IMPORTANT SAFETY INFORMATION

WARNING: AGRANULOCYTOSIS; ORTHOSTATIC HYPOTENSION, BRADYCARDIA, AND SYNCOPE; SEIZURE; MYOCARDITIS AND CARDIOMYOPATHY; INCREASED MORTALITY IN ELDERLY PATIENTS WITH DEMENTIA-RELATED PSYCHOSIS
Agranulocytosis
Clozapine treatment has caused agranulocytosis, defined as an absolute neutrophil count (ANC) less than 500/mm3. Agranulocytosis can lead to serious infection and death. Prior to initiating treatment with FAZACLO, obtain a baseline white blood cell count (WBC) and ANC. The ANC must be greater than or equal to 2000/mm3 and the WBC must be greater than or equal to 3500/mm3 for a patient to begin treatment with FAZACLO. During treatment, patients must have regular monitoring of ANC and WBC. Discontinue FAZACLO and do not rechallenge if the ANC is less than 1000/mm3 or the WBC is less than 2000/mm3. Advise patients to immediately report symptoms consistent with agranulocytosis or infection (e.g., fever, weakness, lethargy, or sore throat).

Because of the risk of agranulocytosis, FAZACLO is available only through a restricted program called the FAZACLO Patient Registry. Under the FAZACLO Patient Registry, prescribers, patients, and pharmacies must enroll in the 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 FAZACLO 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 FAZACLO 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 FAZACLO and obtain a cardiac evaluation upon suspicion of these reactions. Generally, patients with FAZACLO-related myocarditis or cardiomyopathy should not be rechallenged with FAZACLO. 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. FAZACLO is not approved for use in patients with dementia-related psychosis.

Adverse Event Reporting

To report an adverse event please call 1-877-329-2256
You are encouraged to report negative side effects of prescription drugs to the FDA. Visit www.fda.gov/medwatch, or call 1-800-FDA-1088.

INDICATIONS AND USAGE

Treatment Resistant Schizophrenia

FAZACLO is indicated for the treatment of severely ill patients with schizophrenia. Because of the significant risk of agranulocytosis and seizure associated with its use, FAZACLO should be used only in patients who have failed to respond adequately to standard antipsychotic treatment.

Efficacy was established in a 6-week, randomized, double-blind, active-controlled study comparing clozapine and chlorpromazine in patients who had failed other antipsychotics.

Reduction in the Risk of Recurrent Suicidal Behavior in Schizophrenia or Schizoaffective Disorder

FAZACLO is indicated for reducing the risk of recurrent suicidal behavior in patients with schizophrenia or schizoaffective disorder at chronic risk for re-experiencing suicidal behavior, based on history and recent clinical state.

Efficacy was demonstrated over a two-year treatment period in the InterSePT trial.

IMPORTANT SAFETY INFORMATION

CONTRAINDICATIONS:

  • History of clozapine-induced agranulocytosis or severe granuloctopenia
  • Known hypersensitivity to clozapine (e.g., photosensitivity, vasculitis, erythema multiforme, or Stevens-Johnson Syndrome) or any other component of FAZACLO

Agranulocytosis

WBC Count and ANC Clinical Monitoring Schedule

Conduct baseline WBC count and ANC before initiation of treatment, and every week for the first 6 months of treatment. Thereafter, if acceptable WBC counts and ANCs (WBC count ≥3500/mm3 and ANC ≥2000/mm3) have been maintained, monitor every 2 weeks for the next 6 months. If acceptable WBC counts and ANCs have been maintained during the second 6 months of continuous therapy, WBC count and ANC can be monitored every 4 weeks.

When treatment with FAZACLO is discontinued (regardless of reason), WBC count and ANC must be monitored weekly for at least 4 weeks from the day of discontinuation or until WBC count ≥3500/mm3 and ANC ≥2000/mm3.

Nonrechallengeable Patients
Discontinue treatment and do not rechallenge patients if WBC count <2000/mm3 and/or ANC <1000/mm3. Consider bone-marrow aspiration to ascertain granulopoietic status, with protective isolation and close monitoring if indicated. Perform cultures and initiate appropriate antibiotics if evidence of infection develops.

Treatment of Rechallengeable Patients
Patients may be rechallenged with FAZACLO if their WBC count does not fall below 2000/mm3 and the ANC does not fall below 1000/mm3. However, data from the Clozapine National Registry suggest that patients who have an initial episode of moderate leukopenia have up to a 12-fold increased risk of having a subsequent episode of agranulocytosis when rechallenged as compared to the full cohort of patients treated with clozapine. Monitor patients as recommended in the Full Prescribing Information for FAZACLO.

Although FAZACLO therapy may be resumed if no symptoms of infection develop and when the WBC count and the ANC are acceptable, prescribers are strongly advised to consider whether the benefit of continuing FAZACLO treatment outweighs the increased risk of agranulocytosis.

Eosinophilia

Eosinophilia, defined as a blood eosinophil count > 700/mm3, has occurred with clozapine treatment, usually within the first month of treatment. In clinical trials, approximately 1% of patients developed eosinophilia. Clozapine-related eosinophilia has been associated with myocarditis, pancreatitis, hepatitis, colitis, and nephritis. If eosinophilia develops, assess for organ involvement, rash or other allergic symptoms. Discontinue immediately if these occur.

