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Medications: Clozaril® – clozapine

MEDICATIONS

Clozaril® – clozapine (View the FDA label)

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).

Eosinophilia: Assess for organ involvement (e.g., myocarditis, pancreatitis, hepatitis, colitis, nephritis). Discontinue if these occur. (5.7).

QT Interval Prolongation: Can be fatal. Consider additional risk factors for prolonged QT interval (disorders and drugs) (5.8).

Metabolic Changes: Atypical antipsychotic drugs have been associated with metabolic changes that may increase cardiovascular/ cerebrovascular risk. These metabolic changes include:

  • 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. (5.9).
  • Dyslipidemia: Undesirable alterations in lipids have occurred in patients treated with atypical antipsychotics. (5.9).
  • Weight Gain: Significant weight gain has occurred. Monitor weight gain. (5.9).

Neuroleptic Malignant Syndrome (NMS): Immediately discontinue and monitor closely. Assess for co-morbid conditions. (5.10).

Fever: Evaluate for infection, agranulocytosis, NMS (5.11).

Pulmonary Embolism (PE): Consider PE if respiratory distress, chest, pain, or deep vein thrombosis occur (5.12).

Anticholinergic Toxicity: Use cautiously in presence of specific conditions (e.g., narrow angle glaucoma, use of anticholinergic drugs) (5.13).

Interference with Cognitive and Motor Performance: Advise

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 (e.g., tobacco smoke) or CYP3A4 inducers (e.g., carbamazepine) are discontinued (2.6, 7.1).

Overdosage Experience

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

For the most up-to-date information on the management of CLOZARIL overdosage, contact a certified Regional Poison Control Center (1-800-222-1222). Telephone numbers of certified Regional Poison Control Centers are listed in the Physicians’ Desk Reference®, a registered trademark of Thomson PDR. Establish and maintain an airway; ensure adequate oxygenation and ventilation. Monitor cardiac status and vital signs. Use general symptomatic and supportive measures. There are no specific antidotes for CLOZARIL.

In managing overdosage, consider the possibility of multiple-drug involvement.

Uses

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).
Side Effects

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).

Precautions

Eosinophilia: Assess for organ involvement (e.g., myocarditis, pancreatitis, hepatitis, colitis, nephritis). Discontinue if these occur. (5.7).

QT Interval Prolongation: Can be fatal. Consider additional risk factors for prolonged QT interval (disorders and drugs) (5.8).

Metabolic Changes: Atypical antipsychotic drugs have been associated with metabolic changes that may increase cardiovascular/ cerebrovascular risk. These metabolic changes include:

  • 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. (5.9).
  • Dyslipidemia: Undesirable alterations in lipids have occurred in patients treated with atypical antipsychotics. (5.9).
  • Weight Gain: Significant weight gain has occurred. Monitor weight gain. (5.9).

Neuroleptic Malignant Syndrome (NMS): Immediately discontinue and monitor closely. Assess for co-morbid conditions. (5.10).

Fever: Evaluate for infection, agranulocytosis, NMS (5.11).

Pulmonary Embolism (PE): Consider PE if respiratory distress, chest, pain, or deep vein thrombosis occur (5.12).

Anticholinergic Toxicity: Use cautiously in presence of specific conditions (e.g., narrow angle glaucoma, use of anticholinergic drugs) (5.13).

Interference with Cognitive and Motor Performance: Advise

Interactions

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 (e.g., tobacco smoke) or CYP3A4 inducers (e.g., carbamazepine) are discontinued (2.6, 7.1).

Overdose

Overdosage Experience

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

For the most up-to-date information on the management of CLOZARIL overdosage, contact a certified Regional Poison Control Center (1-800-222-1222). Telephone numbers of certified Regional Poison Control Centers are listed in the Physicians’ Desk Reference®, a registered trademark of Thomson PDR. Establish and maintain an airway; ensure adequate oxygenation and ventilation. Monitor cardiac status and vital signs. Use general symptomatic and supportive measures. There are no specific antidotes for CLOZARIL.

In managing overdosage, consider the possibility of multiple-drug involvement.

Interpreting the GeneSight® Test:
Gene-Drug Interaction Chart

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