ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS. The following clinically significant adverse reactions are discussed in detail in other sections of the labeling:CNS Depressant Effects and Daytime Impairment [see Warnings and Precautions 5.1 )] Sleep Paralysis, Hypnagogic/Hypnopompic Hallucinations, and Cataplexy-like Symptoms [see Warnings and Precautions 5.2 )] Complex Sleep Behaviors [see Warnings and Precautions 5.3 )] Patients with Compromised Respiratory Function [see Warnings and Precautions 5.4 )] Worsening of Depression/Suicidal Ideation [see Warnings and Precautions 5.5 )] CNS Depressant Effects and Daytime Impairment [see Warnings and Precautions 5.1 )] Sleep Paralysis, Hypnagogic/Hypnopompic Hallucinations, and Cataplexy-like Symptoms [see Warnings and Precautions 5.2 )] Complex Sleep Behaviors [see Warnings and Precautions 5.3 )] Patients with Compromised Respiratory Function [see Warnings and Precautions 5.4 )] Worsening of Depression/Suicidal Ideation [see Warnings and Precautions 5.5 )] The most common adverse reaction (reported in >=5% of patients treated with DAYVIGO and at least twice the rate of placebo) was somnolence. (6.1)To report SUSPECTED ADVERSE REACTIONS, contact Eisai Inc. at 1-888-274-2378 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 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 DAYVIGO was evaluated in 1418 adult patients with insomnia disorder (age 18 to 88 years) from two controlled efficacy trials (Study and Study 2). Study was 6-month placebo-controlled trial assessing DAYVIGO or 10 mg once nightly, followed by 6-month parallel-group extension period in which patients initially treated with DAYVIGO continued on the same dose, and patients who received placebo were re-randomized to receive DAYVIGO or 10 mg once nightly. In Study 1, 434 patients were treated with DAYVIGO for one year. Study was 30-day placebo- and active-controlled trial assessing DAYVIGO or 10 mg once nightly.Adverse Reactions Resulting in Discontinuation of TreatmentThe frequencies of discontinuation due to adverse reactions in Study (the first 30 days) and Study were 2.6% and 1.4% for patients treated with 10 mg and mg DAYVIGO, respectively, compared to 1.5% for patients in the placebo group. The most common adverse reactions leading to discontinuation of DAYVIGO were somnolence (1.0% for 10 mg, 0.7% for mg, and 0.4% for placebo) and nightmares (0.3% for 10 mg, 0.3% for mg, and 0% for placebo).The frequencies of discontinuation due to adverse reactions in the 6-month placebo-controlled period of Study were 8.3% and 4.1% for patients treated with DAYVIGO 10 mg and mg, respectively, compared to 3.8% for patients in the placebo group. The most common reasons for discontinuation of DAYVIGO and occurring in more than one patient within treatment arm were somnolence (2.9% for 10 mg, 1.0% for mg, and 0.6% for placebo), nightmares (1.3% for 10 mg, 0.3% for mg, and 0% for placebo), and palpitations (0.6% for 10 mg, 0% for mg, and 0% for placebo). Most Common Adverse Reactions The most common adverse reaction (reported in 5% or more of patients treated with DAYVIGO and at least twice the rate of placebo) in Study (the first 30 days) and Study was somnolence (10% for DAYVIGO 10 mg, 7% for DAYVIGO mg, and 1% for placebo). Table presents the adverse reactions based on the pooled data from the first 30 days of Study (6-month controlled efficacy trial) and Study (1-month controlled efficacy trial) where the incidence was >=2% in DAYVIGO-treated patients and greater than in placebo-treated patients.Table 1: Adverse Reactions Reported in >=2% of DAYVIGO-Treated Patients and at Greater Frequency than Placebo-Treated Patients During the First 30 Days of Study and Study 2DAYVIGOPlacebo5 mg10 mgn=528n=580n=582(%)(%)(%)Somnolence or fatigue 1.36.99.6Headache3.45.94.5Nightmare or abnormal dreams0.90.92.2Combines preferred terms somnolence, lethargy, fatigue, sluggishnessOther Adverse Reactions Observed During Clinical Trials (Studies and 2)Other adverse reactions of <2% incidence but greater than placebo are shown below. The following list does not include adverse reactions 1) for which drug cause was remote, 2) that were so general to be uninformative, or 3) that were not considered to have clinically significant implications.Sleep paralysis was reported in 1.6% and 1.3% of patients receiving DAYVIGO 10 mg and mg, respectively, compared to no reports for placebo. Hypnagogic hallucinations were reported in 0.7% and 0.1% of patients receiving DAYVIGO 10 mg and mg, respectively, compared to no reports for placebo [see Warnings and Precautions 5.2 )]. Two events of complex sleep behavior were reported, both in patients receiving DAYVIGO 10 mg [see Warnings and Precautions 5.3 )]. Sleep paralysis was reported in 1.6% and 1.3% of patients receiving DAYVIGO 10 mg and mg, respectively, compared to no reports for placebo. Hypnagogic hallucinations were reported in 0.7% and 0.1% of patients receiving DAYVIGO 10 mg and mg, respectively, compared to no reports for placebo [see Warnings and Precautions 5.2 )]. Two events of complex sleep behavior were reported, both in patients receiving DAYVIGO 10 mg [see Warnings and Precautions 5.3 )].

