Testosterone

6 AD VERSE 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 Actavis at 1-800-272-5525 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. Cli nical 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 Dose of Testosterone Gel 1% Adverse Event 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 Percent of Subjects Adverse Event (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 nocturia, urinary hesitancy, urinary incontinence, urinary retention, urinary urgency and weak urinary stream. ** Testis disorders included three patients. There were two with a non-palpable testis and one with slight right testicular tenderness. Two patients reported serious adverse events considered possibly related to treatment: deep vein thrombosis (DVT) and prostate disorder requiring a transurethral resection of the prostate (TURP). Discontinuation for adverse events in this study included: two patients with application site reactions, one with kidney failure, and five with prostate disorders (including increase in serum PSA in 4 patients, and increase in PSA with prostate enlargement in a fifth patient). Increases in Serum PSA Observed in Clinical Trials of Hypogonadal Men During the initial 6-month study, the mean change in PSA values had a statistically significant increase of 0.26 ng/mL. Serum PSA was measured every 6 months thereafter in the 162 hypogonadal men on testosterone gel 1% in the 3-year extension study. There was no additional statistically significant increase observed in mean PSA from 6 months through 36 months. However, there were increases in serum PSA observed in approximately 18% of individual patients. The overall mean change from baseline in serum PSA values for the entire group from month 6 to 36 was 0.11 ng/mL. Twenty-nine patients (18%) met the per-protocol criterion for increase in serum PSA, defined as greater than 2X the baseline or any single serum PSA greater than 6 ng/mL. Most of these (25/29) met this criterion by at least doubling of their PSA from baseline. In most cases where PSA at least doubled (22/25), the maximum serum PSA value was still less than 2 ng/mL. The first occurrence of a pre-specified, post-baseline increase in serum PSA was seen at or prior to Month 12 in most of the patients who met this criterion (23 of 29; 79%). Four patients met this criterion by having a serum PSA greater than 6 ng/mL and in these, maximum serum PSA values were 6.2 ng/mL, 6.6 ng/mL, 6.7 ng/mL, and 10.7 ng/mL. In two of these patients, prostate cancer was detected on biopsy. The first patient’s PSA levels were 4.7 ng/mL and 6.2 ng/mL at baseline and at Month 6/Final, respectively. The second patient’s PSA levels were 4.2 ng/mL, 5.2 ng/mL, 5.8 ng/mL, and 6.6 ng/mL at baseline, Month 6, Month 12, and Final, respectively. 6.2 Postmarketing Experience The following adverse reactions have been identified during post approval use of testosterone gel 1%. Because the 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 (Table 4). Table 4: Adverse Drug Reactions from Postmarketing Experience of Testosterone Gel 1% by MedDRA System Organ Class Blood and the lymphatic system disorders: Elevated Hgb, Hct (polycythemia) Cardiovascular disorders: Myocardial infarction, stroke Endocrine disorders: Hirsutism Gastrointestinal disorders: Nausea General disorders and administration site reactions: Asthenia, edema, malaise Genitourinary disorders: Impaired urination Hepatobiliary disorders: Abnormal liver function tests (e.g. transaminases, elevated GGTP, bilirubin) Investigations: Elevated PSA, electrolyte changes (nitrogen, calcium, potassium, phosphorus, sodium), changes in serum lipids (hyperlipidemia, elevated triglycerides, decreased HDL), impaired glucose tolerance, fluctuating testosterone concentrations, weight increase Neoplasms benign, malignant and unspecified (cysts and polyps): Prostate cancer Nervous system: Headache, dizziness, sleep apnea, insomnia Psychiatric disorders: Depression, emotional lability, decreased libido, nervousness, hostility, amnesia, anxiety Reproductive system and breast disorders: Gynecomastia, mastodynia, prostatic enlargement, testicular atrophy, oligospermia, priapism (frequent or prolonged erections) Respiratory disorders: Dyspnea Skin and subcutaneous tissue disorders: Acne, alopecia, application site reaction (pruritus, dry skin, erythema, rash, discolored hair, paresthesia), sweating Vascular disorders: Hypertension, vasodilation (hot flushes), venous thromboembolism Secondary Expos ure to Testosterone in Children Cases of secondary exposure to testosterone resulting in virilization of children have been reported in postmarket surveillance. Signs and symptoms of these reported cases have included enlargement of the clitoris (with surgical intervention) or the penis, development of pubic hair, increased erections and libido, aggressive behavior, and advanced bone age. In most cases with a reported outcome, these signs and symptoms were reported to have regressed with removal of the testosterone gel exposure. 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. In some of the cases, direct contact with the sites of application on the skin of men using testosterone gel was reported. In at least one reported case, the reporter considered the possibility of secondary exposure from items such as the testosterone gel user's shirts and/or other fabric, such as towels and sheets [see Warnings and Precautions ( 5.2 )] .

