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Updated External Questions and Answers – Ongoing safety review of birth control pills containing drospirenone and a possible increased risk of blood clots

[4/10/2012]

This set of Questions and Answers was originally posted on May 31, 2011. It is being updated to provide additional information to healthcare professionals and the public.

The U.S. Food and Drug Administration (FDA) previously informed the public about new information that was being assessed as part of FDA’s ongoing safety review of birth control pills (oral contraceptives) containing the progestin hormone drospirenone.  FDA communicated on this issue in three previous Drug Safety Communications (DSCs) on May 31, 2011, September 26, 2011, and October 27, 2011.

In these DSCs, FDA discussed the risk of blood clots or deep vein thrombosis (DVT) in women taking birth control pills.  DVT is a rare condition in which blood clots form inside a vein, most commonly in the legs.  A blood clot can break loose, move through the body to the lungs, and cause a serious, potentially fatal, problem called a pulmonary embolism (PE).1  

The following questions and answers provide an overview of this potential safety issue.

Q1. What is drospirenone?
Q2.  Which birth control pills (oral contraceptives) contain drospirenone?
Q3.  What is a deep vein thrombosis (DVT) and pulmonary embolus (PE)?
Q4.  What is already known about combination birth control pills and the risk of venous thromboembolism (VTE)?
Q5.  Why did FDA review the risk of venous thromboembolism (VTE) with birth control pills containing drospirenone?
Q6.  How did FDA evaluate conflicting study results regarding the risk of venous thromboembolism (VTE) in users of oral contraceptives containing drospirenone in order to decide if any regulatory action would be needed? 
Q7.  What should women do if they are currently taking birth control pills containing drospirenone?
Q8.  Are there women who should not take birth control pills containing drospirenone?
Q9.  Has FDA communicated to the public about this issue before?       

Q1. What is drospirenone?

A.  Most birth control pills (combination oral contraceptives) combine a synthetic version of the female hormone progesterone (referred to as a progestin) with a synthetic version of the female hormone estrogen.  Drospirenone is one of several different progestins that are used in birth control pills. 

Q2.  Which birth control pills (oral contraceptives) contain drospirenone?

Birth control pills containing drospirenone include: Beyaz, Gianvi, Loryna, Ocella, Safyral, Syeda, Yasmin, Yaz, and Zarah.

Some birth control pills containing drospirenone are also approved to treat symptoms of premenstrual dysphoric disorder (PMDD) and to treat moderate acne in women who choose to use an oral contraceptive for contraception.  Two products (Beyaz and Safyral) contain levomefolate calcium in addition to the contraceptive hormones, and may also be used to improve folate levels in women who choose to use an oral contraceptive for contraception. 

Q3. What is a deep vein thrombosis (DVT) and pulmonary embolus (PE)?

A.  Deep vein thrombosis (DVT) is a rare but serious condition where a blood clot forms inside a vein.  These blood clots usually form in the lower leg or thigh, but can break loose and travel to other areas of the body such as the lungs.  If the clot travels to the lung, it is called a pulmonary embolism (PE), a potentially fatal condition where an artery in the lung becomes blocked.  DVTs and PEs are also called venous thromboembolic events, or VTEs.

The symptoms of a DVT include the new onset of persistent leg pain, while those of a PE include severe chest pain, and sudden shortness of breath.  Women experiencing these symptoms should contact a healthcare professional immediately because VTEs can be life-threatening.

Q4. What is already known about combination birth control pills and the risk of venous thromboembolism (VTE)?

A.  VTE is already known to be a rare but serious potential side effect of taking any birth control pill containing a progestin and estrogen.  The risk of VTE in users of birth control pills is low, although it is higher than the risk of VTE in women who do not take birth control pills.  The risk of VTE in pregnant women (about 5 to 20 cases per 10,000 women)2 is even higher than that in women who take birth control pills.

The drug labels for all combination birth control pills include warning information on the potential risk of VTE and describe additional factors that increase this risk.  The risk of VTE associated with birth control pills increases as a woman gets older and is also higher in women who smoke.  Usually the risk of VTE is highest during the first year after starting to use a combination birth control pill.

On April 10, 2012, FDA updated the drug labels for drospirenone-containing birth control pills.  The new labels (Beyaz, Safyral, Yasmin and Yaz) will report that some epidemiologic studies reported as high as a three-fold increase in the risk of blood clots for drospirenone-containing products 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.

The studies reviewed by FDA did not provide consistent estimates of the comparative risk of blood clots between birth control pills that contain drospirenone and those that do not.  The studies also did not account for important known and unknown patient characteristics that may influence prescribing and that likely affect the risk of blood clots.  For these reasons, it is unclear whether the increased risk of blood clots seen in some of the epidemiologic studies is actually due to use of drospirenone-containing birth control pills.  At this time, FDA has concluded that the risk may be higher for drospirenone-containing pills.  However, the risk of blood clots, although higher when using any birth control pills than not using them, still remains lower than the risk of developing blood clots in pregnancy and the postpartum period.

Q5. Why did FDA review the risk of venous thromboembolism (VTE) with birth control pills containing drospirenone?

