Xyosted - Drug Monograph

Introduction

Xyosted (testosterone enanthate) is a subcutaneous auto-injector formulation of an endogenous androgen used for testosterone replacement therapy in adult males with primary hypogonadism (congenital or acquired) or hypogonadotropic hypogonadism (congenital or acquired). It is the first subcutaneous testosterone enanthate product approved in the United States, offering a self-administered, needle-based delivery option distinct from traditional intramuscular (IM) testosterone esters. Its clinical relevance lies in providing a convenient, weekly dosing alternative for hypogonadal men while requiring careful cardiovascular and prostate monitoring.

Drug Class and Overview

• Drug class: Androgen; anabolic steroid (Schedule III controlled substance in the United States).
• Related agents: Other testosterone esters (testosterone cypionate, testosterone propionate), transdermal testosterone (gels, patches, solutions), buccal testosterone, nasal testosterone, and implantable testosterone pellets.
• Distinguishing features: Xyosted is supplied as a single-dose, disposable, prefilled auto-injector delivering testosterone enanthate subcutaneously into the abdomen, typically once weekly. Subcutaneous administration may reduce the need for deep intramuscular injection and allows patient self-administration after training.

Mechanism of Action

Testosterone is the principal endogenous androgen. After absorption, testosterone enters target cells and binds the intracellular androgen receptor (AR), a ligand-activated nuclear transcription factor. The hormone–receptor complex dimerizes, translocates to the nucleus, and binds androgen response elements (AREs) on DNA, modulating transcription of androgen-responsive genes. Testosterone also serves as a circulating prohormone:

• 5α-reductase converts testosterone to dihydrotestosterone (DHT), a more potent androgen responsible for external virilization and prostate growth.
• Aromatase (CYP19A1) converts testosterone to estradiol, which contributes to bone mineralization and other physiologic effects.

Clinical effects in hypogonadal men include restoration of serum testosterone into the physiologic range, improvement in libido, sexual function, lean body mass, bone mineral density, mood, and secondary sexual characteristics.

Indications

• Testosterone replacement therapy in adult males with primary hypogonadism (congenital or acquired; e.g., testicular failure due to cryptorchidism, bilateral torsion, orchitis, Klinefelter syndrome, orchiectomy, chemotherapy, toxic damage).
• Testosterone replacement therapy in adult males with hypogonadotropic (secondary) hypogonadism (congenital or acquired; e.g., idiopathic gonadotropin or luteinizing hormone-releasing hormone deficiency, pituitary–hypothalamic injury, or pituitary adenoma).
• Confirmation of hypogonadism requires two separate early-morning serum total testosterone measurements below the laboratory reference range, along with consistent signs and symptoms, prior to initiating therapy.

Dosage and Administration

• Route: Subcutaneous injection into the abdomen (avoiding the 2-inch area around the navel), alternating sides weekly. The auto-injector is for single use only.
• Starting dose: 75 mg subcutaneously once weekly.
• Dose titration: Adjust dose (available strengths: 50 mg/0.5 mL, 75 mg/0.5 mL, 100 mg/0.5 mL) based on serum total testosterone trough levels drawn approximately 7 days after the most recent dose, just before the next scheduled injection. Target a mid-normal physiologic range consistent with the laboratory reference.
• Renal/hepatic impairment: Use with caution in patients with hepatic or renal impairment; no formal dose adjustments are specified in the FDA label. Severe hepatic disease is a relative contraindication.
• Geriatric: Use cautiously; older men have higher baseline risk of prostate cancer and cardiovascular disease.
• Pediatric: Not indicated; safety and efficacy in patients <18 years have not been established.
• Pregnancy: Not indicated; contraindicated in pregnant women due to virilization risk to a female fetus.

Pharmacokinetics

• Absorption: Following subcutaneous administration of testosterone enanthate, the ester is slowly hydrolyzed to release free testosterone, producing sustained serum concentrations over approximately 1 week.
• Distribution: Circulating testosterone is approximately 98% bound to plasma proteins, primarily sex hormone-binding globulin (SHBG) and albumin; only the free fraction is biologically active.
• Metabolism: Hepatic metabolism via cytochrome P450 enzymes (notably CYP3A4); testosterone is converted to DHT by 5α-reductase and to estradiol by aromatase. Both active metabolites undergo further conjugation (glucuronidation, sulfation).
• Elimination: Approximately 90% renal as conjugates of testosterone and metabolites; ~10% fecal.
• Half-life: The terminal half-life of testosterone enanthate after intramuscular dosing is approximately 4.5 days; subcutaneous administration produces comparable weekly exposure when dosed accordingly.

