Lemborexant
Lemborexant Uses, Dosage, Side Effects, Food Interaction and all others data.
Lemborexant is a novel dual orexin receptor antagonist used in the treatment of insomnia characterized by difficulties with sleep onset and/or sleep maintenance. Recent research in the field of sleep disorders has revealed that insomnia is likely driven not by the inability of the brain to "switch on" sleep-related circuits, but rather an inability to "switch-off" wake-promoting circuits. Whereas historically popular pharmacologic treatments for insomnia (e.g. zopiclone, zolpidem, benzodiazepines) focus on enhancing sleep drive via modulation of GABA and melatonin receptors, lemborexant and other orexin antagonists (e.g. suvorexant) act to counteract inappropriate wakefulness. This novel mechanism of action offers potential advantages over classic hypnotic agents, including a more favorable adverse effect profile and potentially greater efficacy, and may signal the beginning of a new wave of treatment options for patients suffering from insomnia.
Lemborexant promotes sleep by antagonizing the actions of wake-promoting chemicals in the brain. Episodes of complex sleep behaviors (e.g. eating food, having sex, making phone calls) have been reported in patients using lemborexant - these events may occur in hypnotic-naive and hyponotic-experienced patients, and patients are unlikely to remember these events. Patients exhibiting complex sleep behaviors should discontinue lemborexant immediately. Lemborexant may carry some risk of abuse, and should be used with caution in patients with a history of alcohol or drug addiction. Its controlled substance schedule is currently under review by the Drug Enforcement Administration.
| Trade Name | Lemborexant |
| Availability | Prescription only |
| Generic | Lemborexant |
| Lemborexant Other Names | Lemborexant |
| Related Drugs | amitriptyline, lorazepam, melatonin, zolpidem, diphenhydramine, Ativan |
| Weight | 10mg, 5mg |
| Type | Oral tablet |
| Formula | C22H20F2N4O2 |
| Weight | Average: 410.425 Monoisotopic: 410.155432226 |
| Protein binding | Lemborexant is approximately 94% protein-bound in vitro, though the specific proteins to which it binds in plasma have not been elucidated. |
| Groups | Approved, Investigational |
| Therapeutic Class | |
| Manufacturer | |
| Available Country | United States |
| Last Updated: | September 19, 2023 at 7:00 am |
Uses
Lemborexant is a dual orexin antagonist indicated for the treatment of sleep-onset and/or sleep maintenance insomnia.
Lemborexant is indicated for the treatment of adult patients with insomnia characterized by difficulties with sleep onset and/or sleep maintenance.
Lemborexant is also used to associated treatment for these conditions: Insomnia
How Lemborexant works
The orexin neuropeptide signaling system is involved in many physiologic functions, including sleep/wake control. Orexin-A and orexin-B activate post-synaptic G-protein coupled orexin-1 receptors (OX1R) and orexin-2 receptors (OX2R), which are found on neurons in the hypothalamus that project to numerous wake-controlling nuclei. Each receptor carries slightly different activity - activation of OX1R appears to suppress the onset of rapid eye movement (REM) sleep, whereas activation of OX2R appears to suppress non-REM sleep.
Lemborexant is an competitive antagonist of OX1R and OX2R. By blocking the binding of wake-promoting orexin-A and -B at these receptors, lemborexant suppresses the wake-drive, thereby promoting sleep.
Toxicity
Clinical experience with lemborexant overdose is limited. In clinical studies, healthy patients receiving doses up to 10x the recommended maximum dose experienced dose-dependent increases in the frequency of adverse effects such as somnolence - it is likely, then, that symptoms of overdose will be consistent with lemborexant's adverse effect profile. In the event of an overdosage, implement supportive measures and consult the nearest poison control center for the most up to date management strategies. As lemborexant is highly protein-bound, hemodialysis is likely to be of little use in overdose situations.
Food Interaction
- Take on an empty stomach. Co-administration with food delays absorption and sleep onset.
[Major] GENERALLY AVOID: Grapefruit juice may increase the plasma concentrations of lemborexant, which is primarily metabolized by CYP450 3A4.
