Class: Anxiolytics, Sedatives, and Hypnotics; Miscellaneous
Chemical Name: (1R,2S)-2-[(2,4-dimethylpyrimidin-5-yl)oxymethyl]-2-(3-fluorophenyl)-N-(5-fluoropyridin-2-yl)cyclopropane-1-carboxamide
Molecular Formula: C22H20F2N4O2
CAS Number: 1369764-02-2
Lemborexant is an anxiolytic, sedative, or hypnotic.
Uses for Lemborexant
Lemborexant has the following uses:
Lemborexant is an orexin receptor antagonist indicated for the treatment of adult patients with insomnia characterized by difficulties with sleep onset and/or sleep maintenance.
Lemborexant Dosage and Administration
Lemborexant is available in the following dosage form(s) and strength(s):
Tablets: 5 mg, 10 mg.
It is essential that the manufacturer's labeling be consulted for more detailed information on dosage and administration of this drug. Dosage summary:
Dosage and Administration
Recommended dose is 5 mg taken no more than once per night, immediately before going to bed, with at least 7 hours remaining before the planned time of awakening. Dosage may be increased to 10 mg based on clinical response and tolerability.
The maximum recommended dose is 10 mg once daily.
Time to sleep onset may be delayed if taken with or soon after a meal.
Moderate hepatic impairment: Initial and maximum recommended dosage is 5 mg no more than once per night. Severe hepatic impairment: Not recommended.
Cautions for Lemborexant
Lemborexant is contraindicated in patients with narcolepsy.
CNS Depressant Effects and Daytime Impairment
Lemborexant is a central nervous system (CNS) depressant that can impair daytime wakefulness even when used as prescribed. CNS depressant effects may persist in some patients for up to several days after discontinuing lemborexant. Prescribers should advise patients about the potential for next-day somnolence.
Driving ability was impaired in some subjects taking lemborexant 10 mg. The risk of daytime impairment is increased if lemborexant is taken with less than a full night of sleep remaining or if a higher than recommended dose is taken. If lemborexant is taken in these circumstances, patients should be cautioned against driving and other activities requiring complete mental alertness.
Co-administration with other CNS depressants (e.g., benzodiazepines, opioids, tricyclic antidepressants, alcohol) increases the risk of CNS depression, which can cause daytime impairment. Dosage adjustments of lemborexant and of concomitant CNS depressants may be necessary when administered together because of potentially additive effects. The use of lemborexant with other drugs to treat insomnia is not recommended. Patients should be advised not to consume alcohol in combination with lemborexant because of additive effects.
Because lemborexant can cause drowsiness, patients, particularly the elderly, are at a higher risk of falls.
Sleep Paralysis, Hypnagogic/Hypnopompic Hallucinations, and Cataplexy-like Symptoms
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 with the use of lemborexant. Prescribers should explain the nature of these events to patients when prescribing lemborexant.
Symptoms similar to mild cataplexy can occur with lemborexant. Such symptoms can include periods of leg weakness lasting from seconds to a few minutes, can occur either at night or during the day, and may not be associated with an identified triggering event (e.g., laughter or surprise).
Complex Sleep Behaviors
Complex sleep behaviors, including sleep-walking, sleep-driving, and engaging in other activities while not fully awake (e.g., preparing and eating food, making phone calls, having sex), have been reported to occur with the use of hypnotics such as lemborexant. These events can occur in hypnotic-naïve as well as in hypnotic-experienced persons. Patients usually do not remember these events. Complex sleep behaviors may occur following the first or any subsequent use of lemborexant, with or without the concomitant use of alcohol and other CNS depressants. Discontinue lemborexant immediately if a patient experiences a complex sleep behavior.
Patients with Compromised Respiratory Function
The effect of lemborexant on respiratory function should be considered if prescribed to patients with compromised respiratory function. Lemborexant has not been studied in patients with moderate to severe obstructive sleep apnea (OSA) or in patients with chronic obstructive pulmonary disease (COPD).
