Medroxyprogesterone Acetate (Page 2 of 8)

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 MPA with food increases the bioavailability of MPA. A 10 mg dose of MPA, 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. Specific Populations

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.

Renal Insufficiency

The effect of renal impairment on the pharmacokinetics of MPA has not been studied.

F. Drug Interactions

Medroxyprogesterone acetate (MPA) is metabolized in-vitro primarily by hydroxylation via the CYP3A4. Specific drug-drug interaction studies evaluating the clinical effects with CYP3A4 inducers or inhibitors on MPA have not been conducted. Inducers and/or inhibitors of CYP3A4 may affect the metabolism of MPA.

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 MPA (n=118), results showed a reduced risk of endometrial hyperplasia in the treatment group receiving 10 mg MPA 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 Results Placebo (n=119) CEE (n=119) MPA + CEE (n=118)
*
Includes most extreme abnormal result
CEE = conjugated equine estrogens 0.625 mg/day
MPA = 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 (%)

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 MPA or 10 mg cyclic MPA (days 15–28), or daily 0.625 mg conjugated estrogen only. The treatment groups receiving 5 or 10 mg cyclic MPA (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 atypia

2 (1)

0

0

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.

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