AHFS Class:

• Orexin Receptor Antagonists 28:24.40

Generic Name(s):

• Lemborexant

Chemical Name:

• (1 R ,2 S )-2-[(2,4-dimethylpyrimidin-5-yl)oxymethyl]-2-(3-fluorophenyl)- N -(5-fluoropyridin-2-yl)cyclopropane-1-carboxamide

Molecular Formula:

• C₂₂H₂₀F₂N₄O₂

Lemborexant, an orexin receptor antagonist, is a hypnotic agent.1,7,8,9

Insomnia

Lemborexant is used for the treatment of insomnia characterized by difficulty with sleep onset and/or sleep maintenance.1 In controlled clinical studies, lemborexant demonstrated efficacy in improving sleep onset and sleep maintenance compared with placebo.1,3,4

Efficacy of lemborexant in the management of insomnia was established in 2 multicenter, randomized, double-blind controlled studies (SUNRISE 1 and SUNRISE 2) in adults who met DSM-5 criteria for insomnia disorder.1

SUNRISE 1 was a placebo- and active-controlled study of 1 month's duration in 1006 older adults (i.e., women ≥55 years of age and men ≥65 years of age) with insomnia.1,3 Patients were randomized to receive lemborexant 5 mg, lemborexant 10 mg, zolpidem tartrate 6.25 mg, or placebo once nightly for 30 days.1,3 In this study, the efficacy endpoints were measured objectively using polysomnographic monitoring at baseline, and during the first 2 nights of treatment and the last 2 nights of treatment (days 29 and 30).1,3 At days 29 and 30, both dosages of lemborexant were superior to placebo for decreasing sleep latency, as assessed by polysomnographic latency to persistent sleep (LPS).1,3 Lemborexant also was superior to placebo in improving objective measures of sleep maintenance as assessed by polysomnographic sleep efficiency (SEF) and polysomnographic wake after sleep onset (WASO).1,3 Improvements in these measures of sleep latency and sleep maintenance were apparent when measured during the first 2 nights of treatment and the last 2 nights of treatment (days 29 and 30).3

SUNRISE 2 was a placebo-controlled study of 6 months' duration in 971 adults with insomnia disorder.1,2 Patients were randomized to receive lemborexant 5 mg, lemborexant 10 mg, or placebo once nightly.1,2 In this study, the efficacy endpoints were assessed subjectively using patient-reported sleep diaries.1,2 At 6 months, both dosages of lemborexant were superior to placebo for decreasing sleep latency, as assessed by patient-reported subjective sleep onset latency (sSOL).1,2 Lemborexant also was superior to placebo in improving patient-reported measures of sleep maintenance, as assessed by subjective sleep efficiency (sSEF) and subjective wake after sleep onset (sWASO).1,2 Improvements in these measures of sleep latency and sleep maintenance were apparent within the first week of treatment and were maintained throughout the study.2

General

Pretreatment Screening

• Because sleep disturbances may be a manifestation of a physical and/or psychiatric disorder, symptomatic treatment of insomnia should be initiated only after careful evaluation of the patient.1

Administration

Lemborexant is administered orally; the drug should be administered no more than once per night, immediately before going to bed and at least 7 hours before the planned time of awakening.1

Administration with or soon after a meal decreases the rate of drug absorption and may delay the onset of effect.1

Dosage

For the management of insomnia, the recommended adult dosage of lemborexant is 5 mg administered no more than once per night immediately before bedtime.1 Dosage may be increased based on clinical response and tolerability to a maximum of 10 mg taken no more than once per night.1

Dosage Modification for Concomitant Therapy

When administered concomitantly with a weak cytochrome P-450 (CYP) 3A inhibitor, the recommended maximum dosage of lemborexant is 5 mg taken no more than once per night.1 Concomitant use of strong or moderate CYP3A inhibitors or strong or moderate CYP3A inducers should be avoided.1

Special Populations

Hepatic Impairment

In patients with moderate hepatic impairment, the maximum recommended dose of lemborexant is 5 mg no more than once per night.1 Use of lemborexant is not recommended in patients with severe hepatic impairment.1