A.  FDA was aware of two published studies in 2011 that evaluated the risk of VTE in women who use birth control pills that contain drospirenone.  The two published studies compared the risk of blood clots in women taking birth control pills containing the progestin drospirenone to similar women taking birth control pills containing a different progestin called levonorgestrel.1,2 These two studies reported that there is a greater risk of VTE associated with birth control pills that contain drospirenone.  This risk was reported to be up to 2 to 3 times greater than the risk of VTE associated with using levonorgestrel-containing pills.

Conflicting information already existed on this potential increased risk. Two previously published studies, which were conducted at the request of FDA or the European regulatory agencies after drug approval, did not report any difference in risk of VTEs between the drospirenone-containing product and products containing levonorgestrel or other progestins.3,4   However, two publications in 2009 reported that the risk of VTEs is higher in women using a drospirenone-containing product than in women who use levonorgestrel-containing products.5,6  These four earlier studies were already described in the labeling for drospirenone-containing birth control pills.

On April 10, 2012, FDA informed the public that it has completed its review of recent  observational studies regarding the risk of blood clots in women taking drospirenone-containing birth control pills compared to the risk in women taking birth control pills containing other progestins.  Based on this review, FDA believes that drospirenone-containing products may be associated with a higher risk of blood clots and is adding information about these observational studies to the drug labels for drospirenone-containing products. The revised drug labels will report that some epidemiologic studies reported as high as a three-fold increase in the risk of blood clots for drospirenone-containing products 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.

The studies reviewed by FDA did not provide consistent estimates of the comparative risk of blood clots nor did they account for important known and unknown patient characteristics that may influence prescribing and that likely affect the risk of blood clots.  For these reasons, it is not possible to provide a definitive statement about how the risk of blood clots may differ for drospirenone-containing birth control pills compared to pills that contain levonorgestrel or some other progestin.  At this time, FDA has concluded that the risk may be higher for drospirenone-containing pills.  However, the risk of blood clots, although higher when using any birth control pills than not using them, still remains lower than the risk of developing blood clots in pregnancy and the postpartum period.

FDA will continue to communicate any new safety information to the public as it becomes available.

Q6. How did FDA evaluate conflicting study results regarding the risk of venous thromboembolism (VTE) in users of oral contraceptives containing drospirenone in order to decide if any regulatory action would be needed?

A.  FDA reviewed available information from observational studies, including the two recently published studies, and an additional, large, FDA-funded study.  The strengths and weaknesses of the epidemiologic methods used in the studies were carefully evaluated.  FDA’s overall assessment of VTE risk for drospirenone contraceptives was based on the strength of the scientific evidence from each of the studies.  FDA’s analysis was presented and discussed at a joint meeting of the Reproductive Health Drugs Advisory Committee and the Drug Safety and Risk Management Advisory Committee on December 8, 2011.

Q7. What should women do if they are currently taking birth control pills containing drospirenone?
Women taking birth control pills containing drospirenone should continue taking their pills as directed unless told otherwise by their healthcare professional.  Women should talk to healthcare professionals about their risk for blood clots before deciding which birth control pill to use.

Women should know how to recognize the symptoms of VTE and should contact their healthcare professional immediately if they experience persistent leg pain, severe chest pain, or sudden shortness of breath.  Women should also discuss any questions or concerns about their use of combination birth control pills with their healthcare professional and report any side effects to the FDA MedWatch program using the “Contact FDA” information at the bottom of the page.

Q8.  Are there women who should not take birth control pills, particularly those containing drospirenone?
A.  Women with certain conditions or risk factors should not use any combination birth control pill.  FDA recommends that women who are over age 35 and smoke should not take any type of combination birth control pill (including those containing drospirenone), due to an increased risk of serious cardiovascular events.  The risk of VTE also increases with age and smoking.  Women with a history of blood clots, heart attack, or stroke should not take combination birth control pills.  Additionally, women who are pregnant or think they may be pregnant should not use combination birth control pills.

The risks and benefits of a drospirenone-containing birth control pill should be considered in light of a woman’s risk of developing a blood clot before starting drospirenone-containing birth control pills.  Women should talk to healthcare professionals about their risk for blood clots before deciding which birth control pill to use.

Because drospirenone, in contrast to other progestins used in combination oral contraceptives, has the potential to increase serum potassium levels, women with renal or adrenal disease should not use birth control pills containing drospirenone.

For additional labeling information on all combination birth control pills, visit Drugs@FDA at http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm.

Q9. Has FDA communicated to the public about this issue before?   

A.  FDA has included warning information about the risk of VTEs in the labels of all combination birth control products and in the patient package inserts for these products.  The risk of VTEs with these products was also discussed at a joint meeting of the Reproductive Health Drugs Advisory Committee and the Drug Safety and Risk Management Advisory Committee on December 8, 2011.  FDA has also communicated previously about the potentially greater risk of VTE with drospirenone-containing birth control products.  These prior communications can be found on the Agency’s website:

References

  1. Parkin L, Sharples K, Hernandez R, 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; 342: d2139 doi:10.1136/bmj.d2139.
  2. 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; 342: d2151 doi:10.1136/bmj.d2151.
  3. Dinger JC, Heinemann LA, Kühl-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.
  4. 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.
  5. Lidegaard Ø, Løkkegaard E, Svendsen AL, Agger C. Hormonal contraception and risk of venous thromboembolism: national follow-up study. BMJ 2009; 339:b2890.
  6. 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.