Maintenance of ovulation inhibition with a new progestogen-only pill containing drospirenone after scheduled 24-h delays in pill intake

Abstract

Objectives

Traditional progestogen-only pills (POPs) have stringent daily timing and missed pill rules that might affect contraceptive reliability. A new-generation oestrogen-free pill has been developed, containing 4-mg drospirenone with a unique regimen of 24 active treatment days followed by four placebo tablets. A previous study showed that this new drospirenone-only pill effectively inhibited ovulation. Clinical efficacy, however, can be affected by compliance, and delayed or forgotten pill intake often occurs in daily life. The aim of this study was to investigate if inhibition of ovulation was maintained after four scheduled 24-h delays in tablet intake.

Study design

One hundred thirty healthy women with proven ovulatory cycles were randomized, and 127 were treated with the drospirenone-only pill during two cycles. In treatment Group A (n = 62), 24-h delays in tablet intake were scheduled on days 3, 6, 11 and 22 during Cycle 2 and, in treatment Group B (n = 65) during Cycle 1, respectively. Ovulation was defined as disappearance or persistence of a large follicle and progesterone levels higher than 5 ng/mL for at least 5 consecutive days.

Results

The overall ovulation rate was 0.8%; only one subject in Group A fulfilled the ovulation criteria in Cycle 2. Follicular diameters in the regular-intake and the delayed-intake cycles were similar.

Conclusion

Despite the 4-day hormone-free period and multiple intentional 24-h delays in tablet intake, ovulation inhibition was maintained. This property distinguishes this new-generation oestrogen-free pill from traditional POPs by allowing the same “safety window” or flexibility in intake as combined oral contraceptives without compromising contraceptive reliability.

Implications

Delayed or forgotten pill intake is very common. Ovulation inhibition by the new-generation oestrogen-free pill, containing 4-mg drospirenone for 24 days followed by a 4-day treatment-free period, was maintained despite four 24-h delays in tablet intake, so the impact of delayed intake on contraceptive reliability will be low.

Introduction

The World Health Organization has acknowledged that users of progestogen-only pills (POPs) have little or no increased risk of stroke, myocardial infarction or venous thromboembolism [1], [2], [3], [4]. For this reason, more and more physicians prefer to prescribe POPs instead of combined contraceptive preparations. Furthermore, an increasing number of women are overweight and have risks factors for cardiovascular diseases. These women have contraindications for the use of combined hormonal contraceptives but could be offered a POP. Notably, the WHO Medical Eligibility Criteria for POPs do not include any restriction for use of POP in obese women [1].

Traditional POPs inhibit ovulation in only 60–70% of users, so the efficacy of these POPs is dependent on the other mechanisms of action, that is, the effects on cervical mucus penetrability, endometrial receptivity and ciliary activity in the fallopian tubes [5], [6], [7]. The effect on cervical mucus penetrability is short-lasting and greatly diminished by 24 h after tablet intake [5]. Therefore, tablet intake instructions of traditional POPs allow for a delay of maximally 3 h, recommending additional contraceptive measures if the intake delay exceeds 3 h, whereas for combined pills the allowed intake delay is 12 or 24 h. Adhering to such a strict intake regimen requires a high level of discipline of the users, and it is very likely that delays of more than 3 h occur frequently, reducing the contraceptive reliability.

For a more recent POP containing 75-mcg desogestrel (Cerazette®), it has been shown that ovulation inhibition is maintained after three 12-h delays in tablet intake, allowing for more flexibility in the intake regimen [8].

A new-generation oestrogen-free pill has been developed, containing 4-mg drospirenone in a regimen of 24 active treatment days followed by 4 days of placebo treatment. Drospirenone is a progestogen derived from spironolactone, with antimineralocorticoid and antiandrogenic properties [9]. A previous study showed that the drospirenone-only pill effectively inhibited ovulation despite the 4-day treatment-free period [10]. Return of ovulation after stopping treatment occurred at the earliest on day 13 after the last active drospirenone tablet, indicating very efficient ovarian suppression. In this previous study, tablets were taken every 24 h with an allowed variation of maximally 3 h. Because ovarian suppression appeared to be very efficient, it was expected that the same flexibility in tablet intake would be allowed for the drospirenone-only pill as for combined pills, without compromising contraceptive efficacy.

The aim of the present study was accordingly to investigate if ovulation inhibition with the drospirenone-only pill taken for 24 days followed by 4 days of placebo treatment was maintained after four scheduled 24-h delays in tablet intake. The effects of scheduled intake delays in the first and in the second treatment cycle, after a treatment-free period, were compared.