Renal Impairment

Dosage adjustments of lemborexant are not necessary in patients with renal impairment.1

Geriatric Patients

In geriatric patients, the manufacturer states that doses higher than 5 mg should be used with caution.1

Contraindications

• Patients with narcolepsy.1

Warnings/Precautions

CNS Depressant Effects, Middle of the Night Safety, and Daytime Impairment

Lemborexant, like other hypnotic agents, has CNS depressant effects and may impair daytime wakefulness even when used as prescribed.1 Such effects may persist for up to several days after discontinuance of the drug.1 The CNS depressant effects of lemborexant may increase the risk of falls, particularly in geriatric patients.1

The risk of daytime impairment is increased if lemborexant is taken with less than a full night of sleep remaining, if a higher than recommended dose of lemborexant is administered, or if lemborexant is used concomitantly with other CNS depressants.1 Patients taking lemborexant under these circumstances, including those receiving a 10-mg dose of lemborexant, should be cautioned against driving and other activities requiring complete mental alertness the day after use.1

The effect of lemborexant on next-morning driving performance was evaluated in a randomized, active- and placebo-controlled, crossover study in 48 healthy adults, half of whom were ≥65 years of age.1,6 Overall, single-dose and multiple-day dosing with lemborexant 5 and 10 mg did not have clinically important effects on standard driving performance tests compared with placebo when assessed 9 hours following bedtime administration.1,6 However, impaired driving ability was reported in some individuals taking the 10-mg dose of lemborexant.1,4 Because of potential individual variation in sensitivity to lemborexant, patients receiving the 10-mg dose of lemborexant should be cautioned about the potential for next-morning driving impairment.1,4

The effect of lemborexant on middle of the night safety was evaluated in a randomized, placebo- and active-controlled trial in healthy older individuals (women ≥55 years of age and men ≥65 years of age).1 In this study, impairments in postural stability, attention, and memory were observed during a scheduled awakening 4 hours following administration of lemborexant 5 and 10 mg at bedtime.1 No substantial differences between lemborexant or placebo on the ability to awaken to sound in the middle of the night were observed.1 Patients should be cautioned about the potential for impairments in balance, attention, and memory in the middle of the night following use of lemborexant.1

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 transition) and hypnagogic/hypnopompic hallucinations, including vivid and disturbing perceptions, may occur in patients taking lemborexant.1 In addition, symptoms similar to mild cataplexy (e.g, leg weakness lasting from seconds to a few minutes) may occur either at night and/or during the day and may not be associated with an identified triggering event (e.g., laughter or surprise).1 Patients should be informed of the possibility of these effects.1

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 following use of hypnotic agents, including lemborexant.1 Patients usually did not remember experiencing these complex sleep behaviors.1 These events can occur in hypnotic agent-naive as well as in hypnotic agent-experienced patients, and can occur following the first dose or at any time during treatment with lemborexant, with or without concomitant use of alcohol or other CNS depressants.1

Discontinue lemborexant immediately if a complex sleep behavior occurs.1

Patients with Compromised Respiratory Function

Effects of lemborexant on respiratory function should be considered if the drug is used in patients with compromised respiratory function.1 In a randomized, placebo-controlled crossover study in 39 patients with mild obstructive sleep apnea (OSA; apnea-hypopnea index [AHI] of ≥5 and <15 events per hour of sleep), lemborexant 10 mg administered for 8 consecutive nights was not associated with increased AHI or oxygen desaturation.1,5 Lemborexant has not been studied in patients with moderate to severe OSA or in patients with chronic obstructive pulmonary disease (COPD); the manufacturer states that clinically meaningful respiratory effects of the drug in these patients cannot be excluded.1

Worsening of Depression and Suicidal Ideation

A higher incidence of suicidal ideation or behavior has been observed in patients receiving lemborexant compared with placebo for the treatment of insomnia in controlled clinical studies.1

Worsening of depression and suicidal thoughts and actions (including completed suicides) have been reported in primarily depressed patients receiving sedative and hypnotic agents.1 Suicidal tendencies may be present in such patients and protective measures may be required.1 Intentional overdose is more common in this patient population; therefore, the least amount of drug that is feasible should be prescribed and dispensed at any one time.1 Immediately evaluate the patient if emergence of any new behavioral abnormalities occurs during lemborexant therapy.1

