Testosterone Gel, 1%

1 INDICATIONS AND USAGE Testosterone gel, 1% is indicated for replacement therapy in adult 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 (follicle-stimulating hormone [FSH], luteinizing hormone [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 gel, 1% in men with "age-related hypogonadism" (also referred to as "late-onset hypogonadism") have not been established. Safety and efficacy of testosterone gel, 1% in males less than 18 years old have not been established [ see Use in Specific Populations ( 8.4 ) ]. Topical testosterone products may have different doses, strengths or application instructions that may result in different systemic exposure ( 1 , 12.3 ). Testosterone gel, 1% 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 gel, 1% in men with “age-related hypogonadism” have not been established. ( 1 ) Safety and efficacy of testosterone gel, 1% in males less than 18 years old have not been established. ( 8.4 ) Topical testosterone products may have different doses, strengths or application instructions that may result in different systemic exposure. ( 1 , 12.3 )

2 DOSAGE AND ADMINISTRATION Dosage and Administration for testosterone gel, 1% differs from testosterone gel, 1.62%. For dosage and administration of testosterone gel, 1.62% refer to its full prescribing information. (2) Prior to initiating testosterone gel, 1%, 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. Dosage and Administration for testosterone gel, 1% differs from testosterone gel, 1.62%. For dosage and administration of testosterone gel, 1.62% refer to its full prescribing information. (2) Prior to initiating testosterone gel, 1%., 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 dose of testosterone gel, 1% is 50 mg of testosterone (4 pump actuations, two 25 mg packets, or one 50 mg packet), applied once daily in the morning. ( 2.1 ) Apply to clean, dry, intact skin of shoulders and upper arms and/or abdomen. Do NOT apply Testosterone Gel, 1% to any other parts of the body including the genitals, chest, armpits (axillae), knees, or back. ( 2.2 ) Dose adjustment: Testosterone gel, 1% can be dose adjusted using 50 mg, 75 mg, or 100 mg of testosterone on the basis of total serum testosterone concentration. The dose should be titrated based on the serum testosterone concentration. Additionally, serum testosterone concentration should be assessed periodically. ( 2.1 ) Patients should wash hands immediately with soap and water after applying testosterone gel, 1% and cover the application site(s) with clothing after the gel 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 ) 2.1 Dosing and Dose Adjustment The recommended starting dose of testosterone gel, 1% is 50 mg of testosterone (4 pump actuations, two 25 mg packets, or one 50 mg packet), applied topically once daily in the morning to the shoulders and upper arms and/or abdomen area (preferably at the same time every day). Dose Adjustment To ensure proper dosing, serum testosterone concentrations should be measured at intervals. If the serum testosterone concentration is below the normal range, the daily testosterone gel, 1% dose may be increased from 50 mg to 75 mg and from 75 mg to 100 mg for adult males as instructed by the physician (see Table 1, Dosing Information for testosterone gel 1%). If the serum testosterone concentration exceeds the normal range, the daily Testosterone Gel, 1% dose may be decreased. If the serum testosterone concentration consistently exceeds the normal range at a daily dose of 50 mg, Testosterone Gel, 1% therapy should be discontinued. In addition, serum testosterone concentrations should be assessed periodically. The application site and dose of testosterone gel, 1% are not interchangeable with other topical testosterone products. 2.2 Administration Instructions Testosterone gel, 1% should be applied to clean, dry, healthy, intact skin of the right and left upper arms/shoulders and/or right and left abdomen. Area of application should be limited to the area that will be covered by the patient’s short sleeve T-shirt. Do not apply testosterone gel, 1% to any other part of the body including the genitals, chest, armpits (axillae), knees, or back. Testosterone gel, 1% should be evenly distributed between the right and left upper arms/shoulders or both sides of the abdomen. The prescribed daily dose of testosterone gel, 1% should be applied to the right and left upper arms/shoulders and/or right/left abdomen as shown in the shaded areas in the figure below. After applying the gel, the application site should be allowed to dry prior to dressing. Hands should be washed thorough…

