PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.

PRINCIPAL DISPLAY PANEL. NDC 69238-2548-3Tasimelteon Capsules, 20 mg30 CapsulesRx onlyAmneal Pharmaceuticals LLC. 1.

ABUSE SECTION.

9.2Abuse. Tasimelteon did not produce any abuse-related signals in animal behavioral studies. Rats did not self-administer tasimelteon, suggesting that the drug does not have rewarding properties. There were also no signs or symptoms indicative of abuse potential in clinical studies with tasimelteon.

ADVERSE REACTIONS SECTION.

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 Amneal Pharmaceuticals at 1-877-835-5472 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1Clinical Trials Experience. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of 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. randomized-withdrawal, placebo- controlled study of 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 shows the incidence of adverse reactions from Study 1. Table 2: Adverse Reactions in Study 1Tasimelteon N=42 Placebo N=42 Headache 17 7 Alanine aminotransferase increased 10 5 Nightmare/abnormal dreams 10 0 Upper respiratory tract infection % % Urinary tract infection % % Adverse reactions with an incidence 5% and at least twice as high on Tasimelteon than on placebo are displayed.

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

13.1Carcinogenesis, Mutagenesis, Impairment of Fertility. CarcinogenesisTasimelteon 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 mg/m2 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 mg/m2 body surface area.MutagenesisTasimelteon 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 FertilityWhen 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 times the MRHD based on mg/m2 body surface area.

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action. The mechanism by which tasimelteon exerts its therapeutic effect in patients with Non-24 is unclear. However, tasimelteon is an agonist at melatonin MT1 and MT2 receptors which are thought to be involved in the control of circadian rhythms. 12.2 Pharmacodynamics. Tasimelteon is an agonist at MT1 and MT2 receptors with greater affinity for the MT2 as compared to the MT1 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 MT1 and MT2 receptors. 12.3 Pharmacokinetics. The pharmacokinetics of tasimelteon is linear overdoses ranging from 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.AbsorptionThe absolute oral bioavailability is 38.3%. The peak concentration (Tmax) of tasimelteon occurred approximately 0.5 to hours 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 foodWhen administered with high-fat meal, the Cmax of tasimelteon was 44% lower than when given in fasted state, and the median Tmax was delayed by approximately 1.75 hours. Therefore, tasimelteon should be taken without food.DistributionThe 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.MetabolismTasimelteon 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 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.EliminationFollowing oral administration of radiolabeled tasimelteon, 80% of total radioactivity was excreted in urine and approximately 4% in feces, resulting in 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 PopulationsElderlyIn elderly subjects, tasimelteon exposure increased by approximately two-fold compared with non-elderly adults.Pediatric PatientsBody 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 AUCinf at the recommended dose was 231 ng/mL and 310 ng.h/mL. No data are available in patients less than years old.GenderThe mean overall exposure of tasimelteon was approximately 20 to 30% greater in female than in male subjects.RaceThe effect of race on exposure of tasimelteon was not evaluated.Hepatic ImpairmentThe pharmacokinetic profile of 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 ImpairmentThe pharmacokinetic profile of 20 mg dose of tasimelteon was compared among eight subjects with severe renal impairment (estimated glomerular filtration rate [eGFR] <= 29 mL/min/1.73m2), eight subjects with end-stage renal disease (ESRD) (GFR 15 mL/min/1.73m2) 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 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 moderate CYP1A2 inducer)Tasimelteon exposure decreased by approximately 40% in smokers, compared to non-smokers [see Use in Specific Populations (8.7)]. Drug Interaction StudiesNo 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 TasimelteonDrugs that inhibit CYP1A2 and CYP3A4 are expected to alter the metabolism of tasimelteon.Fluvoxamine (strong CYP1A2 inhibitor): the AUC0-inf and Cmax of tasimelteon increased by 7-fold and 2-fold, respectively, when co-administered with fluvoxamine 50 mg (after 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 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 DrugsMidazolam (CYP3A4 substrate): Administration of tasimelteon 20 mg once day for 14 days did not produce any significant changes in the Tmax, Cmax, 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 day for 16 days did not produce any clinically significant changes in the Tmax, Cmax, or AUC of rosiglitazone after oral administration of mg. This indicates that there is no induction of CYP2C8 by tasimelteon at this dose.Effect of Alcohol on TasimelteonIn study of 28 healthy volunteers, single dose of ethanol (0.6 g/kg for women and 0.7 g/kg for men) was co-administered with 20 mg dose of tasimelteon. There was trend for an additive effect of tasimelteon and ethanol on some psychomotor tests.

