1. 12-16-031 Safety Review for Plan B Daniel Davis, MD, MPH Division of Reproductive/Urologic Drugs

2. 12-16-032 Outline of Topics Considerations for Non-prescription Switch Marketing Data and Distribution Patterns Sponsor’s Safety Data Office of Drug Safety Consultation Potential for Misuse and Abuse Contraindications FDA Safety Review Summary

3. 12-16-033 Prescription to Non-prescription Switch Is there an acceptable margin of safety? Is the misuse and abuse potential low? Is the product safe and effective when used under non-prescription conditions? Do the benefits from the switch outweigh the risks?

4. 12-16-034 Sponsor’s Exposure Data Plan B dose is 0.75 mg levonorgestrel x 2 USA: 2.4 million uses since 7/99 approval Worldwide: EC available in 101 countries –Use of products identical to Plan B: UK ~2.1 M uses France ~1.8 M uses Canada ~72,000 uses in most recent year

5. 12-16-035 EC Distribution Patterns Routine prescription –68 countries, including the US Advance provision of a Rx or product Pharmacy access –From a pharmacist in 33 countries and 5 states –WA (‘97)- 300 pharmacies; ~1,700 pharmacists –CA (1/02), AK (3/02), NM (12/02), HI (6/03) Truly OTC in Norway and Sweden

6. 12-16-036 Original NDA Safety Data Original NDA trial data –Pivotal World Health Org.(WHO) trial: N=1,955 –3 ongoing WHO trials + several smaller trials –Extensive literature review (N > 15,000 pts.) No deaths or SAEs ( serious adverse events ) AEs ( adverse events ) as labeled and consistent across all studies FDA found no signals of concern

7. 12-16-037 Postmarketing Safety Data Postmarketing (PM) data limitations –exposure is estimated –likelihood of reporting certain AEs may be greater or lesser –under reporting of AEs –incomplete information in AE reports Many different PM data sources –overlap of reports

8. 12-16-038 Plan B Postmarketing Safety Sponsor PM data since July ‘99 –Data from required periodic safety reports (n=345) AEs: most are mild, short-term, labeled AEs No reported transfusions, SAEs, or deaths –Safety data from many US and global sources National PM agencies worldwide WHO Drug Monitoring program Manufacturer and other databases –Global SAEs Death = 0 Strokes = 0 Thromboembolism = 0 Vascular event = 1 phlebitis

9. 12-16-039 ODS Safety Consultation Office of Drug Safety (ODS) consult –Review of FDA AE data (AERS) and UK database –Focus on SAEs and ectopic pregnancy ODS consult findings (116 reports; 60% non-serious labeled events) –No deaths or cardiovascular events –Allergic reactions (10) - no hospitalizations –Fetal risk (8) - 5 spontaneous abortions; 3 anomalies

10. 12-16-0310 Ectopic Pregnancy ODS consult AERS findings (continued) –28 ectopics; none in US and no deaths Six large randomized clinical EC trials: –N = 7,889; 1.5 mg total dose –2 ectopics in 135 total pregnancies =1.5% UK and US ectopic rates are 1.2 and 2.0% in the general population

11. 12-16-0311 Potential Misuse and Abuse Overdose: review found no reports –unlikely with  cost Repeat doses up to 2.25 mg, single doses up to 1.5 mg demonstrated no safety concerns Repeat EC use: shown to be safe, uncommon –studies of advance provision and Rx EC users Use during pregnancy: no evidence that use will result in abortion or fetal injury Timing of 1 st and 2 nd dose

12. 12-16-0312 Contraindications [Prescription Plan B Label ] Prescription Plan B label lists 3 based on the class label for progestin-only OC pills –hypersensitivity to any component –known or suspected pregnancy (not a safety issue; the product will not work) –undiagnosed abnormal genital bleeding

13. 12-16-0313 Evidence of Safety Original NDA trial data Four additional published RCTs with ~6500 women in levonorgestrel only arms –same total dose as Plan B Findings from all 6 RCTs: –Deaths =0 –Vascular events = 0 –Thromboembolic events = 0 –2 ectopics in 135 pregnancies

14. 12-16-0314 Postmarketing Safety Data Postmarketing Data/Surveillance –Extensive EC use in US and Europe since 1999 –No reported deaths, cardiovascular events –No overdose –8 fetal AEs (3 congen. anomalies; 5 miscarriages) is low compared to background rates –10 allergic reactions: no hospitalizations or deaths

15. 12-16-0315 Summary of FDA Safety Review Review of RCTs, medical literature, and large safety surveillance databases –safety profile with no reported deaths, vascular or thromboembolic events –low misuse and abuse potential –risks are very limited –contraindication is allergy: rare –no demonstrated risks to a fetus or a pregnancy

16. 12-16-0316 Discussion Time

17. 12-16-0317 Timing of 1 st dose and treatment effect WHO pivotal study Time to treatment Pregnancy rate Plan B <24 hr0.4% (N = 450) 25-48 hr1.2% (N = 338) 49-72 hr2.7% (N = 187) All women 1.1% (N = 976)

18. 12-16-0318 Timing of the Second Dose WHO 2002 study –single 1.5 mg: 20/1356 = 1.48% pregnancies –two 0.75 mg: 24/1356 = 1.77% pregnancies Arowojolu 2002 study –single 1.5 mg: 4/573 = 0.67% pregnancies –two 0.75 mg: 7/545 = 1.28% pregnancies WHO 1998 study –2nd dose >18 hr in 86/1955: 0 pregnancies

19. 12-16-0319 Delayed First Dose (72-120 hr) Expected pregnancy rate is 8.0% WHO study (2002)- levonorgestrel –N= 164, 2.4 % pregnancies CND study (2001)- Yuzpe –N= 169, 1.8% pregnancies Ellertson (2003)- Yuzpe –N= 111, 3.6% pregnancies Total N= 444; 11 pregnancies = 2.5%

20. 12-16-0320 Labeling Recommendations From a safety perspective: –Do not take if allergic to levonorgestrel –Contact your HCP if you experience: severe stomach or pelvic pain no menses within 1 week of expected menses any severe symptoms or symptoms > 48 hrs –Plan B does not protect against STIs; condoms should be used if at risk for STIs