University of Oulu

Chen, M. J., Jensen, J. T., Kaunitz, A. M., Achilles, S. L., Zatik, J., Weyers, S., Piltonen, T., Suturina, L., Apolikhina, I., Bouchard, C., Archer, D. F., Jost, M., Foidart, J.-M., & Creinin, M. (2022). Tolerability and safety of the estetrol/drospirenone combined oral contraceptive: Pooled analysis of two multicenter, open-label phase 3 trials. Contraception, 116, 44–50.

Tolerability and safety of the estetrol/drospirenone combined oral contraceptive : pooled analysis of two multicenter, open-label phase 3 trials

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Author: Chen, Melissa J.1; Jensen, Jeffrey T.2; Kaunitz, Andrew M.3;
Organizations: 1Department of Obstetrics and Gynecology, University of California, Davis, Sacramento, California, USA
2Department of Obstetrics and Gynecology, Oregon Health and Science University, Portland, Oregon, USA
3Department of Obstetrics and Gynecology, University of Florida College of Medicine, Jacksonville, Jacksonville, Florida, USA
4Department of Obstetrics, Gynecology, and Reproductive Sciences, University of Pittsburgh and Magee-Womens Research Institute, Pittsburgh, Pennsylvania, USA
5Gynecological Praxis St. Anna, Debrecen, Hungary
6Department of Obstetrics and Gynecology, University Hospital, Gent, Belgium
7Department of Obstetrics and Gynecology, PEDEGO Research Unit, Medical Research Center, Oulu University Hospital, University of Oulu, Oulu, Finland
8Scientific Centre for Family Health and Human Reproduction Problems, Irkutsk, Russia
9National Medical Research Center for Obstetrics, Gynecology and Perinatology named after Academician V.I. Kulakov, Ministry of Healthcare of the Russia, Moscow, Russia
10Clinique de Recherche en Santé de la Femme (RSF), Québec, Canada
11Department of Obstetrics and Gynecology, Eastern Virginia Medical School, Norfolk, Virginia, USA
12Estetra SRL, an affiliate company of Mithra Pharmaceuticals, Liège, Belgium
13Department of Obstetrics and Gynecology, University of Liège, Liège, Belgium
Format: article
Version: published version
Access: open
Online Access: PDF Full Text (PDF, 0.9 MB)
Persistent link:
Language: English
Published: Elsevier, 2022
Publish Date: 2023-05-24


Objectives: To evaluate tolerability and safety of estetrol (E4) 15 mg/drospirenone (DRSP) 3 mg oral contraceptive using pooled data from two, multicenter, phase 3 trials.

Study design: The two trials enrolled participants aged 16−50 years with a body mass index ≤35.0 kg/m² to use E4/DRSP in a 24/4-day regimen for up to 13 cycles. We pooled data from participants who used at least one E4/DRSP dose and had a follow-up assessment to analyze adverse events (AEs), vital signs, and laboratory parameters, including serum lipids, glucose, glycated hemoglobin, and potassium. We consolidated similar Medical Dictionary for Regulatory Activities preferred terms into groupings.

Results: Of 3725 participants enrolled, we included 3417 in the analyses of whom 1786 (52.3%) reported ≥1 AE. Most participants with reported AEs had AEs that investigators rated as mild or moderate (n = 1665, 93.2%); of participants reporting AEs, 1105 (61.9%) did so during cycles 1 to 3. In total, 981 (28.7%) participants experienced ≥1 treatment-related AE, most frequently related to bleeding complaints (n = 323, 9.5%), breast pain or tenderness (n = 136, 4.0%), acne (n = 113, 3.3%), and mood disturbance (n = 111, 3.2%). Discontinuation due to treatment-related AEs occurred in 272 participants (8.0%), with only bleeding complaints (n = 97, 2.8%) and mood disturbance (n = 38, 1.1%) at rates exceeding 1%. Three participants experienced serious AEs, which the site investigators considered treatment-related: one venous thromboembolism, one worsening of depression, and one ectopic pregnancy. We found no clinically relevant changes in weight, blood pressure, heart rate, or laboratory parameters during treatment.

Conclusions: E4/DRSP is associated with a favorable tolerability and safety profile.

Implications statement: Pooling data allowed for a robust assessment of tolerability and safety, including relatively infrequent events. Other than bleeding complaints and mood disturbance, no adverse event resulted in E4/DRSP discontinuation at rates >1%. Post-marketing surveillance studies are needed to evaluate long-term safety of the E4/DRSP COC and population-based venous thromboembolism risks.

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Series: Contraception
ISSN: 0010-7824
ISSN-E: 1879-0518
ISSN-L: 0010-7824
Volume: 116
Pages: 44 - 50
DOI: 10.1016/j.contraception.2022.10.004
Type of Publication: A1 Journal article – refereed
Field of Science: 3123 Gynaecology and paediatrics
Funding: Estetra SRL (an affiliate company of Mithra Pharmaceuticals) funded this study.
Copyright information: © 2022 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY license (