Adequate Patient Evaluation

Because sleep disturbances may be a manifestation of a physical and/or psychiatric disorder, symptomatic treatment of insomnia should be initiated only after careful evaluation of the patient.1 Failure of insomnia to remit after 7-10 days of lemborexant therapy, worsening of insomnia, or emergence of new cognitive or behavioral abnormalities may indicate the presence of an underlying psychiatric, physical, and/or medical condition requiring evaluation.1

Patients should be reevaluated if insomnia persists after 7-10 days of treatment with lemborexant.1

Abuse Potential and Dependence

Lemborexant is a schedule IV controlled substance (C-IV).1

In an abuse-potential study conducted in recreational sedative drug users, administration of high doses of lemborexant (10-30 mg) produced positive subjective responses (e.g., “drug liking”, “take drug again”) similar to those produced by higher than recommended doses of zolpidem tartrate (30 mg) and suvorexant (40 mg).1 Because patients with a history of drug or alcohol abuse or addiction are at increased risk for abuse of and addiction to lemborexant, such patients should be monitored carefully when receiving the drug.1

In clinical studies, there was no evidence of insomnia or withdrawal effects following discontinuance of lemborexant.1

Specific Populations

Pregnancy

There are no adequate data on the use of lemborexant in pregnant women to evaluate the risk of adverse developmental effects or adverse maternal or fetal outcomes.1 In animal reproduction studies in rats and rabbits administered lemborexant during pregnancy, developmental and maternal toxicities were observed only at high multiples of the exposure achieved in humans at the maximum recommended human dosage.1

A pregnancy registry has been established to monitor pregnancy outcomes in women exposed to lemborexant during pregnancy; clinicians are encouraged to register patients by calling 888-274-2378.1

Lactation

Lemborexant and its metabolites are distributed into milk in rats; it is not known whether the drug or its metabolites are distributed into human milk.1 The effects of the drug on the breast-fed infant or on milk production also are unknown.1 Consider the developmental and health benefits of breast-feeding along with the mother's clinical need for the drug and any potential adverse effects on the breast-fed infant from the drug or underlying maternal condition.1

The manufacturer states that infants exposed to lemborexant through breast milk should be monitored for excessive sedation.1

Pediatric Use

Safety and efficacy of lemborexant have not been established in pediatric patients.1

Geriatric Use

In controlled clinical studies, 34.6% of patients who received lemborexant were ≥65 years of age and 6.1% were ≥75 years of age.1 The overall efficacy of lemborexant was similar between geriatric patients and younger patients.1 However, among patients receiving the 10-mg dose, those ≥65 years of age had a higher incidence of somnolence compared with younger patients (9.8 versus 7.7%).1 The incidence of somnolence with the 5-mg dose was similar between the age groups.1

Because of the CNS depressant effects of lemborexant, geriatric patients in particular are at higher risk of falls.1 The manufacturer states that doses higher than 5 mg should be used with caution in patients ≥65 years of age.1

Hepatic Impairment

In individuals with mild hepatic impairment (Child-Pugh class A), peak plasma concentrations and AUC of lemborexant were increased by 58 and 25%, respectively, but half-life of the drug was not substantially affected.1,4 Although no dosage adjustment of lemborexant is recommended in patients with mild hepatic impairment, such patients may have an increased risk of somnolence.1

In individuals with moderate hepatic impairment (Child-Pugh class B), peak plasma concentrations and AUC of lemborexant were increased by 22 and 54%, respectively, and half-life of the drug was prolonged from 67 hours to 105 hours.1,4 In patients with moderate hepatic impairment, the initial and maximum dosage of lemborexant is 5 mg no more than once per night.1

Lemborexant has not been studied in patients with severe hepatic impairment and use of the drug in such patients is not recommended.1

Renal Impairment

In individuals with severe renal impairment (estimated glomerular filtration rate [eGFR] of 15-29 mL/minute per 1.73 m² and not requiring dialysis), lemborexant AUC was 1.5-fold higher than in individuals with normal renal function, but peak plasma concentrations and half-life were not substantially affected.4

