FDA label 14a12387-5802-4ec9-8a75-85faebddd18c

WARNING: SECONDARY EXPOSURE TO TESTOSTERONE Virilization has been reported in children who were secondarily exposed to testosterone gel [see Warnings and Precautions ( 5.1 ) 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 ( 5.1 )]. Healthcare providers should advise patients to strictly adhere to recommended instructions for use [see Dosage and Administration ( 2.2 ), Warnings and Precautions ( 5.1 ) 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 ( 5.1 , 6.2 ). Children should avoid contact with unwashed or unclothed application sites in men using testosterone gel ( 2.2 , 5.1 ). Healthcare providers should advise patients to strictly adhere to recommended instructions for use ( 2.2 , 5.1 , 17 ).

5 WARNINGS AND PRECAUTIONS Worsening of Benign Prostatic Hyperplasia (BPH) and Potential Risk of Prostate Cancer: Monitor patients with benign prostatic hyperplasia (BPH) for worsening of signs and symptoms of BPH. ( 5.4 ) Potential for Secondary Exposure to Testosterone: Avoid unintentional exposure of women or children to AndroGel 1%. Secondary exposure to testosterone can produce signs of virilization. AndroGel 1% should be discontinued until the cause of virilization is identified ( 5.1 ) Venous Thromboembolism (VTE): 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. ( 5.3 ) Blood Pressure Increases: AndroGel 1% can increase blood pressure, which can increase cardiovascular risk over time. Measure blood pressure periodically. Not recommended for use in men with uncontrolled hypertension ( 5.5 ) Potential for Adverse Effects on Spermatogenesis: Exogenous administration of androgens may lead to azoospermia ( 5.8 ) Edema: 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: 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 ( 5.4 , 5.6 , 5.9 , 5.13 ) Flammability: AndroGel 1% is flammable until dry ( 5.16 ) 5.1 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 AndroGel 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. 5.2 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. 5.3 Venous Thromboembolism There have been postmarketing reports of venous thromboembolic events (VTE), including deep vein thrombosis (DVT) and pulmonary embolism (PE), in patients using testosterone products such as AndroGel 1%. In the Testosterone Replacement therapy for Assessment of long-term Vascular Events and efficacy ResponSE in hypogonadal men (TRAVERSE) Study, a randomized, double-blind, placebo-controlled, cardiovascular (CV) outcomes study, compared to placebo, AndroGel 1% was associated with a numerically higher incidence of VTE (1.7% vs 1.2%) which included DVT (0.6% vs 0.5%) and PE events (0.9% vs 0.5%) [see Adverse Reactions ( 6.1 )]. Evaluate patients who report symptoms of pain, edema, warmth and erythema in the lower extremity for DVT and those who present with acute shortness of breath for PE. If a venous thromboembolic event is suspected, discontinue treatment with AndroGel 1% and initiate appropriate workup and management [see Adverse Reactions ( 6.2 )]. 5.4 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 )]. 5.5 Blood Pressure Increases AndroGel 1% can increase blood pressure. In an ambulatory blood pressure monitoring (ABPM) study, AndroGel 1.62% increased the mean systolic/diastolic blood pressure by 1.9/1.3 mm Hg from baseline after 16 weeks of treatment. In patients with hypertension on antihypertensive therapy, AndroGel 1.62% increased the mean systolic/diastolic BP by 3.0/2.2 mm Hg from baseline. Blood pressure increases can increase cardiovascular (CV) risk over time. The CV risk associated with AndroGel 1.62% was evaluated in TRAVERSE, a randomized, double-blind, placebo-controlled, CV outcomes study in men with a history of CV disease or multiple CV risk factors. In TRAVERSE, mean systolic blood pressure in the group treated with AndroGel 1.62% was increased by 1.0 mm Hg from baseline to 36 months, whereas a mean decrease from baseline of 0.5 mm Hg was observed in the placebo group at this timepoint, for a mean between-group difference of 1.5 mm Hg. However, the incidences of major adverse cardiovascular events (MACE), including cardiovascular death, non-fatal myocardial infarction [MI] and non-fatal stroke, were similar between treatment groups (7% for AndroGel 1.62% vs 7.3% for placebo) [See Adverse Reactions ( 6.1 )]. Monitor blood pressure periodically in men using AndroGel 1.62%, especially men with hypertension. AndroGel 1.62% is not recommended for use in patients with uncontrolled hypertension. 