Amoxapine

MEDICATION SAFETY ISSUES
Sound-alike/look-alike issues:
Amoxapine may be confused with amoxicillin, Amoxil®
Asendin may be confused with aspirin

MEDICATION GUIDE — An FDA-approved patient medication guide, which is available with the product information and at http://www.fda.gov/downloads/Drugs/DrugSafety/ucm088622.pdf, must be dispensed with this medication for each new outpatient prescription and refill.

PHARMACOLOGIC CATEGORY
Antidepressant, Tricyclic (Secondary Amine)

DOSING: ADULTS — Once symptoms are controlled, decrease gradually to lowest effective dose. Maintenance dose is usually given at bedtime to reduce daytime sedation.

Depression: Oral: 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.
Maximum daily dose: 600 mg (inpatients); 400 mg (outpatients)

DOSING: PEDIATRIC
Depression: 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.

Note: Once symptoms are controlled, decrease gradually to lowest effective dose. Maintenance dose is usually given at bedtime to reduce daytime sedation.

DOSING: ELDERLY — Oral: 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. Note: Once symptoms are controlled, decrease gradually to lowest effective dose. See Geriatric Considerations.

DOSAGE FORMS — Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

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

DOSAGE FORMS: CONCISE
Tablet: 25 mg, 50 mg, 100 mg, 150 mg

GENERIC EQUIVALENT AVAILABLE — Yes

ADMINISTRATION — May be administered with food to decrease GI distress.

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

ADVERSE REACTIONS SIGNIFICANT
>10%:
Central nervous system: Drowsiness
Gastrointestinal: Xerostomia, constipation

1% to 10%:
Central nervous system: Anxiety, ataxia, confusion, dizziness, excitement, headache, insomnia, nervousness, restlessness
Dermatologic: Edema, skin rash
Endocrine: Prolactin levels increased
Gastrointestinal: Nausea
Neuromuscular & skeletal: Tremor, weakness
Ocular: Blurred vision
Miscellaneous: Diaphoresis

<1% (Limited to important or life-threatening): Agranulocytosis, allergic reactions, diarrhea, extrapyramidal symptoms, galactorrhea, hypertension, impotence, incoordination, intraocular pressure increased, leukopenia, menstrual irregularity, mydriasis, neuroleptic malignant syndrome, numbness, painful ejaculation, paresthesia, photosensitivity, seizure, SIADH, syncope, tardive dyskinesia, testicular edema, tinnitus, urinary retention, vomiting

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
Boxed warnings: Suicidal thinking/behavior: See "Major psychiatric warnings" below.

Major psychiatric warnings:
• [U.S. Boxed Warning]: Antidepressants increase the risk of suicidal thinking and behavior in children, adolescents, and young adults (18-24 years of age) with major depressive disorder (MDD) and other psychiatric disorders; consider risk prior to prescribing. Short-term studies did not show an increased risk in patients >24 years of age and showed a decreased risk in patients ≥ 65 years. Closely monitor patients for clinical worsening, suicidality, or unusual changes in behavior, particularly during the initial 1-2 months of therapy or during periods of dosage adjustments (increases or decreases); the patient's family or caregiver should be instructed to closely observe the patient and communicate condition with healthcare provider. A medication guide concerning the use of antidepressants should be dispensed with each prescription. Amoxapine is not FDA approved for use in patients <16 years of age. The possibility of a suicide attempt is inherent in major depression and may persist until remission occurs. Patients treated with antidepressants should be observed for clinical worsening and suicidality, especially during the initial few months of a course of drug therapy, or at times of dose changes, either increases or decreases. Worsening depression and severe abrupt suicidality that are not part of the presenting symptoms may require discontinuation or modification of drug therapy. Use caution in high-risk patients during initiation of therapy. Prescriptions should be written for the smallest quantity consistent with good patient care. The patient's family or caregiver should be alerted to monitor patients for the emergence of suicidality and associated behaviors such as anxiety, agitation, panic attacks, insomnia, irritability, hostility, impulsivity, akathisia, hypomania, and mania; patients should be instructed to notify their healthcare provider if any of these symptoms or worsening depression or psychosis occur. May worsen psychosis in some patients or precipitate a shift to mania or hypomania in patients with bipolar disorder. Monotherapy in patients with bipolar disorder should be avoided. Patients presenting with depressive symptoms should be screened for bipolar disorder. Amoxapine is not FDA approved for the treatment of bipolar depression.

Concerns related to adverse effects: Anticholinergic effects: May cause anticholinergic effects (constipation, xerostomia, blurred vision, urinary retention); use with caution in patients with decreased gastrointestinal motility, paralytic ileus, urinary retention, BPH, xerostomia, or visual problems. The degree of anticholinergic blockade produced by this agent is moderate relative to other antidepressants. Extrapyramidal symptoms: May cause extrapyramidal symptoms, including pseudoparkinsonism, acute dystonic reactions, akathisia, and tardive dyskinesia (risk of these reactions is low). Neuroleptic malignant syndrome (NMS): Use may be associated with NMS; monitor for mental status changes, fever, muscle rigidity, and/or autonomic instability (risk may be increased in patients with Parkinson's disease or Lewy body dementia). Orthostatic hypotension: May cause orthostatic hypotension (risk is moderate relative to other antidepressants); use with caution in patients at risk of this effect or in those who would not tolerate transient hypotensive episodes (cerebrovascular disease, cardiovascular disease, hypovolemia, or concurrent medication use which may predispose to hypotension/bradycardia). Sedation: May cause sedation, which may impair physical or mental abilities; patients must be cautioned about performing tasks which require mental alertness (eg, operating machinery or driving). The degree of sedation is moderate relative to other antidepressants.

