MethylTESTOSTERone

METHYLTESTOSTERONE- methyltestosterone capsule
Amneal Pharmaceuticals of New York LLC

DESCRIPTION

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:

Chemical Structure

C20 H30 O2 M.W. 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: corn starch, D&C Yellow #10, gelatin, FD&C Blue #1, FD&C Red #40, and magnesium stearate. Additionally, the capsule printing inks contain D&C Yellow #10, FD&C Blue #1, FD&C Blue #2, FD&C Red #40, iron oxide black, propylene glycol, and shellac.

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 chord 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 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 erythropoietic stimulating factor.

During exogenous administration of androgens, endogenous testosterone release is inhibited through feedback inhibition of pituitary luteinizing hormone (LH). At large doses of exogenous androgens, spermatogenesis may also be suppressed through feedback inhibition of pituitary follicle stimulating hormone (FSH).

There is a lack of substantial evidence that androgens are effective in fractures, surgery, convalescence and functional uterine bleeding.

Pharmacokinetics

Testosterone given orally is metabolized by the gut and 44 percent is cleared by the liver of 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 a longer half-life. It is more suitable than testosterone for oral administration.

Testosterone in plasma is 98 percent bound to a specific testosterone-estradiol binding globulin, and about 2 percent 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 percent of a dose of testosterone is excreted in the urine as glucuronic and sulfuric acid conjugates of testosterone and its metabolites; and 6 percent of a 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. There are considerable variations of the half-life of testosterone as reported in the literature, 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.

INDICATIONS AND USAGE

1. Males

Androgens are indicated for replacement therapy in conditions associated with a deficiency or absence of endogenous testosterone:

  1. Primary hypogonadism (congenital or acquired) — testicular failure due to cryptorchidism, bilateral torsions, orchitis, vanishing testis syndrome; or orchidectomy.
  2. 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.
  3. 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.

CONTRAINDICATIONS

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.

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 PRECAUTIONSCarcinogenesis). 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.

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

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 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 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 preexisting 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.

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