August 2, 2015
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Provera

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Provera




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 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. Reference ID: 3749814

Table 1: Mean (SD) Pharmacokinetic Parameters for Medroxyprogesterone Acetate (MPA)

Tablet Strength Cmax (ng/mL) Tmax(h) Auc 0-(∞) (ng•h/mL) t ½(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 (15.0) 40564 (38256) 41963 (38402)
*Following Day 7 dose

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 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.

Distribution

MPA is approximately 90% protein bound, primarily to albumin; no MPA binding occurs with sex hormone binding globulin.

Metabolism

Following oral dosing, MPA is extensively metabolized in the liver via hydroxylation, with subsequent conjugation and elimination in the urine.

Excretion

Most MPA metabolites are excreted in the urine as glucuronide conjugates with only minor amounts excreted as sulfates.

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. Reference ID: 3749814

Renal Insufficiency

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

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 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 *

Histological Results Placebo (n=119) CEE †
(n=119)
PROVERA‡+ 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
† CEE = conjugated equine estrogens 0.625 mg/day
‡ PROVERA = medroxyprogesterone acetate tablets 10 mg/day for 12 days

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 PROVERA or 10 mg cyclic PROVERA (days 15-28), 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

  CEE *
(n=283)
MPA† + CEE *
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
* CEE = conjugated equine estrogen 0.625 mg every day of a 28-day cycle.
† Cyclic medroxyprogesterone acetate on days 15 to 28

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 a,b

Event Relative Risk CE/MPA vs placebo (95%nCI c) 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 thrombosisd 1.95 (1.43-2.67) 26 13
Pulmonary embolism 2.13 (1.45-3.11) 18 8
Invasive breast cancere 1.24 (1.01-1.54) 41 33
Colorectal cancer 0.61 (0.42-0.87) 10 16
Endometrial cancerd 0.81 (0.48-1.36) 6 7
Cervical cancerd 1.44 (0.47-4.42) 2 1
Hip fracture 0.67 (0.47-0.96) 11 16
Vertebral fracturesd 0.65 (0.46-0.92) 11 17
Lower arm/wrist fracturesd 0.71 (0.59-0.85) 44 62
Total fracturesd 0.76 (0.69-0.83) 152 199
Overall mortalityf 1.00 (0.83-1.19) 52 52
Global Indexg 1.13 (1.02-1.25) 184 165
aAdapted from numerous WHI publications. WHI publications can be viewed at www.nhlbi.nih.gov/whi.
bResults are based on centrally adjudicated data.
cNominal confidence intervals unadjusted for multiple looks and multiple comparisons.
dNot included in “global index”.
eIncludes metastatic and non-metastatic breast cancer, with the exception of in situ breast cancer.
fAll deaths, except from breast or colorectal cancer, definite or probable CHD, PE or cerebrovascular disease.
gA 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.

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, 0.441.07)].

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. Reference ID: 3749814

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).

Last reviewed on RxList: 4/9/2008
This monograph has been modified to include the generic and brand name in many instances.

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