ESTROGENS INCREASE THE RISK OF ENDOMETRIAL CANCER Close clinical surveillance of all women taking estrogens 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 estrogen doses (see WARNINGS: Malignant Neoplasms: Endometrial Cancer). CARDIOVASCULAR AND OTHER RISKS Estrogens with or without progestins should not be used for the prevention of cardiovascular disease (see WARNINGS: Cardiovascular Disorders). 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 (50 to 79 years of age) during 5 years of treatment with oral conjugated estrogens (CE 0.625 mg) combined with medroxyprogesterone acetate (MPA 2.5 mg) relative to placebo (see CLINICAL PHARMACOLOGY: Clinical Studies). The Women’s Health Initiative Memory Study (WHIMS), a substudy of WHI, reported increased risk of developing probable dementia in postmenopausal women 65 years of age or older during 4 years of treatment with oral conjugated estrogens plus medroxyprogesterone acetate relative to placebo. It is unknown whether this finding applies to younger postmenopausal women or to women taking estrogen alone therapy (see CLINICAL PHARMACOLOGY: Clinical Studies). Other doses of oral conjugated estrogens with medroxyprogesterone acetate, and other combinations and dosage forms of estrogens and progestins were not studied in the WHI clinical trials 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.
INDICATIONS AND USAGE Estradiol tablets are indicated in the: 1.Treatment of moderate to severe vasomotor symptoms associated with the menopause. 2.Treatment of moderate to severe symptoms of vulvar and vaginal atrophy associated with the menopause. When prescribing solely for the treatment of symptoms of vulvar and vaginal atrophy, topical vaginal products should be considered. 3.Treatment of hypoestrogenism due to hypogonadism, castration or primary ovarian failure. 4.Treatment of breast cancer (for palliation only) in appropriately selected women and men with metastatic disease. 5.Treatment of advanced androgen-dependent carcinoma of the prostate (for palliation only). 6.Prevention of osteoporosis. When prescribing solely for the prevention of postmenopausal osteoporosis, therapy should only be considered for women at significant risk of osteoporosis and for whom non-estrogen medications are not considered to be appropriate (see CLINICAL PHARMACOLOGY: Clinical Studies). The mainstays for decreasing the risk of postmenopausal osteoporosis are weight bearing exercise, adequate calcium and vitamin D intake, and when indicated, pharmacologic therapy. Postmenopausal women require an average of 1500 mg/day of elemental calcium. Therefore, when not contraindicated, calcium supplementation may be helpful for women with suboptimal dietary intake. Vitamin D supplementation of 400 to 800 IU/day may also be required to ensure adequate daily intake in postmenopausal women.
CONTRAINDICATIONS Estrogens should not be used in individuals with any of the following conditions: 1.Undiagnosed abnormal genital bleeding. 2.Known, suspected or history of cancer of the breast except in appropriately selected patients being treated for metastatic disease. 3.Known or suspected estrogen-dependent neoplasia. 4.Active deep vein thrombosis, pulmonary embolism or history of these conditions. 5.Active or recent (e.g., within the past year) arterial thromboembolic disease (e.g., stroke, myocardial infarction). 6.Liver dysfunction or disease. 7.Estradiol tablets should not be used in patients with known hypersensitivity to its ingredients. 8.Known or suspected pregnancy. There is no indication for estradiol in pregnancy. There appears to be little or no increased risk of birth defects in children born to women who have used estrogens and progestins from oral contraceptives inadvertently during early pregnancy (see PRECAUTIONS).
ADVERSE REACTIONS See BOXED WARNINGS, WARNINGS and PRECAUTIONS. The following additional adverse reactions have been reported with estrogen and/or progestin therapy. 1. Genitourinary system Changes in vaginal bleeding pattern and abnormal withdrawal bleeding or flow; breakthrough bleeding, spotting, dysmenorrhea 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 Steepening of corneal curvature 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 Arthralgias; leg cramps Changes in libido Urticaria Angioedema Anaphylactoid/anaphylactic reactions Hypocalcemia Exacerbation of asthma Increased triglycerides