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 Prasco Laboratories at 1-866-525-0688 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.

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 )] .