ADVERSE REACTIONS SECTION.

ADVERSE REACTIONS. Endocrine and UrogenitalFemale: 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 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 dosage (see CLINICAL PHARMACOLOGY). Skin and Appendages: Hirsutism, male pattern of 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 neoplasma 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 Amneal Pharmaceuticals at 1-877-835-5472 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

CLINICAL PHARMACOLOGY SECTION.

CLINICAL PHARMACOLOGY. 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 which is brought about by fusion of the epiphyseal growth centers. In children, exogenous androgens accelerate linear growth rates, but may cause 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 erythropoietic stimulating factor.During exogenous administration of androgens, endogenous testosterone release is inhibited through feedback inhibition of pituitary luteinizing hormone (LH). With large doses of exogenous androgens, spermatogenesis may also be suppressed through feedback inhibition of pituitary follicle stimulating hormone (FSH). There is lack of substantial evidence that androgens are effective in fractures, surgery, convalescence, and functional uterine bleeding. PharmacokineticsTestosterone given orally is metabolized by the gut and 44% is cleared by the liver in the first pass. Oral doses as high as 400 mg per day are needed to achieve clinically effective blood levels for full replacement therapy. The synthetic androgen (methyltestosterone) is less extensively metabolized by the liver and has longer half-life. It is more suitable than testosterone for oral administration. Testosterone in plasma is 98% bound to specific testosterone-estradiol binding globulin, and about 1% is free. Generally, the amount of this sex-hormone binding globulin in the plasma will determine the distribution of testosterone between free and bound forms, and the free testosterone concentration will determine its half-life. About 90% of dose of testosterone is excreted in the urine as glucuronic and sulfuric acid conjugates of testosterone and its metabolites; about 6% of dose is excreted in the feces, mostly in the unconjugated form. Inactivation of testosterone occurs primarily in the liver. Testosterone is metabolized to various 17-keto steroids through two different pathways. As reported in the literature, the half-life of testosterone varies considerably, ranging from 10 to 100 minutes. In many tissues the activity of testosterone appears to depend on reduction to dihydrotestosterone, which binds to cytosol receptor proteins. The steroid-receptor complex is transported to the nucleus where it initiates transcription events and cellular changes related to androgen action.

DESCRIPTION SECTION.

DESCRIPTION. METHITEST(TM) (methyltestosterone) tablets, USP contain methyltestosterone USP, synthetic androgen. Androgens are steroids that develop and maintain primary and secondary male sex characteristics. METHITEST(TM) (methyltestosterone) tablets, USP are to be taken orally. Androgens are derivatives of cyclopentanoperhydrophenanthrena. Endogenous androgens are C-19 steroids with 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 17-beta-hydroxy group. 17-alpha alkylation (methyltestosterone) increases the pharmacologic activity per unit weight compared to testosterone when given orally. Methyltestosterone is the 17-methyl derivative of testosterone, the true testicular hormone. Chemically, methyltestosterone is 17b-hydroxy-17-methylandrost-4-en-3-one, with the empirical formula C20H30O2, molecular weight of 302.5, and the following structural formula:C20H30O2 M.W. 302.46 (CAS-58-18-4)17 -Hydroxy-17-methylandrost-4-en-3-oneMethyltestosterone, USP is white to creamy-white, odorless, slightly hydroscopic powder. It is practically insoluble in water, and is soluble in alcohol and other organic solvents. METHITEST(TM) (methyltestosterone) tablets, USP contain methyltestosterone, USP and acacia, lactose monohydrate, confectioners sugar, corn starch, powdered cellulose, sodium lauryl sulfate, magnesium stearate, pregelatinized starch, and guar gum.. 1.

DOSAGE & ADMINISTRATION SECTION.

DOSAGE AND ADMINISTRATION. Prior to initiating METHITEST(TM) (methyltestosterone) tablets, 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.Dosage must be strictly individualized. The suggested dosage for androgens varies depending on the age, sex, and diagnosis of the individual patient. Adjustments and duration of dosage will depend upon the patients response and the appearance of adverse reactions.Males: In the androgen-deficient male the guideline for replacement therapy indicates the usual initial dosage of 10 mg to 50 mg daily.Various dosage regimens have been used to induce pubertal changes in hypogonadel males: some experts have advocated lower dosages initially, gradually increasing the dose as puberty progresses, with or without 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.Dosages used in delayed puberty generally are in the lower ranges of those given above, and are for limited duration, for example, to months.Females: 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. Guideline dosages of androgens for use in the palliative treatment of women with metastatic breast cancer are 50 mg to 200 mg daily.

DRUG ABUSE AND DEPENDENCE SECTION.

