Each tablet contains 10 mg medroxyprogesterone acetate (MPA).
Provera contains medroxyprogesterone acetate, a derivative of progesterone, as its active ingredient. Medroxyprogesterone acetate is active by the parenteral and oral routes of administration. It is a white to off-white, odorless crystalline powder that is stable in air and that melts between 200°C and 210°C. It is freely soluble in chloroform, soluble in acetone and dioxane, sparingly soluble in alcohol and 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).
Pharmacology: Pharmacodynamics: Mechanism of Action: Medroxyprogesterone acetate (17α-hydroxy-6α-methylprogesterone acetate) is a derivative of progesterone. MPA acetate is a synthetic progestin (structurally related to the endogenous hormone progesterone) which has been demonstrated to possess several pharmacologic actions on the endocrine system: Inhibition of pituitary gonadotropins (FSH and LH); decrease circulating ACTH and hydrocortisone blood levels; decrease circulating testosterone; decrease circulating estrogen level (as a result of both FSH inhibition and enzymatic induction of hepatic reductase, resulting in increased clearance of testosterone and consequent decreased conversion of androgens to estrogens).
All of these actions result in a number of pharmacological effects as described as follows.
Gynecology: 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 depot-medroxyprogesterone acetate (DMPA) 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.
Oncology: MPA demonstrates antitumor activity. When MPA is given to patients at high doses (either by the oral route or by IM injection) it is effective in the palliative treatment of hormone-response, malignant neoplasms.
Clinical Studies: Women's Health Initiative Study: The WHI CEE (0.625mg)/MPA (2.5 mg) trial enrolled 16,608 postmenopausal women aged 50-79 years with intact uteri at baseline, to assess the risks and benefits of the combined therapy compared with placebo in the prevention of certain chronic diseases. The primary endpoint was the incidence of coronary heart disease (CHD) (nonfatal myocardial infarction and CHD death), with invasive breast cancer as the primary adverse outcome studied. The study was stopped early after an average follow-up of 5.2 years (planned duration 8.5 years) because, according to the predefined stopping rule, the increased risk of breast cancer and cardiovascular events exceeded the specified benefits included in the "global index" (see Precautions).
The combination CEE/MPA therapy reported a significant decrease in osteoporotic (23%) and total (24%) fractures.
Million Women Study: The MWS was a prospective cohort study enrolling 1,084,110 women in the UK aged 50-64 years of whom 828,923 with defined time since menopause were included in the main analyses of risk of breast cancer in relation to HT.
Overall, 50% of the study population had used HT at some point. Most current users of HT at baseline reported using preparations containing estrogen only (41%) or estrogen-progestin combinations (50%). The average duration of follow-up was 2.6 years for analyses of cancer incidence and 4.1 years for analyses of mortality (see Precautions)
Heart and Estrogen/Progestin Replacement Studies: HERS and HERS II studies were two randomized, prospective secondary prevention trials on the long-term effects of oral continuous combined CEE/MPA (0.625 mg CEE plus 2.5 mg MPA) regimen in postmenopausal women with CHD (see Precautions.) 2,763 postmenopausal women with a mean age of 66.7 years and with intact uteri were enrolled in this study. The average duration of follow-up was 4.1 years for HERS and 2.7 additional years (for a total of 6.8 years) for HERS II (see Precautions).
Women's Health Initiative Memory Study: The WHIMS, a substudy of WHI, enrolled 4,532 predominantly healthy postmenopausal women age 65 to 79 years to evaluate the effects of CEE/MPA (0.625 mg CEE plus 2.5 mg MPA) or CEE-alone (0.625 mg) on the incidence of probable dementia compared with placebo. The average duration of follow-up was 4.05 years for the CEE/MPA (see Precautions).
Pharmacokinetics: Absorption: Oral medroxyprogesterone (MPA) is rapidly absorbed with maximum concentration obtained between 2 to 4 hours. The half-life of oral MPA is approximately 17 hours. It is 90% protein-bound and is mainly excreted in the urine.
Administration with food increases the bioavailability of MPA. A 10 mg dose of oral MPA, taken immediately before or after a meal, increased average MPA Cmax (51% and 77%, respectively) and average AUC (18% and 33% respectively). 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. The unbound MPA modulates pharmacologic responses.
