Contraceptive efficacy and tolerability of ethinylestradiol 20 μg/drospirenone 3 mg in a flexible extended regimen: an open-label, multicentre, randomised, controlled study

Christine Klipping, Ingrid Duijkers, Michel P Fortier, Joachim Marr, Dietmar Trummer, Jörg Elliesen, Christine Klipping, Ingrid Duijkers, Michel P Fortier, Joachim Marr, Dietmar Trummer, Jörg Elliesen

Abstract

Background: The contraceptive efficacy and tolerability of a new flexible extended regimen of ethinylestradiol (EE) 20 μg/drospirenone (DRSP) 3 mg to extend the menstrual cycle and enable management of intracyclic (breakthrough) bleeding (flexible(MIB)) was investigated and the bleeding pattern compared with a conventional 28-day regimen and a fixed extended 124-day regimen.

Study design: This Phase III, 2-year, multicentre, open-label study randomly (4:1:1) allocated women (aged 18-35 years) to the following regimens: flexible(MIB) (24-120 days' active hormonal intake with 4-day tablet-free intervals); conventional (24 days' active hormonal intake followed by a 4-day hormone-free interval); or fixed extended (120 days' uninterrupted active hormonal intake followed by a 4-day tablet-free interval). Primary outcomes included the number of bleeding/spotting days during Year 1 (all regimens) and the number of observed unintended pregnancies over 2 years (flexible(MIB) only).

Results: Results were analysed in 1067 women (full analysis set). The mean number of bleeding/spotting days was lower with the flexible(MIB) vs the conventional regimen [41.0±29.1 (95% CI 38.8-43.3) vs 65.8±27.0 (95% CI 62.2-69.4) days, p<0.0001; treatment difference -24.8 (95% CI -29.2 to -20.3) days]. The corresponding value for the fixed extended regimen was 60.9±51.1 (95% CI 53.9-67.9) days. The Pearl Index for the flexible(MIB) regimen was 0.64 (95% CI 0.28-1.26). All regimens had comparable tolerability profiles.

Conclusions: EE 20 μg/DRSP 3 mg administered as a flexible extended regimen with MIB is effective, well tolerated and is associated with statistically significantly fewer bleeding/spotting days and fewer withdrawal bleeding episodes vs EE/DRSP in a conventional 28-day regimen. The flexible(MIB) also provided statistically significantly fewer spotting days vs EE/DRSP in a fixed extended 124-day regimen (post hoc evaluation). The flexible(MIB) regimen allows women to extend their menstrual cycle and manage their intracyclic (breakthrough) bleeding.

Conflict of interest statement

Competing interests Christine Klipping and Ingrid Duijkers are employees of Dinox BV, one of the centres in which the study was conducted. Michael P Fortier is a physician collaborating with the Clinique de Recherche en Santé des Femmes, one of the centres in which the study was conducted. Joachim Marr, Dietmar Trummer and Jörg Elliesen are employees of Bayer HealthCare Pharmaceuticals.

Figures

Figure 1
Figure 1
Disposition of women in the 1-year comparative phase of the study. FAS, full analysis set (defined as subjects who received at least one dose of study medication and had at least one clinical observation after administration of study medication). MIB, management of intracyclic (breakthrough) bleeding.
Figure 2
Figure 2
Mean number of bleeding/spotting days in the comparative phase with ethinylestradiol 20 μg/drospirenone 3 mg administered as a flexibleMIB, conventional 28-day or fixed extended regimen (full analysis set). Data are presented as mean (95% CI). The full analysis set was defined as all subjects who received at least one dose of study medication and had at least one clinical observation after administration of study medication. *p<0.0001 vs flexibleMIB (post hoc analysis for the fixed extended regimen comparison). MIB, management of intracyclic (breakthrough) bleeding.
Figure 3
Figure 3
Analysis of bleeding/spotting days in the comparative phase with ethinylestradiol 20 μg/drospirenone 3 mg administered as (a) flexibleMIB, (b) conventional 28-day and (c) fixed extended regimens (full analysis set). The full analysis set was defined as all subjects who received at least one dose of study medication and had at least one clinical observation after administration of study medication. MIB, management of intracyclic (breakthrough) bleeding.
Figure 4
Figure 4
Analysis of cycle length with ethinylestradiol 20 μg/drospirenone 3 mg administered as a flexibleMIB regimen (full analysis set). The full analysis set was defined as all subjects who received at least one dose of study medication and had at least one clinical observation after administration of study medication. MIB, management of intracyclic (breakthrough) bleeding.

