2. Consideration of Issues John M. Kane, MD Chairman, Department of Psychiatry The Zucker Hillside Hospital The North Shore–Long Island Jewish Health System Professor of Psychiatry, Neurology and Neuroscience Albert Einstein College of Medicine

3. Clozaril ® - Indications l First approved in 1969 for treatment of schizophrenia l First approved in the United States in 1989 for the management of treatment-resistant schizophrenia l Approved in 2002 for treatment of recurrent suicidal behavior in patients with schizophrenia and schizoaffective disorder

4. Clozaril associated agranulocytosis l Serious disease in an affected individual l Represents a significant burden to health care l Early detection decreases risk l Mortality associated with agranulocytosis

5. WBC Monitoring System l NO BLOOD, NO DRUG l Early detection of moderate leukopenia in order to reduce or prevent the occurrence of severe leukopenia, agranulocytosis and death.

6. Question to Committee Should the frequency of monitoring be reduced? If so, when, how and to what frequency?

7. Benefits of Monitoring System Ensures safe use of Clozaril ® :  through early detection of leukopenia and/or agranulocytosis, which reduces: morbidity (hospitalizations and intensive care) mortality  by maintaining non-rechallengable database: 4,526 patients (Feb. 2003) Provides a very important safety net

8. Disadvantages of Frequent Monitoring l Inconvenient to patients and caregivers l Patients who may benefit from Clozaril never start because of the monitoring requirement l Premature discontinuation of treatment

9. Agranulocytosis rates after 52 weeks No significant differences after changes in systems Rates are low after 52 weeks Differences between Systems (with CI’s and p values) US rates 0.273 (0.1,0.45) (p = 0.0022) UK rates -0.28 (-0.78, 0.22) (p < 0.274)

10. Data that Support a Reduction in Monitoring Frequency l Changes in monitoring frequency was not associated with a statistically significant increase in the rates of moderate leukopenia, severe leukopenia, or agranulocytosis l Rate of agranulocytosis has decreased by calendar year l Risk of developing agranulocytosis is greatest during the first 6 months of treatment and stabilizes thereafter

11. Considerations that Do Not Support a Change in Monitoring Frequency l Change from bi-weekly (0.3) to monthly (0.6) monitoring in the UK was associated with an increase in the incidence of agranulocytosis (p=0.274) l May diminish the ability of the system to detect moderate leukopenia in order to reduce or prevent the occurrence of severe leukopenia, agranulocytosis and death l May put patients at increased safety risk that cannot be estimated from existing data

12. Overall conclusions  Monitoring systems work  Data don’t preclude a less frequent monitoring schedule  Data don’t rule out an increase in rate of agranulocytosis with less frequent monitoring

13. Psychopharmacologic Drugs Advisory Committee June 16, 2003