Indications and Usage
Medroxyprogesterone acetate tablets are indicated for the treatment of secondary amenorrhea and abnormal uterine bleeding due to hormonal imbalance in the absence of organic pathology, such as fibroids or uterine cancer. They are also indicated for use in the prevention of endometrial hyperplasia in nonhysterectomized postmenopausal women who are receiving daily oral conjugated estrogens 0.625 mg tablets.
Dosage and Administration
Secondary Amenorrhea
MPA tablets may be given in dosages of 5 or 10 mg daily for 5 to 10 days. A dose for inducing an optimum secretory transformation of an endometrium that has been adequately primed with either endogenous or exogenous estrogen is 10 mg of MPA daily for 10 days. In cases of secondary amenorrhea, therapy may be started at any time. Progestin withdrawal bleeding usually occurs within three to seven days after discontinuing MPA therapy.
Abnormal Uterine Bleeding Due to Hormonal Imbalance in the Absence of Organic Pathology
Beginning on the calculated 16th or 21st day of the menstrual cycle, 5 or 10 mg of medroxyprogesterone acetate may be given daily for 5 to 10 days. To produce an optimum secretory transformation of an endometrium that has been adequately primed with either endogenous or exogenous estrogen, 10 mg of medroxyprogesterone acetate daily for 10 days beginning on the 16th day of the cycle is suggested. Progestin withdrawal bleeding usually occurs within three to seven days after discontinuing therapy with MPA tablets. Patients with a past history of recurrent episodes of abnormal uterine bleeding may benefit from planned menstrual cycling with MPA tablets.
Reduction of Endometrial Hyperplasia in Postmenopausal Women Receiving Daily 0.625 mg Conjugated Estrogens
When estrogen is prescribed for a postmenopausal woman with a uterus, a progestin should also be initiated to reduce the risk of endometrial cancer. A woman without a uterus does not need progestin. Use of estrogen, alone or in combination with a progestin, should be with the lowest effective dose and for the shortest duration consistent with treatment goals and risks for the individual woman. Patients should be re-evaluated periodically as clinically appropriate (for example, 3 to 6 month intervals) to determine if treatment is still necessary (see WARNINGS ). For women who have a uterus, adequate diagnostic measures, such as endometrial sampling, when indicated, should be undertaken to rule out malignancy in cases of undiagnosed persistent or recurring abnormal vaginal bleeding.
MPA tablets may be given in dosages of 5 or 10 mg daily for 12 to 14 consecutive days per month, in postmenopausal women receiving daily 0.625 mg conjugated estrogens, either beginning on the 1st day of the cycle or the 16th day of the cycle.
Patients should be started at the lowest dose.
The lowest effective dose of MPA has not been determined.
Contraindications
MPA tablets is contraindicated in women with any of the following conditions:
1. Undiagnosed abnormal genital bleeding.
2. Known, suspected, or history of breast cancer.
3. Known or suspected estrogen- or progesterone-dependent neoplasia.
4. Active DVT, PE, or a history of these conditions.
5. Active arterial thromboembolic disease (for example, stroke and MI), or a history of these conditions.
6. Known anaphylactic reaction or angioedema to MPA.
7. Known liver impairment or disease.
8. Known or suspected pregnancy.
Adverse Reactions
See BOXED WARNINGS , WARNINGS , and PRECAUTIONS .
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice
The following adverse reactions have been reported in women taking MPA tablets, without concomitant estrogens treatment:
1. Genitourinary system
Abnormal uterine bleeding (irregular, increase, decrease), change in menstrual flow, breakthrough bleeding, spotting, amenorrhea, changes in cervical erosion and cervical secretions.
2. Breasts
Breast tenderness, mastodynia or galactorrhea has been reported.
3. Cardiovascular
Thromboembolic disorders including thrombophlebitis and pulmonary embolism have been reported.
4. Gastrointestinal
Nausea, cholestatic jaundice.
5. Skin
Sensitivity reactions consisting of urticaria, pruritus, edema and generalized rash have occurred. Acne, alopecia and hirsutism have been reported.
6. Eyes
Neuro-ocular lesions, for example, retinal thrombosis, and optic neuritis.
7. Central nervous system
Mental depression, insomnia, somnolence, dizziness, headache, nervousness.
8. Miscellaneous
Hypersensitivity reactions (for example, anaphylaxis and anaphylactoid reactions, angioedema), rash (allergic) with and without pruritus, change in weight (increase or decrease), pyrexia, edema/fluid retention, fatigue, decreased glucose tolerance.
The following adverse reactions have been reported with estrogen plus progestin therapy.
1. Genitourinary system
Abnormal uterine bleeding/spotting, or flow; breakthrough bleeding; spotting; dysmenorrheal/pelvic pain; increase in size of uterine leiomyomata; vaginitis, including vaginal candidiasis; change in amount of cervical secretion; changes in cervical ectropion; ovarian cancer; endometrial hyperplasia; endometrial cancer.
2. Breasts
Tenderness, enlargement, pain, nipple discharge, galactorrhea; fibrocystic breast changes; breast cancer.
3. Cardiovascular
Deep and superficial venous thrombosis; pulmonary embolism; thrombophlebitis; myocardial infarction; stroke; increase in blood pressure.
4. Gastrointestinal
Nausea, vomiting; abdominal cramps, bloating; cholestatic jaundice; increased incidence of gallbladder disease; pancreatitis; enlargement of hepatic hemangiomas.
5. Skin
Chloasma or melasma that may persist when drug is discontinued; erythema multiforme; erythema nodosum; hemorrhagic eruption; loss of scalp hair; hirsutism; pruritus, rash.
6. Eyes
Retinal vascular thrombosis, intolerance to contact lenses.
