Medroxyprogesterone Acetate

MEDROXYPROGESTERONE ACETATE- medroxyprogesterone acetate tablet
RedPharm Drug, Inc.

0872

0873

0779

Rx only

WARNING: CARDIOVASCULAR DISORDERS, BREAST CANCER AND PROBABLE DEMENTIA FOR ESTROGEN PLUS PROGESTIN THERAPY

Cardiovascular Disorders and Probable Dementia

Estrogen plus progestin therapy should not be used for the prevention of cardiovascular disease or dementia. (SEE CLINICAL STUDIES and WARNINGS, CARDIOVASCULAR DISORDERS and PROBABLE DEMENTIA.)

The Women’s Health Initiative (WHI) estrogen plus progestin substudy reported an increased risk of deep vein thrombosis (DVT), pulmonary embolism (PE), stroke and myocardial infarction (MI) 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.)

The WHI Memory Study (WHIMS) estrogen plus progestin ancillary study reported an 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 STUDIESand WARNINGS,PROBABLE DEMENTIA and PRECAUTIONS,GERIATRIC USE.)

Breast Cancer

The WHI estrogen plus progestin substudy demonstrated an increased risk of invasive breast cancer. (See CLINICAL STUDIES and WARNINGS, MALIGNANT NEOPLASM,BREAST CANCER.)

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.

Progestins with estrogens 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 USP contain medroxyprogesterone acetate, USP 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:

[structure formula]


C 24H 34O 4 M.W. 386.53

Each tablet, for oral administration, contains 2.5 mg, 5 mg or 10 mg of medroxyprogesterone acetate, USP and the following inactive ingredients: crospovidone, lactose monohydrate, magnesium stearate, methylcellulose, pregelatinized corn 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)

(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)

*Following Day 7 dose

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. 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 medroxyprogesterone acetate 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 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*

*
CEE = conjugated equine estrogens 0.625 mg/day

Medroxyprogesterone acetate = medroxyprogesterone acetate tablets 10 mg/day for 12 days

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

* Includes most extreme abnormal result

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 to 28), plus either 5 mg cyclic medroxyprogesterone acetate or 10 mg cyclic medroxyprogesterone acetate (days 15 to 28), or daily 0.625 mg conjugated estrogen only. The treatment groups receiving 5 or 10 mg cyclic medroxyprogesterone acetate (days 15 to 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 = conjugated equine estrogen 0.625 mg every day of a 28-day cycle.

Cyclic medroxyprogesterone acetate on days 15 to 28

CEE*

MPA† + CEE*

(n=283)

MPA 5 mg

(n=277)

MPA 10 mg

(n=272)

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.

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*†

*
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.

Event

Relative Risk

CE/MPA vs placebo

(95% nCI‡)

CE/MPA

n = 8,506

Placebo

n = 8,102

Absolute Risk per 10,000 Women-Years

CHD events
Non-fatal MI
CHD death

1.23 (0.99 to 1.53)

1.28 (1 to 1.63)

1.10 (0.70 to 1.75)

41

31

8

34

25

8

All strokes

1.31 (1.03 to 1.68)

33

25

Ischemic stroke

1.44 (1.09 to 1.90)

26

18

Deep vein thrombosis§

1.95 (1.43 to 2.67)

26

13

Pulmonary embolism

2.13 (1.45 to 3.11)

18

8

Invasive breast cancer¶

1.24 (1.01 to 1.54)

41

33

Colorectal cancer

0.61 (0.42 to 0.87)

10

16

Endometrial cancer§

0.81 (0.48 to 1.36)

6

7

Cervical Cancer§

1.44 (0.47 to 4.42)

2

1

Hip fracture

0.67 (0.47 to 0.96)

11

16

Vertebral fractures§

0.65 (0.46 to 0.92)

11

17

Lower arm/wrist fractures§

0.71 (0.59 to 0.85)

44

62

Total fractures§

0.76 (0.69 to 0.83)

152

199

Overall mortality#

1 (0.83 to 1.19)

52

52

Global IndexÞ

1.13 (1.02 to 1.25)

184

165

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 to 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 to 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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