December 15, 2015
Division of Dockets Management (HFA-305)
Food and Drug Administration
5630 Fishers Lane, Rm. 1061
Rockville, MD 20852
Comments of members of the Patient, Consumer, and Public Health Coalition on “Drug Interactions with Hormonal Contraceptives: Public Health and Drug Development Implications”
[Docket No. FDA-2015-N-3156-0001]
As members of the Patient, Consumer, and Public Health Coalition, we support FDA’s effort to better characterize drug interactions with hormonal contraceptives since reliable and accurate information is necessary to ensure women’s health. In particular, we recommend clinical evaluation of drug interactions for all drugs that are likely to be used in women of reproductive age and that have the potential to cause birth defects, in addition to improving the quality and usefulness of information in FDA-approved labeling.
There are currently 61 million women of childbearing age in the United States and 62% of them use a contraceptive. In addition, 12% of women ages 18-44 take three or more prescriptions, which means that millions of women may be affected by drug interactions with their hormonal contraceptives. Despite the large public health impact, women and their providers do not have access to adequate information that helps provide a recommended course of action, especially for women who are on medication for chronic disease at the same time they are using hormonal birth control.
There are numerous gaps in currently available drug interaction information. For example, many hormonal contraceptives were developed before the availability of modern methods for studying drug interactions; as a result, drug interaction information is lacking on these contraceptives. Unfortunately, many new drugs still do not examine effects on hormonal contraceptives before they are used in large numbers of women. In fact, a recent FDA review of new drugs with the potential to cause birth defects found that drug interaction studies were not routinely conducted. When information is lacking, information from one contraceptive is often extrapolated to others, even though the specific type of hormone or route of administration may be different (e.g. pills versus IUD). Information is also limited for other patient-specific factors (e.g. obesity, age) that may affect drug interactions with hormonal contraceptives.
We offer the following recommendations:
- Prior to phase 3 studies, FDA should require clinical evaluation of drug interactions for all drugs that are likely to be used in women of reproductive age and that have the potential to cause birth defects.
Current FDA drug interaction guidance states that a drug with the potential to cause birth defects “needs to be studied in vivo for effects on contraceptive steroids if the drug is intended for use in fertile women, regardless of in vitro induction study results.” In other words, studies in people are still required even if non-human studies are negative for drugs with the potential to cause birth defects. However, an FDA review of new drugs with the potential to cause birth defects found that only 4 of 18 drugs had clinical (in vivo) drug interaction information available in time for phase 3 studies.2 Drug interaction studies for an additional 4 drugs were completed after phase 3 studies. Therefore, many women may have been exposed to drugs with the potential to cause birth defects without accurate information regarding appropriate contraception.
This is clearly unacceptable since drugs with the potential to cause birth defects require the use of contraception in women of reproductive age. Women and their providers need information about potential interactions and, in order to determine the risks to individual patients, the potential interactions should be known prior to phase 3 studies.
- Improve the clinical usefulness of drug interaction information in FDA-approved labeling for hormonal contraceptives.
Providers and pharmacists need specific and useful information in drug labeling so they can accurately instruct women on the appropriate course of action. The same FDA review mentioned previously found significant variability with regard to contraception recommendations in drug labeling, with some recommending use of hormonal contraceptives without studying drug interactions and others not including any information about contraception. For example, the study found that 50% of the drugs with the potential to cause birth defects included only general contraception instructions in their labeling and 17% had no contraceptive information at all.2 Consistent recommendations regarding reliable contraceptive methods are needed to adequately protect women who are taking drugs with the potential to cause birth defects.
- In addition to being available, information about drug interactions should also provide guidance on the recommended course of action.
A label that states only that drug levels may be increased or decreased does not give enough information for providers to know what to do. For example, the label for Yaz (drospirenone/ethinyl estradiol) states, “Significant changes (increase or decrease) in the plasma concentrations of estrogen and progestin have been noted in some cases of co-administration with HIV/HCV protease inhibitors.” In this situation, it is unclear to what extent the effectiveness of hormonal contraception is affected. Providers need evidence-based, specific, and concise information to guide their decisions.
Additionally, the clinical usefulness, or even applicability, of drug interaction labeling for non-oral hormonal contraceptives (e.g. IUD, vaginal ring) is unclear since they are labelled with the same information as the oral contraceptives but potentially have a different level of interaction. Labeling should address this difference.
Lastly, obese women have a higher risk of both venous thromboembolism AND contraceptive failure due to inadequate hormone levels with hormonal contraceptives but information on the recommended course of action is sparse. More labeling guidance for these women and their providers and pharmacists is needed.
In summary, women and their providers need accurate information about drug interactions with hormonal contraceptives that provides clear guidance on the recommended course of action. We strongly urge the FDA to require clinical evaluation of drug interactions for all drugs that are likely to be used in women of reproductive age and that have the potential to cause birth defects. We also strongly urge the FDA to improve the quality of information about drug interactions in FDA-approved labeling, ensuring that it is more clinically useful.
National Center for Health Research
The Medication-Induced Suicide Prevention and Education Foundation in Memory of Stewart Dolin (MISSD)
MRSA Survivors Network
National Consumers League
For questions, please contact Tracy Rupp at the National Center for Health Research at
(202) 223-4000 or firstname.lastname@example.org.
 National Center for Health Statistics. Health, United States, 2013: In Brief. Hyattsville, MD. 2014.
 Li L. Drug-Drug Interactions Between Hormonal Contraceptives and Drugs with Teratogenic Potential. Center for Drug Evaluation and Research. FDA Workshop: Drug Interactions with Hormonal Contraceptives: Public Health and Drug Development Implications. November 9, 2015. Available at: http://www.fda.gov/downloads/Drugs/NewsEvents/UCM473692.pdf.
 Guidance for Industry: Drug Interaction Studies – Study Design, Data Analysis, Implications for Dosing and Labeling Recommendations. Draft Guidance. FDA Center for Drug Evaluation and Research, Feb. 2012. Available at: http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm292362.pdf.
 Yaz® [package insert]. Bayer HealthCare Pharmaceuticals Inc., Wayne NJ; June 2015. http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=065f33e4-b587-4e66-b896-ca9ab7b7c876. Accessed Dec. 8, 2015.
 De Bastos M, Stegeman BH, and Rosendaal FR, et al. Combined Oral Contraceptives: Venous Thrombosis. Cochrane Database Syst Rev. 2014 Mar 3:3:CD010813.