PROVERA® tablets contain medroxyprogesterone acetate, which is a derivative of progesterone. It is a white to off-white, odorless crystalline powder, stable in air, melting between 200 and 210°C. It is freely soluble in chloroform, soluble in acetone and in dioxane, sparingly soluble in alcohol and in methanol, slightly soluble in ether, and insoluble in water.
The chemical name for medroxyprogesterone acetate is pregn-4-ene-3, 20-dione, 17-(acetyloxy)-6-methyl-, (6alpha)-. The structural formula is:
Each PROVERA tablet for oral administration contains 2.5 mg, 5 mg or 10 mg of medroxyprogesterone acetate and the following inactive ingredients: calcium stearate, corn starch, lactose, mineral oil, sorbic acid, sucrose, and talc. The 2.5 mg tablet contains FD&C Yellow No. 6.
Medroxyprogesterone acetate (MPA) administered orally or parenterally in the recommended doses to women with adequate endogenous estrogen, transforms proliferative into secretory endometrium. Androgenic and anabolic effects have been noted, but the drug is apparently devoid of significant estrogenic activity. While parenterally administered MPA inhibits gonadotropin production, which in turn prevents follicular maturation and ovulation, available data indicate that this does not occur when the usually recommended oral dosage is given as single daily doses.
The pharmacokinetics of MPA were determined in 20 postmenopausal women following a single-dose administration of eight PROVERA 2.5 mg tablets or a single administration of two PROVERA 10 mg tablets under fasting conditions. In another study, the steady-state pharmacokinetics of MPA were determined under fasting conditions in 30 postmenopausal women following daily administration of one PROVERA 10 mg tablet for 7 days. In both studies, MPA was quantified in serum using a validated gas chromatography-mass spectrometry (GC-MS) method. Estimates of the pharmacokinetic parameters of MPA after single and multiple doses of PROVERA tablets were highly variable and are summarized in Table 1.
Table 1. Mean (SD) Pharmacokinetic Parameters for Medroxyprogesterone Acetate (MPA)
|Tablet Strength ||C max |
|T max |
|Auc 0â€“(âˆž) |
|t 1/2 |
|Single Dose |
|2 — 10 mg ||1.01 (0.599) ||2.65 (1.41) ||6.95 (3.39) ||12.1 (3.49) ||78024 |
|8 — 2.5 mg ||0.805 (0.413) ||2.22 (1.39) ||5.62 (2.79) ||11.6 (2.81) ||62748 |
|Multiple Dose |
|10 mg Following Day 7 dose ||0.71 (0.35) ||2.83 (1.83) ||6.01 (3.16) ||16.6 (15.0) ||40564 |
No specific investigation on the absolute bioavailability of MPA in humans has been conducted. MPA is rapidly absorbed from the gastrointestinal tract, and maximum MPA concentrations are obtained between 2 to 4 hours after oral administration.
Administration of PROVERA with food increases the bioavailability of MPA. A 10 mg dose of PROVERA, taken immediately before or after a meal, increased MPA Cmax (50 to 70%) and AUC (18 to 33%). The half-life of MPA was not changed with food.
MPA is approximately 90% protein bound, primarily to albumin; no MPA binding occurs with sex-hormone binding globulin.
Following oral dosing, MPA is extensively metabolized in the liver via hydroxylation, with subsequent conjugation and elimination in the urine
Most MPA metabolites are excreted in the urine as glucuronide conjugates with only minor amounts excreted as sulfates.
E. Special Populations
The pharmacokinetics of MPA in patients with varying degrees of renal insufficiency have not been investigated.
MPA is almost exclusively eliminated via hepatic metabolism. In 14 patients with advanced liver disease, MPA disposition was significantly altered (reduced elimination). In patients with fatty liver, the mean percent dose excreted in the 24-hour urine as intact MPA after a 10 mg or 100 mg dose was 7.3% and 6.4%, respectively.
