Amoxapine

Pronunciation

(a MOKS a peen)

Synonyms

Asendin [DSC]

Generic Available

Yes

Use

Treatment of depression, psychotic depression, depression accompanied by anxiety or agitation

Pregnancy Risk Factor

Lactation

Enters breast milk/contraindicated (AAP rates "of concern")

Contraindications

Hypersensitivity to amoxapine or any component of the formulation; use of MAO inhibitors within past 14 days; acute recovery phase following myocardial infarction

Warnings/Precautions

May cause sedation, resulting in impaired performance of tasks requiring alertness (eg, operating machinery or driving). Sedative effects may be additive with other CNS depressants and/or ethanol. The degree of sedation is moderate relative to other antidepressants. May worsen psychosis in some patients or precipitate a shift to mania or hypomania in patients with bipolar disease. May increase the risks associated with electroconvulsive therapy. This agent should be discontinued, when possible, prior to elective surgery. Therapy should not be abruptly discontinued in patients receiving high doses for prolonged periods.

May cause extrapyramidal symptoms, including pseudoparkinsonism, acute dystonic reactions, akathisia, and tardive dyskinesia (risk of these reactions is low). May be associated with neuroleptic malignant syndrome.

May cause orthostatic hypotension (risk is moderate relative to other antidepressants) - use with caution in patients at risk of hypotension or in patients where transient hypotensive episodes would be poorly tolerated (cardiovascular disease or cerebrovascular disease). The degree of anticholinergic blockade produced by this agent is moderate relative to other cyclic antidepressants - use caution in patients with urinary retention, benign prostatic hyperplasia, narrow-angle glaucoma, xerostomia, visual problems, constipation, or history of bowel obstruction.

The possibility of a suicide attempt is inherent in major depression and may persist until remission occurs. Use caution in high-risk patients during initiation of therapy. Prescriptions should be written for the smallest quantity consistent with good patient care. Use with caution in patients with a history of cardiovascular disease (including previous MI, stroke, tachycardia, or conduction abnormalities). The risk conduction abnormalities with this agent is moderate relative to other antidepressants. May lower seizure threshold - use caution in patients with a previous seizure disorder or condition predisposing to seizures such as brain damage, alcoholism, or concurrent therapy with other drugs which lower the seizure threshold. Use with caution in hyperthyroid patients or those receiving thyroid supplementation. Use with caution in patients with hepatic or renal dysfunction and in elderly patients.

Adverse Reactions

>10%:

Central nervous system: Drowsiness

Gastrointestinal: Xerostomia, constipation

1% to 10%:

Central nervous system: Dizziness, headache, confusion, nervousness, restlessness, insomnia, ataxia, excitement, anxiety

Dermatologic: Edema, skin rash

Endocrine: Elevated prolactin levels

Gastrointestinal: Nausea

Neuromuscular & skeletal: Tremor, weakness

Ocular: Blurred vision

Miscellaneous: Diaphoresis

<1%: Abdominal pain, abnormal taste, agranulocytosis, allergic reactions, breast enlargement, delayed micturition, diarrhea, elevated liver enzymes, epigastric distress, extrapyramidal symptoms, flatulence, galactorrhea, hyper-/hypotension, impotence, incoordination, increased intraocular pressure, increased or decreased libido, lacrimation, leukopenia, menstrual irregularity, mydriasis, nasal stuffiness, neuroleptic malignant syndrome, numbness, painful ejaculation, paresthesia, photosensitivity, seizure, SIADH, syncope, tachycardia, tardive dyskinesia, testicular edema, tinnitus, urinary retention, vomiting

Overdosage/Toxicology

Symptoms of overdose include grand mal convulsions, acidosis, coma, and renal failure. Following initiation of essential overdose management, toxic symptoms should be treated. Ventricular arrhythmias often respond to phenytoin 15-20 mg/kg (adults) with concurrent systemic alkalinization (sodium bicarbonate 0.5-2 mEq/kg I.V.). Physostigmine (1-2 mg I.V. slowly for adults) may be indicated for reversing cardiac arrhythmias that are due to vagal blockade, or for anticholinergic effects, but should only be used as a last measure in life-threatening situations.

