Prescription Drugs

CLINICAL PHARMACOLOGY Anabolic steroids are synthetic derivatives of testosterone. Certain clinical effects and adverse reactions demonstrate the androgenic properties of this class of drugs. Complete dissociation of anabolic and androgenic effects has not been achieved. The actions of anabolic steroids are therefore similar to those of male sex hormones with the possibility of causing serious disturbances of growth and sexual development if given to young children. They suppress the gonadotropic functions of the pituitary and may exert a direct effect upon the testes. WINSTROL (anabolic steroids) has been found to increase low-density lipoproteins and decrease high-density lipoproteins. These changes are not associated with any increase in total cholesterol or triglyceride levels and revert to normal on discontinuation of treatment. Hereditary angioedema (HAE) is an autosomal dominant disorder caused by a deficient or nonfunctional C1 esterase inhibitor (C1 INH) and clinically characterized by episodes of swelling of the face, extremities, genitalia, bowel wall, and upper respiratory tract. In small scale clinical studies, stanozolol was effective in controlling the frequency and severity of attacks of angioedema and in increasing serum levels of C1 INH and C4. WINSTROL (anabolic steroids) is not effective in stopping HAE attacks while they are under way. The effect of WINSTROL (anabolic steroids) on increasing serum levels of C1 INH and C4 may be related to an increase in protein anabolism.

DESCRIPTION WINSTROL (anabolic steroids) , brand of stanozolol tablets, is an anabolic steroid, a synthetic derivative of testosterone. Each tablet for oral administration contains 2 mg of stanozolol. It is designated chemically as 17-methyl-2' H -5(alpha)-androst-2-eno[3,2- c ]pyrazol-17(beta)-ol. Inactive Ingredients: Dibasic Calcium Phosphate, D&C Red #28, FD&C Red #40, Lactose, Magnesium Stearate, Starch.

INDICATIONS Hereditary Angioedema. WINSTROL (anabolic steroids) is indicated prophylactically to decrease the frequency and severity of attacks of angioedema. DOSAGE AND ADMINISTRATION The use of anabolic steroids may be associated with serious adverse reactions, many of which are dose related; therefore, patients should be placed on the lowest possible effective dose. Hereditary Angioedema. The dosage requirements for continuous treatment of hereditary angioedema with WINSTROL (anabolic steroids) should be individualized on the basis of the clinical response of the patient. It is recommended that the patient be started on 2 mg, three times a day. After a favorable initial response is obtained in terms of prevention of episodes of edematous attacks, the proper continuing dosage should be determined by decreasing the dosage at intervals of one to three months to a maintenance dosage of 2 mg a day. Some patients may be successfully managed on a 2 mg alternate day schedule. During the dose adjusting phase, close monitoring of the patient's response is indicated, particularly if the patient has a history of airway involvement. The prophylactic dose of WINSTROL (anabolic steroids) , to be used prior to dental extraction, or other traumatic or stressful situations has not been established and may be substantially larger. Attacks of hereditary angioedema are generally infrequent in childhood and the risks from stanozolol administration are substantially increased. Therefore, long-term prophylactic therapy with this drug is generally not recommended in children, and should only be undertaken with due consideration of the benefits and risks involved (see PRECAUTIONS, Pediatric Use ). HOW SUPPLIED WINSTROL (anabolic steroids) tablets for oral administration are pink, round tablets scored on one side. Bottles of 100 NDC 0024-2253-04 Store at controlled room temperature 15° to 30° C (59° to 86° F)

PATIENT INFORMATIONINFORMATION FOR PATIENTS The 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, appearance or aggravation of acne. 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.

OVERDOSE No Information Provided. CONTRAINDICATIONS The use of WINSTROL (anabolic steroids) is contraindicated in the following: Male patients with carcinoma of the breast, or with known or suspected carcinoma of the prostate. Carcinoma of the breast in females with hypercalcemia; androgenic anabolic steroids may stimulate osteolytic resorption of bone. Nephrosis or the nephrotic phase of nephritis. WINSTROL (anabolic steroids) can cause fetal harm when administered to a pregnant woman. WINSTROL (anabolic steroids) is contraindicated in women who are or may become pregnant. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus.

