Are Bayer’s Birth Control Pills too Risky?

By Dana Casciotti, PhD, Diana Zuckerman, PhD, Nyedra Booker, PharmD,  and Juliana Stebbins

 

If you are taking one of Bayer’s birth control pills (YASMIN, YAZ, BEYAZ, SAFYRAL) or a generic version, you will want to know about the latest research indicating that these pills have higher risks than other types of oral contraceptives.  While all birth controls contain the hormones estrogen, progestin, or both, manufactures use different types of each in their products.  Bayer’s oral contraceptive products and their generic versions contain drospirenone, a type of progestin not found in most other oral contraceptives.

In December 2011, the Food and Drug Administration (FDA) held a public meeting to discuss the benefits and risks of oral contraceptives containing drospirenone. [1] While these products effectively prevent pregnancy, there are alarming risks that can be fatal.  Advisory Committee members discussed the growing evidence that drospirenone increases the risk of blood clots (deep vein thrombosis) more than other forms of progestin.  Blood clots are dangerous because they can detach from the vein and travel through the blood stream, blocking blood flow to the lungs or brain.  They can cause disability or death, even in young, healthy women.  Several families testified at the meeting about the death of their healthy, young daughters are a result of taking Yaz and similar pills made with drospirenone.

FDA Decision

In 2012, the FDA announced its conclusion that women taking Yaz and other drospirenone-containing oral contraceptives may be at an increased risk for developing blood clots compared to women taking pills containing other forms of progestin.  Rather than taking the drugs off the market, the FDA decided to change the labels for Yaz, Yasmin, Beyaz and Safyral to warn patients and doctors about the increased risk for developing blood clots.  The FDA is encouraging women to discuss their risk for blood clots with a healthcare professional before deciding which birth control method is best for them.  Healthcare professionals are also being encouraged to consider the possible increased risk for blood clots with drosperinone-containing oral contraceptives before prescribing these medications to their patients.  Unfortunately, the warning about drospirenone is in the 5th section of very long labels, and many patients (and doctors) are unlikely to ever notice them.

The Evidence

Although all birth control pills can cause blood clots, and all contain a warning about that risk, the FDA has reviewed six studies published over the last three years to evaluate whether these risks are higher with oral contraceptives containing drospirenone. Four of the six studies showed higher risks.  Two studies published in 2009 reported that taking oral contraceptives containing drospirenone increases the risk of blood clots by 1.5-to-2 times compared to taking pills containing the progestin levonorgestrel.[2],[3]Additionally, two articles published in 2011 in the British Medical Journal reported an increased risk of blood clots that was 2 to 3 times as high with drospirenone compared to other types of birth control pills.[4],[5]Only two published studies of drospirenone-a study led by J.D. Seeger and a study conducted by J.C. Dinger-report there is not an elevated risk with Yaz and generic versions.[6],[7]

What could account for the different findings?  The authors of the studies that found no increased risk for drospirenone had financial and professional ties to the manufacturer that makes these pills, they included women with high risk of blood clots, and the authors did not separately analyze women younger or older than 35,  which could have influenced the results.  The Seeger study investigated the safety of Yasmin, and compared “ethinylestradiol/drospirenone initiators and medically similar initiators of other oral contraceptives….”  The authors did not specify the types of “other oral contraceptives” that were compared to Yasmin, nor did they specify the dosage of estrogen and progestin taken by women in the comparison group.  That could have also influenced the findings.  The Dinger study compared drospirenone-containing oral contraceptives to pills containing levonorgestrel (a type of progestin), pills containing other progestins, and non-hormonal types of contraceptives.  There were several differences in the way that these two studies were conducted and analyzed that might explain why their results were more favorable than the studies by independent researchers.  For example, the four studies that reported higher risk of drospirenone-containing pills statistically controlled for the estrogen doses in their analyses.2-5

In addition to reviewing the six studies, the FDA funded its own enormous study to further evaluate the relative safety of drospirenone in oral contraceptives. The FDA study reviewed the medical records of 800,000 women taking birth control between 2001 and 2007 and reported that women taking birth control pills containing drospirenone were significantly more likely to have blood clots: drospirenone increases the risk of blood clots from six in 10,000 women to 10 in 10,000 women (or 1 per 1,000).[8]The study also suggests that although women below the age of 35 have a higher risk of blood clots regardless of the type of birth control pill they take, the risk of blood clots associated with Yaz, Yasmin, and other pills with drospirenone are significantly higher than other types of birth control pills only among women over 35.[9] In contrast, the FDA study also found that when they focused only on women taking birth control pills for the first time, drospirenone increased the risk of blood clots and heart attacks, especially for women under 35.

The FDA study also found that the birth control patch and vaginal ring was associated with higher risks of blood clots than pills containing levonorgestrel, but tended to be less risky than pills containing drospirenone.

