Action And Clinical Pharmacology: Amoxapine is a tricyclic antidepressant of the dibenzoxazepine class. The mechanism of clinical action of amoxapine in man is not well understood. Amoxapine is not a monoamine oxidase (MAO) inhibitor. In animals, amoxapine inhibits the re-uptake of norepinephrine and, to a lesser degree, of serotonin, at adrenergic nerve endings and blocks the response of dopamine receptors to dopamine. Its major metabolite, 8-hydroxyamoxapine, has similar norepinephrine uptake inhibiting activity but greater serotonin blocking effect than the parent compound, while the other major metabolite, 7-hydroxyamoxapine, has a dopamine receptor blocking effect.
Amoxapine is absorbed rapidly and reaches peak blood levels approximately 90 minutes after ingestion. It has a serum elimination half-life of 8 hours and is almost completely metabolized in the liver to 7-hydroxyamoxapine and 8-hydroxyamoxapine. The major active metabolite, 8-hydroxyamoxapine, has a serum half-life of 30 hours, while 7-hydroxyamoxapine is present in serum only in low concentrations with a half-life of 6.5 hours. Most of the drug is excreted in the urine and smaller amounts in the feces. The urinary metabolites appear in conjugated form as glucuronides with 33% of the dose accounted for as the 8-hydroxy metabolite and 25% as the 7-hydroxy metabolite. Only 2% is excreted unchanged. In vitro tests show that amoxapine binding to human serum protein is approximately 90%. The drug crosses the placental barrier and is excreted in human milk. The initial clinical effect usually occurs within 2 weeks of administration, but may be seen in some patients within 4 to 7 days.
Indications And Clinical Uses: The relief of symptoms of depression. Patients who have failed to respond satisfactorily to other antidepressants may show response to amoxapine.
Contra-Indications: Hypersensitivity to dibenzoxazepine compounds. It should not be given concomitantly with MAO inhibitors. When replacing MAO inhibitors with amoxapine, a minimum of 14 days should be allowed to elapse after the former is discontinued. Amoxapine should then be initiated cautiously with gradual increase in dosage until optimum response is achieved. Amoxapine is also contraindicated during the acute recovery phase following myocardial infarction and in the presence of acute congestive heart failure.
Manufacturers’ Warnings In Clinical States: Tardive Dyskinesia: Tardive dyskinesia is known to occur in patients treated with neuroleptics with antipsychotic properties and other drugs with substantial neuroleptic activity. It has also been observed with amoxapine administration (see Adverse Effects). Although the dyskinetic syndrome may remit partially or completely if the medication is withdrawn, it is irreversible in some patients. At the present time there is uncertainty as to whether neuroleptic drugs differ in their potential to cause tardive dyskinesia.
Since there is a significant prevalence of this syndrome associated with the use of neuroleptic drugs, and since there is no known effective treatment, chronic use of these drugs should generally be restricted to patients for whom neuroleptics are known to be effective and for whom there is no alternative therapy available with better risk acceptability. If manifestations of tardive dyskinesia are detected during the use of amoxapine, the drug should be discontinued. The risk of a patient developing tardive dyskinesia and of the syndrome becoming irreversible appear to increase with the duration of treatment and the total amount of drugs administered, although, in some instances, tardive dyskinesia may develop after relatively short periods of treatment at low doses. The risk of developing tardive dyskinesia may, therefore, be minimized by reducing the dose of the neuroleptic drug used and its duration of administration, consistent with the effective management of the patient’s condition. Continued use of neuroleptics should be periodically reassessed.
Withdrawal Emergent Neurological Signs: As with antipsychotic agents, withdrawal emergent dyskinetic signs have been reported in some patients on maintenance therapy with amoxapine following its discontinuation. The signs are very similar to those described under Tardive Dyskinesia (see Adverse Effects), except that they are usually less persistent. Although it is not known whether gradual withdrawal will decrease the incidence of withdrawal emergent neurological signs, gradual withdrawal would appear to be advisable.
