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PROVERA®Clinical Studies (medroxyprogesterone acetate)

CLINICAL STUDIES

Effects on the Endometrium

In a 3-year, double-blind, placebo-controlled study of 356 nonhysterectomized, postmenopausal women between 45 and 64 years of age randomized to receive placebo (n=119), 0.625 mg conjugated estrogen only (n=119), or 0.625 mg conjugated estrogen plus cyclic PROVERA (n=118), results showed a reduced risk of endometrial hyperplasia in the treatment group receiving 10 mg PROVERA plus 0.625 mg conjugated estrogens compared to the group receiving 0.625 mg conjugated estrogens only. See Table 2.

Table 2. Number (%) of Endometrial Biopsy Changes Since Baseline After 3 Years of Treatment *
Histological ResultsPlacebo
(n=119)
CEE
(n=119)
PROVERA + CEE
(n=118)
*
Includes most extreme abnormal result
CEE = conjugated equine estrogens 0.625 mg/day
PROVERA = medroxyprogesterone acetate tablets 10 mg/day for 12 days
Normal/No hyperplasia (%)116 (97)45 (38)112 (95)
Simple (cystic) hyperplasia (%)1 (1)33 (28)4 (3)
Complex (adenomatous) hyperplasia (%)1 (1)27 (22)2 (2)
Atypia (%)014 (12)0
Adenocarcinoma (%)1 (1)00

In a second 1-year study, 832 postmenopausal women between 45 and 65 years of age were treated with daily 0.625 mg conjugated estrogen (days 1–28), plus either 5 mg cyclic PROVERA or 10 mg cyclic PROVERA (days 15–28), or daily 0.625 mg conjugated estrogen only. The treatment groups receiving 5 or 10 mg cyclic PROVERA (days 15–28) plus daily conjugated estrogens showed a significantly lower rate of hyperplasia as compared to the conjugated estrogens only group. See Table 3.

Table 3. Number (%) of Women with Endometrial Hyperplasia at 1 Year
CEE *MPA + CEE *
(n=283)MPA 5 mg
(n=277)
MPA 10 mg
(n=272)
*
CEE = conjugated equine estrogen 0.625 mg every day of a 28-day cycle.
Cyclic medroxyprogesterone acetate on days 15 to 28
Cystic hyperplasia (%)55 (19)3 (1)0
Adenomatous hyperplasia without atypia2 (1)00

Women's Health Initiative Studies

The WHI enrolled approximately 27,000 predominantly healthy postmenopausal women in two substudies to assess the risks and benefits of daily oral CE (0.625 mg)-alone or in combination with MPA (2.5 mg) compared to placebo in the prevention of certain chronic diseases. The primary endpoint was the incidence of coronary heart disease (CHD) (defined as nonfatal MI, silent MI and CHD death), with invasive breast cancer as the primary adverse outcome. A "global index" included the earliest occurrence of CHD, invasive breast cancer, stroke, PE, endometrial cancer (only in the CE plus MPA substudy), colorectal cancer, hip fracture, or death due to other cause. These substudies did not evaluate the effects of CE-alone or CE plus MPA on menopausal symptoms.

WHI Estrogen Plus Progestin Substudy

The WHI estrogen plus progestin substudy was stopped early. According to the predefined stopping rule, after an average follow-up of 5.6 years of treatment, the increased risk of invasive breast cancer and cardiovascular events exceeded the specified benefits included in the "global index." The absolute excess risk of events included in the "global index" was 19 per 10,000 women-years.

For those outcomes included in the WHI "global index" that reached statistical significance after 5.6 years of follow-up, the absolute excess risks per 10,000 women-years in the group treated with CE plus MPA were 7 more CHD events, 8 more strokes, 10 more PEs, and 8 more invasive breast cancers, while the absolute risk reduction per 10,000 women-years were 6 fewer colorectal cancers and 5 fewer hip fractures.