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 )

11 DESCRIPTION Testosterone gel 1% is a clear, colorless hydroalcoholic gel containing testosterone, USP. The active pharmacologic ingredient in testosterone gel 1% is testosterone, USP, an androgen. Testosterone, USP is a white to practically white crystalline powder chemically described as 17-beta hydroxyandrost-4-en-3-one. The structural formula is: Pharmacologically inactive ingredients in testosterone gel 1% are carbomer homopolymer type C, ethyl alcohol 68.9%, isopropyl myristate, purified water, and sodium hydroxide. These ingredients are not pharmacologically active. The structural formula for testosterone gel 1% is testosterone, USP, an androgen. Testosterone, USP is a white to practically white crystalline powder chemically described as 17-beta hydroxyandrost-4-en-3-one.

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 thoroughly with soap and water after application. Avoid fire, flames or smoking until the gel has dried since alcohol based products, including testosterone gel 1%, are flammable. The patient should be advised to avoid swimming or showering for at least 5 hours after the application of testosterone gel 1%. Multi-Dose Pump To obtain a full first dose, it is necessary to prime the canister pump. To do so, with the canister in the upright position, slowly and fully depress the actuator three times. Safely discard the gel from the first three actuations. It is only necessary to prime the pump before the first dose. After the priming procedure, patients should completely depress the pump one time actuation for every 12.5 mg of testosterone required to achieve the daily prescribed dosage. The product should be delivered directly into the palm of the hand and then applied to the desired application sites. Alternatively, testosterone gel 1% can be applied directly to the application sites. Table 1 provides dosing information for adult males. Table 1: Dosing Information for Testosterone Gel 1% Amount of Testosterone Number of Pump Actuations 50 mg 4 (once daily) 75 mg 6 (once daily) 100 mg 8 (once daily) Packets The entire contents should be squeezed into the palm of the hand and immediately applied to the application sites. Alternately, patients may squeeze a portion of the gel from the packet into the palm of the hand and apply to application sites. Repeat until entire contents have been applied. Strict adherence to the following precautions is advised in order to minimize the potential for secondary exposure to testosterone from testosterone gel 1%-treated skin: Children and women should avoid contact with unwashed or unclothed application site(s) of men using testosterone gel 1%. Patients should wash hands with soap and water immediately after application of testosterone gel 1%. Patients should cover the application site(s) with clothing (e.g., a T-shirt) after the gel has dried. Prior to situation in which direct skin-to-skin contact is anticipated, patients should wash the application site thoroughly with soap and water to remove any testosterone residue. In the event that unwashed or unclothed skin to which testosterone gel 1% has been applied comes in direct contact with the skin of another person, the general area of contact on the other person should be washed with soap and water as soon as possible. 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.

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 )

9.2 Abuse Drug abuse is intentional non-therapeutic use of a 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 a 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 include cardiac 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 bony epiphyses with termination of growth, and precocious puberty. Because these reactions are reported voluntarily from a population of uncertain size and may include abuse of other agents, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

9.1 Controlled Substance Testosterone gel 1% contains testosterone, a Schedule III controlled substance in the Controlled Substances Act.

9.3 Depend ence 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 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 a 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 Physical dependence is characterized by withdrawal symptoms after abrupt drug discontinuation or a significant dose reduction of a drug. Individuals taking supratherapeutic doses of testosterone may experience withdrawal symptoms lasting 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 been documented.

9 DRUG ABUSE AND DEPENDENCE 9.1 Controlled Substance Testosterone gel 1% contains testosterone, a Schedule III controlled substance in the Controlled Substances Act. 9.2 Abuse Drug abuse is intentional non-therapeutic use of a 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 a 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 include cardiac 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 bony epiphyses with termination of growth, and precocious puberty. Because these reactions are reported voluntarily from a population of uncertain size and may include abuse of other agents, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. 9.3 Depend ence 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 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 a 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 Physical dependence is characterized by withdrawal symptoms after abrupt drug discontinuation or a significant dose reduction of a drug. Individuals taking supratherapeutic doses of testosterone may experience withdrawal symptoms lasting 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 been documented.

10 OVERDOSAGE There is one report of acute overdosage with use of an approved injectable testosterone product: this subject had serum testosterone concentrations of up to 11,400 ng/dL with a cerebrovascular accident. Treatment of overdosage would consist of discontinuation of testosterone gel 1%, washing the application site with soap and water, and appropriate symptomatic and supportive care.

