Testim

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 Potential for Secondary Exposure to Testosterone: Avoid unintentional exposure of women or children to TESTIM. Secondary exposure to testosterone can produce signs of virilization. TESTIM 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 ) 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: Edema, with or without congestive heart failure, 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 prostate specific antigen (PSA), hematocrit, and lipid concentrations periodically. ( 5.2 , 5.4 , 5.13 ) TESTIM 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 TESTIM [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 TESTIM. 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 TESTIM 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 )] . 5.5 Blood Pressure Increases TESTIM can increase blood pressure. In an ambulatory blood pressure monitoring (ABPM) study, TESTIM increased the mean systolic/diastolic blood pressure by 2.7/1.1 mm Hg from baseline after 16 weeks of treatment. In patients with hypertension on antihypertensive therapy, TESTIM increased the mean systolic/diastolic BP by 1.9/0.3 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), including 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 TESTIM, especially men with hypertension. TESTIM 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 lack of controlled evaluations in women and potential virilizing effects, TESTIM 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 TESTIM, 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, which elevates blood levels for prolonged periods, has produced multiple hepatic adenomas. TESTIM is not known to cause these adverse effects. Nonetheless, patients should be instructed to report any signs or symptoms of hepatic dysfunction (e.g., jaundice). If these occur, promptly discontinue TESTIM while the cause is evaluated. 5.10 Edema Androgens, including TESTIM, 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. In addition to discontinuation of the drug, diuretic therapy may be required. 5.11 Gynecomastia Gynecomastia occasionally develops and occasionally persists in patients being treated for hypogonadism [see Adverse Reactions ( 6.1 )] . 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 the serum lipid profile may occur. Monitor the lipid profile periodically, particularly after starting testosterone therapy and after dose increases. 5.14 Hypercalcemia Androgens, including TESTIM, 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 TESTIM, may decrease concentrations of thyroxine-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 TESTIM, are flammable; therefore, patients should be advised to avoid fire, flame or smoking until the TESTIM has dried.

6 ADVERSE REACTIONS Most common adverse reactions (incidence ≥ 2% of the TESTIM patients and greater than placebo) are application site reaction and increased hematocrit. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Endo at 1-800-462-3636 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Studies 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. In a controlled clinical study, 304 patients were treated with TESTIM 50 mg or 100 mg or placebo gel for up to 90 days. Two hundred five (205) patients received TESTIM 50 mg or 100 mg daily and 99 patients received placebo. Subjects could be counted in both TESTIM treatment groups if they received both 50 mg and 100 mg at different points in the study and experienced an adverse reaction at both dose levels. Adverse reactions reported by ≥ 1% of the TESTIM patients and greater than placebo are listed in Table 1. Table 1: Incidence of Adverse Reactions (Reported by ≥ 1% of the TESTIM Patients and Greater than Placebo) in the Controlled Clinical Trial Through 90 Days Event TESTIM 50 mg (n=103) TESTIM 100 mg (n=149) Placebo (n=99) Application Site Reactions 2% 4% 3% Blood Pressure Increased 1% 1% 0% Gynecomastia 1% 0% 0% Headache 1% 1% 0% Hematocrit / hemoglobin Increased 1% 2% 0% Hot Flushes 1% 0% 0% Insomnia 1% 0% 0% Mood Swings 1% 0% 0% Smell Disorder 1% 0% 0% Spontaneous Penile Erection 1% 0% 0% Taste Disorder 1% 1% 0% The following adverse reactions occurred in fewer than 1% of patients but were greater in TESTIM groups compared to the placebo group: activated partial thromboplastin time prolonged, blood creatinine increased, prothrombin time prolonged, appetite increased, sensitive nipples, and acne. In this clinical trial of TESTIM, 6 patients had adverse reactions that led to their discontinuation. These events included: depression with suicidal ideation, urinary tract infection, mood swings and hypertension. No TESTIM patients discontinued due to skin reaction. In one foreign Phase 3 trial, one subject discontinued due to a skin-related adverse reaction. In the pivotal US and European Phase 3 trials combined, at the 50-mg dosage strength, the percentage of subjects reporting clinically notable increases in hematocrit or hemoglobin were similar to placebo. However, in the 100-mg dose group, 2.3% and 2.8% of patients had a clinically notable increase in hemoglobin (≥ 19 g/dL) or hematocrit (≥ 58%), respectively, compared to 1.0% and 1.5% of patients in the placebo group, respectively. In the combined US and European open-label extension studies, approximately 140 patients received TESTIM for at least 6 months. The results from these studies are consistent with those reported for the US controlled clinical trial. Blood Pressure Increases In a 4-month clinical study, 24-hour ambulatory blood pressure monitoring (ABPM) was conducted on 225 patients. ABPM was conducted at baseline and at Week 16 of TESTIM therapy. A total of 113 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=113) was 2.7 mm Hg (95% CI 0.7, 4.8) and 1.1 mm Hg (95% CI -0.1, 2.3), respectively. In patients with a history of hypertension who were receiving antihypertensive therapy, the mean ABPM systolic and diastolic BP increased by 1.9 mm Hg [95% CI -1.4, 5.2] and 0.3 mm Hg [95% CI -1.6, 2.2], respectively [n=55]). In patients with no history of hypertension, the mean systolic and diastolic blood pressure increased by 2.2 mm Hg [95% CI -0.4, 4.9] and 1.1 mm Hg [95% CI -0.4, 2.7], respectively [n=56]. 3 patients (2.7%) on TESTIM, all of whom were receiving antihypertensive medications at baseline, either started new antihypertensive medications (n=3) or had their antihypertensive medication regimen adjusted (n=0) during the ABPM study. Of the 225 patients in the ABPM study who used TESTIM, 6 patients (2.7%) were reported to have either an adverse reaction of hypertension (6 patients, 2.7%) or increased blood pressure (0 patients, 0.0%). 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 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 topical testosterone gel or placebo therapy. 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/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=2596). 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=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 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 products. 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. 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 of 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 )] . Vascular Disorders Venous thromboembolism [see Warnings and Precautions ( 5.3 )] Cardiovascular Disorders Myocardial infarction, stroke [see Warnings and Precautions ( 5.5 )] Blood and Lymphatic Disorders Polycythemia [see Warnings and Precautions ( 5.2 )]