Worsening of Depression/Suicidal Ideation
In clinical studies of lemborexant in patients with insomnia, the incidence of suicidal ideation or any suicidal behavior, as assessed by questionnaire, was higher in patients receiving lemborexant than in those receiving placebo (0.3% for lemborexant 10 mg, 0.4% for lemborexant 5 mg, and 0.2% for placebo).
In primarily depressed patients treated with hypnotics, worsening of depression and suicidal thoughts and actions (including completed suicides) have been reported. Suicidal tendencies may be present in such patients and protective measures may be required. Intentional overdose is more common in this group of patients; therefore, the lowest number of tablets that is feasible should be prescribed at any one time.
The emergence of any new behavioral sign or symptom of concern requires careful and immediate evaluation.
Need to Evaluate for Co-morbid Diagnoses
Because sleep disturbances may be the presenting manifestation of a medical and/or psychiatric disorder, treatment of insomnia should be initiated only after careful evaluation of the patient. The failure of insomnia to remit after 7 to 10 days of treatment may indicate the presence of a primary psychiatric and/or medical illness that should be evaluated. Worsening of insomnia or the emergence of new cognitive or behavioral abnormalities may be the result of an unrecognized underlying psychiatric or medical disorder and can emerge during the course of treatment with sleep-promoting drugs such as lemborexant.
Pregnancy Exposure Registry: There is a pregnancy exposure registry that monitors pregnancy outcomes in women who are exposed to lemborexant during pregnancy. Healthcare providers are encouraged to register patients in the lemborexant pregnancy registry by calling 1-888-274-2378.
Risk Summary: There are no available data on lemborexant use in pregnant women to evaluate for drug-associated risks of major birth defects, miscarriage or adverse maternal or fetal outcomes.
In animal reproduction studies, oral administration of lemborexant to pregnant rats and rabbits during the period of organogenesis caused toxicities only at high multiples of the human exposure at the maximum recommended human dose (MRHD) based on AUC. The no observed adverse effect levels (NOAEL) are approximately >100 and 23 times the MRHD based on AUC in rats and rabbits, respectively. Similarly, oral administration of lemborexant to pregnant and lactating rats caused toxicities only at high multiples of the human exposure at the MRHD based on AUC. The NOAEL is 93 times the MRHD based on AUC.
The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risks of major birth defects and miscarriage in clinically recognized pregnancies are 2% to 4% and 15% to 20%, respectively.
Animal Data: Lemborexant was administered orally to pregnant rats during the period of 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 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. The NOAEL of 200 mg/kg/day is approximately 143 times the MRHD based on AUC.
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 to 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. The NOAEL of 30 mg/kg/day is approximately 23 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 to 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. The NOAEL of 100 mg/kg/day is approximately 93 times the MRHD based on AUC.
Risk Summary: There are no data on the presence of lemborexant in human milk, the effects on the breastfed infant, or the 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. Infants exposed to lemborexant through breast milk should be monitored for excessive sedation. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for lemborexant and any potential adverse effects on the breastfed infant from lemborexant or from the underlying maternal condition.
The safety and effectiveness of lemborexant have not been established in pediatric patients.
Of the total number of patients treated with lemborexant (n=1418) in controlled Phase 3 studies, 491 patients were 65 years and over, and 87 patients were 75 years and over. Overall, efficacy results for patients <65 years of age were similar compared to patients ≥65 years.
In a pooled analysis of Study 1 (the first 30 days) and Study 2, the incidence of somnolence in patients ≥65 years with lemborexant 10 mg was higher (9.8%) compared to 7.7% in patients <65 years. The incidence of somnolence with lemborexant 5 mg was similar in patients ≥65 years (4.9%) and <65 years (5.1%). The incidence of somnolence in patients treated with placebo was 2% or less regardless of age. Because lemborexant can increase somnolence and drowsiness, patients, particularly the elderly, are at a higher risk of falls. Exercise caution when using doses higher than 5 mg in patients ≥65 years old.
No dose adjustment is required in patients with mild, moderate, or severe renal impairment.
