to reduce the production of melatonin via specific inhibition of beta-1 adrenergic receptors. nighttime administration of beta- adrenergic receptor antagonists may reduce the efficacy of tasimelteon.

(n=42) compared to placebo (n=42) in patients with non-24. a randomized-withdrawal, placebo-controlled study of 8 weeks duration (study 2) also evaluated tasimelteon (n=10), compared to placebo (n=10), in patients with non-24. in placebo-controlled studies, 6% of patients exposed to tasimelteon discontinued treatment due to an adverse event, compared with 4% of patients who received placebo. table 2 shows the incidence of adverse reactions from study 1. table 2: adverse reactions in study 1 tasimelteon n=42 placebo n=42 headache 17% 7% alanine aminotransferase increased 10% 5% nightmare/abnormal dreams 10% 0% upper respiratory tract infection 7% 0% urinary tract infection 7% 2% *adverse reactions with an incidence >5% and at least twice as high on tasimelteon than on placebo are displayed.

to reduce the production of melatonin via specific inhibition of beta-1 adrenergic receptors. nighttime administration of beta- adrenergic receptor antagonists may reduce the efficacy of tasimelteon.

/day, or 500 mg/kg/day during the period of organogenesis, there were no effects on embryofetal development. the highest dose tested is approximately 240 times the mrhd of 20 mg/day, based on mg/m 2 body surface area. in pregnant rabbits administered tasimelteon at oral doses of 5 mg/kg/day, 30 mg/kg/day, or 200 mg/kg/day during the period of organogenesis, embryolethality and embryofetal toxicity (reduced fetal body weight and delayed ossification) were observed at the highest dose tested. the highest dose is approximately 200 times the mrhd. oral administration of tasimelteon at 50 mg/kg/day, 150 mg/kg/day, or 450 mg/kg/day to rats throughout organogenesis resulted in persistent reductions in body weight, delayed sexual maturation, and physical development, and neurobehavioral impairment in offspring at the highest dose tested which is approximately 220 times the mrhd based on mg/m 2 body surface area. reduced body weight in offspring was also observed at the mid-dose. the no effect dose (noel), (50 mg/kg/day) is approximately 25 times the mrhd based on mg/m 2 body surface area. 8.2 lactation risk summary there are no data on the presence of tasimelteon or its metabolites in human or animal milk, the effects on the breastfed infant, or the effects on milk production. the developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for tasimelteon and any potential adverse effects on the breastfed infant from tasimelteon or from the underlying maternal condition. 8.4 pediatric use safety and effectiveness of tasimelteon for the treatment of non-24 in pediatric patients have not been established. juvenile animal toxicity data juvenile rats received oral doses of tasimelteon at 50, 150, or 450 mg/kg from weaning (day 21) through adulthood (day 90). these doses are approximately 12 to 108 times the maximum recommended human dose (mrhd) of 20 mg based on a mg/m 2 body surface area. toxicity was observed mainly at the highest dose and included mortality (females only), tremors, unsteady gait, decrease in growth and development compared to controls. the former reflected as decreases in bone growth, bone mineral content, bone ossification, and a delay in attainment of sexual maturation. tasimelteon had no effect on fertility, reproduction, or learning and memory. the no observed adverse effect level (noael) is 150 mg/kg/day, which is approximately 178 times the mrhd based on auc. 8.5 geriatric use the risk of adverse reactions may be greater in elderly (>65 years) patients than younger patients because exposure to tasimelteon is increased by approximately 2-fold compared with younger patients. 8.6 hepatic impairment dose adjustment is not necessary in patients with mild or moderate hepatic impairment. tasimelteon has not been studied in patients with severe hepatic impairment (child-pugh class c). therefore, tasimelteon is not recommended for use in patients with severe hepatic impairment [see clinical pharmacology ( 12.3 )] . 8.7 smokers smoking causes induction of cyp1a2 levels. the exposure of tasimelteon in smokers was lower than in non-smokers and therefore the efficacy of tasimelteon may be reduced in smokers [see clinical pharmacology ( 12.3 )] .

