1. Joint Dermatologic and Ophthalmic Drugs & Drug Safety and Risk Management Advisory Committee February 26 & 27, 2004 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 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. Joint Dermatologic and Ophthalmic Drugs & Drug Safety and Risk Management Advisory Committee February 26 & 27, 2004 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. 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. Joint Dermatologic and Ophthalmic Drugs & Drug Safety and Risk Management Advisory Committee February 26 & 27, 2004 3 Outline Objectives Methods Limitations Spontaneous AE Reports – Results –Pregnancy Testing –Contraceptive Use –Pregnancy and Fetal Outcomes Drug Use Data Conclusions Objectives Methods Limitations Spontaneous AE Reports – Results –Pregnancy Testing –Contraceptive Use –Pregnancy and Fetal Outcomes Drug Use Data Conclusions

4. Joint Dermatologic and Ophthalmic Drugs & Drug Safety and Risk Management Advisory Committee February 26 & 27, 2004 4 ObjectivesObjectives 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 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. Joint Dermatologic and Ophthalmic Drugs & Drug Safety and Risk Management Advisory Committee February 26 & 27, 2004 5 MethodsMethods 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 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. Joint Dermatologic and Ophthalmic Drugs & Drug Safety and Risk Management Advisory Committee February 26 & 27, 2004 6 325 Cases Of Women Who Were Pregnant While Using Isotretinoin 325 Cases Of Women Who Were Pregnant While Using Isotretinoin Prior RMP – 127 Current RMP – 120 Unknown - 78 Prior RMP – 127 Current RMP – 120 Unknown - 78

7. Joint Dermatologic and Ophthalmic Drugs & Drug Safety and Risk Management Advisory Committee February 26 & 27, 2004 7 Source of 325 Exposure Reports Source of 325 Exposure Reports Prior RMP Current RMP Unknown RMPTotal 12712078325 Manufacturer998672257 Surveys2532663 Direct - FDA3205

8. Joint Dermatologic and Ophthalmic Drugs & Drug Safety and Risk Management Advisory Committee February 26 & 27, 2004 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 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. Joint Dermatologic and Ophthalmic Drugs & Drug Safety and Risk Management Advisory Committee February 26 & 27, 2004 9 Age of Women Pregnant While Using Isotretinoin Prior RMP Current RMP Unknown RMP N =111/127101/12027/78 Median242324 Range14 – 36 years14 – 42 years15 – 50 years

10. Joint Dermatologic and Ophthalmic Drugs & Drug Safety and Risk Management Advisory Committee February 26 & 27, 2004 10 Estimated Timing of Conception Relative to Isotretinoin Treatment Prior RMP Current RMP Unknown RMP N =12712078 Before treatment12 (10%)7 (6%)1 (1%) During treatment 1 st month 83 (65%) 18 80 (67%) 13 66 (85%) 1 Within 30 days of discontinuation 31 (24%)31 (26%)7 (9%) Indeterminate/ NR1 (1%)2 (1.7%)4 (5%)

11. Joint Dermatologic and Ophthalmic Drugs & Drug Safety and Risk Management Advisory Committee February 26 & 27, 2004 11 Duration of Isotretinoin Exposure After Conception Prior RMP Current RMP Unknown RMP N =71548 Range (days)1 to 911 to 523 to 105 Mean (days)19.119.326.1 Median (days)17 14

12. Joint Dermatologic and Ophthalmic Drugs & Drug Safety and Risk Management Advisory Committee February 26 & 27, 2004 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 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. Joint Dermatologic and Ophthalmic Drugs & Drug Safety and Risk Management Advisory Committee February 26 & 27, 2004 13 Baseline Pregnancy Testing Before Starting Isotretinoin Prior RMP Current RMP N =127120 Any Baseline Pregnancy Test 1 baseline test > 2 baseline tests 63 (50%) 45 (35%) 18 (15%) 60 (50%) 37 (31%) 23 (19%) No Baseline Test Taken4 (3%)2 (2%) Not Reported 60 (47%)58 (48%)

14. Joint Dermatologic and Ophthalmic Drugs & Drug Safety and Risk Management Advisory Committee February 26 & 27, 2004 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 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 Prior RMP Current RMP Unknown RMP Pregnant Before Starting Isotretinoin 1271

