has been shown to promote tumor growth in the above mouse models, analysis of the human cancer genomics database revealed that FAS is not significantly focally amplified across a dataset of 3131 tumors (FAS is not an oncogene), but is significantly focally deleted across the entire dataset of these 3131 tumors,[10] suggesting that FAS functions as a tumor suppressor in humans.
In cultured cells, FasL induces various types of cancer cell apoptosis through the Fas receptor. In AOM-DSS-induced colon carcinoma and MCA-induced sarcoma mouse models, it has been shown that Fas acts as a tumor suppressor.[11] Furthermore, the Fas receptor also mediates tumor-specific cytotoxic T lymphocyte (CTL) anti-tumor cytotoxicity.[12]
# Role in apoptosis
Some reports have suggested that the extrinsic Fas pathway is sufficient to induce complete apoptosis in certain cell types through DISC assembly and subsequent caspase-8 activation.
These cells are dubbed Type 1 cells and are characterized by the inability of anti-apoptotic members of the Bcl-2 family (namely Bcl-2 and Bcl-xL) to protect from Fas-mediated apoptosis.
Characterized Type 1 cells include H9, CH1, SKW6.4 and SW480, all of which are lymphocyte lineages except the latter, which is a colon adenocarcinoma lineage.
However, evidence for crosstalk between the extrinsic and intrinsic pathways exists in the Fas signal cascade.
In most cell types, caspase-8 catalyzes the cleavage of the pro-apoptotic BH3-only protein Bid into its truncated form, tBid. BH-3 only members of the Bcl-2 family exclusively engage anti-apoptotic members of the family (Bcl-2, Bcl-xL), allowing Bak and Bax to translocate to the outer mitochondrial membrane, thus permeabilizing it and facilitating release of pro-apoptotic proteins such as cytochrome c and Smac/DIABLO, an antagonist of inhibitors of apoptosis proteins (IAPs).
# Interactions
Fas receptor has been shown to interact with:
- Caspase 8,[13][14][15]
- Caspase 10,[16]
- CFLAR,[14][15]
- FADD,[13][14][17][18][19][20]
- Fas ligand,[13][21][22][23]
- PDCD6,[24] and
- Small ubiquitin-related modifier 1.[25][26] | https://www.wikidoc.org/index.php/Fas | |
5698e3bf3cc96ea0b75954a4fe2cb439dd56c8c7 | wikidoc | Renal fascia | Renal fascia
The kidney and the adipose capsule are enclosed in a sheath of fibrous tissue continuous with the subperitoneal fascia, and named the renal fascia (also known as Gerota's fascia after the Romanian anatomist Dimitrie Gerota).
At the lateral border of the kidney the renal fascia splits into an anterior and a posterior layer.
- The anterior layer is carried medialward in front of the kidney and its vessels, and is continuous over the aorta with the corresponding layer of the opposite side.
- The posterior layer extends medialward behind the kidney and blends with the fascia on the Quadratus lumborum and Psoas major, and through this fascia is attached to the vertebral column.
Above the suprarenal gland the two layers of the renal fascia fuse, and unite with the fascia of the diaphragm; below they remain separate, and are gradually lost in the subperitoneal fascia of the iliac fossa.
The renal fascia is connected to the fibrous tunic of the kidney by numerous trabeculæ, which traverse the adipose capsule, and are strongest near the lower end of the organ.
Behind the fascia renalis is a considerable quantity of fat, which constitutes the paranephric body.
The kidney is held in position partly through the attachment of the renal fascia and partly by the apposition of the neighboring viscera.
# Layers
The renal fascia relates to the other layers in the following manner (moving from innermost to outermost):
- renal cortex
- renal capsule
- perinephric fat (or "perirenal fat")
- renal fascia
- paranephric fat (or "pararenal fat")
- peritoneum (anteriorly), and transversalis fascia (posteriorly) | Renal fascia
Template:Infobox Anatomy
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
The kidney and the adipose capsule are enclosed in a sheath of fibrous tissue continuous with the subperitoneal fascia, and named the renal fascia (also known as Gerota's fascia after the Romanian anatomist Dimitrie Gerota).
At the lateral border of the kidney the renal fascia splits into an anterior and a posterior layer.
- The anterior layer is carried medialward in front of the kidney and its vessels, and is continuous over the aorta with the corresponding layer of the opposite side.
- The posterior layer extends medialward behind the kidney and blends with the fascia on the Quadratus lumborum and Psoas major, and through this fascia is attached to the vertebral column.
Above the suprarenal gland the two layers of the renal fascia fuse, and unite with the fascia of the diaphragm; below they remain separate, and are gradually lost in the subperitoneal fascia of the iliac fossa.
The renal fascia is connected to the fibrous tunic of the kidney by numerous trabeculæ, which traverse the adipose capsule, and are strongest near the lower end of the organ.
Behind the fascia renalis is a considerable quantity of fat, which constitutes the paranephric body.
The kidney is held in position partly through the attachment of the renal fascia and partly by the apposition of the neighboring viscera.
# Layers
The renal fascia relates to the other layers in the following manner (moving from innermost to outermost):
- renal cortex
- renal capsule
- perinephric fat (or "perirenal fat")
- renal fascia
- paranephric fat (or "pararenal fat")
- peritoneum (anteriorly), and transversalis fascia (posteriorly)
# External links
- Template:EMedicineDictionary
- Template:SUNYAnatomyLabs - "Posterior Abdominal Wall: The Retroperitoneal Fat and Suprarenal Glands"
- Template:SUNYAnatomyImage
- Template:WhoNamedIt
- Template:DartmouthHumanAnatomy
Template:Gray's
Template:Kidney
Template:Torso general
Template:Jb1
Template:WH
Template:WS | https://www.wikidoc.org/index.php/Fascia_renalis | |
6a66c2b0b9db4cb897ce08f9062afcfbd8ee45f5 | wikidoc | Fat necrosis | Fat necrosis
# Overview
Fat necrosis is a focal area of destruction of fat tissue resulting from abnormal release of activated lipases.
Injury to the pancreas (infection, toxins, viruses, trauma, ischemia) causes release of activated pancreatic enzymes which liquefy fat cell membranes. The released lipases split the triglyceride esters contained within the fat cells and these released fatty acids combine with calcium to form the grossly visible chalky white nodules characteristic of fat necrosis.
# Diagnostic Findings
## Mammogram
- Mammographic spectrum of appearances of fat necrosis ranges from the characteristically benign to the potentially malignant.
- Calcifications seen at mammography may be clear-cut, benign rings, rims, or coarse macrocalcifications or may manifest as suspicious pleomorphic or even "branching type" microcalcifications.
## Ultrasound
- Masses are most commonly solid, although they may be complex or cystic.
- Borders may be discrete or ill-defined.
- Posterior shadowing or enhancement may be present.
## MRI
- Signal follows that of fat: Bright on T1 with loss of signal of fat saturated images.
Images courtesy of RadsWiki
- Fat necrosis
- Fat necrosis
- Fat necrosis
- Fat necrosis
# Pathological Findings: Case #1
## Clinical Summary
A 37-year-old female with chronic renal failure that necessitated a renal transplant. Following transplantation, the patient developed a herpes simplex virus infection (HSV) in her nasal cavity, oral candidiasis, pneumonia, hematuria, pyuria, and gastrointestinal bleeding. Subsequently, the patient became septic and died.
## Autopsy Findings
Major findings at autopsy included extensive hemorrhagic bronchopneumonia (Pseudomonas aeruginosa) and multiple ulcers affecting the stomach and esophagus. There was also evidence of disseminated intravascular coagulation (DIC) with multiple hemorrhages present. Firm, whitish foci of necrotic tissue were found in the fat around the pancreas.
Images courtesy of Professor Peter Anderson DVM PhD and published with permission © PEIR, University of Alabama at Birmingham, Department of Pathology
- This gross photograph shows the intestines and omentum at autopsy. Note the small (5-15 mm in diameter) white nodules on the surface of the omental and mesenteric fat tissue (arrows).
- This gross photograph of the pancreas from this case shows white nodules (arrows) in the pancreas and the adjacent mesenteric fat tissue.
- This low-power photomicrograph of the pancreas from this case shows the fat tissue (1) surrounding the pancreas. Note the rim of inflammatory cells (arrows) and the blue areas in the fat adjacent to the pancreas (2).
- This high-power photomicrograph shows areas of inflammation (1) and fat necrosis (arrows) in the peripancreatic fat tissue (2) of the pancreas from this case.
- Another high-power photomicrograph shows blue discoloration in the fat tissue in the interlobular spaces (1) of the pancreas.
- A higher-power photomicrograph of the previous slide contains a small area of fat necrosis (1) in the upper right portion of the image. The fat necrosis is within the fat tissue that is normally found adjacent to the pancreas. The appearance of the pancreatic tissue in this area is somewhat disrupted due to autolysis (the pancreas autolyzes very rapidly after death) but there is some premortem necrosis as well.
- This is a higher-power photomicrograph of the fat necrosis involving the fat cells in the interlobular spaces (arrow) of the pancreas. Note the blue to purple staining of the calcium deposits within the fat cells.
- This high-power photomicrograph demonstrates fat necrosis in the interlobular spaces of the pancreas. Note the granular blue-staining calcium deposits (arrows) within the fat cells. The clear areas represent artifact caused by the "washing-out" of fat from cells during tissue processing for histology.
- This is another high-power photomicrograph demonstrating the calcification (arrows) seen in fat necrosis involving the interlobular spaces of the pancreas. | Fat necrosis
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Associate Editor-In-Chief: Cafer Zorkun, M.D., Ph.D. [2]
# Overview
Fat necrosis is a focal area of destruction of fat tissue resulting from abnormal release of activated lipases.[1] [2]
Injury to the pancreas (infection, toxins, viruses, trauma, ischemia) causes release of activated pancreatic enzymes which liquefy fat cell membranes. The released lipases split the triglyceride esters contained within the fat cells and these released fatty acids combine with calcium to form the grossly visible chalky white nodules characteristic of fat necrosis.
# Diagnostic Findings
## Mammogram
- Mammographic spectrum of appearances of fat necrosis ranges from the characteristically benign to the potentially malignant.
- Calcifications seen at mammography may be clear-cut, benign rings, rims, or coarse macrocalcifications or may manifest as suspicious pleomorphic or even "branching type" microcalcifications.
## Ultrasound
- Masses are most commonly solid, although they may be complex or cystic.
- Borders may be discrete or ill-defined.
- Posterior shadowing or enhancement may be present.
## MRI
- Signal follows that of fat: Bright on T1 with loss of signal of fat saturated images.
Images courtesy of RadsWiki
- Fat necrosis
- Fat necrosis
- Fat necrosis
- Fat necrosis
# Pathological Findings: Case #1
## Clinical Summary
A 37-year-old female with chronic renal failure that necessitated a renal transplant. Following transplantation, the patient developed a herpes simplex virus infection (HSV) in her nasal cavity, oral candidiasis, pneumonia, hematuria, pyuria, and gastrointestinal bleeding. Subsequently, the patient became septic and died.
## Autopsy Findings
Major findings at autopsy included extensive hemorrhagic bronchopneumonia (Pseudomonas aeruginosa) and multiple ulcers affecting the stomach and esophagus. There was also evidence of disseminated intravascular coagulation (DIC) with multiple hemorrhages present. Firm, whitish foci of necrotic tissue were found in the fat around the pancreas.
Images courtesy of Professor Peter Anderson DVM PhD and published with permission © PEIR, University of Alabama at Birmingham, Department of Pathology
- This gross photograph shows the intestines and omentum at autopsy. Note the small (5-15 mm in diameter) white nodules on the surface of the omental and mesenteric fat tissue (arrows).
- This gross photograph of the pancreas from this case shows white nodules (arrows) in the pancreas and the adjacent mesenteric fat tissue.
- This low-power photomicrograph of the pancreas from this case shows the fat tissue (1) surrounding the pancreas. Note the rim of inflammatory cells (arrows) and the blue areas in the fat adjacent to the pancreas (2).
- This high-power photomicrograph shows areas of inflammation (1) and fat necrosis (arrows) in the peripancreatic fat tissue (2) of the pancreas from this case.
- Another high-power photomicrograph shows blue discoloration in the fat tissue in the interlobular spaces (1) of the pancreas.
- A higher-power photomicrograph of the previous slide contains a small area of fat necrosis (1) in the upper right portion of the image. The fat necrosis is within the fat tissue that is normally found adjacent to the pancreas. The appearance of the pancreatic tissue in this area is somewhat disrupted due to autolysis (the pancreas autolyzes very rapidly after death) but there is some premortem necrosis as well.
- This is a higher-power photomicrograph of the fat necrosis involving the fat cells in the interlobular spaces (arrow) of the pancreas. Note the blue to purple staining of the calcium deposits within the fat cells.
- This high-power photomicrograph demonstrates fat necrosis in the interlobular spaces of the pancreas. Note the granular blue-staining calcium deposits (arrows) within the fat cells. The clear areas represent artifact caused by the "washing-out" of fat from cells during tissue processing for histology.
- This is another high-power photomicrograph demonstrating the calcification (arrows) seen in fat necrosis involving the interlobular spaces of the pancreas. | https://www.wikidoc.org/index.php/Fat_necrosis | |
56136273477c7041275f36ce557b94fa44c7f62d | wikidoc | Fate mapping | Fate mapping
Fate mapping is a technique that is used to show how a cell or tissue moves and what it will become during normal development. Fate mapping was developed by Walter Vogt as a means by which to trace the development of specific regions of the early embryo. To do this, Vogt used agar chips impregnated with vital dyes.
A fate map is a representation of the developmental history of each cell in the body of an adult organism. Thus, a fate map traces the products of each mitosis from the single-celled zygote to the multi-celled adult. The process of fate mapping was developed by Walter Vogt.
The fate map of vulval development in C. elegans has been completely characterized at a molecular level. In an adult C. elegans, the vulva is the egg-laying organ that consists of only 22 cells. The differentiation and division of these Px.p cells is dictated by the anchor cell through a morphogen gradient of LIN-3. Mapping each cell's fate was accomplished by studying mutants and through tissue grafts.
File:Celegansfatemap.jpg | Fate mapping
Fate mapping is a technique that is used to show how a cell or tissue moves and what it will become during normal development. Fate mapping was developed by Walter Vogt as a means by which to trace the development of specific regions of the early embryo. To do this, Vogt used agar chips impregnated with vital dyes.
A fate map is a representation of the developmental history of each cell in the body of an adult organism. Thus, a fate map traces the products of each mitosis from the single-celled zygote to the multi-celled adult. The process of fate mapping was developed by Walter Vogt.
The fate map of vulval development in C. elegans has been completely characterized at a molecular level. In an adult C. elegans, the vulva is the egg-laying organ that consists of only 22 cells. The differentiation and division of these Px.p cells is dictated by the anchor cell through a morphogen gradient of LIN-3. Mapping each cell's fate was accomplished by studying mutants and through tissue grafts.
File:Celegansfatemap.jpg
# External links
- http://worms.zoology.wisc.edu/frogs/gast/gast_fatemap.html
- Fate-Mapping Technique: Using Carbocyanine Dyes for Vital Labeling of Cells in Gastrula-Stage Mouse Embryos Cultured in Vitro
Template:WH
Template:WS | https://www.wikidoc.org/index.php/Fate_mapping | |
587f05a43f49b1f8ed0eb14262be116b4c32bc56 | wikidoc | Fatty streak | Fatty streak
Fatty streak, though composed of macrophage white blood cells, not fat, is the term generally given to the earliest stages of atheroma, as viewed at autopsy, looking at the inner surface of arteries, without magnification. It is not visible by current technologies in living humans, even by IVUS, the imaging technology with the highest spatial resolution for visualizing artery walls in vivo.
The fatty streak is the first grossly visible lesion in the development of atherosclerosis. It appears as an irregular off white to yellow-white discoloration near the luminal surface of the artery. Actually the streaks are not fat, but small collections of monocyte-derived macrophages located beneath the inner, endothelial layer of arteries. The fatty streak mainly consists of foamy appearing macrophage cells, sometimes with some additional T lymphocytes, aggregated platelets, localized smooth muscle cells, etc.
The macrophage cells, under a microscope, have a foamy-like appearance because of large collections of membrane bound vesicles within their cytoplasm. Since cholesterol within cells resides primarily within the cell membranes, the large accumulation of membranes results in an elevated local content of membrane bound cholesterol and other fats.
En-mass the foamy macrophages usually have an off white to yellow-white color and were named because they were thought to "look like" (gross, non-microscopic perspecitive) "streaks of fat" against the otherwise quite red/pink muscular tissue background forming the wall of arteries. | Fatty streak
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Fatty streak, though composed of macrophage white blood cells, not fat, is the term generally given to the earliest stages of atheroma, as viewed at autopsy, looking at the inner surface of arteries, without magnification. It is not visible by current technologies in living humans, even by IVUS, the imaging technology with the highest spatial resolution for visualizing artery walls in vivo.
The fatty streak is the first grossly visible lesion in the development of atherosclerosis. It appears as an irregular off white to yellow-white discoloration near the luminal surface of the artery. Actually the streaks are not fat, but small collections of monocyte-derived macrophages located beneath the inner, endothelial layer of arteries. The fatty streak mainly consists of foamy appearing macrophage cells, sometimes with some additional T lymphocytes, aggregated platelets, localized smooth muscle cells, etc.
The macrophage cells, under a microscope, have a foamy-like appearance because of large collections of membrane bound vesicles within their cytoplasm. Since cholesterol within cells resides primarily within the cell membranes, the large accumulation of membranes results in an elevated local content of membrane bound cholesterol and other fats.
En-mass the foamy macrophages usually have an off white to yellow-white color and were named because they were thought to "look like" (gross, non-microscopic perspecitive) "streaks of fat" against the otherwise quite red/pink muscular tissue background forming the wall of arteries. | https://www.wikidoc.org/index.php/Fatty_streak | |
130728b07cb3d77c17647b16bbd165a87726f364 | wikidoc | Femoral vein | Femoral vein
# Overview
In the human body, the femoral vein is a blood vessel that accompanies the femoral artery in the femoral sheath. It begins at the adductor canal (also known as Hunter's canal) and is a continuation of the popliteal vein. It ends at the inferior margin of the inguinal ligament, where it becomes the external iliac vein.
# Drainage
Several large veins drain into the femoral vein:
- popliteal vein
- profunda femoris vein
- great saphenous vein
# Clinical significance
Occlusion of the femoral vein can be life-threatening.
The practice of delivering recreational drugs intravenously using the femoral vein is relatively common amongst injecting drug users (IDUs).
# Use of the term superficial femoral vein
The term superficial femoral vein is not recognized as a legitimate anatomic term.
However, some specialist physicians (e.g. radiologists, vascular surgeons) use the term superficial femoral vein for the distal part of the femoral vein to:
- differentiate the femoral vein segments before and after the profunda femoris vein joins with it, and
- differentiate the distal segment of the femoral vein from the deep femoral vein (profunda femoris vein), which is paired with the profunda femoris artery.
Usage of this term is discouraged by many physicians because it leads to confusion among general medical practitioners.
The femoral vein is considered a deep vein, unlike the adjective superficial suggests and has led some physicians to falsely conclude it is a superficial vein, which has resulted in patients (with deep vein thrombosis) being denied efficacious thrombolytic therapy.
# Additional images
- Structures surrounding right hip-joint.
- Cross-section through the middle of the thigh.
- Femoral sheath laid open to show its three compartments.
- The femoral artery.
- The spermatic cord in the inguinal canal. | Femoral vein
Template:Infobox Vein
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
In the human body, the femoral vein is a blood vessel that accompanies the femoral artery in the femoral sheath. It begins at the adductor canal (also known as Hunter's canal) and is a continuation of the popliteal vein. It ends at the inferior margin of the inguinal ligament, where it becomes the external iliac vein.
# Drainage
Several large veins drain into the femoral vein:
- popliteal vein
- profunda femoris vein
- great saphenous vein
# Clinical significance
Occlusion of the femoral vein can be life-threatening.[1]
The practice of delivering recreational drugs intravenously using the femoral vein is relatively common amongst injecting drug users (IDUs).[2]
# Use of the term superficial femoral vein
The term superficial femoral vein is not recognized as a legitimate anatomic term.[3]
However, some specialist physicians (e.g. radiologists, vascular surgeons) use the term superficial femoral vein for the distal part of the femoral vein to:
- differentiate the femoral vein segments before and after the profunda femoris vein joins with it, and
- differentiate the distal segment of the femoral vein from the deep femoral vein (profunda femoris vein), which is paired with the profunda femoris artery.
Usage of this term is discouraged by many physicians because it leads to confusion among general medical practitioners.[1]
The femoral vein is considered a deep vein, unlike the adjective superficial suggests and has led some physicians to falsely conclude it is a superficial vein, which has resulted in patients (with deep vein thrombosis) being denied efficacious thrombolytic therapy.[3]
# Additional images
- Structures surrounding right hip-joint.
- Cross-section through the middle of the thigh.
- Femoral sheath laid open to show its three compartments.
- The femoral artery.
- The spermatic cord in the inguinal canal. | https://www.wikidoc.org/index.php/Femoral_vein | |
b117af9e72cfd8446502c1089fd089880f8497d3 | wikidoc | Fencamfamine | Fencamfamine
# Overview
Fencamfamine (Glucoenergan, Reactivan) is a stimulant which was developed in the 1960s as an appetite suppressant, but was later withdrawn for this application due to problems with dependence and abuse. It is around half the potency of dexamphetamine, and is prescribed at a dose of 10-60mg, although abusers of the drug tend to rapidly develop tolerance and escalate their dose. Reactivan is still rarely used for treating depressive day-time fatigue, lack of concentration and lethargy, particularly in individuals who have chronic medical conditions, as its favourable safety profile makes it the most suitable drug in some cases.
Legal Status: Schedule IV (USA)
# Pharmacology
Fencamfamine acts as an indirect dopamine agonist. It releases dopamine by a similar mechanism to amphetamines, but is 10x less potent than dexamphetamine at producing this effect. The main mechanism of action is instead inhibition of dopamine reuptake, more similar to that of methylphenidate. Also unlike amphetamines, fencamfamine does not inhibit the action of monoamine oxidase enzymes and so is somewhat safer. Some experiments also suggest a role for opioid receptors in the activity of fencamfamine, as low doses can cause paradoxical sedation, and some effects of the drug are blocked by naloxone.
# Side effects
Side effects include: dry mouth, loss of appetite, restlessness and tremor.
# Contraindications
Contraindications: should not be used in patients with heart disease, angina, glaucoma, thyrotoxicosis or in patients being treated with monoamine oxidase inhibitors. | Fencamfamine
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Fencamfamine (Glucoenergan, Reactivan) is a stimulant which was developed in the 1960s as an appetite suppressant, but was later withdrawn for this application due to problems with dependence and abuse. It is around half the potency of dexamphetamine, and is prescribed at a dose of 10-60mg, although abusers of the drug tend to rapidly develop tolerance and escalate their dose. Reactivan is still rarely used for treating depressive day-time fatigue, lack of concentration and lethargy, particularly in individuals who have chronic medical conditions, as its favourable safety profile makes it the most suitable drug in some cases.[1]
Legal Status: Schedule IV (USA)
# Pharmacology
Fencamfamine acts as an indirect dopamine agonist. It releases dopamine by a similar mechanism to amphetamines, but is 10x less potent than dexamphetamine at producing this effect. The main mechanism of action is instead inhibition of dopamine reuptake, more similar to that of methylphenidate. Also unlike amphetamines, fencamfamine does not inhibit the action of monoamine oxidase enzymes and so is somewhat safer.[2] Some experiments also suggest a role for opioid receptors in the activity of fencamfamine, as low doses can cause paradoxical sedation, and some effects of the drug are blocked by naloxone.[3]
# Side effects
Side effects include: dry mouth, loss of appetite, restlessness and tremor.
# Contraindications
Contraindications: should not be used in patients with heart disease, angina, glaucoma, thyrotoxicosis or in patients being treated with monoamine oxidase inhibitors. | https://www.wikidoc.org/index.php/Fencamfamin | |
095aeee9c7b3b05d71bce3e990316620f221bf30 | wikidoc | Fenfluramine | Fenfluramine
Fenfluramine is a drug that was part of the Fen-Phen anti-obesity medication (the other drug being phentermine). Also known as Pondimin, fenfluramine was introduced on the U.S. market in 1973. It is the racemic mixture of two enantiomers, dexfenfluramine and levofenfluramine. It is designed to increase the level of the neurotransmitter serotonin, a chemical that regulates mood, appetite and other functions. Fenfluramine causes the release of serotonin by disrupting vesicular storage of the neurotransmitter, and reversing serotonin transporter function. The end result is a feeling of fullness and loss of appetite.
The drug was withdrawn from the U.S. market in 1997 after reports of heart valve disease and pulmonary hypertension, including a condition known as cardiac fibrosis. After the US withdrawal of fenfluramine, it was also withdrawn from other markets around the world.
The distinctive valvular abnormality seen with fenfluramine is a thickening of the leaflet and chordae tendinae. Roth suggested a mechanism by which fenfluramine damaged the valves. Heart valves also have serotonin receptors, which regulate their growth. He reported that fenfluramine and its active metabolite norfenfluramine stimulated the serotonin receptors 5-hydroxytryptamine (5-HT). In particular norfenfluramine is a potent agonist (stimulant) of 5-HT2B receptors. These receptors are plentiful in human cardiac valves and appear to be essential for normal cardiac development. Roth suggested that the mechanism by which fenfluramine causes damage is through inappropriately stimulating the valve cells to divide. This valve damage is found in other drugs that act on 5-HT2B receptors. | Fenfluramine
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Fenfluramine is a drug that was part of the Fen-Phen anti-obesity medication (the other drug being phentermine). Also known as Pondimin, fenfluramine was introduced on the U.S. market in 1973. It is the racemic mixture of two enantiomers, dexfenfluramine and levofenfluramine. It is designed to increase the level of the neurotransmitter serotonin, a chemical that regulates mood, appetite and other functions. Fenfluramine causes the release of serotonin by disrupting vesicular storage of the neurotransmitter, and reversing serotonin transporter function.[1] The end result is a feeling of fullness and loss of appetite.
The drug was withdrawn from the U.S. market in 1997 after reports of heart valve disease and pulmonary hypertension, including a condition known as cardiac fibrosis. After the US withdrawal of fenfluramine, it was also withdrawn from other markets around the world.
The distinctive valvular abnormality seen with fenfluramine is a thickening of the leaflet and chordae tendinae. Roth[2] suggested a mechanism by which fenfluramine damaged the valves. Heart valves also have serotonin receptors, which regulate their growth. He reported that fenfluramine and its active metabolite norfenfluramine stimulated the serotonin receptors 5-hydroxytryptamine (5-HT). In particular norfenfluramine is a potent agonist (stimulant) of 5-HT2B receptors. These receptors are plentiful in human cardiac valves and appear to be essential for normal cardiac development. Roth suggested that the mechanism by which fenfluramine causes damage is through inappropriately stimulating the valve cells to divide. This valve damage is found in other drugs that act on 5-HT2B receptors. | https://www.wikidoc.org/index.php/Fenfluramine | |
badee22cac8c923606cdc7f6e3cae776b9ece80b | wikidoc | Fermi energy | Fermi energy
The Fermi energy is a concept in quantum mechanics usually referring to the energy of the highest occupied quantum state in a system of fermions at absolute zero temperature. This article requires a basic knowledge of quantum mechanics.
# Introduction
## Context
In quantum mechanics, a group of particles known as fermions (for example, electrons, protons and neutrons are fermions) obey the Pauli exclusion principle, which states that no two fermions can occupy the same quantum state. The states are labeled by a set of quantum numbers. In a system containing many fermions (like electrons in a metal) each fermion will have a different set of quantum numbers. To determine the lowest energy a system of fermions can have, we first group the states in sets with equal energy and order these sets by increasing energy. Starting with an empty system, we then add particles one at a time, consecutively filling up the unoccupied quantum states with lowest-energy. When all the particles have been put in, the Fermi energy is the energy of the highest occupied state.
What this means is that even if we have extracted all possible energy from a metal by cooling it down to near absolute zero temperature (0 kelvins), the electrons in the metal are still moving around, the fastest ones would be moving at a velocity that corresponds to a kinetic energy equal to the Fermi energy. This is the Fermi velocity. The Fermi energy is one of the important concepts of condensed matter physics. It is used, for example, to describe metals, insulators, and semiconductors. It is a very important quantity in the physics of superconductors, in the physics of quantum liquids like low temperature helium (both normal 3He and superfluid 4He), and it is quite important to nuclear physics and to understand the stability of white dwarf stars against gravitational collapse.
## Advanced context
The Fermi energy (EF) of a system of non-interacting fermions is the increase in the ground state energy when exactly one particle is added to the system. It can also be interpreted as the maximum energy of an individual fermion in this ground state. The chemical potential at zero temperature is equal to the Fermi energy.
# Illustration of the concept for a one dimensional square well
The one dimensional infinite square well is a model for a one dimensional box. It is a standard model-system in quantum mechanics for which the solution for a single particle is well known. The levels are labeled by a single quantum number n and the energies are given by
Suppose now that instead of one particle in this box we have N particles in the box and that these particles are fermions with spin 1/2. Then only two particles can have the same energy i.e. two particles can have the energy of E_1=\frac{\hbar^2 \pi^2}{2 m L^2}, or two particles can have energy E_2=4 E_1 and so forth. The reason that two particles can have the same energy is that a spin-1/2 particle can have a spin of 1/2 (spin up) or a spin of -1/2 (spin down), leading to two states for each energy level. When we look at the total energy of this system, the configuration for which the total energy is lowest (the ground state), is the configuration where all the energy levels up to n=N/2 are occupied and all the higher levels are empty. The Fermi energy is therefore
# The three-dimensional case
The three-dimensional isotropic case is known as the fermi sphere.
Let us now consider a three-dimensional cubical box that has a side length L (see infinite square well). This turns out to be a very good approximation for describing electrons in a metal.
The states are now labeled by three quantum numbers nx, ny, and nz. The single particle energies are
There are multiple states with the same energy, for example E_{100}=E_{010}=E_{001}. Now let's put N non-interacting fermions of spin 1/2 into this box. To calculate the Fermi energy, we look at the case for N is large.
If we introduce a vector \vec{n}=\{n_x,n_y,n_z\} then each quantum state corresponds to a point in 'n-space' with Energy
The number of states with energy less than Ef is equal to the number of states that lie within a sphere of radius |\vec{n}_f| in the region of n-space where nx, ny, nz are positive. In the ground state this number equals the number of fermions in the system.
the factor of two is once again because there are two spin states, the factor of 1/8 is because only 1/8 of the sphere lies in the region where all n are positive.
We find
so the Fermi energy is given by
Which results in a relationship between the fermi energy and the number of particles per volume (when we replace L2 with V2/3):
The total energy of a fermi sphere of N_0 fermions is given by
# Typical fermi energies
## White dwarfs
Stars known as White dwarfs have mass comparable to our Sun, but have a radius about 100 times smaller. The high densities means that the electrons are no longer bound to single nuclei and instead form a degenerate electron gas. The number density of electrons in a White dwarf are on the order of 1036 electrons/m3. This means their fermi energy is:
## Nucleus
Another typical example is that of the particles in a nucleus of an atom. The radius of the nucleus is roughly:
The number density of nucleons in a nucleus is therefore:
Now since the fermi energy only applies to fermions of the same type, one must divide this density in two. This is because the presence of neutrons does not affect the fermi energy of the protons in the nucleus, and vice versa.
So the fermi energy of a nucleus is about:
The radius of the nucleus admits deviations around the value mentioned above, so a typical value for the fermi energy usually given is 38 MeV.
# Fermi level
The Fermi level is the highest occupied energy level at absolute zero, that is, all energy levels up to the Fermi level are occupied by electrons. Since fermions cannot exist in identical energy states (see the exclusion principle), at absolute zero, electrons pack into the lowest available energy states and build up a "Fermi sea" of electron energy states. In this state (at 0 K), the average energy of an electron is given by:
where E_f is the Fermi energy.
The Fermi momentum is the momentum of fermions at the Fermi surface. The Fermi momentum is given by:
where m_e is the mass of the electron.
This concept is usually applied in the case of dispersion relations between the energy and momentum that do not depend on the direction. In more general cases, one must consider the Fermi energy.
The Fermi velocity is the velocity of fermions at the Fermi surface. It is defined by:
where m_e is the mass of the electron.
Below the Fermi temperature, a substance gradually expresses more and more quantum effects of cooling. The Fermi temperature is defined by:
where k is the Boltzmann constant.
# Quantum mechanics
According to quantum mechanics, fermions -- particles with a half-integer spin, usually 1/2, such as electrons -- follow the Pauli exclusion principle, which states that multiple particles may not occupy the same quantum state. Consequently, fermions obey Fermi-Dirac statistics. The ground state of a non-interacting fermion system is constructed by starting with an empty system and adding particles one at a time, consecutively filling up the lowest-energy unoccupied quantum states. When the desired number of particles has been reached, the Fermi energy is the energy of the highest occupied molecular orbital (HOMO). Within conductive materials, this is equivalent to the lowest unoccupied molecular orbital (LUMO); however, within other materials there will be a significant gap between the HOMO and LUMO on the order of 2-3 eV.
# Pinning of Fermi level
When the energy density of surface states is very high (>1012/cm2), the position of the Fermi level is determined by the neutral level of the Surface states and becomes independent of Work Function variations.
# Free electron gas
In the free electron gas, the quantum mechanical version of an ideal gas of fermions, the quantum states can be labeled according to their momentum. Something similar can be done for periodic systems, such as electrons moving in the atomic lattice of a metal, using something called the "quasi-momentum" or "crystal momentum" (see Bloch wave). In either case, the Fermi energy states reside on a surface in momentum space known as the Fermi surface. For the free electron gas, the Fermi surface is the surface of a sphere; for periodic systems, it generally has a contorted shape (see Brillouin zones). The volume enclosed by the Fermi surface defines the number of electrons in the system, and the topology is directly related to the transport properties of metals, such as electrical conductivity. The study of the Fermi surface is sometimes called Fermiology. The Fermi surfaces of most metals are well studied both theoretically and experimentally.
The Fermi energy of the free electron gas is related to the chemical potential by the equation
where EF is the Fermi energy, k is the Boltzmann constant and T is temperature. Hence, the chemical potential is approximately equal to the Fermi energy at temperatures of much less than the characteristic Fermi temperature EF/k. The characteristic temperature is on the order of 105 K for a metal, hence at room temperature (300 K), the Fermi energy and chemical potential are essentially equivalent. This is significant since it is the chemical potential, not the Fermi energy, which appears in Fermi-Dirac statistics. | Fermi energy
The Fermi energy is a concept in quantum mechanics usually referring to the energy of the highest occupied quantum state in a system of fermions at absolute zero temperature. This article requires a basic knowledge of quantum mechanics.
# Introduction
## Context
In quantum mechanics, a group of particles known as fermions (for example, electrons, protons and neutrons are fermions) obey the Pauli exclusion principle, which states that no two fermions can occupy the same quantum state. The states are labeled by a set of quantum numbers. In a system containing many fermions (like electrons in a metal) each fermion will have a different set of quantum numbers. To determine the lowest energy a system of fermions can have, we first group the states in sets with equal energy and order these sets by increasing energy. Starting with an empty system, we then add particles one at a time, consecutively filling up the unoccupied quantum states with lowest-energy. When all the particles have been put in, the Fermi energy is the energy of the highest occupied state.
What this means is that even if we have extracted all possible energy from a metal by cooling it down to near absolute zero temperature (0 kelvins), the electrons in the metal are still moving around, the fastest ones would be moving at a velocity that corresponds to a kinetic energy equal to the Fermi energy. This is the Fermi velocity. The Fermi energy is one of the important concepts of condensed matter physics. It is used, for example, to describe metals, insulators, and semiconductors. It is a very important quantity in the physics of superconductors, in the physics of quantum liquids like low temperature helium (both normal 3He and superfluid 4He), and it is quite important to nuclear physics and to understand the stability of white dwarf stars against gravitational collapse.
## Advanced context
The Fermi energy (EF) of a system of non-interacting fermions is the increase in the ground state energy when exactly one particle is added to the system. It can also be interpreted as the maximum energy of an individual fermion in this ground state. The chemical potential at zero temperature is equal to the Fermi energy.
# Illustration of the concept for a one dimensional square well
The one dimensional infinite square well is a model for a one dimensional box. It is a standard model-system in quantum mechanics for which the solution for a single particle is well known. The levels are labeled by a single quantum number n and the energies are given by
Suppose now that instead of one particle in this box we have N particles in the box and that these particles are fermions with spin 1/2. Then only two particles can have the same energy i.e. two particles can have the energy of <math>E_1=\frac{\hbar^2 \pi^2}{2 m L^2}</math>, or two particles can have energy <math>E_2=4 E_1</math> and so forth. The reason that two particles can have the same energy is that a spin-1/2 particle can have a spin of 1/2 (spin up) or a spin of -1/2 (spin down), leading to two states for each energy level. When we look at the total energy of this system, the configuration for which the total energy is lowest (the ground state), is the configuration where all the energy levels up to n=N/2 are occupied and all the higher levels are empty. The Fermi energy is therefore
# The three-dimensional case
The three-dimensional isotropic case is known as the fermi sphere.
Let us now consider a three-dimensional cubical box that has a side length L (see infinite square well). This turns out to be a very good approximation for describing electrons in a metal.
The states are now labeled by three quantum numbers nx, ny, and nz. The single particle energies are
There are multiple states with the same energy, for example <math>E_{100}=E_{010}=E_{001}</math>. Now let's put N non-interacting fermions of spin 1/2 into this box. To calculate the Fermi energy, we look at the case for N is large.
If we introduce a vector <math>\vec{n}=\{n_x,n_y,n_z\}</math> then each quantum state corresponds to a point in 'n-space' with Energy
The number of states with energy less than Ef is equal to the number of states that lie within a sphere of radius <math>|\vec{n}_f|</math> in the region of n-space where nx, ny, nz are positive. In the ground state this number equals the number of fermions in the system.
the factor of two is once again because there are two spin states, the factor of 1/8 is because only 1/8 of the sphere lies in the region where all n are positive.
We find
so the Fermi energy is given by
Which results in a relationship between the fermi energy and the number of particles per volume (when we replace L2 with V2/3):
The total energy of a fermi sphere of <math>N_0</math> fermions is given by
# Typical fermi energies
## White dwarfs
Stars known as White dwarfs have mass comparable to our Sun, but have a radius about 100 times smaller. The high densities means that the electrons are no longer bound to single nuclei and instead form a degenerate electron gas. The number density of electrons in a White dwarf are on the order of 1036 electrons/m3. This means their fermi energy is:
## Nucleus
Another typical example is that of the particles in a nucleus of an atom. The radius of the nucleus is roughly:
The number density of nucleons in a nucleus is therefore:
Now since the fermi energy only applies to fermions of the same type, one must divide this density in two. This is because the presence of neutrons does not affect the fermi energy of the protons in the nucleus, and vice versa.
So the fermi energy of a nucleus is about:
The radius of the nucleus admits deviations around the value mentioned above, so a typical value for the fermi energy usually given is 38 MeV.
# Fermi level
The Fermi level is the highest occupied energy level at absolute zero, that is, all energy levels up to the Fermi level are occupied by electrons. Since fermions cannot exist in identical energy states (see the exclusion principle), at absolute zero, electrons pack into the lowest available energy states and build up a "Fermi sea" of electron energy states. [1] In this state (at 0 K), the average energy of an electron is given by:
where <math> E_f </math> is the Fermi energy.
The Fermi momentum is the momentum of fermions at the Fermi surface. The Fermi momentum is given by:
where <math> m_e </math> is the mass of the electron.
This concept is usually applied in the case of dispersion relations between the energy and momentum that do not depend on the direction. In more general cases, one must consider the Fermi energy.
The Fermi velocity is the velocity of fermions at the Fermi surface. It is defined by:
where <math> m_e </math> is the mass of the electron.
Below the Fermi temperature, a substance gradually expresses more and more quantum effects of cooling. The Fermi temperature is defined by:
where k is the Boltzmann constant.
# Quantum mechanics
According to quantum mechanics, fermions -- particles with a half-integer spin, usually 1/2, such as electrons -- follow the Pauli exclusion principle, which states that multiple particles may not occupy the same quantum state. Consequently, fermions obey Fermi-Dirac statistics. The ground state of a non-interacting fermion system is constructed by starting with an empty system and adding particles one at a time, consecutively filling up the lowest-energy unoccupied quantum states. When the desired number of particles has been reached, the Fermi energy is the energy of the highest occupied molecular orbital (HOMO). Within conductive materials, this is equivalent to the lowest unoccupied molecular orbital (LUMO); however, within other materials there will be a significant gap between the HOMO and LUMO on the order of 2-3 eV.
# Pinning of Fermi level
When the energy density of surface states is very high (>1012/cm2), the position of the Fermi level is determined by the neutral level of the Surface states [2] and becomes independent of Work Function [3] variations.
# Free electron gas
In the free electron gas, the quantum mechanical version of an ideal gas of fermions, the quantum states can be labeled according to their momentum. Something similar can be done for periodic systems, such as electrons moving in the atomic lattice of a metal, using something called the "quasi-momentum" or "crystal momentum" (see Bloch wave). In either case, the Fermi energy states reside on a surface in momentum space known as the Fermi surface. For the free electron gas, the Fermi surface is the surface of a sphere; for periodic systems, it generally has a contorted shape (see Brillouin zones). The volume enclosed by the Fermi surface defines the number of electrons in the system, and the topology is directly related to the transport properties of metals, such as electrical conductivity. The study of the Fermi surface is sometimes called Fermiology. The Fermi surfaces of most metals are well studied both theoretically and experimentally.
The Fermi energy of the free electron gas is related to the chemical potential by the equation
where EF is the Fermi energy, k is the Boltzmann constant and T is temperature. Hence, the chemical potential is approximately equal to the Fermi energy at temperatures of much less than the characteristic Fermi temperature EF/k. The characteristic temperature is on the order of 105 K for a metal, hence at room temperature (300 K), the Fermi energy and chemical potential are essentially equivalent. This is significant since it is the chemical potential, not the Fermi energy, which appears in Fermi-Dirac statistics. | https://www.wikidoc.org/index.php/Fermi_energy | |
4592cac68311d6ac503d3d317e0cff72bb3108eb | wikidoc | Ferric oxide | Ferric oxide
# Overview
Iron(III) oxide or ferric oxide is the inorganic compound with the formula Fe2O3. It is one of the three main oxides of iron, the other two being iron(II) oxide (FeO), which is rare, and iron(II,III) oxide (Fe3O4), which also occurs naturally as the mineral magnetite. As the mineral known as hematite, Fe2O3 is the main source of iron for the steel industry. Fe2O3 is ferromagnetic, dark red, and readily attacked by acids. Iron(III) oxide is often called rust, and to some extent this label is useful, because rust shares several properties and has a similar composition. To a chemist, rust is considered an ill-defined material, described as hydrated ferric oxide.
# Structure
Fe2O3 can be obtained in various polymorphs. In the main ones, α and γ, iron adopts octahedral coordination geometry. That is, each Fe center is bound to six oxygen ligands.
## Alpha phase
α-Fe2O3 has the rhombohedral, corundum (α-Al2O3) structure and is the most common form. It occurs naturally as the mineral hematite which is mined as the main ore of iron. It is antiferromagnetic below ~260 K (Morin transition temperature), and exhibits weak ferromagnetism between 260 K and the Néel temperature, 950 K. It is easy to prepare using both thermal decomposition and precipitation in the liquid phase. Its magnetic properties are dependent on many factors, e.g. pressure, particle size, and magnetic field intensity.
## Gamma phase
γ-Fe2O3 has a cubic structure. It is metastable and converted from the alpha phase at high temperatures. It occurs naturally as the mineral maghemite. It is ferromagnetic and finds application in recording tapes, although ultrafine particles smaller than 10 nanometers are superparamagnetic. It can be prepared by thermal dehydratation of gamma iron(III) oxide-hydroxide, careful oxidation of iron(II,III) oxide. Another method involves the careful oxidation of Fe3O4. The ultrafine particles can be prepared by thermal decomposition of iron(III) oxalate.
## Other phases
Several other phases have been identified or claimed. The β-phase is cubic body centered (space group Ia3), metastable, and at temperatures above 500 (930 ) converts to alpha phase. It can be prepared by reduction of hematite by carbon, pyrolysis of iron(III) chloride solution, or thermal decomposition of iron(III) sulfate. The epsilon phase is rhombic, and shows properties intermediate between alpha and gamma, and may have useful magnetic properties. Preparation of the pure epsilon phase has proven very challenging due to contamination with alpha and gamma phases. Material with a high proportion of epsilon phase can be prepared by thermal transformation of the gamma phase. This phase is also metastable, transforming to the alpha phase at between 500 (Expression error: Unexpected round operator. ). Can also be prepared by oxidation of iron in an electric arc or by sol-gel precipitation from iron(III) nitrate. Additionally at high pressure an amorphous form is claimed. Recent research has revealed epsilon iron(III) oxide in ancient Chinese Jian ceramic glazes, which may provide insight into ways to produce that form in the lab.
# Hydrated iron(III) oxides
Several hydrates of Iron(III) oxide exists.
When alkali is added to solutions of soluble Fe(III) salts, a red-brown gelatinous precipitate forms. This is not Fe(OH)3, but Fe2O3·H2O (also written as Fe(O)OH).
Several forms of the hydrated oxide of Fe(III) exist as well. The red lepidocrocite γ-Fe(O)OH, occurs on the outside of rusticles, and the orange goethite, which occurs internally in rusticles.
When Fe2O3·H2O is heated, it loses its water of hydration. Further heating at 1670 K converts Fe2O3 to black Fe3O4 (FeIIFeIII2O4), which is known as the mineral magnetite.
Fe(O)OH is soluble in acids, giving 3+. In concentrated aqueous alkali, Fe2O3 gives 3−.
# Reactions
The most important reaction is its carbothermal reduction, which gives iron used in steel-making:
Another redox reaction is the extremely exothermic thermite reaction with aluminium.
This process is used to weld thick metals such as rails of train tracks by using a ceramic container to funnel the molten iron in between two sections of rail. Thermite is also used in weapons and making small-scale cast-iron sculptures and tools.
Partial reduction with hydrogen at about 400 °C gives magnetite, a black magnetic material that contains both Fe(III) and Fe(II):
Iron(III) oxide is insoluble in water but dissolves readily in strong acid, e.g. hydrochloric and sulfuric acids. It also dissolves well in solutions of the chelating agents such as EDTA and oxalic acid.
Heating iron(III) oxides with other metal oxides or carbonates yields materials known as ferrates:
# Preparation
Iron(III) oxide is a product of the oxidation of iron. It can be prepared in the laboratory by electrolyzing a solution of sodium bicarbonate, an inert electrolyte, with an iron anode:
The resulting hydrated iron(III) oxide, written here as Fe(O)OH, dehydrates around 200 °C.
It can also be prepared by the thermal decomposition of iron(III) hydroxide under temperature above 200 °C.
# Uses
## Iron industry
The overwhelming application of iron(III) oxide is as the feedstock of the steel and iron industries, e.g. the production of iron, steel, and many alloys.
## Polishing
A very fine powder of ferric oxide is known as "jeweler's rouge", "red rouge", or simply rouge. It is used to put the final polish on metallic jewelry and lenses, and historically as a cosmetic. Rouge cuts more slowly than some modern polishes, such as cerium(IV) oxide, but is still used in optics fabrication and by jewelers for the superior finish it can produce. When polishing gold, the rouge slightly stains the gold, which contributes to the appearance of the finished piece. Rouge is sold as a powder, paste, laced on polishing cloths, or solid bar (with a wax or grease binder). Other polishing compounds are also often called "rouge", even when they do not contain iron oxide. Jewelers remove the residual rouge on jewelry by use of ultrasonic cleaning. Products sold as "stropping compound" are often applied to a leather strop to assist in getting a razor edge on knives, straight razors, or any other edged tool.
## Pigment
Iron(III) oxide is also used as a pigment, under names "Pigment Brown 6", "Pigment Brown 7", and "Pigment Red 101". Some of them, e.g. Pigment Red 101 and Pigment Brown 6, are Food and Drug Administration (FDA)-approved for use in cosmetics. Iron oxides are used as pigments in dental composites alongside titanium oxides.
Hematite is the characteristic component of the Swedish paint color Falu red.
## Magnetic recording
Iron(III) oxide was the most common magnetic particle used in all types of magnetic storage and recording media, including magnetic disks (for data storage) and magnetic tape (used in audio and video recording as well as data storage).
However, modern magnetic storage media - in particular, the hard disk drives - use more advanced thin film technology, which may consist of a stack of 15 layers or more.
## Photocatalyst
α-Fe2O3 has been studied as a photoanode for the water-splitting reaction for over 25 years.
## Medicine
A mixture of zinc oxide with about 0.5% iron(III) oxide is called calamine, which is the active ingredient of calamine lotion. | Ferric oxide
Template:Chembox new
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Iron(III) oxide or ferric oxide is the inorganic compound with the formula Fe2O3. It is one of the three main oxides of iron, the other two being iron(II) oxide (FeO), which is rare, and iron(II,III) oxide (Fe3O4), which also occurs naturally as the mineral magnetite. As the mineral known as hematite, Fe2O3 is the main source of iron for the steel industry. Fe2O3 is ferromagnetic, dark red, and readily attacked by acids. Iron(III) oxide is often called rust, and to some extent this label is useful, because rust shares several properties and has a similar composition. To a chemist, rust is considered an ill-defined material, described as hydrated ferric oxide.
# Structure
Fe2O3 can be obtained in various polymorphs. In the main ones, α and γ, iron adopts octahedral coordination geometry. That is, each Fe center is bound to six oxygen ligands.
## Alpha phase
α-Fe2O3 has the rhombohedral, corundum (α-Al2O3) structure and is the most common form. It occurs naturally as the mineral hematite which is mined as the main ore of iron. It is antiferromagnetic below ~260 K (Morin transition temperature), and exhibits weak ferromagnetism between 260 K and the Néel temperature, 950 K.[1] It is easy to prepare using both thermal decomposition and precipitation in the liquid phase. Its magnetic properties are dependent on many factors, e.g. pressure, particle size, and magnetic field intensity.
## Gamma phase
γ-Fe2O3 has a cubic structure. It is metastable and converted from the alpha phase at high temperatures. It occurs naturally as the mineral maghemite. It is ferromagnetic and finds application in recording tapes,[2] although ultrafine particles smaller than 10 nanometers are superparamagnetic. It can be prepared by thermal dehydratation of gamma iron(III) oxide-hydroxide, careful oxidation of iron(II,III) oxide. Another method involves the careful oxidation of Fe3O4.[2] The ultrafine particles can be prepared by thermal decomposition of iron(III) oxalate.
## Other phases
Several other phases have been identified or claimed. The β-phase is cubic body centered (space group Ia3), metastable, and at temperatures above 500 (930 ) converts to alpha phase. It can be prepared by reduction of hematite by carbon, pyrolysis of iron(III) chloride solution, or thermal decomposition of iron(III) sulfate. The epsilon phase is rhombic, and shows properties intermediate between alpha and gamma, and may have useful magnetic properties. Preparation of the pure epsilon phase has proven very challenging due to contamination with alpha and gamma phases. Material with a high proportion of epsilon phase can be prepared by thermal transformation of the gamma phase. This phase is also metastable, transforming to the alpha phase at between 500 (Expression error: Unexpected round operator. ). Can also be prepared by oxidation of iron in an electric arc or by sol-gel precipitation from iron(III) nitrate.[citation needed] Additionally at high pressure an amorphous form is claimed.[3] Recent research has revealed epsilon iron(III) oxide in ancient Chinese Jian ceramic glazes, which may provide insight into ways to produce that form in the lab. [4]
# Hydrated iron(III) oxides
Several hydrates of Iron(III) oxide exists.
When alkali is added to solutions of soluble Fe(III) salts, a red-brown gelatinous precipitate forms. This is not Fe(OH)3, but Fe2O3·H2O (also written as Fe(O)OH).
Several forms of the hydrated oxide of Fe(III) exist as well. The red lepidocrocite γ-Fe(O)OH, occurs on the outside of rusticles, and the orange goethite, which occurs internally in rusticles.
When Fe2O3·H2O is heated, it loses its water of hydration. Further heating at 1670 K converts Fe2O3 to black Fe3O4 (FeIIFeIII2O4), which is known as the mineral magnetite.
Fe(O)OH is soluble in acids, giving [Fe(OH2)6]3+. In concentrated aqueous alkali, Fe2O3 gives [Fe(OH)6]3−.[2]
# Reactions
The most important reaction is its carbothermal reduction, which gives iron used in steel-making:
Another redox reaction is the extremely exothermic thermite reaction with aluminium.[5]
This process is used to weld thick metals such as rails of train tracks by using a ceramic container to funnel the molten iron in between two sections of rail. Thermite is also used in weapons and making small-scale cast-iron sculptures and tools.
Partial reduction with hydrogen at about 400 °C gives magnetite, a black magnetic material that contains both Fe(III) and Fe(II):[6]
Iron(III) oxide is insoluble in water but dissolves readily in strong acid, e.g. hydrochloric and sulfuric acids. It also dissolves well in solutions of the chelating agents such as EDTA and oxalic acid.
Heating iron(III) oxides with other metal oxides or carbonates yields materials known as ferrates:[6]
# Preparation
Iron(III) oxide is a product of the oxidation of iron. It can be prepared in the laboratory by electrolyzing a solution of sodium bicarbonate, an inert electrolyte, with an iron anode:
The resulting hydrated iron(III) oxide, written here as Fe(O)OH, dehydrates around 200 °C.[6][7]
It can also be prepared by the thermal decomposition of iron(III) hydroxide under temperature above 200 °C.
# Uses
## Iron industry
The overwhelming application of iron(III) oxide is as the feedstock of the steel and iron industries, e.g. the production of iron, steel, and many alloys.[7]
## Polishing
A very fine powder of ferric oxide is known as "jeweler's rouge", "red rouge", or simply rouge. It is used to put the final polish on metallic jewelry and lenses, and historically as a cosmetic. Rouge cuts more slowly than some modern polishes, such as cerium(IV) oxide, but is still used in optics fabrication and by jewelers for the superior finish it can produce. When polishing gold, the rouge slightly stains the gold, which contributes to the appearance of the finished piece. Rouge is sold as a powder, paste, laced on polishing cloths, or solid bar (with a wax or grease binder). Other polishing compounds are also often called "rouge", even when they do not contain iron oxide. Jewelers remove the residual rouge on jewelry by use of ultrasonic cleaning. Products sold as "stropping compound" are often applied to a leather strop to assist in getting a razor edge on knives, straight razors, or any other edged tool.
## Pigment
Iron(III) oxide is also used as a pigment, under names "Pigment Brown 6", "Pigment Brown 7", and "Pigment Red 101".[9] Some of them, e.g. Pigment Red 101 and Pigment Brown 6, are Food and Drug Administration (FDA)-approved for use in cosmetics. Iron oxides are used as pigments in dental composites alongside titanium oxides.[10]
Hematite is the characteristic component of the Swedish paint color Falu red.
## Magnetic recording
Iron(III) oxide was the most common magnetic particle used in all types of magnetic storage and recording media, including magnetic disks (for data storage) and magnetic tape (used in audio and video recording as well as data storage).
However, modern magnetic storage media - in particular, the hard disk drives - use more advanced thin film technology, which may consist of a stack of 15 layers or more. [11]
## Photocatalyst
α-Fe2O3 has been studied as a photoanode for the water-splitting reaction for over 25 years.[12]
## Medicine
A mixture of zinc oxide with about 0.5% iron(III) oxide is called calamine, which is the active ingredient of calamine lotion. | https://www.wikidoc.org/index.php/Ferric_oxide | |
69d4142c574617cdb24e5e4e5765a5da18172dc0 | wikidoc | Ferrihydrite | Ferrihydrite
Ferrihydrite is a ubiquitous iron oxyhydroxide mineral. Its chemical formula is generally presented as Fe5HO84H2O, also written as 5Fe2O39H2O or as Fe2O32FeOOH2.6H2O . It is found throughout soil and water systems and is important to many industrial applications . It can even be found within many living organisms, including humans In particular, it is found in the iron core of the ferritin protein, with serves as an intra-cellular iron storage.
Two types of material are commonly called ferrihydrite: 2-line ferrihydrite (sometimes termed protoferrihydrite) and 6-line ferrihydrite. The distinction refers to the number of X-ray diffraction lines in their respective X-ray patterns. While 6-line ferrihydrite has been classified as a mineral by the IMA since 1973 , its structure is still a subject of debate. The less crystalline 2-line ferrihydrite, on the other hand, is not considered a mineral. Compared to most minerals, both 2-line and 6-line ferrihydrite show very broad diffraction lines.
Ferrihydrite only exists as a nanomaterial, showing crystals 2-4 nanometers wide for 2-line ferrihydrite and 5-6 nanometers wide for 6-line ferrihydrite .
With its high surface area per volume , ferrihydrite is a very reactive mineral. It can interact, either by surface adsorption or by co-precipitation, with a number of environmentally important chemical species, including arsenic, heavy metals like lead or mercury, phosphate, as well as many organic molecules.
Ferrihydrite is a metastable mineral. It is known to be a precursor of more crystalline minerals like hematite and goethite . | Ferrihydrite
Ferrihydrite is a ubiquitous iron oxyhydroxide mineral. Its chemical formula is generally presented as Fe5HO8•4H2O, also written as 5Fe2O3•9H2O or as Fe2O3•2FeOOH•2.6H2O [1]. It is found throughout soil and water systems [2] and is important to many industrial applications [3] [4]. It can even be found within many living organisms, including humans[5] In particular, it is found in the iron core of the ferritin protein, with serves as an intra-cellular iron storage.
Two types of material are commonly called ferrihydrite: 2-line ferrihydrite (sometimes termed protoferrihydrite) and 6-line ferrihydrite. The distinction refers to the number of X-ray diffraction lines in their respective X-ray patterns. While 6-line ferrihydrite has been classified as a mineral by the IMA since 1973 [6] [7], its structure is still a subject of debate. The less crystalline 2-line ferrihydrite, on the other hand, is not considered a mineral. Compared to most minerals, both 2-line and 6-line ferrihydrite show very broad diffraction lines.
Ferrihydrite only exists as a nanomaterial, showing crystals 2-4 nanometers wide for 2-line ferrihydrite and 5-6 nanometers wide for 6-line ferrihydrite[8] [9] [10].
With its high surface area per volume [11], ferrihydrite is a very reactive mineral. It can interact, either by surface adsorption or by co-precipitation, with a number of environmentally important chemical species, including arsenic, heavy metals like lead or mercury, phosphate, as well as many organic molecules.
Ferrihydrite is a metastable mineral. It is known to be a precursor of more crystalline minerals like hematite and goethite [12]. | https://www.wikidoc.org/index.php/Ferrihydrite | |
bb4124a56ebdb15207fb396b46b25d815fded593 | wikidoc | Ferrosilicon | Ferrosilicon
Ferrosilicon, or ferrosilicium, is a ferroalloy an alloy of iron and silicon with between 15 and 90% silicon. It contains a high proportion of iron silicides. Its melting point is about 1200 °C to 1250 °C with a boiling point of 2355 °C. It also contains about 1 to 2% of calcium and aluminium.
Ferrosilicon is used in steelmaking and foundries as a source of silicon in production of carbon steels, stainless steels, and other ferrous alloys for its deoxidizing properties, to prevent loss of carbon from the molten steel (so called blocking the heat); ferromanganese, spiegeleisen, silicides of calcium, and many other materials are used for the same purpose. It can be used to make other ferroalloys. Ferrosilicon is also used for manufacture of silicon, corrosion-resistant and high-temperature resistant ferrous silicon alloys, and silicon steel for electromotors and transformer cores. In manufacture of cast iron, ferrosilicon is used for inoculation of the iron to accelerate graphitization. In arc welding, ferrosilicon can be found in some electrode coatings.
Ferrosilicon is a basis for manufacture of prealloys like magnesium ferrosilicon (FeSiMg), used for modification of melted malleable iron; FeSiMg contains between 3-42% of magnesium and small amounts of rare earth metals. Ferrosilicon is also important as an additive to cast irons for controlling the initial content of silicon.
In contact with water, ferrosilicon may slowly produce hydrogen.
Ferrosilicon is produced by reduction of silica or sand with coke in presence of scrap iron, millscale, or other source of iron. Ferrosilicons with silicon content up to about 15% are made in blast furnaces lined with acid fire bricks. Ferrosilicons with higher silicon content are made in electric arc furnaces. An overabundance of silica is used to prevent formation of silicon carbide. Microsilica is a useful byproduct.
The usual formulations on the market are ferrosilicons with 15, 45, 75, and 90% of silicon. The remainder is iron, with about 2% of other elements like aluminium and calcium.
Its CAS number is Template:CASREF.
A mineral perryite is similar to ferrosilicon, with its composition Fe5Si2.
Ferrosilicon is used by the military to quickly produce hydrogen for balloons by the ferrosilicon method. The chemical reaction uses sodium hydroxide, ferrosilicon, and water. The generator is small enough to fit a truck and requires only a small amount of electric power, the materials are stable and not combustible, and they do not generate hydrogen until mixed.
The melting point and density of ferrosilicon is dependent on its silicon content. | Ferrosilicon
Ferrosilicon, or ferrosilicium, is a ferroalloy an alloy of iron and silicon with between 15 and 90% silicon. It contains a high proportion of iron silicides. Its melting point is about 1200 °C to 1250 °C with a boiling point of 2355 °C. It also contains about 1 to 2% of calcium and aluminium.
Ferrosilicon is used in steelmaking and foundries as a source of silicon in production of carbon steels, stainless steels, and other ferrous alloys for its deoxidizing properties, to prevent loss of carbon from the molten steel (so called blocking the heat); ferromanganese, spiegeleisen, silicides of calcium, and many other materials are used for the same purpose. It can be used to make other ferroalloys. Ferrosilicon is also used for manufacture of silicon, corrosion-resistant and high-temperature resistant ferrous silicon alloys, and silicon steel for electromotors and transformer cores. In manufacture of cast iron, ferrosilicon is used for inoculation of the iron to accelerate graphitization. In arc welding, ferrosilicon can be found in some electrode coatings.
Ferrosilicon is a basis for manufacture of prealloys like magnesium ferrosilicon (FeSiMg), used for modification of melted malleable iron; FeSiMg contains between 3-42% of magnesium and small amounts of rare earth metals. Ferrosilicon is also important as an additive to cast irons for controlling the initial content of silicon.
In contact with water, ferrosilicon may slowly produce hydrogen.
Ferrosilicon is produced by reduction of silica or sand with coke in presence of scrap iron, millscale, or other source of iron. Ferrosilicons with silicon content up to about 15% are made in blast furnaces lined with acid fire bricks. Ferrosilicons with higher silicon content are made in electric arc furnaces. An overabundance of silica is used to prevent formation of silicon carbide. Microsilica is a useful byproduct.
The usual formulations on the market are ferrosilicons with 15, 45, 75, and 90% of silicon. The remainder is iron, with about 2% of other elements like aluminium and calcium.
Its CAS number is Template:CASREF.
A mineral perryite is similar to ferrosilicon, with its composition Fe5Si2.
Ferrosilicon is used by the military to quickly produce hydrogen for balloons by the ferrosilicon method. The chemical reaction uses sodium hydroxide, ferrosilicon, and water. The generator is small enough to fit a truck and requires only a small amount of electric power, the materials are stable and not combustible, and they do not generate hydrogen until mixed.[1]
The melting point and density of ferrosilicon is dependent on its silicon content. | https://www.wikidoc.org/index.php/Ferrosilicon | |
f5c5ee12b53e523f7414f3b5fda624a3f4727c1d | wikidoc | Ferulic acid | Ferulic acid
Ferulic acid is an organic compound that is an abundant phenolic phytochemical found in plant cell walls. It is a derivative of trans-cinnamic acid. As a component of lignin, ferulic acid is a precursor in the manufacture of other aromatic compounds.
# Occurrence in nature
Ferulic acid, together with dihydroferulic acid, is a component of lignocellulose, serving to crosslink the lignin and polysaccharides, thereby conferring rigidity to the cell walls. It is found in seeds of plants such as in rice, wheat, and oats, as well as in coffee, apple, artichoke, peanut, orange and pineapple. It can be extracted from wheat bran and maize bran using concentrated alkali. Biosynthesis of ferulic acid is by the action of the enzyme O-methyl transferase on caffeic acid Template:Ref label.
# Bio-medical considerations
Ferulic acid, like many phenols, is an antioxidant in the sense that it is reactive toward free radicals such as reactive oxygen species (ROS). ROS and free radicals are implicated in DNA damage, cancer, accelerated cell aging. Animal studies and in vitro studies suggest that ferulic acid may have direct antitumor activity against breast cancer Template:Ref label and liver cancer Template:Ref label. Ferulic acid may have pro-apoptotic effects in cancer cells, thereby leading to their destruction Template:Ref label. Ferulic acid may be effective at preventing cancer induced by exposure to the carcinogenic compounds benzopyrene Template:Ref label and 4-nitroquinoline 1-oxide Template:Ref label. Note that these are not randomized controlled trials done with human participants, and therefore, the results of these studies may not be directly applicable to human use.
