ESTROGENS, ESTERIFIED: 106 Adverse Event Reports & Safety Profile

DESCRIPTION Esterified Estrogens and Methyltestosterone Tablets: Each dark green, capsule shaped, sugar-coated oral tablet imprinted with “1490” contains: 1.25 mg of Esterified Estrogens, USP and 2.5 mg of Methyltestosterone, USP.

Esterified

Estrogens and Methyltestosterone Half-Strength Tablets: Each light green, capsule shaped, sugar-coated oral tablet imprinted with “1507” contains: 0.625 mg of Esterified Estrogens, USP and 1.25 mg of Methyltestosterone, USP.

Esterified Estrogens Esterified

Estrogens, USP is a mixture of the sodium salts of the sulfate esters of the estrogenic substances, principally estrone, that are of the type excreted by pregnant mares.

Esterified

Estrogens contain not less than 75.0 percent and not more than 85.0 percent of sodium estrone sulfate, and not less than 6.0 percent and not more than 15.0 percent of sodium equilin sulfate, in such proportion that the total of these two components is not less than 90.0 percent.

Methyltestosterone

Methyltestosterone, USP is an androgen. Androgens are derivatives of cyclopentano-perhydrophenanthrene. Endogenous androgens are C-19 steroids with a side chain at C-17, and with two angular methyl groups. Testosterone is the primary endogenous androgen. Fluoxymesterone and methyltestosterone are synthetic derivatives of testosterone. Methyltestosterone is a white to light yellow crystalline substance that is virtually insoluble in water but soluble in organic solvents. It is stable in air but decomposes in light. Methyltestosterone structural formula: Esterified Estrogens and Methyltestosterone Full and Half-Strength Tablets contain the following inactive ingredients: acacia, calcium carbonate, carnauba wax, citric acid, colloidal silicon dioxide, di-acetylated monoglycerides, gelatin, lactose, magnesium stearate, methylparaben, microcrystalline cellulose, pharmaceutical glaze, povidone, propylene glycol, propylparaben, shellac glaze, sodium benzoate, sodium bicarbonate, sorbic acid, starch, sucrose, talc, titanium dioxide, tromethamol, FD&C Blue No. 1 Aluminum Lake, and D&C Yellow No. 10 Aluminum Lake.

Esterified

Estrogens and Methyltestosterone Tablets also contain: FD&C Yellow No. 6 Aluminum Lake.

Esterified

Estrogens and Methyltestosterone Half-Strength Tablets also contain: FD&C Blue No. 2 Aluminum Lake and Iron Oxide Black. 21328e7b-figure-01

INDICATIONS AND USAGE ESTERIFIED ESTROGENS AND METHYLTESTOSTERONE FULL STRENGTH and ESTERIFIED ESTROGENS AND METHYLTESTOSTERONE HALF STRENGTH 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 FULL STRENGTH and ESTERIFIED ESTROGENS AND METHYLTESTOSTERONE HALF STRENGTH HAVE NOT BEEN SHOWN TO BE EFFECTIVE FOR ANY PURPOSE DURING PREGNANCY AND ITS USE MAY CAUSE SEVERE HARM TO THE FETUS (SEE BOXED WARNING ).

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. 1. Given cyclically for short term use only: For treatment of moderate to severe vasomotor symptoms, or moderate to severe symptoms of vulvar and vaginal atrophy associated with the menopause. Administration should be cyclic (e.g., 3 weeks on and 1 week off). USUAL DOSAGE RANGES: Vasomotor symptoms – 1.25 mg daily. If the patient has not menstruated within the last 2 months or more, cyclic administration is started arbitrarily. If the patient is menstruating, cyclic administration is started on day 5 of bleeding. Moderate to severe symptoms of vulvar and vaginal atrophy – 0.3 mg to 1.25 mg or more daily, depending upon the tissue response of the individual patient. Administer cyclically. 2. Given cyclically: Female hypogonadism; female castration; primary ovarian failure. USUAL DOSAGE RANGES: Female hypogonadism – 2.5 to 7.5 mg daily, in divided doses for 20 days, followed by a rest period of 10 days' duration. If bleeding does not occur by the end of this period, the same dosage schedule is repeated. The number of courses of estrogen therapy necessary to produce bleeding may vary depending on responsiveness of the endometrium. If bleeding occurs before the end of the 10 day period, begin a 20 day estrogen-progestin cyclic regimen with Menest (esterified estrogens tablets), 2.5 to 7.5 mg daily in divided doses, for 20 days. During the last 5 days of estrogen therapy, give an oral progestin. If bleeding occurs before this regimen is concluded, therapy is discontinued and may be resumed on the fifth day of bleeding. Female castration and primary ovarian failure – 1.25 mg daily, cyclically. Adjust dosage upward or downward according to severity of symptoms and response of the patient. For maintenance, adjust dosage to lowest level that will provide effective control. 3. Given chronically: Inoperable progressing prostatic cancer — 1.25 to 2.5 mg three times daily. The effectiveness of therapy can be judged by phosphatase determinations as well as by symptomatic improvement of the patient. Inoperable progressing breast cancer in appropriately selected men and postmenopausal women. (See INDICATIONS AND USAGE ) – Suggested dosage is 10 mg three times daily for a period of at least 3 months. 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. The lowest effective dose of Menest has not been determined.