g/day, based on mg/m 2 body surface area. in pregnant rabbits administered tasimelteon at oral doses of 5 mg/kg/day, 30 mg/kg/day, or 200 mg/kg/day during the period of organogenesis, embryolethality and embryofetal toxicity (reduced fetal body weight and delayed ossification) were observed at the highest dose tested. the highest dose is approximately 200 times the mrhd. oral administration of tasimelteon at 50 mg/kg/day, 150 mg/kg/day, or 450 mg/kg/day to rats throughout organogenesis resulted in persistent reductions in body weight, delayed sexual maturation, and physical development, and neurobehavioral impairment in offspring at the highest dose tested which is approximately 220 times the mrhd based on mg/m 2 body surface area. reduced body weight in offspring was also observed at the mid-dose. the no effect dose (noel), (50 mg/kg/day) is approximately 25 times the mrhd based on mg/m 2 body surface area.

ly 0.5 to 3 hours after fasted oral administration. effect of food when administered with a high-fat meal, the c max of tasimelteon was 44% lower than when given in a fasted state, and the median t max was delayed by approximately 1.75 hours. therefore, tasimelteon should be taken without food. distribution the apparent oral volume of distribution of tasimelteon at steady state in young healthy subjects is approximately 59 l to 126 l. at therapeutic concentrations, tasimelteon is about 90% bound to proteins. metabolism tasimelteon is extensively metabolized. metabolism of tasimelteon consists primarily of oxidation at multiple sites and oxidative dealkylation resulting in opening of the dihydrofuran ring followed by further oxidation to give a carboxylic acid. cyp1a2 and cyp3a4 are the major isozymes involved in the metabolism of tasimelteon. phenolic glucuronidation is the major phase ii metabolic route. major metabolites had 13-fold or less activity at melatonin receptors compared to tasimelteon. elimination following oral administration of radiolabeled tasimelteon, 80% of total radioactivity was excreted in urine and approximately 4% in feces, resulting in a mean recovery of 84%. less than 1% of the dose was excreted in urine as the parent compound. the observed mean elimination half-life for tasimelteon is 1.3 ± 0.4 hours. the mean terminal elimination half-life ± standard deviation of the main metabolites ranges from 1.3 ± 0.5 to 3.7 ± 2.2. repeated once daily dosing with tasimelteon does not result in changes in pharmacokinetic parameters or significant accumulation of tasimelteon. studies in specific populations elderly in elderly subjects, tasimelteon exposure increased by approximately two-fold compared with non-elderly adults. gender the mean overall exposure of tasimelteon was approximately 20% to 30% greater in female than in male subjects. race the effect of race on exposure of tasimelteon was not evaluated. hepatic impairment the pharmacokinetic profile of a 20 mg dose of tasimelteon was compared among eight subjects with mild hepatic impairment (child-pugh score ≥5 and ≤6 points), eight subjects with moderate hepatic impairment (child-pugh score ≥7 and ≤9 points), and 13 healthy matched controls. tasimelteon exposure was increased less than two-fold in subjects