SIDE EFFECTS Hepatic: Cholestatic jaundice with, rarely, hepatic necrosis and death. Hepatocellular neoplasms and peliosis hepatis have been reported in association with long-term androgenic-anabolic steroid therapy (see WARNINGS). Reversible changes in liver function tests also occur including increased bromsulphalein (BSP) retention and increases in serum bilirubin, glutamic oxaloacetic transaminase (SGOT), and alkaline phosphatase. Genitourinary System: In men. Prepubertal: Phallic enlargement and increased frequency of erections. Postpubertal: Inhibition of testicular function, testicular atrophy and oligospermia, impotence, chronic priapism, epididymitis and bladder irritability. In women: Clitoral enlargement, menstrual irregularities. In both sexes: Increased or decreased libido. CNS: Habituation, excitation, insomnia, depression. Gastrointestinal: Nausea, vomiting, diarrhea. Hematologic: Bleeding in patients on concomitant anticoagulant therapy. Breast: Gynecomastia. Larynx: Deepening of the voice in women. Hair: Hirsutism and male pattern baldness in women. Skin: Acne (especially in women and prepubertal boys). Skeletal: Premature closure of epiphyses in children (see PRECAUTIONS, Pediatric Use ). Fluid and Electrolytes: Edema, retention of serum electrolytes (sodium, chloride, potassium, phosphate, calcium). Metabolic/Endocrine: Decreased glucose tolerance (see PRECAUTIONS), increased serum levels of low-density lipoproteins and decreased levels of high-density lipoproteins (see PRECAUTIONS, Laboratory Tests ), increased creatine and creatinine excretion, increased serum levels of creatinine phosphokinase (CPK). Some virilizing changes in women are irreversible even after prompt discontinuance of therapy and are not prevented by concomitant use of estrogens (see PRECAUTIONS). DRUG ABUSE AND DEPENDENCE Controlled Substance Class: WINSTROL (anabolic steroids) is classified as a controlled substance under the Anabolic Steroids Control Act of 1990 and has been assigned to Schedule III. DRUG INTERACTIONS Anabolic steroids may increase sensitivity to anticoagulants; therefore, dosage of an anticoagulant may have to be decreased in order to maintain the prothrombin time at the desired therapeutic level.

