Original research articleEfficacy and safety of a low-dose 24-day combined oral contraceptive containing 20 μg ethinylestradiol and 3 mg drospirenone
Introduction
Combined oral contraceptives (COCs) are among the most effective reversible forms of contraception available [1], [2]. In addition to their proven contraceptive effects, they are widely recognized as providing menstrual cycle-related benefits, including regular menses, decreased menstrual flow and relief from dysmenorrhea [2]. Nevertheless, many women requiring contraception stop using oral contraceptives for a variety of reasons that include adverse effects and tolerability issues (e.g., bleeding irregularities, nausea, headaches and fluid-related symptoms such as breast tenderness and bloating) [3]. Consequently, ongoing hormonal contraceptive research has focused on maintaining efficacy while improving convenience and acceptability. Strategies have included reducing exposure to hormones through “phasing”, lowering the dose of the estrogen component and introducing new progestins with improved tolerability.
Drospirenone is a novel progestin in that it is an analog of spironolactone and its pharmacological profile more closely resembles that of natural progesterone compared to other progestins [4]. Unlike other progestins, it has antimineralocorticoid properties characteristic of endogenous progesterone. As such, drospirenone can counteract estrogen-induced stimulation of the renin-angiotensin-aldosterone system that can lead to sodium and water retention and symptoms such as breast tenderness and edema. Clinical studies with the COC formulated with 30 μg ethinylestradiol and 3 mg drospirenone (Yasmin®) have shown it to have reliable contraceptive effects and a good safety profile, as well as the ability to reduce water retention-related symptoms [5], [6], [7]. The 3-mg dose of drospirenone has been shown to be equivalent to 25 mg of spironolactone. Other benefits include improved acne and other skin-related problems, which are in part related to the antiandrogenic activity of drospirenone [7], [8].
A new contraceptive formulation based on drospirenone has been developed that contains 20 μg of ethinylestradiol and 3 mg drospirenone. One treatment cycle consists of once daily oral treatment for 24 days followed by 4 hormone-free days. An extended contraceptive regimen and a shortened hormone-free interval may reduce the incidence of hormone withdrawal symptoms, such as pelvic pain, headaches, bloating and breast tenderness, which are more commonly reported by women during the 7-day hormone-free interval than during the active treatment period [9], [10]. Furthermore, reducing the number of hormone-free days has been shown to result in more pronounced ovarian suppression [11], which is expected to increase contraceptive effectiveness.
The aim of this study was to determine the efficacy, safety and bleeding profile of this new low-dose, monophasic COC containing 20 μg ethinylestradiol and 3 mg drospirenone administered once daily for 24 consecutive days followed by a 4-day hormone-free interval.
Section snippets
Study design
This was an open-label, noncomparative, multicenter study conducted at 35 centers in Austria, Argentina, Brazil, Poland and the United States. The study was approved by the appropriate ethics committees or institutional review boards of the participating study sites and was conducted in accordance with the Declaration of Helsinki (as revised in 1996) and the International Conference on Harmonization-Good Clinical Practice guidelines. All study participants gave written and informed consent
Subject disposition
A total of 1049 women were recruited to the study, of whom 22 (2.1%) did not start treatment or did not have a study observation. As such, 1027 formed the full analysis set. In total, 303 (28.9%) women discontinued the study prematurely for reasons that included: 77 (7.5%) women for adverse events (including 1 woman who became pregnant during the study, but for whom the reason for discontinuation was reported as vomiting at the time of withdrawal); 48 (4.6%) women lost to follow-up; 34 (3.2%)
Discussion
Results of this study show that the COC formulation of 20 μg ethinylestradiol plus 3 mg drospirenone administered once daily for 24 days followed by a 4-day hormone-free interval provides highly effective contraception with acceptable bleeding profile, and is well tolerated. Eleven pregnancies occurred during 11,140 cycles of treatment, resulting in a Pearl Index of 1.29 (upper limit of the 95% CI, 2.30); of these pregnancies, 5 were considered to be due to method failure, giving an adjusted
Acknowledgements
We acknowledge all the other study investigators for their clinical contribution to the study: Drs. W. Bartl, G. Bartl, M. Boeckl, G. Heytmanek, J. Hosmann, H. Kahr, R. Lassmann, P. Mayr, W. Neunteufel, B. Pötsch, A. Rogan, W. Sacher, S. Schmidl-Amann, M. Stiglbauer, and Profs. J. Huber, D. Gruber, A. Staudach (Austria); Drs. D. Bellmann, C. Gurucharri, J. Morozovsky, G. Orrico, C. Sala, R. Tozzini and Profs. A. Alfonsin, A. Badano (Argentina); Profs. M. Diógenes Yazlle, E. Chada Baracat, A.
References (26)
- et al.
Oral contraceptive discontinuationa prospective evaluation of frequency and reasons
Am J Obstet Gynecol
(1998) Drospirenonepharmacology and pharmacokinetics of a unique progestogen
Contraception
(2000)- et al.
An open-label, multicenter study to evaluate Yasmin, a low-dose combination oral contraceptive containing drospirenone, a new progestogen
Contraception
(2000) - et al.
Hormone withdrawal symptoms in oral contraceptive users
Obstet Gynecol
(2000) - et al.
Acceptance of altering the standard 21-day/7-day oral contraceptive regimen to delay menses and reduce hormone withdrawal symptoms
Am J Obstet Gynecol
(2002) - et al.
Shorter pill-free interval in combined oral contraceptives decreases follicular development
Contraception
(1996) - et al.
The analysis of vaginal bleeding patterns induced by fertility regulating methods. World Health Organization Special Programme of Research, Development and Research Training in Human Reproduction
Contraception
(1986) - et al.
The analysis of menstrual bleeding patternsa review
Contraception
(1988) - et al.
Comparison of efficacy, cycle control, and tolerability of two low-dose oral contraceptives in a multicenter clinical study
Contraception
(1999) - et al.
A multicenter, randomized study of an extended cycle oral contraceptive
Contraception
(2003)
A new low-dose monophasic combination oral contraceptive (Alesse) with levonorgestrel 100 micrograms and ethinyl estradiol 20 micrograms. North American Levonorgestrel Study Group (NALSG)
Contraception
A twelve-month comparative clinical investigation of two low-dose oral contraceptives containing 20 μg ethinylestradiol/75 μg gestodene and 30 μg ethinylestradiol/75 μg gestodene, with respect to efficacy, cycle control and tolerance
Contraception
Contraceptive efficacy
Cited by (112)
The benefits of estetrol addition to drospirenone for contraception
2023, AJOG Global ReportsRationale for eliminating the hormone-free interval in modern oral contraceptives
2016, International Journal of Gynecology and ObstetricsMotherisk Rounds. The Effectiveness of Folate-Fortified Oral Contraceptives in Maintaining Optimal Folate Levels to Protect Against Neural Tube Defects: A Systematic Review.
2015, Journal of Obstetrics and Gynaecology Canada