Long-term tolerability of ethinylestradiol 20 μg/drospirenone 3 mg in a flexible extended regimen: results from a randomised, controlled, multicentre 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: This study was designed to assess the long-term safety and tolerability of a new flexible extended regimen of ethinylestradiol (EE) 20 μg/drospirenone (DRSP) 3 mg, which allows management of intracyclic (breakthrough) bleeding [flexible management of intracyclic (breakthrough) bleeding (MIB)], in comparison to conventional 28-day and fixed extended regimens.

Study design: In this Phase III, multicentre, open-label study, women (aged 18-35 years) were randomised to EE/DRSP in the following regimens: flexible(MIB) (24-120 days' active hormonal intake followed by a 4-day tablet-free interval), conventional 28-day (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) during a 1-year comparative phase. Thereafter, women entered a 1-year safety extension phase in which the majority received the flexible(MIB) regimen. Safety/tolerability outcomes were measured over 2 years. A separate analysis of certain safety parameters (endometrial, hormonal, lipid, haemostatic and metabolic variables) was conducted at two of the study centres.

Results: Results were analysed in 1067 and 783 women in the comparative and safety extension phases. Overall, 56.3% of women experienced ≥1 adverse event (AE) in the safety extension phase. Serious AEs occurred in 3.0%, 1.4% and 3.3% of women receiving the flexible(MIB), conventional and fixed extended regimens, respectively. No unexpected endometrial, hormonal, lipid, haemostatic or metabolic findings occurred with any of the three regimens.

Conclusions: EE/DRSP in a flexible extended regimen with management of intracyclic (breakthrough) bleeding is well-tolerated and, when administered for up to 2 years, has a good safety profile comparable to other estrogen/progestogen oral contraceptives.

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
Overview of subgroup analyses undertaken during the 1-year comparative treatment phase and the 1-year safety extension phase. MIB, management of intracyclic (breakthrough) bleeding.
Figure 2
Figure 2
Disposition of women through the 1-year comparative phase and the 1-year safety extension phase. MIB, management of intracyclic (breakthrough) bleeding. *Additional information on the disposition of women through the comparative phase of the study is published separately.5 **All women who entered the safety extension phase received ethinylestradiol 20 µg/drospirenone 3 mg in the flexibleMIB regimen with the exception of 28 women participating in the bone mineral density analysis. Such women continued to receive either the conventional or the fixed extended, as shown in the figure.

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