1 INDICATIONS AND USAGE Testosterone gel, 1.62% 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, 1.62% in men with “age-related hypogonadism” (also referred to as “late-onset hypogonadism”) have not been established.

Safety and efficacy of testosterone gel, 1.62% 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 [see Indications and Usage ( 1 ), and Clinical Pharmacology ( 12.3 )].

Testosterone gel, 1.62% 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, 1.62% in men with “age-related hypogonadism” have not been established.

( 1 ) Safety and efficacy of testosterone gel, 1.62% in males less than 18 years old have not been established.

( 1 , 8.4 ) Topical testosterone products may have different doses, strengths, or application instructions that may result in different systemic exposure.

( 1 , 12.3 )

6 ADVERSE REACTIONS The most common adverse reaction (incidence ≥ 5%) is an increase in prostate specific antigen (PSA).

( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Northstar Rx LLC at 1-800-206-7821 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.

Testosterone gel, 1.62% was evaluated in a two-phase, 364-day, controlled clinical study.

The first phase was a multi-center, randomized, double-blind, parallel-group, placebo-controlled period of 182 days, in which 234 hypogonadal men were treated with testosterone gel, 1.62% and 40 received placebo.

Patients could continue in an open-label, non-comparative, maintenance period for an additional 182 days [see Clinical Studies ( 14.1 )].

The most common adverse reaction reported in the double-blind period was increased prostate specific antigen (PSA) reported in 26 testosterone gel, 1.62%-treated patients (11.1%).

In 17 patients, increased PSA was considered an adverse event by meeting one of the two pre-specified criteria for abnormal PSA values, defined as (1) average serum PSA >4 ng/mL based on two separate determinations, or (2) an average change from baseline in serum PSA of greater than 0.75 ng/mL on two determinations.

During the 182-day, double-blind period of the clinical trial, the mean change in serum PSA value was 0.14 ng/mL for patients receiving testosterone gel, 1.62% and -0.12 ng/mL for the patients in the placebo group.

During the double-blind period, seven patients had a PSA value >4.0 ng/mL, four of these seven patients had PSA less than or equal to 4.0 ng/mL upon repeat testing.

The other three patients did not undergo repeat PSA testing.

During the 182-day, open-label period of the study, the mean change in serum PSA values was 0.10 ng/mL for both patients continuing on active therapy and patients transitioning onto active from placebo.

During the open-label period, three patients had a serum PSA value > 4.0 ng/mL, two of whom had a serum PSA less than or equal to 4.0 ng/mL upon repeated testing.

The other patient did not undergo repeat PSA testing.

Among previous placebo patients, 3 of 28 (10.7%), had increased PSA as an adverse event in the open-label period.

Table 4 shows adverse reactions reported by >2% of patients in the 182-day, double-blind period of the testosterone gel, 1.62% clinical trial and more frequent in the testosterone gel, 1.62% treated group versus placebo.

Table 4: Adverse Reactions Reported in >2% of Patients in the 182-Day, Double-Blind Period of Testosterone Gel, 1.62% Clinical Trial Number (%) of Patients Adverse Reaction Testosterone Gel, 1.62% N=234 Placebo N=40 PSA increased* 26 (11.1%) 0% Emotional lability** 6 (2.6%) 0% Hypertension 5 (2.1%) 0% Hematocrit or hemoglobin increased 5 (2.1%) 0% Contact dermatitis*** 5 (2.1%) 0% * PSA increased includes: PSA values that met pre-specified criteria for abnormal PSA values (an average change from baseline > 0.75 ng/mL and/or an average PSA value >4.0 ng/mL based on two measurements) as well as those reported as adverse events.

** Emotional lability includes: mood swings, affective disorder, impatience, anger, and aggression.

*** Contact dermatitis includes: 4 patients with dermatitis at non-application sites.

Other adverse reactions occurring in less than or equal to 2% of testosterone gel, 1.62%-treated patients and more frequently than placebo included: frequent urination, and hyperlipidemia.

In the open-label period of the study (N=191), the most commonly reported adverse reaction (experienced by greater than 2% of patients) was increased PSA (n=13; 6.2%) and sinusitis.