Dosage adjustments of lemborexant are not necessary in patients with renal impairment; however patients with severe renal impairment may have an increased risk of somnolence.1

Common Adverse Effects

The most common adverse effect of lemborexant reported in ≥5% of patients receiving the drug in clinical studies was somnolence.1

Lemborexant is metabolized principally by cytochrome P-450 (CYP) isoenzyme 3A4 and, to a lesser extent, by CYP3A5.1 The major active metabolite, M10, is a substrate of P-glycoprotein (P-gp), and lemborexant is a potential poor substrate of P-gp.1

Lemborexant and M10 do not inhibit CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, P-gp, breast cancer resistance protein (BCRP), bile salt export pump (BSEP), organic anion transporter (OAT)1, OAT3, organic anion-transporting polypeptide (OATP)1B1, OATP1B3, organic cation transporter (OCT)1, OCT2, multidrug and toxin extrusion transporter (MATE)1, and MATE2-K.1

Lemborexant and M10 have the potential to induce CYP3A, inhibit CYP3A, and induce CYP2B6 in vitro.1

Lemborexant and M10 do not induce CYP2C8, CYP2C9, and CYP2C19 at clinically relevant concentrations.1

Drugs Affecting Hepatic Microsomal Enzymes

CYP3A Inhibitors

Concomitant use of lemborexant with CYP3A inhibitors may result in increased plasma concentrations and adverse effects of lemborexant.1

Concomitant use of lemborexant and potent (e.g., itraconazole, clarithromycin) or moderate (e.g., fluconazole, verapamil) CYP3A inhibitors should be avoided.1

Physiologically-based pharmacokinetic modeling predicted that concomitant use of weak CYP3A inhibitors increased lemborexant exposure by less than 2-fold.1 In patients receiving weak CYP3A inhibitors (e.g., chlorzoxazone, ranitidine), the maximum recommended dose of lemborexant is 5 mg no more than once per night.1

CYP3A Inducers

Concomitant use of lemborexant with a potent or moderate CYP3A inducer may result in decreased systemic exposure and efficacy of lemborexant.1

Concomitant use of lemborexant and a potent (e.g., rifampin, carbamazepine, St. John's wort) or moderate (e.g., bosentan, efavirenz, etravirine, modafinil) CYP3A inducer should be avoided.1

Drugs Metabolized by Hepatic Microsomal Enzymes

Substrates of CYP2B6

Concomitant use of lemborexant and drugs that are metabolized by CYP2B6 (e.g., bupropion, methadone) may result in decreased systemic exposure and decreased efficacy of the CYP2B6 substrate.1

The manufacturer of lemborexant states that if the drug is used concomitantly with a CYP2B6 substrate, patients should be monitored for reduced efficacy of the CYP2B6 substrate and a dosage increase of the CYP2B6 substrate may be considered as clinically appropriate.1

Substrates of CYP2C8, CYP2C9, or CYP2C19

Based on physiologically-based pharmacokinetic modeling, lemborexant is expected to have minimal effect on the pharmacokinetics of CYP2C8, CYP2C9, or CYP2C19 substrate drugs.1

Bupropion

Concomitant use of lemborexant and bupropion (a CYP2B6 substrate) decreased peak plasma concentration and AUC of S -bupropion by 49.9 and 45.5%, respectively, and of ( S,S )-hydroxybupropion by 17 and 24.5%, respectively.1,4

The manufacturer of lemborexant states that if the drug is used concomitantly with a CYP2B6 substrate, patients should be monitored for reduced efficacy of the CYP2B6 substrate and a dosage increase of the CYP2B6 substrate may be considered as clinically appropriate.1

CNS Depressants

Concomitant use of lemborexant and other CNS depressants (e.g., alcohol, benzodiazepines, opiates, tricyclic antidepressants) may result in additive CNS depression and impaired daytime wakefulness.1 When lemborexant is used concomitantly with other CNS depressant drugs, dosage reduction of lemborexant and/or the CNS depressant may be necessary.1 Concomitant use of lemborexant with other hypnotic agents is not recommended.1

