Medications: Clozaril^® – clozapine

CLOZARIL is an atypical antipsychotic indicated for:

• Treatment-resistant schizophrenia. Efficacy was established in an active-controlled study. (1.1, 14.1)
• Reducing suicidal behavior in patients with schizophrenia or schizoaffective disorder. Efficacy was established in an active-controlled study. (1.2, 14.2)

DOSAGE AND ADMINISTRATION

• Starting Dose: 12.5 mg once daily or twice daily. (2.2)
• Use cautious titration and divided dosage schedule. (2.2, 5.3)
• Titration: increase the total daily dosage in increments of 25 mg to 50 mg per day, if well-tolerated. (2.2)
• Target dose: 300 mg to 450 mg per day, in divided doses, by the end of 2 weeks. (2.2)
• Subsequent increases: increase in increments of 100 mg or less, once or twice weekly. (2.2)
• Maximum daily dose: 900 mg (2.2)

Most common adverse reactions (≥5%) were: CNS reactions (sedation, dizziness/vertigo, headache, and tremor); cardiovascular reactions (tachycardia, hypotension, and syncope); autonomic nervous system reactions (hypersalivation, sweating, dry mouth, and visual disturbances); gastrointestinal reactions (constipation and nausea); and fever. (6.1)

Known serious hypersensitivity to clozapine or any other component of CLOZARIL. (4)

WARNINGS AND PRECAUTIONS:

• Gastrointestinal Hypomotility with Severe Complications: Severe gastrointestinal adverse reactions have occurred with the use of CLOZARIL. If constipation is identified close monitoring and prompt treatment is advised. (5.9)
• Eosinophilia: Assess for organ involvement (e.g., myocarditis, pancreatitis, hepatitis, colitis, nephritis). Discontinue if these occur. (5.9)
• QT Interval Prolongation: Can be fatal. Consider additional risk factors for prolonged QT interval (disorders and drugs). (5.10)
• Metabolic Changes: Atypical antipsychotic drugs have been associated with metabolic changes that may increase cardiovascular/cerebrovascular risk. These metabolic changes include: o Hyperglycemia and Diabetes Mellitus: Monitor for symptoms of hyperglycemia including polydipsia, polyuria, polyphagia, and weakness. Monitor glucose regularly in patients with diabetes or at risk for diabetes. (5.11) o Dyslipidemia: Undesirable alterations in lipids have occurred in patients treated with atypical antipsychotics. (5.11) o Weight Gain: Significant weight gain has occurred. Monitor weight gain. (5.11)
• Neuroleptic Malignant Syndrome (NMS): Immediately discontinue and monitor closely. Assess for co-morbid conditions. (5.12)
• Hepatotoxicity: Can be fatal. Monitor for hepatotoxicity. Discontinue treatment if hepatitis or transaminase elevations combined with other symptoms occur (5.13).
• Fever: Evaluate for infection and for neutropenia, NMS. (5.14)
• Pulmonary Embolism (PE): Consider PE if respiratory distress, chest pain, or deep-vein thrombosis occur. (5.15)
• Anticholinergic Toxicity: When possible, avoid use with other anticholinergic drugs and use with caution in patients with a current diagnosis or prior history of constipation, urinary retention, clinically significant prostatic hypertrophy, or other conditions in which anticholinergic effects can lead to significant adverse reactions.(5.16, 7.1)
• Interference with Cognitive and Motor Performance: Advise caution when operating machinery, including automobiles. (5.17)

• Concomitant use of Strong CYP1A2 Inhibitors: Reduce CLOZARIL dose to one-third when coadministered with strong CYP1A2 inhibitors (e.g., fluvoxamine, ciprofloxacin, enoxacin). (2.6, 7.1)
• Concomitant use of Strong CYP3A4 Inducers is not recommended. (2.6, 7.1)
• Discontinuation of CYP1A2 or CYP3A4 Inducers: Consider reducing CLOZARIL dose when CYP1A2 inducers (e.g., tobacco smoke) or CYP3A4 inducers (e.g., carbamazepine) are discontinued. (2.6, 7.1)
• Anticholinergic drugs: Concomitant use may increase the risk for anticholinergic toxicity. (5.8, 5.16, 7.1)

The most commonly reported signs and symptoms associated with clozapine overdose are: sedation, delirium, coma, tachycardia, hypotension, respiratory depression or failure; and hypersalivation. There are reports of aspiration pneumonia, cardiac arrhythmias, and seizure. 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 g.

Management of Overdosage: There is no available specific antidote to an overdose of CLOZARIL. Establish and maintain an airway; ensure adequate oxygenation and ventilation. Monitor cardiac status and vital signs. Use general symptomatic and supportive measures. Consider the possibility of multiple-drug involvement. Contact a Certified Poison Control Center for the most up to date information on the management of overdosage (1-800­ 222-1222).