Testosterone

1 INDICATIONS AND USAGE Testosterone topical solution USP is indicated for replacement therapy in males for conditions associated with a deficiency or absence of endogenous testosterone: Primary hypogonadism (congenital or acquired) ( 1 ) Hypogonadotropic hypogonadism (congenital or acquired) ( 1 ) Limitations of use: Safety and efficacy of testosterone topical solution USP in men with "age-related hypogonadism" have not been established. ( 1 ) Safety and efficacy of testosterone topical solution USP in males <18 years old have not been established ( 8.4 ) Testosterone topical solution USP is indicated for replacement therapy in males for conditions associated with a deficiency or absence of endogenous testosterone: Primary hypogonadism (congenital or acquired): testicular failure due to conditions such as cryptorchidism, bilateral torsion, orchitis, vanishing testis syndrome, orchiectomy, Klinefelter's syndrome, chemotherapy, or toxic damage from alcohol or heavy metals. These men usually have low serum testosterone concentrations and gonadotropins (FSH, LH) above the normal range. Hypogonadotropic hypogonadism (congenital or acquired): gonadotropin or luteinizing hormone-releasing hormone (LHRH) deficiency or pituitary-hypothalamic injury from tumors, trauma, or radiation. These men have low testosterone serum concentrations but have gonadotropins in the normal or low range. Limitations of use: Safety and efficacy of testosterone topical solution USP in men with "age-related hypogonadism" (also referred to as "late-onset hypogonadism") have not been established. Safety and efficacy of testosterone topical solution USP in males <18 years old have not been established [see USE IN SPECIFIC POPULATIONS ( 8.4 )] .

2 DOSAGE AND ADMINISTRATION Prior to initiating testosterone topical solution USP, confirm the diagnosis of hypogonadism by ensuring that serum testosterone concentrations have been measured in the morning on at least two separate days and that these serum testosterone concentrations are below the normal range. Prior to initiating testosterone topical solution USP, confirm the diagnosis of hypogonadism by ensuring that serum testosterone has been measured in the morning on at least two separate days and that these concentrations are below the normal range ( 2 ). Starting testosterone topical solution USP dose is 60 mg of testosterone (1 pump actuation of 30 mg of testosterone to each axilla), applied once daily, at the same time each morning. ( 2.1 ) Apply to clean, dry intact skin of the axilla, not to any other parts of the body including the abdomen or genitals ( 2.2 ) Dose adjustment: The dose of testosterone may be decreased from 60 mg (2 pump actuations) to 30 mg (1 pump actuation) or increased from 60 mg to 90 mg (3 pump actuations) or from 90 mg to 120 mg (4 pump actuations) based on the serum testosterone concentration from a single blood draw 2 to 8 hours after applying testosterone topical solution USP and at least 14 days after starting treatment or following dose adjustment. ( 2.2 ) Patients should wash hands immediately with soap and water after applying testosterone topical solution USP and cover the application site with clothing after the solution has dried. Wash the application site thoroughly with soap and water prior to any situation where skin-to-skin contact of the application site with another person is anticipated. ( 2.2 ) The application site and dose of testosterone topical solution USP are not interchangeable with other topical testosterone products. ( 2.1 ) 2.1 Dosing and Dose Adjustment The recommended starting dose of testosterone topical solution USP is 60 mg of testosterone (2 pump actuations) applied once daily. To ensure proper dosing, serum testosterone concentrations should be measured after initiation of therapy to ensure that the desired concentrations (300 ng/dL to 1050 ng/dL) are achieved. The testosterone topical solution USP dose can be adjusted based on the serum testosterone concentration from a single blood draw 2 to 8 hours after applying testosterone topical solution USP and at least 14 days after starting treatment or following dose adjustment. If the measured serum testosterone concentration is below 300 ng/dL, the daily testosterone dose may be increased from 60 mg (2 pump actuations) to 90 mg (3 pump actuations) or from 90 mg to 120 mg (4 pump actuations). If the serum testosterone concentration exceeds 1050 ng/dL, the daily testosterone dose should be decreased from 60 mg (2 pump actuations) to 30 mg (1 pump actuation) as instructed by a physician. If the serum testosterone concentration consistently exceeds 1050 ng/dL at the lowest daily dose of 30 mg (1 pump actuation), testosterone topical solution USP therapy should be discontinued. The application site and dose of testosterone topical solution USP are not interchangeable with other topical testosterone products. 2.2 Administration Instructions Testosterone topical solution USP is applied to the axilla, preferably at the same time each morning, to clean, dry, intact skin. Do not apply testosterone topical solution USP to other parts of the body including to the scrotum, penis, abdomen, shoulders or upper arms. After applying the solution, the application site should be allowed to dry completely prior to dressing. Avoid fire, flames or smoking until the solution has dried since alcohol based products, including testosterone topical solution USP, are flammable. When deodorants or antiperspirants are used as part of a regular program for personal hygiene, they should not interfere with the efficacy of testosterone topical solution USP in treating hypogonadism. If patients use an antiperspirant or deodorant (stick or roll-on)…