CONTRAINDICATIONS Esterified Estrogens and Methyltestosterone Tablets F.S. 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 F.S. 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 F.S. 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. To report SUSPECTED ADVERSE REACTIONS, contact ANI Pharmaceuticals, Inc. at 1-855-204-1431 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

9- Warnings and Precautions Associated with Estrogens Induction of malignant neoplasms. Long term continuous administration of natural and synthetic estrogens in certain animal species increases this frequency of carcinomas of the breast, cervix, vagina, and liver. There is now evidence that estrogens increase the risk of carcinoma of the endometrium in humans. At the present time there is no satisfactory evidence that estrogens given to postmenopausal women increase the risk of cancer of the breast,18 although a recent long-term follow-up of a single physician's practice has raised this possibility.18a Because of the animal data, there is a need for caution in prescribing estrogens for women with a strong family history of breast cancer or who have breast nodules, fibrocystic disease, or abnormal mammograms. Gallbladder disease. A recent study has reported a 2 to 3-fold increase in the risk of surgically confirmed gallbladder disease in women receiving postmenopausal estrogens,18 similar to the 2-fold increase previously noted in users of oral contraceptives as in the case of oral contraceptives the increased risk appeared after two years of use. Effects similar to those caused by estrogen-progesterone oral contraceptives. There are several serious adverse effects of oral contraceptives, most of which have not, up to now, been documented as consequences of postmenopausal estrogen therapy. This may reflect the comparatively low doses of estrogen used in postmenopausal women. It would be expected that the larger doses of estrogen used to treat prostatic or breast cancer or postpartum breast engorgement are more likely to result in these adverse effects, and, in fact, it has been shown that there is an increased risk of thrombosis in men receiving estrogens for prostatic cancer and women for postpartum breast engorgement. a. Thromboembolic disease. It is now well established that users of oral contraceptives have an increased risk of various thromboembolic and thrombotic vascular diseases, such as thrombophlebitis, pulmonary embolism, stroke, and myocardial infarction. Cases of retinal thrombosis, mesenteric thrombosis, and optic neuritis have been reported in oral contraceptive users. There is evidence that the risk of several of these adverse reactions is related to the dose of the drug. An increased risk of post- surgery thromboembolic complications has also been reported in users of oral contraceptives. If feasible, estrogen should be discontinued at least 4 weeks before surgery of the type associated with an increased risk of thromboembolism, or during periods of prolonged immobilization. While an increased rate of thromboembolic and thrombotic disease in postmenopausal users of estrogens has not been found, this does not rule out the possibility that such an increase may be present or that subgroups of women who have underlying risk factors or who are receiving relatively large doses of estrogens may have increased risk. Therefore, estrogens should not be used in persons with active thrombophlebitis or thromboembolic disorders, and they should not be used (except in treatment of malignancy) in persons with a history of such disorders in association with estrogen use. They should be used with caution in patients with cerebral vascular or coronary artery disease and only for those in whom estrogens are clearly needed. Large doses of estrogen (5 mg esterified 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 risk of nonfatal myocardial infarction, pulmonary embolism and thrombophlebitis. When estrogen doses of this size are used, any of the thromboembolic and thrombotic adverse effects associated with oral contraceptive use should be considered a clear risk. b. Hepatic adenoma. Benign hepatic adenomas appear to be associated with the use of oral contraceptives. Although benign and rare, these may rupture and may cause death through intra-abdominal hemorrhage. Such lesions have not yet been reported in association with other estrogen or progestogen preparations but should be considered in estrogen users having abdominal pain and tenderness, abdominal mass, or hypovolemic shock. Hepatocellular carcinoma has also been reported in women taking estrogen- containing oral contraceptives. The relationship of this malignancy to these drugs is not known at this time. c. Elevated blood pressure. Increased blood pressure is not uncommon in women using oral contraceptives. There is now a report that this may occur with use of estrogens in the menopause and blood pressure should be monitored with estrogen use, especially if high doses are used. d. Glucose tolerance. A worsening of glucose tolerance has been observed in a significant percentage of patients of estrogen- containing oral contraceptives. For this reason, diabetic patients should be carefully observed while receiving estrogens. Hypercalcemia. Administration of estrogens may lead to severe hypercalcemia in patients with breast cancer and bone metastases. If this occurs, the drug should be stopped and appropriate measures taken to reduce the serum calcium level. Associated with Methyltestosterone In patients with breast cancer, androgen therapy may cause hypercalcemia by stimulating osteolysis. In this case the drug should be discontinued. Prolonged use of high doses of androgens has been associated with the development of peliosis hepatis and hepatic neoplasms including hepatocellular carcinoma. (See PRECAUTIONS – Carcinogenesis ). Peliosis hepatis can be a life-threatening or fatal complication. Cholestatic hepatitis and jaundice occur with 17-alpha-alkylandrogens at a relatively low dose. If cholestatic hepatitis with jaundice appears or if liver function tests become abnormal, the androgen should be discontinued and the etiology should be determined. Drug-induced jaundice is reversible when the medication is discontinued. Edema with or without heart failure may be a serious complication in patients with preexisting cardiac, renal, or hepatic disease. In addition to discontinuation of the drug, diuretic therapy may be required.