7 DRU G 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.

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Endogenous androgens, including testosterone and dihydrotestosterone (DHT), 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 facial, pubic, chest and axillary hair; laryngeal enlargement, vocal cord thickening, alterations in body musculature and fat distribution. Testosterone and DHT are necessary for the normal development of secondary sex characteristics. Male hypogonadism, a clinical syndrome resulting from insufficient secretion of testosterone, has two main etiologies. Primary hypogonadism is caused by defects of the gonads, such as Klinefelter’s syndrome or Leydig cell aplasia, whereas secondary hypogonadism is the failure of the hypothalamus (or pituitary) to produce sufficient gonadotropins (FSH, LH). 12.2 Pharmacodynamics No specific pharmacodynamic studies were conducted using testosterone gel 1%. 12.3 Pharmacokinetics Absorption Testosterone gel 1% delivers physiologic amounts of testosterone, producing circulating testosterone concentrations that approximate normal concentrations (298 to 1043 ng/dL) seen in healthy men. Testosterone gel 1% provides continuous transdermal delivery of testosterone for 24 hours following a single application to intact, clean, dry skin of the shoulders, upper arms and/or abdomen. Testosterone gel 1% is a hydroalcoholic formulation that dries quickly when applied to the skin surface. The skin serves as a reservoir for the sustained release of testosterone into the systemic circulation. Approximately 10% of the testosterone dose applied on the skin surface from testosterone gel is absorbed into systemic circulation. In a study with testosterone gel 1% 100 mg, all patients showed an increase in serum testosterone within 30 minutes, and eight of nine patients had a serum testosterone concentration within normal range by 4 hours after the initial application. Absorption of testosterone into the blood continues for the entire 24-hour dosing interval. Serum concentrations approximate the steady-state concentration by the end of the first 24 hours and are at steady state by the second or third day of dosing. With single daily applications of testosterone gel 1%, follow-up measurements 30, 90 and 180 days after starting treatment have confirmed that serum testosterone concentrations are generally maintained within the eugonadal range. Figure 1 summarizes the 24-hour pharmacokinetic profiles of testosterone for hypogonadal men (less than 300 ng/dL) maintained on testosterone gel 1% 50 mg or 100 mg for 30 days. The average (± SD) daily testosterone concentration produced by testosterone gel 1% 100 mg on Day 30 was 792 (± 294) ng/dL and by testosterone gel 1% 50 mg 566 (± 262) ng/dL. Figure 1: Mean (± SD) Steady-State Serum Testosterone Concentrations on Day 30 in Patients Applying Testosterone Gel 1% Once Daily Distribution Circulating testosterone is primarily bound in the serum to sex hormone-binding globulin (SHBG) and albumin. Approximately 40% of testosterone in plasma is bound to SHBG, 2% remains unbound (free) and the rest is bound to albumin and other proteins. Metabolism Testosterone is metabolized to various 17-keto steroids through two different pathways. The major active metabolites of testosterone are estradiol and dihydrotestosterone (DHT). DHT concentrations increased in parallel with testosterone concentrations during testosterone gel 1% treatment. The mean steady-state DHT/T ratio during 180 days of testosterone gel treatment ranged from 0.23 to 0.29 (50 mg of testosterone gel 1%/day) and from 0.27 to 0.33 (100 mg of testosterone gel 1%/day). Excretion There is considerable variation in the half-life of testosterone concentration as reported in the literature, ranging from 10 to 100 minutes. About 90% of a dose of testosterone given intramuscularly is excreted in the urine as glucuronic and sulfuric acid conjugates of testosterone and its metabolites. About 6% of a dose is excreted in the feces, mostly in the unconjugated form. Inactivation of testosterone occurs primarily in the liver. When testosterone gel 1% treatment is discontinued after achieving steady state, serum testosterone concentrations remain in the normal range for 24 to 48 hours but return to their pretreatment concentrations by the fifth day after the last application. Testosterone Transfer from Male Patients to Female Partners The potential for dermal testosterone transfer following testosterone gel 1% use was evaluated in a clinical study between males dosed with testosterone gel 1% and their untreated female partners. Two (2) to 12 hours after application of 100 mg of testosterone administered as testosterone gel 1% by the male subjects, the couples (N = 38 couples) engaged in daily, 15-minute sessions of vigorous skin-to-skin contact so that the female partners gained maximum exposure to the testosterone gel 1% application sites. Under these study conditions, all unprotected female partners had a serum testosterone concentration greater than 2 times the baseline value at some time during the study. When a shirt covered the application site(s), the transfer of testosterone from the males to the female partners was completely prevented. Figure 1: Mean (± SD) Steady-State Serum Testosterone Concentrations on Day 30 in Patients Applying Testosterone Gel 1% Once Daily

12.1 Mechanism of Action Endogenous androgens, including testosterone and dihydrotestosterone (DHT), 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 facial, pubic, chest and axillary hair; laryngeal enlargement, vocal cord thickening, alterations in body musculature and fat distribution. Testosterone and DHT are necessary for the normal development of secondary sex characteristics. Male hypogonadism, a clinical syndrome resulting from insufficient secretion of testosterone, has two main etiologies. Primary hypogonadism is caused by defects of the gonads, such as Klinefelter’s syndrome or Leydig cell aplasia, whereas secondary hypogonadism is the failure of the hypothalamus (or pituitary) to produce sufficient gonadotropins (FSH, LH).