5 WARNINGS AND PRECAUTIONS Monitor patients with benign prostatic hyperplasia (BPH) for worsening of signs and symptoms of BPH ( 5.1 ) Avoid unintentional exposure of women or children to testosterone topical solution. Secondary exposure to testosterone can produce signs of virilization. Testosterone topical solution should be discontinued until the cause of the virilization is identified ( 2.2 , 5.2 ) Venous thromboembolism (VTE), including deep vein thrombosis (DVT) and pulmonary embolism (PE) have been reported in patients using testosterone products. Evaluate patients with signs or symptoms consistent with DVT or PE. ( 5.4 ) Some postmarketing studies have shown an increased risk of myocardial infarction and stroke associated with use of testosterone replacement therapy. ( 5.5 ) Exogenous administration of testosterone may lead to azoospermia ( 5.9 ) Edema with or without congestive heart failure, may be a complication in patients with preexisting cardiac, renal, or hepatic disease ( 5.11 ). Sleep apnea may occur in those with risk factors ( 5.13 ) Monitor serum testosterone, prostate specific antigen (PSA), liver function, lipid concentrations, hematocrit and hemoglobin periodically ( 5.1 , 5.3 , 5.10 , 5.14 ) Testosterone topical solution is flammable until dry ( 5.17 ) 5.1 Worsening of Benign Prostatic Hyperplasia and Potential Risk of Prostate Cancer Monitor patients with benign prostatic hyperplasia (BPH) for worsening of signs and symptoms of BPH. Patients treated with Androgens may be at increased risk for prostate cancer. Evaluate patients for prostate cancer prior to initiating treatment. It would be appropriate to reevaluate patients 3 to 6 months after initiation of treatment, and then in accordance with prostate cancer screening practices. [see CONTRAINDICATIONS ( 4 )] . 5.2 Potential for Secondary Exposure to Testosterone Cases of secondary exposure to testosterone in children and women have been reported with topical testosterone products applied to the abdomen or upper arms, including cases of secondary exposure resulting in virilization of children. Signs and symptoms have included enlargement of the penis or clitoris, development of pubic hair, increased erections and libido, aggressive behavior, and advanced bone age. In most cases, these signs and symptoms regressed with removal of the exposure to testosterone. In a few cases, however, enlarged genitalia did not fully return to age-appropriate normal size, and bone age remained modestly greater than chronological age. The risk of transfer was increased in some of these cases by not adhering to precautions for the appropriate use of the topical testosterone product. Children and women should avoid contact with unwashed or unclothed application sites in men using testosterone topical solution [see DOSAGE AND ADMINISTRATION ( 2.2 ), USE IN SPECIFIC POPULATIONS ( 8.1 ) and CLINICAL PHARMACOLOGY ( 12.3 )] . Inappropriate changes in genital size or development of pubic hair or libido in children, or changes in body hair distribution, significant increase in acne, or other signs of virilization in adult women should be brought to the attention of a physician and the possibility of secondary exposure to testosterone should also be brought to the attention of a physician. Testosterone therapy should be promptly discontinued at least until the cause of virilization has been identified. [see DOSAGE AND ADMINISTRATION ( 2.2 )] . 5.3 Polycythemia Increases in hematocrit, reflective of increases in red blood cell mass, may require lowering or discontinuation of testosterone. Check hematocrit prior to initiating testosterone treatment. It would be appropriate to re-evaluate the hematocrit 3 to 6 months after starting testosterone treatment, and then annually. If hematocrit becomes elevated, stop therapy until hematocrit decreases to an acceptable level. An increase in red blood cell mass may increase the risk of thromboembolic events. 5.4 Venous Thromboembolism There h…

4 CONTRAINDICATIONS Men with carcinoma of the breast or known or suspected carcinoma of the prostate ( 4 , 5.1 ) Pregnant or breastfeeding women. Testosterone may cause fetal harm ( 4 , 8.1 , 8.3 ) Testosterone topical solution is contraindicated in men with carcinoma of the breast or known or suspected carcinoma of the prostate [see WARNINGS AND PRECAUTION ( 5.1 )] . Testosterone topical solution is contraindicated in women who are, or who may become pregnant, or who are breastfeeding. Testosterone topical solution may cause fetal harm when administered to a pregnant woman. Testosterone topical solution may cause serious adverse reactions in nursing infants. If a pregnant woman is exposed to testosterone topical solution, she should be apprised of the potential hazard to the fetus. [see USE IN SPECIFIC POPULATIONS ( 8.1 , 8.3 )] .

