Safety Review for Plan B Daniel Davis, MD, MPH Division of Reproductive/Urologic Drugs

1. Safety Review for Plan B Daniel Davis, MD, MPHDivision of Reproductive/Urologic Drugs

2. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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 1st and 2nd dose

12. 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. 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. 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. 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. Discussion Time

17. Timing of 1st dose and treatment effectWHO pivotal study Time to treatment Pregnancy rate Plan B<24 hr 0.4% (N = 450)25-48 hr 1.2% (N = 338)49-72 hr 2.7% (N = 187)All women 1.1% (N = 976)

18. 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. 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. 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