e necessary in patients taking anticoagulants, 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 should be monitored cautiously, particularly in patients with cardiac, renal or hepatic disease. 7.4 drugs that may also increase blood pressure some prescription drugs and nonprescription analgesic and cold medications can increase blood pressure. concomitant administration of these medications with tlando may lead to additional increases in blood pressure [ see warnings and precautions ( 5.1 ) ] .

use safety and efficacy of tlando in males less than 18 years old have not been established [see use in specific populations ( 8.4 ) ] . tlando 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 tlando in males less than 18 years old have not been established ( 1 ).

er anabolic androgenic steroids is suspected, check serum testosterone concentration ( 5.6 ). potential for adverse effects on spermatogenesis : tlando may cause azoospermia ( 5.8 , 8.3 ). edema : edema, with or without congestive heart failure (chf) may occur in patients with preexisting cardiac, renal, or hepatic disease. discontinue tlando and initiate appropriate workup ( 5.10 ). sleep apnea: tlando may potentiate sleep apnea in those with risk factors ( 5.11 ). lipid changes : testosterone may affect serum lipid profile. monitor patient lipid concentrations; if necessary, adjust dosage of lipid lowering drug(s) or discontinue tlando ( 5.13 ). increases in prolactin : monitor serum prolactin levels prior to initiation of tlando and 3 to 4 months after starting tlando. discontinue tlando if serum prolactin levels remain elevated ( 5.16 ). 5.1 increase in blood pressure in study 18-001, tlando increased systolic bp after 4 months of treatment by an average of 4.3 mmhg based on ambulatory blood pressure monitoring (abpm) and 4.8 mmhg from baseline based on blood pressure cuff measurements [see adverse reactions ( 6.1 )] . these bp increases can increase the risk of major adverse cardiovascular events (mace), with greater risk in patients with established cardiovascular disease or risk factors for cardiovascular disease. in some patients, the increase in bp with tlando may be too small to detect but can still increase the risk for mace. before initiating tlando, consider the patient’s baseline cardiovascular risk and ensure blood pressure is adequately controlled. check bp approximately 3 weeks after initiating tlando and periodically thereafter. treat new-onset hypertension or exacerbations of pre-existing hypertension. re-evaluate whether the benefits of continued treatment with tlando outweigh its risks in patients who develop cardiovascular risk factors or cardiovascular disease. 5.2 polycythemia increases in hematocrit levels, reflective of increases in red blood cell mass, may require discontinuation of tlando. check hematocrit prior to initiating tlando. evaluate hematocrit approximately every 3 months during the first year of treatment, and then every 6 months thereafter while the patient is taking tlando. if hematocrit becomes elevated, stop tlando until hematocrit decreases to an acceptable concentration. if tlando is restarted and again causes hematocrit to become elevated, stop tlando permanently. an increase in red blood cell mass may increase the risk of thromboembolic events [ see warnings and precautions ( 5.5 ) ] . 5.3 cardiovascular risk long term clinical safety trials have not been conducted to assess the cardiovascular outcomes of testosterone replacement therapy in men. to date, epidemiologic studies and randomized controlled trials have been inconclusive for determining the risk of major adverse cardiovascular events (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 men. tlando 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 tlando. 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 for worsening of signs and symptoms of bph. monitor patients with bph for worsening signs and symptoms. patients treated with androgens may be at increased risk for prostate cancer. evaluate patients for prostate cancer, including measurement of prostate specific antigen (psa), prior to initiating and during treatment with androgens [see contraindications ( 4 )] . 5.5 venous thromboembolism there have been post marketing reports of venous thromboembolic events, including deep vein thrombosis (dvt) and pulmonary embolism (pe), in patients using testosterone replacement products such as tlando. 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 tlando and initiate appropriate workup and management [ see adverse reactions ( 6.2 ) ] . 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 the potential for virilizing effects, tlando is not indicated for use in women [ see use in specific populations ( 8.1 , 8.2 ) ] . 5.8 potential for adverse effects on spermatogenesis with large doses of exogenous androgens, including tlando, spermatogenesis may be suppressed through feedback inhibition of pituitary follicle-stimulating hormone (fsh) possibly leading 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 tlando. 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 has produced multiple hepatic adenomas. tlando is not a 17 alpha-alkyl androgen and is not known to produce hepatic adverse effects associated with 17-alpha-alkyl androgens. nonetheless, patients should be instructed to report any signs or symptoms of hepatic dysfunction (e.g., jaundice). if these occur, promptly discontinue tlando while the cause is evaluated. 5.10 edema androgens, including tlando, 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 [ see adverse reactions ( 6.1 ) ] . in addition to discontinuation of the drug, appropriate work up and management of edema may be required. 5.11 sleep apnea the treatment of hypogonadal men with testosterone products may potentiate sleep apnea in some patients, especially those with risk factors such as obesity or chronic lung diseases. 5.12 gynecomastia gynecomastia may develop and persist in patients being treated for hypogonadism. 5.13 lipid changes changes in serum lipid profile may require dose adjustment of lipid lowering drugs or discontinuation of testosterone therapy. monitor the lipid profile periodically after starting testosterone therapy. 5.14 hypercalcemia androgens, including tlando, should be used with caution in cancer patients at risk of hypercalcemia (and associated hypercalciuria). monitor serum calcium concentrations periodically in these patients. 5.15 decreased thyroxine-binding globulin androgens, including tlando, may decrease concentrations of thyroxin-binding globulins, resulting in decreased total t4 serum concentrations and increased resin uptake of triiodothyronine (t3) and thyroxine (t4). free thyroid hormone concentrations remain unchanged, however, and there is no clinical evidence of thyroid dysfunction. 5.16 increases in prolactin increases in serum prolactin have been reported in patients treated with tlando in clinical trials. evaluate serum prolactin levels prior to initiating treatment with tlando. re-evaluate serum prolactin levels 3 to 4 months after starting treatment. if serum prolactin remains elevated, discontinue tlando [ s ee adverse reactions ( 6.1 ) ] .