7. Central nervous system
Headache; migraine; dizziness; mental depression; chorea; nervousness; mood disturbances; irritability; exacerbation of epilepsy, dementia.
8. Miscellaneous
Increase or decrease in weight; reduced carbohydrate tolerance; aggravation of porphyria; edema; arthalgias; leg cramps; changes in libido; urticaria, angioedema, anaphylactoid/anaphylactic reactions; hypocalcemia; exacerbation of asthma; increased triglycerides.
Overdosage
Overdosage of estrogen plus progestin therapy may cause nausea and vomiting, breast tenderness, dizziness, abdominal pain, drowsiness/fatigue and withdrawal bleeding may occur in women. Treatment of overdose consists of discontinuation of CE plus MPA together with institution of appropriate symptomatic care.
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 medroxyprogesterone acetate 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, sucrose and talc.
The 2.5 mg tablets also contain: FD&C Yellow No. 6.
The 5 mg tablets also contain: FD&C Blue No.2–Aluminum Lake.
Chemical StructureClinical 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 MPA 2.5 mg tablets or a single administration of two MPA 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 MPA 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 MPA tablets were highly variable and are summarized in Table 1.
| Tablet Strength |
C max
(ng/mL) |
T max
(h) |
Auc 0–(∞)
(ng∙h/mL) |
t 1/2
(h) |
Vd/f
(L) |
CL/f
(mL/min) |
|---|---|---|---|---|---|---|
|
Single Dose |
||||||
|
2 × 10 mg |
1.01 (0.599) |
2.65 (1.41) |
6.95 (3.39) |
12.1 (3.49) |
78024 |
64110 |
|
8 × 2.5 mg |
0.805 (0.413) |
2.22 (1.39) |
5.62 (2.79) |
11.6 (2.81) |
62748 |
74123 |
|
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 |
41963 |
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.
| Histological Results |
Placebo
(n=119) |
CEE
CEE = conjugated equine estrogens 0.625 mg/day
(n=119) |
MPA
MPA = medroxyprogesterone acetate tablets 10 mg/day for 12 days
+ 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 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.
| CEE CEE = conjugated equine estrogen 0.625 mg every day of a 28-day cycle. | MPA Cyclic medroxyprogesterone acetate on days 15 to 28 + 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.
| Event Nominal confidence intervals unadjusted for multiple looks and multiple comparisons. |
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 |
1.23 (0.99–1.53) |
41 |
34 |
|
Non-fatal MI |
1.28 (1.00–1.63) |
31 |
25 |
|
CHD death |
1.10 (0.70–1.75) |
8 |
8 |
|
All strokes |
1.31 (1.03–1.68) |
33 |
25 |
|
Ischemic stroke |
1.44 (1.09–1.90) |
26 |
18 |
|
Deep vein thrombosisNot included in "global index". |
1.95 (1.43–2.67) |
26 |
13 |
|
Pulmonary embolism |
2.13 (1.45–3.11) |
18 |
8 |
|
Invasive breast cancerIncludes metastatic and non-metastatic breast cancer, with the exception of in situ breast cancer. |
1.24 (1.01–1.54) |
41 |
33 |
|
Colorectal cancer |
0.61 (0. 42–0.87) |
10 |
16 |
|
Endometrial cancer |
0.81 (0.48–1.36) |
6 |
7 |
|
Cervical cancer |
1.44 (0.47–4.42) |
2 |
1 |
|
Hip fracture |
0.67 (0.47–0.96) |
11 |
16 |
|
Vertebral fractures |
0.65 (0.46–0.92) |
11 |
17 |
|
Lower arm/wrist fractures |
0.71 (0.59–0.85) |
44 |
62 |
|
Total fractures |
0.76 (0.69–0.83) |
152 |
199 |
|
Overall mortalityAll deaths, except from breast or colorectal cancer, definite or probable CHD, PE or cerebrovascular disease. |
1.00 (0.83–1.19) |
52 |
52 |
|
Global IndexA 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. |
1.13 (1.02–1.25) |
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, 0.44–1.07)].
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.)
How Supplied / Storage and Handling
Medroxyprogesterone acetate tablets are available in the following strengths and package sizes:
2.5 mg tablets
Bottles of 100: NDC 59762-0055-1 (scored, round, orange, imprinted PROVERA 2.5)
Bottles of 1000: NDC 59762-0055-2 (scored, round, orange, imprinted PROVERA 2.5)
5 mg tablets
Bottles of 100: NDC 59762-0058-1 (scored, round, blue, imprinted PROVERA 5)
Bottles of 1000: NDC 59762-0058-2 (scored, round, blue, imprinted PROVERA 5)
10 mg tablets
Bottles of 100: NDC 59762-0056-1 (scored, round, white, imprinted PROVERA 10)
Bottles of 1000: NDC 59762-0056-2 (scored, round, white, imprinted PROVERA 10)
Store at controlled room temperature 20° to 25°C (68° to 77°F) [see USP].
"Keep out of reach of children"
Patient Counseling Information
Physicians are advised to discuss the Patient Information leaflet with women for whom they prescribe MPA tablets.
There may be an increased risk of minor birth defects in children whose mothers are exposed to progestins during the first trimester of pregnancy. The possible risk to the male baby is hypospadias, a condition in which the opening of the penis is on the underside rather than the tip of the penis. This condition occurs naturally in approximately 5 to 8 per 1,000 male births. The risk may be increased with exposure to MPA tablets. Enlargement of the clitoris and fusion of the labia may occur in female babies. However, a clear association between hypospadias, clitoral enlargement and labial fusion with use of MPA tablets has not been established.
Inform the patient of the importance of reporting exposure to MPA tablets in early pregnancy.