Clozapine

Severe Neutropenia

Clozapine has caused severe neutropenia which is associated with an increased risk of serious and potentially fatal infections. Prior to initiating clozapine treatment, obtain baseline ANC(s). Clozapine initiation is not recommended in patients with a baseline ANC less than 1500/μL (less than 1000/μL for those with Benign Ethnic Neutropenia (also known as Duffy-null associated neutrophil count)). See recommendations for dosage modifications based on ANC levels during clozapine treatment [see Dosage and Administration (2.3, 2.4)]. Consider a hematology consultation before initiating clozapine or during clozapine treatment [see Warnings and Precautions (5.1)].

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, or when restarting patients who have had even a brief interruption in treatment with clozapine. Initiate treatment at 12.5 mg once or twice daily; titrate slowly; and use divided dosages to minimize risk. Use clozapine 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, 2.6), Warnings and Precautions (5.2)].

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 [see Dosage and Administration (2.2), Warnings and Precautions (5.4)].

Myocarditis, Pericarditis, Cardiomyopathy and Mitral Valve Incompetence

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, pericarditis, 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. C lozapine is not approved for use in patients with dementia-related psychosis [see Warnings and Precautions (5.6)].