WARNINGS

1. AGRANULOCYTOSIS
BECAUSE OF A SIGNIFICANT RISK OF AGRANULOCYTOSIS, A POTENTIALLY LIFE-THREATENING ADVERSE EVENT, CLOZAPINE SHOULD BE RESERVED FOR USE IN (1) THE TREATMENT OF SEVERELY ILL PATIENTS WITH SCHIZOPHRENIA WHO FAIL TO SHOW AN ACCEPTABLE RESPONSE TO ADEQUATE COURSES OF STANDARD ANTIPSYCHOTIC DRUG TREATMENT, OR (2) FOR REDUCING THE RISK OF RECURRENT SUICIDAL BEHAVIOR IN PATIENTS WITH SCHIZOPHRENIA OR SCHIZOAFFECTIVE DISORDER WHO ARE JUDGED TO BE AT RISK OF REEXPERIENCING SUICIDAL BEHAVIOR. PATIENTS BEING TREATED WITH CLOZAPINE MUST HAVE A BASELINE WHITE BLOOD CELL (WBC) COUNT AND ABSOLUTE NEUTROPHIL COUNT (ANC) BEFORE INITIATION OF TREATMENT AS WELL AS REGULAR WBC COUNTS AND ANCs DURING TREATMENT AND FOR AT LEAST 4 WEEKS AFTER DISCONTINUATION OF TREATMENT. (SEE WARNINGS.) CLOZAPINE IS AVAILABLE ONLY THROUGH A DISTRIBUTION SYSTEM THAT ENSURES MONITORING OF WBC COUNTS AND ANCs ACCORDING TO THE SCHEDULE DESCRIBED BELOW PRIOR TO DELIVERY OF THE NEXT SUPPLY OF MEDICATION. (SEE WARNINGS.)

2. SEIZURES
SEIZURES HAVE BEEN ASSOCIATED WITH THE USE OF CLOZAPINE. DOSE APPEARS TO BE AN IMPORTANT PREDICTOR OF SEIZURE, WITH A GREATER LIKELIHOOD AT HIGHER CLOZAPINE DOSES. CAUTION SHOULD BE USED WHEN ADMINISTERING CLOZAPINE TO PATIENTS HAVING A HISTORY OF SEIZURES OR OTHER PREDISPOSING FACTORS. PATIENTS SHOULD BE ADVISED NOT TO ENGAGE IN ANY ACTIVITY WHERE SUDDEN LOSS OF CONSCIOUSNESS COULD CAUSE SERIOUS RISK TO THEMSELVES OR OTHERS. (SEE WARNINGS.)

3. MYOCARDITIS
ANALYSES OF POSTMARKETING SAFETY DATABASES SUGGEST THAT CLOZAPINE IS ASSOCIATED WITH AN INCREASED RISK OF FATAL MYOCARDITIS, ESPECIALLY DURING, BUT NOT LIMITED TO, THE FIRST MONTH OF THERAPY. IN PATIENTS IN WHOM MYOCARDITIS IS SUSPECTED, CLOZAPINE TREATMENT SHOULD BE PROMPTLY DISCONTINUED. (SEE WARNINGS.)

4. OTHER ADVERSE CARDIOVASCULAR AND RESPIRATORY EFFECTS ORTHOSTATIC HYPOTENSION, WITH OR WITHOUT SYNCOPE, CAN OCCUR WITH CLOZAPINE TREATMENT. RARELY, COLLAPSE CAN BE PROFOUND AND BE ACCOMPANIED BY RESPIRATORY AND/OR CARDIAC ARREST. ORTHOSTATIC HYPOTENSION IS MORE LIKELY TO OCCUR DURING INITIAL TITRATION IN ASSOCIATION WITH RAPID DOSE ESCALATION. IN PATIENTS WHO HAVE HAD EVEN A BRIEF INTERVAL OFF CLOZAPINE (IE, 2 OR MORE DAYS SINCE THE LAST DOSE) TREATMENT SHOULD BE STARTED WITH 12.5 MG ONCE OR TWICE DAILY. (SEE WARNINGS AND DOSAGE AND ADMINISTRATION.) SINCE COLLAPSE, RESPIRATORY ARREST, AND CARDIAC ARREST DURING INITIAL TREATMENT HAS OCCURRED IN PATIENTS WHO WERE BEING ADMINISTERED BENZODIAZEPINES OR OTHER PSYCHOTROPIC DRUGS, CAUTION IS ADVISED WHEN CLOZAPINE IS INITIATED IN PATIENTS TAKING A BENZODIAZEPINE OR ANY OTHER PSYCHOTROPIC DRUG. (SEE WARNINGS.)