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES. 14.1 Non-24-Hour Sleep-Wake Disorder (Non-24). The effectiveness of tasimelteon 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 (Studies and 2) in totally blind patients with Non-24.In study 1, 84 patients with Non-24 (median age 54 years) were randomized to receive tasimelteon 20 mg or placebo, one hour prior to bedtime, at the same time every night for up to months.Study was randomized withdrawal trial in 20 patients with Non-24 (median age 55 years) that was designed to evaluate the maintenance of efficacy of tasimelteon after 12-weeks. Patients were treated for approximately 12-weeks with tasimelteon 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 tasimelteon 20 mg for weeks.Study and Study 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 patients 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 tasimelteon 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 tasimelteon resulted in significant improvement, compared with placebo, for both of these endpoints in Study and Study (see Table 3).Table 3: Effects of Tasimelteon 20 MG on Nighttime Sleep Time and Daytime Nap Time in Study and Study 2Study 1Study 2Change from Baseline Tasimelteon 20 MGN=42PlaceboN=42Tasimelteon 20 MGN=10 PlaceboN=10Nighttime sleep time on 25% most symptomatic nights (minutes)5022-7-74Daytime nap time on 25% most symptomatic days (minutes)-49-22-950A 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 tasimelteon, compared with 12% (n=5) of patients treated with placebo met the responder criteria.

CLINICAL TRIALS EXPERIENCE SECTION.

6.1Clinical Trials Experience. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of 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. randomized-withdrawal, placebo- controlled study of 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 shows the incidence of adverse reactions from Study 1. Table 2: Adverse Reactions in Study 1Tasimelteon N=42 Placebo N=42 Headache 17 7 Alanine aminotransferase increased 10 5 Nightmare/abnormal dreams 10 0 Upper respiratory tract infection % % Urinary tract infection % % Adverse reactions with an incidence 5% and at least twice as high on Tasimelteon than on placebo are displayed.

CONTRAINDICATIONS SECTION.

4 CONTRAINDICATIONS. None. None (4).

CONTROLLED SUBSTANCE SECTION.

9.1Controlled Substance. Tasimelteon is not controlled substance under the Controlled Substances Act.

DEPENDENCE SECTION.

9.3Dependence. Discontinuation of tasimelteon in humans following chronic administration did not produce withdrawal signs. Tasimelteon. does not appear to produce physical dependence.

DESCRIPTION SECTION.

11 DESCRIPTION. Tasimelteon capsules contains tasimelteon, melatonin receptor agonist, chemically designated as (1R, 2R)-N-[2 (2,3-dihydrobenzofuran-4-yl) cyclopropylmethyl]propanamide, containing two chiral centers. The molecular formula is C15H19NO2, and the molecular weight is 245.32. The structural formula is:Tasimelteon is white to off-white crystalline powder. freely soluble in methanol and in 95% ethanol. Tasimelteon capsules are intended for oral administration. Each capsule contains 20 mg of tasimelteon and the following inactive ingredients: colloidal silicon dioxide, croscarmellose sodium, lactose monohydrate and magnesium stearate. Each hard gelatin capsule consists of gelatin, titanium dioxide, FD&C Blue and FD&C Red 40.. 1.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION. Indicated Population Dosage FormBody WeightRecommended DosageNon-24 (2.2) Adults CapsulesNot applicable20 mg one hour prior to bedtimeTasimelteon capsules and tasimelteon oral suspension are not substitutable (2.1)Administer at the same time every night (2.2)Take without food (2.2). Tasimelteon capsules and tasimelteon oral suspension are not substitutable (2.1). Administer at the same time every night (2.2). Take without food (2.2). 2.1Non-Interchangeability between Tasimelteon Capsules and Tasimelteon OralSuspension. Tasimelteon capsules and tasimelteon oral suspension are not substitutable [see Clinical Pharmacology (12.3)]. 2.2Recommended 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. 2.4Important Administration Information. Administer tasimelteon capsules without food [see Clinical Pharmacology (12.3)]. If patient is unable to take tasimelteon approximately the same time on given night, they should skip that dose and take the next dose as scheduled.

