Pharmacology: Mechanism of action: In a calcium influx assay, Ki values of lemborexant for human orexin receptor types 1 (OX1) and 2 (OX2) were 8.1 nmol/L and 0.48 nmol/L, respectively. The metabolite M10, which can be found in human plasma, displayed binding affinity at orexin receptors comparable to that of unchanged drug.
Lemborexant is presumed to shift the brain from wakefulness state to sleep state by reversibly blocking the binding of wake-promoting neuropeptides orexin A and orexin B to the receptors OX1 and OX2, thereby inducing sleep.
Effects on sleep: Lemborexant reduced sleep latency and increased total sleep time in rats. No significant difference was noted in the ratio of rapid eye movement (REM) sleep time to total sleep time.
Pharmacokinetics: Plasma concentration: The plasma concentration-time profile after administration of DAYVIGO 10 mg on Day 14 in healthy Japanese adult males who received the drug repeatedly for 14 days at 2.5, 10 or 25 mg once daily is shown in the figure. The pharmacokinetic parameters at Day 1 and Day 14 in those who received DAYVIGO 2.5 mg and 10mg are shown in Table 2. The maximum concentration (C
max) and area under the concentration-time curve from 0 to 24 hours (AUC
0-24h) of lemborexant increased with increasing dose. C
max was 70.2 ng/mL, and plasma lemborexant concentrations at 3 and 8 hours postdose were 31.4 ng/mL and 17.9 ng/mL, respectively, on Day 14 after administration of 10 mg. (See figure and Table 2.)
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Effects of meals: In 24 healthy adults who received DAYVIGO at 10 mg orally as a single dose, the geometric mean ratios (fed/fasted) with 90% confidence intervals (CIs) for C
max and AUC
(0-t) of lemborexant were 0.771 (0.687, 0.866) and 1.18 (1.09, 1.28), respectively. C
max was 23% lower and AUC
(0-t) was 18% higher under fed conditions compared with fasted conditions. Furthermore, t
max (median) was delayed by 2 hours. The terminal elimination half-life (mean) of lemborexant was 50.8 h under fasted conditions and 53.8 h under fed conditions (see Precautions regarding dosage and administration under Dosage & Administration).
Distribution: The plasma protein binding (
in vitro in human plasma) was 87.4-88.7% at concentrations of 100 to 1000 ng/mL.
Metabolism: Lemborexant was mainly eliminated from the body through metabolism, with the metabolite with systemic exposure greater than 10% of total drug-related exposure being M10 (N-oxide) alone (13%). M10 was confirmed to contribute to a lesser extent to the pharmacological effects than lemborexant.
An in vitro metabolism study showed that CYP3A is mainly involved in the metabolism of lemborexant. Furthermore, M10 was shown to be generated by oxidative metabolism of lemborexant via CYP3A.
Excretion: In 8 healthy adult males who received C-labelled lemborexant at 10 mg orally as a single dose, the total recovery rate for radioactivity was 86.5%, with 57.4% excreted in feces and 29.1% in urine.
Special population: Elderly: In 5 healthy elderly subjects (66-76 years) who received DAYVIGO repeatedly for 14 days at 25 mg once daily, geometric mean ratios (healthy elderly/healthy adult) with 90% confidence intervals for C
max and AUC
(0-24h) of lemborexant on Day 14 were 1.18 [0.770, 1.79] and 1.12 [0.762, 1.64], respectively. C
max and AUC
(0-24h) were 18% and 12% higher in elderly subjects than in healthy adult subjects, respectively. The terminal elimination half-life (mean) of lemborexant was 49.6 h in healthy adult subjects and 60.1 h in healthy elderly subjects. In population pharmacokinetic analysis involving healthy adult subjects and patients with insomnia in phase I-III clinical studies, apparent clearance of lemborexant was 26% lower in elderly subjects (≥65 years old). (See Use in the Elderly under Precautions.)
Patients with hepatic function disorder: In 8 patients with mild hepatic function disorder (Child-Pugh score: 5-6) and 8 patients with moderate hepatic function disorder (Child-Pugh score: 7-9) who received DAYVIGO at 10 mg as a single dose, geometric mean ratios (patients with hepatic function disorder/healthy adults) with 90% CIs for C
max of lemborexant were 1.58 [1.18, 2.11] and 1.22 [0.915, 1.63], respectively, and those for AUC
(0-inf) were 1.25 [0.880, 1.78] and 1.54 [1.06, 2.22], respectively. C
max was 58% and 22% higher and AUC
(0-inf) was 25% and 54% higher in patients with mild hepatic function disorder and those with moderate hepatic function disorder, respectively, than in healthy adults. The terminal elimination half-lives (mean) of lemborexant were 69.0 h, 78.7 h and 108 h in healthy adult subjects, patients with mild hepatic function disorder and those with moderate hepatic function disorder, respectively. Geometric mean ratios (patients with hepatic function disorder/healthy adults) with 90% CIs for C
max of the main metabolite M10 were 0.947 [0.684, 1.31] and 0.766 [0.552, 1.06], respectively, and those for AUC
(0-inf) of M10 were 0.950 [0.703, 1.28] and 1.04 [0.754, 1.42], respectively.