Other adverse reactions reported by less than or equal to 2% of patients included increased hemoglobin or hematocrit, hypertension, acne, libido decreased, insomnia, and benign prostatic hypertrophy.

During the 182-day, double-blind period of the clinical trial, 25 testosterone gel, 1.62%-treated patients (10.7%) discontinued treatment because of adverse reactions.

These adverse reactions included 17 patients with PSA increased and 1 report each of: hematocrit increased, blood pressure increased, frequent urination, diarrhea, fatigue, pituitary tumor, dizziness, skin erythema and skin nodule (same patient – neither at application site), vasovagal syncope, and diabetes mellitus.

During the 182-day, open-label period, 9 patients discontinued treatment because of adverse reactions.

These adverse reactions included 6 reports of PSA increased, 2 of hematocrit increased, and 1 each of triglycerides increased and prostate cancer.

Application Site Reactions In the 182-day double-blind period of the study, application site reactions were reported in two (2/234; 0.9%) patients receiving testosterone gel, 1.62%, both of which resolved.

Neither of these patients discontinued the study due to application site adverse reactions.

In the open-label period of the study, application site reactions were reported in three (3/219; 1.4%) additional patients that were treated with testosterone gel, 1.62%.

None of these subjects were discontinued from the study due to application site reactions.

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 testosterone gel, 1.62% therapy.

A total of 169 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=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 receiving 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, 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 testosterone gel, 1.62%, all of whom were receiving antihypertensive medications at baseline, either started new antihypertensive medications (n=2) or had their antihypertensive medication regimen adjusted (n=2) during the ABPM study.

Of the 246 patients in the ABPM study who used testosterone gel, 1.62%, 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 cardiovascular (CV) safety of testosterone gel, 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 testosterone gel, 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 (about 45%) patients 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 testosterone gel, 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 testosterone gel, 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 testosterone gel, 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 testosterone gel, 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 testosterone gel, 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 testosterone gel, 1.62%.

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 5 ).

Table 5: Adverse Reactions from Post Approval Experience of Testosterone Gel, 1.62% by System Organ Class System Organ Class Adverse Reaction Blood and lymphatic system disorders: Elevated hemoglobin or hematocrit, polycythemia, anemia Cardiovascular disorders: Myocardial infarction, stroke Endocrine disorders: Hirsutism Gastrointestinal disorders: Nausea General disorders: Asthenia, edema, malaise Genitourinary disorders: Impaired urination* Hepatobiliary disorders: Abnormal liver function tests Investigations: Lab test abnormal**, elevated PSA, electrolyte changes (nitrogen, calcium, potassium [includes hypokalemia] , phosphorus, sodium), impaired glucose tolerance, hyperlipidemia, HDL, fluctuating testosterone levels, weight increase Neoplasms: Prostate cancer Nervous system disorders: Dizziness, headache, insomnia, sleep apnea Psychiatric disorders: Amnesia, anxiety, depression, hostility, emotional lability, decreased libido, nervousness Reproductive system and breast disorders: Gynecomastia, mastodynia, oligospermia, priapism (frequent or prolonged erections), prostate enlargement, BPH, testis disorder*** Respiratory disorders: Dyspnea Skin and subcutaneous tissue disorders: Acne, alopecia, application site reaction (discolored hair, dry skin, erythema, paresthesia, pruritus, rash), skin dry, pruritus, sweating Vascular disorders: Hypertension, vasodilation (hot flushes), venous thromboembolism * Impaired urination includes nocturia, urinary hesitancy, urinary incontinence, urinary retention, urinary urgency and weak urinary stream ** Lab test abnormal includes elevated AST, elevated ALT, elevated testosterone, elevated hemoglobin or hematocrit, elevated cholesterol, elevated cholesterol/LDL ratio, elevated triglycerides, or elevated serum creatinine *** Testis disorder includes atrophy or non-palpable testis, varicocele, testis sensitivity or tenderness 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 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 )].

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.

Testosterone gel, 1.62% was evaluated in a two-phase, 364-day, controlled clinical study.

