amoxapine

Available forms
Available by prescription only
Tablets: 25 mg, 50 mg, 100 mg, 150 mg

Indications and dosages
 Depression. Adults: Initial dosage is 50 mg P.O. b.i.d. or t.i.d; may increase to 100 mg b.i.d. or t.i.d. by end of first week. Increases above 300 mg daily should be made only if this dose has been ineffective during a trial period of at least 2 weeks. When effective dose is established, entire dose (not exceeding 300 mg) may be given h.s. No more than 400 mg daily for outpatients. Maximum dose in hospitalized patients is 600 mg. Don’t give more than 300 mg in a single dose.
≡ Dosage adjustment. For geriatric patients, recommended starting dosage is 25 mg P.O. b.i.d. to t.i.d.

Pharmacodynamics
Antidepressant action: Drug is thought to exert its antidepressant effects by inhibiting reuptake of norepinephrine and serotonin in CNS nerve terminals (presynaptic neurons), which results in increased levels and enhanced activity of these neurotransmitters in the synaptic cleft. Amoxapine has a greater inhibitory effect on norepinephrine reuptake than on serotonin. Drug also blocks CNS dopamine receptors, which may account for the higher occurrence of movement disorders during therapy.

Pharmacokinetics
Absorption: Absorbed rapidly and completely from the GI tract after oral administration.
Distribution: Distributed widely into the body, including the CNS and breast milk. Drug is 92% protein-bound. Steady state is reached within 2 to 7 days. Proposed therapeutic plasma levels (parent drug and metabolite) range from 200 to 500 ng/ml.
Metabolism: Metabolized by the liver to the active metabolite 8-hydroxyamoxapine; a significant first-pass effect may explain variability of serum levels in different patients taking the same dosage.
Excretion: Excreted in urine and feces (7% to 18%); about 60% of a given dose is excreted as the conjugated form within 6 days.

Contraindications and precautions
Contraindicated in patients hypersensitive to amoxapine, in those in the acute recovery phase of MI, and in those who have taken an MAO inhibitor within 14 days.
  Use cautiously in patients with history of urine retention, CV disease, angle-closure glaucoma, or increased intraocular pressure. Use with extreme caution in patients with history of seizures.

Interactions
Drug-drug. Antiarrhythmics (including disopyramide, procainamide, and quinidine), pimozide, thyroid drugs: Increases risk of arrhythmias and conduction defects. Avoid use together.
Anticholinergics (including antihistamines, antiparkinsonians, atropine, meperidine, and phenothiazines): Increase risk of oversedation, paralytic ileus, visual changes, and severe constipation. Use together cautiously.
Barbiturates: Induce amoxapine metabolism and decrease therapeutic efficacy. Monitor patient for clinical effects.
Beta blockers, cimetidine, hormonal contraceptives, methylphenidate, propoxyphene: May inhibit amoxapine metabolism, increasing plasma levels. Monitor patient for toxicity.
Centrally acting antihypertensives (such as clonidine, guanabenz, guanadrel, guanethidine, methyldopa, and reserpine): Decreases hypotensive effects of these drugs. Monitor clinical response.
CNS depressants (including analgesics, anesthetics, barbiturates, narcotics, and tranquilizers): Increase sedation. Use together cautiously.
Disulfiram, ethchlorvynol: May cause delirium and tachycardia. Use together cautiously.
Haloperidol, phenothiazines: Decrease metabolism, decreasing therapeutic efficacy. Monitor patient for clinical effects.
Metrizamide: Increases risk of seizures. Avoid use together.
Sympathomimetics, including epinephrine, phenylephrine, and ephedrine (commonly found in nasal sprays): May increase blood pressure. Avoid use together.
Warfarin: Increases PT, INR, and risk of bleeding. Monitor laboratory values, and decrease warfarin dosage.
Drug-herb. Evening primrose oil: May cause additive or synergistic effect, resulting in lower seizure threshold and increased risk of seizures. Discourage use together.
Drug-lifestyle. Alcohol use: Increases sedation. Discourage alcohol use.
Heavy smoking: Induces amoxapine metabolism and decreases therapeutic efficacy. Discourage smoking.
Sun exposure: May cause photosensitivity reactions. Advise patient to take precautions.

Adverse reactions
CNS: drowsiness, dizziness, excitation, tremor, weakness, confusion, anxiety, insomnia, restlessness, nightmares, ataxia, fatigue, headache, nervousness, tardive dyskinesia, EEG changes,seizures, extrapyramidal reactions, neuroleptic malignant syndrome (high fever, tachycardia, tachypnea, profuse diaphoresis).
CV: edema, orthostatic hypotension, tachycardia, hypertension, palpitations, prolonged conduction time (elongation of QT and PR intervals, flattened T waves on ECG).
EENT: blurred vision.
GI: dry mouth, constipation, nausea, excessive appetite.
GU: urine retention, acute renal failure (with overdose).
Hematologic: decreased WBC counts.
Hepatic: liver dysfunction.
Metabolic: hyperglycemia, hypoglycemia.
Skin: rash, diaphoresis.