with moderate hepatic impairment. therefore, no dose adjustment is needed in patients with mild or moderate hepatic impairment. tasimelteon has not been studied in patients with severe hepatic impairment (child-pugh class c) and is not recommended in these patients. renal impairment the pharmacokinetic profile of a 20 mg dose of tasimelteon was compared among eight subjects with severe renal impairment (estimated glomerular filtration rate [egfr] ≤29 ml/min/1.73 m 2 ), eight subjects with end-stage renal disease (esrd) (gfr <15 ml/min/1.73 m 2 ) requiring hemodialysis, and sixteen healthy matched controls. there was no apparent relationship between tasimelteon cl/f and renal function, as measured by either estimated creatinine clearance or egfr. subjects with severe renal impairment had a 30% lower clearance, and clearance in subjects with esrd was comparable to that of healthy subjects. no dose adjustment is necessary for patients with renal impairment. smokers (smoking is a moderate cyp1a2 inducer) tasimelteon exposure decreased by approximately 40% in smokers, compared to non-smokers [see use in specific populations ( 8.7 )] . drug interaction studies no potential drug interactions were identified in in vitro studies with cyp inducers or inhibitors of cyp1a1, cyp1a2, cyp2b6, cyp2c9/2c19, cyp2e1, cyp2d6, and transporters including p-glycoprotein, oatp1b1, oatp1b3, oct2, oat1, and oat3. effect of other drugs on tasimelteon drugs that inhibit cyp1a2 and cyp3a4 are expected to alter the metabolism of tasimelteon. fluvoxamine (strong cyp1a2 inhibitor): the auc 0-inf and c max of tasimelteon increased by 7-fold and 2-fold, respectively, when coadministered with fluvoxamine 50 mg (after 6 days of fluvoxamine 50 mg per day) [see drug interactions ( 7.1 )] . ketoconazole (strong cyp3a4 inhibitor): tasimelteon exposure increased by approximately 50% when coadministered with ketoconazole 400 mg (after 5 days of ketoconazole 400 mg per day) [see drug interactions ( 7.2 )] . rifampin (strong cyp3a4 and moderate cyp2c19 inducer): the exposure of tasimelteon decreased by approximately 90% when coadministered with rifampin 600 mg (after 11 days of rifampin 600 mg per day). efficacy may be reduced when tasimelteon is used in combination with strong cyp3a4 inducers, such as rifampin [see drug interactions ( 7.2 )] . effect of tasimelteon on other drugs midazolam (cyp3a4 substrate): administration of tasimelteon 20 mg once a day for 14 days did not produce any significant changes in the t max , c max , or auc of midazolam or 1-oh midazolam. this indicates there is no induction of cyp3a4 by tasimelteon at this dose. rosiglitazone (cyp2c8 substrate): administration of tasimelteon 20 mg once a day for 16 days did not produce any clinically significant changes in the t max , c max , or auc of rosiglitazone after oral administration of 4 mg. this indicates that there is no induction of cyp2c8 by tasimelteon at this dose. effect of alcohol on tasimelteon in a study of 28 healthy volunteers, a single dose of ethanol (0.6 g/kg for women and 0.7 g/kg for men) was coadministered with a 20 mg dose of tasimelteon. there was a trend for an additive effect of tasimelteon and ethanol on some psychomotor tests.