5.6 Abuse of Testosterone and Monitoring of Serum Testosterone Concentrations Testosterone has been subject to abuse, typically at doses higher than recommended for the approved indication and in combination with other anabolic androgenic steroids. Anabolic androgenic steroid abuse can lead to serious cardiovascular and psychiatric adverse reactions [see Drug Abuse and Dependence ( 9 )]. If testosterone abuse is suspected, check serum testosterone concentrations to ensure they are within therapeutic range. However, testosterone levels may be in the normal or subnormal range in men abusing synthetic testosterone derivatives. Counsel patients concerning the serious adverse reactions associated with abuse of testosterone and anabolic androgenic steroids. Conversely, consider the possibility of testosterone and anabolic androgenic steroid abuse in suspected patients who present with serious cardiovascular or psychiatric adverse events. 5.7 Not for Use in Women Due to the lack of controlled evaluations in women and potential virilizing effects, AndroGel 1% is not indicated for use in women [see Contraindications ( 4 ) and Use in Specific Populations ( 8.1 , 8.2 )]. 5.8 Potential for Adverse Effects on Spermatogenesis With large doses of exogenous androgens, including AndroGel 1%, spermatogenesis may be suppressed through feedback inhibition of pituitary follicle-stimulating hormone (FSH) which could possibly lead to adverse effects on semen parameters including sperm count. 5.9 Hepatic Adverse Effects Prolonged use of high doses of orally active 17-alpha-alkyl androgens (e.g., methyltestosterone) has been associated with serious hepatic adverse effects (peliosis hepatis, hepatic neoplasms, cholestatic hepatitis, and jaundice). Peliosis hepatis can be a life-threatening or fatal complication. Long-term therapy with intramuscular testosterone enanthate has produced multiple hepatic adenomas. AndroGel 1% is not known to cause these adverse effects. 5.10 Edema Androgens, including AndroGel 1%, may promote retention of sodium and water. Edema, with or without congestive heart failure, may be a serious complication in patients with preexisting cardiac, renal, or hepatic disease [see Adverse Reactions ( 6.2 )]. 5.11 Gynecomastia Gynecomastia may develop and persist in patients being treated with androgens, including AndroGel 1%, for hypogonadism. 5.12 Sleep Apnea The treatment of hypogonadal men with testosterone may potentiate sleep apnea in some patients, especially those with risk factors such as obesity or chronic lung diseases [see Adverse Reactions ( 6.2 )]. 5.13 Lipid Changes Changes in serum lipid profile may require dose adjustment or discontinuation of testosterone therapy, such as AndroGel 1%. Monitor the lipid profile periodically, particularly after starting testosterone therapy. 5.14 Hypercalcemia Androgens, including AndroGel 1%, should be used with caution in cancer patients at risk of hypercalcemia (and associated hypercalciuria). Regular monitoring of serum calcium concentrations is recommended in these patients. 5.15 Decreased Thyroxine-binding Globulin Androgens, including AndroGel 1%, may decrease concentrations of thyroxin-binding globulins, resulting in decreased total T4 serum concentrations and increased resin uptake of T3 and T4. Free thyroid hormone concentrations remain unchanged, however, and there is no clinical evidence of thyroid dysfunction. 5.16 Flammability Alcohol based products, including AndroGel 1%, are flammable; therefore, patients should be advised to avoid fire, flame or smoking until the AndroGel 1% has dried.