If added to a topical preparation of ascorbic acid and vitamin E, ferulic acid may reduce oxidative stress and formation of thymine dimers in skin Template:Ref label.
# Applications
## As a precursor to vanillin
Ferulic acid, being highly abundant, may be useful as a precursor in the manufacturing of vanillin, a synthetic flavoring agent often used in place of natural vanilla extract Template:Ref label. However, biotechnological processes may be the most efficient method to use ferulic acid as a precursor Template:Ref label, and as such, research is still ongoing.
## Mass spectrometry
It is used as a matrix for proteins in MALDI mass spectroscopy analyses. Template:Ref label | Ferulic acid
Template:Chembox new
Ferulic acid is an organic compound that is an abundant phenolic phytochemical found in plant cell walls. It is a derivative of trans-cinnamic acid. As a component of lignin, ferulic acid is a precursor in the manufacture of other aromatic compounds.
# Occurrence in nature
Ferulic acid, together with dihydroferulic acid, is a component of lignocellulose, serving to crosslink the lignin and polysaccharides, thereby conferring rigidity to the cell walls.[1] It is found in seeds of plants such as in rice, wheat, and oats, as well as in coffee, apple, artichoke, peanut, orange and pineapple. It can be extracted from wheat bran and maize bran using concentrated alkali. Biosynthesis of ferulic acid is by the action of the enzyme O-methyl transferase on caffeic acid Template:Ref label.
# Bio-medical considerations
Ferulic acid, like many phenols, is an antioxidant in the sense that it is reactive toward free radicals such as reactive oxygen species (ROS). ROS and free radicals are implicated in DNA damage, cancer, accelerated cell aging. Animal studies and in vitro studies suggest that ferulic acid may have direct antitumor activity against breast cancer Template:Ref label and liver cancer Template:Ref label. Ferulic acid may have pro-apoptotic effects in cancer cells, thereby leading to their destruction Template:Ref label. Ferulic acid may be effective at preventing cancer induced by exposure to the carcinogenic compounds benzopyrene Template:Ref label and 4-nitroquinoline 1-oxide Template:Ref label. Note that these are not randomized controlled trials done with human participants, and therefore, the results of these studies may not be directly applicable to human use.
If added to a topical preparation of ascorbic acid and vitamin E, ferulic acid may reduce oxidative stress and formation of thymine dimers in skin Template:Ref label.
# Applications
## As a precursor to vanillin
Ferulic acid, being highly abundant, may be useful as a precursor in the manufacturing of vanillin, a synthetic flavoring agent often used in place of natural vanilla extract Template:Ref label. However, biotechnological processes may be the most efficient method to use ferulic acid as a precursor Template:Ref label, and as such, research is still ongoing.
## Mass spectrometry
It is used as a matrix for proteins in MALDI mass spectroscopy analyses. Template:Ref label | https://www.wikidoc.org/index.php/Ferulic_acid | |
1c87dd696ae5ea0818cba00f46a10e8e86493635 | wikidoc | Fesoterodine | Fesoterodine
# Disclaimer
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# Overview
Fesoterodine is a muscarinic antagonist that is FDA approved for the {{{indicationType}}} of overactive bladder with symptoms of urge urinary incontinence, urgency, and frequency. Common adverse reactions include dry mouth and constipation.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- The recommended starting dose of Toviaz is 4 mg once daily. Based upon individual response and tolerability, the dose may be increased to 8 mg once daily.
- The daily dose of Toviaz should not exceed 4 mg in the following populations:
- Patients with severe renal impairment (CLCR <30 mL/min).
- Patients taking potent CYP3A4 inhibitors, such as ketoconazole, itraconazole, and clarithromycin.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Fesoterodine in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Fesoterodine in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding FDA-Labeled Use of Fesoterodine in pediatric patients.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Fesoterodine in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Fesoterodine in pediatric patients.
# Contraindications
- Toviaz is contraindicated in patients with urinary retention, gastric retention, or uncontrolled narrow-angle glaucoma. Toviaz is also contraindicated in patients with known hypersensitivity to the drug or its ingredients, or to tolterodine tartrate tablets or tolterodine tartrate extended-release capsules.
# Warnings
### Precautions
- Angioedema
- Angioedema of the face, lips, tongue, and/or larynx has been reported with fesoterodine. In some cases angioedema occurred after the first dose. Angioedema associated with upper airway swelling may be life-threatening. If involvement of the tongue, hypopharynx, or larynx occurs, fesoterodine should be promptly discontinued and appropriate therapy and/or measures to ensure a patent airway should be promptly provided.
- Bladder Outlet Obstruction
- Toviaz should be administered with caution to patients with clinically significant bladder outlet obstruction because of the risk of urinary retention.
- Decreased Gastrointestinal Motility
- Toviaz, like other antimuscarinic drugs, should be used with caution in patients with decreased gastrointestinal motility, such as those with severe constipation.
- Controlled Narrow-Angle Glaucoma
- Toviaz should be used with caution in patients being treated for narrow-angle glaucoma, and only where the potential benefits outweigh the risks.
- Central Nervous System Effects
- Toviaz is associated with anticholinergic central nervous sytem (CNS) effects. A variety of CNS anticholinergic effects have been reported, including headache, dizziness, and somnolence. Patients should be monitored for signs of anticholinergic CNS effects, particularly after beginning treatment or increasing the dose. Advise patients not to drive or operate heavy machinery until they know how Toviaz affects them. If a patient experiences anticholinergic CNS effects, dose reduction or drug discontinuation should be considered.
- Hepatic Impairment
- Toviaz has not been studied in patients with severe hepatic impairment and therefore is not recommended for use in this patient population.
- Renal Impairment
- Doses of Toviaz greater than 4 mg are not recommended in patients with severe renal impairment.
- Concomitant Administration with CYP3A4 Inhibitors
- Doses of Toviaz greater than 4 mg are not recommended in patients taking a potent CYP3A4 inhibitor (e.g., ketoconazole, itraconazole, clarithromycin).
- No dosing adjustments are recommended in the presence of moderate CYP3A4 inhibitors (e.g., erythromycin, fluconazole, diltiazem, verapamil and grapefruit juice).
- While the effect of weak CYP3A4 inhibitors (e.g. cimetidine) was not examined by clinical study, some pharmacokinetic interaction is expected, albeit less than that observed with moderate CYP3A4 inhibitors.
- Myasthenia Gravis
- Toviaz should be used with caution in patients with myasthenia gravis, a disease characterized by decreased cholinergic activity at the neuromuscular junction.
# Adverse Reactions
## Clinical Trials Experience
- The safety of Toviaz was evaluated in Phase 2 and 3 controlled trials in a total of 2859 patients with overactive bladder, of which 2288 were treated with fesoterodine. Of this total, 782 received Toviaz 4 mg/day, and 785 received Toviaz 8 mg/day in Phase 2 or 3 studies with treatment periods of 8 or 12 weeks. Approximately 80% of these patients had >10 weeks exposure to Toviaz in these trials.
- A total of 1964 patients participated in two 12-week, Phase 3 efficacy and safety studies and subsequent open-label extension studies. In these two studies combined, 554 patients received Toviaz 4 mg/day and 566 patients received Toviaz 8 mg/day.
- In Phase 2 and 3 placebo-controlled trials combined, the incidences of serious adverse events in patients receiving placebo, Toviaz 4 mg, and Toviaz 8 mg were 1.9%, 3.5%, and 2.9%, respectively. All serious adverse events were judged to be not related or unlikely to be related to study medication by the investigator, except for four patients receiving Toviaz who reported one serious adverse event each: angina, chest pain, gastroenteritis, and QT prolongation on ECG.
- The most commonly reported adverse event in patients treated with Toviaz was dry mouth. The incidence of dry mouth was higher in those taking 8 mg/day (35%) and in those taking 4 mg/day (19%), as compared to placebo (7%). Dry mouth led to discontinuation in 0.4%, 0.4%, and 0.8% of patients receiving placebo, Toviaz 4 mg, and Toviaz 8 mg, respectively. For those patients who reported dry mouth, most had their first occurrence of the event within the first month of treatment.
- The second most commonly reported adverse event was constipation. The incidence of constipation was 2% in those taking placebo, 4% in those taking 4 mg/day, and 6% in those taking 8 mg/day.
- Table 1 lists adverse events, regardless of causality, that were reported in the combined Phase 3, randomized, placebo-controlled trials at an incidence greater than placebo and in 1% or more of patients treated with Toviaz 4 or 8 mg once daily for up to 12 weeks.
- Patients also received Toviaz for up to three years in open-label extension phases of one Phase 2 and two Phase 3 controlled trials. In all open-label trials combined, 857, 701, 529, and 105 patients received Toviaz for at least 6 months, 1 year, 2 years, and 3 years, respectively. The adverse events observed during long-term, open-label studies were similar to those observed in the 12-week, placebo-controlled studies, and included dry mouth, constipation, dry eyes, dyspepsia, and abdominal pain. Similar to the controlled studies, most adverse events of dry mouth and constipation were mild to moderate in intensity. Serious adverse events, judged to be at least possibly related to study medication by the investigator and reported more than once during the open-label treatment period of up to 3 years, included urinary retention (3 cases), diverticulitis (3 cases), constipation (2 cases), irritable bowel syndrome (2 cases), and electrocardiogram QT corrected interval prolongation (2 cases).
## Postmarketing Experience
- The following events have been reported in association with fesoterodine use in worldwide post-marketing experience: Eye disorders: Blurred vision; Cardiac disorders: Palpitations; General disorders and administrative site conditions: Hypersensitivity reactions, including angioedema with airway obstruction, face edema; Central nervous system disorders: Dizziness, headache, somnolence; Skin and subcutaneous tissue disorders: Urticaria, pruritus
- Because these spontaneously reported events are from the worldwide post-marketing experience, the frequency of events and the role of fesoterodine in their causation cannot be reliably determined.
# Drug Interactions
- Antimuscarinic Drugs
- Coadministration of Toviaz with other antimuscarinic agents that produce dry mouth, constipation, urinary retention, and other anticholinergic pharmacological effects may increase the frequency and/or severity of such effects. Anticholinergic agents may potentially alter the absorption of some concomitantly administered drugs due to anticholinergic effects on gastrointestinal motility.
- CYP3A4 Inhibitors
- Doses of Toviaz greater than 4 mg are not recommended in patients taking potent CYP3A4 inhibitors, such as ketoconazole, itraconazole, and clarithromycin. Coadministration of the potent CYP3A4 inhibitor ketoconazole with fesoterodine led to approximately a doubling of the maximum concentration (Cmax) and area under the concentration versus time curve (AUC) of 5-hydroxymethyl tolterodine (5-HMT), the active metabolite of fesoterodine. Compared with CYP2D6 extensive metabolizers not taking ketoconazole, further increases in the exposure to 5-HMT were observed in subjects who were CYP2D6 poor metabolizers taking ketoconazole.
- There is no clinically relevant effect of moderate CYP3A4 inhibitors on the pharmacokinetics of fesoterodine. Following blockade of CYP3A4 by coadministration of the moderate CYP3A4 inhibitor fluconazole 200 mg twice a day for 2 days, the average (90% confidence interval) increase in Cmax and AUC of the active metabolite of fesoterodine was approximately 19% (11% – 28%) and 27% (18% – 36%) respectively. No dosing adjustments are recommended in the presence of moderate CYP3A4 inhibitors (e.g., erythromycin, fluconazole, diltiazem, verapamil and grapefruit juice).
- The effect of weak CYP3A4 inhibitors (e.g. cimetidine) was not examined; it is not expected to be in excess of the effect of moderate inhibitors.
- CYP3A4 Inducers
- No dosing adjustments are recommended in the presence of CYP3A4 inducers, such as rifampin and carbamazepine. Following induction of CYP3A4 by coadministration of rifampin 600 mg once a day, Cmax and AUC of the active metabolite of fesoterodine decreased by approximately 70% and 75%, respectively, after oral administration of Toviaz 8 mg. The terminal half-life of the active metabolite was not changed.
- CYP2D6 Inhibitors
- The interaction with CYP2D6 inhibitors was not tested clinically. In poor metabolizers for CYP2D6, representing a maximum CYP2D6 inhibition, Cmax and AUC of the active metabolite are increased 1.7- and 2-fold, respectively.
- No dosing adjustments are recommended in the presence of CYP2D6 inhibitors.
- Drugs Metabolized by Cytochrome P450
- In vitro data indicate that at therapeutic concentrations, the active metabolite of fesoterodine does not have the potential to inhibit or induce Cytochrome P450 enzyme systems.
- Oral Contraceptives
- In the presence of fesoterodine, there are no clinically significant changes in the plasma concentrations of combined oral contraceptives containing ethinyl estradiol and levonorgestrel.
- Warfarin
- A clinical study has shown that fesoterodine 8 mg once daily has no significant effect on the pharmacokinetics or the anticoagulant activity (PT/INR) of warfarin 25 mg. Standard therapeutic monitoring for warfarin should be continued
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
- Pregnancy Category C
- There are no adequate and well-controlled studies using Toviaz in pregnant women.
- No dose-related teratogenicity was observed in reproduction studies performed in mice and rabbits. In mice at 6 to 27 times the expected exposure at the maximum recommended human dose (MRHD) of 8 mg based on AUC (75 mg/kg/day, oral), increased resorptions and decreased live fetuses were observed. One fetus with cleft palate was observed at each dose (15, 45, and 75 mg/kg/day), at an incidence within the background historical range. In rabbits treated at 3 to 11 times the MRHD (27 mg/kg/day, oral), incompletely ossified sternebrae (retardation of bone development) were observed in fetuses. In rabbits at 9 to 11 times the MRHD (4.5 mg/kg/day, subcutaneous), maternal toxicity and incompletely ossified sternebrae were observed in fetuses (at an incidence within the background historical range). In rabbits at 3 times the MRHD (1.5 mg/kg/day, subcutaneous), decreased maternal food consumption in the absence of any fetal effects was observed. Oral administration of 30 mg/kg/day fesoterodine to mice in a pre- and post-natal development study resulted in decreased body weight of the dams and delayed ear opening of the pups. No effects were noted on mating and reproduction of the F1 dams or on the F2 offspring.
- Toviaz should be used during pregnancy only if the potential 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 Fesoterodine in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Fesoterodine during labor and delivery.
### Nursing Mothers
- It is not known whether fesoterodine is excreted in human milk. Toviaz should not be administered during nursing unless the potential benefit outweighs the potential risk to the neonate.
### Pediatric Use
- The pharmacokinetics of fesoterodine have not been evaluated in pediatric patients.
- The safety and effectiveness of Toviaz in pediatric patients have not been established.
### Geriatic Use
- No dose adjustment is recommended for the elderly. The pharmacokinetics of fesoterodine are not significantly influenced by age.
- Of 1567 patients who received Toviaz 4 mg/day or 8 mg/day in the Phase 2 and 3, placebo-controlled, efficacy and safety studies, 515 (33%) were 65 years of age or older, and 140 (9%) were 75 years of age or older. No overall differences in safety or effectiveness were observed between patients younger than 65 years of age and those 65 years of age or older in these studies; however, the incidence of antimuscarinic adverse events, including dry mouth, constipation, dyspepsia, increase in residual urine, dizziness (at 8 mg only) and urinary tract infection, was higher in patients 75 years of age and older as compared to younger patients.
### Gender
- No dose adjustment is recommended based on gender. The pharmacokinetics of fesoterodine are not significantly influenced by gender.
### Race
- Available data indicate that there are no differences in the pharmacokinetics of fesoterodine between Caucasian and Black healthy subjects following administration of Toviaz.
### Renal Impairment
- In patients with severe renal impairment (CLCR < 30 mL/min), Cmax and AUC are increased 2.0- and 2.3-fold, respectively. Doses of Toviaz greater than 4 mg are not recommended in patients with severe renal impairment. In patients with mild or moderate renal impairment (CLCR ranging from 30–80 mL/min), Cmax and AUC of the active metabolite are increased up to 1.5- and 1.8-fold, respectively, as compared to healthy subjects. No dose adjustment is recommended in patients with mild or moderate renal impairment.
### Hepatic Impairment
- Patients with severe hepatic impairment (Child-Pugh C) have not been studied; therefore Toviaz is not recommended for use in these patients. In patients with moderate (Child-Pugh B) hepatic impairment, Cmax and AUC of the active metabolite are increased 1.4- and 2.1-fold, respectively, as compared to healthy subjects. No dose adjustment is recommended in patients with mild or moderate hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Fesoterodine in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Fesoterodine in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Oral
### Monitoring
There is limited information regarding Monitoring of Fesoterodine in the drug label.
# IV Compatibility
There is limited information regarding IV Compatibility of Fesoterodine in the drug label.
# Overdosage
## Acute Overdose
### Signs and Symptoms
- Overdosage with Toviaz can result in severe anticholinergic effects.
### Management
- Treatment should be symptomatic and supportive. In the event of overdosage, ECG monitoring is recommended.
## Chronic Overdose
There is limited information regarding Chronic Overdose of Fesoterodine in the drug label.
# Pharmacology
## Mechanism of Action
- Fesoterodine is a competitive muscarinic receptor antagonist. After oral administration, fesoterodine is rapidly and extensively hydrolyzed by nonspecific esterases to its active metabolite, 5-hydroxymethyl tolterodine, which is responsible for the antimuscarinic activity of fesoterodine and is also one of the active moieties of tolterodine tartrate tablets and tolterodine tartrate extended-release capsules.
- Muscarinic receptors play a role in contractions of urinary bladder smooth muscle and stimulation of salivary secretion. Inhibition of these receptors in the bladder is presumed to be the mechanism by which fesoterodine produces its effects.
## Structure
- Toviaz contains fesoterodine fumarate and is an extended-release tablet. Fesoterodine is rapidly de-esterified to its active metabolite (R)-2-(3-diisopropylamino-1-phenylpropyl)-4-hydroxymethyl-phenol, or 5-hydroxymethyl tolterodine, which is a muscarinic receptor antagonist.
- Chemically, fesoterodine fumarate is designated as isobutyric acid 2-((R)-3-diisopropylammonium-1-phenylpropyl)-4-(hydroxymethyl) phenyl ester hydrogen fumarate. The empirical formula is C30H41NO7 and its molecular weight is 527.66. The structural formula is:
- Fesoterodine fumarate is a white to off-white powder, which is freely soluble in water. Each Toviaz extended-release tablet contains either 4 mg or 8 mg of fesoterodine fumarate and the following inactive ingredients: glyceryl behenate, hypromellose, indigo carmine aluminum lake, lactose monohydrate, soya lecithin, microcrystalline cellulose, polyethylene glycol, polyvinyl alcohol, talc, titanium dioxide, and xylitol.
## Pharmacodynamics
- In a urodynamic study involving patients with involuntary detrusor contractions, the effects after the administration of fesoterodine on the volume at first detrusor contraction and bladder capacity were assessed. Administration of fesoterodine increased the volume at first detrusor contraction and bladder capacity in a dose-dependent manner. These findings are consistent with an antimuscarinic effect on the bladder.
- Cardiac Electrophysiology
- The effect of fesoterodine 4 mg and 28 mg on the QT interval was evaluated in a double-blind, randomized, placebo- and positive-controlled (moxifloxacin 400 mg once a day) parallel trial with once-daily treatment over a period of 3 days in 261 male and female subjects aged 44 to 65 years. Electrocardiographic parameters were measured over a 24-hour period at pre-dose, after the first administration, and after the third administration of study medication. Fesoterodine 28 mg was chosen because this dose, when administered to CYP2D6 extensive metabolizers, results in an exposure to the active metabolite that is similar to the exposure in a CYP2D6 poor metabolizer receiving fesoterodine 8 mg together with CYP3A4 blockade. Corrected QT intervals (QTc) were calculated using Fridericia's correction and a linear individual correction method. Analyses of 24-hour average QTc, time-matched baseline-corrected QTc, and time-matched placebo-subtracted QTc intervals indicate that fesoterodine at doses of 4 and 28 mg/day did not prolong the QT interval. The sensitivity of the study was confirmed by positive QTc prolongation by moxifloxacin.
- Toviaz is associated with an increase in heart rate that correlates with increasing dose. In the study described above, when compared to placebo, the mean increase in heart rate associated with a dose of 4 mg/day and 28 mg/day of fesoterodine was 3 beats/minute and 11 beats/minute, respectively.
- In the two, phase 3, placebo-controlled studies in patients with overactive bladder, the mean increase in heart rate compared to placebo was approximately 3–4 beats/minute in the 4 mg/day group and 3–5 beats/minute in the 8 mg/day group.
## Pharmacokinetics
- Absorption
- After oral administration, fesoterodine is well absorbed. Due to rapid and extensive hydrolysis by nonspecific esterases to its active metabolite 5-hydroxymethyl tolterodine, fesoterodine cannot be detected in plasma. Bioavailability of the active metabolite is 52%. After single or multiple-dose oral administration of fesoterodine in doses from 4 mg to 28 mg, plasma concentrations of the active metabolite are proportional to the dose. Maximum plasma levels are reached after approximately 5 hours. No accumulation occurs after multiple-dose administration.
- A summary of pharmacokinetic parameters for the active metabolite after a single dose of Toviaz 4 mg and 8 mg in extensive and poor metabolizers of CYP2D6 is provided in Table 2.
- Effect of Food
- There is no clinically relevant effect of food on the pharmacokinetics of fesoterodine. In a study of the effects of food on the pharmacokinetics of fesoterodine in 16 healthy male volunteers, concomitant food intake increased the active metabolite of fesoterodine AUC by approximately 19% and Cmax by 18% .
- Distribution
- Plasma protein binding of the active metabolite is low (approximately 50%) and is primarily bound to albumin and alpha-1-acid glycoprotein. The mean steady-state volume of distribution following intravenous infusion of the active metabolite is 169 L.
- Metabolism
- After oral administration, fesoterodine is rapidly and extensively hydrolyzed to its active metabolite. The active metabolite is further metabolized in the liver to its carboxy, carboxy-N-desisopropyl, and N-desisopropyl metabolites via two major pathways involving CYP2D6 and CYP3A4. None of these metabolites contribute significantly to the antimuscarinic activity of fesoterodine.
- Variability in CYP2D6 Metabolism
- A subset of individuals (approximately 7% of Caucasians and approximately 2% of African Americans) are poor metabolizers for CYP2D6. Cmax and AUC of the active metabolite are increased 1.7- and 2-fold, respectively, in CYP2D6 poor metabolizers, as compared to extensive metabolizers.
- Excretion
- Hepatic metabolism and renal excretion contribute significantly to the elimination of the active metabolite. After oral administration of fesoterodine, approximately 70% of the administered dose was recovered in urine as the active metabolite (16%), carboxy metabolite (34%), carboxy-N-desisopropyl metabolite (18%), or N-desisopropyl metabolite (1%), and a smaller amount (7%) was recovered in feces.
- The terminal half-life of the active metabolite is approximately 4 hours following an intravenous administration. The apparent terminal half-life following oral administration is approximately 7 hours.
- Pharmacokinetics in Specific Populations:
- Geriatric Patients
- Following a single 8 mg oral dose of fesoterodine, the mean (±SD) AUC and Cmax for the active metabolite 5-hydroxymethyl tolterodine in 12 elderly men (mean age 67 years) were 51.8 ± 26.1 h*ng/mL and 3.8 ± 1.7 ng/mL, respectively. In the same study, the mean (±SD) AUC and Cmax in 12 young men (mean age 30 years) were 52.0 ± 31.5 h*ng/mL and 4.1 ± 2.1 ng/mL, respectively. The pharmacokinetics of fesoterodine were not significantly influenced by age.
- Pediatric Patients
- The pharmacokinetics of fesoterodine have not been evaluated in pediatric patients.
- Gender
- Following a single 8 mg oral dose of fesoterodine, the mean (±SD) AUC and Cmax for the active metabolite 5-hydroxymethyl tolterodine in 12 elderly men (mean age 67 years) were 51.8 ± 26.1 h*ng/mL and 3.8 ± 1.7 ng/mL, respectively. In the same study, the mean (±SD) AUC and Cmax in 12 elderly women (mean age 68 years) were 56.0 ± 28.8 h*ng/mL and 4.6 ± 2.3 ng/mL, respectively. The pharmacokinetics of fesoterodine were not significantly influenced by gender.
- Race
- The effects of Caucasian or Black race on the pharmacokinetics of fesoterodine were examined in a study of 12 Caucasian and 12 Black African young male volunteers. Each subject received a single oral dose of 8 mg fesoterodine. The mean (±SD) AUC and Cmax for the active metabolite 5-hydroxymethyl tolterodine in Caucasian males were 73.0 ± 27.8 h*ng/mL and 6.1 ± 2.7 ng/mL, respectively. The mean (±SD) AUC and Cmax in Black males were 65.8 ± 23.2 h*ng/mL and 5.5 ± 1.9 ng/mL, respectively. The pharmacokinetics of fesoterodine were not significantly influenced by race.
- Renal Impairment
- In patients with mild or moderate renal impairment (CLCR ranging from 30–80 mL/min), Cmax and AUC of the active metabolite are increased up to 1.5- and 1.8-fold, respectively, as compared to healthy subjects. In patients with severe renal impairment (CLCR < 30 mL/min), Cmax and AUC are increased 2.0- and 2.3-fold, respectively.
- Hepatic Impairment
- In patients with moderate (Child-Pugh B) hepatic impairment, Cmax and AUC of the active metabolite are increased 1.4- and 2.1-fold, respectively, as compared to healthy subjects.
- Subjects with severe hepatic impairment (Child-Pugh C) have not been studied.
- Drug-Drug Interactions:
- Drugs Metabolized by Cytochrome P450
- At therapeutic concentrations, the active metabolite of fesoterodine does not inhibit CYP1A2, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, or 3A4, or induce CYP1A2, 2B6, 2C9, 2C19, or 3A4 in vitro.
- CYP3A4 Inhibitors
- Following blockade of CYP3A4 by coadministration of the potent CYP3A4 inhibitor ketoconazole 200 mg twice a day for 5 days, Cmax and AUC of the active metabolite of fesoterodine increased 2.0- and 2.3-fold, respectively, after oral administration of Toviaz 8 mg to CYP2D6 extensive metabolizers. In CYP2D6 poor metabolizers, Cmax and AUC of the active metabolite of fesoterodine increased 2.1- and 2.5-fold, respectively, during coadministration of ketoconazole 200 mg twice a day for 5 days. Cmax and AUC were 4.5- and 5.7-fold higher, respectively, in subjects who were CYP2D6 poor metabolizers and taking ketoconazole compared to subjects who were CYP2D6 extensive metabolizers and not taking ketoconazole. In a separate study coadministering fesoterodine with ketoconazole 200 mg once a day for 5 days, the Cmax and AUC values of the active metabolite of fesoterodine were increased 2.2-fold in CYP2D6 extensive metabolizers and 1.5- and 1.9-fold, respectively, in CYP2D6 poor metabolizers. Cmax and AUC were 3.4- and 4.2-fold higher, respectively, in subjects who were CYP2D6 poor metabolizers and taking ketoconazole compared to subjects who were CYP2D6 extensive metabolizers and not taking ketoconazole.
- There is no clinically relevant effect of moderate CYP3A4 inhibitors on the pharmacokinetics of fesoterodine. In a drug-drug interaction study evaluating the coadministration of the moderate CYP3A4 inhibitor fluconazole 200 mg twice a day for 2 days, a single 8 mg dose of fesoterodine was administered 1 hour following the first dose of fluconazole on day 1 of the study. The average (90% confidence interval) for the increase in Cmax and AUC of the active metabolite of fesoterodine was approximately 19% (11% – 28%) and 27% (18% – 36%) respectively.
- The effect of weak CYP3A4 inhibitors (e.g. cimetidine) was not examined; it is not expected to be in excess of the effect of moderate inhibitors.
- CYP3A4 Inducers
- Following induction of CYP3A4 by coadministration of rifampicin 600 mg once a day, Cmax and AUC of the active metabolite of fesoterodine decreased by approximately 70% and 75%, respectively, after oral administration of Toviaz 8 mg. The terminal half-life of the active metabolite was not changed.
- Induction of CYP3A4 may lead to reduced plasma levels. No dosing adjustments are recommended in the presence of CYP3A4 inducers.
- CYP2D6 Inhibitors
- The interaction with CYP2D6 inhibitors was not studied. In poor metabolizers for CYP2D6, representing a maximum CYP2D6 inhibition, Cmax and AUC of the active metabolite are increased 1.7- and 2-fold, respectively.
- Oral Contraceptives
- Thirty healthy female subjects taking an oral contraceptive containing 0.03 mg ethinyl estradiol and 0.15 mg levonorgestrel were evaluated in a 2-period crossover study. Each subject was randomized to receive concomitant administration of either placebo or fesoterodine 8 mg once daily on days 1 – 14 of hormone cycle for 2 consecutive cycles. Pharmacokinetics of ethinyl estradiol and levonorgestrel were assessed on day 13 of each cycle. Fesoterodine increased the AUC and Cmax of ethinyl estradiol by 1 – 3% and decreased the AUC and Cmax of levonorgestrel by 11 – 13%.
- Warfarin
- In a cross-over study in 14 healthy male volunteers (18–55 years), a single oral dose of warfarin 25 mg was given either alone or on day 3 of once daily dosing for 9 days with fesoterodine 8 mg. Compared to warfarin alone dosing, the Cmax and AUC of S-warfarin were lower by ~ 4 %, while the Cmax and AUC of R-warfarin were lower by approximately 8 % and 6% for the co-administration, suggesting absence of a significant pharmacokinetic interaction.
- There were no statistically significant changes in the measured pharmacodynamic parameters for anti-coagulant activity of warfarin (INRmax, AUCINR), with only a small decrease noted in INRmax of ~ 3 % with the co-administration relative to warfarin alone. INR versus time profiles across individual subjects in the study suggested some differences following co-administration with fesoterodine, although there was no definite trend with regard to the changes noted
## Nonclinical Toxicology
- No evidence of drug-related carcinogenicity was found in 24-month studies with oral administration to mice and rats. The highest tolerated doses in mice (females 45 to 60 mg/kg/day, males 30 to 45 mg/kg/day) correspond to 11 to 19 times (females) and 4 to 9 times (males) the estimated human AUC values reached with fesoterodine 8 mg, which is the Maximum Recommended Human Dose (MRHD). In rats, the highest tolerated dose (45 to 60 mg/kg/day) corresponds to 3 to 8 times (females) and 3 to 14 times (males) the estimated human AUC at the MRHD.
- Fesoterodine was not mutagenic or genotoxic in vitro (Ames tests, chromosome aberration tests) or in vivo (mouse micronucleus test).
- Fesoterodine had no effect on reproductive function, fertility, or early embryonic development of the fetus at non-maternally toxic doses in mice. The maternal No-Observed-Effect Level (NOEL) and the NOEL for effects on reproduction and early embryonic development were both 15 mg/kg/day. Based on AUC, the systemic exposure was 0.6 to 1.5 times higher in mice than in humans at the MRHD, whereas based on peak plasma concentrations, the exposure in mice was 5 to 9 times higher. The Lowest-Observed-Effect Level (LOEL) for maternal toxicity was 45 mg/kg/day.
# Clinical Studies
- Toviaz extended-release tablets were evaluated in two, Phase 3, randomized, double-blind, placebo-controlled, 12-week studies for the treatment of overactive bladder with symptoms of urge urinary incontinence, urgency, and urinary frequency. Entry criteria required that patients have symptoms of overactive bladder for ≥ 6-months duration, at least 8 micturitions per day, and at least 6 urinary urgency episodes or 3 urge incontinence episodes per 3-day diary period. Patients were randomized to a fixed dose of Toviaz 4 or 8 mg/day or placebo. In one of these studies, 290 patients were randomized to an active control arm (an oral antimuscarinic agent). For the combined studies, a total of 554 patients received placebo, 554 patients received Toviaz 4 mg/day, and 566 patients received Toviaz 8 mg/day. The majority of patients were Caucasian (91%) and female (79%) with a mean age of 58 years (range 19–91 years).
- The primary efficacy endpoints were the mean change in the number of urge urinary incontinence episodes per 24 hours and the mean change in the number of micturitions (frequency) per 24 hours. An important secondary endpoint was the mean change in the voided volume per micturition.
- Results for the primary endpoints and for mean change in voided volume per micturition from the two 12-week clinical studies of Toviaz are reported in Table 3.
- Figures 1–4: The following figures show change from baseline over time in number of micturitions and urge urinary incontinence episodes per 24 h in the two studies.
- A reduction in number of urge urinary incontinence episodes per 24 hours was observed for both doses as compared to placebo as early as two weeks after starting Toviaz therapy.
# How Supplied
- Toviaz (fesoterodine fumarate) extended-release tablets 4 mg are light blue, oval, biconvex, film-coated, and engraved with "FS" on one side. They are supplied as follows:
- Bottles of 30 NDC 0069-0242-30
- Bottles of 90 NDC 0069-0242-68
- Unit Dose Package of 100 NDC 0069-0242-41
- Toviaz (fesoterodine fumarate) extended-release tablets 8 mg are blue, oval, biconvex, film-coated, and engraved with "FT" on one side. They are supplied as follows:
- Bottles of 30 NDC 0069-0244-30
- Bottles of 90 NDC 0069-0244-68
- Unit Dose Package of 100 NDC 0069-0244-41
- Store at 20° to 25°C (68° to 77°F); excursions permitted between 15° to 30°C (59° to 86°F). Protect from moisture.
## Storage
There is limited information regarding Fesoterodine Storage in the drug label.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- Patients should be informed that fesoterodine may produce angioedema, which could result in life-threatening airway obstruction. Patients should be advised to promptly discontinue fesoterodine therapy and seek immediate medical attention if they experience edema of the tongue or laryngopharynx, or difficult breathing.
- Patients should be informed that Toviaz, like other antimuscarinic agents, may produce clinically significant adverse effects related to antimuscarinic pharmacological activity including constipation and urinary retention. Toviaz, like other antimuscarinics, may be associated with blurred vision, therefore, patients should be advised to exercise caution in decisions to engage in potentially dangerous activities until the drug's effects on the patient have been determined. Heat prostration (due to decreased sweating) can occur when Toviaz, like other antimuscarinic drugs, is used in a hot environment.
- Patients should also be informed that alcohol may enhance the drowsiness caused by Toviaz, like other anticholinergic agents. Patients should read the patient leaflet entitled "Patient Information TOVIAZ" before starting therapy with Toviaz.
# Precautions with Alcohol
- Alcohol-Fesoterodine interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- TOVIAZ®
# Look-Alike Drug Names
There is limited information regarding Fesoterodine Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | Fesoterodine
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Vignesh Ponnusamy, M.B.B.S. [2]
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# Overview
Fesoterodine is a muscarinic antagonist that is FDA approved for the {{{indicationType}}} of overactive bladder with symptoms of urge urinary incontinence, urgency, and frequency. Common adverse reactions include dry mouth and constipation.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- The recommended starting dose of Toviaz is 4 mg once daily. Based upon individual response and tolerability, the dose may be increased to 8 mg once daily.
- The daily dose of Toviaz should not exceed 4 mg in the following populations:
- Patients with severe renal impairment (CLCR <30 mL/min).
- Patients taking potent CYP3A4 inhibitors, such as ketoconazole, itraconazole, and clarithromycin.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Fesoterodine in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Fesoterodine in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding FDA-Labeled Use of Fesoterodine in pediatric patients.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Fesoterodine in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Fesoterodine in pediatric patients.
# Contraindications
- Toviaz is contraindicated in patients with urinary retention, gastric retention, or uncontrolled narrow-angle glaucoma. Toviaz is also contraindicated in patients with known hypersensitivity to the drug or its ingredients, or to tolterodine tartrate tablets or tolterodine tartrate extended-release capsules.
# Warnings
### Precautions
- Angioedema
- Angioedema of the face, lips, tongue, and/or larynx has been reported with fesoterodine. In some cases angioedema occurred after the first dose. Angioedema associated with upper airway swelling may be life-threatening. If involvement of the tongue, hypopharynx, or larynx occurs, fesoterodine should be promptly discontinued and appropriate therapy and/or measures to ensure a patent airway should be promptly provided.
- Bladder Outlet Obstruction
- Toviaz should be administered with caution to patients with clinically significant bladder outlet obstruction because of the risk of urinary retention.
- Decreased Gastrointestinal Motility
- Toviaz, like other antimuscarinic drugs, should be used with caution in patients with decreased gastrointestinal motility, such as those with severe constipation.
- Controlled Narrow-Angle Glaucoma
- Toviaz should be used with caution in patients being treated for narrow-angle glaucoma, and only where the potential benefits outweigh the risks.
- Central Nervous System Effects
- Toviaz is associated with anticholinergic central nervous sytem (CNS) effects. A variety of CNS anticholinergic effects have been reported, including headache, dizziness, and somnolence. Patients should be monitored for signs of anticholinergic CNS effects, particularly after beginning treatment or increasing the dose. Advise patients not to drive or operate heavy machinery until they know how Toviaz affects them. If a patient experiences anticholinergic CNS effects, dose reduction or drug discontinuation should be considered.
- Hepatic Impairment
- Toviaz has not been studied in patients with severe hepatic impairment and therefore is not recommended for use in this patient population.
- Renal Impairment
- Doses of Toviaz greater than 4 mg are not recommended in patients with severe renal impairment.
- Concomitant Administration with CYP3A4 Inhibitors
- Doses of Toviaz greater than 4 mg are not recommended in patients taking a potent CYP3A4 inhibitor (e.g., ketoconazole, itraconazole, clarithromycin).
- No dosing adjustments are recommended in the presence of moderate CYP3A4 inhibitors (e.g., erythromycin, fluconazole, diltiazem, verapamil and grapefruit juice).
- While the effect of weak CYP3A4 inhibitors (e.g. cimetidine) was not examined by clinical study, some pharmacokinetic interaction is expected, albeit less than that observed with moderate CYP3A4 inhibitors.
- Myasthenia Gravis
- Toviaz should be used with caution in patients with myasthenia gravis, a disease characterized by decreased cholinergic activity at the neuromuscular junction.
# Adverse Reactions
## Clinical Trials Experience
- The safety of Toviaz was evaluated in Phase 2 and 3 controlled trials in a total of 2859 patients with overactive bladder, of which 2288 were treated with fesoterodine. Of this total, 782 received Toviaz 4 mg/day, and 785 received Toviaz 8 mg/day in Phase 2 or 3 studies with treatment periods of 8 or 12 weeks. Approximately 80% of these patients had >10 weeks exposure to Toviaz in these trials.
- A total of 1964 patients participated in two 12-week, Phase 3 efficacy and safety studies and subsequent open-label extension studies. In these two studies combined, 554 patients received Toviaz 4 mg/day and 566 patients received Toviaz 8 mg/day.
- In Phase 2 and 3 placebo-controlled trials combined, the incidences of serious adverse events in patients receiving placebo, Toviaz 4 mg, and Toviaz 8 mg were 1.9%, 3.5%, and 2.9%, respectively. All serious adverse events were judged to be not related or unlikely to be related to study medication by the investigator, except for four patients receiving Toviaz who reported one serious adverse event each: angina, chest pain, gastroenteritis, and QT prolongation on ECG.
- The most commonly reported adverse event in patients treated with Toviaz was dry mouth. The incidence of dry mouth was higher in those taking 8 mg/day (35%) and in those taking 4 mg/day (19%), as compared to placebo (7%). Dry mouth led to discontinuation in 0.4%, 0.4%, and 0.8% of patients receiving placebo, Toviaz 4 mg, and Toviaz 8 mg, respectively. For those patients who reported dry mouth, most had their first occurrence of the event within the first month of treatment.
- The second most commonly reported adverse event was constipation. The incidence of constipation was 2% in those taking placebo, 4% in those taking 4 mg/day, and 6% in those taking 8 mg/day.
- Table 1 lists adverse events, regardless of causality, that were reported in the combined Phase 3, randomized, placebo-controlled trials at an incidence greater than placebo and in 1% or more of patients treated with Toviaz 4 or 8 mg once daily for up to 12 weeks.
- Patients also received Toviaz for up to three years in open-label extension phases of one Phase 2 and two Phase 3 controlled trials. In all open-label trials combined, 857, 701, 529, and 105 patients received Toviaz for at least 6 months, 1 year, 2 years, and 3 years, respectively. The adverse events observed during long-term, open-label studies were similar to those observed in the 12-week, placebo-controlled studies, and included dry mouth, constipation, dry eyes, dyspepsia, and abdominal pain. Similar to the controlled studies, most adverse events of dry mouth and constipation were mild to moderate in intensity. Serious adverse events, judged to be at least possibly related to study medication by the investigator and reported more than once during the open-label treatment period of up to 3 years, included urinary retention (3 cases), diverticulitis (3 cases), constipation (2 cases), irritable bowel syndrome (2 cases), and electrocardiogram QT corrected interval prolongation (2 cases).
## Postmarketing Experience
- The following events have been reported in association with fesoterodine use in worldwide post-marketing experience: Eye disorders: Blurred vision; Cardiac disorders: Palpitations; General disorders and administrative site conditions: Hypersensitivity reactions, including angioedema with airway obstruction, face edema; Central nervous system disorders: Dizziness, headache, somnolence; Skin and subcutaneous tissue disorders: Urticaria, pruritus
- Because these spontaneously reported events are from the worldwide post-marketing experience, the frequency of events and the role of fesoterodine in their causation cannot be reliably determined.
# Drug Interactions
- Antimuscarinic Drugs
- Coadministration of Toviaz with other antimuscarinic agents that produce dry mouth, constipation, urinary retention, and other anticholinergic pharmacological effects may increase the frequency and/or severity of such effects. Anticholinergic agents may potentially alter the absorption of some concomitantly administered drugs due to anticholinergic effects on gastrointestinal motility.
- CYP3A4 Inhibitors
- Doses of Toviaz greater than 4 mg are not recommended in patients taking potent CYP3A4 inhibitors, such as ketoconazole, itraconazole, and clarithromycin. Coadministration of the potent CYP3A4 inhibitor ketoconazole with fesoterodine led to approximately a doubling of the maximum concentration (Cmax) and area under the concentration versus time curve (AUC) of 5-hydroxymethyl tolterodine (5-HMT), the active metabolite of fesoterodine. Compared with CYP2D6 extensive metabolizers not taking ketoconazole, further increases in the exposure to 5-HMT were observed in subjects who were CYP2D6 poor metabolizers taking ketoconazole.
- There is no clinically relevant effect of moderate CYP3A4 inhibitors on the pharmacokinetics of fesoterodine. Following blockade of CYP3A4 by coadministration of the moderate CYP3A4 inhibitor fluconazole 200 mg twice a day for 2 days, the average (90% confidence interval) increase in Cmax and AUC of the active metabolite of fesoterodine was approximately 19% (11% – 28%) and 27% (18% – 36%) respectively. No dosing adjustments are recommended in the presence of moderate CYP3A4 inhibitors (e.g., erythromycin, fluconazole, diltiazem, verapamil and grapefruit juice).
- The effect of weak CYP3A4 inhibitors (e.g. cimetidine) was not examined; it is not expected to be in excess of the effect of moderate inhibitors.
- CYP3A4 Inducers
- No dosing adjustments are recommended in the presence of CYP3A4 inducers, such as rifampin and carbamazepine. Following induction of CYP3A4 by coadministration of rifampin 600 mg once a day, Cmax and AUC of the active metabolite of fesoterodine decreased by approximately 70% and 75%, respectively, after oral administration of Toviaz 8 mg. The terminal half-life of the active metabolite was not changed.
- CYP2D6 Inhibitors
- The interaction with CYP2D6 inhibitors was not tested clinically. In poor metabolizers for CYP2D6, representing a maximum CYP2D6 inhibition, Cmax and AUC of the active metabolite are increased 1.7- and 2-fold, respectively.
- No dosing adjustments are recommended in the presence of CYP2D6 inhibitors.
- Drugs Metabolized by Cytochrome P450
- In vitro data indicate that at therapeutic concentrations, the active metabolite of fesoterodine does not have the potential to inhibit or induce Cytochrome P450 enzyme systems.
- Oral Contraceptives
- In the presence of fesoterodine, there are no clinically significant changes in the plasma concentrations of combined oral contraceptives containing ethinyl estradiol and levonorgestrel.
- Warfarin
- A clinical study has shown that fesoterodine 8 mg once daily has no significant effect on the pharmacokinetics or the anticoagulant activity (PT/INR) of warfarin 25 mg. Standard therapeutic monitoring for warfarin should be continued
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
- Pregnancy Category C
- There are no adequate and well-controlled studies using Toviaz in pregnant women.
- No dose-related teratogenicity was observed in reproduction studies performed in mice and rabbits. In mice at 6 to 27 times the expected exposure at the maximum recommended human dose (MRHD) of 8 mg based on AUC (75 mg/kg/day, oral), increased resorptions and decreased live fetuses were observed. One fetus with cleft palate was observed at each dose (15, 45, and 75 mg/kg/day), at an incidence within the background historical range. In rabbits treated at 3 to 11 times the MRHD (27 mg/kg/day, oral), incompletely ossified sternebrae (retardation of bone development) were observed in fetuses. In rabbits at 9 to 11 times the MRHD (4.5 mg/kg/day, subcutaneous), maternal toxicity and incompletely ossified sternebrae were observed in fetuses (at an incidence within the background historical range). In rabbits at 3 times the MRHD (1.5 mg/kg/day, subcutaneous), decreased maternal food consumption in the absence of any fetal effects was observed. Oral administration of 30 mg/kg/day fesoterodine to mice in a pre- and post-natal development study resulted in decreased body weight of the dams and delayed ear opening of the pups. No effects were noted on mating and reproduction of the F1 dams or on the F2 offspring.
- Toviaz should be used during pregnancy only if the potential 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 Fesoterodine in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Fesoterodine during labor and delivery.
### Nursing Mothers
- It is not known whether fesoterodine is excreted in human milk. Toviaz should not be administered during nursing unless the potential benefit outweighs the potential risk to the neonate.
### Pediatric Use
- The pharmacokinetics of fesoterodine have not been evaluated in pediatric patients.
- The safety and effectiveness of Toviaz in pediatric patients have not been established.
### Geriatic Use
- No dose adjustment is recommended for the elderly. The pharmacokinetics of fesoterodine are not significantly influenced by age.
- Of 1567 patients who received Toviaz 4 mg/day or 8 mg/day in the Phase 2 and 3, placebo-controlled, efficacy and safety studies, 515 (33%) were 65 years of age or older, and 140 (9%) were 75 years of age or older. No overall differences in safety or effectiveness were observed between patients younger than 65 years of age and those 65 years of age or older in these studies; however, the incidence of antimuscarinic adverse events, including dry mouth, constipation, dyspepsia, increase in residual urine, dizziness (at 8 mg only) and urinary tract infection, was higher in patients 75 years of age and older as compared to younger patients.
### Gender
- No dose adjustment is recommended based on gender. The pharmacokinetics of fesoterodine are not significantly influenced by gender.
### Race
- Available data indicate that there are no differences in the pharmacokinetics of fesoterodine between Caucasian and Black healthy subjects following administration of Toviaz.
### Renal Impairment
- In patients with severe renal impairment (CLCR < 30 mL/min), Cmax and AUC are increased 2.0- and 2.3-fold, respectively. Doses of Toviaz greater than 4 mg are not recommended in patients with severe renal impairment. In patients with mild or moderate renal impairment (CLCR ranging from 30–80 mL/min), Cmax and AUC of the active metabolite are increased up to 1.5- and 1.8-fold, respectively, as compared to healthy subjects. No dose adjustment is recommended in patients with mild or moderate renal impairment.
### Hepatic Impairment
- Patients with severe hepatic impairment (Child-Pugh C) have not been studied; therefore Toviaz is not recommended for use in these patients. In patients with moderate (Child-Pugh B) hepatic impairment, Cmax and AUC of the active metabolite are increased 1.4- and 2.1-fold, respectively, as compared to healthy subjects. No dose adjustment is recommended in patients with mild or moderate hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Fesoterodine in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Fesoterodine in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Oral
### Monitoring
There is limited information regarding Monitoring of Fesoterodine in the drug label.
# IV Compatibility
There is limited information regarding IV Compatibility of Fesoterodine in the drug label.
# Overdosage
## Acute Overdose
### Signs and Symptoms
- Overdosage with Toviaz can result in severe anticholinergic effects.
### Management
- Treatment should be symptomatic and supportive. In the event of overdosage, ECG monitoring is recommended.
## Chronic Overdose
There is limited information regarding Chronic Overdose of Fesoterodine in the drug label.
# Pharmacology
## Mechanism of Action
- Fesoterodine is a competitive muscarinic receptor antagonist. After oral administration, fesoterodine is rapidly and extensively hydrolyzed by nonspecific esterases to its active metabolite, 5-hydroxymethyl tolterodine, which is responsible for the antimuscarinic activity of fesoterodine and is also one of the active moieties of tolterodine tartrate tablets and tolterodine tartrate extended-release capsules.
- Muscarinic receptors play a role in contractions of urinary bladder smooth muscle and stimulation of salivary secretion. Inhibition of these receptors in the bladder is presumed to be the mechanism by which fesoterodine produces its effects.
## Structure
- Toviaz contains fesoterodine fumarate and is an extended-release tablet. Fesoterodine is rapidly de-esterified to its active metabolite (R)-2-(3-diisopropylamino-1-phenylpropyl)-4-hydroxymethyl-phenol, or 5-hydroxymethyl tolterodine, which is a muscarinic receptor antagonist.
- Chemically, fesoterodine fumarate is designated as isobutyric acid 2-((R)-3-diisopropylammonium-1-phenylpropyl)-4-(hydroxymethyl) phenyl ester hydrogen fumarate. The empirical formula is C30H41NO7 and its molecular weight is 527.66. The structural formula is:
- Fesoterodine fumarate is a white to off-white powder, which is freely soluble in water. Each Toviaz extended-release tablet contains either 4 mg or 8 mg of fesoterodine fumarate and the following inactive ingredients: glyceryl behenate, hypromellose, indigo carmine aluminum lake, lactose monohydrate, soya lecithin, microcrystalline cellulose, polyethylene glycol, polyvinyl alcohol, talc, titanium dioxide, and xylitol.
## Pharmacodynamics
- In a urodynamic study involving patients with involuntary detrusor contractions, the effects after the administration of fesoterodine on the volume at first detrusor contraction and bladder capacity were assessed. Administration of fesoterodine increased the volume at first detrusor contraction and bladder capacity in a dose-dependent manner. These findings are consistent with an antimuscarinic effect on the bladder.
- Cardiac Electrophysiology
- The effect of fesoterodine 4 mg and 28 mg on the QT interval was evaluated in a double-blind, randomized, placebo- and positive-controlled (moxifloxacin 400 mg once a day) parallel trial with once-daily treatment over a period of 3 days in 261 male and female subjects aged 44 to 65 years. Electrocardiographic parameters were measured over a 24-hour period at pre-dose, after the first administration, and after the third administration of study medication. Fesoterodine 28 mg was chosen because this dose, when administered to CYP2D6 extensive metabolizers, results in an exposure to the active metabolite that is similar to the exposure in a CYP2D6 poor metabolizer receiving fesoterodine 8 mg together with CYP3A4 blockade. Corrected QT intervals (QTc) were calculated using Fridericia's correction and a linear individual correction method. Analyses of 24-hour average QTc, time-matched baseline-corrected QTc, and time-matched placebo-subtracted QTc intervals indicate that fesoterodine at doses of 4 and 28 mg/day did not prolong the QT interval. The sensitivity of the study was confirmed by positive QTc prolongation by moxifloxacin.
- Toviaz is associated with an increase in heart rate that correlates with increasing dose. In the study described above, when compared to placebo, the mean increase in heart rate associated with a dose of 4 mg/day and 28 mg/day of fesoterodine was 3 beats/minute and 11 beats/minute, respectively.
- In the two, phase 3, placebo-controlled studies in patients with overactive bladder, the mean increase in heart rate compared to placebo was approximately 3–4 beats/minute in the 4 mg/day group and 3–5 beats/minute in the 8 mg/day group.
## Pharmacokinetics
- Absorption
- After oral administration, fesoterodine is well absorbed. Due to rapid and extensive hydrolysis by nonspecific esterases to its active metabolite 5-hydroxymethyl tolterodine, fesoterodine cannot be detected in plasma. Bioavailability of the active metabolite is 52%. After single or multiple-dose oral administration of fesoterodine in doses from 4 mg to 28 mg, plasma concentrations of the active metabolite are proportional to the dose. Maximum plasma levels are reached after approximately 5 hours. No accumulation occurs after multiple-dose administration.
- A summary of pharmacokinetic parameters for the active metabolite after a single dose of Toviaz 4 mg and 8 mg in extensive and poor metabolizers of CYP2D6 is provided in Table 2.
- Effect of Food
- There is no clinically relevant effect of food on the pharmacokinetics of fesoterodine. In a study of the effects of food on the pharmacokinetics of fesoterodine in 16 healthy male volunteers, concomitant food intake increased the active metabolite of fesoterodine AUC by approximately 19% and Cmax by 18% [see Dosage and Administration (2)].
- Distribution
- Plasma protein binding of the active metabolite is low (approximately 50%) and is primarily bound to albumin and alpha-1-acid glycoprotein. The mean steady-state volume of distribution following intravenous infusion of the active metabolite is 169 L.
- Metabolism
- After oral administration, fesoterodine is rapidly and extensively hydrolyzed to its active metabolite. The active metabolite is further metabolized in the liver to its carboxy, carboxy-N-desisopropyl, and N-desisopropyl metabolites via two major pathways involving CYP2D6 and CYP3A4. None of these metabolites contribute significantly to the antimuscarinic activity of fesoterodine.
- Variability in CYP2D6 Metabolism
- A subset of individuals (approximately 7% of Caucasians and approximately 2% of African Americans) are poor metabolizers for CYP2D6. Cmax and AUC of the active metabolite are increased 1.7- and 2-fold, respectively, in CYP2D6 poor metabolizers, as compared to extensive metabolizers.
- Excretion
- Hepatic metabolism and renal excretion contribute significantly to the elimination of the active metabolite. After oral administration of fesoterodine, approximately 70% of the administered dose was recovered in urine as the active metabolite (16%), carboxy metabolite (34%), carboxy-N-desisopropyl metabolite (18%), or N-desisopropyl metabolite (1%), and a smaller amount (7%) was recovered in feces.
- The terminal half-life of the active metabolite is approximately 4 hours following an intravenous administration. The apparent terminal half-life following oral administration is approximately 7 hours.
- Pharmacokinetics in Specific Populations:
- Geriatric Patients
- Following a single 8 mg oral dose of fesoterodine, the mean (±SD) AUC and Cmax for the active metabolite 5-hydroxymethyl tolterodine in 12 elderly men (mean age 67 years) were 51.8 ± 26.1 h*ng/mL and 3.8 ± 1.7 ng/mL, respectively. In the same study, the mean (±SD) AUC and Cmax in 12 young men (mean age 30 years) were 52.0 ± 31.5 h*ng/mL and 4.1 ± 2.1 ng/mL, respectively. The pharmacokinetics of fesoterodine were not significantly influenced by age.
- Pediatric Patients
- The pharmacokinetics of fesoterodine have not been evaluated in pediatric patients.
- Gender
- Following a single 8 mg oral dose of fesoterodine, the mean (±SD) AUC and Cmax for the active metabolite 5-hydroxymethyl tolterodine in 12 elderly men (mean age 67 years) were 51.8 ± 26.1 h*ng/mL and 3.8 ± 1.7 ng/mL, respectively. In the same study, the mean (±SD) AUC and Cmax in 12 elderly women (mean age 68 years) were 56.0 ± 28.8 h*ng/mL and 4.6 ± 2.3 ng/mL, respectively. The pharmacokinetics of fesoterodine were not significantly influenced by gender.
- Race
- The effects of Caucasian or Black race on the pharmacokinetics of fesoterodine were examined in a study of 12 Caucasian and 12 Black African young male volunteers. Each subject received a single oral dose of 8 mg fesoterodine. The mean (±SD) AUC and Cmax for the active metabolite 5-hydroxymethyl tolterodine in Caucasian males were 73.0 ± 27.8 h*ng/mL and 6.1 ± 2.7 ng/mL, respectively. The mean (±SD) AUC and Cmax in Black males were 65.8 ± 23.2 h*ng/mL and 5.5 ± 1.9 ng/mL, respectively. The pharmacokinetics of fesoterodine were not significantly influenced by race.
- Renal Impairment
- In patients with mild or moderate renal impairment (CLCR ranging from 30–80 mL/min), Cmax and AUC of the active metabolite are increased up to 1.5- and 1.8-fold, respectively, as compared to healthy subjects. In patients with severe renal impairment (CLCR < 30 mL/min), Cmax and AUC are increased 2.0- and 2.3-fold, respectively.
- Hepatic Impairment
- In patients with moderate (Child-Pugh B) hepatic impairment, Cmax and AUC of the active metabolite are increased 1.4- and 2.1-fold, respectively, as compared to healthy subjects.
- Subjects with severe hepatic impairment (Child-Pugh C) have not been studied.
- Drug-Drug Interactions:
- Drugs Metabolized by Cytochrome P450
- At therapeutic concentrations, the active metabolite of fesoterodine does not inhibit CYP1A2, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, or 3A4, or induce CYP1A2, 2B6, 2C9, 2C19, or 3A4 in vitro.
- CYP3A4 Inhibitors
- Following blockade of CYP3A4 by coadministration of the potent CYP3A4 inhibitor ketoconazole 200 mg twice a day for 5 days, Cmax and AUC of the active metabolite of fesoterodine increased 2.0- and 2.3-fold, respectively, after oral administration of Toviaz 8 mg to CYP2D6 extensive metabolizers. In CYP2D6 poor metabolizers, Cmax and AUC of the active metabolite of fesoterodine increased 2.1- and 2.5-fold, respectively, during coadministration of ketoconazole 200 mg twice a day for 5 days. Cmax and AUC were 4.5- and 5.7-fold higher, respectively, in subjects who were CYP2D6 poor metabolizers and taking ketoconazole compared to subjects who were CYP2D6 extensive metabolizers and not taking ketoconazole. In a separate study coadministering fesoterodine with ketoconazole 200 mg once a day for 5 days, the Cmax and AUC values of the active metabolite of fesoterodine were increased 2.2-fold in CYP2D6 extensive metabolizers and 1.5- and 1.9-fold, respectively, in CYP2D6 poor metabolizers. Cmax and AUC were 3.4- and 4.2-fold higher, respectively, in subjects who were CYP2D6 poor metabolizers and taking ketoconazole compared to subjects who were CYP2D6 extensive metabolizers and not taking ketoconazole.
- There is no clinically relevant effect of moderate CYP3A4 inhibitors on the pharmacokinetics of fesoterodine. In a drug-drug interaction study evaluating the coadministration of the moderate CYP3A4 inhibitor fluconazole 200 mg twice a day for 2 days, a single 8 mg dose of fesoterodine was administered 1 hour following the first dose of fluconazole on day 1 of the study. The average (90% confidence interval) for the increase in Cmax and AUC of the active metabolite of fesoterodine was approximately 19% (11% – 28%) and 27% (18% – 36%) respectively.
- The effect of weak CYP3A4 inhibitors (e.g. cimetidine) was not examined; it is not expected to be in excess of the effect of moderate inhibitors.
- CYP3A4 Inducers
- Following induction of CYP3A4 by coadministration of rifampicin 600 mg once a day, Cmax and AUC of the active metabolite of fesoterodine decreased by approximately 70% and 75%, respectively, after oral administration of Toviaz 8 mg. The terminal half-life of the active metabolite was not changed.
- Induction of CYP3A4 may lead to reduced plasma levels. No dosing adjustments are recommended in the presence of CYP3A4 inducers.
- CYP2D6 Inhibitors
- The interaction with CYP2D6 inhibitors was not studied. In poor metabolizers for CYP2D6, representing a maximum CYP2D6 inhibition, Cmax and AUC of the active metabolite are increased 1.7- and 2-fold, respectively.
- Oral Contraceptives
- Thirty healthy female subjects taking an oral contraceptive containing 0.03 mg ethinyl estradiol and 0.15 mg levonorgestrel were evaluated in a 2-period crossover study. Each subject was randomized to receive concomitant administration of either placebo or fesoterodine 8 mg once daily on days 1 – 14 of hormone cycle for 2 consecutive cycles. Pharmacokinetics of ethinyl estradiol and levonorgestrel were assessed on day 13 of each cycle. Fesoterodine increased the AUC and Cmax of ethinyl estradiol by 1 – 3% and decreased the AUC and Cmax of levonorgestrel by 11 – 13%.
- Warfarin
- In a cross-over study in 14 healthy male volunteers (18–55 years), a single oral dose of warfarin 25 mg was given either alone or on day 3 of once daily dosing for 9 days with fesoterodine 8 mg. Compared to warfarin alone dosing, the Cmax and AUC of S-warfarin were lower by ~ 4 %, while the Cmax and AUC of R-warfarin were lower by approximately 8 % and 6% for the co-administration, suggesting absence of a significant pharmacokinetic interaction.
- There were no statistically significant changes in the measured pharmacodynamic parameters for anti-coagulant activity of warfarin (INRmax, AUCINR), with only a small decrease noted in INRmax of ~ 3 % with the co-administration relative to warfarin alone. INR versus time profiles across individual subjects in the study suggested some differences following co-administration with fesoterodine, although there was no definite trend with regard to the changes noted
## Nonclinical Toxicology
- No evidence of drug-related carcinogenicity was found in 24-month studies with oral administration to mice and rats. The highest tolerated doses in mice (females 45 to 60 mg/kg/day, males 30 to 45 mg/kg/day) correspond to 11 to 19 times (females) and 4 to 9 times (males) the estimated human AUC values reached with fesoterodine 8 mg, which is the Maximum Recommended Human Dose (MRHD). In rats, the highest tolerated dose (45 to 60 mg/kg/day) corresponds to 3 to 8 times (females) and 3 to 14 times (males) the estimated human AUC at the MRHD.
- Fesoterodine was not mutagenic or genotoxic in vitro (Ames tests, chromosome aberration tests) or in vivo (mouse micronucleus test).
- Fesoterodine had no effect on reproductive function, fertility, or early embryonic development of the fetus at non-maternally toxic doses in mice. The maternal No-Observed-Effect Level (NOEL) and the NOEL for effects on reproduction and early embryonic development were both 15 mg/kg/day. Based on AUC, the systemic exposure was 0.6 to 1.5 times higher in mice than in humans at the MRHD, whereas based on peak plasma concentrations, the exposure in mice was 5 to 9 times higher. The Lowest-Observed-Effect Level (LOEL) for maternal toxicity was 45 mg/kg/day.
# Clinical Studies
- Toviaz extended-release tablets were evaluated in two, Phase 3, randomized, double-blind, placebo-controlled, 12-week studies for the treatment of overactive bladder with symptoms of urge urinary incontinence, urgency, and urinary frequency. Entry criteria required that patients have symptoms of overactive bladder for ≥ 6-months duration, at least 8 micturitions per day, and at least 6 urinary urgency episodes or 3 urge incontinence episodes per 3-day diary period. Patients were randomized to a fixed dose of Toviaz 4 or 8 mg/day or placebo. In one of these studies, 290 patients were randomized to an active control arm (an oral antimuscarinic agent). For the combined studies, a total of 554 patients received placebo, 554 patients received Toviaz 4 mg/day, and 566 patients received Toviaz 8 mg/day. The majority of patients were Caucasian (91%) and female (79%) with a mean age of 58 years (range 19–91 years).
- The primary efficacy endpoints were the mean change in the number of urge urinary incontinence episodes per 24 hours and the mean change in the number of micturitions (frequency) per 24 hours. An important secondary endpoint was the mean change in the voided volume per micturition.
- Results for the primary endpoints and for mean change in voided volume per micturition from the two 12-week clinical studies of Toviaz are reported in Table 3.
- Figures 1–4: The following figures show change from baseline over time in number of micturitions and urge urinary incontinence episodes per 24 h in the two studies.
- A reduction in number of urge urinary incontinence episodes per 24 hours was observed for both doses as compared to placebo as early as two weeks after starting Toviaz therapy.
# How Supplied
- Toviaz (fesoterodine fumarate) extended-release tablets 4 mg are light blue, oval, biconvex, film-coated, and engraved with "FS" on one side. They are supplied as follows:
- Bottles of 30 NDC 0069-0242-30
- Bottles of 90 NDC 0069-0242-68
- Unit Dose Package of 100 NDC 0069-0242-41
- Toviaz (fesoterodine fumarate) extended-release tablets 8 mg are blue, oval, biconvex, film-coated, and engraved with "FT" on one side. They are supplied as follows:
- Bottles of 30 NDC 0069-0244-30
- Bottles of 90 NDC 0069-0244-68
- Unit Dose Package of 100 NDC 0069-0244-41
- Store at 20° to 25°C (68° to 77°F); excursions permitted between 15° to 30°C (59° to 86°F). Protect from moisture.
