Lemborexant Risks
Lemborexant carries risks of somnolence, CNS depression with concomitant depressants or alcohol, and should be avoided in severe hepatic impairment and with moderate CYP3A4 inhibitors like fluconazole. 1, 2
Primary Contraindications and Warnings
Severe Hepatic Impairment
- Lemborexant is contraindicated in patients with severe hepatic impairment due to altered drug metabolism 1
Drug Interactions Requiring Avoidance
- Concomitant use with fluconazole (moderate CYP3A4 inhibitor) should be avoided, as it increases lemborexant exposure by approximately 1.6-fold (Cmax) and 4.2-fold (AUC), significantly increasing risk of adverse reactions including somnolence 2
- Alcohol use is contraindicated due to additive CNS depression effects 1
Common Adverse Effects
Somnolence and Sedation
- Somnolence is the most clinically significant adverse effect, occurring at statistically higher rates compared to placebo (RR = 4.95, P < 0.0001) 3
- Treatment-emergent adverse events (TEAEs) overall are significantly more common with lemborexant (RR = 1.94, P < 0.0001) 3
- Most TEAEs are mild to moderate in severity; the most common include nasopharyngitis, somnolence, and headache 4
CNS Depression
- Concomitant use with other CNS depressants may potentiate sedative effects and should be approached with caution 1
Driving and Performance Impairment
- Patients should be cautioned about potential driving impairment, though studies demonstrate minimal impact on driving performance 8-9 hours after administration compared to placebo 1
- This represents a practical consideration for timing of medication administration relative to driving activities
Abuse Potential
Controlled Substance Classification
- Lemborexant is classified as Schedule IV, the same as zolpidem and suvorexant 5, 6
- In recreational sedative users, lemborexant demonstrated abuse potential versus placebo with drug-liking scores significantly greater than placebo but similar to zolpidem and suvorexant 5
Real-World Abuse Risk
- Despite positive abuse potential signals in controlled studies, real-world postmarketing data suggests very low abuse-related risks in the community, similar to other dual orexin receptor antagonists 6
- Nonclinical studies showed no evidence of physical dependence or withdrawal signs following abrupt discontinuation 7
- The incidence of abuse-related adverse events was low in clinical trials with insomnia patients 6
Dose-Related Considerations
Optimal Dosing for Safety
- Both 5 mg and 10 mg doses are effective, but the 5 mg dose should be preferred in patients at risk for excessive daytime somnolence 3
- No significant difference in efficacy exists between doses, but somnolence risk increases with higher doses 3
Long-Term Safety Profile
- Long-term treatment up to 12 months demonstrates maintained efficacy without evidence of tolerance 4
- No rebound insomnia or withdrawal symptoms occur following treatment discontinuation, even after 12 months of continuous use 4
- This favorable withdrawal profile distinguishes lemborexant from benzodiazepines and some nonbenzodiazepine hypnotics 6
Key Clinical Pitfalls to Avoid
- Do not combine with moderate or strong CYP3A4 inhibitors (e.g., fluconazole, ketoconazole) due to significant drug exposure increases 2
- Avoid prescribing to patients with severe liver disease 1
- Counsel patients explicitly about alcohol avoidance during treatment 1
- Screen for concomitant CNS depressant use before prescribing 1
- Start with 5 mg dose in elderly or vulnerable populations to minimize somnolence risk 3