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. 8.1 Pregnancy Pregnancy Exposure Registry There is pregnancy exposure registry that monitors pregnancy outcomes in women who are exposed to DAYVIGO during pregnancy. Healthcare providers are encouraged to register patients in the DAYVIGO pregnancy registry by calling 1-888-274-2378.Risk SummaryThere are no available data on DAYVIGO use in pregnant women to evaluate for drug-associated risks of major birth defects, miscarriage or adverse maternal or fetal outcomes.In animal reproduction studies, oral administration of lemborexant to pregnant rats and rabbits during the period of organogenesis caused toxicities only at high multiples of the human exposure at the maximum recommended human dose (MRHD) based on AUC. The no observed adverse effect levels (NOAEL) are approximately >100 and 23 times the MRHD based on AUC in rats and rabbits, respectively. Similarly, oral administration of lemborexant to pregnant and lactating rats caused toxicities only at high multiples of the human exposure at the MRHD based on AUC. The NOAEL is 93 times the MRHD based on AUC see Data . The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risks of major birth defects and miscarriage in clinically recognized pregnancies are 2% to 4% and 15% to 20%, respectively.DataAnimal DataLemborexant was administered orally to pregnant rats during the period of organogenesis in studies at doses of 60, 200, and 600 mg/kg/day or 20, 60, and 200 mg/kg/day, which are approximately to >300 times the MRHD based on AUC. Lemborexant caused maternal toxicity, manifested by decreased body weight and food consumption, decreased mean fetal body weight, an increased number of dead fetuses, and skeletal, external and visceral malformations (omphalocele, cleft palate, and membranous ventricular septal defect) at >300 times the MRHD based on AUC. The NOAEL of 200 mg/kg/day is approximately 143 times the MRHD based on AUC. Lemborexant was administered orally to pregnant rabbits during the period of organogenesis at doses of 10, 30, and 100 mg/kg/day, which are approximately to 139 times the MRHD based on AUC. Lemborexant caused maternal toxicity that consisted of decreased body weight and food consumption and higher incidence of skeletal variations (presence of cervical ribs and supernumerary lung lobes) at approximately 139 times the MRHD based on AUC. The NOAEL of 30 mg/kg/day is approximately 23 times the MRHD based on AUC.Lemborexant was administered orally to pregnant rats during pregnancy and lactation at doses of 30, 100, and 300 mg/kg/day, which are approximately 15 to 206 times the MRHD based on AUC. Lemborexant caused maternal toxicity that consisted of decreased body weight and food consumption and toxicity to offspring consisting of decreased pup body weights, decreased femur length, and decreased acoustic startle responses at 206 times the MRHD based on AUC. The NOAEL of 100 mg/kg/day is approximately 93 times the MRHD based on AUC.. 8.2 Lactation. Risk SummaryThere are no data on the presence of lemborexant in human milk, the effects on the breastfed infant, or the effects on milk production. Lemborexant and its metabolites are present in the milk of lactating rats. When drug is present in animal milk, it is likely that the drug will be present in human milk. Infants exposed to DAYVIGO through breastmilk should be monitored for excessive sedation. The developmental and health benefits of breastfeeding should be considered along with the mothers clinical need for DAYVIGO and any potential adverse effects on the breastfed infant from DAYVIGO or from the underlying maternal condition.. 8.4 Pediatric Use. The safety and effectiveness of DAYVIGO have not been established in pediatric patients.. 8.5 Geriatric Use. Of the total number of patients treated with DAYVIGO (n=1418) in controlled Phase studies, 491 patients were 65 years and over, and 87 patients were 75 years and over. Overall, efficacy results for patients <65 years of age were similar compared to patients >=65 years. In pooled analysis of Study (the first 30 days) and Study 2, the incidence of somnolence in patients >=65 years with DAYVIGO 10 mg was higher (9.8%) compared to 7.7% in patients <65 years. The incidence of somnolence with DAYVIGO mg was similar in patients >=65 years (4.9%) and <65 years (5.1%). The incidence of somnolence in patients treated with placebo was 2% or less regardless of age [see Clinical Studies 14.2 )]. Because DAYVIGO can increase somnolence and drowsiness, patients, particularly the elderly, are at higher risk of falls [see Warning and Precautions 5.1 )]. Exercise caution when using doses higher than mg in patients >=65 years old. 8.6 Renal Impairment. No dose adjustment is required in patients with mild, moderate, or severe renal impairment. DAYVIGO exposure (AUC) was increased in patients with severe renal impairment. Patients with severe renal impairment may experience an increased risk of somnolence [see Clinical Pharmacology 12.3 )]. 8.7 Hepatic Impairment. DAYVIGO has not been studied in patients with severe hepatic impairment. Use in this population is not recommended [see Dosage and Administration 2.3 ), Clinical Pharmacology 12.3 )]. DAYVIGO exposure (AUC and Cmax) and terminal half-life were increased in patients with moderate hepatic impairment (Child-Pugh class B). Dosage adjustment is recommended in patients with moderate hepatic impairment (Child-Pugh class B) [see Dosage and Administration 2.3 ), Clinical Pharmacology 12.3 )]. DAYVIGO exposure (AUC) was increased in patients with mild hepatic impairment (Child-Pugh class A), but the terminal half-life was not changed. Patients with mild hepatic impairment may experience an increased risk of somnolence [see Clinical Pharmacology 12.3 )]. 8.8 Patients with Compromised Respiratory Function. In study of patients with mild OSA (apnea-hypopnea index <15 events per hour of sleep), DAYVIGO did not increase the frequency of apneic events or cause oxygen desaturation. DAYVIGO has not been studied in patients with COPD or moderate to severe OSA. Clinically meaningful respiratory effects of DAYVIGO in COPD or moderate to severe OSA cannot be excluded [see Warnings and Precautions 5.4 )].

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS. CNS Depressant Effects and Daytime Impairment: Impairs alertness and motor coordination including morning impairment. Risk increases with dose and use with other central nervous system (CNS) depressants. For patients taking DAYVIGO 10 mg, caution against next-day driving and other activities requiring complete mental alertness. (5.1) Sleep Paralysis, Hypnagogic/Hypnopompic Hallucinations, and Cataplexy-like Symptoms: May occur with use of DAYVIGO. (5.2) Complex Sleep Behaviors: Behaviors including sleep-walking, sleep-driving, and engaging in other activities while not fully awake may occur. Discontinue immediately if complex sleep behavior occurs. (5.3) Compromised Respiratory Function: Effect on respiratory function should be considered. (5.4, 8.8) Worsening of Depression/Suicidal Ideation: Worsening of depression or suicidal thinking may occur. Prescribe the lowest number of tablets feasible to avoid intentional overdosage. (5.5) Need to Evaluate for Co-morbid Diagnoses: Reevaluate if insomnia persists after to 10 days of treatment. (5.6). CNS Depressant Effects and Daytime Impairment: Impairs alertness and motor coordination including morning impairment. Risk increases with dose and use with other central nervous system (CNS) depressants. For patients taking DAYVIGO 10 mg, caution against next-day driving and other activities requiring complete mental alertness. (5.1) Sleep Paralysis, Hypnagogic/Hypnopompic Hallucinations, and Cataplexy-like Symptoms: May occur with use of DAYVIGO. (5.2) Complex Sleep Behaviors: Behaviors including sleep-walking, sleep-driving, and engaging in other activities while not fully awake may occur. Discontinue immediately if complex sleep behavior occurs. (5.3) Compromised Respiratory Function: Effect on respiratory function should be considered. (5.4, 8.8) Worsening of Depression/Suicidal Ideation: Worsening of depression or suicidal thinking may occur. Prescribe the lowest number of tablets feasible to avoid intentional overdosage. (5.5) Need to Evaluate for Co-morbid Diagnoses: Reevaluate if insomnia persists after to 10 days of treatment. (5.6). 5.1 CNS Depressant Effects and Daytime Impairment. DAYVIGO is central nervous system (CNS) depressant that can impair daytime wakefulness even when used as prescribed. CNS depressant effects may persist in some patients for up to several days after discontinuing DAYVIGO. Prescribers should advise patients about the potential for next-day somnolence. Driving ability was impaired in some subjects taking DAYVIGO 10 mg [see Clinical Studies 14.2 )]. The risk of daytime impairment is increased if DAYVIGO is taken with less than full night of sleep remaining or if higher than recommended dose is taken [see Dosage and Administration 2.1 )]. If DAYVIGO is taken in these circumstances, patients should be cautioned against driving and other activities requiring complete mental alertness.Co-administration with other CNS depressants (e.g., benzodiazepines, opioids, tricyclic antidepressants, alcohol) increases the risk of CNS depression, which can cause daytime impairment. Dosage adjustments of DAYVIGO and of concomitant CNS depressants may be necessary when administered together because of potentially additive effects. The use of DAYVIGO with other drugs to treat insomnia is not recommended. Patients should be advised not to consume alcohol in combination with DAYVIGO because of additive effects [see Drug Interactions 7.1 )]. Because DAYVIGO can cause drowsiness, patients, particularly the elderly, are at higher risk of falls.. 5.2 Sleep Paralysis, Hypnagogic/Hypnopompic Hallucinations, and Cataplexy-like Symptoms. Sleep paralysis, an inability to move or speak for up to several minutes during sleep-wake transitions, and hypnagogic/hypnopompic hallucinations, including vivid and disturbing perceptions, can occur with the use of DAYVIGO. Prescribers should explain the nature of these events to patients when prescribing DAYVIGO. Symptoms similar to mild cataplexy can occur with DAYVIGO. Such symptoms can include periods of leg weakness lasting from seconds to few minutes, can occur either at night or during the day, and may not be associated with an identified triggering event (e.g., laughter or surprise).. 5.3 Complex Sleep Behaviors Complex sleep behaviors, including sleep-walking, sleep-driving, and engaging in other activities while not fully awake (e.g., preparing and eating food, making phone calls, having sex), have been reported to occur with the use of hypnotics such as DAYVIGO. These events can occur in hypnotic-naive as well as in hypnotic-experienced persons. Patients usually do not remember these events. Complex sleep behaviors may occur following the first or any subsequent use of DAYVIGO, with or without the concomitant use of alcohol and other CNS depressants [see Drug Interactions 7.1 )]. Discontinue DAYVIGO immediately if patient experiences complex sleep behavior.. 5.4 Patients with Compromised Respiratory Function The effect of DAYVIGO on respiratory function should be considered if prescribed to patients with compromised respiratory function. DAYVIGO has not been studied in patients with moderate to severe obstructive sleep apnea (OSA) or in patients with chronic obstructive pulmonary disease (COPD) [see Use in Special Populations 8.8 )]. 5.5 Worsening of Depression/Suicidal Ideation. In clinical studies of DAYVIGO in patients with insomnia, the incidence of suicidal ideation or any suicidal behavior, as assessed by questionnaire, was higher in patients receiving DAYVIGO than in those receiving placebo (0.3% for DAYVIGO 10 mg, 0.4% for DAYVIGO mg, and 0.2% for placebo).In primarily depressed patients treated with hypnotics, worsening of depression and suicidal thoughts and actions (including completed suicides) have been reported. Suicidal tendencies may be present in such patients and protective measures may be required. Intentional overdose is more common in this group of patients; therefore, the lowest number of tablets that is feasible should be prescribed at any one time. The emergence of any new behavioral sign or symptom of concern requires careful and immediate evaluation.. 5.6 Need to Evaluate for Co-morbid Diagnoses. Because sleep disturbances may be the presenting manifestation of medical and/or psychiatric disorder, treatment of insomnia should be initiated only after careful evaluation of the patient. The failure of insomnia to remit after to 10 days of treatment may indicate the presence of primary psychiatric and/or medical illness that should be evaluated. Worsening of insomnia or the emergence of new cognitive or behavioral abnormalities may be the result of an unrecognized underlying psychiatric or medical disorder and can emerge during the course of treatment with sleep-promoting drugs such as DAYVIGO.