## Storage
There is limited information regarding Fesoterodine Storage in the drug label.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- Patients should be informed that fesoterodine may produce angioedema, which could result in life-threatening airway obstruction. Patients should be advised to promptly discontinue fesoterodine therapy and seek immediate medical attention if they experience edema of the tongue or laryngopharynx, or difficult breathing.
- Patients should be informed that Toviaz, like other antimuscarinic agents, may produce clinically significant adverse effects related to antimuscarinic pharmacological activity including constipation and urinary retention. Toviaz, like other antimuscarinics, may be associated with blurred vision, therefore, patients should be advised to exercise caution in decisions to engage in potentially dangerous activities until the drug's effects on the patient have been determined. Heat prostration (due to decreased sweating) can occur when Toviaz, like other antimuscarinic drugs, is used in a hot environment.
- Patients should also be informed that alcohol may enhance the drowsiness caused by Toviaz, like other anticholinergic agents. Patients should read the patient leaflet entitled "Patient Information TOVIAZ" before starting therapy with Toviaz.
# Precautions with Alcohol
- Alcohol-Fesoterodine interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- TOVIAZ®[1]
# Look-Alike Drug Names
There is limited information regarding Fesoterodine Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Fesoterodine | |
eec33d9d96a453e6d32eab9cb15c5528b692a4f3 | wikidoc | Fexinidazole | Fexinidazole
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# Overview
Fexinidazole is a nitroimidazole antimicrobial that is FDA approved for the treatment of human African trypanosomiasis caused by the parasite Trypanosoma brucei gambiense. Common adverse reactions include hypocalcemia, upper abdominal pain, insomnia, dyspepsia, decreased appetite, hyperkalemia, back pain, nausea, dizziness, asthenia, tremor, and headache..
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Administer Fexinidazole dosage once daily for a total of 10 days.
- Administer Fexinidazole dosage with food at around the same time each day.
Table 1 summarizes Recommended Dosage of Fexinidazole Tablets in Patients 6 Years of Age and Older and Weighing at Least 20 kg.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Fexinidazole in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Fexinidazole in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding Fexinidazole 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 Fexinidazole in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Fexinidazole in pediatric patients.
# Contraindications
- Patients with known hypersensitivity to any nitroimidazole-class drugs or Fexinidazole Tablets.
- Patients with hepatic impairment.
- Patients with Cockayne syndrome.
# Warnings
Decreased Efficacy in Severe Human African Trypanosomiasis Caused by Trypanosoma brucei gambiense
- In a clinical study, patients treated with Fexinidazole Tablets observed a decreased efficacy in comparison to patients treated with nifurtimox-eflornithine combination therapy.
- 86.9% with Fexinidazole Tablets is the 18-month success rate for patients with severe second stage disease.
- 98.7% with NECT is the 18-month success rate for patients with severe second stage disease.
- Use of Fexinidazole Tablets are recommended for treatment in patients with severe second stage HAT due to T. brucei gambiense disease.
QT Interval Prolongation
- QT interval is prolonged in Fexinidazole Tablets in a concentration-dependent manner.
- 19 msec increase was seen in the QTcF interval due to the Fexinidazole Tablets.
- Advise patients with QTcF interval greater than 470 msec to avoid Fexinidazole treatment.
- Advise patients with a history of torsade de pointes, congenital long QT syndrome, cardiac arrhythmias, uncompensated heart failure, or family history of sudden death to avoid Fexinidazole treatment.
- Advise patients with uncorrected hypokalemia to avoid Fexinidazole treatment.
- Advise patients to avoid concomitant administration of inducers of hepatic CYP450 and Fexinidazole.
- Advise patients to avoid concomitant administration with drugs that block cardiac potassium channels, prolong the QT interval, or those that induce bradycardia with Fexinidazole.
Neuropsychiatric Adverse Reactions
- In clinical studies, a higher percentage of psychiatric-related adverse reactions and Central Nervous System adverse reactions were reported in patients part of the group receiving Fexinidazole than those receiving nifurtimox eflornithine combination therapy.
- Headaches, insomnia, and tremor were more reported in patients part of the group receiving Fexinidazole than those receiving nifurtimox eflornithine combination therapy.
- Some patients reported suicidal ideation when treated with Fexinidazole.
- Advise patients who are about to start Fexinidazole treatment about potential neuropsychiatric adverse reactions.
- Alternative therapy or extreme monitoring of patient may needed if patient currently have or a history of psychiatric disorders.
Neutropenia
- Patients have reported experiencing neutropenia when treated with Fexinidazole.
- Patients with a baseline absolute neutrophil count of less than 5,000 cells/mm3 experienced adverse reactions in Trial 1 studies.
- Advise patients to avoid concomitant administration with drugs that may cause neutropenia with Fexinidazole.
- Monitor patients leukocyte count periodically when they are taking Fexinidazole.
- Advise patients to seek proper treatment if they experience fever or other symptoms or signs of infection.
Potential for Hepatotoxicity
- Less than 2% of patients receiving Fexinidazole experienced elevations in liver transaminases.
- Monitor lab results of the liver in patients both baseline and during Fexinidazole treatment.
- Monitor patients for abnormal liver-related laboratory tests during Fexinidazole treatment.
Risk of Disulfiram-like Reaction Due to Concomitant Use with Alcohol
- Disulfiram-like reactions may occur in patients who consume alcohol.
- Advise patients to avoid during and 48 hours after completing Fexinidazole treatment the consumption of alcohol.
Risk of Psychotic Reactions Due to Concomitant Use with Disulfiram
- Advise patients that the concomitant administration of nitroimidazole or disulfiram drugs with Fexinidazole may cause psychotic reactions.
- If patients have taken disulfiram during the last two weeks, avoid administration of Fexinidazole.
# Adverse Reactions
## Clinical Trials Experience
Clinical Trials 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.
- Trial 1 looked at 394 patients with second stage, meningoencephalitic HAT to understand the safety of Fexinidazole in comparison to nifurtimox-eflornithine combination therapy.
- 264 patients in Trial 1 were part of the group receiving Fexinidazole while the other 130 patients were part of nifurtimox-eflornithine combination therapy.
- Trial 2 looked into the safety of Fexinidazole for 230 patients with stage 1 hemolymphatic and early stage 2 HAT.
- Trial 3 looked into the safety of Fexinidazole for pediatric patients that had any stage of HAT with an age older than 6 years of age.
- The patient population tended to be more males than females in Trial 1 and 3 while it was equally distributed in Trial 2.
- 16.1 to 19.3 kg/m2 is the mean BMI in all trials being conducted.
- Dizziness, hypocalcemia, dyspepsia, back pain, insomnia, nausea, asthenia, tremor, decreased appetite, hyperkalemia, upper abdominal pain, vomiting, and headaches were the most common adverse reactions reported in Trial 1 studies.
- Elevated liver transaminases and pychiatric disorders were reported in less 2% of patients for Trial 1 studies.
- Vomiting occurred more in pediatric patients taking Fexinidazole than adult patients taking Fexinidazole.
Table 2 shows the Selected Adverse Reactions Occurring in ≥2% of HAT Patients 15 Years of Age and Older Receiving Fexinidazole Tablets in Trial 1.
## Postmarketing Experience
- Patients with Cockayne syndrome experienced acute liver failure and severe irreversible hepatotoxicity after use of metronidazole.
# Drug Interactions
Pharmacodynamic Interactions
- Herbal medicines/supplements with Fexinidazole has the potential for pharmacodynamic interactions and/or toxicities.
- Advise patients to avoid concomitant administration with herbal medicines/supplements with Fexinidazole.
- Avoid co-administration of block potassium channels and Fexinidazole as it prolongs the QT interval.
Pharmacokinetic Drug Interactions
Table 3 shows Effect of Fexinidazole on other Drugs.
Table 4 shows Effect of other Drugs on Fexinidazole.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
During pregnancy, both the mother and fetus are at risk with untreated HAT due to T. brucei gambiense. Insufficient data has been conducted looking into the risk of major birth defects or miscarriage of pregnant women. Animal studies done on pregnant rats given oral Fexinidazole showed no effects on prenatal development. Lower body weights were observed in first generation offspring when pregnant rats were given oral Fexinidazole. Advise pregnant women with HAT due to T. brucei gambiense, to be treated which can prevent vertical transmission.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Fexinidazole in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Fexinidazole 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 Fexinidazole. Animal studies done on nursing rats show that rat milk contains Fexinidazole. Advise patients about potential adverse reactions associated with Fexinidazole on the breastfed child.
### Pediatric Use
Studies done on pediatric patients aged 6 years and older have tested the safety and effectiveness of Fexinidazole. Pediatric patients were more likely to experience vomiting. When comparing pediatric patients and adults, the safety profile of Fexinidazole was similar in both.
### Geriatic Use
There is not enough elderly patients to look into the safety and effectiveness of Fexinidazole when comparing young and elderly patients.
### Gender
There is no FDA guidance on the use of Fexinidazole with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Fexinidazole with respect to specific racial populations.
### Renal Impairment
Patients with mild to moderate renal impairment do not need to adjust dosage of Fexinidazole. Advise patients to avoid use of Fexinidazole if they have severe renal impairment.
### Hepatic Impairment
The pharmacokinetics of Fexinidazole is unknown in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Fexinidazole in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Fexinidazole in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Advise patients to eat food when taking Fexinidazole.
- Advise patients to avoid alcoholic beverages during and 48 hours after completing Fexinidazole treatment.
- Advise patients do not re-dose on Fexinidazole tablets if they vomit for the first time.
### Monitoring
- Monitor patients signs and symptoms during Fexinidazole treatment.
- If a dosage is missed on a day, advise patients to continue normal Fexinidazole dosing next day.
# IV Compatibility
There is limited information regarding the compatibility of Fexinidazole and IV administrations.
# Overdosage
- In clinical studies, males given up to 3,600 mg of Fexinidazole daily for 14 days experienced adverse reactions such as vomiting, increased transaminases, and panic attack.
- Vomiting, decreased calcium levels, and increased potassium levels are symptoms of overdosage.
# Pharmacology
## Mechanism of Action
- Fexinidazole is an antiprotozoal drug.
## Structure
- Fexinidazole is a nitroimidazole antimicrobial drug. It has an empirical formula of C12H13N3O3S and a molecular weight of 279.3 g/mol.
## Pharmacodynamics
Cardiac Electrophysiology
- 19.0 msec is the mean increase in QTcF for the recommended dosage of Fexinidazole.
- M2 metabolite is the potential reason for the increase in QTcF.
## Pharmacokinetics
Pharmacokinetics
Table 5 summarizes the Pharmacokinetics of Fexinidazole and its two pharmacologically active M1 and M2 metabolites.
Specific Populations
Elderly patients:
- Pharmacokinetic studies have not been done patients older than 65 years of age.
- No significant covariate affecting the PK of fexinidazole was due to age.
Pediatric patients:
- Similar systemic exposures of plasma AUC values was seen in both adult and pediatric patients.
Hepatic impairment:
- Studies on patients with hepatic impairment have not been conducted that look at the pharmacokinetics.
Renal Impairment:
- Clinical studies show similar AUC0–24 for Fexinidazole and its metabolites between patients without renal impairment and patients with mild or moderate renal impairment.
Race/ethnicity:
- When looking at race and ethnicity, no studies have been conducted to make any conclusions on its effects of the pharmacokinetics of Fexinidazole.
Drug Interaction Studies
In vitro studies:
- CYP2B6, CYP3A4/5, CYP2C19, CYP1A2, and CYP2D6 are potentially inhibited by Fexinidazole.
- CYP2C19 is potentially inhibited by M1.
- CYPs are not inhibited by M2.
- CYP3A4 is not induced by Fexinidazole, M1, or M2.
- CYP2B6 and CYP1A2 are potentially induced by Fexinidazole and M1.
- OCT2, OAT1, OAT3, MATE2-K, OATP1B1, MATE1, and OATP1B3 are inhibited by Fexinidazole.
- MATE1, OAT3, and MATE2-K are inhibited by M1.
- OAT1, OAT3, MATE2-K, OCT2, and MATE1 are inhibited M2.
- P-gp or BCRP is not inhibited by Fexinidazole, M1, or M2.
## Nonclinical Toxicology
Carcinogenicity
- When looking into Fexinidazole, no carcinogenicity study was conducted.
Mutagenesis
- In the Ames test, Fexinidazole and the M2 metabolite were mutagenic.
- In the rat liver unscheduled DNA synthesis assay, in the in vitro micronucleus test, and in the vivo mouse micronucleus assay, Fexinidazole was negative.
Impairment of Fertility
- In animal studies, there is no effect on fertility parameters and no evidence of impairment of reproductive performance in rats given Fexinidazole.
# Clinical Studies
Trial 1
- A randomized, comparative open-label trial that looked into the safety and effectiveness of Fexinidazole.
- Trial included 394 patients with late second-stage HAT due to T. brucei gambiense.
- Patients in the trial either received Fexinidazole Tablets (264) or Nifurtimox-eflornithine combination therapy (130).
- Patient population of the trial had a mean age of 35 years of age and mostly consisted of men (61%).
- The trial looked at success rate of patients in each group.
- Success is defined as a patient that is alive with no evidence of trypanosomes in any body fluid and CSF WBC ≤20 cells/µL. Another definition of success was patients had no parasites in the blood or lymph and a satisfactory clinical condition without clinical signs or symptoms.
Table 6 summarizes the success rate in Trial 1 at 18 months.
Trial 2 and Trial 3
- Trial 2 was a single-arm trial in adult patients with in early stage HAT due to T. brucei gambiense that looked into the efficacy of Fexinidazole.
- 98.7% is the success rate of Fexinidazole treatment in Trial 2 patients.
- Trial 3 was a single-arm trial in pediatric patients with in early stage HAT due to T. brucei gambiense that looked into the efficacy of Fexinidazole.
- 97.6% is the success rate of Fexinidazole treatment in Trial 3 patients.
# How Supplied
- 600 mg yellow/pale tablets as either a 14 pack for pediatric patients older than 6 years weighing 20 kg to less than 35 kg.
- 600 mg yellow/pale tablets as either a 24 pack for adult and pediatric patients weighing 35 kg or more.
## Storage
- Store below 30°C.
- To protect against moisture or light, store Fexinidazole tablets in original packaging.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
Administration with Food
- Advise patients that Fexinidazole should be taken at the same time each day with a meal.
Alcohol Consumption
- Advise patients during and 48 hours after Fexinidazole treatment to refrain from alcohol consumption.
Vomiting
- Advise patients if vomiting occurs to not take an additional dosage, but to take the next scheduled dosage.
- Advise patients to seek medical counseling if vomiting occurs more than once.
Missed Doses
- Advise patients to resume dosage the next day if a scheduled dosage is missed.
Neuropsychiatric Adverse Reactions
- Advise patients when taking Fexinidazole about the neuropsychiatric adverse reactions that may occur.
- Headache, mood changes, insomnia, suicidal ideation, psychiatric disorders, and tremors are some of the neuropsychiatric adverse reactions when taking Fexinidazole that may occur.
- Advise patients to seek medical consultation if they experience neuropsychiatric adverse reactions.
Dizziness
- Advise patients to avoid driving if experiencing dizziness or tiredness.
- Advise patients that side effects of taking Fexinidazole include asthenia, dizziness, somnolence, and fatigue.
Drug Interactions
- Advise patients who are taking other medications to consult with their medical provider.
# Precautions with Alcohol
Alcohol-Fexinidazole interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Fexinidazole
# Look-Alike Drug Names
There is limited information regarding Fexinidazole Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | Fexinidazole
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Tejasvi Aryaputra
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# Overview
Fexinidazole is a nitroimidazole antimicrobial that is FDA approved for the treatment of human African trypanosomiasis caused by the parasite Trypanosoma brucei gambiense. Common adverse reactions include hypocalcemia, upper abdominal pain, insomnia, dyspepsia, decreased appetite, hyperkalemia, back pain, nausea, dizziness, asthenia, tremor, and headache..
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Administer Fexinidazole dosage once daily for a total of 10 days.
- Administer Fexinidazole dosage with food at around the same time each day.
Table 1 summarizes Recommended Dosage of Fexinidazole Tablets in Patients 6 Years of Age and Older and Weighing at Least 20 kg.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Fexinidazole in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Fexinidazole in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding Fexinidazole 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 Fexinidazole in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Fexinidazole in pediatric patients.
# Contraindications
- Patients with known hypersensitivity to any nitroimidazole-class drugs or Fexinidazole Tablets.
- Patients with hepatic impairment.
- Patients with Cockayne syndrome.
# Warnings
Decreased Efficacy in Severe Human African Trypanosomiasis Caused by Trypanosoma brucei gambiense
- In a clinical study, patients treated with Fexinidazole Tablets observed a decreased efficacy in comparison to patients treated with nifurtimox-eflornithine combination therapy.
- 86.9% with Fexinidazole Tablets is the 18-month success rate for patients with severe second stage disease.
- 98.7% with NECT is the 18-month success rate for patients with severe second stage disease.
- Use of Fexinidazole Tablets are recommended for treatment in patients with severe second stage HAT due to T. brucei gambiense disease.
QT Interval Prolongation
- QT interval is prolonged in Fexinidazole Tablets in a concentration-dependent manner.
- 19 msec increase was seen in the QTcF interval due to the Fexinidazole Tablets.
- Advise patients with QTcF interval greater than 470 msec to avoid Fexinidazole treatment.
- Advise patients with a history of torsade de pointes, congenital long QT syndrome, cardiac arrhythmias, uncompensated heart failure, or family history of sudden death to avoid Fexinidazole treatment.
- Advise patients with uncorrected hypokalemia to avoid Fexinidazole treatment.
- Advise patients to avoid concomitant administration of inducers of hepatic CYP450 and Fexinidazole.
- Advise patients to avoid concomitant administration with drugs that block cardiac potassium channels, prolong the QT interval, or those that induce bradycardia with Fexinidazole.
Neuropsychiatric Adverse Reactions
- In clinical studies, a higher percentage of psychiatric-related adverse reactions and Central Nervous System adverse reactions were reported in patients part of the group receiving Fexinidazole than those receiving nifurtimox eflornithine combination therapy.
- Headaches, insomnia, and tremor were more reported in patients part of the group receiving Fexinidazole than those receiving nifurtimox eflornithine combination therapy.
- Some patients reported suicidal ideation when treated with Fexinidazole.
- Advise patients who are about to start Fexinidazole treatment about potential neuropsychiatric adverse reactions.
- Alternative therapy or extreme monitoring of patient may needed if patient currently have or a history of psychiatric disorders.
Neutropenia
- Patients have reported experiencing neutropenia when treated with Fexinidazole.
- Patients with a baseline absolute neutrophil count of less than 5,000 cells/mm3 experienced adverse reactions in Trial 1 studies.
- Advise patients to avoid concomitant administration with drugs that may cause neutropenia with Fexinidazole.
- Monitor patients leukocyte count periodically when they are taking Fexinidazole.
- Advise patients to seek proper treatment if they experience fever or other symptoms or signs of infection.
Potential for Hepatotoxicity
- Less than 2% of patients receiving Fexinidazole experienced elevations in liver transaminases.
- Monitor lab results of the liver in patients both baseline and during Fexinidazole treatment.
- Monitor patients for abnormal liver-related laboratory tests during Fexinidazole treatment.
Risk of Disulfiram-like Reaction Due to Concomitant Use with Alcohol
- Disulfiram-like reactions may occur in patients who consume alcohol.
- Advise patients to avoid during and 48 hours after completing Fexinidazole treatment the consumption of alcohol.
Risk of Psychotic Reactions Due to Concomitant Use with Disulfiram
- Advise patients that the concomitant administration of nitroimidazole or disulfiram drugs with Fexinidazole may cause psychotic reactions.
- If patients have taken disulfiram during the last two weeks, avoid administration of Fexinidazole.
# Adverse Reactions
## Clinical Trials Experience
Clinical Trials 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.
- Trial 1 looked at 394 patients with second stage, meningoencephalitic HAT to understand the safety of Fexinidazole in comparison to nifurtimox-eflornithine combination therapy.
- 264 patients in Trial 1 were part of the group receiving Fexinidazole while the other 130 patients were part of nifurtimox-eflornithine combination therapy.
- Trial 2 looked into the safety of Fexinidazole for 230 patients with stage 1 hemolymphatic and early stage 2 HAT.
- Trial 3 looked into the safety of Fexinidazole for pediatric patients that had any stage of HAT with an age older than 6 years of age.
- The patient population tended to be more males than females in Trial 1 and 3 while it was equally distributed in Trial 2.
- 16.1 to 19.3 kg/m2 is the mean BMI in all trials being conducted.
- Dizziness, hypocalcemia, dyspepsia, back pain, insomnia, nausea, asthenia, tremor, decreased appetite, hyperkalemia, upper abdominal pain, vomiting, and headaches were the most common adverse reactions reported in Trial 1 studies.
- Elevated liver transaminases and pychiatric disorders were reported in less 2% of patients for Trial 1 studies.
- Vomiting occurred more in pediatric patients taking Fexinidazole than adult patients taking Fexinidazole.
Table 2 shows the Selected Adverse Reactions Occurring in ≥2% of HAT Patients 15 Years of Age and Older Receiving Fexinidazole Tablets in Trial 1.
## Postmarketing Experience
- Patients with Cockayne syndrome experienced acute liver failure and severe irreversible hepatotoxicity after use of metronidazole.
# Drug Interactions
Pharmacodynamic Interactions
- Herbal medicines/supplements with Fexinidazole has the potential for pharmacodynamic interactions and/or toxicities.
- Advise patients to avoid concomitant administration with herbal medicines/supplements with Fexinidazole.
- Avoid co-administration of block potassium channels and Fexinidazole as it prolongs the QT interval.
Pharmacokinetic Drug Interactions
Table 3 shows Effect of Fexinidazole on other Drugs.
Table 4 shows Effect of other Drugs on Fexinidazole.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
During pregnancy, both the mother and fetus are at risk with untreated HAT due to T. brucei gambiense. Insufficient data has been conducted looking into the risk of major birth defects or miscarriage of pregnant women. Animal studies done on pregnant rats given oral Fexinidazole showed no effects on prenatal development. Lower body weights were observed in first generation offspring when pregnant rats were given oral Fexinidazole. Advise pregnant women with HAT due to T. brucei gambiense, to be treated which can prevent vertical transmission.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Fexinidazole in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Fexinidazole 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 Fexinidazole. Animal studies done on nursing rats show that rat milk contains Fexinidazole. Advise patients about potential adverse reactions associated with Fexinidazole on the breastfed child.
### Pediatric Use
Studies done on pediatric patients aged 6 years and older have tested the safety and effectiveness of Fexinidazole. Pediatric patients were more likely to experience vomiting. When comparing pediatric patients and adults, the safety profile of Fexinidazole was similar in both.
### Geriatic Use
There is not enough elderly patients to look into the safety and effectiveness of Fexinidazole when comparing young and elderly patients.
### Gender
There is no FDA guidance on the use of Fexinidazole with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Fexinidazole with respect to specific racial populations.
### Renal Impairment
Patients with mild to moderate renal impairment do not need to adjust dosage of Fexinidazole. Advise patients to avoid use of Fexinidazole if they have severe renal impairment.
### Hepatic Impairment
The pharmacokinetics of Fexinidazole is unknown in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Fexinidazole in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Fexinidazole in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Advise patients to eat food when taking Fexinidazole.
- Advise patients to avoid alcoholic beverages during and 48 hours after completing Fexinidazole treatment.
- Advise patients do not re-dose on Fexinidazole tablets if they vomit for the first time.
### Monitoring
- Monitor patients signs and symptoms during Fexinidazole treatment.
- If a dosage is missed on a day, advise patients to continue normal Fexinidazole dosing next day.
# IV Compatibility
There is limited information regarding the compatibility of Fexinidazole and IV administrations.
# Overdosage
- In clinical studies, males given up to 3,600 mg of Fexinidazole daily for 14 days experienced adverse reactions such as vomiting, increased transaminases, and panic attack.
- Vomiting, decreased calcium levels, and increased potassium levels are symptoms of overdosage.
# Pharmacology
## Mechanism of Action
- Fexinidazole is an antiprotozoal drug.
## Structure
- Fexinidazole is a nitroimidazole antimicrobial drug. It has an empirical formula of C12H13N3O3S and a molecular weight of 279.3 g/mol.
## Pharmacodynamics
Cardiac Electrophysiology
- 19.0 msec is the mean increase in QTcF for the recommended dosage of Fexinidazole.
- M2 metabolite is the potential reason for the increase in QTcF.
## Pharmacokinetics
Pharmacokinetics
Table 5 summarizes the Pharmacokinetics of Fexinidazole and its two pharmacologically active M1 and M2 metabolites.
Specific Populations
Elderly patients:
- Pharmacokinetic studies have not been done patients older than 65 years of age.
- No significant covariate affecting the PK of fexinidazole was due to age.
Pediatric patients:
- Similar systemic exposures of plasma AUC values was seen in both adult and pediatric patients.
Hepatic impairment:
- Studies on patients with hepatic impairment have not been conducted that look at the pharmacokinetics.
Renal Impairment:
- Clinical studies show similar AUC0–24 for Fexinidazole and its metabolites between patients without renal impairment and patients with mild or moderate renal impairment.
Race/ethnicity:
- When looking at race and ethnicity, no studies have been conducted to make any conclusions on its effects of the pharmacokinetics of Fexinidazole.
Drug Interaction Studies
In vitro studies:
- CYP2B6, CYP3A4/5, CYP2C19, CYP1A2, and CYP2D6 are potentially inhibited by Fexinidazole.
- CYP2C19 is potentially inhibited by M1.
- CYPs are not inhibited by M2.
- CYP3A4 is not induced by Fexinidazole, M1, or M2.
- CYP2B6 and CYP1A2 are potentially induced by Fexinidazole and M1.
- OCT2, OAT1, OAT3, MATE2-K, OATP1B1, MATE1, and OATP1B3 are inhibited by Fexinidazole.
- MATE1, OAT3, and MATE2-K are inhibited by M1.
- OAT1, OAT3, MATE2-K, OCT2, and MATE1 are inhibited M2.
- P-gp or BCRP is not inhibited by Fexinidazole, M1, or M2.
## Nonclinical Toxicology
Carcinogenicity
- When looking into Fexinidazole, no carcinogenicity study was conducted.
Mutagenesis
- In the Ames test, Fexinidazole and the M2 metabolite were mutagenic.
- In the rat liver unscheduled DNA synthesis assay, in the in vitro micronucleus test, and in the vivo mouse micronucleus assay, Fexinidazole was negative.
Impairment of Fertility
- In animal studies, there is no effect on fertility parameters and no evidence of impairment of reproductive performance in rats given Fexinidazole.
# Clinical Studies
Trial 1
- A randomized, comparative open-label trial that looked into the safety and effectiveness of Fexinidazole.
- Trial included 394 patients with late second-stage HAT due to T. brucei gambiense.
- Patients in the trial either received Fexinidazole Tablets (264) or Nifurtimox-eflornithine combination therapy (130).
- Patient population of the trial had a mean age of 35 years of age and mostly consisted of men (61%).
- The trial looked at success rate of patients in each group.
- Success is defined as a patient that is alive with no evidence of trypanosomes in any body fluid and CSF WBC ≤20 cells/µL. Another definition of success was patients had no parasites in the blood or lymph and a satisfactory clinical condition without clinical signs or symptoms.
Table 6 summarizes the success rate in Trial 1 at 18 months.
Trial 2 and Trial 3
- Trial 2 was a single-arm trial in adult patients with in early stage HAT due to T. brucei gambiense that looked into the efficacy of Fexinidazole.
- 98.7% is the success rate of Fexinidazole treatment in Trial 2 patients.
- Trial 3 was a single-arm trial in pediatric patients with in early stage HAT due to T. brucei gambiense that looked into the efficacy of Fexinidazole.
- 97.6% is the success rate of Fexinidazole treatment in Trial 3 patients.
# How Supplied
- 600 mg yellow/pale tablets as either a 14 pack for pediatric patients older than 6 years weighing 20 kg to less than 35 kg.
- 600 mg yellow/pale tablets as either a 24 pack for adult and pediatric patients weighing 35 kg or more.
## Storage
- Store below 30°C.
- To protect against moisture or light, store Fexinidazole tablets in original packaging.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
Administration with Food
- Advise patients that Fexinidazole should be taken at the same time each day with a meal.
Alcohol Consumption
- Advise patients during and 48 hours after Fexinidazole treatment to refrain from alcohol consumption.
Vomiting
- Advise patients if vomiting occurs to not take an additional dosage, but to take the next scheduled dosage.
- Advise patients to seek medical counseling if vomiting occurs more than once.
Missed Doses
- Advise patients to resume dosage the next day if a scheduled dosage is missed.
Neuropsychiatric Adverse Reactions
- Advise patients when taking Fexinidazole about the neuropsychiatric adverse reactions that may occur.
- Headache, mood changes, insomnia, suicidal ideation, psychiatric disorders, and tremors are some of the neuropsychiatric adverse reactions when taking Fexinidazole that may occur.
- Advise patients to seek medical consultation if they experience neuropsychiatric adverse reactions.
Dizziness
- Advise patients to avoid driving if experiencing dizziness or tiredness.
- Advise patients that side effects of taking Fexinidazole include asthenia, dizziness, somnolence, and fatigue.
Drug Interactions
- Advise patients who are taking other medications to consult with their medical provider.
# Precautions with Alcohol
Alcohol-Fexinidazole interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Fexinidazole
# Look-Alike Drug Names
There is limited information regarding Fexinidazole Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Fexinidazole | |
c2d8c1eb827097943359c15e7e518f86789c2e26 | wikidoc | Fibrillation | Fibrillation
Fibrillation is the rapid, irregular, and unsynchronized contraction of the muscle fibers of the heart. There are two major classes of fibrillation, atrial fibrillation and ventricular fibrillation.
- Atrial fibrillation can be a chronic condition, usually treated with anticoagulation and sometimes with conversion to normal sinus rhythm.
- Ventricular fibrillation is rapidly fatal if not reversed by defibrillation.
Fibrillation may sometimes be used after heart surgery to stop the heart from beating while any minor leaks are stitched up. Medifib
# Links
- Simulated Ventricular Fibrillation Interactive Java applet, with information.
- Simulated Atrial Fibrillation Interactive Java applet, with information. | Fibrillation
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Fibrillation is the rapid, irregular, and unsynchronized contraction of the muscle fibers of the heart. There are two major classes of fibrillation, atrial fibrillation and ventricular fibrillation.
- Atrial fibrillation can be a chronic condition, usually treated with anticoagulation and sometimes with conversion to normal sinus rhythm.
- Ventricular fibrillation is rapidly fatal if not reversed by defibrillation.
Fibrillation may sometimes be used after heart surgery to stop the heart from beating while any minor leaks are stitched up. Medifib
# Links
- Simulated Ventricular Fibrillation Interactive Java applet, with information.
- Simulated Atrial Fibrillation Interactive Java applet, with information.
Template:WikiDoc Sources | https://www.wikidoc.org/index.php/Fibrillation | |
61099f28c0cddd1f305ee6a72e8e897b45de7b3c | wikidoc | Fibrinolysin | Fibrinolysin
# Overview
Fibrinolysin is an enzyme derived from plasma of bovine origin or extracted from cultures of certain bacteria. It is used locally only and exclusively together with the enzyme desoxyribonuclease (extracted from bovine pancreas). Fibrinolysin and desoxyribonuclease both act as lytic enzymes. The combination is available as ointment containing 1 BU (Biological Unit) fibrinolysin and 666 BUs desoxyribonuclease per gram.
Fibrinolysin attacks and inactivates fibrin molecules occurring in undesirable exudates on the surface of the human body and on human mucosa, e.g., in superficial wounds and burns, while desoxyribonuclease targets and destroys (human) DNA. The combination of the two enzymes has a synergistic effect on necrotic but not on living tissue. According to the manufacturer the ointment provides enhanced wound cleaning and accelerates the healing process.
Both enzymes are marginally resorbed into systemic circulation because of their very high molecular weight and their macromolecular structure.
The activity of both enzymes is almost completely exhausted after 24 hours. Usually, it is necessary to repeat the application (and renew the dressing) every 6 to 8 hours until healing becomes complete.
The ointment is marketed by Pfizer under the brand name Fibrolan® in a variety of countries (e.g. Switzerland). It is currently not approved in the USA.
Where approved, Fibrolan® has been licensed on the basis of claimed good therapeutical experience, but adequate and well controlled studies are still lacking.
In the past, combinations with the antibiotic chloramphenicol were available, but because chloramphenicol in any form of application has led to aplastic anemia and death, these were banned. Additionally, combinations with the antifibrinolytic agent tranexamic acid have been withdrawn from pharma markets.
# Indications
Enzymatic wound cleaning to assist healing of minor burns, superficial wounds, ulcus cruris, and superficial hematoma.
# Contraindications and Precautions
The ointment should not be used in patients with a known hypersensitivity to any ingredient. It should be used with caution in patients with hypersensitivity to bovine proteins in general and in pregnant women (category C), because no human data is available.
# Side-Effects
Infrequently, local reactions such as increased pain or a stitching/burning sensation are noticed. No systemic anticoagulant activity has been seen due to the exclusively local character of treatment.
# Interactions
Not known.
# External References
- Swiss scientific product information
- (on chemical/biochemical properties) | Fibrinolysin
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Fibrinolysin is an enzyme derived from plasma of bovine origin or extracted from cultures of certain bacteria. It is used locally only and exclusively together with the enzyme desoxyribonuclease (extracted from bovine pancreas). Fibrinolysin and desoxyribonuclease both act as lytic enzymes. The combination is available as ointment containing 1 BU (Biological Unit) fibrinolysin and 666 BUs desoxyribonuclease per gram.
Fibrinolysin attacks and inactivates fibrin molecules occurring in undesirable exudates on the surface of the human body and on human mucosa, e.g., in superficial wounds and burns, while desoxyribonuclease targets and destroys (human) DNA. The combination of the two enzymes has a synergistic effect on necrotic but not on living tissue. According to the manufacturer the ointment provides enhanced wound cleaning and accelerates the healing process.
Both enzymes are marginally resorbed into systemic circulation because of their very high molecular weight and their macromolecular structure.
The activity of both enzymes is almost completely exhausted after 24 hours. Usually, it is necessary to repeat the application (and renew the dressing) every 6 to 8 hours until healing becomes complete.
The ointment is marketed by Pfizer under the brand name Fibrolan® in a variety of countries (e.g. Switzerland). It is currently not approved in the USA.
Where approved, Fibrolan® has been licensed on the basis of claimed good therapeutical experience, but adequate and well controlled studies are still lacking.
In the past, combinations with the antibiotic chloramphenicol were available, but because chloramphenicol in any form of application has led to aplastic anemia and death, these were banned. Additionally, combinations with the antifibrinolytic agent tranexamic acid have been withdrawn from pharma markets.
# Indications
Enzymatic wound cleaning to assist healing of minor burns, superficial wounds, ulcus cruris, and superficial hematoma.
# Contraindications and Precautions
The ointment should not be used in patients with a known hypersensitivity to any ingredient. It should be used with caution in patients with hypersensitivity to bovine proteins in general and in pregnant women (category C), because no human data is available.
# Side-Effects
Infrequently, local reactions such as increased pain or a stitching/burning sensation are noticed. No systemic anticoagulant activity has been seen due to the exclusively local character of treatment.
# Interactions
Not known.
# External References
- Swiss scientific product information
- http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=6226244&dopt=Abstract (on chemical/biochemical properties) | https://www.wikidoc.org/index.php/Fibrinolysin | |
e55f473b81eb7953728689ba3c98e96671a291ae | wikidoc | Fibrinolysis | Fibrinolysis
Fibrinolysis is the process where a fibrin clot, the product of coagulation, is broken down. Its main enzyme, plasmin, cuts the fibrin mesh at various places, leading to the production of circulating fragments that are cleared by other proteinases or by the kidney and liver.
# Physiology
Plasmin is produced in an inactive form, plasminogen, in the liver. Although plasminogen cannot cleave fibrin, it still has an affinity for it, and is incorporated into the clot when it is formed.
Plasminogen contains secondary structure motifs known as kringles, which bind specifically to lysine and arginine residues on fibrin(ogen). When converted from plasminogen into plasmin it functions as a serine protease, cutting specifically C-terminal to these lysine and arginine residues. Fibrin monomers, when polymerized, form protofibrils. These protofibrils contain two strands, anti-parallel, associated non-covalently. Within a single strand, the fibrin monomers are covalently linked through the actions of coagulation factor XIII. Thus, plasmin action on a clot initially creates nicks in the fibrin; further digestion leads to solubilization (Walker & Nesheim 1999).
Tissue plasminogen activator (t-PA) and urokinase are the agents that convert plasminogen to the active plasmin, thus allowing fibrinolysis to occur. t-PA is released into the blood very slowly by the damaged endothelium of the blood vessels, such that after several days (when the bleeding has stopped) the clot is broken down. This occurs because plasminogen became entrapped within the clot when it formed; as it is slowly activated, it breaks down the fibrin mesh. t-PA and urokinase are themselves inhibited by plasminogen activator inhibitor-1 and plasminogen activator inhibitor-2 (PAI-1 and PAI-2). In contrast, plasmin further stimulates plasmin generation by producing more active forms of both tPA and urokinase.
Alpha 2-antiplasmin and alpha 2-macroglobulin inactivate plasmin. Plasmin activity is also reduced by thrombin-activatable fibrinolysis inhibitor (TAFI), which modifies fibrin to make a less potent cofactor for the tPA-mediated plasminogen activation.
# Measurement
When plasmin breaks down fibrin, a number of soluble parts are produced. These are called fibrin degradation products (FDPs). FDPs compete with thrombin, and so slow down the conversion of fibrinogen to fibrin (and thus slows down clot formation). This effect can be seen in the thrombin clotting time (TCT) test, which is prolonged in a person who has active fibrinolysis.
FDPs, and a specific FDP, the D-dimer, can be measured using antibody-antigen technology. This is more specific than the TCT, and virtually confirms that fibrinolysis has occurred. It is therefore used to indicate deep vein thrombosis or a pulmonary embolism.
# Role in disease
Few disorders of the fibrinolytic system have been documented. Nevertheless, excess levels of PAI and alpha 2-antiplasmin have been implicated in the metabolic syndrome and various other disease states.
The fibrinolytic system is closely linked to control of inflammation, and plays a role in disease states associated with inflammation. Plasmin, in addition to lysing fibrin clots, also cleaves the complement system component C3, and fibrin degradation products have some vascular permeability inducing effects.
# Pharmacology
Fibrinolytic drugs are given after a heart attack to dissolve the thrombus blocking the coronary artery, experimentally in stroke to reperfuse the affected part of the brain, and in massive pulmonary embolism. The process is called thrombolysis.
Antifibrinolytics, such as aminocaproic acid (ε-aminocaproic acid) and tranexamic acid are used as inhibitors of fibrinolysis | Fibrinolysis
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Fibrinolysis is the process where a fibrin clot, the product of coagulation, is broken down. Its main enzyme, plasmin, cuts the fibrin mesh at various places, leading to the production of circulating fragments that are cleared by other proteinases or by the kidney and liver.
# Physiology
Plasmin is produced in an inactive form, plasminogen, in the liver. Although plasminogen cannot cleave fibrin, it still has an affinity for it, and is incorporated into the clot when it is formed.
Plasminogen contains secondary structure motifs known as kringles, which bind specifically to lysine and arginine residues on fibrin(ogen). When converted from plasminogen into plasmin it functions as a serine protease, cutting specifically C-terminal to these lysine and arginine residues. Fibrin monomers, when polymerized, form protofibrils. These protofibrils contain two strands, anti-parallel, associated non-covalently. Within a single strand, the fibrin monomers are covalently linked through the actions of coagulation factor XIII. Thus, plasmin action on a clot initially creates nicks in the fibrin; further digestion leads to solubilization (Walker & Nesheim 1999).
Tissue plasminogen activator (t-PA) and urokinase are the agents that convert plasminogen to the active plasmin, thus allowing fibrinolysis to occur. t-PA is released into the blood very slowly by the damaged endothelium of the blood vessels, such that after several days (when the bleeding has stopped) the clot is broken down. This occurs because plasminogen became entrapped within the clot when it formed; as it is slowly activated, it breaks down the fibrin mesh. t-PA and urokinase are themselves inhibited by plasminogen activator inhibitor-1 and plasminogen activator inhibitor-2 (PAI-1 and PAI-2). In contrast, plasmin further stimulates plasmin generation by producing more active forms of both tPA and urokinase.
Alpha 2-antiplasmin and alpha 2-macroglobulin inactivate plasmin. Plasmin activity is also reduced by thrombin-activatable fibrinolysis inhibitor (TAFI), which modifies fibrin to make a less potent cofactor for the tPA-mediated plasminogen activation.
# Measurement
When plasmin breaks down fibrin, a number of soluble parts are produced. These are called fibrin degradation products (FDPs). FDPs compete with thrombin, and so slow down the conversion of fibrinogen to fibrin (and thus slows down clot formation). This effect can be seen in the thrombin clotting time (TCT) test, which is prolonged in a person who has active fibrinolysis.
FDPs, and a specific FDP, the D-dimer, can be measured using antibody-antigen technology. This is more specific than the TCT, and virtually confirms that fibrinolysis has occurred. It is therefore used to indicate deep vein thrombosis or a pulmonary embolism.
# Role in disease
Few disorders of the fibrinolytic system have been documented. Nevertheless, excess levels of PAI and alpha 2-antiplasmin have been implicated in the metabolic syndrome and various other disease states.
The fibrinolytic system is closely linked to control of inflammation, and plays a role in disease states associated with inflammation. Plasmin, in addition to lysing fibrin clots, also cleaves the complement system component C3, and fibrin degradation products have some vascular permeability inducing effects.
# Pharmacology
Fibrinolytic drugs are given after a heart attack to dissolve the thrombus blocking the coronary artery, experimentally in stroke to reperfuse the affected part of the brain, and in massive pulmonary embolism. The process is called thrombolysis.
Antifibrinolytics, such as aminocaproic acid (ε-aminocaproic acid) and tranexamic acid are used as inhibitors of fibrinolysis | https://www.wikidoc.org/index.php/Fibrinolysis | |
6799340342b6220e5a5dcb62b199ca8777c2d546 | wikidoc | Fibromodulin | Fibromodulin
Fibromodulin is a protein that in humans is encoded by the FMOD gene.
Fibromodulin is a 42kDa protein of a family of small interstitial leucine-rich repeat proteoglycans (SLRPs). It can have up to four N-linked keratan sulfate chains attached to the core protein within the leucine-rich region. It shares significant sequence homology with biglycan and decorin.
# Function
Fibromodulin participates in the assembly of the collagen fibers of the extracellular matrix. It binds to the same site on the collagen type I molecule as lumican. It also inhibits fibrillogenesis of collagen type I and collagen type III in vitro. It regulates TGF-beta activities by sequestering TGF-beta into the extracellular matrix.
# Clinical significance
There is an age-dependent decline in the synthesis of keratan sulfate chains, so non-glycated forms of fibromodulin can accumulate in tissues such as cartilage.
Fibromodulin is found in the epidermis of human skin and is expressed by skin cells (keratinocytes) in culture. Mice with the gene for fibromodulin knocked out (Fmod-/-) have very fragile skin and abnormal tail and Achilles tendons. The collagen fiber bundles in these tendons are fewer and disorganised and there is less endotenon surrounding the tendon tissue. The levels of lumican, a SLRP with one of the same collagen binding sites as fibromodulin, is increased 4 fold in the tail tendons of Fmod-knockout mice. | Fibromodulin
Fibromodulin is a protein that in humans is encoded by the FMOD gene.[1][2]
Fibromodulin is a 42kDa protein of a family of small interstitial leucine-rich repeat proteoglycans (SLRPs). It can have up to four N-linked keratan sulfate chains attached to the core protein within the leucine-rich region. It shares significant sequence homology with biglycan and decorin.[3]
# Function
Fibromodulin participates in the assembly of the collagen fibers of the extracellular matrix. It binds to the same site on the collagen type I molecule as lumican.[4] It also inhibits fibrillogenesis of collagen type I and collagen type III in vitro.[5][6] It regulates TGF-beta activities by sequestering TGF-beta into the extracellular matrix.[2]
# Clinical significance
There is an age-dependent decline in the synthesis of keratan sulfate chains, so non-glycated forms of fibromodulin can accumulate in tissues such as cartilage.[7]
Fibromodulin is found in the epidermis of human skin and is expressed by skin cells (keratinocytes) in culture. Mice with the gene for fibromodulin knocked out (Fmod-/-) have very fragile skin[8] and abnormal tail and Achilles tendons.[9] The collagen fiber bundles in these tendons are fewer and disorganised and there is less endotenon surrounding the tendon tissue. The levels of lumican, a SLRP with one of the same collagen binding sites as fibromodulin, is increased 4 fold in the tail tendons of Fmod-knockout mice. | https://www.wikidoc.org/index.php/Fibromodulin | |
82b37603345288701da7d096b2b4c3713989b491 | wikidoc | Flammability | Flammability
# Overview
Flammability is the ease with which a substance will ignite, causing fire or combustion. The degree of difficulty required to cause the combustion of a substance is subject to quantification through fire testing. Internationally, a variety of test protocols exist to quantify flammability. The ratings achieved are used in building codes, insurance requirements, fire codes and other regulations governing the use of building materials as well as the storage and handling of highly flammable substances inside and outside of structures and in surface and air transportation. For instance, changing an occupancy by altering the flammability of the contents requires the owner of a building to apply for a building permit to make sure that the overall fire protection design basis of the facility can take the change into account.
# Important Characteristics
## Vapour pressure
- The vapour pressure is an important parameter in determining the ease of ignition. The higher the vapour pressure, the more flammable vapour is evolved from a free liquid surface at a given temperature.
# Examples of flammable liquids
Flammable liquids include, but are not limited to:
- gasoline
- ethanol
- acetone
- Diesel
# Examples of nonflammable liquids
- Water
- Sodium silicate
# Linguistics: Flammable vs. inflammable
The word "inflammable" came from Latin inflammāre = "to set fire to", where the prefix in- means "in" as in "inside" (compare English "in flames"). But there have been instances of people thinking that this "in-" prefix means "not" as in "invisible" and "incombustible" etc, and thus wrongly thinking that "inflammable" means "cannot burn". To avoid this safety hazard, the shortened word "flammable" has come into use in recent years. | Flammability
# Overview
Flammability is the ease with which a substance will ignite, causing fire or combustion. The degree of difficulty required to cause the combustion of a substance is subject to quantification through fire testing. Internationally, a variety of test protocols exist to quantify flammability. The ratings achieved are used in building codes, insurance requirements, fire codes and other regulations governing the use of building materials as well as the storage and handling of highly flammable substances inside and outside of structures and in surface and air transportation. For instance, changing an occupancy by altering the flammability of the contents requires the owner of a building to apply for a building permit to make sure that the overall fire protection design basis of the facility can take the change into account.
# Important Characteristics
## Vapour pressure
- The vapour pressure is an important parameter in determining the ease of ignition. The higher the vapour pressure, the more flammable vapour is evolved from a free liquid surface at a given temperature.
# Examples of flammable liquids
Flammable liquids include, but are not limited to:
- gasoline
- ethanol
- acetone
- Diesel
# Examples of nonflammable liquids
- Water
- Sodium silicate
# Linguistics: Flammable vs. inflammable
The word "inflammable" came from Latin inflammāre = "to set fire to", where the prefix in- means "in" as in "inside" (compare English "in flames"). But there have been instances of people thinking that this "in-" prefix means "not" as in "invisible" and "incombustible" etc, and thus wrongly thinking that "inflammable" means "cannot burn". To avoid this safety hazard, the shortened word "flammable" has come into use in recent years. | https://www.wikidoc.org/index.php/Flammability | |
7edcf6d1daf8c8dde05160da7588a97f7e6bd5b3 | wikidoc | Floctafenine | Floctafenine
# Overview
Floctafenine is a non-steroidal anti-inflammatory drug (NSAID).
# Synthesis
The scheme involves first the conversion of ortho-trifluoromethyl aniline (1) to a quinolol. The compound is thus condensed
with EMME (Ethoxy Methylene Malonic Diethyl Ester) and cyclized thermally (2). That intermediate is then saponified; the
resulting acid is decarboxylated and finally converted to the 4-chloroquinoline (3) by reaction with phosphorus oxychloride. The displacement of chlorine with methyl anthranilate (4) then affords the coupled intermediate (5). An ester interchange
-f that product with glycerol leads to the glyceryl ester. There is thus obtained the NSAID floctafenine. | Floctafenine
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Floctafenine is a non-steroidal anti-inflammatory drug (NSAID).
# Synthesis
The scheme involves first the conversion of ortho-trifluoromethyl aniline (1) to a quinolol. The compound is thus condensed
with EMME (Ethoxy Methylene Malonic Diethyl Ester) and cyclized thermally (2). That intermediate is then saponified; the
resulting acid is decarboxylated and finally converted to the 4-chloroquinoline (3) by reaction with phosphorus oxychloride. The displacement of chlorine with methyl anthranilate (4) then affords the coupled intermediate (5). An ester interchange
of that product with glycerol leads to the glyceryl ester. There is thus obtained the NSAID floctafenine. | https://www.wikidoc.org/index.php/Floctafenine | |
0580418add71b5f8e24d212cfa0a601af14aba49 | wikidoc | Prostacyclin | Prostacyclin
Please Join in Editing This Page and Apply to be an Editor-In-Chief for this topic:
There can be one or more than one Editor-In-Chief. You may also apply to be an Associate Editor-In-Chief of one of the subtopics below. Please mail us to indicate your interest in serving either as an Editor-In-Chief of the entire topic or as an Associate Editor-In-Chief for a subtopic. Please be sure to attach your CV and or biographical sketch.
# Overview
Prostacyclin is a member of the family of lipid molecules known as eicosanoids. A synthetic form of prostacyclin, used as a medicine, is referred to as epoprostenol.
# Production
It is produced in endothelial cells from prostaglandin H2 (PGH2) by the action of the enzyme prostacyclin synthase. Although prostacyclin is considered an independent mediator, it is called PGI2 (prostaglandin I2) in eicosanoid nomenclature, and is a member of the prostanoids (together with the prostaglandins and thromboxane).
The series-3 prostaglandin PGH3 also follows the prostacyclin synthase pathway, yielding another prostacyclin, PGI3.(Fischer, 1985) The unqualified term 'prostacyclin' usually refers to PGI2. PGI2 is derived from the ω-6 arachidonic acid. PGI3 is derived from the ω-3 EPA.
# Mode of action
Prostacyclin acts chiefly to prevent platelet formation and clumping involved in blood clotting. It is also an effective vasodilator. Prostacyclin's interactions in contrast to thromboxane, another eicosanoid, strongly suggest a mechanism of cardiovascular homeostasis between the two hormones in relation to vascular damage.
# Pharmacology
Synthetic prostacyclin analogues (iloprost, cisaprost) are used intravenously, subcutaneously or by inhalation:
- as a vasodilator in severe Raynaud's phenomenon or ischemia of a limb;
- in pulmonary hypertension.
Its production is inhibited indirectly by NSAIDs, which inhibit the cyclooxygenase enzymes COX1 and COX2. These convert arachidonic acid to PGH2, the immediate precursor of prostacyclin. | Prostacyclin
Template:Seealso
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Please Join in Editing This Page and Apply to be an Editor-In-Chief for this topic:
There can be one or more than one Editor-In-Chief. You may also apply to be an Associate Editor-In-Chief of one of the subtopics below. Please mail us [2] to indicate your interest in serving either as an Editor-In-Chief of the entire topic or as an Associate Editor-In-Chief for a subtopic. Please be sure to attach your CV and or biographical sketch.
# Overview
Prostacyclin is a member of the family of lipid molecules known as eicosanoids. A synthetic form of prostacyclin, used as a medicine, is referred to as epoprostenol.
# Production
It is produced in endothelial cells from prostaglandin H2 (PGH2) by the action of the enzyme prostacyclin synthase. Although prostacyclin is considered an independent mediator, it is called PGI2 (prostaglandin I2) in eicosanoid nomenclature, and is a member of the prostanoids (together with the prostaglandins and thromboxane).
The series-3 prostaglandin PGH3 also follows the prostacyclin synthase pathway, yielding another prostacyclin, PGI3.(Fischer, 1985) The unqualified term 'prostacyclin' usually refers to PGI2. PGI2 is derived from the ω-6 arachidonic acid. PGI3 is derived from the ω-3 EPA.
# Mode of action
Prostacyclin acts chiefly to prevent platelet formation and clumping involved in blood clotting. It is also an effective vasodilator. Prostacyclin's interactions in contrast to thromboxane, another eicosanoid, strongly suggest a mechanism of cardiovascular homeostasis between the two hormones in relation to vascular damage.
# Pharmacology
Synthetic prostacyclin analogues (iloprost, cisaprost) are used intravenously, subcutaneously or by inhalation:
- as a vasodilator in severe Raynaud's phenomenon or ischemia of a limb;
- in pulmonary hypertension.
Its production is inhibited indirectly by NSAIDs, which inhibit the cyclooxygenase enzymes COX1 and COX2. These convert arachidonic acid to PGH2, the immediate precursor of prostacyclin. | https://www.wikidoc.org/index.php/Flolan | |
39643fa2d5a2f9ae19b4baa101d33e40ff855845 | wikidoc | Fluorescence | Fluorescence
# Overview
Fluorescence is a luminescence that is mostly found as an optical phenomenon in cold bodies, in which the molecular absorption of a photon triggers the emission of another photon with a longer wavelength. The energy difference between the absorbed and emitted photons ends up as molecular vibrations or heat. Usually the absorbed photon is in the ultraviolet range, and the emitted light is in the visible range, but this depends on the absorbance curve and Stokes shift of the particular fluorophore. Fluorescence is named after the mineral fluorite, composed of calcium fluoride, which often exhibits this phenomenon.
# Equations
## Photochemistry
Fluorescence occurs when a molecule or nanostructure relaxes to its ground state after being electrically excited.
Excitation: S_0 + h \nu \to S_1
Fluorescence (emission): S_1 \to S_0 + h \nu, here
h \nu is a generic term for photon energy where: h = Planck's constant and \nu = frequency of light. (The specific frequencies of exciting and emitted light are dependent on the particular system.)
State S0 is called the ground state of the fluorophore (fluorescent molecule) and S1 is its first (electronically) excited state.
A molecule in its excited state, S1, can relax by various competing pathways. It can undergo 'non-radiative relaxation' in which the excitation energy is dissipated as heat (vibrations) to the solvent. Excited organic molecules can also relax via conversion to a triplet state which may subsequently relax via phosphorescence or by a secondary non-radiative relaxation step.
Relaxation of an S1 state can also occur through interaction with a second molecule through fluorescence quenching. Molecular oxygen (O2) is an extremely efficient quencher of fluorescence because of its unusual triplet ground state.
Molecules that are excited through light absorption or via a different process (e.g. as the product of a reaction) can transfer energy to a second 'sensitized' molecule, which is converted to its excited state and can then fluoresce. This process is used in lightsticks.
## Quantum yield
The fluorescence quantum yield gives the efficiency of the fluorescence process. It is defined as the ratio of the number of photons emitted to the number of photons absorbed.
The maximum fluorescence quantum yield is 1.0 (100%); every photon absorbed results in a photon emitted. Compounds with quantum yields of 0.10 are still considered quite fluorescent. Another way to define the quantum yield of fluorescence, is by the rates excited state decay:
where { k}_{ f} is the rate of spontaneous emission of radiation and
is the sum of all rates of excited state decay. Other rates of excited state decay are caused by mechanisms other than photon emission and are therefore often called "non-radiative rates", which can include:
dynamic collisional quenching, near-field dipole-dipole interaction (or resonance energy transfer), internal conversion and intersystem crossing. Thus, if the rate of any pathway changes, this will affect both the excited state lifetime and the fluorescence quantum yield.
Fluorescence quantum yield are measured by comparison to a standard with known quantology; the quinine salt, quinine sulfate, in a sulfuric acid solution is a common fluorescence standard.
## Lifetime
The fluorescence lifetime refers to the average time the molecule stays in its excited state before emitting a photon. Fluorescence typically follows first-order kinetics:
where \left is the concentration of excited state molecules at time t, \left_0 is the initial concentration and \Gamma is the decay rate or the inverse of the fluorescence lifetime. This is an instance of exponential decay. Various radiative and non-radiative processes can de-populate the excited state. In such case the total decay rate is the sum over all rates:
where \Gamma_{tot} is the total decay rate, \Gamma_{rad} the radiative decay rate and \Gamma_{nrad} the non-radiative decay rate. It is similar to a first-order chemical reaction in which the first-order rate constant is the sum of all of the rates (a parallel kinetic model). If the rate of spontaneous emission, or any of the other rates are fast, the lifetime is short. For commonly used fluorescent compounds typical excited state decay times for fluorescent compounds that emit photons with energies from the UV to near infrared are within the range of 0.5 to 20 nanoseconds. The fluorescence lifetime is an important parameter for practical applications of fluorescence such as fluorescence resonance energy transfer.
# Rules
There are several rules that deal with fluorescence. The Kasha – Vavilov rule dictates that the quantum yield of luminescence is independent of the wavelength of exciting radiation.
This is not always true and is violated severely in many simple molecules. A somewhat more reliable statement, although still with exceptions, would be that the fluorescence spectrum shows very little dependence on the wavelength of exciting radiation.
The Jablonski diagram describes most of the relaxation mechanism for excited state molecules.
# Applications
There are many natural and synthetic compounds that exhibit fluorescence, and they have a number of applications. Some deep-sea animals, such as the Greeneye, use fluorescence.
## Lighting
The common fluorescent tube relies on fluorescence. Inside the glass tube is a partial vacuum and a small amount of mercury. An electric discharge in the tube causes the mercury atoms to emit light. The emitted light is in the ultraviolet (UV) range, is invisible, and is harmful to most living organisms. The tube is lined with a coating of a fluorescent material, called the phosphor, which absorbs the ultraviolet and re-emits visible light. Fluorescent lighting is very energy efficient compared to incandescent technology, but the spectra produced may cause certain colours to appear unnatural.
In the mid 1990s, white light-emitting diodes (LEDs) became available, which work through a similar process. Typically, the actual light-emitting semiconductor produces light in the blue part of the spectrum, which strikes a phosphor compound deposited on the chip; the phosphor fluoresces from the green to red part of the spectrum. The combination of the blue light that goes through the phosphor and the light emitted by the phosphor produce a net emission of white light.
The modern mercury vapor streetlight is said to have been evolved from the fluorescent lamp.
Glow sticks oxidise phenyl oxalate ester in order to produce light.
Compact fluorescent lighting (CFL) is the same as any typical fluorescent lamp with advantages. It is self-ballasted and used to replace incandescents in most applications. They produce a quarter of the heat per lumen as incandescent bulbs and last about five times as long. These bulbs contain mercury and must be handled and disposed with care. The disadvantages to the self-ballasting properties of compact fluorescent is that they may not fit properly in all light fixtures. All fluorescent lights have a significant delay in turning on compared to incandescents, a disadvantage in some applications. Additionally, the technology which allows them to be 'plug-and-play' also signifigantly reduces their life-span and reliability in dimming applications.
## Analytical chemistry
Fluorescence in several wavelengths can be detected by an array detector, to detect compounds from HPLC flow. Also, TLC plates can be visualized if the compounds or a coloring reagent is fluorescent. Fluorescence is most effective when there is a larger ratio of atoms at lower levels in a Boltzman distribution because then there is more of a chance those atoms will be excited then release a photon and can be analyzed.
Fingerprints can be visualized with fluorescent compounds such as ninhydrin.
# Biochemistry and medicine
Biological molecules can be tagged with a fluorescent chemical group (fluorophore) by a simple chemical reaction, and the fluorescence of the tag enables sensitive and quantitative detection of the molecule.
Examples:
- Fluorescence microscopy of tissues, cells or subcellular structures is accomplished by labeling an antibody with a fluorophore and allowing the antibody to find its target antigen within the sample. Labeling multiple antibodies with different fluorophores allows visualization of multiple targets within a single image.
- Automated sequencing of DNA by the chain termination method; each of four different chain terminating bases has its own specific fluorescent tag. As the labeled DNA molecules are separated, the fluorescent label is excited by a UV source, and the identity of the base terminating the molecule is identified by the wavelength of the emitted light.
- DNA detection: the compound ethidium bromide, when free to change its conformation in solution, has very little fluorescence. Ethidium bromide's fluorescence is greatly enhanced when it binds to DNA, so this compound is very useful in visualising the location of DNA fragments in agarose gel electrophoresis. Ethidium bromide can be toxic - a safer alternative is the dye SYBR Green.
- The DNA microarray
- Immunology: An antibody has a fluorescent chemical group attached, and the sites (e.g., on a microscopic specimen) where the antibody has bound can be seen, and even quantified, by the fluorescence.
- FACS (fluorescent-activated cell sorting)
- Fluorescence has been used to study the structure and conformations of DNA and proteins with techniques such as Fluorescence resonance energy transfer, which measures distance at the angstrom level. This is especially important in complexes of multiple biomolecules.
- Aequorin, from the jellyfish Aequorea victoria, produces a blue glow in the presence of Ca2+ ions (by a chemical reaction). It has been used to image calcium flow in cells in real time. The success with aequorin spurred further investigation of A. victoria and led to the discovery of Green Fluorescent Protein (GFP), which has become an extremely important research tool. GFP and related proteins are used as reporters for any number of biological events including such things as sub-cellular localization. Levels of gene expression are sometimes measured by linking a gene for GFP production to another gene.
Also, many biological molecules have an intrinsic fluorescence that can sometimes be used without the need to attach a chemical tag. Sometimes this intrinsic fluorescence changes when the molecule is in a specific environment, so the distribution or binding of the molecule can be measured. Bilirubin, for instance, is highly fluorescent when bound to a specific site on serum albumin. Zinc protoporphyrin, formed in developing red blood cells instead of hemoglobin when iron is unavailable or lead is present, has a bright fluorescence and can be used to detect these problems.
As of 2006, the number of fluorescence applications is growing in the biomedical biological and related sciences. Methods of analysis in these fields are also growing, albeit with increasingly unfortunate nomenclature in the form of acronyms such as: FLIM, FLI, FLIP, CALI, FLIE, FRET, FRAP, FCS, PFRAP, smFRET, FIONA, FRIPS, SHREK, SHRIMP, TIRF. Most of these techniques rely on fluorescence microscopes. These microscopes use high intensity light sources, usually mercury or xenon lamps, LEDs, or lasers, to excite fluorescence in the samples under observation. Optical filters then separate excitation light from emitted fluorescence, to be detected by eye, or with a (CCD) camera or other light detectors (photomultiplier tubes, spectrographs, etc). Much research is underway to improve the capabilities of such microscopes, the fluorescent probes used, and the applications they are applied to. Of particular note are confocal microscopes, which use a pinhole to achieve optical sectioning – affording a quantitative, 3D view of the sample.
# Gemology, mineralogy, geology and forensics
Gemstones, minerals, fibers and many other materials which may be encountered in forensics or with a relationship to various collectibles may have a distinctive fluorescence or may fluoresce differently under short-wave ultraviolet, long-wave ultra violet, or X-rays.
Many types of calcite and amber will fluoresce under shortwave UV. Rubies, emeralds, and the Hope Diamond exhibit red fluorescence under short-wave UV light; diamonds also emit light under X ray radiation.
Crude oil (petroleum) fluoresces in a range of colors, from dull brown for heavy oils and tars through to bright yellowish and bluish white for very light oils and condensates. This phenomenon is used in oil exploration drilling to identify very small amounts of oil in drill cuttings and core sample.
# Organic liquids
Organic liquids such as mixtures of anthracene in benzene or toluene, or stilbene in the same solvents, fluoresce with ultraviolet or gamma ray irradiation. The decay times of this fluorescence is of the order of nanoseconds since the duration of the light depends on the lifetime of the excited states of the fluorescent material, in this case anthracene or stilbene. | Fluorescence
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Fluorescence is a luminescence that is mostly found as an optical phenomenon in cold bodies, in which the molecular absorption of a photon triggers the emission of another photon with a longer wavelength. The energy difference between the absorbed and emitted photons ends up as molecular vibrations or heat. Usually the absorbed photon is in the ultraviolet range, and the emitted light is in the visible range, but this depends on the absorbance curve and Stokes shift of the particular fluorophore. Fluorescence is named after the mineral fluorite, composed of calcium fluoride, which often exhibits this phenomenon.
# Equations
## Photochemistry
Fluorescence occurs when a molecule or nanostructure relaxes to its ground state after being electrically excited.
Excitation: <math> S_0 + h \nu \to S_1 </math>
Fluorescence (emission): <math>S_1 \to S_0 + h \nu</math>, here
<math>h \nu</math> is a generic term for photon energy where: h = Planck's constant and <math>\nu</math> = frequency of light. (The specific frequencies of exciting and emitted light are dependent on the particular system.)
State S0 is called the ground state of the fluorophore (fluorescent molecule) and S1 is its first (electronically) excited state.
