1. Overview of Issues for Psychopharmacological Drugs Advisory Committee June 16, 2003 WBC Monitoring for Clozapine Judith A. Racoosin, MD, MPH Safety Team Leader Division of Neuropharmacological Drug Products, CDER, FDA

2. Outline Introduction Background rates of agranulocytosis Incidence of agranulocytosis with other drugs marketed in the US Brief summary of July1997 PDAC meeting Current labeling Questions to the committee

3. Introduction The clinical development program of Clozaril TM (clozapine) identified agranulocytosis (agran) as a serious adverse event associated with use of the drug FDA approved labeling required that the drug only be available through a distribution system that ensured weekly WBC monitoring (NO BLOOD, NO DRUG) Data on WBC counts and agran occurrence have been collected by the Clozaril National Registry Previous analyses of this database suggested that the incidence of agran decreases substantially after 6 months from first drug exposure

4. Background Rate of Agran in the General Population

5. Background Rates of Agran in the General Population Medical record review of all patients discharged from the hospital with a diagnosis of a blood dyscrasia in the Uppsala health care region of Sweden from 1964-1968 (Bottiger and Westerholm, 1973) definition of agran: < 180 neutrophils/mm 3 all-cause agran rate: 12.8 cases/million/year

6. Background Rates of Agran in the General Population International Agranulocytosis and Aplastic Anemia Study (IAAAS) –population-based case control study –8 sites in Europe and Israel –definition of agran: < 500 neutrophils/mm 3 plus symptoms such as fever, chills, or sore throat –overall rate of agran: 4.7 cases/million/year –1.7-7.0 cases/million/year (range of the 8 sites) IAAAS extension (1 Swedish and 2 US sites) –3.4 cases/million/year

7. Background Rates of Agran in the General Population Study of Medicaid billing database in Minnesota, Michigan, and Florida to estimate agran incidence, excluding recurrent or chronic neutropenia (Strom, et al, 1992) Based on hospital discharge diagnosis with medical record verification Agran definition: < 500 neutrophils/mm 3 Incidence rate: 7.2 cases/million/yr Range (by state): 2.3 - 15.4 cases/million/yr

8. Summary of Agran Rates in the General Population

9. Background Rates of Agran in Patients with Schizophrenia There is no published data on this topic accessible through Medline Due to chronic exposure to medications, the background rate of agran may be higher than the general population

10. Agran Rates Observed with Other Drugs Marketed in the US

11. Drugs with a Boxed Warning for Agran clozapine ticlopidine carbamazepine procainamide tocainide

12. Drugs with Agran in the Warning Section of the Labeling bepridil captopril and all ace inhibitors dapsone fosphenytoin levamisole methimazole mirtazapine norfloxacin ofloxacin penicillamine promethazine propafenone sulfasalazine and all sulfonamides

13. Definitions risk: # of cases # of people exposed rate: # of cases sum of person-time exposure

14. Phenothiazine-Associated Agran Data on phenothiazine-associated agran is derived primarily from case series in the 1950’s and 1960’s In these series, the agran risk ranges from 0.004 - 6.8 cases per 1000 persons In the IAAAS, phenothiazine use did not differ significantly between cases and controls

15. Ticlopidine-Associated Agran data from clinical trials definitions: agran= <450 neutrophils/mm 3 ; neutropenia= 450-1200 neutrophils/mm 3 risk of agran = 17/2048 = 8 cases /1000 persons risk of neutropenia = 33/2048 = 16 cases /1000 persons recommended WBC monitoring: every 2 weeks for the first 3 months of therapy

16. Sulfasalazine-Associated Agran agran data based on two post-marketing studies (agran defined in both as <500 neutrophils/mm 3 ) –Swedish Adverse Drug Reactions Advisory Committee case series They calculated risk of agran using the number of cases reported over a denominator estimate of persons at risk based on an average daily dose calculated from pharmacy records; risk = 0.57 cases/1000 persons I estimated person-years of exposure from the distribution of the estimated length of drug use in 34,500 patients; rate = 3 cases/ 1000 person-years

17. Sulfasalazine-Associated Agran (continued) –United Kingdom’s General Practice Research Database Study data submitted by primary care physicians; risk = 0.68 cases/ 1000 persons I estimated person-years of exposure from number of recorded prescription fills; rate = 3 cases/ 1000 person-year –recommended WBC monitoring: CBC should be done “frequently”

18. July 1997 PDAC meeting on WBC monitoring for clozapine

19. Questions for the July 1997 Clozaril Advisory Committee Meeting Should the frequency of WBC monitoring be reduced at some time point after initiation of therapy, and if so, when and what reduced frequency of WBC monitoring would be acceptable? –Should WBC monitoring stop altogether at some time point, and if so, when? –Should the program be changed overall, e.g.., should it become voluntary, as is most advice in labeling regarding monitoring for adverse events?

20. Discussion at the July 1997 PDAC meeting Agran rates in first 5.25 years of CNR

22. Additional discussion and recommendation of July 1997 PDAC meeting Projected rates of agran given change in monitoring frequency Recommendation of PDAC –to allow decrease in monitoring to biweekly after six months as long as WBC counts were stable

23. Current US clozapine labeling with regard to WBC monitoring

25. Questions for the June 2003 Clozaril Advisory Committee Meeting Should the frequency of WBC monitoring be further reduced after some duration of biweekly monitoring, and if so, when and what reduced frequency of WBC monitoring would be acceptable? –Should WBC monitoring stop altogether at some time point, and if so, when? –Should the program be changed overall, e.g.., should it become voluntary, as is most advice in labeling regarding monitoring for adverse events? Should the ANC be required as a part of WBC monitoring?

27. Agran Rates in the US Stratified by Age and Cohort