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. Figure 1. Effects of Hepatic and Renal Impairment on Lemborexant Pharmacokinetics. Figure 2. Effects of Co-administered Drugs on the Pharmacokinetics of Lemborexant 10 mg. Figure 3. Effects of Lemborexant 10 mg on the Pharmacokinetics of Co-Administered Drugs. 12.1 Mechanism of Action. The mechanism of action of lemborexant in the treatment of insomnia is presumed to be through antagonism of orexin receptors. The orexin neuropeptide signaling system plays role in wakefulness. Blocking the binding of wake-promoting neuropeptides orexin and orexin to receptors OX1R and OX2R is thought to suppress wake drive.. 12.2 Pharmacodynamics. Lemborexant binds to orexin receptors OX1R and OX2R and acts as competitive antagonist (IC50 values of 6.1 nM and 2.6 nM, respectively). major metabolite of lemborexant, M10, binds with comparable affinity as the parent drug to orexin receptors OX1R and OX2R (IC50 values of 4.2 nM and 2.9 nM), respectively.Cardiac ElectrophysiologyIn concentration-QTcF analysis using the data from two randomized, double-blind, placebo-controlled, multiple ascending dose studies in healthy subjects, lemborexant does not prolong the QTcF interval to any clinically relevant extent at dose times the maximum recommended dose.Drug Interactions Lemborexant co-administered with alcohol produced numerically greater negative impact on postural stability and memory as compared with alcohol alone at approximately hours post-dose [see Drug Interactions 7.1 ]. 12.3 Pharmacokinetics. Following single doses of lemborexant 2.5 to 75 mg, geometric mean Cmax and AUC0-24h increased slightly less than in proportion to dose. The extent of accumulation of lemborexant at steady-state is 1.5- to 3-fold across this dose range. AbsorptionThe time to peak concentration (tmax) of lemborexant is approximately to hours.Effect of FoodLemborexant Cmax decreased by 23%, AUC0-inf increased by 18%, and tmax was delayed by hours following administration of high-fat and high-calorie meal (containing approximately 150, 250, and 500 to 600 calories from protein, carbohydrate, and fat, respectively).DistributionThe volume of distribution of lemborexant is 1970 L. Protein binding of lemborexant is approximately 94% in vitro. The blood to plasma concentration ratio of lemborexant is 0.65.EliminationMetabolismLemborexant is primarily metabolized by CYP3A4, and to lesser extent by CYP3A5. The major circulating metabolite is M10. ExcretionFollowing administration of an oral dose, 57.4% of the dose was recovered in the feces and 29.1% in the urine (<1% as unchanged). The effective half-life for lemborexant mg and 10 mg is 17 and 19 hours, respectively. Specific PopulationsNo clinically significant differences in the pharmacokinetics of lemborexant were observed based on age, sex, race/ethnicity, or body mass index. No studies have been conducted to investigate the pharmacokinetics of lemborexant in pediatric patients. Exposures of lemborexant in patients with hepatic and renal impairment are summarized in Figure 1.Figure 1. Effects of Hepatic and Renal Impairment on Lemborexant PharmacokineticsDrug Interaction StudiesThe effects of other drugs on the exposures of lemborexant are summarized in Figure 2. The effects of lemborexant on the exposures of other drugs are summarized in Figure 3. Physiologically-based pharmacokinetic (PBPK) modeling predicted that concomitant use of weak CYP3A inhibitors increased lemborexant exposure by less than 2-fold. Based on these results, drug interactions between lemborexant and strong CYP3A inducers, strong CYP3A inhibitors, moderate CYP3A inhibitors, and CYP2B6 substrates are clinically significant. Figure 2. Effects of Co-administered Drugs on the Pharmacokinetics of Lemborexant 10 mg Figure 3. Effects of Lemborexant 10 mg on the Pharmacokinetics of Co-Administered DrugsIn Vitro Studies In vitro metabolism studies demonstrated that lemborexant and M10 have the potential to induce CYP3A and the weak potential to inhibit CYP3A and induce CYP2B6. Lemborexant and M10 do not inhibit other CYP isoforms (CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2D6, CYP2A6, CYP2C19, and CYP2E1) or transporters (P-gp, BCRP, BSEP, OAT1, OAT3, OATP1B1, OATP1B3, OCT1, OCT2, MATE1, and MATE2-K). Lemborexant is potential poor substrate of P-gp, but M10 is substrate of P-gp. Lemborexant and M10 are not substrates of BCRP, OATP1B1, or OATP1B3.