DOSAGE FORMS & STRENGTHS SECTION.

3 DOSAGE FORMS AND STRENGTHS. Capsules with Blue opaque body imprinted with 20 mg and circular band in white ink, blue opaque cap imprinted with MT1 in white ink filled with white to off white powder. Capsules: 20 mg (3).

DRUG ABUSE AND DEPENDENCE SECTION.

9 DRUG ABUSE AND DEPENDENCE. 9.1Controlled Substance. Tasimelteon is not controlled substance under the Controlled Substances Act. 9.2Abuse. Tasimelteon did not produce any abuse-related signals in animal behavioral studies. Rats did not self-administer tasimelteon, suggesting that the drug does not have rewarding properties. There were also no signs or symptoms indicative of abuse potential in clinical studies with tasimelteon. 9.3Dependence. Discontinuation of tasimelteon in humans following chronic administration did not produce withdrawal signs. Tasimelteon. does not appear to produce physical dependence.

OVERDOSAGE SECTION.

10 OVERDOSAGE. There is limited premarketing clinical experience with the effects of an overdosage of tasimelteon. As with the management of any overdose, general symptomatic and supportive measures should be used, along with immediate gastric lavage where appropriate. Intravenous fluids should be administered as needed. Respiration, pulse, blood pressure, and other appropriate vital signs should be monitored, and general supportive measures employed. While hemodialysis was effective at clearing tasimelteon and the majority of its major metabolites in patients with renal impairment, it is not known if hemodialysis will effectively reduce exposure in the case of overdose. As with the management of any overdose, the possibility of multiple drug ingestion should be considered. Contact poison control center for current information on the management of overdose.

DRUG INTERACTIONS SECTION.

7 DRUG INTERACTIONS. Strong CYP1A2 inhibitors (e.g., fluvoxamine): Avoid use of tasimelteon in combination with strong CYP1A2 inhibitors because of increased exposure (7.1, 12.3)Strong CYP3A4 inducers (e.g., rifampin): Avoid use of tasimelteon in combination with rifampin or other CYP3A4 inducers, because of decreased exposure (7.2, 12.3) Strong CYP1A2 inhibitors (e.g., fluvoxamine): Avoid use of tasimelteon in combination with strong CYP1A2 inhibitors because of increased exposure (7.1, 12.3). Strong CYP3A4 inducers (e.g., rifampin): Avoid use of tasimelteon in combination with rifampin or other CYP3A4 inducers, because of decreased exposure (7.2, 12.3) 7.1 Strong CYP1A2 Inhibitors (e.g., fluvoxamine). Avoid use of tasimelteon in combination with fluvoxamine or other strong CYP1A2 inhibitors because of potentially large increase in tasimelteon exposure and greater risk of adverse reactions [see Clinical Pharmacology (12.3)]. 7.2 Strong CYP3A4 Inducers (e.g., rifampin). Avoid use of tasimelteon in combination with rifampin or other CYP3A4 inducers because of potentially large decrease in tasimelteon exposure with reduced efficacy [see Clinical Pharmacology (12.3)]. 7.3 Beta-Adrenergic Receptor Antagonists (e.g.,acebutolol, metoprolol). Beta-adrenergic receptor antagonists have been shown 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.

GERIATRIC USE SECTION.

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.

HEPATIC IMPAIRMENT SUBSECTION.

8.6Hepatic 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)].

HOW SUPPLIED SECTION.

