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Clozapine information from DrugsUpdate  

See Available Brands of Clozapine in India

P - Contraindicated in pregnancy
L - Contraindicated in lactation

Clozapine is an antipsychotic medication used in the treatment of schizophrenia. The first of the atypical antipsychotics to be developed, it was first introduced in Europe in 1971, but was voluntarily withdrawn by the manufacturer in 1975 after it was shown to cause agranulocytosis, a condition involving a dangerous decrease in the number of white blood cells, that led to death in some patients. In 1989, after studies demonstrated that it was more effective than any other antipsychotic for treating schizophrenia, the U.S. Food and Drug Administration (FDA) approved clozapine's use but only for treatment-resistant schizophrenia. The FDA requires blood testing for patients taking clozapine. The FDA also requires clozapine to carry five black box warnings for agranulocytosis, seizures, myocarditis, for "other adverse cardiovascular and respiratory effects", and for "increased mortality in elderly patients with dementia-related psychosis." In 2002 the FDA approved clozapine for reducing the risk of suicidal behavior for patients with schizophrenia.
Clozapine is used in patients after other anti-psychotics have failed.[citation needed] Use of clozapine requires blood monitoring. Patients are monitored weekly for the first six months. If there are no low counts the patient can be monitored every two weeks for an additional six months. Afterwards, the patient may qualify for every 4 week monitoring.

Pharmacodynamics

Clozapine is classified as an ‘atypical’ antipsychotic drug because its profile of binding to dopamine receptors and its effects on various dopamine mediated behaviors differ from those exhibited by more 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, it does not induce catalepsy nor inhibit apomorphine-induced stereotypy. This evidence, consistent with the view that Clozapine is preferentially more active at limbic than at striatal dopamine receptors, may explain the relative freedom of Clozapine from extrapyramidal side effects.
Clozapine also acts as an antagonist at adrenergic, cholinergic, histaminergic, and serotonergic receptors.

Pharmacokinetics

Clozapine has relatively weak dopamine receptor-blocking activity at D1, D2, D3 and D5 receptors but has high affinity for the D4 receptor. It has also blocking effects on serotonin, α-adrenergic histamine H1 and cholinergic receptors.
Absorption: Absorbed well from the GI tract (oral); peak plasma concentrations after 2.5 hr.
Distribution: Protein-binding: 95%.
Metabolism: Hepatic; N-demethylation and N-oxidation by cytochrome P-450 isoenzyme CYP1A2.
Excretion: Via urine and faeces (as metabolites and trace amounts of unchanged drug); 12 hr (elimination half-life)

Clozapine Indications / Clozapine Uses

Information Not Available

Clozapine Adverse Reactions / Clozapine Side Effects

Drowsiness, dizziness, headache; nausea, vomiting, constipation; anxiety, confusion, fatigue, transient fever. Rarely, dysphagia, acute pancreatitis, cholestatic jaundice; orthostatic hypotension, tachycardia; seizures; hypersalivation.
Potentially Fatal: Rarely, thromboembolism. Reversible neutropenia which may progress to a potentially fatal agranulocytosis. Fatal myocarditis.

Precautions

Because of the significant risk of agranulocytosis and seizure, both of which present a continuing risk over time, the extended treatment of patients failing to show an acceptable level of clinical response should ordinarily be avoided. In addition, the need for continuing treatment in patients exhibiting beneficial clinical responses should be periodically re-evaluated. Although it is not known whether the risk would be increased, it is prudent either to avoid Clozapine or use it cautiously in patients with a previous history of agranulocytosis induced by other drugs.

Special Precautions

Leucocyte counts should be monitored regularly and for at least 4 wk after treatment discontinuation. Renal, hepatic or cardiac impairment; prostatic enlargement, narrow-angle glaucoma; elderly; immobilised patients.

Other Drug Interactions

Reduced plasma concentrations with concomitant use of phenytoin. May enhance the central effects of MAOIs.
Potentially Fatal: Concurrent use with bone marrow suppressants e.g. carbamazepine, co-trimoxazole, chloramphenicol, penicillamine, sulfonamides, antineoplastics or pyrazolone analgesics; long-acting depot antipsychotics.

Other Interactions

Information Not Available

Dosage

Oral
Schizophrenia
Adult: 12.5 mg 1-2 times on day 1 followed by 25 mg 1-2 times on day 2, increased gradually in increments of 25-50 mg up to a daily dose of 300 mg within 14-21 days. Subsequent increments of 50-100 mg may be made 1-2 times wkly. Usual dose: 200-450 mg/day. Max: 900 mg/day.
Elderly: Initially, 12.5 mg on day 1 increased subsequently by increments of 25 mg.
Renal impairment: Mild-moderate renal impairment: use with caution. Severe impairment: contra-indicated.
Hepatic impairment: Use with caution and avoid in symptomatic or progressive liver disease or hepatic failure.
Oral
Psychoses in Parkinson's disease
Adult: Initially, 12.5 mg once daily at night, increased in steps of 12.5 mg up to 2 times each wk, not >50 mg/day at the end of the 2nd wk. Usual dose: 25-37.5 mg daily. Max: 100 mg daily.
Renal impairment: Mild-moderate renal impairment: use with caution. Severe impairment: contra-indicated.
Hepatic impairment: Use with caution and avoid in symptomatic or progressive liver disease or hepatic failure.

Food(before/after)

May be taken with or without food

List of Contraindications

Clozapine and Pregnancy

Contraindicated in pregnancy.
Category B: Either animal-reproduction studies have not demonstrated a foetal risk but there are no controlled studies in pregnant women or animal-reproduction studies have shown an adverse effect (other than a decrease in fertility) that was not confirmed in controlled studies in women in the 1st trimester (and there is no evidence of a risk in later trimesters).

Clozapine and Lactation

Contraindicated in lactation

Clozapine and Children

Safety and effectiveness in pediatric patients have not been established.

Clozapine and Geriatic

Clinical studies of Clozapine did not include sufficient numbers of subjects age 65 and over to determine whether they respond differently from younger subjects.
Orthostatic hypotension can occur with Clozapine treatment and tachycardia, which may be sustained, has been observed in about 25% of patients taking Clozapine. Elderly patients, particularly those with compromised cardiovascular functioning, may be more susceptible to these effects.
Also, elderly patients may be particularly susceptible to the anticholinergic effects of Clozapine, such as urinary retention and constipation.
Dose selection for an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. Other reported clinical experience does suggest that the prevalence of tardive dyskinesia appears to be highest among the elderly, especially elderly women

Clozapine and Other Contraindications

History of bone marrow disorders including agranulocytosis, circulatory collapse, alcoholic or toxic psychosis, drug intoxication, uncontrolled epilepsy, severe renal, hepatic or cardiac disease; paralytic ileus. Pregnancy and lactation.

Storage

Oral: Store below 25°C

Lab interference

Oral: Store below 25°C

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