TESTOSTERONE ENANTHATE: 1,682 Adverse Event Reports & Safety Profile

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

INDICATIONS AND USAGE Males Testosterone Enanthate Injection, USP is indicated for replacement therapy in 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, or orchidectomy. Hypogonadotropic hypogonadism (congenital or acquired) – Gonadotropin or luteinizing hormone‑releasing hormone (LHRH) deficiency, or pituitary-hypothalamic injury from tumors, trauma, or radiation. (Appropriate adrenal cortical and thyroid hormone replacement therapy are still necessary, however, and are actually of primary importance.) If the above conditions occur prior to puberty, androgen replacement therapy will be needed during the adolescent years for development of secondary sexual characteristics. Prolonged androgen treatment will be required to maintain sexual characteristics in these and other males who develop testosterone deficiency after puberty. Safety and efficacy of Testosterone Enanthate Injection, USP in men with age-related hypogonadism have not been established. Delayed puberty – Testosterone Enanthate Injection, USP may be used to stimulate puberty in carefully selected males with clearly delayed puberty. These patients usually have a familial pattern of delayed puberty that is not secondary to a pathological disorder; puberty is expected to occur spontaneously at a relatively late date. Brief treatment with conservative doses may occasionally be justified in these patients if they do not respond to psychological support. The potential adverse effect on bone maturation should be discussed with the patient and parents prior to androgen administration. An X-ray of the hand and wrist to determine bone age should be obtained every six months to assess the effect of treatment on the epiphyseal centers (see WARNINGS ).

Females

Metastatic mammary cancer – Testosterone Enanthate Injection, USP may be used secondarily in women with advancing inoperable metastatic (skeletal) mammary cancer who are one to five years postmenopausal. Primary goals of therapy in these women include ablation of the ovaries. Other methods of counteracting estrogen activity are adrenalectomy, hypophysectomy, and/or antiestrogen therapy. This treatment has also been used in premenopausal women with breast cancer who have benefited from oophorectomy and are considered to have a hormone-responsive tumor. Judgment concerning androgen therapy should be made by an oncologist with expertise in this field.

DOSAGE AND ADMINISTRATION Prior to initiating testosterone enanthate injection, confirm the diagnosis of hypogonadism by ensuring that serum testosterone concentrations have been measured in the morning in the morning on at least two separate days and that these serum testosterone concentrations are below the normal range. Dosage and duration of therapy with testosterone enanthate injection will depend on age, sex, diagnosis, patient’s response to treatment, and appearance of adverse effects. When properly given, injections of testosterone enanthate are well tolerated. Care should be taken to slowly inject the preparation deeply into the gluteal muscle, being sure to follow the usual precautions for intramuscular administration, such as the avoidance of intravascular injection (see PRECAUTIONS ). In general, total doses above 400 mg per month are not required because of the prolonged action of the preparation. Injections more frequently than every two weeks are rarely indicated. NOTE: Use of a wet needle or wet syringe may cause the solution to become cloudy; however this does not affect the potency of the material. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Testosterone enanthate injection is a clear, colorless to pale yellow color oily solution. Male hypogonadism : As replacement therapy, i.e., for eunuchism, the suggested dosage is 50 to 400 mg every 2 to 4 weeks. In males with delayed puberty : Various dosage regimens have been used; some call for lower dosages initially with gradual increases as puberty progresses, with or without a decrease to maintenance levels. Other regimens call for higher dosage to induce pubertal changes and lower dosage for maintenance after puberty. The chronological and skeletal ages must be taken into consideration, both in determining the initial dose and in adjusting the dose. Dosage is within the range of 50 to 200 mg every 2 to 4 weeks for a limited duration, for example, 4 to 6 months. X-rays should be taken at appropriate intervals to determine the amount of bone maturation and skeletal development (see INDICATIONS AND USAGE , and WARNINGS ). Palliation of inoperable mammary cancer in women : A dosage of 200 to 400 mg every 2 to 4 weeks is recommended. Women with metastatic breast carcinoma must be followed closely because androgen therapy occasionally appears to accelerate the disease.

CONTRAINDICATIONS Androgens are contraindicated in men with carcinomas of the breast or with known or suspected carcinomas of the prostate and in women who are or may become pregnant. When administered to pregnant women, androgens cause virilization of the external genitalia of the female fetus. This virilization includes clitoromegaly, abnormal vaginal development, and fusion of genital folds to form a scrotal-like structure. The degree of masculinization is related to the amount of drug given and the age of the fetus and is most likely to occur in the female fetus when the drugs are given in the first trimester. If the patient becomes pregnant while taking androgens, she should be apprised of the potential hazard to the fetus. This preparation is also contraindicated in patients with a history of hypersensitivity to any of its components.

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.