Yaz, Yasmin, Beyaz, Safyral: Higher Cost and More Risk

When new medications come on the market, they tend to cost more and be widely advertised, and this often gives the impression that they are better.  Unfortunately, newer often does not mean more effective or safer, because the FDA does not require that new drugs be an improvement over older drugs, and often the FDA doesn’t even require that they be as effective or as safe.  In addition, since FDA approval is usually based on patients taking a drug for one year or less, the risks may not be obvious at first.

Bayer has advertised Yaz and its other birth control pills in many TV commercials featuring attractive and happy young women, and this has resulted in the pills’ widespread popularity.   Bayer warns that women who smoke or have a history of blood clots, heart attacks or strokes, or particular cancers should avoid their contraceptive pills but the new research raises questions about the risks to healthy, nonsmoking women as well.

Is there more risk information that has not been made public yet?  Plaintiffs’ attorneys wanted to provide confidential documents to the FDA for the agency to consider in their review of Yaz and other birth control pills, but in November, 2011, Judge Herndon ruled that the documents should not be made available to the FDA or the public.  Several of the documents were finally made available two days before the December 8 meeting.  One was a report from former FDA Commissioner David Kessler.  It documented how Bayer had repeatedly misled the FDA when FDA officials expressed concerns about the risks of Yasmin before and after the drug was approved.

Should birth control pills containing drospirenone remain on the market?  There is no evidence that they have significant advantages compared to other contraceptive pills that would outweigh the risks of blood clots or heart attacks.  If patients and their doctors understood the latest research, why would anyone choose to take those risks?

Table of the FDA Approved Oral Contraceptives Containing Drospirenone that are currently under review:

Name Generic Name
Drospirenone and ethinyl Drospirenone 3 mg ethinyl estradiol 0.03 mg
Ocella Drospirenone 3 mg and ethinyl estradiol 0.03 mg
Safyral Drospirenone 3 mg, enthinyl estadiol 0.03 mg, and leyomefolate calcium 0.451 mg
Syeda Drospirenone 3 mg and ethinyl estradiol 0.03 mg
Yasmin Drospirenone 3 mg and ethinyl estradiol 0.03 mg
Zarah Drospirenone 3 mg and ethinyl estradiol 0.03 mg
Beyaz Drospirenone 3 mg, ethinyl estradiol 0.02 mg and leyomefolate calcium 0.451 mg
Drospirenone and Ethinyl Estradiol Drospirenone 3 mg and ethinyl estradiol 0.02 mg
Giavi Drospirenone 3 mg and ethinyl estradiol 0.02 mg
Loryna Drospirenone 3 mg and ethinyl estradiol 0.02 mg
Yaz Drospirenone 3 mg and ethinyl estradiol 0.02 mg

1Joint Meeting on the Reproductive Health Drugs Advisory Committee and the Drug Safety and Risk Management Advisory Committee Meeting Announcement. December, 8 2011: http://www.fda.gov/AdvisoryCommittees/Calendar/ucm273236.htm

2 Lidegaard Ø, Løkkegaard E, Svendsen AL, Agger C. Hormonal contraception and risk of venous thromboembolism: national follow-up study. BMJ 2009; 339:b2890.

3 Van Kylckama V, Helmerhorst Fm, Vanderbrouke Jp, Doggen CJM, Rosendale FR. The venous thrombotic risk of oral contraceptives, effects of oestrogen dose and progestogen type: results of the MEGA case-control study. BMJ 2009; 339:b2921.

4 Parkin L, Sharples K, Hernandez RK, Jick SS. Risk of venous thromboembolism in users of oral contraceptives containing drospirenon or levonorrgestrl: nexted case-control study based on study based on UK General Practice Research Database. BMJ 2011; 342:d2139.

5 Jick SS, Hernandez RK. Risk of non-fatal venous thromboembolism in women using oral contraceptives containing drospirenon compared with women using oral contraceptives containing levonorgestrel: case-control study using United States claims data. BMJ 2011; 342:d2151.

6 Seeger JD, Loughlin J, Eng PM, Clifford CR, Cutone J, Walker AM. Riske of thromboembolism in women taking ethinylestradiol/drospirenone and other oral contraceptives. Obstet Gynecol 2007; 110(3):587-93.

7 Dinger JC, Heinemann LA, Kuh-Habich D. The Safety of a drospirenone-containing oral contraceptives: final results from the European Active Surveillance Study on Oral contraceptives based on 142,475 women-years of observation. Contraception 2007; 75:344-54.

8 Food and Drug Administrative. Drug Safety Communication: Safety review update on the possible increase risked of blood clots with birth control pills containing drospirenon. 26, September 2011.

9 USA. Food and Drug Administration. Office of Surveillance and Epidemiology. Combined Hormonal Contraceptives (CHCs) and the Risk of Cardiovascular Disease Endpoints. By Rita Ouellet-Hellstrom, David J. Graham, and Judy A. Staffa. Silver Spring, 2011. Print. CHC-CVD Final Report 111022v2.