DRUG ABUSE AND DEPENDENCE. Controlled SubstanceMETHITEST(TM) (methyltestosterone) tablets contain testosterone, Schedule III controlled substance in the Controlled Substances Act.Abuse Drug abuse is intentional non-therapeutic use of drug, even once, for its rewarding psychological and physiological effects. Abuse and misuse of testosterone are seen in male and female adults and adolescents. Testosterone, often in combination with other anabolic androgenic steroids (AAS), and not obtained by prescription through pharmacy, may be abused by athletes and bodybuilders. There have been reports of misuse by men taking higher doses of legally obtained testosterone than prescribed and continuing testosterone despite adverse events or against medical advice.Abuse-Related Adverse ReactionsSerious adverse reactions have been reported in individuals who abuse anabolic androgenic steroids and include cardiac arrest, myocardial infarction, hypertrophic cardiomyopathy, congestive heart failure, cerebrovascular accident, hepatotoxicity, and serious psychiatric manifestations, including major depression, mania, paranoia, psychosis, delusions, hallucinations, hostility and aggression.The following adverse reactions have also been reported in men: transient ischemic attacks, convulsions, hypomania, irritability, dyslipidemias, testicular atrophy, subfertility, and infertility.The following additional adverse reactions have been reported in women: hirsutism, virilization, deepening of voice, clitoral enlargement, breast atrophy, male-pattern baldness, and menstrual irregularities.The following adverse reactions have been reported in male and female adolescents: premature closure of bony epiphyses with termination of growth, and precocious puberty.Because these reactions are reported voluntarily from population of uncertain size and may include abuse of other agents, it is not always possible to reliably estimate their frequency or establish causal relationship to drug exposure.DependenceBehaviors Associated with AddictionContinued abuse of testosterone and other anabolic steroids, leading to addiction is characterized by the following behaviors:Taking greater dosages than prescribedContinued drug use despite medical and social problems due to drug useSpending significant time to obtain the drug when supplies of the drug are interruptedGiving higher priority to drug use than other obligationsHaving difficulty in discontinuing the drug despite desires and attempts to do soExperiencing withdrawal symptoms upon abrupt discontinuation of usePhysical dependence is characterized by withdrawal symptoms after abrupt drug discontinuation or significant dose reduction of drug. Individuals taking supratherapeutic doses of testosterone may experience withdrawal symptoms lasting for weeks or months which include depressed mood, major depression, fatigue, craving, restlessness, irritability, anorexia, insomnia, decreased libido and hypogonadotropic hypodgonadism. Drug dependence in individuals using approved doses of testosterone for approved indications has not been documented.. Taking greater dosages than prescribed. Continued drug use despite medical and social problems due to drug use. Spending significant time to obtain the drug when supplies of the drug are interrupted. Giving higher priority to drug use than other obligations. Having difficulty in discontinuing the drug despite desires and attempts to do so. Experiencing withdrawal symptoms upon abrupt discontinuation of use.

INDICATIONS & USAGE SECTION.

INDICATIONS AND USAGE. 1. MalesAndrogens are indicated for replacement therapy in conditions associated with deficiency or absence of endogenous testosterone:Primary hypogonadism (congenita or acquired) -- Testicular failure due to cryptohidism, bilateral torsion, 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 familial pattern of delayed puberty that is not secondary to pathological disorder; puberty is expected to occur spontaneously at 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 months to assess the effect of treatment on the epiphyseal centers (see WARNINGS).2. FemalesAndrogens may be used secondarily in women with advancing inoperable metastatic (skeletal) mammary cancer who are to 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 hormone-responsive tumor. Judgment concerning androgen therapy should be made by an oncologist with expertise in this field. Primary hypogonadism (congenita or acquired) -- Testicular failure due to cryptohidism, bilateral torsion, 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. Androgens may be used to stimulate puberty in carefully selected males with clearly delayed puberty. These patients usually have familial pattern of delayed puberty that is not secondary to pathological disorder; puberty is expected to occur spontaneously at 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 months to assess the effect of treatment on the epiphyseal centers (see WARNINGS).

PRECAUTIONS SECTION.

