Methyltestosterone

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 ).

CLINICAL PHARMACOLOGY Estrogens Estrogens are important in the development and maintenance of the female reproductive system and secondary sex characteristics. They promote growth and development of the vagina, uterus, and fallopian tubes, and enlargement of the breasts. Indirectly, they contribute to the shaping of the skeleton, maintenance of tone and elasticity of urogenital structures, changes in the epiphyses of the long bones that allow for the pubertal growth spurt and its termination, growth of axillary and pubic hair, and pigmentation of the nipples and genitals. Decline of estrogenic activity at the end of the menstrual cycle can bring on menstruation, although the cessation of progesterone secretion is the most important factor in the mature ovulatory cycle. However, in the preovulatory or nonovulatory cycle, estrogen is the primary determinant in the onset of menstruation. Estrogens also affect the release of pituitary gonadotropins. The pharmacologic effects of esterified estrogens are similar to those of endogenous estrogens. They are soluble in water and are well absorbed from the gastrointestinal tract. In responsive tissues (female genital organs, breasts, hypothalamus, pituitary) estrogens enter the cell and are transported into the nucleus. As a result of estrogen action, specific RNA and protein synthesis occurs. Estrogen Pharmacokinetics Metabolism and inactivation occur primarily in the liver. Some estrogens are excreted into the bile; however they are reabsorbed from the intestine and returned to the liver through the portal venous system. Water soluble esterified estrogens are strongly acidic and are ionized in body fluids, which favor excretion through the kidneys since tubular reabsorption is minimal. Androgens Endogenous androgens are responsible for the normal growth and development of the male sex organs and for maintenance of secondary sex characteristics. These effects include the growth and maturation of prostate, seminal vesicles, penis, and scrotum; the development of male hair distribution, such as beard, pubic, chest and axillary hair, laryngeal enlargement, vocal cord thickening, alterations in body musculature, and fat distribution. Drugs in this class also cause retention of nitrogen, sodium, potassium, phosphorus, and decreased urinary excretion of calcium. Androgens have been reported to increase protein anabolism and decrease protein catabolism. Nitrogen balance is improved only when there is sufficient intake of calories and protein. Androgens are responsible for the growth spurt of adolescence and for the eventual termination of linear growth centers. In children, exogenous androgens accelerate linear growth rates, but may cause a disproportionate advancement in bone maturation. Use over long periods may result in fusion of the epiphyseal growth centers and termination of growth process. Androgens have been reported to stimulate the production of red blood cells by enhancing the production of erythropoi

DOSAGE AND ADMINISTRATION 1. 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 FULL STRENGTH or 1 to 2 tablets of ESTERIFIED ESTROGENS AND METHYLTESTOSTERONE HALF STRENGTH 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.

ADVERSE REACTIONS 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 estrogenic therapy, including oral contraceptives: Genitourinary system. Breakthrough bleeding, spotting, change in menstrual flow. Dysmenorrhea. Premenstrual-like syndrome. Amenorrhea during and after treatment. Increase in size of uterine fibromyomata. Vaginal candidiasis. Change in cervical erosion and in degree of cervical secretion. Cystitis-like syndrome. Breasts. Tenderness, enlargement, secretion. Gastrointestinal. Nausea, vomiting. Abdominal cramps, bloating. Cholestatic jaundice. Skin. Chloasma or melasma which may persist when drug is discontinued. Erythema multiforme. Erythema nodosum. Hemorrhagic eruption. Loss of scalp hair. Hirsutism. Eyes. Steepening of corneal curvature. Intolerance to contact lenses. CNS. Headache, migraine, dizziness. Mental depression. Chorea. Miscellaneous. Increase or decrease in weight. Reduced carbohydrate tolerance. Aggravation of porphyria. Edema. Changes in libido. Associated with Methyltestosterone A. Endocrine and Urogenital. 1. 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. 2. Skin and Appendages: Hirsutism, male pattern of baldness, and acne. 3. Fluid and Electrolyte Disturbances: Retention of sodium, chloride, water, potassium, calcium, and inorganic phosphates. 4. Gastrointestinal: Nausea, cholestatic jaundice, alterations in liver function test, rarely hepatocellular neoplasms, and peliosis hepatis (see WARNINGS ). 5. Hematologic: Suppression of clotting factors, II, V, VII, and X, bleeding in patients on concomitant anticoagulant therapy, and polycythemia. 6. Nervous System: Increased or decreased libido, headache, anxiety, depression, and generalized paresthesia. 7. Metabolic: Increased serum cholesterol. 8. Miscellaneous: Inflammation and pain at site of intramuscular injection or subcutaneous implantation of testosterone containing pellets, stomatitis with buccal preparations, and rarely anaphylactoid reactions.

WARNINGS 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 (See Boxed Warning ). 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. 2. 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. 19-24a In the case of oral contraceptives the increased risk appeared after two years of use. 24 3. 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. 20-23 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. 24-31 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. 32-33 An increased risk of postsurgery thromboembolic complications has also been reported in users of oral contraceptives. 34-35 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, 18-36 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 37 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.

CONTRAINDICATIONS Estrogens should not be used in women with any of the following conditions: 1. Known or suspected cancer of the breast except in appropriately selected patients being treated for metastatic disease. 2. Known or suspected estrogen-dependent neoplasia. 3. Known or suspected pregnancy (See Boxed Warning ). 4. Undiagnosed abnormal genital bleeding. 5. Active thrombophlebitis or thromboembolic disorders. 6. A past history of thrombophlebitis, thrombosis, or thromboembolic disorders associated with previous estrogen use (except when in treatment of breast malignancy). 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.