Alcohol

Concomitant use of lemborexant and alcohol increases peak plasma concentration and AUC of lemborexant by 35 and 70%, respectively,1,4 but had no effect on alcohol concentrations.4

In a placebo-controlled study, concomitant use of lemborexant and alcohol was associated with greater impairments in postural stability and cognitive performance at 2 hours post-dose (at approximately peak plasma lemborexant concentration) compared with use of alcohol alone.1,4

Alcohol consumption should be avoided during therapy with lemborexant.1

Famotidine

Concomitant use of lemborexant and famotidine had no clinically important effects on the pharmacokinetics of lemborexant.1,4

Fluconazole

Concomitant use of lemborexant and fluconazole (a moderate CYP3A inhibitor) increased lemborexant peak plasma concentration and AUC by 1.6- and 4.2-fold, respectively.4 Concomitant use should be avoided.1

Itraconazole

Concomitant use of lemborexant and itraconazole (a potent CYP3A inhibitor) increased lemborexant peak plasma concentration and AUC by 1.4- and 3.7-fold, respectively.4 Concomitant use should be avoided.1

Midazolam

Concomitant use of lemborexant and midazolam had no clinically important effects on the pharmacokinetics of midazolam.4

Oral Contraceptives

No clinically important pharmacokinetic interactions have been observed with concomitant use of lemborexant and an oral contraceptive containing ethinyl estradiol and norethindrone.1,4

Ranitidine

Concomitant use of lemborexant and ranitidine (a weak CYP3A inhibitor) is predicted to increase peak plasma concentration and AUC of lemborexant by 1.13- and 1.58-fold, respectively, based on pharmacokinetic modeling.4 The maximum recommended dose of lemborexant is 5 mg no more than once per night if used concomitantly with ranitidine.1

Rifampin

Concomitant use of lemborexant and rifampin (a potent CYP3A inducer) decreased lemborexant peak plasma concentration and AUC by 91 and 97%, respectively.4 Concomitant use should be avoided.1

Description

Lemborexant is a dual orexin-1 and orexin-2 receptor antagonist.1,7,8,9 The mechanism of action of lemborexant in the treatment of insomnia is thought to be related to antagonism of orexin receptors.1 The orexin neuropeptide signaling system, comprising the neuropeptides orexin A and orexin B and orexin receptor types 1 and 2, plays a role in promoting and maintaining wakefulness.1,7,8,9 Orexins A and B (also known as hypocretins) are produced in the lateral hypothalamus and activate orexin receptors which are distributed throughout the brain.7,8,9 Loss of orexin-producing neurons and decreased CSF orexin concentrations have been associated with narcolepsy and cataplexy in humans,7,8,9 while increased orexin activity may be associated with insomnia.7,9 Lemborexant binds to orexin-1 and orexin-2 receptors and competitively blocks the binding of orexin A and B;1 blockade of these receptors is thought to suppress the wake drive and promote sleep.1,7,8

The pharmacokinetics of lemborexant increase in a slightly less than dose proportional manner over a single oral dose range of 2.5-75 mg; steady-state accumulation is 1.5- to threefold across this dose range.1 Following oral administration, peak plasma concentrations of lemborexant are achieved in approximately 1-3 hours.1 Administration of lemborexant with a high-fat, high-calorie meal delays time to peak plasma concentration by 2 hours, decreases peak plasma concentrations by 23%, and increases AUC by 18% compared with administration in the fasted state.1,4 Lemborexant is approximately 88-94% bound to plasma proteins.1 Lemborexant is metabolized principally by CYP3A4 and, to a lesser extent, by CYP3A5.1 The major circulating metabolite, M10, is pharmacologically active with comparable binding affinity for orexin-1 and orexin-2 receptors as the parent drug.1 Following oral administration, 57.4% of the dose is excreted in the feces and 29.1% in the urine; less than 1% is excreted as unchanged drug.1 The half-life of lemborexant is 17 or 19 hours following oral doses of 5 or 10 mg, respectively.1

The pharmacokinetics of lemborexant are not affected by age, sex, race/ethnicity, or body mass index.1