A molecule in its excited state, S1, can relax by various competing pathways. It can undergo 'non-radiative relaxation' in which the excitation energy is dissipated as heat (vibrations) to the solvent. Excited organic molecules can also relax via conversion to a triplet state which may subsequently relax via phosphorescence or by a secondary non-radiative relaxation step.
Relaxation of an S1 state can also occur through interaction with a second molecule through fluorescence quenching. Molecular oxygen (O2) is an extremely efficient quencher of fluorescence because of its unusual triplet ground state.
Molecules that are excited through light absorption or via a different process (e.g. as the product of a reaction) can transfer energy to a second 'sensitized' molecule, which is converted to its excited state and can then fluoresce. This process is used in lightsticks.
## Quantum yield
The fluorescence quantum yield gives the efficiency of the fluorescence process. It is defined as the ratio of the number of photons emitted to the number of photons absorbed.
The maximum fluorescence quantum yield is 1.0 (100%); every photon absorbed results in a photon emitted. Compounds with quantum yields of 0.10 are still considered quite fluorescent. Another way to define the quantum yield of fluorescence, is by the rates excited state decay:
where <math>{ k}_{ f}</math> is the rate of spontaneous emission of radiation and
is the sum of all rates of excited state decay. Other rates of excited state decay are caused by mechanisms other than photon emission and are therefore often called "non-radiative rates", which can include:
dynamic collisional quenching, near-field dipole-dipole interaction (or resonance energy transfer), internal conversion and intersystem crossing. Thus, if the rate of any pathway changes, this will affect both the excited state lifetime and the fluorescence quantum yield.
Fluorescence quantum yield are measured by comparison to a standard with known quantology; the quinine salt, quinine sulfate, in a sulfuric acid solution is a common fluorescence standard.
## Lifetime
The fluorescence lifetime refers to the average time the molecule stays in its excited state before emitting a photon. Fluorescence typically follows first-order kinetics:
where <math>\left[S 1 \right]</math> is the concentration of excited state molecules at time <math>t</math>, <math>\left[S 1 \right]_0</math> is the initial concentration and <math>\Gamma</math> is the decay rate or the inverse of the fluorescence lifetime. This is an instance of exponential decay. Various radiative and non-radiative processes can de-populate the excited state. In such case the total decay rate is the sum over all rates:
where <math>\Gamma_{tot}</math> is the total decay rate, <math>\Gamma_{rad}</math> the radiative decay rate and <math>\Gamma_{nrad}</math> the non-radiative decay rate. It is similar to a first-order chemical reaction in which the first-order rate constant is the sum of all of the rates (a parallel kinetic model). If the rate of spontaneous emission, or any of the other rates are fast, the lifetime is short. For commonly used fluorescent compounds typical excited state decay times for fluorescent compounds that emit photons with energies from the UV to near infrared are within the range of 0.5 to 20 nanoseconds. The fluorescence lifetime is an important parameter for practical applications of fluorescence such as fluorescence resonance energy transfer.
# Rules
There are several rules that deal with fluorescence. The Kasha – Vavilov rule dictates that the quantum yield of luminescence is independent of the wavelength of exciting radiation.
This is not always true and is violated severely in many simple molecules. A somewhat more reliable statement, although still with exceptions, would be that the fluorescence spectrum shows very little dependence on the wavelength of exciting radiation.
The Jablonski diagram describes most of the relaxation mechanism for excited state molecules.
# Applications
There are many natural and synthetic compounds that exhibit fluorescence, and they have a number of applications. Some deep-sea animals, such as the Greeneye, use fluorescence.
## Lighting
The common fluorescent tube relies on fluorescence. Inside the glass tube is a partial vacuum and a small amount of mercury. An electric discharge in the tube causes the mercury atoms to emit light. The emitted light is in the ultraviolet (UV) range, is invisible, and is harmful to most living organisms. The tube is lined with a coating of a fluorescent material, called the phosphor, which absorbs the ultraviolet and re-emits visible light. Fluorescent lighting is very energy efficient compared to incandescent technology, but the spectra produced may cause certain colours to appear unnatural.
In the mid 1990s, white light-emitting diodes (LEDs) became available, which work through a similar process. Typically, the actual light-emitting semiconductor produces light in the blue part of the spectrum, which strikes a phosphor compound deposited on the chip; the phosphor fluoresces from the green to red part of the spectrum. The combination of the blue light that goes through the phosphor and the light emitted by the phosphor produce a net emission of white light.
The modern mercury vapor streetlight is said to have been evolved from the fluorescent lamp.
Glow sticks oxidise phenyl oxalate ester in order to produce light.
Compact fluorescent lighting (CFL) is the same as any typical fluorescent lamp with advantages. It is self-ballasted and used to replace incandescents in most applications. They produce a quarter of the heat per lumen as incandescent bulbs and last about five times as long. These bulbs contain mercury and must be handled and disposed with care. The disadvantages to the self-ballasting properties of compact fluorescent is that they may not fit properly in all light fixtures. All fluorescent lights have a significant delay in turning on compared to incandescents, a disadvantage in some applications. Additionally, the technology which allows them to be 'plug-and-play' also signifigantly reduces their life-span and reliability in dimming applications.
## Analytical chemistry
Fluorescence in several wavelengths can be detected by an array detector, to detect compounds from HPLC flow. Also, TLC plates can be visualized if the compounds or a coloring reagent is fluorescent. Fluorescence is most effective when there is a larger ratio of atoms at lower levels in a Boltzman distribution because then there is more of a chance those atoms will be excited then release a photon and can be analyzed.
Fingerprints can be visualized with fluorescent compounds such as ninhydrin.
# Biochemistry and medicine
Biological molecules can be tagged with a fluorescent chemical group (fluorophore) by a simple chemical reaction, and the fluorescence of the tag enables sensitive and quantitative detection of the molecule.
Examples:
- Fluorescence microscopy of tissues, cells or subcellular structures is accomplished by labeling an antibody with a fluorophore and allowing the antibody to find its target antigen within the sample. Labeling multiple antibodies with different fluorophores allows visualization of multiple targets within a single image.
- Automated sequencing of DNA by the chain termination method; each of four different chain terminating bases has its own specific fluorescent tag. As the labeled DNA molecules are separated, the fluorescent label is excited by a UV source, and the identity of the base terminating the molecule is identified by the wavelength of the emitted light.
- DNA detection: the compound ethidium bromide, when free to change its conformation in solution, has very little fluorescence. Ethidium bromide's fluorescence is greatly enhanced when it binds to DNA, so this compound is very useful in visualising the location of DNA fragments in agarose gel electrophoresis. Ethidium bromide can be toxic - a safer alternative is the dye SYBR Green.
- The DNA microarray
- Immunology: An antibody has a fluorescent chemical group attached, and the sites (e.g., on a microscopic specimen) where the antibody has bound can be seen, and even quantified, by the fluorescence.
- FACS (fluorescent-activated cell sorting)
- Fluorescence has been used to study the structure and conformations of DNA and proteins with techniques such as Fluorescence resonance energy transfer, which measures distance at the angstrom level. This is especially important in complexes of multiple biomolecules.
- Aequorin, from the jellyfish Aequorea victoria, produces a blue glow in the presence of Ca2+ ions (by a chemical reaction). It has been used to image calcium flow in cells in real time. The success with aequorin spurred further investigation of A. victoria and led to the discovery of Green Fluorescent Protein (GFP), which has become an extremely important research tool. GFP and related proteins are used as reporters for any number of biological events including such things as sub-cellular localization. Levels of gene expression are sometimes measured by linking a gene for GFP production to another gene.
Also, many biological molecules have an intrinsic fluorescence that can sometimes be used without the need to attach a chemical tag. Sometimes this intrinsic fluorescence changes when the molecule is in a specific environment, so the distribution or binding of the molecule can be measured. Bilirubin, for instance, is highly fluorescent when bound to a specific site on serum albumin. Zinc protoporphyrin, formed in developing red blood cells instead of hemoglobin when iron is unavailable or lead is present, has a bright fluorescence and can be used to detect these problems.
As of 2006, the number of fluorescence applications is growing in the biomedical biological and related sciences. Methods of analysis in these fields are also growing, albeit with increasingly unfortunate nomenclature in the form of acronyms such as: FLIM, FLI, FLIP, CALI, FLIE, FRET, FRAP, FCS, PFRAP, smFRET, FIONA, FRIPS, SHREK, SHRIMP, TIRF. Most of these techniques rely on fluorescence microscopes. These microscopes use high intensity light sources, usually mercury or xenon lamps, LEDs, or lasers, to excite fluorescence in the samples under observation. Optical filters then separate excitation light from emitted fluorescence, to be detected by eye, or with a (CCD) camera or other light detectors (photomultiplier tubes, spectrographs, etc). Much research is underway to improve the capabilities of such microscopes, the fluorescent probes used, and the applications they are applied to. Of particular note are confocal microscopes, which use a pinhole to achieve optical sectioning – affording a quantitative, 3D view of the sample.
# Gemology, mineralogy, geology and forensics
Gemstones, minerals, fibers and many other materials which may be encountered in forensics or with a relationship to various collectibles may have a distinctive fluorescence or may fluoresce differently under short-wave ultraviolet, long-wave ultra violet, or X-rays.
Many types of calcite and amber will fluoresce under shortwave UV. Rubies, emeralds, and the Hope Diamond exhibit red fluorescence under short-wave UV light; diamonds also emit light under X ray radiation.
Crude oil (petroleum) fluoresces in a range of colors, from dull brown for heavy oils and tars through to bright yellowish and bluish white for very light oils and condensates. This phenomenon is used in oil exploration drilling to identify very small amounts of oil in drill cuttings and core sample.
# Organic liquids
Organic liquids such as mixtures of anthracene in benzene or toluene, or stilbene in the same solvents, fluoresce with ultraviolet or gamma ray irradiation. The decay times of this fluorescence is of the order of nanoseconds since the duration of the light depends on the lifetime of the excited states of the fluorescent material, in this case anthracene or stilbene. | https://www.wikidoc.org/index.php/Florescence | |
00a633d51891a2ff108ae76f6a414fb65b0718df | wikidoc | Fluocinonide | Fluocinonide
# 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
Fluocinonide is an adrenal glucocorticoid that is FDA approved for the {{{indicationType}}} of corticosteroid-responsive dermatoses. Common adverse reactions include sensation of burning of skin, headache, nasal congestion, nasopharyngitis.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Dosing Information
- Fluocinonide Cream USP, 0.05% is indicated for the relief of the inflammatory and pruritic manifestations of corticosteroid-responsive dermatoses.
- Fluocinonide cream 0.05% is generally applied to the affected area as a thin film from two to four times daily depending on the severity of the condition.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Fluocinonide in adult patients.
### Non–Guideline-Supported Use
- Dosing Information
- Fluocinonide ointment twice daily.
- Dosing Information
- Fluocinonide 0.025% in an adhesive base
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding FDA-Labeled Use of Fluocinonide in pediatric patients.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Fluocinonide in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Fluocinonide in pediatric patients.
# Contraindications
- Fluocinonide cream is contraindicated in those patients with a history of hypersensitivity to any of the components of the preparation.
# Warnings
### Precautions
- General: Systemic absorption of topical corticosteroids has produced reversible hypothalamic-pituitary-adrenal (HPA) axis suppression, manifestations of Cushing's syndrome, hyperglycemia, and glucosuria in some patients.
- Conditions which augment systemic absorption include the application of the more potent steroids, use over large surface areas, prolonged use, and the addition of occlusive dressings.
- Therefore, patients receiving a large dose of a potent topical steroid applied to a large surface area or under an occlusive dressing should be evaluated periodically for evidence of HPA axis suppression by using the urinary free cortisol and ACTH stimulation tests. If HPA axis suppression is noted, an attempt should be made to withdraw the drug, to reduce the frequency of application, or to substitute a less potent steroid.
- Recovery of HPA axis function is generally prompt and complete upon discontinuation of the drug. Infrequently, signs and symptoms of steroid withdrawal may occur, requiring supplemental systemic corticosteroids.
- Children may absorb proportionally larger amounts of topical corticosteroids and thus be more susceptible to systemic toxicity. If irritation develops, topical corticosteroids should be discontinued and appropriate therapy instituted.
- As with any topical corticosteroid product, prolonged use may produce atrophy of the skin and subcutaneous tissues. When used on intertriginous or flexor areas, or on the face, this may occur even with short term use.
- In the presence of dermatological infections, the use of an appropriate antifungal or antibacterial agent should be instituted. If a favorable response does not occur promptly, the corticosteroid should be discontinued until the infection has been adequately controlled.
# Adverse Reactions
## Clinical Trials Experience
- The following local adverse reactions are reported infrequently with topical corticosteroids, but may occur more frequently with the use of occlusive dressings. These reactions are listed in an approximate decreasing order of occurrence: burning, itching, irritation, dryness, folliculitis, hypertrichosis, acneiform eruptions, hypopigmentation, perioral dermatitis, allergic contact dermatitis, maceration of the skin, secondary infection, skin atrophy, striae, miliaria.
## Postmarketing Experience
There is limited information regarding Postmarketing Experience of Fluocinonide in the drug label.
# Drug Interactions
There is limited information regarding Fluocinonide Drug Interactions in the drug label.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
- Pregnancy Category C
- Corticosteroids are generally teratogenic in laboratory animals when administered systemically at relatively low dosage levels. The more potent corticosteroids have been shown to be teratogenic after dermal application in laboratory animals. There are no adequate and well-controlled studies in pregnant women on teratogenic effects from topically applied corticosteroids. Therefore topical corticosteroids should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Drugs of this class should not be used extensively on pregnant patients, in large amounts, or for prolonged periods of time.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Fluocinonide in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Fluocinonide during labor and delivery.
### Nursing Mothers
- It is not known whether topical administration of corticosteroids could result in sufficient systemic absorption to produce detectable quantities in breast milk. Systemically administered corticosteroids are secreted into breast milk in quantities not likely to have a deleterious effect on the infant. Nevertheless, caution should be exercised when topical corticosteroids are administered to a nursing woman.
### Pediatric Use
- Pediatric patients may demonstrate greater susceptibility to topical corticosteroid-induced hypothalamic-pituitary-adrenal (HPA) axis suppression and Cushing's syndrome than mature patients because of a larger skin area to body weight ratio.
- HPA axis suppression, Cushing's syndrome, and intracranial hypertension have been reported in children receiving topical corticosteroids. Manifestations of adrenal suppression in children include linear growth retardation, delayed weight gain, low plasma cortisol levels, and absence of response to ACTH stimulation. Manifestations of intracranial hypertension include bulging fontanelles, headaches, and bilateral papilledema.
- Administration of topical corticosteroids to children should be limited to the least amount compatible with an effective therapeutic regimen. Chronic corticosteroid therapy may interfere with the growth and development of children.
### Geriatic Use
There is no FDA guidance on the use of Fluocinonide with respect to geriatric patients.
### Gender
There is no FDA guidance on the use of Fluocinonide with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Fluocinonide with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Fluocinonide in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Fluocinonide in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Fluocinonide in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Fluocinonide in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Topical
### Monitoring
There is limited information regarding Monitoring of Fluocinonide in the drug label.
# IV Compatibility
There is limited information regarding IV Compatibility of Fluocinonide in the drug label.
# Overdosage
## Acute Overdose
### Signs and Symptoms
- Topically applied corticosteroids can be absorbed in sufficient amount to produce systemic effects.
## Chronic Overdose
There is limited information regarding Chronic Overdose of Fluocinonide in the drug label.
# Pharmacology
## Mechanism of Action
- The mechanism of anti-inflammatory activity of the topical corticosteroids is unclear. Various laboratory methods, including vasoconstrictor assays, are used to compare and predict potencies and/or clinical efficacies of the topical corticosteroids. There is some evidence to suggest that a recognizable correlation exists between vasoconstrictor potency and the therapeutic efficacy in man.
## Structure
- Fluocinonide Cream USP, 0.05% is intended for topical administration. The active component is the corticosteroid fluocinonide, which is the 21-acetate ester of fluocinolone acetonide and has the chemical name pregna-1,4-diene-3,20-dione, 21-(acetyloxy)-6,9-difluoro-11-hydroxy-16,17--, (6ą,11ß,16ą). Its molecular formula is C26H32F2O7, and has the molecular weight of 494.53. It has the following chemical structure:
- Fluocinonide Cream USP, 0.05% contains fluocinonide 0.5 mg/g in a cream base consisting of citric acid, 1,2,6-hexanetriol, polyethylene glycol-8000, propylene glycol and stearyl alcohol. This white cream vehicle is greaseless, non-staining, anhydrous and completely water miscible. The base provides emollient and hydrophilic properties.
## Pharmacodynamics
There is limited information regarding Pharmacodynamics of Fluocinonide in the drug label.
## Pharmacokinetics
- The extent of percutaneous absorption of topical corticosteroids is determined by many factors including the vehicle, the integrity of the epidermal barrier, and the use of occlusive dressings.
- Topical corticosteroids can be absorbed from normal intact skin. Inflammation and/or other disease processes in the skin increase percutaneous absorption. Occlusive dressings substantially increase the percutaneous absorption of topical corticosteroids. Thus, occlusive dressings may be a valuable therapeutic adjunct for treatment of resistant dermatoses. (See DOSAGE AND ADMINISTRATION.)
- Once absorbed through the skin, topical corticosteroids are handled through pharmacokinetic pathways similar to systemically administered corticosteroids.
- Corticosteroids are bound to plasma proteins in varying degrees. Corticosteroids are metabolized primarily in the liver and are then excreted by the kidneys. Some of the topical corticosteroids and their metabolites are also excreted into the bile.
## Nonclinical Toxicology
- Long-term animal studies have not been performed to evaluate the carcinogenic potential or the effect on fertility of topical corticosteroids.
- Studies to determine mutagenicity with prednisolone and hydrocortisone have revealed negative results.
# Clinical Studies
There is limited information regarding Clinical Studies of Fluocinonide in the drug label.
# How Supplied
- Fluocinonide Cream USP, 0.05% is supplied in 15 g (NDC 0472-3901-15), 30 g (NDC 0472-3901-30), and 60 g (NDC 0472-3901-60) tubes.
- Store at 20°-25°C (68°-77°F).
## Storage
There is limited information regarding Fluocinonide Storage in the drug label.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- Patients using topical corticosteroids should receive the following information and instructions:
- This medication is to be used as directed by the physician. It is for external use only. Avoid contact with the eyes.
- Patients should be advised not to use this medication for any disorder other than for which it was prescribed.
- The treated skin area should not be bandaged or otherwise covered or wrapped as to be occlusive unless directed by the physician.
- Patients should report any signs of local adverse reactions especially under occlusive dressing.
- Parents of pediatric patients should be advised not to use tight-fitting diapers or plastic pants on a child being treated in the diaper area, as these garments may constitute occlusive dressings.
# Precautions with Alcohol
- Alcohol-Fluocinonide interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- FLUOCINONIDE®
# Look-Alike Drug Names
There is limited information regarding Fluocinonide Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | Fluocinonide
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
Fluocinonide is an adrenal glucocorticoid that is FDA approved for the {{{indicationType}}} of corticosteroid-responsive dermatoses. Common adverse reactions include sensation of burning of skin, headache, nasal congestion, nasopharyngitis.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Dosing Information
- Fluocinonide Cream USP, 0.05% is indicated for the relief of the inflammatory and pruritic manifestations of corticosteroid-responsive dermatoses.
- Fluocinonide cream 0.05% is generally applied to the affected area as a thin film from two to four times daily depending on the severity of the condition.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Fluocinonide in adult patients.
### Non–Guideline-Supported Use
- Dosing Information
- Fluocinonide ointment twice daily.
- Dosing Information
- Fluocinonide 0.025% in an adhesive base
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding FDA-Labeled Use of Fluocinonide in pediatric patients.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Fluocinonide in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Fluocinonide in pediatric patients.
# Contraindications
- Fluocinonide cream is contraindicated in those patients with a history of hypersensitivity to any of the components of the preparation.
# Warnings
### Precautions
- General: Systemic absorption of topical corticosteroids has produced reversible hypothalamic-pituitary-adrenal (HPA) axis suppression, manifestations of Cushing's syndrome, hyperglycemia, and glucosuria in some patients.
- Conditions which augment systemic absorption include the application of the more potent steroids, use over large surface areas, prolonged use, and the addition of occlusive dressings.
- Therefore, patients receiving a large dose of a potent topical steroid applied to a large surface area or under an occlusive dressing should be evaluated periodically for evidence of HPA axis suppression by using the urinary free cortisol and ACTH stimulation tests. If HPA axis suppression is noted, an attempt should be made to withdraw the drug, to reduce the frequency of application, or to substitute a less potent steroid.
- Recovery of HPA axis function is generally prompt and complete upon discontinuation of the drug. Infrequently, signs and symptoms of steroid withdrawal may occur, requiring supplemental systemic corticosteroids.
- Children may absorb proportionally larger amounts of topical corticosteroids and thus be more susceptible to systemic toxicity. If irritation develops, topical corticosteroids should be discontinued and appropriate therapy instituted.
- As with any topical corticosteroid product, prolonged use may produce atrophy of the skin and subcutaneous tissues. When used on intertriginous or flexor areas, or on the face, this may occur even with short term use.
- In the presence of dermatological infections, the use of an appropriate antifungal or antibacterial agent should be instituted. If a favorable response does not occur promptly, the corticosteroid should be discontinued until the infection has been adequately controlled.
# Adverse Reactions
## Clinical Trials Experience
- The following local adverse reactions are reported infrequently with topical corticosteroids, but may occur more frequently with the use of occlusive dressings. These reactions are listed in an approximate decreasing order of occurrence: burning, itching, irritation, dryness, folliculitis, hypertrichosis, acneiform eruptions, hypopigmentation, perioral dermatitis, allergic contact dermatitis, maceration of the skin, secondary infection, skin atrophy, striae, miliaria.
## Postmarketing Experience
There is limited information regarding Postmarketing Experience of Fluocinonide in the drug label.
# Drug Interactions
There is limited information regarding Fluocinonide Drug Interactions in the drug label.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
- Pregnancy Category C
- Corticosteroids are generally teratogenic in laboratory animals when administered systemically at relatively low dosage levels. The more potent corticosteroids have been shown to be teratogenic after dermal application in laboratory animals. There are no adequate and well-controlled studies in pregnant women on teratogenic effects from topically applied corticosteroids. Therefore topical corticosteroids should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Drugs of this class should not be used extensively on pregnant patients, in large amounts, or for prolonged periods of time.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Fluocinonide in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Fluocinonide during labor and delivery.
### Nursing Mothers
- It is not known whether topical administration of corticosteroids could result in sufficient systemic absorption to produce detectable quantities in breast milk. Systemically administered corticosteroids are secreted into breast milk in quantities not likely to have a deleterious effect on the infant. Nevertheless, caution should be exercised when topical corticosteroids are administered to a nursing woman.
### Pediatric Use
- Pediatric patients may demonstrate greater susceptibility to topical corticosteroid-induced hypothalamic-pituitary-adrenal (HPA) axis suppression and Cushing's syndrome than mature patients because of a larger skin area to body weight ratio.
- HPA axis suppression, Cushing's syndrome, and intracranial hypertension have been reported in children receiving topical corticosteroids. Manifestations of adrenal suppression in children include linear growth retardation, delayed weight gain, low plasma cortisol levels, and absence of response to ACTH stimulation. Manifestations of intracranial hypertension include bulging fontanelles, headaches, and bilateral papilledema.
- Administration of topical corticosteroids to children should be limited to the least amount compatible with an effective therapeutic regimen. Chronic corticosteroid therapy may interfere with the growth and development of children.
### Geriatic Use
There is no FDA guidance on the use of Fluocinonide with respect to geriatric patients.
### Gender
There is no FDA guidance on the use of Fluocinonide with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Fluocinonide with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Fluocinonide in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Fluocinonide in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Fluocinonide in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Fluocinonide in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Topical
### Monitoring
There is limited information regarding Monitoring of Fluocinonide in the drug label.
# IV Compatibility
There is limited information regarding IV Compatibility of Fluocinonide in the drug label.
# Overdosage
## Acute Overdose
### Signs and Symptoms
- Topically applied corticosteroids can be absorbed in sufficient amount to produce systemic effects.
## Chronic Overdose
There is limited information regarding Chronic Overdose of Fluocinonide in the drug label.
# Pharmacology
## Mechanism of Action
- The mechanism of anti-inflammatory activity of the topical corticosteroids is unclear. Various laboratory methods, including vasoconstrictor assays, are used to compare and predict potencies and/or clinical efficacies of the topical corticosteroids. There is some evidence to suggest that a recognizable correlation exists between vasoconstrictor potency and the therapeutic efficacy in man.
## Structure
- Fluocinonide Cream USP, 0.05% is intended for topical administration. The active component is the corticosteroid fluocinonide, which is the 21-acetate ester of fluocinolone acetonide and has the chemical name pregna-1,4-diene-3,20-dione, 21-(acetyloxy)-6,9-difluoro-11-hydroxy-16,17-[(1-methylethylidene)bis(oxy)]-, (6ą,11ß,16ą). Its molecular formula is C26H32F2O7, and has the molecular weight of 494.53. It has the following chemical structure:
- Fluocinonide Cream USP, 0.05% contains fluocinonide 0.5 mg/g in a cream base consisting of citric acid, 1,2,6-hexanetriol, polyethylene glycol-8000, propylene glycol and stearyl alcohol. This white cream vehicle is greaseless, non-staining, anhydrous and completely water miscible. The base provides emollient and hydrophilic properties.
## Pharmacodynamics
There is limited information regarding Pharmacodynamics of Fluocinonide in the drug label.
## Pharmacokinetics
- The extent of percutaneous absorption of topical corticosteroids is determined by many factors including the vehicle, the integrity of the epidermal barrier, and the use of occlusive dressings.
- Topical corticosteroids can be absorbed from normal intact skin. Inflammation and/or other disease processes in the skin increase percutaneous absorption. Occlusive dressings substantially increase the percutaneous absorption of topical corticosteroids. Thus, occlusive dressings may be a valuable therapeutic adjunct for treatment of resistant dermatoses. (See DOSAGE AND ADMINISTRATION.)
- Once absorbed through the skin, topical corticosteroids are handled through pharmacokinetic pathways similar to systemically administered corticosteroids.
- Corticosteroids are bound to plasma proteins in varying degrees. Corticosteroids are metabolized primarily in the liver and are then excreted by the kidneys. Some of the topical corticosteroids and their metabolites are also excreted into the bile.
## Nonclinical Toxicology
- Long-term animal studies have not been performed to evaluate the carcinogenic potential or the effect on fertility of topical corticosteroids.
- Studies to determine mutagenicity with prednisolone and hydrocortisone have revealed negative results.
# Clinical Studies
There is limited information regarding Clinical Studies of Fluocinonide in the drug label.
# How Supplied
- Fluocinonide Cream USP, 0.05% is supplied in 15 g (NDC 0472-3901-15), 30 g (NDC 0472-3901-30), and 60 g (NDC 0472-3901-60) tubes.
- Store at 20°-25°C (68°-77°F).
## Storage
There is limited information regarding Fluocinonide Storage in the drug label.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- Patients using topical corticosteroids should receive the following information and instructions:
- This medication is to be used as directed by the physician. It is for external use only. Avoid contact with the eyes.
- Patients should be advised not to use this medication for any disorder other than for which it was prescribed.
- The treated skin area should not be bandaged or otherwise covered or wrapped as to be occlusive unless directed by the physician.
- Patients should report any signs of local adverse reactions especially under occlusive dressing.
- Parents of pediatric patients should be advised not to use tight-fitting diapers or plastic pants on a child being treated in the diaper area, as these garments may constitute occlusive dressings.
# Precautions with Alcohol
- Alcohol-Fluocinonide interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- FLUOCINONIDE®[1]
# Look-Alike Drug Names
There is limited information regarding Fluocinonide Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Fluocinonide | |
9c4e32527759683c439f1520862e55b7dd941297 | wikidoc | Fluphenazine | Fluphenazine
# Disclaimer
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# Overview
Fluphenazine is a antipsychotic agent that is FDA approved for the treatment of chronic schizophrenia. Common adverse reactions include hypotension, orthostatic hypotension, diminished sweating, photosensitivity, constipation, xerostomia, akathisia, dizziness, drug-induced tardive dystonia, dystonia, extrapyramidal disease, parkinsonian, somnolence, tardive dyskinesia, blurred vision, epithelial keratopathy, eye / vision finding, retinitis pigmentosa, nasal congestion.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
Fluphenazine Decanoate Injection is a long-acting parenteral antipsychotic drug intended for use in the management of patients requiring prolonged parenteral neuroleptic therapy (e.g., chronic schizophrenics).
- Dosing Information
- Fluphenazine Decanoate Injection may be given IM or SC. A dry syringe and needle of at least 21 gauge should be used. Use of a wet needle or syringe may cause the solution to become cloudy.
- To begin therapy with Fluphenazine Decanoate Injection, the following regimens are suggested:
- For most patients, a dose of 12.5 to 25 mg (0.5 to 1 mL) may be given to initiate therapy. The onset of action generally appears between 24 and 72 hours after injection and the effects of the drug on psychotic symptoms becomes significant within 48 to 96 hours. Subsequent injections and the dosage interval are determined in accordance with the patient's response. When administered as maintenance therapy, a single injection may be effective in controlling schizophrenic symptoms up to four weeks or longer. The response to a single dose has been found to last as long as six weeks in a few patients on maintenance therapy.
- It may be advisable that patients who have no history of taking phenothiazines should be treated initially with a shorter-acting form of fluphenazine before administering the decanoate to determine the patient's response to fluphenazine and to establish appropriate dosage. For psychotic patients who have been stabilized on a fixed daily dosage of Fluphenazine Hydrochloride Tablets, USP or Fluphenazine Hydrochloride Elixir, USP conversion of therapy from these short-acting oral forms to the long-acting Fluphenazine Decanoate Injection may be indicated.
- Appropriate dosage of Fluphenazine Decanoate Injection should be individualized for each patient and responses carefully monitored. No precise formula can be given to convert to use of Fluphenazine Decanoate Injection; however, a controlled multicentered study,1 in patients receiving oral doses from 5 to 60 mg fluphenazine hydrochloride daily, showed that 20 mg fluphenazine hydrochloride daily was equivalent to 25 mg (1 mL) of Fluphenazine Decanoate Injection every three weeks. This represents an approximate conversion ratio of 12.5 mg (0.5 mL) of decanoate every three weeks for every 10 mg of fluphenazine hydrochloride daily.
- Once conversion to Fluphenazine Decanoate Injection is made, careful clinical monitoring of the patient and appropriate dosage adjustment should be made at the time of each injection.
- Severely agitated patients may be treated initially with a rapid-acting phenothiazine compound such as Fluphenazine Hydrochloride Injection—see Package Insert accompanying that product for complete information. When acute symptoms have subsided, 25 mg (1 mL) of Fluphenazine Decanoate Injection may be administered; subsequent dosage is adjusted as necessary.
- "Poor risk" patients (those with known hypersensitivity to phenothiazines, or with disorders that predispose to undue reactions): Therapy may be initiated cautiously with oral or parenteral fluphenazine hydrochloride (see Package Inserts accompanying these products for complete information). When the pharmacologic effects and an appropriate dosage are apparent, an equivalent dose of fluphenazine decanoate may be administered. Subsequent dosage adjustments are made in accordance with the response of the patient.
- The optimal amount of the drug and the frequency of administration must be determined for each patient, since dosage requirements have been found to vary with clinical circumstances as well as with individual response to the drug.
- Dosage should not exceed 100 mg. If doses greater than 50 mg are deemed necessary, the next dose and succeeding doses should be increased cautiously in increments of 12.5 mg.
- Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
- There is limited information regarding Off-Label Guideline-Supported Use of Fluphenazine in adult patients.
### Non–Guideline-Supported Use
- There is limited information regarding Off-Label Non–Guideline-Supported Use of Fluphenazine in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
- There is limited information regarding FDA-Labeled Use of Fluphenazine in pediatric patients.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
- There is limited information regarding Off-Label Guideline-Supported Use of Fluphenazine in pediatric patients.
### Non–Guideline-Supported Use
- There is limited information regarding Off-Label Non–Guideline-Supported Use of Fluphenazine in pediatric patients.
# Contraindications
- Phenothiazines are contraindicated in patients with suspected or established subcortical brain damage.
- Phenothiazine compounds should not be used in patients receiving large doses of hypnotics.
- Fluphenazine Decanoate Injection is contraindicated in comatose or severely depressed states.
- The presence of blood dyscrasia or liver damage precludes the use of fluphenazine decanoate.
- Fluphenazine Decanoate Injection is not intended for use in children under 12 years of age.
- Fluphenazine Decanoate Injection is contraindicated in patients who have shown hypersensitivity to fluphenazine; cross-sensitivity to phenothiazine derivatives may occur.
# Warnings
Tardive Dyskinesia
- Tardive dyskinesia, a syndrome consisting of potentially irreversible, involuntary, dyskinetic movements, may develop in patients treated with neuroleptic (antipsychotic) drugs. Although the prevalence of the syndrome appears to be highest among the elderly, especially elderly women, it is impossible to rely upon prevalence estimates to predict, at the inception of neuroleptic treatment, which patients are likely to develop the syndrome. Whether neuroleptic drug products differ in their potential to cause tardive dyskinesia is unknown.
- Both the risk of developing the syndrome and the likelihood that it will become irreversible are believed to increase as the duration of treatment and the total cumulative dose of neuroleptic drugs administered to the patient increase. However, the syndrome can develop, although much less commonly, after relatively brief treatment periods at low doses.
- There is no known treatment for established cases of tardive dyskinesia, although the syndrome may remit, partially or completely, if neuroleptic treatment is withdrawn. Neuroleptic treatment, itself, however, may suppress (or partially suppress) the signs and symptoms of the syndrome and thereby may possibly mask the underlying disease process. The effect that symptomatic suppression has upon the long-term course of the syndrome is unknown.
- Given these considerations, neuroleptics should be prescribed in a manner that is most likely to minimize the occurrence of tardive dyskinesia. Chronic neuroleptic treatment should generally be reserved for patients who suffer from a chronic illness that, 1) is known to respond to neuroleptic drugs, and, 2) for whom alternative equally effective, but potentially less harmful treatments are not available or appropriate. In patients who do require chronic treatment, the smallest dose and the shortest duration of treatment producing a satisfactory clinical response should be sought. The need for continued treatment should be reassessed periodically.
- If signs and symptoms of tardive dyskinesia appear in a patient on neuroleptics, drug discontinuation should be considered. However, some patients may require treatment despite the presence of the syndrome.
- (For further information about the description of tardive dyskinesia and its clinical detection, please refer to the sections on PRECAUTIONS, Information for Patients, and ADVERSE REACTIONS, Tardive Dyskinesia.)
Neuroleptic Malignant Syndrome (NMS)
- A potentially fatal symptom complex sometimes referred to as Neuroleptic Malignant Syndrome (NMS) has been reported in association with antipsychotic drugs. Clinical manifestations of NMS are hyperpyrexia, muscle rigidity, altered mental status and evidence of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac dysrhythmias).
- The diagnostic evaluation of patients with this syndrome is complicated. In arriving at a diagnosis, it is important to identify cases where the clinical presentation includes both serious medical illness (e.g., pneumonia, systemic infection, etc.) and untreated or inadequately treated extrapyramidal signs and symptoms (EPS). Other important considerations in the differential diagnosis include central anticholinergic toxicity, heat stroke, drug fever and primary CNS pathology.
- The management of NMS should include 1) immediate discontinuation of antipsychotic drugs and other drugs not essential to concurrent therapy, 2) intensive symptomatic treatment and medical monitoring, and 3) treatment of any concomitant serious medical problems for which specific treatments are available. There is no general agreement about specific pharmacological treatment regimens for uncomplicated NMS.
- If a patient requires antipsychotic drug treatment after recovery from NMS, the potential reintroduction of drug therapy should be carefully considered. The patient should be carefully monitored, since recurrences of NMS have been reported.
Others
- The use of this drug may impair the mental and physical abilities required for driving a car or operating heavy machinery.
- Physicians should be alert to the possibility that severe adverse reactions may occur which require immediate medical attention.
- Potentiation of the effects of alcohol may occur with the use of this drug.
- Since there is no adequate experience in children who have received this drug, safety and efficacy in children have not been established.
Usage In Pregnancy
- The safety for the use of this drug during pregnancy has not been established; therefore, the possible hazards should be weighed against the potential benefits when administering this drug to pregnant patients.
### PRECAAUTIONS
General
- Because of the possibility of cross-sensitivity, fluphenazine decanoate should be used cautiously in patients who have developed cholestatic jaundice, dermatoses, or other allergic reactions to phenothiazine derivatives.
- Psychotic patients on large doses of a phenothiazine drug who are undergoing surgery should be watched carefully for possible hypotensive phenomena. Moreover, it should be remembered that reduced amounts of anesthetics or CNS depressants may be necessary.
- The effects of atropine may be potentiated in some patients receiving fluphenazine because of added anticholinergic effects.
- Fluphenazine decanoate should be used cautiously in patients exposed to extreme heat or phosphorus insecticides.
- The preparation should be used with caution in patients with a history of convulsive disorders, since grand mal convulsions have been known to occur.
- Use with caution in patients with special medical disorders such as mitral insufficiency or other cardiovascular disease and pheochromocytoma.
- The possibility of liver damage, pigmentary retinopathy, lenticular and corneal deposits, and development of irreversible dyskinesia should be remembered when patients are on prolonged therapy.
- Outside state hospitals or other psychiatric institutions, fluphenazine decanoate should be administered under the direction of a physician experienced in the clinical use of psychotropic drugs, particularly phenothiazine derivatives. Furthermore, facilities should be available for periodic checking of hepatic function, renal function, and the blood picture. Renal function of patients on long-term therapy should be monitored; if blood urea nitrogen (BUN) becomes abnormal, treatment should be discontinued.
- As with any phenothiazine, the physician should be alert to the possible development of "silent pneumonias" in patients under treatment with fluphenazine decanoate.
- Neuroleptic drugs elevate prolactin levels; the elevation persists during chronic administration. Tissue culture experiments indicate that approximately one-third of human breast cancers are prolactin dependent in vitro, a factor of potential importance if the prescription of these drugs is contemplated in a patient with a previously detected breast cancer. Although disturbances such as galactorrhea, amenorrhea, gynecomastia, and impotence have been reported, the clinical significance of elevated serum prolactin levels is unknown for most patients. An increase in mammary neoplasms has been found in rodents after chronic administration of neuroleptic drugs. Neither clinical studies nor epidemiologic studies conducted to date, however, have shown an association between chronic administration of these drugs and mammary tumorigenesis; the available evidence is considered too limited to be conclusive at this time.
Leukopenia, Neutropenia and Agranulocytosis
- In clinical trial and postmarketing experience, events of leukopenia/neutropenia and agranulocytosis have been reported temporally related to antipsychotic agents.
- Possible risk factors for leukopenia/neutropenia include pre-existing low white blood cell count (WBC) and history of drug induced leukopenia/neutropenia. Patients with a pre-existing low WBC or a history of drug induced leukopenia/neutropenia should have their complete blood count (CBC) monitored frequently during the first few months of therapy and should discontinue Fluphenazine Decanoate Injection, USP at the first sign of a decline in WBC in the absence of other causative factors.
- Patients with neutropenia should be carefully monitored for fever or other symptoms or signs of infection and treated promptly if such symptoms or signs occur. Patients with severe neutropenia (absolute neutrophil count <1000/mm3) should discontinue Fluphenazine Decanoate Injection, USP and have their WBC followed until recovery.
# Adverse Reactions
## Clinical Trials Experience
Central Nervous System
- The side effects most frequently reported with phenothiazine compounds are extrapyramidal symptoms including pseudoparkinsonism, dystonia, dyskinesia, akathisia, oculogyric crises, opisthotonos, and hyperreflexia. Muscle rigidity sometimes accompanied by hyperthermia has been reported following use of fluphenazine decanoate. Most often these extrapyramidal symptoms are reversible; however, they may be persistent (see below). The frequency of such reactions is related in part to chemical structure: one can expect a higher incidence with fluphenazine decanoate than with less potent piperazine derivatives or with straight-chain phenothiazines such as chlorpromazine. With any given phenothiazine derivative, the incidence and severity of such reactions depend more on individual patient sensitivity than on other factors, but dosage level and patient age are also determinants.
- Extrapyramidal reactions may be alarming, and the patient should be forewarned and reassured. These reactions can usually be controlled by administration of antiparkinsonian drugs such as Benztropine Mesylate or Intravenous Caffeine and Sodium Benzoate Injection, and by subsequent reduction in dosage.
Tardive Dyskinesia
- See WARNINGS. The syndrome is characterized by involuntary choreoathetoid movements which variously involve the tongue, face, mouth, lips, or jaw (e.g., protrusion of the tongue, puffing of cheeks, puckering of the mouth, chewing movements), trunk and extremities. The severity of the syndrome and the degree of impairment produced vary widely.
- The syndrome may become clinically recognizable either during treatment, upon dosage reduction, or upon withdrawal of treatment. Early detection of tardive dyskinesia is important. To increase the likelihood of detecting the syndrome at the earliest possible time, the dosage of the neuroleptic drug should be reduced periodically (if clinically possible) and the patient observed for signs of the disorder. This maneuver is critical, since neuroleptic drugs may mask the signs of the syndrome.
Other CNS Effects
- Occurrences of neuroleptic malignant syndrome (NMS) have been reported in patients on neuroleptic therapy (see WARNINGS, Neuroleptic Malignant Syndrome); leukocytosis, elevated CPK, liver function abnormalities, and acute renal failure may also occur with NMS.
- Drowsiness or lethargy, if they occur, may necessitate a reduction in dosage; the induction of a catatonic-like state has been known to occur with dosages of fluphenazine far in excess of the recommended amounts. As with other phenothiazine compounds, reactivation or aggravation of psychotic processes may be encountered.
- Phenothiazine derivatives have been known to cause, in some patients, restlessness, excitement, or bizarre dreams.
Autonomic Nervous System
- Hypertension and fluctuations in blood pressure have been reported with fluphenazine.
- Hypotension has rarely presented a problem with fluphenazine. However, patients with pheochromocytoma, cerebral, vascular or renal insufficiency, or a severe cardiac reserve deficiency such as mitral insufficiency appear to be particularly prone to hypotensive reactions with phenothiazine compounds, and should therefore be observed closely when the drug is administered. If severe hypotension should occur, supportive measures including the use of intravenous vasopressor drugs should be instituted immediately. Norepinephrine Bitartrate Injection is the most suitable drug for this purpose: epinephrine should not be used since phenothiazine derivatives have been found to reverse its action, resulting in a further lowering of blood pressure.
- Autonomic reactions including nausea and loss of appetite, salivation, polyuria, perspiration, dry mouth, headache, and constipation may occur. Autonomic effects can usually be controlled by reducing or temporarily discontinuing dosage.
- In some patients, phenothiazine derivatives have caused blurred vision, glaucoma, bladder paralysis, fecal impaction, paralytic ileus, tachycardia, or nasal congestion.
Metabolic and Endocrine
- Weight change, peripheral edema, abnormal lactation, gynecomastia, menstrual irregularities, false results on pregnancy tests, impotency in men and increased libido in women have all been known to occur in some patients on phenothiazine therapy.
Allergic Reactions
- Skin disorders such as itching, erythema, urticaria, seborrhea, photosensitivity, eczema and even exfoliative dermatitis have been reported with phenothiazine derivatives. The possibility of anaphylactoid reactions occurring in some patients should be borne in mind.
Hematologic
- Routine blood counts are advisable during therapy since blood dyscrasias including leukopenia, agranulocytosis, thrombocytopenic or nonthrombocytopenic purpura, eosinophilia, and pancytopenia have been observed with phenothiazine derivatives. Furthermore, if any soreness of the mouth, gums, or throat, or any symptoms of upper respiratory infection occur and confirmatory leukocyte count indicates cellular depression, therapy should be discontinued and other appropriate measures instituted immediately.
Hepatic
- Liver damage as manifested by cholestatic jaundice may be encountered, particularly during the first months of therapy; treatment should be discontinued if this occurs. An increase in cephalin flocculation, sometimes accompanied by alterations in other liver function tests, has been reported in patients receiving the enanthate ester of fluphenazine (a closely related compound) who have had no clinical evidence of liver damage.
Others
- Sudden, unexpected and unexplained deaths have been reported in hospitalized psychotic patients receiving phenothiazines. Previous brain damage or seizures may be predisposing factors; high doses should be avoided in known seizure patients. Several patients have shown sudden flare-ups of psychotic behavior patterns shortly before death. Autopsy findings have usually revealed acute fulminating pneumonia or pneumonitis, aspiration of gastric contents, or intramyocardial lesions.
- Although this is not a general feature of fluphenazine, potentiation of CNS depressants (opiates, analgesics, antihistamines, barbiturates, alcohol) may occur.
- The following adverse reactions have also occurred with phenothiazine derivatives: Systemic lupus erythematosus-like syndrome, hypotension severe enough to cause fatal cardiac arrest, altered electrocardiographic and electroencephalographic tracings, altered cerebrospinal fluid proteins, cerebral edema, asthma, laryngeal edema, and angioneurotic edema; with long-term use, skin pigmentation, and lenticular and corneal opacities.
- Injections of fluphenazine decanoate are extremely well tolerated, local tissue reactions occurring only rarely.
- To report SUSPECTED ADVERSE REACTIONS, contact Par Pharmaceutical, Inc. at 1-800-828-9393 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
## Postmarketing Experience
- There is limited information regarding Postmarketing Experience of Fluphenazine in the drug label.
# Drug Interactions
There is limited information regarding Fluphenazine Drug Interactions in the drug label.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
Non-teratogenic Effects
- Neonates exposed to antipsychotic drugs, during the third trimester of pregnancy are at risk for extrapyramidal and/or withdrawal symptoms following delivery. There have been reports of agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress and feeding disorder in these neonates. These complications have varied in severity; while in some cases symptoms have been self- limited, in other cases neonates have required intensive care unit support and prolonged hospitalization.
- Fluphenazine Decanoate should be used during pregnancy only if 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 Fluphenazine in women who are pregnant.
### Labor and Delivery
- There is no FDA guidance on use of Fluphenazine during labor and delivery.
### Nursing Mothers
- There is no FDA guidance on the use of Fluphenazine with respect to nursing mothers.
### Pediatric Use
- There is no FDA guidance on the use of Fluphenazine with respect to pediatric patients.
### Geriatic Use
- There is no FDA guidance on the use of Fluphenazine with respect to geriatric patients.
### Gender
- There is no FDA guidance on the use of Fluphenazine with respect to specific gender populations.
### Race
- There is no FDA guidance on the use of Fluphenazine with respect to specific racial populations.
### Renal Impairment
- There is no FDA guidance on the use of Fluphenazine in patients with renal impairment.
### Hepatic Impairment
- There is no FDA guidance on the use of Fluphenazine in patients with hepatic impairment.
### Females of Reproductive Potential and Males
- There is no FDA guidance on the use of Fluphenazine in women of reproductive potentials and males.
### Immunocompromised Patients
- There is no FDA guidance one the use of Fluphenazine in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Fluphenazine Decanoate Injection may be given IM or SC. A dry syringe and needle of at least 21 gauge should be used. Use of a wet needle or syringe may cause the solution to become cloudy.
- To begin therapy with Fluphenazine Decanoate Injection, the following regimens are suggested:
- For most patients, a dose of 12.5 to 25 mg (0.5 to 1 mL) may be given to initiate therapy. The onset of action generally appears between 24 and 72 hours after injection and the effects of the drug on psychotic symptoms becomes significant within 48 to 96 hours. Subsequent injections and the dosage interval are determined in accordance with the patient's response. When administered as maintenance therapy, a single injection may be effective in controlling schizophrenic symptoms up to four weeks or longer. The response to a single dose has been found to last as long as six weeks in a few patients on maintenance therapy.
- It may be advisable that patients who have no history of taking phenothiazines should be treated initially with a shorter-acting form of fluphenazine before administering the decanoate to determine the patient's response to fluphenazine and to establish appropriate dosage. For psychotic patients who have been stabilized on a fixed daily dosage of Fluphenazine Hydrochloride Tablets, USP or Fluphenazine Hydrochloride Elixir, USP conversion of therapy from these short-acting oral forms to the long-acting Fluphenazine Decanoate Injection may be indicated.
- Appropriate dosage of Fluphenazine Decanoate Injection should be individualized for each patient and responses carefully monitored. No precise formula can be given to convert to use of Fluphenazine Decanoate Injection; however, a controlled multicentered study,1 in patients receiving oral doses from 5 to 60 mg fluphenazine hydrochloride daily, showed that 20 mg fluphenazine hydrochloride daily was equivalent to 25 mg (1 mL) of Fluphenazine Decanoate Injection every three weeks. This represents an approximate conversion ratio of 12.5 mg (0.5 mL) of decanoate every three weeks for every 10 mg of fluphenazine hydrochloride daily.
- Once conversion to Fluphenazine Decanoate Injection is made, careful clinical monitoring of the patient and appropriate dosage adjustment should be made at the time of each injection.
- Severely agitated patients may be treated initially with a rapid-acting phenothiazine compound such as Fluphenazine Hydrochloride Injection—see Package Insert accompanying that product for complete information. When acute symptoms have subsided, 25 mg (1 mL) of Fluphenazine Decanoate Injection may be administered; subsequent dosage is adjusted as necessary.
- "Poor risk" patients (those with known hypersensitivity to phenothiazines, or with disorders that predispose to undue reactions): Therapy may be initiated cautiously with oral or parenteral fluphenazine hydrochloride (see Package Inserts accompanying these products for complete information). When the pharmacologic effects and an appropriate dosage are apparent, an equivalent dose of fluphenazine decanoate may be administered. Subsequent dosage adjustments are made in accordance with the response of the patient.
- The optimal amount of the drug and the frequency of administration must be determined for each patient, since dosage requirements have been found to vary with clinical circumstances as well as with individual response to the drug.
- Dosage should not exceed 100 mg. If doses greater than 50 mg are deemed necessary, the next dose and succeeding doses should be increased cautiously in increments of 12.5 mg.
- Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.
- Schooler, N.R.: The Initiation of Long-Term Pharmacotherapy in Schizophrenia: Dosage and Side Effect Comparisons between Oral and Depot Fluphenazine. Pharmakopsych. 9:159-169, 1976.
### Monitoring
- There is limited information regarding Monitoring of Fluphenazine in the drug label.
- Description
# IV Compatibility
- There is limited information regarding IV Compatibility of Fluphenazine in the drug label.
# Overdosage
- There is limited information regarding Chronic Overdose of Fluphenazine in the drug label.
# Pharmacology
## Mechanism of Action
- The basic effects of fluphenazine decanoate appear to be no different from those of fluphenazine hydrochloride, with the exception of duration of action. The esterification of fluphenazine markedly prolongs the drug's duration of effect without unduly attenuating its beneficial action.
- Fluphenazine decanoate has activity at all levels of the central nervous system (CNS) as well as on multiple organ systems. The mechanism whereby its therapeutic action is exerted is unknown.
- Fluphenazine differs from other phenothiazine derivatives in several respects: it is more potent on a milligram basis, it has less potentiating effect on CNS depressants and anesthetics than do some of the phenothiazines and appears to be less sedating, and it is less likely than some of the older phenothiazines to produce hypotension (nevertheless, appropriate cautions should be observed, see PRECAUTIONS and ADVERSE REACTIONS).
## Structure
- Fluphenazine decanoate is the decanoate ester of a trifluoromethyl phenothiazine derivative. It is a highly potent behavior modifier with a markedly extended duration of effect and has the following structural formula:
- Fluphenazine Decanoate Injection, USP is available as a clear, pale yellow solution for intramuscular (IM) or subcutaneous (SC) use providing 25 mg fluphenazine decanoate per mL in a sesame oil vehicle with 12 mg benzyl alcohol as a preservative.
## Pharmacodynamics
- There is limited information regarding Pharmacodynamics of Fluphenazine in the drug label.
## Pharmacokinetics
- There is limited information regarding Pharmacokinetics of Fluphenazine in the drug label.
## Nonclinical Toxicology
- There is limited information regarding Nonclinical Toxicology of Fluphenazine in the drug label.
# Clinical Studies
- There is limited information regarding Clinical Studies of Fluphenazine in the drug label.
# How Supplied
- Fluphenazine Decanoate Injection, USP
- NDC 42023-129-01: 25 mg/mL in 5 mL multiple dose, flip-top vial individually packaged.
## Storage
- Store at 20° to 25°C (68° to 77°F) .
- PROTECT FROM LIGHT.
- Retain vial in carton until ready for use.
- Vial stoppers do not contain natural rubber latex.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
Information for Patients
- Given the likelihood that a substantial proportion of patients exposed chronically to neuroleptics will develop tardive dyskinesia, it is advised that all patients in whom chronic use is contemplated be given, if possible, full information about this risk. The decision to inform patients and/or their guardians must obviously take into account the clinical circumstances and the competency of the patient to understand the information provided.
# Precautions with Alcohol
- Alcohol-Fluphenazine interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
Prolixin Decanoate
# Look-Alike Drug Names
- A® — B®
# Drug Shortage Status
# Price | Fluphenazine
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Deepika Beereddy, MBBS [2]
# Disclaimer
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# Overview
Fluphenazine is a antipsychotic agent that is FDA approved for the treatment of chronic schizophrenia. Common adverse reactions include hypotension, orthostatic hypotension, diminished sweating, photosensitivity, constipation, xerostomia, akathisia, dizziness, drug-induced tardive dystonia, dystonia, extrapyramidal disease, parkinsonian, somnolence, tardive dyskinesia, blurred vision, epithelial keratopathy, eye / vision finding, retinitis pigmentosa, nasal congestion.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
Fluphenazine Decanoate Injection is a long-acting parenteral antipsychotic drug intended for use in the management of patients requiring prolonged parenteral neuroleptic therapy (e.g., chronic schizophrenics).
- Dosing Information
- Fluphenazine Decanoate Injection may be given IM or SC. A dry syringe and needle of at least 21 gauge should be used. Use of a wet needle or syringe may cause the solution to become cloudy.
- To begin therapy with Fluphenazine Decanoate Injection, the following regimens are suggested:
- For most patients, a dose of 12.5 to 25 mg (0.5 to 1 mL) may be given to initiate therapy. The onset of action generally appears between 24 and 72 hours after injection and the effects of the drug on psychotic symptoms becomes significant within 48 to 96 hours. Subsequent injections and the dosage interval are determined in accordance with the patient's response. When administered as maintenance therapy, a single injection may be effective in controlling schizophrenic symptoms up to four weeks or longer. The response to a single dose has been found to last as long as six weeks in a few patients on maintenance therapy.
- It may be advisable that patients who have no history of taking phenothiazines should be treated initially with a shorter-acting form of fluphenazine before administering the decanoate to determine the patient's response to fluphenazine and to establish appropriate dosage. For psychotic patients who have been stabilized on a fixed daily dosage of Fluphenazine Hydrochloride Tablets, USP or Fluphenazine Hydrochloride Elixir, USP conversion of therapy from these short-acting oral forms to the long-acting Fluphenazine Decanoate Injection may be indicated.
- Appropriate dosage of Fluphenazine Decanoate Injection should be individualized for each patient and responses carefully monitored. No precise formula can be given to convert to use of Fluphenazine Decanoate Injection; however, a controlled multicentered study,1 in patients receiving oral doses from 5 to 60 mg fluphenazine hydrochloride daily, showed that 20 mg fluphenazine hydrochloride daily was equivalent to 25 mg (1 mL) of Fluphenazine Decanoate Injection every three weeks. This represents an approximate conversion ratio of 12.5 mg (0.5 mL) of decanoate every three weeks for every 10 mg of fluphenazine hydrochloride daily.
- Once conversion to Fluphenazine Decanoate Injection is made, careful clinical monitoring of the patient and appropriate dosage adjustment should be made at the time of each injection.
- Severely agitated patients may be treated initially with a rapid-acting phenothiazine compound such as Fluphenazine Hydrochloride Injection—see Package Insert accompanying that product for complete information. When acute symptoms have subsided, 25 mg (1 mL) of Fluphenazine Decanoate Injection may be administered; subsequent dosage is adjusted as necessary.
- "Poor risk" patients (those with known hypersensitivity to phenothiazines, or with disorders that predispose to undue reactions): Therapy may be initiated cautiously with oral or parenteral fluphenazine hydrochloride (see Package Inserts accompanying these products for complete information). When the pharmacologic effects and an appropriate dosage are apparent, an equivalent dose of fluphenazine decanoate may be administered. Subsequent dosage adjustments are made in accordance with the response of the patient.
- The optimal amount of the drug and the frequency of administration must be determined for each patient, since dosage requirements have been found to vary with clinical circumstances as well as with individual response to the drug.
- Dosage should not exceed 100 mg. If doses greater than 50 mg are deemed necessary, the next dose and succeeding doses should be increased cautiously in increments of 12.5 mg.
- Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
- There is limited information regarding Off-Label Guideline-Supported Use of Fluphenazine in adult patients.
### Non–Guideline-Supported Use
- There is limited information regarding Off-Label Non–Guideline-Supported Use of Fluphenazine in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
- There is limited information regarding FDA-Labeled Use of Fluphenazine in pediatric patients.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
- There is limited information regarding Off-Label Guideline-Supported Use of Fluphenazine in pediatric patients.
### Non–Guideline-Supported Use
- There is limited information regarding Off-Label Non–Guideline-Supported Use of Fluphenazine in pediatric patients.
# Contraindications
- Phenothiazines are contraindicated in patients with suspected or established subcortical brain damage.
- Phenothiazine compounds should not be used in patients receiving large doses of hypnotics.
- Fluphenazine Decanoate Injection is contraindicated in comatose or severely depressed states.
- The presence of blood dyscrasia or liver damage precludes the use of fluphenazine decanoate.
- Fluphenazine Decanoate Injection is not intended for use in children under 12 years of age.
- Fluphenazine Decanoate Injection is contraindicated in patients who have shown hypersensitivity to fluphenazine; cross-sensitivity to phenothiazine derivatives may occur.
# Warnings
Tardive Dyskinesia
- Tardive dyskinesia, a syndrome consisting of potentially irreversible, involuntary, dyskinetic movements, may develop in patients treated with neuroleptic (antipsychotic) drugs. Although the prevalence of the syndrome appears to be highest among the elderly, especially elderly women, it is impossible to rely upon prevalence estimates to predict, at the inception of neuroleptic treatment, which patients are likely to develop the syndrome. Whether neuroleptic drug products differ in their potential to cause tardive dyskinesia is unknown.
- Both the risk of developing the syndrome and the likelihood that it will become irreversible are believed to increase as the duration of treatment and the total cumulative dose of neuroleptic drugs administered to the patient increase. However, the syndrome can develop, although much less commonly, after relatively brief treatment periods at low doses.
- There is no known treatment for established cases of tardive dyskinesia, although the syndrome may remit, partially or completely, if neuroleptic treatment is withdrawn. Neuroleptic treatment, itself, however, may suppress (or partially suppress) the signs and symptoms of the syndrome and thereby may possibly mask the underlying disease process. The effect that symptomatic suppression has upon the long-term course of the syndrome is unknown.
- Given these considerations, neuroleptics should be prescribed in a manner that is most likely to minimize the occurrence of tardive dyskinesia. Chronic neuroleptic treatment should generally be reserved for patients who suffer from a chronic illness that, 1) is known to respond to neuroleptic drugs, and, 2) for whom alternative equally effective, but potentially less harmful treatments are not available or appropriate. In patients who do require chronic treatment, the smallest dose and the shortest duration of treatment producing a satisfactory clinical response should be sought. The need for continued treatment should be reassessed periodically.
- If signs and symptoms of tardive dyskinesia appear in a patient on neuroleptics, drug discontinuation should be considered. However, some patients may require treatment despite the presence of the syndrome.
- (For further information about the description of tardive dyskinesia and its clinical detection, please refer to the sections on PRECAUTIONS, Information for Patients, and ADVERSE REACTIONS, Tardive Dyskinesia.)
Neuroleptic Malignant Syndrome (NMS)
- A potentially fatal symptom complex sometimes referred to as Neuroleptic Malignant Syndrome (NMS) has been reported in association with antipsychotic drugs. Clinical manifestations of NMS are hyperpyrexia, muscle rigidity, altered mental status and evidence of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac dysrhythmias).
- The diagnostic evaluation of patients with this syndrome is complicated. In arriving at a diagnosis, it is important to identify cases where the clinical presentation includes both serious medical illness (e.g., pneumonia, systemic infection, etc.) and untreated or inadequately treated extrapyramidal signs and symptoms (EPS). Other important considerations in the differential diagnosis include central anticholinergic toxicity, heat stroke, drug fever and primary CNS pathology.
- The management of NMS should include 1) immediate discontinuation of antipsychotic drugs and other drugs not essential to concurrent therapy, 2) intensive symptomatic treatment and medical monitoring, and 3) treatment of any concomitant serious medical problems for which specific treatments are available. There is no general agreement about specific pharmacological treatment regimens for uncomplicated NMS.
- If a patient requires antipsychotic drug treatment after recovery from NMS, the potential reintroduction of drug therapy should be carefully considered. The patient should be carefully monitored, since recurrences of NMS have been reported.
Others
- The use of this drug may impair the mental and physical abilities required for driving a car or operating heavy machinery.
- Physicians should be alert to the possibility that severe adverse reactions may occur which require immediate medical attention.
- Potentiation of the effects of alcohol may occur with the use of this drug.
- Since there is no adequate experience in children who have received this drug, safety and efficacy in children have not been established.
Usage In Pregnancy
- The safety for the use of this drug during pregnancy has not been established; therefore, the possible hazards should be weighed against the potential benefits when administering this drug to pregnant patients.
### PRECAAUTIONS
General
- Because of the possibility of cross-sensitivity, fluphenazine decanoate should be used cautiously in patients who have developed cholestatic jaundice, dermatoses, or other allergic reactions to phenothiazine derivatives.
- Psychotic patients on large doses of a phenothiazine drug who are undergoing surgery should be watched carefully for possible hypotensive phenomena. Moreover, it should be remembered that reduced amounts of anesthetics or CNS depressants may be necessary.
- The effects of atropine may be potentiated in some patients receiving fluphenazine because of added anticholinergic effects.
- Fluphenazine decanoate should be used cautiously in patients exposed to extreme heat or phosphorus insecticides.
- The preparation should be used with caution in patients with a history of convulsive disorders, since grand mal convulsions have been known to occur.
- Use with caution in patients with special medical disorders such as mitral insufficiency or other cardiovascular disease and pheochromocytoma.
- The possibility of liver damage, pigmentary retinopathy, lenticular and corneal deposits, and development of irreversible dyskinesia should be remembered when patients are on prolonged therapy.
- Outside state hospitals or other psychiatric institutions, fluphenazine decanoate should be administered under the direction of a physician experienced in the clinical use of psychotropic drugs, particularly phenothiazine derivatives. Furthermore, facilities should be available for periodic checking of hepatic function, renal function, and the blood picture. Renal function of patients on long-term therapy should be monitored; if blood urea nitrogen (BUN) becomes abnormal, treatment should be discontinued.
- As with any phenothiazine, the physician should be alert to the possible development of "silent pneumonias" in patients under treatment with fluphenazine decanoate.
- Neuroleptic drugs elevate prolactin levels; the elevation persists during chronic administration. Tissue culture experiments indicate that approximately one-third of human breast cancers are prolactin dependent in vitro, a factor of potential importance if the prescription of these drugs is contemplated in a patient with a previously detected breast cancer. Although disturbances such as galactorrhea, amenorrhea, gynecomastia, and impotence have been reported, the clinical significance of elevated serum prolactin levels is unknown for most patients. An increase in mammary neoplasms has been found in rodents after chronic administration of neuroleptic drugs. Neither clinical studies nor epidemiologic studies conducted to date, however, have shown an association between chronic administration of these drugs and mammary tumorigenesis; the available evidence is considered too limited to be conclusive at this time.
Leukopenia, Neutropenia and Agranulocytosis
- In clinical trial and postmarketing experience, events of leukopenia/neutropenia and agranulocytosis have been reported temporally related to antipsychotic agents.
- Possible risk factors for leukopenia/neutropenia include pre-existing low white blood cell count (WBC) and history of drug induced leukopenia/neutropenia. Patients with a pre-existing low WBC or a history of drug induced leukopenia/neutropenia should have their complete blood count (CBC) monitored frequently during the first few months of therapy and should discontinue Fluphenazine Decanoate Injection, USP at the first sign of a decline in WBC in the absence of other causative factors.
- Patients with neutropenia should be carefully monitored for fever or other symptoms or signs of infection and treated promptly if such symptoms or signs occur. Patients with severe neutropenia (absolute neutrophil count <1000/mm3) should discontinue Fluphenazine Decanoate Injection, USP and have their WBC followed until recovery.