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES. 14.1 Controlled Clinical Studies. DAYVIGO was evaluated in two clinical trials in patients with insomnia characterized by difficulties with sleep onset and/or sleep maintenance (Study 1, NCT02952820 and Study 2, NCT02783729). Study was 6-month, randomized, double-blind, placebo-controlled, multi-center trial in adult patients age 18 or older who met DSM-5 criteria for insomnia disorder. Patients were randomized to placebo (n=325), DAYVIGO mg (n=323), or DAYVIGO 10 mg (n=323) once nightly. The primary efficacy endpoint was the mean change from baseline to end of treatment at months for log-transformed patient-reported (subjective) sleep onset latency (sSOL), defined as the estimated minutes from the time that the patient attempted to sleep until sleep onset. Pre-specified secondary efficacy endpoints for sleep maintenance were change from baseline to end of treatment at months for patient-reported sleep efficiency (sSEF) and wake after sleep onset (sWASO). sSEF is defined as the proportion of time spent asleep per time in bed. sWASO is defined as the minutes of wake from the onset of sleep until wake time. The primary and pre-specified secondary efficacy endpoints were measured by sleep diary. The demographic characteristics of patients in Study were similar across the treatment arms. Patients had median age of 55 years (range 18 to 88) and were 68% female, 72% White, 8% Black or African American, 17% Japanese, and 3.5% other; 28% were elderly (>=65 years).Examination of subgroups by age, race, and sex did not suggest differences in response to DAYVIGO. In Study 1, DAYVIGO mg and 10 mg demonstrated statistically significant superiority on the primary efficacy measure, sSOL, compared to placebo (Table 3). DAYVIGO mg and 10 mg also showed statistically significant superiority in sSEF and sWASO.Table 3: Primary and Secondary Efficacy Results for Change from Baseline in Sleep Onset and Sleep Maintenance at Months in Patients with Insomnia (Study 1)EndpointTreatment GroupNumber of PatientsITTBaseline Meana(SD)Month 6LS Meana(SE)Treatment Effect(95% CI)Sleep OnsetsSOL(minutes)DAYVIGO mg 31643.0 (31.5)20.0 (1.1)0.7 (0.6, 0.8)DAYVIGO 10 mg 31545.0 (33.4)19.2 (1.1)0.7 (0.6, 0.8)Placebo31845.0 (31.8)27.3 (1.4)(ratio vs placebo)b Sleep MaintenancesSEF(%)DAYVIGO mg 31663.1 (18.2)75.9 (0.9)4.5 (2.2, 6.9)DAYVIGO 10 mg 31562.0 (17.2)75.9 (0.9)4.7 (2.4, 7.0)Placebo31861.3 (17.8)71.4 (0.8)(%)c Sleep MaintenancesWASO(minutes)DAYVIGO mg 316132.8 (82.5)87.9 (3.7)-17.5 (-27.3, -7.6)DAYVIGO 10 mg 315136.8 (87.4)92.7 (3.7)-12.7 (-22.4, -3.0)Placebo318132.5 (80.2)105.3 (3.6)(minutes)c ITT (intention to treat); sSOL (subjective sleep onset latency); SD (standard deviation); LS (least squares); SE (standard error); CI (unadjusted confidence interval); sSEF (subjective sleep efficiency); sWASO (subjective wake after sleep onset) For the sleep onset sSOL endpoint, the mean refers to geometric mean, which was used due to the approximately log normal distribution of the outcomes; SD for the geometric mean is calculated as GMSD (log transformed sSOL); SE for the least squares geometric mean is calculated in the same way as the SD. For the sleep onset sSOL endpoint, treatment effect refers to the ratio of [Month sSOL Baseline sSOL] for DAYVIGO versus placebo, such that smaller ratio corresponds to greater improvement. Treatment effect refers to the treatment difference between DAYVIGO versus placebo, such that larger value for sSEF and smaller value for sWASO correspond to greater improvement. Doses that were statistically significantly superior (p<0.05) to placebo after multiplicity adjustment.Study was 1-month, randomized, double-blind, placebo- and active-controlled, multi-center, parallel-group clinical trial in adult female patients age 55 and older and male patients 65 years and older who met DSM-5 criteria for insomnia disorder. Patients were randomized to placebo (n=208), DAYVIGO mg (n=266) or 10 mg (n=269), or active comparator (n=263) once nightly.The primary efficacy endpoint was the mean change in log-transformed latency to persistent sleep (LPS) from baseline to end of treatment (Days 29/30), as measured by overnight polysomnography (PSG) monitoring. LPS was defined as the number of minutes from lights off to the first 10 consecutive minutes of non-wakefulness. The pre-specified secondary efficacy endpoints in Study were the mean change from baseline to end of treatment (Days 29/30) in sleep efficiency (SEF) and wake after sleep onset (WASO) measured by PSG. The demographic and baseline characteristics of patients in Study were similar across the treatment arms. Patients had median age of 63 years (range 55 to 88) and were 86% female, 72% White, 25% Black or African American, and 2% other; 45% were elderly (>=65 years).In Study 2, DAYVIGO mg and 10 mg demonstrated statistically significant superiority on the primary efficacy measure, LPS, compared to placebo (Table 4). DAYVIGO mg and 10 mg demonstrated statistically significant improvement in SEF and WASO compared to placebo.Table 4: Primary and Secondary Efficacy Results for Change from Baseline in Sleep Onset and Sleep Maintenance at Month in Patients with Insomnia (Study 2)EndpointTreatment GroupNumber of PatientsITTBaseline Meana(SD)Day 29/30LS Meana(SE)Treatment Effect(95% CI)Sleep OnsetLPS(minutes)DAYVIGO mg 26633.0 (27.2) 15.5 (0.8)0.8 (0.7, 0.9)DAYVIGO 10 mg 26933.3 (27.2)14.5 (0.7)0.7 (0.6, 0.8)Placebo20833.6 (25.9)20.0 (1.1)(ratio vs. placebo)b Sleep MaintenanceSEF(%)DAYVIGO mg 26668.4 (11.3)80.7 (0.5)7.1 (5.6, 8.5)DAYVIGO 10 mg 26967.8 (10.8)82.7 (0.5)8.0 (6.6, 9.5)Placebo20868.9 (9.6)74.6 (0.6)(%)c Sleep MaintenanceWASO(minutes)DAYVIGO mg 266113.4 (39.0)68.3 (2.2)-24.0 (-30.0, -18.0)DAYVIGO 10 mg 269114.8 (40.0)66.9 (2.2)-25.3 (-31.4, -19.3)Placebo208111.7 (37.2)92.2 (2.5)(minutes)c ITT (intention to treat); LPS (latency to persistent sleep); SD (standard deviation); LS (least squares); SE (standard error); CI (unadjusted confidence interval); SEF (sleep efficiency); WASO (wake after sleep onset) For the sleep onset LPS endpoint, the mean refers to geometric mean, which was used due to the approximately log normal distribution of the outcomes; SD for the geometric mean is calculated as GMSD (log transformed LPS); SE for the least squares geometric mean is calculated in the same way as the SD. For the LPS endpoint, treatment effect refers to the ratio of [Day 29/30 LPS Baseline LPS] for DAYVIGO versus placebo, such that smaller ratio corresponds to greater improvement. Treatment effect refers to the treatment difference between DAYVIGO versus placebo, such that larger value for SEF and smaller value for WASO correspond to greater improvement. Doses that were statistically significantly superior (p<0.05) to placebo after multiplicity adjustment.The effects of DAYVIGO at the beginning of treatment were generally consistent with later timepoints.. 14.2 Special Safety Studies. Middle of the Night Safety The effect of DAYVIGO on middle of the night safety was evaluated in randomized, placebo- and active-controlled trial in healthy female subjects >=55 years or male subjects >=65 years. Postural stability, the ability to awaken in response to sound stimulus, and attention and memory were assessed following scheduled awakening hours after the start of the 8-hour time in bed. Postural stability was measured by assessing body sway using an ataxia meter. Nighttime dosing of DAYVIGO mg and 10 mg resulted in impairment of balance (measured by body sway area) at hours as compared to placebo.The ability to awaken to sound in the middle of the night was assessed using an audiometer that delivered 1000 Hz tones up to 105 dB. There were no meaningful differences between DAYVIGO (5 mg or 10 mg) and placebo on ability to awaken to sound.A computerized performance assessment battery was administered to assess attention and memory after middle of the night awakening (4 hours postdose) in subjects receiving DAYVIGO mg or 10 mg. DAYVIGO was associated with dose-dependent worsening on measures of attention and memory as compared to placebo.Patients should be cautioned about the potential for middle of the night postural instability, as well as attention and memory impairment.Effects on Next-day Postural Stability and MemoryThe effects of DAYVIGO on next day postural stability and memory were evaluated in two randomized, placebo- and active-controlled trials in healthy subjects and insomnia patients age 55 and older.There were no meaningful differences between DAYVIGO (5 mg or 10 mg) and placebo on next-day postural stability or memory compared to placebo.Effects on DrivingA randomized, double-blind, placebo- and active-controlled, four-period crossover study evaluated the effects of nighttime administration of DAYVIGO on next-morning driving performance approximately hours after dosing in 24 healthy elderly subjects (>=65 years, median age 67 years; 14 men, 10 women) and 24 adult subjects (median age 49 years; 12 men, 12 women). The primary driving performance outcome measure was change in Standard Deviation of Lateral Position (SDLP). Testing was conducted after one night (a single dose) and after eight consecutive nights of treatment with DAYVIGO. Although DAYVIGO at doses of mg and 10 mg did not cause statistically significant impairment in next-morning driving performance in adult or elderly subjects (compared with placebo), driving ability was impaired in some subjects taking 10 mg DAYVIGO. Patients using the 10 mg dose should be cautioned about the potential for next-morning driving impairment because there is individual variation in sensitivity to DAYVIGO.Rebound InsomniaRebound insomnia was assessed by comparing sleep diary-recorded sSOL and sWASO from the screening period to the two weeks following treatment discontinuation in both Studies and 2. Analyses of group means and the proportion of patients with rebound insomnia suggest that DAYVIGO was not associated with rebound insomnia following treatment discontinuation.Withdrawal EffectsIn 12-month and 1-month controlled safety and efficacy trials (Studies and 2, respectively), withdrawal effects were assessed by the Tyrer Benzodiazepine Withdrawal Symptom Questionnaire following discontinuation from study drug in patients who received DAYVIGO mg or 10 mg. There was no evidence of withdrawal effects following DAYVIGO discontinuation at either dose.

