Generic Name

Clozapine

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Classification

FDA Approved Indications

• Schizophrenia in treatment-resistant cases
• Reducing risk of recurrent suicidal behavior in schizophrenia or schizoaffective disorder

Mechanism of Action

Clozapine acts on multiple neurotransmitter receptors in the brain, notably dopamine and serotonin receptors. It reduces psychotic symptoms by modulating these neurotransmitters but differs from typical antipsychotics by its broader receptor activity and lower propensity to cause extrapyramidal symptoms.

Dosage and Administration

Adult: Start at 12.5 mg once or twice daily, titrate gradually to a target dose usually between 300-450 mg/day, divided into doses. Adjust based on clinical response and tolerability.

Pediatric: Limited data; use in children is off-label and cautious titration is recommended.

Geriatric: Start at lower doses due to increased sensitivity and risk of adverse effects; careful titration and monitoring required.

Renal Impairment: No initial dosage adjustment necessary, but monitor closely.

Hepatic Impairment: Start with lower doses and titrate carefully; hepatic function monitoring recommended.

Pharmacokinetics

Absorption: Well absorbed orally, with peak plasma levels in 2-4 hours.

Distribution: Widely distributed, highly protein-bound (~95%).

Metabolism: Extensively metabolized in the liver via CYP1A2, CYP3A4, and other enzymes.

Excretion: Mainly via urine (primarily as metabolites); minor fecal excretion.

Half Life: Approx. 12 hours; active metabolites may have longer half-lives.

Contraindications

• History of hypersensitivity to clozapine.
• History of agranulocytosis or severe granulocytopenia.

Precautions

• Myocarditis, cardiomyopathy, seizures, orthostatic hypotension, anticoagulant therapy, and pre-existing metabolic conditions such as diabetes and obesity are critical considerations. Caution in patients with a history of infections or bone marrow suppression.

Adverse Reactions - Common

• Constipation (Common)
• Drowsiness (Common)
• Increased salivation (Common)
• Weight gain (Common)
• Tachycardia (Common)

Adverse Reactions - Serious

• Agranulocytosis (Rare but serious)
• Seizures (Dose-dependent)
• Myocarditis and cardiomyopathy (Rare)
• Neuroleptic malignant syndrome (Rare)

Drug-Drug Interactions

• CYP1A2 inhibitors/inducers (e.g., fluvoxamine, tobacco smoking)

Drug-Food Interactions

• Avoid grapefruit juice (CYP3A4 interaction)

Drug-Herb Interactions

N/A

Nursing Implications

Patient/Family Teaching

• Advise on regular blood tests and adherence to dosing.
• Report signs of infection, fever, sore throat immediately.
• Educate about potential weight gain, hyperglycemia, and lipid abnormalities.
• Warn about signs of myocarditis (chest pain, shortness of breath).

Special Considerations

Black Box Warnings:

• Significant risk of neutropenia/agranulocytosis, severe cardiovascular, and metabolic side effects.

Genetic Factors: Polymorphisms in CYP1A2 may affect drug metabolism.

Lab Test Interference: May interfere with certain laboratory tests, including white blood cell counts.

Overdose Management

Signs/Symptoms: Toxic effects may include severe hypotension, seizures, tachycardia, respiratory depression, and coma.

Treatment: Supportive care; no specific antidote. Monitor cardiac and neurological status. Consider activated charcoal if ingested recently.

Storage and Handling

Storage: Store at room temperature (20-25°C), protected from moisture.

Stability: Stable under recommended storage conditions.