clomipramine hydrochloride
Anafranil

Available forms
Available by prescription only
Capsules: 25 mg, 50 mg, 75 mg

Indications and dosages
 Obsessive-compulsive disorder (OCD). Adults: Initially, 25 mg P.O. daily, gradually increasing to 100 mg P.O. daily (in divided doses, with meals) during the first 2 weeks. Maximum dosage is 250 mg daily. After adjustment, entire daily dose may be given h.s.
Children and adolescents: Initially, 25 mg P.O. daily, gradually increased to a maximum of 3 mg/kg or 100 mg P.O. daily, whichever is smaller (in divided doses, with meals) over the first 2 weeks. Maximum daily dose is 3 mg/kg or 200 mg, whichever is smaller. After adjustment, entire daily dose may be given h.s.

Pharmacodynamics
Antiobsessional and antidepressant actions: A selective inhibitor of serotonin (5-HT) reuptake into neurons within the CNS. It also may have some blocking activity at postsynaptic dopamine receptors. The exact mechanism by which clomipramine treats OCD is unknown.

Pharmacokinetics
Absorption: Well absorbed from GI tract, but extensive first-pass metabolism limits bioavailability to about 50%.
Distribution: Distributed well into lipophilic tissues; the volume of distribution is about 12 L/kg; 98% is bound to plasma proteins.
Metabolism: Metabolism is primarily hepatic. Several metabolites have been identified; desmethylclomipramine is the primary active metabolite.
Excretion: About 66% is excreted in the urine and the remainder in the feces. Mean elimination half-life of the parent compound is about 36 hours; the mean elimination half-life of desmethylclomipramine is 69 hours. After multiple dosing, the half-life may increase.

Contraindications and precautions
Contraindicated in patients hypersensitive to drug or other TCAs, in those who have taken an MAO inhibitor within the previous 14 days, and in patients during acute recovery period after MI.
  Use cautiously in patients with CV disease, urine retention, suicidal tendencies, glaucoma, increased intraocular pressure, brain damage, or seizure disorders and in those taking medications that may lower the seizure threshold. Also use cautiously in patients with impaired renal or hepatic function, hyperthyroidism, or tumors of the adrenal medulla and in those undergoing elective surgery or receiving thyroid medication or electroconvulsive treatment.

Interactions
Drug-drug. Barbiturates: Decreases TCA blood levels. Monitor patient for decreased effectiveness.
Barbiturates, CNS depressants: May cause exaggerated depressant effect. Avoid use together.
Epinephrine, norepinephrine: May produce increased hypertensive effect. Avoid use together.
MAO inhibitors: May cause hyperpyretic crisis, seizures, coma, and death. Don’t use together.
Methylphenidate: May increase TCA blood levels. Monitor patient closely.
Drug-herb. Evening primrose oil: May cause additive or synergistic effect resulting in lower seizure threshold and increasing risk of seizure. Discourage use together.
Drug-food. Grapefruit juice: Elevates levels of clomipramine and reduces levels of the metabolite, desmethylclomipramine. Discourage intake of grapefruit juice.
Drug-lifestyle. Alcohol use: Exaggerates depressant effect. Discourage use together.
Smoking: Decreases clomipramine levels. Discourage smoking.
Sun exposure: Causes increased risk of photosensitivity. Advise patient to take precautions.

Adverse reactions
CNS: somnolence, tremor, dizziness, headache, insomnia, nervousness, myoclonus, fatigue, syncope, EEG changes, seizures, confusion.
CV: orthostatic hypotension, palpitations, tachycardia, chest pain, ECG changes.
EENT: pharyngitis, rhinitis, visual changes.
GI: dry mouth, constipation, nausea, dyspepsia, increased appetite, diarrhea, anorexia, abdominal pain.
GU: urinary hesitancy, urinary tract infection, dysmenorrhea, ejaculation failure, impotence.
Hematologic: purpura, anemia.
Metabolic: weight gain.
Musculoskeletal: myalgia.
Skin: diaphoresis, rash, pruritus, dry skin.
Other: altered libido.

Effects on lab test results
None reported.

Overdose and treatment
Signs and symptoms of clomipramine overdose are similar to those of other TCAs and include sinus tachycardia, intraventricular block, hypotension, irritability, fixed and dilated pupils, drowsiness, delirium, stupor, hyperreflexia, and hyperpyrexia.
 Treatment should include gastric lavage with large quantities of fluid. Continue lavage for 12 hours because the anticholinergic effects of the drug slow gastric emptying. Hemodialysis, peritoneal dialysis, and forced diuresis are ineffective because of the high degree of plasma protein binding. Support respirations and monitor cardiac function. Treat shock with plasma expanders or corticosteroids; treat seizures with diazepam.

Special considerations
 ALERT To minimize risk of overdose, dispense drug in small quantities.
• Don’t withdraw drug abruptly.
• Mania or hypomania may occur with clomipramine therapy.
• Observe patient for urine retention and constipation. Suggest stool softener or high-fiber diet, as needed, and encourage adequate fluid intake.
Breast-feeding patients
• Drug appears in breast milk. Use cautiously in breast-feeding women.

Patient education
• Warn patient to avoid hazardous activities that require alertness or good psychomotor coordination until adverse CNS effects are known. This is especially important during initial titration period when daytime sedation and dizziness may occur.
• Suggest that patient relieve dry mouth with saliva substitutes or sugarless candy or gum.
• Tell patient that adverse GI effects can be minimized by taking drug with meals during the titration period. Later, the entire daily dose may be taken at bedtime to limit daytime drowsiness.
• Inform patient to avoid using OTC medications, particularly antihistamines and decongestants.
• Encourage patient to continue therapy, even if adverse reactions are troublesome. Advise patient not to stop taking it without medical approval.

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