# Adverse Reactions
## Clinical Trials Experience
Central Nervous System
- The side effects most frequently reported with phenothiazine compounds are extrapyramidal symptoms including pseudoparkinsonism, dystonia, dyskinesia, akathisia, oculogyric crises, opisthotonos, and hyperreflexia. Muscle rigidity sometimes accompanied by hyperthermia has been reported following use of fluphenazine decanoate. Most often these extrapyramidal symptoms are reversible; however, they may be persistent (see below). The frequency of such reactions is related in part to chemical structure: one can expect a higher incidence with fluphenazine decanoate than with less potent piperazine derivatives or with straight-chain phenothiazines such as chlorpromazine. With any given phenothiazine derivative, the incidence and severity of such reactions depend more on individual patient sensitivity than on other factors, but dosage level and patient age are also determinants.
- Extrapyramidal reactions may be alarming, and the patient should be forewarned and reassured. These reactions can usually be controlled by administration of antiparkinsonian drugs such as Benztropine Mesylate or Intravenous Caffeine and Sodium Benzoate Injection, and by subsequent reduction in dosage.
Tardive Dyskinesia
- See WARNINGS. The syndrome is characterized by involuntary choreoathetoid movements which variously involve the tongue, face, mouth, lips, or jaw (e.g., protrusion of the tongue, puffing of cheeks, puckering of the mouth, chewing movements), trunk and extremities. The severity of the syndrome and the degree of impairment produced vary widely.
- The syndrome may become clinically recognizable either during treatment, upon dosage reduction, or upon withdrawal of treatment. Early detection of tardive dyskinesia is important. To increase the likelihood of detecting the syndrome at the earliest possible time, the dosage of the neuroleptic drug should be reduced periodically (if clinically possible) and the patient observed for signs of the disorder. This maneuver is critical, since neuroleptic drugs may mask the signs of the syndrome.
Other CNS Effects
- Occurrences of neuroleptic malignant syndrome (NMS) have been reported in patients on neuroleptic therapy (see WARNINGS, Neuroleptic Malignant Syndrome); leukocytosis, elevated CPK, liver function abnormalities, and acute renal failure may also occur with NMS.
- Drowsiness or lethargy, if they occur, may necessitate a reduction in dosage; the induction of a catatonic-like state has been known to occur with dosages of fluphenazine far in excess of the recommended amounts. As with other phenothiazine compounds, reactivation or aggravation of psychotic processes may be encountered.
- Phenothiazine derivatives have been known to cause, in some patients, restlessness, excitement, or bizarre dreams.
Autonomic Nervous System
- Hypertension and fluctuations in blood pressure have been reported with fluphenazine.
- Hypotension has rarely presented a problem with fluphenazine. However, patients with pheochromocytoma, cerebral, vascular or renal insufficiency, or a severe cardiac reserve deficiency such as mitral insufficiency appear to be particularly prone to hypotensive reactions with phenothiazine compounds, and should therefore be observed closely when the drug is administered. If severe hypotension should occur, supportive measures including the use of intravenous vasopressor drugs should be instituted immediately. Norepinephrine Bitartrate Injection is the most suitable drug for this purpose: epinephrine should not be used since phenothiazine derivatives have been found to reverse its action, resulting in a further lowering of blood pressure.
- Autonomic reactions including nausea and loss of appetite, salivation, polyuria, perspiration, dry mouth, headache, and constipation may occur. Autonomic effects can usually be controlled by reducing or temporarily discontinuing dosage.
- In some patients, phenothiazine derivatives have caused blurred vision, glaucoma, bladder paralysis, fecal impaction, paralytic ileus, tachycardia, or nasal congestion.
Metabolic and Endocrine
- Weight change, peripheral edema, abnormal lactation, gynecomastia, menstrual irregularities, false results on pregnancy tests, impotency in men and increased libido in women have all been known to occur in some patients on phenothiazine therapy.
Allergic Reactions
- Skin disorders such as itching, erythema, urticaria, seborrhea, photosensitivity, eczema and even exfoliative dermatitis have been reported with phenothiazine derivatives. The possibility of anaphylactoid reactions occurring in some patients should be borne in mind.
Hematologic
- Routine blood counts are advisable during therapy since blood dyscrasias including leukopenia, agranulocytosis, thrombocytopenic or nonthrombocytopenic purpura, eosinophilia, and pancytopenia have been observed with phenothiazine derivatives. Furthermore, if any soreness of the mouth, gums, or throat, or any symptoms of upper respiratory infection occur and confirmatory leukocyte count indicates cellular depression, therapy should be discontinued and other appropriate measures instituted immediately.
Hepatic
- Liver damage as manifested by cholestatic jaundice may be encountered, particularly during the first months of therapy; treatment should be discontinued if this occurs. An increase in cephalin flocculation, sometimes accompanied by alterations in other liver function tests, has been reported in patients receiving the enanthate ester of fluphenazine (a closely related compound) who have had no clinical evidence of liver damage.
Others
- Sudden, unexpected and unexplained deaths have been reported in hospitalized psychotic patients receiving phenothiazines. Previous brain damage or seizures may be predisposing factors; high doses should be avoided in known seizure patients. Several patients have shown sudden flare-ups of psychotic behavior patterns shortly before death. Autopsy findings have usually revealed acute fulminating pneumonia or pneumonitis, aspiration of gastric contents, or intramyocardial lesions.
- Although this is not a general feature of fluphenazine, potentiation of CNS depressants (opiates, analgesics, antihistamines, barbiturates, alcohol) may occur.
- The following adverse reactions have also occurred with phenothiazine derivatives: Systemic lupus erythematosus-like syndrome, hypotension severe enough to cause fatal cardiac arrest, altered electrocardiographic and electroencephalographic tracings, altered cerebrospinal fluid proteins, cerebral edema, asthma, laryngeal edema, and angioneurotic edema; with long-term use, skin pigmentation, and lenticular and corneal opacities.
- Injections of fluphenazine decanoate are extremely well tolerated, local tissue reactions occurring only rarely.
- To report SUSPECTED ADVERSE REACTIONS, contact Par Pharmaceutical, Inc. at 1-800-828-9393 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
## Postmarketing Experience
- There is limited information regarding Postmarketing Experience of Fluphenazine in the drug label.
# Drug Interactions
There is limited information regarding Fluphenazine Drug Interactions in the drug label.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
Non-teratogenic Effects
- Neonates exposed to antipsychotic drugs, during the third trimester of pregnancy are at risk for extrapyramidal and/or withdrawal symptoms following delivery. There have been reports of agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress and feeding disorder in these neonates. These complications have varied in severity; while in some cases symptoms have been self- limited, in other cases neonates have required intensive care unit support and prolonged hospitalization.
- Fluphenazine Decanoate should be used during pregnancy only if 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 Fluphenazine in women who are pregnant.
### Labor and Delivery
- There is no FDA guidance on use of Fluphenazine during labor and delivery.
### Nursing Mothers
- There is no FDA guidance on the use of Fluphenazine with respect to nursing mothers.
### Pediatric Use
- There is no FDA guidance on the use of Fluphenazine with respect to pediatric patients.
### Geriatic Use
- There is no FDA guidance on the use of Fluphenazine with respect to geriatric patients.
### Gender
- There is no FDA guidance on the use of Fluphenazine with respect to specific gender populations.
### Race
- There is no FDA guidance on the use of Fluphenazine with respect to specific racial populations.
### Renal Impairment
- There is no FDA guidance on the use of Fluphenazine in patients with renal impairment.
### Hepatic Impairment
- There is no FDA guidance on the use of Fluphenazine in patients with hepatic impairment.
### Females of Reproductive Potential and Males
- There is no FDA guidance on the use of Fluphenazine in women of reproductive potentials and males.
### Immunocompromised Patients
- There is no FDA guidance one the use of Fluphenazine in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Fluphenazine Decanoate Injection may be given IM or SC. A dry syringe and needle of at least 21 gauge should be used. Use of a wet needle or syringe may cause the solution to become cloudy.
- To begin therapy with Fluphenazine Decanoate Injection, the following regimens are suggested:
- For most patients, a dose of 12.5 to 25 mg (0.5 to 1 mL) may be given to initiate therapy. The onset of action generally appears between 24 and 72 hours after injection and the effects of the drug on psychotic symptoms becomes significant within 48 to 96 hours. Subsequent injections and the dosage interval are determined in accordance with the patient's response. When administered as maintenance therapy, a single injection may be effective in controlling schizophrenic symptoms up to four weeks or longer. The response to a single dose has been found to last as long as six weeks in a few patients on maintenance therapy.
- It may be advisable that patients who have no history of taking phenothiazines should be treated initially with a shorter-acting form of fluphenazine before administering the decanoate to determine the patient's response to fluphenazine and to establish appropriate dosage. For psychotic patients who have been stabilized on a fixed daily dosage of Fluphenazine Hydrochloride Tablets, USP or Fluphenazine Hydrochloride Elixir, USP conversion of therapy from these short-acting oral forms to the long-acting Fluphenazine Decanoate Injection may be indicated.
- Appropriate dosage of Fluphenazine Decanoate Injection should be individualized for each patient and responses carefully monitored. No precise formula can be given to convert to use of Fluphenazine Decanoate Injection; however, a controlled multicentered study,1 in patients receiving oral doses from 5 to 60 mg fluphenazine hydrochloride daily, showed that 20 mg fluphenazine hydrochloride daily was equivalent to 25 mg (1 mL) of Fluphenazine Decanoate Injection every three weeks. This represents an approximate conversion ratio of 12.5 mg (0.5 mL) of decanoate every three weeks for every 10 mg of fluphenazine hydrochloride daily.
- Once conversion to Fluphenazine Decanoate Injection is made, careful clinical monitoring of the patient and appropriate dosage adjustment should be made at the time of each injection.
- Severely agitated patients may be treated initially with a rapid-acting phenothiazine compound such as Fluphenazine Hydrochloride Injection—see Package Insert accompanying that product for complete information. When acute symptoms have subsided, 25 mg (1 mL) of Fluphenazine Decanoate Injection may be administered; subsequent dosage is adjusted as necessary.
- "Poor risk" patients (those with known hypersensitivity to phenothiazines, or with disorders that predispose to undue reactions): Therapy may be initiated cautiously with oral or parenteral fluphenazine hydrochloride (see Package Inserts accompanying these products for complete information). When the pharmacologic effects and an appropriate dosage are apparent, an equivalent dose of fluphenazine decanoate may be administered. Subsequent dosage adjustments are made in accordance with the response of the patient.
- The optimal amount of the drug and the frequency of administration must be determined for each patient, since dosage requirements have been found to vary with clinical circumstances as well as with individual response to the drug.
- Dosage should not exceed 100 mg. If doses greater than 50 mg are deemed necessary, the next dose and succeeding doses should be increased cautiously in increments of 12.5 mg.
- Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.
- Schooler, N.R.: The Initiation of Long-Term Pharmacotherapy in Schizophrenia: Dosage and Side Effect Comparisons between Oral and Depot Fluphenazine. Pharmakopsych. 9:159-169, 1976.
### Monitoring
- There is limited information regarding Monitoring of Fluphenazine in the drug label.
- Description
# IV Compatibility
- There is limited information regarding IV Compatibility of Fluphenazine in the drug label.
# Overdosage
- There is limited information regarding Chronic Overdose of Fluphenazine in the drug label.
# Pharmacology
## Mechanism of Action
- The basic effects of fluphenazine decanoate appear to be no different from those of fluphenazine hydrochloride, with the exception of duration of action. The esterification of fluphenazine markedly prolongs the drug's duration of effect without unduly attenuating its beneficial action.
- Fluphenazine decanoate has activity at all levels of the central nervous system (CNS) as well as on multiple organ systems. The mechanism whereby its therapeutic action is exerted is unknown.
- Fluphenazine differs from other phenothiazine derivatives in several respects: it is more potent on a milligram basis, it has less potentiating effect on CNS depressants and anesthetics than do some of the phenothiazines and appears to be less sedating, and it is less likely than some of the older phenothiazines to produce hypotension (nevertheless, appropriate cautions should be observed, see PRECAUTIONS and ADVERSE REACTIONS).
## Structure
- Fluphenazine decanoate is the decanoate ester of a trifluoromethyl phenothiazine derivative. It is a highly potent behavior modifier with a markedly extended duration of effect and has the following structural formula:
- Fluphenazine Decanoate Injection, USP is available as a clear, pale yellow solution for intramuscular (IM) or subcutaneous (SC) use providing 25 mg fluphenazine decanoate per mL in a sesame oil vehicle with 12 mg benzyl alcohol as a preservative.
## Pharmacodynamics
- There is limited information regarding Pharmacodynamics of Fluphenazine in the drug label.
## Pharmacokinetics
- There is limited information regarding Pharmacokinetics of Fluphenazine in the drug label.
## Nonclinical Toxicology
- There is limited information regarding Nonclinical Toxicology of Fluphenazine in the drug label.
# Clinical Studies
- There is limited information regarding Clinical Studies of Fluphenazine in the drug label.
# How Supplied
- Fluphenazine Decanoate Injection, USP
- NDC 42023-129-01: 25 mg/mL in 5 mL multiple dose, flip-top vial individually packaged.
## Storage
- Store at 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature].
- PROTECT FROM LIGHT.
- Retain vial in carton until ready for use.
- Vial stoppers do not contain natural rubber latex.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
Information for Patients
- Given the likelihood that a substantial proportion of patients exposed chronically to neuroleptics will develop tardive dyskinesia, it is advised that all patients in whom chronic use is contemplated be given, if possible, full information about this risk. The decision to inform patients and/or their guardians must obviously take into account the clinical circumstances and the competency of the patient to understand the information provided.
# Precautions with Alcohol
- Alcohol-Fluphenazine interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
Prolixin Decanoate
# Look-Alike Drug Names
- A® — B®[1]
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Fluphenazine | |
60c93ad87e452f405bdc7c4f951b12b6d6b64d59 | wikidoc | Focal length | Focal length
The focal length of an optical system is a measure of how strongly it converges (focuses) or diverges (diffuses) light. A system with a shorter focal length has greater optical power than one with a long focal length.
# Thin lens approximation
For a thin lens in air, the focal length is the distance from the center of the lens to the principal foci (or focal points) of the lens. For a converging lens (for example a convex lens), the focal length is positive, and is the distance at which a beam of collimated light will be focused to a single spot. For a diverging lens (for example a concave lens), the focal length is negative, and is the distance to the point from which a collimated beam appears to be diverging after passing through the lens.
# General optical systems
For a thick lens (one which has a non-negligible thickness), or an imaging system consisting of several lenses and/or mirrors (e.g., a photographic lens or a telescope), the focal length is often called the effective focal length (EFL), to distinguish it from other commonly-used parameters:
- Front focal length (FFL) or Front focal distance (FFD) is the distance from the front focal point of the system to the vertex of the first optical surface.
- Back focal length (BFL) or Back focal distance (BFD) is the distance from the vertex of the last optical surface of the system to the rear focal point.
For an optical system in air, the effective focal length gives the distance from the front and rear principal planes to the corresponding focal points. If the surrounding medium is not air, then the distance is multiplied by the refractive index of the medium. Some authors call this distance the front (rear) focal length, distinguishing it from the front (rear) focal distance, defined above.
In general, the focal length or EFL is the value that describes the ability of the optical system to focus light, and is the value used to calculate the magnification of the system. The other parameters are used in determining where an image will be formed for a given object position.
For the case of a lens of thickness d in air, and surfaces with radii of curvature R1 and R2, the effective focal length f is given by:
where n is the refractive index of the lens medium. The quantity 1/f is also known as the optical power of the lens.
The corresponding front focal distance is:
and the back focal distance:
In the sign convention used here, the value of R1 will be positive if the first lens surface is convex, and negative if it is concave. The value of R2 is positive if the second surface is concave, and negative if convex. Note that sign conventions vary between different authors, which results in different forms of these equations depending on the convention used.
For a spherically curved mirror in air, the magnitude of the focal length is equal to the radius of curvature of the mirror divided by two. The focal length is positive for a concave mirror, and negative for a convex mirror. In the sign convention used in optical design, a concave mirror has negative radius of curvature, so
where R is the radius of curvature of the mirror's surface.
See Radius of curvature (optics) for more information on the sign convention for radius of curvature used here.
# In photography
When a photographic lens is set to "infinity", its rear nodal point is separated from the sensor or film, at the focal plane, by the lens's focal length. Objects far away from the camera then produce sharp images on the sensor or film, which is also at the image plane. Photographers sometimes refer to the image plane as the focal plane; these planes coincide when the object is at infinity, but for closer objects the focal plane is fixed, relative to the lens, and the image plane moves, by the standard optical definitions.
The focal length of a lens determines the magnification at which it images distant objects. The focal length of a lens is equal to the distance between the image plane and a pinhole (see pinhole camera model) that images distant small objects the same size as the lens in question. Combining this definition with an assumption of rectilinear imaging (that is, with no image distortion) leads to a simple geometric model the photographers use for computing the angle of view of a camera.
To render closer objects in sharp focus, the lens must be adjusted to increase the distance between the rear nodal point and the film, to put the film at the image plane. The focal length f, the distance from the front nodal point to the object to photograph S_1, and the distance from the rear nodal point to the image plane S_2 are then related by:
As S_1 is decreased, S_2 must be increased. For example, consider a normal lens for a 35 mm camera with a focal length of f=50 \text{ mm}. To focus a distant object (S_1\approx \infty), the rear nodal point of the lens must be located a distance S_2=50 \text{ mm} from the image plane. To focus an object 1 m away (S_1=1000 \text{ mm}), the lens must be moved 2.6 mm further away from the image plane, to S_2=52.6 \text{ mm}.
Note that some simple and usually inexpensive cameras have fixed focus lenses which cannot be adjusted.
Focal lengths are usually specified in millimetres (mm), but older lenses marked in centimetres (cm) and inches are still to be found. The angle of view depends on the ratio between the focal length and the film size.
A lens with a focal length about equal to the diagonal size of the film or sensor format is known as a normal lens; its angle of view is similar to the angle subtended by a large-enough print viewed at a typical viewing distance of the print diagonal, which therefore yields a normal perspective when viewing the print; this angle of view is about 53 degrees diagonally. For full-frame 35mm-format cameras, the diagonal is 43 mm and a typical "normal" lens has a 50 mm focal length. A lens with a focal length shorter than normal is often referred to as a wide-angle lens (typically 35 mm and less, for 35mm-format cameras), while a lens significantly longer than normal may be referred to as a telephoto lens (typically 85 mm and more, for 35mm-format cameras), though the use of the term is inaccurate as it implies specific optical design qualities that may or may not apply to a given lens.
Due to the popularity of the 35 mm standard, camera–lens combinations are often described in terms of their 35 mm equivalent focal length, that is, the focal length of a lens that would have the same angle of view, or field of view, if used on a full-frame 35 mm camera. Use of a 35 mm equivalent focal length is particularly common with digital cameras, which often use sensors smaller than 35 mm film, and so require correspondingly shorter focal lengths to achieve a given angle of view, by a factor known as the crop factor. | Focal length
The focal length of an optical system is a measure of how strongly it converges (focuses) or diverges (diffuses) light. A system with a shorter focal length has greater optical power than one with a long focal length.
# Thin lens approximation
For a thin lens in air, the focal length is the distance from the center of the lens to the principal foci (or focal points) of the lens. For a converging lens (for example a convex lens), the focal length is positive, and is the distance at which a beam of collimated light will be focused to a single spot. For a diverging lens (for example a concave lens), the focal length is negative, and is the distance to the point from which a collimated beam appears to be diverging after passing through the lens.
# General optical systems
For a thick lens (one which has a non-negligible thickness), or an imaging system consisting of several lenses and/or mirrors (e.g., a photographic lens or a telescope), the focal length is often called the effective focal length (EFL), to distinguish it from other commonly-used parameters:
- Front focal length (FFL) or Front focal distance (FFD) is the distance from the front focal point of the system to the vertex of the first optical surface.[1]
- Back focal length (BFL) or Back focal distance (BFD) is the distance from the vertex of the last optical surface of the system to the rear focal point.[1]
For an optical system in air, the effective focal length gives the distance from the front and rear principal planes to the corresponding focal points. If the surrounding medium is not air, then the distance is multiplied by the refractive index of the medium. Some authors call this distance the front (rear) focal length, distinguishing it from the front (rear) focal distance, defined above.[1]
In general, the focal length or EFL is the value that describes the ability of the optical system to focus light, and is the value used to calculate the magnification of the system. The other parameters are used in determining where an image will be formed for a given object position.
For the case of a lens of thickness d in air, and surfaces with radii of curvature R1 and R2, the effective focal length f is given by:
where n is the refractive index of the lens medium. The quantity 1/f is also known as the optical power of the lens.
The corresponding front focal distance is:
and the back focal distance:
In the sign convention used here, the value of R1 will be positive if the first lens surface is convex, and negative if it is concave. The value of R2 is positive if the second surface is concave, and negative if convex. Note that sign conventions vary between different authors, which results in different forms of these equations depending on the convention used.
For a spherically curved mirror in air, the magnitude of the focal length is equal to the radius of curvature of the mirror divided by two. The focal length is positive for a concave mirror, and negative for a convex mirror. In the sign convention used in optical design, a concave mirror has negative radius of curvature, so
where <math>R</math> is the radius of curvature of the mirror's surface.
See Radius of curvature (optics) for more information on the sign convention for radius of curvature used here.
# In photography
When a photographic lens is set to "infinity", its rear nodal point is separated from the sensor or film, at the focal plane, by the lens's focal length. Objects far away from the camera then produce sharp images on the sensor or film, which is also at the image plane. Photographers sometimes refer to the image plane as the focal plane; these planes coincide when the object is at infinity, but for closer objects the focal plane is fixed, relative to the lens, and the image plane moves, by the standard optical definitions.
The focal length of a lens determines the magnification at which it images distant objects. The focal length of a lens is equal to the distance between the image plane and a pinhole (see pinhole camera model) that images distant small objects the same size as the lens in question. Combining this definition with an assumption of rectilinear imaging (that is, with no image distortion) leads to a simple geometric model the photographers use for computing the angle of view of a camera.
To render closer objects in sharp focus, the lens must be adjusted to increase the distance between the rear nodal point and the film, to put the film at the image plane. The focal length <math>f</math>, the distance from the front nodal point to the object to photograph <math>S_1</math>, and the distance from the rear nodal point to the image plane <math>S_2</math> are then related by:
As <math>S_1</math> is decreased, <math>S_2</math> must be increased. For example, consider a normal lens for a 35 mm camera with a focal length of <math>f=50 \text{ mm}</math>. To focus a distant object (<math>S_1\approx \infty</math>), the rear nodal point of the lens must be located a distance <math>S_2=50 \text{ mm}</math> from the image plane. To focus an object 1 m away (<math>S_1=1000 \text{ mm}</math>), the lens must be moved 2.6 mm further away from the image plane, to <math>S_2=52.6 \text{ mm}</math>.
Note that some simple and usually inexpensive cameras have fixed focus lenses which cannot be adjusted.
Focal lengths are usually specified in millimetres (mm), but older lenses marked in centimetres (cm) and inches are still to be found. The angle of view depends on the ratio between the focal length and the film size.
A lens with a focal length about equal to the diagonal size of the film or sensor format is known as a normal lens; its angle of view is similar to the angle subtended by a large-enough print viewed at a typical viewing distance of the print diagonal, which therefore yields a normal perspective when viewing the print;[2] this angle of view is about 53 degrees diagonally. For full-frame 35mm-format cameras, the diagonal is 43 mm and a typical "normal" lens has a 50 mm focal length. A lens with a focal length shorter than normal is often referred to as a wide-angle lens (typically 35 mm and less, for 35mm-format cameras), while a lens significantly longer than normal may be referred to as a telephoto lens (typically 85 mm and more, for 35mm-format cameras), though the use of the term is inaccurate as it implies specific optical design qualities that may or may not apply to a given lens.
Due to the popularity of the 35 mm standard, camera–lens combinations are often described in terms of their 35 mm equivalent focal length, that is, the focal length of a lens that would have the same angle of view, or field of view, if used on a full-frame 35 mm camera. Use of a 35 mm equivalent focal length is particularly common with digital cameras, which often use sensors smaller than 35 mm film, and so require correspondingly shorter focal lengths to achieve a given angle of view, by a factor known as the crop factor. | https://www.wikidoc.org/index.php/Focal_distance | |
99119adbadfaac1a21df3e4a54be83a8e30ace5f | wikidoc | Folie à deux | Folie à deux
# Overview
Folie à deux (literally, "a madness shared by two") is a rare psychiatric syndrome in which a symptom of psychosis (particularly a paranoid or delusional belief) is transmitted from one individual to another. The same syndrome shared by more than two people may be called folie à trois, folie à quatre, folie à famille or even folie à plusieurs (madness of many). Recent psychiatric classifications refer to the syndrome as shared psychotic disorder (DSM-IV) (297.3) and induced delusional disorder (folie à deux) (F.24) in the ICD-10, although the research literature largely uses the original name.
# Presentation
This case study is taken from Enoch and Ball's 'Uncommon Psychiatric Syndromes' (2001, p181):
This syndrome is most commonly diagnosed when the two or more individuals concerned live in proximity and may be socially or physically isolated and have little interaction with other people.
Various sub-classifications of folie à deux have been proposed to describe how the delusional belief comes to be held by more than one person.
- Folie imposée is where a dominant person (known as the 'primary', 'inducer' or 'principal') initially forms a delusional belief during a psychotic episode and imposes it on another person or persons (known as the 'secondary', 'acceptor' or 'associate') with the assumption that the secondary person might not have become deluded if left to their own devices. If the parties are admitted to hospital separately then the delusions in the person with the induced beliefs usually resolve without the need of medication.
- Folie simultanée describes the situation where two people, considered to independently suffer from psychosis, influence the content of each other's delusions so they become identical or strikingly similar.
Folie à deux and its more populous cousins are in many ways a psychiatric curiosity. The current Diagnostic and Statistical Manual of Mental Disorders states that a person cannot be diagnosed as being delusional if the belief in question is one "ordinarily accepted by other members of the person's culture or subculture" (see entry for delusion). It is not clear at what point a belief considered to be delusional escapes from the folie à... diagnostic category and becomes legitimate because of the number of people holding it. When a large number of people may come to believe obviously false and potentially distressing things based purely on hearsay, these beliefs are not considered to be clinical delusions by the psychiatric profession and are labelled instead as mass hysteria.
Being defined as a rare pathological manifestation, folie à deux is rarely found in general psychology or social psychology text books, and is relatively unknown outside abnormal psychology, psychiatry and psychopathology.
## Related phenomena
There have been reports that a similar phenomenon to folie à deux had been induced by the military incapacitating agent BZ in the late 60s, and most recently again by anthropologists in the South American rainforest consuming the hallucinogen ayahuasca (Metzner, 1999).
# In the media
- (1994) Heavenly Creatures is a film directed by Peter Jackson and starring Kate Winslet and Melanie Lynskey. It was set in New Zealand and inspired by a true story where two teenage girls develop a relationship so strong and peculiar that they believe the only way to stay together was to kill one of the girls's mother. These girls were thought to have folie à deux.
- (1998) Folie à deux was the title of an episode from season 5 of The X-Files, aired in 1998, where Agent Mulder shares the belief with a telemarketer that employees of the telemarketing firm are monsters.
- (2006) 'Folie à Deux' is the title of a short film written and directed by Devin Anderson. The film was shot in 2006 and is currently in post-production.
- (2006) Folie à deux was referenced and defined in an episode from season 2 of Criminal Minds entitled "The Perfect Storm", which aired October 4, 2006 on CBS, in which a pair of serial killers kidnapped, tortured, and murdered several young women; in this episode, the primary, or dominant, perpetrator was a woman.
- (2007) The film Bug portrays a folie à deux involving a man and woman who believe they are infested with government-implanted, nano-technological insects. | Folie à deux
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Folie à deux (literally, "a madness shared by two") is a rare psychiatric syndrome in which a symptom of psychosis (particularly a paranoid or delusional belief) is transmitted from one individual to another. The same syndrome shared by more than two people may be called folie à trois, folie à quatre, folie à famille or even folie à plusieurs (madness of many). Recent psychiatric classifications refer to the syndrome as shared psychotic disorder (DSM-IV) (297.3) and induced delusional disorder (folie à deux) (F.24) in the ICD-10, although the research literature largely uses the original name.
# Presentation
This case study is taken from Enoch and Ball's 'Uncommon Psychiatric Syndromes' (2001, p181):
This syndrome is most commonly diagnosed when the two or more individuals concerned live in proximity and may be socially or physically isolated and have little interaction with other people.
Various sub-classifications of folie à deux have been proposed to describe how the delusional belief comes to be held by more than one person.
- Folie imposée is where a dominant person (known as the 'primary', 'inducer' or 'principal') initially forms a delusional belief during a psychotic episode and imposes it on another person or persons (known as the 'secondary', 'acceptor' or 'associate') with the assumption that the secondary person might not have become deluded if left to their own devices. If the parties are admitted to hospital separately then the delusions in the person with the induced beliefs usually resolve without the need of medication.
- Folie simultanée describes the situation where two people, considered to independently suffer from psychosis, influence the content of each other's delusions so they become identical or strikingly similar.
Folie à deux and its more populous cousins are in many ways a psychiatric curiosity. The current Diagnostic and Statistical Manual of Mental Disorders states that a person cannot be diagnosed as being delusional if the belief in question is one "ordinarily accepted by other members of the person's culture or subculture" (see entry for delusion). It is not clear at what point a belief considered to be delusional escapes from the folie à... diagnostic category and becomes legitimate because of the number of people holding it. When a large number of people may come to believe obviously false and potentially distressing things based purely on hearsay, these beliefs are not considered to be clinical delusions by the psychiatric profession and are labelled instead as mass hysteria.
Being defined as a rare pathological manifestation, folie à deux is rarely found in general psychology or social psychology text books, and is relatively unknown outside abnormal psychology, psychiatry and psychopathology.
## Related phenomena
There have been reports that a similar phenomenon to folie à deux had been induced by the military incapacitating agent BZ in the late 60s, and most recently again by anthropologists in the South American rainforest consuming the hallucinogen ayahuasca (Metzner, 1999).
# In the media
- (1994) Heavenly Creatures is a film directed by Peter Jackson and starring Kate Winslet and Melanie Lynskey. It was set in New Zealand and inspired by a true story where two teenage girls develop a relationship so strong and peculiar that they believe the only way to stay together was to kill one of the girls's mother. These girls were thought to have folie à deux.
- (1998) Folie à deux was the title of an episode from season 5 of The X-Files, aired in 1998, where Agent Mulder shares the belief with a telemarketer that employees of the telemarketing firm are monsters.
- (2006) 'Folie à Deux' is the title of a short film written and directed by Devin Anderson. The film was shot in 2006 and is currently in post-production.
- (2006) Folie à deux was referenced and defined in an episode from season 2 of Criminal Minds entitled "The Perfect Storm", which aired October 4, 2006 on CBS, in which a pair of serial killers kidnapped, tortured, and murdered several young women; in this episode, the primary, or dominant, perpetrator was a woman.
- (2007) The film Bug portrays a folie à deux involving a man and woman who believe they are infested with government-implanted, nano-technological insects. | https://www.wikidoc.org/index.php/Folie_%C3%A0_deux | |
ae864102ec531be5d0d2ea69cef1a3e2500ac5e9 | wikidoc | Food allergy | Food allergy
For the WikiPatient page for this topic, click here
# Overview
A food allergy is an immunologic response to a food protein. It is estimated that up to 12 million Americans have food allergies of one type or another, and the prevalence is rising. Six to eight percent of children have food allergies and two percent of adults have them. The most common food allergies in adults are shellfish, peanuts, tree nuts, sesame seeds, fish, and eggs, and the most common food allergies present in children are milk, eggs, and peanuts.
At this time, there is no cure for food allergies. Treatment consists of avoidance diets, where the allergic person avoids any and all forms of the food to which they are allergic. For people who are extremely sensitive, this may involve the total avoidance of any exposure with the allergen, including touching or inhaling the problematic food as well as any surfaces that may have come into contact with it. Food allergy is distinct from food intolerance, which is not caused by an immune reaction.
Persons diagnosed with a food allergy may carry an autoinjector of epinephrine such as an EpiPen or Twinject, wear some form of medical alert jewelry, or develop an emergency action plan, in accordance with their doctor.
# Signs and symptoms
Symptoms of food allergies include:
- Anaphylaxis: a severe, whole-body allergic reaction that can result in death (see below)
- Angioedema: swelling, especially of the eyelids, face, lips, and tongue
- Eczema
- Hives
- Itching of the mouth, throat, eyes, skin, or any area
- Nausea, vomiting, diarrhea, stomach cramps, or abdominal pain
- Runny nose or nasal congestion
- Wheezing, scratchy throat, shortness of breath, or difficulty swallowing
- Mood swings, depression
Angioedema is a skin reaction where the tissues swell. It can result in swelling/edema of the lips, skin tongue and airways (causing constriction, wheezing and difficulty breathing). It can also cause swelling of the face, eyes, hands, etc.
The symptoms of an Immunoglobulin E (IgE) allergic reaction can take place within a few minutes to an hour. The process of eating and digesting food affects the timing and location of a reaction. IgG reactions build over a period of hours to days, and therefore symptoms can be difficult to notice as allergy-related.
Food allergy can lead to anaphylactic shock: A systemic reaction involving several different bodily systems including hypotension (low blood pressure) and loss of consciousness. This is a medical emergency. Allergens commonly associated with this type of reaction are peanuts, nuts, milk, egg, and seafood. Food anaphylaxis can also be caused by various types of fruit. Latex products can induce similar reactions.
Food allergy is thought to develop more easily in patients with the atopic syndrome, a very common combination of diseases: allergic rhinitis and conjunctivitis, eczema and asthma. The syndrome has a strong inherited component; a family history of allergic diseases can be indicative of the atopic syndrome.
Another type of food allergy is called Gastrointestinal Food Hypersensitivity. It can be IgE or Non-IgE mediated.
In this class, IgE mediated responsese include:
- Immediate GI Hypersensitivity
- Oral allergy syndrome
Conditions that have been shown to have both IgE and Non-IgE causes of gastrointestinal food hypersensitity include:
- Allergic eosinophilic esophagitis
- Allergic eosinophilic gastritis
- Allergic eosinophilic gastroenteritis
Conditions of Non-IgE gastrointestinal food hypersensitivity include:
- Enterocolitis syndrome
- Dietary protein proctitis
- Celiac disease
# The Big Eight
The most common food allergies are:
- Milk allergy
- Egg allergy
- Peanut allergy
- Tree nut allergy
- Seafood allergy
- Shellfish allergy
- Soy allergy
- Wheat allergy
These are often referred to as "the big eight." They account for over 90% of the food allergies in the United States of America.
Likelihood of allergy can increase with exposure. For example, rice allergy is more common in East Asia where rice forms a large part of the diet. In Central Europe, celery allergy is more common. The top allergens vary somewhat from country to country but milk, eggs, peanuts, treenuts, fish, shellfish, soy, wheat and sesame tend to be in the top 10 in many countries.
# Diagnosis
The best method for diagnosing food allergy is to be assessed by an allergist. The allergist will review the patient's history and the symptoms or reactions that have been noted after food ingestion. If the allergist feels the symptoms or reactions are in keeping with a food allergy, he/she will perform allergy tests.
There are two basic types of allergy tests: Skin Prick Tests and blood tests. The skin prick is easy to do and results are available in minutes. Different allergists may use different devices for skin prick testing. Some use a "bifurcated needle", which looks like a fork with 2 prongs. Others use a "multi-test", which may look like a small board with several pins sticking out of it. In these tests, a tiny amount of the suspected allergen is put onto the skin or into a testing device, and the device is placed on the skin to prick, or break through, the top layer of skin. This puts a small amount of the allergen under the skin. A hive will form at any spot where the person is allergic. This test generally yields a positive or negative result. It is good for quickly learning if a person is allergic to a particular food or not, because it detects allergic antibodies known as IgE. Skin tests cannot predict if a reaction would occur or what kind of reaction might occur if a person ingests that particular allergen. They can however confirm an allergy in light of a patient's history of reactions to a particular food.
Blood tests are another useful diagnostic tool. For example, the RAST (RadioAllergoSorbent Test)detects the presence of IgE antibodies to a particular allergen. A CAP-RAST test is a specific type of RAST test with greater specificity: it can show the amount of IgE present to each allergen . Researchers have been able to determine "predictive values" for certain foods. These predictive values can be compared to the RAST blood test results. If a persons RAST score is higher than the predictive value for that food, then there is over a 95% chance the person will have an allergic reaction (limited to rash and anaphylaxis reactions) if they ingest that food. Currently, predictive values are available for the following foods: milk, egg, peanut, fish, soy, and wheat. Blood tests allow for hundreds of allergens to be screened from a single sample, and cover food allergies as well as inhalants. However, non-IgE mediated allergies cannot be detected by this method.
Blood testing methodologies currently available that can measure antibodies of IgG are not acceptable as a method of allergy evaluation. IgG-type anitbodies are not implicated in a food allergy reactions. The significance of IgG anti-allergen antibodies was reviewed by the American Academy of Allergy and Immunology and found to be lacking. Although a number of commercial labs sell tests that reportedly measure IgG antibodies against common allergens there is no clinical significance of such findings. It is not established that these commercial assays actually measure the IgG antibodies that they report. Also, even if the assays are measuring IgG anti- allergen antibodies, the clinical significance of such antibodies is certainly not established. The significance of IgG anti-food antibodies is particularly questionable since the sera of many children with such antibodies in their serum tolerate the foods in question perfectly well. There was one study that showed a hypothetical possibility, in rheumatoid arthritis diarrhea, and constipation, among others.
Diagnostic tools for gastrointestinal food hypersensitivity often include endoscopy, colonoscopy, and biopsy.
Important differential diagnoses are:
- Lactose intolerance; this generally develops later in life but can present in young patients in severe cases. This is due to an enzyme deficiency (lactase) and not allergy. It occurs in many non-Western people.
- Celiac disease; this is an autoimmune disorder triggered by specific proteins such as gliadin (present in wheat, rye and barley).
- Irritable bowel syndrome (IBS); although many IBS cases might be due to food allergy, this is an important diagnosis in patients with diarrhea in whom no allergens can be identified.
- C1 esterase inhibitor deficiency (hereditary angioedema); this rare disease generally causes attacks of angioedema, but can present solely with abdominal pain and occasional diarrhea.
# Pathophysiology
Generally, introduction of allergens through the digestive tract is thought to induce immune tolerance. In individuals who are predisposed to developing allergies (atopic syndrome), the immune system produces IgE antibodies against protein epitopes on non-pathogenic substances, including dietary components. The IgE molecules are coated onto mast cells, which inhabit the mucosal lining of the digestive tract.
Upon ingesting an allergen, the IgE reacts with its protein epitopes and release (degranulate) a number of chemicals (including histamine), which lead to oedema of the intestinal wall, loss of fluid and altered motility. The product is diarrhea.
Any food allergy has the potential to cause a fatal reaction.
# Causes
The immune system's eosinophils, once activated in a histamine reaction, will register any foreign proteins they see. One theory regarding the causes of food allergies focuses on proteins presented in the blood along with vaccines, which are designed to provoke an immune response. Flu vaccines and the Yellow Fever vaccine are still egg-based, but the Measles-Mumps-Rubella vaccine stopped using eggs in 1994.
There is resistance to this theory, especially as it applies to autoimmune disease.
Another theory focuses on whether an infant's immune system is ready for complex proteins in a new food when it is first introduced.
The most popular theory at this time is the Hygiene hypothesis. Researches speculate that in the modern, industrialized nations, such as the United States, food allergy is more common due to the lack of early exposure to dirt and germs, in part due to the over use of antibiotics and antibiotic cleansers. This theory is based partly on studies showing less allergy in third world countries. Research has found that the body, with less dirt and germs to fight off, turns on itself and attacks food proteins as if they were foreign invaders.
# Treatment
The mainstay of treatment for food allergy is avoidance of the foods that have been identified as allergens.
If the food is accidentally ingested and a systemic reaction occurs, then epinephrine (best delivered with an autoinjector of epinephrine such as an Epipen) or Twinject should be used. It is possible that a second dose of epinephrine may be required for severe reactions. The patient should also seek medical care immediately.
At this time, there is no cure for food allergies. There are no allergy desensitization or allergy "shots" available for food allergies. Some doctors feel they do not work in food allergies because even minute amounts of the food in question or even food extracts (as in the case of allergy shots) can cause an allergic response in many sufferers.
According to experts at the BA Festival of Science in Norwich, England, vaccines can in theory be created using genetic engineering to cure allergies. If this can be done, food allergies could be eradicated in about ten years.
# Statistics
For reasons that are not entirely understood, the diagnosis of food allergies has become more common in Western nations in recent times. Food allergy affects as many as 6% of young children and 3% to 4% of adults.
The most common food allergens include peanuts, milk, eggs, tree nuts, fish, shellfish, soy, and wheat - these foods account for about 90% of all allergic reactions.
# Differing views
Various medical practitioners have a differing views on food allergies. Irritable Bowel Syndrome (IBS) patients have been studied with regards to food allergies. Some studies have reported on the role of food allergy in IBS; only one epidemiological study on functional dyspepsia and food allergy has been published. The mechanism by which food activates mucosal immune system is uncertain, but food specific IgE and IgG4 appeared to mediate the hypersensitivity reaction in a subgroup of IBS patients. Exclusion diets based on skin prick test, RAST for IgE or IgG4, hypoallergic diet and clinical trials with oral disodium cromoglycate have been conducted, and some success has been reported in a subset of IBS patients.
Studies comparing skin prick testing and ELISA blood testing have found that the results of skin prick testing correlate poorly with symptoms of irritable bowel syndrome demonstrated through dietary challenge.
Extensive clinical experience has demonstrated significant improvement of patients with IBS whose ELISA-based food allergy testing is positive and where treatment includes a careful exclusion diet.
In addition, many practitioners of alternative medicine ascribe symptoms to food allergy where other doctors do not. The causal relationships between these various conditions and food allergies have not been studied extensively enough to provide sufficient evidence to become authoritative. The interaction of histamine with the nervous system receptors has been demonstrated, but more study is needed. Other immune response effects are commonly known (swelling, irritation, etc.), but their relationships to some conditions has not been extensively studied. Examples are arthritis, fatigue, headaches, and hyperactivity. Nevertheless, hypoallergenic diets reportedly can be of benefit in these conditions, indicating that the current medical views on food allergy may be too narrow. Holford and Brady (2005) suggest three levels of response; classical immediate-onset allergy (IgE), delayed-onset allergy (giving a positive response on an ELISA IgG test but rarely on an IgE skin prick test), and food intolerance (non-allergic), and claim the last two to be more common. It is important to note that IgG is present in the body and is known to respond to foods. So some medical practitioners, especially allergists, state that there is no predictive value to these types of tests, despite the studies cited above.
# In children
Milk and soy allergies in children can often go undiagnosed for many months, causing much worry for parents and health risks for infants and children. Many infants with milk and soy allergies can show signs of colic, blood in the stool, mucous in the stool, reflux, rashes and other harmful medical conditions. These conditions are often misdiagnosed as viruses or colic.
Many children who are allergic to cow's milk protein also show a cross sensitivity to soy-based products. There are infant formulas in which the milk and soy proteins are degraded so when taken by an infant, their immune system does not recognize the allergen and they can safely consume the product. Hypoallergenic infant formulas can be based on hydrolyzed proteins, which are proteins partially predigested in a less antigenic form. Other formulas, based on free amino acids, are the least antigenic and provide complete nutrition support in severe forms of milk allergy.
About 50% of children with allergies to milk, egg, soy, and wheat will outgrow their allergy by the age of 6. Those that don't, and those that are still allergic by the age of 12 or so, have less than an 8% chance of outgrowing the allergy .
Peanut and tree nut allergies are less likely to be outgrown, although evidence now shows that about 20% of those with nut allergies do eventually outgrow the allergy. In such a case, they need to consume nuts in some regular fashion to maintain the non-allergic status. This should be discussed with a doctor.
Those with other food allergies may or may not outgrow their allergies.
# Labeling laws
In response to the risk that certain foods pose to those with food allergies, countries have responded by instituting labeling laws that require food products to clearly inform consumers if their products contain major allergens or by-products of major allergens.
## United States law
Under the Food Allergen Labeling and Consumer Protection Act of 2004 (Public Law 108-282), companies are required to disclose on the label whether the product contains a major food allergen in clear, plain language. | Food allergy
For the WikiPatient page for this topic, click here
# Overview
A food allergy is an immunologic response to a food protein. It is estimated that up to 12 million Americans have food allergies of one type or another,[1] and the prevalence is rising.[2] Six to eight percent of children have food allergies and two percent of adults have them.[3] The most common food allergies in adults are shellfish, peanuts, tree nuts, sesame seeds, fish, and eggs[3], and the most common food allergies present in children are milk, eggs, and peanuts.[3]
At this time, there is no cure for food allergies. Treatment consists of avoidance diets, where the allergic person avoids any and all forms of the food to which they are allergic. For people who are extremely sensitive, this may involve the total avoidance of any exposure with the allergen, including touching or inhaling the problematic food as well as any surfaces that may have come into contact with it. Food allergy is distinct from food intolerance, which is not caused by an immune reaction.
Persons diagnosed with a food allergy may carry an autoinjector of epinephrine such as an EpiPen or Twinject, wear some form of medical alert jewelry, or develop an emergency action plan, in accordance with their doctor.
# Signs and symptoms
Symptoms of food allergies include:[4]
- Anaphylaxis: a severe, whole-body allergic reaction that can result in death (see below)
- Angioedema: swelling, especially of the eyelids, face, lips, and tongue
- Eczema
- Hives
- Itching of the mouth, throat, eyes, skin, or any area
- Nausea, vomiting, diarrhea, stomach cramps, or abdominal pain
- Runny nose or nasal congestion
- Wheezing, scratchy throat, shortness of breath, or difficulty swallowing
- Mood swings, depression
Angioedema is a skin reaction where the tissues swell. It can result in swelling/edema of the lips, skin tongue and airways (causing constriction, wheezing and difficulty breathing). It can also cause swelling of the face, eyes, hands, etc.
The symptoms of an Immunoglobulin E (IgE) allergic reaction can take place within a few minutes to an hour.[3] The process of eating and digesting food affects the timing and location of a reaction.[3] IgG reactions build over a period of hours to days[1], and therefore symptoms can be difficult to notice as allergy-related.
Food allergy can lead to anaphylactic shock: A systemic reaction involving several different bodily systems including hypotension (low blood pressure) and loss of consciousness. This is a medical emergency. Allergens commonly associated with this type of reaction are peanuts, nuts, milk, egg, and seafood. Food anaphylaxis can also be caused by various types of fruit.[5] Latex products can induce similar reactions.
Food allergy is thought to develop more easily in patients with the atopic syndrome, a very common combination of diseases: allergic rhinitis and conjunctivitis, eczema and asthma.[6] The syndrome has a strong inherited component; a family history of allergic diseases can be indicative of the atopic syndrome.
Another type of food allergy is called Gastrointestinal Food Hypersensitivity.[7] It can be IgE or Non-IgE mediated.
In this class, IgE mediated responsese include:
- Immediate GI Hypersensitivity
- Oral allergy syndrome
Conditions that have been shown to have both IgE and Non-IgE causes of gastrointestinal food hypersensitity include:
- Allergic eosinophilic esophagitis
- Allergic eosinophilic gastritis
- Allergic eosinophilic gastroenteritis
Conditions of Non-IgE gastrointestinal food hypersensitivity include:
- Enterocolitis syndrome
- Dietary protein proctitis
- Celiac disease
# The Big Eight
The most common food allergies are:[8]
- Milk allergy
- Egg allergy
- Peanut allergy
- Tree nut allergy
- Seafood allergy
- Shellfish allergy
- Soy allergy
- Wheat allergy
These are often referred to as "the big eight."[9] They account for over 90% of the food allergies in the United States of America.[10]
Likelihood of allergy can increase with exposure[citation needed]. For example, rice allergy is more common in East Asia where rice forms a large part of the diet.[11] In Central Europe, celery allergy is more common. The top allergens vary somewhat from country to country but milk, eggs, peanuts, treenuts, fish, shellfish, soy, wheat and sesame tend to be in the top 10 in many countries.
# Diagnosis
The best method for diagnosing food allergy is to be assessed by an allergist. The allergist will review the patient's history and the symptoms or reactions that have been noted after food ingestion. If the allergist feels the symptoms or reactions are in keeping with a food allergy, he/she will perform allergy tests.
There are two basic types of allergy tests: Skin Prick Tests and blood tests. The skin prick is easy to do and results are available in minutes. Different allergists may use different devices for skin prick testing. Some use a "bifurcated needle", which looks like a fork with 2 prongs. Others use a "multi-test", which may look like a small board with several pins sticking out of it. In these tests, a tiny amount of the suspected allergen is put onto the skin or into a testing device, and the device is placed on the skin to prick, or break through, the top layer of skin. This puts a small amount of the allergen under the skin. A hive will form at any spot where the person is allergic. This test generally yields a positive or negative result. It is good for quickly learning if a person is allergic to a particular food or not, because it detects allergic antibodies known as IgE. Skin tests cannot predict if a reaction would occur or what kind of reaction might occur if a person ingests that particular allergen. They can however confirm an allergy in light of a patient's history of reactions to a particular food.
Blood tests are another useful diagnostic tool. For example, the RAST (RadioAllergoSorbent Test)detects the presence of IgE antibodies to a particular allergen. A CAP-RAST test is a specific type of RAST test with greater specificity: it can show the amount of IgE present to each allergen [12]. Researchers have been able to determine "predictive values" for certain foods. These predictive values can be compared to the RAST blood test results. If a persons RAST score is higher than the predictive value for that food, then there is over a 95% chance the person will have an allergic reaction (limited to rash and anaphylaxis reactions) if they ingest that food.[citation needed] Currently, predictive values are available for the following foods: milk, egg, peanut, fish, soy, and wheat.[13][14][15] Blood tests allow for hundreds of allergens to be screened from a single sample, and cover food allergies as well as inhalants. However, non-IgE mediated allergies cannot be detected by this method.
Blood testing methodologies currently available that can measure antibodies of IgG are not acceptable as a method of allergy evaluation. IgG-type anitbodies are not implicated in a food allergy reactions[16]. The significance of IgG anti-allergen antibodies was reviewed by the American Academy of Allergy and Immunology and found to be lacking. Although a number of commercial labs sell tests that reportedly measure IgG antibodies against common allergens there is no clinical significance of such findings. It is not established that these commercial assays actually measure the IgG antibodies that they report. Also, even if the assays are measuring IgG anti- allergen antibodies, the clinical significance of such antibodies is certainly not established. The significance of IgG anti-food antibodies is particularly questionable since the sera of many children with such antibodies in their serum tolerate the foods in question perfectly well. There was one study that showed a hypothetical possibility, in rheumatoid arthritis[17] diarrhea, and constipation, among others.
Diagnostic tools for gastrointestinal food hypersensitivity often include endoscopy, colonoscopy, and biopsy.
Important differential diagnoses are:
- Lactose intolerance; this generally develops later in life but can present in young patients in severe cases. This is due to an enzyme deficiency (lactase) and not allergy. It occurs in many non-Western people.
- Celiac disease; this is an autoimmune disorder triggered by specific proteins such as gliadin (present in wheat, rye and barley).
- Irritable bowel syndrome (IBS); although many IBS cases might be due to food allergy, this is an important diagnosis in patients with diarrhea in whom no allergens can be identified.
- C1 esterase inhibitor deficiency (hereditary angioedema); this rare disease generally causes attacks of angioedema, but can present solely with abdominal pain and occasional diarrhea.
# Pathophysiology
Generally, introduction of allergens through the digestive tract is thought to induce immune tolerance. In individuals who are predisposed to developing allergies (atopic syndrome), the immune system produces IgE antibodies against protein epitopes on non-pathogenic substances, including dietary components.[citation needed] The IgE molecules are coated onto mast cells, which inhabit the mucosal lining of the digestive tract.
Upon ingesting an allergen, the IgE reacts with its protein epitopes and release (degranulate) a number of chemicals (including histamine), which lead to oedema of the intestinal wall, loss of fluid and altered motility. The product is diarrhea.[citation needed]
Any food allergy has the potential to cause a fatal reaction.
# Causes
The immune system's eosinophils, once activated in a histamine reaction, will register any foreign proteins they see. One theory regarding the causes of food allergies focuses on proteins presented in the blood along with vaccines, which are designed to provoke an immune response. Flu vaccines and the Yellow Fever vaccine are still egg-based, but the Measles-Mumps-Rubella vaccine stopped using eggs in 1994.[18]
There is resistance to this theory, especially as it applies to autoimmune disease.[19]
Another theory focuses on whether an infant's immune system is ready for complex proteins in a new food when it is first introduced.[20]
The most popular theory at this time is the Hygiene hypothesis. Researches speculate[citation needed] that in the modern, industrialized nations, such as the United States, food allergy is more common due to the lack of early exposure to dirt and germs, in part due to the over use of antibiotics and antibiotic cleansers. This theory is based partly on studies showing less allergy in third world countries.[citation needed] Research has found[citation needed] that the body, with less dirt and germs to fight off, turns on itself and attacks food proteins as if they were foreign invaders.
# Treatment
The mainstay of treatment for food allergy is avoidance of the foods that have been identified as allergens.
If the food is accidentally ingested and a systemic reaction occurs, then epinephrine (best delivered with an autoinjector of epinephrine such as an Epipen) or Twinject should be used. It is possible that a second dose of epinephrine may be required for severe reactions.[citation needed] The patient should also seek medical care immediately.
At this time, there is no cure for food allergies.[21] There are no allergy desensitization or allergy "shots" available for food allergies.[citation needed] Some doctors feel they do not work in food allergies because even minute amounts of the food in question or even food extracts (as in the case of allergy shots) can cause an allergic response in many sufferers.
According to experts at the BA Festival of Science in Norwich, England, vaccines can in theory be created using genetic engineering to cure allergies. If this can be done, food allergies could be eradicated in about ten years.[22]
# Statistics
For reasons that are not entirely understood, the diagnosis of food allergies has become more common in Western nations in recent times. Food allergy affects as many as 6% of young children and 3% to 4% of adults.[23]
The most common food allergens include peanuts, milk, eggs, tree nuts, fish, shellfish, soy, and wheat - these foods account for about 90% of all allergic reactions.[citation needed]
# Differing views
Various medical practitioners have a differing views on food allergies. Irritable Bowel Syndrome (IBS) patients have been studied with regards to food allergies. Some studies have reported on the role of food allergy in IBS; only one epidemiological study on functional dyspepsia and food allergy has been published. The mechanism by which food activates mucosal immune system is uncertain, but food specific IgE and IgG4 appeared to mediate the hypersensitivity reaction in a subgroup of IBS patients. Exclusion diets based on skin prick test, RAST for IgE or IgG4, hypoallergic diet and clinical trials with oral disodium cromoglycate have been conducted, and some success has been reported in a subset of IBS patients.[24]
Studies comparing skin prick testing and ELISA blood testing have found that the results of skin prick testing correlate poorly with symptoms of irritable bowel syndrome demonstrated through dietary challenge. [25]
Extensive clinical experience has demonstrated significant improvement of patients with IBS whose ELISA-based food allergy testing is positive and where treatment includes a careful exclusion diet. [26]
In addition, many practitioners of alternative medicine ascribe symptoms to food allergy where other doctors do not. The causal relationships between these various conditions and food allergies have not been studied extensively enough to provide sufficient evidence to become authoritative. The interaction of histamine with the nervous system receptors has been demonstrated, but more study is needed.[27] Other immune response effects are commonly known (swelling, irritation, etc.), but their relationships to some conditions has not been extensively studied. Examples are arthritis, fatigue, headaches, and hyperactivity. Nevertheless, hypoallergenic diets reportedly can be of benefit in these conditions, indicating that the current medical views on food allergy may be too narrow. Holford and Brady (2005) suggest three levels of response; classical immediate-onset allergy (IgE), delayed-onset allergy (giving a positive response on an ELISA IgG test but rarely on an IgE skin prick test), and food intolerance (non-allergic), and claim the last two to be more common.[28] It is important to note that IgG is present in the body and is known to respond to foods. So some medical practitioners, especially allergists, state that there is no predictive value to these types of tests, despite the studies cited above.
# In children
Milk and soy allergies in children can often go undiagnosed for many months, causing much worry for parents and health risks for infants and children. Many infants with milk and soy allergies can show signs of colic, blood in the stool, mucous in the stool, reflux, rashes and other harmful medical conditions.[citation needed] These conditions are often misdiagnosed as viruses or colic.
Many children who are allergic to cow's milk protein also show a cross sensitivity to soy-based products.[citation needed] There are infant formulas in which the milk and soy proteins are degraded so when taken by an infant, their immune system does not recognize the allergen and they can safely consume the product. Hypoallergenic infant formulas can be based on hydrolyzed proteins, which are proteins partially predigested in a less antigenic form. Other formulas, based on free amino acids, are the least antigenic and provide complete nutrition support in severe forms of milk allergy.
About 50% of children with allergies to milk, egg, soy, and wheat will outgrow their allergy by the age of 6. Those that don't, and those that are still allergic by the age of 12 or so, have less than an 8% chance of outgrowing the allergy [29].
Peanut and tree nut allergies are less likely to be outgrown, although evidence now shows[citation needed] that about 20% of those with nut allergies do eventually outgrow the allergy. In such a case, they need to consume nuts in some regular fashion to maintain the non-allergic status.[citation needed] This should be discussed with a doctor.
Those with other food allergies may or may not outgrow their allergies.
# Labeling laws
In response to the risk that certain foods pose to those with food allergies, countries have responded by instituting labeling laws that require food products to clearly inform consumers if their products contain major allergens or by-products of major allergens.
## United States law
Under the Food Allergen Labeling and Consumer Protection Act of 2004 (Public Law 108-282), companies are required to disclose on the label whether the product contains a major food allergen in clear, plain language. [30] | https://www.wikidoc.org/index.php/Food_allergies | |
6b7801c4748a1b570a32cda2540dc198fb40fd59 | wikidoc | Foraminifera | Foraminifera
The Foraminifera, ("Hole Bearers") or forams for short, are a large group of amoeboid protists with reticulating pseudopods, fine strands of cytoplasm that branch and merge to form a dynamic net. They typically produce a test, or shell, which can have either one or multiple chambers, some becoming quite elaborate in structure. About 275,000 species are recognized, both living and fossil. They are usually less than 1 mm in size, but some are much larger, and the largest recorded specimen reached 19 cm.
Although as yet unsupported by morphological correlates, molecular data strongly suggest that Foraminifera are closely related to the Cercozoa and Radiolaria, both of which also include amoeboids with complex shells; these three groups make up the Rhizaria However, the exact relationships of the forams to the other groups and to one another are still not entirely clear.
# Living forams
Modern forams are primarily marine, although they can survive in brackish conditions A few species survive in fresh water and one even lives in damp rainforest soil. They are very common in the meiobenthos, and about 40 morphospecies are planktonic. This count may however represent only a fraction of actual diversity, since many genetically discrepant species may be morphologically indistinguishable The cell is divided into granular endoplasm and transparent ectoplasm. The pseudopodial net may emerge through a single opening or many perforations in the test, and characteristically has small granules streaming in both directions.
The pseudopods are used for locomotion, anchoring, and in capturing food, which consists of small organisms such as diatoms or bacteria. A number of forms have unicellular algae as endosymbionts, from diverse lineages such as the green algae, red algae, golden algae, diatoms, and dinoflagellates. Some forams are kleptoplastic, retaining chloroplasts from ingested algae to conduct photosynthesis
The foraminiferal life-cycle involves an alternation between haploid and diploid generations, although they are mostly similar in form. The haploid or gamont initially has a single nucleus, and divides to produce numerous gametes, which typically have two flagella. The diploid or schizont is multinucleate, and after meiosis fragments to produce new gamonts. Multiple rounds of asexual reproduction between sexual generations is not uncommon in benthic forms.
# Tests
The form and composition of the test is the primary means by which forams are identified and classified. Most have calcareous tests, composed of calcium carbonate. In other forams the test may be composed of organic material, made from small pieces of sediment cemented together (agglutinated), and in one genus of silica. Openings in the test, including those that allow cytoplasm to flow between chambers, are called apertures.
Tests are known as fossils as far back as the Cambrian period, and many marine sediments are composed primarily of them. For instance, the limestone that makes up the pyramids of Egypt is composed almost entirely of nummulitic benthic foraminifera. Production estimates indicate that reef foraminifera annually generate approximately 43 million tons of calcium carbonate and thus play an essential role in the production of reef carbonates.
Genetic studies have identified the naked amoeba "Reticulomyxa" and the peculiar xenophyophores as foraminiferans without tests. A few other amoeboids produce reticulose pseudopods, and were formerly classified with the forams as the Granuloreticulosa, but this is no longer considered a natural group, and most are now placed among the Cercozoa .
# Evolutionary significance
Dying planktonic foraminifera continuously rain down on the sea floor in vast numbers, their mineralized tests preserved as fossils in the accumulating sediment. Beginning in the 1960s, and largely under the auspices of the Deep Sea Drilling, Ocean Drilling, and International Ocean Drilling Programmes, as well as for the purposes of oil exploration, advanced deep-sea drilling techniques have been bringing up sediment cores bearing foraminifera fossils by the millions. The effectively unlimited supply of these fossil tests and the relatively high-precision age-control models available for cores has produced an exceptionally high-quality planktonic foraminifera fossil record dating back to the mid-Jurassic, and presents an unparalleled record for scientists testing and documenting the evolutionary process. The exceptional quality of the fossil record has allowed an impressively detailed picture of species inter-relationships to be developed on the basis of fossils, in many cases subsequently validated independently through molecular genetic studies on extant specimens.
# Uses of forams
Because of their diversity, abundance, and complex morphology, fossil foraminiferal assemblages are useful for biostratigraphy, and can accurately give relative dates to rocks. The oil industry relies heavily on microfossils such as forams to find potential oil deposits.
Calcareous fossil foraminifera are formed from elements found in the ancient seas they lived in. Thus they are very useful in paleoclimatology and paleoceanography. They can be used to reconstruct past climate by examining the stable isotope ratios of oxygen, and the history of the carbon cycle and oceanic productivity by examining the stable isotope ratios of carbon ; see δ18O, see δ13C. Geographic patterns seen in the fossil records of planktonic forams are also used to reconstruct ancient ocean currents. Because certain types of foraminifera are found only in certain environments, they can be used to figure out the kind of environment under which ancient marine sediments were deposited.
For the same reasons they make useful biostratigraphic markers, living foraminiferal assemblages have been used as bioindicators in coastal environments, including indicators of coral reef health. Because calcium carbonate is susceptible to dissolution in acidic conditions, foraminifera may be particularly affected by changing climate and ocean acidification. | Foraminifera
The Foraminifera, ("Hole Bearers") or forams for short, are a large group of amoeboid protists with reticulating pseudopods, fine strands of cytoplasm that branch and merge to form a dynamic net.[1] They typically produce a test, or shell, which can have either one or multiple chambers, some becoming quite elaborate in structure.[2] About 275,000 species are recognized, both living and fossil[citation needed]. They are usually less than 1 mm in size, but some are much larger, and the largest recorded specimen reached 19 cm[citation needed].
Although as yet unsupported by morphological correlates, molecular data strongly suggest that Foraminifera are closely related to the Cercozoa and Radiolaria, both of which also include amoeboids with complex shells; these three groups make up the Rhizaria[3] However, the exact relationships of the forams to the other groups and to one another are still not entirely clear.
# Living forams
Modern forams are primarily marine, although they can survive in brackish conditions[4] A few species survive in fresh water and one even lives in damp rainforest soil[citation needed]. They are very common in the meiobenthos, and about 40 morphospecies are planktonic.[1] This count may however represent only a fraction of actual diversity, since many genetically discrepant species may be morphologically indistinguishable[5] The cell is divided into granular endoplasm and transparent ectoplasm. The pseudopodial net may emerge through a single opening or many perforations in the test, and characteristically has small granules streaming in both directions.[4]
The pseudopods are used for locomotion, anchoring, and in capturing food, which consists of small organisms such as diatoms or bacteria.[1] A number of forms have unicellular algae as endosymbionts, from diverse lineages such as the green algae, red algae, golden algae, diatoms, and dinoflagellates.[1] Some forams are kleptoplastic, retaining chloroplasts from ingested algae to conduct photosynthesis[6]
The foraminiferal life-cycle involves an alternation between haploid and diploid generations, although they are mostly similar in form. The haploid or gamont initially has a single nucleus, and divides to produce numerous gametes, which typically have two flagella. The diploid or schizont is multinucleate, and after meiosis fragments to produce new gamonts. Multiple rounds of asexual reproduction between sexual generations is not uncommon in benthic forms.[4]
# Tests
The form and composition of the test is the primary means by which forams are identified and classified[citation needed]. Most have calcareous tests, composed of calcium carbonate.[4] In other forams the test may be composed of organic material, made from small pieces of sediment cemented together (agglutinated), and in one genus of silica. Openings in the test, including those that allow cytoplasm to flow between chambers, are called apertures.