Lemborexant exposure (AUC) was increased in patients with severe renal impairment. Patients with severe renal impairment may experience an increased risk of somnolence.
Lemborexant has not been studied in patients with severe hepatic impairment. Use in this population is not recommended.
Lemborexant exposure (AUC and Cmax) and terminal half-life were increased in patients with moderate hepatic impairment (Child-Pugh class B). Dosage adjustment is recommended in patients with moderate hepatic impairment (Child-Pugh class B).
Lemborexant exposure (AUC) was increased in patients with mild hepatic impairment (Child-Pugh class A), but the terminal half-life was not changed. Patients with mild hepatic impairment may experience an increased risk of somnolence.
Patients with Compromised Respiratory Function
In a study of patients with mild OSA (apnea-hypopnea index <15 events per hour of sleep), lemborexant did not increase the frequency of apneic events or cause oxygen desaturation.
Lemborexant has not been studied in patients with COPD or moderate to severe OSA. Clinically meaningful respiratory effects of lemborexant in COPD or moderate to severe OSA cannot be excluded.
Common Adverse Effects
The most common adverse reaction (reported in ≥5% of patients treated with lemborexant and at least twice the rate of placebo) was somnolence.
It is essential that the manufacturer's labeling be consulted for more detailed information on interactions with this drug, including possible dosage adjustments. Interaction highlights:
Strong or moderate CYP3A inhibitors: Avoid concomitant use.
Weak CYP3A inhibitors: The maximum recommended dose is 5 mg.
Strong or moderate CYP3A inducers: Avoid concomitant use.
Mechanism of Action
The mechanism of action of lemborexant in the treatment of insomnia is presumed to be through antagonism of orexin receptors. The orexin neuropeptide signaling system plays a role in wakefulness. Blocking the binding of wake-promoting neuropeptides orexin A and orexin B to receptors OX1R and OX2R is thought to suppress wake drive.
Advice to Patients
Patient Counseling Information
Advise the patient to read the FDA-approved patient labeling.
Advise patients to take lemborexant only when preparing for or getting into bed and only if they can stay in bed for a full night (at least 7 hours) before being active again.
Advise patients that the effect of lemborexant may be delayed if taken with or soon after a meal.
Advise patients that lemborexant can impair daytime wakefulness even when used as prescribed. The risk of daytime impairment is increased if lemborexant is taken with less than a full night of sleep remaining or if a higher than recommended dose is taken. If lemborexant is taken in these circumstances, caution patients against driving and other activities requiring complete mental alertness. Advise patients that increased drowsiness may increase the risk of falls in some patients.
Advise patients and their families that lemborexant may cause sleep paralysis, which is an inability to move or speak for several minutes during sleep-wake transitions, despite being aware of surroundings; hypnagogic/hypnopompic hallucinations, including vivid and disturbing perceptions; and symptoms similar to mild cataplexy.
Instruct patients and their families that lemborexant may cause complex sleep behaviors, including sleep-walking, sleep-driving, preparing and eating food, making phone calls, or having sex, while not being fully awake. Tell patients to discontinue lemborexant and notify their healthcare provider immediately if they develop any of these symptoms.
Tell patients to report any worsening of depression or suicidal thoughts immediately.
Advise patients that there is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to lemborexant during pregnancy.
Ask patients about alcohol consumption, medicines they are taking, and drugs they may be taking without a prescription. Advise patients not to consume alcohol in combination with lemborexant.
Tell patients not to increase the dose of lemborexant on their own, and to inform you if they believe the drug “does not work”.
AHFSfirstRelease™. For additional information until a more detailed monograph is developed and published, the manufacturer's labeling should be consulted. It is essential that the manufacturer's labeling be consulted for more detailed information on usual uses, dosage and administration, cautions, precautions, contraindications, potential drug interactions, laboratory test interferences, and acute toxicity.
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.
Lemborexant is subject to control under the Federal Controlled Substances Act of 1970 as a schedule IV (C-IV) drug.
AHFS Drug Information. © Copyright 2021, Selected Revisions May 25, 2020. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.
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