Dayvigo

Lemborexant.

Each film-coated tablet contains 5 mg of lemborexant.
Pale yellow, round, biconvex film-coated tablet, debossed 'LЄM' on one side and '5' on the other side.

Pharmacotherapeutic group: None. ATC code: None.
Pharmacology: Mechanism of Action: Lemborexant is a competitive antagonist of both orexin receptors, OX1R and OX2R, with a higher affinity for OX2R. It belongs to the pharmacologic class of orexin receptor antagonists. The orexin neuropeptide signaling system is a central promoter of wakefulness. Blocking the binding of wake-promoting neuropeptides orexin A and orexin B to receptors OX1R and OX2R is thought to suppress wake drive.
Pharmacodynamics: Cardiac Electrophysiology: The effect of lemborexant on the QTc interval using a high precision analysis was measured in multiple dose studies in human patients administered daily doses up to 75 mg. The concentration-response relationship was analyzed using a linear mixed-effects model. The model-predicted QTc effect at the highest observed concentration was 1.1 msec (90% CI: -3.49 to 5.78), indicating that a QTc prolongation effect >10 msec could be excluded at a dose 7.5-times the maximum recommended dose. Thus, lemborexant does not prolong the QTc interval at clinically relevant doses.
Clinical Efficacy: 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 active-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 1, 2, & 3).
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 1). 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 active comparator.
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 1, 2 and 3.)

