Pooled analysis of two phase 3 trials evaluating the effects of a novel combined oral contraceptive containing estetrol/drospirenone on bleeding patterns in healthy women
“…E4-DRSP users experience predictable bleeding episodes with a high stable rate of scheduled bleeding (89% in cycle 2, 90% in cycle 12) and a decreasing rate of unscheduled bleeding (21% in cycle 2 to ≤18% from cycle 5 onwards) ( Figures 1 and 2 ; Table 2 ); 67% of unscheduled bleeding or spotting episodes included only spotting, 27% included mixed bleeding and spotting, and 6% included only bleeding with a duration of bleeding or spotting of 3 to 4 days. 64 Most frequently (>2%) reported treatment-related AEs during E4-DRSP use were bleeding complaints, breast pain or tenderness, acne, mood disturbance, headache, dysmenorrhea, and increased weight. 56 Discontinuation rates owing to AEs were 10% overall and 3% for AEs specifically related to bleeding in both trials.…”
Section: Summary Of the 2 New Contraceptive Productsmentioning
confidence: 97%
“… a FDA criteria for Pearl Index: at risk cycles are defined as cycles with no back-up contraception and confirmed vaginal intercourse; pregnancies within 7 days after last use are considered on treatment. EMA criteria for Pearl Index: at risk cycles are defined as cycles with no back-up contraception; pregnancies within 2 days after last use are considered on treatment; Figure 1 Bleeding with 15mgE4/3mgDRSP, 20μgEE/3mgDRSP and 4mgDRSP E4-DRSP data from Kaunitz et al's 64 Contraception 2022, EE-DRSP data from the US Food and Drug (FDA) assessment report YAZ 2006 52 and DRSP alone data from the FDA assessment report SLYND. 51 DRSP , drospirenone; E4 , estetrol; EE , ethinylestradiol.…”
Section: Summary Of the 2 New Contraceptive Productsmentioning
confidence: 99%
“… E4-DRSP data from Kaunitz et al's 64 Contraception 2022, EE-DRSP data from the US Food and Drug (FDA) assessment report YAZ 2006 52 and DRSP alone data from the FDA assessment report SLYND. 51 …”
Section: Summary Of the 2 New Contraceptive Productsmentioning
“…E4-DRSP users experience predictable bleeding episodes with a high stable rate of scheduled bleeding (89% in cycle 2, 90% in cycle 12) and a decreasing rate of unscheduled bleeding (21% in cycle 2 to ≤18% from cycle 5 onwards) ( Figures 1 and 2 ; Table 2 ); 67% of unscheduled bleeding or spotting episodes included only spotting, 27% included mixed bleeding and spotting, and 6% included only bleeding with a duration of bleeding or spotting of 3 to 4 days. 64 Most frequently (>2%) reported treatment-related AEs during E4-DRSP use were bleeding complaints, breast pain or tenderness, acne, mood disturbance, headache, dysmenorrhea, and increased weight. 56 Discontinuation rates owing to AEs were 10% overall and 3% for AEs specifically related to bleeding in both trials.…”
Section: Summary Of the 2 New Contraceptive Productsmentioning
confidence: 97%
“… a FDA criteria for Pearl Index: at risk cycles are defined as cycles with no back-up contraception and confirmed vaginal intercourse; pregnancies within 7 days after last use are considered on treatment. EMA criteria for Pearl Index: at risk cycles are defined as cycles with no back-up contraception; pregnancies within 2 days after last use are considered on treatment; Figure 1 Bleeding with 15mgE4/3mgDRSP, 20μgEE/3mgDRSP and 4mgDRSP E4-DRSP data from Kaunitz et al's 64 Contraception 2022, EE-DRSP data from the US Food and Drug (FDA) assessment report YAZ 2006 52 and DRSP alone data from the FDA assessment report SLYND. 51 DRSP , drospirenone; E4 , estetrol; EE , ethinylestradiol.…”
Section: Summary Of the 2 New Contraceptive Productsmentioning
confidence: 99%
“… E4-DRSP data from Kaunitz et al's 64 Contraception 2022, EE-DRSP data from the US Food and Drug (FDA) assessment report YAZ 2006 52 and DRSP alone data from the FDA assessment report SLYND. 51 …”
Section: Summary Of the 2 New Contraceptive Productsmentioning
