What the FDA Says about Blood Clots and Drospirenone

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FDA on Blood Clots and Drospirenone Pills. Photo © 2015 Dawn Stacey

Drospirenone is one of the types of progestin found in the pill. It is a different type of progestin. Drospirenone can restrain the secretion of hormones that regulate the body's water and electrolytes. It may also cause potassium levels to rise and/or have interactions with other drugs that increase potassium.

Drospirenone-containing combination oral contraceptives include:

    For women who choose to use the pill for birth control, in addition to prevention of pregnancy, Yaz and Beyaz have been FDA-approved to treat symptoms of premenstrual dysphoric disorder (PMDD) and to treat moderate acne while Beyaz is also approved to raise folate levels.

    Though all birth control pills pose a risk of blood clots, there has been concern that birth control pills containing drospirenone have a higher blood clot risk than birth control pills that contain other progestins.

    Previous Research on Blood Clots and Drospirenone:

    Previous research on the topic of blood clots and drospirenone has revealed mixed findings. Two postmarketing studies (conducted by Seeger JD, et al., 2007 and Dinger JC, et al. 2007) didn't find any difference in the risk of blood clots between drospirenone-containing products and products containing levonorgestrel or other progestins. Yet, two other studies published in the British Medical Journal in 2009 revealed that the risk of blood clots (VTE) is higher (1.5- to 2-fold higher) in women using drospirenone pills than in women who use pills with levonorgestrel.

    The results of these four studies prompted the FDA to require the manufacturers of drospirenone-containing birth control pills to include blood clot risks under the "Warnings and Precautions" section of current prescribing labels. For instance, under the label of Yaz it reads,

    "Thromboembolic Disorders and Other Vascular Problems: Stop Yaz if an arterial or venous thrombotic (VTE) event occurs. The use of COCs increases the risk of venous thromboembolism. COCs have been shown to increase both the relative and attributable risks of cerebrovascular events (thrombotic and hemorrhagic strokes), although, in general, the risk is greatest among older (>35 years of age), hypertensive women who also smoke."

    "Epidemiologic studies including a DRSP-containing COC: Several studies have investigated the relative risks of thromboembolism in women using Yasmin compared to those in women using COCs containing other progestins. Two prospective cohort studies, both evaluating the risk of venous and arterial thromboembolism and death, were initiated at the time of Yasmin approval. The first showed the risk of thromboembolism (particularly venous thromboembolism) and death in Yasmin users to be comparable to that of other oral contraceptive preparations, including those containing levonorgestrel. The second prospective cohort study also showed a comparable risk of thromboembolism in Yasmin users compared to users of other COCs, including those containing levonorgestrel. In the second study, COC comparator groups were selected based on their having similar characteristics to those being prescribed Yasmin."

    "Two additional epidemiological studies, one case-control study and one retrospective cohort study suggested that the risk of venous thromboembolism occurring in Yasmin users was higher than that for users of levonorgestrel-containing COCs and lower than that for users of desogestrel-containing COCs. In the case-control study, however, the number of Yasmin cases was very small (1.2% of all cases) making the risk estimates unreliable. The relative risk for Yasmin users in the retrospective cohort study was greater than that for users of other COC products when considering women who used the products for less than one year. Among women who used the product for 1 to 4 years, the relative risk was similar for users of Yasmin to that for users of other COC products."

    Timeline: The FDA on Blood Clots and Drospirenone:

    May 2011: The European Medicines Agency (EMA) announced that it is updating the product information on oral contraceptives containing drospirenone and ethinyl estradiol regarding the risk of venous thromboembolism after review of all available data (which includes the same newly published data FDA is reviewing). The EMA has concluded that the risk of blood clots (deep vein thrombosis and/or pulmonary embolism) for drospirenone containing oral contraceptives is higher than that for levonorgestrel-containing pills. Yet, this risk with any birth control pill (including those with drospirenone) is very small and that there is no reason for women to stop taking drospirenone-containing birth control pills.

    June 2011: The FDA chose to inform the public that new information is being investigated as part of the FDA's ongoing safety review of the risk of blood clots with birth control pills that contain drospirenone. Two recently published studies by Van Hylckama, et al., 2009 and Lidegaard Ø, et al., 2009 in the British Medical Journal had investigated whether there is greater risk of deep vein thrombosis and pulmonary embolism in women taking combination pills with drospirenone.