capsules), orally twice daily, once in the morning and once in the evening. take with food. monitoring for continued use or discontinuation monitor serum testosterone (8 to 9 hours after the morning dose) 3 to 4 weeks after initiating tlando, and periodically thereafter. based on serum testosterone measurements, determine if tlando should be continued or discontinued: serum testosterone 300 - 1080 ng/dl: continue tlando serum testosterone < 300 ng/dl: discontinue tlando serum testosterone > 1080 ng/dl: discontinue tlando

nings and precautions ( 5.12 )] lipid changes [see warnings and precautions ( 5.13 )] hypercalcemia [see warnings and precautions ( 5.14 )] decreased thyroxine-binding globulin [see warnings and precautions ( 5.15 )] increases in prolactin [see warnings and precautions ( 5.16 )] 6.1 clinical trial 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 to rates in the clinical trials of another drug and may not reflect the rates observed in practice. the safety of tlando 225 mg twice daily, without dose titration, was evaluated in 233 hypogonadal males during two clinical studies: study lpcn 1021-18-001 (18-001) and study lpcn 1021-16-002 (16-002) [see clinical studies ( 14 )]. in study 18-001, an uncontrolled ambulatory blood pressure monitoring (abpm) study, 138 hypogonadal males were treated with tlando 225 mg twice daily with morning and evening meals for approximately four months. patients had a median age of 54 years (range 26-75), 79% were white, 18% were black, and 2% were asian. in 138 hypogonadal male patients, 70% (n=96) were obese (bmi≥30 kg/m 2 ), 24% (n=33) reported a history of type 2 diabetes, and 48% (n=66) reported a history of hypertension. table 1 summarizes adverse reactions ( > 2%) reported in patients receiving tlando in study 18-001. table 1. adverse reactions ≥ 2% in patients receiving tlando in study 18-001 adverse reaction overall (n=138) n (%) hypertension 7 (5.1) hematocrit increased 6 (4.3) upper respiratory tract infection 5 (3.6) four of the 138 patients (2.9%) in study 18-001 reported adverse reactions that led to premature discontinuation from the study, including dizziness (n=1), weight increased (n=1), insomnia (n=1), and hypertension (n=2). in study 16-002, 95 hypogonadal males were treated with tlando 225 mg twice daily with morning and evening meals for approximately 24 days. the dose of tlando was not titrated. patients had a median age of 56 years (range 29-74), 81% were white, 16% were black, 2% were mixed race, and 1% were asian; 26% were hispanic. in 95 hypogonadal male patients, 70% (n=66) were obese (bmi≥30 kg/m 2 ), 23% (n=22) reported a history of type 2 diabetes, and 50% (n=47) reported a history of hypertension. table 2 summarized adverse reactions ( > 2%) reported during study 16-002 in patients receiving tlando. table 2. adverse reactions ≥2% in patients receiving tlando in study 16-002 adverse reaction overall (n=95) n (%) blood prolactin increased 6 (6.3) weight increased 2 (2.1) headache 2 (2.1) musculoskeletal pain 2 (2.1) one of the 95 patients (1.1%) in the 24-day study reported an adverse reaction (gastric ulcer hemorrhage) that led to premature discontinuation from the study. blood pressure increases in study 18-001 24-hour ambulatory blood pressure monitoring (abpm) was conducted in 138 male patients, 126 of whom completed the study. abpm was conducted at 2 distinct 24-hour time periods: at baseline and following approximately 16 weeks of treatment with tlando. a total of 123 patients had acceptable 24-hour abpm recordings at both time periods. in that group, the mean change in systolic bp from baseline to end of study was + 4.3 mmhg (95% ci 2.1, 6.5) and the mean change in diastolic bp was 1.4 mmhg (95% ci 0.5, 2.3). the abpm systolic and diastolic blood pressure increased in patients with a history of hypertension at baseline [4.8 mmhg (95% ci 1.0, 8.5) and 1.6 mmhg (95% ci 0.1, 3.0), respectively (n=60)]. in patients with no history of hypertension at baseline systolic and diastolic blood pressure increased [3.9 mmhg (95% ci 0.9, 6.8) and 1.2 mmhg (95% ci -0.1, 2.5), respectively (n =63)]. increases in hematocrit increases in hematocrit were reported in 6 of the 138 patients (4.3%) in study 18-001. none of these increases led to premature discontinuation of tlando. increases in prolactin increases in serum prolactin were reported in 6 (6.3%) of the 95 patients in the 24-day clinical study. the mean increase from baseline in serum prolactin was 7.0 ng/ml (n=93). the 4-month clinical study did not assess serum prolactin concentrations after the screening visit. 6.2 postmarketing experience the following adverse reactions have been identified during post-approval use of testosterone replacement products. because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. cardiovascular disorders : myocardial infarction, stroke vascular disorders: venous thromboembolism

