Generic
Clozapine
Pharmacology
Clozapine is classified as an 'atypical' antipsychotic drug because of its profile of binding to dopamine receptors and its effects on various dopamine-mediated behaviors differ from those exhibited by other typical antipsychotic drug products. In particular, although Clozapine does interfere with the binding of dopamine at D1, D2, D3 and D5 receptors, and has a high affinity for the D4 receptor. This evidence, consistent with the view that Clozapine is preferentially more active at limbic than at striatal dopamine receptors. This may explain the relative freedom of Clozapine from extrapyramidal side effects. Clozapine also acts as an antagonist at adrenergic, cholinergic, histaminergic and serotonergic receptors.
Dosage Administration
Schizophrenia: Adult over 16 years, 12.5 mg once or twice (elderly 12.5 mg once) on first day then 25-50 mg (elderly 25-37.5 mg) on second day then increased gradually (if well tolerated) in steps of 25-50 mg daily (elderly max. increment 25 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) Psychosis in Parkinson's disease: Adult over 16 years, 12.5 mg at bedtime then increased according to response in steps of 12.5 mg up to twice weekly; usual dose range 25-37.5 mg at bedtime, usual maximum 50 mg daily; exceptionally, dose may be increased further in steps of 12.5 mg weekly to maximum 100 mg daily in 1-2 divided doses.
Contraindications
Myelosuppression may be aggravated with concomitant use of myelosuppressants. Clozapine may interact with other CNS active drugs or alcohol. Orthostatic hypotension may occur with benzodiazepine usage or other psychotropics. Since Clozapine is highly bound to proteins. It may be displaced by other drugs, which are also highly protein bound. Conversely, Clozapine may also displace protein bound drugs (e.g. warfarin, digoxin). Cimetidine may decrease plasma Clozapine levels. Although concomitant administration of Carbamazepine and Clozapine is not recommended, it should be noted that discontinuation of concomitant Carbamazepine may result in an increase in plasma Clozapine levels. A reduced Clozapine dosage should be used when it is combined with drugs like fluvoxamine, paroxetine and sertraline. The action of hypotensive drugs may be potentiated. Other anticholinergic drug action may also be increased. Administration of adrenaline should generally be avoided due to possibility of reversal of adrenaline effect due to alpha adrenergic blockade by Clozapine. Concomitant use of Clozapine with other drugs metabolized by cytochrome P450 2D6 (such as phenothiazines, antidepressants, propafenone, flecainide and encainide) or those that inhibit this enzyme such as quinidine; require lower doses of either Clozapine or the other drugs.
Side Effects
Severe cardiac disorders (e.g. myocarditis); renal impairment (avoid if creatinine clearance less than 10 ml/minute); history of neutropenia or agranulocytosis; bone-marrow disorders; paralytic ileus; alcoholic and toxic psychoses; history of circulatory collapse; drug intoxication; coma or severe CNS depression; uncontrolled epilepsy; breast-feeding.
Pregnancy And Lactation
Common side effects are constipation, dizziness or lightheadedness (mild), drowsiness, headache (mild), increased watering of mouth, nausea or vomiting, unusual weight gain. Less common side effects include abdominal discomfort or heartburn, dryness of mouth.
Therapeutic
The most commonly reported signs and symptoms associated with Clozapine overdose are: altered states of consciousness, including drowsiness, delirium and coma; tachycardia; hypotension; respiratory depression or failure; hypersalivation. Aspiration pneumonia and cardiac arrhythmias have also been reported. Seizures have occurred in a minority of reported cases. Fatal overdoses have been reported with Clozapine, generally at doses above 2500 mg. There have also been reports of patients recovering from overdoses well in excess of 4 gm. Management of Overdose: Should be established and maintained an airway; should be ensured adequate oxygenation and ventilation. Activated charcoal, which may be used with sorbitol, may be as or more effective than emesis or lavage, and should be considered in treating overdosage. Cardiac and vital signs monitoring is recommended along with general symptomatic and supportive measures. Additional surveillance should be continued for several days because of the risk of delayed effects. Avoid epinephrine and derivatives when treating hypotension, and quinidine and procainamide when treating cardiac arrhythmia. There are no specific antidotes for Clozapine. Forced diuresis, dialysis, hemoperfusion and exchange transfusion are unlikely to be of benefit. ln managing overdosage, the physician should consider the possibility of multiple drug involvement.
Storage Conditions
Do not store above 30�C. Keep away from light and out of the reach of children.
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