WARNING:

1. AGRANULOCYTOSIS: BECAUSE OF A SIGNIFICANT RISK OF AGRANULOCYTOSIS, A POTENTIALLY LIFETHREATENING

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 COUNT AND ANC 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 POST-MARKETING 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, i.e., 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 COMPARED TO PLACEBO. ANALYSES OF SEVENTEEN PLACEBO-CONTROLLED TRIALS

(MODAL DURATION OF 10 WEEKS), LARGELY IN PATIENTS TAKING ATYPICAL ANTIPSYCHOTIC DRUGS,

REVEALED A RISK OF DEATH IN THE DRUG-TREATED PATIENTS OF BETWEEN 1.6 TO 1.7 TIMES THAT SEEN

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 (e.g., HEART FAILURE, SUDDEN DEATH) OR INFECTIOUS (e.g., 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.

CLOZAPINE IS NOT APPROVED FOR THE TREATMENT OF PATIENTS WITH DEMENTIA-RELATED PSYCHOSIS.