e necessary in patients taking anticoagulants, 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 should be monitored cautiously, particularly in patients with cardiac, renal or hepatic disease. 7.4 drugs that may also increase blood pressure some prescription drugs and nonprescription analgesic and cold medications can increase blood pressure. concomitant administration of these medications with tlando may lead to additional increases in blood pressure [ see warnings and precautions ( 5.1 ) ] .

sus 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 anogenital 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 tlando is not indicated for use in females. 8.3 females and males of reproductive potential infertility males during treatment with large doses of exogenous androgens, including tlando, 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. testicular atrophy, subfertility, and infertility have also been reported in men who abuse anabolic androgenic steroids [ see drug abuse and dependence ( 9.2 ) ] . 8.4 pediatric use the safety and effectiveness of tlando 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 tlando to determine whether efficacy or safety in those over 65 years of age differs from younger subjects. of the 95 patients enrolled in study 16-002, the 24-day major safety and effectiveness study utilizing tlando, 16 (16.8%) were over 65 years of age. additionally, there is insufficient long-term safety data in geriatric patients utilizing tlando 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 and hypertension [see warnings and precautions ( 5.1 )] and 5.4 ].

for testosterone replacement therapy resulted in structural impairments in both female and male offspring. structural impairments observed in females included increased anogenital 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.

hip or time course of pharmacodynamic response. 12.3 pharmacokinetics absorption testosterone undecanoate is a lipophilic molecule that is primarily absorbed into the lymph system after oral administration and then released into the general blood circulation by the thoracic duct, avoiding absorption into the portal vein thereby circumventing first-pass metabolism in the liver. testosterone undecanoate is converted to testosterone following absorption. following administration of 225 mg of tlando in ninety-five hypogonadal males, maximum serum testosterone concentrations were observed at a median (tmax) of about 5 hours. the mean maximum (cmax) serum testosterone concentrations observed were 979 ng/dl and 989 ng/dl following the morning and evening tlando doses, respectively. the average serum testosterone concentrations over 24 hours (cavg0-24h) observed following tlando administration was 476 ng/dl. figure 1 shows the mean serum total testosterone concentration-time profile for hypogonadal men (n=90) administered tlando. figure 1: mean (±sem) serum total testosterone concentrations (ng/dl) following tlando administration, the mean serum dihydrotestosterone (dht) cavg0-24h was 108 ng/dl, the mean serum testosterone undecanoate cavg0-24h was 11,100 ng/dl and the mean serum dihydrotestosterone undecanoate cavg0-24h was 4,700 ng/dl. effect of food administration of tlando with moderate fat containing food did not significantly impact the pharmacokinetic parameters of testosterone compared to high or low fat. however, there is decrease in exposure when administered without food compared to fed conditions. in studies with 13 to 14 hypogonadal males, mean testosterone cmax and auc were comparable when tlando was administered with food containing low, moderate or high fat amounts. administration in fasting conditions resulted in approximately 65 % and 38% lower cmax and auc, respectively, compared to administration with food (high fat). 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 bound to albumin and other proteins. elimination the elimination half-life of testosterone undecanoate is approximately 2 hours. once testosterone is formed from testosterone undecanoate, there is considerable variation in the half-life of testosterone as reported in the literature, ranging from 10 to 100 minutes. metabolism testosterone undecanoate is metabolized to testosterone via ester cleavage of the undecanoate group and reduced to dhtu by 5α-reductase. testosterone is metabolized to various 17-keto steroids. the major active metabolites of testosterone are dht and estradiol. excretion about 90% of a dose of testosterone given intramuscularly is excreted in the urine as glucuronic and sulfuric acid conjugates of testosterone and its 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

