gens, 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 [see boxed warning and warnings and precautions ( 5.1 )].

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 males less than 18 years old have not been established ( 1 , 8.4 ).

odically ( 5.4 , 5.13 ). depression and suicidal ideation and behavior, including completed suicide, have occurred during clinical trials in patients treated with xyosted ( 5.16 ). 5.1 blood pressure increases in clinical trials, xyosted increased systolic bp in the first 12 weeks of treatment by an average of 4 mmhg based on ambulatory blood pressure monitoring (abpm) and by an average of 4 mmhg from baseline following 1 year of treatment based on blood pressure cuff measurements [see adverse reactions ( 6.1 )]. in the one-year trial, 10% of xyosted-treated patients were started on antihypertensive medications or required changes to their antihypertensive medication regimen. these bp increases can increase the risk of mace, with greater risk in patients with established cardiovascular disease or risk factors for cardiovascular disease [see boxed warning ]. in some patients, the increase in bp with xyosted may be too small to detect, but can still increase the risk for mace. before initiating xyosted, consider the patient’s baseline cardiovascular risk and ensure blood pressure is adequately controlled. check bp approximately 6 weeks after initiating xyosted and periodically thereafter. treat new-onset hypertension or exacerbations of pre-existing hypertension. re-evaluate whether the benefits of continued treatment with xyosted outweigh its risks in patients who develop cardiovascular risk factors or cardiovascular disease. 5.2 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. 5.3 cardiovascular risk long term clinical safety trials have not been completed to assess the cardiovascular outcomes of testosterone replacement therapy in adult males. to date, epidemiologic studies and randomized controlled trials have been inconclusive for determining the risk of mace, such as non-fatal myocardial infarction, non-fatal stroke, and cardiovascular death, with the use of testosterone compared to non-use. some studies, but not all, have reported an increased risk of mace in association with use of testosterone replacement therapy in adult males. xyosted can cause bp increases that can increase the risk of mace [see boxed warning and warnings and precautions ( 5.1 )]. patients should be informed of this possible risk when deciding whether to use or to continue to use xyosted. 5.4 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 )]. 5.5 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. 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. 5.6 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 [see drug abuse and dependence ( 9 )] . 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. 5.7 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 [see contraindications ( 4 ) and use in specific populations ( 8.1 , 8.2 )] . 5.8 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 [see use in specific populations ( 8.3 )] . patients should be informed of this possible risk when deciding whether to use or to continue to use xyosted. 5.9 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. 5.10 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. 5.11 gynecomastia gynecomastia may develop and may persist in patients being treated for hypogonadism. 5.12 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. 5.13 lipids 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. 5.14 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. 5.15 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. 5.16 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.

utaneously 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.

rted 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 bp from baseline to week 12 was + 3.9 mmhg (95% ci 1.4-6.4) and the mean change in diastolic bp was + 1.5 mmhg (95% ci 0.4-2.6). 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.

gens, 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 [see boxed warning and warnings and precautions ( 5.1 )].

jection 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 )].

ctural 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.

