What are the safety considerations for Lemborexant (Doxylamine) use?

Lemborexant Safety Considerations

Lemborexant should be avoided in combination with fluconazole and other moderate CYP3A4 inhibitors due to significant increases in drug exposure (1.6-fold increase in Cmax and 4.2-fold increase in AUC) which substantially increases the risk of adverse reactions, particularly somnolence. 1

Key Safety Profile

Pharmacokinetics and Exposure

• Lemborexant has a mean effective half-life of 17-19 hours for the 5-10 mg doses, with time to maximum concentration ranging from 1-3 hours 2
• Plasma concentration at 9 hours post-dose remains at approximately 27% of maximum concentration following multiple dosing with 10 mg 2
• No clinically relevant effects of age, sex, or race on lemborexant pharmacokinetics have been observed 2

Common Adverse Effects

• Most common adverse effects are mild to moderate in severity 3
• Somnolence is the most frequently reported adverse effect, particularly with drug interactions that increase exposure 1, 2
• In clinical trials, lemborexant was generally well-tolerated through doses of 25 mg 2
• Mild somnolence was observed in some patients using lemborexant for insomnia with nocturia 4

Drug Interactions

Critical Interactions

• Concomitant use with fluconazole is contraindicated as it increases lemborexant Cmax by approximately 1.6-fold and AUC by 4.2-fold, significantly increasing the risk of adverse reactions 1
• Other moderate to strong CYP3A4 inhibitors should be avoided due to similar potential for increased exposure 1

Special Population Considerations

• No significant dose adjustments are needed based on age, as studies have shown no clinically relevant effects of age on lemborexant pharmacokinetics 2
• Lemborexant has been specifically studied in older adults (≥55 years) with insomnia disorder and demonstrated a favorable safety profile in this population 3, 5

Clinical Efficacy and Safety Balance

• In comparative studies, lemborexant demonstrated significantly greater improvements in sleep onset and maintenance compared to both placebo and zolpidem, measured objectively using polysomnography 3
• Lemborexant significantly increases total sleep time and REM sleep while decreasing latency to REM sleep compared to both placebo and zolpidem in older adults with insomnia 5
• In systematic reviews, lemborexant has shown a favorable profile for both acute and long-term treatment of insomnia, though some safety data for long-term use remains inconclusive 6

Monitoring Recommendations

• Monitor for excessive daytime sleepiness, particularly when initiating therapy or increasing doses 2
• Assess for potential drug interactions before prescribing, with particular attention to CYP3A4 inhibitors 1
• No specific laboratory monitoring is required based on available evidence 2, 3

Practical Prescribing Guidance

• Start with lower doses (5 mg) in patients who may be sensitive to CNS depressants 2, 3
• Doses through 10 mg/day have not shown clinically relevant effects on next-morning residual sleepiness based on objective measures (Karolinska Sleepiness Scale, Digital Symbol Substitution Test, Psychomotor Vigilance Test) 2
• Lemborexant may be particularly beneficial in older adults with insomnia who have alterations in sleep architecture 5
• Consider lemborexant as a potential option for patients with comorbid insomnia and nocturia, as it has shown efficacy in reducing nocturia episodes and improving sleep quality in this population 4