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%) <span class="opacity-50 text-xs">[see Adverse Reactions ( 6.1 )]</span> . 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 <span class="opacity-50 text-xs">[see Contraindications ( 4 )]</span> .

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 <span class="opacity-50 text-xs">[see Adverse Reactions ( 6.1 )]</span>. 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 associated with topical testosterone gel was evaluated in TRAVERSE, a randomized, double-blind, placebo-controlled, CV outcomes study in men with a history of CV disease or multiple CV risk factors. In TRAVERSE, topical testosterone gel increased mean systolic blood pressure by 1.0 mm Hg from baseline to 36 months, whereas a mean decrease from baseline of 0.5 mm Hg was observed in the placebo group at this timepoint, for a mean between-group difference of 1.5 mm Hg. However, the incidences of major adverse cardiovascular events (MACE), including cardiovascular death, nonfatal myocardial infarction [MI] and non-fatal stroke, were similar between treatment groups (7% for topical testosterone gel vs 7.3% for placebo) [See Adverse Reactions ( 6.1 )] . Monitor blood pressure periodically in men using XYOSTED, especially men with hypertension. XYOSTED is not recommended for use in patients with uncontrolled hypertension.

5.5 Abuse of Testosterone and Monitoring of Serum Testosterone Concentrations Testosterone has been subject to abuse, typically at doses higher than recommended for the approved indication and in combination with other anabolic androgenic steroids. Anabolic androgenic steroid abuse can lead to serious cardiovascular and psychiatric adverse reactions <span class="opacity-50 text-xs">[see Drug Abuse and Dependence ( 9 )]</span> . If testosterone abuse is suspected, check serum testosterone concentrations to ensure they are within therapeutic range. However, testosterone levels may be in the normal or subnormal range in men abusing synthetic testosterone derivatives. Counsel patients concerning the serious adverse reactions associated with abuse of testosterone and anabolic androgenic steroids. Conversely, consider the possibility of testosterone and anabolic androgenic steroid abuse in suspected patients who present with serious cardiovascular or psychiatric adverse events.

5.6 Not for Use in Women Due to lack of controlled studies in women and potential virilizing effects, XYOSTED is not indicated for use in women <span class="opacity-50 text-xs">[see Contraindications ( 4 ) and Use in Specific Populations ( 8.1 , 8.2 )]</span> .

5.7 Potential for Adverse Effects on Spermatogenesis With large doses of exogenous androgens, including XYOSTED, spermatogenesis may be suppressed through feedback inhibition of pituitary follicle-stimulating hormone (FSH) which could possibly lead to adverse effects on semen parameters including sperm count <span class="opacity-50 text-xs">[see Use in Specific Populations ( 8.3 )]</span> . Patients should be informed of this possible risk when deciding whether to use or to continue to use XYOSTED.

5.8 Hepatic Adverse Effects Prolonged use of high doses of orally active 17-alpha-alkyl androgens (e.g., methyltestosterone) has been associated with serious hepatic adverse effects (peliosis hepatis, hepatic neoplasms, cholestatic hepatitis, and jaundice). Peliosis hepatis can be a life-threatening or fatal complication. Long-term therapy with intramuscular testosterone enanthate, which elevates blood levels for prolonged periods, has produced multiple hepatic adenomas. XYOSTED is not known to produce these adverse effects. Nonetheless, patients should be instructed to report any signs or symptoms of hepatic dysfunction (e.g., jaundice). If these occur, promptly discontinue XYOSTED while the cause is evaluated.

5.9 Edema Androgens, including XYOSTED, may promote retention of sodium and water. Edema with or without congestive heart failure may be a serious complication in patients with preexisting cardiac, renal, or hepatic disease. In addition to discontinuation of the drug, diuretic therapy may be required.

5.10 Gynecomastia Gynecomastia may develop and may persist in patients being treated for hypogonadism.

5.11 Sleep Apnea Treatment with testosterone products including XYOSTED may potentiate sleep apnea in some patients, especially those with risk factors such as obesity or chronic lung disease.

5.12 Lipid Changes Changes in the serum lipid profile may require dose adjustment of lipid lowering drugs or discontinuation of testosterone therapy. Monitor the lipid profile periodically, particularly after starting testosterone therapy.

5.13 Hypercalcemia Androgens, including XYOSTED, should be used with caution in cancer patients at risk of hypercalcemia (and associated hypercalciuria). Monitor serum calcium concentrations regularly during treatment with XYOSTED in these patients.

5.14 Decreased Thyroxine-binding Globulin Androgens, including XYOSTED, may decrease concentrations of thyroxine-binding globulin, resulting in decreased total T4 serum concentrations and increased resin uptake of T3 and T4. Free thyroid hormone concentrations remain unchanged, however, and there is no clinical evidence of thyroid dysfunction.

