BOXED WARNING ESTROGENS INCREASE THE RISK OF ENDOMETRIAL CANCER Close clinical surveillance of all women taking estrogen 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 at equivalent estrogenic doses. CARDIOVASCULAR AND OTHER RISKS Estrogens with or without progestins should not be used for the prevention of cardiovascular disease. The Women’s Health Initiative (WHI) study reported increased risks of myocardial infarction, stroke, invasive breast cancer, pulmonary emboli, and deep vein thrombosis in postmenopausal women during 5 years of treatment with conjugated equine estrogens CE 0.625 mg) combined with medroxyprogesterone acetate (MPA 2.5 mg) relative to placebo ( see CLINICAL PHARMACOLOGY, Clinical Studies ). Other doses of conjugated estrogens and medroxyprogesterone acetate, and other combinations of estrogens and progestins were not studied in the WHI and, in the absence of comparable data, these risks should be assumed to be similar. 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.
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warnings
WARNINGS See BOXED WARNINGS . The use of unopposed estrogens in women who have a uterus is associated with an increased risk of endometrial cancer. 1. Cardiovascular disorders. Estrogen and estrogen/progestin therapy have been associated with an increased risk of cardiovascular events such as myocardial infarction and stroke, as well as venous thrombosis and pulmonary embolism (venous thromboembolism or VTE). Should any of these occur or be suspected, estrogens should be discontinued immediately. Risk factors for arterial vascular disease (e.g., hypertension, diabetes mellitus, tobacco use, hypercholesterolemia, and obesity) and/or venous thromboembolism (e.g., personal history or family history of VTE, obesity, and systemic lupus erythematosus) should be managed appropriately. a. Coronary heart disease and stroke. In the Women’s Health Initiative (WHI) study, an increase in the number of myocardial infarctions and strokes has been observed women receiving CE compared to placebo. These observations are preliminary, and the study is continuing. ( See CLINICAL PHARMACOLOGY, Clinical Studies .) In the CE/MPA substudy of WHI an increased risk of coronary heart disease (CHD) events (defined as non-fatal myocardial infarction and CHD death) was observed in women receiving CE/MPA compared to women receiving placebo (37 vs 30 per 10,000 personyears). The increase in risk was observed after the first year and persisted. In the same substudy of WHI, an increased risk of stroke was observed in women receiving CE/MPA compared to women receiving placebo (29 vs 21 per 10,000 person-years). The increase in risk was observed after the first year and persisted. In postmenopausal women with documented heart disease (n = 2,763, average age 66.7 years) a controlled clinical trial of secondary prevention of cardiovascular disease (Heart and Estrogen/Progestin Replacement Study; HERS) treatment with CE/MPA (0.625 mg/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 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. Large doses of estrogen (5 mg conjugated estrogens per day), comparable to those used to treat cancer of the prostate and breast, have been shown in a large prospective clinical trial in men to increase the risks of nonfatal myocardial infarction, pulmonary embolism, and thrombophlebitis. b. Venous thromboembolism (VTE). In the Woman’s Health Initiative (WHI) study, increase in VTE has been observed in women receiving CE compared to placebo. These observations are preliminary, and the study is continuing. ( See CLINICAL PHARMACOLOGY, Clinical Studies .) In the CE/MPA substudy of WHI, a 2-fold greater rate of VTE, including deep venous thrombosis and pulmonary embolism, was observed in women receiving CE/MPA compared to women receiving placebo. The rate of VTE was 34 per 10,000 person-years in the CE/MPA group compared to 16 per 10,000 person-years in the placebo group. The increase in VTE risk was observed during the first year and persisted. If feasible, estrogens should be discontinued at least 4 to 6 weeks before surgery of type associated with an increased risk of thromboembolism, or during periods of prolonged immobilization. 