Since tricyclic agents are known to reduce the seizure threshold and since grand mal seizures have occurred at therapeutic dosage levels, extreme caution should be taken in administering the drug to patients with a history of convulsive disorders. Concurrent administration of ECT and amoxapine may be hazardous and, therefore, such treatment should be limited to patients for whom it is essential.
Because of its anticholinergic properties, amoxapine should be used with extreme caution in patients with a history of urinary retention, angle closure glaucoma or increased intraocular pressure.
Tricyclic antidepressant drugs, particularly when given in high doses, can induce sinus tachycardia, changes in conduction time and arrhythmias. A few instances of unexpected death have been reported in patients with cardiovascular disorders. Myocardial infarction and stroke have also been reported with drugs of this class. Therefore, amoxapine should be administered with extreme caution to patients with a history of cardiovascular disease, those with circulatory lability and elderly patients. In such cases, treatment should be initiated with low doses with progressive increases only if required and tolerated, and the patients should be under close surveillance at all dosage levels.
Close supervision is required when amoxapine is given to hyperthyroid patients or those receiving thyroid medication because of the possibility of cardiovascular toxicity. Tricyclic drugs may also block the antihypertensive effects of guanethidine and related compounds.
Pregnancy and Lactation: Safety during pregnancy and lactation has not been established. It should not be used in women of childbearing potential or nursing mothers, unless, in the opinion of the physician, the potential benefits to the patient outweigh the possible hazards to the fetus. Amoxapine is excreted in breast milk.
Children: Amoxapine is not recommended for use in children since safety and efficacy in this age group have not been established.
Precautions: Occupational Hazards: Since amoxapine has a sedative component to its action, patients should be advised against driving or engaging in activities requiring mental alertness and physical coordination until their response to the drug has been well established.
Patients should be warned that the effects of other drugs acting on the CNS, such as alcohol, barbiturates and other CNS depressants, may be potentiated by amoxapine.
The possibility of suicide in seriously depressed patients may remain until significant remission occurs. Such patients should be closely supervised throughout therapy and consideration should be given to the possible need for hospitalization. This type of patient should not have easy access to large quantities of amoxapine.
Tricyclic antidepressants may precipitate or aggravate psychotic manifestations in schizophrenic patients and hypomanic or manic episodes in manic-depressive patients. This may require a reduction of dosage, discontinuation of the drug, and/or administration of an antipsychotic agent.
Tricyclic antidepressants may also give rise to paralytic ileus, particularly in the elderly and in hospitalized patients. Therefore, appropriate measures should be taken if constipation occurs.
When amoxapine is given concomitantly with anticholinergic or sympathomimetic drugs, close supervision and careful adjustment of dosages are required.
Amoxapine should be discontinued prior to elective surgery for as long as the clinical situation will allow.
Amoxapine should be used with caution in patients with impaired liver function or with a history of hepatic damage or blood dyscrasias. Periodic blood counts and liver function tests should be performed when patients receive amoxapine in large doses or over prolonged periods.
As with other dopamine antagonists, amoxapine elevates serum prolactin levels. 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 amoxapine 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.
Caution should be exercised if amoxapine is administered together with cimetidine since cimetidine inhibits tricyclic antidepressant metabolism, and clinically significant increases in plasma levels of amoxapine may occur.
Adverse Reactions: Although some of the adverse reactions included in the following list have not been reported with amoxapine, pharmacological similarities among the tricyclic antidepressants require that each of the reactions be considered when prescribing amoxapine. With amoxapine, as with other tricyclic antidepressant drugs, the side effects most often reported are sedation and anticholinergic effects.
Behavioral: drowsiness, fatigue, excitement, agitation, restlessness, insomnia, nightmares, hypomania, anxiety, confusion, disorientation, disturbed concentration, delusions, hallucinations, activation of latent psychosis.
Neurological: seizures, alteration in EEG patterns, dizziness, tremors, extrapyramidal symptoms, numbness, tingling, paresthesias of the extremities, peripheral neuropathy, tinnitus, syndrome of inappropriate ADH (antidiuretic hormone) secretion.
