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Clozapine

Severe Neutropenia; Orthostatic Hypotension, Bradycardia, and Syncope; Seizure; Myocarditis and Cardiomyopathy; Increased Mortality in Elderly Patients with Dementia-Related Psychosis

Severe Neutropenia

  • Clozapine treatment has caused severe neutropenia, defined as an absolute neutrophil count (ANC) less than 500/?L . Severe neutropenia can lead to serious infection and death. Prior to initiating treatment with clozapine a baseline ANC must be at least 1500/ ?L for the general population; and must be at least 1000/?L for patients with documented Benign Ethnic Neutropenia (BEN). During treatment, patients must have regular ANC monitoring. Advise patients to immediately report symptoms consistent with severe neutropenia or infection (e.g., fever, weakness, lethargy, or sore throat) 
  • Because of the risk of severe neutropenia, clozapine is available only through a restricted program under a Risk Evaluation Mitigation Strategy (REMS) called the Clozapine REMS Program. [see Warnings and Precautions 

Orthostatic Hypotension, Bradycardia, Syncope

  • Orthostatic hypotension, bradycardia, syncope, and cardiac arrest have occurred with clozapine treatment. The risk is highest during the initial titration period, particularly with rapid dose escalation. These reactions can occur with the first dose, with doses as low as 12.5 mg per day. Initiate treatment at 12.5 mg once or twice daily; titrate slowly; and use divided dosages. Use clozapine cautiously in patients with cardiovascular or cerebrovascular disease or conditions predisposing to hypotension (e.g., dehydration, use of antihypertensive medications) 

Seizures

  • Seizures have occurred with clozapine treatment. The risk is dose-related. Initiate treatment at 12.5 mg, titrate gradually, and use divided dosing. Use caution when administering clozapine to patients with a history of seizures or other predisposing risk factors for seizure (CNS pathology, medications that lower the seizure threshold, alcohol abuse). Caution patients about engaging in any activity where sudden loss of consciousness could cause serious risk to themselves or others 

Myocarditis and Cardiomyopathy

  • Fatal myocarditis and cardiomyopathy have occurred with clozapine treatment. Discontinue clozapine and obtain a cardiac evaluation upon suspicion of these reactions. Generally, patients with clozapine-related myocarditis or cardiomyopathy should not be rechallenged with clozapine. Consider the possibility of myocarditis or cardiomyopathy if chest pain, tachycardia, palpitations, dyspnea, fever, flu-like symptoms, hypotension, or ECG changes occur

Increased Mortality in Elderly Patients with Dementia-Related Psychosis

  • Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. Clozapine is not approved for use in patients with dementia-related psychosis

MONITORING RECOMMENDATIONS RELATED TO BLACK BOX DATA

  • New Monitoring Recommendations
  • Patients should be instructed to report signs of infection immediately
  • See package insert for instructions regarding WBC values and therapy decisions
  • After brief interval off clozapine, restart at dose 12.5 mg once or twice daily to avoid serious cardiorespiratory events
  • Seizures: Counsel patients to avoid activities where sudden loss of consciousness could cause serious risk to themselves or others (e.g., swimming, climbing,etc).

 

FDA and Industry Communications

Approved Risk Evaluation and Mitigation Strategies (REMS)

Clozapine

Patient Counseling Information

Package Inserts

Clozapine

Additional Information

Updated January 2018