QT Interval Prolongation

QT prolongation, Torsades de Pointes and other life-threatening ventricular arrhythmias, cardiac arrest, and sudden death have occurred with clozapine treatment. Exercise caution in patient with a history (including family history) of QT prolongation, long QT syndrome or sudden cardiac death, significant cardiac arrhythmia, recent myocardial infarction, uncompensated heart failure, treatment with other medications that cause QT prolongation or that inhibit the metabolism of FAZACLO, and electrolyte abnormalities.

Prior to initiating treatment, perform a careful physical examination, medical history, and concomitant medication history. Consider obtaining a baseline ECG and serum chemistry panel. Correct electrolyte abnormalities. Discontinue FAZACLO if the QTc interval exceeds 500 msec. If patients experience symptoms consistent with Torsades de Pointes or other arrhythmias, (e.g., syncope, presyncope, dizziness, or palpitations), obtain a cardiac evaluation and discontinue FAZACLO.

Metabolic Changes

Atypical antipsychotic drugs, including clozapine, have been associated with metabolic changes that can increase cardiovascular and cerebrovascular risk. These include:

  • Hyperglycemia and Diabetes Mellitus: Monitor all patients for symptoms of hyperglycemia including polydipsia, polyuria, polyphagia, and weakness. Monitor glucose prior to starting treatment and periodically thereafter in patients with diabetes or at risk for diabetes. Hyperglycemia, in some cases extreme associated with ketoacidosis and hyperosmolar coma or death, has been reported in patients treated with atypical antipsychotics including clozapine.
  • Dyslipidemia: Undesirable alterations in lipids have occurred in patients treated with atypical antipsychotics. Baseline and periodic follow-up lipid evaluations are recommended.
  • Weight Gain: Significant weight gain has occurred. Monitor weight during treatment with FAZACLO.

Neuroleptic Malignant Syndrome (NMS)

NMS, a potentially fatal symptom complex, has been reported with administration of antipsychotic drugs, including clozapine. Clinical manifestations of NMS include hyperpyrexia, muscle rigidity, altered mental status and autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac dysrhythmias). Additional signs may include elevated creatine phosphokinase, myoglobinuria, rhabdomyolysis, and acute renal failure. Management should include immediate discontinuation of antipsychotics and other drugs not essential to concurrent therapy, intensive symptomatic treatment and medical monitoring, and treatment of comorbidities, including agranulocytosis, infection, heat stroke, primary CNS pathology, central anticholinergic toxicity, extrapyramidal symptoms, and drug fever.

Fever

Patients have experienced transient, clozapine-related fever during therapy, often within the first 3 weeks of treatment. Carefully evaluate patients with fever for agranulocytosis, infection, or NMS. While this fever is generally benign and self-limited, discontinuation may be necessary.

Pulmonary Embolism

Pulmonary embolism (PE) and deep vein thrombosis (DVT) have occurred in patients treated with clozapine. Consider PE if respiratory distress, chest pain, or DVT occur.

Anticholinergic Toxicity

Treatment with FAZACLO can result in CNS and peripheral anticholinergic toxicity. Use with caution in the presence of narrow-angle glaucoma, concomitant anticholinergic medications, prostatic hypertrophy, or other conditions in which anticholinergic effects can lead to significant adverse reactions.

Treatment with FAZACLO can result in gastrointestinal adverse reactions, sometimes fatal, including constipation, intestinal obstruction, fecal impaction, and paralytic ileus. Treat constipation and consult with a gastroenterologist in more serious cases.

Interference with Cognitive and Motor Performance

FAZACLO can cause sedation and impairment of cognitive and motor performance. Caution patients about operating machinery, including automobiles, until they are reasonably certain that FAZACLO does not affect them adversely. Consider reducing FAZACLO dose if these reactions occur.

Tardive Dyskinesia

Tardive dyskinesia (TD) has occurred in patients treated with antipsychotic drugs, including clozapine. The risk of TD and the likelihood that it will become irreversible are believed to increase with greater durations of treatment and higher total cumulative doses, although it can occur after short periods and at low doses. Use the lowest effective dose and the shortest duration necessary to control symptoms. Periodically assess the need for continued treatment. Consider discontinuing FAZACLO if TD occurs.

Patients with Phenylketonuria

Phenylketonuric patients should be informed that FAZACLO contains phenylalanine (a component of aspartame).

Cerebrovascular Adverse Reactions

In controlled trials, elderly patients with dementia-related psychosis treated with some atypical antipsychotics had an increased risk (compared to placebo) of cerebrovascular adverse reactions (e.g., stroke, transient ischemic attack), including fatalities. FAZACLO should be used with caution in patients with risk factors for cerebrovascular adverse reactions.

Recurrence of Psychosis and Cholinergic Rebound after Abrupt Discontinuation

If abrupt discontinuation is necessary, monitor carefully for the recurrence of psychotic symptoms and adverse reactions related to cholinergic rebound, such as profuse sweating, headache, nausea, vomiting, and diarrhea.

DRUG INTERACTIONS

Clozapine is a substrate for many cytochrome P450 isozymes, in particular CYP1A2, CYP3A4, and CYP2D6. Use caution when administering FAZACLO concomitantly with drugs that are inducers or inhibitors of these enzymes.

ADVERSE REACTIONS

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.

You may contact the FazaClo Patient Registry at 1-877-FAZACLO (329-2256) or at www.fazaclo.com.

Please see full Prescribing Information, including BOXED Warning, for additional important safety information.