imipramine hydrochloride
Apo-Imipramine ◆, Impril ◆, Novopramine ◆, Tofranil

imipramine pamoate
Tofranil-PM

Available forms
Available by prescription only
imipramine hydrochloride
Tablets: 10 mg, 25 mg, 50 mg
imipramine pamoate
Capsules: 75 mg, 100 mg, 125 mg, 150 mg

Indications and dosages
 Depression. Adults: Initially, 75 to 100 mg P.O. daily in divided doses, with 25- to 50-mg increments, up to 200 mg. Or, some patients can start with lower doses (25 mg P.O.) and dosage is adjusted slowly in 25-mg increments every other day. Maximum dose is 300 mg daily. Or, entire dosage may be given h.s. Maximum daily dose is 200 mg for outpatients, 300 mg for inpatients, 100 mg for elderly patients.
Elderly patients: Give 30 to 40 mg P.O. daily, not to exceed 100 mg daily. Start therapy at low doses (10 mg) and adjust slowly.
 Childhood enuresis. Children age 6 and older: 25 to 75 mg P.O. daily, 1 hour before bedtime. Usual dose is 1.5 mg/kg daily in three divided doses. Maximum dose is 2.5 mg/kg daily.

Pharmacodynamics
Antidepressant action: Imipramine 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. Drug also has anticholinergic activity and is used to treat nocturnal enuresis in children older than age 6.

Pharmacokinetics
Absorption: Absorbed rapidly from GI tract.
Distribution: Distributed widely throughout the body, including the CNS and breast milk. Drug is 90% protein-bound. Steady state is achieved within 2 to 5 days. Therapeutic plasma levels (parent drug and metabolite) range from 150 to 300 ng/ml.
Metabolism: Metabolized by the liver to the active metabolite desipramine. 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 during acute recovery phase of MI, in patients hypersensitive to drug, and in those receiving MAO inhibitors.
  Use cautiously in patients at risk for suicide; in those with impaired renal or hepatic function, history of urine retention, angle-closure glaucoma, increased intraocular pressure, CV disease, hyperthyroidism, and in patients receiving thyroid medications.

Interactions
Drug-drug. Antiarrhythmics (disopyramide, procainamide, quinidine), pimozide, thyroid medication: May increase risk of arrhythmias and conduction defects. Avoid use together.
Atropine or other anticholinergic drugs, including antihistamines, antiparkinsonian agents, meperidine, and phenothiazines; CNS depressants, including analgesics, anesthetics, barbiturates, narcotics, and tranquilizers: Causes oversedation, paralytic ileus, visual changes, and severe constipation. Avoid use together.
Barbiturates: Induces imipramine metabolism and decreases therapeutic efficacy. Avoid use together.
Beta blockers, cimetidine, methylphenidate, hormonal contraceptives, propoxyphene: Inhibits imipramine metabolism, increasing plasma levels and toxicity. Use together cautiously.
Centrally acting antihypertensives, such as clonidine, guanabenz, guanadrel, guanethidine, methyldopa, and reserpine: Decreases hypotensive effects of antihypertensives. Use cautiously.
Disulfiram or ethchlorvynol: May cause delirium and tachycardia. Observe patient closely.
Haloperidol and phenothiazines: Decreases metabolism of imipramine, decreasing therapeutic efficacy. Monitor patient closely.
Metrizamide: Increases risk of seizures. Monitor patient closely.
Sympathomimetics, including ephedrine, epinephrine, and phenylephrine (often found in nasal sprays): May increase blood pressure. Patient needs frequent blood pressure checks.
Warfarin: May prolong PT and cause bleeding. Monitor PT and INR.
Drug-herb. Evening primrose oil: May cause additive or synergistic effect, resulting in lower seizure threshold and increasing the risk of seizure. Discourage use together.
Drug-lifestyle. Alcohol use: Causes additive CNS depressant effects. Discourage alcohol use.
Heavy smoking: Induces imipramine metabolism and decreases therapeutic efficacy. Discourage smoking and monitor patient for therapeutic effect.

Adverse reactions
CNS: drowsiness, dizziness, excitation, tremor, confusion, hallucinations, anxiety, ataxia, paresthesia, nervousness, EEG changes, seizures, extrapyramidal reactions, CVA.
CV: orthostatic hypotension, tachycardia, ECG changes, hypertension, MI, arrhythmias, heart block, precipitation of heart failure.
EENT: blurred vision, tinnitus, mydriasis.
GI: dry mouth, constipation, nausea, vomiting, anorexia, paralytic ileus, abdominal cramps.
GU: urine retention, testicular swelling, impotence.
Skin: diaphoresis, rash, urticaria, photosensitivity, pruritus.
Other: gynecomastia, galactorrhea and breast enlargement, altered libido, SIADH, hypersensitivity reaction.

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

Overdose and treatment
Drug overdose is typically life-threatening, particularly when combined with alcohol. The first 12 hours after acute ingestion are a stimulatory phase characterized by excessive anticholinergic activity including agitation, irritation, confusion, hallucinations, hyperthermia, parkinsonian symptoms, seizure, 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 the QRS complex, which usually represents a serum level in excess of 1,000 ng/ml; serum levels are usually not helpful. Metabolic acidosis may follow hypotension, hypoventilation, and seizures.
 Treatment is symptomatic and supportive, including maintaining airway, stable body temperature, and fluid or electrolyte balance. Induce emesis 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 and arrhythmias with parenteral phenytoin or lidocaine. Don’t use quinidine, procainamide, and atropine during an overdose. Treat acidosis with sodium bicarbonate. Don’t give barbiturates; these may enhance CNS and respiratory depressant effects.

Special considerations
• Drug causes a high risk of orthostatic hypotension. Measure supine and standing blood pressures before and after initial dose.
• Discontinue drug at least 48 hours before surgical procedures.
• Don’t withdraw drug abruptly, but taper gradually over time. After abrupt withdrawal of long-term therapy, patient may experience nausea, headache, and malaise. These symptoms don’t indicate addiction.
• Tolerance to sedative effects of drug usually develops over several weeks.
Breast-feeding patients
• Drug appears in breast milk in low levels. The potential benefit to the woman should outweigh possible risks to the infant.
Pediatric patients
• Drug isn’t recommended for treating depression in patients younger than age 12. Don’t use pamoate salt for enuresis in children.
Geriatric patients
• Elderly patients may be at greater risk for adverse cardiac reactions.

Patient education
• Tell patient to take drug exactly as prescribed.
• Explain that full effects of drug may not become apparent for 4 to 6 weeks.
• Warn patient not to discontinue drug abruptly, not to share drug with others, and not to drink alcoholic beverages while taking drug.
• Advise patient to take drug with food or milk if it causes stomach upset.
• Suggest relieving dry mouth with sugarless chewing gum or hard candy. Encourage good dental prophylaxis because persistent dry mouth may lead to dental caries.
• Encourage patient to report unusual or troublesome effects immediately, including confusion, movement disorders, rapid heartbeat, dizziness, fainting, or difficulty urinating.

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