boxed warning
WARNING: SEVERE NEUTROPENIA; ORTHOSTATIC HYPOTENSION, BRADYCARDIA, AND SYNCOPE; SEIZURE; MYOCARDITIS AND CARDIOMYOPATHY; INCREASED MORTALITY IN ELDERLY PATIENTS WITH DEMENTIA-RELATED PSYCHOSIS Severe Neutropenia Clozapine tablets treatment has caused severe neutropenia, defined as an absolute neutrophil count (ANC) less than 500/µL. Severe neutropenia can lead to serious infection and death. Prior to initiating treatment with clozapine tablets, a baseline ANC must be at least 1500/µL for the general population; and must be at least 1000/µL 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) [see Dosage and Administration ( 2.1 ) and Warnings and Precautions ( 5.1 )] . Because of the risk of severe neutropenia, clozapine tablets are available only through a restricted program under a Risk Evaluation Mitigation Strategy (REMS) called the Clozapine REMS Program [see Warnings and Precautions ( 5.2 )] . Orthostatic Hypotension, Bradycardia, Syncope Orthostatic hypotension, bradycardia, syncope, and cardiac arrest have occurred with clozapine tablets 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 tablets cautiously in patients with cardiovascular or cerebrovascular disease or conditions predisposing to hypotension (e.g., dehydration, use of antihypertensive medications) [see Dosage and Administration ( 2.2 , 2.5 ), Warnings and Precautions ( 5.3 )] . Seizures Seizures have occurred with clozapine tablets treatment. The risk is dose-related. Initiate treatment at 12.5 mg, titrate gradually, and use divided dosing. Use caution when administering clozapine tablets 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 [see Dosage and Administration ( 2.2 ), Warnings and Precautions ( 5.4 )] . Myocarditis and Cardiomyopathy Fatal myocarditis and cardiomyopathy have occurred with clozapine tablets treatment. Discontinue clozapine tablets and obtain a cardiac evaluation upon suspicion of these reactions. Generally, patients with clozapine-related myocarditis or cardiomyopathy should not be rechallenged with clozapine tablets. Consider the possibility of myocarditis or cardiomyopathy if chest pain, tachycardia, palpitations, dyspnea, fever, flu-like symptoms, hypotension, or ECG changes occur [see Warnings and Precautions ( 5.5 )] . 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 Tablets is not approved for use in patients with dementia-related psychosis [see Warnings and Precautions ( 5.6 )] . WARNING: SEVERE NEUTROPENIA; ORTHOSTATIC HYPOTENSION, BRADYCARDIA, AND SYNCOPE; SEIZURE; MYOCARDITIS AND CARDIOMYOPATHY; INCREASED MORTALITY IN ELDERLY PATIENTS WITH DEMENTIA-RELATED PSYCHOSIS See full prescribing information for complete boxed warning. Severe Neutropenia: Clozapine tablets can cause severe neutropenia, which can lead to serious and fatal infections. Patients initiating and continuing treatment with clozapine tablets must have a baseline blood absolute neutrophil count (ANC) measured before treatment initiation and regular ANC monitoring during treatment ( 2.1 , 5.1 ) . Clozapine tablets are available only through a restricted program called the Clozapine REMS ( 5.2 ) . Orthostatic Hypotension, Bradycardia, and Syncope: Risk is dose-related. Starting dose is 12.5 mg. Titrate gradually and use divided dosages. ( 2.2 , 2.5 , 5.3 ) Seizure: Risk is dose-related. Titrate gradually and use divided doses. Use with caution in patients with history of seizure or risk factors for seizure. ( 2.2 , 5.4 ) Myocarditis and Cardiomyopathy: Can be fatal. Discontinue and obtain cardiac evaluation if findings suggest these cardiac reactions. ( 5.5 ) Increased Mortality in Elderly Patients with Dementia-Related Psychosis: Clozapine tablets are not approved for this condition. ( 5.6 )