Hetlioz LQ tasimelteon 4 mg/mL Suspension — NDC 43068-304-06 (Billing 43068-0304-06)

12 CLINICAL PHARMACOLOGY

12.1Mechanism of Action The mechanism by which tasimelteon exerts its therapeutic effect in patients with Non-24 or nighttime sleep disturbances in SMS is unclear. However, tasimelteon is an agonist at melatonin MT 1 and MT 2 receptors which are thought to be involved in the control of circadian rhythms.

12.2Pharmacodynamics Tasimelteon is an agonist at MT 1 and MT 2 receptors with greater affinity for the MT 2 as compared to the MT 1 receptor (Ki = 0.304 nM and 0.07 nM, respectively). The major metabolites of tasimelteon have less than one-tenth of the binding affinity of the parent molecule for both the MT 1 and MT 2 receptors.

12.3Pharmacokinetics The pharmacokinetics of tasimelteon is linear over doses ranging from 3 to 300 mg (0.15 to 15 times the recommended daily dosage). The pharmacokinetics of tasimelteon and its metabolites did not change with repeated daily dosing. Absorption The absolute oral bioavailability is 38.3%.

The peak concentration (T max ) of tasimelteon capsule occurred approximately 0.5 to 3 hours after fasted oral administration. The Tmax of tasimelteon suspension occurred approximately 15 to 30 minutes after fasted oral administration. The pharmacokinetic profile of oral suspension has not been directly compared to capsules; therefore, capsules are the only dosage form recommended for use in adults.

Effect of food When administered with a high-fat meal, the Cmax of tasimelteon was 44% lower than when given in a fasted state, and the median Tmax was delayed by approximately 1.75 hours. Therefore, HETLIOZ should be taken without food. Distribution The apparent oral volume of distribution of tasimelteon at steady state in young healthy subjects is approximately 59 - 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 HETLIOZ 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.

Pediatric Patients Pharmacokinetic information in pediatric patients are available only for the oral suspension formulation. Body weight was found to have significant effect on the pharmacokinetics. The increase in body weight was associated with increase in tasimelteon clearance up to 28 kg.

The average dose normalized Cmax and AUC inf at the recommended dose was 231 ng/mL and 310 ng.h/mL. No data are available in patients less than 3 years old. Gender The mean overall exposure of tasimelteon was approximately 20-30% greater in female than in male subjects.

Race The effect of race on exposure of HETLIOZ was not evaluated. Hepatic Impairment The pharmacokinetic profile of a 20 mg dose of HETLIOZ 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.… [Excerpted — this section continues on DailyMed.]

12.1Mechanism of Action The mechanism by which tasimelteon exerts its therapeutic effect in patients with Non-24 or nighttime sleep disturbances in SMS is unclear. However, tasimelteon is an agonist at melatonin MT 1 and MT 2 receptors which are thought to be involved in the control of circadian rhythms.

12.3Pharmacokinetics The pharmacokinetics of tasimelteon is linear over doses ranging from 3 to 300 mg (0.15 to 15 times the recommended daily dosage). The pharmacokinetics of tasimelteon and its metabolites did not change with repeated daily dosing. Absorption The absolute oral bioavailability is 38.3%.

The peak concentration (T max ) of tasimelteon capsule occurred approximately 0.5 to 3 hours after fasted oral administration. The Tmax of tasimelteon suspension occurred approximately 15 to 30 minutes after fasted oral administration. The pharmacokinetic profile of oral suspension has not been directly compared to capsules; therefore, capsules are the only dosage form recommended for use in adults.

Effect of food When administered with a high-fat meal, the Cmax of tasimelteon was 44% lower than when given in a fasted state, and the median Tmax was delayed by approximately 1.75 hours. Therefore, HETLIOZ should be taken without food. Distribution The apparent oral volume of distribution of tasimelteon at steady state in young healthy subjects is approximately 59 - 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 HETLIOZ 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.

Pediatric Patients Pharmacokinetic information in pediatric patients are available only for the oral suspension formulation. Body weight was found to have significant effect on the pharmacokinetics. The increase in body weight was associated with increase in tasimelteon clearance up to 28 kg.

The average dose normalized Cmax and AUC inf at the recommended dose was 231 ng/mL and 310 ng.h/mL. No data are available in patients less than 3 years old. Gender The mean overall exposure of tasimelteon was approximately 20-30% greater in female than in male subjects.

Race The effect of race on exposure of HETLIOZ was not evaluated. Hepatic Impairment The pharmacokinetic profile of a 20 mg dose of HETLIOZ 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. HETLIOZ 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 HETLIOZ was compared among eight subjects with severe renal impairment (estimated glomerular filtration rate [eGFR] ≤ 29 mL/min/1.73m 2 ), eight subjects with end-stage renal disease (ESRD) (GFR < 15 mL/min/1.73m 2 ) requiring hemodialysis, and sixteen healthy matched con… [Excerpted — this section continues on DailyMed.]

12.2Pharmacodynamics Tasimelteon is an agonist at MT 1 and MT 2 receptors with greater affinity for the MT 2 as compared to the MT 1 receptor (Ki = 0.304 nM and 0.07 nM, respectively). The major metabolites of tasimelteon have less than one-tenth of the binding affinity of the parent molecule for both the MT 1 and MT 2 receptors.

