Esterified Estrogens and Methyltestosterone

INDICATIONS AND USAGE Esterified Estrogens and Methyltestosterone Tablets and Esterified Estrogens and Methyltestosterone Tablets H.S. are indicated in the: Treatment of moderate to severe vasomotor symptoms associated with the menopause in those patients not improved by estrogens alone. (There is no evidence that estrogens are effective for nervous symptoms or depression without associated vasomotor symptoms, and they should not be used to treat such conditions.) Esterified Estrogens and Methyltestosterone Tablets and Esterified Estrogens and Methyltestosterone Tablets H.S. have not been shown to be effective for any purpose during pregnancy and its use may cause severe harm to the fetus.

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. Given cyclically for short-term use only: For treatment of moderate to severe vasomotor symptoms associated with the menopause in patients not improved by estrogen alone. The lowest dose that will control symptoms should be chosen and medication should be discontinued as promptly as possible. Administration should be cyclic (e.g., three weeks on and one week off). Attempts to discontinue or taper medication should be made at three- to six month intervals. Usual Dosage Range: 1 tablet of Esterified Estrogens and Methyltestosterone Tablets or 1 to 2 tablets of Esterified Estrogens and Methyltestosterone Tablets H.S. daily as recommended by the physician. Treated patients with an intact uterus should be monitored closely for signs of endometrial cancer and appropriate diagnostic measures should be taken to rule out malignancy in the event of persistent or recurring abnormal vaginal bleeding.

WARNINGS See BOXED WARNINGS . Warnings Associated with Estrogens Cardiovascular Disorders Estrogen and estrogen/progestin therapy has 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. Coronary Heart Disease and Stroke: In the Women’s Health Initiative (WHI) study, an increase in the number of myocardial infarctions and strokes was observed in women receiving CE compared to placebo. The CE-only substudy has concluded. The impact of those results are under review. (See CLINICAL PHARMACOLOGY, Clinical Studies . ) In the CE/MPA substudy of WHI, an increased risk of coronary heart disease (CHD) events (defined as nonfatal myocardial infarction and CHD death) was observed in women receiving CE/MPA compared to women receiving placebo (37 versus 30 per 10,000 women-years). The increase in risk was observed in year 1 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 versus 21 per 10,000 women-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. Venous Thromboembolism (VTE.): In the Women’s Health Initiative (WHI) study, an increase in VTE was observed in women receiving CE compared to placebo. The CE-only substudy has concluded. The impact of those results are under review. (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 women-years in the CE/MPA group compared to 16 per 10,000 women-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 the type associated with an increased risk of thromboembolism, or during periods of prolonged immobilization. Malignant Neoplasms 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 in …

CONTRAINDICATIONS Esterified Estrogens and Methyltestosterone Tablets and Esterified Estrogens and Methyltestosterone Tablets H.S. should not be used in women with any of the following conditions: 1. Undiagnosed abnormal genital bleeding. 2. Known, suspected, or history of cancer of the breast. 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. Esterified Estrogens and Methyltestosterone Tablets and Esterified Estrogens and Methyltestosterone Tablets H.S. should not be used in patients with known hypersensitivity to its ingredients. 8. Known or suspected pregnancy. There is no indication for Esterified Estrogens and Methyltestosterone Tablets and Esterified Estrogens and Methyltestosterone Tablets H.S. 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 . ) Methyltestosterone should not be used in: 1. The presence of severe liver damage. 2. Pregnancy and in breast-feeding mothers because of the possibility of masculinization of the female fetus or breast-fed infant.

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. Associated with Estrogens (See WARNINGS regarding induction of neoplasia, adverse effects on the fetus, increased incidence of gallbladder disease, and adverse effects similar to those of oral contraceptives, including thromboembolism). The following additional adverse reactions have been reported with estrogen and/or progestin therapy. 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; cystitis-like syndrome. Breasts: Tenderness; enlargement; pain, nipple discharge, galactorrhea; fibrocystic breast changes; breast cancer. Cardiovascular: Deep and superficial venous thrombosis; pulmonary embolism; thrombophlebitis; myocardial infarction; stroke; increase in blood pressure. Gastrointestinal: Nausea; vomiting; abdominal cramps; bloating; cholestatic jaundice; increased incidence of gallbladder disease; pancreatitis, enlargement of hepatic hemangiomas. Skin: Chloasma or melasma that may persist when drug is discontinued; erythema multiforme; erythema nodosum; hemorrhagic eruption; loss of scalp hair; hirsutism; pruritus, rash. Eyes: Retinal vascular thrombosis, steepening of corneal curvature, intolerance to contact lenses. Central Nervous System: Headache, migraine, dizziness; mental depression; chorea; nervousness; mood disturbances; irritability; exacerbation of epilepsy, dementia. 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. Associated with Methyltestosterone Endocrine and Urogenital Female: The most common side effects of androgen therapy are amenorrhea and other menstrual irregularities, inhibition of gonadotropin secretion, and virilization, including deepening of the voice and clitoral enlargement. The latter usually is not reversible after androgens are discontinued. When administered to a pregnant woman, androgens cause virilization of external genitalia of the female fetus. Skin and Appendages: Hirsutism, male pattern of baldness, and acne. Fluid and Electrolyte Disturbances: Retention of sodium, chloride, water, potassium, calcium, and inorganic phosphates. Gastrointestinal: Nausea, cholestatic jaundice, alterations in liver function test, rarely hepatocellular neoplasms, and peliosis hepatis. (See WARNINGS .) Hematologic: Suppression of clotting factors II, V, VII, and X, bleeding in patients on concomitant anticoagulant therapy, and polycythemia. Central Nervous System: Increased or decreased libido, headache, anxiety, depression, and generalized paresthesia. Metabolic: Increased serum cholesterol. Miscellaneous: Inflammation and pain at the site of intramuscular injection or subcutaneous implantation of testosterone containing pellets, stomatitis with buccal preparations, and rarely anaphylactoid reactions.