Cigarette smoking increases the risk of serious cardiovascular side effects from hormonal contraceptive use. This risk increases with age and with heavy smoking (15 or more cigarettes per day) and is quite marked in women over 35 years of age. Women who use hormonal contraceptives, including ORTHO EVRA, should be strongly advised not to smoke. |
The Associated Press published an investigative report on July 18, 2005 that links the birth control patch containing a combination of norelgestromin with ethinyl estradiol (ORTHO EVRA) to an increased risk of blood clots and deaths (compared to older contraceptives) in some young healthy women. The Ortho Evra patch, like many of its oral counterparts, contains two hormones, a progestin and an estrogen. The progestin in this case is a new drug, norelgestromin, and the estrogen is ethinyl estradiol, an older estrogen.
Ortho Evra, like the other hormonal contraceptives, has a black box warning about an increased risk of cardiovascular adverse reactions in older women who smoke. This type of warning is the strongest that the FDA can request and appears with this article.
Ortho Evra was approved by the Food and Drug Administration (FDA) in November 2001. It is the first contraceptive product to be approved as a skin patch. In 2004, the drug accounted for more than 9.9 million prescriptions with sales topping $411 million. The drug is sold by Ortho-McNeil Pharmaceuticals, Inc. of Raritan, N.J.
The progestin in Ortho Evra, norelgestromin, entered the market for the first time in 2001. Norelgestromin is the active breakdown product, or metabolite, of norgestimate, the progestin contained in the oral contraceptives Ortho-Cyclen and Ortho Tri-Cyclen.
Contraceptives are commonly referred to as second- or third-generation based on their progestin component. Some authorities classify norelgestromin as a third-generation progestin. Thus Ortho Evra is a third-generation contraceptive. We first listed the third-generation oral contraceptives containing the combination of the progestin desogestrel with the estrogen ethinyl estradiol (DESOGEN, MIRCETTE, ORTHO-CEPT) as DO NOT USE drugs in the 1998 edition of Worst Pills, Best Pills because of an increased risk of blood clots compared to the older, second-generation birth control pills (also see Worst Pills, Best Pills News May 1999).
Second-generation contraceptives contain the progestins norgestrel, levonorgestrel, or norethindrone. Examples of second-generation products are Lo/Ovral, Alesse, and Ortho-Novum, to name only a few.
The Associated Press used the Freedom of Information Act to obtain adverse drug reaction reports for Ortho Evra from the FDA. They reported that of the 23 cases in which death was the outcome, doctors reviewing the cases found 17 that appeared to be blood-clot-related, including 12 from last year. The FDA estimates that it receives reports of only 1 in 10 to 1 in 100 of the serious adverse drug reactions that actually occur, indicating that the actual rate of death may be much higher.
In addition, the Associated Press looked at the reviews of clinical trial results done by FDA physicians and scientists prior to the drug’s approval. The results were submitted for review by Ortho-McNeil in support of Ortho-Evra. These reviews are available on the agency’s Web site at: http://www.fda.gov/cder/foi/nda/2001/021-180_ORTHO.htm.
Ortho-McNeil and the FDA medical officer reviewing Ortho Evra disagreed about whether or not two cases of blood clots in the lungs (pulmonary embolus) in young women participating in the pre-approval clinical trials were caused by the drug. The medical officer wrote:
THE REVIEWER DOES NOT AGREE WITH THE SPONSOR’S [Ortho-McNeil] ABOVE CONCLUSIONS. The two cases of pulmonary embolus, a serious and potentially fatal condition, must be counted as two cases in the ... group [emphasis in the original].
The medical officer also included the following statement in his comments:
The professional product labeling and information written specifically for women using Ortho-Evra “should reflect the possible increased risk of venous thromboembolism (VTE) [blood clots] associated with this new transdermal combination hormonal contraceptive containing the new molecular entity progestin norelgestromin (17d-norgestimate) [emphasis in the original].
The medical officer also expressed concern that 211 out of 3,088 women (6.8 percent) in the pre-approval clinical trials gained 10 or more pounds in the trials. He also noted that the contraceptive effectiveness of Ortho-Evra was reduced in women weighing or than 198 pounds (90 kilograms).
The professional product label warns that Ortho-Evra should not be used in the following circumstances:
- A history of heart attack or stroke
- Blood clots in the legs (thrombophlebitis), lungs (pulmonary embolism), or eyes
- A history of blood clots in the deep veins of your legs
- Chest pain (angina pectoris)
- Known or suspected breast cancer or cancer of the lining of the uterus, cervix or vagina
- Unexplained vaginal bleeding (until your doctor reaches a diagnosis)
- Hepatitis or yellowing of the whites of your eyes or of the skin (jaundice) during pregnancy or during previous use of hormonal contraceptives such as ORTHO EVRA, NORPLANT [levonorgestrel], or the birth control pill
- Liver tumor (benign or cancerous)
- Known or suspected pregnancy
- Severe high blood pressure
- Diabetes with complications of the kidneys, eyes, nerves, or blood vessels
- Headaches with neurological symptoms
- Use of oral contraceptives (birth control pills)
- Disease of heart valves with complications
- Need for a prolonged period of bed rest following major surgery
- An allergic reaction to any of the components of Ortho Evra
Women who may be using Ortho Evra should contact their physician if any of the following warning signals develop:
- Sharp chest pain, coughing of blood, or sudden shortness of breath (indicating a possible clot in the lung)
- Pain in the calf (indicating a possible clot in the leg)
- Crushing chest pain or tightness in the chest (indicating a possible heart attack)
- Sudden severe headache or vomiting, dizziness or fainting, disturbances of vision or speech, weakness, or numbness in an arm or leg (indicating a possible stroke)
- Sudden partial or complete loss of vision (indicating a possible clot in the eye)
- Breast lumps (indicating possible breast cancer or fibrocystic disease of the breast; ask your doctor or health care professional to show you how to examine your breasts)
- Severe pain or tenderness in the stomach area (indicating a possibly ruptured liver tumor)
- Severe problems with sleeping, weakness, lack of energy, fatigue, or change in mood (possibly indicating severe depression)
- Jaundice or a yellowing of the skin or eyeballs accompanied frequently by fever, fatigue, loss of appetite, dark colored urine, or light colored bowel movements (indicating possible liver problems)
Contraceptives are prescribed to young, healthy women and should be associated with the lowest possible risk of serious adverse drug reactions. Blood clots in the lungs were seen in two women given Ortho Evra in clinical trials conducted before the drug was approved (in addition to many similar cases in women after the drug was marketed), and there is no evidence that the patch is a superior contraceptive compared to older second-generation birth control pills. Rarely do randomized pre-approval studies, the scientific “gold standard” for proving safety or efficacy, present such strong evidence of a serious problem.
What You Can Do
There is no medical reason for women to use the more dangerous Ortho Evra rather than one of the older, better understood, and equally effective oral contraceptives.