12.2 Pharmacodynamics No specific pharmacodynamic studies were conducted using testosterone gel 1%.

12.3 Pharmacokinetics Absorption Testosterone gel 1% delivers physiologic amounts of testosterone, producing circulating testosterone concentrations that approximate normal concentrations (298 to 1043 ng/dL) seen in healthy men. Testosterone gel 1% provides continuous transdermal delivery of testosterone for 24 hours following a single application to intact, clean, dry skin of the shoulders, upper arms and/or abdomen. Testosterone gel 1% is a hydroalcoholic formulation that dries quickly when applied to the skin surface. The skin serves as a reservoir for the sustained release of testosterone into the systemic circulation. Approximately 10% of the testosterone dose applied on the skin surface from testosterone gel is absorbed into systemic circulation. In a study with testosterone gel 1% 100 mg, all patients showed an increase in serum testosterone within 30 minutes, and eight of nine patients had a serum testosterone concentration within normal range by 4 hours after the initial application. Absorption of testosterone into the blood continues for the entire 24-hour dosing interval. Serum concentrations approximate the steady-state concentration by the end of the first 24 hours and are at steady state by the second or third day of dosing. With single daily applications of testosterone gel 1%, follow-up measurements 30, 90 and 180 days after starting treatment have confirmed that serum testosterone concentrations are generally maintained within the eugonadal range. Figure 1 summarizes the 24-hour pharmacokinetic profiles of testosterone for hypogonadal men (less than 300 ng/dL) maintained on testosterone gel 1% 50 mg or 100 mg for 30 days. The average (± SD) daily testosterone concentration produced by testosterone gel 1% 100 mg on Day 30 was 792 (± 294) ng/dL and by testosterone gel 1% 50 mg 566 (± 262) ng/dL. Figure 1: Mean (± SD) Steady-State Serum Testosterone Concentrations on Day 30 in Patients Applying Testosterone Gel 1% Once Daily Distribution Circulating testosterone is primarily bound in the serum to sex hormone-binding globulin (SHBG) and albumin. Approximately 40% of testosterone in plasma is bound to SHBG, 2% remains unbound (free) and the rest is bound to albumin and other proteins. Metabolism Testosterone is metabolized to various 17-keto steroids through two different pathways. The major active metabolites of testosterone are estradiol and dihydrotestosterone (DHT). DHT concentrations increased in parallel with testosterone concentrations during testosterone gel 1% treatment. The mean steady-state DHT/T ratio during 180 days of testosterone gel treatment ranged from 0.23 to 0.29 (50 mg of testosterone gel 1%/day) and from 0.27 to 0.33 (100 mg of testosterone gel 1%/day). Excretion There is considerable variation in the half-life of testosterone concentration as reported in the literature, ranging from 10 to 100 minutes. About 90% of a dose of testosterone given intramuscularly is excreted in the urine as glucuronic and sulfuric acid conjugates of testosterone and its metabolites. About 6% of a dose is excreted in the feces, mostly in the unconjugated form. Inactivation of testosterone occurs primarily in the liver. When testosterone gel 1% treatment is discontinued after achieving steady state, serum testosterone concentrations remain in the normal range for 24 to 48 hours but return to their pretreatment concentrations by the fifth day after the last application. Testosterone Transfer from Male Patients to Female Partners The potential for dermal testosterone transfer following testosterone gel 1% use was evaluated in a clinical study between males dosed with testosterone gel 1% and their untreated female partners. Two (2) to 12 hours after application of 100 mg of testosterone administered as testosterone gel 1% by the male subjects, the couples (N = 38 couples) engaged in daily, 15-minute sessions of vigorous skin-to-skin contact so that the female partners gained maximum exposure to the testosterone gel 1% application sites. Under these study conditions, all unprotected female partners had a serum testosterone concentration greater than 2 times the baseline value at some time during the study. When a shirt covered the application site(s), the transfer of testosterone from the males to the female partners was completely prevented. Figure 1: Mean (± SD) Steady-State Serum Testosterone Concentrations on Day 30 in Patients Applying Testosterone Gel 1% Once Daily

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3 DOSAGE FORMS AND STRENGTHS Testosterone gel 1% for topical use is available as follows: A metered-dose pump. Each pump actuation delivers 12.5 mg of testosterone in 1.25 g of gel. A unit dose packet containing 25 mg of testosterone provided in 2.5 g of gel. A unit dose packet containing 50 mg of testosterone provided in 5 g of gel. Testosterone gel 1% for topical use is available as follows: Metered-dose pump that delivers 12.5 mg of testosterone per actuation. ( 3 ) Packets containing 25 mg of testosterone. ( 3 ) Packets containing 50 mg of testosterone. ( 3 )

Testosterone Testosterone TESTOSTERONE TESTOSTERONE CARBOMER HOMOPOLYMER TYPE C ALCOHOL ISOPROPYL MYRISTATE WATER SODIUM HYDROXIDE Testosterone Testosterone TESTOSTERONE TESTOSTERONE CARBOMER HOMOPOLYMER TYPE C ALCOHOL ISOPROPYL MYRISTATE WATER SODIUM HYDROXIDE Testosterone Testosterone TESTOSTERONE TESTOSTERONE CARBOMER HOMOPOLYMER TYPE C ALCOHOL ISOPROPYL MYRISTATE WATER SODIUM HYDROXIDE

13.1 Carcinogenesis, Mutage nesis, Impairment of Fertility Carcinogenesis Testosterone has been tested by subcutaneous injection and implantation in mice and rats. In mice, the implant induced cervical-uterine tumors 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. Mutagenesis Testosterone was negative in the in vitro Ames and in the in vivo mouse micronucleus assays. Impairment of Fertility The administration of exogenous testosterone has been reported to suppress spermatogenesis in rats, dogs, and non-human primates, which was reversible on cessation of the treatment.