Tests are known as fossils as far back as the Cambrian period[citation needed], and many marine sediments are composed primarily of them. For instance, the limestone that makes up the pyramids of Egypt is composed almost entirely of nummulitic benthic foraminifera[7]. Production estimates indicate that reef foraminifera annually generate approximately 43 million tons of calcium carbonate and thus play an essential role in the production of reef carbonates[8].
Genetic studies have identified the naked amoeba "Reticulomyxa" and the peculiar xenophyophores as foraminiferans without tests[citation needed]. A few other amoeboids produce reticulose pseudopods, and were formerly classified with the forams as the Granuloreticulosa, but this is no longer considered a natural group, and most are now placed among the Cercozoa [9].
# Evolutionary significance
Dying planktonic foraminifera continuously rain down on the sea floor in vast numbers, their mineralized tests preserved as fossils in the accumulating sediment. Beginning in the 1960s, and largely under the auspices of the Deep Sea Drilling, Ocean Drilling, and International Ocean Drilling Programmes, as well as for the purposes of oil exploration, advanced deep-sea drilling techniques have been bringing up sediment cores bearing foraminifera fossils by the millions. The effectively unlimited supply of these fossil tests and the relatively high-precision age-control models available for cores has produced an exceptionally high-quality planktonic foraminifera fossil record dating back to the mid-Jurassic, and presents an unparalleled record for scientists testing and documenting the evolutionary process. The exceptional quality of the fossil record has allowed an impressively detailed picture of species inter-relationships to be developed on the basis of fossils, in many cases subsequently validated independently through molecular genetic studies on extant specimens.
# Uses of forams
Because of their diversity, abundance, and complex morphology, fossil foraminiferal assemblages are useful for biostratigraphy, and can accurately give relative dates to rocks. The oil industry relies heavily on microfossils such as forams to find potential oil deposits[citation needed].
Calcareous fossil foraminifera are formed from elements found in the ancient seas they lived in. Thus they are very useful in paleoclimatology and paleoceanography. They can be used to reconstruct past climate by examining the stable isotope ratios of oxygen, and the history of the carbon cycle and oceanic productivity by examining the stable isotope ratios of carbon [10]; see δ18O, see δ13C. Geographic patterns seen in the fossil records of planktonic forams are also used to reconstruct ancient ocean currents[citation needed]. Because certain types of foraminifera are found only in certain environments, they can be used to figure out the kind of environment under which ancient marine sediments were deposited[citation needed].
For the same reasons they make useful biostratigraphic markers, living foraminiferal assemblages have been used as bioindicators in coastal environments, including indicators of coral reef health[citation needed]. Because calcium carbonate is susceptible to dissolution in acidic conditions, foraminifera may be particularly affected by changing climate and ocean acidification[citation needed]. | https://www.wikidoc.org/index.php/Foraminifera | |
dfa91cbdf1d6a60dc096cd19673792eb722e867d | wikidoc | Formaldehyde | Formaldehyde
# Overview
Formaldehyde is a chemical compound with the formula H2CO. It is the simplest aldehyde—an organic compound containing a terminal carbonyl group: it consists
-f exactly one carbonyl. It was first synthesized by the Russian chemist Aleksandr Butlerov (1828-1886), but was conclusively identified by August Wilhelm von Hofmann. Formaldehyde exists in several forms aside from H2CO: the cyclic trimer trioxane and the polymer paraformaldehyde. It exists in water as the hydrate H2C(OH)2. Aqueous solutions of formaldehyde are referred to as formalin. "100%" formalin consists of a saturated solution of formaldehyde (roughly 40% by mass) in water, with a small amount of stabilizer, usually methanol to limit oxidation and polymerization.
Formaldehyde is an intermediate in the oxidation (or combustion) of methane as well as other carbon compounds, e.g. forest fires, in automobile exhaust, and in tobacco smoke. It is produced in the atmosphere by the action of sunlight and oxygen on atmospheric methane and other hydrocarbons; thus, it becomes part of smog. Small amounts of formaldehyde are produced as a metabolic byproduct in most organisms, including humans.
# Production
Formaldehyde is produced industrially by the catalytic oxidation of methanol. The most common catalysts are silver metal or a mixture of an iron oxide with molybdenum and vanadium. In the more commonly used FORMOX process methanol and oxygen react at ca 250-400 °C in presence of iron oxide in combination with molybdenum and/or vanadium to produce formaldehyde according to the chemical equation
The silver-based catalyst is usually operated at a higher temperature, about 650 °C. Two chemical reactions on it simultaneously produce formaldehyde: that shown above and the dehydrogenation reaction
Formaldehyde is readily oxidized by atmospheric oxygen to form formic acid. Formic acid is found in ppm levels in commercial formaldehyde.
Formalin can be produced on a smaller scale using a whole range of other methods including conversion from ethanol instead of the normally-fed methanol feedstock. Such methods are of less commercial importance.
# Organic chemistry
Formaldehyde is a central building block in the synthesis of many other compounds. It exhibits most of the chemical properties of other aldehydes but is more reactive. Formaldehyde is a good electrophile, participating in electrophilic aromatic substitution reactions with aromatic compounds, and can undergo electrophilic addition reactions with alkenes. Formaldehyde undergoes a Cannizzaro reaction in the presence of basic catalysts to produce formic acid and methanol.
Condensation with acetaldehyde affords pentaerythritol. Condensation with phenols gives phenol-formaldehyde resins. With 4-substituted phenols one obtains calixarenes.
When combined with hydrogen sulfide it forms trithiane.
# Biology
Formaldehyde solutions are used as a fixative for microscopy and histology. Pure solutions that are free of the oxidation product formic acid and of the stabilizer methanol are often produced by depolymerization of paraformaldehyde in hot water.
Formaldehyde (and its oligomers and hydrates) are rarely encountered in living organisms. Methanogenesis, which can start from many C1 sources, proceeds via the equivalent of formaldehyde, but this one-carbon species is masked as a methylene group carried by methanopterin. The formaldehyde is the primary cause of the methanol's toxicity, since methanol is metabolised into toxic formaldehyde by alcohol dehydrogenase.
# Applications
## As a disinfectant and biocide
An aqueous solution of formaldehyde can be useful as a disinfectant as it kills most bacteria and fungi (including their spores). It is also used as a preservative in vaccines. Formaldehyde solutions are applied topically in medicine to dry the skin, such as in the treatment of warts. Many aquarists use formaldehyde as a treatment for the parasite ichthyophthirius.
Formaldehyde preserves or fixes tissue or cells by irreversibly cross-linking primary amino groups in proteins with other nearby nitrogen atoms in protein or DNA through a -CH2- linkage. This is exploited in ChIP-on-chip transcriptomics experiments.
Formaldehyde is also used as a detergent in RNA gel electrophoresis, preventing RNA from forming secondary structures.
Formaldehyde is converted to formic acid in the body, leading to a rise in blood acidity (acidosis).
## Industry
Formaldehyde is a common building block for the synthesis of more complex compounds and materials.
Most formaldehyde is used in the production of polymers and other chemicals. When reacted with phenol, urea, or melamine formaldehyde produces, respectively, hard thermoset phenol formaldehyde resin, urea formaldehyde resin, and melamine resin. These resins are commonly used in permanent adhesives such as those used in plywood or carpeting. It is used as the wet-strength resin added to sanitary paper products such as (listed in increasing concentrations injected into the paper machine headstock chest) facial tissue, table napkins, and roll towels. They are also foamed to make insulation, or cast into moulded products. Production of formaldehyde resins accounts for more than half of formaldehyde consumption.
Many of these are polyfunctional alcohols such as pentaerythritol, which is used to make paints and explosives. Other formaldehyde derivatives include methylene diphenyl diisocyanate, an important component in polyurethane paints and foams, and hexamine, which is used in phenol-formaldehyde resins as well as the explosive RDX.
Formaldehyde is still used in low concentrations for process C-41 (color negative film) stabilizer in the final wash step, as well as in the process E-6 pre-bleach step, to obviate the need for it in the final wash.
Formaldehyde is used to produce glues used in the manufacture of particleboard, plywood, veneers, and other wood products, as well as spray-on insulating foams.
Formaldehyde, along with 18 M (concentrated) sulfuric acid (the entire solution often called the Marquis reagent), is used as an MDMA "testing kit" by such groups as Dancesafe as well as MDMA consumers. The solution alone cannot verify the presence of MDMA but reacts with many other chemicals that the MDMA tablet itself may be adulterated with. The reaction itself produces colors that correlate with these components.
The textile industry uses formaldehyde-based resins as finishers to make fabrics crease-resistant.
## Embalming
Formaldehyde-based solutions are used in embalming to disinfect and temporarily preserve human remains. It is the ability of formaldehyde to fix the tissue that produces the tell-tale firmness of flesh in an embalmed body. Whereas other heavier aldehydes produce a similar firming action none approaches the completeness of formaldehyde. Several European countries restrict the use of formaldehyde, including the import of formaldehyde-treated products and embalming, and the European Union is considering a complete ban on formaldehyde usage (including embalming), subject to a review of List 4B of the Technical Annex to the Report from the Commission to the European Parliament and the Council on the Evaluation of the Active Substances of Plant Protection Products by the European Commission Services. Countries with a strong tradition of embalming corpses, such as Ireland and other colder-weather countries, have raised concerns. The European Union decided on September 22, 2007 to ban Formaldehyde use throughout Europe due to its carcinogenic properties.
# Safety
Occupational exposure to formaldehyde by inhalation is mainly from three types of sources: thermal or chemical decomposition of formaldehyde-based resins, formaldehyde emission from aqueous solutions (for example, embalming fluids), and the production of formaldehyde resulting from the combustion of a variety of organic compounds (for example, exhaust gases). Formaldehyde can be toxic, allergenic, and carcinogenic. Because formaldehyde resins are used in many construction materials it is one of the more common indoor air pollutants. At concentrations above 0.1 ppm in air formaldehyde can irritate the eyes and mucous membranes, resulting in watery eyes. Formaldehyde inhaled at this concentration may cause headaches, a burning sensation in the throat, and difficulty breathing, as well as triggering or aggravating asthma symptoms.
Formaldehyde is classified as a probable human carcinogen by the U.S. Environmental Protection Agency. The International Agency for Research on Cancer (IARC) has determined that there is "sufficient evidence" that occupational exposure to formaldehyde causes nasopharyngeal cancer in humans.
The United States Environmental Protection Agency USEPA allows no more than 0.016 ppm formaldehyde in the air in new buildings constructed for that agency.
Formaldehyde can cause allergies and is part of the standard patch test series. People with formaldehyde allergy are advised to avoid formaldehyde releasers as well (e.g., Quaternium-15, imidazolidinyl urea, and diazolidinyl urea). Formaldehyde has been banned in cosmetics in both Sweden and Japan.
## FEMA Trailer Formaldehyde Exposures
The Federal Emergency Management Agency (FEMA) provided travel trailers and mobile homes starting in 2006 for habitation by Gulf Coast residents displaced by Hurricane Katrina and Hurricane Rita. Some of the people who moved into the trailers complained of breathing difficulties, nosebleeds, and persistent headaches. Formaldehyde exposure can cause burning eyes and nose, coughing, difficulty breathing, headaches, and has been shown to be carcinogenic, causing nasal and nasopharyngeal cancer and possibly leukemia. Formaldehyde-catalyzed resins are used in the manufacture of engineered wood products such as particle board, medium-density fibreboard (MDF), plywood, and oriented strand board (OSB), all of which have applications in site-built homes, mobile homes, and travel trailers.
The United States Centers For Disease Control and Prevention (CDC) performed indoor air quality testing for formaldehyde in some of the units. On Thursday, February 14, 2008 the CDC announced that potentially hazardous levels of formaldehyde were found in many of the travel trailers and mobile homes provided by the agency. The CDC's preliminary evaluation of a scientifically established random sample of 519 travel trailers and mobile homes tested between Dec. 21, 2007 and Jan. 23, 2008 (2+ years after manufacture) showed average levels of formaldehyde in all units of about 77 parts per billion (ppb). Long-term exposure to levels in this range can be linked to an increased risk of cancer and, at levels above this range, there can also be a risk of respiratory illness. These levels are higher than expected in indoor air, where levels are commonly in the range of 10-20 ppb, and are higher than the Agency for Toxic Substance Disease Registry (ATSDR, division of the CDC) Minimal Risk Level (MRL) of 8 ppb . Levels measured ranged from 3 ppb to 590 ppb.
The Federal Emergency Management Agency, which requested the testing by the CDC, said it would work aggressively to relocate all residents of the temporary housing as soon as possible. Lawsuits are being filed against FEMA as a result of the exposures. | Formaldehyde
Template:Chembox new
# Overview
Formaldehyde is a chemical compound with the formula H2CO. It is the simplest aldehyde—an organic compound containing a terminal carbonyl group: it consists
of exactly one carbonyl. It was first synthesized by the Russian chemist Aleksandr Butlerov (1828-1886), but was conclusively identified by August Wilhelm von Hofmann.[1] Formaldehyde exists in several forms aside from H2CO: the cyclic trimer trioxane and the polymer paraformaldehyde. It exists in water as the hydrate H2C(OH)2. Aqueous solutions of formaldehyde are referred to as formalin. "100%" formalin consists of a saturated solution of formaldehyde (roughly 40% by mass) in water, with a small amount of stabilizer, usually methanol to limit oxidation and polymerization.
Formaldehyde is an intermediate in the oxidation (or combustion) of methane as well as other carbon compounds, e.g. forest fires, in automobile exhaust, and in tobacco smoke. It is produced in the atmosphere by the action of sunlight and oxygen on atmospheric methane and other hydrocarbons; thus, it becomes part of smog. Small amounts of formaldehyde are produced as a metabolic byproduct in most organisms, including humans.
# Production
Formaldehyde is produced industrially by the catalytic oxidation of methanol. The most common catalysts are silver metal or a mixture of an iron oxide with molybdenum and vanadium. In the more commonly used FORMOX process methanol and oxygen react at ca 250-400 °C in presence of iron oxide in combination with molybdenum and/or vanadium to produce formaldehyde according to the chemical equation
The silver-based catalyst is usually operated at a higher temperature, about 650 °C. Two chemical reactions on it simultaneously produce formaldehyde: that shown above and the dehydrogenation reaction
Formaldehyde is readily oxidized by atmospheric oxygen to form formic acid. Formic acid is found in ppm levels in commercial formaldehyde.
Formalin can be produced on a smaller scale using a whole range of other methods including conversion from ethanol instead of the normally-fed methanol feedstock. Such methods are of less commercial importance.
# Organic chemistry
Formaldehyde is a central building block in the synthesis of many other compounds. It exhibits most of the chemical properties of other aldehydes but is more reactive. Formaldehyde is a good electrophile, participating in electrophilic aromatic substitution reactions with aromatic compounds, and can undergo electrophilic addition reactions with alkenes. Formaldehyde undergoes a Cannizzaro reaction in the presence of basic catalysts to produce formic acid and methanol.
Condensation with acetaldehyde affords pentaerythritol.[2] Condensation with phenols gives phenol-formaldehyde resins. With 4-substituted phenols one obtains calixarenes.[3]
When combined with hydrogen sulfide it forms trithiane.[4]
# Biology
Formaldehyde solutions are used as a fixative for microscopy and histology. Pure solutions that are free of the oxidation product formic acid and of the stabilizer methanol are often produced by depolymerization of paraformaldehyde in hot water.
Formaldehyde (and its oligomers and hydrates) are rarely encountered in living organisms. Methanogenesis, which can start from many C1 sources, proceeds via the equivalent of formaldehyde, but this one-carbon species is masked as a methylene group carried by methanopterin. The formaldehyde is the primary cause of the methanol's toxicity, since methanol is metabolised into toxic formaldehyde by alcohol dehydrogenase.
# Applications
## As a disinfectant and biocide
An aqueous solution of formaldehyde can be useful as a disinfectant as it kills most bacteria and fungi (including their spores). It is also used as a preservative in vaccines. Formaldehyde solutions are applied topically in medicine to dry the skin, such as in the treatment of warts. Many aquarists use formaldehyde as a treatment for the parasite ichthyophthirius.
Formaldehyde preserves or fixes tissue or cells by irreversibly cross-linking primary amino groups in proteins with other nearby nitrogen atoms in protein or DNA through a -CH2- linkage. This is exploited in ChIP-on-chip transcriptomics experiments.
Formaldehyde is also used as a detergent in RNA gel electrophoresis, preventing RNA from forming secondary structures.
Formaldehyde is converted to formic acid in the body, leading to a rise in blood acidity (acidosis).
## Industry
Formaldehyde is a common building block for the synthesis of more complex compounds and materials.
Most formaldehyde is used in the production of polymers and other chemicals. When reacted with phenol, urea, or melamine formaldehyde produces, respectively, hard thermoset phenol formaldehyde resin, urea formaldehyde resin, and melamine resin. These resins are commonly used in permanent adhesives such as those used in plywood or carpeting. It is used as the wet-strength resin added to sanitary paper products such as (listed in increasing concentrations injected into the paper machine headstock chest) facial tissue, table napkins, and roll towels. They are also foamed to make insulation, or cast into moulded products. Production of formaldehyde resins accounts for more than half of formaldehyde consumption.
Many of these are polyfunctional alcohols such as pentaerythritol, which is used to make paints and explosives. Other formaldehyde derivatives include methylene diphenyl diisocyanate, an important component in polyurethane paints and foams, and hexamine, which is used in phenol-formaldehyde resins as well as the explosive RDX.
Formaldehyde is still used in low concentrations for process C-41 (color negative film) stabilizer in the final wash step, as well as in the process E-6 pre-bleach step, to obviate the need for it in the final wash.
Formaldehyde is used to produce glues used in the manufacture of particleboard, plywood, veneers, and other wood products, as well as spray-on insulating foams.
Formaldehyde, along with 18 M (concentrated) sulfuric acid (the entire solution often called the Marquis reagent)[5], is used as an MDMA "testing kit" by such groups as Dancesafe as well as MDMA consumers. The solution alone cannot verify the presence of MDMA but reacts with many other chemicals that the MDMA tablet itself may be adulterated with. The reaction itself produces colors that correlate with these components.
The textile industry uses formaldehyde-based resins as finishers to make fabrics crease-resistant.
## Embalming
Formaldehyde-based solutions are used in embalming to disinfect and temporarily preserve human remains. It is the ability of formaldehyde to fix the tissue that produces the tell-tale firmness of flesh in an embalmed body. Whereas other heavier aldehydes produce a similar firming action none approaches the completeness of formaldehyde. Several European countries restrict the use of formaldehyde, including the import of formaldehyde-treated products and embalming, and the European Union is considering a complete ban on formaldehyde usage (including embalming), subject to a review of List 4B of the Technical Annex to the Report from the Commission to the European Parliament and the Council on the Evaluation of the Active Substances of Plant Protection Products by the European Commission Services. Countries with a strong tradition of embalming corpses, such as Ireland and other colder-weather countries, have raised concerns. The European Union decided on September 22, 2007 to ban Formaldehyde use throughout Europe due to its carcinogenic properties.[6]
# Safety
Occupational exposure to formaldehyde by inhalation is mainly from three types of sources: thermal or chemical decomposition of formaldehyde-based resins, formaldehyde emission from aqueous solutions (for example, embalming fluids), and the production of formaldehyde resulting from the combustion of a variety of organic compounds (for example, exhaust gases). Formaldehyde can be toxic, allergenic, and carcinogenic.[7] Because formaldehyde resins are used in many construction materials it is one of the more common indoor air pollutants.[8] At concentrations above 0.1 ppm in air formaldehyde can irritate the eyes and mucous membranes, resulting in watery eyes. Formaldehyde inhaled at this concentration may cause headaches, a burning sensation in the throat, and difficulty breathing, as well as triggering or aggravating asthma symptoms.[9]
Formaldehyde is classified as a probable human carcinogen by the U.S. Environmental Protection Agency. The International Agency for Research on Cancer (IARC) has determined that there is "sufficient evidence" that occupational exposure to formaldehyde causes nasopharyngeal cancer in humans. [10]
The United States Environmental Protection Agency USEPA allows no more than 0.016 ppm formaldehyde in the air in new buildings constructed for that agency.[11]
Formaldehyde can cause allergies and is part of the standard patch test series. People with formaldehyde allergy are advised to avoid formaldehyde releasers as well (e.g., Quaternium-15, imidazolidinyl urea, and diazolidinyl urea).[12] Formaldehyde has been banned in cosmetics in both Sweden and Japan.
## FEMA Trailer Formaldehyde Exposures
The Federal Emergency Management Agency (FEMA) provided travel trailers and mobile homes starting in 2006 for habitation by Gulf Coast residents displaced by Hurricane Katrina and Hurricane Rita. Some of the people who moved into the trailers complained of breathing difficulties, nosebleeds, and persistent headaches. Formaldehyde exposure can cause burning eyes and nose, coughing, difficulty breathing, headaches, and has been shown to be carcinogenic, causing nasal and nasopharyngeal cancer and possibly leukemia.[13] Formaldehyde-catalyzed resins are used in the manufacture of engineered wood products such as particle board, medium-density fibreboard (MDF), plywood, and oriented strand board (OSB), all of which have applications in site-built homes, mobile homes, and travel trailers.
The United States Centers For Disease Control and Prevention (CDC) performed indoor air quality testing for formaldehyde [14] in some of the units. On Thursday, February 14, 2008 the CDC announced that potentially hazardous levels of formaldehyde were found in many of the travel trailers and mobile homes provided by the agency.[15][16] The CDC's preliminary evaluation of a scientifically established random sample of 519 travel trailers and mobile homes tested between Dec. 21, 2007 and Jan. 23, 2008 (2+ years after manufacture) showed average levels of formaldehyde in all units of about 77 parts per billion (ppb). Long-term exposure to levels in this range can be linked to an increased risk of cancer and, at levels above this range, there can also be a risk of respiratory illness. These levels are higher than expected in indoor air, where levels are commonly in the range of 10-20 ppb, and are higher than the Agency for Toxic Substance Disease Registry (ATSDR, division of the CDC) Minimal Risk Level (MRL) of 8 ppb [17]. Levels measured ranged from 3 ppb to 590 ppb.[18]
The Federal Emergency Management Agency, which requested the testing by the CDC, said it would work aggressively to relocate all residents of the temporary housing as soon as possible. Lawsuits are being filed against FEMA as a result of the exposures.[19] | https://www.wikidoc.org/index.php/Formaldehyde | |
c9d518aa309c14b5583b54b8463dcf3f60b3d70b | wikidoc | Formula unit | Formula unit
A formula unit in chemistry is the empirical formula of an ionic or covalent network solid compound used as an independent entity for stoichiometric calculations. It is the lowest whole number ratio of ions represented in an ionic compound. Examples include ionic NaCl and K2O and covalent networks such as SiO2 and C (as diamond or graphite).
Ionic compounds do not exist as individual molecules; a formula unit thus indicates the lowest reduced ratio of ions in the compound.
A formula unit shows the kinds and numbers of atoms in the smallest representative unit of a substance. | Formula unit
A formula unit in chemistry is the empirical formula of an ionic or covalent network solid compound used as an independent entity for stoichiometric calculations. It is the lowest whole number ratio of ions represented in an ionic compound. Examples include ionic NaCl and K2O and covalent networks such as SiO2 and C (as diamond or graphite).
Ionic compounds do not exist as individual molecules; a formula unit thus indicates the lowest reduced ratio of ions in the compound.
A formula unit shows the kinds and numbers of atoms in the smallest representative unit of a substance.
Template:WH
Template:WS | https://www.wikidoc.org/index.php/Formula_unit | |
0c7eeed388321f15ea8c6fd44920db66227c51a1 | wikidoc | Teriparatide | Teriparatide
# 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
Teriparatide is a calcium regulator that is FDA approved for the treatment of postmenopausal women with osteoporosis at high risk for fracture, men and women with glucocorticoid-induced osteoporosis at high risk for fracture and increase of bone mass in men with primary or hypogonadal osteoporosis at high risk for fracture.. There is a Black Box Warning for this drug as shown here. Common adverse reactions include arthralgia and nausea.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
### Treatment of Postmenopausal Women with Osteoporosis at High Risk for Fracture
- Teriparatide is indicated for the treatment of postmenopausal women with osteoporosis at high risk for fracture, defined as a history of osteoporotic fracture, multiple risk factors for fracture, or patients who have failed or are intolerant to other available osteoporosis therapy.
- In postmenopausal women with osteoporosis, teriparatide reduces the risk of vertebral and nonvertebral fractures.
- Dosage: 20 mcg subcutaneously once a day.
### Increase of Bone Mass in Men with Primary or Hypogonadal Osteoporosis at High Risk for Fracture
- Teriparatide is indicated to increase bone mass in men with primary or hypogonadal osteoporosis at high risk for fracture, defined as a history of osteoporotic fracture, multiple risk factors for fracture, or patients who have failed or are intolerant to other available osteoporosis therapy.
- Dosage: 20 mcg subcutaneously once a day.
### Treatment of Men and Women with Glucocorticoid-Induced Osteoporosis at High Risk for Fracture
- Teriparatide is indicated for the treatment of men and women with osteoporosis associated with sustained systemic glucocorticoid therapy (daily dosage equivalent to 5 mg or greater of prednisone) at high risk for fracture, defined as a history of osteoporotic fracture, multiple risk factors for fracture, or patients who have failed or are intolerant to other available osteoporosis therapy.
- Dosage: 20 mcg subcutaneously once a day
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Teriparatide in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Teriparatide in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
Safety and efficacy have not been established in pediatric patients
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Teriparatide in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Teriparatide in pediatric patients.
# Contraindications
Do not use teriparatide in patients with:
- Hypersensitivity to teriparatide or to any of its excipients. Reactions have included angioedema and anaphylaxis
# Warnings
### Osteosarcoma
In male and female rats, teriparatide caused an increase in the incidence of osteosarcoma (a malignant bone tumor) that was dependent on dose and treatment duration. Teriparatide should not be prescribed for patients at increased baseline risk of osteosarcoma.
These include:
- Paget's disease of bone. Unexplained elevations of alkaline phosphatase may indicate Paget's disease of bone.
- Pediatric and young adult patients with open epiphyses.
- Prior external beam or implant radiation therapy involving the skeleton.
Patients should be encouraged to enroll in the voluntary teriparatide Patient Registry, which is designed to collect information about any potential risk of osteosarcoma in patients who have taken teriparatide.
### Treatment Duration
The safety and efficacy of teriparatide have not been evaluated beyond 2 years of treatment. Consequently, use of the drug for more than 2 years during a patients' lifetime is not recommended.
### Bone Metastases and Skeletal Malignancies
Patients with bone metastases or a history of skeletal malignancies should not be treated with teriparatide.
### Metabolic Bone Diseases
Patients with metabolic bone diseases other than osteoporosis should not be treated with teriparatide.
### Hypercalcemia and Hypercalcemic Disorders
teriparatide has not been studied in patients with pre-existing hypercalcemia. These patients should not be treated with teriparatide because of the possibility of exacerbating hypercalcemia. Patients known to have an underlying hypercalcemic disorder, such as primary hyperparathyroidism, should not be treated with teriparatide.
### Urolithiasis or Pre-existing Hypercalciuria
In clinical trials, the frequency of urolithiasis was similar in patients treated with teriparatide and placebo. However, teriparatide has not been studied in patients with active urolithiasis. If active urolithiasis or pre-existing hypercalciuria are suspected, measurement of urinary calcium excretion should be considered. Teriparatide should be used with caution in patients with active or recent urolithiasis because of the potential to exacerbate this condition.
### Orthostatic Hypotension
teriparatide should be administered initially under circumstances in which the patient can sit or lie down if symptoms of orthostatic hypotension occur. In short-term clinical pharmacology studies with teriparatide, transient episodes of symptomatic orthostatic hypotension were observed in 5% of patients. Typically, an event began within 4 hours of dosing and spontaneously resolved within a few minutes to a few hours. When transient orthostatic hypotension occurred, it happened within the first several doses, it was relieved by placing the person in a reclining position, and it did not preclude continued treatment.
### Drug Interactions
Hypercalcemia may predispose patients to digitalis toxicity. Because teriparatide transiently increases serum calcium, patients receiving digoxin should use teriparatide with caution.
# 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 the rates observed in practice.
### Treatment of Osteoporosis in Men and Postmenopausal Women
The safety of teriparatide in the treatment of osteoporosis in men and postmenopausal women was assessed in two randomized, double-blind, placebo-controlled trials of 1382 patients (21% men, 79% women) aged 28 to 86 years (mean 67 years). The median durations of the trials were 11 months for men and 19 months for women, with 691 patients exposed to teriparatide and 691 patients to placebo. All patients received 1000 mg of calcium plus at least 400 IU of vitamin D supplementation per day.
The incidence of all cause mortality was 1% in the teriparatide group and 1% in the placebo group. The incidence of serious adverse events was 16% in teriparatide patients and 19% in placebo patients. Early discontinuation due to adverse events occurred in 7% of teriparatide patients and 6% of placebo patients.
TABLE 1 lists adverse events from the two principal osteoporosis trials in men and postmenopausal women that occurred in ≥2% of teriparatide-treated and more frequently than placebo-treated patients.
- Immunogenicity: In the clinical trial, antibodies that cross-reacted with teriparatide were detected in 3% of women (15/541) receiving teriparatide. Generally, antibodies were first detected following 12 months of treatment and diminished after withdrawal of therapy. There was no evidence of hypersensitivity reactions or allergic reactions among these patients. Antibody formation did not appear to have effects on serum calcium, or on bone mineral density (BMD) response.
- Serum Calcium: teriparatide transiently increased serum calcium, with the maximal effect observed at approximately 4 to 6 hours post-dose. Serum calcium measured at least 16 hours post-dose was not different from pretreatment levels. In clinical trials, the frequency of at least 1 episode of transient hypercalcemia in the 4 to 6 hours after teriparatide administration was increased from 2% of women and none of the men treated with placebo to 11% of women and 6% of men treated with teriparatide. The number of patients treated with teriparatide whose transient hypercalcemia was verified on consecutive measurements was 3% of women and 1% of men.
- Urinary Calcium: teriparatide increased urinary calcium excretion, but the frequency of hypercalciuria in clinical trials was similar for patients treated with teriparatide and placebo.
- Serum Uric Acid: teriparatide increased serum uric acid concentrations. In clinical trials, 3% of teriparatide patients had serum uric acid concentrations above the upper limit of normal compared with 1% of placebo patients. However, the hyperuricemia did not result in an increase in gout, arthralgia, or urolithiasis.
- Renal Function: No clinically important adverse renal effects were observed in clinical studies. Assessments included creatinine clearance; measurements of blood urea nitrogen (BUN), creatinine, and electrolytes in serum; urine specific gravity and pH; and examination of urine sediment.
### Studies in Men and Women with Glucocorticoid-Induced Osteoporosis
The safety of teriparatide in the treatment of men and women with glucocorticoid-induced osteoporosis was assessed in a randomized, double-blind, active-controlled trial of 428 patients (19% men, 81% women) aged 22 to 89 years (mean 57 years) treated with ≥ 5mg per day prednisone or equivalent for a minimum of 3 months. The duration of the trial was 18 months with 214 patients exposed to teriparatide and 214 patients exposed to oral daily bisphosphonate (active control). All patients received 1000 mg of calcium plus 800 IU of vitamin D supplementation per day.
The incidence of all cause mortality was 4% in the teriparatide group and 6% in the active control group. The incidence of serious adverse events was 21% in teriparatide patients and 18% in active control patients, and included pneumonia (3% teriparatide, 1% active control). Early discontinuation because of adverse events occurred in 15% of teriparatide patients and 12% of active control patients, and included dizziness (2% teriparatide, 0% active control).
Adverse events reported at a higher incidence in the teriparatide group and with at least a 2% difference in teriparatide-treated patients compared with active control-treated patients were: nausea (14%, 7%), gastritis (7%, 3%), pneumonia (6%, 3%), dyspnea (6%, 3%), insomnia (5%, 1%), anxiety (4%, 1%), and herpes zoster (3%, 1%), respectively.
## Postmarketing Experience
The following adverse reactions have been identified during postapproval use of teriparatide. 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.
- Osteosarcoma: Cases of bone tumor and osteosarcoma have been reported rarely in the postmarketing period. The causality to teriparatide use is unclear. Long term osteosarcoma surveillance studies are ongoing.
- Hypercalcemia: Hypercalcemia greater than 13.0 mg/dL has been reported with teriparatide use.
Adverse events reported since market introduction that were temporally (but not necessarily causally) related to teriparatide therapy include the following:
- Allergic Reactions: Anaphylactic reactions, drug hypersensitivity, angioedema, urticaria
- Investigations: Hyperuricemia
- Respiratory System: Acute dyspnea, chest pain
- Musculoskeletal: Muscle spasms of the leg or back
- Other: Injection site reactions including injection site pain, swelling and bruising; oro-facial edema.
# Drug Interactions
### Digoxin
- A single teriparatide dose did not alter the effect of digoxin on the systolic time interval (from electrocardiographic Q-wave onset to aortic valve closure, a measure of digoxin's calcium-mediated cardiac effect).
- However, because teriparatide may transiently increase serum calcium, teriparatide should be used with caution in patients taking digoxin.
### Hydrochlorothiazide
- The coadministration of hydrochlorothiazide 25 mg with teriparatide did not affect the serum calcium response to teriparatide 40 mcg.
- The effect of coadministration of a higher dose of hydrochlorothiazide with teriparatide on serum calcium levels has not been studied.
### Furosemide
- Coadministration of intravenous furosemide (20 to 100 mg) with teriparatide 40 mcg in healthy people and patients with mild, moderate, or severe renal impairment (CrCl 13 to 72 mL/min) resulted in small increases in the serum calcium (2%) and 24-hour urine calcium (37%) responses to teriparatide that did not appear to be clinically important.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): C
There are no adequate and well-controlled studies of teriparatide in pregnant women. In animal studies, teriparatide increased skeletal deviations and variations in mouse offspring at doses more than 60 times the equivalent human dose and produced mild growth retardation and reduced motor activity in rat offspring at doses more than 120 times the equivalent human dose. teriparatide should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
In animal studies, pregnant mice received teriparatide during organogenesis at subcutaneous doses 8 to 267 times the human dose. At doses ≥ 60 times the human dose, the fetuses showed an increased incidence of skeletal deviations or variations (interrupted rib, extra vertebra or rib). When pregnant rats received subcutaneous teriparatide during organogenesis at doses 16 to 540 times the human dose, the fetuses showed no abnormal findings.
In a perinatal/postnatal study, pregnant rats received subcutaneous teriparatide from organogenesis through lactation. Mild growth retardation in female offspring at doses ≥120 times the human dose (based on surface area, mcg/m2). Mild growth retardation in male offspring and reduced motor activity in both male and female offspring occurred at maternal doses 540 times the human dose. There were no developmental or reproductive effects in mice or rats at doses 8 or 16 times the human dose, respectively.
Exposure multiples were normalized based on body surface area (mcg/m2). Actual animal doses: mice (30 to 1000 mcg/kg/day); rats (30 to 1000 mcg/kg/day).
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Teriparatide in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Teriparatide during labor and delivery.
### Nursing Mothers
It is not known whether teriparatide is excreted in human milk. Because of the potential for tumorigenicity shown for teriparatide in animal studies, 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
The safety and efficacy of teriparatide have not been established in any pediatric population. teriparatide should not be prescribed in patients at an increased baseline risk of osteosarcoma which include pediatric and young adult patients with open epiphyses. Therefore, teriparatide is not indicated for use in pediatric or young adult patients with open epiphyses.
### Geriatic Use
Of the patients receiving teriparatide in the osteoporosis trial of 1637 postmenopausal women, 75% were 65 years of age and over and 23% were 75 years of age and over. Of the patients receiving teriparatide in the osteoporosis trial of 437 men, 39% were 65 years of age and over and 13% were 75 years of age and over. 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.
### Gender
Although systemic exposure to teriparatide was approximately 20% to 30% lower in men than women, the recommended dose for both genders is 20 mcg/day.
### Race
The populations included in the pharmacokinetic analyses were 98.5% Caucasian. The influence of race has not been determined.
### Renal Impairment
In 5 patients with severe renal impairment (CrCl<30 mL/min), the AUC and T1/2 of teriparatide were increased by 73% and 77%, respectively. Maximum serum concentration of teriparatide was not increased.
No pharmacokinetic differences were identified in 11 patients with mild or moderate renal impairment administered a single dose of teriparatide. In 5 patients with severe renal impairment (CrCl<30 mL/min), the AUC and T1/2 of teriparatide were increased by 73% and 77%, respectively. Maximum serum concentration of teriparatide was not increased. No studies have been performed in patients undergoing dialysis for chronic renal failure.
### Hepatic Impairment
No studies have been performed in patients with hepatic impairment.
### Females of Reproductive Potential and Males
No effects on fertility were observed in male and female rats given subcutaneous teriparatide doses of 30, 100, or 300 mcg/kg/day prior to mating and in females continuing through gestation Day 6 (16 to 160 times the human dose of 20 mcg based on surface area, mcg/m2).
### Immunocompromised Patients
There is no FDA guidance one the use of Teriparatide in patients who are immunocompromised.
# Administration and Monitoring
### Administration
Subcutaneous
### Monitoring
There is limited information regarding Teriparatide Monitoring in the drug label.
# IV Compatibility
There is limited information regarding the compatibility of Teriparatide and IV administrations.
# Overdosage
Incidents of overdose in humans have not been reported in clinical trials. Teriparatide has been administered in single doses of up to 100 mcg and in repeated doses of up to 60 mcg/day for 6 weeks. The effects of overdose that might be expected include a delayed hypercalcemic effect and risk of orthostatic hypotension. Nausea, vomiting, dizziness, and headache might also occur.
In postmarketing spontaneous reports, there have been cases of medication errors in which the entire contents (up to 800 mcg) of the teriparatide delivery device (pen) have been administered as a single dose. Transient events reported have included nausea, weakness/lethargy and hypotension. In some cases, no adverse events occurred as a result of the overdose. No fatalities associated with overdose have been reported.
There is no specific antidote for teriparatide. Treatment of suspected overdose should include discontinuation of teriparatide, monitoring of serum calcium and phosphorus, and implementation of appropriate supportive measures, such as hydration.
# Pharmacology
## Mechanism of Action
Endogenous 84-amino acid parathyroid hormone (PTH) is the primary regulator of calcium and phosphate metabolism in bone and kidney. Physiological actions of PTH include regulation of bone metabolism, renal tubular reabsorption of calcium and phosphate, and intestinal calcium absorption. The biological actions of PTH and teriparatide are mediated through binding to specific high-affinity cell-surface receptors. Teriparatide and the 34 N-terminal amino acids of PTH bind to these receptors with the same affinity and have the same physiological actions on bone and kidney. Teriparatide is not expected to accumulate in bone or other tissues.
The skeletal effects of teriparatide depend upon the pattern of systemic exposure. Once-daily administration of teriparatide stimulates new bone formation on trabecular and cortical (periosteal and/or endosteal) bone surfaces by preferential stimulation of osteoblastic activity over osteoclastic activity. In monkey studies, teriparatide improved trabecular microarchitecture and increased bone mass and strength by stimulating new bone formation in both cancellous and cortical bone. In humans, the anabolic effects of teriparatide manifest as an increase in skeletal mass, an increase in markers of bone formation and resorption, and an increase in bone strength. By contrast, continuous excess of endogenous PTH, as occurs in hyperparathyroidism, may be detrimental to the skeleton because bone resorption may be stimulated more than bone formation.
## Structure
It has an identical sequence to the 34 N-terminal amino acids (the biologically active region) of the 84-amino acid human parathyroid hormone.
Teriparatide has a molecular weight of 4117.8 daltons and its amino acid sequence is shown below:
## Pharmacodynamics
Effects on Mineral Metabolism — Teriparatide affects calcium and phosphorus metabolism in a pattern consistent with the known actions of endogenous PTH (e.g., increases serum calcium and decreases serum phosphorus).
Serum Calcium Concentrations — When teriparatide 20 mcg is administered once daily, the serum calcium concentration increases transiently, beginning approximately 2 hours after dosing and reaching a maximum concentration between 4 and 6 hours (median increase, 0.4 mg/dL). The serum calcium concentration begins to decline approximately 6 hours after dosing and returns to baseline by 16 to 24 hours after each dose.
In a clinical study of postmenopausal women with osteoporosis, the median peak serum calcium concentration measured 4 to 6 hours after dosing with teriparatide (teriparatide 20 mcg) was 2.42 mmol/L (9.68 mg/dL) at 12 months. The peak serum calcium remained below 2.76 mmol/L (11.0 mg/dL) in >99% of women at each visit. Sustained hypercalcemia was not observed.
In this study, 11.1% of women treated with teriparatide had at least 1 serum calcium value above the upper limit of normal compared with 1.5% of women treated with placebo. The percentage of women treated with teriparatide whose serum calcium was above the upper limit of normal on consecutive 4- to 6-hour post-dose measurements was 3.0% compared with 0.2% of women treated with placebo. In these women, calcium supplements and/or teriparatide doses were reduced. The timing of these dose reductions was at the discretion of the investigator. teriparatide dose adjustments were made at varying intervals after the first observation of increased serum calcium (median 21 weeks). During these intervals, there was no evidence of progressive increases in serum calcium.
In a clinical study of men with either primary or hypogonadal osteoporosis, the effects on serum calcium were similar to those observed in postmenopausal women. The median peak serum calcium concentration measured 4 to 6 hours after dosing with teriparatide was 2.35 mmol/L (9.44 mg/dL) at 12 months. The peak serum calcium remained below 2.76 mmol/L (11.0 mg/dL) in 98% of men at each visit. Sustained hypercalcemia was not observed.
In this study, 6.0% of men treated with teriparatide daily had at least 1 serum calcium value above the upper limit of normal compared with none of the men treated with placebo. The percentage of men treated with teriparatide whose serum calcium was above the upper limit of normal on consecutive measurements was 1.3% (2 men) compared with none of the men treated with placebo. Although calcium supplements and/or teriparatide doses could have been reduced in these men, only calcium supplementation was reduced.
In a clinical study of women previously treated for 18 to 39 months with raloxifene (n=26) or alendronate (n=33), mean serum calcium >12 hours after teriparatide injection was increased by 0.09 to 0.14 mmol/L (0.36 to 0.56 mg/dL), after 1 to 6 months of teriparatide treatment compared with baseline. Of the women pretreated with raloxifene, 3 (11.5%) had a serum calcium >2.76 mmol/L (11.0 mg/dL), and of those pretreated with alendronate, 3 (9.1%) had a serum calcium >2.76 mmol/L (11.0 mg/dL). The highest serum calcium reported was 3.12 mmol/L (12.5 mg/dL). None of the women had symptoms of hypercalcemia. There were no placebo controls in this study.
In the study of patients with glucocorticoid-induced osteoporosis, the effects of teriparatide on serum calcium were similar to those observed in postmenopausal women with osteoporosis not taking glucocorticoids.
Urinary Calcium Excretion — In a clinical study of postmenopausal women with osteoporosis who received 1000 mg of supplemental calcium and at least 400 IU of vitamin D, daily teriparatide increased urinary calcium excretion. The median urinary excretion of calcium was 4.8 mmol/day (190 mg/day) at 6 months and 4.2 mmol/day (170 mg/day) at 12 months. These levels were 0.76 mmol/day (30 mg/day) and 0.3 mmol/day (12 mg/day) higher, respectively, than in women treated with placebo. The incidence of hypercalciuria (>7.5 mmol Ca/day or 300 mg/day) was similar in the women treated with teriparatide or placebo.
In a clinical study of men with either primary or hypogonadal osteoporosis who received 1000 mg of supplemental calcium and at least 400 IU of vitamin D, daily teriparatide had inconsistent effects on urinary calcium excretion. The median urinary excretion of calcium was 5.6 mmol/day (220 mg/day) at 1 month and 5.3 mmol/day (210 mg/day) at 6 months. These levels were 0.5 mmol/day (20 mg/day) higher and 0.2 mmol/day (8.0 mg/day) lower, respectively, than in men treated with placebo. The incidence of hypercalciuria (>7.5 mmol Ca/day or 300 mg/day) was similar in the men treated with teriparatide or placebo.
Phosphorus and Vitamin D — In single-dose studies, teriparatide produced transient phosphaturia and mild transient reductions in serum phosphorus concentration. However, hypophosphatemia (<0.74 mmol/L or 2.4 mg/dL) was not observed in clinical trials with teriparatide.
In clinical trials of daily teriparatide, the median serum concentration of 1,25-dihydroxyvitamin D was increased at 12 months by 19% in women and 14% in men, compared with baseline. In the placebo group, this concentration decreased by 2% in women and increased by 5% in men. The median serum 25-hydroxyvitamin D concentration at 12 months was decreased by 19% in women and 10% in men compared with baseline. In the placebo group, this concentration was unchanged in women and increased by 1% in men.
In the study of patients with glucocorticoid-induced osteoporosis, the effects of teriparatide on serum phosphorus were similar to those observed in postmenopausal women with osteoporosis not taking glucocorticoids.
Effects on Markers of Bone Turnover — Daily administration of teriparatide to men and postmenopausal women with osteoporosis in clinical studies stimulated bone formation, as shown by increases in the formation markers serum bone-specific alkaline phosphatase (BSAP) and procollagen I carboxy-terminal propeptide (PICP). Data on biochemical markers of bone turnover were available for the first 12 months of treatment. Peak concentrations of PICP at 1 month of treatment were approximately 41% above baseline, followed by a decline to near-baseline values by 12 months. BSAP concentrations increased by 1 month of treatment and continued to rise more slowly from 6 through 12 months. The maximum increases of BSAP were 45% above baseline in women and 23% in men. After discontinuation of therapy, BSAP concentrations returned toward baseline. The increases in formation markers were accompanied by secondary increases in the markers of bone resorption: urinary N-telopeptide (NTX) and urinary deoxypyridinoline (DPD), consistent with the physiological coupling of bone formation and resorption in skeletal remodeling. Changes in BSAP, NTX, and DPD were lower in men than in women, possibly because of lower systemic exposure to teriparatide in men.
In the study of patients with glucocorticoid-induced osteoporosis, the effects of teriparatide on serum markers of bone turnover were similar to those observed in postmenopausal women with osteoporosis not taking glucocorticoids.
## Pharmacokinetics
Teriparatide is absorbed after subcutaneous injection; the absolute bioavailability is approximately 95% based on pooled data from 20-, 40-, and 80- mcg doses. The rates of absorption and elimination are rapid. The peptide reaches peak serum concentrations about 30 minutes after subcutaneous injection of a 20-mcg dose and declines to non-quantifiable concentrations within 3 hours.
Systemic clearance of teriparatide (approximately 62 L/hr in women and 94 L/hr in men) exceeds the rate of normal liver plasma flow, consistent with both hepatic and extra-hepatic clearance. Volume of distribution, following intravenous injection, is approximately 0.12 L/kg. Intersubject variability in systemic clearance and volume of distribution is 25% to 50%. The half-life of teriparatide in serum is 5 minutes when administered by intravenous injection and approximately 1 hour when administered by subcutaneous injection. The longer half-life following subcutaneous administration reflects the time required for absorption from the injection site.
No metabolism or excretion studies have been performed with teriparatide. However, the mechanisms of metabolism and elimination of PTH(1-34) and intact PTH have been extensively described in published literature. Peripheral metabolism of PTH is believed to occur by non-specific enzymatic mechanisms in the liver followed by excretion via the kidneys.
## Nonclinical Toxicology
Two carcinogenicity bioassays were conducted in Fischer 344 rats. In the first study, male and female rats were given daily subcutaneous teriparatide injections of 5, 30, or 75 mcg/kg/day for 24 months from 2 months of age. These doses resulted in systemic exposures that were, respectively, 3, 20, and 60 times higher than the systemic exposure observed in humans following a subcutaneous dose of 20 mcg (based on AUC comparison). Teriparatide treatment resulted in a marked dose-related increase in the incidence of osteosarcoma, a rare malignant bone tumor, in both male and female rats. Osteosarcomas were observed at all doses and the incidence reached 40% to 50% in the high-dose groups. Teriparatide also caused a dose-related increase in osteoblastoma and osteoma in both sexes. No osteosarcomas, osteoblastomas or osteomas were observed in untreated control rats. The bone tumors in rats occurred in association with a large increase in bone mass and focal osteoblast hyperplasia.
The second 2-year study was carried out in order to determine the effect of treatment duration and animal age on the development of bone tumors. Female rats were treated for different periods between 2 and 26 months of age with subcutaneous doses of 5 and 30 mcg/kg (equivalent to 3 and 20 times the human exposure at the 20-mcg dose, based on AUC comparison). The study showed that the occurrence of osteosarcoma, osteoblastoma and osteoma was dependent upon dose and duration of exposure. Bone tumors were observed when immature 2-month old rats were treated with 30 mcg/kg/day for 24 months or with 5 or 30 mcg/kg/day for 6 months. Bone tumors were also observed when mature 6-month old rats were treated with 30 mcg/kg/day for 6 or 20 months. Tumors were not detected when mature 6-month old rats were treated with 5 mcg/kg/day for 6 or 20 months. The results did not demonstrate a difference in susceptibility to bone tumor formation, associated with teriparatide treatment, between mature and immature rats.
The relevance of these animal findings to humans is uncertain.
Teriparatide was not genotoxic in any of the following test systems: the Ames test for bacterial mutagenesis; the mouse lymphoma assay for mammalian cell mutation; the chromosomal aberration assay in Chinese hamster ovary cells, with and without metabolic activation; and the in vivo micronucleus test in mice.
In single-dose rodent studies using subcutaneous injection of teriparatide, no mortality was seen in rats given doses of 1000 mcg/kg (540 times the human dose based on surface area, mcg/m2) or in mice given 10,000 mcg/kg (2700 times the human dose based on surface area, mcg/m2).
In a long-term study, skeletally mature ovariectomized female monkeys (N=30 per treatment group) were given either daily subcutaneous teriparatide injections of 5 mcg/kg or vehicle. Following the 18-month treatment period, the monkeys were removed from teriparatide treatment and were observed for an additional 3 years. The 5 mcg/kg dose resulted in systemic exposures that were approximately 6 times higher than the systemic exposure observed in humans following a subcutaneous dose of 20 mcg (based on AUC comparison). Bone tumors were not detected by radiographic or histologic evaluation in any monkey in the study.
# Clinical Studies
### Treatment of Osteoporosis in Postmenopausal Women
The safety and efficacy of once-daily teriparatide, median exposure of 19 months, were examined in a double-blind, multicenter, placebo-controlled clinical study of 1637 postmenopausal women with osteoporosis (teriparatide 20 mcg, n=541).
All women received 1000 mg of calcium and at least 400 IU of vitamin D per day. Baseline and endpoint spinal radiographs were evaluated using the semiquantitative scoring. Ninety percent of the women in the study had 1 or more radiographically diagnosed vertebral fractures at baseline. The primary efficacy endpoint was the occurrence of new radiographically diagnosed vertebral fractures defined as changes in the height of previously undeformed vertebrae. Such fractures are not necessarily symptomatic.
New Vertebral Fractures: teriparatide, when taken with calcium and vitamin D and compared with calcium and vitamin D alone, reduced the risk of 1 or more new vertebral fractures from 14.3% of women in the placebo group to 5.0% in the teriparatide group. This difference was statistically significant (p<0.001); the absolute reduction in risk was 9.3% and the relative reduction was 65%. teriparatide was effective in reducing the risk for vertebral fractures regardless of age, baseline rate of bone turnover, or baseline BMD.
New Nonvertebral Osteoporotic Fractures: teriparatide significantly reduced the risk of any nonvertebral fracture from 5.5% in the placebo group to 2.6% in the teriparatide group (p<0.05). The absolute reduction in risk was 2.9% and the relative reduction was 53%. The incidence of new nonvertebral fractures in the teriparatide group compared with the placebo group was ankle/foot (0.2%, 0.7%), hip (0.2%, 0.7%), humerus (0.4%, 0.4%), pelvis (0%, 0.6%), ribs (0.6%, 0.9%), wrist (0.4%, 1.3%), and other sites (1.1%, 1.5%), respectively.
The cumulative percentage of postmenopausal women with osteoporosis who sustained new nonvertebral fractures was lower in women treated with teriparatide than in women treated with placebo (see FIGURE 1).
teriparatide increased lumbar spine BMD in postmenopausal women with osteoporosis. Statistically significant increases were seen at 3 months and continued throughout the treatment period. Postmenopausal women with osteoporosis who were treated with teriparatide had statistically significant increases in BMD from baseline to endpoint at the lumbar spine, femoral neck, total hip, and total body.
teriparatide treatment increased lumbar spine BMD from baseline in 96% of postmenopausal women treated. Seventy-two percent of patients treated with teriparatide achieved at least a 5% increase in spine BMD, and 44% gained 10% or more.
Both treatment groups lost height during the trial. The mean decreases were 3.61 and 2.81 mm in the placebo and teriparatide groups, respectively.
The effects of teriparatide on bone histology were evaluated in iliac crest biopsies of 35 postmenopausal women treated for 12 to 24 months with calcium and vitamin D and teriparatide 20 or 40 mcg/day. Normal mineralization was observed with no evidence of cellular toxicity. The new bone formed with teriparatide was of normal quality (as evidenced by the absence of woven bone and marrow fibrosis).
### Treatment to Increase Bone Mass in Men with Primary or Hypogonadal Osteoporosis
The safety and efficacy of once-daily teriparatide, median exposure of 10 months, were examined in a double-blind, multicenter, placebo-controlled clinical study of 437 men with either primary (idiopathic) or hypogonadal osteoporosis (teriparatide 20 mcg, n=151). All men received 1000 mg of calcium and at least 400 IU of vitamin D per day. The primary efficacy endpoint was change in lumbar spine BMD.
teriparatide increased lumbar spine BMD in men with primary or hypogonadal osteoporosis. Statistically significant increases were seen at 3 months and continued throughout the treatment period. teriparatide was effective in increasing lumbar spine BMD regardless of age, baseline rate of bone turnover, and baseline BMD. The effects of teriparatide at additional skeletal sites are shown in TABLE 4.
teriparatide treatment for a median of 10 months increased lumbar spine BMD from baseline in 94% of men treated. Fifty-three percent of patients treated with teriparatide achieved at least a 5% increase in spine BMD, and 14% gained 10% or more.
### Treatment of Men and Women with Glucocorticoid-Induced Osteoporosis
The efficacy of teriparatide for treating glucocorticoid-induced osteoporosis was assessed in a randomized, double-blind, active-controlled trial of 428 patients (19% men, 81% women) aged 22 to 89 years (mean 57 years) treated with ≥5 mg/day prednisone or equivalent for a minimum of 3 months. The duration of the trial was 18 months with 214 patients exposed to teriparatide. In the teriparatide group, the baseline median glucocorticoid dose was 7.5 mg/day and the median duration of glucocorticoid use was 1.5 years. The mean (SD) baseline lumbar spine BMD was 0.85 ± 0.13 g/cm2 and lumbar spine BMD T-score was –2.5 ± 1 (number of standard deviations below the mean BMD value for healthy adults). A total of 30% of patients had prevalent vertebral fracture(s) and 43% had prior non-vertebral fracture(s). The patients had chronic rheumatologic, respiratory or other diseases that required sustained glucocorticoid therapy. All patients received 1000 mg of calcium plus 800 IU of vitamin D supplementation per day.
Because of differences in mechanism of action (anabolic vs. anti-resorptive) and lack of clarity regarding differences in BMD as an adequate predictor of fracture efficacy, data on the active comparator are not presented.
In patients with glucocorticoid-induced osteoporosis, teriparatide increased lumbar spine BMD compared with baseline at 3 months through 18 months of treatment. In patients treated with teriparatide, the mean percent change in BMD from baseline to endpoint was 7.2% at the lumbar spine, 3.6% at the total hip, and 3.7% at the femoral neck (p<0.001 all sites). The relative treatment effects of teriparatide were consistent in subgroups defined by gender, age, geographic region, body mass index, underlying disease, prevalent vertebral fracture, baseline glucocorticoid dose, prior bisphosphonate use, and glucocorticoid discontinuation during trial.
# How Supplied
Teripatide delivery device (pen) is available in the following package size:
- 2.4 mL prefilled delivery device NDC 0002-8400-01 (MS8400).
## Storage
Store at 2° to 8°C (36° to 46°F)
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
### Potential Risk of Osteosarcoma and Voluntary teriparatide Patient Registry
Patients should be made aware that in rats, teriparatide caused an increase in the incidence of osteosarcoma (a malignant bone tumor) that was dependent on dose and treatment duration. Patients should be encouraged to enroll in the voluntary teriparatide Patient Registry, which is designed to collect information about any potential risk of osteosarcoma in patients who have taken teriparatide.
### Orthostatic Hypotension
teriparatide should be administered initially under circumstances where the patient can immediately sit or lie down if symptoms occur. Patients should be instructed that if they feel lightheaded or have palpitations after the injection, they should sit or lie down until the symptoms resolve. If symptoms persist or worsen, patients should be instructed to consult a physician before continuing treatment.
### Hypercalcemia
Although symptomatic hypercalcemia was not observed in clinical trials, physicians should instruct patients taking teriparatide to contact a health care provider if they develop persistent symptoms of hypercalcemia (e.g., nausea, vomiting, constipation, lethargy, muscle weakness).
### Other Osteoporosis Treatment Modalities
Patients should be informed regarding the roles of supplemental calcium and/or vitamin D, weight-bearing exercise, and modification of certain behavioral factors such as cigarette smoking and/or alcohol consumption.
### Use of Delivery Device (Pen)
Patients and caregivers who administer teriparatide should be instructed on how to properly use the delivery device (refer to User Manual), properly dispose of needles, and be advised not to share their delivery device with other patients. The contents of the delivery device should NOT be transferred to a syringe.
Each teriparatide delivery device can be used for up to 28 days including the first injection from the delivery device. After the 28-day use period, discard the teriparatide delivery device, even if it still contains some unused solution.
### Availability of Medication Guide and User Manual
Patients should read the Medication Guide and delivery device (pen) User Manual before starting therapy with teriparatide and re-read them each time the prescription is renewed. Patients need to understand and follow the instructions in the teriparatide delivery device User Manual. Failure to do so may result in inaccurate dosing.
# Precautions with Alcohol
Alcohol-Teriparatide interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Forteo
# Look-Alike Drug Names
There is limited information regarding Teriparatide Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | Teriparatide
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Gloria Picoy [2]
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# Black Box Warning
# Overview
Teriparatide is a calcium regulator that is FDA approved for the treatment of postmenopausal women with osteoporosis at high risk for fracture, men and women with glucocorticoid-induced osteoporosis at high risk for fracture and increase of bone mass in men with primary or hypogonadal osteoporosis at high risk for fracture.. There is a Black Box Warning for this drug as shown here. Common adverse reactions include arthralgia and nausea.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
### Treatment of Postmenopausal Women with Osteoporosis at High Risk for Fracture
- Teriparatide is indicated for the treatment of postmenopausal women with osteoporosis at high risk for fracture, defined as a history of osteoporotic fracture, multiple risk factors for fracture, or patients who have failed or are intolerant to other available osteoporosis therapy.
- In postmenopausal women with osteoporosis, teriparatide reduces the risk of vertebral and nonvertebral fractures.
- Dosage: 20 mcg subcutaneously once a day.
### Increase of Bone Mass in Men with Primary or Hypogonadal Osteoporosis at High Risk for Fracture
- Teriparatide is indicated to increase bone mass in men with primary or hypogonadal osteoporosis at high risk for fracture, defined as a history of osteoporotic fracture, multiple risk factors for fracture, or patients who have failed or are intolerant to other available osteoporosis therapy.
- Dosage: 20 mcg subcutaneously once a day.
### Treatment of Men and Women with Glucocorticoid-Induced Osteoporosis at High Risk for Fracture
- Teriparatide is indicated for the treatment of men and women with osteoporosis associated with sustained systemic glucocorticoid therapy (daily dosage equivalent to 5 mg or greater of prednisone) at high risk for fracture, defined as a history of osteoporotic fracture, multiple risk factors for fracture, or patients who have failed or are intolerant to other available osteoporosis therapy.
- Dosage: 20 mcg subcutaneously once a day
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Teriparatide in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Teriparatide in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
Safety and efficacy have not been established in pediatric patients
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Teriparatide in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Teriparatide in pediatric patients.
# Contraindications
Do not use teriparatide in patients with:
- Hypersensitivity to teriparatide or to any of its excipients. Reactions have included angioedema and anaphylaxis
# Warnings
### Osteosarcoma
In male and female rats, teriparatide caused an increase in the incidence of osteosarcoma (a malignant bone tumor) that was dependent on dose and treatment duration. Teriparatide should not be prescribed for patients at increased baseline risk of osteosarcoma.
These include:
- Paget's disease of bone. Unexplained elevations of alkaline phosphatase may indicate Paget's disease of bone.
- Pediatric and young adult patients with open epiphyses.
- Prior external beam or implant radiation therapy involving the skeleton.
Patients should be encouraged to enroll in the voluntary teriparatide Patient Registry, which is designed to collect information about any potential risk of osteosarcoma in patients who have taken teriparatide.
### Treatment Duration
The safety and efficacy of teriparatide have not been evaluated beyond 2 years of treatment. Consequently, use of the drug for more than 2 years during a patients' lifetime is not recommended.
### Bone Metastases and Skeletal Malignancies
Patients with bone metastases or a history of skeletal malignancies should not be treated with teriparatide.
### Metabolic Bone Diseases
Patients with metabolic bone diseases other than osteoporosis should not be treated with teriparatide.
### Hypercalcemia and Hypercalcemic Disorders
teriparatide has not been studied in patients with pre-existing hypercalcemia. These patients should not be treated with teriparatide because of the possibility of exacerbating hypercalcemia. Patients known to have an underlying hypercalcemic disorder, such as primary hyperparathyroidism, should not be treated with teriparatide.
### Urolithiasis or Pre-existing Hypercalciuria
In clinical trials, the frequency of urolithiasis was similar in patients treated with teriparatide and placebo. However, teriparatide has not been studied in patients with active urolithiasis. If active urolithiasis or pre-existing hypercalciuria are suspected, measurement of urinary calcium excretion should be considered. Teriparatide should be used with caution in patients with active or recent urolithiasis because of the potential to exacerbate this condition.
### Orthostatic Hypotension
teriparatide should be administered initially under circumstances in which the patient can sit or lie down if symptoms of orthostatic hypotension occur. In short-term clinical pharmacology studies with teriparatide, transient episodes of symptomatic orthostatic hypotension were observed in 5% of patients. Typically, an event began within 4 hours of dosing and spontaneously resolved within a few minutes to a few hours. When transient orthostatic hypotension occurred, it happened within the first several doses, it was relieved by placing the person in a reclining position, and it did not preclude continued treatment.
### Drug Interactions
Hypercalcemia may predispose patients to digitalis toxicity. Because teriparatide transiently increases serum calcium, patients receiving digoxin should use teriparatide with caution.
# 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 the rates observed in practice.
### Treatment of Osteoporosis in Men and Postmenopausal Women
The safety of teriparatide in the treatment of osteoporosis in men and postmenopausal women was assessed in two randomized, double-blind, placebo-controlled trials of 1382 patients (21% men, 79% women) aged 28 to 86 years (mean 67 years). The median durations of the trials were 11 months for men and 19 months for women, with 691 patients exposed to teriparatide and 691 patients to placebo. All patients received 1000 mg of calcium plus at least 400 IU of vitamin D supplementation per day.
The incidence of all cause mortality was 1% in the teriparatide group and 1% in the placebo group. The incidence of serious adverse events was 16% in teriparatide patients and 19% in placebo patients. Early discontinuation due to adverse events occurred in 7% of teriparatide patients and 6% of placebo patients.
TABLE 1 lists adverse events from the two principal osteoporosis trials in men and postmenopausal women that occurred in ≥2% of teriparatide-treated and more frequently than placebo-treated patients.
- Immunogenicity: In the clinical trial, antibodies that cross-reacted with teriparatide were detected in 3% of women (15/541) receiving teriparatide. Generally, antibodies were first detected following 12 months of treatment and diminished after withdrawal of therapy. There was no evidence of hypersensitivity reactions or allergic reactions among these patients. Antibody formation did not appear to have effects on serum calcium, or on bone mineral density (BMD) response.
- Serum Calcium: teriparatide transiently increased serum calcium, with the maximal effect observed at approximately 4 to 6 hours post-dose. Serum calcium measured at least 16 hours post-dose was not different from pretreatment levels. In clinical trials, the frequency of at least 1 episode of transient hypercalcemia in the 4 to 6 hours after teriparatide administration was increased from 2% of women and none of the men treated with placebo to 11% of women and 6% of men treated with teriparatide. The number of patients treated with teriparatide whose transient hypercalcemia was verified on consecutive measurements was 3% of women and 1% of men.
- Urinary Calcium: teriparatide increased urinary calcium excretion, but the frequency of hypercalciuria in clinical trials was similar for patients treated with teriparatide and placebo.