Drug Interactions

Substrate of CYP2D6 (major)

Anticholinergics: Combined use with TCAs may produce additive anticholinergic effects

Altretamine: Concurrent use may cause orthostatic hypertension

Amphetamines: TCAs may enhance the effect of amphetamines; monitor for adverse CV effects

Antihypertensives: Amitriptyline inhibits the antihypertensive response to bethanidine, clonidine, debrisoquin, guanadrel, guanethidine, guanabenz, guanfacine; monitor BP; consider alternate antihypertensive agent

Beta-agonists: When combined with TCAs may predispose patients to cardiac arrhythmias

Bupropion: May increase the levels of tricyclic antidepressants; based on limited information; monitor response

Carbamazepine: Tricyclic antidepressants may increase carbamazepine levels; monitor

Cholestyramine and colestipol: May bind TCAs and reduce their absorption; monitor for altered response

Clonidine: Abrupt discontinuation of clonidine may cause hypertensive crisis, amitriptyline may enhance the response

CNS depressants: Sedative effects may be additive with TCAs; monitor for increased effect; includes benzodiazepines, barbiturates, antipsychotics, ethanol and other sedative medications

CYP2D6 inhibitors: May increase the levels/effects of amoxapine. Example inhibitors include chlorpromazine, delavirdine, fluoxetine, miconazole, paroxetine, pergolide, quinidine, quinine, ritonavir, and ropinirole.

Epinephrine (and other direct alpha-agonists): Pressor response to I.V. epinephrine, norepinephrine, and phenylephrine may be enhanced in patients receiving TCAs ( Note: Effect is unlikely with epinephrine or levonordefrin dosages typically administered as infiltration in combination with local anesthetics)

Fenfluramine: May increase tricyclic antidepressant levels/effects

Hypoglycemic agents (including insulin): TCAs may enhance the hypoglycemic effects of tolazamide, chlorpropamide, or insulin; monitor for changes in blood glucose levels; reported with chlorpropamide, tolazamide, and insulin

Levodopa: Tricyclic antidepressants may decrease the absorption (bioavailability) of levodopa; rare hypertensive episodes have also been attributed to this combination

Linezolid: Hyperpyrexia, hypertension, tachycardia, confusion, seizures, and deaths have been reported with agents which inhibit MAO (serotonin syndrome); this combination should be avoided

Lithium: Concurrent use with a TCA may increase the risk for neurotoxicity

MAO inhibitors: Hyperpyrexia, hypertension, tachycardia, confusion, seizures, and deaths have been reported (serotonin syndrome); this combination should be avoided

Methylphenidate: Metabolism of amitriptyline may be decreased

Phenothiazines: Serum concentrations of some TCAs may be increased; in addition, TCAs may increase concentration of phenothiazines; monitor for altered clinical response

QTc-prolonging agents: Concurrent use of tricyclic agents with other drugs which may prolong QTc interval may increase the risk of potentially fatal arrhythmias; includes type Ia and type III antiarrhythmics agents, selected quinolones (sparfloxacin, gatifloxacin, moxifloxacin, grepafloxacin), cisapride, and other agents

Ritonavir: Combined use of high-dose tricyclic antidepressants with ritonavir may cause serotonin syndrome in HIV-positive patients; monitor

Sucralfate: Absorption of tricyclic antidepressants may be reduced with coadministration.

Sympathomimetics, indirect-acting: Tricyclic antidepressants may result in a decreased sensitivity to indirect-acting sympathomimetics; includes dopamine and ephedrine; also see interaction with epinephrine (and direct-acting sympathomimetics)

Tramadol: Tramadol's risk of seizures may be increased with TCAs

Valproic acid: May increase serum concentrations/adverse effects of some tricyclic antidepressants

Warfarin (and other oral anticoagulants): Amitriptyline may increase the anticoagulant effect in patients stabilized on warfarin; monitor INR

Ethanol/Nutrition/Herb Interactions

Ethanol: Avoid ethanol (may increase CNS depression).

Food: Grapefruit juice may inhibit the metabolism of some TCAs and clinical toxicity may result.