Effects on lab test results
• May increase serum transaminase and alkaline phosphatase levels. May increase or decrease glucose levels.

Overdose and treatment
The first 12 hours after acute ingestion are a stimulatory phase characterized by excessive anticholinergic activity (agitation, irritation, confusion, hallucinations, hyperthermia, parkinsonian symptoms, seizures, urine retention, dry mucous membranes, pupillary dilation, constipation, and ileus). This is followed by CNS depressant effects, including hypothermia, decreased or absent reflexes, sedation, hypotension, cyanosis, and cardiac irregularities, including tachycardia, conduction disturbances, and quinidine-like effects on the ECG.
 Overdose with amoxapine produces a much higher risk of CNS toxicity than do other antidepressants. Acute deterioration of renal function (evidenced by myoglobin in urine) occurs in 5% of overdosed patients; this is most likely to occur in patients with repeated seizures after the overdose. Seizures may progress to status epilepticus within 12 hours.
 Severity of overdose is best indicated by widening of the QRS complex, which generally represents a serum level in excess of 1,000 ng/ml; serum levels aren’t usually helpful. Metabolic acidosis may follow hypotension, hypoventilation, and seizures.
 Treatment is symptomatic and supportive, including maintaining airway, stable body temperature, and fluid and electrolyte balance; monitor renal status because of the risk of renal failure. Induce emesis with ipecac if patient is conscious; follow with gastric lavage and activated charcoal to prevent further absorption. Dialysis is of little use. Treat seizures with parenteral diazepam or phenytoin (the value of physostigmine is less certain); arrhythmias, with parenteral phenytoin or lidocaine; and acidosis, with sodium bicarbonate. Don’t give barbiturates; these may enhance CNS and respiratory depressant effects.

Special considerations
 ALERT Don’t confuse amoxapine with amoxicillin.
• Amoxapine causes a high risk of seizures.
• Antidepressants can cause manic episodes during the depressed phase in patients with bipolar disorder.
• The full dose may be given at bedtime to help reduce daytime sedation.
• Monitor patient for tardive dyskinesia and other extrapyramidal effects, which may occur because of the dopamine-blocking activity of amoxapine.
• Watch for gynecomastia in men and women because amoxapine may increase cellular division in breast tissue.
• The full dose shouldn’t be withdrawn abruptly. After abrupt withdrawal of long-term therapy, patient may experience nausea, headache, and malaise. This doesn’t indicate addiction.
• Tolerance to sedative effects usually develops over the first few weeks of therapy.
• Discontinue drug at least 48 hours before surgical procedures.
• Sugarless chewing gum, hard candy, or ice may alleviate dry mouth.
Pregnant patients
• Safe use of tricyclic antidepressants in pregnancy hasn’t been established. Fetal malformations, urinary retention, CNS effects (lethargy), developmental delay, and withdrawal symptoms have occurred in neonates born to mothers taking tricyclic antidepressants during pregnancy.
Breast-feeding patients
• Amoxapine appears in breast milk at levels that are 20% those of maternal serum as parent drug and 30% as metabolites. The potential benefits to the woman should outweigh the possible adverse reactions in the infant.
Pediatric patients
• Drug isn’t recommended for patients younger than age 16.
Geriatric patients
• Lower doses are indicated for geriatric patients because they’re more sensitive to the therapeutic and adverse effects of drug.
• Geriatric patients are much more susceptible to tardive dyskinesia and extrapyramidal symptoms.

Patient education
• Explain that full effects of drug may not become apparent for 2 weeks or more after therapy begins, perhaps not for 4 to 6 weeks.
• Tell patient to take drug exactly as prescribed; however, full dose may be taken at bedtime to alleviate daytime sedation. Patient shouldn’t double the dose to make up for missing a dose.
• Warn patient to avoid hazardous activities that require alertness until full effects of the drug are known; it may cause drowsiness or dizziness.
• Tell patient not to drink alcoholic beverages while taking drug.
• Suggest that patient take drug with food or milk if it causes stomach upset; dry mouth can be relieved with sugarless gum or hard candy.
• After initial doses, tell patient to lie down for about 30 minutes and rise slowly to prevent dizziness.
• Warn patient not to discontinue drug suddenly.
• Encourage patient to report unusual or troublesome reactions immediately, especially confusion, movement disorders, rapid heartbeat, dizziness, fainting, or difficulty urinating.
• Inform patient that exposure to sunlight, sunlamps, or tanning beds may cause burning of the skin or abnormal pigmentary changes.

Reactions may be common, uncommon, life-threatening, or COMMON AND LIFE THREATENING.
◆ Canada only
◇ Unlabeled clinical use