C
max was slightly lower in patients with mild and moderate hepatic function disorder than in healthy adults, but AUC
(0-inf) was similar between these patients and healthy adult subjects. The terminal elimination half-lives (mean) of M10 were 64.3 h, 66.6 h and 91.2 h in healthy adults, patients with mild hepatic function disorder and those with moderate hepatic function disorder, respectively. No study of pharmacokinetics has been conducted in patients with severe hepatic function disorder (Child-Pugh score: 10-15). (See CONTRAINDICATIONS and Careful Administration under Precautions.)
Patients with renal impairment: In 8 patients with severe renal impairment (estimated glomerular filtration rate [eGFR] by MDRD equation, 15-29 mL/min/1.73 m
2) who received DAYVIGO at 10 mg as a single dose, geometric mean ratios (patients with renal impairment/healthy adults) with 90% CIs for C
max and AUC
(0-inf) of lemborexant were 1.05 [0.774, 1.42] and 1.50 [1.13, 1.99], respectively. C
max and AUC
(0-inf) were 5% and 50% higher in patients with severe renal impairment than in healthy adults, respectively. The terminal elimination half-lives (mean) of lemborexant were 70.0 h and 74.8 h in healthy adults and patients with severe renal impairment, respectively. Geometric mean ratios (patients with renal impairment/healthy adults) with 90% CIs for C
max and AUC
(0-inf) of the main metabolite M10 were 0.725 [0.481, 1.09] and 1.36 [0.982, 1.90], respectively. C
max was 28% lower and AUC
(0-inf) was 36% higher in patients with severe renal impairment than in healthy adults, respectively. The terminal elimination half-lives (mean) of M10 were 64.0 h and 64.7 h in healthy adults and patients with severe renal impairment, respectively. (See Careful Administration under Precautions.)
Drug interactions: Itraconazole (Strong CYP3A Inhibitor): In 15 healthy adults on itraconazole at 200 mg once daily as repeated doses who received DAYVIGO at 10 mg as a single dose, geometric mean ratios (combination therapy/monotherapy) with 90% CIs for Cmax and AUC
(0-inf) of lemborexant were 1.36 [1.18, 1.57] and 3.70 [3.18, 4.31], respectively. C
max and AUC
(0-inf) of lemborexant were 36% and 270% higher with combination therapy than those with monotherapy, respectively. Terminal elimination half-lives (mean) of lemborexant with monotherapy and combination therapy were 54.4 h and 118 h, respectively. Geometric mean ratios (combination therapy/monotherapy) with 90% CIs for C
max and AUC
(0-inf) of M10 were 0.130 [0.107, 0.158] and 0.626 [0.465, 0.844], respectively. The terminal elimination half-lives (mean) of M10 with monotherapy and combination therapy were 48.1 h and 150 h, respectively. (See Precautions regarding dosage and administration under Dosage & Administration and Interactions.)
Fluconazole (Moderate CYP3A Inhibitor): In 14 healthy adults on fluconazole at 200 mg once daily as repeated doses who received DAYVIGO at 10 mg as a single dose, geometric mean ratios (combination therapy/monotherapy) with 90% CIs for Cmax and AUC
(0-inf) of lemborexant were 1.62 [1.34, 1.97] and 4.17 [3.83, 4.55], respectively. C
max and AUC
(0-inf) of lemborexant were 62% and 317% higher with combination therapy than those with monotherapy, respectively. The terminal elimination half-lives (mean) of lemborexant with monotherapy and combination therapy were 55.4 h and 99.5 h, respectively. Geometric mean ratios (combination therapy/monotherapy) with 90% CIs for C
max and AUC
(0-inf) of M10 were 0.580 [0.513, 0.657] and 2.33 [1.73, 3.14], respectively. Terminal elimination half-life (mean) of M10 with monotherapy and combination therapy were 45.5 h and 78.6 h, respectively. (See Precautions regarding dosage and administration under Dosage & Administration and Interactions.)
