Clozapine

Tranquilizer, Sedative/Hypnotic · Dibenzodiazepine

Indications

Treatment-resistant schizophrenia in patients unresponsive to or intolerant of conventional neuroleptics.

Dosage

Adults: Day 1: 12.5 mg once or twice daily; day 2, 25 mg once or twice daily. Increase by 25-50 mg daily, over two to three wk, to 300 mg daily in divided doses. If necessary, continue to increase by 50-100 mg increments at 4-7 day intervals, up to max dose of 900 mg daily. Maintenance: 150-300 mg daily in divided doses. If treatment break exceeds 2 days re-titrate from initial dose. Elderly: Initially 12.5 mg daily increasing gradually in increments of 25 mg daily. Children: Not recommended.

Adverse Effects

Leucopenia, neutropenia, agranulocytosis, anaemia, eosinophilia, leukocytosis, wt gain, drowsiness, dizziness, blurred vision, headache, tremor, rigidity, akathisia, extrapyramidal reactions, seizures, myoclonic jerks, tachycardia, ECG changes, hypertension, postural hypotension, syncope, constipation, hypersalivation, anorexia, GI upset, dry mouth, raised liver enzymes, urinary incontinence, urinary retention, fatigue, fever, disturbed temperature regulation, dysarthria. Reports of impaired peristalsis, falls caused by seizures, somnolence, postural hypotension, motor and sensory instability.

Risk Factor (Pregnancy/Lactation)

Pregnancy: No evidence of risk in humans. Lactation: Contraindicated or not recommended. Contraindications: History of drug induced neutropenia/agranulocytosis or myeloproliferative disorders. Alcoholic and toxic psychosis, drug intoxication, comatose states, circulatory collapse, CNS depression, severe hepatic or renal disease, cardiac failure, paralytic ileus. Myelosuppression, uncontrolled epilepsy. Precautions: Monitor leukocyte counts prior to treatment, then weekly during weeks 1-18, fortnightly for weeks 19-52, then every 4 weeks thereafter; withdraw immediately if WBC count below 3 x 10^9/l or neutrophil count below 1.5 x 10^9/l. Patients should report symptoms of infection. Use adequate contraception. Monitor patients with history of epilepsy. Prostatic hypertrophy, glaucoma, paralytic ileus. Liver disease. History of GI obstruction, colonic disease or lower abdominal surgery,…

Interactions

Myelosuppressants, depot antipsychotics, centrally acting agents, lithium, CNS depressants, narcotic analgesics, alcohol, MAOIs, benzodiazepines, antihistamines, valproic acid, anticholinergics, hypotensives, respiratory depressants, adrenaline, nor adrenaline, cimetidine, erythromycin, fluvoxamine, SSRIs, azole antifungals, venlafaxine, protease inhibitors, carbamazepine, phenytoin, rifampicin, omeprazole, TCADs, phenothiazines, class 1c antiarrhythmics, digoxin, warfarin, inducers and inhibitors of CYP1A2, drugs that prolong QT interval or cause electrolyte imbalance.

Advice to Patient

Take with or without meals. Open the blister pack of disintegrating tablets only when you are ready to take the tablet. Peel back the foil and do not push tablet through the foil because doing so could damage the tablet. Place the tablet on tongue without breaking it and let it dissolve. Water is not needed. If you stop taking medication for more than 2 days, consult prescriber because dosage may need to be changed. Contact prescriber if there is fatigue, fever, sore throat, weakness, difficulty in breathing, changes in vision, increased saliva, depression, lack of sleep, change in consciousness, severe dizziness, fast heartbeat, palpitations, increased sweating, increased tearing or if there is worsening of condition. Avoid alcohol and caffeine during therapy. Take sufficient amount of fluids (2-3 litres per day) to maintain hydration, unless restricted by the prescriber. If you have…

Pharmacokinetics

Onset of action: Within 1 wk for sedation, improvement in sleep; 6-12 wks for antipsychotic effects; Adequate trial: 6-12 wks at a therapeutic dose and blood level; Max effect: 6-12 mths; improvement may continue 6-12 mths after clozapine initiation. Duration of action: Variable. Metabolism: Extensively hepatic. Bioavailability: 27%-50% (not affected by food); orally disintegrating tabs, regular tabs, and oral susp are bioequivalent. Half-life elimination: Steady state: 12 hrs (range: 4-66 hrs). Time to peak: Susp: 2.2 hrs. Tabs: 2.5 hrs; Dispersible tabs: 2.3 hrs. Excretion: Urine (approx. 50%). Faeces (30%).

Unlicensed Use

Children: Schizophrenia in children unresponsive to, or intolerant of, conventional antipsychotic drugs: 12-18 yr, 12.5 mg once or twice on first day then 25-50 mg on 2nd day then increased gradually (if well tolerated) in steps of 25-50 mg daily over 14-21 days up to 300 mg daily in divided doses (larger dose at night, up to 200 mg daily may be taken as a single dose at bedtime). If necessary may be further increased in steps of 50-100 mg once (preferably) or twice weekly; usual dose 200-450 mg daily, max 900 mg daily. Restarting after interval of more than 2 days, 12.5 mg once or twice on first day (but may be feasible to increase more quickly than on initiation); extreme caution if previous respiratory or cardiac arrest with initial dosing.

Brands with this active ingredient

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