ADVERSE REACTIONS SECTION.

ADVERSE REACTIONS. The following adverse reactions in the male have occurred with some androgens:Endocrine and urogenital: Gynecomastia and excessive frequency and duration of penile erections. Oligospermia may occur at high dosages.Skin and appendages: Hirsutism, male pattern of baldness, seborrhea, 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 neoplasms 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.Allergic: Hypersensitivity, including skin manifestations and anaphylactoid reactions.Vascular Disorders: Venous thromboembolism.Special senses: Rare cases of central serous chorioretinopathy (CSCR). Miscellaneous: Inflammation and pain at the site of intramuscular injection.To report SUSPECTED ADVERSE REACTIONS, contact West-Ward Pharmaceuticals Corp. at 1-877-233-2001 or FDAat 1-800-FDA-1088 or www.fda.gov/medwatch.

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

Carcinogenesis. Animal dataTestosterone has been tested by subcutaneous injection and implantation in mice and rats. The implantinduced cervical-uterine tumors in mice, which metastasized in some cases. There is suggestiveevidence 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 chemicallyinduced carcinomas of the liver in rats.Human dataThere are rare reports of hepatocellular carcinoma in patients receiving long-term therapy with androgens in highdoses. 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.

CLINICAL PHARMACOLOGY SECTION.

CLINICAL PHARMACOLOGY. Endogenous androgens are responsible for normal growth and development of the male sex organs and formaintenance of secondary sex characteristics. These effects include growth and maturation of the prostate, seminalvesicles, penis, and scrotum; development of male hair distribution, such as beard, pubic, chest, and axillary hair;laryngeal enlargement, vocal cord thickening, and alterations in body musculature and fat distribution. Drugs inthis class also cause retention of nitrogen, sodium, potassium, and phosphorus, and decreased urinary excretionof calcium. Androgens have been reported to increase protein anabolism and decrease protein catabolism. Nitrogenbalance is improved only when there is sufficient intake of calories and protein.Androgens are responsible for the growth spurt of adolescence and for eventual termination of linear growth, broughtabout 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 ofthe epiphyseal growth centers and termination of the growth process. Androgens have been reported to stimulateproduction of red blood cells by enhancing production of erythropoietic stimulation factor.During exogenous administration of androgens, endogenous testosterone release is inhibited through feedbackinhibition of pituitary luteinizing hormone (LH). At large doses of exogenous androgens, spermatogenesis may also besuppressed through feedback inhibition of pituitary follicle stimulating hormone (FSH).There is lack of substantial evidence that androgens are effective in fractures, surgery, convalescence, and functionaluterine bleeding.. Pharmacokinetics. Testosterone esters are less polar than free testosterone. Testosterone esters in oil injected intramuscularly areabsorbed slowly from the lipid phase; thus, testosterone cypionate can be given at intervals of two to four weeks.Testosterone in plasma is 98 percent bound to specific testosterone-estradiol binding globulin, and about percentis free. Generally, the amount of this sex-hormone binding globulin in the plasma will determine the distribution oftestosterone between free and bound forms, and the free testosterone concentration will determine its half-life.About 90 percent of dose of testosterone is excreted in the urine as glucuronic and sulfuric acid conjugates oftestosterone and its metabolites; about percent of dose is excreted in the feces, mostly in the unconjugatedform. Inactivation of testosterone occurs primarily in the liver. Testosterone is metabolized to various 17-keto steroidsthrough two different pathways.The half-life of testosterone cypionate when injected intramuscularly is approximately eight days.In many tissues the activity of testosterone appears to depend on reduction to dihydrotestosterone, which binds tocytosol receptor proteins. The steroid-receptor complex is transported to the nucleus where it initiates transcriptionevents and cellular changes related to androgen action.

CONTROLLED SUBSTANCE SECTION.

Controlled Substance. Testosterone Cypionate Injection contains testosterone, Schedule III controlled substance in the ControlledSubstances Act.AbuseDrug 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 Reactions Serious adverse reactions have been reported in individuals who abuse anabolic androgenic steroids and includecardiac 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 bonyepiphyses with termination of growth, and precocious puberty.Because these reactions are reported voluntarily from population of uncertain size and may include abuse of otheragents, it is not always possible to reliably estimate their frequency or establish causal relationship to drug exposure. Dependence Behaviors Associated with Addiction Continued 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 obligations Having 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 dosereduction of drug. Individuals taking supratherapeutic doses of testosterone may experience withdrawal symptomslasting for weeks or months which include depressed mood, major depression, fatigue, craving, restlessness,irritability, anorexia, insomnia, decreased libido and hypogonadotropic hypogonadism.Drug dependence in individuals using approved doses of testosterone for approved indications has not beendocumented.. 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.

DESCRIPTION SECTION.