The first phase was a multi-center, randomized, double-blind, parallel-group, placebo-controlled period of 182 days, in which 234 hypogonadal men were treated with testosterone gel, 1.62% and 40 received placebo.

Patients could continue in an open-label, non-comparative, maintenance period for an additional 182 days [see Clinical Studies ( 14.1 )].

The most common adverse reaction reported in the double-blind period was increased prostate specific antigen (PSA) reported in 26 testosterone gel, 1.62%-treated patients (11.1%).

In 17 patients, increased PSA was considered an adverse event by meeting one of the two pre-specified criteria for abnormal PSA values, defined as (1) average serum PSA >4 ng/mL based on two separate determinations, or (2) an average change from baseline in serum PSA of greater than 0.75 ng/mL on two determinations.

During the 182-day, double-blind period of the clinical trial, the mean change in serum PSA value was 0.14 ng/mL for patients receiving testosterone gel, 1.62% and -0.12 ng/mL for the patients in the placebo group.

During the double-blind period, seven patients had a PSA value >4.0 ng/mL, four of these seven patients had PSA less than or equal to 4.0 ng/mL upon repeat testing.

The other three patients did not undergo repeat PSA testing.

During the 182-day, open-label period of the study, the mean change in serum PSA values was 0.10 ng/mL for both patients continuing on active therapy and patients transitioning onto active from placebo.

During the open-label period, three patients had a serum PSA value > 4.0 ng/mL, two of whom had a serum PSA less than or equal to 4.0 ng/mL upon repeated testing.

The other patient did not undergo repeat PSA testing.

Among previous placebo patients, 3 of 28 (10.7%), had increased PSA as an adverse event in the open-label period.

Table 4 shows adverse reactions reported by >2% of patients in the 182-day, double-blind period of the testosterone gel, 1.62% clinical trial and more frequent in the testosterone gel, 1.62% treated group versus placebo.

Table 4: Adverse Reactions Reported in >2% of Patients in the 182-Day, Double-Blind Period of Testosterone Gel, 1.62% Clinical Trial Number (%) of Patients Adverse Reaction Testosterone Gel, 1.62% N=234 Placebo N=40 PSA increased* 26 (11.1%) 0% Emotional lability** 6 (2.6%) 0% Hypertension 5 (2.1%) 0% Hematocrit or hemoglobin increased 5 (2.1%) 0% Contact dermatitis*** 5 (2.1%) 0% * PSA increased includes: PSA values that met pre-specified criteria for abnormal PSA values (an average change from baseline > 0.75 ng/mL and/or an average PSA value >4.0 ng/mL based on two measurements) as well as those reported as adverse events.

** Emotional lability includes: mood swings, affective disorder, impatience, anger, and aggression.

*** Contact dermatitis includes: 4 patients with dermatitis at non-application sites.

Other adverse reactions occurring in less than or equal to 2% of testosterone gel, 1.62%-treated patients and more frequently than placebo included: frequent urination, and hyperlipidemia.

In the open-label period of the study (N=191), the most commonly reported adverse reaction (experienced by greater than 2% of patients) was increased PSA (n=13; 6.2%) and sinusitis.

Other adverse reactions reported by less than or equal to 2% of patients included increased hemoglobin or hematocrit, hypertension, acne, libido decreased, insomnia, and benign prostatic hypertrophy.

During the 182-day, double-blind period of the clinical trial, 25 testosterone gel, 1.62%-treated patients (10.7%) discontinued treatment because of adverse reactions.

These adverse reactions included 17 patients with PSA increased and 1 report each of: hematocrit increased, blood pressure increased, frequent urination, diarrhea, fatigue, pituitary tumor, dizziness, skin erythema and skin nodule (same patient – neither at application site), vasovagal syncope, and diabetes mellitus.

During the 182-day, open-label period, 9 patients discontinued treatment because of adverse reactions.

These adverse reactions included 6 reports of PSA increased, 2 of hematocrit increased, and 1 each of triglycerides increased and prostate cancer.