Results of the CE plus MPA substudy, which included 16,608 women (average 63 years of age, range 50 to 79; 83.9 percent White, 6.8 percent Black, 5.4 percent Hispanic, 3.9 percent Other) are presented in Table 4. These results reflect centrally adjudicated data after an average follow-up of 5.6 years.

Table 4 : RELATIVE AND ABSOLUTE RISK SEEN IN THE ESTROGEN PLUS PROGESTIN SUBSTUDY OF WHI AT AN AVERAGE OF 5.6 YEARS *,
EventRelative Risk
CE/MPA vs placebo
(95%nCI )
CE/MPA
n = 8,506
Placebo
n = 8,102
Absolute Risk per 10,000 Women-Years
*
Adapted from numerous WHI publications. WHI publications can be viewed at www.nhlbi.nih.gov/whi.
Results are based on centrally adjudicated data.
Nominal confidence intervals unadjusted for multiple looks and multiple comparisons.
§
Not included in "global index".
Includes metastatic and non-metastatic breast cancer, with the exception of in situ breast cancer.
#
All deaths, except from breast or colorectal cancer, definite or probable CHD, PE or cerebrovascular disease.
Þ
A subset of the events was combined in a "global index", defined as the earliest occurrence of CHD events, invasive breast cancer, stroke, pulmonary embolism, colorectal cancer, hip fracture, or death due to other causes.
CHD events1.23 (0.99–1.53)4134
    Non-fatal MI1.28 (1.00–1.63)3125
    CHD death1.10 (0.70–1.75)88
All strokes1.31 (1.03–1.68)3325
  Ischemic stroke1.44 (1.09–1.90)2618
Deep vein thrombosis§1.95 (1.43–2.67)2613
Pulmonary embolism2.13 (1.45–3.11)188
Invasive breast cancer1.24 (1.01–1.54)4133
Colorectal cancer0.61 (0.42–0.87)1016
Endometrial cancer§0.81 (0.48–1.36)67
Cervical cancer§1.44 (0.47–4.42)21
Hip fracture0.67 (0.47–0.96)1116
Vertebral fractures§0.65 (0.46–0.92)1117
Lower arm/wrist fractures§0.71 (0.59–0.85)4462
Total fractures§0.76 (0.69–0.83)152199
Overall mortality#1.00 (0.83–1.19)5252
Global IndexÞ1.13 (1.02–1.25)184165

Timing of the initiation of estrogen plus progestin therapy relative to the start of menopause may affect the overall risk benefit profile. The WHI estrogen plus progestin substudy stratified by age showed in women 50 to 59 years of age a nonsignificant trend toward reduced risk in overall mortality [hazard ration (HR) 0.69 (95 percent CI, 0.44–1.07)].

Women's Health Initiative Memory Study

The WHIMS estrogen plus progestin ancillary study of WHI enrolled 4,532 predominantly healthy postmenopausal women 65 years of age and older (47 percent were aged 65 to 69 years of age, 35 percent were 70 to 74 years of age, and 18 percent were 75 years of age and older) to evaluate the effects of daily CE (0.625 mg) plus MPA (2.5 mg) on the incidence of probable dementia (primary outcome) compared to placebo.

After an average follow-up of 4 years, the relative risk of probable dementia for CE plus MPA versus placebo was 2.05 (95 percent CI, 1.21–3.48). The absolute risk of probable dementia for CE plus MPA versus placebo was 45 versus 33 per 10,000 women-years. Probable dementia as defined in this study included Alzheimer's disease (AD), vascular dementia (VaD) and mixed type (having features of both AD and VaD). The most common classification of probable dementia in the treatment group and the placebo group was AD. Since the ancillary study was conducted in women 65 to 79 years of age, it is unknown whether these findings apply to younger postmenopausal women. (See WARNINGS, Probable Dementia and PRECAUTIONS, Geriatric Use).

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