Metabolism: Following oral dosing, MPA is extensively metabolized in the liver via ring A and/or side-chain hydroxylation, with subsequent conjugation and elimination in the urine. At least 16 MPA metabolites have been identified. In a study designed to measure the metabolism of medroxyprogesterone acetate (MPA), the results suggest that human cytochrome P450 3A4 is primarily involved in the overall metabolism of MPA in human liver microsomes.
Elimination: Most medroxyprogesterone acetate metabolites are excreted in the urine as glucuronide conjugates with only minor amounts excreted as sulfates. Mean percent dose excreted in the 24-hour urine of patients with fatty liver as intact MPA after a 10-mg or 100-mg dose was 7.3% and 6.4%, respectively. Elimination half-life of oral MPA is 12 to 17 hours.
Toxicology: Preclinical Safety Data: Carcinogenesis, Mutagenesis, Impairment of Fertility: There was no evidence of a carcinogenic effect associated with the oral administration of oral MPA to rats and mice.
Medroxyprogesterone acetate was not mutagenic in a battery of in vitro or in vivo genetic toxicity assays. Medroxyprogesterone acetate at high doses is an antifertility drug and high doses would be expected to impair fertility until the cessation of treatment.
Gynecology: Medroxyprogesterone acetate tablets are indicated for: Treatment of endometriosis; treatment of menopausal vasomotor symptoms; diagnosis of primary amenorrhea; diagnosis and treatment of secondary amenorrhea; treatment of dysfunctional (anovulatory) uterine bleeding; opposition of endometrial effects of estrogen in menopausal women being treated with estrogen [hormone therapy (HT)].
Oncology: Recurrent and/or metastatic breast cancer; endometrial cancer, renal cancer; metastatic prostate cancer; anorexia and cachexia syndrome.
Gynecology: Use of combined estrogen/progestin therapy in postmenopausal women should be limited to the lower effective dose and shortest duration consistent with treatment goals and risks for the individual woman and should be periodically evaluated (see Precautions).
Periodic check-ups are recommended with a frequency and nature adapted to the individual woman (see Precautions).
Unless there is a previous diagnosis of endometriosis, it is not recommended to add progestin in a woman without an intact uterus.
Endometriosis: Oral MPA 10 mg three times per day orally for 90 consecutive days, beginning on the first day of the menstrual cycle.
Menopausal Vasomotor Symptoms: Oral MPA 10 to 20 mg/day orally given continuously.
Diagnosis of Primary and Secondary Amenorrhea: Oral MPA 2.5 to 10 mg daily orally for 5 to 10 days, for consecutive cycles. In patients with hypotrophy of endometrium, estrogens should be used concomitantly with MPA therapy.
Treatment of Secondary Amenorrhea: Oral MPA 2.5 to 10 mg/day for 5 to 10 days for 3 consecutive cycles. In patients with hypotrophy of the endometrium, estrogens should be used concomitantly with MPA therapy.
Dysfunctional (Anovulatory) Uterine Bleeding: Oral MPA 2.5 to 10 mg per day for 5 to 10 days for 2-3 cycles and then discontinued to see if the dysfunction uterine bleeding has regressed. If bleeding occurs from a poorly proliferated endometrium, estrogens should be used concomitantly with MPA therapy.
Opposition of Endometrial Effects of Estrogen in Menopausal Women being Treated with Estrogen (Hormone Therapy): For women taking 0.625 mg of conjugated estrogen or an equivalent daily dose of another estrogen, MPA can be given in 1 or 2 regimens: Continuous Regimen: 2.5-5 mg daily.
Sequential Regimen: 5-10 mg daily for 10 to 14 consecutive days of a 28-day or monthly cycle.
Metastatic Prostate Cancer: Oral MPA 100 to 600 mg per day.
Anorexia and Cachexia Syndrome: Oral MPA 1000 mg per day.
Oncology: Recurrent and/or Metastatic Breast Cancer: Oral MPA 400 to 1500 mg per day.
Recurrent and/or Metastatic Endometrial or Renal Cancer: Oral MPA 100 to 600 mg per day.
Metastatic Prostate Cancer: Oral MPA 100 to 500 mg per day.
Anorexia and Cachexia Syndrome: 1000 mg per day.