<table><caption>Table 1: Incidence of Adverse Reactions (Reported by &#x2265; 1% of the TESTIM Patients and Greater than Placebo) in the Controlled Clinical Trial Through 90 Days</caption><col width="1px"/><col width="1px"/><col width="1px"/><col width="1px"/><tbody><tr><td align="center" styleCode=" Lrule Rrule"><content styleCode="bold"> Event</content></td><td align="center" styleCode=" Rrule"><content styleCode="bold"> TESTIM 50 mg (n=103)</content></td><td align="center" styleCode=" Rrule"><content styleCode="bold"> TESTIM 100 mg (n=149)</content></td><td align="center" styleCode=" Rrule"><content styleCode="bold"> Placebo (n=99)</content></td></tr><tr><td styleCode=" Lrule Rrule"> Application Site Reactions</td><td align="center" styleCode=" Rrule"> 2%</td><td align="center" styleCode=" Rrule"> 4%</td><td align="center" styleCode=" Rrule"> 3%</td></tr><tr><td styleCode=" Lrule Rrule"> Blood Pressure Increased</td><td align="center" styleCode=" Rrule"> 1%</td><td align="center" styleCode=" Rrule"> 1%</td><td align="center" styleCode=" Rrule"> 0%</td></tr><tr><td styleCode=" Lrule Rrule"> Gynecomastia</td><td align="center" styleCode=" Rrule"> 1%</td><td align="center" styleCode=" Rrule"> 0%</td><td align="center" styleCode=" Rrule"> 0%</td></tr><tr><td styleCode=" Lrule Rrule"> Headache</td><td align="center" styleCode=" Rrule"> 1%</td><td align="center" styleCode=" Rrule"> 1%</td><td align="center" styleCode=" Rrule"> 0%</td></tr><tr><td styleCode=" Lrule Rrule"> Hematocrit / hemoglobin Increased</td><td align="center" styleCode=" Rrule"> 1%</td><td align="center" styleCode=" Rrule"> 2%</td><td align="center" styleCode=" Rrule"> 0%</td></tr><tr><td styleCode=" Lrule Rrule"> Hot Flushes</td><td align="center" styleCode=" Rrule"> 1%</td><td align="center" styleCode=" Rrule"> 0%</td><td align="center" styleCode=" Rrule"> 0%</td></tr><tr><td styleCode=" Lrule Rrule"> Insomnia</td><td align="center" styleCode=" Rrule"> 1%</td><td align="center" styleCode=" Rrule"> 0%</td><td align="center" styleCode=" Rrule"> 0%</td></tr><tr><td styleCode=" Lrule Rrule"> Mood Swings</td><td align="center" styleCode=" Rrule"> 1%</td><td align="center" styleCode=" Rrule"> 0%</td><td align="center" styleCode=" Rrule"> 0%</td></tr><tr><td styleCode=" Lrule Rrule"> Smell Disorder</td><td align="center" styleCode=" Rrule"> 1%</td><td align="center" styleCode=" Rrule"> 0%</td><td align="center" styleCode=" Rrule"> 0%</td></tr><tr><td styleCode=" Lrule Rrule"> Spontaneous Penile Erection</td><td align="center" styleCode=" Rrule"> 1%</td><td align="center" styleCode=" Rrule"> 0%</td><td align="center" styleCode=" Rrule"> 0%</td></tr><tr><td styleCode=" Lrule Rrule"> Taste Disorder</td><td align="center" styleCode=" Rrule"> 1%</td><td align="center" styleCode=" Rrule"> 1%</td><td align="center" styleCode=" Rrule"> 0%</td></tr></tbody></table>