Overview

1
Overview

• Isotretinoin Pregnancy Exposures Spontaneous
  Reports 1-year Prior to, 1-year After
  Implementation of the Current RMP
• Marilyn R. Pitts, Pharm.D., Office of Drug
  Safety
• Isotretinoin Pregnancy Prevention Program
  Evaluation
• Allen Brinker, M.D., M.S., Office of Drug Safety

2
Isotretinoin Pregnancy Exposures Spontaneous
Reports 1-year Prior to, 1-year After
Implementation of the Current RMP

• February 26, 2004
• Marilyn R. Pitts, Pharm.D.,
• Office of Drug Safety
• In Collaboration
• Claudia Karwoski, Pharm.D.,
• Aaron Mendelsohn, Ph.D., M.P.H.

3
Outline

• Objectives
• Methods
• Limitations
• Spontaneous AE Reports Results
• Pregnancy Testing
• Contraceptive Use
• Pregnancy and Fetal Outcomes
• Drug Use Data
• Conclusions

4
Objectives

• Compare spontaneous adverse event reports of
  women who were pregnant while using isotretinoin
  one year before RMP and one year after RMP
• Provide isotretinoin drug use data before RMP and
  after RMP

RMP risk management program
5
Methods

• Case Search
• All reported cases of maternal exposure
• Exposure during or lt 30 days after
  discontinuation of isotretinoin
• August 15, 2003
• Categorized by Conception Date
• Prior RMP 04-01-01 to 03-31-02
• Current RMP 04-01-02 to 03-31-03
• Unknown

6
325 Cases Of Women Who Were Pregnant While Using
Isotretinoin

• Prior RMP 127
• Current RMP 120
• Unknown - 78

7
Source of 325 Exposure Reports
Prior RMP Current RMP Unknown RMP Total
Total 127 120 78 325
Manufacturer 99 86 72 257
Surveys 25 32 6 63
Direct - FDA 3 2 0 5
8
Limitations of Case Reports

• Spontaneous Adverse Event Reports
• Variable reporting
• Variable quality
• Variable completeness
• Lack of RMP specific information
• Experiences of women who were pregnant in our
  case series may not be representative to general
  isotretinoin users

9
Age of Women Pregnant While Using Isotretinoin
Prior RMP Current RMP Unknown RMP
N 111/127 101/120 27/78
Median 24 23 24
Range 14 36 years 14 42 years 15 50 years
10
Estimated Timing of Conception Relative to
Isotretinoin Treatment
Prior RMP Current RMP Unknown RMP
N 127 120 78
Before treatment 12 (10) 7 (6) 1 (1)
During treatment 1st month 83 (65) 18 80 (67) 13 66 (85) 1
Within 30 days of discontinuation 31 (24) 31 (26) 7 (9)
Indeterminate/ NR 1 (1) 2 (1.7) 4 (5)
11
Duration of Isotretinoin Exposure After
Conception
Prior RMP Current RMP Unknown RMP
N 71 54 8
Range (days) 1 to 91 1 to 52 3 to 105
Mean (days) 19.1 19.3 26.1
Median (days) 17 17 14
12
Pregnancy Testing - Baseline Current Label
Information

• Baseline (Before Starting Isotretinoin)
• Screening test at time of decision to pursue
  isotretinoin
• Confirmatory test during first 5 days of cycle
  immediately preceding initiation of isotretinoin

13
Baseline Pregnancy Testing Before Starting
Isotretinoin
Prior RMP Current RMP
N 127 120
Any Baseline Pregnancy Test 1 baseline test gt 2 baseline tests 63 (50) 45 (35) 18 (15) 60 (50) 37 (31) 23 (19)
No Baseline Test Taken 4 (3) 2 (2)
Not Reported 60 (47) 58 (48)
14
Baseline Pregnancy Testing in 20 Women Pregnant
Before Isotretinoin
Prior RMP Current RMP Unknown RMP
Pregnant Before Starting Isotretinoin 12 7 1

• Baseline Pregnancy Testing
• 16 reported at least one baseline pregnancy test
• 9 reported at least 2 baseline pregnancy tests
• 11 reported pregnancy test results
• 8 reported negative baseline test results
• 3 reported positive baseline test results
• 14 of 16 did not have test during menses

15
Pregnancy Testing During Treatment Current
Label Information

• Each month of therapy, the patient must have a
  negative result from a urine or serum pregnancy
  test.
• A pregnancy test must be repeated every month
  prior to the female patient receiving each
  prescription

