Bioequivalence of a Fixed-Dose Combination of Relugolix, Estradiol, and Norethindrone Acetate: An Open-Label, Randomized, Fully Replicate Crossover Study in Healthy Postmenopausal Women Under Fasting Conditions

Abstract

Uterine fibroids are the most common benign gynecological tumors, often causing heavy menstrual bleeding (HMB), anemia, and impaired quality of life. A fixed-dose combination (FDC) of relugolix (40 mg), estradiol (1 mg), and norethindrone acetate (0.5 mg) was developed to address these limitations. This open-label, randomized, two-treatment, two-sequence, four-period, crossover bioequivalence study was conducted in 48 healthy postmenopausal women under fasting conditions. Participants received a single oral dose of either the RELUEASE (Sun Pharmaceutical Industries Limited, India) or the reference product (MYFEMBREE) (Patheon Inc., Mississauga, Ontario), with a 21-day washout. Pharmacokinetics parameters were derived using non-compartmental analysis. Bioequivalence assessment was performed using a linear mixed-effects model applied to ln-transformed pharmacokinetic parameters. A total of 39 participants completed all study periods. The point estimates and 90% confidence intervals (CIs), or the 95% upper bound for the pharmacokinetic parameters (C_max and AUC) of relugolix, estradiol, norethindrone, and estrone met the predefined bioequivalence acceptance criteria. Six adverse events were reported, all mild, transient in nature, and resolving without sequelae. No clinically significant safety concerns were observed during the study. The relugolix/estradiol/norethindrone acetate FDC demonstrated bioequivalence to the globally approved reference product (MYFEMBREE) with comparable tolerability. This provides a safe, effective, reversible non-surgical therapy for fibroid-related HMB, fulfilling an unmet need beyond surgery.