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 < 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

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

10. Estimated Timing of Conception Relative to Isotretinoin Treatment

11. Duration of Isotretinoin Exposure After Conception

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

14. Baseline Pregnancy Testing in 20 Women Pregnant Before Isotretinoin • 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

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

19. Any Birth Control Use Prior RMP and Current RMP

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

23. Outcome of 29 Live Births

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. Source: *IMS Health, IMS National Prescription Audit PlusTM (3 Dec 03) & **AdvancePCSTM(11 Dec 03)

29. Drug UtilizationConclusions • 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