mean (±sem) serum total testosterone concentrations (ng/dl) following tlando administration, the mean serum dihydrotestosterone (dht) cavg0-24h was 108 ng/dl, the mean serum testosterone undecanoate cavg0-24h was 11,100 ng/dl and the mean serum dihydrotestosterone undecanoate cavg0-24h was 4,700 ng/dl. effect of food administration of tlando with moderate fat containing food did not significantly impact the pharmacokinetic parameters of testosterone compared to high or low fat. however, there is decrease in exposure when administered without food compared to fed conditions. in studies with 13 to 14 hypogonadal males, mean testosterone cmax and auc were comparable when tlando was administered with food containing low, moderate or high fat amounts. administration in fasting conditions resulted in approximately 65 % and 38% lower cmax and auc, respectively, compared to administration with food (high fat). 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 bound to albumin and other proteins. elimination the elimination half-life of testosterone undecanoate is approximately 2 hours. once testosterone is formed from testosterone undecanoate, there is considerable variation in the half-life of testosterone as reported in the literature, ranging from 10 to 100 minutes. metabolism testosterone undecanoate is metabolized to testosterone via ester cleavage of the undecanoate group and reduced to dhtu by 5α-reductase. testosterone is metabolized to various 17-keto steroids. the major active metabolites of testosterone are dht and estradiol. excretion about 90% of a dose of testosterone given intramuscularly is excreted in the urine as glucuronic and sulfuric acid conjugates of testosterone and its 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

administration of exogenous testosterone has been reported to suppress spermatogenesis in the rat, dog and non-human primates, which was reversible on cessation of the treatment.

s testosterone has been reported to suppress spermatogenesis in the rat, dog and non-human primates, which was reversible on cessation of the treatment.

rone in the normal range (300-1080 ng/dl) at day 24 parameter n=95 % subjects with testosterone, cavg0-24h 300 to 1080 ng/dl 80% 95 % confidence interval (72%, 88%) secondary endpoints were the percentage of patients with maximum total testosterone concentration (c max ) meeting three predetermined limits: less than or equal to 1.5 times the upper limit of the normal range (uln) (1620 ng/dl), between 1.8 and 2.5 times uln (1944 - 2700 ng/dl), and greater than 2.5 times uln (2700 ng/dl). the percentage of patients who received tlando and had t cmax threshold less than or equal to 1620 ng/dl, between 1944 ng/dl and 2700 ng/dl, and greater than 2700 ng/dl at the pk visit were 82%, 5%, and 0%, respectively.

of completing laboratory testing as instructed by their health care provider while on tlando. [see warnings and precautions ( 5.2 )]. worsening of benign prostatic hyperplasia (bph) and potential risk of prostate cancer advise patients that tlando can cause increased symptoms of bph and can increase the risk for prostate cancer. advise patients to contact their health care provider if they have any prostate-related symptoms [see warnings and precautions ( 5.4 )]. edema advise patients with preexisting cardiac, renal, or hepatic disease that tlando can cause edema. advise patients to notify their health care provider if edema develops or worsens [see warnings and precautions ( 5.10 )]. sleep apnea advise patients that tlando can worsen sleep apnea especially in patients with risk factors such as obesity or chronic lung diseases [see warnings and precautions ( 5.11 )]. gynecomastia advise patients that tlando can cause gynecomastia. [see warnings and precautions ( 5.12 )]. administration instructions advise patients to take tlando with food [see dosage and administration ( 2.3 )]. manufactured for: manufactured for antares pharma, inc. ewing, nj 08628 manufactured in the united kingdom lb-0190 v02 image description