Precautions

Associated with Estrogens A.

General

Precautions A complete medical and family history should be taken prior to the initiation of any estrogen therapy. The pretreatment and periodic physical examinations should include special reference to blood pressure, breasts, abdomen, and pelvic organs, and should include a Papanicolaou smear. As a general rule, estrogen should not be prescribed for longer than one year without another physical examination being performed. Fluid retention– Because estrogens may cause some degree of fluid retention, conditions which might be influenced by this factor such as asthma, epilepsy, migraine, and cardiac or renal dysfunction, require careful observation. Certain patients may develop undesirable manifestations of excessive estrogenic stimulation, such as abnormal or excessive uterine bleeding, mastodynia, etc. Oral contraceptives appear to be associated with an increased incidence of mental depression. Although it is not clear whether this is due to the estrogenic or progestogenic component of the contraceptive, patients with a history of depression should be carefully observed. Preexisting uterine leiomyomata may increase in size during estrogen use. The pathologist should be advised of estrogen therapy when relevant specimens are submitted. Patients with a past history of jaundice during pregnancy have an increased risk of recurrence of jaundice while receiving estrogen- containing oral contraceptive therapy. If jaundice develops in any patient receiving estrogen, the medication should be discontinued while the cause is investigated. Estrogens may be poorly metabolized in patients with impaired liver function and they should be administered with caution in such patients. Because estrogens influence the metabolism of calcium and phosphorus, they should be used with caution in patients with metabolic bone diseases that are associated with hypercalcemia or in patients with renal insufficiency. Because of the effects of estrogens on epiphyseal closure, they should be used judiciously in young patients in whom bone growth is not complete. Certain endocrine and liver function tests may be affected by estrogen-containing oral contraceptives. The following similar changes may be expected with larger doses of estrogen: a. Increased sulfobromophthalein retention. b. Increased prothrombin and factors VII, VIII, IX and X; decreased antithrombin 3: increased norepinephrine induced platelet aggregability. c. Increased thyroid binding globulin (TBG) leading to increased circulating total thyroid hormone, as measured by PBI, T4 by column, or T4 by radioimmunoassay. Free T3 resin uptakes is decreased, reflecting the elevated TBG; free T4 concentration is unaltered. d. Impaired glucose tolerance. e. Decreased pregnanediol excretion. f. Reduced response to metyrapone test. g. Reduced serum folate concentration. h. Increased serum triglyceride and phospholipid concentration. B.

