Comparison of the efficacy and endometrial safety of two estradiol valerate/dienogest combinations and Kliogest for continuous combined hormone replacement therapy in postmenopausal women.

OBJECTIVE: To compare the efficacy and endometrial safety of two estradiol valerate/dienogest combinations with Kliogest in the treatment of postmenopausal symptoms. DESIGN: This was a double-blind, randomized, multicenter study. METHODS: Patients were randomized to estradiol valerate 2.0 mg/dienogest 2.0 mg (Climodien), estradiol valerate 2.0 mg/dienogest 3.0 mg (E2Val 2/DNG 3); or estradiol 2.0 mg/estriol 1.0 mg/norethisterone acetate 1.0 mg (Kliogest) once daily for 1 year. The primary efficacy variable was the Kupperman index. Endometrial safety was determined primarily by biopsy. RESULTS AND CONCLUSIONS: Climodien and E2Val 2/DNG 3 were therapeutically equivalent to Kliogest (mean changes in Kupperman index -20.1, -19.0 and -18.3, respectively). No statistically significant differences existed between treatment groups in the severity of postmenopausal symptoms. The incidences of endometrial atrophy were similar in all groups. Climodien appeared to be superior to Kliogest in terms of vaginal bleeding pattern, whereas E2Val 2/DNG 3 was associated with a slightly higher incidence and greater intensity of vaginal bleeding. The incidences of adverse events were similar in all groups. A greater proportion of women in the Kliogest and E2Val 2/DNG 3 groups experienced vaginal bleeding, whereas breast problems were more common with Climodien. Climodien and E2Val 2/DNG 3 induced desirable changes in insulin-like growth factor I (decrease) and sex hormone binding globulin (increase) that were not seen with Kliogest.

Pharmacokinetics of orally administered estradiol valerate. Results of a single-dose cross-over bioequivalence study in postmenopausal women.

A randomized, single-dose cross-over study in 32 postmenopausal women was performed to demonstrate bioequivalence of two estradiol valerate containing formulations (first sequence of Klimonorm as test preparation). The serum levels of estradiol, free and conjugated estrone were measured until 48 h after an oral dosage of 4 mg estradiol valerate (CAS 979-32-8). The mean AUC(0-48) of estradiol was calculated as 1006.6 +/- 479.4 h x pg x ml-1 (Test) and 1015.2 +/- 555.2 h x pg x ml-1 (Reference). The corresponding (AUC(0-48) of the active metabolite, free estrone, exceeded that of estradiol at 3578.3 h x pg x ml-1 (Test) and 3485.1 h x pg x ml-1 (Reference). Much higher was the AUC(0-48) for conjugated estrone at 132.4 h x ng x ml-1 (Test) and 133.6 h x ng x ml-1 (Reference). Mean estradiol Cmax values of 39.8 +/- 17.7 pg/ml (Test) and 42.9 +/- 21.0 pg/ml (Reference) were attained 8.2 +/- 4.5 h (Test) and 10.0 +/- 5.9 h (Reference) after the administration of 4 mg estradiol valerate. Maximal free estrone concentrations of 163 pg/ml (Test) and 174.3 pg/ml (Reference) were reached after 7.2 h (Test) and 7.5 h (Reference). Maximal conjugated estrone concentrations of 15.5 ng/ml (Test) and 16.2 ng/ml (Reference) were reached after 2.4 h (Test) and 2.0 h (Reference). The terminal elimination half-life of estradiol was calculated at 16.9 +/- 6.0 h (Test) and 15.0 +/- 4.8 h (Reference), that of free estrone at 16.3 h (Test) and 13.5 h (Reference), that of conjugated estrone at 11.8 h (Test) and 10.6 h (Reference). After logarithmic transformation, the 90% confidence intervals of the AUC(0-48) and Cmax ratios for estradiol and also for the metabolites (free and conjugated estrone) were within the acceptance ranges for bioequivalence. Therefore the test preparation and the reference preparation are bioequivalent.