1 INDICATIONS AND USAGE XYOSTED (testosterone enanthate) injection is an androgen indicated for testosterone 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 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 XYOSTED in men with “age-related hypogonadism” has not been established.

Safety and efficacy of XYOSTED in males less than 18 years old have not been established [see Use in Specific Populations ( 8.4 )] .

XYOSTED (testosterone enanthate) injection is an androgen indicated for testosterone replacement therapy in adult males for conditions associated with a deficiency or absence of endogenous testosterone ( 1 ).

Limitations of Use: Safety and efficacy of XYOSTED in men with “age-related hypogonadism” has not been established ( 1 ).

Safety and efficacy of XYOSTED in males less than 18 years old have not been established ( 1 , 8.4 ).

6 ADVERSE REACTIONS The most commonly reported adverse reactions (>5%) were: hematocrit increased, hypertension, PSA increased, injection site bruising, and headache.

( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Antares at 1-844-XYOSTED (1-844-996-7833) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .

6.1 Clinical Trials 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 with rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The safety of XYOSTED was evaluated in 2 clinical studies in a total of 283 men who received weekly subcutaneous doses for up to one year.

All patients were started on 75 mg weekly, then the dose was titrated to 50 mg or 100 mg weekly, as needed, to achieve pre-dose total testosterone concentrations of ≥350 ng/dL and <650 ng/dL.

Table 1 summarizes adverse reactions (≥2%) reported in a one-year study with XYOSTED.

Table 1.

Number (%) of Patients with Adverse Reactions ≥2% in a 1 Year study with XYOSTED Preferred Term Overall (N=150) n (%) Hematocrit increased 21 (14.0) Hypertension 19 (12.7) Prostatic specific antigen (PSA) increased 18 (12.0) Injection site bruising 10 (6.7) Headache 8 (5.3) Back pain 5 (3.3) Blood creatine phosphokinase increased 5 (3.3) Injection site hemorrhage 5 (3.3) Acne 4 (2.7) Blood testosterone increased 4 (2.7) Cough 4 (2.7) Edema peripheral 4 (2.7) Injection site erythema 4 (2.7) Prostatitis 4 (2.7) Urinary tract infection 4 (2.7) Abdominal pain 3 (2.0) Arthralgia 3 (2.0) Fatigue 3 (2.0) Hematuria 3 (2.0) Polycythemia 3 (2.0) Sleep apnea syndrome 3 (2.0) Note: Includes events that started on or after the first dosing, or existed prior to the first dose and worsened in severity or relatedness after dosing.

Percentage was calculated using the number of patients in the column heading as the denominator.

Table 2 summarizes the adverse reactions (≥2%) reported in a 6-month study with XYOSTED.

Table 2.

Number (%) of Patients with Adverse Reactions ≥2% in a 6-Month Study with XYOSTED Preferred Term Overall (N = 133) n (%) Hematocrit increased 11 (8.3) Injection site hemorrhage 8 (6.0) Blood creatine phosphokinase increased 5 (3.8) Injection site bruising 5 (3.8) Prostatitis 4 (3.0) Prostatic specific antigen (PSA) increased 4 (3.0) Urinary tract infection 4 (3.0) Fatigue 3 (2.3) Hypertension 3 (2.3) Insomnia 3 (2.3) Nausea 3 (2.3) Note: Includes events that started on or after the first dosing, or existed prior to the first dose and worsened in severity or relatedness after dosing.

Percentage was calculated using the number of patients in the column heading as the denominator.

BP Increases in the 6-Month Clinical Study In the 6-month clinical study, 24-hour ambulatory blood pressure monitoring (ABPM) was conducted in 133 patients, 113 of whom completed the study.

ABPM was conducted at 3 distinct 24-hour time periods: at Baseline and following 6 and 12 weeks of XYOSTED therapy.

A total of 62 patients had acceptable ABPM recordings at baseline and Week 12.

In that group, the mean change in systolic and diastolic BP from baseline to Week 12 was + 3.9 mm Hg (95% CI 1.4-6.4) and + 1.5 mm Hg (95% CI 0.4-2.6), respectively.

In patients with a history of hypertension who were receiving antihypertensive therapy, the mean ABPM systolic and diastolic BP increased by +3.9 mm Hg [95% CI 0.19-7.7] and +1.3 mm Hg [95% CI -0.37-3.0], respectively [n=33]).

In patients with no history of hypertension, the mean ABPM systolic and diastolic blood pressure increased by +4.1 mm Hg [95% CI 0.43-7.8] and +1.9 mm Hg [95% CI 0.055-3.7], respectively [n=28]).

10% of XYOSTED-treated patients were either started on antihypertensive medications or required changes to their antihypertensive medication regimen during the 1-year study.

A total of 3 patients were reported to have an adverse reaction of hypertension (2 patients with hypertension and 1 patient with worsening hypertension), and 1 was reported to have an adverse reaction of increased blood pressure.

Increases in Hematocrit Increases in hematocrit to ≥55% were reported for 12 of the 283 patients in the 2 clinical studies, representing 4.2% of patients who received XYOSTED for up to one year.

While the studies did not pre-define clinical adverse events related to increased hematocrit, polycythemia was reported as a medically significant adverse event in the investigator’s clinical judgment in 1.8% of treated patients.

XYOSTED dosing resulted in mean hemoglobin increases of 1.0 ± 1.1 g/dL at 6 months and 1.1 ± 1.4 g/dL at 1 year and mean hematocrit increases of 3.8 ± 3.4% at 6 months and 5.4 ± 3.4% at 1 year.

Injection Site Reactions Injection site reactions, including injection site bruising, injection site hemorrhage, injection site erythema and injection site induration were reported in 36 of the 283 patients in the 2 clinical studies, representing 12.7% of patients who received XYOSTED for up to one year.

No patients discontinued XYOSTED because of injection site reactions.

Depression and Suicide Attempts Depression requiring discontinuation was reported in 2 of the 283 patients in the two clinical studies and suicide attempts (one complete and one incomplete) were reported in 2 additional patients, comprising a total of 4 patients, representing 1.4% of patients who received XYOSTED for up to one year.

Increases in Serum PSA 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, led to discontinuation in 4.6% of the 283 patients in the 2 clinical studies.

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 (7.9) 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 35 kg/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 noninferiority of topical testosterone gel versus placebo because the upper bound of 95% CI was less than the prespecified 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.