Pregnancy

Category X See CONTRAINDICATIONS . C.

Nursing

Mothers As a general principle, the administration of any drug to nursing mothers should be done only when clearly necessary since many drugs are excreted in human milk. Associated with Methyltestosterone A.

General Precautions

Women should be observed for signs of virilization (deepening of the voice, hirsutism, acne, clitoromegaly, and menstrual irregularities). Discontinuation of drug therapy at the time of evidence of mild virilism is necessary to prevent irreversible virilization. Such virilization is usual following androgen use at high doses. Prolonged dosage of androgen may result in sodium and fluid retention. This may present a problem, especially in patients with compromised cardiac reserve or renal disease. Hypersensitivity may occur rarely. PBI may be decreased in patients taking androgens. Hypercalcemia may occur. If this does occur, the drug should be discontinued. B. Information for the Patient The physician should instruct patients to report any of the following side effects of androgens: Women: Hoarseness, acne, changes in menstrual periods, or more hair on the face.

All

Patients: Any nausea, vomiting, changes in skin color of ankle swelling. C.

Laboratory Tests

Women with disseminated breast carcinoma should have frequent determination of urine and serum calcium levels during the course of androgen therapy. Because of the hepatotoxicity associated with the use of 17-alpha-alkylated androgens, liver function tests should be obtained periodically. Hemoglobin and hematocrit should be checked periodically for polycythemia in patients who are receiving high doses of androgens. D.

Drug Interactions

Anticoagulants C-17 substituted derivatives of testosterone, such as methandrostenolone, have been reported to decrease the anticoagulant requirements of patients receiving oral anticoagulants. Patients receiving oral anticoagulant therapy require close monitoring, especially when androgens are started or stopped. Oxyphenbutazone. Concurrent administration of oxyphenbutazone and androgens may result in elevated serum levels of oxyphenbutazone. Insulin. In diabetic patients the metabolic effects of androgens may decrease blood glucose and insulin requirements. E.

Drug/Laboratory

Test Interferences Androgens may decrease levels of thyroxine-binding globulin, resulting in decreased T4 serum levels and increased resin uptake of T3 and T4. Free thyroid hormone levels remain unchanged, however, and there is no clinical evidence of thyroid dysfunction. F.

Carcinogenesis Animal

Data. Testosterone has been tested by subcutaneous injection and implantation in mice and rats. The implant induced cervical-uterine tumours in mice, which metastasized in some cases. There is suggestive evidence that injection of testosterone into some strains of female mice increases their susceptibility to hepatoma. Testosterone is also known to increase the number of tumours and decrease the degree of differentiation of chemically induced carcinomas of the liver in rats.

Human

Data. There are rare reports of hepatocellular carcinoma in patients receiving long-term therapy with androgens in high doses. Withdrawal of the drugs did not lead to regression of the tumours in all cases.

Geriatric

Patients treated with androgens may be at an increased risk for the development of prostatic hypertrophy and prostatic carcinoma. G.

Pregnancy Teratogenic

Effects.

Pregnancy

Category X (see CONTRAINDICATIONS ). H.

Nursing

Mothers It is not known whether androgens are excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from androgens, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

