Clozapine

Approved Indications:

• Treatment-resistant schizophrenia in adults (patients who have failed to respond adequately to standard antipsychotic treatments).
• Reduction of risk of recurrent suicidal behavior in patients with schizophrenia or schizoaffective disorder.

Clinically Accepted Off-label Uses:

• Management of severe psychosis in Parkinson’s disease (low-dose use).
• Treatment of other psychotic disorders unresponsive to conventional therapy (off-label, specialist use).

• Initial dose: Typically, 12.5 mg once or twice daily on day 1.
• Titration: Gradually increase by 25–50 mg/day, divided doses, to reduce risk of adverse effects.
• Maintenance dose: Usually 300–450 mg/day in divided doses (e.g., 150 mg twice daily).
• Maximum dose: Generally not exceeding 900 mg/day.
• Special populations:
• Elderly: Start at lower doses with slow titration due to increased sensitivity.
• Renal impairment: No specific adjustment, but use caution.
• Hepatic impairment: Use with caution; monitor liver function.
• Administration route: Oral tablets or orally disintegrating tablets; taken with or without food.
• Monitoring: Mandatory blood monitoring (absolute neutrophil count) due to risk of agranulocytosis.

Clozapine is an atypical antipsychotic with a complex pharmacodynamic profile. It acts as an antagonist at multiple neurotransmitter receptors, including dopamine D1, D2, D4 receptors, serotonin 5-HT2A/2C receptors, adrenergic, histaminergic (H1), and muscarinic receptors. The blockade of D4 and 5-HT2A receptors is believed to contribute to its antipsychotic efficacy with reduced extrapyramidal symptoms. Clozapine’s unique receptor profile leads to modulation of dopaminergic and serotonergic pathways, resulting in improvement of positive and negative symptoms of schizophrenia and reduction in suicidal behavior.

• Absorption: Well absorbed orally; bioavailability approximately 60–70%.
• Distribution: Highly lipophilic; volume of distribution ~1.6–5.1 L/kg.
• Metabolism: Extensively metabolized in the liver primarily by CYP1A2, with contributions from CYP3A4 and CYP2D6, producing active metabolite norclozapine (desmethylclozapine).
• Elimination: Metabolites and unchanged drug excreted in urine and feces.
• Half-life: Approximately 8–16 hours; longer with chronic dosing due to accumulation.
• Onset of action: Clinical effects usually appear after 2–4 weeks; full benefit may take up to 6–12 weeks.

• Pregnancy: Category B or C (depending on region). Animal studies show potential risks; limited human data suggest use only if benefits justify risks. Potential for neonatal withdrawal or adverse effects.
• Lactation: Excreted in breast milk; potential for adverse effects in nursing infants. Breastfeeding not generally recommended during treatment.

• Primary Class: Atypical Antipsychotic
• Subclass: Dibenzodiazepine derivative

• Known hypersensitivity to clozapine or formulation excipients.
• History of agranulocytosis or severe granulocytopenia related to previous clozapine treatment.
• Uncontrolled epilepsy.
• Severe cardiovascular disease (e.g., myocarditis, recent myocardial infarction).
• Bone marrow suppression or severe leukopenia.
• Paralytic ileus or gastrointestinal obstruction.

• Agranulocytosis: Life-threatening; mandatory regular hematologic monitoring required.
• Myocarditis and cardiomyopathy: Monitor for signs of cardiac dysfunction; discontinue if suspected.
• Seizure risk: Dose-dependent; titrate slowly, and monitor.
• Orthostatic hypotension and syncope: Monitor blood pressure during dose initiation and titration.
• Metabolic effects: Weight gain, hyperglycemia, diabetes mellitus, dyslipidemia; monitor metabolic parameters regularly.
• Neuroleptic malignant syndrome: Rare but serious; immediate discontinuation required.
• Pulmonary embolism risk: Use with caution in patients with thromboembolic risk factors.
• Fever and flu-like symptoms: May indicate neutropenia or infection; immediate evaluation required.
• Smoking: Induces CYP1A2 and reduces clozapine levels; dose adjustments may be necessary upon smoking cessation or initiation.

Common:

• Sedation, dizziness, hypersalivation, tachycardia, constipation, weight gain.
• Orthostatic hypotension.

Serious (Less common but critical):

• Agranulocytosis, leukopenia, neutropenia.
• Myocarditis, cardiomyopathy.
• Seizures.
• Neuroleptic malignant syndrome.
• Severe constipation and paralytic ileus.

Onset: Hematologic adverse effects usually occur within the first 6 months; others may occur anytime during therapy.

• CYP1A2 inhibitors (e.g., fluvoxamine, ciprofloxacin): Increase clozapine plasma levels, increasing toxicity risk.
• CYP1A2 inducers (e.g., smoking, carbamazepine): Decrease clozapine levels, reducing efficacy.
• Other CNS depressants: Additive sedation.
• Drugs lowering seizure threshold: Increase seizure risk.
• Fluoxetine and other CYP2D6 inhibitors: May increase clozapine levels.

• Updated guidelines emphasize the critical importance of hematologic monitoring and risk management programs.
• Newer protocols recommend less frequent monitoring after one year of stable therapy.
• Ongoing research into metabolic side effect management, including early intervention strategies.
• No changes in approved indications but emphasis on individualized dose titration and monitoring.

• Store at 20°C to 25°C (68°F to 77°F).
• Protect from light and moisture.
• Keep container tightly closed.
• Use within expiry date.
• Keep out of reach of children.