Contraindications

• Known or suspected prostate cancer (androgen-sensitive malignancy).
• Known or suspected breast cancer in men.
• Pregnancy (risk of fetal virilization).
• Known hypersensitivity to testosterone enanthate or any component of the formulation.
• Men with elevated hematocrit at baseline (e.g., >48–50%) should generally not initiate therapy without addressing the underlying cause.

Warnings and Precautions

• Blood pressure increases: Xyosted carries a boxed warning that testosterone can cause increases in blood pressure, which may contribute to major adverse cardiovascular events (MACE), particularly in patients with pre-existing hypertension, cardiovascular disease, or risk factors. Blood pressure should be assessed at baseline and periodically; optimize BP control before and during therapy.
• Cardiovascular risk: Evaluate cardiovascular status before initiating therapy; use cautiously in patients with established cardiac disease, heart failure, or recent MI/stroke.
• Polycythemia: Androgens stimulate erythropoiesis; monitor hematocrit/hemoglobin and withhold or reduce dose if polycythemia develops.
• Prostate monitoring: Perform digital rectal exam (DRE) and PSA at baseline and periodically. Rising PSA warrants urologic evaluation.
• Venous thromboembolism (VTE): Thromboembolism, including DVT and PE, has been reported; discontinue if suspected.
• Hepatic effects: Peliosis hepatis, hepatic adenomas, cholestatic hepatitis, and hepatocellular carcinoma have been associated with androgens.
• Abuse potential: Schedule III; misuse, particularly at supraphysiologic doses, carries risk of dependence and serious cardiovascular, psychiatric, and metabolic effects.
• Edema: May cause fluid retention; caution in patients with cardiac, renal, or hepatic disease predisposing to edema.
• Gynecomastia: May occur due to aromatization to estradiol.
• Sleep apnea: May worsen pre-existing obstructive sleep apnea.
• Lipid changes: May decrease HDL and increase LDL.
• Worsening of benign prostatic hyperplasia (BPH): Monitor urinary symptoms.

Drug Interactions

• Anticoagulants (e.g., warfarin): Testosterone may potentiate the effect of oral anticoagulants and increase bleeding risk; monitor INR closely.
• Insulin and other hypoglycemic agents: Androgens may improve insulin sensitivity and alter glucose metabolism; monitor blood glucose and adjust antidiabetic therapy as needed.
• Corticosteroids (especially mineralocorticoids): Concurrent use increases risk of edema; use cautiously, particularly in patients with cardiac or hepatic disease.
• CYP3A4 inducers (e.g., rifampin, carbamazepine, phenytoin, St. John's wort): May decrease testosterone exposure.
• CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, ritonavir): May increase testosterone exposure.
• Propranolol: Reported to increase the clearance of testosterone in some studies.
• Thyroid hormone: Androgens may decrease thyroxine-binding globulin, reducing total T4 without affecting free T4 or TSH in euthyroid patients.

Adverse Effects

Common (≥1–5%):

• Injection site reactions (bruising, erythema, induration, pain)
• Increased hematocrit/hemoglobin
• Acne
• Hypertension
• Headache
• Mood swings, irritability, anxiety
• Increased PSA
• Insomnia

Serious/rare:

• Major adverse cardiovascular events (MI, stroke, CV death)
• Venous thromboembolism
• Polycythemia vera–like erythrocytosis
• Prostate cancer progression
• Hepatotoxicity (cholestatic jaundice, peliosis hepatis, hepatic neoplasms)
• Severe depression, suicidal ideation
• Priapism
• Anaphylaxis/hypersensitivity

Monitoring Parameters

• Serum total testosterone (trough level, ~7 days after injection) at baseline, after dose changes, and periodically thereafter.
• Hematocrit/hemoglobin at baseline, at 3–6 months, then annually; withhold if Hct >54%.
• PSA and digital rectal exam at baseline and per guideline-based intervals (commonly annually in men >40 or with risk factors).
• Blood pressure at baseline and at each visit.
• Liver function tests (ALT, AST, bilirubin) periodically.
• Lipid panel at baseline and periodically.
• Bone mineral density in patients with prolonged hypogonadism or risk of osteoporosis.
• Mood/behavioral assessment, particularly in patients with a history of psychiatric disease.
• Signs of VTE, edema, sleep apnea, and gynecomastia at each visit.

