Overview of Issues for Psychopharmacological Drugs Advisory Committee June 16, 2003 WBC Monitoring for Clozapine

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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

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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

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Introduction

• The clinical development program of ClozarilTM
  (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

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Background Rate of Agran in the General
Population
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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 lt 180 neutrophils/mm3
• all-cause agran rate 12.8 cases/million/year

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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 lt 500 neutrophils/mm3 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

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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 lt 500 neutrophils/mm3
• Incidence rate 7.2 cases/million/yr
• Range (by state) 2.3 - 15.4 cases/million/yr

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Summary of Agran Rates in the General Population
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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

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Agran Rates Observed with Other Drugs Marketed
in the US
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Drugs with a Boxed Warning for Agran

• clozapine
• ticlopidine
• carbamazepine
• procainamide
• tocainide

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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

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Definitions

• risk of cases
• of people exposed
• rate of cases
• sum of person-time exposure

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Phenothiazine-Associated Agran

• Data on phenothiazine-associated agran is derived
  primarily from case series in the 1950s and
  1960s
• 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

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Ticlopidine-Associated Agran

• data from clinical trials
• definitions agran lt450 neutrophils/mm3
  neutropenia 450-1200 neutrophils/mm3
• 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

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Sulfasalazine-Associated Agran

• agran data based on two post-marketing studies
  (agran defined in both as lt500 neutrophils/mm3)
• 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

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Sulfasalazine-Associated Agran(continued)

• United Kingdoms 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

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July 1997 PDAC meeting on WBC monitoring for
clozapine
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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?

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Discussion at the July 1997 PDAC meeting

• Agran rates in first 5.25 years of CNR

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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

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Current US clozapine labeling with regard to WBC
monitoring
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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?

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Agran Rates in the US Stratified by Age and
Cohort