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

Safety and efficacy of testosterone gel, 1% 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 ( 1 , 12.3 ).

Testosterone gel, 1% 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% in men with “age-related hypogonadism” have not been established.

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

( 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 Most common adverse reactions (incidence greater than or equal to 5%) are acne, application site reaction, abnormal lab tests, and prostatic disorders.

( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Encube Ethicals Private Limited at 1-833-285-4151 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 testosterone gel, 1% and reported by greater than 1% of patients in a 180 Day, Phase 3 study.

Table 2: Adverse Events Possibly, Probably or Definitely Related to Use of Testosterone Gel, 1% in the 180-Day Controlled Clinical Trial Adv erse Event Dose of Testosterone Gel, 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 testosterone gel, 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 testosterone gel, 1%.

These events included: cerebral hemorrhage, convulsion (neither of which were considered related to testosterone gel, 1% administration), depression, sadness, memory loss, elevated prostate specific antigen, and hypertension.

No testosterone gel, 1% patient discontinued due to skin reactions.

In a separate uncontrolled pharmacokinetic study of 10 patients, two had adverse events associated with testosterone gel, 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 testosterone gel, 1% and reported by greater than 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 Adverse Event Percent of Subjects (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 testosterone gel, 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 greater than 2X the baseline or any single serum PSA greater than 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 less than 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 greater than 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.

6.2 Postmarketing Experience The following adverse reactions have been identified during post approval use of testosterone gel, 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 ( 5.2 )] .