FDA revises Evra safety labeling due to increased estrogen levels
Patch may expose users to about 60% more estrogen than 35 mcg pill
Get ready to discuss questions about the safety of the Evra contraceptive patch (Ortho-McNeil Pharmaceutical, Raritan, NJ) now that the Food and Drug Administration (FDA) has revised the transdermal contraceptive’s labeling. The labeling change includes an addition to the drug’s warning section to note that the patch exposes women to higher levels of estrogen than most birth control pills. Your patients now will be reading the new bolded warning:
"Hormones from patches applied to the skin get into the blood stream and are removed from the body differently than hormones from birth control pills taken by mouth. You will be exposed to about 60% more estrogen if you use Ortho Evra than if you use a typical birth control pill containing 35 mcg estrogen. In general, increased estrogen exposure may increase the risk of side effects. However, it is not known if there are differences in the risk of serious side effects based on the differences between Ortho Evra and a birth control pill containing 35 mcg estrogen. Talk to your health care provider about how this information relates to your use of Ortho Evra."1
The pharmacokinetic profile for the patch differs from that of oral contraceptives in that it has higher steady state concentrations and lower peak concentrations. Since the level of estrogen fluctuates greatly in the course of the 24 hours after a birth control pill is taken, the peak level of estrogen actually is higher in women using pills than it is in women using the patch. Peak concentrations for ethinyl estradiol are approximately 25% lower in women using the patch. It is the area under the curve (AUC) that is 60% higher in patch users.
According to the FDA, the label revision comes as a result of an analysis of the drug, performed by the agency and the manufacturer, which directly compares the estrogen and progestin levels of patch users with those in a typical birth control pill. The agency continues to monitor safety reports for the Ortho Evra patch, while the company is conducting additional studies to compare the risk of developing serious blood clots in women using the patch vs. those using a typical 35 mcg pill.
Ortho-McNeil is issuing a "Dear Health Care Provider" letter to advise clinicians on the labeling change, reports Julie Keenan, a company spokeswoman. Information also may be retrieved from the product’s web site, www.orthoevra.com, or by calling the Ortho call center at (800) 682-6532, she states.
Is the method safe?
Ortho Evra has been used by more than 5 million women since it received FDA approval in November 2001, and it was studied in 3,300 women prior to its launch. It has gained wide acceptance since its market debut; almost 93% of Contraceptive Technology Update’s 2005 Contraception Survey participants said their facility is offering the transdermal contraceptive.
The contraceptive patch has not been recalled. It remains a safe and effective product when used according to the product’s label, the company maintains. Its prescribing cautions remain in place: Some women should not use the patch, including women who have blood clots, certain cancers, a history of heart attack or stroke, as well as those who are or may be pregnant, the company advises.
Clinicians already have been fielding questions about the patch’s safety after media reports were issued following the April 2004 death of an 18-year-old woman who had been using the transdermal contraceptive and a resulting July 2005 Associated Press (AP) analysis of adverse events reports filed with the FDA surrounding the patch. The AP analysis said 17 patch users had suffered fatal heart attacks, blood clots, and possible strokes since August 2002.
According to Robert Hatcher, MD, MPH, professor of gynecology and obstetrics at Emory University School of Medicine in Atlanta and chairman of the CTU Editorial Advisory Board, the 17 deaths reported by the AP tells nothing of the relative risks of serious complications or deaths in patch users compared to women on combined pills. Numerator data are incomplete, and denominator data are nonexistent; what is needed is a careful epidemiologic analysis of deep vein thrombosis, strokes, heart attacks, and deaths in women on patches and pills, says Hatcher.
"We have no evidence today to say whether very serious complications are more likely in patch users than pill users," says Hatcher. "The fact that estrogen levels in patch users is roughly comparable to levels in women using 50 mcg pills — which are almost never used as a routine contraceptive today — will undoubtedly cause some clinicians to look for a lower estrogen contraceptive than the current patch."