2. Malignant neoplasms. a. Endometrial cancer . The use of unopposed estrogens in women with intact uteri has been associated with an increased risk of endometrial cancer. The reported endometrial cancer risk among unopposed estrogen users is about 2- to 12-fold greater than 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 use over 5 to 10 years or more, and this risk has been shown persist at least 8 to 15 years after estrogen therapy is discontinued. Clinical surveillance of all women taking estrogen/progestin combinations 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 postmenopausal estrogen therapy has been shown to reduce the risk of endometrial hyperplasia, which may be a precursor to endometrial cancer. b. Breast cancer. Estrogen and estrogen/progestin therapy in postmenopausal women has been associated with an increased risk of breast cancer. In the CE/MPA substudy of the Women’s Health Initiative (WHI) study, a 26% increase in invasive breast cancer (38 vs 30 per 10,000 person-years) after an average of 5.2 years of treatment was observed in women receiving CE/MPA compared to women receiving placebo. The increased risk of breast cancer became apparent after 4 years of treatment with CE/MPA. The women reporting prior postmenopausal use of estrogens and/or estrogens with progestin had higher relative risk for breast cancer associated with CE/MPA than those who had never used these hormones. ( See CLINICAL PHARMACOLOGY, Clinical Studies .) In the WHI, no increased risk of breast cancer in CE-treated women compared to placebo was reported after an average of 5.2 years of therapy. These data are preliminary and that substudy of WHI is continuing. Epidemiologic studies have reported an increased risk of breast cancer in association with increasing duration of postmenopausal treatment with estrogens with or without a progestin. This association was reanalyzed in original data from 51 studies that involved various doses and types of estrogens, with and without progestin. In the reanalysis, an increased risk of having breast cancer diagnosed became apparent after about 5 years of continuous treatment and subsided after treatment had been discontinued for 5 years or longer. Some later studies have suggested that postmenopausal treatment with estrogens and progestin increases the risk of breast cancer more than treatment with estrogen alone. 3. Gallbladder disease. A 2- to 4-fold increase in the risk of gallbladder disease requiring surgery in postmenopausal women receiving estrogens has been reported. 4. Hypercalcemia. Estrogen administration may lead to severe hypercalcemia in patients with breast cancer and bone metastases. If hypercalcemia occurs, the drug should be stopped and appropriate measures taken to reduce the serum calcium level. 5. Visual abnormalities. Retinal vascular thrombosis has been reported in patients receiving estrogens. 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, estrogens should be 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 adverse reaction information from clinical trials does, however, provide a basis for identifying the adverse events that appear to be related to drug use and for approximating rates. Table 4 summarizes the treatment-emergent adverse events with Estrasorb® therapy. Table 4. Number (%) of Patients Reporting ≥ 5% Treatment-Emergent Adverse Events Treatment group Body System/ Preferred term Statistic Placebo (n=134 ) Estrasorb ® 3.45 grams (n=139) Number of subjects with ≥ 1 TEAE n (%) 82 (61) 95 (68) Body as a whole n(%) 40 (30) 49 (35) Headache n(%) 17 (13) 12 (9) Infection n(%) 10 (7) 16 (12) Respiratory n(%) 15(11) 19 (14) Sinusitis n(%) 6 (4) 9 (6) Skin and appendages n(%) 7 (5) 15(11) Pruritus n(%) 0 5 (4) Urogenital n(%) 20 (15) 44 (32) Breast pain n(%) 4 (3) 14 (10) Endometrial disorder n(%) 11 (8) 21 (15) TEAE=Treatment-emergent adverse event. The following adverse reactions have been reported with estrogen therapy: 1. Genitourinary system . Changes in vaginal bleeding pattern and abnormal withdrawal bleeding or flow; breakthrough bleeding, spotting; increase in size of uterine leiomyomata; 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 gall bladder disease; pancreatitis. 5. Skin. Chloasma or melasma that may persist when drug is discontinued; erythema multiforme; erythema nodosum; hemorrhagic eruption; loss of scalp hair; hirsutism; pruritis, rash. 6. Eyes. Retinal vascular thrombosis, steepening of corneal curvature, intolerance to contact lenses. 7. Central Nervous System . Headache, migraine, dizziness; mental depression; chorea; nervousness; mood disturbance; anxiety; irritability; insomnia; somnolence; exacerbation of epilepsy. 8. Miscellaneous . Increase or decrease in weight; reduced carbohydrate tolerance; aggravation of porphyria; edema; arthralgia; leg cramps; changes in libido; anaphylactoid/ anaphylactic reactions; hypocalcemia; exacerbation of asthma; increased triglycerides.