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 gel, 1%. Secondary exposure to testosterone can produce signs of virilization. Testosterone gel, 1% should be discontinued until the cause of virilization is identified. ( 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 androgens may lead to azoospermia. ( 5.8 ) Edema, with or without congestive heart failure (CHF), may be a complication in patients with preexisting cardiac, renal, or hepatic disease. ( 5.10 , 6.2 ) Sleep apnea may occur in those with risk factors. ( 5.12 ) Monitor serum testosterone, prostate specific antigen (PSA), hemoglobin, hematocrit, liver function tests, and lipid concentrations periodically. ( 5.1 , 5.3 , 5.9 , 5.13 ) Testosterone gel, 1% is flammable until dry. ( 5.16 ) 5.1 Worsening of Benign Prostatic Hyperplasia (BPH) and Potential Risk of Prostate Cancer Patients with BPH treated with androgens are at an increased risk for worsening of signs and symptoms of BPH. Monitor patients with BPH for worsening signs and symptoms. Patients treated with androgens may be at increased risk for prostate cancer. Evaluate patients for prostate cancer prior to initiating and during treatment with androgens [see Contraindications ( 4 ), Adverse Reactions ( 6.1 ) and Nonclinical Toxicology ( 13.1 )] . 5.2 Potential for Secondary Exposure to Testosterone Cases of secondary exposure resulting in virilization of children have been reported in postmarketing surveillance. 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 gel. 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 gel, 1% [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 gel should also be brought to the attention of a physician. Testosterone gel should be promptly discontinued until the cause of virilization has been identified. 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 treatment. It would also be appropriate to re-evaluate the hematocrit 3 to 6 months after starting treatment, and then annually. If hematocrit becomes elevated, stop therapy until hematocrit decreases to an acceptable concentration. An increase in red blood cell mass may increase the risk of thromboembolic events. 5.4 Venous Thromboembolism 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 testosterone gel, 1%…

4 CONTRAINDICATIONS Testosterone gel, 1% is contraindicated in men with carcinoma of the breast or known or suspected carcinoma of the prostate [see Warnings and Precautions ( 5.1 ), Adverse Reactions ( 6.1 ), and Nonclinical Toxicology ( 13.1 )] . Testosterone gel, 1% is contraindicated in women who are pregnant. Testosterone gel, 1% can cause virilization of the female fetus when administered to a pregnant woman. Pregnant women need to be aware of the potential for transfer of testosterone from men treated with testosterone gel, 1%. If a pregnant woman is exposed to testosterone gel, 1%, she should be apprised of the potential hazard to the fetus [see Warnings and Precautions ( 5.2 ) and Use in Specific Populations ( 8.1 )] . Men with carcinoma of the breast or known or suspected prostate cancer. ( 4 , 5.1 ) Women who are pregnant. Testosterone may cause fetal harm. ( 4 , 8.1 )

7 DRUG INTERACTIONS Androgens may decrease blood glucose and therefore may decrease insulin requirements in diabetic patients. ( 7.1 ) Changes in anticoagulant activity may be seen with androgens. More frequent monitoring of INR and prothrombin time is recommended. ( 7.2 ) Use of testosterone with adrenocorticotrophic 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, may decrease insulin requirements. 7.2 Oral Anticoagulants Changes in anticoagulant activity may be seen with androgens, therefore more frequent monitoring of international normalized ratio (INR) and prothrombin time are recommended in patients taking anticoagulants, especially at the initiation and termination of androgen therapy. 7.3 Corticosteroids The concurrent use of testosterone with adrenocorticotropic hormone (ACTH) or corticosteroids may result in increased fluid retention and requires careful monitoring particularly in patients with cardiac, renal or hepatic disease.

8.1 Pregnancy Risk Summary Testosterone gel, 1% is contraindicated in pregnant women. Testosterone is teratogenic and may cause fetal harm when administered to a pregnant woman based on data from animal studies and its mechanism of action [see Contraindications ( 4 ) and Clinical Pharmacology ( 12.1 )] . Exposure of a female fetus to androgens may result in varying degrees of virilization. In animal developmental studies, exposure to testosterone in utero resulted in hormonal and behavioral changes in offspring and structural impairments of reproductive tissues in female and male offspring. These studies did not meet current standards for nonclinical development toxicity studies. Data Animal Data In developmental studies conducted in rats, rabbits, pigs, sheep and rhesus monkeys, pregnant animals received intramuscular injection of testosterone during the period of organogenesis. Testosterone treatment at doses that were comparable to those used for testosterone replacement therapy resulted in structural impairments in both female and male offspring. Structural impairments observed in females included increased ano-genital distance, phallus development, empty scrotum, no external vagina, intrauterine growth retardation, reduced ovarian reserve, and increased ovarian follicular recruitment. Structural impairments seen in male offspring included increased testicular weight, larger seminal tubular lumen diameter, and higher frequency of occluded tubule lumen. Increased pituitary weight was seen in both sexes. Testosterone exposure in utero also resulted in hormonal and behavioral changes in offspring. Hypertension was observed in pregnant female rats and their offspring exposed to doses approximately twice those used for testosterone replacement therapy.