Click on icon to see table/diagram/image


Click on icon to see table/diagram/image


Click on icon to see table/diagram/image

Special Safety Studies: Effects on Driving: A randomized, double-blind, placebo- and active-controlled, four-period crossover study evaluated the effects of nighttime administration of lemborexant on next-morning driving performance approximately 9 hours after dosing in 24 healthy elderly patients (≥65 years old, median age 67 years; 14 men, 10 women) and 24 adult patients (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 lemborexant. Although lemborexant at doses of 5 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 lemborexant. 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 lemborexant. The results of a symmetry analysis support the findings from the primary outcome.
Effects on Next-day Postural Stability and Cognitive Performance: The effect of lemborexant on next-day postural stability and cognitive performance (tests of attention and memory) compared to placebo was evaluated in 2 randomized, placebo-and active-controlled trials in healthy subjects and insomnia patients age 55 and older. There were no meaningful differences between lemborexant (5 mg or 10 mg) and placebo on next-day postural stability or memory.
Middle of the Night Safety in Older Patients (age 55 years and older): The effect of lemborexant was evaluated in a randomized, placebo- and active-controlled trial with a scheduled awakening 4 hours after the start of the 8-hour time in bed. Postural stability, the ability to awaken in response to a sound stimulus, and attention and memory were tested following the awakening. The active comparator in the study, showed a statistically significant decrease in postural stability (increased body sway) compared to both lemborexant and placebo. There were no statistical differences between lemborexant and placebo on the ability to awaken in response to sound. There were no statistically significant differences between lemborexant 5 mg and placebo on measures of attention and memory.
Rebound Insomnia: Rebound insomnia was assessed by comparing sleep diary-recorded sSOL and sWASO from the screening period to the two weeks following treatment discontinuation in both Study 303 (12 months) and Study 304 (1 month). Analyses of group means and the proportion of patients with rebound insomnia suggest that lemborexant was not associated with rebound insomnia following treatment discontinuation.
Withdrawal Effects: In a 12-month and 1-month controlled safety and efficacy trials (Study 303, Study 304, respectively), withdrawal effects were assessed by the Tyrer Benzodiazepine Withdrawal Symptom Questionnaire following discontinuation from study drug in patients who received lemborexant 5 mg or 10 mg. There was no evidence of withdrawal effects following lemborexant discontinuation at either dose.
Respiratory Safety: 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 mean peripheral capillary oxygen saturation during sleep. In a study of patients with mild sleep apnea, overall, lemborexant did not increase the frequency of apneic events or decrease mean peripheral capillary oxygen saturation when compared with placebo following single and multiple doses of 10 mg.
In a study of patients with moderate or severe obstructive sleep apnea (apnea-hypopnea index ≥15 events per hour of sleep), overall, lemborexant did not increase the frequency of apneic events or decrease mean peripheral capillary oxygen saturation following single or multiple doses of 10 mg. In a study of patients with moderate or severe chronic obstructive pulmonary disease (COPD), overall, lemborexant did not increase the frequency of apneic events or decrease mean peripheral capillary oxygen saturation following single or multiple doses of 10 mg.
Daily Functioning: In Study 303 and Study 304, the effect of lemborexant on daily functioning was assessed by scores on the Insomnia Severity Index (ISI). For patients treated with lemborexant, the ISI score decreased significantly compared to placebo, indicating that patients treated with lemborexant had improvement of functional impairment.
Sleep Stages: In Study 304, sleep stages for patients treated with lemborexant were assessed by polysomnography. Lemborexant demonstrated a significant increase in rapid eye movement (REM) sleep compared to placebo and to zolpidem tartrate ER.
Pharmacokinetics: Absorption: In healthy patients, the pharmacokinetic profile of lemborexant was examined after single doses of up to 200 mg and after once-daily administration of up to 75 mg for 14 days. Lemborexant is rapidly absorbed, with a time to peak concentration (tmax) of approximately 1 to 3 hours. Lemborexant exhibits linear pharmacokinetics with multi-exponential decline in plasma concentrations. The extent of accumulation of lemborexant at steady-state is 1.5- to 2-fold across the dose range. The effective half-life for 5 mg and 10 mg is 17 and 19 hours respectively. The plasma concentration at 9 hours after administration is approximately 10% to 13% of the Cmax.
Ingestion of lemborexant with a high-fat meal resulted in a decrease in the rate of absorption as demonstrated by 23% decrease in C_max and delay in t_max of 2 hours and 18% increase in total exposure AUC.
Time to sleep onset may be delayed if taken with or soon after a meal.
Distribution: The volume of distribution of lemborexant is 1970 L. Plasma protein binding of lemborexant in clinical samples is approximately 94%. The blood to plasma concentration ratio of lemborexant is 0.65.
In vitro binding of lemborexant and its major circulating metabolite, M10 (the N-oxide of lemborexant) to human plasma proteins ranged from 87.4% to 88.7% and 91.5% to 92.0%, respectively, at concentrations of 100 to 1000 ng/mL. At these concentrations in vitro, lemborexant was bound primarily to human serum albumin, low-density lipoprotein, and high-density lipoprotein. In vitro blood to plasma concentration ratios of lemborexant and M10 in humans were 0.610 to 0.656 and 0.562 to 0.616, respectively, at concentrations of 100 to 1,000 ng/mL.
Metabolism: Lemborexant is primarily metabolized by CYP3A4, and to a lesser extent by CYP3A5. M10 is the only major circulating metabolite (12% of parent). The contribution of this metabolite to the pharmacologic activity of lemborexant is considered to be minimal.
Elimination: The primary route of elimination is through the feces, with 57.4% of radiolabeled dose recovered in the feces and 29.1% in the urine. The percent of lemborexant excreted unchanged in the urine is negligible (<1% dose). The effective half-life of lemborexant 5 mg and 10 mg is 17 and 19 hours respectively.
Special Populations: Age, Sex, Race/Ethnicity and BMI: No clinically significant differences in the pharmacokinetics of lemborexant were observed based on age, sex, race/ethnicity, or body mass index.
Geriatric Patients: Based on a population pharmacokinetic analysis in patients receiving 5 or 10 mg lemborexant once daily, apparent clearance was 26% lower in elderly (>65 years of age). However, this effect was not clinically relevant.
Pediatric Patients: No studies have been conducted to investigate the pharmacokinetics of lemborexant in pediatric patients.
Patients with Renal Impairment: Severe renal impairment (urinary creatinine clearance ≤30 mL/min/1.73m²) increased lemborexant exposure (AUC) 1.5-fold but had no effect on C_max. No dose adjustment is required in patients with renal impairment.
Patients with Hepatic Impairment: Lemborexant has not been studied in patients with severe hepatic impairment. Use in this population is not recommended.
Mild (Child-Pugh A) and moderate (Child-Pugh B) hepatic insufficiency increased lemborexant AUC and C_max by 1.5-fold. Terminal half-life was only increased in patients with moderate hepatic impairment (Child-Pugh class B). No relationship between these findings and hepatic function was observed.
Exposures of lemborexant in patients with hepatic and renal impairment are summarized in Figure 1. (See Figure 1.)