Advice to Patients

• Advise patients to read the manufacturer's medication guide.1
• Advise patients to take lemborexant only when preparing for or getting into bed and only when able to stay in bed for at least 7 hours before it is necessary to be active again.1 Advise patients that taking lemborexant with or soon after a meal may delay its effect.1
• Inform patients that lemborexant can cause CNS depressant effects and impair daytime wakefulness even when used as prescribed.1 CNS depressant effects may increase the risk of falls in some patients.1 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 recommended dose is taken; patients should be cautioned to avoid driving or other activities requiring complete mental alertness if the drug is taken under these circumstances.1
• Inform patients and their families that sleep paralysis, hypnagogic/hypnopompic hallucinations, and mild cataplexy-like symptoms may occur.1
• Risk of complex sleep behaviors, including sleep-walking, sleep-driving, preparing and eating food, making phone calls, or having sex while not being fully awake.1 Advise patients to discontinue lemborexant and immediately contact a clinician if a complex sleep behavior occurs.1
• Advise patients to be alert to and immediately report worsening depression or suicidal ideation.1
• Inform patients about the abuse potential of the drug.1 Advise patients to not increase the dose unless otherwise instructed by a clinician and to inform a clinician if insomnia worsens or does not improve.1
• Advise women to inform their clinicians if they are or plan to become pregnant or plan to breast-feed.1 Advise patients of the existence of a pregnancy registry that monitors pregnancy outcomes in women exposed to the drug during pregnancy.1
• Inform clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements, as well as any concomitant or past illnesses (e.g., depression, substance abuse, sleep apnea).1
• Inform patients of other important precautionary information.1 (See Cautions.)

Additional Information

Overview^® (see Users Guide). For additional information on this drug until a more detailed monograph is developed and published, the manufacturer's labeling should be consulted. It is essential that the manufacturer's labeling be consulted for more detailed information on usual cautions, precautions, contraindications, potential drug interactions, laboratory test interferences, and acute toxicity.

1. Eisai Inc. Dayvigo^® (lemborexant) tablets prescribing information. Woodclif Lake, NJ; 2022 Mar. [Web]

2. Kärppä M, Yardley J, Pinner K et al. Long-term efficacy and tolerability of lemborexant compared with placebo in adults with insomnia disorder: results from the phase 3 randomized clinical trial SUNRISE 2. Sleep . 2020; [PubMed 32585700]

3. Rosenberg R, Murphy P, Zammit G et al. Comparison of Lemborexant With Placebo and Zolpidem Tartrate Extended Release for the Treatment of Older Adults With Insomnia Disorder: A Phase 3 Randomized Clinical Trial. JAMA Netw Open . 2019; 2:e1918254. [PubMedCentral][PubMed 31880796]

4. US Food and Drug Administration. Center for Drug Evaluation and Research. Application number 212028Orig1s000: Multi-discipline review. From FDA website. [Web]

5. Cheng JY, Filippov G, Moline M et al. Respiratory safety of lemborexant in healthy adult and elderly subjects with mild obstructive sleep apnea: A randomized, double-blind, placebo-controlled, crossover study. J Sleep Res . 2020; :e13021. [PubMed 32187781]

6. Vermeeren A, Jongen S, Murphy P et al. On-the-road driving performance the morning after bedtime administration of lemborexant in healthy adult and elderly volunteers. Sleep . 2019; 42 [PubMedCentral][PubMed 30597112]

7. Wang C, Wang Q, Ji B et al. The Orexin/Receptor System: Molecular Mechanism and Therapeutic Potential for Neurological Diseases. Front Mol Neurosci . 2018; 11:220. [PubMedCentral][PubMed 30002617]

8. Janto K, Prichard JR, Pusalavidyasagar S. An Update on Dual Orexin Receptor Antagonists and Their Potential Role in Insomnia Therapeutics. J Clin Sleep Med . 2018; 14:1399-1408. [PubMedCentral][PubMed 30092886]

9. Herring WJ, Roth T, Krystal AD et al. Orexin receptor antagonists for the treatment of insomnia and potential treatment of other neuropsychiatric indications. J Sleep Res . 2019; 28:e12782. [PubMed 30338596]