Extrapyramidal symptoms reported with amoxapine include: akinesia, akathisia, chorea, cogwheel rigidity, dysarthria, mask-like facies, oculogyric crisis, torticollis and dyskinesia, including tardive dyskinesia. Although most of these symptoms have been reported infrequently, the possibility of their occurrence should be borne in mind when prescribing amoxapine.
As with antipsychotic agents, tardive dyskinesia may appear in some patients on long-term therapy with amoxapine or may appear after drug therapy has been discontinued (withdrawal tardive dyskinesia). The risk appears to be greater in elderly patients on high-dose therapy, especially females. The symptoms are persistent and in some patients may be irreversible. The syndrome is usually characterized by rhythmical involuntary movements of the tongue, face, mouth or jaw (e.g. protrusion of tongue, puffing of cheeks, puckering of mouth, chewing movements), but may also be manifested by abnormal involuntary movements of extremities and other extrapyramidal symptoms, such as akathisia.
There is, at present, no known effective treatment for tardive dyskinesia; anticholinergic agents may worsen the symptoms of this syndrome and the results from studies with other agents (e.g. dopamine agonists, cholinergics, GABA agonists) are not clear. Therefore, it is suggested that amoxapine be discontinued if symptoms of tardive dyskinesia appear, and the patient be switched to a different antidepressant.
On no account should the dosage be increased in an attempt to mask the syndrome. It has been reported that fine vermicular movements of the tongue may be an early sign of the syndrome, and, if the medication is stopped at that time, the syndrome may not develop.
Cardiovascular: hypotension, hypertension, tachycardia, palpitations, syncope, atrial arrhythmias (including premature atrial contractions and fibrillation), heart block, stroke and cardiac arrest have been reported with amoxapine. A quinidine-like effect and other reversible ECG changes such as flattening or inversion of T waves, bundle branch block, depressed ST segments, prolonged conduction time and asystole have been reported with other tricyclic antidepressants.
Autonomic: dry mouth, blurred vision, disturbances of accom- modation, mydriasis, constipation, nasal stuffiness, delayed micturition, sublingual adenitis, paralytic ileus, urinary retention, dilation of the urinary tract, precipitation of latent and aggravation of existing glaucoma, vertigo.
Endocrine: increased or decreased libido, impotence, menstrual irregularity, testicular swelling, painful ejaculation, inhibition of orgasm, breast enlargement and galactorrhea in the female, gynecomastia in the male, elevation and lowering of blood sugar levels, and increased prolactin levels.
Allergic or toxic: pruritus, skin rash, photosensitization, edema, drug fever, leukopenia, urticaria, petechiae, obstructive jaundice, bone marrow depression, including agranulocytosis, eosinophilia, purpura and thrombocytopenia, toxic epidermal necrolysis and neuroleptic malignant syndrome.
Gastrointestinal: nausea, epigastric distress, vomiting, flatulence, abdominal pain, diarrhea, peculiar taste, stomatitis.
Miscellaneous: weakness, headache, weight gain or loss, excessive appetite, anorexia, increased perspiration, urinary frequency, lacrimation, alopecia, parotid swelling, black tongue, hepatitis.
Withdrawal Symptoms: Abrupt cessation of treatment with tricyclic antidepressants after prolonged administration may produce nausea, headache and malaise. These symptoms are not indicative of addiction. Withdrawal emergent dyskinesia has been reported with amoxapine.
Symptoms And Treatment Of Overdose: Symptoms: Toxic manifestations of overdosage differ significantly from those of other tricyclic antidepressants. CNS effects such as drowsiness, delirium, lethargy with diminished deep tendon reflexes and particularly grand mal convulsions, occur frequently, and treatment should be directed primarily toward prevention or control of seizures. Status epilepticus may develop and constitutes a neurologic emergency. Coma and acidosis are other serious complications of substantial overdosage in some cases.
Fatalities have resulted from amoxapine overdosage and permanent neurologic damage has occurred in some patients who recovered after prolonged status epilepticus and severe acidosis.
