lemborexant (Rx)

1-10%

5 mg/night

• Somnolence or fatigue (6.9%)
• Headache (5.9%)
• Sleep paralysis (1.3%)

10 mg/night

• Somnolence or fatigue (9.6%)
• Headache (4.5%)
• Nightmare or abnormal dreams (2.2%)
• Sleep paralysis (1.6%)

<1%

5 mg/night

• Nightmare or abnormal dreams (0.9%)
• Hypnagogic hallucinations (0.1%)

10 mg/night

• Hypnagogic hallucinations (0.7%)

Contraindications

Narcolepsy

Cautions

CNS depressant that can impair daytime wakefulness even when used as prescribed; CNS depression may persist and affect next-day tasks (eg, driving ability); CNS depression may persist in some patients for several days after discontinuing; coadministration with other CNS depressants may increase risk

Sleep paralysis, an inability to move or speak for up to several minutes during sleep-wake transitions, and hypnagogic/hypnopompic hallucinations, including vivid and disturbing perceptions, can occur; mild cataplexy can occur, with symptoms that include periods of leg weakness lasting from seconds to a few minutes

Complex sleep behaviors, including sleep-walking, sleep-driving, and engaging in other activities while not fully awake (eg, preparing and eating food, making phone calls, having sex), reported with hypnotic use

Consider effect on respiratory function if prescribed to patients with compromised respiratory function; has not been studied with moderate-to-severe obstructive sleep apnea or COPD

In primarily depressed patients treated with hypnotics, worsening of depression and suicidal thoughts and actions (including completed suicides) have been reported; monitor for new behavioral signs or symptoms

Evaluate for comorbid diagnoses where insomnia may be presenting manifestation of a medial and/or psychiatric disorder

Drug interaction overview

• CNS depressants

  • Coadministration with other CNS depressants (eg, benzodiazepines, opioids, tricyclic antidepressants, alcohol) increases the risk of CNS depression, which can cause daytime impairment

• CYP3A inhibitors

  • Coadministration with a strong, moderate, or weak CYP3A inhibitor increases lemborexant AUC and peak plasma concentration which may increase the risk of lemborexant adverse reactions

• CYP3A inducers

  • Concomitant use with a strong or moderate CYP3A inducer decreases lemborexant exposure, which may reduce lemborexant efficacy

• CYP2B6 substrates

  • Coadministration decreases AUC of CYP2B6 substrates
  • Check prescribing information for CYP2B6 substrate for dosage recommendations if coadministered

Pregnancy

Data are not available on use in pregnant women to evaluate for drug-associated risks of major birth defects, miscarriage, or adverse maternal or fetal outcomes

Clinicians are encouraged to register patients in the Dayvigo pregnancy registry by calling 1-888-274-2378

Animal studies

• Rats

  • Lemborexant was administered orally to pregnant rats during organogenesis in 2 studies at doses of 60, 200, and 600 mg/kg/day or 20, 60, and 200 mg/kg/day, which are approximately 6 to >300 times the maximum recommended human dose (MRHD) based on AUC

  • Lemborexant caused maternal toxicity, manifested by decreased body weight and food consumption, decreased mean fetal body weight, an increased number of dead fetuses, and skeletal, external, and visceral malformations (omphalocele, cleft palate, and membranous ventricular septal defect) at >300 times the MRHD based on AUC

  • Lemborexant was administered orally to pregnant rats during pregnancy and lactation at doses of 30, 100, and 300 mg/kg/day, which are approximately 15-206 times the MRHD based on AUC

  • Lemborexant caused maternal toxicity that consisted of decreased body weight and food consumption and toxicity to offspring consisting of decreased pup body weights, decreased femur length, and decreased acoustic startle responses at 206 times the MRHD based on AUC

• Rabbits

  • Lemborexant was administered orally to pregnant rabbits during the period of organogenesis at doses of 10, 30, and 100 mg/kg/day, which are approximately 7-139 times the MRHD based on AUC

  • Lemborexant caused maternal toxicity that consisted of decreased body weight and food consumption and a higher incidence of skeletal variations (presence of cervical ribs and supernumerary lung lobes) at approximately 139 times the MRHD based on AUC

Lactation

Data are not available on the presence of lemborexant in human milk, effects on breastfed infants, or effects on milk production

Lemborexant and its metabolites are present in the milk of lactating rats; when a drug is present in animal milk, it is likely that the drug will be present in human milk

Monitor infants exposed through breastmilk for excessive sedation

Consider the developmental and health benefits of breastfeeding along with the mother’s clinical need for the drug and any potential adverse effects on the breastfed infant from the drug or from the underlying maternal condition

Pregnancy Categories

A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

NA: Information not available.

Mechanism of Action

Dual orexin antagonist (DORA)

Orexins are neuropeptides that regulate the sleep-wake cycle; orexins promote wakefulness by binding G-protein-coupled receptors, OX1R and OX2R

A major metabolite of lemborexant, M10, binds with comparable affinity as the parent drug to orexin receptors OX1R and OX2R

Absorption

Peak plasma concentration: 1-3 hr

Food (high-fat, high-calorie meal) decreases peak plasma concentration by 23%, AUC by 18%, and delays peak plasma time by 2 hr

Distribution

Protein bound: ~94%

Vd: 1970 L

Blood-plasma ratio: 0.65

Metabolism

CYP3A4 (primary); CYP3A5 (less extent)

Major circulating metabolite: M10

Elimination

Half-life: 17 hr (5 mg); 19 hr (10 mg)

Excretion: Feces 29.1%; urine <1%

Oral Administration

Time to sleep onset may be delayed if taken with or soon after a meal

Take at least 7 hr before planned awakening

Do not take more than 1 dose/night

Avoid alcohol consumption

Storage

Store at controlled room temperature of 20-25ºC (68-77ºF); excursions permitted to 15-30ºC (59-86ºF)