DESCRIPTION. Testosterone Cypionate Injection, USP for intramuscular injection, contains Testosterone Cypionate, USPwhich is the oil-soluble 17 (beta)- cyclopentylpropionate ester of the androgenic hormone testosterone.Testosterone Cypionate, USP is white or creamy white crystalline powder, odorless or nearly so andstable in air. It is insoluble in water, freely soluble in alcohol, chloroform, dioxane, ether, and soluble invegetable oils.The chemical name for Testosterone Cypionate, USP is androst-4-en-3-one,17-(3-cyclopentyl-1-oxopropoxy)-, (17)-. Its molecular formula is C27H40O3, and the molecular weight 412.61.The structural formula is represented below:Testosterone Cypionate Injection, USP is available in one strength, 200 mg/mL Testosterone Cypionate, USP.Each mL of the 200 mg/mL solution contains:Testosterone Cypionate, USP200 mgBenzyl Benzoate, USP0.2 mLCottonseed Oil, USP560 mgBenzyl Alcohol, USP (as preservative)9.45 mg. Chemical Structure.

DOSAGE & ADMINISTRATION SECTION.

DOSAGE AND ADMINISTRATION. Prior to initiating testosterone cypionate, confirm the diagnosis of hypogonadism by ensuring that serum testosteroneconcentrations have been measured in the morning on at least two separate days and that these serum testosteroneconcentrations are below the normal range.Testosterone cypionate injection is for intramuscular use only.It should not be given intravenously. Intramuscular injections should be given deep in the gluteal muscle.The suggested dosage for testosterone cypionate injection varies depending on the age, sex, and diagnosis of theindividual patient. Dosage is adjusted according to the patients response and the appearance of adverse reactions.Various dosage regimens have been used to induce pubertal changes in hypogonadal males; some experts haveadvocated lower dosages initially, gradually increasing the dose as puberty progresses, with or without decreaseto maintenance levels. Other experts emphasize that higher dosages are needed to induce pubertal changes andlower dosages can be used for maintenance after puberty. The chronological and skeletal ages must be taken intoconsideration, both in determining the initial dose and in adjusting the dose.For replacement in the hypogonadal male, 50 to 400 mg should be administered every two to four weeks.Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration,whenever solution and container permit. Warming and shaking the vial should redissolve any crystals that may haveformed during storage at temperatures lower than recommended.

DRUG ABUSE AND DEPENDENCE SECTION.

DRUG ABUSE AND DEPENDENCE. Controlled Substance. Testosterone Cypionate Injection contains testosterone, Schedule III controlled substance in the ControlledSubstances Act.AbuseDrug 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 Reactions Serious adverse reactions have been reported in individuals who abuse anabolic androgenic steroids and includecardiac 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 bonyepiphyses with termination of growth, and precocious puberty.Because these reactions are reported voluntarily from population of uncertain size and may include abuse of otheragents, it is not always possible to reliably estimate their frequency or establish causal relationship to drug exposure. Dependence Behaviors Associated with Addiction Continued 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 obligations Having 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 dosereduction of drug. Individuals taking supratherapeutic doses of testosterone may experience withdrawal symptomslasting for weeks or months which include depressed mood, major depression, fatigue, craving, restlessness,irritability, anorexia, insomnia, decreased libido and hypogonadotropic hypogonadism.Drug dependence in individuals using approved doses of testosterone for approved indications has not beendocumented.. 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. Testosterone Cypionate Injection, USP is indicated for replacement therapy in the male in conditions associated with symptoms of deficiency, or absence of endogenous testosterone.Primary hypogonadism (congenital or acquired): testicular failure due to cryptorchidism, 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.Safety and efficacy of testosterone cypionate in men with age-related hypogonadism (also referred to as late-onsethypogonadism) have not been established.. Primary hypogonadism (congenital or acquired): testicular failure due to cryptorchidism, 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.

PHARMACOKINETICS SECTION.

Pharmacokinetics. Testosterone esters are less polar than free testosterone. Testosterone esters in oil injected intramuscularly areabsorbed slowly from the lipid phase; thus, testosterone cypionate can be given at intervals of two to four weeks.Testosterone in plasma is 98 percent bound to specific testosterone-estradiol binding globulin, and about percentis free. Generally, the amount of this sex-hormone binding globulin in the plasma will determine the distribution oftestosterone between free and bound forms, and the free testosterone concentration will determine its half-life.About 90 percent of dose of testosterone is excreted in the urine as glucuronic and sulfuric acid conjugates oftestosterone and its metabolites; about percent of dose is excreted in the feces, mostly in the unconjugatedform. Inactivation of testosterone occurs primarily in the liver. Testosterone is metabolized to various 17-keto steroidsthrough two different pathways.The half-life of testosterone cypionate when injected intramuscularly is approximately eight days.In many tissues the activity of testosterone appears to depend on reduction to dihydrotestosterone, which binds tocytosol receptor proteins. The steroid-receptor complex is transported to the nucleus where it initiates transcriptionevents and cellular changes related to androgen action.

