Fyavolv (Page 6 of 10)

13 NONCLINICAL TOXICOLOGY

13.3 Carcinogenesis, Mutagenesis, Impairment of Fertility

Long-term continuous administration of natural and synthetic estrogens in certain animal species increases the frequency of carcinomas of the breast, uterus, cervix, vagina, testis, and liver.

14 CLINICAL STUDIES

14.1 Effects on Vasomotor Symptoms

A 12-week placebo-controlled, multicenter, randomized clinical trial was conducted in 266 symptomatic women who had at least 56 moderate to severe hot flushes during the week prior to randomization. On average, patients had 12 hot flushes per day upon study entry.

A total of 66 women were randomized to receive norethindrone acetate and ethinyl estradiol 1/5 and 66 women were randomized to the placebo group. Norethindrone acetate and ethinyl estradiol 1/5 was shown to be statistically better than placebo at weeks 4 and 12 for relief of the frequency of moderate to severe vasomotor symptoms (see Table 3). In Table 4, norethindrone acetate and ethinyl estradiol 1/5 was shown to be statistically better than placebo at weeks 4 and 12 for relief of the severity of moderate to severe vasomotor symptoms.

Table 3. Mean Change from Baseline in the Number of Moderate to Severe Vasomotor Symptoms per Week -ITT Population, LOCF

* Denotes statistical significance at the 0.05 level

[1] The baseline number of moderate to severe vasomotor symptoms (MSVS) is the weekly average number of MSVS during the two week pre-randomization observation period.

[2] ANCOVA -Analysis of Covariance model where the observation variable is change from baseline; independent variables include treatment, center and baseline as covariate. The 95 percent CI -Mann-Whitney confidence interval for the difference between means (not stratified by center).

ITT = intent to treat; LOCF = last observation carried forward; CI = confidence interval 2 randomized subjects (1 in Placebo and 1 in norethindrone acetate and ethinyl estradiol) did not return diaries.

Visit Placebo ( N = 66 ) Norethindrone Acetate and Ethinyl Estradiol 0 . 5 / 2 . 5 ( N = 67 ) Norethindrone Acetate and Ethinyl Estradiol 1 / 5 ( N = 66 )
Baseline [ 1 ] Mean (SD) 76.5 (21.4)77.6 (26.5)70.0 (16.6)
Week 4 Mean (SD) Mean Change from Baseline (SD) p-Value vs. Placebo (95 percent CI) [2] 39.4 (27.6) -37.0 (26.6) 30.2 (26.1) -47.4* (26.1) 0.041 (-20.0, -1.0) 20.4 (22.7) -49.6* (22.1) <0.001 (-22.0,-6.0)
Week 12 Mean (SD) Mean Change from Baseline (SD) 31.1 (27.0) -45.3 (30.2) 13.8 (20.4) -63.8* (27.5) 11.3 (18.9) -58.7* (23.1)
p-Value vs. Placebo(95 percent CI) [2] <0.001 (-27.0, -7.0)<0.001 (-25.0, -5.0)
Table 4. Mean Change from Baseline in the Daily Severity Score of Moderate to Severe Vasomotor Symptoms per Week -ITT Population, LOCF

* Denotes statistical significance at the 0.05 level

[1] The baseline severity of moderate to severe vasomotor symptoms (MSVS) is the daily severity score of MSVS during the two week pre-randomization observation period.

[2] ANCOVA -Analysis of Covariance model where the observation variable is change from baseline; independent variables include treatment, center and baseline as covariate. The 95 percent CI -Mann-Whitney confidence interval for the difference between means (not stratified by center).

ITT = intent to treat; LOCF = last observation carried forward; CI = confidence interval 2 randomized subjects (1 in Placebo and 1 in norethindrone acetate and ethinyl estradiol) did not return diaries.

Visit Placebo ( N = 66 ) Norethindrone Acetate and Ethinyl Estradiol 0 . 5 / 2 . 5 ( N = 67 ) Norethindrone Acetate and Ethinyl Estradiol 1 / 5 ( N = 66 )
Baseline [ 1 ] Mean (SD) 2.49 (0.26)2.48 (0.22)2.47 (0.23)
Week 4 Mean (SD) Mean Change from Baseline (SD) p-Value vs. Placebo (95 percent CI) [2] 2.13 (0.74) -0.36 (0.68) –1.88 (0.89) -0.59 (0.83) 0.130 (-0.3, 0.0) 1.45 (1.03) -1.02* (1.06) <0.001 (-0.9, -0.2)
Week 5 Mean (SD) Mean Change from Baseline (SD) p-Value vs. Placebo (95 percent CI) [2] 2.06 (0.79) -0.44 (0.74) –1.68 (0.99) -0.80* (0.94) 0.041 (-0.4, -0.0) 1.23 (1.03) -1.24* (1.07) <0.001 (-1.2, -0.3)
Week 12 Mean (SD) Mean Change from Baseline (SD) p-Value vs. Placebo(95 percent CI) [2] 1.82 (1.03) -0.67 (1.02) –1.22 (1.11) -1.26* (1.08) 0.002 (-0.9, -0.2) 1.02 (1.16) -1.45* (1.19) <0.001 (-1.4, -0.3)

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