Tasimelteon

1 INDICATIONS AND USAGE Tasimelteon capsules are a melatonin receptor agonist. Tasimelteon capsules are indicated for the treatment of Non ­24-Hour Sleep-Wake Disorder (Non-24) in adults ( 1 ) 1.1 Non-24-Hour Sleep-Wake Disorder (Non-24) Tasimelteon capsules are indicated for the treatment of Non-24 in adults.

2 DOSAGE AND ADMINISTRATION Indicated Population Dosage Form Body Weight Recommended Dosage Non-24 ( 2.2 ) Adults Capsules Not applicable 20 mg one hour prior to bedtime Tasimelteon capsules and tasimelteon oral suspension are not substitutable ( 2.1 ) Administer at the same time every night ( 2.2 ) Take without food ( 2.4 ) 2.1 Non-Interchangeability between Tasimelteon Capsules and Tasimelteon Oral Suspension Tasimelteon capsules and tasimelteon oral suspension are not substitutable [see Clinical Pharmacology ( 12.3 )]. 2.2 Recommended Dosage for Tasimelteon Capsules for Non-24 Adults The recommended dosage of tasimelteon capsules in adults is 20 mg one hour before bedtime, at the same time every night. Because of individual differences in circadian rhythms, drug effect may not occur for weeks or months. 2.4 Important Administration Information Administer tasimelteon capsules without food [see Clinical Pharmacology ( 12.3 )]. If a patient is unable to take tasimelteon capsules at approximately the same time on a given night, they should skip that dose and take the next dose as scheduled.

6 ADVERSE REACTIONS The most common adverse reactions (incidence >5% and at least twice as high on tasimelteon than on placebo) were headache, increased alanine aminotransferase, nightmares or unusual dreams, and upper respiratory or urinary tract infection ( 6.1) To report SUSPECTED ADVERSE REACTIONS, contact Apotex Corp. at 1-800-706-5575 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 to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. More than 2080 subjects have been treated with at least one dose of tasimelteon, of which more than 380 have been treated for > 26 weeks and more than 170 have been treated for > 1 year. Non-24-Hour Sleep-Wake Disorder (Non-24) A 26-week, parallel-arm placebo-controlled study (Study 1) evaluated 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.

12.3 Pharmacokinetics 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. 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 capsules should be taken without food. Distribution The apparent oral volume of distribution of tasimelteon at steady state in young healthy subjects is approximately 59 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/1.73m 2 ), eight subjects with end-stage renal disease (ESRD) (GFR < 15 mL/min/1.73m 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 co-administered 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 co-administered 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 co-administered 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 capsules 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 capsules 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 co-administered with a 20 mg dose of tasimelteon. There was a trend for an additive effect of tasimelteon and ethanol on some psychomotor tests.