Oral contraceptives: Look for more options to emerge from pipeline
Lower doses, new formulations of hormone combinations now under review
Check the last 10 contraceptive counseling sessions you conducted in your exam room. While some of your patients may have chosen new forms of birth control, chances are that most of them picked the Pill.
Oral contraceptives (OCs) continue to be the most popular form of reversible contraception among American women; 30.6% of contracepting women in 2002 named the Pill as their chosen method.1 According to the National Survey of Family Growth, oral contraceptives represent the method most widely used by women who are in their teens and 20s, never-married women, and women with at least a college degree.1
While there may be a wide array of current pill choices, get set to add more options to your formulary list. Scientists are looking at new formulations that, if proven to be safe and effective, will arrive at pharmacy shelves following federal approval.
While OCs are primarily used for contraception, investigators also are researching other treatment modalities for pill formulations. Berlex of Montville, NJ, is looking at possible treatment of premenstrual dysphoric disorder (PMDD) for its new OC, Yaz (20 mcg ethinyl estradiol/3 mg drospirenone). The Food and Drug Administration (FDA) issued an approvable letter for the drug in November 2004 and has asked for further documentation on the pill’s unique dosing regimen: 24 days of active pills followed by four days of placebo pills. In addition to seeking an indication as an oral contraceptive with its FDA submission, Berlex also is asking for approval of Yaz as a treatment option for women with symptoms of PMDD who desire pregnancy prevention. The company looks to receive word from the FDA by the end of 2005, reports Kim Schillace, Berlex spokeswoman.
Berlex has been looking at ethinyl estradiol/ drospirenone combinations as a potential PMDD treatment, including use of its currently available ethinyl estradiol/drospirenone pill, Yasmin.2 Information on the new formulation was presented at the May 2005 annual meeting of the Washington, DC-based American College of Obstetricians and Gynecologists (ACOG).3 Scientists believe Yaz’s effectiveness in relieving PMDD symptoms lies in its shortened pill-free interval of its dosing regimen, combined with its progestin, drospirenone, which exhibits anti-mineralocorticoid and anti-androgenic activity.4
Novel combination eyed
Organon NV in Oss, the Netherlands, is conducting research on a novel contraceptive, EMM 310066, obtained from Darmstadt, Germany-based Merck Group. The drug has shown success in Phase II clinical trials, say Organon officials.
EMM 310066 is a natural estrogen-containing oral contraceptive, says Monique Mols, Organon spokeswoman. Contraceptive products that contain the natural estrogen are not yet available on the market, she states; several attempts have been made in the past by Organon and others to develop such products, but so far none of them have been successful, she notes. EMM 310066 appears to be the first pill containing natural estrogen that is able to combine good contraceptive efficacy with an expected cyclic bleeding pattern and safety profile, states Mols.
"The final product profile of a combined contraceptive product is determined by the combination of a progestogen and estrogen; so far, none of the progestogennatural estrogen combinations that have been tested appeared to be successful," she reports. "The combination of this specific progestogen, nomegestrol acetate, combined with the natural estrogen seems to be an exception, as this combination seems to be able to combine good contraceptive efficacy with an acceptable cyclic bleeding pattern and safety profile."
The Phase III clinical trial program, scheduled to begin in 2006, will be held in Europe and the United States, reports Mols. The company plans to file submission for regulatory approval in the United States and Europe, she states.
Scientists at Wyeth Research in Collegeville, PA, have been investigating use of tanaproget, a tissue-selective, nonsteroidal contraceptive progesterone receptor agonist, as a possible agent in contraception.
Current OCs contain steroid-based progesterone receptor agonist that can interact with other receptors and pathways, which results in such side effects as nausea, headaches, cramps, tenderness, and pain; tanaproget’s chemical make-up may lend itself to an improved side-effect profile.5
Results from a small multicenter, randomized, double-blind, sequential-group, ascending multiple-dose study of tanaproget indicate that it exhibits an acceptable safety profile for use as a once-daily contraceptive.6 However, Wyeth has suspended active development of tanaproget while the scope of its commercial profile is further evaluated, says Gerald Burr, vice president of scientific communications for Wyeth Pharmaceuticals. Strategic alternatives for advancing tanaproget into Phase III development are under consideration, including external partnering or out-licensure, he adds.
"Wyeth will continue to explore the use of tanaproget for other potential indications, [such as] vasomotor symptoms while also evaluating potential licensing options," Burr notes. "A tanaproget OC remains a viable option for women who need or want nonsteroidal contraceptive options."
Barr Pharmaceuticals of Woodcliff Lake, NJ, is seeking FDA approval for Seasonique, an extended regimen OC. It is a 91-day extended-cycle pill that includes 84 active tablets of 0.15 mg of levonorgestrel/0.03 mg of ethinyl estradiol, followed by seven days of 0.01 mg ethinyl estradiol. The regimen is designed to reduce the number of withdrawal bleeding periods from 13 to four per year. The pill, if approved, will be marketed under the company’s Duramed subsidiary.
In filing its request with the FDA, Barr submitted data from a large pivotal randomized, open-label, multicenter trial and a supportive randomized, open-label, multicenter trial, both currently unpublished. About 2,500 women ages 18-40 participated in the investigation; an extension study of the pivotal trial is ongoing, according to Barr.7
Barr currently offers 22 generic oral contraceptives, along with its proprietary extended-regimen pill, Seasonale. Its latest addition to its generic line includes Kelnor (ethynodiol diacetate and ethinyl estradiol tablets, 1 mg/35 mcg), which clinicians may recognize as the generic version of New York City-based Pfizer’s Demulen OC.
References
- Alan Guttmacher Institute. Contraceptive Use. New York City; accessed at: www.guttmacher.org/pubs/fb_contr_use.html.
- Freeman EW, Kroll R, Rapkin A, et al. Evaluation of a unique oral contraceptive in the treatment of premenstrual dysphoric disorder. J Womens Health Gend Based Med 2001; 10:561-569.
- Bachmann G, Yonkers KA, Marr J. New low-dose OC containing drospirenone for the treatment of emotional and physical symptoms of PMDD. Presented at the American College of Obstetricians and Gynecologists Annual Clinical Meeting. San Francisco; May 2005.
- Bachmann G, Sulak PJ, Sampson-Landers C, et al. Efficacy and safety of a low-dose 24-day combined oral contraceptive containing 20 micrograms ethinyl estradiol and 3 mg drospirenone. Contraception 2004; 70:191-198.
- Borman S. Compound may have fewer side effects than current steroidal agents. Chemical & Engineering News 2004; 82(35). Accessed at: http://pubs.acs.org/cen/news/8235/8235notw6.html.
- Bapst JL. Clinical pharmacology of tanaproget, a novel selective nonsteroidal progesterone receptor agonist. Presented at the American College of Obstetricians and Gynecologists Annual Clinical Meeting. San Francisco; May 2005.
- Barr Pharmaceuticals. Duramed’s Seasonique NDA accepted for filing by FDA. Press release. Dec. 22, 2004. Press release. Accessed at www.barrlabs.com/pages/nprpr.html.
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