Introduction
Dayvigo (lemborexant) is a dual orexin receptor antagonist approved by the FDA in December 2019 for the treatment of insomnia characterized by difficulties with sleep onset and/or sleep maintenance. It represents a novel mechanism of action in the sleep medication class, distinguishing itself from traditional GABAergic hypnotics.
Mechanism of Action
Lemborexant exerts its therapeutic effects by competitively antagonizing both orexin receptor types 1 and 2 (OX1R and OX2R). Orexins (hypocretins) are neuropeptides produced in the hypothalamus that promote wakefulness. By blocking the binding of orexin neuropeptides to their receptors, lemborexant suppresses wake drive, thereby facilitating sleep initiation and maintenance without generalized CNS depression.
Indications
- Treatment of insomnia characterized by difficulties with sleep onset
- Treatment of insomnia characterized by difficulties with sleep maintenance
Dosage and Administration
Recommended dosage: 5 mg taken no more than once per night, immediately before bedtime Maximum dosage: 10 mg (may be considered if 5 mg is well-tolerated but insufficient) Administration: Take within 30 minutes of going to bed, with at least 7 hours remaining before planned awakening Special populations:- Hepatic impairment: Not recommended in severe hepatic impairment
- Renal impairment: No dosage adjustment necessary
- Geriatric patients: Consider lower 5 mg dose
- CYP3A inhibitors: Avoid concomitant use with strong CYP3A inhibitors
Pharmacokinetics
Absorption: Rapid absorption with Tmax of 1-3 hours; high-fat meal delays absorption by approximately 2 hours Distribution: Volume of distribution ~1,000 L; protein binding ~94% Metabolism: Primarily via CYP3A4 with minor contribution from CYP3C19; forms inactive metabolites Elimination: Half-life ~17-19 hours; fecal excretion (~57%) predominates over renal excretion (~29%)Contraindications
- Narcolepsy
- Concomitant use with strong CYP3A inhibitors
- History of hypersensitivity to lemborexant or any component of the formulation
Warnings and Precautions
CNS Depression: May impair next-day alertness and performance; risk increases with higher doses Sleep Paralysis/Hypnagogic-Hypnopompic Hallucinations: Cases reported with orexin receptor antagonists Complex Sleep Behaviors: Risk of sleep-walking, sleep-driving, and other complex behaviors Respiratory Depression: Caution in patients with compromised respiratory function Worsening Depression/Suicidal Ideation: Monitor for emergence of depression symptoms Drug Abuse and Dependence: Schedule IV controlled substance; potential for abuse and dependenceDrug Interactions
Strong CYP3A inhibitors (e.g., ketoconazole, clarithromycin): Contraindicated - significantly increases lemborexant exposure Moderate CYP3A inhibitors (e.g., fluconazole, verapamil): Not recommended - may increase lemborexant exposure CYP3A inducers (e.g., rifampin, carbamazepine): May decrease efficacy CNS depressants (alcohol, benzodiazepines, opioids): Additive CNS depression effects Digoxin: May increase digoxin concentrations (monitor digoxin levels)Adverse Effects
Common (≥5%):- Somnolence (10%)
- Fatigue (5%)
- Headache (5%)
- Nightmare/abnormal dreams
- Dry mouth
- Dizziness
- Next-day somnolence
- Complex sleep behaviors
- Sleep paralysis
- Hypnagogic/hypnopompic hallucinations
- Respiratory depression
- Worsening depression/suicidal ideation
Monitoring Parameters
- Efficacy: Sleep latency, wake after sleep onset, total sleep time
- Next-day impairment: Assess alertness, cognitive function, motor coordination
- Mental status: Monitor for emerging depression, suicidal thoughts, behavioral changes
- Adherence and misuse patterns
- Respiratory function in susceptible patients
Patient Education
- Take immediately before bedtime with at least 7 hours remaining for sleep
- Avoid alcohol and other CNS depressants
- Report any sleep-walking, sleep-driving, or other unusual behaviors
- Be aware of potential next-day impairment; use caution when driving or operating machinery
- Do not increase dose without medical supervision
- Inform healthcare providers of all medications being taken
- Report symptoms of depression or suicidal thoughts
- Avoid high-fat meals close to dosing time
References
1. FDA Prescribing Information: Dayvigo (lemborexant). December 2019. 2. Murphy P, et al. Lemborexant, A Dual Orexin Receptor Antagonist (DORA) for the Treatment of Insomnia Disorder: Results From a Bayesian, Adaptive, Randomized, Double-Blind, Placebo-Controlled Study. J Clin Sleep Med. 2017;13(11):1289-1299. 3. Rosenberg R, et al. Safety and efficacy of lemborexant in adults with insomnia: 12-month results from Study E2006-G000-303. Curr Med Res Opin. 2020;36(9):1575-1584. 4. Yardley J, et al. Long-term effectiveness and safety of lemborexant in adults with insomnia disorder: results from a 12-month extension study. Sleep Med. 2021;81:401-410. 5. Mignot E, et al. Safety and efficacy of lemborexant in older adults with insomnia disorder. Sleep Med. 2022;91:32-41.