14 CLINICAL STUDIES

14.1Non-24-Hour Sleep-Wake Disorder (Non-24) The effectiveness of HETLIOZ in the treatment of Non-24-Hour Sleep-Wake Disorder (Non-24) was established in two randomized double-masked, placebo-controlled, multicenter, parallel-group studies (Study 1; NCT 01163032 and Study 2; NCT 01430754) in totally blind patients with Non-24. In study 1, 84 patients with Non-24 (median age 54 years) were randomized to receive HETLIOZ 20 mg or placebo, one hour prior to bedtime, at the same time every night for up to 6 months. Study 2 was a randomized withdrawal trial in 20 patients with Non-24 (median age 55 years) that was designed to evaluate the maintenance of efficacy of HETLIOZ after 12-weeks.

Patients were treated for approximately 12 weeks with HETLIOZ 20 mg one hour prior to bedtime, at the same time every night. Patients in whom the calculated time of peak melatonin level (melatonin acrophase) occurred at approximately the same time of day (in contrast to the expected daily delay) during the run-in phase were randomized to receive placebo or continue treatment with HETLIOZ 20 mg for 8 weeks. Study 1 and Study 2 evaluated the duration and timing of nighttime sleep and daytime naps via patient-recorded diaries.

During Study 1, patient diaries were recorded for an average of 88 days during screening, and 133 days during randomization. During Study 2, patient diaries were recorded for an average of 57 days during the run-in phase, and 59 days during the randomized-withdrawal phase. Because symptoms of nighttime sleep disruption and daytime sleepiness are cyclical in patients with Non-24, with severity varying according to the state of alignment of the individual patient’s circadian rhythm with the 24-hour day (least severe when fully aligned, most severe when 12 hours out of alignment), efficacy endpoints for nighttime total sleep time and daytime nap duration were based on the 25% of nights with the least nighttime sleep, and the 25% of days with the most daytime nap time.

In Study 1, patients in the HETLIOZ group had, at baseline, an average 195 minutes of nighttime sleep and 137 minutes of daytime nap time on the 25% of most symptomatic nights and days, respectively. Treatment with HETLIOZ resulted in a significant improvement, compared with placebo, for both of these endpoints in Study 1 and Study 2 (see Table 3 ). Table 3: Effects of HETLIOZ 20 MG on Nighttime Sleep Time and Daytime Nap Time in Study 1 and Study 2 Study 1 Study 2 Change from Baseline HETLIOZ 20 MG N=42 Placebo N=42 HETLIOZ 20 MG N=10 Placebo N=10 Nighttime sleep time on 25% most symptomatic nights (minutes) 50 22 -7 -74 Daytime nap time on 25% most symptomatic days (minutes) -49 -22 -9 50 A responder analysis of patients with both ≥ 45 minutes increase in nighttime sleep and ≥ 45 minutes decrease in daytime nap time was conducted in Study 1: 29% (n=12) of patients treated with HETLIOZ, compared with 12% (n=5) of patients treated with placebo met the responder criteria.

14.2Nighttime Sleep Disturbances in Smith-Magenis Syndrome (SMS) The effectiveness of HETLIOZ in the treatment of nighttime sleep disturbances in Smith-Magenis Syndrome (SMS) was established in a 9-week, double-blind, placebo- controlled cross-over study in adults and pediatric patients with SMS (Study 3; NCT 02231008). Patients 16 years of age and older received HETLIOZ 20 mg capsules, and pediatric patients 3 years to 15 years of age received a weight-based dose of oral suspension. Study 3 had two 4-week periods, separated by a 1-week washout interval.

Patients were randomized to a treatment sequence of HELTIOZ in the first period and placebo in the second period, or placebo in the first period and HETLIOZ in the second period. Patients were to take the study drug one hour prior to bedtime. The primary endpoints in Study 3 were nighttime total sleep time and nighttime sleep quality from a parent/guardian-recorded diary.

Nighttime total sleep time was reported as a time unit in… [Excerpted — this section continues on DailyMed.]

13 NONCLINICAL TOXICOLOGY

13.1Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis Tasimelteon was administered orally for up to two years to mice (30, 100, and 300 mg/kg/day) and rats (20, 100, and 250 mg/kg/day). No evidence of carcinogenic potential was observed in mice; the highest dose tested is approximately 75 times the maximum recommended human dose (MRHD) of 20 mg/day, based on a mg/m 2 body surface area. In rats, the incidence of liver tumors was increased in males (adenoma and carcinoma) and females (adenoma) at 100 and 250 mg/kg/day; the incidence of tumors of the uterus (endometrial adenocarcinoma) and uterus and cervix (squamous cell carcinoma) were increased at 250 mg/kg/day.

There was no increase in tumors at the lowest dose tested in rats, which is approximately 10 times the MRHD based on a mg/m 2 body surface area. Mutagenesis Tasimelteon was negative in an in vitro bacterial reverse mutation (Ames) assay, 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, 50, 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.