Clomipramine Hydrochloride

Pronunciation: (kloe-MIH-pruh-meen HIGH-droe-KLOR-ide)Class: Tricyclic compound

Trade Names:Anafranil- Capsules 25 mg- Capsules 50 mg- Capsules 75 mg

Apo-Clopamine (Canada)CO Clomipramine (Canada)Gen-Clomipramine (Canada)

Pharmacology

Inhibits reuptake of serotonin in CNS.

Pharmacokinetics

Absorption

C _max is approximately 92 ng/mL (single 50 mg dose). T _max is approximately 4.7 h (single 50 mg dose). C _max at steady state is approximately 218 ng/mL (multiple 150 mg doses). Concentrations and AUC are not dose-proportional. Time to steady state is 7 to 14 days.

Distribution

Distributes into brain, breast milk, and CSF. Approximately 97% protein bound, principally to albumin.

Metabolism

Extensively biotransformed to desmethylclomipramine (active) and other metabolites.

Elimination

The t _½ is 19 to 37 h. Metabolites are excreted in the urine and feces following biliary elimination.

Indications and Usage

Relief of obsessive-compulsive disorder.

Unlabeled Uses

Treatment of panic disorder; treatment of premenstrual symptoms.

Contraindications

Hypersensitivity to any tricyclic antidepressant. Not to be given in combination with or within 14 days of treatment with MAOIs. Not to be given during acute recovery phases of MI.

Dosage and Administration

Adults Initial dose

PO 25 mg/day; gradually increase dose to 100 mg/day during first 2 wk. Dose then may be gradually increased to max of 250 mg/day.

Children 10 yr of age and younger Initial dose

PO 25 mg/day; gradually increase dose to 3 mg/kg/day or 100 mg/day (whichever is less) during first 2 wk; then slowly increase dose to max 3 mg/kg/day or 200 mg/day (whichever is less).

General Advice

• During titration phase, administer drug in divided doses daily with meals to lessen GI side effects.
• After titration, to minimize daytime sedation, give daily dose at bedtime with large glass of water.

Storage/Stability

Store at 68° to 77°F. Protect from moisture.

Drug Interactions

Anticholinergics

Effects may be increased.

Charcoal

May increase effects of clomipramine.

Cisapride

Cisapride is contraindicated in patients receiving tricyclic antidepressants.

Clonidine

May result in hypertensive crisis.

CNS depressants

Depressant effects may be additive.

Drugs highly protein bound (eg, digoxin, warfarin)

Clomipramine may displace these agents from their plasma protein-binding sites, resulting in transient increases in plasma concentrations.

Guanethidine

Antihypertensive effects may be decreased.

Hepatic enzyme inducers (eg, barbiturates, hydantoins, rifamycins)

May decrease effects of clomipramine.

Hepatic enzyme inhibitors (cimetidine, fluoxetine, haloperidol, oral contraceptives, phenothiazine antipsychotics)

May increase effects of clomipramine.

MAOIs

Sweating, convulsions, and death may occur. Coadministration or use within 14 days before or after treatment with an MAOI is contraindicated.

Phenobarbital

Levels may be elevated by clomipramine, increasing the pharmacologic and adverse effects.

Quinolones (gatifloxacin, levofloxacin, moxifloxacin, sparfloxacin)

The risk of life-threatening cardiac arrhythmias may be increased.

Laboratory Test Interactions

None well documented.

Adverse Reactions

Cardiovascular

Postural hypotension (6%); palpitation, tachycardia (4%); syncope (2%).

CNS

Dizziness, somnolence, tremor (54%); headache (52%); insomnia (25%); libido change (21%); nervousness (18%); myoclonus (13%); increased appetite (11%); anxiety, impaired memory, paresthesia (9%); twitching (7%); depression, impaired coordination (5%); hypertonia, sleep disorder (4%); abnormal dreaming, agitation, confusion, migraine, psychosomatic disorder, speech disorder, yawning (3%); aggressive reaction, asthenia, depersonalization, emotional lability, irritability, panic disorder, paresis (2%); abnormal thinking, vertigo (at least 1%); confusion, delusion, hallucinations, hypomania, mania, paranoia, psychotic episodes.

Dermatologic

Increased sweating (29%); flushing, rash (8%); pruritus (6%); abnormal skin odor, acne, dermatitis, dry skin (2%); urticaria (1%).