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutage nesis, Impairment of Fertility Carcinogenesis Testosterone has been tested by subcutaneous injection and implantation in mice and rats. In mice, the implant induced cervical-uterine tumors 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. Mutagenesis Testosterone was negative in the in vitro Ames and in the in vivo mouse micronucleus assays. Impairment of Fertility The administration of exogenous testosterone has been reported to suppress spermatogenesis in rats, dogs, and non-human primates, which was reversible on cessation of the treatment.

ANDA076737

Testosterone

Testosterone

0591-3216

HUMAN PRESCRIPTION DRUG

TOPICAL

PRINCIPAL DISPLAY PANEL - 2.5 grams Actavis For topical use only. Rx Only NDC 0591-3216-30 Testosterone Gel 1% CIII 2.5 grams per unit dose Contains 25 mg of testosterone in 2.5 grams of gel per unit dose Clear, colorless gel provides transdermal delivery of testosterone through the skin of the shoulders, upper arms, or abdomen.* PHARMACIST: Dispense the accompanying Medication Guide to each patient. *See accompanying package insert. 30 Unit-Dose Packets new

17 PATIENT COUNSELING INFORMATION See FDA-Approved Patient Labeling ( Medication Guide ) Patients should be informed of the following: 17.1 Use in Men with Known or Suspe cted Prostate or Breast Cancer Men with known or suspected prostate or breast cancer should not use testosterone gel 1% [see Contraindications ( 4 ) and Warnings and Precautions ( 5.1 )] . 17.2 Potential for Secondary Exposure to Testosterone and Steps to Prevent Secondary Exposure Secondary exposure to testosterone in children and women can occur with the use of testosterone gel in men [see Warnings and Precautions ( 5.2 )] . Cases of secondary exposure to testosterone have been reported in children. Physicians should advise patients of the reported signs and symptoms of secondary exposure which may include the following: In children; unexpected sexual development including inappropriate enlargement of the penis or clitoris, premature development of pubic hair, increased erections, and aggressive behavior In women; changes in hair distribution, increase in acne, or other signs of testosterone effects The possibility of secondary exposure to testosterone gel should be brought to the attention of a healthcare provider Testosterone gel 1% should be promptly discontinued until the cause of virilization is identified Strict adherence to the following precautions is advised to minimize the potential for secondary exposure to testosterone from testosterone gel in men [see Medication Guide ] : Children and women should avoid contact with unwashed or unclothed application site(s) of men using testosterone gel Patients using testosterone gel 1% should apply the product as directed and strictly adhere to the following: ○ Wash hands with soap and water after application ○ Cover the application site(s) with clothing after the gel has dried ○ Wash the application site(s) thoroughly with soap and water prior to any situation where skin-to-skin contact of the application site with another person is anticipated ○ In the event that unwashed or unclothed skin to which testosterone gel 1% has been applied comes in contact with the skin of another person, the general area of contact on the other person should be washed with soap and water as soon as possible [see Dosage and Administration ( 2.2 ), Warnings and Precautions ( 5.2 ) and Clinical Pharmacology ( 12.3 )] . 17.3 Potential Ad verse Reactions with Androgens Patients should be informed that treatment with androgens may lead to adverse reactions which include: Changes in urinary habits such as increased urination at night, trouble starting your urine stream, passing urine many times during the day, having an urge that you have to go to the bathroom right away, having a urine accident, being unable to pass urine and weak urine flow. Breathing disturbances, including those associated with sleep, or excessive daytime sleepiness. Too frequent or persistent erections of the penis. Nausea, vomiting, changes in skin color, or ankle swelling. 17.4 Patients Should Be Advised of the Following Instructions for Use: Read the Medication Guide before starting testosterone gel 1% therapy and to reread it each time the prescription is renewed Testosterone gel 1% should be applied and used appropriately to maximize the benefits and to minimize the risk of secondary exposure in children and women Keep testosterone gel 1% out of the reach of children Testosterone gel 1% is an alcohol based product and is flammable; therefore avoid fire, flame or smoking until the gel has dried It is important to adhere to all recommended monitoring Report any changes in their state of health, such as changes in urinary habits, breathing, sleep, and mood Testosterone gel 1% is prescribed to meet the patient’s specific needs; therefore, the patient should never share testosterone gel 1% with anyone. Wait 5 hours before swimming or washing following application of testosterone gel 1%. This will ensure that the greatest amount of testosterone gel 1% is absorbed into their system. Manufactured by: Actavis Laboratories UT, Inc. Salt Lake City, UT 84108 USA Distributed by: Actavis Pharma, Inc. Parsippany, NJ 07054 USA Rev. A 5/2019

