# Presentation: 794165

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

- 12-16-03

## 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

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## 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?

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## 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

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## 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

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## 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

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## 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

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## 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

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## 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

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## 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

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## 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

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## 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

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## 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

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## 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

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## 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

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## Discussion Time

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## Timing of 1st dose and treatment effectWHO 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)  

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## 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

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## 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%

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## 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

- 12-16-03