16HOW SUPPLIED/STORAGE AND HANDLING. Tasimelteon Capsules20 mg capsules are available as size 1, blue opaque, hard gelatin capsules, body imprinted with 20 mg and circular band in white and cap imprinted with MT1 in white, containing 20 mg of tasimelteon per capsule.NDC 69238-2548-3 Bottles of 30Storage and HandlingTasimelteon CapsulesStore tasimelteon 20 mg capsules at controlled room temperature, 20C to 25C (68F to 77F); excursions permitted to 15C to 30C (59F to 86F) [See USP Controlled Room Temperature]. Protect from exposure to light and moisture.. NDC 69238-2548-3 Bottles of 30.

INDICATIONS & USAGE SECTION.

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

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION. Advise patients to limit their activities to preparing for going to bed after taking tasimelteon capsules because tasimelteon can potentially impair the performance of activities requiring complete mental alertness [see Warnings and Precautions (5.1)]. Administration Information for tasimelteon capsules [see Dosage and Administration (2.1, 2.2, 2.4)]. Advise patients to take tasimelteon without food. Advise patients to take tasimelteon before bedtime at the same time every night. Advise patients to skip the dose that night if they cannot take tasimelteon at approximately the same time on given night. Advise patients to swallow tasimelteon capsules whole. Non-24 (tasimelteon capsules) Advise patients that because of individual differences in circadian rhythms, daily use for several weeks or months may be necessary before benefit from tasimelteon is observed [see Dosage and Administration (2.2)]. Manufactured by:MSN Laboratories Private LimitedTelangana 509 228,INDIADistributed by:Amneal Pharmaceuticals LLCBridgewater, NJ 08807Rev. 01-2023-00 Advise patients to limit their activities to preparing for going to bed after taking tasimelteon capsules because tasimelteon can potentially impair the performance of activities requiring complete mental alertness [see Warnings and Precautions (5.1)]. Administration Information for tasimelteon capsules [see Dosage and Administration (2.1, 2.2, 2.4)]. Advise patients to take tasimelteon without food. Advise patients to take tasimelteon before bedtime at the same time every night. Advise patients to skip the dose that night if they cannot take tasimelteon at approximately the same time on given night. Advise patients to swallow tasimelteon capsules whole. Non-24 (tasimelteon capsules).

LACTATION SECTION.

8.2Lactation. 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 mothers clinical need for tasimelteon and any potential adverse effects on the breastfed infant from tasimelteon or from the underlying maternal condition.

MECHANISM OF ACTION SECTION.

12.1 Mechanism of Action. The mechanism by which tasimelteon exerts its therapeutic effect in patients with Non-24 is unclear. However, tasimelteon is an agonist at melatonin MT1 and MT2 receptors which are thought to be involved in the control of circadian rhythms.

NONCLINICAL TOXICOLOGY SECTION.

13 NONCLINICAL TOXICOLOGY. 13.1Carcinogenesis, Mutagenesis, Impairment of Fertility. CarcinogenesisTasimelteon 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 mg/m2 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 mg/m2 body surface area.MutagenesisTasimelteon 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 FertilityWhen 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 times the MRHD based on mg/m2 body surface area.

PEDIATRIC USE SECTION.

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 mg/m2 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 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.

PHARMACODYNAMICS SECTION.

12.2 Pharmacodynamics. Tasimelteon is an agonist at MT1 and MT2 receptors with greater affinity for the MT2 as compared to the MT1 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 MT1 and MT2 receptors.