6 ADVERSE REACTIONS Most common adverse reactions (incidence ≥ 5%) are acne, application site reaction, abnormal lab tests, and prostatic disorders. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact ASCEND Therapeutics US, LLC at 1-877-204-1013 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 AndroGel 1% and reported by >1% of patients in a 180 Day, Phase 3 study. Table 2: Adverse Events Possibly, Probably or Definitely Related to Use of AndroGel 1% in the 180-Day Controlled Clinical Trial Adverse Event Dose of AndroGel 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 AndroGel 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 AndroGel 1%. These events included: cerebral hemorrhage, convulsion (neither of which were considered related to AndroGel 1% administration), depression, sadness, memory loss, elevated prostate specific antigen, and hypertension. No AndroGel 1% patient discontinued due to skin reactions. In a separate uncontrolled pharmacokinetic study of 10 patients, two had adverse events associated with AndroGel 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 AndroGel 1% and reported by > 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 AndroGel 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 >2X the baseline or any single serum PSA >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 <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 >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. Blood Pressure Increases In a 4-month clinical study, 24-hour ambulatory blood pressure monitoring (ABPM) was conducted on 246 patients. ABPM was conducted at baseline and at Week 16 of AndroGel 1.62% therapy. A total of 169 patients had acceptable ABPM recordings at both baseline and Week 16 and also were at least 85% compliant with study drug. In that group, the mean change in 24-hour systolic blood pressure (BP) and diastolic BP from baseline to end-of-treatment at Week 16 (n=169) was 1.9 mm Hg (95% CI 0.6, 3.1) and 1.3 mm Hg (95% CI 0.5, 2.1), respectively. In patients with a history of hypertension who were being treated with antihypertensive therapy, the mean ABPM systolic and diastolic BP increased by 3.0 mm Hg [95% CI 0.8, 5.2] and 2.2 mm Hg [95% CI 0.8, 3.5], respectively [n=72]). In patients with no history of hypertension at baseline, the mean systolic and diastolic blood pressure increased by 1.2 mm Hg [95% CI -0.2, 2.7] and 0.9 mm Hg [95% CI -0.1, 1.8], respectively [n=91]). Four patients (2.8%) on AndroGel 1.62%, all of whom were receiving antihypertensive medications at baseline, either started new antihypertensive medications (n=2) or had their antihypertensive regimen adjusted during the ABPM study. Of the 246 patients who used AndroGel during the study, 10 patients (4.1%) were reported to have either an adverse reaction of hypertension (5 patients, 2.0%) or increased blood pressure (5 patients, 2.0%). Cardiovascular Outcomes TRAVERSE was a randomized, double-blind, cardiovascular outcomes study to assess the CV safety of AndroGel 1.62% compared to placebo in 5198 hypogonadal men aged 45 to 80 years with a history of CV disease or with multiple CV risk factors. The primary outcome was the incidence of the composite endpoint of major adverse cardiovascular events (MACE), consisting of CV death, non-fatal myocardial infarction (MI), and non-fatal stroke. The mean duration of therapy was approximately 22 months. The mean duration of follow-up was 33 months. Approximately 61% of all patients discontinued AndroGel 1.62% or placebo therapy. The mean (±SD) daily dose of testosterone was 65±22 mg. The mean patient age (±SD) was 63.3 (7.9) years, with 2452 patients aged 65 years or more (47%); 2847 (about 55%) patients had pre-existing cardiovascular disease, whereas 2357 patients (about 45%) had an elevated cardiovascular risk at baseline, and mean BMI was 35kg/m2. Approximately 80% of patients were White, 17% were Black, and 3% were of other races or ethnic groups. Approximately 69%, 84%, and 93% had diabetes mellitus, hyperlipidemia, and hypertension, respectively. The mean serum testosterone concentration at baseline in patients receiving AndroGel 1.62% was 220.4 ng/dL (n= 2596). The mean serum testosterone concentrations at 12 months, 24 months, 36 months, and 48 months in patients receiving AndroGel 1.62% were 440.5 ng/dL (n=1683), 420.9 ng/dl (n=1125), 428.7 ng/dL (n=731), and 365.2 ng/dL (n=220), respectively. For patients treated with AndroGel 1.62%, the incidence of MACE was 7.0% (n=182 events) and for those receiving placebo, the incidence of MACE was 7.3% (n=190 events). The study demonstrated non-inferiority of AndroGel 1.62% versus placebo because the upper bound of 95% CI was less than the pre-specified risk margin, of 1.5 for MACE (Hazard Ratio 0.96 [95% CI: 0.78, 1.17]). Additional Adverse Reactions Reported in TRAVERSE Additional adverse reactions reported in TRAVERSE at an incidence rate >2% in either treatment group and greater in AndroGel 1.62% versus placebo included: nonfatal arrythmias warranting intervention (5.2% vs 3.3%), atrial fibrillation (3.5% vs 2.4%), acute kidney injury (2.3% vs 1.5%) and bone fracture (3.5% vs 2.5%). For the adverse reaction of bone fracture, each event was adjudicated by clinical review. 6.2 Postmarketing Experience The following adverse reactions have been identified during post approval use of AndroGel 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 Exposure 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 ( 5.1 )] .

