PROGESTERONE (Page 2 of 7)

CLINICAL STUDIES

Effects on the endometrium

In a randomized, double-blind clinical trial, 358 postmenopausal women, each with an intact uterus, received treatment for up to 36 months. The treatment groups were: progesterone capsules at the dose of 200 mg/day for 12 days per 28-day cycle in combination with conjugated estrogens 0.625 mg/day (n=120); conjugated estrogens

0.625 mg/day only (n=119); or placebo (n=119). The subjects in all three treatment groups were primarily Caucasian women (87 percent or more of each group). The results for the incidence of endometrial hyperplasia in women receiving up to 3 years of treatment are shown in Table 3. A comparison of the progesterone capsules plus conjugated estrogens treatment group to the conjugated estrogens only group showed a significantly lower rate of hyperplasia (6 percent combination product versus 64 percent estrogen alone) in the progesterone capsules plus conjugated estrogens treatment group throughout 36 months of treatment.

TABLE 3. Incidence of Endometrial Hyperplasia in Women Receiving 3 Years of Treatment
Endometrial Diagnosis Treatment Group
Conjugated Estrogens 0.625 mg + Progesterone Capsules 200 mg (cyclical)Conjugated Estrogens 0.625 mg alonePlacebo
Number of patients% of patientsNumber of patients% of patientsNumber of patients% of patients
n=117n=115n=116
a Most advanced result to least advanced result: Adenocarcinoma > atypical hyperplasia > complex hyperplasia >simple hyperplasia
HYPERPLASIAa 76746433
Adenocarcinoma 000011
Atypical hyperplasia 11141200
Complex hyperplasia 00272311
Simple hyperplasia 65332911

The times to diagnosis of endometrial hyperplasia over 36 months of treatment are shown in Figure 1. This figure illustrates graphically that the proportion of patients with hyperplasia was significantly greater for the conjugated estrogens group (64 percent) compared to the conjugated estrogens plus progesterone capsules group (6 percent).

graph1
(click image for full-size original)

Figure 1. Time to Hyperplasia in Women Receiving up to 36 Months of Treatment

The discontinuation rates due to hyperplasia over the 36 months of treatment are as shown in Table 4. For any degree of hyperplasia, the discontinuation rate for patients who received conjugated estrogens plus progesterone capsules was similar to that of the placebo only group, while the discontinuation rate for patients who received conjugated estrogens alone was significantly higher. Women who permanently discontinued treatment due to hyperplasia were similar in demographics to the overall study population.

TABLE 4. Discontinuation Rate Due to Hyperplasia Over 36 Months of Treatment
Most Advanced Biopsy Result Through 36 Months of Treatment Treatment Group
Conjugated Estrogens + Progesterone Capsules (cyclical)Conjugated Estrogens (alone)Placebo
n=120n=119 n=119
Number of patients % of patients Number of patients % of patients Number of patients % of patients
Adenocarcinoma 0 0 0 0 1 1
Atypical hyperplasia 1 1 10 8 0 0
Complex hyperplasia 0 0 21 18 1 1
Simple hyperplasia 1 1 13 11 0 0

Effects on secondary amenorrhea

In a single-center, randomized, double-blind clinical study that included premenopausal women with secondary amenorrhea for at least 90 days, administration of 10 days of progesterone capsules therapy resulted in 80 percent of women experiencing withdrawal bleeding within 7 days of the last dose of progesterone capsules, 300 mg/day (n=20), compared to 10 percent of women experiencing withdrawal bleeding in the placebo group (n=21).

In a multicenter, parallel-group, open label, postmarketing dosing study that included premenopausal women with secondary amenorrhea for at least 90 days, administration of 10 days of PROMETRIUM Capsules during two 28-day treatment cycles, 300 mg per day (n=107) or 400 mg per day (n=99), resulted in 73.8 percent and 76.8 percent of women, respectively, experiencing withdrawal bleeding.

The rate of secretory transformation was evaluated in a multicenter, randomized, double-blind clinical study in estrogen-primed postmenopausal women. Progesterone capsules administered orally for 10 days at 400 mg/day (n=22) induced complete secretory changes in the endometrium in 45 percent of women compared to 0 percent in the placebo group (n=23).

A second multicenter, parallel-group, open label postmarketing dosing study in premenopausal women with secondary amenorrhea for at least 90 days also evaluated the rate of secretory transformation. All subjects received daily oral conjugated estrogens over 3 consecutive 28-day treatment cycles and PROMETRIUM Capsules, 300 mg per day (n=107) or 400 mg per day (n=99) for 10 days of each treatment cycle. The rate of complete secretory transformation was 21.5 percent and 28.3 percent, respectively.

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