By William Elliott, MD, FACP, and James Chan, PharmD, PhD

Dr. Elliott is Assistant Clinical Professor of Medicine, University of California, San Francisco.
Dr. Chan is Associate Clinical Professor, School of Pharmacy, University of California, San Francisco.

Drs. Elliott and Chan report no financial relationships relevant to this field of study.

The FDA has approved a second dual orexin receptor antagonist (DORA), following suvorexant (2014), to treat insomnia. The orexin signaling pathway plays a role in wakefulness.1 In individuals with sleep-wake disorders, it is possible that orexin signaling is not functioning normally. Lemborexant will be distributed as Dayvigo, pending scheduling by the Drug Enforcement Administration.

INDICATIONS

Lemborexant should be prescribed to treat adults with insomnia characterized by difficulties with sleep onset and/or sleep maintenance.1

DOSAGE

The recommended dose is 5 mg taken immediately before going to bed, with at least seven hours remaining before planned time of awakening.1 Lemborexant should not be taken more than one time per night. The maximum dose of lemborexant is 10 mg. In patients with moderate hepatic impairment, the dose is 5 mg.

Food delays the peak plasma concentration of lemborexant; taking the drug after a meal may delay the time to sleep onset. Lemborexant is available as a 5 mg tablet and as a 10 mg tablet.

POTENTIAL ADVANTAGES

Lemborexant does not appear to be associated with rebound insomnia or withdrawal effects.1 Additionally, there are no clinically meaningful effects on driving performance nine hours following a dose (2.5 mg, 5 mg, 10 mg).2

POTENTIAL DISADVANTAGES

Central nervous system depression, sleep paralysis, worsening of depression, suicidal ideation, and complex sleep behavior (e.g., sleep walking, sleep driving) may occur with lemborexant.1 Avoid the concomitant use of lemborexant with strong or moderate CYP3A inhibitors and inducers.1 The most frequently reported adverse reactions (vs. placebo) were somnolence or fatigue (6.9-9.6% vs. 1.3%) and headache (4.5-5.9% vs. 3.4%).1 At doses between 10 mg and 30 mg, lemborexant showed abuse potential similar to zolpidem 30 mg and suvorexant 40 mg.1

COMMENTS

The approval of lemborexant was based on the results from two Phase III studies that included subjects with insomnia disorder characterized by difficulties with sleep onset and/or sleep maintenance.1 Study 1 was a six-month investigation of adult subjects randomized to lemborexant 5 mg (n = 325), 10 mg (n = 323), or placebo (n = 325). The primary outcome was subject-reported sleep onset latency (sSOL), defined as the time from attempt to sleep until sleep onset. Sleep maintenance was a secondary endpoint, assessed by sleep efficiency and wake after sleep onset (WASO).

At six months, both doses of lemborexant reduced sleep onset by 30% (baseline of 43 minutes and 45 minutes to 20 minutes and 19.2 minutes, respectively, vs. 45 minutes to 27.3 minutes for placebo). The percent of time asleep while in bed improved, and the time awake after sleep onset shortened.

Study 2 was a one-month randomized, double-blind, placebo- and active-controlled investigation of older adults (women ≥ age 55 years, men ≥ age 65 years). Subjects were randomized to lemborexant 5 mg (n = 266), 10 mg (n = 269), placebo (n = 208), or 6.25 mg of zolpidem (n = 263).1,3 The primary endpoint was latency to persistent sleep at days 29-30 as measured by overnight polysomnography (PSG) monitoring. Secondary endpoints were sleep efficiency and WASO.

Sleep onset improved by 20% and 30% with the 5 mg and 10 mg doses, respectively, compared to placebo (mean reduction of 17-20 minutes vs. seven reduction minutes for placebo). Sleep efficiency and WASO also improved significantly. Both doses of lemborexant were much more effective than zolpidem, based on PSG data, but only more effective on sleep sSOL based on self-reported data. Dosing of lemborexant at night resulted in impairment of balance at four hours compared to placebo, but no difference was detected in ability to awaken to sound.1 The dose range of 2.5-10 mg proved efficacious and still minimized next-morning residual sleepiness.4

CLINICAL IMPLICATIONS

Insomnia is a prevalent disorder, with short-term insomnia affecting 30-50% of the population, and chronic insomnia affecting 5-10%.5 FDA-approved drugs include benzodiazepines (temazepam, triazolam), nonbenzodiazepine Z-drugs (eszopiclone, zaleplon, zolpidem), DORA (suvorexant, lemborexant), melatonin receptor agonists (ramelteon), antidepressants (doxepin), and others used off-label (e.g., diphenhydramine, trazodone).

Suvorexant is better for sleep maintenance than for reducing sleep latency. In fact, the American Academy of Sleep Medicine (AASM) does not recommend suvorexant for reducing sleep latency.5,6

Lemborexant appears to be effective in reducing sleep latency and improving sleep maintenance, but has not demonstrated clear advantages over existing drugs. AASM recommends considering suvorexant or doxepin for sleep maintenance; eszopiclone, temazepam, and zolpidem ER for sleep onset and sleep maintenance; and zaleplon, triazolam, ramelteon, or zolpidem IR for sleep onset insomnia. The FDA has recommended classifying lemborexant as a controlled substance. A decision on scheduling is expected by February. Price is not available yet.

REFERENCES

  1. Eisai Inc. Dayvigo Prescribing Information, December 2019. Available at: http://bit.ly/36HMcBw. Accessed Jan. 10, 2020.
  2. Vermeeren A, Jongen S, Murphy P, et al. On-the-road driving performance the morning after bedtime administration of lemborexant in healthy adult and elderly volunteers. Sleep 2019; Apr 1;42(4). pii: zsy260. doi: 10.1093/sleep/zsy260.
  3. Rosenberg R, Murphy P, Zammit G, et al. Comparison of lemborexant with placebo and zolpidem tartrate extended release for the treatment of older adults with insomnia disorder: A phase 3 randomized clinical trial. JAMA Netw Open 2019;2:e1918254.
  4. Murphy P, Moline M, Mayleben D, 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;13:1289-1299.
  5. Sateia MJ, Buysse DJ, Krystal AD, et al. Clinical practice guideline for the pharmacologic treatment of chronic insomnia in adults: An American Academy of Sleep Medicine clinical practice guideline. J Clin Sleep Med 2017;13:307-349.
  6. Abad VC, Guilleminault C. Insomnia in elderly patients: Recommendations for pharmacological management. Drugs Aging 2018;35:791-817.