PRECAUTIONS General Precautions Associated with Estrogens Addition of a progestin when a woman has not had a hysterectomy: Studies of the addition of a progestin for 10 or more days of a cycle of estrogen administration, or daily with estrogen in a continuous regimen, have reported a lowered incidence of endometrial hyperplasia than would be induced by estrogen treatment alone. Endometrial hyperplasia may be a precursor to endometrial cancer. There are, however, possible risks that may be associated with the use of progestins with estrogens compared to estrogen-alone regimens. These include a possible increased risk of breast cancer. Elevated blood pressure: In a small number of case reports, substantial increases in blood pressure have been attributed to idiosyncratic reactions to estrogens. In a large, randomized, placebo-controlled clinical trial, a generalized effect of estrogens on blood pressure was not seen. Blood pressure should be monitored at regular intervals with estrogen use. Hypertriglyceridemia: In patients with pre-existing hypertriglyceridemia, estrogen therapy may be associated with elevations of plasma triglycerides leading to pancreatitis and other complications. Impaired liver function and past history of cholestatic jaundice: Estrogens may be poorly metabolized in patients with impaired liver function. For patients with a history of cholestatic jaundice associated with past estrogen use or with pregnancy, caution should be exercised and in the case of recurrence, medication should be discontinued. Hypothyroidism: Estrogen administration leads to increased thyroid-binding globulin (TBG) levels. Patients with normal thyroid function can compensate for the increased TBG by making more thyroid hormone, thus maintaining free T4 and T3 serum concentrations in the normal range. Patients dependent on thyroid hormone replacement therapy who are also receiving estrogens may require increased doses of their thyroid replacement therapy. These patients should have their thyroid function monitored in order to maintain their free thyroid hormone levels in an acceptable range. Fluid retention: Because estrogens may cause some degree of fluid retention, patients with conditions that might be influenced by this factor, such as a cardiac or renal dysfunction, warrant careful observation when estrogens are prescribed. Hypocalcemia: Estrogens should be used with caution in individuals with severe hypocalcemia. Ovarian cancer: The CE/MPA substudy of WHI reported that estrogen plus progestin 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% confidence interval 0.77 – 3.24) but was not statistically significant. The absolute risk for CE/MPA versus placebo was 4.2 versus 2.7 cases per 10,000 women-years. In some epidemiologic studies, the use of estrogen alone, in particular for 10 or more years, has been associated with an increased risk of ovarian cancer. Other epidemiologic studies have not found these associations. Exacerbation of endometriosis: Endometriosis may be exacerbated with administration of estrogens. A few cases of malignant transformation of residual endometrial implants have been reported in women treated post-hysterectomy with estrogen alone therapy. For patients known to have residual endometriosis post-hysterectomy, the addition of progestin should be considered. Exacerbation of other conditions: Estrogens may cause an exacerbation of asthma, diabetes mellitus, epilepsy, migraine or porphyria, systemic lupus erythematosus, and hepatic hemangiomas and should be used with caution in women with these conditions.

General Precautions

Associated with Methyltestosterone 1. Women should be observed for signs of virilization (deepening of the voice, hirsutism, acne, clitoromegaly, and menstrual irregularities). Discontinuation of drug therapy at the time of evidence of mild virilism is necessary to prevent irreversible virilization. Such virilization is usual following androgen use at high doses. 2. Prolonged dosage of androgen may result in sodium and fluid retention. This may present a problem, especially in patients with compromised cardiac reserve or renal disease. 3. Hypersensitivity may occur rarely. 4. Protein-bound iodine (PBI) may be decreased in patients taking androgens. 5. Hypercalcemia may occur. If this does occur, the drug should be discontinued.

Patient

Information (Estrogens) Physicians are advised to discuss the PATIENT INFORMATION leaflet with patients for whom they prescribe Esterified Estrogens and Methyltestosterone Tablets F.S. and Esterified Estrogens and Methyltestosterone Tablets H.S.

Patient

Information (Androgens) The physician should instruct patients to report any of the following side effects of androgens: Women: Hoarseness, acne, changes in menstrual periods, or more hair on the face.

All

Patients: Any nausea, vomiting, changes in skin color or ankle swelling.

Laboratory

Tests (Estrogens) Estrogen administration should be initiated at the lowest dose approved for the indication and then guided by clinical response rather than by serum hormone levels (e.g., estradiol, FSH).

Laboratory

Tests (Androgens) 1. Women with disseminated breast carcinoma should have frequent determination of urine and serum calcium levels during the course of androgen therapy. (See WARNINGS .) 2. Because of the hepatotoxicity associated with the use of 17-alpha-alkylated androgens, liver function tests should be obtained periodically. 3. Hemoglobin and hematocrit should be checked periodically for polycythemia in patients who are receiving high doses of androgens.

Drug/Laboratory

Test Interactions (Estrogens) 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 antifactor 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) levels leading to increased circulating total thyroid hormone levels as measured by protein-bound iodine (PBI), T4 levels (by column or by radioimmunoassay) or T3 levels by radioimmunoassay. T3 resin uptake is decreased, reflecting the elevated TBG. Free T4 and free T3 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 total 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 HDL2 cholesterol subfraction concentrations, reduced LDL cholesterol concentration, increased triglycerides levels. 5. Impaired glucose tolerance. 6. Reduced response to metyrapone test.