Patient Education

• Administer Xyosted once weekly by subcutaneous injection into the abdomen, rotating sides each week; avoid the area around the navel.
• Do not inject into areas of skin that are irritated, scarred, or abnormal.
• Review proper use of the auto-injector; never share needles or devices with another person.
• Report symptoms of blood clots (leg swelling/pain, chest pain, shortness of breath, sudden headache, vision changes) immediately.
• Report increased blood pressure, severe headaches, mood changes, or worsening sleep apnea.
• Undergo regular blood tests (testosterone, hematocrit, PSA, liver tests) and prostate exams as directed.
• Women and children should avoid skin contact with the injection site; if contact occurs, wash with soap and water.
• Do not donate blood during therapy and for at least 1 month after the last dose.
• Store at controlled room temperature; do not freeze or expose to extreme heat.
• This medication is a Schedule III controlled substance; do not share with others.

Clinical Pearls

1. Confirm hypogonadism before treating. Two separate early-morning total testosterone values below the reference range, plus consistent symptoms, are required before initiating therapy—testosterone should not be prescribed for nonspecific fatigue or "low T" alone.
2. The boxed warning is unique to Xyosted among testosterone products. It specifically highlights blood pressure increases and potential MACE risk; baseline and ongoing BP monitoring is mandatory.
3. Subcutaneous ≠ intramuscular. Although the active ester is the same as older IM products, the route changes the pharmacokinetic profile and patient experience; do not interchange without dose re-evaluation.
4. Polycythemia is the most common laboratory abnormality. It is dose-related and reversible with dose reduction or temporary discontinuation; it is also a key driver of VTE risk.
5. PSA and prostate monitoring are not optional. Testosterone is contraindicated in known prostate cancer and should be used cautiously in men with elevated PSA or untreated BPH.
6. Watch for aromatization effects. Gynecomastia, edema, and mood changes may reflect estradiol excess; consider dose reduction or, in select cases, aromatase inhibitor consultation.

References

1. Antares Pharma, Inc. Xyosted (testosterone enanthate) injection, for subcutaneous use. U.S. Food and Drug Administration Prescribing Information. 2018.
2. U.S. Food and Drug Administration. Drug Safety Communication: FDA cautions about using testosterone products for low testosterone due to aging; requires labeling change to inform of possible increased risk of heart attack and stroke. 2015 (updated 2018).
3. Bhasin S, Brito JP, Cunningham GR, et al. Testosterone Therapy in Men With Hypogonadism: An Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2018;103(5):1715–1744.
4. Mulhall JP, Trost LW, Brannigan RE, et al. Evaluation and Management of Testosterone Deficiency: AUA Guideline. J Urol. 2018;200(2):423–432.
5. Goodman & Gilman's The Pharmacological Basis of Therapeutics, 14th Edition. Androgens and Antiandrogens. McGraw-Hill Education.
6. Lexicomp Online. Testosterone Enanthate: Drug Information. Wolters Kluwer Clinical Drug Information.
7. World Health Organization. WHO Model List of Essential Medicines for Adults – Androgens section. (Reference for testosterone as a recognized essential medicine.)
8. Basaria S, Coviello AD, Travison TG, et al. Adverse Events Associated with Testosterone Administration. N Engl J Med. 2010;363(2):109–122.
9. Snyder PJ, Bhasin S, Cunningham GR, et al. Effects of Testosterone Treatment in Older Men. N Engl J Med. 2016;374(7):611–624.
10. Corona G, Sforza A, Maggi M. Testosterone Replacement Therapy: Long-Term Safety and Efficacy. World J Mens Health. 2017;35(2):65–76.