INSTRUCTIONS FOR USE Testosterone ( tes tosʹ ter one) Gel 1% CIII for topical use Read this Instructions for Use for testosterone gel 1% before you start using it and each time you get a refill. There may be new information. This leaflet does not take the place of talking to your healthcare provider about your medical condition or treatment. Applying testosterone gel 1%: Before applying testosterone gel 1%, make sure that your shoulders, upper arms or stomach are clean, dry, and there is no broken skin. The application sites for testosterone gel 1% are the shoulders, upper arms or stomach area (abdomen) that will be covered by a short sleeve t-shirt (see Figure A). Do not apply testosterone gel 1% to any other parts of your body such as your penis, scrotum, chest, armpits (axillae), knees, or back. Tear open the packet completely at the dotted line. Squeeze from the bottom of the packet to the top. Squeeze all of the testosterone gel 1% out of the packet into the palm of your hand. Apply testosterone gel 1% to the application site. You may also apply testosterone gel 1% from the packet directly to the application site. Let the application areas dry completely before putting on a t-shirt. Testosterone gel 1% is flammable until dry. Let testosterone gel 1% dry before smoking or going near an open flame. Wash your hands with soap and water right away after applying testosterone gel 1%. Avoid showering, swimming, or bathing for at least 5 hours after you apply testosterone gel 1%. How should I store testosterone gel 1%? Store testosterone gel 1% at room temperature between 68ºF to 77ºF (20ºC to 25ºC). Safely throw away used testosterone gel 1% in the household trash. Be careful to prevent accidental exposure of children or pets. Keep testosterone gel 1% away from fire. Keep testosterone gel 1% and all medicines out of the reach of children. This Instructions for Use has been approved by the U.S. Food and Drug Administration. Manufactured by: Actavis Laboratories UT, Inc. Salt Lake City, UT 84108 USA Distributed by: Actavis Pharma, Inc. Parsippany, NJ 07054 USA Rev. A 5/2019 instructions for use image

MEDICATION GUIDE Testosterone ( tes tosʹ ter one) Gel 1% CIII for topical use What is the most important information I should know about testosterone gel 1%? Testosterone gel 1% can transfer from your body to others including, children and women. Children and women should avoid contact with the unwashed or not covered (unclothed) areas where testosterone gel 1% has been applied to your skin. Early signs and symptoms of puberty have occurred in young children who have come in direct contact with testosterone by touching areas where men have used testosterone gel 1%. Children Signs and symptoms of early puberty in a child when they come in direct contact with testosterone gel 1% may include: Abnormal sexual changes: Behavior problems: Women Signs and symptoms in women when they come in direct contact with t estosterone gel 1% may include: Stop using testosterone gel 1% and call your healthcare provider right away if you see any signs and symptoms in a child or a woman that may have happened through accidental touching of the area where you have applied testosterone gel 1%. To lower the risk of transfer of testosterone gel 1% from your body to others, follow these important instructions: Apply testosterone gel 1% only to areas of your shoulders, upper arms, or stomach area (abdomen) that will be covered by a short sleeve T-shirt. Wash your hands right away with soap and water after applying testosterone gel 1%. After the gel has dried, cover the application area with clothing. Keep the area covered until you have washed the gel off the application area well or have showered. If you expect to have skin-to-skin contact with another person, first wash the application area well with soap and water. If a child or woman touches the area where you have applied testosterone gel 1%, that area on the child or woman should be washed well with soap and water right away. What is testosterone gel 1%? Testosterone gel 1% is a prescription medicine that contains testosterone. Testosterone gel 1% is used to treat adult males who have low or no testosterone due to certain medical conditions. Your healthcare provider will test your blood before you start and while you are using testosterone gel 1%. It is not known if testosterone gel 1% is safe or effective to treat men who have low testosterone due to aging. It is not known if testosterone gel 1% is safe or effective in children younger than 18 years old. Improper use of testosterone gel 1% may affect bone growth in children. Testosterone gel 1% is a controlled substance (CIII) because it contains testosterone that can be a target for people who abuse prescription medicines. Keep your testosterone gel 1% in a safe place to protect it. Never give your testosterone gel 1% to anyone else, even if they have the same symptoms you have. Selling or giving away this medicine may harm others and is against the law. Testosterone gel 1% is not meant for use in women. Do not use testosterone gel 1% if you: have breast cancer have or might have prostate cancer are pregnant. Testosterone gel 1% may harm your unborn baby. Women who are pregnant should avoid contact with the area of skin where testosterone gel 1% has been applied. Before using testosterone gel 1%, tell your healthcare provider about all of your medical conditions, including if you: have breast cancer have or might have prostate cancer have urinary problems due to an enlarged prostate have heart problems have liver or kidney problems. have problems breathing while you sleep (sleep apnea). Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Using testosterone gel 1% with certain other medicines can affect each other. Especially, tell your healthcare provider if you take: insulin corticosteroids medicines that decrease blood clotting (blood thinners) How should I use testosterone gel 1%? See the detailed Instructions for Use for information about how to use testosterone gel 1% at the end of this Medication Guide. It is important that you apply testosterone gel 1% exactly as your healthcare provider tells you to. Your healthcare provider may change your testosterone gel 1% dose. Do not change your testosterone gel 1% dose without talking to your healthcare provider. Apply testosterone gel 1% at the same time each morning. Testosterone gel 1% should be applied after showering or bathing. What are the possible side effects of testosterone gel 1%? Testosterone gel 1% can cause serious side effects including: See “What is the most important information I should know about testosterone gel 1%?” If you already have an enlarged prostate, your symptoms can get worse while using testosterone gel 1%. This can include: increased urination at night. trouble starting your urine stream. having to pass urine many times during the day. having an urge to go to the bathroom right away. having a urine accident. being unable to pass urine or weak urine flow. Possible increased risk of prostate cancer. Your healthcare provider should check you for prostate cancer or any other prostate problems before you start and while you use testosterone gel 1%. Blood clots in the legs or lungs. Signs and symptoms of a blood clot in your leg can include leg pain, swelling or redness. Signs and symptoms of a blood clot in your lungs can include difficulty breathing or chest pain. Possible increased risk of heart attack or stroke. In large doses testosterone gel 1% may lower your sperm count. Swelling of your ankles, feet, or body, with or without heart failure. Enlarged or painful breasts. Have problems breathing while you sleep (sleep apnea). Call your healthcare provider right away if you have any of the serious side effects listed above. The most common side effects of testosterone gel 1% include: acne skin irritation where testosterone gel 1% is applied lab test changes increased prostate specific antigen (a test used to screen for prostate cancer). Other side effects include more erections than are normal for you or erections that last a long time. Tell your healthcare provider if you have any side effect that bothers you or that does not go away. These are not all the possible side effects of testosterone gel 1%. For more information, ask your healthcare provider or pharmacist. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. General information about the safe and effective use of testosterone gel 1% Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use testosterone gel 1% for a condition for which it was not prescribed. Do not give testosterone gel 1% to other people, even if they have the same symptoms you have. It may harm them. You can ask your pharmacist or healthcare provider for information about testosterone gel 1% that is written for health professionals. What are the ingredients in testosterone gel 1%? Active ingredient: testosterone Inactive ingredients: carbomer homopolymer type C, ethyl alcohol 68.9%, isopropyl myristate, purified water, and sodium hydroxide. For more information, go to www.actavis.com or call Actavis at 1-800-272-5525. This Medication Guide has been approved by the U.S. Food and Drug Administration. Manufactured by: Actavis Laboratories UT, Inc. Salt Lake City, UT 84108 USA Distributed by: Actavis Pharma, Inc. Parsippany, NJ 07054 USA Rev. A 5/2019

