Vagifem 10 mcg

A 12-month double-blind, randomized, parallel group, placebo-controlled multicenter study was conducted in the U.S. and Canada to evaluate the efficacy and safety of Vagifem 10 mcg in the treatment of atrophic vaginitis in 309 postmenopausal women between 46 and 81 years of age (mean age = 57.6 years) who at baseline identified their most bothersome symptom of atrophic vaginitis from among six symptoms (vaginal dryness, vaginal and/or vulvar irritation/itching, vaginal soreness, dysuria, dyspareunia and vaginal bleeding associated with intercourse). Women inserted one tablet intravaginally each day for 14 days, then one tablet twice weekly for the remaining 50 weeks. The majority (92.9%) of the women were Caucasian (n=287), 3.2% were Black (n=10), 1.6% were Asian (n=5) and 2.2% were Other (n=7). All subjects were assessed for improvement in the mean change from baseline to Week 12 for co-primary efficacy variables of: a composite of most bothersome symptoms of atrophic vaginitis; percentage of vaginal superficial cells and percentage of vaginal parabasal cells on a vaginal smear; and vaginal pH.

Relief of Vaginal Symptoms

Vagifem 10 mcg was statistically superior to placebo in reducing the severity of a composite score of most bothersome symptoms associated with atrophic vaginitis at Week 12 (see Table 5).

Also demonstrated for Vagifem 10 mcg compared to placebo was a statistically significant increase in the percentage of superficial cells at Week 12 (13.2 percent compared to 3.8 percent for matching placebo, p<0.001), a statistically significant decrease in parabasal cells at Week 12 (-37.0 percent compared to -9.3 percent for matching placebo, p<0.001), and a statistically significant mean reduction between baseline and Week 12 in vaginal pH score (-1.3 compared to -0.4 for matching placebo, p<0.001).

Endometrial safety was assessed by endometrial biopsy at the screening and final study visit. Of the 172 subjects in the Vagifem 10 mcg group who had a biopsy performed at end of study, 92 subjects had endometrial tissue that was atrophic or inactive and 73 subjects had no tissue or tissue insufficient for diagnosis. There was one case of adenocarcinoma grade 2 and one case of complex hyperplasia without atypia. Three subjects exhibited polyps (two atrophic polyps and one adenomyomatus type polyp) and two others had adenomyosis and an atypical epithelial proliferation.

Endometrial safety of Vagifem 10 mcg was additionally evaluated in a second, 12 month, open-label, multicenter safety study. Of the 297 subjects who had a biopsy performed at end of study, 183 subjects had endometrial tissue that was atrophic or inactive and 111 subjects had no tissue or tissue insufficient for diagnosis. There was one case of complex hyperplasia without atypia. Two subjects exhibited polyps.

Vagifem 25 mcg

A placebo-controlled comparison study was done in the U.S., in which 230 women were randomized to receive either placebo, Vagifem 25 mcg or 10 mcg estradiol vaginal tablets. Women inserted one tablet intravaginally each day for 14 days, then one tablet twice weekly for the remaining 10 weeks. All subjects were assessed for vaginal symptoms. Vagifem 25 mcg was superior to placebo in reducing the severity of a composite score of symptoms associated with atrophic vaginitis (see Table 6).

An open-label, controlled comparison study was done in Canada in which 159 women were randomized to receive either Vagifem 25 mcg or a comparator drug. Two (2) grams of the comparator drug was given daily for 3 weeks, withheld for 1 week, then repeated cyclically (3 weeks on, 1 week off) for up to 24 weeks; Vagifem 25 mcg was administered daily for 2 weeks, then twice weekly for the remaining 22 weeks. In this study, subjects were assessed for relief of symptoms. Vagifem 25 mcg was equally effective as the approved comparator product at the 2.0 gm dose in the relief of symptoms.

In the placebo-controlled study endometrial biopsies in non-hysterectomized women at week 12 were performed on 86 subjects (Vagifem 25 mcg: 32 subjects, estradiol 10 mcg: 33 subjects, Placebo: 21 subjects). Of these, 3 subjects each from the Vagifem 25 mcg and placebo groups and 8 from the 10 mcg estradiol group had insufficient tissue samples. Among those with biopsies that yielded sufficient tissue, results were normal with the exception of one subject in the Vagifem 25 mcg group, who had a simple hyperplasia without atypia. 

In the open-label study comparing Vagifem 25 mcg with a comparator vaginal cream on 49 women in each treatment group, endometrial biopsies were obtained at the screening visit and at the end of treatment. At the end of the study (Week 24), all subjects in the Vagifem treatment group whose biopsies yielded sufficient tissue showed an atrophic endometrium with the exception of one subject who had a proliferative endometrium.