Hepatic Insufficiency: No clinical studies have evaluated the effect of hepatic disease on the pharmacokinetics of MPA. However, MPA is almost exclusively eliminated by hepatic metabolism and steroid hormones may be poorly metabolized in patients with severe liver insufficiency (see Contraindications).
Renal Insufficiency: No clinical studies have evaluated the effect of renal disease on the pharmacokinetics of MPA. However, since MPA is almost exclusively eliminated by hepatic metabolism, no dosage adjustment should be necessary in women with renal insufficiency.
Oral doses up to 3 g per day have been well tolerated. Overdose treatment is symptomatic and supportive.
MPA is contraindicated in patients with the following conditions: Known or suspected pregnancy.
Undiagnosed vaginal bleeding.
Severe liver dysfunction.
Known hypersensitivity to MPA or any component of the drug, such as Lactose monohydrate, Maize starch, Sucrose, Liquid paraffin, Talc and Calcium stearate.
Additional Contraindication(s) for Specific Use: Gynecology: Known or suspected malignancy of the breast.
General: Unexpected vaginal bleeding during therapy with MPA should be investigated.
MPA may cause some degree of fluid retention; therefore, caution should be exercised in treating any patient with a preexisting medical condition that might be adversely affected by fluid retention.
Patients with a history of treatment for clinical depression should be carefully monitored while receiving MPA therapy.
Some patients receiving medroxyprogesterone may exhibit a decrease in glucose tolerance. Diabetic patients should be carefully observed while receiving such therapy.
The pathologist (laboratory) should be informed of the patient's use of MPA if endometrial or endocervical tissue is submitted for examination.
The physician/laboratory should be informed that use of MPA may decrease the levels of the following endocrine biomarkers: Plasma/urinary steroids (eg, cortisol, estrogen, pregnanediol, progesterone, testosterone); plasma/urinary gonadotrophins (eg, luteinizing hormone (LH) and follicle-stimulating hormone (FSH); sex-hormone-binding-globulin.
Medication should not be re-administered pending examination if there is a sudden partial or complete loss of vision or if there is a sudden onset of proptosis, diplopia or migraine. If examination reveals papilledema or retinal vascular lesions, medication should not be re-administered.
MPA has not been causally associated with the induction of thrombotic or thromboembolic disorders, however, MPA is not recommended in any patient with a history of venous thromboembolism (VTE). Discontinuation of MPA is recommended in patients who develop VTE while undergoing therapy with MPA.
Additional Warnings and Precautions: Gynecology: Treatment of Menopausal Vasomotor Symptoms/Opposition of Endometrial Effects of Estrogen in Menopausal Women Being Treated with Estrogen (Hormone Therapy) All Formulations: Other doses of oral conjugated estrogens with medroxyprogesterone and other combinations and dosage forms of Hormone Therapy (HT) were not studied in the WHI trial (see Pharmacology: Pharmacodynamics under Actions) and in the absence of comparable data, these risks should be assumed to be similar.
Breast Cancer: The use of combined estrogen/progestin by postmenopausal women has been reported to increase the risk of breast cancer. Results from a randomized placebo-controlled trial, the WHI trial, and epidemiological studies (see Pharmacology: Pharmacodynamics under Actions) have reported an increased risk of breast cancer in women taking estrogen/progestin combinations for HT for several years. In the WHI conjugated equine estrogens (CEE) plus MPA trial and observational studies, the excess risk increased with duration of use (see Dosage & Administration). The use of estrogen plus progestin has been reported to result in an increase in abnormal mammograms requiring further evaluation.
Cardiovascular Disorders: Estrogens with or without progestins should not be used for the prevention of cardiovascular disease. Several randomized, prospective trials on the long-term effects (see Dosage & Administration) of a combined estrogen/progestin regimen in postmenopausal women have reported an increased risk of cardiovascular events eg, myocardial infarction, coronary heart disease, stroke and venous thromboembolism.
Coronary Artery Disease: There is no evidence from randomized controlled trials of cardiovascular benefit with continuous combined conjugated estrogen and medroxyprogesterone. Two (2) large clinical trials [WHI CEE/ MPA and Heart and Estrogen/Progestin Replacement Study (HERS) (see Pharmacology: Pharmacodynamics under Actions)] showed a possible increased risk of cardiovascular morbidity in the 1st year of use and no overall benefit.
