XYOSTED

Boxed Warnings, Blood Pressure Increases Removed 03/2025 Warnings and Precautions, Venous Thromboembolism ( 5.2 ) 03/2025 Warnings and Precautions, Blood Pressure Increases ( 5.4 ) 03/2025 Warnings and Precautions, Cardiovascular Risk ( 5.4 ) Removed 03/2025

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.

3 DOSAGE FORMS AND STRENGTHS XYOSTED injection is available as 0.5 mL of a sterile, preservative-free and nonpyrogenic, clear, colorless to yellow solution containing testosterone enanthate. It is supplied in a single-dose syringe assembled in an autoinjector for subcutaneous administration. XYOSTED is available in three dosage strengths: 50 mg/0.5 mL 75 mg/0.5 mL 100 mg/0.5 mL XYOSTED (testosterone enanthate) Injection is supplied as 0.5 mL of sterile solution in a single-dose autoinjector for subcutaneous administration in three strengths ( 3 ): 50 mg/0.5 mL 75 mg/0.5 mL 100 mg/0.5 mL

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 ).

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 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.

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 USE IN SPECIFIC POPULATIONS Geriatric Patients: There are insufficient long-term safety data to assess the potential risks of cardiovascular disease and prostate cancer ( 8.5 ). 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. 8.2 Lactation Risk Summary XYOSTED is not indicated for use in females. 8.3 Females and Males of Reproductive Potential Infertility During treatment with large doses of exogenous androgens, including XYOSTED, spermatogenesis may be suppressed through feedback inhibition of the hypothalamic-pituitary-testicular axis [ see Warnings and Precautions ( 5.8 ) ] . Reduced fertility is observed in some men taking testosterone replacement therapy. The impact on fertility may be irreversible. 8.4 Pediatric Use Safety and effectiveness of XYOSTED in pediatric patients less than 18 years old have not been established. Improper use may result in acceleration of bone age and premature closure of epiphyses. 8.5 Geriatric Use There have not been sufficient numbers of geriatric patients in controlled clinical studies with XYOSTED to determine whether efficacy or safety in those over 65 years of age differs from younger subjects. Of the 283 patients enrolled in the 6-month and one-year efficacy and safety clinical study utilizing XYOSTED, 49 (17%) were over 65 years of age. Additionally, there are insufficient long-term safety data in geriatric patients to assess the potentially increased risk of cardiovascular disease and prostate cancer. Geriatric patients treated with androgens may also be at risk for worsening of signs and symptoms of BPH [see Warnings and Precautions ( 5.4 )].

12.1 Mechanism of Action Endogenous androgens, including testosterone and dihydrotestosterone (DHT) are responsible for the normal growth and development of the male sex organs and for maintenance of secondary sex characteristics. These effects include the growth and maturation of the prostate, seminal vesicles, penis, and scrotum; the development of male hair distribution, such as facial, pubic, chest, and axillary hair; laryngeal enlargement, vocal cord thickening, and alterations in body musculature and fat distribution. Male hypogonadism, a clinical syndrome resulting from insufficient secretion of testosterone, has two main etiologies. Primary hypogonadism is caused by defects of the gonads, such as Klinefelter’s syndrome or Leydig cell aplasia, whereas secondary hypogonadism is the failure of the hypothalamus (or pituitary) to produce sufficient gonadotropins (FSH, LH).

11 DESCRIPTION XYOSTED (testosterone enanthate) injection contains testosterone enanthate, an ester derivative of an endogenous androgen, testosterone. Testosterone enanthate is a white to creamy white crystalline powder described by the chemical name (17β)-17-[(1-Oxoheptyl) oxy]-androst-4-en-3-one. Testosterone enanthate has the molecular formula C 26 H 40 O 3 , the molecular weight 400.59, and the molecular structure with the chemical formula: XYOSTED (testosterone enanthate) injection is a sterile, preservative-free, and nonpyrogenic colorless to pale yellow solution supplied in a single-dose syringe assembled in a pressure-assisted autoinjector for subcutaneous administration. Each XYOSTED autoinjector contains 50 mg, 75 mg, or 100 mg of testosterone in sesame oil to form 0.5 mL solution providing three product strengths of 50 mg/0.5 mL, 75 mg/0.5 mL, and 100 mg/0.5 mL. Testosterone enanthate structure

10 OVERDOSAGE There have been no reports of overdosage in the XYOSTED clinical trials. There is a single report of acute overdosage with use of an approved injectable testosterone product. This subject had serum testosterone concentrations of up to 11,400 ng/dL, which were implicated in a cerebrovascular accident. Treatment of overdosage consists of discontinuation of XYOSTED together with appropriate symptomatic and supportive care.

16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied XYOSTED (testosterone enanthate) injection is provided as 0.5 mL of a sterile, preservative-free, and nonpyrogenic colorless to pale yellow solution in a single-dose syringe pre-assembled in an autoinjector for a single subcutaneous administration. XYOSTED is packaged in cartons containing four (4) or one (1) autoinjectors. XYOSTED is available in the following strengths and configurations. XYOSTED (testosterone enanthate) injection, USP, 50 mg/0.5 mL Carton of 4 autoinjectors NDC 54436-250-04 Autoinjector NDC 54436-250-02 XYOSTED (testosterone enanthate) injection, USP, 75 mg/0.5 mL Carton of 4 autoinjectors NDC 54436-275-04 Carton of 1 autoinjector NDC 54436-275-05 Autoinjector NDC 54436-275-02 XYOSTED (testosterone enanthate) injection, USP, 100 mg/0.5 mL Carton of 4 autoinjectors NDC 54436-200-04 Carton of 1 autoinjector NDC 54436-200-05 Autoinjector NDC 54436-200-02 Before use, each autoinjector should be visually inspected. XYOSTED should be clear to light yellow in color and free of visible particles. Do not use if the liquid is cloudy or if visible particles are present. You may notice an air bubble, this is normal. 16.2 Storage and Handling Do Not refrigerate or freeze. Use at room temperature. Store at controlled room temperature, 20°C to 25°C (68°F - 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F). Protect from light (keep in carton until time of use).

16.1 How Supplied XYOSTED (testosterone enanthate) injection is provided as 0.5 mL of a sterile, preservative-free, and nonpyrogenic colorless to pale yellow solution in a single-dose syringe pre-assembled in an autoinjector for a single subcutaneous administration. XYOSTED is packaged in cartons containing four (4) or one (1) autoinjectors. XYOSTED is available in the following strengths and configurations. XYOSTED (testosterone enanthate) injection, USP, 50 mg/0.5 mL Carton of 4 autoinjectors NDC 54436-250-04 Autoinjector NDC 54436-250-02 XYOSTED (testosterone enanthate) injection, USP, 75 mg/0.5 mL Carton of 4 autoinjectors NDC 54436-275-04 Carton of 1 autoinjector NDC 54436-275-05 Autoinjector NDC 54436-275-02 XYOSTED (testosterone enanthate) injection, USP, 100 mg/0.5 mL Carton of 4 autoinjectors NDC 54436-200-04 Carton of 1 autoinjector NDC 54436-200-05 Autoinjector NDC 54436-200-02 Before use, each autoinjector should be visually inspected. XYOSTED should be clear to light yellow in color and free of visible particles. Do not use if the liquid is cloudy or if visible particles are present. You may notice an air bubble, this is normal.