Renal failure may develop 2 to 5 days after toxic overdosage in patients who may appear otherwise recovered. Acute tubular necrosis with rhabdomyolysis and myoglobinuria is the most common renal complication in such cases. This reaction typically occurs in those who have experienced multiple seizures, and most patients recover with appropriate treatment.
Cardiovascular effects, when they occur, are usually limited to sinus tachycardia and transient minor ECG changes. Hence, prolongation of the QRS interval beyond 100 milliseconds within the first 24 hours is not a useful guide to the severity of overdosage with amoxapine. Serious hypotension, hypertension, incomplete bundle branch block and cardiac arrhythmias have been rarely observed with amoxapine.
The smallest estimated lethal overdoses reported with amoxapine in adults have been 1.5 to 2 g. A 15-month old child died after ingesting approximately 250 mg. On the other hand, some patients have survived much larger overdoses. Age and physical condition of the patient, concomitant ingestion of other drugs, and especially the interval between drug ingestion and initiation of emergency treatment, are important determining factors in the probability of survival.
Symptoms of overdosage reported with other tricyclic antidepressants include: drowsiness, mydriasis, dysarthria, general weakness, excitement, agitation, hyperactive reflexes, muscle spasms and rigidity, hypothermia, hyperpyrexia, vomiting, perspiration, rapid thready pulse, convulsions, severe hypotension, hypertension, tachycardia, disturbances of cardiac conduction, arrhythmia, congestive heart failure, circulatory collapse, respiratory depression and coma. In patients with glaucoma, even average doses may precipitate an attack.
Treatment: Treatment should be symptomatic and supportive, but with special attention to prevention or control of seizures. Renal failure may develop a few days after substantial amoxapine overdosage in patients who may appear otherwise recovered. Therefore, patients who may have ingested an overdosage of amoxapine, particularly children, should be hospitalized and kept under close surveillance.
In all comatose patients basic life support measures must be instituted, including establishment of an adequate airway and assisted ventilation, if necessary. Emesis should be induced only in conscious, asymptomatic patients. In all other patients, gastric lavage, with appropriate precautions to prevent pulmonary aspiration, should be performed as soon as possible. These measures are recommended up to 12 hours or even more after the overdose since the anticholinergic effect of the drug may delay gastric emptying. Following lavage or emesis activated charcoal may be administered to reduce absorption, and repeated administration may facilitate drug elimination. Acidosis may be treated by cautious administration of sodium bicarbonate. Treatment of renal impairment is the same as that for non-drug-induced renal dysfunction. The value of dialysis is doubtful due to the extensive plasma protein binding of amoxapine.
External stimulation should be minimized to reduce the tendency to convulsions. Convulsions, when they occur, typically begin within 12 hours after ingestion of amoxapine. Because seizures may occur precipitously in some overdosage patients who appear otherwise relatively asymptomatic, the treating physician may wish to consider prophylactic administration of anticonvulsant medication during this period. Standard anticonvulsants, such as i.v. diazepam and/or phenytoin should be administered. Barbiturates may intensify respiratory depression, particularly in children, and aggravate hypotension and coma. Paraldehyde may be used in some children to counteract muscular hypertonus and convulsions with less likelihood of causing respiratory depression. Prompt control of convulsions, including status epilepticus, is essential since they aggravate hypoxia and acidosis and may thereby precipitate cardiac arrhythmias and arrest, as well as cause permanent neurological damage.
ECG monitoring in an intensive care unit is recommended in all patients with tricyclic antidepressant overdosage, although cardiac complications do not appear to be as serious a problem with amoxapine overdosage as with some other tricyclic antidepressants, and the ECG typically remains within normal limits except for sinus tachycardia.
Shock should be treated with supportive measures such as i.v. fluids, oxygen and corticosteroids. Pressor agents, such as norepinephrine (but not epinephrine), are rarely indicated and should be given only after careful consideration and under continuous monitoring.