Disease-related concerns: Cardiovascular disease: 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. Hepatic impairment: Use with caution in patients with hepatic impairment. Renal impairment: Use with caution in patients with renal impairment. Seizure disorder: Use with caution in patients at risk of seizures, including those with a history of seizures, head trauma, brain damage, alcoholism, or concurrent therapy with medications which may lower seizure threshold. Thyroid dysfunction: Use with caution in patients with hyperthyroidism or those receiving thyroid supplementation.

Concurrent drug therapy issues: Sedatives: Effects may be potentiated when used with other sedative drugs or ethanol.

Special populations: Elderly: Use with caution in the elderly.

Other warnings/precautions: Discontinuation of therapy: Therapy should not be abruptly discontinued in patients receiving high doses for prolonged periods. Electroconvulsive therapy: May increase the risks associated with electroconvulsive therapy; consider discontinuing, when possible, prior to ECT treatment.

METABOLISM / TRANSPORT EFFECTS — Substrate of CYP2D6 (major)

DRUG INTERACTIONS
Acetylcholinesterase Inhibitors (Central): Anticholinergics may diminish the therapeutic effect of Acetylcholinesterase Inhibitors (Central). Acetylcholinesterase Inhibitors (Central) may diminish the therapeutic effect of Anticholinergics. If the anticholinergic action is a side effect of the agent, the result may be beneficial. Risk C: Monitor therapy

Alcohol (Ethyl): CNS Depressants may enhance the CNS depressant effect of Alcohol (Ethyl). Risk C: Monitor therapy

Alfuzosin: May enhance the QTc-prolonging effect of QTc-Prolonging Agents. Risk C: Monitor therapy

Alpha-/Beta-Agonists (Direct-Acting): Tricyclic Antidepressants may enhance the vasopressor effect of Alpha-/Beta-Agonists (Direct-Acting). Exceptions: Dipivefrin. Risk D: Consider therapy modification

Alpha1-Agonists: Tricyclic Antidepressants may enhance the vasopressor effect of Alpha1-Agonists. Risk D: Consider therapy modification

Alpha2-Agonists: Tricyclic Antidepressants may diminish the antihypertensive effect of Alpha2-Agonists. Exceptions: Apraclonidine; Brimonidine. Risk D: Consider therapy modification

Altretamine: May enhance the orthostatic effect of Tricyclic Antidepressants. Risk C: Monitor therapy

Amphetamines: Tricyclic Antidepressants may enhance the stimulatory effect of Amphetamines. Tricyclic Antidepressants may also potentiate the cardiovascular effects of Amphetamines. Risk C: Monitor therapy

Anticholinergics: May enhance the adverse/toxic effect of other Anticholinergics. Exceptions: Paliperidone. Risk C: Monitor therapy

Artemether: May enhance the QTc-prolonging effect of QTc-Prolonging Agents. Risk X: Avoid combination

Barbiturates: May increase the metabolism of Tricyclic Antidepressants. Risk D: Consider therapy modification

Beta2-Agonists: Tricyclic Antidepressants may enhance the adverse/toxic effect of Beta2-Agonists. Risk C: Monitor therapy

CarBAMazepine: May increase the metabolism of Tricyclic Antidepressants. Risk C: Monitor therapy

Chloroquine: May enhance the QTc-prolonging effect of QTc-Prolonging Agents. Risk C: Monitor therapy

Cimetidine: May decrease the metabolism of Tricyclic Antidepressants. Risk C: Monitor therapy

Cinacalcet: May increase the serum concentration of Tricyclic Antidepressants. Risk C: Monitor therapy

Ciprofloxacin: May enhance the QTc-prolonging effect of QTc-Prolonging Agents. Risk C: Monitor therapy

CNS Depressants: May enhance the adverse/toxic effect of other CNS Depressants. Risk C: Monitor therapy

CYP2D6 Inhibitors (Moderate): May decrease the metabolism of CYP2D6 Substrates. Risk C: Monitor therapy

CYP2D6 Inhibitors (Strong): May decrease the metabolism of CYP2D6 Substrates. Risk D: Consider therapy modification

Desmopressin: Tricyclic Antidepressants may enhance the adverse/toxic effect of Desmopressin. Risk C: Monitor therapy

Dexmethylphenidate: May decrease the metabolism of Tricyclic Antidepressants. Risk C: Monitor therapy

Dronedarone: QTc-Prolonging Agents may enhance the QTc-prolonging effect of Dronedarone. Risk X: Avoid combination

DULoxetine: May decrease the metabolism of Tricyclic Antidepressants. Risk C: Monitor therapy

