New OC formulation now in research focus

Results from a multi-country clinical trial of a combined oral contraceptive (OC) containing nomegestrol acetate and 17-beta estradiol indicate it is an effective pill with good cycle control.1

The monophasic combined oral contraceptive formulation was granted marketing authorization for birth control purposes within the European market in August 2011.2-5 Trademarked as Zoely, the drug's marketing authorization covers 27 European Union (EU) member states plus Iceland, Liechtenstein, and Norway, says Megan Wilkinson, a Merck & Co. spokesperson. Teva Pharmaceutical Industries Ltd. of Jerusalem, Israel holds exclusive marketing rights for Zoely in France, Italy, Belgium, and Spain; Merck & Co.'s parent company, MSD, will market Zoely in all other EU and European countries, including the United States.

Initial Phase 3 testing of the drug began in the United States in 2007. Merck received a Complete Response letter from the Food and Drug Administration in November 2011, says Wilkinson. According to the FDA web site, the agency issues such letters when an application cannot be approved in its present form. Upon review of the complete response letter, Merck decided to conduct an additional Phase III study as requested by the FDA, says Wilkinson.

Look at results

The current study was designed to estimate the efficacy, cycle control, tolerability, and safety of the study drug in comparison with a combined oral contraceptive containing drospirenone and ethinyl estradiol. Researchers conducted a randomized, open-label, comparative multicenter trial, including 2,281 healthy women ages 18-50 at risk for pregnancy and in need of contraception. Participants were allocated in a 3:1 ratio to receive the study drug, nomegestrol acetate (2.5 mg) and 17-beta estradiol (1.5 mg in a 24-4-day regimen), or a pill containing 3.0 mg drospirenone and 30 mg in a 21-7-day regimen.

The trial looked at 13 consecutive 28-day cycles. The primary end point was the Pearl Index. The Pearl Indices for 18-to 35-year-old women in the study drug group (1,375 women) and comparator groups (463 women) were 1.27 (95% confidence interval [CI] 0.66-2.22) and 1.89 (95% CI 0.69-4.11), respectively. Respective one-year cumulative pregnancy rates were 1.22 (95% CI 0.69-2.16) and 1.82 (95% CI 0.81-4.05).

By the end of the trial, shorter, lighter scheduled bleeding or an absence of scheduled bleeding occurred with greater frequency (32.9%) in the investigational group, while unscheduled bleeding or spotting episodes were low: 16.2% and 15.0% in the investigational and comparator groups, respectively, researchers note. The prevalence of acne decreased from about 33% at baseline to 22% and 14% at cycle 13 in the respective groups. The most frequently reported adverse events in the investigational group were acne (16.4%), weight gain (9.5%), and irregular withdrawal bleeding (9.1%). Discontinuation rates were 3.8% and 1.8% in the two groups respectively. This discontinuation rate might have been a result of the unanticipated higher rate of irregular or absent withdrawal bleeding (9% versus 0.5%), which some participants might have equated with unintended pregnancy, researchers note.1

"The report of this large clinical trial indicate use of this OC is associated with excellent contraceptive efficacy and tolerability, says Andrew Kaunitz, MD, professor and associate chair in the Obstetrics and Gynecology Department at the University of Florida College of Medicine — Jacksonville. Kaunitz served as a co-investigator and co-author of the current research.

Check pill-free interval

The 24-4 dosing regimen of the drug now under study follows a trend toward shortened pill-free intervals. Pregnancy rates are lower in the 24/4 formulations of low-dose pills (20 mcg of ethinyl estradiol) compared to 21/7 formulations.6

A shorter hormone-free interval also might benefit patients by reducing unscheduled bleeding.7 The enhanced suppression of follicular development and endogenous estrogen levels might decrease unscheduled bleeding, which might help patient satisfaction with and continuation of the pill.7

References

  1. Westhoff C, Kaunitz AM, Korver T, et al. Efficacy, safety, and tolerability of a monophasic oral contraceptive containing nomegestrol acetate and 17β-estradiol: a randomized controlled trial. Obstet Gynecol 2012; 119(5):989-999.
  2. Duijkers IJM, Klipping C, Grob P, et al. Effects of a monophasic combined oral contraceptive containing nomegestrol acetate and 17β-oestradiol on ovarian function in comparison to a monophasic combined oral contraceptive containing drospirenone and ethinylestradiol. Eur J Contracept Reprod Health Care 2010; 15:314-325.
  3. Gaussem P, Alhenc-Gelas M, Thomas JL, et al. Haemostatic effects of a new combined oral contraceptive, nomegestrol acetate/17β-estradiol, compared with those of levonorgestrel/ethinyl estradiol: a double-blind, randomised study. Thromb Haemost 2011; 105:560-567.
  4. Mansour D, Verhoeven C, Sommer W, et al. Efficacy and tolerability of a monophasic combined oral contraceptive containing nomegestrol acetate and 17β-oestradiol in a 24/4 regimen, in comparison to an oral contraceptive containing ethinylestradiol and drospirenone in a 21/7 regimen. Eur J Contracept Reprod Health Care 2011; 16:430-443.
  5. Lello S. Nomegestrol acetate: pharmacology, safety profile and therapeutic efficacy. Drugs 2010; 70:541-559.
  6. Dinger J, Minh TD, Buttmann N, et al. Effectiveness of oral contraceptive pills in a large U.S. cohort comparing progestogen and regimen. Obstet Gynecol 2011; 117(1):33-40.
  7. Kaunitz AM. Making the patient-pill match. Sex Reprod Menopause 2008; 6(2):13-16.