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Androgens are derivatives of cyclopentanoperhydrophenanthrene. 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. Each capsule contains 10 mg of Methyltestosterone USP. It has the following structural formula:
C 20 H 30 O 2 M.W. 302.46
Each capsule, for oral administration, contains 10 mg of Methyltestosterone. In addition, each capsule contains the following inactive ingredients: Corn starch NF, Gelatin NF, FD&C Blue #1, FD&C Red #40.
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).
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.
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 benefited 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.
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 woman, 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.
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 ). 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.
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.
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.
Women 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. A decision may be made by the patient and the physician that some virilization will be tolerated during treatment for breast carcinoma.
Androgens 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.
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.
Teratogenic effects. Pregnacy Category X (See CONTRAINDICATIONS ).
It 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, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
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 hand and wrist (See INDICATIONS AND USAGE and WARNINGS ).
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 excesssive frequency and duration of penile erections. Oligospermia may occur at high dosages (see CLINICAL PHARMACOLOGY ).
Gastrointestinal: Nausea, cholestatic jaundice, alterations in liver function tests, rarely hepatocellular neoplasms and peliosis hepatitis (see WARNINGS ).
Miscellaneous: Rarely anaphylactoid reactions.
There have been no reports of acute overdosage with the androgens.
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' response and the appearance of adverse reactions.
Replacement therapy in androgen-deficient males is 10 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.
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 50-200 mg daily.
Methyltestosterone capsules USP 10 mg are red capsules imprinted "ICN 0901" on both sections. They are available in bottles of 100 (NDC 0187-0902-01).
Store at 25°C (77°F); excursion permitted to 15°C-30°C (59°F-86°F).
ICN Pharmaceuticals, Inc.
3300 Hyland Avenue
Costa Mesa, CA 92626
7004821 Revision May 1999