5.15 Risk of Depression and Suicide Depression and suicidal ideation and behavior, including completed suicide, have occurred during clinical trials in patients treated with XYOSTED. Advise patients and caregivers to seek medical attention for manifestations of suicidal ideation or behavior, new onset or worsening depression, anxiety, or other mood changes.

PRECAUTIONS General Women should be observed for signs of virilization (deepening of the voice, hirsutism, acne, clitoromegaly, and menstrual irregularities). Discontinuation of drug therapy at the time of evidence of mild virilism is necessary to prevent irreversible virilization. Such virilization is usual following androgen use at high doses and is not prevented by concomitant use of estrogens. A decision may be made by the patient and the physician that some virilization will be tolerated during treatment for breast carcinoma. Because androgens may alter serum cholesterol concentration, caution should be used when administering these drugs to patients with a history of myocardial infarction or coronary artery disease. Serial determinations of serum cholesterol should be made and therapy adjusted accordingly. A causal relationship between myocardial infarction and hypercholesterolemia has not been established. Information for Patients Male adolescent patients receiving androgens for delayed puberty should have bone development checked every six months. The physician should instruct patients to report any of the following side effects of androgens: Adult or adolescent males – too frequent or persistent erections of the penis. Women – hoarseness, acne, changes in menstrual periods, or more facial hair. All patients – any nausea, vomiting, changes in skin color, or ankle swelling.

Geriatric Use

Clinical studies of testosterone enanthate did not include sufficient numbers of subjects, aged 65 and older, to determine whether they respond differently from younger subjects. Testosterone replacement is not indicated in geriatric patients who have age-related hypogonadism only (“andropause”), because there is insufficient safety and efficacy information to support such use. Current studies do not assess whether testosterone use increases risks of prostate cancer, prostate hyperplasia, and cardiovascular disease in the geriatric population.

Intramuscular Administration

When properly given, injections of testosterone enanthate are well tolerated. Care should be taken to slowly inject the preparation deeply into the gluteal muscle, being sure to follow the usual precautions for intramuscular administration, such as the avoidance of intravascular injection. There have been rare postmarketing reports of transient reactions involving urge to cough, coughing fits, and respiratory distress immediately after the injection of testosterone enanthate, an oil-based depot preparation (see DOSAGE AND ADMINISTRATION ).

Laboratory Tests

Women with disseminated breast carcinoma should have frequent determination of urine and serum calcium levels during the course of androgen therapy (see WARNINGS ). Periodic (every six months) X-ray examinations of bone age should be made during treatment of pre-pubertal males to determine the rate of bone maturation and the effects of androgen therapy on the epiphyseal centers. Hemoglobin and hematocrit should be checked periodically for polycythemia in patients who are receiving high doses of androgens.

Drug Interactions

When administered concurrently, the following drugs may interact with androgens: Anticoagulants, oral – C-17 substituted derivatives of testosterone, such as methandrostenolone, have been reported to decrease the anticoagulant requirement. Patients receiving oral anticoagulant therapy require close monitoring especially when androgens are started or stopped. Antidiabetic drugs and insulin – In diabetic patients, the metabolic effects of androgens may decrease blood glucose and insulin requirements. ACTH and corticosteroids – Enhanced tendency toward edema. Use caution when giving these drugs together, especially in patients with hepatic or cardiac disease. Oxyphenbutazone – Elevated serum levels of oxyphenbutazone may result.

Drug/Laboratory

Test Interferences Androgens may decrease levels of thyroxine-binding globulin, resulting in decreased total T 4 serum levels and increased resin uptake of T 3 and T 4 . Free thyroid hormone levels remain unchanged, however, and there is no clinical evidence of thyroid dysfunction.

Carcinogenesis

Testosterone has been tested by subcutaneous injection and implantation in mice and rats. The implant induced cervical-uterine tumors in mice, which metastasized in some cases. There is suggestive evidence that injection of testosterone into some strains of female mice increases their susceptibility to hepatoma. Testosterone is also known to increase the number of tumors and decrease the degree of differentiation of chemically induced carcinomas of the liver in rats. There are rare reports of hepatocellular carcinoma in patients receiving long-term therapy with androgens in high doses. Withdrawal of the drugs did not lead to regression of the tumors in all cases. Geriatric patients treated with androgens may be at an increased risk for the development of prostatic hypertrophy and prostatic carcinoma. Pregnancy: Teratogenic Effects (see CONTRAINDICATIONS ).

Nursing

Mothers It is not known whether androgens are excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from androgens, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use

Androgen therapy should be used very cautiously in pediatric patients and only by specialists who are aware of the adverse effects on bone maturation. Skeletal maturation must be monitored every six months by an X-ray of the hand and wrist (see INDICATIONS AND USAGE , and WARNINGS ).

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.