Click on icon to see table/diagram/image

Drug Interaction Studies: Effects of Other Drugs on Lemborexant: The effects of other drugs on the pharmacokinetics of lemborexant (10 mg) are presented in Figure 2 as change relative to lemborexant alone (test/reference). Based on these results, drug interactions between lemborexant and strong CYP3A inducers, strong CYP3A inhibitors, and moderate CYP3A inhibitors are clinically significant. Using a physiologically based pharmacokinetic (PBPK) model, a weak effect is predicted when weak CYP3A inhibitors (e.g.,fluoxetine) are co-administered with lemborexant. Co-administration of moderate (e.g., fluconazole) or strong (e.g., itraconazole) CYP3A inhibitors significantly increased lemborexant exposure. CYP3A inducers (e.g., rifampin) significantly decreased lemborexant exposure.
There was no evidence of an additive effect on impairing postural stability (as evidenced by body sway) when lemborexant was co-administered with alcohol; lemborexant did not impact postural stability when dosed alone. An additive negative effect on cognitive performance was observed up to 6 hours post dose when lemborexant 10 mg was co-administered with a single dose of alcohol (0.6 g/kg for females and 0.7 g/kg for males).
Co-administration of an H2 blocker (famotidine) with lemborexant decreased C_max by 27% and delayed t_max by 0.5 hours, but had no statistically significant effect on overall lemborexant exposure (AUC). A population analysis of Phase 1-3 data also showed no effect of proton pump inhibitors (PPIs) on apparent clearance of lemborexant. A pooled analysis conducted on patients with a medical history of gastroesophageal reflex disease (GERD) or taking PPIs or H2 blockers in Study 303 and 304 showed that there was no effect on sleep latency or on safety parameters. Thus lemborexant can be co-administered with gastric acid-reducing agents (PPIs or H2 blockers).
Co-administration of an oral contraceptive containing norethindrone (NE) and ethinyl estradiol (EE) with lemborexant had no statistically significant effect on lemborexant pharmacokinetics. (See Figure 2.)

Click on icon to see table/diagram/image

Effects of Lemborexant on Other Drugs: In vitro metabolism studies demonstrated that lemborexant and M10 have a potential to induce CYP3A and a weak potential to inhibit CYP3A and induce CYP2B6. Lemborexant and M10 do not have the potential to inhibit other CYP isoforms or transporters (P-gp, BCRP, BSEP, OAT1, OAT3, OATP1B1, OATP1B3, OCT1, OCT2, MATE1, and MATE2-K). Lemborexant and M10 do not induce CYP2C8, CYP2C9, and CYP2C19 at clinically relevant concentrations. Lemborexant is a poor substrate of P-gp, but M10 is a substrate of P-gp. Lemborexant and M10 are not substrates of BCRP, OATP1B1, or OATP1B3.
Specific in vivo effects of lemborexant (10 mg) on the pharmacokinetics of bupropion, oral contraceptives, and midazolam are presented in Figure 3 as a change relative to the interacting drug administered alone (test/reference). Based on these results, drug interactions between lemborexant and CYP2B6 substrates are clinically significant. Lemborexant is expected to have minimal effect on the pharmacokinetics of CYP2C8, CYP2C9, or CYP2C19 substrates.
Co-administration of an oral contraceptive containing norethindrone (NE) and ethinyl estradiol (EE) with lemborexant (10 mg) did not affect the Cmax and AUC of NE or the Cmax of EE, and increased AUC of EE by 13%. This latter small change is not considered clinically relevant.
Clinical studies with substrates of CYP3A or CYP2B6: Despite the in vitro findings, lemborexant does not induce or inhibit CYP3A4. Lemborexant weakly induces CYP2B6 (e.g., bupropion is CYP2B6 substrate). CYP3A and CYP2B6 substrates can be co-administered with lemborexant. (See Figure 3.)