multiple sites and oxidative dealkylation resulting in opening of the dihydrofuran ring followed by further oxidation to give a carboxylic acid. cyp1a2 and cyp3a4 are the major isozymes involved in the metabolism of tasimelteon. phenolic glucuronidation is the major phase ii metabolic route. major metabolites had 13-fold or less activity at melatonin receptors compared to tasimelteon. elimination following oral administration of radiolabeled tasimelteon, 80% of total radioactivity was excreted in urine and approximately 4% in feces, resulting in a mean recovery of 84%. less than 1% of the dose was excreted in urine as the parent compound. the observed mean elimination half-life for tasimelteon is 1.3 ± 0.4 hours. the mean terminal elimination half-life ± standard deviation of the main metabolites ranges from 1.3 ± 0.5 to 3.7 ± 2.2. repeated once daily dosing with tasimelteon does not result in changes in pharmacokinetic parameters or significant accumulation of tasimelteon. studies in specific populations elderly in elderly subjects, tasimelteon exposure increased by approximately two-fold compared with non-elderly adults. gender the mean overall exposure of tasimelteon was approximately 20% to 30% greater in female than in male subjects. race the effect of race on exposure of tasimelteon was not evaluated. hepatic impairment the pharmacokinetic profile of a 20 mg dose of tasimelteon was compared among eight subjects with mild hepatic impairment (child-pugh score ≥5 and ≤6 points), eight subjects with moderate hepatic impairment (child-pugh score ≥7 and ≤9 points), and 13 healthy matched controls. tasimelteon exposure was increased less than two-fold in subjects with moderate hepatic impairment. therefore, no dose adjustment is needed in patients with mild or moderate hepatic impairment. tasimelteon has not been studied in patients with severe hepatic impairment (child-pugh class c) and is not recommended in these patients. renal impairment the pharmacokinetic profile of a 20 mg dose of tasimelteon was compared among eight subjects with severe renal impairment (estimated glomerular filtration rate [egfr] ≤29 ml/min/1.73 m 2 ), eight subjects with end-stage renal disease (esrd) (gfr <15 ml/min/1.73 m 2 ) requiring hemodialysis, and sixteen healthy matched controls. there was no apparent relationship between tasimelteon cl/f and renal function, as measured by either estimated creatinine clearance or egfr. subjects with severe renal impairment had a 30% lower clearance, and clearance in subjects with esrd was comparable to that of healthy subjects. no dose adjustment is necessary for patients with renal impairment. smokers (smoking is a moderate cyp1a2 inducer) tasimelteon exposure decreased by approximately 40% in smokers, compared to non-smokers [see use in specific populations ( 8.7 )] . drug interaction studies no potential drug interactions were identified in in vitro studies with cyp inducers or inhibitors of cyp1a1, cyp1a2, cyp2b6, cyp2c9/2c19, cyp2e1, cyp2d6, and transporters including p-glycoprotein, oatp1b1, oatp1b3, oct2, oat1, and oat3. effect of other drugs on tasimelteon drugs that inhibit cyp1a2 and cyp3a4 are expected to alter the metabolism of tasimelteon. fluvoxamine (strong cyp1a2 inhibitor): the auc 0-inf and c max of tasimelteon increased by 7-fold and 2-fold, respectively, when coadministered with fluvoxamine 50 mg (after 6 days of fluvoxamine 50 mg per day) [see drug interactions ( 7.1 )] . ketoconazole (strong cyp3a4 inhibitor): tasimelteon exposure increased by approximately 50% when coadministered with ketoconazole 400 mg (after 5 days of ketoconazole 400 mg per day) [see drug interactions ( 7.2 )] . rifampin (strong cyp3a4 and moderate cyp2c19 inducer): the exposure of tasimelteon decreased by approximately 90% when coadministered with rifampin 600 mg (after 11 days of rifampin 600 mg per day). efficacy may be reduced when tasimelteon is used in combination with strong cyp3a4 inducers, such as rifampin [see drug interactions ( 7.2 )] . effect of tasimelteon on other drugs midazolam (cyp3a4 substrate): administration of tasimelteon 20 mg once a day for 14 days did not produce any significant changes in the t max , c max , or auc of midazolam or 1-oh midazolam. this indicates there is no induction of cyp3a4 by tasimelteon at this dose. rosiglitazone (cyp2c8 substrate): administration of tasimelteon 20 mg once a day for 16 days did not produce any clinically significant changes in the t max , c max , or auc of rosiglitazone after oral administration of 4 mg. this indicates that there is no induction of cyp2c8 by tasimelteon at this dose. effect of alcohol on tasimelteon in a study of 28 healthy volunteers, a single dose of ethanol (0.6 g/kg for women and 0.7 g/kg for men) was coadministered with a 20 mg dose of tasimelteon. there was a trend for an additive effect of tasimelteon and ethanol on some psychomotor tests.

ay, an in vitro cytogenetics assay in primary human lymphocytes, and an in vivo micronucleus assay in rats. impairment of fertility when male and female rats were given tasimelteon at oral doses of 5 mg/kg/day, 50 mg/kg/day, or 500 mg/kg/day prior to and throughout mating and continuing in females to gestation day 7, estrus cycle disruption and decreased fertility were observed at all but the lowest dose tested. the no-effect dose for effects on female reproduction (5 mg/kg/day) is approximately 2 times the mrhd based on a mg/m 2 body surface area.

cs assay in primary human lymphocytes, and an in vivo micronucleus assay in rats. impairment of fertility when male and female rats were given tasimelteon at oral doses of 5 mg/kg/day, 50 mg/kg/day, or 500 mg/kg/day prior to and throughout mating and continuing in females to gestation day 7, estrus cycle disruption and decreased fertility were observed at all but the lowest dose tested. the no-effect dose for effects on female reproduction (5 mg/kg/day) is approximately 2 times the mrhd based on a mg/m 2 body surface area.

goa 403 722 india manufactured for: teva pharmaceuticals parsippany, nj 07054 iss. 5/2022