16
Pregnancy Testing During Isotretinoin Treatment
Prior RMP Current RMP
N 127 120
Any Pregnancy Test during Treatment 45 (35) 47 (39)
No Pregnancy Test during Treatment 4 (3) 2 (2)
No Report of Pregnancy Testing Info 78 (61) 71 (59)
17
Contraception Current Label Information

• 2 forms of effective contraception
• At least one primary method
• Oral contraceptives, implantable hormones,
  injectable hormones, hormonal patch, hormonal
  vaginal contraceptive ring, IUD, surgical
  sterilization
• Exceptions
• Absolute abstinence
• Hysterectomy

18
Contraceptive Use during Isotretinoin Therapy
Prior RMP Current RMP
N 127 120
Any Birth Control Method 68 (54) 70 (59)
No Birth Control Used/Abstinence 15 (12) 6 (5)
No Report of Birth Control Info 44 (34) 44 (36)
19
Any Birth Control Use Prior RMP and Current RMP
Prior RMP Current RMP
N 68 70
One Method 50/68(74) 61/70 (87)
Two Methods 18/68 (26) 9/70 (13)
20
Other Findings Related to Contraceptive Use

• Non-Adherence to Contraception Directions
• Prior RMP 18
• Current RMP 25
• Contraceptive Failure Reported equally

21
Outcomes

• Pregnancy and Fetal

22
Pregnancy Outcomes of Isotretinoin Exposures
Prior RMP Current RMP Unknown RMP
N 127 120 78
Terminations 62 (49) 54 (45) 20 (26)
Elective 47 48 18
Spontaneous and/or Ectopic 15 6 2
Live Births 18 (14) 7 (6) 4 (5)
Unknown 47 (37) 59 (49) 54 (69)
23
Outcome of 29 Live Births
Prior RMP Current RMP Unknown RMP Total
No abnormalities identified at birth 13 5 2 20
Abnormal 4 2 1 7
Unknown Outcome 1 ------- 1 2
Total 18 7 4 29
24
Drug Utilization
25
National Prescription Audit Plus? (NPA Plus?)

• Measures the retail outflow of prescriptions
  from pharmacies to consumers in retail stores,
  mail order and long-term care
• Obtained from a sample of approximately 22,000
  pharmacies in the U.S.
• Represents 45 of US prescriptions
• Data are projected nationally

26
AdvancePCS?

• Large U.S. Pharmacy Benefits Manager (PBM)
• Covers over 50 million patient lives over 300
  million prescriptions annually
• Dimension Rx tool accesses information on paid
  prescription claims for patients with
  prescription drug benefits administered by
  AdvancePCS

27
Limitations

• Data do not permit a more detailed analysis of
  the observed trends
• National estimates from IMS health may be
  variable due to small numbers in certain
  subgroups
• AdvancePCS data may not be nationally
  representative

28
Isotretinoin Utilization in the U.S.
Prior RMP (Apr 01 Mar 02) Current RMP (Apr 02 Mar 03)
of Prescriptions 1.5 million 1.2 million
Refills 15.6 2.4
Generic ----- 10.3
Rxes by Dermatologists 76.1 79.9
Female 50.4 49.2
Source IMS Health, IMS National Prescription
Audit PlusTM (3 Dec 03) AdvancePCSTM (11 Dec
03)
29
Drug Utilization Conclusions

• Number of dispensed isotretinoin prescriptions
  declined 23 following RMP implementation
• Percent of refill prescriptions for isotretinoin
  dropped from 16 to 2
• Other utilization variables did not appear to be
  influenced by RMP (prescriber, gender)

30
Pregnancy Exposures Conclusions

• Women who were pregnant while using isotretinoin
  (prior -127, current 120)
• Slight decline reported in number of women
  pregnant prior to starting isotretinoin (prior
  12, current 7)
• Pregnancies reported occurring throughout
  isotretinoin therapy for both risk management
  programs

31
Pregnancy Exposures Conclusions

• No difference reported in days of exposure after
  conception between programs
• No improvement reported in baseline pregnancy
  testing between programs
• Slight improvement reported in pregnancy testing
  during treatment in current RMP
• Slight improvement reported in the use of at
  least one method of contraception in current RMP

32
Pregnancy Exposures Conclusions

• Among 325 pregnant woman using isotretinoin 15
  of women used at least two methods of
  contraception, with one being a primary method
• Of the 138 women who used contraception, 38
  reported non-adherence to health care providers
  directions for use