FDA label fef9649c-0739-4c37-8e39-2f65caeea755

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 Avoid unintentional exposure of women or children to testosterone gel. Secondary exposure to testosterone can produce signs of virilization. Testosterone gel should be discontinued until the cause of virilization is identified. ( 5.1 ) Venous thromboembolism (VTE), including deep vein thrombosis (DVT) and pulmonary embolism (PE) have been reported in patients using testosterone products. Evaluate patients with signs or symptoms consistent with DVT or PE. ( 5.3 ) 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 ) Blood Pressure Increases: Testosterone 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 ) Abuse of Testosterone: Testosterone has been subject to abuse, typically at doses higher than recommended for the approved indication and in combination with other anabolic androgenic steroids ( 5.6 ). Potential for Adverse Effects on Spermatogenesis: Exogenous administration of androgens may lead to azoospermia. ( 5.8 ) Edema with or without congestive heart failure (CHF) may be a complication in patients with pre-existing cardiac, renal, or hepatic disease. ( 5.10 ) 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. ( 5.2 , 5.4 , 5.9 , 5.13 ) Testosterone gel 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 of testosterone gel products. Signs and symptoms have included enlargement of the penis or clitoris, development of pubic hair, increased erections and libido, aggressive behavior, and advanced bone age. In most cases, these signs and symptoms regressed with removal of the exposure to testosterone gel. In a few cases, however, enlarged genitalia did not fully return to age-appropriate normal size, and bone age remained modestly greater than chronological age. The risk of transfer was increased in some of these cases by not adhering to precautions for the appropriate use of the topical testosterone product. Children and women should avoid contact with unwashed or unclothed application sites in men using testosterone gel [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 (VTE) There have been postmarketing reports of venous thromboembolic events, including deep vein thrombosis (DVT) and pulmonary embolism (PE), in patients using testosterone products, such as testosterone gel. 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, topical testosterone gel 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 testosterone gel and initiate appropriate workup and management. 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 of 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. Evaluation of the patients for the presence of prostate cancer prior to initiating and during treatment with androgens is appropriate [see Contraindications ( 4 )] . 5.5 Blood Pressure Increases Testosterone can increase blood pressure. In an ambulatory blood pressure monitoring (ABPM) study, testosterone increased the mean systolic/diastolic blood pressure by 3.1/1.2 m m Hg from baseline after 16 weeks of treatment. In patients with hypertension on antihypertensive therapy, testosterone increased the mean systolic/diastolic BP by 4.0/1.3 mm Hg from baseline. Blood pressure increases can increase cardiovascular (CV) risk over time. The CV risk associated with topical testosterone gel 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, topical testosterone gel increased mean systolic blood pressure 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), includin g cardiovascular death, non-fatal myocardial infarction [MI] and non-fatal stroke, were similar between treatment groups (7% for topical testosterone gel vs 7.3% for placebo) [See Adverse Reactions (6.1)]. Monitor blood pressure periodically in men using testosterone, especially men with hypertension. Testosterone is not recommended for use in patients with 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, testosterone gel 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 testosterone gel, spermatogenesis may be suppressed through feedback inhibition of pituitary 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 testosterone enanthate has produced multiple hepatic adenomas. Testosterone gel is not known to cause these adverse effects. 5.10 Edema Androgens, including testosterone gel, 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 testosterone gel, 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. 5.13 Lipid Changes Changes in serum lipid profile may require dose adjustment or discontinuation of testosterone therapy, such as testosterone. Monitor the lipid profile periodically, particularly after starting testosterone therapy. 5.14 Hypercalcemia Androgens, including testosterone gel, 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 testosterone gel, 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 testosterone gel, are flammable; therefore, patients should be advised to avoid smoking, fire, or flame until the testosterone gel has dried.