CLINICAL TRIALS EXPERIENCE SECTION.

6.1 Clinical 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 practice.The safety of DAYVIGO was evaluated in 1418 adult patients with insomnia disorder (age 18 to 88 years) from two controlled efficacy trials (Study and Study 2). Study was 6-month placebo-controlled trial assessing DAYVIGO or 10 mg once nightly, followed by 6-month parallel-group extension period in which patients initially treated with DAYVIGO continued on the same dose, and patients who received placebo were re-randomized to receive DAYVIGO or 10 mg once nightly. In Study 1, 434 patients were treated with DAYVIGO for one year. Study was 30-day placebo- and active-controlled trial assessing DAYVIGO or 10 mg once nightly.Adverse Reactions Resulting in Discontinuation of TreatmentThe frequencies of discontinuation due to adverse reactions in Study (the first 30 days) and Study were 2.6% and 1.4% for patients treated with 10 mg and mg DAYVIGO, respectively, compared to 1.5% for patients in the placebo group. The most common adverse reactions leading to discontinuation of DAYVIGO were somnolence (1.0% for 10 mg, 0.7% for mg, and 0.4% for placebo) and nightmares (0.3% for 10 mg, 0.3% for mg, and 0% for placebo).The frequencies of discontinuation due to adverse reactions in the 6-month placebo-controlled period of Study were 8.3% and 4.1% for patients treated with DAYVIGO 10 mg and mg, respectively, compared to 3.8% for patients in the placebo group. The most common reasons for discontinuation of DAYVIGO and occurring in more than one patient within treatment arm were somnolence (2.9% for 10 mg, 1.0% for mg, and 0.6% for placebo), nightmares (1.3% for 10 mg, 0.3% for mg, and 0% for placebo), and palpitations (0.6% for 10 mg, 0% for mg, and 0% for placebo). Most Common Adverse Reactions The most common adverse reaction (reported in 5% or more of patients treated with DAYVIGO and at least twice the rate of placebo) in Study (the first 30 days) and Study was somnolence (10% for DAYVIGO 10 mg, 7% for DAYVIGO mg, and 1% for placebo). Table presents the adverse reactions based on the pooled data from the first 30 days of Study (6-month controlled efficacy trial) and Study (1-month controlled efficacy trial) where the incidence was >=2% in DAYVIGO-treated patients and greater than in placebo-treated patients.Table 1: Adverse Reactions Reported in >=2% of DAYVIGO-Treated Patients and at Greater Frequency than Placebo-Treated Patients During the First 30 Days of Study and Study 2DAYVIGOPlacebo5 mg10 mgn=528n=580n=582(%)(%)(%)Somnolence or fatigue 1.36.99.6Headache3.45.94.5Nightmare or abnormal dreams0.90.92.2Combines preferred terms somnolence, lethargy, fatigue, sluggishnessOther Adverse Reactions Observed During Clinical Trials (Studies and 2)Other adverse reactions of <2% incidence but greater than placebo are shown below. The following list does not include adverse reactions 1) for which drug cause was remote, 2) that were so general to be uninformative, or 3) that were not considered to have clinically significant implications.Sleep paralysis was reported in 1.6% and 1.3% of patients receiving DAYVIGO 10 mg and mg, respectively, compared to no reports for placebo. Hypnagogic hallucinations were reported in 0.7% and 0.1% of patients receiving DAYVIGO 10 mg and mg, respectively, compared to no reports for placebo [see Warnings and Precautions 5.2 )]. Two events of complex sleep behavior were reported, both in patients receiving DAYVIGO 10 mg [see Warnings and Precautions 5.3 )]. Sleep paralysis was reported in 1.6% and 1.3% of patients receiving DAYVIGO 10 mg and mg, respectively, compared to no reports for placebo. Hypnagogic hallucinations were reported in 0.7% and 0.1% of patients receiving DAYVIGO 10 mg and mg, respectively, compared to no reports for placebo [see Warnings and Precautions 5.2 )]. Two events of complex sleep behavior were reported, both in patients receiving DAYVIGO 10 mg [see Warnings and Precautions 5.3 )].