    Both studies found a twofold to threefold greater risk of venous thromboembolic events (blood clots) for women using birth control pills containing drospirenone as compared to those taking pills containing the progestin levonorgestrel. Because of this recent research, the FDA had decided to further evaluate the risk of blood clots in women who use these products by examining all currently available information as well as these two most recent British Medical Journal studies.

    September 26, 2011: The FDA made a public announcement that it has finished its review of the six conflicting published studies evaluating the risk of blood clots in women using drospirenone birth control pills. This six studies included in this review:

    • The two postmarketing studies conducted by Seeger JD, et al., 2007 and Dinger JC, et al. 2007: These two articles didn't find any difference in VTE (blood clot) risk between drospirenone-containing products and products containing levonorgestrel or other progestins.
    • The two latest articles published in the British Medical Journal by Van Hylckama, et al., 2009 and Lidegaard Ø, et al., 2009: These two studies reported a 1.5- to 2-fold higher VTE risk in women who use drospirenone-containing contraceptives as compared to the risk in women who use levonorgestrel-containing birth control pills.
    • Two additional studies published in the British Medical Journal by Parkin L, et al., 2011 and Jick SS & Hernandez RK, 2011: These two reports revealed a 2- to 3-fold greater risk of blood clots in women using drospirenone birth control pills rather than levonorgestrel pills.

    The FDA explained that there are methodological issues that make the interpretation of the data from these studies complex. Due to that, the FDA had still not reached a formal a conclusion on a woman's blood clots risk. The agency had also begun to receive preliminary data from an FDA-funded epidemiologic study exploring the association of blood clots with several different hormonal contraceptives.

    October 27, 2011: The FDA issued another safety warning stating that the agency is continuing its review of the possible increased blood clot risk with the use of birth control pills that contain drospirenone. The FDA also released its final report of the agency's self-funded research, based on over 800,000 US women, that examined the risk of blood clots in users of various hormonal birth control methods (such as the Patch, NuvaRing, and different combo pills like Yaz, Seasonique, Loestrin 1/20).

    Though the FDA had not yet reached a conclusion on blood clots and drospirenone, the agency remained concerned about the potential increased blood clot risk. Results from this study had the agency showing concern over a possible 1.5-fold increase in the risk of blood clots for users of drospirenone pills when compared to standard low-dose oral contraceptives (like Ortho Tri-Cyclen Lo, for example). The FDA also pointed out that the available studies have only examined the risk of VTE in users of birth control pills that contain drospirenone and 0.03 mg of ethinyl estradiol and not other pills that contain drospirenone combined with a lower dose of estrogen (e.g., 0.02 mg ethinyl estradiol, like Yaz and Beyaz).

    December 7, 2011: The FDA presented a completed full review of the results of its self-funded study, discussing the risks and benefits of drospirenone-containing pills at a joint meeting of the Reproductive Health Drugs Advisory Committee and the Drug Safety and Risk Management Advisory Committee. The panel voted 21-5 that current labels of these pills were inadequate in explaining the potential increased blood clot risk and recommended that the FDA require updated labels that specifically explain the potential risk as well stressing that such blood clots could lead to death. The FDA had not yet decided whether it would follow the advisory panel's recommendations. The panel was also almost split (15-11) about the benefits of these pills, with only 58% of the panelists felt the benefits outweighed the risks -- 42% of the members felt that the risk was not worth the advantages given that there are alternative combination pill options currently available that could be safer to use.

    April 10, 2012: The FDA released an updated safety announcement explaining that the agency has finished its review of recent observational/epidemiologic research regarding the risk of blood clots and drospirenone-containing birth control pills. Based on this review, the FDA has concluded that pills containing drospirenone may be linked to a higher blood clot risk. In this advisory, the FDA reiterated that the research they examined,

    "Did not provide consistent estimates of the comparative blood clot risk between birth control pills that contain drospirenone and those that do not. The studies also did not account for important patient characteristics (both known and unknown) that could influence prescribing and that likely affect the blood clot risk."

    Because of these findings the FDA concluded that the agency is still,

    "Unclear whether the increased risk seen for blood clots in some of the epidemiologic studies is actually due to drospirenone-containing birth control pills."