“…A regular and predictable bleeding profile is an important factor influencing COC choice, acceptability and adherence. Bleeding data from different clinical trials highlight the favorable and highly predictable bleeding pattern with limited unscheduled bleeding/spotting for the combination of E4/DRSP [38,39,48,49]. A pooled analysis of two phase III trials including bleeding data from over 3400 participants showed that the use of the E4 15mg/DRSP 3mg COC in a 24/4-day treatment regimen is associated with a regular and predictable bleeding pattern [48].…”
Section: Effects Of E4 On Uterovaginal Tissuesmentioning
Estetrol (E4) is the most recently described natural estrogen. It is produced by the human fetal liver during pregnancy and its physiological function remains unclear. E4 is the estrogenic component of a recently approved combined oral contraceptive. It is also in development for use as menopausal hormone therapy. In the context of these developments, the pharmacological activity of E4, alone or in combination with a progestin, has been extensively characterized in preclinical models as well as in clinical studies in women of reproductive age and postmenopausal women. Despite the clinical benefits, the use of oral estrogens for contraception or menopause is also associated with unwanted effects, such as an increased risk of breast cancer and thromboembolic events, due to their impact on non-target tissues. Preclinical and clinical data for E4 point to a tissue-specific activity and a more selective pharmacological profile compared with other estrogens, including a low impact on the liver and hemostasis balance. This review summarizes the characterization of the pharmacological properties of E4 as well as recent advances made in the understanding of the molecular mechanisms of action driving its activity. How the unique mode of action and the different metabolism of E4 might support its favorable benefit–risk ratio is also discussed.
“…E4 does not stimulate the synthesis of coagulation factors by the liver, nor does it mitigate natural anticoagulants, suggesting a limited impact on venous thromboembolic risk for women taking E4 compared with women taking E2and EE-containing combined oral contraception (COC) [28,29]. The European Medicines Agency and the Food and Drug Administration have approved the use of E4 combined with DRSP as a new generation of COC [26,27,[30][31][32][33][34][35][36].…”
Estetrol (E4) is a natural estrogen with promising therapeutic applications in humans. The European Medicines Agency and the Food and Drug Administration have approved the use of 15 mg E4/3 mg drospirenone for contraceptive indication. Phase III clinical trials with 15–20 mg E4 for the relief of climacteric complaints are currently running. Relevant data from preclinical animal models are needed to characterize the molecular mechanisms and the pharmacological effects of E4 and possibly to reveal new therapeutic applications and to anticipate potential adverse effects. Therefore, it is important to design experimental procedures in rodents that closely mimic or anticipate human E4 exposure. In this study, we compared the effects of E4 exposure after acute or chronic administration in women and mice. Women who received chronic E4 treatment per os at a dose of 15 mg once daily reached a steady state within 6 to 8 days, with a mean plasma concentration of 3.20 ng/mL. Importantly, with subcutaneous, intraperitoneal or oral administration of E4 in mice, a stable concentration over time that would mimic human pharmacokinetics could not be achieved. The use of osmotic minipumps continuously releasing E4 for several weeks provided an exposure profile mimicking chronic oral administration in women. Measurements of the circulating concentration of E4 in mice revealed that the mouse equivalent dose necessary to mimic human treatment does not fit with the allometric prediction. In conclusion, this study highlights the importance of precise definition of the most appropriate dose and route of administration to utilize when developing predictive preclinical animal models to mimic or anticipate specific human treatment.
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