Rifampicin (Strong CYP3A Inducer): In 15 healthy adults on rifampicin at 600 mg once daily as repeated doses who received DAYVIGO at 10 mg as a single dose, geometric mean ratios (combination therapy/monotherapy) with 90% CIs for C
max and AUC
(0-inf) of lemborexant were 0.085 [0.067, 0.107] and 0.034 [0.026, 0.045], respectively. Cmax and AUC
(0-inf) of lemborexant were 92% and 97% lower with combination therapy than those with monotherapy, respectively. The terminal elimination half-lives (mean) of lemborexant with monotherapy and combination therapy were 45.6 h and 10.8 h, respectively. Geometric mean ratios (combination therapy/monotherapy) with 90% CIs for C
max and AUC
(0-inf) of M10 were 1.00 [0.884, 1.13] and 0.127 [0.112, 0.145], respectively. The terminal elimination half-lives (mean) of M10 with monotherapy and combination therapy were 39.4 h and 4.07 h, respectively. (See Interactions.)
Midazolam (Sensitive CYP3A Substrate): In 28 healthy adults on DAYVIGO at 10 mg once daily as repeated doses who received midazolam at 2 mg as a single dose, geometric mean ratios (combination therapy/monotherapy) with 90% CIs for C
max and AUC(0-inf) of midazolam were 1.13 [1.03, 1.24] and 1.13 [1.02, 1.25], respectively. C
max and AUC
(0-inf) of midazolam were 13% and 13% higher with combination therapy than those with monotherapy, respectively. The terminal elimination half-lives (mean) of midazolam with monotherapy and combination therapy were 4.00 h and 4.21 h, respectively.
Alcohol: In 21 healthy adults on DAYVIGO at 10 mg once daily as a single dose, concomitant intake of alcohol resulted in additive declines in cognition. Moreover, geometric mean ratios (with concomitant intake of alcohol/without concomitant intake of alcohol) with 90% CIs for C
max and AUC
(0-72h) of lemborexant were 1.35 [1.14, 1.60] and 1.70 [1.54, 1.89], respectively. C
max and AUC
(0-72h) of lemborexant were 35% and 70% higher with concomitant intake of alcohol than without concomitant intake of alcohol, respectively. The terminal elimination half-lives (mean) of lemborexant were 33.9 h and 29.9 h with and without concomitant intake of alcohol, respectively. (See Interactions.)
Note: The maximum approved dose of DAYVIGO is 10 mg.
CLINICAL STUDIES: Phase III clinical studies (Study 303 and Study 304): Lemborexant was evaluated for efficacy and safety in 2 clinical trials (each with >900 patients) in patients with insomnia characterized by difficulties with sleep onset and/or sleep maintenance.
The efficacy and safety of lemborexant was evaluated in Study E2006-G000-303 (Study 303), a randomized, double-blind and placebo-controlled 6-month sleep diary study, followed by an additional 6 months of blinded active treatment period where all patients received lemborexant. Study E2006-G000-304 (Study 304) was a 1-month, randomized, double-blind, placebo- and zolpidem tartrate extended release-controlled, parallel-group polysomnography (PSG) and sleep diary study. In both studies, adult patients (mean age 51.8 years; 714 females, 213 males) were treated with lemborexant 5 mg (n=467) or 10 mg (n=460). Elderly patients (≥65 years; mean age 70.4 years, 342 females, 149 males) were treated with lemborexant 5 mg (n=246) or 10 mg (n=245). In Study 303 and Study 304, as measured by subjective and/or objective methods, lemborexant led to significantly larger decreases (improvements) in both the time needed to fall asleep and the amount of time spent awake during the night after sleep onset compared to placebo, and significantly larger increases in sleep efficiency (time spent asleep/time spent in bed) compared to placebo, all of which were sustained through 6 months (Tables 3, 4, & 5).
In Study 304, lemborexant 5 mg and 10 mg led to significantly larger decreases in sleep onset (latency to persistent sleep [LPS]) and wake after sleep onset (WASO) during the full sleep period and during the second half of the sleep period) compared to placebo as assessed objectively by PSG. Lemborexant led to significantly larger increases in sleep efficiency (SE) compared to placebo (Table 5). As measured by PSG, lemborexant 5 mg and 10 mg led to significantly larger decreases in sleep onset (LPS), WASO across the entire night, and WASO in the second half of the night compared with zolpidem tartrate extended release (ER). The statistically significant effects of lemborexant on patient-reported (subjective) sleep onset and sleep maintenance (sWASO and sSE) after the first 7 nights of treatment remained statistically significant compared with placebo through 6 months (Study 303). The efficacy of lemborexant was similar between women and men, adult and elderly, and between Caucasians and non-Caucasians. (See Tables 3, 4 and 5.)
