Ultra-low-dose continuous combined estradiol and dydrogesterone in postmenopausal women: A pooled safety and tolerability analysis.

Objective: To assess the safety and tolerability of ultra-low dose estradiol and dydrogesterone (E0.5 mg/D2.5 mg) among postmenopausal women. Methods: This pooled analysis of data from three clinical studies assessed the effects of continuous combined ultra-low-dose estradiol and dydrogesterone among postmenopausal women. Participants received E0.5 mg/D2.5 mg or placebo for 13 weeks (double-blind, randomized, European study), E0.5 mg/D2.5 mg or placebo for 12 weeks (double-blind, randomized, Chinese study), or E0.5 mg/D2.5 mg for 52 weeks (open-label, European study). Safety outcomes included treatment-emergent adverse events (TEAEs), treatment-emergent serious adverse events (TESAEs), treatment discontinuation due to a TEAE, and adverse events of special interest (AESIs). Results: Overall, 1027 women were included in the pooled analysis (E0.5 mg/D2.5 mg, n = 736; placebo, n = 291). Mean treatment exposure was 288.9 days in the E0.5 mg/D2.5 mg group and 86.6 days in the placebo group. The proportion of women experiencing ≥1 TEAE was similar in the E0.5 mg/D2.5 mg and placebo groups (50.1% vs 49.5%, respectively). TESAEs occurred in 12 (1.6%) women receiving E0.5 mg/D2.5 mg and 9 (3.1%) women receiving placebo. Discontinuation of study treatment was infrequent in both groups (E0.5 mg/D2.5 mg: 1.5%; placebo: 2.4%). The occurrence of breast pain was more common in the E0.5 mg/D2.5 mg group than in the placebo group (2.0% vs 0.3%) as was uterine hemorrhage (6.5% vs 2.4%). The incidence of acne, hypertrichoses and weight increased was similar between groups. Conclusions: Across three studies, ultra-low-dose estradiol plus dydrogesterone was well tolerated among postmenopausal women, with no increase in TEAEs or TESAEs compared with placebo.