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION. Recommended dose is mg taken no more than once per night, immediately before going to bed, with at least hours remaining before the planned time of awakening. Dosage may be increased to 10 mg based on clinical response and tolerability. (2.1) The maximum recommended dose is 10 mg once daily. (2.1) Time to sleep onset may be delayed if taken with or soon after meal. (2.1) Hepatic Impairment: (2.3) Moderate hepatic impairment: Initial and maximum recommended dosage is mg no more than once per night. Severe hepatic impairment: Not recommended.. Recommended dose is mg taken no more than once per night, immediately before going to bed, with at least hours remaining before the planned time of awakening. Dosage may be increased to 10 mg based on clinical response and tolerability. (2.1) The maximum recommended dose is 10 mg once daily. (2.1) Time to sleep onset may be delayed if taken with or soon after meal. (2.1) Hepatic Impairment: (2.3) Moderate hepatic impairment: Initial and maximum recommended dosage is mg no more than once per night. Severe hepatic impairment: Not recommended.. 2.1 Dosing Information. The recommended dosage of DAYVIGO is mg taken no more than once per night, immediately before going to bed, with at least hours remaining before the planned time of awakening. The dose may be increased to the maximum recommended dose of 10 mg based on clinical response and tolerability. Time to sleep onset may be delayed if taken with or soon after meal [see Clinical Pharmacology 12.3 )]. 2.2 Dosage Recommendations for Concomitant Use with CYP3A Inhibitors or CYP3A Inducers Co-administration with Strong or Moderate CYP3A InhibitorsAvoid concomitant use of DAYVIGO with strong or moderate CYP3A inhibitors [see Drug Interactions 7.1 ), Clinical Pharmacology 12.3 )]. Co-administration with Weak CYP3A InhibitorsThe maximum recommended dosage of DAYVIGO is mg no more than once per night when co-administered with weak CYP3A inhibitors [see Drug Interactions 7.1 ), Clinical Pharmacology 12.3 )]. Co-administration with Strong or Moderate CYP3A InducersAvoid concomitant use of DAYVIGO with strong or moderate CYP3A inducers [see Drug Interactions 7.1 ), Clinical Pharmacology 12.3 )]. 2.3 Dosage Recommendations for Patients with Hepatic Impairment The maximum recommended dose of DAYVIGO is mg no more than once per night in patients with moderate hepatic impairment [see Use in Specific Populations 8.7 ), Clinical Pharmacology 12.3 )]. DAYVIGO is not recommended in patients with severe hepatic impairment [see Use in Specific Populations 8.7 )].

DRUG INTERACTIONS SECTION.

7 DRUG INTERACTIONS. Strong or moderate CYP3A inhibitors: Avoid concomitant use. (7.1) Weak CYP3A inhibitors: The maximum recommended dose is mg. (2.2, 7.1) Strong or moderate CYP3A inducers: Avoid concomitant use. (7.1) Strong or moderate CYP3A inhibitors: Avoid concomitant use. (7.1) Weak CYP3A inhibitors: The maximum recommended dose is mg. (2.2, 7.1) Strong or moderate CYP3A inducers: Avoid concomitant use. (7.1). 7.1 Drugs Having Clinically Important Interactions with DAYVIGO. Table 2: Clinically Important Drug Interactions with DAYVIGOEffect of Other Drugs on DAYVIGOStrong, Moderate, and Weak CYP3A InhibitorsClinical Impact:Concomitant use with strong, moderate, or weak CYP3A inhibitor increases lemborexant AUC and Cmax which may increase the risk of DAYVIGO adverse reactions [see Clinical Pharmacology 12.3 )]. Intervention:Avoid concomitant use of DAYVIGO with strong or moderate CYP3A inhibitors [see Dosage and Administration 2.2 )]. The maximum recommended dose of DAYVIGO with weak CYP3A inhibitors is mg [see Dosage and Administration 2.2 )]. Examples:Strong CYP3A inhibitors: itraconazole, clarithromycinModerate CYP3A inhibitors: fluconazole, verapamilWeak CYP3A inhibitors: chlorzoxazone, ranitidineStrong and Moderate CYP3A InducersClinical Impact:Concomitant use with strong or moderate CYP3A inducer decreases lemborexant exposure, which may reduce DAYVIGO efficacy [see Clinical Pharmacology 12.3 )]. Intervention:Avoid concomitant use of DAYVIGO with strong or moderate CYP3A inducers [see Dosage and Administration 2.2 )]. Examples:Strong CYP3A inducers: rifampin, carbamazepine, St. Johns wortModerate CYP3A inducers: bosentan, efavirenz, etravirine, modafinilAlcoholClinical Impact:Concomitant use of alcohol increases lemborexant Cmax and AUC. Co-administration of DAYVIGO with alcohol produced numerically greater negative impact on postural stability and memory as compared with alcohol alone when assessed near the tmax of DAYVIGO (2 hours post-dose) [see Clinical Pharmacology 12.2 )]. Intervention:Avoid alcohol consumption with DAYVIGO [see Warnings and Precautions 5.1 )]. Effect of DAYVIGO on Other Drugs CYP2B6 SubstratesClinical Impact:Concomitant use of DAYVIGO decreases the AUC of drugs that are CYP2B6 substrates, which may result in reduced efficacy for these concomitant medications [see Clinical Pharmacology 12.3 )]. Intervention:Patients receiving DAYVIGO and CYP2B6 substrates concurrently should be monitored for adequate clinical response. Increasing the doses of CYP2B6 substrates may be considered as needed.Examples:Bupropion, methadone.

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION. Advise the patient to read the FDA-approved patient labeling (Medication Guide).Administration Instructions Advise patients to take DAYVIGO only when preparing for or getting into bed and only if they can stay in bed for full night (at least hours) before being active again [see Dosage and Administration 2.1)]. Advise patients that the effect of DAYVIGO may be delayed if taken with or soon after meal [see Dosage and Administration 2.1 ), Clinical Pharmacology 12.3 )].CNS Depressant Effects and Daytime ImpairmentAdvise patients that DAYVIGO can impair daytime wakefulness even when used as prescribed. The risk of daytime impairment is increased if DAYVIGO is taken with less than full night of sleep remaining or if higher than recommended dose is taken. If DAYVIGO is taken in these circumstances, caution patients against driving and other activities requiring complete mental alertness. Advise patients that increased drowsiness may increase the risk of falls in some patients [see Warnings and Precautions 5.1 )]. Sleep Paralysis, Hypnagogic/Hypnopompic Hallucinations, and Cataplexy-Like SymptomsAdvise patients and their families that DAYVIGO may cause sleep paralysis, which is an inability to move or speak for several minutes during sleep-wake transitions, despite being aware of surroundings; hypnagogic/hypnopompic hallucinations, including vivid and disturbing perceptions; and symptoms similar to mild cataplexy [see Warnings and Precautions 5.2 )]. Complex Sleep Behaviors Instruct patients and their families that DAYVIGO may cause complex sleep behaviors, including sleep-walking, sleep-driving, preparing and eating food, making phone calls, or having sex while not being fully awake. Tell patients to discontinue DAYVIGO and notify their healthcare provider immediately if they develop any of these symptoms [see Warnings and Precautions 5.3 )]. Worsening of Depression/Suicidal IdeationTell patients to report any worsening of depression or suicidal thoughts immediately [see Warnings and Precautions 5.4 )]. PregnancyAdvise patients that there is pregnancy exposure registry that monitors pregnancy outcomes in women exposed to DAYVIGO during pregnancy [see Use in Specific Populations 8.1 )]. Concomitant MedicationsAsk patients about alcohol consumption, medicines they are taking, and drugs they may be taking without prescription. Advise patients not to consume alcohol in combination with DAYVIGO [see Drug Interactions 7.1 ), Clinical Pharmacology 12.3 )]. Tolerance, Abuse, and DependenceTell patients not to increase the dose of DAYVIGO on their own, and to inform you if they believe the drug does not work [see Drug Abuse and Dependence 9 )]. Distributed by: Eisai Inc. Nutley, NJ 07110DAYVIGO(R) is registered trademark of Eisai R&D Management Co., Ltd. and is licensed to Eisai Inc.(C) 2019-2021 Eisai Inc.

