XYOSTED

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 ).

2 DOSAGE AND ADMINISTRATION Prior to initiating XYOSTED : confirm the diagnosis of hypogonadism by ensuring that serum testosterone has been measured in the morning on at least two separate days and that these concentrations are below the normal range ( 2.1 ). Starting dose: 75 mg subcutaneously in the abdominal region once weekly. Avoid intramuscular and intravascular administration ( 2.2 , 2.3 ). Dose Adjustment: Based upon total testosterone trough concentrations (measured 7 days after most recent dose) obtained following 6 weeks of dosing and periodically thereafter ( 2.2 ). Discard unused portion ( 2.3 ) 2.1 Confirmation of Hypogonadism Before Initiation of XYOSTED Prior to initiating XYOSTED, confirm the diagnosis of hypogonadism by ensuring that serum testosterone concentrations have been measured in the morning on at least two separate days and that these serum testosterone concentrations are below the normal range. 2.2 Starting Dose and Dose Adjustment The starting dose of XYOSTED is 75 mg, administered subcutaneously in the abdominal region once a week. Dose adjustment Measure total testosterone trough concentrations (measured 7 days after the most recent dose) following 6 weeks of dosing, following 6 weeks after dose adjustment, and periodically while on treatment with XYOSTED. A trough concentration between 350 ng/dL and 650 ng/dL generally provides testosterone exposures in the normal range during the entire dosing interval. Decrease the dose by 25 mg if the total testosterone trough concentration (C trough ) is ≥650 ng/dL. Increase the dose by 25 mg if the total testosterone C trough is <350 ng/dL. Maintain the same dose if the total testosterone C trough is ≥350 ng/dL and <650 ng/dL. 2.3 Important Administration Instructions XYOSTED is for subcutaneous injection in the abdominal region only. Avoid intramuscular or intravascular injection. Instruct patients on the proper use of XYOSTED and direct them to use the proper injection site. Refer to the Instructions for Use for proper use of XYOSTED. Visually inspect XYOSTED for particulate matter and discoloration prior to administration. Do not use if the liquid is cloudy or if visible particles are present. Do not use XYOSTED if the seal is broken. Discard unused portion.

5 WARNINGS AND PRECAUTIONS Polycythemia: Monitor hematocrit approximately every 3 months to detect increased red blood cell mass and polycythemia ( 5.1 ). Venous thromboembolism (VTE): VTE including deep vein thrombosis (DVT) and pulmonary embolism (PE), have been reported in patients using testosterone products. Evaluate patients with signs or symptoms consistent with DVT or PE ( 5.2 ). Worsening of Benign Prostatic Hyperplasia (BPH) and Potential Risk of Prostate Cancer: Monitor patients with BPH for worsening signs and symptoms of BPH ( 5.3 ). Blood Pressure Increases: Testosterone can increase blood pressure, which can increase cardiovascular risk over time. Measure blood pressure periodically. Not recommended for use in men with uncontrolled hypertension ( 5.4 ). Abuse of Testosterone: Testosterone has been subject to abuse, typically at doses higher than recommended for the approved indication and in combination with other anabolic androgenic steroids ( 5.5 ). Potential for Adverse Effects on Spermatogenesis: Exogenous administration of androgens may lead to azoospermia ( 5.7 ). Edema: Edema with or without congestive heart failure may be a complication in patients with preexisting cardiac, renal, or hepatic disease ( 5.9 ). Sleep apnea: Sleep apnea may occur in those with risk factors ( 5.11 ). Monitor prostatic specific antigen (PSA) and lipid concentrations periodically ( 5.3 , 5.12 ). Depression and suicidal ideation and behavior, including completed suicide, have occurred during clinical trials in patients treated with XYOSTED ( 5.15 ). 5.1 Polycythemia Increases in hematocrit reflective of increases in red blood cell mass may require discontinuation of XYOSTED. Check that hematocrit is not elevated prior to initiating XYOSTED. Evaluate hematocrit approximately every 3 months while the patient is on XYOSTED. If hematocrit becomes elevated, stop XYOSTED until the hematocrit decreases to an acceptable level. If XYOSTED is restarted and again causes hematocrit to become elevated, stop XYOSTED permanently. An increase in red blood cell mass may increase the risk of thromboembolic events. 5.2 Venous Thromboembolism There have been postmarketing reports of venous thromboembolic events, including deep vein thrombosis (DVT) and pulmonary embolism (PE), in patients using testosterone products, such as XYOSTED. In the Testosterone Replacement therapy for Assessment of long-term Vascular Events and efficacy Response in hypogonadal men (TRAVERSE) Study, a randomized, double-blind, placebo-controlled, cardiovascular (CV) outcomes study, compared to placebo, topical testosterone gel was associated with a numerically higher incidence of VTE (1.7% vs 1.2%) which included DVT (0.6% vs 0.5%) and PE events (0.9% vs 0.5%) [see Adverse Reactions ( 6.1 )] . Evaluate patients who report symptoms of pain, edema, warmth and erythema in the lower extremity for DVT and those who present with acute shortness of breath for PE. If a venous thromboembolic event is suspected, discontinue treatment with XYOSTED and initiate appropriate workup and management. 5.3 Worsening of Benign Prostatic Hyperplasia (BPH) and Potential Risk of Prostate Cancer Patients with BPH treated with androgens are at an increased risk of worsening of signs and symptoms of BPH. Monitor patients with BPH for worsening signs and symptoms. Patients treated with androgens may be at an increased risk for prostate cancer. Evaluate patients for prostate cancer prior to initiating and during treatment with androgens [see Contraindications ( 4 )] . 5.4 Blood Pressure Increases XYOSTED can increase blood pressure. Ambulatory blood pressure monitoring (ABPM) demonstrated XYOSTED increased systolic/diastolic BP by an average of 3.9/1.5 mm Hg from baseline after 12 weeks of treatment in clinical trials [see Adverse Reactions ( 6.1 )]. In patients with hypertension on antihypertensive therapy, XYOSTED increased the mean systolic/diastolic BP by 3.9/1.3 mm Hg from baseline. The CV risk a…