Herb/Nutraceutical: Avoid valerian, St John's wort, SAMe, kava kava.

Mechanism of Action

Reduces the reuptake of serotonin and norepinephrine. The metabolite, 7-OH-amoxapine has significant dopamine receptor blocking activity similar to haloperidol.

Pharmacodynamics/Kinetics

Onset of antidepressant effect: Usually occurs after 1-2 weeks, but may require 4-6 weeks

Absorption: Rapid and well absorbed

Distribution: Vd: 0.9-1.2 L/kg; enters breast milk

Protein binding: 80%

Metabolism: Primarily hepatic

Half-life elimination: Parent drug: 11-16 hours; Active metabolite (8-hydroxy): Adults: 30 hours

Time to peak, serum: 1-2 hours

Excretion: Urine (as unchanged drug and metabolites)

Dosage

Oral:

Children: Not established in children <16 years of age.

Adolescents: Initial: 25-50 mg/day; increase gradually to 100 mg/day; may administer as divided doses or as a single dose at bedtime

Adults: Initial: 25 mg 2-3 times/day, if tolerated, dosage may be increased to 100 mg 2-3 times/day; may be given in a single bedtime dose when dosage <300 mg/day

Elderly: Initial: 25 mg at bedtime increased by 25 mg weekly for outpatients and every 3 days for inpatients if tolerated; usual dose: 50-150 mg/day, but doses up to 300 mg may be necessary

Maximum daily dose:

Inpatient: 600 mg

Outpatient: 400 mg

Administration

May be administered with food to decrease GI distress.

Monitoring Parameters

Monitor blood pressure and pulse rate prior to and during initial therapy evaluate mental status; monitor weight; ECG in older adults

Reference Range

Therapeutic: Amoxapine: 20-100 ng/mL (SI: 64-319 nmol/L); 8-OH amoxapine: 150-400 ng/mL (SI: 478-1275 nmol/L); both: 200-500 ng/mL (SI: 637-1594 nmol/L)

Patient Education

Inform prescriber of all prescriptions (including oral contraceptives), OTC medications, or herbal products you are taking, and any allergies you have. Take exactly as directed; do not increase dose or frequency. It may take several weeks to achieve desired results. Restrict use of alcohol and caffeine; avoid grapefruit juice. Maintain adequate hydration (2-3 L/day of fluids) unless instructed to restrict fluid intake. If you have diabetes, monitor glucose levels closely; this medication may alter glucose levels. May cause drowsiness, lightheadedness, impaired coordination, dizziness, or blurred vision (use caution when driving or engaging in tasks requiring alertness until response to drug is known); nausea, vomiting, increased appetite, or dry mouth (small, frequent meals, frequent mouth care, chewing gum, or sucking lozenges may help); constipation (increased exercise, fluids, fruit, or fiber may help); or altered sexual drive or ability (reversible). Report persistent CNS effects (eg, confusion, restlessness, anxiety, insomnia, excitation, headache, dizziness, fatigue, impaired coordination); muscle cramping, weakness, tremors, rigidity or alterations in ambulation; visual disturbances; excessive GI symptoms (eg, cramping, constipation, vomiting); or worsening of condition. Pregnancy/breast-feeding precautions: Inform prescriber if you are or intend to become pregnant. Do not breast-feed.

Additional Information

Extrapyramidal reactions and tardive dyskinesia may occur.

Dental Health: Effects on Dental Treatment

Key adverse event(s) related to dental treatment: Xerostomia and changes in salivation (normal salivary flow resumes upon discontinuation). Long-term treatment with TCAs, such as amoxapine, increases the risk of caries by reducing salivation and salivary buffer capacity.

Dental Health: Vasoconstrictor/Local Anesthetic Precautions

Use with caution; epinephrine, norepinephrine and levonordefrin have been shown to have an increased pressor response in combination with TCAs

Dosage Forms

Tablet: 25 mg, 50 mg, 100 mg, 150 mg

References

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International Brand Names

Asendin® (ID, NZ); Asendis® (GB); Défanyl® (FR); Demolox® (AR, ES, IN)

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