- Serum Uric Acid: teriparatide increased serum uric acid concentrations. In clinical trials, 3% of teriparatide patients had serum uric acid concentrations above the upper limit of normal compared with 1% of placebo patients. However, the hyperuricemia did not result in an increase in gout, arthralgia, or urolithiasis.
- Renal Function: No clinically important adverse renal effects were observed in clinical studies. Assessments included creatinine clearance; measurements of blood urea nitrogen (BUN), creatinine, and electrolytes in serum; urine specific gravity and pH; and examination of urine sediment.
### Studies in Men and Women with Glucocorticoid-Induced Osteoporosis
The safety of teriparatide in the treatment of men and women with glucocorticoid-induced osteoporosis was assessed in a randomized, double-blind, active-controlled trial of 428 patients (19% men, 81% women) aged 22 to 89 years (mean 57 years) treated with ≥ 5mg per day prednisone or equivalent for a minimum of 3 months. The duration of the trial was 18 months with 214 patients exposed to teriparatide and 214 patients exposed to oral daily bisphosphonate (active control). All patients received 1000 mg of calcium plus 800 IU of vitamin D supplementation per day.
The incidence of all cause mortality was 4% in the teriparatide group and 6% in the active control group. The incidence of serious adverse events was 21% in teriparatide patients and 18% in active control patients, and included pneumonia (3% teriparatide, 1% active control). Early discontinuation because of adverse events occurred in 15% of teriparatide patients and 12% of active control patients, and included dizziness (2% teriparatide, 0% active control).
Adverse events reported at a higher incidence in the teriparatide group and with at least a 2% difference in teriparatide-treated patients compared with active control-treated patients were: nausea (14%, 7%), gastritis (7%, 3%), pneumonia (6%, 3%), dyspnea (6%, 3%), insomnia (5%, 1%), anxiety (4%, 1%), and herpes zoster (3%, 1%), respectively.
## Postmarketing Experience
The following adverse reactions have been identified during postapproval use of teriparatide. 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.
- Osteosarcoma: Cases of bone tumor and osteosarcoma have been reported rarely in the postmarketing period. The causality to teriparatide use is unclear. Long term osteosarcoma surveillance studies are ongoing.
- Hypercalcemia: Hypercalcemia greater than 13.0 mg/dL has been reported with teriparatide use.
Adverse events reported since market introduction that were temporally (but not necessarily causally) related to teriparatide therapy include the following:
- Allergic Reactions: Anaphylactic reactions, drug hypersensitivity, angioedema, urticaria
- Investigations: Hyperuricemia
- Respiratory System: Acute dyspnea, chest pain
- Musculoskeletal: Muscle spasms of the leg or back
- Other: Injection site reactions including injection site pain, swelling and bruising; oro-facial edema.
# Drug Interactions
### Digoxin
- A single teriparatide dose did not alter the effect of digoxin on the systolic time interval (from electrocardiographic Q-wave onset to aortic valve closure, a measure of digoxin's calcium-mediated cardiac effect).
- However, because teriparatide may transiently increase serum calcium, teriparatide should be used with caution in patients taking digoxin.
### Hydrochlorothiazide
- The coadministration of hydrochlorothiazide 25 mg with teriparatide did not affect the serum calcium response to teriparatide 40 mcg.
- The effect of coadministration of a higher dose of hydrochlorothiazide with teriparatide on serum calcium levels has not been studied.
### Furosemide
- Coadministration of intravenous furosemide (20 to 100 mg) with teriparatide 40 mcg in healthy people and patients with mild, moderate, or severe renal impairment (CrCl 13 to 72 mL/min) resulted in small increases in the serum calcium (2%) and 24-hour urine calcium (37%) responses to teriparatide that did not appear to be clinically important.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): C
There are no adequate and well-controlled studies of teriparatide in pregnant women. In animal studies, teriparatide increased skeletal deviations and variations in mouse offspring at doses more than 60 times the equivalent human dose and produced mild growth retardation and reduced motor activity in rat offspring at doses more than 120 times the equivalent human dose. teriparatide should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
In animal studies, pregnant mice received teriparatide during organogenesis at subcutaneous doses 8 to 267 times the human dose. At doses ≥ 60 times the human dose, the fetuses showed an increased incidence of skeletal deviations or variations (interrupted rib, extra vertebra or rib). When pregnant rats received subcutaneous teriparatide during organogenesis at doses 16 to 540 times the human dose, the fetuses showed no abnormal findings.
In a perinatal/postnatal study, pregnant rats received subcutaneous teriparatide from organogenesis through lactation. Mild growth retardation in female offspring at doses ≥120 times the human dose (based on surface area, mcg/m2). Mild growth retardation in male offspring and reduced motor activity in both male and female offspring occurred at maternal doses 540 times the human dose. There were no developmental or reproductive effects in mice or rats at doses 8 or 16 times the human dose, respectively.
Exposure multiples were normalized based on body surface area (mcg/m2). Actual animal doses: mice (30 to 1000 mcg/kg/day); rats (30 to 1000 mcg/kg/day).
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Teriparatide in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Teriparatide during labor and delivery.
### Nursing Mothers
It is not known whether teriparatide is excreted in human milk. Because of the potential for tumorigenicity shown for teriparatide in animal studies, 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
The safety and efficacy of teriparatide have not been established in any pediatric population. teriparatide should not be prescribed in patients at an increased baseline risk of osteosarcoma which include pediatric and young adult patients with open epiphyses. Therefore, teriparatide is not indicated for use in pediatric or young adult patients with open epiphyses.
### Geriatic Use
Of the patients receiving teriparatide in the osteoporosis trial of 1637 postmenopausal women, 75% were 65 years of age and over and 23% were 75 years of age and over. Of the patients receiving teriparatide in the osteoporosis trial of 437 men, 39% were 65 years of age and over and 13% were 75 years of age and over. 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.
### Gender
Although systemic exposure to teriparatide was approximately 20% to 30% lower in men than women, the recommended dose for both genders is 20 mcg/day.
### Race
The populations included in the pharmacokinetic analyses were 98.5% Caucasian. The influence of race has not been determined.
### Renal Impairment
In 5 patients with severe renal impairment (CrCl<30 mL/min), the AUC and T1/2 of teriparatide were increased by 73% and 77%, respectively. Maximum serum concentration of teriparatide was not increased.
No pharmacokinetic differences were identified in 11 patients with mild or moderate renal impairment [creatinine clearance (CrCl) 30 to 72 mL/min] administered a single dose of teriparatide. In 5 patients with severe renal impairment (CrCl<30 mL/min), the AUC and T1/2 of teriparatide were increased by 73% and 77%, respectively. Maximum serum concentration of teriparatide was not increased. No studies have been performed in patients undergoing dialysis for chronic renal failure.
### Hepatic Impairment
No studies have been performed in patients with hepatic impairment.
### Females of Reproductive Potential and Males
No effects on fertility were observed in male and female rats given subcutaneous teriparatide doses of 30, 100, or 300 mcg/kg/day prior to mating and in females continuing through gestation Day 6 (16 to 160 times the human dose of 20 mcg based on surface area, mcg/m2).
### Immunocompromised Patients
There is no FDA guidance one the use of Teriparatide in patients who are immunocompromised.
# Administration and Monitoring
### Administration
Subcutaneous
### Monitoring
There is limited information regarding Teriparatide Monitoring in the drug label.
# IV Compatibility
There is limited information regarding the compatibility of Teriparatide and IV administrations.
# Overdosage
Incidents of overdose in humans have not been reported in clinical trials. Teriparatide has been administered in single doses of up to 100 mcg and in repeated doses of up to 60 mcg/day for 6 weeks. The effects of overdose that might be expected include a delayed hypercalcemic effect and risk of orthostatic hypotension. Nausea, vomiting, dizziness, and headache might also occur.
In postmarketing spontaneous reports, there have been cases of medication errors in which the entire contents (up to 800 mcg) of the teriparatide delivery device (pen) have been administered as a single dose. Transient events reported have included nausea, weakness/lethargy and hypotension. In some cases, no adverse events occurred as a result of the overdose. No fatalities associated with overdose have been reported.
There is no specific antidote for teriparatide. Treatment of suspected overdose should include discontinuation of teriparatide, monitoring of serum calcium and phosphorus, and implementation of appropriate supportive measures, such as hydration.
# Pharmacology
## Mechanism of Action
Endogenous 84-amino acid parathyroid hormone (PTH) is the primary regulator of calcium and phosphate metabolism in bone and kidney. Physiological actions of PTH include regulation of bone metabolism, renal tubular reabsorption of calcium and phosphate, and intestinal calcium absorption. The biological actions of PTH and teriparatide are mediated through binding to specific high-affinity cell-surface receptors. Teriparatide and the 34 N-terminal amino acids of PTH bind to these receptors with the same affinity and have the same physiological actions on bone and kidney. Teriparatide is not expected to accumulate in bone or other tissues.
The skeletal effects of teriparatide depend upon the pattern of systemic exposure. Once-daily administration of teriparatide stimulates new bone formation on trabecular and cortical (periosteal and/or endosteal) bone surfaces by preferential stimulation of osteoblastic activity over osteoclastic activity. In monkey studies, teriparatide improved trabecular microarchitecture and increased bone mass and strength by stimulating new bone formation in both cancellous and cortical bone. In humans, the anabolic effects of teriparatide manifest as an increase in skeletal mass, an increase in markers of bone formation and resorption, and an increase in bone strength. By contrast, continuous excess of endogenous PTH, as occurs in hyperparathyroidism, may be detrimental to the skeleton because bone resorption may be stimulated more than bone formation.
## Structure
It has an identical sequence to the 34 N-terminal amino acids (the biologically active region) of the 84-amino acid human parathyroid hormone.
Teriparatide has a molecular weight of 4117.8 daltons and its amino acid sequence is shown below:
## Pharmacodynamics
Effects on Mineral Metabolism — Teriparatide affects calcium and phosphorus metabolism in a pattern consistent with the known actions of endogenous PTH (e.g., increases serum calcium and decreases serum phosphorus).
Serum Calcium Concentrations — When teriparatide 20 mcg is administered once daily, the serum calcium concentration increases transiently, beginning approximately 2 hours after dosing and reaching a maximum concentration between 4 and 6 hours (median increase, 0.4 mg/dL). The serum calcium concentration begins to decline approximately 6 hours after dosing and returns to baseline by 16 to 24 hours after each dose.
In a clinical study of postmenopausal women with osteoporosis, the median peak serum calcium concentration measured 4 to 6 hours after dosing with teriparatide (teriparatide 20 mcg) was 2.42 mmol/L (9.68 mg/dL) at 12 months. The peak serum calcium remained below 2.76 mmol/L (11.0 mg/dL) in >99% of women at each visit. Sustained hypercalcemia was not observed.
In this study, 11.1% of women treated with teriparatide had at least 1 serum calcium value above the upper limit of normal [2.64 mmol/L (10.6 mg/dL)] compared with 1.5% of women treated with placebo. The percentage of women treated with teriparatide whose serum calcium was above the upper limit of normal on consecutive 4- to 6-hour post-dose measurements was 3.0% compared with 0.2% of women treated with placebo. In these women, calcium supplements and/or teriparatide doses were reduced. The timing of these dose reductions was at the discretion of the investigator. teriparatide dose adjustments were made at varying intervals after the first observation of increased serum calcium (median 21 weeks). During these intervals, there was no evidence of progressive increases in serum calcium.
In a clinical study of men with either primary or hypogonadal osteoporosis, the effects on serum calcium were similar to those observed in postmenopausal women. The median peak serum calcium concentration measured 4 to 6 hours after dosing with teriparatide was 2.35 mmol/L (9.44 mg/dL) at 12 months. The peak serum calcium remained below 2.76 mmol/L (11.0 mg/dL) in 98% of men at each visit. Sustained hypercalcemia was not observed.
In this study, 6.0% of men treated with teriparatide daily had at least 1 serum calcium value above the upper limit of normal [2.64 mmol/L (10.6 mg/dL)] compared with none of the men treated with placebo. The percentage of men treated with teriparatide whose serum calcium was above the upper limit of normal on consecutive measurements was 1.3% (2 men) compared with none of the men treated with placebo. Although calcium supplements and/or teriparatide doses could have been reduced in these men, only calcium supplementation was reduced.
In a clinical study of women previously treated for 18 to 39 months with raloxifene (n=26) or alendronate (n=33), mean serum calcium >12 hours after teriparatide injection was increased by 0.09 to 0.14 mmol/L (0.36 to 0.56 mg/dL), after 1 to 6 months of teriparatide treatment compared with baseline. Of the women pretreated with raloxifene, 3 (11.5%) had a serum calcium >2.76 mmol/L (11.0 mg/dL), and of those pretreated with alendronate, 3 (9.1%) had a serum calcium >2.76 mmol/L (11.0 mg/dL). The highest serum calcium reported was 3.12 mmol/L (12.5 mg/dL). None of the women had symptoms of hypercalcemia. There were no placebo controls in this study.
In the study of patients with glucocorticoid-induced osteoporosis, the effects of teriparatide on serum calcium were similar to those observed in postmenopausal women with osteoporosis not taking glucocorticoids.
Urinary Calcium Excretion — In a clinical study of postmenopausal women with osteoporosis who received 1000 mg of supplemental calcium and at least 400 IU of vitamin D, daily teriparatide increased urinary calcium excretion. The median urinary excretion of calcium was 4.8 mmol/day (190 mg/day) at 6 months and 4.2 mmol/day (170 mg/day) at 12 months. These levels were 0.76 mmol/day (30 mg/day) and 0.3 mmol/day (12 mg/day) higher, respectively, than in women treated with placebo. The incidence of hypercalciuria (>7.5 mmol Ca/day or 300 mg/day) was similar in the women treated with teriparatide or placebo.
In a clinical study of men with either primary or hypogonadal osteoporosis who received 1000 mg of supplemental calcium and at least 400 IU of vitamin D, daily teriparatide had inconsistent effects on urinary calcium excretion. The median urinary excretion of calcium was 5.6 mmol/day (220 mg/day) at 1 month and 5.3 mmol/day (210 mg/day) at 6 months. These levels were 0.5 mmol/day (20 mg/day) higher and 0.2 mmol/day (8.0 mg/day) lower, respectively, than in men treated with placebo. The incidence of hypercalciuria (>7.5 mmol Ca/day or 300 mg/day) was similar in the men treated with teriparatide or placebo.
Phosphorus and Vitamin D — In single-dose studies, teriparatide produced transient phosphaturia and mild transient reductions in serum phosphorus concentration. However, hypophosphatemia (<0.74 mmol/L or 2.4 mg/dL) was not observed in clinical trials with teriparatide.
In clinical trials of daily teriparatide, the median serum concentration of 1,25-dihydroxyvitamin D was increased at 12 months by 19% in women and 14% in men, compared with baseline. In the placebo group, this concentration decreased by 2% in women and increased by 5% in men. The median serum 25-hydroxyvitamin D concentration at 12 months was decreased by 19% in women and 10% in men compared with baseline. In the placebo group, this concentration was unchanged in women and increased by 1% in men.
In the study of patients with glucocorticoid-induced osteoporosis, the effects of teriparatide on serum phosphorus were similar to those observed in postmenopausal women with osteoporosis not taking glucocorticoids.
Effects on Markers of Bone Turnover — Daily administration of teriparatide to men and postmenopausal women with osteoporosis in clinical studies stimulated bone formation, as shown by increases in the formation markers serum bone-specific alkaline phosphatase (BSAP) and procollagen I carboxy-terminal propeptide (PICP). Data on biochemical markers of bone turnover were available for the first 12 months of treatment. Peak concentrations of PICP at 1 month of treatment were approximately 41% above baseline, followed by a decline to near-baseline values by 12 months. BSAP concentrations increased by 1 month of treatment and continued to rise more slowly from 6 through 12 months. The maximum increases of BSAP were 45% above baseline in women and 23% in men. After discontinuation of therapy, BSAP concentrations returned toward baseline. The increases in formation markers were accompanied by secondary increases in the markers of bone resorption: urinary N-telopeptide (NTX) and urinary deoxypyridinoline (DPD), consistent with the physiological coupling of bone formation and resorption in skeletal remodeling. Changes in BSAP, NTX, and DPD were lower in men than in women, possibly because of lower systemic exposure to teriparatide in men.
In the study of patients with glucocorticoid-induced osteoporosis, the effects of teriparatide on serum markers of bone turnover were similar to those observed in postmenopausal women with osteoporosis not taking glucocorticoids.
## Pharmacokinetics
Teriparatide is absorbed after subcutaneous injection; the absolute bioavailability is approximately 95% based on pooled data from 20-, 40-, and 80- mcg doses. The rates of absorption and elimination are rapid. The peptide reaches peak serum concentrations about 30 minutes after subcutaneous injection of a 20-mcg dose and declines to non-quantifiable concentrations within 3 hours.
Systemic clearance of teriparatide (approximately 62 L/hr in women and 94 L/hr in men) exceeds the rate of normal liver plasma flow, consistent with both hepatic and extra-hepatic clearance. Volume of distribution, following intravenous injection, is approximately 0.12 L/kg. Intersubject variability in systemic clearance and volume of distribution is 25% to 50%. The half-life of teriparatide in serum is 5 minutes when administered by intravenous injection and approximately 1 hour when administered by subcutaneous injection. The longer half-life following subcutaneous administration reflects the time required for absorption from the injection site.
No metabolism or excretion studies have been performed with teriparatide. However, the mechanisms of metabolism and elimination of PTH(1-34) and intact PTH have been extensively described in published literature. Peripheral metabolism of PTH is believed to occur by non-specific enzymatic mechanisms in the liver followed by excretion via the kidneys.
## Nonclinical Toxicology
Two carcinogenicity bioassays were conducted in Fischer 344 rats. In the first study, male and female rats were given daily subcutaneous teriparatide injections of 5, 30, or 75 mcg/kg/day for 24 months from 2 months of age. These doses resulted in systemic exposures that were, respectively, 3, 20, and 60 times higher than the systemic exposure observed in humans following a subcutaneous dose of 20 mcg (based on AUC comparison). Teriparatide treatment resulted in a marked dose-related increase in the incidence of osteosarcoma, a rare malignant bone tumor, in both male and female rats. Osteosarcomas were observed at all doses and the incidence reached 40% to 50% in the high-dose groups. Teriparatide also caused a dose-related increase in osteoblastoma and osteoma in both sexes. No osteosarcomas, osteoblastomas or osteomas were observed in untreated control rats. The bone tumors in rats occurred in association with a large increase in bone mass and focal osteoblast hyperplasia.
The second 2-year study was carried out in order to determine the effect of treatment duration and animal age on the development of bone tumors. Female rats were treated for different periods between 2 and 26 months of age with subcutaneous doses of 5 and 30 mcg/kg (equivalent to 3 and 20 times the human exposure at the 20-mcg dose, based on AUC comparison). The study showed that the occurrence of osteosarcoma, osteoblastoma and osteoma was dependent upon dose and duration of exposure. Bone tumors were observed when immature 2-month old rats were treated with 30 mcg/kg/day for 24 months or with 5 or 30 mcg/kg/day for 6 months. Bone tumors were also observed when mature 6-month old rats were treated with 30 mcg/kg/day for 6 or 20 months. Tumors were not detected when mature 6-month old rats were treated with 5 mcg/kg/day for 6 or 20 months. The results did not demonstrate a difference in susceptibility to bone tumor formation, associated with teriparatide treatment, between mature and immature rats.
The relevance of these animal findings to humans is uncertain.
Teriparatide was not genotoxic in any of the following test systems: the Ames test for bacterial mutagenesis; the mouse lymphoma assay for mammalian cell mutation; the chromosomal aberration assay in Chinese hamster ovary cells, with and without metabolic activation; and the in vivo micronucleus test in mice.
In single-dose rodent studies using subcutaneous injection of teriparatide, no mortality was seen in rats given doses of 1000 mcg/kg (540 times the human dose based on surface area, mcg/m2) or in mice given 10,000 mcg/kg (2700 times the human dose based on surface area, mcg/m2).
In a long-term study, skeletally mature ovariectomized female monkeys (N=30 per treatment group) were given either daily subcutaneous teriparatide injections of 5 mcg/kg or vehicle. Following the 18-month treatment period, the monkeys were removed from teriparatide treatment and were observed for an additional 3 years. The 5 mcg/kg dose resulted in systemic exposures that were approximately 6 times higher than the systemic exposure observed in humans following a subcutaneous dose of 20 mcg (based on AUC comparison). Bone tumors were not detected by radiographic or histologic evaluation in any monkey in the study.
# Clinical Studies
### Treatment of Osteoporosis in Postmenopausal Women
The safety and efficacy of once-daily teriparatide, median exposure of 19 months, were examined in a double-blind, multicenter, placebo-controlled clinical study of 1637 postmenopausal women with osteoporosis (teriparatide 20 mcg, n=541).
All women received 1000 mg of calcium and at least 400 IU of vitamin D per day. Baseline and endpoint spinal radiographs were evaluated using the semiquantitative scoring. Ninety percent of the women in the study had 1 or more radiographically diagnosed vertebral fractures at baseline. The primary efficacy endpoint was the occurrence of new radiographically diagnosed vertebral fractures defined as changes in the height of previously undeformed vertebrae. Such fractures are not necessarily symptomatic.
New Vertebral Fractures: teriparatide, when taken with calcium and vitamin D and compared with calcium and vitamin D alone, reduced the risk of 1 or more new vertebral fractures from 14.3% of women in the placebo group to 5.0% in the teriparatide group. This difference was statistically significant (p<0.001); the absolute reduction in risk was 9.3% and the relative reduction was 65%. teriparatide was effective in reducing the risk for vertebral fractures regardless of age, baseline rate of bone turnover, or baseline BMD.
New Nonvertebral Osteoporotic Fractures: teriparatide significantly reduced the risk of any nonvertebral fracture from 5.5% in the placebo group to 2.6% in the teriparatide group (p<0.05). The absolute reduction in risk was 2.9% and the relative reduction was 53%. The incidence of new nonvertebral fractures in the teriparatide group compared with the placebo group was ankle/foot (0.2%, 0.7%), hip (0.2%, 0.7%), humerus (0.4%, 0.4%), pelvis (0%, 0.6%), ribs (0.6%, 0.9%), wrist (0.4%, 1.3%), and other sites (1.1%, 1.5%), respectively.
The cumulative percentage of postmenopausal women with osteoporosis who sustained new nonvertebral fractures was lower in women treated with teriparatide than in women treated with placebo (see FIGURE 1).
teriparatide increased lumbar spine BMD in postmenopausal women with osteoporosis. Statistically significant increases were seen at 3 months and continued throughout the treatment period. Postmenopausal women with osteoporosis who were treated with teriparatide had statistically significant increases in BMD from baseline to endpoint at the lumbar spine, femoral neck, total hip, and total body.
teriparatide treatment increased lumbar spine BMD from baseline in 96% of postmenopausal women treated. Seventy-two percent of patients treated with teriparatide achieved at least a 5% increase in spine BMD, and 44% gained 10% or more.
Both treatment groups lost height during the trial. The mean decreases were 3.61 and 2.81 mm in the placebo and teriparatide groups, respectively.
The effects of teriparatide on bone histology were evaluated in iliac crest biopsies of 35 postmenopausal women treated for 12 to 24 months with calcium and vitamin D and teriparatide 20 or 40 mcg/day. Normal mineralization was observed with no evidence of cellular toxicity. The new bone formed with teriparatide was of normal quality (as evidenced by the absence of woven bone and marrow fibrosis).
### Treatment to Increase Bone Mass in Men with Primary or Hypogonadal Osteoporosis
The safety and efficacy of once-daily teriparatide, median exposure of 10 months, were examined in a double-blind, multicenter, placebo-controlled clinical study of 437 men with either primary (idiopathic) or hypogonadal osteoporosis (teriparatide 20 mcg, n=151). All men received 1000 mg of calcium and at least 400 IU of vitamin D per day. The primary efficacy endpoint was change in lumbar spine BMD.
teriparatide increased lumbar spine BMD in men with primary or hypogonadal osteoporosis. Statistically significant increases were seen at 3 months and continued throughout the treatment period. teriparatide was effective in increasing lumbar spine BMD regardless of age, baseline rate of bone turnover, and baseline BMD. The effects of teriparatide at additional skeletal sites are shown in TABLE 4.
teriparatide treatment for a median of 10 months increased lumbar spine BMD from baseline in 94% of men treated. Fifty-three percent of patients treated with teriparatide achieved at least a 5% increase in spine BMD, and 14% gained 10% or more.
### Treatment of Men and Women with Glucocorticoid-Induced Osteoporosis
The efficacy of teriparatide for treating glucocorticoid-induced osteoporosis was assessed in a randomized, double-blind, active-controlled trial of 428 patients (19% men, 81% women) aged 22 to 89 years (mean 57 years) treated with ≥5 mg/day prednisone or equivalent for a minimum of 3 months. The duration of the trial was 18 months with 214 patients exposed to teriparatide. In the teriparatide group, the baseline median glucocorticoid dose was 7.5 mg/day and the median duration of glucocorticoid use was 1.5 years. The mean (SD) baseline lumbar spine BMD was 0.85 ± 0.13 g/cm2 and lumbar spine BMD T-score was –2.5 ± 1 (number of standard deviations below the mean BMD value for healthy adults). A total of 30% of patients had prevalent vertebral fracture(s) and 43% had prior non-vertebral fracture(s). The patients had chronic rheumatologic, respiratory or other diseases that required sustained glucocorticoid therapy. All patients received 1000 mg of calcium plus 800 IU of vitamin D supplementation per day.
Because of differences in mechanism of action (anabolic vs. anti-resorptive) and lack of clarity regarding differences in BMD as an adequate predictor of fracture efficacy, data on the active comparator are not presented.
In patients with glucocorticoid-induced osteoporosis, teriparatide increased lumbar spine BMD compared with baseline at 3 months through 18 months of treatment. In patients treated with teriparatide, the mean percent change in BMD from baseline to endpoint was 7.2% at the lumbar spine, 3.6% at the total hip, and 3.7% at the femoral neck (p<0.001 all sites). The relative treatment effects of teriparatide were consistent in subgroups defined by gender, age, geographic region, body mass index, underlying disease, prevalent vertebral fracture, baseline glucocorticoid dose, prior bisphosphonate use, and glucocorticoid discontinuation during trial.
# How Supplied
Teripatide delivery device (pen) is available in the following package size:
- 2.4 mL prefilled delivery device NDC 0002-8400-01 (MS8400).
## Storage
Store at 2° to 8°C (36° to 46°F)
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
### Potential Risk of Osteosarcoma and Voluntary teriparatide Patient Registry
Patients should be made aware that in rats, teriparatide caused an increase in the incidence of osteosarcoma (a malignant bone tumor) that was dependent on dose and treatment duration. Patients should be encouraged to enroll in the voluntary teriparatide Patient Registry, which is designed to collect information about any potential risk of osteosarcoma in patients who have taken teriparatide.
### Orthostatic Hypotension
teriparatide should be administered initially under circumstances where the patient can immediately sit or lie down if symptoms occur. Patients should be instructed that if they feel lightheaded or have palpitations after the injection, they should sit or lie down until the symptoms resolve. If symptoms persist or worsen, patients should be instructed to consult a physician before continuing treatment.
### Hypercalcemia
Although symptomatic hypercalcemia was not observed in clinical trials, physicians should instruct patients taking teriparatide to contact a health care provider if they develop persistent symptoms of hypercalcemia (e.g., nausea, vomiting, constipation, lethargy, muscle weakness).
### Other Osteoporosis Treatment Modalities
Patients should be informed regarding the roles of supplemental calcium and/or vitamin D, weight-bearing exercise, and modification of certain behavioral factors such as cigarette smoking and/or alcohol consumption.
### Use of Delivery Device (Pen)
Patients and caregivers who administer teriparatide should be instructed on how to properly use the delivery device (refer to User Manual), properly dispose of needles, and be advised not to share their delivery device with other patients. The contents of the delivery device should NOT be transferred to a syringe.
Each teriparatide delivery device can be used for up to 28 days including the first injection from the delivery device. After the 28-day use period, discard the teriparatide delivery device, even if it still contains some unused solution.
### Availability of Medication Guide and User Manual
Patients should read the Medication Guide and delivery device (pen) User Manual before starting therapy with teriparatide and re-read them each time the prescription is renewed. Patients need to understand and follow the instructions in the teriparatide delivery device User Manual. Failure to do so may result in inaccurate dosing.
# Precautions with Alcohol
Alcohol-Teriparatide interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Forteo [1]
# Look-Alike Drug Names
There is limited information regarding Teriparatide Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Forteo | |
9f906b4fcabf68359f536dbaf1a5900f679c9a37 | wikidoc | Fostamatinib | Fostamatinib
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# Overview
Fostamatinib is a tyrosine kinase inhibitor that is FDA approved for the treatment of chronic immune thrombocytopenia (ITP) in adults who have had an insufficient response to a previous treatment. Common adverse reactions include diarrhea, hypertension, nausea, respiratory infection, dizziness, ALT/AST increased, rash, abdominal pain, fatigue, chest pain and neutropenia.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Fostamatinib is indicated for the treatment of thrombocytopenia in adult patients with chronic immune thrombocytopenia (ITP) who have had an insufficient response to a previous treatment.
- Initiate fostamatinib at a dose of 100 mg taken orally twice daily. After a month, if platelet count has not increased to at least 50 × 109/L, increase fostamatinib dose to 150 mg twice daily.
- Use the lowest dose of fostamatinib to achieve and maintain a platelet count at least 50 × 109/L as necessary to reduce the risk of bleeding.
- Fostamatinib may be taken with or without food. In the case of a missed dose of fostamatinib, instruct patients to take their next dose at its regularly scheduled time.
- Fostamatinib dose modification is recommended based on individual safety and tolerability. Management of some adverse reactions may require dose-interruption, reduction, or discontinuation.
- A dose reduction schedule is provided in Table 1, based on daily dose. For example, if a patient is on the maximum dose at the time of an adverse reaction, the first dose reduction would be from 300 mg/day to 200 mg/day.
- The recommended dose modifications for adverse reactions are provided in Table 2.
- Concomitant use with a strong CYP3A4 inhibitor increases exposure to R406 (the major active metabolite). Monitor for toxicities of fostamatinib that may require fostamatinib dose modifications (see TABLE 1) when given concurrently with a strong CYP3A4 inhibitor
- Discontinue fostamatinib after 12 weeks of treatment if the platelet count does not increase to a level sufficient to avoid clinically important bleeding.
- Fostamatinib is available as:
- 100 mg tablet: orange, film-coated, round, biconvex tablets debossed with "100" on one side and "R" on the reverse side.
- 150 mg tablet: orange, film-coated, oval, biconvex tablets debossed with "150" on one side and "R" on the reverse side.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding fostamatinib Off-Label Guideline-Supported Use and Dosage (Adult) in the drug label.
### Non–Guideline-Supported Use
There is limited information regarding fostamatinib 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 Fostamatinib FDA-Labeled Indications and Dosage (Pediatric) in the drug label.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding fostamatinib Off-Label Guideline-Supported Use and Dosage (Pediatric) in the drug label.
### Non–Guideline-Supported Use
There is limited information regarding fostamatinib Off-Label Non-Guideline-Supported Use and Dosage (Pediatric) in the drug label.
# Contraindications
- None.
# Warnings
- Hypertension can occur with fostamatinib treatment; hypertensive crisis occurred in 1% of patients. Patients with pre-existing hypertension may be more susceptible to the hypertensive effects of fostamatinib.
- Monitor blood pressure every 2 weeks until stable, then monthly and adjust or initiate antihypertensive therapy to ensure maintenance of blood pressure control during fostamatinib therapy. If increased blood pressure persists despite appropriate therapy, fostamatinib interruption, reduction or discontinuation may be necessary.
- Elevated liver function tests (LFTs), mainly ALT and AST, can occur with fostamatinib.
- In the placebo-controlled studies, laboratory testing showed maximum ALT/AST levels more than 3 × the upper limit of normal (ULN) in 9% of patients receiving fostamatinib. For most patients, transaminases recovered to baseline levels within 2 to 6 weeks of dose-modification.
- Monitor liver function tests monthly during treatment. If ALT or AST increase more than 3 × ULN, manage hepatotoxicity using fostamatinib interruption, reduction, or discontinuation.
- Diarrhea occurred in 31% of patients treated with fostamatinib. Severe diarrhea occurred in 1% of patients treated with fostamatinib. Monitor patients for the development of diarrhea. Manage diarrhea using supportive care measures, including dietary changes, hydration and/or antidiarrheal medication, early after the onset of symptoms. Interrupt, dose reduce, or discontinue fostamatinib if diarrhea becomes severe (Grade 3 or above).
- Neutropenia occurred in 6% of patients treated with fostamatinib; febrile neutropenia occurred in 1% of patients.
- Monitor the ANC monthly, and for infection during treatment. Manage toxicity with fostamatinib interruption, reduction or discontinuation.
- Based on findings from animal studies and its mechanism of action, fostamatinib can cause fetal harm when administered to a pregnant woman. In animal reproduction studies, administration of fostamatinib to pregnant rats and rabbits during organogenesis caused adverse developmental outcomes including embryo-fetal mortality (post-implantation loss), alterations to growth (lower fetal weights), and structural abnormalities (variations and malformations) at maternal exposures (AUCs) approximately 0.3 and 10 times the human exposure at the maximum recommended human dose (MRHD), respectively. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment and for at least 1 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.
- Fostamatinib was studied in two randomized, double-blind, placebo-controlled trials that were identical in design. The data described below reflect exposure to fostamatinib in 102 patients with chronic ITP who had received one or more prior ITP treatment(s). Groups were stratified with respect to splenectomy and severity of thrombocytopenia. Patients randomized to the fostamatinib arm received 100 mg orally twice daily. Based upon platelet count and tolerability, if a patient's platelet count did not increase to at least 50 × 109/L, the fostamatinib dose could be increased to 150 mg twice daily after one month. In the placebo controlled studies, the median duration of fostamatinib exposure in these studies was 86 days (range 8 to 183).
- In the ITP double-blind studies, serious adverse drug reactions were febrile neutropenia, diarrhea, pneumonia, and hypertensive crisis, which each occurred in 1% of patients receiving fostamatinib. In addition, severe adverse reactions observed in patients receiving fostamatinib included dyspnea and hypertension (both 2%); and neutropenia, arthralgia, chest pain, diarrhea, dizziness, nephrolithiasis, pain in extremity, toothache, syncope and hypoxia (all 1%). Table 3 presents the common adverse reactions from these studies.
## Postmarketing Experience
There is limited information regarding Fostamatinib Postmarketing Experience in the drug label.
# Drug Interactions
- Strong CYP3A4 Inhibitors
- Strong CYP3A4 Inducers
- Concomitant use with strong CYP3A4 inhibitors increases exposure to R406 (the major active metabolite), which may increase the risk of adverse reactions. Monitor for toxicities of fostamatinib that may require dose reduction when given concurrently with a strong CYP3A4 inhibitor.
- Concomitant use with a strong CYP3A4 inducer reduces exposure to R406. Concomitant use of fostamatinib with strong CYP3A4 inducers is not recommended.
- CYP3A4 Substrates
- BCRP Substrates
- P-Glycoprotein (P-gp) Substrates
- Concomitant use of fostamatinib may increase concentrations of some CYP3A4 substrate drugs. Monitor for toxicities of CYP3A4 substrate drug that may require dosage reduction when given concurrently with fostamatinib.
- Concomitant use of fostamatinib may increase concentrations of BCRP substrate drugs (e.g., rosuvastatin). Monitor for toxicities of BCRP substrate drug that may require dosage reduction when given concurrently with fostamatinib
- Concomitant use of fostamatinib may increase concentrations of P-gp substrates (e.g., digoxin). Monitor for toxicities of the P-gp substrate drug that may require dosage reduction when given concurrently with fostamatinib
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
- Based on findings from animal studies and the mechanism of action, fostamatinib can cause fetal harm when administered to a pregnant woman.
- There are no available data in pregnant women to inform the drug-associated risk. In animal reproduction studies, administration of fostamatinib to pregnant rats and rabbits during organogenesis caused adverse developmental outcomes that were directly attributed to exposure in utero to the major fostamatinib metabolite (R406) at maternal exposures (AUC) as low as 0.3 and 10 times the exposure in patients at the maximum recommended human dose (MRHD), respectively. Advise pregnant women of the potential risk to a fetus.
- 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. An estimated background risk of major birth defects and miscarriage for the chronic ITP population is 8% and 4-11%, respectively.
- In a fertility and early embryonic development study in female rats, fostamatinib was administered orally for 15 days before mating to Day 7 of pregnancy, which caused a slight decrease in pregnancy rates and an increase in post-implantation loss were seen at maternal doses approximately 4.2 times the dose in patients at the MRHD.
- In embryo-fetal development studies, pregnant animals were orally administered fostamatinib during the period of organogenesis at doses up to 25 and 50 mg/kg/day in rats and rabbits, respectively. The adverse developmental outcomes included an increase in embryo-fetal mortality (post-implantation loss), alterations to growth (lower fetal weights), and structural abnormalities (variations and malformations). These effects occurred at maternal exposures (AUCs) of 3,763 ng.h/mL in rats and 111,105 ng.h/mL in rabbits that were approximately 0.3 and 10 times the human exposure at the MRHD in rats and rabbits, respectively.
- In a peri and postnatal development study in rats, fostamatinib was orally administered at doses of 2.5, 12.5, and 25 mg/kg/day from gestation day 7 until lactation day 20. The dose of 25 mg/kg/day was associated with maternal toxicity, including decreased body weights, body weight gains, and food consumption. At doses as low as 12.5 mg/kg/day fostamatinib caused increases in newborn mortality (neonatal mortality), alterations in growth and/or development (lower neonatal weights into post-weaning and structural abnormalities ). Functional impairment (delayed sexual maturation) was observed at 25 mg/kg/day. There was no evidence of neurobehavioral defects (maze learning and shuttle box avoidance) or immunological compromise (influenza host resistance challenge) in the F1 generation or latent untoward effects in the F2 generation. The maternal doses were approximately 2.1 and 4.2 times the MHRD in patients.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Fostamatinib in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Fostamatinib during labor and delivery.
### Nursing Mothers
- There are no data on the presence of fostamatinib and/or its metabolites in human milk, the effects on the breastfed child, or on milk production. In rodents, R406 (the major active metabolite) was detected in maternal milk in concentrations 5- to 10-fold higher than in maternal plasma. Because of the potential for serious adverse reactions in a breastfed child from fostamatinib, advise a lactating woman not to breastfeed during treatment with fostamatinib and for at least 1 month after the last dose.
### Pediatric Use
- Safety and effectiveness in pediatric patients have not been established. fostamatinib is not recommended for use in patients less than 18 years of age because adverse effects on actively growing bones were observed in nonclinical studies. In subchronic, chronic, and carcinogenicity studies of fostamatinib, chondrodystrophy of the femoral head was seen in rodents. In a study in juvenile rabbits, growth plate dysplasia was observed in the proximal femur and femoro-tibial joint, and bone marrow cellularity was reduced in the femur and sternum.
### Geriatic Use
- Of the 102 patients with ITP who received fostamatinib, 28 (27%) were 65 years of age and older, while 11 (11%) were 75 years of age and older. In patients 65 years of age and older, 6 (21%) patients experienced serious adverse events and 5 (18%) experienced adverse events leading to treatment withdrawal while in patients under 65 years of age, 7 (9%) and 5 (7%) experienced serious adverse events and adverse events leading to treatment withdrawal, respectively. In patients 65 years of age and older who received fostamatinib, 11 (39%) patients experienced hypertension versus 2 (18%) placebo compared to 17 (23%) in patients under 65 of age versus 4 (11%) placebo. No overall differences in effectiveness were observed in these patients compared to younger patients.
### Gender
There is no FDA guidance on the use of Fostamatinib with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Fostamatinib with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Fostamatinib in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Fostamatinib in patients with hepatic impairment.
### Females of Reproductive Potential and Males
- Based on animal studies, fostamatinib can cause fetal harm when administered to a pregnant woman. For females of reproductive potential, verify pregnancy status prior to initiating fostamatinib.
Females
- Based on animal studies, fostamatinib can cause fetal harm when administered to a pregnant woman. Advise females of reproductive potential to use effective contraception during treatment with fostamatinib and for at least 1 month after the last dose.
- There are no data on the effect of fostamatinib on human fertility. Based on the finding of reduced pregnancy rates in animal studies, fostamatinib may affect female fertility
### Immunocompromised Patients
There is no FDA guidance one the use of Fostamatinib in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Oral
### Monitoring
- After obtaining baseline assessments:
- Monitor CBCs, including platelet counts, monthly until a stable platelet count (at least 50 × 109/L) is achieved. Thereafter, continue to monitor CBCs, including neutrophils, regularly.
- Monitor liver function tests (LFTs) (e.g., ALT, AST, and bilirubin) monthly.
- Monitor blood pressure every 2 weeks until establishment of a stable dose, then monthly thereafter.
# IV Compatibility
There is limited information regarding the compatibility of Fostamatinib and IV administrations.
# Overdosage
- There is no specific antidote for overdose with fostamatinib, and the amount of R406 (the pharmacologically active metabolite of fostamatinib) cleared by dialysis is negligible. In the event of an overdose, monitor patient closely for signs and symptoms of adverse reactions, and treat the reactions with supportive care.
# Pharmacology
## Mechanism of Action
- Fostamatinib is a tyrosine kinase inhibitor with demonstrated activity against spleen tyrosine kinase (SYK). The major metabolite of fostamatinib, R406, inhibits signal transduction of Fc-activating receptors and B-cell receptor. The fostamatinib metabolite R406 reduces antibody-mediated destruction of platelets.
## Structure
## Pharmacodynamics
- Mean treatment-related increases of 2.93 mmHg in systolic blood pressure and 3.53 mmHg in diastolic blood pressure over placebo were observed following fostamatinib doses of 100 mg twice daily for 28 days. About 31% of patients in the fostamatinib group experienced blood pressures ≥140/90 mmHg compared to 15% of patients in the placebo group. Blood pressure returned to baseline within 1 week following fostamatinib discontinuation in 58% (11 of 19) of patients in the fostamatinib group who had blood pressures ≥140/90 mmHg.
- At 2 times the maximum recommended dose, fostamatinib did not prolong the QT interval to a clinically relevant extent.
## Pharmacokinetics
- Fostamatinib is a prodrug that is converted in the gut to the major active metabolite, R406. Mean (± standard deviation ) exposure estimates of R406 are 550 (± 270) ng/mL for Cmax and 7080 (± 2670) ng∙h/mL for AUC. R406 exposure is approximately dose proportional up to 200 mg twice daily (1.3 times the 150 mg dosage). R406 accumulates approximately 2- to 3-fold upon twice daily dosing at 100–160 mg (0.67 to 1.06 times the 150 mg dosage).
Effect of Food
- Administration of fostamatinib with a high-calorie, high-fat meal (deriving approximately 150, 250, and 500–600 calories from protein, carbohydrate, and fat, respectively) increased R406 AUC by 23% and Cmax by 15%
- In in vitro studies, the R406 is 98.3% protein bound in human plasma. The red blood cell to plasma concentration ratio is approximately 2.6. The mean (± SD) volume of distribution at steady-state of R406 is 256 (± 92) L.
- The mean (± SD) terminal half-life of R406 is approximately 15 (± 4.3) hours.
Metabolism
- Fostamatinib is metabolized in the gut by alkaline phosphatase to the major active metabolite, R406. R406 is extensively metabolized, primarily through pathways of CYP450-mediated oxidation (by CYP3A4) and glucuronidation (by UDP glucuronosyltransferase 1A9). R406 is the predominant moiety in the systemic circulation, and there was minimal exposure to any R406 metabolites.
Excretion
- Following an oral dose of fostamatinib, approximately 80% of the R406 metabolite is excreted in feces with approximately 20% excreted in the urine. The major component excreted in urine was R406 N-glucuronide. The major components excreted in feces were R406, O-desmethyl R406 and a metabolite produced by gut bacteria from the O-desmethyl metabolite of R406.
- Population pharmacokinetics analyses indicate fostamatinib is not altered based on age, sex, race/ethnicity. In addition, the pharmacokinetics of fostamatinib is not altered in patients with renal impairment (creatinine clearance ≥ 30 to < 50 mL/min, estimated by Cockcroft Gault equation and end stage renal disease requiring dialysis), or hepatic impairment (Child-Pugh Class A, B and C).
- Clinical Pharmacology Studies
- No significant interactions were seen with concomitant use of fostamatinib with the following drugs: methotrexate (OAT1/3 transporters), midazolam (CYP3A4 substrate), microgynon (ethinyl estradiol and levonorgestrel), warfarin, pioglitazone (CYP2C8 substrate) and ranitidine (H2-antagonist that increases gastric pH).
Effect of Other Drugs on Fostamatinib
- Strong CYP3A4 inhibitor: Concomitant use of ketoconazole (200 mg twice daily for 3.5 days) with a single dose of 80 mg fostamatinib (0.53 times the 150 mg dosage) increased R406 AUC by 102% and Cmax by 37%.
- Moderate CYP3A4 Inhibitor: Concomitant use of verapamil (80 mg three times daily for 4 days) with a single dose of 150 mg fostamatinib increased R406 AUC by 39% and Cmax by 6%.
- CYP3A4 inducer: Concomitant use of rifampicin (600 mg once daily for 8 days) with a single dose of 150 mg fostamatinib decreased R406 AUC by 75% and Cmax by 59%.
Effect of Fostamatinib on Other Drugs
- CYP3A4 substrate: Concomitant use of simvastatin (single dose 40 mg) with 100 mg twice daily fostamatinib increased simvastatin AUC by 64% and Cmax by 113% and simvastatin acid AUC by 64% and Cmax by 83%.
- BCRP substrate: Concomitant use of rosuvastatin (single dose 20 mg) with 100 mg twice daily fostamatinib increased rosuvastatin AUC by 95% and Cmax by 88%.
- P-gp substrate: Concomitant use of digoxin (0.25 mg once daily) with 100 mg twice daily fostamatinib increased digoxin AUC by 37% and Cmax by 70%.
- Fostamatinib is an inhibitor of the human P-gp efflux transporter in vitro.
- CYP3A4 and UGT1A9 are involved in the metabolism of R406. R406 is a substrate of P-gp but not of other major transporters (OAT1/3, OCT2, OATP1B1/3, MRP2, and BCRP). R406 can inhibit CYP3A4 and BCRP, and can induce CYP2C8 activity.
- R406 is an inhibitor of UGT1A1. Inhibition of UGT1A1 may result in increased unconjugated bilirubin in the absence of other LFT abnormalities.
## Nonclinical Toxicology
- Fostamatinib was not carcinogenic in a 2-year study in mice when administered daily by oral gavage at doses up to 500/250 mg/kg/day, and was not carcinogenic in rats when administered by oral gavage at 45 mg/kg/day.
- Fostamatinib and its major active metabolite (R406) were not mutagenic in an in vitro bacterial reverse mutation (Ames) assay or clastogenic in an in vitro human lymphocyte chromosomal aberration assay or an in vivo mouse bone marrow micronucleus assay.
- In a fertility study with oral fostamatinib, all mating (e.g., time to mating, breeding proficiency), sperm assessments (e.g., number and motility), and organ weight (e.g., paired testis weight) parameters in male rats were unaffected by dosages as high as 40 mg/kg/day, which is 6.7 times the MRHD. All mating and fertility parameters in female rats were unaffected by dosages as high as 11 mg/kg/day (which is 1.8 times the MRHD), but a slight decrease in pregnancy rates and an increase in post-implantation loss were seen at 25 mg/kg/day, which is 4.2 times the MRHD.
# Clinical Studies
- Fostamitinib was studied in two placebo-controlled efficacy and safety studies (referred to as FIT-1 and FIT-2 ), and in an open-label extension study referred to as FIT-3 (NCT 02077192).
- A total of 150 patients with persistent or chronic ITP, who had an insufficient response to previous treatment (which included corticosteroids, immunoglobulins, splenectomy, and/or a thrombopoietin receptor agonists) were enrolled in two identical, double-blind, placebo-controlled studies that were conducted in different countries. For each study, patients were randomized 2:1 to fostamatinib or placebo for 24 weeks; randomization was stratified with respect to prior splenectomy and severity of thrombocytopenia. Stable concurrent ITP therapy (glucocorticoids , azathioprine, or danazol) was allowed, and rescue therapy was permitted, if needed. All patients initially received study drug at 100 mg twice daily (or matching placebo). Based on platelet count and tolerability, dose escalation to 150 mg twice daily (or matching placebo) was undertaken in 88% of patients at Week 4 or later. Patients who did not respond to treatment after 12 weeks, as well as patients who completed the 24-week double blind study, were eligible to enroll in open-label extension study (FIT-3).
- Patients enrolled in the placebo-controlled studies had a median age of 54 years (range: 20 to 88), and the majority were female (61%) and were White (93%). Prior ITP treatments were varied, with the most common including corticosteroids (94%), immunoglobulins (53%), and thrombopoietin receptor agonists (TPO-RA) (48%). Most patients had chronic ITP (93%), with a median time since ITP diagnosis of 8.45 years, and 35% had undergone splenectomy. At baseline, the median platelet count was 16 × 109/L (with almost half %) less than 15 × 109/L) and 47% were on stable ITP therapy.
- In Study FIT-1, 76 patients were randomized; 51 to the fostamatinib group and 25 to the placebo group. In Study FIT-2, 74 patients were randomized; 50 to the fostamatinib group and 24 to the placebo group. The efficacy of fostamatinib was based on stable platelet response (at least 50 ×109/L on at least 4 of the 6 visits between Weeks 14 to 24). Study outcomes for FIT-1 and FIT-2 are shown in Table 5.
- In the FIT-1 and FIT-2 studies a total of 47 patients in the fostamatinib arm had received a prior TPO-RA treatment; among these patients, 8 patients (17%) achieved a stable response to fostamatinib. All 8 patients had previously discontinued TPO-RA due to loss of effect. Rescue medication was required by 30% and 45% of patients receiving fostamatinib or placebo, respectively.
- During the placebo-controlled studies, the incidence of bleeding occurred in 29% and 37% of patients in the fostamatinib and placebo arms, respectively. Moderate, severe and serious bleeding events are described in Table 6. All severe events led to hospitalizations.
- The FIT-3 trial is an open label extension study. Patients from FIT-1 and FIT-2 who completed 24 weeks of treatment, or who did not respond to treatment any time after 12 weeks, were eligible to enroll in this study. Patients remained blinded to their treatment assignment from the previous study (fostamatinib or placebo), so their starting dose in this study was based on their final platelet count. Patients designated as responders (defined as achievement of platelet count of at least 50 × 109/L) at the time of roll over continued in the extension study at their current trial dose and regimen. Patients who entered the extension study as non-responders (defined as platelet count less than 50 × 109/L) received fostamatinib 100 mg twice daily regardless of their dose and regimen in the prior study.
- For the FIT-3 trial, 123 patients were enrolled, 44 patients previously randomized to placebo and 79 patients previously randomized to fostamatinib. Stable response in this study was prospectively defined as no 2 visits, at least 4 weeks apart, with a platelet count less than 50 × 109/L, without an intervening visit with a platelet count of at least 50 × 109/L (unrelated to rescue therapy), within a period of 12 weeks following initial achievement of the target platelet count. Sixty-one of the 123 subjects (50%) have discontinued from the study early.
- In a prospectively defined analysis, the 44 subjects treated with placebo in the prior study were evaluated for stable response for fostamatinib. Ten of these subjects (23%) (including a single subject who was classified as a placebo responder in the prior study) met the criteria for stable response.
- Among the subjects who achieved stable response in FIT-1, FIT-2 and FIT-3 trials, 18 subjects maintained the platelet count of at least 50 × 109/L for 12 months or longer.
# How Supplied
- Fostamatinib 100 mg tablets are round, biconvex, orange, film-coated tablets debossed with "100" on one side and "R" on the reverse side.
- Fostamatinib 150 mg tablets are oval, biconvex, orange, film-coated tablets debossed with "150" on one side and "R" on the reverse side.
## Storage
- Store at room temperature, 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C to 30°C (59°F to 86°F) . Do not remove desiccants.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- Advise the patient to read the FDA-approved patient labeling.
- Hypertension: Inform patients that periodic monitoring of their blood pressure is required, as high blood pressure has occurred in patients taking fostamatinib. Inform patients of the signs and symptoms of hypertension. Advise patients to undergo routine blood pressure monitoring and to contact their health care provider if blood pressure is elevated or if they experience signs or symptoms of hypertension.
- Hepatotoxicity: Inform patients that periodic monitoring of their liver enzymes is required, and any elevations (which may indicate liver injury) will be managed appropriately, including interruption, reduction, or discontinuation of fostamatinib.
- Diarrhea: Advise patients to use supportive care measures, and if diarrhea becomes severe, it may necessitate interruption, reduction, or discontinuation of fostamatinib.
- Neutropenia: Inform patients that monitoring of their complete blood counts is required, and a decrease in neutrophils may necessitate interruption, reduction, or discontinuation of fostamatinib.
- Advise patients to inform their healthcare providers of all their medications, including prescription medicines, over-the-counter drugs, vitamins, and herbal products.
- Embryo-Fetal Toxicity: Advise females to inform their healthcare provider if they are pregnant or become pregnant. Inform female patients of the potential risk to a fetus.
- Advise females of reproductive potential to use effective contraception during treatment and for at least 1 month after receiving the last dose of fostamatinib.
- Lactation: Advise lactating women not to breastfeed during treatment with fostamatinib and for at least 1 month after the last dose.
- Inform patients that fostamatinib may be taken with or without food. In the case of a missed dose of fostamatinib, instruct patients to take their next dose at its regularly scheduled time.
# Precautions with Alcohol
Alcohol-Fostamatinib interaction has not been established. Talk to your doctor regarding the effects of taking alcohol with this medication.
# Brand Names
- Tavalisse
# Look-Alike Drug Names
There is limited information regarding Fostamatinib Look-Alike Drug Names in the drug label.
# Drug Shortage Status
Drug Shortage
# Price | Fostamatinib
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Sonya Gelfand
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# Overview
Fostamatinib is a tyrosine kinase inhibitor that is FDA approved for the treatment of chronic immune thrombocytopenia (ITP) in adults who have had an insufficient response to a previous treatment. Common adverse reactions include diarrhea, hypertension, nausea, respiratory infection, dizziness, ALT/AST increased, rash, abdominal pain, fatigue, chest pain and neutropenia.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Fostamatinib is indicated for the treatment of thrombocytopenia in adult patients with chronic immune thrombocytopenia (ITP) who have had an insufficient response to a previous treatment.
- Initiate fostamatinib at a dose of 100 mg taken orally twice daily. After a month, if platelet count has not increased to at least 50 × 109/L, increase fostamatinib dose to 150 mg twice daily.
- Use the lowest dose of fostamatinib to achieve and maintain a platelet count at least 50 × 109/L as necessary to reduce the risk of bleeding.
- Fostamatinib may be taken with or without food. In the case of a missed dose of fostamatinib, instruct patients to take their next dose at its regularly scheduled time.
- Fostamatinib dose modification is recommended based on individual safety and tolerability. Management of some adverse reactions may require dose-interruption, reduction, or discontinuation.
- A dose reduction schedule is provided in Table 1, based on daily dose. For example, if a patient is on the maximum dose at the time of an adverse reaction, the first dose reduction would be from 300 mg/day to 200 mg/day.
- The recommended dose modifications for adverse reactions are provided in Table 2.
- Concomitant use with a strong CYP3A4 inhibitor increases exposure to R406 (the major active metabolite). Monitor for toxicities of fostamatinib that may require fostamatinib dose modifications (see TABLE 1) when given concurrently with a strong CYP3A4 inhibitor
- Discontinue fostamatinib after 12 weeks of treatment if the platelet count does not increase to a level sufficient to avoid clinically important bleeding.
- Fostamatinib is available as:
- 100 mg tablet: orange, film-coated, round, biconvex tablets debossed with "100" on one side and "R" on the reverse side.
- 150 mg tablet: orange, film-coated, oval, biconvex tablets debossed with "150" on one side and "R" on the reverse side.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding fostamatinib Off-Label Guideline-Supported Use and Dosage (Adult) in the drug label.
### Non–Guideline-Supported Use
There is limited information regarding fostamatinib 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 Fostamatinib FDA-Labeled Indications and Dosage (Pediatric) in the drug label.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding fostamatinib Off-Label Guideline-Supported Use and Dosage (Pediatric) in the drug label.
### Non–Guideline-Supported Use
There is limited information regarding fostamatinib Off-Label Non-Guideline-Supported Use and Dosage (Pediatric) in the drug label.
# Contraindications
- None.
# Warnings
- Hypertension can occur with fostamatinib treatment; hypertensive crisis occurred in 1% of patients. Patients with pre-existing hypertension may be more susceptible to the hypertensive effects of fostamatinib.
- Monitor blood pressure every 2 weeks until stable, then monthly and adjust or initiate antihypertensive therapy to ensure maintenance of blood pressure control during fostamatinib therapy. If increased blood pressure persists despite appropriate therapy, fostamatinib interruption, reduction or discontinuation may be necessary.
- Elevated liver function tests (LFTs), mainly ALT and AST, can occur with fostamatinib.
- In the placebo-controlled studies, laboratory testing showed maximum ALT/AST levels more than 3 × the upper limit of normal (ULN) in 9% of patients receiving fostamatinib. For most patients, transaminases recovered to baseline levels within 2 to 6 weeks of dose-modification.
- Monitor liver function tests monthly during treatment. If ALT or AST increase more than 3 × ULN, manage hepatotoxicity using fostamatinib interruption, reduction, or discontinuation.
- Diarrhea occurred in 31% of patients treated with fostamatinib. Severe diarrhea occurred in 1% of patients treated with fostamatinib. Monitor patients for the development of diarrhea. Manage diarrhea using supportive care measures, including dietary changes, hydration and/or antidiarrheal medication, early after the onset of symptoms. Interrupt, dose reduce, or discontinue fostamatinib if diarrhea becomes severe (Grade 3 or above).
- Neutropenia occurred in 6% of patients treated with fostamatinib; febrile neutropenia occurred in 1% of patients.
- Monitor the ANC monthly, and for infection during treatment. Manage toxicity with fostamatinib interruption, reduction or discontinuation.
- Based on findings from animal studies and its mechanism of action, fostamatinib can cause fetal harm when administered to a pregnant woman. In animal reproduction studies, administration of fostamatinib to pregnant rats and rabbits during organogenesis caused adverse developmental outcomes including embryo-fetal mortality (post-implantation loss), alterations to growth (lower fetal weights), and structural abnormalities (variations and malformations) at maternal exposures (AUCs) approximately 0.3 and 10 times the human exposure at the maximum recommended human dose (MRHD), respectively. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment and for at least 1 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.
- Fostamatinib was studied in two randomized, double-blind, placebo-controlled trials that were identical in design. The data described below reflect exposure to fostamatinib in 102 patients with chronic ITP who had received one or more prior ITP treatment(s). Groups were stratified with respect to splenectomy and severity of thrombocytopenia. Patients randomized to the fostamatinib arm received 100 mg orally twice daily. Based upon platelet count and tolerability, if a patient's platelet count did not increase to at least 50 × 109/L, the fostamatinib dose could be increased to 150 mg twice daily after one month. In the placebo controlled studies, the median duration of fostamatinib exposure in these studies was 86 days (range 8 to 183).
- In the ITP double-blind studies, serious adverse drug reactions were febrile neutropenia, diarrhea, pneumonia, and hypertensive crisis, which each occurred in 1% of patients receiving fostamatinib. In addition, severe adverse reactions observed in patients receiving fostamatinib included dyspnea and hypertension (both 2%); and neutropenia, arthralgia, chest pain, diarrhea, dizziness, nephrolithiasis, pain in extremity, toothache, syncope and hypoxia (all 1%). Table 3 presents the common adverse reactions from these studies.
## Postmarketing Experience
There is limited information regarding Fostamatinib Postmarketing Experience in the drug label.
# Drug Interactions
- Strong CYP3A4 Inhibitors
- Strong CYP3A4 Inducers
- Concomitant use with strong CYP3A4 inhibitors increases exposure to R406 (the major active metabolite), which may increase the risk of adverse reactions. Monitor for toxicities of fostamatinib that may require dose reduction when given concurrently with a strong CYP3A4 inhibitor.
- Concomitant use with a strong CYP3A4 inducer reduces exposure to R406. Concomitant use of fostamatinib with strong CYP3A4 inducers is not recommended.
- CYP3A4 Substrates
- BCRP Substrates
- P-Glycoprotein (P-gp) Substrates
- Concomitant use of fostamatinib may increase concentrations of some CYP3A4 substrate drugs. Monitor for toxicities of CYP3A4 substrate drug that may require dosage reduction when given concurrently with fostamatinib.
- Concomitant use of fostamatinib may increase concentrations of BCRP substrate drugs (e.g., rosuvastatin). Monitor for toxicities of BCRP substrate drug that may require dosage reduction when given concurrently with fostamatinib
- Concomitant use of fostamatinib may increase concentrations of P-gp substrates (e.g., digoxin). Monitor for toxicities of the P-gp substrate drug that may require dosage reduction when given concurrently with fostamatinib
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
- Based on findings from animal studies and the mechanism of action, fostamatinib can cause fetal harm when administered to a pregnant woman.
- There are no available data in pregnant women to inform the drug-associated risk. In animal reproduction studies, administration of fostamatinib to pregnant rats and rabbits during organogenesis caused adverse developmental outcomes that were directly attributed to exposure in utero to the major fostamatinib metabolite (R406) at maternal exposures (AUC) as low as 0.3 and 10 times the exposure in patients at the maximum recommended human dose (MRHD), respectively. Advise pregnant women of the potential risk to a fetus.
- 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. An estimated background risk of major birth defects and miscarriage for the chronic ITP population is 8% and 4-11%, respectively.
- In a fertility and early embryonic development study in female rats, fostamatinib was administered orally for 15 days before mating to Day 7 of pregnancy, which caused a slight decrease in pregnancy rates and an increase in post-implantation loss were seen at maternal doses approximately 4.2 times the dose in patients at the MRHD.
- In embryo-fetal development studies, pregnant animals were orally administered fostamatinib during the period of organogenesis at doses up to 25 and 50 mg/kg/day in rats and rabbits, respectively. The adverse developmental outcomes included an increase in embryo-fetal mortality (post-implantation loss), alterations to growth (lower fetal weights), and structural abnormalities (variations and malformations). These effects occurred at maternal exposures (AUCs) of 3,763 ng.h/mL in rats and 111,105 ng.h/mL in rabbits that were approximately 0.3 and 10 times the human exposure at the MRHD in rats and rabbits, respectively.
- In a peri and postnatal development study in rats, fostamatinib was orally administered at doses of 2.5, 12.5, and 25 mg/kg/day from gestation day 7 until lactation day 20. The dose of 25 mg/kg/day was associated with maternal toxicity, including decreased body weights, body weight gains, and food consumption. At doses as low as 12.5 mg/kg/day fostamatinib caused increases in newborn mortality (neonatal mortality), alterations in growth and/or development (lower neonatal weights into post-weaning and structural abnormalities [malformations]). Functional impairment (delayed sexual maturation) was observed at 25 mg/kg/day. There was no evidence of neurobehavioral defects (maze learning and shuttle box avoidance) or immunological compromise (influenza host resistance challenge) in the F1 generation or latent untoward effects in the F2 generation. The maternal doses were approximately 2.1 and 4.2 times the MHRD in patients.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Fostamatinib in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Fostamatinib during labor and delivery.
### Nursing Mothers
- There are no data on the presence of fostamatinib and/or its metabolites in human milk, the effects on the breastfed child, or on milk production. In rodents, R406 (the major active metabolite) was detected in maternal milk in concentrations 5- to 10-fold higher than in maternal plasma. Because of the potential for serious adverse reactions in a breastfed child from fostamatinib, advise a lactating woman not to breastfeed during treatment with fostamatinib and for at least 1 month after the last dose.
### Pediatric Use
- Safety and effectiveness in pediatric patients have not been established. fostamatinib is not recommended for use in patients less than 18 years of age because adverse effects on actively growing bones were observed in nonclinical studies. In subchronic, chronic, and carcinogenicity studies of fostamatinib, chondrodystrophy of the femoral head was seen in rodents. In a study in juvenile rabbits, growth plate dysplasia was observed in the proximal femur and femoro-tibial joint, and bone marrow cellularity was reduced in the femur and sternum.
### Geriatic Use
- Of the 102 patients with ITP who received fostamatinib, 28 (27%) were 65 years of age and older, while 11 (11%) were 75 years of age and older. In patients 65 years of age and older, 6 (21%) patients experienced serious adverse events and 5 (18%) experienced adverse events leading to treatment withdrawal while in patients under 65 years of age, 7 (9%) and 5 (7%) experienced serious adverse events and adverse events leading to treatment withdrawal, respectively. In patients 65 years of age and older who received fostamatinib, 11 (39%) patients experienced hypertension versus 2 (18%) placebo compared to 17 (23%) in patients under 65 of age versus 4 (11%) placebo. No overall differences in effectiveness were observed in these patients compared to younger patients.
