Drug Profile

Combination oral contraceptives contain the hormones estrogen and progestin. These pills are commonly referred to as second- or third-generation, based on their progestin component. Ethinyl estradiol and desogestrel (DESOGEN, MIRCETTE, ORTHO-CEPT) is a third-generation oral contraceptive.

Second-generation oral contraceptives contain the progestins norgestrel, levonorgestrel and norethindrone. These are preferred over third-generation pills because they are safer.

In late 1995 and early 1996, four observational studies were published showing that the risk of blood clots (deep venous thrombosis) with third-generation oral contraceptives containing desogestrel is two times higher than with second-generation birth control pills.

Although the risk of blood clots with combined oral contraceptives is small, it is a real risk, and it is greater with the third-generation pills than with the second-generation pills. There is no acceptable scientific evidence that a woman taking third-generation pills reduces her risk of a heart attack compared with a woman using the second-generation products, and the second- and third-generation pills are equally effective in preventing pregnancy.

There is no reason why women should be using third-generation pills when equally effective and safer oral contraceptives are available.

A 1995 worldwide study conducted by the World Health Organization found that the third-generation oral contraceptives containing the progestins desogestrel and gestodene (the latter of which is not available in the United States) were associated with an increased risk of blood clots.[1] Shortly thereafter, four more observational studies published in rapid succession confirmed that the risk of blood clots with the third-generation pills was two times greater than with the older, second-generation contraceptives.[2],[3],[4],[5]

The U.K. warns about added risks

In October 1995, the Committee on Safety of Medicines (CSM; the United Kingdom ’s equivalent of the U.S. Food and Drug Administration [FDA]) warned the British public that third-generation birth control pills containing the progestins desogestrel or gestodene could double the risk of blood clots compared with older, second-generation oral contraceptives containing the progestins norgestrel, levonorgestrel or norethindrone.

British doctors were told that the third-generation products should not be prescribed routinely and that women who were already taking them should be offered the choice to switch to the older, safer, second-generation pills. The CSM decided that the increased risk — estimated at 30 cases of blood clots for every 100,000 users of third-generation pills per year, compared with 15 cases for every 100,000 women using second-generation pills per year — was sufficient to warrant an urgent alert to women and their doctors.[6]

Proponents of the third-generation pills maintain that any increase in the risks of blood clots may be offset by a reduced risk of heart attack.[7],[8] However, there is no convincing evidence of any difference in the heart attack risk between women using second- or third-generation pills.

Public Citizen urges ban

Although the British authorities took the responsible step in 1995 to inform women and their doctors about the risk of blood clots with the third-generation pills, the FDA took no similar action in alerting the public.

The professional product labeling (package insert) and the patient labeling for ORTHO-CEPT warn doctors and women about the risk of blood clots. The statement contained in the ORTHO-CEPT professional package insert says:

Data from case-control and cohort studies report that oral contraceptives containing desogestrel (ORTHO-CEPT contains desogestrel) are associated with a twofold increase in the risk of venous thromboembolic disease as compared to other low-dose (containing less than 50 micrograms of estrogen) pills containing other progestins. According to these studies, this twofold risk increases the yearly occurrence of venous thromboembolic disease by about 10–15 cases per 100,000 women.

Because of this doubled risk of life-threatening blood clots, Public Citizen filed a petition with the FDA on Feb. 6, 2007, to ban the sale of all third-generation oral contraceptives. To date, more than 21,000 people have supported our petition to the FDA to ban these drugs.

The ORTHO-CEPT package insert also makes reference to the unsubstantiated theory that third-generation birth control pills protect users from heart attacks:

Desogestrel has minimum androgenic activity, and there is some evidence that the risk of myocardial infarction (heart attack) associated with oral contraceptives is lower when the progestogen has minimal androgenic activity.

Organon, the producer of DESOGEN, makes similar statements about the risks of blood clots and heart attacks in the DESOGEN professional package insert and the patient labeling for the drug.

To settle questions about oral contraceptives, the World Health Organization convened an international meeting of experts in Switzerland in November 1997. Experts met in this forum with the overall objective of reviewing the current scientific data on the use of oral contraceptives and the risk of heart attack, stroke and blood clots. Regarding blood clots and heart attack, the Scientific Group concluded the following:

Current users of combined oral contraceptives have a low absolute risk of venous thromboembolism, which is nonetheless which is nonetheless threefold to sixfold higher than in nonusers. The risk is probably highest in the first year of use and declines thereafter, but it persists until discontinuation..

Combined oral contraceptive preparations containing desogestrel and gestodene probably carry a small risk of venous thromboembolism beyond that attributable to combined oral contraceptives containing levonorgestrel. There are insufficient data to draw conclusions with regard to combined oral contraceptives or combined oral contraceptives containing norgestimate.

The available data do not allow a conclusion that the risk of myocardial infarction (heart attack) in users of low-dose combined oral contraceptives is related to progestogen type. The suggestion that gestodene- or desogestrel-containing low-dose combined oral contraceptives may carry a lower risk of myocardial infarction compared with low-dose formulations containing levonorgestrel remains to be substantiated.[9]

In March 2014, the Medicines and Healthcare products Regulatory Agency (an agency in the U.K. similar to the FDA) issued a drug safety update that St. John's wort, when used with hormonal contraceptives, reduces the effectiveness of the contraceptives and increases the risk of unplanned pregnancy.[10]

Regulatory actions

2012: In June and July, the FDA issued advisory information concerning the use of combined hormonal contraceptives and the drug lamotrigine, which is used for seizure control. The FDA reported that co-administration of these medications may reduce seizure control; therefore, dosage adjustments of lamotrigine may be necessary.[11]

2013: The FDA issued an advisory for women with a history of hypertension, hypertension-related disease or renal disease who use hormonal oral contraceptives. These women should be closely monitored for a persistent increase in blood pressure.[12]

2017: In March, the labeling for the seizure drug valproate (DEPAKENE) was revised to warn that using hormonal contraceptives containing estrogen with valproate may cause an increased rate of seizures.[13]

2023: The FDA updated the drug product label of desogestrel/ethinyl estradiol to include warnings on depression, hereditary severe swelling and discoloration of the skin.[14]