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics. The pharmacokinetics of tasimelteon is linear overdoses ranging from 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.AbsorptionThe absolute oral bioavailability is 38.3%. The peak concentration (Tmax) of tasimelteon occurred approximately 0.5 to hours 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 foodWhen administered with high-fat meal, the Cmax of tasimelteon was 44% lower than when given in fasted state, and the median Tmax was delayed by approximately 1.75 hours. Therefore, tasimelteon should be taken without food.DistributionThe 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.MetabolismTasimelteon 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 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.EliminationFollowing oral administration of radiolabeled tasimelteon, 80% of total radioactivity was excreted in urine and approximately 4% in feces, resulting in 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 PopulationsElderlyIn elderly subjects, tasimelteon exposure increased by approximately two-fold compared with non-elderly adults.Pediatric PatientsBody 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 AUCinf at the recommended dose was 231 ng/mL and 310 ng.h/mL. No data are available in patients less than years old.GenderThe mean overall exposure of tasimelteon was approximately 20 to 30% greater in female than in male subjects.RaceThe effect of race on exposure of tasimelteon was not evaluated.Hepatic ImpairmentThe pharmacokinetic profile of 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 ImpairmentThe pharmacokinetic profile of 20 mg dose of tasimelteon was compared among eight subjects with severe renal impairment (estimated glomerular filtration rate [eGFR] <= 29 mL/min/1.73m2), eight subjects with end-stage renal disease (ESRD) (GFR 15 mL/min/1.73m2) 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 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 moderate CYP1A2 inducer)Tasimelteon exposure decreased by approximately 40% in smokers, compared to non-smokers [see Use in Specific Populations (8.7)]. Drug Interaction StudiesNo 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 TasimelteonDrugs that inhibit CYP1A2 and CYP3A4 are expected to alter the metabolism of tasimelteon.Fluvoxamine (strong CYP1A2 inhibitor): the AUC0-inf and Cmax of tasimelteon increased by 7-fold and 2-fold, respectively, when co-administered with fluvoxamine 50 mg (after 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 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 DrugsMidazolam (CYP3A4 substrate): Administration of tasimelteon 20 mg once day for 14 days did not produce any significant changes in the Tmax, Cmax, 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 day for 16 days did not produce any clinically significant changes in the Tmax, Cmax, or AUC of rosiglitazone after oral administration of mg. This indicates that there is no induction of CYP2C8 by tasimelteon at this dose.Effect of Alcohol on TasimelteonIn study of 28 healthy volunteers, single dose of ethanol (0.6 g/kg for women and 0.7 g/kg for men) was co-administered with 20 mg dose of tasimelteon. There was trend for an additive effect of tasimelteon and ethanol on some psychomotor tests.

PREGNANCY SECTION.

8.1 Pregnancy. Risk Summary Available postmarketing case reports with tasimelteon use in pregnant women are not sufficient to evaluate drug-associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes. In pregnant rats, no embryofetal developmental toxicity was observed at exposures of 50 mg/kg/day, or up to 24 times higher than the human exposure at the maximum recommended human dose (MRHD) (see Data). The estimated background risk of major birth defects and miscarriage for the indicated populations are unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. DataAnimal Data In pregnant rats administered tasimelteon at oral doses of 5, 50, 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/m2 body surface area.In pregnant rabbits administered tasimelteon at oral doses of 5, 30, 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, 150, 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/m2 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/m2 body surface area.

SPL UNCLASSIFIED SECTION.

1.1Non-24-Hour Sleep-Wake Disorder (Non-24). Tasimelteon capsules are indicated for the treatment of Non-24-Hour in adults.. Tasimelteon capsules are indicated for the treatment of Non-24-Hour in adults.

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. Hepatic impairment: Tasimelteon has not been studied in patients with severe hepatic impairment and is not recommended in these patients (8.6) Hepatic impairment: Tasimelteon has not been studied in patients with severe hepatic impairment and is not recommended in these patients (8.6) 8.1 Pregnancy. Risk Summary Available postmarketing case reports with tasimelteon use in pregnant women are not sufficient to evaluate drug-associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes. In pregnant rats, no embryofetal developmental toxicity was observed at exposures of 50 mg/kg/day, or up to 24 times higher than the human exposure at the maximum recommended human dose (MRHD) (see Data). The estimated background risk of major birth defects and miscarriage for the indicated populations are unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. DataAnimal Data In pregnant rats administered tasimelteon at oral doses of 5, 50, 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/m2 body surface area.In pregnant rabbits administered tasimelteon at oral doses of 5, 30, 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, 150, 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/m2 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/m2 body surface area. 8.2Lactation. 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 mothers 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 mg/m2 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 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. 8.6Hepatic 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)]. 8.7Smokers. 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)].

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS. May cause somnolence: After taking tasimelteon, patients should limit their activity to preparing for going to bed, because tasimelteon can impair the performance of activities requiring complete mental alertness (5.1) 5.1Somnolence. After taking tasimelteon, patients should limit their activity to preparing for going to bed. tasimelteon can potentially impair the performance of activities requiring complete mental alertness.