FDA label 11b99f8b-d06a-50c3-e054-00144ff88e88

WARNINGS CARDIOVASCULAR AND OTHER RISKS Estrogens with progestins should not be used for the prevention of cardiovascular disease or dementia. ( See CLINICAL STUDIES and WARNINGS, Cardiovascular Disorders and Dementia .) The Women’s Health Initiative (WHI) estrogen plus progestin substudy reported increased risks of myocardial infarction, stroke, invasive breast cancer, pulmonary emboli, and deep vein thrombosis (DVT) 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 and Malignant Neoplasms , Breast Cancer .) The Women’s Health Initiative Memory Study (WHIMS), a substudy of the WHI study, reported 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 STUDIES and WARNINGS, Dementia , and PRECAUTIONS , Geriatric Use. ) 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. Because of these risks, estrogens with or without progestins should be prescribed at the lowest effective doses and for the shortest duration consistent with treatment goals and risks for the individual woman.

WHAT IS THE MOST IMPORTANT INFORMATION I SHOULD KNOW ABOUT MEDROXYPROGESTERONE ACETATE (A PROGESTIN HORMONE)? * Vaginal bleeding after menopause may be a warning sign of cancer of the uterus (womb). Your health care provider should check any unusual vaginal bleeding to find out the cause. * Do not use estrogens with or without progestins to prevent heart disease, heart attacks, or strokes. Using estrogens with or without progestins may increase your chance of getting heart attacks, strokes, breast cancer, and blood clots. * Using estrogens with or without progestins may increase your risk of dementia, based on a study of women age 65 years or older. You and your health care provider should talk regularly about whether you still need treatment with medroxyprogesterone acetate.

