Oral Contraceptives Containing Drospirenone - Increased Risk of Blood Clots

An article in the February 2011 issue of the French medical journal Prescrire International reviewed four studies examining the link between blood clots and oral contraceptives containing the progestin drospirenone. Two of the reviewed studies showed increases in the risk of blood clots in women taking drospirenone.

The other two reviewed studies found no increase in the risk of blood clots in women taking the drug. However, these two “negative” studies were funded by Bayer, the company that makes drospirenone-containing pills YASMIN and YAZ. There is clear evidence from previous studies on the increased risk of blood clots with other oral contraceptives containing desogestrel (see Table 1), that industry-funded studies found lower risks than independently funded studies.

The two most recent studies, which were published in 2009, showed increases in the risk of blood clots from drospirenone. These studies were publicly funded. One study, conducted in Denmark between 1995 and 2005, showed a statistically significant increase in the risk of blood clots in women taking drospirenone compared to those taking a combined contraceptive containing the older progestin levonorgestrel. It included all women in Denmark, ages 15 to 49, who did not have a previous history of heart disease or cancer. The large study involved the equivalent of 3.3 million women years (the equivalent of 3.3 million women using an oral contraceptive for one year).

The second study was conducted in The Netherlands between March 1999 and September 2004. The study included 1,524 women ages 18 to 50 years of age and 1,760 controls. As found in the Danish study, there was also an increased risk of blood clots in women taking drospirenone compared to those taking levonorgestrel (3.6 vs. 6.3), but the difference was not statistically significant.

Risk of blood clots with combined oral contraceptives

Epidemiologists and drug safety experts express risk, such as blood clots, as the number of cases per person-year of exposure to a drug. For example, the estimate of the risk of blood clots with combined oral contraceptives containing the progestins levonorgestrel or norethisterone with ethinyl estradiol is 20 cases of blood clots for every 100,000 women taking levonorgestrel- or norethisterone-containing combined oral contraceptives for a year.

Table 1 summarizes the estimates for blood clots in women using combined contraceptives containing ethinyl estradiol and various progestins including drospirenone, desogestrel and levonorgestrel or norethisterone. The risk is clearly lower with combined contraceptives containing the latter two, levonorgestrel or norethisterone.

Oral contraceptives containing drospirenone

The first combined oral contraceptive containing drospirenone in the U.S. was YASMIN, which was approved by the Food and Drug Administration (FDA) in April 2001. YASMIN is a combination of the estrogen ethinyl estradiol and the progestin drospirenone. In March 2006, YAZ, which is similar to YASMIN but with a lower concentration of the estrogen ethinyl estradiol, was approved in the U.S. There are now seven combined oral contraceptives marketed in the U.S. that contain drospirenone with ethinyl estradiol. These are listed in Table 2. In 2009, two of these products, YASMIN and YAZ, accounted for more than 11 million prescriptions dispensed in pharmacies.

We reviewed YASMIN in the April 2002 Worst Pills, Best Pills News and listed it as a “Do Not Use” drug for two reasons: 1) Drospirenone causes elevated blood levels of potassium that may cause serious heart and other health problems such as a change in blood acid balance and muscle weakness; and 2) There is no evidence that YASMIN is superior in any way to older contraceptive products. For the same reasons, we subsequently listed YAZ as a “Do Not Use” drug.

Drospirenone is a close chemical cousin of spironolactone (ALDACTONE), a diuretic or water pill that causes the body to retain potassium. A 3-milligram dose of drospirenone, the amount in a daily contraceptive pill, is equivalent to 25 milligrams of spironolactone.

Oral contraceptives containing desogestrel

We listed combined contraceptives containing the progestin desogestrel as “Do Not Use” drugs in the May 1999 Worst Pills, Best Pills News because of an increased risk of blood clots with the use of these products. In February 2007, Public Citizen’s Health Research Group petitioned the FDA to ban desogestrel-containing products from the market.

Table 3 lists the desogestrel-containing combined contraceptives approved for use in the U.S.

Oral contraceptives containing levonorgestrel

The lowest risk of blood clots is seen in women using products containing levonorgestrel or norethisterone with ethinyl estradiol (in doses of 50 micrograms or less). These drugs have been on the market for several decades; therefore more is known about their safety.

The editors of Prescrire International recommended that levonorgestrel or norethisterone with ethinyl estradiol in doses of less than 50 micrograms should be the first choices for women who wish to use a combined oral contraceptive. We agree, because these older drugs are safer as far as the risk of blood clots and are just as effective as the riskier, newer drugs. Table 4 lists the levonorgestrel or norethisterone with ethinyl estradiol products in doses of less than 50 micrograms available in the U.S.

What You Can Do

You should not use combined oral contraceptives containing either drospirenone or desogestrel due to the increased risk of blood clots in people taking these drugs. Products containing drospirenone rank near the top in terms of blood clot risk. If you wish to use a combined oral contraceptive, use levonorgestrel or norethisterone with ethinyl estradiol products.

Consumers may report serious adverse events with oral contraceptives or other product quality problems to the FDA’s MedWatch Adverse Event Reporting program either online or by regular mail, fax or phone.

• Online: www.accessdata.fda.gov/scripts/medwatch/medwatch-online.htm
• Regular mail: Use postage-paid, pre-addressed FDA form 3500 and mail to MedWatch, 5600 Fishers Lane, Rockville, MD 20852-9787
• Fax: (800) FDA-0178
• Phone: (800) FDA-1088

Table 1. Estimate of the Risk of Blood Clots With Combined Oral Contraceptives Containing Different Progestins

* Gestodene and cyproterone are not approved for use in the U.S.

Table 2. Currently Available Oral Contraceptives Containing Drospirenone Marketed in the U.S.: Estimated Risk of Blood Clots: 78 cases out of 100,000 Women Using These Products for One Year

Table 3. Oral Contraceptives Containing Desogestrel With Ethinyl Estradiol Marketed in the U.S.:  Estimated Risk of Blood Clots: 30 to 40 Cases out of 100,000 Women Using These Products for One Year

Table 4. Currently Available Oral Contraceptives Containing Levonorgestrel With Ethinyl Estradiol Marketed in the U.S.:  Estimated Risk of Blood Clots: 20 Cases out of 100,000 Women Using These Products for One Year