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
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
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
Background Rate of Agran
in the General Population
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/mm3
• all-cause agran rate: 12.8 cases/million/year
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/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
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/mm3
• Incidence rate: 7.2 cases/million/yr
• Range (by state): 2.3 - 15.4 cases/million/yr
Summary of Agran Rates in the General
Population
Study
Agranulocytosis Rate
Bottiger and 12.8 cases/million persons/year
Westerholm
IAAAS
4.7 cases/million persons/year
(range: 1.7 - 7.0)
Strom, et al
7.2 cases/million persons/year
(range: 2.3 - 15.4)
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
Agran Rates Observed with
Other Drugs Marketed in the US
Drugs with a Boxed Warning for
Agran
clozapine
ticlopidine
carbamazepine
procainamide
tocainide
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
Definitions
risk:
# of cases
# of people exposed
rate:
# of cases
sum of person-time exposure
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
Ticlopidine-Associated Agran
• data from clinical trials
• definitions: agran= <450 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
Sulfasalazine-Associated Agran
• agran data based on two post-marketing studies
(agran defined in both as <500 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
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”
July 1997 PDAC meeting on WBC
monitoring for clozapine
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?
Discussion at the
July 1997 PDAC meeting
• Agran rates in first 5.25 years of CNR
Time Since First
Exposure
Rate/1000
person-yrs
95% CI lower
95% CI upper
0 - 6 months
8.6
7.7
9.6
6 months - 2 yrs
0.7
0.5
0.9
2 - 3.5 yrs
0.4
0.2
0.7
3.5 - 5.25 yrs
0.2
0.05
0.7
Rate of Agranulocytosis with Clozapine
over 5.25 Years Since First Exposure
Cases/ 1,000 person years
12.0
10.0
rate/1000 pyrs
8.0
95% CI - lower
95% CI - upper
6.0
4.0
2.0
0.0
0
0.5
1
1.5
2
2.5
3
3.5
Time Since First Exposure (in Years)
4
4.5
5
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
Current US clozapine labeling with
regard to WBC monitoring
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?
Agran Rates in the US Stratified by
Age and Cohort
Cohort
Agranulocytosis
Number
Person
Rate/ 1000
years
person years
Initial <40
122
32252
3.8
Initial >=40
271
25364
10.7
Current <40
14
6766
2.1
Current >40
32
7204
4.4
Source: June 5, 2003 Additional data submission Tables 2.1, 2.2