The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruit.
Inhibition of hepatic CYP450 3A4 may also contribute.
The interaction has not been studied with grapefruit juice but has been reported for other CYP450 3A4 inhibitors.
When coadministered with itraconazole, a potent CYP450 3A4 inhibitor, lemborexant peak plasma concentration (Cmax) and systemic exposure (AUC) increased approximately 1.4-fold and 3.8-fold, respectively.
When coadministered with fluconazole, a moderate CYP450 3A4 inhibitor, lemborexant Cmax and AUC increased approximately 1.6-fold and 4.2-fold, respectively.
In general, the effect of grapefruit juice is concentration-, dose- and preparation-dependent, and can vary widely among brands.
Certain preparations of grapefruit juice (e.g., high dose, double strength) have sometimes demonstrated potent inhibition of CYP450 3A4, while other preparations (e.g., low dose, single strength) have typically demonstrated moderate inhibition.
Increased exposure to lemborexant may increase the risk of adverse reactions such as central nervous system (CNS) depression, sleep paralysis, hallucinations, complex sleep behaviors, worsening of depression or suicidal ideation, nightmares, palpitations, or headache.
After administration of a high-fat, high-calorie meal (approximately 1000 calories with 500 to 600 calories from fat), lemborexant Cmax decreased by 23%, AUC increased by 18%, and the time to maximum concentration (Tmax) was delayed by 2 hours.
MANAGEMENT: The manufacturer makes no recommendation regarding administration with food; however, the time to sleep onset may be delayed if taken with or soon after a meal.
Patients should avoid consumption of grapefruit, grapefruit juice, or supplements that contain grapefruit during treatment with lemborexant.
Lemborexant Alcohol interaction
[Major] GENERALLY AVOID:
Alcohol may increase the plasma concentrations and potentiate some of the pharmacologic effects of the central nervous system (CNS)-active agent, lemborexant.
Coadministration with alcohol increased the peak plasma concentration (Cmax) and systemic exposure (AUC) of lemborexant by 35% and 70%, respectively; however, the mechanism of the interaction has not been established.
Use in combination may result in additive CNS depression and/or impairment of judgment, thinking, and psychomotor skills.
According to the manufacturer, due to their potentially additive effects, the concomitant use of lemborexant with alcohol should be avoided.
Patients should be advised to avoid consumption of alcohol.
Ambulatory patients should be counseled against driving, operating machinery, or engaging in potentially hazardous activities requiring mental alertness and motor coordination until they know how these agents affect them, and to notify their doctor if they experience excessive or prolonged CNS effects that interfere with their normal activities.
Lemborexant Drug Interaction
Major: morphineModerate: citalopram, duloxetine, azelastine / fluticasone nasalUnknown: amphetamine / dextroamphetamine, amphetamine / dextroamphetamine, testosterone, aspirin, aspirin, bisacodyl, clomiphene, ubiquinone, cholecalciferol, methylprednisolone, docusate, ferrous sulfate, semaglutide, cyanocobalamin, ascorbic acid, cholecalciferol
Lemborexant Disease Interaction
Volume of Distribution
The volume of distribution of lemborexant is 1970 L, indicating extensive tissue distribution.
Elimination Route
Animal models of lemborexant disposition have demonstrated rapid absorption following oral administration. The Tmax of lemborexant is approximately 1-3 hours, or 3-5 hours following administration of a high-fat, high-calorie meal. Cmax and AUC0-24h increase at a rate slightly less than proportionate to the given dose. Following administration of a high-fat, high-calorie meal, Cmax is decreased by 23% and AUC0-inf is increased by 18%. AUC, Cmax, and terminal half-life are increased in the presence of moderate hepatic impairment, and AUC (but not half-life) is increased in the presence of mild hepatic impairment.
Half Life
The half-life for lemborexant at doses of 5mg and 10mg is 17 and 19 hours, respectively.
Elimination Route
Following oral administration, 57.4% of the dose is found in the feces and 29.1% in the urine. Less than 1% of the dose recovered in the urine exists as unchanged parent drug, suggesting extensive metabolism.
Innovators Monograph
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