Testosteroneside effects

Most common adverse reactions (incidence > 2%): polycythemia, diarrhea, dyspepsia, eructation, peripheral edema, nausea, increased hematocrit, headache, prostatomegaly, and hypertension. To report SUSPECTED ADVERSE REACTIONS, contact Tolmar, Inc. at 1-844-4TO-LMAR 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. The safety of JATENZO was evaluated in a randomized, controlled clinical study with 166 patients treated with JATENZO twice daily with morning and evening meals for approximately 4 months. All patients were started on 237 mg twice daily, then the dose was titrated to 158 mg, 198 mg, 316 mg, or 396 mg twice daily to achieve testosterone concentrations in the eugonadal range. Table 2 summarizes adverse reactions (≥2%) reported in this 4-month study.

Table 2: Number (%) of Patients with Adverse Reactions ≥ 2% in a 4-Month Study with JATENZO Among the 569 patients who received JATENZO in all Phase 2 and 3 trials combined, the following adverse reactions were reported in >2% of patients: polycythemia, diarrhea, dyspepsia, eructation, peripheral edema, nausea, increased hematocrit, headache, prostatomegaly, and hypertension. Three of the 166 patients (1.8%) in the 4-month study experienced adverse reactions that led to premature discontinuation from the study, including rash (n=1) and headache (n=2). Preferred Term Overall (N = 166) n (%) Headache 8 Hematocrit increased 8 Hypertension 6 High-density lipoprotein decreased 5 Nausea 4 BP Increases In the 4-month clinical study, 24-hour ABPM was conducted on 166 patients. ABPM was conducted at baseline and at Day 139 of JATENZO therapy. A total of 135 patients had acceptable ABPM recordings at both time periods and were at least 85% compliant with study drug. In that group, the mean change in 24-hour systolic BP and diastolic BP from baseline to final on-treatment visit on Day 139 (n=135) was +4.9 mm Hg (95% CI 3.5, 6.4) and +2.5 mm Hg (95% CI 1.5, 3.6), respectively. In patients with a history of hypertension who were receiving antihypertensive therapy, the mean ABPM systolic and diastolic BP increased by 5.4 mm Hg [95% CI 3.3, 7.6] and 3.2 mm Hg [95% CI 1.7, 4.7], respectively [n=67]. In patients with no history of hypertension, the mean ABPM systolic and diastolic blood pressure increased by 4.4 mm Hg [95% CI 2.3, 6.4] and 1.8 mm Hg [95% CI 0.2, 3.3], respectively [n=63]. Twelve (7.2%) patients on JATENZO either started antihypertensive medications or had their antihypertensive regimen increased during the study. A total of 6 patients were reported to have an adverse reaction of hypertension (2 patients with hypertension and 4 patients with worsening hypertension), and 3 were reported to have an adverse reaction of increased blood pressure. HR Increases JATENZO increased mean heart rate by an average of 2.2 beats per minute (bpm) [95% CI, N=135] during the study. Patients without a history of hypertension had a greater average increase in mean heart rate (2.7 bpm [95% CI, N=63]) compared to patients with treated hypertension (1.9 bpm [95% CI, N=67)]). Increases in Hematocrit Increases in hematocrit were reported in 8 of the 166 (4.8%) patients, which occurred in the second half of the study. None of these increases led to premature discontinuation of JATENZO. Headaches Headaches were reported in 8 of the 166 patients (4.8%) of which three required treatment with analgesics or non-steroidal anti-inflammatory drugs and 2 led to premature discontinuation from the study. Five of these 8 patients had headache events that resolved within 1 to 2 days. Depression and suicidal ideation Two of the 166 patients (1.2%) reported either worsening depression (n=1) or new-onset depression (n=1). One of the 569 patients (0.2%) in clinical trials had suicidal ideation. Each patient completed the study. Increases in Serum PSA The mean increase from baseline in PSA was 0.2 ng/mL (n=161). Increases in serum PSA concentrations, defined as an increase from baseline of at least 1.4 ng/mL or PSA greater than 4 ng/mL, occurred in 3 (1.9%) of the patients at the final visit. 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 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. Because these 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.

Cardiovascular Disorders: myocardial infarction, stroke Vascular Disorders: Venous thromboembolism