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Clinical pharmacology studies: Effects on driving performance (Study 106) A total of 24 healthy adult male/female subjects (median age, 49 years), including 1 Japanese subject, and 24 healthy elderly male/female subjects (median age, 67 years) received DAYVIGO 5 or 10 mg before bedtime and were evaluated for effects on driving performance the next morning (approximately 9 h after taking the drug). With DAYVIGO administered at 5 or 10 mg over 8 days, no statistically significant effects on driving performance after one or multiple doses were noted in either healthy adult or healthy elderly subjects as compared to placebo, although driving performance was slightly impaired in subjects receiving DAYVIGO 10 mg than in those receiving DAYVIGO 5 mg.
Effects on postural stability and cognitive functions during the night and the next morning (Studies 108 and 304): Healthy subjects (≥55 years old) received DAYVIGO 5 or 10 mg before bedtime and were evaluated for the effects on postural stability and cognitive functions (attention and memory) upon awakening during the night (approximately 4 h after administration of DAYVIGO) and upon awakening the next morning (approximately 8 h after administration of DAYVIGO). Approximately 4 h after administration of DAYVIGO, as compared with placebo, increased body sway was noted with DAYVIGO 5 and 10 mg, and decreased attention and memory were noted with DAYVIGO 10 mg. Moreover, in patients with insomnia (≥55 years old) receiving DAYVIGO 5 or 10 mg before bedtime, decreased attention was noted upon awakening the next morning (approximately 8 h after administration) with DAYVIGO 5 and 10 mg, as compared with placebo.
There was no effect of DAYVIGO on tests of memory or body sway in the morning.
Respiratory Safety (Study 102): In a study of healthy adult and elderly patients, there were no differences between placebo and lemborexant 10 mg and 25 mg with respect to oxygen saturation during sleep. In a study of patients with mild sleep apnea, there was no effect of lemborexant on the apnea-hypopnea index when compared with placebo following single and multiple doses of lemborexant 10 mg. (See Careful Administration under Precautions.)
Effects on drug abuse (Study 103): With administration of DAYVIGO at 10, 20 or 30 mg in healthy adults (n=39) with experience of drug abuse, subjective assessments regarding DAYVIGO drug preference and other tendencies toward abuse were higher than those with placebo and similar to those with zolpidem at 30 mg and suvorexant at 40 mg.
Because individuals with a history of abuse or addiction to alcohol or other drugs may be at increased risk for abuse and addiction to DAYVIGO, follow such patients carefully.
Note: The maximum approved dose of DAYVIGO is 10 mg.
Toxicology: NON-CLINICAL TOXICOLOGY: Fertility: Lemborexant was orally administered to female rats at doses of 30, 100, or 1000 mg/kg/day prior to and throughout mating and continuing to gestation Day 6. These doses are approximately 12 to >500 times the MRHD based on AUC. Irregular estrous cycles and decreased pregnancy rate were observed at 60 times the MRHD based on AUC, and decreased numbers of corpora lutea, implantations, and live embryos were observed at >500 times the MRHD based on AUC. The exposure at the NOAEL of 30 mg/kg/day is approximately 12 times the MRHD based on AUC. Lemborexant did not affect fertility when orally administered to male rats at doses of 30, 100, or 1000 mg/kg/day prior to and throughout mating; the highest dose is approximately 138 times the MRHD based on AUC.
Carcinogenesis: Lemborexant did not increase the incidence of tumors in rats treated for 2 years at oral doses of 30, 100, and 300 mg/kg/day (males) and 10, 30, and 100 mg/kg/day (females), which are >80 times the MRHD based on AUC. Lemborexant did not increase the incidence of tumors in Tg ras H2 mice treated for 26 weeks at oral doses of 50, 150, and 500 mg/kg/day.
Mutagenesis: Lemborexant was neither mutagenic nor clastogenic in a standard battery of in vitro and in vivo genotoxicity studies.
Animal Toxicology and/or Pharmacology: Lemborexant administered to mice at oral doses of 10 or 30 mg/kg resulted in behavior characteristic of cataplexy when presented with chocolate. Chocolate is a stimulus that has been demonstrated to increase cataplexy occurrences in narcoleptic mice.
RISK OF DEPENDENCE: Physical dependence is a state that develops as a result of physiological adaptation in response to repeated drug use, manifested by withdrawal signs and symptoms after abrupt discontinuation or a significant dose reduction of a drug. In animal studies and clinical trials evaluating physical dependence, chronic administration of lemborexant did not produce withdrawal signs or symptoms upon drug discontinuation. This suggests that lemborexant does not produce physical dependence.
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