Lemborexant

Indications

• FDA-approved for the treatment of insomnia characterized by difficulties with sleep onset, sleep maintenance, or both, in adults.
• Efficacy and tolerability were maintained across 12 months in the SUNRISE-2 trial, supporting longer-term use than most hypnotics.
• In SUNRISE-1 it improved objective sleep-onset latency and sleep efficiency more than zolpidem extended release in adults over 55.
• It is a reasonable choice when a patient cannot tolerate Z-drugs or when complex sleep behaviors have already occurred on zolpidem.
• Off-label interest exists in irregular sleep-wake rhythm in Alzheimer disease, where orexin antagonists have preliminary support.
• Contraindicated in narcolepsy, since orexin signaling is already deficient and further blockade worsens cataplexy and sleep attacks.

Mechanism of action

• Dual orexin receptor antagonist with competitive binding at both OX1R and OX2R and faster dissociation from OX2R than OX1R.
• Blocks the wake-promoting orexin signal from lateral hypothalamus to histaminergic, noradrenergic and serotonergic arousal nuclei.
• Because it suppresses arousal rather than depressing the CNS globally, sleep architecture is preserved and REM sleep increases.
• No GABA-A activity means no muscle relaxation, no anticonvulsant effect, and less amnesia than benzodiazepine hypnotics produce.
• Orexin deficiency is the pathology of narcolepsy, which explains the contraindication and the sleep paralysis reported on treatment.

Pharmacokinetics

• Peak concentrations occur at 1-3 hours; a high-fat meal delays the peak by about 2 hours and lowers peak concentration by 23 percent.
• Elimination half-life is 17-19 hours and is dose dependent, which is why next-morning residual effects are the dose-limiting issue.
• Metabolized principally by CYP3A4 with a CYP3A5 contribution; the main metabolite M10 is active but circulates at low levels.
• Excretion is largely fecal at about 57 percent with roughly 29 percent in urine, and less than 1 percent is excreted unchanged.
• Exposure roughly doubles in moderate hepatic impairment, which caps the dose at 5 mg; severe hepatic impairment is not recommended.

Dosing

• Adults: 5 mg PO once nightly immediately before going to bed, with at least 7 hours remaining before planned awakening.
• The dose may be increased to a maximum of 10 mg once nightly based on response and tolerability after adequate trial at 5 mg.
• With a weak or moderate CYP3A inhibitor, cap the dose at 5 mg nightly; concomitant strong CYP3A inhibitors should be avoided.
• Moderate hepatic impairment: maximum 5 mg nightly; use in severe hepatic impairment is not recommended.
• No dose adjustment is needed for renal impairment at any stage, including severe renal impairment.
• No taper is required on discontinuation, and rebound insomnia and withdrawal are not seen as they are with benzodiazepines.

Adverse effects

• Somnolence or fatigue in about 7 percent at 5 mg and 10 percent at 10 mg, headache 6 percent, and abnormal dreams or nightmares.
• Next-morning driving impairment demonstrated at the 10 mg dose, so counsel patients about morning activities requiring alertness.
• Sleep paralysis, hypnagogic and hypnopompic hallucinations, and mild cataplexy-like leg weakness reflecting orexin receptor blockade.
• Complex sleep behaviors including sleepwalking and sleep-driving have been reported, and any episode should prompt discontinuation.
• Worsening of depression and suicidal ideation have been reported; assess mood before starting and at each follow-up visit.
• Additive respiratory depression with opioids and alcohol, and caution is warranted in severe obstructive sleep apnea or COPD.

Monitoring

• Assess next-morning alertness and driving safety, particularly at the 10 mg dose and in the first weeks of treatment.
• Ask specifically about sleep paralysis, hallucinations on falling asleep or waking, leg weakness and complex sleep behaviors.
• Screen for depression and suicidal ideation before initiating and at each visit, since worsening mood has been reported.
• Evaluate and treat obstructive sleep apnea, restless legs, alcohol use and chronic pain before or alongside hypnotic therapy.
• Check the prescription monitoring program before prescribing this schedule IV agent and periodically reassess ongoing need.

Interactions

• Concomitant strong CYP3A inhibitors such as ketoconazole, itraconazole and clarithromycin should be avoided altogether.
• Weak and moderate CYP3A inhibitors including fluconazole, verapamil and diltiazem require capping the dose at 5 mg nightly.
• Strong and moderate CYP3A inducers such as rifampin, carbamazepine and efavirenz substantially reduce exposure and efficacy.
• Additive sedation and respiratory depression with opioids, alcohol, benzodiazepines, gabapentinoids and sedating antihistamines.
• Contraindicated in narcolepsy; use caution in patients with compromised respiratory function or severe untreated sleep apnea.

Special populations

• Pregnancy: human data are insufficient and animal studies showed developmental effects; a pregnancy exposure registry is available.
• Lactation: lemborexant is present in animal milk and human data are lacking; monitor a nursing infant for sedation and poor feeding.
• Pediatrics: safety and effectiveness under age 18 are not established and use is not recommended in that age group.
• Older adults: not flagged for avoidance in the AGS Beers Criteria, but the long half-life makes next-day sedation and falls a real concern.
• Hepatic and renal impairment: cap at 5 mg in moderate hepatic disease, avoid in severe; no renal dose adjustment is required.

Clinical pearls

• The only hypnotic here with head-to-head objective superiority over zolpidem ER in older adults.
• A 17-19 hour half-life is the trade-off for maintenance benefit; 10 mg impairs morning driving.
• Contraindicated in narcolepsy, and stop it outright after any complex sleep behavior.