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics. Following single doses of lemborexant 2.5 to 75 mg, geometric mean Cmax and AUC0-24h increased slightly less than in proportion to dose. The extent of accumulation of lemborexant at steady-state is 1.5- to 3-fold across this dose range. AbsorptionThe time to peak concentration (tmax) of lemborexant is approximately to hours.Effect of FoodLemborexant Cmax decreased by 23%, AUC0-inf increased by 18%, and tmax was delayed by hours following administration of high-fat and high-calorie meal (containing approximately 150, 250, and 500 to 600 calories from protein, carbohydrate, and fat, respectively).DistributionThe volume of distribution of lemborexant is 1970 L. Protein binding of lemborexant is approximately 94% in vitro. The blood to plasma concentration ratio of lemborexant is 0.65.EliminationMetabolismLemborexant is primarily metabolized by CYP3A4, and to lesser extent by CYP3A5. The major circulating metabolite is M10. ExcretionFollowing administration of an oral dose, 57.4% of the dose was recovered in the feces and 29.1% in the urine (<1% as unchanged). The effective half-life for lemborexant mg and 10 mg is 17 and 19 hours, respectively. Specific PopulationsNo clinically significant differences in the pharmacokinetics of lemborexant were observed based on age, sex, race/ethnicity, or body mass index. No studies have been conducted to investigate the pharmacokinetics of lemborexant in pediatric patients. Exposures of lemborexant in patients with hepatic and renal impairment are summarized in Figure 1.Figure 1. Effects of Hepatic and Renal Impairment on Lemborexant PharmacokineticsDrug Interaction StudiesThe effects of other drugs on the exposures of lemborexant are summarized in Figure 2. The effects of lemborexant on the exposures of other drugs are summarized in Figure 3. Physiologically-based pharmacokinetic (PBPK) modeling predicted that concomitant use of weak CYP3A inhibitors increased lemborexant exposure by less than 2-fold. Based on these results, drug interactions between lemborexant and strong CYP3A inducers, strong CYP3A inhibitors, moderate CYP3A inhibitors, and CYP2B6 substrates are clinically significant. Figure 2. Effects of Co-administered Drugs on the Pharmacokinetics of Lemborexant 10 mg Figure 3. Effects of Lemborexant 10 mg on the Pharmacokinetics of Co-Administered DrugsIn Vitro Studies In vitro metabolism studies demonstrated that lemborexant and M10 have the potential to induce CYP3A and the weak potential to inhibit CYP3A and induce CYP2B6. Lemborexant and M10 do not inhibit other CYP isoforms (CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2D6, CYP2A6, CYP2C19, and CYP2E1) or transporters (P-gp, BCRP, BSEP, OAT1, OAT3, OATP1B1, OATP1B3, OCT1, OCT2, MATE1, and MATE2-K). Lemborexant is potential poor substrate of P-gp, but M10 is substrate of P-gp. Lemborexant and M10 are not substrates of BCRP, OATP1B1, or OATP1B3.

PREGNANCY SECTION.

8.1 Pregnancy Pregnancy Exposure Registry There is pregnancy exposure registry that monitors pregnancy outcomes in women who are exposed to DAYVIGO during pregnancy. Healthcare providers are encouraged to register patients in the DAYVIGO pregnancy registry by calling 1-888-274-2378.Risk SummaryThere are no available data on DAYVIGO use in pregnant women to evaluate for drug-associated risks of major birth defects, miscarriage or adverse maternal or fetal outcomes.In animal reproduction studies, oral administration of lemborexant to pregnant rats and rabbits during the period of organogenesis caused toxicities only at high multiples of the human exposure at the maximum recommended human dose (MRHD) based on AUC. The no observed adverse effect levels (NOAEL) are approximately >100 and 23 times the MRHD based on AUC in rats and rabbits, respectively. Similarly, oral administration of lemborexant to pregnant and lactating rats caused toxicities only at high multiples of the human exposure at the MRHD based on AUC. The NOAEL is 93 times the MRHD based on AUC see Data . The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risks of major birth defects and miscarriage in clinically recognized pregnancies are 2% to 4% and 15% to 20%, respectively.DataAnimal DataLemborexant was administered orally to pregnant rats during the period of organogenesis in studies at doses of 60, 200, and 600 mg/kg/day or 20, 60, and 200 mg/kg/day, which are approximately to >300 times the MRHD based on AUC. Lemborexant caused maternal toxicity, manifested by decreased body weight and food consumption, decreased mean fetal body weight, an increased number of dead fetuses, and skeletal, external and visceral malformations (omphalocele, cleft palate, and membranous ventricular septal defect) at >300 times the MRHD based on AUC. The NOAEL of 200 mg/kg/day is approximately 143 times the MRHD based on AUC. Lemborexant was administered orally to pregnant rabbits during the period of organogenesis at doses of 10, 30, and 100 mg/kg/day, which are approximately to 139 times the MRHD based on AUC. Lemborexant caused maternal toxicity that consisted of decreased body weight and food consumption and higher incidence of skeletal variations (presence of cervical ribs and supernumerary lung lobes) at approximately 139 times the MRHD based on AUC. The NOAEL of 30 mg/kg/day is approximately 23 times the MRHD based on AUC.Lemborexant was administered orally to pregnant rats during pregnancy and lactation at doses of 30, 100, and 300 mg/kg/day, which are approximately 15 to 206 times the MRHD based on AUC. Lemborexant caused maternal toxicity that consisted of decreased body weight and food consumption and toxicity to offspring consisting of decreased pup body weights, decreased femur length, and decreased acoustic startle responses at 206 times the MRHD based on AUC. The NOAEL of 100 mg/kg/day is approximately 93 times the MRHD based on AUC.

SPL MEDGUIDE SECTION.