    Thus, the FDA has only concluded that drospirenone-containing birth control pills may be associated with a higher risk for blood clots than other progestin-containing pills.

    The FDA also required new labeling for drospirenone-containing pills. The updated labels must include the following information: that some epidemiologic studies have reported as high as a three-fold increase in blood clots risks for these pills when compared to products containing levonorgestrel or some other progestins, whereas other epidemiological studies found no additional risk of blood clots with drospirenone-containing products. Additionally, the revised labels will include a summary of the previously released results of the FDA-funded blood clot risk study.

    The FDA's Advice on Using Drospirenone-Containing Pills:

    It is important to point out that birth control pills containing the progestin drospirenone are typically a safe contraceptive option for most healthy women. Thousands of women use these pills everyday without any complications or serious side effects. That being said, it is essential that you discuss your complete medical history with your doctor before using Yaz, Yasmin, Beyaz or Safyral. Even if you have certain risk factors, you may still be able to use these pills as long as you remain under close medical supervision. Combination pills (including those that contain drospirenone) are highly effective birth control methods: they are 92%-99.7% effective.

    The FDA points outs, 

    "To put the risk of developing a blood clot from a birth control pill into perspective: The risk of blood clots is higher when using any birth control pills than not using them, but still remains lower than the risk of developing blood clots in pregnancy and in the postpartum period."

         ---> I Use Yaz, Yasmin, Beyaz or Safyral - What Should I Do?

    The FDA has also set up MedWatch: The FDA Safety Information and Adverse Event Reporting Program. This is a place where you can report serious side effects/adverse events that you may have experienced while using any FDA-regulated medication (whether or not the side effect occurred because of the medication itself or potential or actual user errors). If you have encountered a serious side effect (like a blood clot) from a birth control pill that contains drospirenone, the FDA encourages you to report this to MedWatch.

    Sources:

    Bayer HealthCare. "Yaz: Prescribing Information." Accessed 1/27/15.

    Dinger JC, Heinemann LA & Kuhl-Habich D. "The safety of a drospirenone-containing oral contraceptive: Final results from the European Active Surveillance Study on oral contraceptives based on 142,475 women-years of observation." Contraception 2007; 75:344-54. Accessed via private subscription.

    European Medicines Agency. [26 May 2011, Issue 1105] "Monthly Report: Patient Health Protection." Accessed 1/27/15.

    FDA. [5-31-2011] "FDA Drug Safety Communication: Safety review of possible increased risk of blood clots with birth control pills containing drospirenone." Accessed 1/27/15.

    FDA. [9-26-2011] "FDA Drug Safety Communication: Safety review update on the possible increased risk of blood clots with birth control pills containing drospirenone." Accessed 1/27/15.

    FDA. [10-27-2011] "FDA Drug Safety Communication: Updated information about the FDA-funded study on risk of blood clots in women taking birth control pills containing drospirenone." Accessed 1/27/15.

    FDA. [4-10-2012] "Updated External Questions and Answers – Ongoing safety review of birth control pills containing drospirenone and a possible increased risk of blood clots." Accessed 1/27/15.

    FDA. [4-10-2012] "FDA Drug Safety Communication: Updated information about the risk of blood clots in women taking birth control pills containing drospirenone" Accessed 1/27/14.

    Lidegaard Ø, Løkkegaard E, Svendsen AL, Agger C. "Hormonal contraception and risk of venous thromboembolism: National follow-up study." BMJ 2009; 339:b2890. Accessed via private subscription.

    Jick SS, Hernandez RK. "Risk of non-fatal venous thromboembolism in women using oral contraceptives containing drospirenone compared with women using oral contraceptives containing levonorgestrel: Case-control study using United States claims data." BMJ 2011; 340:d2151. Accessed via private subscription.

    Parkin L, Sharples K, Hernandez RK, Jick SS. "Risk of venous thromboembolism in users of oral contraceptives containing drospirenone or levonorgestrel: Nested case-control study based on UK General Practice Research Database." BMJ 2011; 340:d2139. Accessed via private subscription.

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

    Van Hylckama V, Helmerhorst FM, Vandenbroucke JP, Doggen CJM, Rosendaal 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. Accessed via private subscription.

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