6 ADVERSE REACTIONS The most common adverse reaction (incidence ≥3%) is skin reactions at the application site (16.1%). ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Teva at 1-888-838-2872 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 clinical practice. In a controlled multicenter, open-label, non-comparative 90-day clinical study, 149 hypogonadal patients were treated with testosterone gel [ see Clinical Studies (14.1) ] . Adverse reactions occurred in 22.8% (34/149) of patients. The most common adverse reaction reported in this study was skin reactions associated with the site of application (16.1%; 24/149) of which 79% (19/24) were mild and the remainder were moderate (21%; 5/24) (Table 3). Table 3: Adverse Reactions Reported in >1% of Patients in the US Phase 3 Clinical Trial of Testosterone Gel Adverse Reaction Number (%) of Patients N = 149 Skin reaction 24 (16.1%) Prostatic specific antigen increased 2 (1.3%) Abnormal dreams 2 (1.3%) During the 90-day trial 5 patients (3.4%) discontinued treatment because of adverse reactions. These reactions were: 1 patient with contact dermatitis (considered probably related to testosterone gel application), 1 with application site reaction (considered probably related to testosterone gel application), 1 with gastrointestinal hypomotility (considered possibly related to testosterone gel application), 1 with severe dyspnea (considered not related to testosterone gel application), and 1 with moderate contusion (considered not related to testosterone gel application). Blood Pressure Increases In a 4-month clinical study, 24-hour ambulatory blood pressure monitoring (ABPM) was conducted on 223 patients. ABPM was conducted at baseline and at Week 16 of testosterone gel therapy. A total of 92 patients had acceptable ABPM recordings at both baseline and Week 16 and 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=92) was 3.1 mm Hg (95% CI 0.9, 5.3) and 1.2 mm Hg (95% CI -0.1, 2.5), respectively. In patients with a history of hypertension who were receiving antihypertensive therapy, the mean ABPM systolic and diastolic BP increased by 4.0 mm Hg [95% CI 0.3, 7.8] and 1.3 mm Hg [95% CI -0.9, 3.4], respectively [n=42]). In patients with no history of hypertension, the mean systolic and diastolic blood pressure increased by 1.5 mm Hg [95% CI -1.1, 4.1] and 0.6 mm Hg [95% CI -1.0, 2.1], respectively [n=45]. One patient (1.1 %) on testosterone gel, who was receiving antihypertensive medications at baseline, either started new antihypertensive medications (n=1) or had their antihypertensive medication regimen adjusted (n=0) during the ABPM study. Of the 223 patients in the ABPM study who used testosterone gel, 7 patients (3.1%) were reported to have either an adverse reaction of hypertension (5 patients, 2.2%) or increased blood pressure (2 patients, 0.9%). Cardiovascular Outcomes TRAVERSE was a randomized, double-blind, cardiovascular outcomes study to assess the cardiovascular (CV) safety of topical testosterone gel compared to placebo in 5,198 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 topical testosterone gel or placebo therapy. The mean patient age (±SD) was 63.3 (7.9) years, with 2,452 patients aged 65 years or more (47%); 2847 (about 55%) patients had pre-existing cardiovascular disease, whereas 2,357 patients (about 45%) had an elevated cardiovascular risk at baseline, and mean BMI was 35kg/m 2 . 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 topical testosterone gel was 220.4 ng/dL (n=2,596). The mean serum testosterone concentrations at 12 months, 24 months, 36 months, and 48 months in patients receiving topical testosterone gel were 440.5 ng/dL (n=1,683), 420.9 ng/dl (n=1,125), 428.7 ng/dL (n=731), and 365.2 ng/dL (n=220), respectively. For patients treated with topical testosterone gel, 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 topical testosterone gel 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 topical testosterone gel 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 testosterone gel. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure (Table 4). Table 4: Adverse Drug Reactions from Post Approval Experience of Testosterone Gel by System Organ Class System Organ Class Adverse Reaction Blood and lymphatic system disorders Polycythemia Eye disorders Vitreous detachment Gastrointestinal disorders Abdominal symptoms General disorders and administrative site conditions Application site erythema, irritation, pruritus, and swelling; fatigue, influenza like illness, and malaise Investigations Decreased serum testosterone, increased hematocrit and hemoglobin Musculoskeletal and connective tissue disorders Pain in extremity Nervous system disorders Dizziness, headache, and migraine Reproductive system and breast disorders Erectile dysfunction and priapism Skin and subcutaneous tissue disorders Allergic dermatitis, erythema, rash, and papular rash Vascular disorders Venous thromboembolism Cardiovascular disorders Myocardial infarction and stroke Secondary Exposure to Testosterone in Children Cases of secondary exposure to testosterone resulting in virilization of children have been reported in postmarketing surveillance of testosterone gel products. 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 1 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="600px" cellpadding="5"><caption>Table 3: Adverse Reactions Reported in &gt;1% of Patients in the US Phase 3 Clinical Trial of Testosterone Gel</caption><col/><col/><thead><tr><th align="center" styleCode=" Botrule Toprule Lrule Rrule"> Adverse Reaction</th><th align="center" styleCode=" Botrule Toprule Lrule Rrule"> Number (%) of Patients N = 149</th></tr></thead><tbody><tr><td styleCode=" Botrule Toprule Lrule Rrule"> Skin reaction</td><td align="center" styleCode=" Botrule Toprule Lrule Rrule"> 24 (16.1%)</td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"> Prostatic specific antigen increased</td><td align="center" styleCode=" Botrule Toprule Lrule Rrule"> 2 (1.3%)</td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"> Abnormal dreams</td><td align="center" styleCode=" Botrule Toprule Lrule Rrule"> 2 (1.3%)</td></tr></tbody></table>

<table width="700px" cellpadding="5"><caption>Table 4: Adverse Drug Reactions from Post Approval Experience of Testosterone Gel by System Organ Class</caption><col/><col/><thead><tr><th styleCode=" Botrule Toprule Lrule Rrule"> System Organ Class</th><th styleCode=" Botrule Toprule Lrule Rrule"> Adverse Reaction</th></tr></thead><tbody><tr><td styleCode=" Botrule Toprule Lrule Rrule"> Blood and lymphatic system disorders</td><td styleCode=" Botrule Toprule Lrule Rrule"> Polycythemia</td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"> Eye disorders</td><td styleCode=" Botrule Toprule Lrule Rrule"> Vitreous detachment</td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"> Gastrointestinal disorders</td><td styleCode=" Botrule Toprule Lrule Rrule"> Abdominal symptoms</td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"> General disorders and administrative site conditions</td><td styleCode=" Botrule Toprule Lrule Rrule"> Application site erythema, irritation, pruritus, and swelling; fatigue, influenza like illness, and malaise</td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"> Investigations</td><td styleCode=" Botrule Toprule Lrule Rrule"> Decreased serum testosterone, increased hematocrit and hemoglobin </td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"> Musculoskeletal and connective tissue disorders</td><td styleCode=" Botrule Toprule Lrule Rrule"> Pain in extremity</td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"> Nervous system disorders</td><td styleCode=" Botrule Toprule Lrule Rrule"> Dizziness, headache, and migraine</td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"> Reproductive system and breast disorders</td><td styleCode=" Botrule Toprule Lrule Rrule"> Erectile dysfunction and priapism</td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"> Skin and subcutaneous tissue disorders</td><td styleCode=" Botrule Toprule Lrule Rrule"> Allergic dermatitis, erythema, rash, and papular rash </td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"> Vascular disorders </td><td styleCode=" Botrule Toprule Lrule Rrule"> Venous thromboembolism</td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"> Cardiovascular disorders</td><td styleCode=" Botrule Toprule Lrule Rrule"> Myocardial infarction and stroke</td></tr></tbody></table>