New progestins eyed for contraception in U.S.
While not yet available in the United States, international researchers are examining use of contraceptive progestins in two birth control methods: a transdermal patch using gestodene and an oral contraceptive formulation using dienogest.
Bayer Schering Pharma AG, Germany, has initiated two Phase III trials to examine a transdermal patch using ethinyl estradiol and gestodene. The first one is in the United States, and another one is in Germany, Italy, Spain, France, Australia, Argentina, Chile, and Mexico. About 3,300 women will be enrolled in the two studies, which began in May, says Friederike Lorenzen, a company spokeswoman. Gestodene is a synthetic progestogen that belongs to the 19-nortestosterone derivative chemical family, which includes norethisterone, levonorgestrel, desogestrel, and norgestimate.1
The patch under review contains a formulation comparable to an oral dose of 20 mcg ethinyl estradiol and 50 mcg gestodene, she reports. The patch, transparent in color, will be applied once per week, which will result in three patches per cycle (21 days) and one week off. Early research indicates the patch is effective in reversibly inhibiting ovulation, is well tolerated, and is regarded as "very convenient" by most users.2
Company officials plan to submit the new patch for registration worldwide, with first filing expected in 2012. Lorenzen confirms that Food and Drug Administration (FDA) approval will be sought for U.S. use.
Women in the United States are familiar with transdermal contraception; the FDA approved Ortho Evra (Ortho Women's Health & Urology; Raritan, NJ) in 2002. The patch delivers 150 mcg of the progestin norelgestromin and 20 mcg ethinyl estradiol per day.
When the Ortho Evra patch first became available, many women were enthusiastic regarding use of transdermal contraception, observes Andrew Kaunitz, MD, professor and associate chair in the Obstetrics and Gynecology Department at the University of Florida College of Medicine — Jacksonville. However, pharmacokinetic data indicated that the release of ethinyl estradiol (EE) from this first-generation patch was associated with substantially higher area under the curve for EE than low-dose oral contraceptives.3-6 The FDA added this information to the package insert for Evra; reports then emerged that Evra might be associated with a higher risk of thromboembolic disease than oral contraceptives, says Kaunitz.
"The result of this history is that clinicians and women became wary regarding the patch's safety, and prescriptions and use declined," he says. "Provided that efficacy and adequate cycle control can be achieved, I believe U.S. clinicians and women would be receptive to a second-generation, lower-estrogen contraceptive patch."
Dienogest pill released
Women in several European countries now have access to a new estradiol valerate/dienogest oral contraceptive, Qlaira. The pill, developed by Bayer Schering Pharma AG, is available in Germany and other European countries, with more countries to be added in fall 2009. Bayer also plans to seek FDA approval for the pill, Lorenzen confirms.
Research presented during the 2008 annual clinical meeting of the American College of Obstetricians and Gynecologists indicates the 4-phasic oral contraceptive is effective, safe, and well tolerated.7 Dienogest is one of several new progestins such as drospirenone, Nestorone, nomegestrol acetate, and trimegestone that have been synthesized in the last two decades. These new progestins are formulated to have no androgenic or estrogenic actions and to be closer in activity to the physiological hormone progesterone.8
Bayer also is developing Qlaira for the treatment of heavy and/or prolonged menstrual bleeding in women without organic pathology who desire oral contraception. Why is the company pursuing this line of research? "It's an unmet medical need, and no other contraceptive has yet been approved for treating this disease," says Lorenzen.
References
- Benagiano G, Primiero FM, Farris M. Clinical profile of contraceptive progestins. Eur J Contracept Reprod Health Care 2004; 9:182-193.
- Heger-Mahn D, Warlimont C, Faustmann T, et al. Combined ethinylestradiol/gestodene contraceptive patch: Two-center, open-label study of ovulation inhibition, acceptability and safety over two cycles in female volunteers. Eur J Contracept Reprod Health Care 2004; 9:173-181.
- Jick SS, Kaye JA, Russmann S, et al. Risk of nonfatal venous thromboembolism in women using a contraceptive transdermal patch and oral contraceptives containing norgestimate and 35 mcg of ethinyl estradiol. Contraception 2006; 73:223-228.
- Cole JA, Norman H, Doherty M, et al. Venous thromboembolism, myocardial infarction, and stroke among transdermal contraceptive system users. Obstet Gynecol 2007; 109(2 Pt 1):339-346.
- Boston Collaborative Drug Surveillance Program. Postmarketing study of ORTHO EVRA and levonorgestrel oral contraceptives containing hormonal contraceptives with 30 µg of EE in relation to nonfatal venous thromboembolism, ischemic stroke, and myocardial infarction. Accessed at www.clinicaltrials.gov/ct2/show/NCT00511784.
- Jick S, Kaye JA, Li L, et al. Further results on the risk of nonfatal venous thromboembolism in users of the contraceptive transdermal patch compared to users of oral contraceptives containing norgestimate and 35 microg of ethinyl estradiol. Contraception 2007; 76:4-7.
- Nahum GG, Parke S, Wildt L, et al. Efficacy and tolerability of a new oral contraceptive containing estradiol and dienogest. Presented at the 56th Annual Clinical Meeting of the American College of Obstetricians and Gynecologists. New Orleans; May 2008.
- Sitruk-Ware R. New progestagens for contraceptive use. Hum Reprod Update 2006; 12:169-178.
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