References

    1. Klipping C, Duijkers I, Trummer D, et al. Suppression of ovarian activity with a drospirenone-containing oral contraceptive in a 24/4 regimen. Contraception 2008;78:16–25
    1. Szarewski A. Sisters doing it for themselves. J Fam Plann Reprod Health Care 2009;35:71–72
    1. Rutter W, Knight C, Vizzard J, et al. Women's attitudes to withdrawal bleeding and their knowledge and beliefs about the oral contraceptive pill. Med J Aust 1988;149:417–419
    1. den Tonkelaar I, Oddens BJ. Preferred frequency and characteristics of menstrual bleeding in relation to reproductive status, oral contraceptive use, and hormone replacement therapy use. Contraception 1999;59:357–362
    1. Miller L, Notter KM. Menstrual reduction with extended use of combination oral contraceptive pills: randomized controlled trial. Obstet Gynecol 2001;98:771–778
    1. Glasier AF, Smith KB, van der Spuy ZM, et al. Amenorrhea associated with contraception – an international study on acceptability. Contraception 2003;67:1–8
    1. Wiegratz I, Hommel HH, Zimmermann T, et al. Attitude of German women and gynecologists towards long-cycle treatment with oral contraceptives. Contraception 2004;69:37–42
    1. Andrist LC, Arias RD, Nucatola D, et al. Women's and providers' attitudes toward menstrual suppression with extended use of oral contraceptives. Contraception 2004;70:359–363
    1. Anderson FD, Gibbons W, Portman D. Safety and efficacy of an extended-regimen oral contraceptive utilizing continuous low-dose ethinyl estradiol. Contraception 2006;73:229–234
    1. Archer DF, Jensen JT, Johnson JV, et al. Evaluation of a continuous regimen of levonorgestrel/ethinyl estradiol: phase 3 study results. Contraception 2006;74:439–445
    1. Kroll R, Reape KZ, Margolis M. The efficacy and safety of a low-dose, 91-day, extended-regimen oral contraceptive with continuous ethinyl estradiol. Contraception 2010;81:41–48
    1. Anderson FD, Hait H. A multicenter, randomized study of an extended cycle oral contraceptive. Contraception 2003;68:89–96
    1. Kwiecien M, Edelman A, Nichols MD, et al. Bleeding patterns and patient acceptability of standard or continuous dosing regimens of a low-dose oral contraceptive: a randomized trial. Contraception 2003;67:9–13
    1. Legro RS, Pauli JG, Kunselman AR, et al. Effects of continuous versus cyclical oral contraception: a randomized controlled trial. J Clin Endocrinol Metab 2008;93:420–429
    1. Anttila L, Kunz M, Marr J. Contraceptive efficacy of a combined oral contraceptive containing ethinylestradiol 20 mcg/drospirenone 3 mg administered in 24/4 regimen: a pooled analysis of four, open-label studies. Int J Gynecol Obstet 2009;107:s622
    1. Bachmann G, Sulak PJ, Sampson-Landers C, et al. Efficacy and safety of a low-dose 24-day combined oral contraceptive containing 20 micrograms ethinylestradiol and 3 mg drospirenone. Contraception 2004;70:191–198
    1. Hernádi L, Marr J, Trummer D, et al. Efficacy and safety of a low-dose combined oral contraceptive containing drospirenone 3 mg and ethinylestradiol 20 mcg in a 24/4-day regimen. Contraception 2009;80:18–24
    1. Klipping C, Duijkers I, Fortier MP, et al. Long-term tolerability of ethinylestradiol 20 µg/drospirenone 3 mg in a flexible extended regimen: results from a randomised, controlled, multicentre study. J Fam Plann Reprod Health Care 2012;38:84–93
    1. Ferrero S, Abbamonte LH, Giordano M, et al. What is the desired menstrual frequency of women without menstruation-related symptoms? Contraception 2006;73:537–541
    1. Palacios S, Wildt L, Parke S, et al. Efficacy and safety of a novel oral contraceptive based on oestradiol (oestradiol valerate/dienogest): a Phase III trial. Eur J Obstet Gynecol Reprod Biol 2010;149:57–62
    1. Brucker C, Hedon B, The HS, et al. Long-term efficacy and safety of a monophasic combined oral contraceptive containing 0.02 mg ethinylestradiol and 2 mg chlormadinone acetate administered in a 24/4-day regimen. Contraception 2010;81:501–509
    1. Endrikat J, Müller U, Düsterberg B. A twelve-month comparative clinical investigation of two low-dose oral contraceptives containing 20 micrograms ethinylestradiol/ 75 micrograms gestodene and 30 micrograms ethinylestradiol/75 micrograms gestodene, with respect to efficacy, cycle control, and tolerance. Contraception 1997;55:131–137

Source: PubMed

Sponsorzy i współpracownicy

Warunki medyczne

Interwencje lekowe

3
Subskrybuj