14 CLINICAL STUDIES 14.1 Clinical Tr ials in Adult Hypogonadal Males Testosterone gel 1% was evaluated in a multi-center, randomized, parallel-group, active-controlled, 180-day trial in 227 hypogonadal men. The study was conducted in 2 phases. During the Initial Treatment Period (Days 1 to 90), 73 patients were randomized to testosterone gel 1% 50 mg daily, 78 patients to testosterone gel 1% 100 mg daily, and 76 patients to a non-scrotal testosterone transdermal system. The study was double-blind for dose of testosterone gel 1% but open-label for active control. Patients who were originally randomized to testosterone gel 1% and who had single-sample serum testosterone concentrations above or below the normal range on Day 60 were titrated to 75 mg daily on Day 91. During the Extended Treatment Period (Days 91 to 180), 51 patients continued on testosterone gel 1% 50 mg daily, 52 patients continued on testosterone gel 1% 100 mg daily, 41 patients continued on a non-scrotal testosterone transdermal system (5 mg daily), and 40 patients received testosterone gel 1% 75 mg daily. Upon completion of the initial study, 163 enrolled and 162 patients received treatment in an open-label extension study of testosterone gel 1% for an additional period of up to 3 years. Mean peak, trough and average serum testosterone concentrations within the normal range (298 to 1043 ng/dL) were achieved on the first day of treatment with doses of 50 mg and 100 mg of testosterone gel 1%. In patients continuing on testosterone gel 1% 50 mg and 100 mg, these mean testosterone concentrations were maintained within the normal range for the 180-day duration of the original study. Figure 2 summarizes the 24-hour pharmacokinetic profiles of testosterone administered as testosterone gel 1% for 30, 90 and 180 days. Testosterone concentrations were maintained as long as the patient continued to properly apply the prescribed testosterone gel 1% treatment. Figure 2: Mean Steady-State Testosterone Concentrations in Patients with Once Daily Testosterone Gel 1% Therapy Table 5 summarizes the mean testosterone concentrations on Treatment Day 180 for patients receiving 50 mg, 75 mg, or 100 mg of testosterone gel 1%. The 75 mg dose produced mean concentrations intermediate to those produced by 50 mg and 100 mg of testosterone gel 1%. Table 5: Mean (± SD) Steady-State Serum Testosterone Concentrations During Therapy (Day 180) 50 mg 75 mg 100 mg N = 44 N = 37 N = 48 C avg 555 ± 225 601 ± 309 713 ± 209 C max 830 ± 347 901 ± 471 1083 ± 434 C min 371 ± 165 406 ± 220 485 ± 156 Of 129 hypogonadal men who were appropriately titrated with testosterone gel 1% and who had sufficient data for analysis, 87% achieved an average serum testosterone concentration within the normal range on Treatment Day 180. In patients treated with testosterone gel 1%, there were no observed differences in the average daily serum testosterone concentrations at steady-state based on age, cause of hypogonadism, or body mass index. DHT concentrations increased in parallel with testosterone concentrations at testosterone gel 1% doses of 50 mg/day and 100 mg/day, but the DHT/T ratio stayed within the normal range, indicating enhanced availability of the major physiologically active androgen. Serum estradiol (E2) concentrations increased significantly within 30 days of starting treatment with testosterone gel 1% 50 or 100 mg/day and remained elevated throughout the treatment period but remained within the normal range for eugonadal men. Serum levels of SHBG decreased very slightly (1 to 11%) during testosterone gel 1% treatment. In men with hypergonadotropic hypogonadism, serum levels of LH and FSH fell in a dose- and time-dependent manner during treatment with testosterone gel 1%. Figure 2: Mean Steady-State Testosterone Concentrations in Patients with Once Daily Testosterone Gel 1% Therapy 14.2 Phototoxicity in Humans The phototoxic potential of testosterone gel 1% was evaluated in a double-blind, single-dose study in 27 subjects with photosensitive skin types. The Minimal Erythema Dose (MED) of ultraviolet radiation was determined for each subject. A single 24 (+1) hour application of duplicate patches containing test articles (placebo gel, testosterone gel, or saline) was made to naive skin sites on Day 1. On Day 2, each subject received five exposure times of ultraviolet radiation, each exposure being 25% greater than the previous one. Skin evaluations were made on Days 2 to 5. Exposure of test and control article application sites to ultraviolet light did not produce increased inflammation relative to non-irradiated sites, indicating no phototoxic effect.

