The Food and Drug Administration (FDA) is now requiring updated labeling regarding clot risk for oral contraceptives containing the progesterone, drospirenone. Drospirenone is a synthetic progestin which is chemically similar to spironolactone. Birth control brands Yasmin, Yaz, Beyaz, Safyral and their various generics contain drospirenone and are indicated for pregnancy prevention, acne treatment and treatment of premenstrual dysphoric disorder (PMDD). These hormonal contraceptives are also used off-label to treat polycystic ovarian syndrome (PCOS)¹.

FDA began its review of these products in 2011 after studies showed an increased risk of blood clots in women using oral contraceptives with drospirenone over oral contraceptives with other forms of progesterone². The label change comes on the heels of an FDA-sponsored study which showed a three-fold increase in thromboembolism in women on these birth control pills².

This observational study was conducted in four sites around the U.S. and reviewed data for over 835,000 women enrolled in three different health plans³. Women ranged in age from 10 to 55 and had record of at least one contraceptive prescription over a 6 ½-year period from 2000 to 2007. Patients with diagnosis of serious illness such as sickle cell anemia, HIV, cancer and organ transplant were excluded.

Drospirenone-containing contraceptives were compared to norelgestromin contraceptive patches, etonogestrol/ethinyl-estradiol contraceptive ring as well as four oral hormonal contraceptives with low dose (up to 35 mcg) ethinyl estradiol. Outcomes included patient record of diagnostic codes for hospitalization for acute myocardial infarction, ischemic stroke, and thromboemoblic disease such as pulmonary embolism (PE) and deep venous thrombolism (DVT). Overall and cardiovascular deaths were also measured³.

Average length of contraceptive use was 155 days with a total of nearly 900,000 person- years. Incidence rates were calculated according to how long the patient had used contraceptives, 0 to 3 months, 4 to 6 months, 7 to 12 months or more than 12 months. The incidence rate ratio for venous thromboembolism (VTE) for drospirenone contraceptives was nearly double other contraceptives after 3 months of use (IRR = 1.9, 95% CI 1.26 – 2.95) and nearly triple at 7 to 12 months of use (IRR = 2.9, 95% CI 1.59 – 5.28). Risk of VTE was also increased for the patch (IRR = 1.55, 95% CI 1.17 – 2.07) and the ring (IRR = 1.74, 95% CI 1.42 – 2.14), particularly after 12 months of use when the VTE risk nearly triples for the patch². When analyzed by age, patients from 10 – 34 were found to have an increased VTE risk over those 35 – 55. Few cardiovascular outcomes were identified in this study, thus no specific association with contraceptive use was noted³.

The risk of blood clot with hormonal contraceptives is well-established and as high as five times the risk of clot in women not using hormones⁴. A 2009 study published in BMJ suggested drospirenone itself could put patients at a six-fold increase of thromboembolism⁴. Ultimately, this new FDA study confirms an increased risk of venous blood clot with drospirenone contraceptives as well as the contraceptive patch, particularly in users under age 35.

The FDA now requires all contraceptives containing drospirenone to include label warnings for patients who smoke and are over 35 as well as stronger concerns for vascular incidents. Recommendations for patients who are having major surgery are to stop these birth control pills four weeks prior to the procedure and for two weeks after surgery. Women who are not breastfeeding and wish to use oral contraceptives after birth should wait until four weeks post-partum before starting a drospirenone contraceptive¹.

Though the risk of blood clot is increased in patients taking hormonal contraceptives over those who do not, this risk is still overall less than the hypercoagulability that occurs during pregnancy or immediately post-partum. To put things into perspective, the FDA estimates the risk of blood clot in women not using hormonal contraceptives to be up to 5 in 10,000 women per year¹. This risk increases up to 9 in 10,000 women using oral contraceptives, while during pregnancy blood clot can occur in as many as 20 women in 10,000. The post-partum period carries the greatest risk of thromboembolism with as many as 65 women in 10,000 affected¹.

Providers should counsel patients on risks of contraceptives that contain drospirenone and advise them of signs of blood clots. Any adverse events that occur can also be reported to the MedWatch program to assist in post-marketing surveillance⁵.

References

1. FDA Drug Safety Communication: Safety review of possible increased risk of blood clots with birth control pills containing drospirenone.  http://www.fda.gov/Drugs/DrugSafety/ucm257164.htm. Accessed April 16, 2012.
2. FDA Drug Safety Communication: Updated information about the risk of blood clots in women taking birth control pills containing drospirenone. http://www.fda.gov/Drugs/DrugSafety/ucm299305.htm. Accessed April 16, 2012.
3. Ouellet-Hellstrom, R. et al. Combined Hormonal Contraceptives (CHCs) and the Risk of Cardiovascular Disease Endpoints. http://www.fda.gov/downloads/Drugs/DrugSafety/UCM277384.pdf. Accessed April 16, 2012.
4. Vlieg, A. 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. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2726929/pdf/bmj.b2921.pdf. Accessed April 16, 2012.
5. FDA Drug Safety Communication: Safety review update on the possible increased risk of blood clots with birth control pills containing drospirenone. http://www.fda.gov/Drugs/DrugSafety/ucm273021.htm. Accessed April 18, 2012.