Known brand names include Clozaril.
An atypical (second-generation) antipsychotic taken by mouth as tablets. It is reserved for severe schizophrenia that has not responded to standard antipsychotics, and it also lowers the risk of repeated suicidal behavior in schizophrenia or schizoaffective disorder. Its boxed warnings include severe neutropenia, which requires regular blood counts, along with low blood pressure and fainting, seizures, and heart inflammation.
Labeled use. Severely ill patients who have not responded adequately to standard antipsychotics, and reducing recurrent suicidal behavior in patients at chronic risk.
Labeled use. Reducing the risk of recurrent suicidal behavior in patients judged at chronic risk.
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Clozapine is the most effective antipsychotic for treatment-resistant schizophrenia, usually defined as failure of two adequate trials of other antipsychotics, and the only one approved to reduce recurrent suicidal behavior. It rarely causes extrapyramidal symptoms or tardive dyskinesia and is used off-label for psychosis in Parkinson disease. Its neutropenia monitoring, myocarditis, seizure, metabolic, and constipation risks keep it a later-line choice.
Mechanism unknown; efficacy is proposed to come from dopamine D2 and serotonin 5-HT2A antagonism. It also antagonizes adrenergic, cholinergic, histaminergic, and other dopaminergic and serotonergic receptors, binding H1, alpha-1A, 5-HT6, 5-HT2A, and M1 receptors much more tightly than D2, and it causes little or no prolactin elevation. About 97% protein bound and almost completely metabolized, mainly by CYP1A2, CYP2D6, and CYP3A4. Peak levels at about 2.5 hours; steady-state half-life averages 12 hours (range 4 to 66).
The label does not describe a narrow therapeutic index or direct dosing by measured blood levels of the drug.
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Doses come from the FDA label. Study tool, not for clinical decisions.
A lower dose may be needed with significant renal impairment, because clozapine is almost completely metabolized and then excreted and levels are likely higher. No specific studies were done.
A lower dose may be needed with significant hepatic impairment, because levels are likely higher; no specific studies were done. Watch for hepatotoxicity and consider permanently stopping for clozapine-related hepatitis or transaminase rises with systemic symptoms.
Severe neutropenia with a risk of serious, potentially fatal infection: get a baseline ANC and do not start if it is below 1500/μL (below 1000/μL with benign ethnic neutropenia). Orthostatic hypotension, bradycardia, syncope, and cardiac arrest, highest during initial titration and after interruptions; start at 12.5 mg once or twice daily and titrate slowly in divided doses. Dose-related seizures. Fatal myocarditis, pericarditis, and cardiomyopathy. Higher mortality in older adults with dementia-related psychosis.
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No specific antidote. Common overdose findings are sedation, delirium, coma, tachycardia, hypotension, hypersalivation, and respiratory depression or failure, with aspiration pneumonia, arrhythmias, and seizures reported; fatal overdoses generally involved more than 2500 mg. Establish an airway with adequate oxygenation and ventilation, monitor cardiac status and vital signs, give supportive care, consider other drugs taken, and contact a poison control center.
Decades of published epidemiologic data show no established drug-related risk of major birth defects, miscarriage, or other adverse maternal or fetal outcomes. Newborns exposed in the third trimester can have extrapyramidal or withdrawal symptoms such as agitation, abnormal muscle tone, tremor, sleepiness, breathing trouble, and feeding problems. Untreated schizophrenia carries risks of relapse, hospitalization, and suicide. A pregnancy registry exists.
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Clozapine is present in human milk; there are reports of sedation in one breastfed infant and agranulocytosis in another. Monitor breastfed infants for excess sedation and neutropenia, and weigh breastfeeding benefits against the mother's need for the drug.
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Too few older patients were studied to judge differences in response. Older adults, especially with heart disease, may be more prone to orthostatic hypotension and tachycardia and to anticholinergic effects such as urinary retention and constipation, and tardive dyskinesia appears most common in older women. Choose doses carefully; it is not approved for dementia-related psychosis.