Estradiol

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.

DOSAGE AND ADMINISTRATION When estrogen is prescribed for a postmenopausal woman with a uterus, a progestin should also be initiated to reduce the risk of endometrial cancer. A woman without a uterus does not need progestin. Use of estrogen, alone or in combination with a progestin, should be with the lowest effective dose and for the shortest duration consistent with treatment goals and risks for the individual woman. Patients should be reevaluated periodically as clinically appropriate (e.g., 3-month to 6-month intervals) to determine if treatment is still necessary (see BOXED WARNINGS and WARNINGS ). For women who have a uterus, adequate diagnostic measures, such as endometrial sampling, when indicated, should be undertaken to rule out malignancy in cases of undiagnosed persistent or recurring abnormal vaginal bleeding. Patients should be started at the lowest dose for the indication. 1. For treatment of moderate to severe vasomotor symptoms, vulval and vaginal atrophy associated with the menopause, the lowest dose and regimen that will control symptoms should be chosen and medication should be discontinued as promptly as possible. Attempts to discontinue or taper medication should be made at 3-month to 6-month intervals. The usual initial dosage range is 1 to 2 mg daily of estradiol adjusted as necessary to control presenting symptoms. The minimal effective dose for maintenance therapy should be determined by titration. Administration should be cyclic (e.g., 3 weeks on and 1 week off). 2. For treatment of female hypoestrogenism due to hypogonadism, castration, or primary ovarian failure. Treatment is usually initiated with a dose of 1 to 2 mg daily of estradiol, adjusted as necessary to control presenting symptoms; the minimal effective dose for maintenance therapy should be determined by titration. 3. For treatment of breast cancer, for palliation only, in appropriately selected women and men with metastatic disease. Suggested dosage is 10 mg three times daily for a period of at least three months. 4. For treatment of advanced androgen-dependent carcinoma of the prostate, for palliation only. Suggested dosage is 1 to 2 mg three times daily. The effectiveness of therapy can be judged by phosphatase determinations as well as by symptomatic improvement of the patient. 5. For prevention of osteoporosis. When prescribing solely for the prevention of postmenopausal osteoporosis, therapy should be considered only for women at significant risk of osteoporosis and for whom non-estrogen medications are not considered to be appropriate. The lowest effective dose of estradiol has not been determined.

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. Estradiol tablets 2 mg contain FD&C Yellow No. 5 (tartrazine) which may cause allergic-type reactions (including bronchial asthma) in certain susceptible individuals. Although the overall incidence of FD&C Yellow No. 5 (tartrazine) sensitivity in the general population is low, it is frequently seen in patients who also have aspirin hypersensitivity. 8. Known or suspected pregnancy. There is no indication for estradiol tablets 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 To report SUSPECTED ADVERSE REACTIONS, contact ANI Pharmaceuticals, Inc. at 1-855-204-1431 or FDA at 1-800-FDA-1088 or http://www.fda.gov/medwatch.

D. Drug/Laboratory Test Interactions 1. Accelerated prothrombin time, partial thromboplastin time, and platelet aggregation time; increased platelet count; increased factors II, VII antigen, VIII antigen, VIII coagulant activity, IX, X, XII, VII-X complex, II-VII-X complex, and beta-thromboglobulin; decreased levels of anti-factor Xa and antithrombin III, decreased antithrombin III activity; increased levels of fibrinogen and fibrinogen activity; increased plasminogen antigen and activity. 2. Increased thyroid-binding globulin (TBG) leading to increased circulating total thyroid hormone, as measured by protein-bound iodine (PBI), T 4 levels (by column or by radioimmunoassay) or T 3 levels by radioimmunoassay. T 3 resin uptake is decreased, reflecting the elevated TBG. Free T 4 and free T 3 concentrations are unaltered. Patients on thyroid replacement therapy may require higher doses of thyroid hormone. 3. Other binding proteins may be elevated in serum, i.e., corticosteroid binding globulin (CBG), sex hormone-binding globulin (SHBG), leading to increased circulating corticosteroids and sex steroids, respectively. Free hormone concentrations may be decreased. Other plasma proteins may be increased (angiotensinogen/renin substrate, alpha-1-antitrypsin, ceruloplasmin). 4. Increased plasma HDL and HDL 2 subfraction concentrations, reduced LDL cholesterol concentration, increased triglycerides levels. 5. Impaired glucose tolerance. 6. Reduced response to metyrapone test.

DESCRIPTION Estradiol Tablets USP for oral administration contains 0.5, 1 or 2 mg of micronized estradiol, USP per tablet. Estradiol, USP (17β-estradiol) is a white to practically white powder, chemically described as estra-1,3,5,(10)-triene-3, 17β-diol. The structural formula is: C 18 H 24 O 2 M.W. 272.38 Inactive Ingredients: Colloidal silicon dioxide, corn starch, microcrystalline cellulose, lactose monohydrate, magnesium stearate, and sodium starch glycolate. In addition, the 1 mg also contains FD&C blue no. 1 aluminum lake and D&C red no. 27 aluminum lake. The 2 mg also contains FD&C blue no. 1 aluminum lake and D&C yellow no. 10 aluminum lake. FDA approved dissolution test specifications differ from USP. structure

OVERDOSAGE Serious ill effects have not been reported following acute ingestion of large doses of estrogen-containing oral contraceptives by young children. Overdosage of estrogen may cause nausea and vomiting, and withdrawal bleeding may occur in females.

HOW SUPPLIED Estradiol Tablets, USP, 0.5 mg are white to off-white, round, convex, bisected tablets, debossed “ Є ” above the bisect and “87” below the bisect on one side, and plain on the other side. NDC 76420-021-30 in bottles of 30 (repackaged from NDC 42806-087-XX) NDC 76420-021-90 in bottles of 90 (repackaged from NDC 42806-087-XX) Estradiol Tablets, USP, 1 mg are white to off-white, round, convex, bisected tablets, debossed “ Є ” above the bisect and “88” below the bisect on one side and plain on the other side. NDC 76420-022-30 in bottles of 30 (repackaged from NDC 42806-088-01) NDC 76420-022-90 in bottles of 90 (repackaged from NDC 42806-088-01) Estradiol Tablets, USP, 2 mg are white to off-white, round, convex, bisected tablets, debossed “ Є ” above the bisect and “89” below the bisect on one side and plain on the other side. NDC 76420-023-30 in bottles of 30 (repackaged from NDC 42806-089-01) NDC 76420-023-90 in bottles of 90 (repackaged from NDC 42806-089-01) Store at 20° to 25°C (68° to 77°F) [See USP Controlled Room Temperature]. Dispense contents in a tight, light-resistant container as defined in the USP, with a child-resistant closure, as required. KEEP THIS AND ALL MEDICATIONS OUT OF THE REACH OF CHILDREN. Repackaged by: Enovachem PHARMACEUTICALS Torrance, CA 90501