osted. 12.3 pharmacokinetics absorption and bioavailability xyosted delivers physiologic amounts of testosterone, producing circulating testosterone concentrations that approximate normal concentrations (300-1100 ng/dl) seen in healthy men. following weekly subcutaneous injection of xyosted for 12 weeks, serum testosterone concentrations reached a maximum after a median of 11.9 hours post-dose (range: 5.8-168.7 hours) then slowly declined (figure 1). in this study, the starting dose of xyosted was 75 mg weekly then the xyosted dose was adjusted based upon total testosterone trough concentrations obtained following 6 weeks of dosing [see dosage and administration ( 2.2 )] . steady state serum testosterone concentration was achieved by week 6. figure 1. mean (±sd) of total testosterone (tt) concentration (ng/dl) following weekly administration of xyosted for 12 weeks (n=137) at week 12, total testosterone concentrations were measured before and at specified times up to 168 hours after xyosted administration then analyzed for pharmacokinetic (pk) parameters (table 3). table 3. arithmetic mean (sd) and range for total testosterone pharmacokinetic parameters at week 12 following weekly administration of 50 mg, 75 mg, or 100 mg xyosted (n=137) c avg (0-168 hr) (ng/dl) c max (ng/dl) t max (hr) a c min (ng/dl) auc (0-168 hr) (ng·hr/dl) mean (sd) 553 (127) 790 (215) 11.9 436 (109) 92,955 (21,385) min - max 276 - 1036 389 - 1410 6 - 168 166 - 788 46432 - 173,987 a reported as median distribution circulating testosterone is primarily bound in serum to sex hormone-binding globulin (shbg) and albumin. approximately 40% of testosterone in plasma is bound to shbg, 2% remains unbound (free), and the rest is loosely bound to albumin and other proteins. elimination metabolism testosterone enanthate is metabolized to testosterone via ester cleavage of the enanthate group. the mean (sd) maximum concentration of testosterone enanthate was 169 (68) ng/dl at week 12 following weekly administration of xyosted. testosterone is metabolized to various 17-keto steroids through two different pathways. the major active metabolites of testosterone are estradiol and dihydrotestosterone (dht). at pre-dose of week 12 treatment, the mean dht/testosterone ratio was 0.07 which was within the normal range. excretion about 90% of a testosterone dose given intramuscularly is excreted in the urine as glucuronic and sulfuric acid-conjugates of testosterone or as metabolites. about 6% of a dose is excreted in the feces, mostly in the unconjugated form. inactivation of testosterone occurs primarily in the liver. figure 1

d administration then analyzed for pharmacokinetic (pk) parameters (table 3). table 3. arithmetic mean (sd) and range for total testosterone pharmacokinetic parameters at week 12 following weekly administration of 50 mg, 75 mg, or 100 mg xyosted (n=137) c avg (0-168 hr) (ng/dl) c max (ng/dl) t max (hr) a c min (ng/dl) auc (0-168 hr) (ng·hr/dl) mean (sd) 553 (127) 790 (215) 11.9 436 (109) 92,955 (21,385) min - max 276 - 1036 389 - 1410 6 - 168 166 - 788 46432 - 173,987 a reported as median distribution circulating testosterone is primarily bound in serum to sex hormone-binding globulin (shbg) and albumin. approximately 40% of testosterone in plasma is bound to shbg, 2% remains unbound (free), and the rest is loosely bound to albumin and other proteins. elimination metabolism testosterone enanthate is metabolized to testosterone via ester cleavage of the enanthate group. the mean (sd) maximum concentration of testosterone enanthate was 169 (68) ng/dl at week 12 following weekly administration of xyosted. testosterone is metabolized to various 17-keto steroids through two different pathways. the major active metabolites of testosterone are estradiol and dihydrotestosterone (dht). at pre-dose of week 12 treatment, the mean dht/testosterone ratio was 0.07 which was within the normal range. excretion about 90% of a testosterone dose given intramuscularly is excreted in the urine as glucuronic and sulfuric acid-conjugates of testosterone or as metabolites. about 6% of a dose is excreted in the feces, mostly in the unconjugated form. inactivation of testosterone occurs primarily in the liver. figure 1

a maximum total testosterone concentration (cmax) above three predetermined limits: greater than 1500 ng/dl, between 1800 and 2500 ng/dl, and greater than 2500 ng/dl. one hundred and thirty five (90%) of the 150 hypogonadal men who received xyosted had a serum total testosterone concentration c avg(0-168h) within the normal range (300 to 1100 ng/dl) at week 12. there were no patients (0%) with c max >1500 ng/dl at week 12.

e 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).

icles are present. you may notice an air bubble, this is normal.

structive sleep apnea, including those associated with sleep or excessive daytime sleepiness. too frequent or persistent erections of the penis. ankle swelling that may reflect peripheral edema. red blood cell count increase, psa increase, injection site bruising, injection site bleeding. instruct patients to report any changes in their state of health, such as changes in urinary habits, breathing, sleep, and mood, including new onset or worsening of depression, or suicidal ideation. keep xyosted out of the reach of children for more information call: 1-844-xyosted (1-844-996-7833) or visit www.xyosted.com manufactured for: antares pharma, inc. ewing, nj 08628 xyosted is a trademark of antares pharma, inc. ©2019 antares pharma, inc. all rights reserved