<table width="630"><caption>Table 2: Adverse Events Possibly, Probably or Definitely Related to Use of AndroGel 1% in the 180-Day Controlled Clinical Trial</caption><colgroup><col width="49%" align="left"/><col width="17%" align="center"/><col width="17%" align="center"/><col width="17%" align="center"/></colgroup><tbody><tr styleCode="Bold"><td styleCode="Lrule Rrule Toprule" rowspan="2" valign="middle" align="center">Adverse Event</td><td styleCode="Lrule Rrule Toprule" colspan="3" align="center">Dose of AndroGel 1%</td></tr><tr styleCode="Bold"><td styleCode="Lrule Rrule Toprule" align="center">50 mg</td><td styleCode="Lrule Rrule Toprule">75 mg</td><td styleCode="Lrule Rrule Toprule">100 mg</td></tr><tr styleCode="Bold"><td styleCode="Lrule Rrule Toprule"/><td styleCode="Lrule Rrule Toprule">N = 77</td><td styleCode="Lrule Rrule Toprule">N = 40</td><td styleCode="Lrule Rrule Toprule">N = 78</td></tr><tr><td styleCode=" Toprule Lrule Rrule"> Acne </td><td align="center" styleCode=" Toprule Lrule Rrule"> 1%</td><td align="center" styleCode=" Toprule Lrule Rrule"> 3%</td><td align="center" styleCode=" Toprule Lrule Rrule"> 8%</td></tr><tr><td styleCode=" Toprule Lrule Rrule"> Alopecia</td><td align="center" styleCode=" Toprule Lrule Rrule"> 1%</td><td align="center" styleCode=" Toprule Lrule Rrule"> 0%</td><td align="center" styleCode=" Toprule Lrule Rrule"> 1%</td></tr><tr><td styleCode=" Toprule Lrule Rrule"> Application Site Reaction </td><td align="center" styleCode=" Toprule Lrule Rrule"> 5%</td><td align="center" styleCode=" Toprule Lrule Rrule"> 3%</td><td align="center" styleCode=" Toprule Lrule Rrule"> 4%</td></tr><tr><td styleCode=" Toprule Lrule Rrule"> Asthenia </td><td align="center" styleCode=" Toprule Lrule Rrule"> 0%</td><td align="center" styleCode=" Toprule Lrule Rrule"> 3%</td><td align="center" styleCode=" Toprule Lrule Rrule"> 1%</td></tr><tr><td styleCode=" Toprule Lrule Rrule"> Depression </td><td align="center" styleCode=" Toprule Lrule Rrule"> 1%</td><td align="center" styleCode=" Toprule Lrule Rrule"> 0%</td><td align="center" styleCode=" Toprule Lrule Rrule"> 1%</td></tr><tr><td styleCode=" Toprule Lrule Rrule"> Emotional Lability</td><td align="center" styleCode=" Toprule Lrule Rrule"> 0%</td><td align="center" styleCode=" Toprule Lrule Rrule"> 3%</td><td align="center" styleCode=" Toprule Lrule Rrule"> 3%</td></tr><tr><td styleCode=" Toprule Lrule Rrule"> Gynecomastia </td><td align="center" styleCode=" Toprule Lrule Rrule"> 1%</td><td align="center" styleCode=" Toprule Lrule Rrule"> 0%</td><td align="center" styleCode=" Toprule Lrule Rrule"> 3%</td></tr><tr><td styleCode=" Toprule Lrule Rrule"> Headache</td><td align="center" styleCode=" Toprule Lrule Rrule"> 4%</td><td align="center" styleCode=" Toprule Lrule Rrule"> 3%</td><td align="center" styleCode=" Toprule Lrule Rrule"> 0%</td></tr><tr><td styleCode=" Toprule Lrule Rrule"> Hypertension </td><td align="center" styleCode=" Toprule Lrule Rrule"> 3%</td><td align="center" styleCode=" Toprule Lrule Rrule"> 0%</td><td align="center" styleCode=" Toprule Lrule Rrule"> 3%</td></tr><tr><td styleCode=" Toprule Lrule Rrule"> Lab Test Abnormal*</td><td align="center" styleCode=" Toprule Lrule Rrule"> 6%</td><td align="center" styleCode=" Toprule Lrule Rrule"> 5%</td><td align="center" styleCode=" Toprule Lrule Rrule"> 3%</td></tr><tr><td styleCode=" Toprule Lrule Rrule"> Libido Decreased</td><td align="center" styleCode=" Toprule Lrule Rrule"> 0%</td><td align="center" styleCode=" Toprule Lrule Rrule"> 3%</td><td