EENT

Abnormal vision (18%); pharyngitis (14%); rhinitis (12%); tinnitus (6%); otitis media (4%); abnormal lacrimation (3%); anisocoria, blepharospasm, laryngitis, mydriasis, ocular allergy, vestibular disorder (2%); conjunctivitis (1%).

GI

Dry mouth (84%); constipation (47%); nausea (33%), dyspepsia (22%); diarrhea (13%); anorexia (12%); abdominal pain (11%); vomiting (7%); flatulence (6%); tooth disorder (5%); dysphagia, eructation, GI disorder, halitosis, ulcerative stomatitis (2%); esophagitis (1%).

Genitourinary

Ejaculation failure (42%); impotence (20%); micturition disorder (14%); dysmenorrhea (12%); urinary retention (7%); UTI (6%); micturition frequency (5%); menstrual disorder, nonpuerperal lactation (4%); breast enlargement, cystitis, dysuria, leucorrhea, vaginitis (2%); amenorrhea, breast pain (1%).

Hematologic

Agranulocytosis, anemia, leucopenia, pancytopenia, thrombocytopenia.

Hepatic

Elevated ALT (3%); elevated AST (1%).

Metabolic-Nutritional

Weight increase (18%); weight decrease (7%).

Respiratory

Bronchospasm (7%); coughing, sinusitis (6%); dyspnea, epistaxis (2%).

Miscellaneous

Fatigue (39%); allergy (7%); hot flashes (5%); chest pain, fever, pain (4%); chills, local edema (2%).

Precautions

Warnings Antidepressants increase the risk of suicidal thinking and behavior in short-term studies in children and adolescents with major depressive disorders and other psychiatric disorders. Closely observe patients who are started on therapy for clinical worsening, suicidal, or unusual changes in behavior.

Monitor Monitor blood counts (CBC with differential), blood sugars (in patients with diabetes), ECG, and LFTs as needed.

Pregnancy

Category C . Neonatal withdrawal symptoms have been reported.

Lactation

Excreted in breast milk.

Children

Not recommended for children younger than 10 yr of age.

Special Risk Patients

Use with caution in patients with angle-closure glaucoma or increased IOP, CV disorders, hepatic or renal function impairment, history of seizures, urethral or ureteral spasm, or urinary retention; hyperthyroid patients or those receiving thyroid medication; and schizophrenic or paranoid patients.

Mania/Hypomania

May precipitate hypomania or mania.

Neuroleptic malignant syndrome

Cases have been reported.

Psychiatric effects

Signs and symptoms (eg, confusion, delusions, hallucinations, paranoia, psychotic episodes) have been reported.

Suicide

Closely monitor patients at risk. Prescribe the smallest quantity consistent with good patient management to reduce the risk of overdose.

Withdrawal

Symptoms including dizziness, headache, hyperthermia, irritability, malaise, nausea, sleep disturbances, and vomiting have been associated with sudden withdrawal of clomipramine.

Overdosage

Symptoms

Agitation, anuria, ataxia, athetoid and choreiform movement, cardiac dysrhythmias, CNS depression including coma, convulsions, cyanosis, delirium, drowsiness, ECG changes (particularly in QRS axis or width), hyperactivity reflexes, hyperpyrexia, muscle rigidity, mydriasis, oliguria, rare cardiac arrest, respiratory depression, restlessness, severe hypotension, severe perspiration, shock, signs of CHF, stupor, tachycardia, and vomiting.

Patient Information

• Advise patient, family, and caregiver to be alert to changes in behavior, worsening of depression, and suicidal thinking, all of which indicate a need for very close monitoring and possible change in medication.
• Instruct patient to keep weekly record of weight and to decrease caloric intake if necessary.
• Teach patient how to monitor BP and heart rate.
• Instruct patient on oral hygiene habits to prevent and treat dry mucous membranes.
• Advise patient to increase fluid intake.
• Instruct patient not to discontinue taking drug abruptly.
• Inform men of possible impotence or ejaculation failure.
• Caution patient to avoid sudden position changes to prevent orthostatic hypotension.
• Advise patient that drug may cause drowsiness and to use caution while driving or performing other tasks requiring mental alertness.
• Caution patient to avoid exposure to sunlight, use sunscreen, and wear protective clothing to avoid photosensitivity reaction.
• Advise patient to avoid intake of alcohol, sedative/hypnotics, or other CNS depressants.

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