Drug

Interactions (Androgens) Anticoagulants: C-17 substituted derivatives of testosterone, such as methandrostenolone, have been reported to decrease the anticoagulant requirements of patients receiving oral anticoagulants. Patients receiving oral anticoagulant therapy require close monitoring, especially when androgens are started or stopped. Oxyphenbutazone: Concurrent administration of oxyphenbutazone and androgens may result in elevated serum levels of oxyphenbutazone. Insulin: In diabetic patients, the metabolic effects of androgens may decrease blood glucose and insulin requirements.

Drug/Laboratory

Test Interferences (Androgens) Androgens may decrease levels of thyroxine-binding globulin, resulting in decreased T4 serum levels and increased resin uptake of T3 and T4. Free thyroid hormone levels remain unchanged, however, and there is no clinical evidence of thyroid dysfunction. Carcinogenesis, Mutagenesis, Impairment of Fertility (Estrogens) Long-term continuous administration of estrogen, with and without progestin, in women with and without a uterus, has shown an increased risk of endometrial cancer, breast cancer, and ovarian cancer. (See BOXED WARNINGS, WARNINGS and PRECAUTIONS .) Long-term continuous administration of natural and synthetic estrogens in certain animal species increases the frequency of carcinomas of the breast, uterus, cervix, vagina, testis, and liver. Carcinogenesis (Androgens)

Animal

Data: Testosterone has been tested by subcutaneous injection and implantation in mice and rats. The implant induced cervical-uterine tumors in mice, which metastasized in some cases. There is suggestive evidence that injection of testosterone into some strains of female mice increases their susceptibility to hepatoma. Testosterone is also known to increase the number of tumors and decrease the degree of differentiation of chemically induced carcinomas of the liver in rats.

Human

Data: There are rare reports of hepatocellular carcinoma in patients receiving long-term therapy with androgens in high doses. Withdrawal of the drugs did not lead to regression of the tumors in all cases. Geriatric patients treated with androgens may be at increased risk for the development of prostatic hypertrophy and prostatic carcinoma. Pregnancy (Estrogens)

Esterified

Estrogens and Methyltestosterone Tablet F.S and Esterified Estrogens and Methyltestosterone Tablets H.S. should not be used during pregnancy. (See CONTRAINDICATIONS .) Pregnancy (Androgens)

Teratogenic

Effects: Pregnancy Category X. (See CONTRAINDICATIONS .)

Nursing

Mothers (Estrogens) Estrogen administration to nursing mothers has been shown to decrease the quantity and quality of the milk. Detectable amounts of estrogens have been identified in the milk of mothers receiving this drug. Caution should be exercised when Esterified Estrogens and Methyltestosterone Tablets F.S. and Esterified Estrogens and Methyltestosterone Tablets H.S. are administered to a nursing woman.

Nursing

Mothers (Androgens) It is not known whether androgens are excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from androgens, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use Esterified

Estrogens and Methyltestosterone Tablets F.S and Esterified Estrogens and Methyltestosterone Tablets H.S. are not indicated for use in children.

Geriatric Use

Clinical studies of Esterified Estrogens and Methyltestosterone Tablets F.S and Esterified Estrogens and Methyltestosterone Tablets H.S. did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. In the Women's Health Initiative Memory Study, including 4,532 women 65 years of age and older, followed for an average of 4 years, 82% (n = 3,729) were 65 to 74 while 18% (n = 803) were 75 and over. Most women (80%) had no prior hormone therapy use. Women treated with conjugated estrogens plus medroxyprogesterone acetate were reported to have a two-fold increase in the risk of developing probable dementia. Alzheimer's disease was the most common classification of probable dementia in both the conjugated estrogens plus medroxyprogesterone acetate group and the placebo group. Ninety percent of the cases of probable dementia occurred in the 54% of women that were older than 70. (See WARNINGS, Dementia .) The estrogen alone substudy of the Women's Health Initiative Memory Study has concluded. It is unknown whether these findings apply to estrogen alone.

Drug Interactions (Androgens) Anticoagulants: C-17 substituted derivatives of testosterone, such as methandrostenolone, have been reported to decrease the anticoagulant requirements of patients receiving oral anticoagulants. Patients receiving oral anticoagulant therapy require close monitoring, especially when androgens are started or stopped. Oxyphenbutazone: Concurrent administration of oxyphenbutazone and androgens may result in elevated serum levels of oxyphenbutazone. Insulin: In diabetic patients, the metabolic effects of androgens may decrease blood glucose and insulin requirements.