doxepin hydrochloride
Sinequan, Triadapin ◆

Available forms
Available by prescription only
Capsules: 10 mg, 25 mg, 50 mg, 75 mg, 100 mg, 150 mg
Oral concentrate: 10 mg/ml

Indications and dosages
 Depression or anxiety. Adults: Initially, 25 to 75 mg P.O. daily in divided doses, to a maximum of 300 mg daily. Or, give entire maintenance dosage once daily with a maximum dose of 150 mg P.O.
≡ Dosage adjustment. Reduce dosage in elderly, debilitated, or adolescent patients and in those receiving other drugs (especially anticholinergics).

Pharmacodynamics
Antidepressant action: Doxepin is thought to exert 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. Doxepin more actively inhibits reuptake of serotonin than norepinephrine. Anxiolytic effects of this drug usually precede antidepressant effects. Doxepin also may be used as an anxiolytic. Doxepin has the greatest sedative effect of all tricyclic antidepressants; tolerance to this effect usually develops in a few weeks.

Pharmacokinetics
Absorption: Absorbed rapidly from the GI tract after oral administration.
Distribution: Distributed widely into the body, including the CNS and breast milk. Drug is 90% protein-bound. Steady-state is achieved within 7 days.
Metabolism: Metabolized by the liver to the active metabolite desmethyldoxepin. A significant first-pass effect may explain variability of serum levels in different patients taking the same dosage.
Excretion: Mostly excreted in urine.

Contraindications and precautions
Contraindicated in patients hypersensitive to drug and in those with glaucoma or a tendency to retain urine. Use cautiously in patients with CV disease because of the increased risk of arrhythmias, patients with suicidal ideation, patients with renal or hepatic impairment, and patients with seizure or thyroid disorders.

Interactions
Drug-drug. Antiarrhythmics such as disopyramide, procainamide, and quinidine; pimozide; thyroid drugs: May increase risk of cardiac arrhythmias and conduction defects. Monitor ECG closely.
Atropine, other anticholinergics: Increases risk of oversedation, paralytic ileus, visual changes, and severe constipation. Monitor patient closely.
Barbiturates: Increases doxepin metabolism and decreases therapeutic efficacy. Monitor patient closely; dosage adjustment may be needed.
Beta blockers, cimetidine, fluoxetine, methylphenidate, hormonal contraceptives, propoxyphene, sertraline: May inhibit doxepin metabolism, increasing plasma levels and toxicity. Monitor serum level closely.
Centrally acting antihypertensives: Decreases hypotensive effects. Monitor blood pressure closely.
Clonidine: Increases hypertensive effect. Monitor blood pressure closely.
CNS depressants: Additive effects are likely. Avoid use together.
Disulfiram, ethchlorvynol: Increases risk of delirium and tachycardia. Monitor patient closely.
Drugs metabolized by CYP2D6 (other antidepressants, phenothiazines, carbamazepine, type 1C antiarrhythmics) or drugs that inhibit this enzyme (quinidine): May increase adverse effects and toxicity of either drug. Decreased drug doses may be necessary.
Haloperidol, phenothiazines: Decreases metabolism and increases doxepin levels. Adjust dosages of both drugs.
MAO inhibitors: Increases risk of severe excitation, hyperpyrexia, or seizures, usually with high dose. Avoid use together.
Metrizamide: Increases risk of seizures. Avoid use together.
Sympathomimetics, such as ephedrine, epinephrine, and norepinephrine: May increase blood pressure. Use cautiously.
Warfarin: May increase PT and INR and risk of bleeding. Monitor PT and INR.
Drug-herb. Evening primrose oil: May cause additive or synergistic effect resulting in lower seizure threshold and increased risk of seizure. Discourage use together.
Drug-food. Carbonated beverages, grape juice: Incompatible. Don’t give together.
Drug-lifestyle. Alcohol use: Enhances CNS depression. Discourage alcohol use.
Heavy smoking: Increases doxepin metabolism and decreases efficacy. Discourage smoking.
Sun exposure: Causes increased risk of photosensitivity reactions. Advise patient to take precautions.

Adverse reactions
CNS: drowsiness, dizziness, agitation, confusion, numbness, hallucinations, paresthesia, ataxia, weakness, headache, seizures, extrapyramidal reactions.
CV: orthostatic hypotension, tachycardia, ECG changes, arrhythmias.
EENT: blurred vision, tinnitus.
GI: dry mouth, constipation, nausea, vomiting, anorexia.
GU: urine retention.
Hematologic: eosinophilia, neutropenia, bone marrow depression.
Metabolic: hyperglycemia, hypoglycemia.
Skin: diaphoresis, rash, urticaria, photosensitivity.
Other: hypersensitivity reaction.

Effects on lab test results
• May increase or decrease glucose levels. May increase liver function test values.
• May increase eosinophil count and decrease neutrophil count.

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 dilatation, 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. Severity of overdose is best indicated by widening of QRS complex. Metabolic acidosis may follow hypotension, hypoventilation, and seizures.
 Treatment is symptomatic and supportive, including maintaining airway, stable body temperature, and fluid and electrolyte balance. Emesis is contraindicated. Gastric lavage and activated charcoal may prevent further absorption. Dialysis is of little use. Physostigmine may be cautiously used to reverse central anticholinergic effects. Treat seizures with parenteral diazepam or phenytoin; 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 Because hypertensive episodes have occurred during surgery in patients receiving TCAs, gradually discontinue drug several days before surgery.
• After abrupt withdrawal of long-term therapy, patient may experience nausea, headache, and malaise. This doesn’t indicate addiction.
• Cross-sensitivity between dibenzoxepines may occur.
Breast-feeding patients
• Drug appears in breast milk. Avoid use of drug in breast-feeding women, especially if high doses are used.
Pediatric patients
• Doxepin is rarely used to treat anxiety in children.
Geriatric patients
• Adverse CNS reactions, orthostatic hypotension, and GI and GU disturbances are more likely to develop in elderly patients.

Patient education
• Teach patient to dilute oral concentrate with 4 oz (120 ml) of water, milk, or juice (grapefruit, orange, pineapple, prune, or tomato). Caution patient that drug is incompatible with carbonated beverages.
• Tell patient to use ice chips, sugarless gum or hard candy, or saliva substitutes to treat dry mouth.
• Warn patient to avoid taking other drugs while taking doxepin unless they’ve been prescribed.
• Instruct patient to take full dose at bedtime.
• Advise patient that tolerance usually develops to sedative effects in a few weeks.
• Inform patient that antidepressant responses may take 2 to 4 weeks.

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