Click on icon to see table/diagram/image

Toxicology: Preclinical Safety Data: 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.

For the treatment of insomnia.

Posology: The recommended dose of lemborexant is 5 mg taken no more than once per night, and within a few minutes before going to bed, with at least 7 hours remaining before the planned time of awakening. If the 5 mg dose is well-tolerated but greater effect is needed, the dose can be increased to 10 mg once daily.
The maximum recommended dose of lemborexant is 10 mg once daily.
Time to sleep onset may be delayed if taken with or soon after a meal.
Patients should be advised not to consume alcohol in combination with lemborexant.
Use with CYP3A Inhibitors: Co-administration with Moderate or Strong CYP3A Inhibitors: Avoid concomitant use of lemborexant 5 or 10 mg with moderate or strong CYP3A inhibitors.
Co-administration with Weak CYP3A Inhibitors: The maximum recommended dose of lemborexant is 5 mg when co-administered with weak CYP3A inhibitors.
Use with CYP3A Inducers: Co-administration with Moderate or Strong CYP3A Inducers: Avoid concomitant use of lemborexant with moderate or strong CYP3A inducers.
Special Populations: Renal Impairment: No dose adjustment is required in patients with mild, moderate, or severe renal impairment.
Hepatic Impairment: No dose adjustment is required in patients with mild hepatic impairment. The maximum recommended dose of lemborexant is 5 mg in patients with moderate hepatic impairment. Lemborexant is not recommended in patients with severe hepatic impairment.
Geriatric Patients: There were no clinically meaningful differences in safety or effectiveness observed between elderly patients (≥65 years) and adult patients at the recommended doses. No dose adjustment is required in geriatric patients.
Of the total number of patients treated with lemborexant (n=1418) in controlled Phase 3 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 a pooled analysis of Study 303 (the first 30 days) and Study 304, the incidence of somnolence in patients ≥65 years with lemborexant 10 mg was higher (9.8%) compared to 7.7% in patients <65 years. The incidence of somnolence with lemborexant 5 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.
Pediatric Patients: The safety and effectiveness of lemborexant have not been established in pediatric patients (below 18 years of age). Lemborexant is not recommended in pediatric patients.
Compromised Respiratory Function: Obstructive Sleep Apnea: In a study of patients with mild obstructive sleep apnea (apnea-hypopnea index <15 events per hour of sleep) lemborexant did not increase the frequency of apneic events or decrease mean peripheral capillary oxygen saturation. In a study of patients with moderate or severe obstructive sleep apnea (apnea-hypopnea index ≥15 events per hour of sleep), overall, lemborexant did not increase the frequency of apneic events or decrease mean peripheral capillary oxygen saturation.
Chronic Obstructive Pulmonary Disease: In a study of patients with moderate or severe chronic obstructive pulmonary disease (COPD), overall, lemborexant did not increase the frequency of apneic events or decrease mean peripheral capillary oxygen saturation.
Method of Administration: For oral use only.

There is limited clinical experience with lemborexant overdose. In clinical pharmacology studies, healthy patients who were administered multiple doses of up to 75 mg (7.5 times the maximum recommended dose) of lemborexant showed dose-dependent increases in the frequency of somnolence.
There is no available specific antidote to an overdose of lemborexant. In the event of overdose, standard medical practice for the management of any overdose should be used.
A certified poison control center should be contacted for updated information.

Lemborexant, like other orexin receptor antagonist, is contraindicated in patients with narcolepsy.

