Lemborexant (Monograph)

Brand name: Dayvigo
Drug class: Orexin Receptor Antagonists
Chemical name: (1R,2S)-2-[(2,4-dimethylpyrimidin-5-yl)oxymethyl]-2-(3-fluorophenyl)-N-(5-fluoropyridin-2-yl)cyclopropane-1-carboxamide
Molecular formula: C₂₂H₂₀F₂N₄O₂
CAS number: 1369764-02-2

Medically reviewed by Drugs.com on Jul 25, 2022. Written by ASHP.

Introduction

Hypnotic; orexin receptor antagonist.

Uses for Lemborexant

Insomnia

Treatment of insomnia characterized by difficulty with sleep onset and/or sleep maintenance.

Decreases sleep latency and improves sleep maintenance.

Lemborexant Dosage and Administration

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.

Administration

Oral Administration

Administer no more than once per night, immediately before going to bed.

Administration with or soon after a meal may delay the onset of effect.

Use only if ≥7 hours remain before planned time of awakening.

Dosage

Concomitant use with certain drugs (e.g., CNS depressants, CYP3A inhibitors) may require dosage adjustment.

Adults

Insomnia

Oral

5 mg no more than once at bedtime. May increase to maximum of 10 mg no more than once per night based on clinical response and tolerability.

Prescribing Limits

Adults

Insomnia

Oral

Maximum 10 mg no more than once per night.

Maximum of 5 mg no more than once per night when coadministered with a weak CYP3A inhibitor.

Special Populations

Hepatic Impairment

Moderate hepatic impairment: Maximum recommended dosage is 5 mg no more than once per night.

Severe hepatic impairment: Use not recommended.

Renal Impairment

No dosage adjustment necessary.

Geriatric Patients

Exercise caution when using doses higher than 5 mg in patients ≥65 years of age.

Cautions for Lemborexant

Contraindications

• Narcolepsy.

Warnings/Precautions

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

CNS depressant; may impair daytime wakefulness even when used as prescribed. May increase risk of falls, particularly in geriatric patients. May impair ability to drive a motor vehicle. Effects may persist for up to several days after drug discontinuance.

Risk of daytime impairment is increased if administered with less than a full night of sleep remaining, if a higher than recommended dose is administered, or if used concomitantly with other CNS depressants.

Caution patients against driving and other activities requiring complete mental alertness the day after use if the drug is taken under these circumstances or if a 10-mg dose is taken.

Caution patients about the potential for impairments in balance, attention, and memory in the middle of the night following use of the drug.

Sleep Paralysis, Hypnagogic/Hypnopompic Hallucinations, and Cataplexy-like Symptoms

Sleep paralysis (inability to move or speak for up to several minutes during sleep-wake transition) and hypnagogic/hypnopompic hallucinations reported. Symptoms similar to mild cataplexy (e.g., leg weakness lasting from seconds to a few minutes) may occur at night and/or during the day; may not be associated with an identified triggering event (e.g., laughter, surprise).

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) with no memory of the event reported following use of hypnotic agents, including lemborexant.

Complex sleep behaviors can occur in hypnotic agent-naive or -experienced patients, following the first dose or at any time during treatment, or with or without concomitant use of alcohol or other CNS depressants.

Discontinue lemborexant immediately if a complex sleep behavior occurs.

Patients with Compromised Respiratory Function

If used in patients with compromised respiratory function, consider possible effects on respiratory function.

Adverse effects on apnea-hypopnea index (AHI) or oxygen saturation not observed in patients with mild obstructive sleep apnea (OSA). Not studied in patients with moderate or severe OSA or COPD; respiratory effects in such patients cannot be excluded.

Worsening of Depression/Suicidal Ideation

Higher incidence of suicidal ideation observed in clinical studies.

Worsening of depression and suicidal thoughts and actions (including completed suicides) reported in primarily depressed patients receiving sedative and hypnotic agents. Suicidal tendencies may be present; intentional overdosage more frequent in such patients. Protective measures may be required.

Prescribe and dispense drug in the smallest feasible quantity.

Evaluate patient immediately if emergence of suicidality or any new behavioral abnormalities occurs.

Adequate Patient Evaluation

Sleep disturbances may be a manifestation of an underlying physical and/or psychiatric disorder; carefully evaluate patient before providing symptomatic treatment of insomnia. Failure of insomnia to remit after 7–10 days of treatment, worsening of insomnia, or emergence of new cognitive or behavioral abnormalities may indicate the presence of an underlying psychiatric or medical condition requiring evaluation.

Reevaluate patients if insomnia persists after 7–10 days of treatment.

Abuse Potential and Dependence

Abuse potential of high doses of lemborexant (10–30 mg) appears to be similar to that of higher than recommended doses of zolpidem tartrate (30 mg) and suvorexant (40 mg).

Patients with a history of drug or alcohol abuse or addiction are at increased risk of abuse and addiction; use only with careful monitoring in such patients.

Rebound insomnia or withdrawal effects not observed following discontinuance of the drug in clinical studies.

Specific Populations

Pregnancy

No adequate data in humans. In animal reproduction studies, developmental and maternal toxicities observed only at high multiples of the exposure achieved in humans at the maximum recommended human dosage.

Pregnancy registry: 888-274-2378.

