METHYLTESTOSTERONE

The androgens are steroids that develop and maintain primary and secondary male sex characteristics. Androgens are derivatives of cyclopentanoper-hydrophenanthrene. 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. In their active form, all drugs in the class have a 17-beta hydroxy group. 17- alpha alkylation (methyltestosterone) increases the pharmacologic activity per unit weight compared to testosterone when given orally. Methyltestosterone, a synthetic derivative of testosterone, is an androgenic preparation given by the oral route in a capsule form. It has the following structural formula: C 20 H 30 O 2 Molecular Weight: 302.46 17-β-hydroxy-17-methylandrost-4-en-3-one Methyltestosterone, USP occurs as white or creamy white crystals or powder, which is soluble in various organic solvents but is practically insoluble in water. Each capsule, for oral administration, contains 10 mg of methyltestosterone, USP. In addition, each capsule contains the following inactive ingredients: pregelatinized starch, lactose anhydrous, D&C Yellow #10, gelatin, FD&C Blue #1, FD&C Red #40. Additionally, the capsule imprinting ink contains strong ammonia solution, potassium hydroxide, iron oxide black, propylene glycol and shellac. FDA approved dissolution test specifications differ from USP. structure

INDICATIONS & USAGE 1. Males Androgens are indicated for replacement therapy in conditions associated with a deficiency or absence of endogenous testosterone: Primary hypogonadism (congenital or acquired) — testicular failure due to cryptorchidism, bilateral torsions, orchitis, vanishing testis syndrome; or orchidectomy. Hypogonadotropic hypogonadism (congenital or acquired) — gonadotropin or luteinizing hormone-releasing hormone (LHRH) deficiency, or pituitary hypothalamic injury from tumors, trauma, or radiation. (Appropriate adrenal cortical and thyroid hormone replacement therapy are still necessary, however, and are actually of primary importance.) If the above conditions occur prior to puberty, androgen replacement therapy will be needed during the adolescent years for development of secondary sexual characteristics. Prolonged androgen treatment will be required to maintain sexual characteristics in these and other males who develop testosterone deficiency after puberty. Safety and efficacy of methyltestosterone in men with “age-related hypogonadism” (also referred to as “late-onset hypogonadism”) have not been established. Androgens may be used to stimulate puberty in carefully selected males with clearly delayed puberty. These patients usually have a familial pattern of delayed puberty that is not secondary to a pathological disorder; puberty is expected to occur spontaneously at a relatively late date. Brief treatment with conservative doses may occasionally be justified in these patients if they do not respond to psychological support. The potential adverse effect on bone maturation should be discussed with the patient and parents prior to androgen administration. An X-ray of the hand and wrist to determine bone age should be obtained every 6 months to assess the effect of treatment on the epiphyseal centers (see WARNINGS ). 2. Females Androgens may be used secondarily in women with advancing inoperable metastatic (skeletal) mammary cancer who are 1 to 5 years postmenopausal. Primary goals of therapy in these women include ablation of the ovaries. Other methods of counteracting estrogen activity are adrenalectomy, hypophysectomy, and/or antiestrogen therapy. This treatment has also been used in premenopausal women with breast cancer who have benefitted from oophorectomy and are considered to have a hormone-responsive tumor. Judgment concerning androgen therapy should be made by an oncologist with expertise in this field.

DOSAGE & ADMINISTRATION Prior to initiating methyltestosterone, confirm the diagnosis of hypogonadism by ensuring that serum testosterone concentrations have been measured in the morning on at least two separate days and that these serum testosterone concentrations are below the normal range. Methyltestosterone capsules are administered orally. The suggested dosage for androgens varies depending on the age, sex, and diagnosis of the individual patient. Dosage is adjusted according to the patient’s response and the appearance of adverse reactions. Replacement therapy in androgen-deficient males is 10 mg to 50 mg of methyltestosterone daily. Various dosage regimens have been used to induce pubertal changes in hypogonadal males, some experts have advocated lower dosages initially, gradually increasing the dose as puberty progresses with or without a decrease to maintenance levels. Other experts emphasize that higher dosages are needed to induce pubertal changes and lower dosages can be used for maintenance after puberty. The chronological and skeletal ages must be taken into consideration both in determining the initial dose and in adjusting the dose. Doses used in delayed puberty generally are in the lower range of that given above, and for a limited duration, for example 4 to 6 months. Women with metastatic breast carcinoma must be followed closely because androgen therapy occasionally appears to accelerate the disease. Thus, many experts prefer to use the shorter acting androgen preparations rather than those with prolonged activity for treating breast carcinoma, particularly during the early stages of androgen therapy. The dosage of methyltestosterone for androgen therapy in breast carcinoma in females is from 50 mg to 200 mg daily.

Androgens are contraindicated in men with carcinomas of the breast or with known or suspected carcinomas of the prostate, and in women who are or may become pregnant. When administered to pregnant women, androgens cause virilization of the external genitalia of the female fetus. This virilization includes clitoromegaly, abnormal vaginal development, and fusion of genital folds to form a scrotal-like structure. The degree of masculinization is related to the amount of drug given and the age of the fetus, and is most likely to occur in the female fetus when the drugs are given in the first trimester. If the patient becomes pregnant while taking these drugs, she should be apprised of the potential hazard to the fetus.

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. Male: Gynecomastia, and excessive frequency and duration of penile erections. Oligospermia may occur at high dosages (see CLINICAL PHARMACOLOGY ). Skin and appendages: Hirsutism, male pattern baldness, and acne. Cardiovascular Disorders: myocardial infarction, stroke. Fluid and Electrolyte Disturbances: Retention of sodium, chloride, water, potassium, calcium and inorganic phosphates. Gastrointestinal: Nausea, cholestatic jaundice, alterations in liver function tests, 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. Nervous System: Increased or decreased libido, headache, anxiety, depression, and generalized paresthesia. Metabolic: Increased serum cholesterol. Vascular Disorders: venous thromboembolism. Miscellaneous: Rarely anaphylactoid reactions. To report SUSPECTED ADVERSE REACTIONS, contact Novitium Pharma LLC at 1-855-204-1431 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

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.