MEDICATION GUIDEDAYVIGO(R) (daye-vi-goe)(lemborexant)tablets, for oral use, CIV What is the most important information should know about DAYVIGO DAYVIGO may cause serious side effects including: Decreased awareness and alertness. The morning after you take DAYVIGO, your ability to drive safely and think clearly may be decreased. You may also have sleepiness during the day. Do not take more DAYVIGO than prescribed. Do not take DAYVIGO unless you are able to stay in bed for full night (at least hours) before you must be active again. Take DAYVIGO right before going to bed.See What are the possible side effects of DAYVIGO for more information about side effects.What is DAYVIGODAYVIGO is prescription medicine for adults who have trouble falling or staying asleep (insomnia). It is not known if DAYVIGO is safe and effective in children under the age of 18 years.DAYVIGO is federally controlled substance (CIV) because it can be abused or cause dependence. Keep DAYVIGO in safe place to prevent misuse and abuse. Selling or giving away DAYVIGO may harm others and is against the law. Tell your doctor if you have ever abused or have been dependent on alcohol, prescription medicines or street drugs.Who should not take DAYVIGODo not take DAYVIGO if you fall asleep often at unexpected times (narcolepsy).Before taking DAYVIGO, tell your healthcare provider about all of your medical conditions, including if you:have history of depression, mental illness, or suicidal thoughts. have history of drug or alcohol abuse or addiction. have history of sudden onset of muscle weakness (cataplexy). have history of daytime sleepiness. have lung problems or breathing problems, including sleep apnea. have liver problems. are pregnant or plan to become pregnant. It is not known if DAYVIGO can harm your unborn baby.Pregnancy Registry: There is pregnancy registry for women who are exposed to DAYVIGO during pregnancy. The purpose of this registry is to collect information about the health of you and your baby. For more information or to participate in the registry, call 1-888-274-2378. Talk with your healthcare provider about the risk to your unborn baby if you take DAYVIGO during pregnancy.are breastfeeding or plan to breastfeed. It is not known if DAYVIGO passes into your breast milk. Talk to your healthcare provider about the best way to feed your baby during treatment with DAYVIGO.Tell your healthcare provider about all of the medicines you take, including prescription and over-the-counter medicines, vitamins and herbal supplements. Taking DAYVIGO with certain other medicines can cause serious side effects. DAYVIGO may affect the way other medicines work and other medicines may affect the way DAYVIGO works. Do not take DAYVIGO with other medicines that can make you sleepy unless your healthcare provider tells you to. Know the medicines you take. Keep list of your medicines with you to show your healthcare provider and pharmacist each time you get new medicine.How should take DAYVIGOTake DAYVIGO exactly as your healthcare provider tells you to take it. Only take DAYVIGO one time each night, right before going to bed. Only take DAYVIGO when you can stay in bed for full night (at least hours). DAYVIGO may take longer to work if you take it with or soon after meal. Do not increase your dose of DAYVIGO without talking to your healthcare provider first. Call your healthcare provider if your insomnia (sleep problem) worsens or is not improved within to 10 days. This may mean that there is another condition causing your sleep problem. If you take too much DAYVIGO, call your healthcare provider or go to the nearest hospital emergency room right away.What should avoid while taking DAYVIGODo not drink alcohol while taking DAYVIGO. It can increase your chances of getting serious side effects. Do not drive, operate heavy machinery, do anything dangerous, or do other activities that require clear thinking if you take DAYVIGO and have had less than full night of sleep (at least hours) or if you have taken more DAYVIGO than prescribed by your healthcare provider.You may still feel drowsy the next day after taking DAYVIGO. Do not drive or do other dangerous activities until you feel fully awake.What are the possible side effects of DAYVIGO See What is the most important information should know about DAYVIGO DAYVIGO may cause serious side effects, including:temporary inability to move or talk (sleep paralysis) for up to several minutes while you are going to sleep or waking up. temporary weakness in your legs that can happen during the day or at night.complex sleep behaviors such as sleep-walking, sleep-driving, preparing and eating food, making phone calls, having sex or doing other activities while not fully awake that you may not remember the next morning. Call your healthcare provider right away if you experience complex sleep behavior. worsening depression and suicidal thoughts have happened during treatment with DAYVIGO. Call your healthcare provider right away if you have any worsening depression or thoughts of suicide or dying.The most common side effect of DAYVIGO is sleepiness.These are not all of the possible side effects of DAYVIGO. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.How should store DAYVIGOStore DAYVIGO at room temperature between 68F to 77F (20C to 25C). Keep DAYVIGO and all medicines out of the reach of children. General information about the safe and effective use of DAYVIGO.Medicines are sometimes prescribed for purposes other than those listed in Medication Guide. Do not use DAYVIGO for condition for which it was not prescribed. Do not give DAYVIGO to other people, even if they have the same symptoms that you have. It may harm them. You can ask your healthcare provider or pharmacist for information about DAYVIGO that is written for healthcare professionals.What are the ingredients in DAYVIGOActive ingredient: lemborexantInactive ingredients: hydroxypropyl cellulose, lactose monohydrate, low-substituted hydroxypropyl cellulose, and magnesium stearate. The tablet film coating contains: hypromellose 2910, polyethylene glycol 8000, talc, titanium dioxide, and either ferric oxide yellow for the mg tablet; or both ferric oxide yellow and ferric oxide red for the 10 mg tablet. Distributed by: Eisai Inc. Nutley, NJ 07110DAYVIGO(R) is registered trademark of Eisai R&D Management Co., Ltd. and is licensed to Eisai Inc.(C) 2019-2021 Eisai Inc. For more information, go to www.DAYVIGO.com or call 1-888-274-2378 This Medication Guide has been approved by the U.S. Food and Drug Administration. Revised: 12/2021. Decreased awareness and alertness. The morning after you take DAYVIGO, your ability to drive safely and think clearly may be decreased. You may also have sleepiness during the day. Do not take more DAYVIGO than prescribed. Do not take DAYVIGO unless you are able to stay in bed for full night (at least hours) before you must be active again. Take DAYVIGO right before going to bed.. DAYVIGO is prescription medicine for adults who have trouble falling or staying asleep (insomnia). It is not known if DAYVIGO is safe and effective in children under the age of 18 years.. have history of depression, mental illness, or suicidal thoughts. have history of drug or alcohol abuse or addiction. have history of sudden onset of muscle weakness (cataplexy). have history of daytime sleepiness. have lung problems or breathing problems, including sleep apnea. have liver problems. are pregnant or plan to become pregnant. It is not known if DAYVIGO can harm your unborn baby.. are breastfeeding or plan to breastfeed. It is not known if DAYVIGO passes into your breast milk. Talk to your healthcare provider about the best way to feed your baby during treatment with DAYVIGO.. Taking DAYVIGO with certain other medicines can cause serious side effects. DAYVIGO may affect the way other medicines work and other medicines may affect the way DAYVIGO works. Do not take DAYVIGO with other medicines that can make you sleepy unless your healthcare provider tells you to. Know the medicines you take. Keep list of your medicines with you to show your healthcare provider and pharmacist each time you get new medicine.. Take DAYVIGO exactly as your healthcare provider tells you to take it. Only take DAYVIGO one time each night, right before going to bed. Only take DAYVIGO when you can stay in bed for full night (at least hours). DAYVIGO may take longer to work if you take it with or soon after meal. Do not increase your dose of DAYVIGO without talking to your healthcare provider first. Call your healthcare provider if your insomnia (sleep problem) worsens or is not improved within to 10 days. This may mean that there is another condition causing your sleep problem. If you take too much DAYVIGO, call your healthcare provider or go to the nearest hospital emergency room right away.. Do not drink alcohol while taking DAYVIGO. It can increase your chances of getting serious side effects. Do not drive, operate heavy machinery, do anything dangerous, or do other activities that require clear thinking if you take DAYVIGO and have had less than full night of sleep (at least hours) or if you have taken more DAYVIGO than prescribed by your healthcare provider.. You may still feel drowsy the next day after taking DAYVIGO. Do not drive or do other dangerous activities until you feel fully awake.. temporary inability to move or talk (sleep paralysis) for up to several minutes while you are going to sleep or waking up. temporary weakness in your legs that can happen during the day or at night.. complex sleep behaviors such as sleep-walking, sleep-driving, preparing and eating food, making phone calls, having sex or doing other activities while not fully awake that you may not remember the next morning. Call your healthcare provider right away if you experience complex sleep behavior. worsening depression and suicidal thoughts have happened during treatment with DAYVIGO. Call your healthcare provider right away if you have any worsening depression or thoughts of suicide or dying.. Store DAYVIGO at room temperature between 68F to 77F (20C to 25C). Keep DAYVIGO and all medicines out of the reach of children.