F. Drug Interactions
No formal pharmacokinetic drug interaction studies have been conducted with PROVERA
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 Includes most extreme abnormal result
|Histological Results ||Placebo |
|CEE CEE = conjugated equine estrogens 0.625 mg/day |
|PROVERA PROVERA = medroxyprogesterone acetate tablets 10 mg/day for 12 days + CEE |
|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 (%) ||0 ||14 (12) ||0 |
|Adenocarcinoma (%) ||1 (1) ||0 ||0 |
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 128) plus either 5 mg cyclic PROVERA or 10 mg cyclic PROVERA (days 1528), or daily 0.625 mg conjugated estrogen only. The treatment groups receiving 5 or 10 mg cyclic PROVERA (days 1528) 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
||MPA Cyclic medroxyprogesterone acetate on days 15 to 28 + CEE |
| ||(n=283) ||MPA 5 mg |
|MPA 10 mg |
|Cystic hyperplasia (%) ||55 (19) ||3 (1) ||0 |
|Adenomatous hyperplasia without atypia ||2 (1) ||0 ||0 |
Women's Health Initiative Studies
The Women's Health Initiative (WHI) enrolled approximately 27,000 predominantly healthy postmenopausal women in two substudies to assess the risks and benefits of either the use of daily oral conjugated estrogens (CE 0.625 mg) alone or in combination with medroxyprogesterone acetate (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) (nonfatal myocardial infarction (MI), silent MI and CHD death), with invasive breast cancer as the primary adverse outcome studied. A "global index" included the earliest occurrence of CHD, invasive breast cancer, stroke, pulmonary embolism (PE), endometrial cancer (only in the CE/MPA substudy), colorectal cancer, hip fracture, or death due to other cause. The study did not evaluate the effects of CE or CE/MPA on menopausal symptoms.
The estrogen plus progestin substudy was stopped early. According to the predefined stopping rule, after an average follow-up of 5.2 years of treatment, the increased risk of 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 (relative risk [RR] 1.15, 95 percent, nominal confidence interval [nCI], 1.031.28).
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/MPA were 6 more CHD events, 7 more strokes, 10 more PEs, and 8 more invasive breast cancers, while the absolute risk reduction per 10,000 women-years were 7 fewer colorectal cancers and 5 fewer hip fractures. (See BOXED WARNINGS, WARNINGS and PRECAUTIONS.)
Results of the CE/MPA substudy which included 16,608 women (average age of 63 years, 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 Results are based on centrally adjudicated data. Mortality data was not part of the adjudicated data; however, data at 5.2 years of follow-up showed no difference between the groups in terms of all-cause mortality (RR 0.98, 95 percent nCI, 0.821.18).
||Relative Risk |
CE/MPA vs placebo
(95%nCI Nominal confidence intervals unadjusted for multiple looks and multiple comparisons)
n = 8102
n = 8506
|Absolute Risk per 10,000 Women-Years |
|CHD events ||1.24 (1.001.54) ||33 ||39 |
| Non-fatal MI || 1.28 (1.001.63) || 25 |
| 31 |
| CHD death || 1.10 (0.701.75) || 8 || 8 |
| All strokes ||1.31 (1.021.68) ||24 ||31 |
|Ischemic stroke ||1.44 (1.091.90) ||18 ||26 |
|Deep vein thrombosis ||1.95 (1.432.67) ||13 ||26 |
|Pulmonary embolism ||2.13 (1.453.11) ||8 ||18 |
|Invasive breast cancer ||1.24 (1.011.54) ||33 ||41 |
|Invasive colorectal cancer ||0.56 (0.380.81) ||16 ||9 |
|Endometrial cancer ||0.81 (0.481.36) ||7 ||6 |
|Cervical Cancer ||1.44 (0.474.42) ||1 ||2 |
|Hip fracture ||0.67 (0.470.96) ||16 ||11 |
|Vertebral fractures ||0.65 (0.460.92) ||17 ||11 |
|Lower arm/wrist fractures ||0.71 (0.590.85) ||62 ||44 |
|Total fractures ||0.76 (0.690.83) ||199 ||152 |
Women's Health Initiative Memory Study
The estrogen plus progestin Women's Health Initiative Memory Study (WHIMS), a substudy of WHI, enrolled 4,532 predominantly healthy postmenopausal women 65 years of age and older (47 percent were aged 65 to 69 years, 35 percent were 70 to 74 years, and 18 percent were 75 years of age and older) to evaluate the effects of daily conjugated estrogens (CE 0.625 mg) plus medroxyprogesterone acetate (MPA 2.5 mg) on the incidence of probable dementia (primary outcome) compared with placebo.
After an average follow-up of 4 years, 40 women in the estrogen plus progestin group (45 per 10,000 women-years) and 21 in the placebo group (22 per 10,000 women-years) were diagnosed with probable dementia. The relative risk of probable dementia in the hormone therapy group was 2.05 (95 percent CI, 1.213.48) compared to placebo.