WARNINGS PELIOSIS HEPATIS, A CONDITION IN WHICH LIVER AND SOMETIMES SPLENIC TISSUE IS REPLACED WITH BLOOD-FILLED CYSTS, HAS BEEN REPORTED IN PATIENTS RECEIVING ANDROGENIC ANABOLIC STEROID THERAPY. THESE CYSTS ARE SOMETIMES PRESENT WITH MINIMAL HEPATIC DYSFUNCTION, BUT AT OTHER TIMES THEY HAVE BEEN ASSOCIATED WITH LIVER FAILURE. THEY ARE OFTEN NOT RECOGNIZED UNTIL LIFE-THREATENING LIVER FAILURE OR INTRA-ABDOMINAL HEMORRHAGE DEVELOPS. WITHDRAWAL OF DRUG USUALLY RESULTS IN COMPLETE DISAPPEARANCE OF LESIONS. LIVER CELL TUMORS ARE ALSO REPORTED. MOST OFTEN THESE TUMORS ARE BENIGN AND ANDROGEN-DEPENDENT, BUT FATAL MALIGNANT TUMORS HAVE BEEN REPORTED. WITHDRAWAL OF DRUG OFTEN RESULTS IN REGRESSION OR CESSATION OF PROGRESSION OF THE TUMOR. HOWEVER, HEPATIC TUMORS ASSOCIATED WITH ANDROGENS OR ANABOLIC STEROIDS ARE MUCH MORE VASCULAR THAN OTHER HEPATIC TUMORS AND MAY BE SILENT UNTIL LIFE-THREATENING INTRA-ABDOMINAL HEMORRHAGE DEVELOPS. BLOOD LIPID CHANGES THAT ARE KNOWN TO BE ASSOCIATED WITH INCREASED RISK OF ATHEROSCLEROSIS ARE SEEN IN PATIENTS TREATED WITH ANDROGENS AND ANABOLIC STEROIDS. THESE CHANGES INCLUDE DECREASED HIGH-DENSITY LIPOPROTEIN AND SOMETIMES INCREASED LOW-DENSITY LIPOPROTEIN. THE CHANGES MAY BE VERY MARKED AND COULD HAVE A SERIOUS IMPACT ON THE RISK OF ATHEROSCLEROSIS AND CORONARY ARTERY DISEASE. Cholestatic hepatitis and jaundice occur with 17-alpha-alkylated androgens at relatively low doses. If cholestatic hepatitis with jaundice appears, the anabolic steroid should be discontinued. If liver function tests become abnormal, the patient should be monitored closely and the etiology determined. Generally, the anabolic steroid should be discontinued although in cases of mild abnormalities, the physician may elect to follow the patient carefully at a reduced drug dosage. In patients with breast cancer, anabolic steroid therapy may cause hypercalcemia by stimulating osteolysis. In this case, the drug should be discontinued. Edema with or without congestive heart failure may be a serious complication in patients with preexisting cardiac, renal, or hepatic disease. Concomitant administration of adrenal cortical steroids or ACTH may add to the edema. Geriatric male patients treated with androgenic anabolic steroids may be at an increased risk for the development of prostatic hypertrophy and prostatic carcinoma. In children, anabolic steroid 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. The effect on bone maturation should be monitored by assessing bone age of the wrist and hand every six months. Anabolic steroids have not been shown to enhance athletic ability. PRECAUTIONSGeneral Anabolic steroids may cause suppression of clotting factors II, V, VII, and X, and an increase in prothrombin time. Women should be observed for signs of virilization (deepening of the voice, hirsutism, acne, and clitoromegaly). To prevent irreversible change, drug therapy must be discontinued, or the dosage significantly reduced when mild virilism is first detected. Such virilization is usual following androgenic anabolic steroid use at high doses. Some virilizing changes in women are irreversible even after prompt discontinuance of therapy and are not prevented by concomitant use of estrogens. Menstrual irregularities may also occur. The insulin or oral hypoglycemic dosage may need adjustment in diabetic patients who receive anabolic steroids. Information for the Patient. The 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, appearance or aggravation of acne. 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. Laboratory Tests. Women with disseminated breast carcinoma should have frequent determination of urine and serum calcium levels during the course of androgenic anabolic steroid 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 6 months) x-ray examinations of bone age should be made during treatment of prepubertal patients to determine the rate of bone maturation and the effects of androgenic anabolic steroid therapy on the epiphyseal centers. In common with other anabolic steroids, WINSTROL (anabolic steroids) has been reported to lower the level of high-density lipoproteins and raise the level of low-density lipoproteins. These changes usually revert to normal on discontinuation of treatment. Increased low-density lipoproteins and decreased high-density lipoproteins are considered cardiovascular risk factors. Serum lipids and high-density lipoprotein cholesterol should be determined periodically. Hemoglobin and hematocrit should be checked periodically for polycythemia in patients who are receiving high doses of anabolic steroids. Drug Interaction. Anabolic steroids may increase sensitivity to anticoagulants; therefore, dosage of an anticoagulant may have to be decreased in order to maintain the prothrombin time at the desired therapeutic level. Drug/Laboratory Test Interferences. Therapy with androgenic anabolic steroids may decrease levels of thyroxine-binding globulin resulting in decreased total T 4 serum levels and increase resin uptake of T 3 and T 4 . Free thyroid hormone levels remain unchanged and there is no clinical evidence of thyroid dysfunction. Carcinogenesis, Mutagenesis, Impairment of Fertility. Animal 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 androgenic hormones. The potential carcinogenic effects likely occur through a hormonal mechanism rather than by a 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 WINSTROL (anabolic steroids) Tablets. Therefore, impairment of fertility is a possible outcome of treatment with WINSTROL (anabolic steroids) . Pregnancy Category X. See CONTRAINDICATIONS section. Nursing Mothers. It is not known whether anabolic steroids are excreted in human milk. Many drugs are excreted in human milk and because of the potential for adverse reactions in nursing infants from WINSTROL (anabolic steroids) , a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother. Pediatric Use. Anabolic agents may accelerate epiphyseal maturation more rapidly than linear growth in children, and the effect may continue for 6 months after the drug has been stopped. Therefore, therapy should be monitored by x-ray studies at 6 month intervals in order to avoid the risk of compromising the adult height. The safety and efficacy of WINSTROL (anabolic steroids) in children with hereditary angioedema have not been established.