WARNING: 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 µ/L. Severe neutropenia can lead to serious infection and death. Prior to initiating treatment with VERSACLOZ a baseline ANC must be at least 1500µ/L for the general population; and must be at least 1000µ/L for patients with documented Benign Ethnic Neutropenia. 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, VERSACLOZ is available only through a restricted program under a Risk Evaluation Mitigation Strategy (REMS) called the Clozapine REMS Program.

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 VERSACLOZ cautiously in patients with cardiovascular/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 VERSACLOZ 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 VERSACLOZ and obtain a cardiac evaluation upon suspicion of these reactions. Generally, patients with clozapine-related myocarditis or cardiomyopathy should not be rechallenged with VERSACLOZ. 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. VERSACLOZ is not approved for use in patients with dementia-related psychosis.

VERSACLOZ is contraindicated in patients with:

Known serious hypersensitivity to clozapine (e.g., photosensitivity, vasculitis, erythema multiforme, or Stevens-Johnson Syndrome) or any other component of VERSACLOZ.

• Eosinophilia has occurred with clozapine, usually within the first month of treatment. Discontinue VERSACLOZ if organ involvement (e.g., myocarditis, pancreatitis, hepatitis, colitis, nephritis) occurs.


• QT prolongation and other life-threatening cardiovascular events, including sudden death have occurred with clozapine treatment. Obtain a cardiac evaluation and discontinue VERSACLOZ if cardiac symptoms develop or if the QTc interval exceeds 500 msec.


• Atypical antipsychotics including VERSACLOZ have been associated with metabolic changes that may increase cardiovascular/ cerebrovascular risk, including hyperglycemia/diabetes mellitus, dyslipidemia, and weight gain.


• Neuroleptic Malignant Syndrome (NMS), a potentially fatal symptom complex, has been reported with administration of antipsychotic drugs, including clozapine. If NMS occurs, immediately discontinue VERSACLOZ, manage with intensive symptomatic treatment, monitor closely, and assess for comorbidities.


• Patients experiencing fever during therapy should be evaluated for infection, severe neutropenia, and NMS.


• Pulmonary embolism, deep vein thrombosis, and anticholinergic toxicity have occurred in patients treated with clozapine. Consider discontinuing VERSACLOZ if tardive dyskinesia occurs.


• Advise caution when operating machinery, including automobiles, and consider reducing the VERSACLOZ dose if cognitive or motor interference occurs.


• Use with caution in patients with risk factors for cerebrovascular adverse reactions.


• If abrupt discontinuation is necessary, monitor carefully for the recurrence of psychotic symptoms and adverse reactions related to cholinergic rebound.

The most commonly reported adverse reactions (≥5%) across clozapine clinical trials were: CNS reactions, including sedation, dizziness/vertigo, headache, and tremor; cardiovascular reactions, including tachycardia, hypotension, and syncope; autonomic nervous system reactions, including hypersalivation, sweating, dry mouth, and visual disturbances; gastrointestinal reactions, including constipation and nausea; and fever.