Application Site Reactions In the 182-day double-blind period of the study, application site reactions were reported in two (2/234; 0.9%) patients receiving testosterone gel, 1.62%, both of which resolved.

Neither of these patients discontinued the study due to application site adverse reactions.

In the open-label period of the study, application site reactions were reported in three (3/219; 1.4%) additional patients that were treated with testosterone gel, 1.62%.

None of these subjects were discontinued from the study due to application site reactions.

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 testosterone gel, 1.62% therapy.

A total of 169 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=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 receiving 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, 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 testosterone gel, 1.62%, all of whom were receiving antihypertensive medications at baseline, either started new antihypertensive medications (n=2) or had their antihypertensive medication regimen adjusted (n=2) during the ABPM study.

Of the 246 patients in the ABPM study who used testosterone gel, 1.62%, 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 cardiovascular (CV) safety of testosterone gel, 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 testosterone gel, 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 (about 45%) patients 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 testosterone gel, 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 testosterone gel, 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 testosterone gel, 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 testosterone gel, 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 testosterone gel, 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.

Application Site Reactions In the 182-day double-blind period of the study, application site reactions were reported in two (2/234; 0.9%) patients receiving testosterone gel, 1.62%, both of which resolved.

Neither of these patients discontinued the study due to application site adverse reactions.

In the open-label period of the study, application site reactions were reported in three (3/219; 1.4%) additional patients that were treated with testosterone gel, 1.62%.

None of these subjects were discontinued from the study due to application site reactions.

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 testosterone gel, 1.62% therapy.

A total of 169 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=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 receiving 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, 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 testosterone gel, 1.62%, all of whom were receiving antihypertensive medications at baseline, either started new antihypertensive medications (n=2) or had their antihypertensive medication regimen adjusted (n=2) during the ABPM study.

Of the 246 patients in the ABPM study who used testosterone gel, 1.62%, 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 cardiovascular (CV) safety of testosterone gel, 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 testosterone gel, 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 (about 45%) patients 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 testosterone gel, 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 testosterone gel, 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 testosterone gel, 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 testosterone gel, 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 testosterone gel, 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 testosterone gel, 1.62%.

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 5 ).

Table 5: Adverse Reactions from Post Approval Experience of Testosterone Gel, 1.62% by System Organ Class System Organ Class Adverse Reaction Blood and lymphatic system disorders: Elevated hemoglobin or hematocrit, polycythemia, anemia Cardiovascular disorders: Myocardial infarction, stroke Endocrine disorders: Hirsutism Gastrointestinal disorders: Nausea General disorders: Asthenia, edema, malaise Genitourinary disorders: Impaired urination* Hepatobiliary disorders: Abnormal liver function tests Investigations: Lab test abnormal**, elevated PSA, electrolyte changes (nitrogen, calcium, potassium [includes hypokalemia] , phosphorus, sodium), impaired glucose tolerance, hyperlipidemia, HDL, fluctuating testosterone levels, weight increase Neoplasms: Prostate cancer Nervous system disorders: Dizziness, headache, insomnia, sleep apnea Psychiatric disorders: Amnesia, anxiety, depression, hostility, emotional lability, decreased libido, nervousness Reproductive system and breast disorders: Gynecomastia, mastodynia, oligospermia, priapism (frequent or prolonged erections), prostate enlargement, BPH, testis disorder*** Respiratory disorders: Dyspnea Skin and subcutaneous tissue disorders: Acne, alopecia, application site reaction (discolored hair, dry skin, erythema, paresthesia, pruritus, rash), skin dry, pruritus, sweating Vascular disorders: Hypertension, vasodilation (hot flushes), venous thromboembolism * Impaired urination includes nocturia, urinary hesitancy, urinary incontinence, urinary retention, urinary urgency and weak urinary stream ** Lab test abnormal includes elevated AST, elevated ALT, elevated testosterone, elevated hemoglobin or hematocrit, elevated cholesterol, elevated cholesterol/LDL ratio, elevated triglycerides, or elevated serum creatinine *** Testis disorder includes atrophy or non-palpable testis, varicocele, testis sensitivity or tenderness 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 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 )].

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 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 )].