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. ANALYSES OF SEVENTEEN PLACEBO-CONTROLLED TRIALS (MODAL DURATION OF 10 WEEKS), LARGELY IN PATIENTS TAKING ATYPICAL ANTIPSYCHOTIC DRUGS, REVEALED A RISK OF DEATH IN DRUG-TREATED PATIENTS OF BETWEEN 1.6 TO 1.7 TIMES THE RISK OF DEATH IN PLACEBO-TREATED PATIENTS. OVER THE COURSE OF A TYPICAL 10-WEEK CONTROLLED TRIAL, THE RATE OF DEATH IN DRUG-TREATED PATIENTS WAS ABOUT 4.5%, COMPARED TO A RATE OF ABOUT 2.6% IN THE PLACEBO GROUP. ALTHOUGH THE CAUSES OF DEATH WERE VARIED, MOST OF THE DEATHS APPEARED TO BE EITHER CARDIOVASCULAR (EG, HEART FAILURE, SUDDEN DEATH) OR INFECTIOUS (EG, PNEUMONIA) IN NATURE. OBSERVATIONAL STUDIES SUGGEST THAT, SIMILAR TO ATYPICAL ANTIPSYCHOTIC DRUGS, TREATMENT WITH CONVENTIONAL ANTIPSYCHOTIC DRUGS MAY INCREASE MORTALITY.
THE EXTENT TO WHICH THE FINDINGS OF INCREASED MORTALITY IN OBSERVATIONAL STUDIES MAY BE ATTRIBUTED TO THE ANTIPSYCHOTIC DRUG AS OPPOSED TO SOME CHARACTERISTIC(S) OF THE PATIENTS IS NOT CLEAR. FAZACLO® (CLOZAPINE, USP) IS NOT APPROVED FOR THE TREATMENT OF PATIENTS WITH DEMENTIA-RELATED PSYCHOSIS. (SEE WARNINGS.)

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.

INDICATION:
Treatment-Resistant Schizophrenia

FazaClo® (clozapine, USP) is indicated for the management of severely ill schizophrenic patients who fail to respond adequately to standard drug treatment for schizophrenia. Because of the significant risk of agranulocytosis and seizure associated with its use, FazaClo should be used only in treatment for 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 treatment with appropriate courses of standard drug treatments for schizophrenia, either because of insufficient effectiveness or the inability to achieve an effective dose due to intolerable adverse effects from those drugs. (See WARNINGS.)

The effectiveness of clozapine in a treatment-resistant schizophrenic population was demonstrated in a 6-week study comparing clozapine and chlorpromazine. Patients meeting DSM-III criteria for schizophrenia and having a mean Brief Psychiatric Rating Scale (BPRS) total score of 61 were demonstrated to be treatment-resistant by history and by open, prospective treatment with haloperidol before entering into the double-blind phase of the study. The superiority of clozapine to chlorpromazine was documented in statistical analyses employing both categorical and continuous measures of treatment effect.

Because of the significant risk of agranulocytosis and seizures, events which both present a continuing risk over time, the extended treatment of patients failing to show an acceptable level of clinical response should ordinarily be avoided. In addition, the need for continuing treatment in patients exhibiting beneficial clinical responses should be periodically reevaluated.

Reduction in the Risk of Recurrent Suicidal Behavior in Schizophrenia or Schizoaffective Disorders
FazaClo is indicated for reducing the risk of recurrent suicidal behavior in patients with schizophrenia or schizoaffective disorder who are judged to be at chronic risk for reexperiencing suicidal behavior, based on history and recent clinical state. Suicidal behavior refers to actions by a patient that put him/herself at risk for death.

The effectiveness of clozapine in reducing the risk of recurrent suicidal behavior was demonstrated over a two-year treatment period in the InterSePT Trial (see Clinical Trial Data under CLINICAL PHARMACOLOGY). Therefore, FazaClo treatment to reduce the risk of suicidal behavior should be continued for at least two years (see DOSAGE AND ADMINISTRATION).

The prescriber should be aware that a majority of patients in both treatment groups in InterSePT received other treatments as well to reduce suicide risk, such as antidepressants and other medications, hospitalization, and/or psychotherapy. The contributions of these additional measures are unknown.

IMPORTANT SAFETY INFORMATION

CONTRAINDICATIONS:
FazaClo is contraindicated in patients with previous hypersensitivity to clozapine, myeloproliferative disorders, uncontrolled epilepsy, paralytic ileus, history of clozapine-induced agranulocytosis or severe granulocytopenia, and in severe central nervous system (CNS) depression or comatose states from any cause. FazaClo should not be used simultaneously with other agents having a well-known potential to cause agranulocytosis or otherwise suppress bone marrow function.

The mechanism of clozapine-induced agranulocytosis is unknown; nonetheless, it is possible that causative factors may interact synergistically to increase the risk and/or severity of bone marrow suppression.

Patients who are being treated with FazaClo must have a baseline WBC count and ANC before initiation of treatment, and a WBC count and ANC every week for the first 6 months. Thereafter, if acceptable WBC counts and ANCs (WBC count ≥3500/mm3 and ANC ≥2000/mm3) have been maintained during the first 6 months of continuous therapy, WBC counts and ANC can be monitored every 2 weeks for the next 6 months. Thereafter, if acceptable WBC counts and ANCs (WBC count ≥3500/mm3 and ANC ≥2000/mm3) 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.