The slow i.v. administration of physostigmine salicylate has been reported to reverse most of the cardiovascular and CNS effects of tricyclic overdosage, such as cardiac arrhythmias and convulsions; however, it should not be used routinely because of its short duration of action and potentially serious adverse effects. The recommended dosage in adults has been 1 to 2 mg in very slow i.v. injection (avoid rapid injection to reduce the possibility of physostigmine-induced convulsions). In children, the initial dosage should not exceed 0.5 mg and should be adjusted to age and response. Since physostigmine has a short duration of action, administration may have to be repeated at 30 to 60 minute intervals.
Deaths by deliberate or accidental overdosage have occurred with this class of drugs. Since the propensity for suicide is high in depressed patients, a suicide attempt by other means may occur during the recovery phase. The possibility of simultaneous ingestion of other drugs should also be considered.
Dosage And Administration: The dosage must be individualized according to the requirements of each patient. Treatment should be initiated at the lowest recommended dose and increased gradually with careful assessment of clinical response and any evidence of intolerance. Once effective dosage is well established, the total daily dosage may be given in a single daily dose (not to exceed 300 mg) at bedtime. Total daily dosages higher than 300 mg should be given in divided doses. Care should be taken not to increase the dosage of amoxapine if manifestations of extrapyramidal effects occur, as there is a possibility of development of tardive dyskinesia with this drug.
Adults: Initially, 50 mg twice daily. Depending on the patient’s tolerance and response, this should be increased to 50 mg 3 times daily as early as the third day of treatment. In severely depressed hospitalized patients or patients under close supervision, a higher initial dose of 50 mg 3 times daily may be indicated, and this may be increased to 100 mg 2 or 3 times daily. The usual optimum dose is 150 to 300 mg daily, but some patients may require higher doses, up to 400 mg or more daily, depending on tolerance and response of each individual patient. Some hospitalized patients have received doses up to 600 mg daily in divided doses. When higher doses are used, it is essential to exclude history of convulsive disorders.
Elderly or Debilitated Patients: The total experience with amoxapine in elderly patients is limited. Therefore, if there is a valid indication for use of amoxapine in an elderly patient, the dosage should be titrated very carefully. As with other drugs of this class, it is recommended to initiate treatment with lower doses and to increase dosage gradually. The recommended starting dosage is 12.5 mg, 3 times daily. This should be increased very gradually, depending on tolerance and response, to 50 mg 2 or 3 times daily.
Maintenance Dosage: The recommended maintenance dosage is the lowest dose that will sustain remission. Medication should be continued for the expected duration of the depressive episode in order to minimize the possibility of relapse following clinical improvement. If symptoms reappear, dosage should be increased to the level which previously induced remission, until symptoms are again controlled.
When a maintenance dosage has been established as described above, amoxapine may be administered in a single dose before bedtime provided such a dosage regimen is well tolerated. However, if the total daily dose exceeds 300 mg, it should be administered in divided doses.
When amoxapine therapy is discontinued, the withdrawal of the drug should be gradual.
Availability And Storage: 25 mg: Each heptagonal, white, scored tablet engraved “LL25” and “A13” contains: amoxapine 25 mg. Nonmedicinal ingredients: calcium phosphate dibasic, magnesium stearate, starch, starch pregelatinized and stearic acid. Tartrazine-free. Bottles of 100.
50 mg: Each heptagonal, mottled, orange, scored tablet engraved “LL50” and “A15” contains: amoxapine 50 mg. Nonmedicinal ingredients: calcium phosphate dibasic, FD&C Yellow No. 6 aluminum lake, magnesium stearate, starch, starch pregelatinized and stearic acid. Tartrazine-free. Bottles of 100 and 500.
100 mg: Each heptagonal, mottled, blue, scored tablet engraved “LL100” and “A17” contains: amoxapine 100 mg. Nonmedicinal ingredients: calcium phosphate dibasic dihydrate, FD&C Blue No. 2 aluminum lake, magnesium stearate, starch, starch pregelatinized and stearic acid. Tartrazine-free. Bottles of 100.
ASENDIN® Wyeth-Ayerst Amoxapine Antidepressant
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