In the CEE/MPA trial, an increased risk of coronary heart disease (CHD) events (defined as nonfatal myocardial infarction and CHD death) was observed in women receiving CEE/MPA compared to women receiving placebo (37 vs 30 per 10,000 person years). The increase in VTE risk was observed in year 1 and persisted over the observation period (see Dosage & Administration).
Stroke: In the WHI CEE/MPA trial, an increased risk of stroke was observed in women receiving CEE/MPA compared to women receiving placebo (29 vs 21 per 10,000 person-years). The increase in risk was observed in year one and persisted over the observation period (see Dosage & Administration).
Venous thromboembolism/Pulmonary embolism: HT is associated with a higher relative risk of developing venous thromboembolism (VTE), i.e., deep vein thrombosis or pulmonary embolism. In the WHI CEE/MPA trial, a 2-fold greater rate of VTE, including deep venous thrombosis and pulmonary embolism was observed in women receiving CEE/MPA compared to women receiving placebo. The increase in risk was observed in year one and persisted over the observation period (see Precautions).
Dementia: The Women's Health Initiative Memory Study (WHIMS) (see Pharmacology: Pharmacodynamics under Actions), an ancillary study of WHI for CEE/MPA, reported an increased risk of probable dementia in postmenopausal women 65 years of age or older. In addition, CEE/MPA therapy did not prevent mild cognitive impairment (MCI) in these women. Use of hormone therapy (HT) to prevent dementia or MCI in women 65 years or older is not recommended.
Ovarian Cancer: Current use of estrogen only or estrogen plus progestin products in post-menopausal women for five or more years, has been associated with an increased risk of ovarian cancer in some epidemiological studies. Past users of estrogen only or estrogen plus progestin products were at no increased risk for ovarian cancer. Other studies did not show a significant association. The WHI CEE/MPA trial reported that estrogen plus progestin increased the risk of ovarian cancer, but this risk was not statistically significant. In one study, women who use HRT are at increased risk of fatal ovarian cancer.
History and Physical Exam Recommendation: A complete medical and family history should be taken before the initiation of any hormone therapy. Pre-treatment and periodic physical examination should include special reference to blood pressure, breasts, abdomen and pelvic organs, including cervical cytology.
Oncology: MPA may produce Cushingoid symptoms.
Some patients receiving MPA may exhibit suppressed adrenal function.
MPA may decrease ACTH and hydrocortisone blood levels.
The physician/laboratory should be informed that in addition to the endocrine biomarkers listed previously, the use of MPA in oncology indications may also cause partial adrenal insufficiency (decrease in pituitary-adrenal axis response) during metyrapone testing. Thus, the ability of adrenal cortex to respond to ACTH should be demonstrated before metyrapone is administered.
Decrease in Bone Mineral Density: There are no studies on the bone mineral density (BMD) effects of orally administered MPA. An evaluation of BMD may be appropriate in some patients who use MPA long-term.
Effects on the Ability to Drive and Use Machines: The effect of medroxyprogesterone acetate on the ability to drive and use machinery has not been systematically evaluated.
Pregnancy: MPA is contraindicated in women who are pregnant.
Some reports suggest under certain circumstances, an association between intrauterine exposure to progestational drugs in the first trimester of pregnancy and genital abnormalities in fetuses.
If the patient becomes pregnant while using this drug, the patient should be apprised of the potential hazard to the fetus.
Lactation: MPA and its metabolites are excreted in the breast milk. There is no evidence to suggest that this presents any hazard to the nursing child.
Gynecology: (See Table 1.)
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Oncology: (See Table 2.)
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Aminoglutethimide administered concomitantly with high doses of oral MPA may significantly depress the serum concentrations of medroxyprogesterone acetate. Users of high-dose oral MPA should be warned of the possibility of decreased efficacy with the use of aminoglutethimide.
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 and therefore, the clinical effects of CYP3A4 inducers or inhibitors are unknown.
Incompatibilities: No incompatibility is known for oral formulation.
Store at temperature not exceeding 25°C.
G03DA02 - medroxyprogesterone ; Belongs to the class of pregnen (4) derivative progestogens.
Tab 10 mg (round, white, biconvex, engraved with "PROVERA 10" around the periphery on one side and scored on the other) x 100's.