Daytime Impairment: Lemborexant, like other sleep-promoting drugs, may impair daytime wakefulness even when used as prescribed. Prescribers should advise patients about the potential for next-day somnolence. The risk of daytime impairment is increased if lemborexant is taken with less than a full night of sleep remaining, or if a higher than the recommended dose is taken. The use of lemborexant with other drugs to treat insomnia is not recommended.
Abuse: In an abuse liability study conducted in recreational sedative abusers (n=39), lemborexant (10, 20 and 30 mg) produced similar effects as zolpidem (30 mg) and suvorexant (40 mg) on subjective ratings of "drug liking", "Overall Drug Liking," "Take Drug Again," and "Good Drug Effects" and other measures of subjective drug effects. Because individuals with a history of abuse or addiction to alcohol or other drugs may be at increased risk for abuse and addiction to lemborexant, follow such patients carefully.
Dependence: In both 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.
Effects on Ability to Drive and Use Machines: Although lemborexant at doses of 5 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 lemborexant. 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 lemborexant.

Pregnancy: There are no adequate and well-controlled studies in pregnant women. Lemborexant should only be used during pregnancy if the potential benefit justifies the potential risk to the foetus.
Administration of lemborexant to pregnant rats during organogenesis in 2 separate studies at oral doses of 60, 200, and 600 mg/kg/day or 20, 60, and 200 mg/kg/day resulted in growth delays, embryotoxicity and malformations at the dose of 600 mg/kg/day, which provided maternal plasma exposures that were 388 times the plasma exposure at the maximum recommended human dose (MRHD) based on AUC. The maternal exposure at the no observed adverse effect level (NOAEL) (200 mg/kg) was approximately 143 times the exposure at the MRHD based on AUC.
Administration of lemborexant to pregnant rabbits during organogenesis at doses of 10, 30, and 100 mg/kg resulted in a higher incidence of skeletal variations but no embryotoxicity or malformations at a dose of 100 mg/kg/day, which provided exposures approximately 139 times the exposure at the MRHD based on AUC. The exposure at the NOAEL (30 mg/kg) was 23 times the exposure at the MRHD based on AUC.
Oral administration of lemborexant (30, 100, and 300 mg/kg/day) to pregnant rats during gestation and lactation resulted in decreased body weights, femur length, and acoustic startle responses in offspring. The exposure at the NOAEL (100 mg/kg) was 93 times the exposure at the MRHD based on AUC.
Breast-feeding: Data from a clinical lactation study show the presence of trace quantities of lemborexant in human milk. The relevant infant dose (RID) is less than 2% of the maximum approved adult dose of 10 mg. A milk-only lactation study was conducted in 8 healthy, adult lactating women. The mean amount of Lemborexant recovered in human milk was 0.0174 mg following a 10 mg maternal dose. The mean calculated daily infant oral dosage was 0.0029 mg/kg/day based on a standardized milk consumption of 150 mL/kg/day.
There are no data on the effects of lemborexant on the breastfed infant, or the effects on milk production. Infants exposed to lemborexant through breastmilk should be monitored for excessive sedation. The developmental and health benefits of breast-feeding should be considered along with the mother's clinical need for lemborexant and any potential adverse effects on the breastfed infant from Lemborexant or from the underlying maternal condition.
Fertility: In female rats administered lemborexant (oral doses of 30, 100, or 1000 mg/kg/day) prior to and throughout mating and continuing to gestation Day 6, effects on female fertility were observed at doses of 100 and 1000 mg/kg/day (approximately 60 and 545 times the exposure at the MRHD based on AUC). Irregular estrous cycle and decreased pregnancy rate were observed at 100 and 1000 mg/kg/day and decreased numbers of corpora lutea, implantations, and live embryos were noted at 1000 mg/kg/day. 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.

