Testosteroneside effects

6 AD VERSE REACTIONS Most common adverse reactions (incidence ≥ 5%) are acne, application site reaction, abnormal lab tests, and prostatic disorders. 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 practice. Cli nical 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 > 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 Dose of Testosterone Gel 1% Adverse Event 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 > 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 Percent of Subjects Adverse Event (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 > 2X the baseline or any single serum PSA > 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 < 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 > 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. 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% therapy. A total of 169 patients had acceptable ABPM recordings at both baseline and Week 16 and also 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 being treated with 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 at baseline, 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%, all of whom were receiving antihypertensive medications at baseline, either started new antihypertensive medications (n=2) or had their antihypertensive regimen adjusted during the ABPM study. Of the 246 patients who used testosterone gel 1% during the study, 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 CV safety of testosterone gel 1% 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% or placebo therapy. The mean (±SD) daily dose of testosterone was 65±22 mg. The mean patient age (±SD) was 63.3 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 testosterone gel 1% 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% 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%, 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% 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% 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%. 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 Expos ure 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.