PRECAUTIONS. GeneralWoman 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. The patient and physician may decide that some virilization will be tolerated during treatment for breast carcinoma.Priapism or excessive sexual stimulation may develop. Males, especially the elderly, may become overstimulated. In treating males for symptoms of climacteric, avoid stimulation to the point of increasing the nervous, mental, and physical activities beyond the patients cardiovascular capacity.Oligospermia and reduced ejaculatory volume may occur after prolonged administration or excessive dosage.Information for the PatientsThe physician should instruct patients to report any of the following side effects of androgens:Adult or Adolescent Males: Too frequent or persistent erections of the penis.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.Any male adolescent patient receiving androgens for delayed puberty should have bone development checked every months.Laboratory TestsWomen with disseminated breast carcinoma should have frequent determination of urine and serum calcium levels during the course of androgen therapy (see WARNINGS).Because of the hepatotoxicity associated with the use of 17-alpha-alkylated androgens, liver function tests should be obtained periodically.Periodic (every months) X-ray examinations of bone age should be made during treatment of prepubertal males to determine the rate of bone maturation and the effects of androgen therapy on the epiphyseal centers.Hemoglobin and hemotocrit should be checked periodically for polycythemia in patients who are receiving high doses of androgens.Drug Interactions1. 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 anticoagulant therapy require close monitoring, especially when androgens are started or stopped.2. Oxyphenbutazone: Concurrent administration of oxyphenbutazone and androgens may result in elevated serum levels of oxyphenbutazone.3. Insulin: In diabetic patients, metabolic effects of androgens may decrease blood glucose and insulin requirements.Drug/Laboratory Test InterferenceAndrogens may decrease levels of thyroxine-binding globulin, resulting in decreased total 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 FertilityAnimal 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 an increased risk of developing prostatic hypertrophy and prostatic carcinoma although conclusive evidence to support this concept is lacking.This compound has not been tested for mutagenic potential. However, as noted above, carcinogenic effects have been attributed to treatment with adrogenic hormones. The potential carcinogenic effects likely occur through hormonal mechanism rather than by direct chemical interaction mechanism.Impairment of fertility was not tested directly in animal species. However, as noted below under ADVERSE REACTIONS, oligospermia in males and amenorrhea in females are potential adverse effects of treatment with METHITEST(TM) (methyltestosterone) tablets. Therefore, impairment of fertility is possible outcome of treatment with METHITEST(TM) (methyltestosterone) tablets. Pregnancy: Teratogenic EffectsPregnancy Category (see CONTRAINDICATIONS)Nursing MothersIt 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, 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 Androgen therapy should be used very cautiously in children and only by specialists who are aware of the adverse effects on bone maturation. Skeletal maturation must be monitored every six months by an X-ray of the hand and wrist (see INDICATIONS USAGE, and WARNINGS).. Women with disseminated breast carcinoma should have frequent determination of urine and serum calcium levels during the course of androgen therapy (see WARNINGS).. Because of the hepatotoxicity associated with the use of 17-alpha-alkylated androgens, liver function tests should be obtained periodically.. Periodic (every months) X-ray examinations of bone age should be made during treatment of prepubertal males to determine the rate of bone maturation and the effects of androgen therapy on the epiphyseal centers.. Hemoglobin and hemotocrit should be checked periodically for polycythemia in patients who are receiving high doses of androgens.

WARNINGS SECTION.

WARNINGS. 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, MUTAGENESIS, IMPAIRMENT OF FERTILITY). Peliosis hepatis can be life-threatening or fatal complication.Cholestatic hepatitis and jaundice occur with 17-alpha-alkylandrogens (such as methyltestosterone) at 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.Geriatric patients treated with androgens may be at an increased risk of developing prostatic hypertrophy and prostatic carcinoma although conclusive evidence to support this concept is lacking.There have been postmarketing reports of venous thromboembolic events, including deep vein thrombosis (DVT) and pulmonary embolism (PE), in patients using testosterone products, such as methyltestosterone. Evaluate patients who report symptoms of pain, edema, warmth and erythema in the lower extremity for DVT and those who present with acute shortness of breath for PE. If venous thromboembolic event is suspected, discontinue treatment with methyltestosterone and initiate appropriate workup and management.Long term clinical safety trials have not been conducted to assess the cardiovascular outcomes of testosterone replacement therapy in men. To date, epidemiologic studies and randomized controlled trials have been inconclusive for determining the risk of major adverse cardiovascular events (MACE), such as non-fatal myocardial infarction, non-fatal stroke, and cardiovascular death, with the use of testosterone compared to non-use. Some studies, but not all, have reported an increased risk of MACE in association with use of testosterone replacement therapy in men. Patients should be informed of this possible risk when deciding whether to use or to continue to use methyltestosterone.Testosterone has been subject to abuse, typically at doses higher than recommended for the approved indication and in combination with other anabolic androgenic steroids. Anabolic androgenic steroid abuse can lead to serious cardiovascular and psychiatric adverse reactions (see DRUG ABUSE and DEPENDENCE).If testosterone abuse is suspected, check serum testosterone concentrations to ensure they are within therapeutic range. However, testosterone levels may be in the normal or subnormal range in men abusing synthetic testosterone derivatives. Counsel patients concerning the serious adverse reactions associated with abuse of testosterone and anabolic androgenic steroids. Conversely, consider the possibility of testosterone and anabolic androgenic steroid abuse in suspected patients who present with serious cardiovascular or psychiatric adverse events.Edema with or without congestive heart failure may be serious complication in patients with pre-existing cardiac, renal or hepatic disease. In addition to discontinuation of the drug, diuretic therapy may be required.Gynecomastia frequently develops and occasionally persists in patients being treated for hypogonadism.Androgen therapy should be used cautiously in healthy males with delayed puberty. The effect on bone maturation should be monitored by assessing bone age of the wrist and hand every months. In children, androgen treatment may accelerate bone maturation without producing compensatory gain in linear growth. This adverse effect may result in compromised adult stature. The younger the child the greater the risk of compromising final mature height. This drug has not been shown to be safe and effective for the enhancement of athletic performance. Because of the potential risk of serious adverse health effects, this drug should not be used for such purpose.