7 DRUG INTERACTIONS Androgens may decrease blood glucose and insulin requirement in diabetic patients ( 7.1 ). Changes in anticoagulant activity may be seen with androgens. More frequent monitoring of International Normalized Ratio (INR) and prothrombin time is recommended ( 7.2 ). Use of testosterone with Adrenocorticotropic Hormone (ACTH) or corticosteroids may result in increased fluid retention. Use with caution, particularly in patients with cardiac, renal, or hepatic disease ( 7.3 ). 7.1 Insulin Changes in insulin sensitivity or glycemic control may occur in patients treated with androgens. In diabetic patients, the metabolic effects of androgens may decrease blood glucose and, therefore, insulin requirement. 7.2 Oral anticoagulants Changes in anticoagulant activity may be seen with androgens. More frequent monitoring of INR and prothrombin time is recommended in patients taking anticoagulants, especially at the initiation and termination of androgen therapy. 7.3 Corticosteroids The concurrent use of testosterone with ACTH or corticosteroids may result in increased fluid retention and should be monitored cautiously, particularly in patients with cardiac, renal or hepatic disease.

8.1 Pregnancy Pregnancy Category X [see CONTRAINDICATIONS ( 4 )] Testosterone topical solution is contraindicated during pregnancy or in women who may become pregnant. Testosterone is teratogenic and may cause fetal harm. Exposure of a female fetus to androgens may result in varying degrees of virilization. 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 a fetus.

8.3 Nursing Mothers Although it is not known how much testosterone transfers into human milk, testosterone topical solution is contraindicated in nursing women because of the potential for serious adverse reactions in nursing infants. Testosterone and other androgens may adversely affect lactation. [see CONTRAINDICATIONS ( 4 )] .

6 ADVERSE REACTIONS Most common adverse reactions (incidence >4%) are skin application site reactions, increased hematocrit, headache, diarrhea, vomiting, and increased serum PSA ( 6.1 ). To report SUSPECTED ADVERSE REACTIONS, contact Lupin Pharmaceuticals, Inc. at 1-800-399-2561 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trial Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Clinical Trials in Hypogonadal Men Table 2 shows the treatment emergent adverse reactions that were reported by either >4% of 155 patients in a 120 day, Phase 3 study or by >4% of 71 patients who continued to use testosterone topical solution for up to 180 days. These data reflect the experience primarily with a testosterone dose of 60 mg, which was taken by all patients at the start of the study, and was the maintenance dose for 97 patients. However, the doses used varied from 30 mg to 120 mg. Event 120 Days (155 Patients) 180 Days (71 Patients) Application Site Irritation 11 (7%) 6 (8%) Application Site Erythema 8 (5%) 5 (7%) Headache 8 (5%) 4 (6%) Hematocrit Increased 6 (4%) 5 (7%) Diarrhea 4 (3%) 3 (4%) Vomiting 4 (3%) 3 (4%) PSA Increased 2 (1%) 3 (4%) Other less common adverse reactions reported by at least 2 patients in the 120 day trial included: application site edema, application site warmth, increased hemoglobin, hypertension, erythema (general), increased blood glucose, acne, nasopharyngitis, anger and anxiety. Other less common adverse reactions reported in fewer than 1% of patients in the 120 day trial included: asthenia, affect lability, folliculitis, increased lacrimation, breast tenderness, increased blood pressure, increased blood testosterone, neoplasm prostate and elevated red blood cell count. During the 120 day trial one patient discontinued treatment because of affect lability/anger which was considered possibly related to testosterone topical solution administration. During the 120 day clinical trial there was an increase in mean PSA values of 0.13 ± 0.68 ng/mL from baseline. At the end of the 180 day extension clinical trial, there was an overall increase in mean PSA values of 0.1 ± 0.54 ng/mL. Following the 120 day study, seventy-one (71) patients entered a two-month extension study with testosterone topical solution. Two patients (3%) had adverse reactions that led to discontinuation of treatment during the period from Day 120 to Day 180. These reactions were: one patient with application site irritation (considered possibly related to testosterone topical solution application) and one patient with dry skin and erythema, but not at the application site (considered not related to testosterone topical solution administration) and application site erythema (considered possibly related to testosterone topical solution administration). No serious adverse reactions to testosterone topical solution were reported during either the 120 day trial, or the extension to 180 days. 6.2 Postmarketing Experience The following adverse reactions have been identified during postapproval use of testosterone topical solution. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Cardiovascular Disorders myocardial infarction, stroke [see WARNINGS AND PRECAUTIONS ( 5.5 )] . Vascular Disorders Venous thromboembolism [see WARNINGS AND PRECAUTIONS ( 5.4 )] .