Gadobutrol: May enhance the QTc-prolonging effect of QTc-Prolonging Agents. Risk D: Consider therapy modification

Iobenguane I 123: Tricyclic Antidepressants may diminish the therapeutic effect of Iobenguane I 123. Risk X: Avoid combination

Lithium: May enhance the neurotoxic effect of Tricyclic Antidepressants. Risk C: Monitor therapy

Lumefantrine: May enhance the QTc-prolonging effect of QTc-Prolonging Agents. Risk X: Avoid combination

MAO Inhibitors: May enhance the serotonergic effect of Tricyclic Antidepressants. This may cause serotonin syndrome. Risk X: Avoid combination

MAO Inhibitors: May enhance the orthostatic effect of Orthostasis Producing Agents. Risk C: Monitor therapy

Methylphenidate: May decrease the metabolism of Tricyclic Antidepressants. Risk C: Monitor therapy

Nilotinib: May enhance the QTc-prolonging effect of QTc-Prolonging Agents. Risk X: Avoid combination

Peginterferon Alfa-2b: May decrease the serum concentration of CYP2D6 Substrates. Risk C: Monitor therapy

Pimozide: QTc-Prolonging Agents may enhance the QTc-prolonging effect of Pimozide. Risk X: Avoid combination

Pramlintide: May enhance the anticholinergic effect of Anticholinergics. These effects are specific to the GI tract. Risk D: Consider therapy modification

Propoxyphene: May enhance the CNS depressant effect of Tricyclic Antidepressants. Risk C: Monitor therapy

Protease Inhibitors: May increase the serum concentration of Tricyclic Antidepressants. Risk C: Monitor therapy

QTc-Prolonging Agents: May enhance the adverse/toxic effect of other QTc-Prolonging Agents. Their effects can be additive, causing life-threatening ventricular arrhythmias. Risk D: Consider therapy modification

QuiNIDine: Tricyclic Antidepressants may enhance the QTc-prolonging effect of QuiNIDine. QuiNIDine may decrease the metabolism of Tricyclic Antidepressants. Risk D: Consider therapy modification

QuiNINE: QTc-Prolonging Agents may enhance the QTc-prolonging effect of QuiNINE. QuiNINE may enhance the QTc-prolonging effect of QTc-Prolonging Agents. Risk X: Avoid combination

Selective Serotonin Reuptake Inhibitors: May decrease the metabolism of Tricyclic Antidepressants. Risk D: Consider therapy modification

Serotonin Modulators: May enhance the adverse/toxic effect of other Serotonin Modulators. The development of serotonin syndrome may occur. Risk D: Consider therapy modification

Sibutramine: May enhance the serotonergic effect of Serotonin Modulators. This may cause serotonin syndrome. Risk X: Avoid combination

St Johns Wort: May increase the metabolism of Tricyclic Antidepressants. The risk of serotonin syndrome may theoretically be increased. Risk D: Consider therapy modification

Sulfonylureas: Cyclic Antidepressants may enhance the hypoglycemic effect of Sulfonylureas. Risk C: Monitor therapy

Terbinafine: May decrease the metabolism of Tricyclic Antidepressants. Risk D: Consider therapy modification

Tetrabenazine: QTc-Prolonging Agents may enhance the QTc-prolonging effect of Tetrabenazine. Risk X: Avoid combination

Thioridazine: QTc-Prolonging Agents may enhance the QTc-prolonging effect of Thioridazine. Risk X: Avoid combination

TraMADol: Tricyclic Antidepressants may enhance the neuroexcitatory and/or seizure-potentiating effect of TraMADol. Risk C: Monitor therapy

Valproic Acid: May increase the serum concentration of Tricyclic Antidepressants. Risk C: Monitor therapy

Vitamin K Antagonists (eg, warfarin): Tricyclic Antidepressants may enhance the anticoagulant effect of Vitamin K Antagonists. Risk C: Monitor therapy

Yohimbine: Tricyclic Antidepressants may increase the serum concentration of Yohimbine. Risk C: Monitor therapy

Ziprasidone: QTc-Prolonging Agents may enhance the QTc-prolonging effect of Ziprasidone. The risk of a severe arrhythmia may be increased. Risk X: Avoid combination

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.

PREGNANCY RISK FACTOR — C (show table)

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

PRICING — (data from drugstore.com)
Tablets (Amoxapine)
25 mg (60): $25.99
50 mg (60): $28.99
100 mg (30): $35.99
150 mg (30): $38.99

MONITORING PARAMETERS — Monitor blood pressure and pulse rate prior to and during initial therapy evaluate mental status, suicidal ideation (especially at the beginning of therapy or when doses are increased or decreased); 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)

INTERNATIONAL BRAND NAMES — Asendin (ID); Defanyl (FR); Demolox (DK, IN)

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)

PATIENT INFORMATION — Dry mouth may be helped by sips of water, sugarless gum, or hard candy; avoid alcohol; very important to maintain established dosage regimen; photosensitivity to sunlight can occur, do not discontinue abruptly; full effect may not occur for 3-4 weeks; full dosage may be taken at bedtime to avoid daytime sedation