Susan Ballagh, MD, associate professor of obstetrics and gynecology at the Norfolk, VA-based Jones Institute for Reproductive Medicine, believes that despite the new labeling, the patch remains a low-dose combination contraceptive product that can be used by any woman who is a candidate for low-dose combination contraceptives, whether delivered orally, vaginally, or transdermally.
"The new labeling verifies data already apparent that shows that the patch delivers estrogen at the higher rather than lower end of low-dose estrogen alternates," Ballard says. "Women successfully using the patch can continue to use it, as they would any of these effective contraceptive products."
For women experiencing estrogen-related side effects such as breast tenderness or dysmenorrhea from their current combination contraceptive, the patch would not be a first choice, Ballard notes. Those side effects already were known and are described in the labeling, she states.
The new labeling and pharmacokinetic data should not be cause for alarm, observes Andrew Kaunitz, MD, professor and assistant chair in the obstetrics and gynecology department at the University of Florida Health Science Center/Jacksonville. Clinicians may wish to think of the patch in the same category as a 50 mcg combined pill, he notes.
If women are currently using or considering patch use, and view the method as more appropriate for them than alternate birth control methods, then ongoing use makes sense, states Kaunitz. However, if women could confidently use an alternate effective method, such as oral contraceptives, the vaginal ring, an injectable or intrauterine contraceptive, such methods should be reviewed, he notes.
Check pharmacokinetics
A recently published pharmacokinetic comparison of ethinyl estradiol (EE) released from the transdermal patch, an oral contraceptive, and the contraceptive vaginal ring looked at the issue of estrogen exposure.2 The study evaluated multiple measurements of EE serum levels in women randomly assigned to use the ring, the patch, or a 30 mcg pill.
Although the transdermal patch is designed to deliver a low daily dose of EE, it does not appear to result in low exposure, researchers conclude.2
"[A]lthough the transdermal patch delivers only 33% more EE daily than NuvaRing, the exposure to EE in the patch group was approximately 250% greater than in the NuvaRing group," the study’s scientists observe.2
Women using the ring had a lower fluctuation in serum estrogen levels than with the other methods; women using the Pill had the highest degree of variation in serum concentrations, data indicate. Women who used the patch reported a higher incidence of estrogen-related side effects, including nausea and breast tenderness, than those in the pill and ring groups.2
According to the FDA, higher levels of estrogen may put some women at increased risk for getting blood clots. When thinking about prescribing or using Ortho Evra, health care professionals and women need to balance the increased exposure to estrogen against the chance of pregnancy if a birth control pill is not taken daily, the agency advises in a question-and-answer statement.3
"Estrogen use is linked to blood clots in the legs and lungs and other clotting problems such as strokes and heart attacks," the FDA advisory states. "It is not known if women using Ortho Evra have a higher risk of serious side effects than women taking the typical 35 mcg estrogen pills."
Women may think that they can decrease the amount of estrogen from the patch by cutting the patch, the FDA advises. Remind them that if the patch is altered or the regimen is not followed as prescribed, the method will not protect against pregnancy.
Remember that the same precautions and danger signals for combined oral contraceptives apply to the patch. Use the "ACHES" mnemonic (Abdominal pain, Chest pain, Headaches that are severe, Eye problems, and Severe leg pain) to teach women the danger signals with patch or Pill use.4
Current or potential contraceptive patch users with such risk factors as hypertension, migraines, obesity, or older reproductive age (women in their 40s or early 50s) might particularly be counseled to consider alternate birth control methods, says Kaunitz.
References
- Ortho-McNeil Pharmaceutical. Ortho Evra. Product labeling. Revised November 2005.
- Van den Heuvel MW, van Bragt AJM, Alnabawy A, et al. Comparison of ethinyl estradiol pharmacokinetics in three hormonal contraceptive formulations: the vaginal ring, the transdermal patch and an oral contraceptive. Contraception 2005; 72:168-174.
- Food and Drug Administration. Question and Answers. Ortho Evra. Nov. 10, 2005. Accessed at: www.fda.gov/cder/drug/infopage/orthoevra/qa.htm.
- Hatcher RA, Trussell J, Stewart F, et al. Contraceptive Technology. 18th revised ed. New York City: Ardent Media; 2004.
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