align="center" styleCode=" Toprule Lrule Rrule"> 1%</td></tr><tr><td styleCode=" Toprule Lrule Rrule"> Nervousness </td><td align="center" styleCode=" Toprule Lrule Rrule"> 0%</td><td align="center" styleCode=" Toprule Lrule Rrule"> 3%</td><td align="center" styleCode=" Toprule Lrule Rrule"> 1%</td></tr><tr><td styleCode=" Toprule Lrule Rrule"> Pain Breast </td><td align="center" styleCode=" Toprule Lrule Rrule"> 1%</td><td align="center" styleCode=" Toprule Lrule Rrule"> 3%</td><td align="center" styleCode=" Toprule Lrule Rrule"> 1%</td></tr><tr><td styleCode=" Toprule Lrule Rrule"> Prostate Disorder** </td><td align="center" styleCode=" Toprule Lrule Rrule"> 3%</td><td align="center" styleCode=" Toprule Lrule Rrule"> 3%</td><td align="center" styleCode=" Toprule Lrule Rrule"> 5%</td></tr><tr><td styleCode=" Toprule Lrule Rrule"> Testis Disorder***</td><td align="center" styleCode=" Toprule Lrule Rrule"> 3%</td><td align="center" styleCode=" Toprule Lrule Rrule"> 0%</td><td align="center" styleCode=" Toprule Lrule Rrule"> 0%</td></tr><tr><td colspan="4" styleCode=" Toprule Lrule Rrule"> *<content styleCode="italics">Lab test abnormal</content> 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.</td></tr><tr><td colspan="4" styleCode=" Toprule Lrule Rrule"> **<content styleCode="italics">Prostate disorders</content> included five patients with enlarged prostate, one with BPH, and one with elevated PSA results.</td></tr><tr><td colspan="4" styleCode=" Toprule Lrule Rrule"> ***<content styleCode="italics">Testis disorders</content> were reported in two patients: one with left varicocele and one with slight sensitivity of left testis.</td></tr></tbody></table>

<table width="630"><caption>Table 3: Adverse Events Possibly, Probably or Definitely Related to Use of Testosterone Gel 1% in the 3 Year, Flexible Dose, Extension Study</caption><col width="55%"/><col width="45%"/><tbody><tr><td align="center" styleCode=" Toprule Lrule Rrule"/><td align="center" styleCode=" Toprule Lrule Rrule"><content styleCode="bold">Percent of Subjects</content></td></tr><tr><td align="center" styleCode=" Lrule Rrule"><content styleCode="bold">Adverse Event</content></td><td align="center" styleCode=" Lrule Rrule"><content styleCode="bold">(N = 162)</content></td></tr><tr><td styleCode=" Toprule Lrule Rrule"> Lab Test Abnormal+</td><td align="center" styleCode=" Toprule Lrule Rrule"> 9.3</td></tr><tr><td styleCode=" Toprule Lrule Rrule"> Skin dry</td><td align="center" styleCode=" Toprule Lrule Rrule"> 1.9</td></tr><tr><td styleCode=" Toprule Lrule Rrule"> Application Site Reaction </td><td align="center" styleCode=" Toprule Lrule Rrule"> 5.6</td></tr><tr><td styleCode=" Toprule Lrule Rrule"> Acne </td><td align="center" styleCode=" Toprule Lrule Rrule"> 3.1</td></tr><tr><td styleCode=" Toprule Lrule Rrule"> Pruritus</td><td align="center" styleCode=" Toprule Lrule Rrule"> 1.9</td></tr><tr><td styleCode=" Toprule Lrule Rrule"> Enlarged Prostate</td><td align="center" styleCode=" Toprule Lrule Rrule"> 11.7</td></tr><tr><td styleCode=" Toprule Lrule Rrule"> Carcinoma of Prostate </td><td align="center" styleCode=" Toprule Lrule Rrule"> 1.2</td></tr><tr><td styleCode=" Toprule Lrule Rrule"> Urinary Symptoms*</td><td align="center" styleCode=" Toprule Lrule Rrule"> 3.7</td></tr><tr><td styleCode=" Toprule Lrule Rrule"> Testis Disorder** </td><td align="center" styleCode=" Toprule Lrule Rrule"> 1.9</td></tr><tr><td styleCode=" Toprule Lrule Rrule"> Gynecomastia </td><td align="center" styleCode=" Toprule Lrule Rrule"> 2.5</td></tr><tr><td styleCode=" Toprule Lrule Rrule"> Anemia</td><td align="center" styleCode=" Toprule Lrule Rrule"> 2.5</td></tr><tr><td colspan="2" styleCode=" Toprule Lrule Rrule"> +<content styleCode="italics">Lab test abnormal</content> 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.