4 CONTRAINDICATIONS XYOSTED is contraindicated in: Men with carcinoma of the breast or known or suspected carcinoma of the prostate [see Warnings and Precautions ( 5.4 )] . Women who are pregnant. Testosterone can cause virilization of the female fetus when administered to a pregnant woman [see Use in Specific Populations ( 8.1 )] . Men with known hypersensitivity to XYOSTED or any of its ingredients (testosterone enanthate and sesame oil). Men with carcinoma of the breast or known or suspected carcinoma of the prostate ( 4 , 5.4 ). Women who are pregnant ( 4 , 8.1 ). Testosterone may cause fetal harm ( 4 , 5.7 , 8.1 , and 8.2 ). Known hypersensitivity to XYOSTED or its ingredients ( 4 ).

7 DRUG INTERACTIONS Androgens may decrease blood glucose, and therefore may decrease insulin requirements in diabetic patients ( 7.1 ). Changes in anticoagulant activity may be seen with androgens. More frequent monitoring of international normalized ratio (INR) and prothrombin time is recommended in patients taking warfarin ( 7.2 ). Use of testosterone with corticosteroids may result in increased fluid retention. Use with caution, particularly in patients with cardiac, renal, or hepatic disease ( 7.3 ). Concomitant administration of medications that are known to increase BP with XYOSTED may lead to additional increases in BP ( 7.4 ). 7.1 Insulin Changes in insulin sensitivity or glycemic control may occur in patients treated with androgens. In diabetic patients, the metabolic effects of androgens may decrease blood glucose and, therefore, may necessitate a decrease in the dose of anti-diabetic medication. 7.2 Oral Anticoagulants Changes in anticoagulant activity may be seen with androgens, therefore more frequent monitoring of international normalized ratio (INR) and prothrombin time are recommended in patients taking warfarin, especially at the initiation and termination of androgen therapy. 7.3 Corticosteroids The concurrent use of testosterone with corticosteroids may result in increased fluid retention and requires careful monitoring, particularly in patients with cardiac, renal or hepatic disease. 7.4 Medications that May Also Increase Blood Pressure Some prescription medications and nonprescription analgesic and cold medications contain drugs known to increase blood pressure. Concomitant administration of these medications with XYOSTED may lead to additional increases in blood pressure.

8.1 Pregnancy Risk Summary XYOSTED is contraindicated in pregnant women. Testosterone is teratogenic and may cause fetal harm when administered to a pregnant woman based on data from animal studies and its mechanism of action [see Contraindications ( 4 ) and Clinical Pharmacology ( 12.1 )] . Exposure of a female fetus to androgens may result in varying degrees of virilization. In animal developmental studies, exposure to testosterone in utero resulted in hormonal and behavioral changes in offspring and structural impairments of reproductive tissues in female and male offspring. These studies did not meet current standards for nonclinical development toxicity studies. Data Animal Data In developmental studies conducted in rats, rabbits, pigs, sheep and rhesus monkeys, pregnant animals received intramuscular injection of testosterone during the period of organogenesis. Testosterone treatment at doses that were comparable to those used for testosterone replacement therapy resulted in structural impairments in both female and male offspring. Structural impairments observed in females included increased ano-genital distance, phallus development, empty scrotum, no external vagina, intrauterine growth retardation, reduced ovarian reserve, and increased ovarian follicular recruitment. Structural impairments seen in male offspring included increased testicular weight, larger seminal tubular lumen diameter, and higher frequency of occluded tubule lumen. Increased pituitary weight was seen in both sexes. Testosterone exposure in utero also resulted in hormonal and behavioral changes in offspring. Hypertension was observed in pregnant females and offspring in rats exposed to doses approximately twice those used for testosterone replacement therapy.

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 hyperten…