MEDROXYPROGESTERONE ACETATE - medroxyprogesterone acetate tablet
Rebel Distributors Corp.
MEDROXYPROGESTERONE ACETATE TABLETS, USP
Rx only
WARNINGS
CARDIOVASCULAR AND OTHER RISKS
Estrogens with progestins should not be used for the prevention of cardiovascular disease or dementia. (See CLINICAL STUDIES and WARNINGS, Cardiovascular Disorders and Dementia.)
The Women’s Health Initiative (WHI) estrogen plus progestin substudy reported increased risks of myocardial infarction, stroke, invasive breast cancer, pulmonary emboli, and deep vein thrombosis (DVT) in postmenopausal women (50 to 79 years of age) during 5.6 years of treatment with daily oral conjugated estrogens (CE 0.625 mg) combined with medroxyprogesterone acetate (MPA 2.5 mg) relative to placebo. (See CLINICAL STUDIES and WARNINGS, Cardiovascular Disorders and Malignant Neoplasms, Breast Cancer.)
The Women’s Health Initiative Memory Study (WHIMS), a substudy of the WHI study, reported increased risk of developing probable dementia in postmenopausal women 65 years of age or older during 4 years of treatment with daily CE 0.625 mg combined with MPA 2.5 mg, relative to placebo. It is unknown whether this finding applies to younger postmenopausal women. (See CLINICAL STUDIES and WARNINGS, Dementia, and PRECAUTIONS, Geriatric Use.)
In the absence of comparable data, these risks should be assumed to be similar for other doses of CE and MPA and other combinations and dosage forms of estrogens and progestins. Because of these risks, estrogens with or without progestins should be prescribed at the lowest effective doses and for the shortest duration consistent with treatment goals and risks for the individual woman.
DESCRIPTION
Medroxyprogesterone acetate 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-, (6α)-. The structural formula is:
Each tablet, for oral administration, contains 2.5 mg, 5 mg or 10 mg of medroxyprogesterone acetate. In addition, each tablet contains the following inactive ingredients: crospovidone, lactose monohydrate, magnesium stearate, methylcellulose, pregelatinized starch, and sodium lauryl sulfate.
CLINICAL PHARMACOLOGY
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.
Pharmacokinetics
The pharmacokinetics of MPA were determined in 20 postmenopausal women following a single-dose administration of eight medroxyprogesterone acetate 2.5 mg tablets or a single administration of two medroxyprogesterone acetate 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 medroxyprogesterone acetate 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 medroxyprogesterone acetate tablets were highly variable and are summarized in Table 1.
Table 1. Mean (SD) Pharmacokinetic Parameters for Medroxyprogesterone Acetate (MPA)
|
|
|
Tablet
Strength |
Cmax
(ng/mL) |
Tmax
(h) |
Auc0-(∞)
(ng·h/mL) |
t½
(h) |
Vd/f
(L) |
CL/f
(mL/min) |
|
Single Dose |
|
2 x 10 mg |
1.01 (0.599) |
2.65 (1.41) |
6.95 (3.39) |
12.1 (3.49) |
78024
(47220) |
64110
(42662) |
|
8 x 2.5 mg |
0.805 (0.413) |
2.22 (1.39) |
5.62 (2.79) |
11.6 (2.81) |
62748
(40146) |
74123
(35126) |
|
Multiple Dose |
|
10 mg* |
0.71 (0.35) |
2.83 (1.83) |
6.01 (3.16) |
16.6
(15) |
40564
(38256) |
41963
(38402) |
A. Absorption
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 medroxyprogesterone acetate with food increases the bioavailability of MPA. A 10 mg dose of medroxyprogesterone acetate, 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.
B. Distribution
MPA is approximately 90% protein bound, primarily to albumin; no MPA binding occurs with sex hormone binding globulin.
C. Metabolism
Following oral dosing, MPA is extensively metabolized in the liver via hydroxylation, with subsequent conjugation and elimination in the urine.
D. Excretion
Most MPA metabolites are excreted in the urine as glucuronide conjugates with only minor amounts excreted as sulfates.
E. Special Populations
Renal Insufficiency
The pharmacokinetics of MPA in patients with varying degrees of renal insufficiency have not been investigated.
Hepatic Insufficiency
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 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 medroxyprogesterone acetate (n=118), results showed a reduced risk of endometrial hyperplasia in the treatment group receiving 10 mg medroxyprogesterone acetate 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
(n=119) |
CEE*
(n=119) |
Medroxyprogesterone
Acetate†
+ CEE
(n=118) |
|
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 1-28), plus either 5 mg cyclic medroxyprogesterone acetate or 10 mg cyclic medroxyprogesterone acetate (days 15-28), or daily 0.625 mg conjugated estrogen only. The treatment groups receiving 5 or 10 mg cyclic medroxyprogesterone acetate (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.
