Medroxyprogesterone: uses, appearance and warnings

PROVERA 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.

PROVERA Tablets are available in the following strengths and package sizes: 2.5 mg tablets (scored, round, orange, imprinted PROVERA 2.5) Bottles of 100: NDC 0009-0065-01 5 mg tablets (scored, round, blue, imprinted PROVERA 5) Bottles of 100: NDC 0009-0287-01 10 mg tablets (scored, round, white, imprinted PROVERA 10) Bottles of 100: NDC 0009-0051-01 Store at controlled room temperature 20° to 25°C (68° to 77°F) [see USP]. "Keep out of reach of children"

PROVERA 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 PROVERA. 7. Known liver impairment or disease. 8. Known or suspected pregnancy.

See BOXED WARNINGS . 1. Cardiovascular Disorders An increased risk of PE, DVT, stroke, and MI has been reported with estrogen plus progestin therapy. Should any of these events occur or be suspected, estrogen plus progestin therapy should be discontinued immediately. Risk factors for arterial vascular disease (for example, hypertension, diabetes mellitus, tobacco use, hypercholesterolemia, and obesity) and/or venous thromboembolism (VTE) (for example, personal history or family history of VTE, obesity, and systemic lupus erythematosus) should be managed appropriately. a. Stroke In the WHI estrogen plus progestin substudy, a statistically significant increased risk of stroke was reported in women 50 to 79 years of age receiving CE (0.625 mg) plus MPA (2.5 mg) compared to women in the same age group receiving placebo (33 versus 25 per 10,000 women-years). (See CLINICAL STUDIES .) The increase in risk was demonstrated after the first year and persisted. Should a stroke occur or be suspected, estrogen plus progestin therapy should be discontinued immediately. b. Coronary Heart Disease In the WHI estrogen plus progestin substudy, there was a statistically non-significant increased risk of CHD events reported in women receiving daily CE (0.625 mg) plus MPA (2.5 mg) compared to women receiving placebo (41 versus 34 per 10,000 women-years). An increase in relative risk was demonstrated in year 1, and a trend toward decreasing relative risk was reported in years 2 through 5. In postmenopausal women with documented heart disease (n = 2,763, average 66.7 years of age), in a controlled clinical trial of secondary prevention of cardiovascular disease (Heart and Estrogen/Progestin Replacement Study [HERS]), treatment with daily CE (0.625 mg) plus MPA (2.5mg) demonstrated no cardiovascular benefit. During an average follow-up of 4.1 years, treatment with CE plus MPA did not reduce the overall rate of CHD events in postmenopausal women with established coronary heart disease. There were more CHD events in the CE plus MPA-treated group than in the placebo group in year 1, but not during the subsequent years. Two thousand three hundred and twenty-one (2,321) women from the original HERS trial agreed to participate in an open label extension of HERS, HERS II. Average follow-up in HERS II was an additional 2.7 years, for a total of 6.8 years overall. Rates of CHD events were comparable among women in the CE plus MPA group and the placebo group in HERS, HERS II, and overall. c. Venous Thromboembolism In the WHI estrogen plus progestin substudy, a statistically significant 2-fold greater rate of VTE (DVT and PE) was reported in women receiving daily CE (0.625 mg) plus MPA (2.5 mg) compared to women receiving placebo (35 versus 17 per 10,000 women-years). Statistically significant increases in risk for both DVT (26 versus 13 per 10,000 women-years) and PE (18 versus 8 per 10,000 women-years) were also demonstrated. The increase in VTE risk was demonstrated during the first year and persisted. (See CLINICAL STUDIES . ) Should a VTE occur or be suspected, estrogen plus progestin therapy should be discontinued immediately. If feasible, estrogens plus progestins should be discontinued at least 4 to 6 weeks before surgery of the type associated with an increased risk of thromboembolism, or during periods of prolonged immobilization. 2. Malignant Neoplasms a. Breast Cancer The WHI substudy of daily CE (0.625 mg)-alone provided information about breast cancer in estrogen-alone users. In the WHI estrogen-alone substudy, after an average follow-up of 7.1 years, daily CE-alone was not associated with an increased risk of invasive breast cancer [relative risk (RR) 0.80] compared to placebo (see CLINICAL STUDIES ). After a mean follow-up of 5.6 years, the estrogen plus progestin substudy reported an increased risk of invasive breast cancer in women who took daily CE plus MPA. In this substudy, prior use of estrogen-alone or estrogen plus progestin therapy was reported by 26 percent of the women. The relative risk of invasive breast cancer was 1.24, and the absolute risk was 41 versus 33 cases per 10,000 women-years, for CE plus MPA compared with placebo. Among women who reported prior use of hormone therapy, the relative risk of invasive breast cancer was 1.86, and the absolute risk was 46 versus 25 cases per 10,000 women-years, for CE plus MPA compared with placebo. Among women who reported no prior use of hormone therapy, the relative risk of invasive breast cancer was 1.09, and the absolute risk was 40 versus 36 cases per 10,000 women-years, for CE plus MPA compared with placebo. In the same substudy, invasive breast cancers were larger, were more likely to be node positive, and were diagnosed at a more advanced stage in the CE (0.625 mg) plus MPA (2.5 mg) group compared with the placebo group. Metastatic disease was rare with no apparent difference between the two groups. Other prognostic factors such as histologic subtype, grade, and hormone receptor status did not differ between the groups. (See CLINICAL STUDIES .) Consistent with the WHI clinical trials, observational studies have also reported an increased risk of breast cancer for estrogen plus progestin therapy, and a smaller, increased risk for estrogen-alone therapy, after several years of use. One large meta-analysis of prospective cohort studies reported increased risks that were dependent upon duration of use and could last up to >10 years after discontinuation of estrogen plus progestin therapy and estrogen-alone therapy. Extension of the WHI trials also demonstrated increased breast cancer risk associated with estrogen plus progestin therapy. Observational studies also suggest that the risk of breast cancer was greater, and became apparent earlier, with estrogen plus progestin therapy as compared to estrogen-alone therapy. …

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 PROVERA 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. …