Lactation

Lemborexant and its metabolites are distributed into milk in rats; not known whether distributed into human milk. Effects on milk production or on breast-fed infant also not known.

Consider benefits of breast-feeding and importance of the drug to the woman; also consider potential adverse effects on the breast-fed infant from the drug or underlying maternal condition.

Monitor infants for excessive sedation if they have been exposed to lemborexant through breast milk.

Pediatric Use

Safety and efficacy not established in pediatric patients.

Geriatric Use

No overall differences in efficacy relative to younger adults; however, higher incidence of somnolence in geriatric patients receiving the 10-mg dose compared with younger adults.

Geriatric patients particularly are at higher risk of falls.

Exercise caution if using doses higher than 5 mg in patients ≥65 years of age.

Hepatic Impairment

Mild hepatic impairment (Child-Pugh class A): Dosage adjustment not necessary; however, such patients may have an increased risk of somnolence.

Moderate hepatic impairment (Child-Pugh class B): Initial and maximum dosage of lemborexant is 5 mg no more than once per night.

Severe hepatic impairment: Not studied; use not recommended.

Renal Impairment

Dosage adjustment not necessary. Patients with severe renal impairment may have an increased risk of somnolence.

Common Adverse Effects

Somnolence.

Drug Interactions

Metabolized principally by CYP3A4 and, to a lesser extent, CYP3A5. Major active metabolite M10 is a substrate of P-glycoprotein (P-gp); lemborexant is a potential poor substrate of P-gp.

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.

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

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

Drugs Affecting Hepatic Microsomal Enzymes

CYP3A Inhibitors: Potential increased plasma concentrations and adverse effects of lemborexant. Avoid concomitant use with potent or moderate CYP3A inhibitors. If used concomitantly with a weak CYP3A inhibitor, maximum recommended lemborexant dose is 5 mg no more than once per night.

CYP3A Inducers: Potential decreased systemic exposure and efficacy of lemborexant. Avoid concomitant use with potent or moderate CYP3A inducers.

Drugs Metabolized by Hepatic Microsomal Enzymes

Substrates of CYP2B6: Potential decreased systemic exposure and efficacy of the CYP2B6 substrate. If used concomitantly, consider dosage increase of the CYP2B6 substrate, if clinically appropriate.

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

Specific Drugs

Lemborexant Pharmacokinetics

Absorption

Bioavailability

Peak plasma concentrations attained in approximately 1–3 hours.

Pharmacokinetics increase in a slightly less than dose proportional manner over single doses of 2.5–75 mg; steady-state accumulation is 1.5- to threefold across this dose range.

Food

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%.

Special Populations

Mild hepatic impairment (Child-Pugh class A): Peak plasma concentration and AUC increased by 58 and 25%, respectively; half-life not substantially affected.

Moderate hepatic impairment (Child-Pugh class B): Peak plasma concentration and AUC increased by 22 and 54%, respectively; half-life prolonged from 67 hours to 105 hours.

Severe renal impairment (eGFR of 15–29 mL/minute per 1.73 m² and not requiring dialysis): AUC increased 1.5-fold; peak plasma concentration and half-life not substantially affected.

Pharmacokinetics not affected by age, sex, race/ethnicity, or BMI.

Distribution

Plasma Protein Binding

Approximately 88–94%.

Elimination

Metabolism

Metabolized principally by CYP3A4 and, to a lesser extent, by CYP3A5. Major circulating metabolite, M10, is pharmacologically active with comparable binding affinity for orexin-1 and orexin-2 receptors as the parent drug.

Elimination Route

Excreted in feces (57.4%) and urine (29.1%); <1% as unchanged drug.

Half-life

17 or 19 hours following oral doses of 5 or 10 mg, respectively.

Stability

Storage

Oral

Tablets

20–25°C (excursions permitted between 15–30°C).

Actions

• Competitive antagonist at orexin-1 and orexin-2 receptors. Blockade of the actions of neuropeptides orexin A and B at these receptors is thought to suppress wake drive and promote sleep.

• The orexin neuropeptide signaling system plays a role in promoting and maintaining wakefulness. Loss of orexin-producing neurons and decreased CSF orexin concentrations have been associated with narcolepsy and cataplexy in humans, while increased orexin activity may be associated with insomnia.

Advice to Patients

• Advise patients to read the manufacturer's medication guide.

• 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. Advise patients that taking lemborexant with or soon after a meal may delay its effect.

• Inform patients that lemborexant can cause CNS depressant effects and impair daytime wakefulness even when used as prescribed. CNS depressant effects may increase the risk of falls in some patients. 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.

• Inform patients and their families that sleep paralysis, hypnagogic/hypnopompic hallucinations, and mild cataplexy-like symptoms may occur.

• 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. Advise patients to discontinue lemborexant and immediately contact a clinician if a complex sleep behavior occurs.

• Advise patients to be alert to and immediately report worsening depression or suicidal ideation.

• Inform patients about the abuse potential of the drug. 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.

• Advise women to inform their clinicians if they are or plan to become pregnant or plan to breast-feed. Advise patients of the existence of a pregnancy registry that monitors pregnancy outcomes in women exposed to the drug during pregnancy.

• 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).

• Inform patients of other important precautionary information. (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Lemborexant is subject to control under the Federal Controlled Substances Act of 1970 as a schedule IV (C-IV) drug.

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Frequently asked questions

• Is Dayvigo addictive?

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