8.3 Females and Males of Reproductive Potential Infertility Testis disorder, testicular atrophy, and oligospermia have been identified during use of Testosterone gel, 1% [see Adverse Reactions ( 6.1 , 6.2 )] . During treatment with large doses of exogenous androgens, including testosterone gel, 1%, spermatogenesis may be suppressed through feedback inhibition of the hypothalamic-pituitary-testicular axis [see Warnings and Precautions ( 5.8 )] . Reduced fertility is observed in some men taking testosterone replacement therapy. Testicular atrophy, subfertility, and infertility have also been reported in men who abuse anabolic androgenic steroids [see Drug Abuse and Dependence ( 9.2 )] . With either type of use, the impact on fertility may be irreversible.

6 ADVERSE REACTIONS Most common adverse reactions (incidence greater than or equal to 5%) are acne, application site reaction, abnormal lab tests, and prostatic disorders. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Encube Ethicals Private Limited at 1-833-285-4151 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 incidence of all adverse events judged by the investigator to be at least possibly related to treatment with testosterone gel, 1% and reported by greater than 1% of patients in a 180 Day, Phase 3 study. Table 2: Adverse Events Possibly, Probably or Definitely Related to Use of Testosterone Gel, 1% in the 180-Day Controlled Clinical Trial Adv erse Event Dose of Testosterone Gel, 1% 50 mg 75 mg 100 mg N = 77 N = 40 N = 78 Acne 1% 3% 8% Alopecia 1% 0% 1% Application Site Reaction 5% 3% 4% Asthenia 0% 3% 1% Depression 1% 0% 1% Emotional Lability 0% 3% 3% Gynecomastia 1% 0% 3% Headache 4% 3% 0% Hypertension 3% 0% 3% Lab Test Abnormal* 6% 5% 3% Libido Decreased 0% 3% 1% Nervousness 0% 3% 1% Pain Breast 1% 3% 1% Prostate Disorder** 3% 3% 5% Testis Disorder*** 3% 0% 0% * Lab test abnormal occurred in nine patients with one or more of the following events reported: elevated hemoglobin or hematocrit, hyperlipidemia, elevated triglycerides, hypokalemia, decreased HDL, elevated glucose, elevated creatinine, elevated total bilirubin.** Prostate disorders included five patients with enlarged prostate, one with BPH, and one with elevated PSA results. *** Testis disorders were reported in two patients: one with left varicocele and one with slight sensitivity of left testis. Other less common adverse reactions, reported in fewer than 1% of patients included: amnesia,anxiety, discolored hair, dizziness, dry skin, hirsutism, hostility, impaired urination, paresthesia, penis disorder, peripheral edema, sweating, and vasodilation. In this 180 day clinical trial, skin reactions at the site of application were reported with testosterone gel, 1%, but none was severe enough to require treatment or discontinuation of drug. Six patients (4%) in this trial had adverse events that led to discontinuation of testosterone gel, 1%. These events included: cerebral hemorrhage, convulsion (neither of which were considered related to testosterone gel, 1% administration), depression, sadness, memory loss, elevated prostate specific antigen, and hypertension. No testosterone gel, 1% patient discontinued due to skin reactions. In a separate uncontrolled pharmacokinetic study of 10 patients, two had adverse events associated with testosterone gel, 1%; these were asthenia and depression in one patient and increased libido and hyperkinesia in the other. In a 3 year, flexible dose, extension study, the incidence of all adverse events judged by the investigator to be at least possibly related to treatment with testosterone gel, 1% and reported by greater than 1% of patients is shown in Table 3. Table 3: Adverse Events Possibly, Probably or Definitely Related to Use of Testosterone Gel, 1% in the 3 Year, Flexible Dose, Extension Study Adverse Event Percent of Subjects (N = 162) Lab Test Abnormal+ 9.3 Skin dry 1.9 Application Site Reaction 5.6 Acne 3.1 Pruritus 1.9 Enlarged Prostate 11.7 Carcinoma of Prostate 1.2 Urinary Symptoms* 3.7 Testis Disorder** 1.9 Gynecomastia 2.5 Anemia 2.5 + Lab test abnormal occurred in 15 patients with one or more of the following events reported: elevated AST, elevated ALT, elevated testosterone, elevated hemoglobin or hematocrit, elevated cholesterol, elevated cholesterol/LDL ratio, elevated triglycerides, elevated HDL, elevated serum creatinine. * Urinary symptoms included noctu…