15. Joint Dermatologic and Ophthalmic Drugs & Drug Safety and Risk Management Advisory Committee February 26 & 27, 2004 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 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. Joint Dermatologic and Ophthalmic Drugs & Drug Safety and Risk Management Advisory Committee February 26 & 27, 2004 16 Pregnancy Testing During Isotretinoin Treatment Prior RMP Current RMP N =127120 Any Pregnancy Test during Treatment 45 (35%)47 (39%) No Pregnancy Test during Treatment4 (3%)2 (2%) No Report of Pregnancy Testing Info78 (61%)71 (59%)

17. Joint Dermatologic and Ophthalmic Drugs & Drug Safety and Risk Management Advisory Committee February 26 & 27, 2004 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 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. Joint Dermatologic and Ophthalmic Drugs & Drug Safety and Risk Management Advisory Committee February 26 & 27, 2004 18 Contraceptive Use during Isotretinoin Therapy Prior RMP Current RMP N =127120 Any Birth Control Method68 (54%)70 (59%) No Birth Control Used/Abstinence15 (12%)6 (5%) No Report of Birth Control Info44 (34%)44 (36%)

19. Joint Dermatologic and Ophthalmic Drugs & Drug Safety and Risk Management Advisory Committee February 26 & 27, 2004 19 Any Birth Control Use Prior RMP and Current RMP Prior RMP Current RMP N =6870 One Method –50/68(74%)61/70 (87%) Two Methods –18/68 (26%)9/70 (13%)

20. Joint Dermatologic and Ophthalmic Drugs & Drug Safety and Risk Management Advisory Committee February 26 & 27, 2004 20 Other Findings Related to Contraceptive Use Non-Adherence to Contraception Directions –Prior RMP 18% –Current RMP 25% Contraceptive Failure Reported equally Non-Adherence to Contraception Directions –Prior RMP 18% –Current RMP 25% Contraceptive Failure Reported equally

21. Joint Dermatologic and Ophthalmic Drugs & Drug Safety and Risk Management Advisory Committee February 26 & 27, 2004 OutcomesOutcomes Pregnancy and Fetal

22. Joint Dermatologic and Ophthalmic Drugs & Drug Safety and Risk Management Advisory Committee February 26 & 27, 2004 22 Pregnancy Outcomes of Isotretinoin Exposures Prior RMP Current RMP Unknown RMP N =12712078 Terminations62 (49%)54 (45%)20 (26%) Elective474818 Spontaneous and/or Ectopic 1562 Live Births18 (14%)7 (6%)4 (5%) Unknown47 (37%)59 (49%)54 (69%)

23. Joint Dermatologic and Ophthalmic Drugs & Drug Safety and Risk Management Advisory Committee February 26 & 27, 2004 23 Outcome of 29 Live Births Prior RMP Current RMP Unknown RMP Total No abnormalities identified – at birth 135220 Abnormal4217 Unknown Outcome 1-------12 Total187429

24. Joint Dermatologic and Ophthalmic Drugs & Drug Safety and Risk Management Advisory Committee February 26 & 27, 2004 Drug Utilization

25. Joint Dermatologic and Ophthalmic Drugs & Drug Safety and Risk Management Advisory Committee February 26 & 27, 2004 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 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. Joint Dermatologic and Ophthalmic Drugs & Drug Safety and Risk Management Advisory Committee February 26 & 27, 2004 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™ 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. Joint Dermatologic and Ophthalmic Drugs & Drug Safety and Risk Management Advisory Committee February 26 & 27, 2004 27 LimitationsLimitations 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 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. Joint Dermatologic and Ophthalmic Drugs & Drug Safety and Risk Management Advisory Committee February 26 & 27, 2004 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*15.62.4 % Generic*-----10.3 % Rx’es by Dermatologists* 76.179.9 % Female**50.449.2 TMTM Source: *IMS Health, IMS National Prescription Audit Plus TM (3 Dec 03) & **AdvancePCS TM (11 Dec 03)

29. Joint Dermatologic and Ophthalmic Drugs & Drug Safety and Risk Management Advisory Committee February 26 & 27, 2004 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) 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. Joint Dermatologic and Ophthalmic Drugs & Drug Safety and Risk Management Advisory Committee February 26 & 27, 2004 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 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. Joint Dermatologic and Ophthalmic Drugs & Drug Safety and Risk Management Advisory Committee February 26 & 27, 2004 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 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. Joint Dermatologic and Ophthalmic Drugs & Drug Safety and Risk Management Advisory Committee February 26 & 27, 2004 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 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