</td></tr><tr><td colspan="2" styleCode=" Toprule Lrule Rrule"> *<content styleCode="italics">Urinary symptoms</content> included nocturia, urinary hesitancy, urinary incontinence, urinary retention, urinary urgency and weak urinary stream.</td></tr><tr><td colspan="2" styleCode=" Toprule Lrule Rrule"> **<content styleCode="italics">Testis disorders</content> included three patients. There were two with a non-palpable testis and one with slight right testicular tenderness. </td></tr></tbody></table>

<table width="630"><caption>Table 4: Adverse Drug Reactions from Postmarketing Experience of Testosterone Gel 1% by MedDRA System Organ Class</caption><col width="30%"/><col width="70%"/><tbody><tr><td styleCode=" Toprule Lrule Rrule">Blood and the lymphatic system disorders:</td><td styleCode=" Toprule Lrule Rrule">Elevated Hgb, Hct (polycythemia) </td></tr><tr><td styleCode=" Toprule Lrule Rrule">Cardiovascular disorders:</td><td styleCode=" Toprule Lrule Rrule">Myocardial infarction, stroke</td></tr><tr><td styleCode=" Toprule Lrule Rrule">Endocrine disorders: </td><td styleCode=" Toprule Lrule Rrule">Hirsutism </td></tr><tr><td styleCode=" Toprule Lrule Rrule">Gastrointestinal disorders:</td><td styleCode=" Toprule Lrule Rrule">Nausea</td></tr><tr><td styleCode=" Toprule Lrule Rrule">General disorders and administration site reactions:</td><td styleCode=" Toprule Lrule Rrule">Asthenia, edema, malaise</td></tr><tr><td styleCode=" Toprule Lrule Rrule">Genitourinary disorders:</td><td styleCode=" Toprule Lrule Rrule">Impaired urination </td></tr><tr><td styleCode=" Toprule Lrule Rrule">Hepatobiliary disorders:</td><td styleCode=" Toprule Lrule Rrule">Abnormal liver function tests (e.g. transaminases, elevated GGTP, bilirubin) </td></tr><tr><td styleCode=" Toprule Lrule Rrule">Investigations:</td><td styleCode=" Toprule Lrule Rrule">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</td></tr><tr><td styleCode=" Toprule Lrule Rrule">Neoplasms benign, malignant and unspecified (cysts and polyps): </td><td styleCode=" Toprule Lrule Rrule">Prostate cancer</td></tr><tr><td styleCode=" Toprule Lrule Rrule">Nervous system:</td><td styleCode=" Toprule Lrule Rrule">Headache, dizziness, sleep apnea, insomnia</td></tr><tr><td styleCode=" Toprule Lrule Rrule">Psychiatric disorders:</td><td styleCode=" Toprule Lrule Rrule">Depression, emotional lability, decreased libido, nervousness, hostility, amnesia, anxiety </td></tr><tr><td styleCode=" Toprule Lrule Rrule">Reproductive system and breast disorders: </td><td styleCode=" Toprule Lrule Rrule">Gynecomastia, mastodynia, prostatic enlargement, testicular atrophy, oligospermia, priapism (frequent or prolonged erections)</td></tr><tr><td styleCode=" Toprule Lrule Rrule">Respiratory disorders:</td><td styleCode=" Toprule Lrule Rrule">Dyspnea </td></tr><tr><td styleCode=" Toprule Lrule Rrule">Skin and subcutaneous tissue disorders:</td><td styleCode=" Toprule Lrule Rrule">Acne, alopecia, application site reaction (pruritus, dry skin, erythema, rash, discolored hair, paresthesia), sweating </td></tr><tr><td styleCode=" Toprule Lrule Rrule">Vascular disorders: </td><td styleCode=" Toprule Lrule Rrule">Hypertension, vasodilation (hot flushes), venous thromboembolism</td></tr></tbody></table>