1. Rational Hematological Monitoring for Clozapine-Treated Patients

2. Representing Our Family David Goldman, M.D. Chief, Lab. of Neurogenetics, NIAAA, NIH, Rockville, Maryland Lynn Goldman, M.D. Professor, Johns Hopkins University Bloomberg School of Public Health, Baltimore, Maryland Daniel Goldman, M.D. Expert Health Data Programming, Inc., Seattle, Washington Armond Goldman, M.D. Professor Emeritus, Univ. of Texas Medical Branch, Galveston, Texas

3. Summary Risks of agranulocytosis associated with various monitoring options Questions regarding how neutropenia is defined in this context Other risks and benefits that should be considered Our recommendation for monthly monitoring after 12 months of treatment

4. USA Clozaril Registry 2003 Report 1990 - 2001: 203,181 clozapine-treated patients enrolled in registry; 178,104 with data Clozapine-associated “moderate leukopenia”/“agranulocytosis” surface in the first 6 months (at a rate of 15/1000 p-y) After 6 months the hazard of “moderate leukopenia”/“agranulocytosis” is reduced to 0.3/1000 person-years

5. USA Clozaril Registry: 2003 Report If “moderate leukopenia”/“agranulocytosis” did not develop during the first 6 months, the chance of a drug-induced agranulocytosis was negligible but not zero Novartis presented a theoretical risk model (based on the median rate of decline of leukocytes among patients with neutropenia for alternative monitoring regimes (monthly or none after 1 yr)

6. US Requirements New patients: weekly blood counts Twice weekly monitoring: WBC 3000- 3500/mm 3 and ANC >1500/mm 3 Temporary discontinuation: WBC 2000- 3000/mm 3 and/or ANC 1000-1500/mm 3 Permanent discontinuation: WBC <2000/mm 3 and/or ANC <1000/mm 3 > 6 months: monitor once every two weeks

7. UK/Australia Requirements New patients: weekly blood counts Weekly monitoring: WBC 3000-3500/mm 3 and/or ANC1500-2000/mm 3 Discontinue: WBC <3000/mm 3 and/or ANC ≤1500/mm 3 Weeks 19-52: at least every 2 weeks > 52 weeks: monitor at least monthly thereafter

8. Theoretical vs. Actual Hazards

9. Hazard of Less Frequent Monitoring after One Year Data from the UK and Australia provide the best estimate of what might occur if blood monitoring were done less frequently after a year or two of therapy (all other things being equal), or an increase from 0.3 to 0.6 cases of agranulocytosis/1000 p-y. Data from the UK and Australia would predict a lower rate of “moderate leukopenia” with decreased monitoring; this is probably spurious.

10. Hematologic Considerations The definitions of agranulocytosis and leukopenia do not correspond to those used by hematologists and leads to confusion and an overestimation of the hematological risks. For example, leukopenias could be due to lymphopenias, such as decreased T cells because of reduced thymic function or increased T cell destruction and/or sequestration.

11. Cases of Late-Onset Neutropenia A 41-year-old male received clozapine for 89 months. Resperidone was initiated shortly before neutropenia. A 28-year-old male received clozapine for 3 years. Human recombinant interferon-  for chronic hepatitis C therapy was provided for two moths prior to neutropenia. A 35-year old female received clozapine off and on for 5 yrs. She was taking quetiamine and clozaril when agranulocytosis and death (reported in 1998) occurred. The cause of death was not given. Quetiamine was first on the market in the US in 1997. It is not clear that clozapine caused neutropenia in these cases.

12. Why Continue Clozapine? The patient has improved and is without side effects during the first several months of therapy'. It is unclear whether other drugs are as efficacious. Newer drugs also have side effects, including neutropenia, most likely at a lower incidence. Inadequate/inappropriate treatment of schizophrenia is associated with a high mortality rate

13. DHHS, PHS FDA ODS Post-marketing Safety Review Oct. 3, 2002 Introduced Neutropenias#/YearIncidence Clozapine1989234183% Risperidone19938810? Olanzapine199616227? Quetiapine199710922? Ziprasidone200122?

14. Annual Cost of Monitoring 100,000 Patients Every Two Weeks $ Initial ($M) Repeat (5%) ($M)Total ($M) Venipuncture5130.613.6 CBC501306.5136.5 Doctor10261.327.3 DIRECT$65$169$8.40$177.40 INDIRECT$25$64.80$3.20$68.00 TOTAL$233.80$11.70$245.40 100,000 patients $245.4 million/yr

15. Non-Monetary Costs Damage to peripheral veins Loss from work and other activities Limitation upon freedom to travel Stigmatization because of frequent clinic visits These factors discourage patient compliance and encourage switching to less effective alternatives

16. Revised Schedule for Hematological Monitoring Duration (Months)Frequency 0 to 6Weekly 6 to 12Every Two Weeks >12Monthly

17. Revised Monitoring Will Decrease Damage to peripheral veins Psychological trauma from procedures Stigmatization Loss of time from work or education Costs to patients, families, and the health care system

18. Revised Monitoring Will Increase Freedom to travel Job and school opportunities Sense of independence

19. Hematology/Immunology Questions Could the FDA benefit from the advice of expert hematologists and immunologists regarding definitions and mechanisms of drug induced neutropenia? Are there data on the risks of significant neutropenias in patients who take other anti- psychotic agents for many years?

20. Summary The proposal for less monitoring is in keeping with the 1998 vote of the FDA Psychopharmacologic Drugs Advisory Committee. The revision should not hamper detection of neutropenias during period of increased risk. Although theoretical calculations point to large increases risk, the experience supports a much smaller change in risk The decreased monitoring should benefit patients, families, and the health care system