8.5 Geriatric Use There have not been sufficient numbers of geriatric patients involved in controlled clinical studies utilizing testosterone gel 1% to determine whether efficacy in those over 65 years of age differs from younger subjects. Additionally, there is insufficient long-term safety data in geriatric patients to assess the potential risks of cardiovascular disease and prostate cancer. Geriatric patients treated with androgens may also be at risk for worsening of signs and symptoms of BPH.

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.

8.4 Pediatric Use The safety and efficacy of testosterone gel 1% in pediatric patients less than 18 years old has not been established. Improper use may result in acceleration of bone age and premature closure of epiphyses.

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 USE IN SPECIFIC POPULATIONS There are insufficient long-term safety data in geriatric patients using testosterone gel 1% to assess the potential risks of cardiovascular disease and prostate cancer. ( 8.5 ) 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. 8.2 Lactation Risk Summary Testosterone gel 1% is not indicated for use in women. 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. 8.4 Pediatric Use The safety and efficacy of testosterone gel 1% in pediatric patients less than 18 years old has not been established. Improper use may result in acceleration of bone age and premature closure of epiphyses. 8.5 Geriatric Use There have not been sufficient numbers of geriatric patients involved in controlled clinical studies utilizing testosterone gel 1% to determine whether efficacy in those over 65 years of age differs from younger subjects. Additionally, there is insufficient long-term safety data in geriatric patients to assess the potential risks of cardiovascular disease and prostate cancer. Geriatric patients treated with androgens may also be at risk for worsening of signs and symptoms of BPH. 8.6 Renal Impairment No studies were conducted in patients with renal impairment. 8.7 Hepatic Impairment No studies were conducted in patients with hepatic impairment.

16 HOW SUPPLIED/STORAGE AND HANDLING Testosterone gel 1% is supplied in non-aerosol, metered-dose pumps that deliver 12.5 mg of testosterone per complete pump actuation. The pumps are composed of plastic and stainless steel and an LDPE/aluminum foil inner liner encased in rigid plastic with a polypropylene cap. Each 88 g metered-dose pump is capable of dispensing 75 g of gel or 60-metered pump actuations; each pump actuation dispenses 1.25 g of gel. NDC Number Package Size 0591-2921-02 2 x 75 g pumps per carton (each pump dispenses 60 metered pump actuations with each pump actuation containing 12.5 mg of testosterone in 1.25 g of gel) Testosterone gel 1% is supplied in unit-dose aluminum foil packets in cartons of 30. Each packet of 2.5 g or 5 g gel contains 25 mg or 50 mg testosterone, USP, respectively. NDC Number Package Size 0591-3216-30 30 packets (2.5 g per packet) 0591-3217-30 30 packets (5 g per packet) Keep testosterone gel out of the reach of children. Storage Store at 20° to 25°C (68° to 77°F) [See USP Controlled Room Temperature]. Disposal Used testosterone gel 1% pumps or used testosterone gel 1% packets should be discarded in household trash in a manner that prevents accidental application or ingestion by children or pets.

WARNING: SECONDARY EXPOSURE TO TESTOSTERONE Virilization has been reported in children who were secondarily exposed to testosterone gel [see Warnings and Precautions ( 5.2 ) and Adverse Reactions ( 6.2 )]. Children should avoid contact with unwashed or unclothed application sites in men using testosterone gel [see Dosage and Administration ( 2.2 ) and Warnings and Precautions ( 5.2 )]. Healthcare providers should advise patients to strictly adhere to recommended instructions for use [see Dosage and Administration ( 2.2 ), Warnings and Precautions ( 5.2 ) and Patient Counseling Information ( 17 )]. WARNING: SECONDARY EXPOSURE TO TESTOSTERONE See full prescribing information for complete boxed warning. Virilization has been reported in children who were secondarily exposed to testosterone gel. ( 5.2 , 6.2 ) Children should avoid contact with unwashed or unclothed application sites in men usi ng testosterone gel. ( 2.2 , 5.2 ) Healthcare providers should advise patients to strictly adhere to recommended instructions for use. ( 2.2 , 5.2 , 17 )