Patients should be advised to immediately report the appearance of lethargy, weakness, fever, sore throat, or any other signs of infection occurring at any time during therapy. Such patients should have a WBC count and an ANC performed promptly. Additionally, patients should be carefully monitored for flu-like symptoms or other symptoms suggestive of infection.

In clinical trials, 1% of patients developed eosinophilia. If a differential count reveals a total eosinophil count above 4000/mm3, FazaClo therapy should be interrupted until the eosinophil count falls below 3000/mm3.

The possibility of myocarditis should be considered in patients receiving FazaClo who present with unexplained fatigue, dyspnea, tachypnea, fever, chest pain, palpitations, other signs or symptoms of heart failure, or electrocardiographic findings such as ST-T wave abnormalities or arrhythmias. Data suggests that the incidence of fatal myocarditis may be highest during the first month of therapy

Tachycardia, which has been associated with clozapine treatment, has also been noted as a presenting sign in patients with myocarditis. Therefore, tachycardia during the first month of therapy warrants close monitoring for other signs of myocarditis.

Prompt discontinuation of FazaClo treatment is warranted upon suspicion of myocarditis. Patients with clozapine-related myocarditis should not be rechallenged with FazaClo.

Treatment with FazaClo has been associated with QT prolongation as well as life-threatening ventricular arrhythmia, Torsades de Pointes, cardiac arrest, and sudden death. Exercise caution in patients with a history (including family history) of long QT syndrome or QT prolongation, or other conditions that may increase their risk for QT prolongation or sudden death, including recent acute myocardial infarction, uncompensated heart failure, or clinically significant cardiac arrhythmia.

Exercise caution when FazaClo is used in combination with other medications (including certain antipsychotic medications) known to prolong the QTc interval. Discontinue FazaClo if the QTc interval exceeds 500 msec. Patients who experience symptoms that could indicate the occurrence of Torsades de Pointes, (e.g., syncope, dizziness and palpitations) should have further evaluation, including cardiac monitoring.

Orthostatic hypotension with or without syncope can occur with FazaClo treatment and may represent a continuing risk in some patients. Tachycardia, which may be sustained, has also been observed in patients taking clozapine. In clinical trials with clozapine, several patients experienced significant cardiac events, including ischemic changes, myocardial infarction, arrhythmias, and sudden death. FazaClo should be used with caution in patients with known cardiovascular and/or pulmonary disease, and the recommendation for gradual titration of dose should be carefully observed.

A potentially fatal symptom complex referred to as Neuroleptic Malignant Syndrome (NMS) has been reported in association with antipsychotic drugs. Clinical manifestations of NMS are hyperpyrexia, muscle rigidity, altered mental status, and evidence of autonomic instability. Immediately discontinue antipsychotic drugs as part of the management of NMS. If a patient requires antipsychotic drug treatment after recovery from NMS, the potential reintroduction of drug therapy should be carefully considered. Cases of NMS have been reported in patients receiving clozapine alone or in combination with lithium or other CNS-active agents.

A few cases of tardive dyskinesia have been reported in patients on clozapine who had been previously treated with other antipsychotic agents. If signs and symptoms of tardive dyskinesia appear in a patient, drug discontinuation should be considered. However, some patients may require treatment with FazaClo despite the presence of the syndrome.

Hyperglycemia and Diabetes Mellitus. Hyperglycemia, in some cases extreme has been reported in patients treated with atypical antipsychotics including clozapine. Patients with an established diagnosis of diabetes mellitus or patients with risk factors for diabetes mellitus who are started on atypical antipsychotics should be monitored for worsening of glucose control. Patients with risk factors for diabetes mellitus (eg, obesity, family history of diabetes) who are starting treatment with atypical antipsychotics should undergo fasting blood glucose testing at the beginning of treatment and periodically during treatment. Any patient treated with atypical antipsychotics should be monitored for symptoms of hyperglycemia.

Because of the significant risk of agranulocytosis and seizure, both of which present a continuing risk over time, the extended treatment of patients failing to show an acceptable level of clinical response should ordinarily be avoided. In addition, the need for continuing treatment in patients exhibiting beneficial clinical responses should be periodically reevaluated.

The following serious medical conditions have been observed in patients on FazaClo therapy. Symptoms should be assessed and treated. Treatment may require discontinuation of FazaClo. Serious medical conditions include: cardiomyopathy, fever, pulmonary embolism, hepatitis, anticholinergic toxicity that may affect the eye, GI system causing intestinal peristalsis, or prostate, sedation/impaired mental and physical abilities and cerebrovascular adverse events.

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

Commonly Observed Adverse Events observed in association with the use of clozapine in clinical trials at an incidence of greater than 5% were: CNS complaints, including drowsiness/sedation, dizziness/vertigo, headache, and tremor; autonomic nervous system complaints, including salivation, sweating, dry mouth, and visual disturbances; cardiovascular findings, including tachycardia, hypotension, and syncope; gastrointestinal complaints, 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.