### Gender
There is no FDA guidance on the use of Fostamatinib with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Fostamatinib with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Fostamatinib in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Fostamatinib in patients with hepatic impairment.
### Females of Reproductive Potential and Males
- Based on animal studies, fostamatinib can cause fetal harm when administered to a pregnant woman. For females of reproductive potential, verify pregnancy status prior to initiating fostamatinib.
Females
- Based on animal studies, fostamatinib can cause fetal harm when administered to a pregnant woman. Advise females of reproductive potential to use effective contraception during treatment with fostamatinib and for at least 1 month after the last dose.
- There are no data on the effect of fostamatinib on human fertility. Based on the finding of reduced pregnancy rates in animal studies, fostamatinib may affect female fertility
### Immunocompromised Patients
There is no FDA guidance one the use of Fostamatinib in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Oral
### Monitoring
- After obtaining baseline assessments:
- Monitor CBCs, including platelet counts, monthly until a stable platelet count (at least 50 × 109/L) is achieved. Thereafter, continue to monitor CBCs, including neutrophils, regularly.
- Monitor liver function tests (LFTs) (e.g., ALT, AST, and bilirubin) monthly.
- Monitor blood pressure every 2 weeks until establishment of a stable dose, then monthly thereafter.
# IV Compatibility
There is limited information regarding the compatibility of Fostamatinib and IV administrations.
# Overdosage
- There is no specific antidote for overdose with fostamatinib, and the amount of R406 (the pharmacologically active metabolite of fostamatinib) cleared by dialysis is negligible. In the event of an overdose, monitor patient closely for signs and symptoms of adverse reactions, and treat the reactions with supportive care.
# Pharmacology
## Mechanism of Action
- Fostamatinib is a tyrosine kinase inhibitor with demonstrated activity against spleen tyrosine kinase (SYK). The major metabolite of fostamatinib, R406, inhibits signal transduction of Fc-activating receptors and B-cell receptor. The fostamatinib metabolite R406 reduces antibody-mediated destruction of platelets.
## Structure
## Pharmacodynamics
- Mean treatment-related increases of 2.93 mmHg in systolic blood pressure and 3.53 mmHg in diastolic blood pressure over placebo were observed following fostamatinib doses of 100 mg twice daily for 28 days. About 31% of patients in the fostamatinib group experienced blood pressures ≥140/90 mmHg compared to 15% of patients in the placebo group. Blood pressure returned to baseline within 1 week following fostamatinib discontinuation in 58% (11 of 19) of patients in the fostamatinib group who had blood pressures ≥140/90 mmHg.
- At 2 times the maximum recommended dose, fostamatinib did not prolong the QT interval to a clinically relevant extent.
## Pharmacokinetics
- Fostamatinib is a prodrug that is converted in the gut to the major active metabolite, R406. Mean (± standard deviation [SD]) exposure estimates of R406 are 550 (± 270) ng/mL for Cmax and 7080 (± 2670) ng∙h/mL for AUC. R406 exposure is approximately dose proportional up to 200 mg twice daily (1.3 times the 150 mg dosage). R406 accumulates approximately 2- to 3-fold upon twice daily dosing at 100–160 mg (0.67 to 1.06 times the 150 mg dosage).
Effect of Food
- Administration of fostamatinib with a high-calorie, high-fat meal (deriving approximately 150, 250, and 500–600 calories from protein, carbohydrate, and fat, respectively) increased R406 AUC by 23% and Cmax by 15%
- In in vitro studies, the R406 is 98.3% protein bound in human plasma. The red blood cell to plasma concentration ratio is approximately 2.6. The mean (± SD) volume of distribution at steady-state of R406 is 256 (± 92) L.
- The mean (± SD) terminal half-life of R406 is approximately 15 (± 4.3) hours.
Metabolism
- Fostamatinib is metabolized in the gut by alkaline phosphatase to the major active metabolite, R406. R406 is extensively metabolized, primarily through pathways of CYP450-mediated oxidation (by CYP3A4) and glucuronidation (by UDP glucuronosyltransferase [UGT]1A9). R406 is the predominant moiety in the systemic circulation, and there was minimal exposure to any R406 metabolites.
Excretion
- Following an oral dose of fostamatinib, approximately 80% of the R406 metabolite is excreted in feces with approximately 20% excreted in the urine. The major component excreted in urine was R406 N-glucuronide. The major components excreted in feces were R406, O-desmethyl R406 and a metabolite produced by gut bacteria from the O-desmethyl metabolite of R406.
- Population pharmacokinetics analyses indicate fostamatinib is not altered based on age, sex, race/ethnicity. In addition, the pharmacokinetics of fostamatinib is not altered in patients with renal impairment (creatinine clearance [CLcr] ≥ 30 to < 50 mL/min, estimated by Cockcroft Gault equation and end stage renal disease requiring dialysis), or hepatic impairment (Child-Pugh Class A, B and C).
- Clinical Pharmacology Studies
- No significant interactions were seen with concomitant use of fostamatinib with the following drugs: methotrexate (OAT1/3 transporters), midazolam (CYP3A4 substrate), microgynon (ethinyl estradiol and levonorgestrel), warfarin, pioglitazone (CYP2C8 substrate) and ranitidine (H2-antagonist that increases gastric pH).
Effect of Other Drugs on Fostamatinib
- Strong CYP3A4 inhibitor: Concomitant use of ketoconazole (200 mg twice daily for 3.5 days) with a single dose of 80 mg fostamatinib (0.53 times the 150 mg dosage) increased R406 AUC by 102% and Cmax by 37%.
- Moderate CYP3A4 Inhibitor: Concomitant use of verapamil (80 mg three times daily for 4 days) with a single dose of 150 mg fostamatinib increased R406 AUC by 39% and Cmax by 6%.
- CYP3A4 inducer: Concomitant use of rifampicin (600 mg once daily for 8 days) with a single dose of 150 mg fostamatinib decreased R406 AUC by 75% and Cmax by 59%.
Effect of Fostamatinib on Other Drugs
- CYP3A4 substrate: Concomitant use of simvastatin (single dose 40 mg) with 100 mg twice daily fostamatinib increased simvastatin AUC by 64% and Cmax by 113% and simvastatin acid AUC by 64% and Cmax by 83%.
- BCRP substrate: Concomitant use of rosuvastatin (single dose 20 mg) with 100 mg twice daily fostamatinib increased rosuvastatin AUC by 95% and Cmax by 88%.
- P-gp substrate: Concomitant use of digoxin (0.25 mg once daily) with 100 mg twice daily fostamatinib increased digoxin AUC by 37% and Cmax by 70%.
- Fostamatinib is an inhibitor of the human P-gp efflux transporter in vitro.
- CYP3A4 and UGT1A9 are involved in the metabolism of R406. R406 is a substrate of P-gp but not of other major transporters (OAT1/3, OCT2, OATP1B1/3, MRP2, and BCRP). R406 can inhibit CYP3A4 and BCRP, and can induce CYP2C8 activity.
- R406 is an inhibitor of UGT1A1. Inhibition of UGT1A1 may result in increased unconjugated bilirubin in the absence of other LFT abnormalities.
## Nonclinical Toxicology
- Fostamatinib was not carcinogenic in a 2-year study in mice when administered daily by oral gavage at doses up to 500/250 mg/kg/day, and was not carcinogenic in rats when administered by oral gavage at 45 mg/kg/day.
- Fostamatinib and its major active metabolite (R406) were not mutagenic in an in vitro bacterial reverse mutation (Ames) assay or clastogenic in an in vitro human lymphocyte chromosomal aberration assay or an in vivo mouse bone marrow micronucleus assay.
- In a fertility study with oral fostamatinib, all mating (e.g., time to mating, breeding proficiency), sperm assessments (e.g., number and motility), and organ weight (e.g., paired testis weight) parameters in male rats were unaffected by dosages as high as 40 mg/kg/day, which is 6.7 times the MRHD. All mating and fertility parameters in female rats were unaffected by dosages as high as 11 mg/kg/day (which is 1.8 times the MRHD), but a slight decrease in pregnancy rates and an increase in post-implantation loss were seen at 25 mg/kg/day, which is 4.2 times the MRHD.
# Clinical Studies
- Fostamitinib was studied in two placebo-controlled efficacy and safety studies (referred to as FIT-1 [NCT02076399] and FIT-2 [NCT02076412]), and in an open-label extension study referred to as FIT-3 (NCT 02077192).
- A total of 150 patients with persistent or chronic ITP, who had an insufficient response to previous treatment (which included corticosteroids, immunoglobulins, splenectomy, and/or a thrombopoietin receptor agonists) were enrolled in two identical, double-blind, placebo-controlled studies that were conducted in different countries. For each study, patients were randomized 2:1 to fostamatinib or placebo for 24 weeks; randomization was stratified with respect to prior splenectomy and severity of thrombocytopenia. Stable concurrent ITP therapy (glucocorticoids [< 20 mg prednisone equivalent per day], azathioprine, or danazol) was allowed, and rescue therapy was permitted, if needed. All patients initially received study drug at 100 mg twice daily (or matching placebo). Based on platelet count and tolerability, dose escalation to 150 mg twice daily (or matching placebo) was undertaken in 88% of patients at Week 4 or later. Patients who did not respond to treatment after 12 weeks, as well as patients who completed the 24-week double blind study, were eligible to enroll in open-label extension study (FIT-3).
- Patients enrolled in the placebo-controlled studies had a median age of 54 years (range: 20 to 88), and the majority were female (61%) and were White (93%). Prior ITP treatments were varied, with the most common including corticosteroids (94%), immunoglobulins (53%), and thrombopoietin receptor agonists (TPO-RA) (48%). Most patients had chronic ITP (93%), with a median time since ITP diagnosis of 8.45 years, and 35% had undergone splenectomy. At baseline, the median platelet count was 16 × 109/L (with almost half [45]%) less than 15 × 109/L) and 47% were on stable ITP therapy.
- In Study FIT-1, 76 patients were randomized; 51 to the fostamatinib group and 25 to the placebo group. In Study FIT-2, 74 patients were randomized; 50 to the fostamatinib group and 24 to the placebo group. The efficacy of fostamatinib was based on stable platelet response (at least 50 ×109/L on at least 4 of the 6 visits between Weeks 14 to 24). Study outcomes for FIT-1 and FIT-2 are shown in Table 5.
- In the FIT-1 and FIT-2 studies a total of 47 patients in the fostamatinib arm had received a prior TPO-RA treatment; among these patients, 8 patients (17%) achieved a stable response to fostamatinib. All 8 patients had previously discontinued TPO-RA due to loss of effect. Rescue medication was required by 30% and 45% of patients receiving fostamatinib or placebo, respectively.
- During the placebo-controlled studies, the incidence of bleeding occurred in 29% and 37% of patients in the fostamatinib and placebo arms, respectively. Moderate, severe and serious bleeding events are described in Table 6. All severe events led to hospitalizations.
- The FIT-3 trial is an open label extension study. Patients from FIT-1 and FIT-2 who completed 24 weeks of treatment, or who did not respond to treatment any time after 12 weeks, were eligible to enroll in this study. Patients remained blinded to their treatment assignment from the previous study (fostamatinib or placebo), so their starting dose in this study was based on their final platelet count. Patients designated as responders (defined as achievement of platelet count of at least 50 × 109/L) at the time of roll over continued in the extension study at their current trial dose and regimen. Patients who entered the extension study as non-responders (defined as platelet count less than 50 × 109/L) received fostamatinib 100 mg twice daily regardless of their dose and regimen in the prior study.
- For the FIT-3 trial, 123 patients were enrolled, 44 patients previously randomized to placebo and 79 patients previously randomized to fostamatinib. Stable response in this study was prospectively defined as no 2 visits, at least 4 weeks apart, with a platelet count less than 50 × 109/L, without an intervening visit with a platelet count of at least 50 × 109/L (unrelated to rescue therapy), within a period of 12 weeks following initial achievement of the target platelet count. Sixty-one of the 123 subjects (50%) have discontinued from the study early.
- In a prospectively defined analysis, the 44 subjects treated with placebo in the prior study were evaluated for stable response for fostamatinib. Ten of these subjects (23%) (including a single subject who was classified as a placebo responder in the prior study) met the criteria for stable response.
- Among the subjects who achieved stable response in FIT-1, FIT-2 and FIT-3 trials, 18 subjects maintained the platelet count of at least 50 × 109/L for 12 months or longer.
# How Supplied
- Fostamatinib 100 mg tablets are round, biconvex, orange, film-coated tablets debossed with "100" on one side and "R" on the reverse side.
- Fostamatinib 150 mg tablets are oval, biconvex, orange, film-coated tablets debossed with "150" on one side and "R" on the reverse side.
## Storage
- Store at room temperature, 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature]. Do not remove desiccants.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- Advise the patient to read the FDA-approved patient labeling.
- Hypertension: Inform patients that periodic monitoring of their blood pressure is required, as high blood pressure has occurred in patients taking fostamatinib. Inform patients of the signs and symptoms of hypertension. Advise patients to undergo routine blood pressure monitoring and to contact their health care provider if blood pressure is elevated or if they experience signs or symptoms of hypertension.
- Hepatotoxicity: Inform patients that periodic monitoring of their liver enzymes is required, and any elevations (which may indicate liver injury) will be managed appropriately, including interruption, reduction, or discontinuation of fostamatinib.
- Diarrhea: Advise patients to use supportive care measures, and if diarrhea becomes severe, it may necessitate interruption, reduction, or discontinuation of fostamatinib.
- Neutropenia: Inform patients that monitoring of their complete blood counts is required, and a decrease in neutrophils may necessitate interruption, reduction, or discontinuation of fostamatinib.
- Advise patients to inform their healthcare providers of all their medications, including prescription medicines, over-the-counter drugs, vitamins, and herbal products.
- Embryo-Fetal Toxicity: Advise females to inform their healthcare provider if they are pregnant or become pregnant. Inform female patients of the potential risk to a fetus.
- Advise females of reproductive potential to use effective contraception during treatment and for at least 1 month after receiving the last dose of fostamatinib.
- Lactation: Advise lactating women not to breastfeed during treatment with fostamatinib and for at least 1 month after the last dose.
- Inform patients that fostamatinib may be taken with or without food. In the case of a missed dose of fostamatinib, instruct patients to take their next dose at its regularly scheduled time.
# Precautions with Alcohol
Alcohol-Fostamatinib interaction has not been established. Talk to your doctor regarding the effects of taking alcohol with this medication.
# Brand Names
- Tavalisse
# Look-Alike Drug Names
There is limited information regarding Fostamatinib Look-Alike Drug Names in the drug label.
# Drug Shortage Status
Drug Shortage
# Price | https://www.wikidoc.org/index.php/Fostamatinib | |
085ff9607a94222251c661f5fb1ae59b199c55fe | wikidoc | Rib fracture | Rib fracture
Synonyms and Keywords:
# Overview
The Rib bone are known as the main structural part of the thoracic cage. Rib bone are protecting the thoracic organs such Heart, Lungs, etc, additionally, the Rib bone helps the respiration process.
# Historical Perspective
There are no reliable information regarding the historical perspective of the Rib bone fracture :
# Causes
The main etiology of the Rib fracture is thought to be due to the any type of energy directly to the thoracic cavity or any energetic force affecting human body around the thoracic cavity such as falling, road figthing, car accident or any type of trauma can affect this area and may lead to the bone and/or cartilage injuries of the thorax. Meanwhile, the Cardiopulmonary resuscitation (CPR) could leads to the thoracic injury with/without rib and/or sternum fractures. On the other hand, diseases such as cancer or rheumatoid arthritis could cause the Rib fracture
The main cause of Rib fracture is trauma. Such as the most fractures the Rib fracture is caused by a falling or automobile accident. Meanwhile, the normal healthy bones are extremely tough and resilient and can withstand most powerful impacts. As a person age, two factors cause higher risk of fractures :
- Weaker bones
- Greater risk of falling
Stress fractures as a common causes of fractures can be found due to the repeated stresses and strains. Importantly children having more physically active lifestyles than adults, are also prone to fractures. People with any underlying diseases such as osteoporosis, infection, or a tumor affecting their bones having a higher risk of fractures. As mentioned in previous chapters, this type of fracture is known as a pathological fracture. Stress fractures, which result from repeated stresses and strains, commonly found among professional sports people, are also common causes of fractures.
## Life-threatening Causes
- There are no life-threatening causes of Rib fracture , however complications resulting from Rib fracture is common.
## Common Causes
Common causes of Rib fracture may include:
- Trauma
## Less Common Causes
Less common causes of Rib fracture include conditions that predisposes to fracture:
- Osteoporosis
- Osteopenia
- Malignancies
## Causes by Organ System
## Causes in Alphabetical Order
List the causes of the disease in alphabetical order:
- Trauma
- Osteopenia
- Osteoporosis
# Pathophysiology
The main etiology of the Rib fracture is thought to thee excessive high-energy axial load to patients heel moving the the talus downward onto the Rib bone and causing the injury.
inversion stress to the ankle joint.
The ankle is more stable and resistant to eversion injuries than inversion injuries Because:
The medial malleolus is shorter than the lateral malleolus causing higher range of the invertion than evertion of the talus bone.
The deltoid ligament stabilized the medial wall of the ankle joint
On the other hand, the transverse malleolar, Vertical malleolar, and posterior malleolar fractures are associated with an avulsion injury, talar impaction, and other bone and/or ligamentous injury, respectively.
## Mechanism
In 80% of ankle fractures the foot is in supination position while, in 20% of fractures the foot is in pronation position. The Rib bone fracture is caused by a falling or direct trauma to the ankle joint. The form and severity of this fracture depends on the position of the ankle joint at the moment of the trauma. The ankle joint is flexible but the medial side of the ankle joint is rigid because the medial malleolus is attached to the tibia and also the medial collateral ligaments are very strong. Also, lateral wall of the ankle include: the fibula, syndesmosis and lateral collateral ligaments play important rolls in this flexibility. This lateral wall of the ankle allows the talus to move in lateral and dorsal sides easily. The fibula has no weight-bearing roll but it provide a flexible lateral support. The syndesmosis is formed by the anterior and posterior tibiofibular ligaments which is the fibrous connection between the fibula and tibia.
If we imagine the ankle as a ring in which bones and ligaments play an important role in the maintaining the stability of this joint. Meanwhile, if this ring is broken in one place it remains stable but when it is broken in two places, the ring is unstable and it is at the higher risk of fracture. Consequently the ankle is unstable when both the medial and the lateral malleoli are fractured.
## Pathophysiology
Its known that the Rib bone fracture in normal healthy adults can be caused due to the high-energy trauma (e.g., motor vehicle accidents), sport related injuries, falling from height. But it should be noted that the most important Risk factors for insufficiency fractures is chronic metabolic disease such as steoporosis, osteopenia, eating-disordered behavior, higher age, prolonged corticosteroid usage, female gender, lower BMI, history of a recent falling, and prior fracture.
- The pattern of bone fracture and severity of injury depends on variety of factors such as:
Patients age
Patients Weight
Patients past medical history specifically any bone diseases affecting the quality of bone (such as osteoporosis, malignancies)
Energy of trauma
Bone quality
Position of the specific organ during the trauma
- Patients age
- Patients Weight
- Patients past medical history specifically any bone diseases affecting the quality of bone (such as osteoporosis, malignancies)
- Energy of trauma
- Bone quality
- Position of the specific organ during the trauma
- The below-mentioned processes cause decreased bone mass density:
Autophagy is the mechanism through which osteocytes evade oxidative stress.
The capability of autophagy in cells decreases as they age, a major factor of aging.
As osteocytes grow, viability of cells decrease thereby decreasing the bone mass density.
- Autophagy is the mechanism through which osteocytes evade oxidative stress.
- The capability of autophagy in cells decreases as they age, a major factor of aging.
- As osteocytes grow, viability of cells decrease thereby decreasing the bone mass density.
# Differentiating Rib bone fracture from other Diseases
In the orthopedic medicine its important to know that the ankle fracture should be evaluated using radiography for both confirming diagnosis and also for evaluating the surrounding tissues.
- Acute compartment syndrome of ankle joint
- Ankle Dislocation
- Soft tissue Injury around the ankle ,
- Deep Venous thrombosis
- Thrombophlebitis
- Foot Fracture
- Gout
- Pseudogout
- Rheumatoid Arthritis
- Tibia Fracture
- Fibula Fracture
- bimalleolar fracture
- trimalleolar fracture
- triplane fracture
- Tillaux fracture
- Bosworth fracture
- pilon fracture
- Wagstaffe-Le Forte fracture
- Charcot-Marie-Tooth disease: in cases with repeated ankle fractures
# Epidemiology and Demographics
- The Rib bone fracture accounts for 2% of all fractures and also is known as the most most frequent tarsal fracture (60% of all tarsal fractures) and including the 17% of open fractures
# Risk Factors
There are different risk factors that presidpose patient for the Rib bone fracture that include:
- High-risk contact sports
- Higher age (elderly adults are higher prone to such fractures)
- Reduced bone density (osteoporosis)
- Direct blow
- Road / traffic accidents
- Falling
- Direct trauma to the ankle
- Taking part in any rough or high-impact sport
- Street fights, gunshot wounds, and domestic violence, may also cause the Ankle fracture
- Road traffic accidents.
# Classification
# Screening
Osteoporosis is an important risk factor for human affecting human bone especially in men with the age of older than 50 years old and postmenopausal and women.
Based on the US Preventive Services Task Force (USPSTF) there are three groups of patients need to be screened for the osteoporosis:
- · Men with no history of osteoporosis
- · Women with the age of 65≤ year old, with no previous history of pathological fracture due to the osteoporosis
- · Women with the age of <65 years, with 10-year fracture risk of not less than a 65-year-old white woman (who has not any other risk factor)
Accordingly women older than age of 50 are the main target for the osteoporosis screening. There is no specific recommendation to screen men for the osteoporosis.
The USPSTF recommendations from 2002 included:
Meanwhile, there are two major modalities for the osteoporosis screening:
- · Dual energy x-ray absorptiometry (DXA) of the hip and lumbar spine bones
- · Quantitative ultrasonography of the Rib
*It should be noted of the two above mentioned modalities for screening the ultrasonograhy is preferred to the DXA due to its lower cost, lower ionizing radiation, more availability.
After the primary evaluation of the osteoporosis, the further evaluation are required in some cases such as:
· Women with normal bone density or mild osteopenia: T-score of greater than −1.50 – should have screening for 15 years.
· Women with moderate osteopenia: T-score of −1.50 to −1.99 – should have screening for 5 years.
· Women with advanced osteopenia: T-score of −2.00 to −2.49 - should have screening for 1 year.
# Natural History, Complications and Prognosis
## Natural History
In cases with untreated Rib bone fracture the malunion and deformity of arm can be occurred.
## Complications
The overall complication rate in the treatment of Rib bone fracture were found in around 40% of cases:
- Neurovascular compromise: such as Ulna nerve damage
- Compartment syndrome
- Chronic disability of the DRUJ
- Physeal Injury
- Malunion of the radius
- Nonunion
- Infection
- Refracture following plate removal
- Neural injury
- Instability of the DRUJ
- Loss of Motion (Stiffness)
- Posttraumatic Arthritis
- Heterotopic Ossification
## Prognosis
Successful treatment of Rib bone fracture depends on the on-time interventions such as: accurate diagnosis and appropriate treatment and referral. Complex open fractures with soft-tissue injuries have a worse prognosis than isolated closed Rib bone fracture.
# Diagnosis
The diagnosis of a Rib bone fracture should be confirmed using a radiographic examination.
# History and Symptoms
The related signs and symptoms include:
- Deformity
- Skin lacerations
- Open fractures
- Erythema
- Edema
- Stiffness
- Decreased range of motion
- Tenderness
- Loss of function of the leg
- Difficulties in detection of pulses
- Nerve damage
In the physical exam the orthopedic surgeon should check the vascular status and amount of swelling in the ankle. In MULTI-trauma patients or in comatose or obtunded patients a tense compartment with neurological signs or stretch pain should be considered as the compartment syndrome, and the compartment pressures should be measured and monitored. Normally the pain and soft-tissue swelling are found at the injury site. This injury should be confirmed using a radiographic evaluations.
# Physical Examination
The related signs and symptoms include:
- Edema of the ankle
Most of the time the edema will be a non-pitting edema
Depends on the edema extent, it may even lead to compartment syndrome in the anterior and internal compartment of the ankle
- Most of the time the edema will be a non-pitting edema
- Depends on the edema extent, it may even lead to compartment syndrome in the anterior and internal compartment of the ankle
- Bruising
As a manifestation of internal injury to the local vessels by trauma or fractures bone
- As a manifestation of internal injury to the local vessels by trauma or fractures bone
- Decrease in range of motion of the ankle
Movement of the ankle will be painful if possible at all
- Movement of the ankle will be painful if possible at all
- Tenderness
- Deformity
Fractured bone deformity may be touchable in the internal side of the ankle if the fracture is displaced
- Fractured bone deformity may be touchable in the internal side of the ankle if the fracture is displaced
In the physical exam the orthopedic surgeon should check the vascular status and amount of swelling in the ankle. In polytrauma patients or in comatose or obtunded patients a tense compartment with neurological signs or stretch pain should be considered as the compartment syndrome, and the compartment pressures should be measured and monitored.
Physical examination of patients with Rib bone fracture is usually remarkable for swelling, tenderness, bruises, ecchymosis, deformity and restricted range of motion of the ankle.
## Appearance of the Patient
- Patients with Rib bone fracture usually appears normal unless the patients had a high energy trauma causing the open wound fracture.
## Vital Signs
- Weak pulse may be seen when associated with polytrauma.
- Low blood pressure with normal pulse pressure may be present due to compound fracture with blood loss.
## Skin
- Skin examination of patients with Rib bone fracture includes:
Bruises
Ecchymosis
- Bruises
- Ecchymosis
## HEENT
- HEENT examination of patients with Rib bone fracture usually normal.
## Neck
- Neck examination of patients with Rib bone fracture is usually normal
## Lungs
- Pulmonary examination of patients with Rib bone fracture usually normal
## Heart
- Cardiovascular examination of patients with Rib bone fracture usually normal
## Abdomen
- Abdominal examination of patients with Rib bone fracture usually normal
## Back
- Back examination of patients with Rib bone fracture usually normal
## Genitourinary
- Genitourinary examination of patients with Rib bone fracture usually normal
## Neuromuscular
- Neuromuscular examination of patients with Rib bone fracture is usually normal
- However, some patients may develop neuropraxia of the branch of the Ulnar nerve resulting in decreased sensation of thumb, index and middle finger.
# Laboratory Findings
There is a limited laboratory tests useful in the diagnosis of bone fractures such as the Rib bone fracture. Meanwhile, aged men and women may have some abnormalities in their laboratory findings suggestive of osteoporosis.
Laboratory tests for the diagnosis of osteoporosis are:
- Complete blood count (CBC)
- Serum total calcium level
- Serum Ionized calcium level
- Serum phosphate level
- Serum alkaline phosphatase level
- Serum 25-(OH)-vitamin D level
# X Ray
There are two main markers regarding the Rib fracture in orthopedic medicine called:
The orthopedic surgeon should consider to have at least two radiographic projections (ie, anteroposterior and lateral) of the ankle. These show the fracture, the extent of displacement, and the extent of comminution. The orthopedic surgeon should pay serious attention toward finding any foreign bodies in open fractures and gunshot injuries. Also imperative is to include the elbow and wrist joint in the radiographs of Rib bone fracture to ensure that the distal radioulnar joint injuries are not missed.
- Calcaneal fracture with decreased Bohler's angle.
- Calcaneal fracture with decreased Bohler's angle.
- Avulsion fracture at the insertion of the Achilles tendon, with marked separation of fragments.
# CT
- CT-scan in the case of the Rib bone fracture is the best modality if you can not have an exclusive diagnosis by X-ray itself can not be made.
- The primary fracture line involves the lateral aspect of the posterior facet of the calcaneus, making this a Sander's type 2a fracture
- The right calcaneal fracture has a primary fracture line that extends into the middle of the posterior facet, making it a Sanders type 2B fracture.
# MRI
- Magnetic resonance imaging (MRI) is an expensive technique that should not be used routinely.
- MRI is a powerful diagnostic tool to assess the abnormalities of the bone, ligaments and soft tissues associated with the Rib bone fracture, but it is known as a limited utility in radioulnar injuries and is not indicated in uncomplicated Rib bone fracture.
- Meanwhile, the MRI can be useful in in following mentioned evaluations:
- Evaluation of occult fractures
- Evaluation of the post-traumatic or avascular necrosis of carpal bones
- Evaluation of tendons
- Evaluation of nerve
- Evaluation of carpal tunnel syndrome
- Small subtle non displaced fissure fracture of persistent dark signal intensity is seen traversing the anterior beak of the Rib bone with surrounding extensive marrow edema signal eliciting high signal at STIR WI.
- Small subtle non displaced fissure fracture of persistent dark signal intensity is seen traversing the anterior beak of the Rib bone with surrounding extensive marrow edema
# Other Imaging Findings
- Dynamic flow and blood pool images show increased perfusion and vascularity at the right heel. Delayed static images show an intense increase in tracer uptake localized to the posterior aspect of the right calcaneum highly suspicious of a fracture.
- Dynamic flow and blood pool images show increased perfusion and vascularity at the right heel. Delayed static images show an intense increase in tracer uptake localized to the posterior aspect of the right calcaneum highly suspicious of a fracture.
# Other Diagnostic Studies
There are no other Diagnostic studies associated with Rib bone fracture
# Treatment
Immediate stabilization of patients is the first step. Then the radial fracture and the DRUJ stabilization is recommended in these cases. Open ankle fractures considered as a surgical emergency. Rib bone fracture occurs in younger patients who are skeletally immature; the normally they treated using a closed reduction and casting. Since closed reduction and cast application have led to unsatisfactory results. Then, Almost always the open reduction are necessary for the Rib bone fracture. There are controversies regarding the indications for intramedullary nailing of ankle fractures.
# Non-Operative Treatment
- The first step in managing a patient with a fracture is to stabilize the patient if he/she is unstable due to blood loss, etc by giving them intravenous fluids and giving them some painkillers if the pain is severe.
- In children, the usual plan is to attempt closed reduction followed by cast immobilization. In adults, treatment with immobilization in a molded long arm cast can be used in those rare occasions of a non-displaced fracture of the ankle joint. If the fracture shifts in position, it may require surgery to put the bones back together.
- Rigid immobilization is suggested in preference to removable splints in nonoperative treatment for the management of the Rib bone fracture
- For all patients with Rib bone fracture, a post-reduction true lateral radiograph is suggested.
- Operative fixation is suggested in preference to cast fixation for fractures with post-reduction radial shortening greater than 3 mm, dorsal tilt greater than 10º, or intra-articular displacement or step-off greater than 2 mm.
- Patients probably do not need to begin early wrist motion routinely after stable fracture fixation.
- Adjuvant treatment of Rib bone fracture with vitamin C is suggested for the prevention of disproportionate pain
- Lateral epicondylar fractures should be immobilized for 7 days with patients elbow flexed at 90º, with the supinated ankle , and the extended wrist for relaxing the extensor muscles.
## Complications of Non-surgical therapy
Failure of non-surgical therapy is common:
- Re-displacement to its original position even in a cast
- Stiffness
- Post traumatic osteoarthritis leading to wrist pain and loss of function
- Other risks specific to cast treatment include:
Compression of the swollen arm causing compartment syndrome
Reflex sympathetic dystrophy is a serious complication
Stiffness is universal following a prolonged period of immobilization and swelling
- Compression of the swollen arm causing compartment syndrome
- Reflex sympathetic dystrophy is a serious complication
- Stiffness is universal following a prolonged period of immobilization and swelling
# Surgery
Returning to the normal physical activity after Rib bone fracture can take weeks to months of therapy under supervision an orthopedist. Meanwhile, a physiotherapy can be helpful for patient to achieve the normal wrist and elbow function caused by the immobilisation. All adult Rib bone fracture should be considered to be treated with open reduction and internal fixation (ORIF).
- Post operation Calcaneal fracture
- Post operation Calcaneal fracture
- Post operation Calcaneal fracture
External fixation: For severe open fractures
Open reduction and internal fixation: For Rib bone fracture which depending on each patients condition the following may be needed:
Nerve placement
Bone grafting
Osteotomy
Arthrodesis
## Operation
- There are a variety of methods and implants useful to stabilize the Rib bone fracture, ranging from closed reduction and percutaneous pin fixation to the use of intra-medullary devices.
- However, the most common fixation methods to treat complex Rib bone fracture include external fixation, and open reduction and internal fixation.
## External Fixation With or Without Percutaneous Pin Fixation
- Ankle spanning external fixation employs ligamentotaxis to restore and maintain length, alignment, and rotation of bone.
- Reduction is typically obtained through closed or minimally open methods and preserves the fracture biology.
- The addition of percutaneous pins enhances the ability to reduce and stabilize fracture fragments.
### Complications of External Fixation
- Pin tract infection
- Injury to the Superficial branch of the nerve
- Complex regional pain syndrome
## Open reduction and internal fixation with plates and screws
- This is the most common type of surgical repair for Rib bone fracture
- During this type of procedure, the bone fragments are first repositioned (reduced) into their normal alignment.
- The bones held together with special screws and metal plates attached to the outer surface of the bone.
### Complications of open reduction and internal fixation with plates and screws =
- Infection
- Damage to nerves and blood vessels
- Synostosis
- Nonunion
## Pain Management
Pain after an injury or surgery is a natural part of the healing process.
Medications are often prescribed for short-term pain relief after surgery or an injury such as:
- opioids
- non-steroidal anti-inflammatory drugs (NSAIDs)
- local anesthetics
## Be aware that although opioids help relieve pain after surgery or an injury, they are a narcotic and can be addictive. It is important to use opioids only as directed by doctor.
## Interventions
The following options can be helpful for patients to rehabilitate after their fracture :
- Joints mobilization
- compression bandage
- Soft tissue massage
- Exercises and Activity modification
# Postoperative Rehabilitation
- Complex Rib bone fracture warrant individualized immobilization and rehabilitation strategies.
- Because most multifragmentary Rib bone fracture are the result of high-energy injuries, a prolonged period of wrist immobilization and soft-tissue rest may be beneficial and has not been shown to affect clinical outcomes.
- The ankle is typically immobilized for 6 weeks post-operatively in a splint with Full weight bearing commences at approximately 3 months post-operatively after consolidation of the fracture is noted on radiographs.
- The presence of varying degrees of ankle stiffness is inevitable and may result from poor pain control, lack of effort in controlled mobilization, edema, concomitant ipsilateral lower extremity fractures, or peripheral nerve injuries. Early stretching and mobilization of the intrinsic and extrinsic tendons of the hand is important to prevent finger stiffness. Edema control can be initiated with compression gloves, digital massage, and active and passive ROM of the ankle. A home exercise program or outpatient occupational therapy is started immediately post-operatively to maintain full range of motion of the ankle and limit the development of intrinsic muscle tightnes
# Primary Prevention
There are various preventive options to reduce the incidence of the Rib bone fracture
- Using ankle guards during practicing sports (skating, biking)
- Using ankle guards during driving motorbikes
- Avoid falls in elderly individuals
- Prevention and/or treatment of osteoporosis
- Healthy diet
# Secondary Prevention
It should be noted that the Post-menopausal women specially older than the age of 65 are at the higher risk of osteoporosis consequently these type of patients at greater risk for the pathological fractures .
So the Calcium and vitamin D supplementation play important role in increasing the bone mineral density (BMD) consequently decrease the risk of fracture in these type of patients. Also, avoiding excessive alcohol and quitting smoking play important role in this regard.
## Detecting osteoporosis
- DEXA(dual-energy x-ray absorptiometry) scan
- Serum calcium and vitamin D levels
- Ultrasonography of the Rib
## Pharmacological therapy
- The primary goal for the treatment of osteoporosis is to reduce longtime fracture risk in patients. Increasing bone mineral density (BMD) in response to the treatment is far less important than improvement of clinical aspects of osteoporosis, i.e., osteoporoticfracture. Therefore, most of the drugs efficacy is measured by the extent they improve the fracture risk instead of increasing BMD.
- During the treatment, if a single fracture happens, it does not necessarily indicate treatment failure or the need to be started on an alternative treatment or patient referral to a specialist.
- Calcium and vitamin D supplementation have been found to be effective in reducing the long term fracture risk, significantly. In order to suggest the people to use vitamin D and calcium supplements, the physician needs to make sure that patient is not able to obtain the nutrients through the daily intake. The available supplemental ions of calcium include calcium carbonate, calcium citrate, and vitamin D3 in various dosage forms.
## Life style modifications
- Exercise: Exercise promotes the mineralization of bone and bone accumulation particularly during growth. High impact exercise, in particular, has been shown to prevent the development of osteoporosis. However, it can have a negative effect on bone mineralization in cases of poor nutrition, such as anorexia nervosa and celiac disease.
- Nutrition: A diet high in calcium and vitamin D prevents bone loss. Patients at risk for osteoporosis, such as persons with chronic steroid use are generally treated with vitamin D and calcium supplementation. In renal disease, more active forms of vitamin D, such as 1,25-dihydroxycholecalciferol or calcitriol are used; as the kidney cannot adequately generate calcitriol from calcidiol (25-hydroxycholecalciferol), which is the storage form of vitamin D.
- By quitting smoking, osteoporosis as well as other diseases can be prevented.
- Avoiding excessive alcohol intake or drinking only in moderation. | Rib fracture
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Mohammadmain Rezazadehsaatlou[2].
Synonyms and Keywords:
# Overview
The Rib bone are known as the main structural part of the thoracic cage. Rib bone are protecting the thoracic organs such Heart, Lungs, etc, additionally, the Rib bone helps the respiration process.
# Historical Perspective
There are no reliable information regarding the historical perspective of the Rib bone fracture :
# Causes
The main etiology of the Rib fracture is thought to be due to the any type of energy directly to the thoracic cavity or any energetic force affecting human body around the thoracic cavity such as falling, road figthing, car accident or any type of trauma can affect this area and may lead to the bone and/or cartilage injuries of the thorax. Meanwhile, the Cardiopulmonary resuscitation (CPR) could leads to the thoracic injury with/without rib and/or sternum fractures. On the other hand, diseases such as cancer or rheumatoid arthritis could cause the Rib fracture
The main cause of Rib fracture is trauma. Such as the most fractures the Rib fracture is caused by a falling or automobile accident. Meanwhile, the normal healthy bones are extremely tough and resilient and can withstand most powerful impacts. As a person age, two factors cause higher risk of fractures :
- Weaker bones
- Greater risk of falling
Stress fractures as a common causes of fractures can be found due to the repeated stresses and strains. Importantly children having more physically active lifestyles than adults, are also prone to fractures. People with any underlying diseases such as osteoporosis, infection, or a tumor affecting their bones having a higher risk of fractures. As mentioned in previous chapters, this type of fracture is known as a pathological fracture. Stress fractures, which result from repeated stresses and strains, commonly found among professional sports people, are also common causes of fractures.
## Life-threatening Causes
- There are no life-threatening causes of Rib fracture , however complications resulting from Rib fracture is common.
## Common Causes
Common causes of Rib fracture may include:
- Trauma
## Less Common Causes
Less common causes of Rib fracture include conditions that predisposes to fracture:
- Osteoporosis
- Osteopenia
- Malignancies
## Causes by Organ System
## Causes in Alphabetical Order
List the causes of the disease in alphabetical order:
- Trauma
- Osteopenia
- Osteoporosis
# Pathophysiology
The main etiology of the Rib fracture is thought to thee excessive high-energy axial load to patients heel moving the the talus downward onto the Rib bone and causing the injury.
inversion stress to the ankle joint.
The ankle is more stable and resistant to eversion injuries than inversion injuries Because:
The medial malleolus is shorter than the lateral malleolus causing higher range of the invertion than evertion of the talus bone.
The deltoid ligament stabilized the medial wall of the ankle joint
On the other hand, the transverse malleolar, Vertical malleolar, and posterior malleolar fractures are associated with an avulsion injury, talar impaction, and other bone and/or ligamentous injury, respectively.
## Mechanism
In 80% of ankle fractures the foot is in supination position while, in 20% of fractures the foot is in pronation position. The Rib bone fracture is caused by a falling or direct trauma to the ankle joint. The form and severity of this fracture depends on the position of the ankle joint at the moment of the trauma. The ankle joint is flexible but the medial side of the ankle joint is rigid because the medial malleolus is attached to the tibia and also the medial collateral ligaments are very strong. Also, lateral wall of the ankle include: the fibula, syndesmosis and lateral collateral ligaments play important rolls in this flexibility. This lateral wall of the ankle allows the talus to move in lateral and dorsal sides easily. The fibula has no weight-bearing roll but it provide a flexible lateral support. The syndesmosis is formed by the anterior and posterior tibiofibular ligaments which is the fibrous connection between the fibula and tibia.
If we imagine the ankle as a ring in which bones and ligaments play an important role in the maintaining the stability of this joint. Meanwhile, if this ring is broken in one place it remains stable but when it is broken in two places, the ring is unstable and it is at the higher risk of fracture. Consequently the ankle is unstable when both the medial and the lateral malleoli are fractured.
## Pathophysiology
Its known that the Rib bone fracture in normal healthy adults can be caused due to the high-energy trauma (e.g., motor vehicle accidents), sport related injuries, falling from height. But it should be noted that the most important Risk factors for insufficiency fractures is chronic metabolic disease such as steoporosis, osteopenia, eating-disordered behavior, higher age, prolonged corticosteroid usage, female gender, lower BMI, history of a recent falling, and prior fracture.
- The pattern of bone fracture and severity of injury depends on variety of factors such as:
Patients age
Patients Weight
Patients past medical history specifically any bone diseases affecting the quality of bone (such as osteoporosis, malignancies)
Energy of trauma
Bone quality
Position of the specific organ during the trauma
- Patients age
- Patients Weight
- Patients past medical history specifically any bone diseases affecting the quality of bone (such as osteoporosis, malignancies)
- Energy of trauma
- Bone quality
- Position of the specific organ during the trauma
- The below-mentioned processes cause decreased bone mass density:
Autophagy is the mechanism through which osteocytes evade oxidative stress.
The capability of autophagy in cells decreases as they age, a major factor of aging.
As osteocytes grow, viability of cells decrease thereby decreasing the bone mass density.
- Autophagy is the mechanism through which osteocytes evade oxidative stress.
- The capability of autophagy in cells decreases as they age, a major factor of aging.
- As osteocytes grow, viability of cells decrease thereby decreasing the bone mass density.
# Differentiating Rib bone fracture from other Diseases
In the orthopedic medicine its important to know that the ankle fracture should be evaluated using radiography for both confirming diagnosis and also for evaluating the surrounding tissues.
- Acute compartment syndrome of ankle joint
- Ankle Dislocation
- Soft tissue Injury around the ankle ,
- Deep Venous thrombosis
- Thrombophlebitis
- Foot Fracture
- Gout
- Pseudogout
- Rheumatoid Arthritis
- Tibia Fracture
- Fibula Fracture
- bimalleolar fracture
- trimalleolar fracture
- triplane fracture
- Tillaux fracture
- Bosworth fracture
- pilon fracture
- Wagstaffe-Le Forte fracture
- Charcot-Marie-Tooth disease: in cases with repeated ankle fractures
# Epidemiology and Demographics
- The Rib bone fracture accounts for 2% of all fractures and also is known as the most most frequent tarsal fracture (60% of all tarsal fractures) and including the 17% of open fractures
# Risk Factors
There are different risk factors that presidpose patient for the Rib bone fracture that include:
- High-risk contact sports
- Higher age (elderly adults are higher prone to such fractures)
- Reduced bone density (osteoporosis)
- Direct blow
- Road / traffic accidents
- Falling
- Direct trauma to the ankle
- Taking part in any rough or high-impact sport
- Street fights, gunshot wounds, and domestic violence, may also cause the Ankle fracture
- Road traffic accidents.
# Classification
# Screening
Osteoporosis is an important risk factor for human affecting human bone especially in men with the age of older than 50 years old and postmenopausal and women.
Based on the US Preventive Services Task Force (USPSTF) there are three groups of patients need to be screened for the osteoporosis:
- · Men with no history of osteoporosis
- · Women with the age of 65≤ year old, with no previous history of pathological fracture due to the osteoporosis
- · Women with the age of <65 years, with 10-year fracture risk of not less than a 65-year-old white woman (who has not any other risk factor)
Accordingly women older than age of 50 are the main target for the osteoporosis screening. There is no specific recommendation to screen men for the osteoporosis.
The USPSTF recommendations from 2002 included:
Meanwhile, there are two major modalities for the osteoporosis screening:
- · Dual energy x-ray absorptiometry (DXA) of the hip and lumbar spine bones
- · Quantitative ultrasonography of the Rib
*It should be noted of the two above mentioned modalities for screening the ultrasonograhy is preferred to the DXA due to its lower cost, lower ionizing radiation, more availability.
After the primary evaluation of the osteoporosis, the further evaluation are required in some cases such as:
· Women with normal bone density or mild osteopenia: T-score of greater than −1.50 – should have screening for 15 years.
· Women with moderate osteopenia: T-score of −1.50 to −1.99 – should have screening for 5 years.
· Women with advanced osteopenia: T-score of −2.00 to −2.49 - should have screening for 1 year.
# Natural History, Complications and Prognosis
## Natural History
In cases with untreated Rib bone fracture the malunion and deformity of arm can be occurred.
## Complications
The overall complication rate in the treatment of Rib bone fracture were found in around 40% of cases:
- Neurovascular compromise: such as Ulna nerve damage
- Compartment syndrome
- Chronic disability of the DRUJ
- Physeal Injury
- Malunion of the radius
- Nonunion
- Infection
- Refracture following plate removal
- Neural injury
- Instability of the DRUJ
- Loss of Motion (Stiffness)
- Posttraumatic Arthritis
- Heterotopic Ossification
## Prognosis
Successful treatment of Rib bone fracture depends on the on-time interventions such as: accurate diagnosis and appropriate treatment and referral. Complex open fractures with soft-tissue injuries have a worse prognosis than isolated closed Rib bone fracture.
# Diagnosis
The diagnosis of a Rib bone fracture should be confirmed using a radiographic examination.
# History and Symptoms
The related signs and symptoms include:
- Deformity
- Skin lacerations
- Open fractures
- Erythema
- Edema
- Stiffness
- Decreased range of motion
- Tenderness
- Loss of function of the leg
- Difficulties in detection of pulses
- Nerve damage
In the physical exam the orthopedic surgeon should check the vascular status and amount of swelling in the ankle. In MULTI-trauma patients or in comatose or obtunded patients a tense compartment with neurological signs or stretch pain should be considered as the compartment syndrome, and the compartment pressures should be measured and monitored. Normally the pain and soft-tissue swelling are found at the injury site. This injury should be confirmed using a radiographic evaluations.
# Physical Examination
The related signs and symptoms include:
- Edema of the ankle
Most of the time the edema will be a non-pitting edema
Depends on the edema extent, it may even lead to compartment syndrome in the anterior and internal compartment of the ankle
- Most of the time the edema will be a non-pitting edema
- Depends on the edema extent, it may even lead to compartment syndrome in the anterior and internal compartment of the ankle
- Bruising
As a manifestation of internal injury to the local vessels by trauma or fractures bone
- As a manifestation of internal injury to the local vessels by trauma or fractures bone
- Decrease in range of motion of the ankle
Movement of the ankle will be painful if possible at all
- Movement of the ankle will be painful if possible at all
- Tenderness
- Deformity
Fractured bone deformity may be touchable in the internal side of the ankle if the fracture is displaced
- Fractured bone deformity may be touchable in the internal side of the ankle if the fracture is displaced
In the physical exam the orthopedic surgeon should check the vascular status and amount of swelling in the ankle. In polytrauma patients or in comatose or obtunded patients a tense compartment with neurological signs or stretch pain should be considered as the compartment syndrome, and the compartment pressures should be measured and monitored.
Physical examination of patients with Rib bone fracture is usually remarkable for swelling, tenderness, bruises, ecchymosis, deformity and restricted range of motion of the ankle.
## Appearance of the Patient
- Patients with Rib bone fracture usually appears normal unless the patients had a high energy trauma causing the open wound fracture.
## Vital Signs
- Weak pulse may be seen when associated with polytrauma.
- Low blood pressure with normal pulse pressure may be present due to compound fracture with blood loss.
## Skin
- Skin examination of patients with Rib bone fracture includes:
Bruises
Ecchymosis
- Bruises
- Ecchymosis
## HEENT
- HEENT examination of patients with Rib bone fracture usually normal.
## Neck
- Neck examination of patients with Rib bone fracture is usually normal
## Lungs
- Pulmonary examination of patients with Rib bone fracture usually normal
## Heart
- Cardiovascular examination of patients with Rib bone fracture usually normal
## Abdomen
- Abdominal examination of patients with Rib bone fracture usually normal
## Back
- Back examination of patients with Rib bone fracture usually normal
## Genitourinary
- Genitourinary examination of patients with Rib bone fracture usually normal
## Neuromuscular
- Neuromuscular examination of patients with Rib bone fracture is usually normal
- However, some patients may develop neuropraxia of the branch of the Ulnar nerve resulting in decreased sensation of thumb, index and middle finger.
# Laboratory Findings
There is a limited laboratory tests useful in the diagnosis of bone fractures such as the Rib bone fracture. Meanwhile, aged men and women may have some abnormalities in their laboratory findings suggestive of osteoporosis.
Laboratory tests for the diagnosis of osteoporosis are:
- Complete blood count (CBC)
- Serum total calcium level
- Serum Ionized calcium level
- Serum phosphate level
- Serum alkaline phosphatase level
- Serum 25-(OH)-vitamin D level
# X Ray
There are two main markers regarding the Rib fracture in orthopedic medicine called:
The orthopedic surgeon should consider to have at least two radiographic projections (ie, anteroposterior [AP] and lateral) of the ankle. These show the fracture, the extent of displacement, and the extent of comminution. The orthopedic surgeon should pay serious attention toward finding any foreign bodies in open fractures and gunshot injuries. Also imperative is to include the elbow and wrist joint in the radiographs of Rib bone fracture to ensure that the distal radioulnar joint injuries are not missed.
- Calcaneal fracture with decreased Bohler's angle.
- Calcaneal fracture with decreased Bohler's angle.
- Avulsion fracture at the insertion of the Achilles tendon, with marked separation of fragments.
# CT
- CT-scan in the case of the Rib bone fracture is the best modality if you can not have an exclusive diagnosis by X-ray itself can not be made.
- The primary fracture line involves the lateral aspect of the posterior facet of the calcaneus, making this a Sander's type 2a fracture
- The right calcaneal fracture has a primary fracture line that extends into the middle of the posterior facet, making it a Sanders type 2B fracture.
# MRI
- Magnetic resonance imaging (MRI) is an expensive technique that should not be used routinely.
- MRI is a powerful diagnostic tool to assess the abnormalities of the bone, ligaments and soft tissues associated with the Rib bone fracture, but it is known as a limited utility in radioulnar injuries and is not indicated in uncomplicated Rib bone fracture.
- Meanwhile, the MRI can be useful in in following mentioned evaluations:
- Evaluation of occult fractures
- Evaluation of the post-traumatic or avascular necrosis of carpal bones
- Evaluation of tendons
- Evaluation of nerve
- Evaluation of carpal tunnel syndrome
- Small subtle non displaced fissure fracture of persistent dark signal intensity is seen traversing the anterior beak of the Rib bone with surrounding extensive marrow edema signal eliciting high signal at STIR WI.
- Small subtle non displaced fissure fracture of persistent dark signal intensity is seen traversing the anterior beak of the Rib bone with surrounding extensive marrow edema
# Other Imaging Findings
- Dynamic flow and blood pool images show increased perfusion and vascularity at the right heel. Delayed static images show an intense increase in tracer uptake localized to the posterior aspect of the right calcaneum highly suspicious of a fracture.
- Dynamic flow and blood pool images show increased perfusion and vascularity at the right heel. Delayed static images show an intense increase in tracer uptake localized to the posterior aspect of the right calcaneum highly suspicious of a fracture.
# Other Diagnostic Studies
There are no other Diagnostic studies associated with Rib bone fracture
# Treatment
Immediate stabilization of patients is the first step. Then the radial fracture and the DRUJ stabilization is recommended in these cases. Open ankle fractures considered as a surgical emergency. Rib bone fracture occurs in younger patients who are skeletally immature; the normally they treated using a closed reduction and casting. Since closed reduction and cast application have led to unsatisfactory results. Then, Almost always the open reduction are necessary for the Rib bone fracture. There are controversies regarding the indications for intramedullary nailing of ankle fractures.
# Non-Operative Treatment
- The first step in managing a patient with a fracture is to stabilize the patient if he/she is unstable due to blood loss, etc by giving them intravenous fluids and giving them some painkillers if the pain is severe.
- In children, the usual plan is to attempt closed reduction followed by cast immobilization. In adults, treatment with immobilization in a molded long arm cast can be used in those rare occasions of a non-displaced fracture of the ankle joint. If the fracture shifts in position, it may require surgery to put the bones back together.
- Rigid immobilization is suggested in preference to removable splints in nonoperative treatment for the management of the Rib bone fracture
- For all patients with Rib bone fracture, a post-reduction true lateral radiograph is suggested.
- Operative fixation is suggested in preference to cast fixation for fractures with post-reduction radial shortening greater than 3 mm, dorsal tilt greater than 10º, or intra-articular displacement or step-off greater than 2 mm.
- Patients probably do not need to begin early wrist motion routinely after stable fracture fixation.
- Adjuvant treatment of Rib bone fracture with vitamin C is suggested for the prevention of disproportionate pain
- Lateral epicondylar fractures should be immobilized for 7 days with patients elbow flexed at 90º, with the supinated ankle , and the extended wrist for relaxing the extensor muscles.
## Complications of Non-surgical therapy
Failure of non-surgical therapy is common:
- Re-displacement to its original position even in a cast
- Stiffness
- Post traumatic osteoarthritis leading to wrist pain and loss of function
- Other risks specific to cast treatment include:
Compression of the swollen arm causing compartment syndrome
Reflex sympathetic dystrophy is a serious complication
Stiffness is universal following a prolonged period of immobilization and swelling
- Compression of the swollen arm causing compartment syndrome
- Reflex sympathetic dystrophy is a serious complication
- Stiffness is universal following a prolonged period of immobilization and swelling
# Surgery [1]
Returning to the normal physical activity after Rib bone fracture can take weeks to months of therapy under supervision an orthopedist. Meanwhile, a physiotherapy can be helpful for patient to achieve the normal wrist and elbow function caused by the immobilisation. All adult Rib bone fracture should be considered to be treated with open reduction and internal fixation (ORIF).
- Post operation Calcaneal fracture
- Post operation Calcaneal fracture
- Post operation Calcaneal fracture
External fixation: For severe open fractures
Open reduction and internal fixation: For Rib bone fracture which depending on each patients condition the following may be needed:
Nerve placement
Bone grafting
Osteotomy
Arthrodesis
## Operation
- There are a variety of methods and implants useful to stabilize the Rib bone fracture, ranging from closed reduction and percutaneous pin fixation to the use of intra-medullary devices.
- However, the most common fixation methods to treat complex Rib bone fracture include external fixation, and open reduction and internal fixation.
## External Fixation With or Without Percutaneous Pin Fixation
- Ankle spanning external fixation employs ligamentotaxis to restore and maintain length, alignment, and rotation of bone.
- Reduction is typically obtained through closed or minimally open methods and preserves the fracture biology.
- The addition of percutaneous pins enhances the ability to reduce and stabilize fracture fragments.
### Complications of External Fixation
- Pin tract infection
- Injury to the Superficial branch of the nerve
- Complex regional pain syndrome
## Open reduction and internal fixation with plates and screws
- This is the most common type of surgical repair for Rib bone fracture
- During this type of procedure, the bone fragments are first repositioned (reduced) into their normal alignment.
- The bones held together with special screws and metal plates attached to the outer surface of the bone.
### Complications of open reduction and internal fixation with plates and screws =
- Infection
- Damage to nerves and blood vessels
- Synostosis
- Nonunion
## Pain Management
Pain after an injury or surgery is a natural part of the healing process.
Medications are often prescribed for short-term pain relief after surgery or an injury such as:
- opioids
- non-steroidal anti-inflammatory drugs (NSAIDs)
- local anesthetics
## Be aware that although opioids help relieve pain after surgery or an injury, they are a narcotic and can be addictive. It is important to use opioids only as directed by doctor.
## Interventions
The following options can be helpful for patients to rehabilitate after their fracture :
- Joints mobilization
- compression bandage
- Soft tissue massage
- Exercises and Activity modification
# Postoperative Rehabilitation
- Complex Rib bone fracture warrant individualized immobilization and rehabilitation strategies.
- Because most multifragmentary Rib bone fracture are the result of high-energy injuries, a prolonged period of wrist immobilization and soft-tissue rest may be beneficial and has not been shown to affect clinical outcomes.
- The ankle is typically immobilized for 6 weeks post-operatively in a splint with Full weight bearing commences at approximately 3 months post-operatively after consolidation of the fracture is noted on radiographs.
- The presence of varying degrees of ankle stiffness is inevitable and may result from poor pain control, lack of effort in controlled mobilization, edema, concomitant ipsilateral lower extremity fractures, or peripheral nerve injuries. Early stretching and mobilization of the intrinsic and extrinsic tendons of the hand is important to prevent finger stiffness. Edema control can be initiated with compression gloves, digital massage, and active and passive ROM of the ankle. A home exercise program or outpatient occupational therapy is started immediately post-operatively to maintain full range of motion of the ankle and limit the development of intrinsic muscle tightnes
# Primary Prevention
There are various preventive options to reduce the incidence of the Rib bone fracture
- Using ankle guards during practicing sports (skating, biking)
- Using ankle guards during driving motorbikes
- Avoid falls in elderly individuals
- Prevention and/or treatment of osteoporosis
- Healthy diet
# Secondary Prevention
It should be noted that the Post-menopausal women specially older than the age of 65 are at the higher risk of osteoporosis consequently these type of patients at greater risk for the pathological fractures .
So the Calcium and vitamin D supplementation play important role in increasing the bone mineral density (BMD) consequently decrease the risk of fracture in these type of patients. Also, avoiding excessive alcohol and quitting smoking play important role in this regard.
## Detecting osteoporosis
- DEXA(dual-energy x-ray absorptiometry) scan
- Serum calcium and vitamin D levels
- Ultrasonography of the Rib
## Pharmacological therapy
- The primary goal for the treatment of osteoporosis is to reduce longtime fracture risk in patients. Increasing bone mineral density (BMD) in response to the treatment is far less important than improvement of clinical aspects of osteoporosis, i.e., osteoporoticfracture. Therefore, most of the drugs efficacy is measured by the extent they improve the fracture risk instead of increasing BMD.
- During the treatment, if a single fracture happens, it does not necessarily indicate treatment failure or the need to be started on an alternative treatment or patient referral to a specialist.
- Calcium and vitamin D supplementation have been found to be effective in reducing the long term fracture risk, significantly. In order to suggest the people to use vitamin D and calcium supplements, the physician needs to make sure that patient is not able to obtain the nutrients through the daily intake. The available supplemental ions of calcium include calcium carbonate, calcium citrate, and vitamin D3 in various dosage forms.
## Life style modifications
- Exercise: Exercise promotes the mineralization of bone and bone accumulation particularly during growth. High impact exercise, in particular, has been shown to prevent the development of osteoporosis. However, it can have a negative effect on bone mineralization in cases of poor nutrition, such as anorexia nervosa and celiac disease.
- Nutrition: A diet high in calcium and vitamin D prevents bone loss. Patients at risk for osteoporosis, such as persons with chronic steroid use are generally treated with vitamin D and calcium supplementation. In renal disease, more active forms of vitamin D, such as 1,25-dihydroxycholecalciferol or calcitriol are used; as the kidney cannot adequately generate calcitriol from calcidiol (25-hydroxycholecalciferol), which is the storage form of vitamin D.
- By quitting smoking, osteoporosis as well as other diseases can be prevented.
- Avoiding excessive alcohol intake or drinking only in moderation.
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193a6d6e5586159d52b07f1deab8169fa3036403 | wikidoc | Fred Epstein | Fred Epstein
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# Overview
Fred J. Epstein, MD (July 26, 1937 - July 9, 2006) was an internationally renowned pediatric neurosurgeon credited for the development of pioneering neurosurgical techniques to treat children threatened by brain and spinal-cord tumors.
His surgical techniques and commitment to patient care saved thousands of children's lives and earned him a reputation as one of the world's leading pediatric neurosurgeons.
# Education
Born in Yonkers, New York, he graduated from New York University and New York Medical College. He did his internship and surgical residency at Montefiore Medical Center in the Bronx and his neurosurgical residency at New York University-Bellevue Medical Center, while serving in the Army reserves, under the tutelage of Joseph Ransohoff.
# Career
In 1983, he was named professor of neurosurgery at New York University (NYU) and two years later director of the division of pediatric neurosurgery by Ransohoff, his former mentor. It was there that he saw the resemblance of operable tumors in the cerebellum and, until then, inoperable ones in the brain stem. He likened the technique he developed to removing lead from a pencil, the pencil being the spinal cord.
He founded the division of pediatric neurosurgery at New York University Medical Center, and he was the founding director of the Institute for Neurology and Neurosurgery (INN) at Beth Israel Hospital in New York City.
He was president of the International Society of Pediatric Neurosurgery and the American Society of Pediatric Neurosurgery. He published more than 175 scholarly papers and was editor in chief of The Journal of Pediatric Neurosurgery.
In 2001, the American Association of Neurological Surgeons awarded him its Lifetime Achievement Award.
He wrote two books for general readers: "If I Get to Five" and "Gifts of Time".
He was the subject of three segments of “20/20” and made news by operating on the son of the Yankee pitcher Tommy John and on a Tibetan monk for whom the Dalai Lama prayed at the institute. In 1997, he operated on a millionaire’s pug in exchange for a donation to help pay for surgery that Epstein then performed on a 5-year-old boy from rural Pennsylvania.
The cause of Epstein's death was melanoma.
# Quotation
The question, "Why do children suffer?" has no answer, unless it's simply, "To break our hearts." Once our hearts get broken, they never fully heal. They always ache. But perhaps a broken heart is a more loving instrument. Perhaps only after our hearts have cracked wide open, have finally and totally unclenched, can we truly know love without boundaries. | Fred Epstein
Please Take Over This Page and Apply to be Editor-In-Chief for this topic:
There can be one or more than one Editor-In-Chief. You may also apply to be an Associate Editor-In-Chief of one of the subtopics below. Please mail us [1] to indicate your interest in serving either as an Editor-In-Chief of the entire topic or as an Associate Editor-In-Chief for a subtopic. Please be sure to attach your CV and or biographical sketch.
# Overview
Fred J. Epstein, MD (July 26, 1937 - July 9, 2006) was an internationally renowned pediatric neurosurgeon credited for the development of pioneering neurosurgical techniques to treat children threatened by brain and spinal-cord tumors.
His surgical techniques and commitment to patient care saved thousands of children's lives and earned him a reputation as one of the world's leading pediatric neurosurgeons.
# Education
Born in Yonkers, New York, he graduated from New York University and New York Medical College. He did his internship and surgical residency at Montefiore Medical Center in the Bronx and his neurosurgical residency at New York University-Bellevue Medical Center, while serving in the Army reserves, under the tutelage of Joseph Ransohoff.
# Career
In 1983, he was named professor of neurosurgery at New York University (NYU) and two years later director of the division of pediatric neurosurgery by Ransohoff, his former mentor. It was there that he saw the resemblance of operable tumors in the cerebellum and, until then, inoperable ones in the brain stem. He likened the technique he developed to removing lead from a pencil, the pencil being the spinal cord.
He founded the division of pediatric neurosurgery at New York University Medical Center, and he was the founding director of the Institute for Neurology and Neurosurgery (INN) at Beth Israel Hospital in New York City.
He was president of the International Society of Pediatric Neurosurgery and the American Society of Pediatric Neurosurgery. He published more than 175 scholarly papers and was editor in chief of The Journal of Pediatric Neurosurgery.
In 2001, the American Association of Neurological Surgeons awarded him its Lifetime Achievement Award.
He wrote two books for general readers: "If I Get to Five" and "Gifts of Time".
He was the subject of three segments of “20/20” and made news by operating on the son of the Yankee pitcher Tommy John and on a Tibetan monk for whom the Dalai Lama prayed at the institute. In 1997, he operated on a millionaire’s pug in exchange for a donation to help pay for surgery that Epstein then performed on a 5-year-old boy from rural Pennsylvania.
The cause of Epstein's death was melanoma.
# Quotation
The question, "Why do children suffer?" has no answer, unless it's simply, "To break our hearts." Once our hearts get broken, they never fully heal. They always ache. But perhaps a broken heart is a more loving instrument. Perhaps only after our hearts have cracked wide open, have finally and totally unclenched, can we truly know love without boundaries.
# External links
- NY Times Obituary
- A Boy, a Dog and Their Neurosurgeon
- AANS Lifetime Achievement Award
- The Society of Neurological Surgeons Profile
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Template:WS | https://www.wikidoc.org/index.php/Fred_Epstein |
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