WARNINGS See BOXED WARNINGS. 1. Cardiovascular Disorders. An increased risk of stroke, deep vein thrombosis (DVT), pulmonary embolism, and myocardial infarction 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 (for example, personal history or family history of venous thromboembolism [VTE]), obesity, and systemic lupus erythematosus should be managed appropriately. a. Stroke In the estrogen plus progestin substudy of the Women’s Health Initiative (WHI) a statistically significant increased risk of stroke was reported in women receiving daily conjugated estrogens (CE 0.625 mg) plus medroxyprogesterone acetate (MPA 2.5 mg) compared to women receiving placebo (31 versus 24 per 10,000 women-years). The increase in risk was demonstrated after the first year and persisted. ( See CLINICAL STUDIES .) b. Coronary heart disease In the estrogen plus progestin substudy of WHI, no statistically significant increase of CHD events (defined as non-fatal myocardial infarction [MI], silent MI or CHD death was reported in women receiving CE/MPA compared to women receiving placebo (39 versus 33 per 10,000 women-years). An increase in relative risk was demonstrated in year one, and a trend toward decreasing relative risk was reported in years 2 through 5. ( See CLINICAL STUDIES .) In postmenopausal women with documented heart disease (n = 2,763, average age 66.7 years), in a controlled clinical trial of secondary prevention of cardiovascular disease (Heart and Estro- gen/Progestin Replacement Study [HERS]), treatment with daily CE 0.625 mg/ MPA 2.5 mg per day demonstrated no cardiovascular benefit. During an average follow-up of 4.1 years, treatment with CE/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/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/MPA group and the placebo group in HERS, HERS II, and overall. c. Venous thromboembolism (VTE) In the estrogen plus progestin substudy of WHI, a statistically significant two-fold greater rate of VTE, (DVT and pulmonary embolism [PE]), was reported in women receiving daily CE/MPA 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 observed during the first year and persisted. ( See CLINICAL STUDIES .) 2. Malignant Neoplasms a. Breast cancer The use of estrogens and progestins by postmenopausal women has been reported to increase the risk of breast cancer in some studies. 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. The risk increased with duration of use and appeared to return to baseline in about 5 years after stopping treatment (only the observational studies have substantial data on risk after stopping). 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. However, these studies have not found significant variation in the risk of breast cancer among different estrogens or among different estrogen plus progestin combinations, doses, or routes of administration. The most important randomized clinical trial providing information about this issue is the Women’s Health Initiative (WHI) substudy of daily conjugated estrogens (CE 0.625 mg) plus medroxyprogesterone acetate (MPA 2.5 mg) ( See CLINICAL STUDIES .) In the estrogen plus progestin substudy of WHI, after a mean follow-up of 5.6 years, the WHI substudy reported an increased risk of breast cancer in women who took daily CE/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 (95 percent nominal confidence interval [nCI], 1.01 to 1.54), and the absolute risk was 41 versus 33 cases per 10,000 women-years, for estrogen plus progestin compared with placebo, respectively. 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/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 estrogen plus progestin compared with placebo. In the same substudy, invasive breast cancers were larger and diagnosed at a more advanced stage in the CE/MPA 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. The use of estrogen plus progestin has been reported to result in an increase in abnormal mammograms requiring further evaluation. All women should receive yearly breast examinations by a health care provider and perform monthly breast self-examinations. In addition, mammography examinations should be scheduled based on patient age, risk factors, and prior mammogram results. b. Endometrial cancer An increased risk of endometrial cancer has been reported with the use of unopposed estrogen therapy in women with a uterus. The reported endometrial cancer risk among unopposed estrogen users is about 2- to 12 times greater than in nonusers, and appears dependent on duration of treatment and on estrogen dose. Most studies show no significant increased risk associated with the use of estrogens for less than 1 year. The greatest risk appears associated with prolonged use, with increased risks of 15- to 24-fold for 5 to 10 years or more. This risk has been shown to persist for at least 8 to 15 years after estrogen therapy is discontinued. Clinical surveillance of all women using estrogen plus progestin therapy is important. Adequate diagnostic measures, including endometrial sampling when indicated, should be undertaken to rule out malignancy in all cases of undiagnosed persistent or recurring abnormal vaginal bleeding. There is no evidence that the use of natural estrogens results in a different endometrial risk profile than synthetic estrogens of equivalent estrogen dose. Adding a progestin to estrogen therapy has been shown to reduce the risk of endometrial hyperplasia, which may be a precursor to endometrial cancer. c. Ovarian cancer The estrogen plus progestin substudy of WHI reported that daily CE/MPA increased the risk of ovarian cancer. After an average follow-up of 5.6 years, the relative risk for ovarian cancer for CE/MPA versus placebo was 1.58 (95 percent nCI, 0.77 to 3.24) but was not statistically significant. The absolute risk for CE/MPA was 4.2 versus 2.7 cases per 10,000 women-years. 3. Dementia In the estrogen plus progestin Women’s Health Initiative Memory Study (WHIMS), a substudy of WHI, a population of 4,532 postmenopausal women aged 65 to 79 years was randomized to daily conjugated estrogens (CE 0.625 mg) plus medroxyprogesterone acetate (MPA 2.5 mg) or placebo. After an average follow-up of 4 years, 40 women in the CE/MPA group and 21 women in the placebo group were diagnosed with probable dementia. The relative risk of probable dementia for CE/MPA versus placebo was 2.05 (95 percent CI, 1.21 to 3.48). The absolute risk of probable dementia for CE/MPA versus placebo was 45 versus 22 cases per 10,000 women-years. It is unknown whether these findings apply to younger postmenopausal women. (See BOXED WARNINGS and PRECAUTIONS, Geriatric Use. ) 4. Visual Abnormalities Discontinue medication pending examination if there is sudden partial or complete loss of vision, or a sudden onset of proptosis, diplopia or migraine. If examination reveals papilledema or retinal vascular lesions, medication should be permanently discontinued.

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 progestins, including medroxyprogesterone acetate 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 additional adverse reactions have been reported with estrogen and/or 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/anaplylactic reactions; hypocalcemia; exacerbation of asthma; increased triglycerides.