INDICATIONS AND USAGE 1.

Males Androgens are indicated for replacement therapy in conditions associated with a 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 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.

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 a life-threatening or fatal complication.

Cholestatic hepatitis and jaundice occur with 17-alpha-alkylandrogens (such as methyltestosterone) 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.

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 post-marketing 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 a 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 can increase blood pressure which can increase cardiovascular (CV) risk over time.

Monitor blood pressure periodically in men using testosterone products, especially in men with hypertension.

Testosterone products are not recommended for use in patients with uncontrolled hypertension.

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 a 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 6 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.

ADVERSE REACTIONS 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 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.