PRECAUTIONS SECTION.

PRECAUTIONS. General. Patients with benign prostatic hypertrophy may develop acute urethral obstruction. Priapism or excessive sexualstimulation may develop. Oligospermia may occur after prolonged administration or excessive dosage. If any of theseeffects appear, the androgen should be stopped and if restarted, lower dosage should be utilized.Testosterone cypionate should not be used interchangeably with testosterone propionate because of differences induration of action.Testosterone cypionate is not for intravenous use.. Information for patients. Patients should be instructed to report any of the following: nausea, vomiting, changes in skin color, ankle swelling,too frequent or persistent erections of the penis.. Laboratory tests. Hemoglobin and hematocrit levels (to detect polycythemia) should be checked periodically in patients receiving long-termandrogen administration.Serum cholesterol may increase during androgen therapy.. Drug interactions. Androgens may increase sensitivity to oral anticoagulants. Dosage of the anticoagulant may requirereduction in order to maintain satisfactory therapeutic hypoprothrombinemia.Concurrent administration of oxyphenbutazone and androgens may result in elevated serum levels ofoxyphenbutazone.In diabetic patients, the metabolic effects of androgens may decrease blood glucose and, therefore,insulin requirements.. Drug/Laboratory test Interferences. Androgens may decrease levels of thyroxine-binding globulin, resulting in decreased total T4 serumlevels 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. Animal dataTestosterone has been tested by subcutaneous injection and implantation in mice and rats. The implantinduced cervical-uterine tumors in mice, which metastasized in some cases. There is suggestiveevidence 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 chemicallyinduced carcinomas of the liver in rats.Human dataThere are rare reports of hepatocellular carcinoma in patients receiving long-term therapy with androgens in highdoses. 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.

WARNINGS SECTION.

WARNINGS. Hypercalcemia may occur in immobilized patients. If this occurs, the drug should be discontinued.Prolonged use of high doses of androgens (principally the 17-a alkyl-androgens) has been associatedwith developmentof hepatic adenomas, hepatocellular carcinoma, and peliosis hepatis --all potentially life-threatening complications.Geriatric patients treated with androgens may be at an increased risk of developing prostatic hypertrophy and prostaticcarcinoma although conclusive evidence to support this concept is lacking.There have been postmarketing reports of venous thromboembolic events, including deep vein thrombosis (DVT) andpulmonary embolism (PE), in patients using testosterone products, such as testosterone cypionate. Evaluate patientswho report symptoms of pain, edema, warmth and erythema in the lower extremity for DVT and those who presentwith acute shortness of breath for PE. If venous thromboembolic event is suspected, discontinue treatment withtestosterone cypionate and initiate appropriate workup and management.Long term clinical safety trials have not been conducted to assess the cardiovascular outcomes of testosteronereplacement therapy in men. To date, epidemiologic studies and randomized controlled trials have been inconclusivefor determining the risk of major adverse cardiovascular events (MACE), such as non-fatal myocardial infarction, non-fatalstroke, 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. Patientsshould be informed of this possible risk when deciding whether to use or to continue to use testosterone cypionate.Testosterone has been subject to abuse, typically at doses higher than recommended for the approved indicationand in combination with other anabolic androgenic steroids. Anabolic androgenic steroid abuse can lead to seriouscardiovascular and psychiatric adverse reactions (see DRUG ABUSE AND DEPENDENCE).If testosterone abuse is suspected, check serum testosterone concentrations to ensure they are within therapeuticrange. However, testosterone levels may be in the normal or subnormal range in men abusing synthetic testosteronederivatives. Counsel patients concerning the serious adverse reactions associated with abuse of testosterone andanabolic androgenic steroids. Conversely, consider the possibility of testosterone and anabolic androgenic steroidabuse 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.Gynecomastia may develop and occasionally persists in patients being treated for hypogonadism.The preservative benzyl alcohol has been associated with serious adverse events, including the gasping syndrome,and death in pediatric patients. Although normal therapeutic doses of this product ordinarily deliver amounts of benzylalcohol that are substantially lower than those reported in association with the gasping syndrome, the minimumamount of benzyl alcohol at which toxicity may occur is not known. The risk of benzyl alcohol toxicity depends on thequantity administered and the liver and kidneys capacity to detoxify the chemical. Premature and low-birth weightinfants may be more likely to develop toxicity.Androgen therapy should be used cautiously in healthy males with delayed puberty. The effect on bone maturationshould be monitored by assessing bone age of the wrist and hand every months. In children, androgen treatmentmay accelerate bone maturation without producing compensatory gain in linear growth. This adverse effect may resultin 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 thepotential risk of serious adverse health effects, this drug should not be used for such purpose.