Clinical Trial Experience: Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
In controlled efficacy trials (Study 303 and Study 304), 1418 patients were exposed to lemborexant. In Study 303, 434 patients were treated with lemborexant for one year.
Adverse Reactions Resulting in Discontinuation of Treatment: The incidence of discontinuation due to adverse reactions for patients treated with 5 mg or 10 mg of lemborexant was 3.5% for 5 mg and 6.1% for 10 mg compared to 2.7% for placebo.
The most common adverse reaction leading to discontinuation was somnolence (lemborexant 5 mg 1.1%, lemborexant 10 mg 2.3%, placebo 0.6%).
Most Common Adverse Reactions: In clinical trials of patients with insomnia treated with lemborexant 5 mg or 10 mg, the most common adverse reaction (reported in 5% or more of patients treated with lemborexant and at a higher rate than placebo) was somnolence (lemborexant 5 mg 6.6%, lemborexant 10 mg 10.5%, placebo 1.6%). The majority of the adverse reactions of somnolence were mild in severity. (See Table 4.)

Click on icon to see table/diagram/image

Other Adverse Reactions: Sleep Paralysis: Sleep paralysis, an inability to move or speak for up to several minutes during sleep-wake transitions, can occur with the use of lemborexant. In clinical trials, lemborexant was associated with sleep paralysis: lemborexant 5 mg 1.1% or lemborexant 10 mg 1.6% compared to no reports for placebo.

Potential for Other Medicinal Products to Affect Lemborexant: Weak, Moderate and Strong CYP3A Inhibitors: Metabolism by CYP3A is the major elimination pathway of lemborexant. Co-administration of lemborexant with moderate CYP3A inhibitors (e.g., fluconazole) or strong CYP3A inhibitors (e.g., itraconazole) increased the exposure (AUC) of lemborexant by approximately 4-fold and Cmax by 1.6-fold. Other moderate and strong inhibitors of CYP3A would be expected to have similar effects on plasma levels of lemborexant.
Using a physiologically based pharmacokinetic (PBPK) model, a weak effect is predicted when weak CYP3A inhibitors (e.g., fluoxetine) are co-administered with lemborexant. Avoid concomitant use of lemborexant 5 or 10 mg with moderate or strong CYP3A inhibitors. The maximum recommended dose of lemborexant is 5 mg when co-administered with weak CYP3A inhibitors.
Moderate and Strong CYP3A Inducers: Avoid co-administration of lemborexant with moderate or strong CYP3A inducers. Co-administration with a strong CYP3A inducer resulted in a 97% reduction in lemborexant systemic exposure. This may result in a decrease in efficacy.
In Vitro Studies with Transporters: Lemborexant is a poor substrate of P-gp, but its major metabolite (M10) is a substrate of P-gp. Lemborexant and M10 are not substrates of BCRP, OATP1B1, or OATP1B3.
Alcohol: Lemborexant Cmax and AUC increased by 35% and 70%, respectively, when co-administered with alcohol. Lemborexant did not affect alcohol concentrations. Alcohol should not be consumed with lemborexant.
Potential for Lemborexant to Affect Other Medicinal Products: Clinical Studies with Substrates of CYP3A or CYP2B6: Lemborexant does not induce or inhibit CYP3A as shown by the absence of a drug-drug interaction with midazolam (a CYP3A substrate). Lemborexant weakly induces CYP2B6 based on study with bupropion as a CYP2B6 substrate. Substrates of CYP3A4 and CYP2B6 can be co-administered with lemborexant.
In Vitro Studies with Substrates of CYP: In vitro, lemborexant has a potential to induce CYP3A and a weak potential to inhibit CYP3A and induce CYP2B6. Lemborexant and M10 do not have the potential to inhibit other CYP isoforms. Lemborexant and M10 do not induce CYP2C8, CYP2C9, and CYP2C19 at clinically relevant concentrations.
In Vitro Studies with Substrates of Transporters: Lemborexant and M10 do not have the potential to inhibit P-gp, BCRP, BSEP, OAT1, OAT3, OATP1B1, OATP1B3, OCT1, OCT 2, MATE1, and MATE2-K.

Special Precautions for Handling and Disposal: Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

Store at temperatures not exceeding 30°C.

Hypnotics & Sedatives

N05CJ02 - lemborexant ; Belongs to the class of orexin receptor antagonists. Used as hypnotics.

Rx