Suvorexant
Indications
| Indication | Approved Population | Therapy Type | Status |
|---|---|---|---|
| Insomnia characterized by difficulties with sleep onset and/or sleep maintenance | Adults | Monotherapy | FDA Approved |
Suvorexant is the first-in-class dual orexin receptor antagonist (DORA) approved by the FDA for insomnia. Unlike the benzodiazepine receptor agonists (Z-drugs and benzodiazepines), it does not enhance GABA neurotransmission; instead, it blocks the wake-promoting orexin signaling system, which is consistent with its broader labeled indication covering both sleep onset and sleep maintenance. The 2017 American Academy of Sleep Medicine clinical practice guideline gives suvorexant a conditional (weak) recommendation specifically for sleep maintenance insomnia in adults. Cognitive behavioral therapy for insomnia (CBT-I) remains first-line in both AASM and ACP guidance, with pharmacotherapy reserved for patients in whom CBT-I is unavailable, has failed, or is needed as a temporary adjunct.
In February 2020 the FDA approved a label update incorporating findings from a phase 3 polysomnography trial of suvorexant in 285 patients with mild-to-moderate Alzheimer disease and insomnia (Herring 2020). Suvorexant produced statistically significant improvements in total sleep time and wake-after-sleep-onset versus placebo. The labeled indication wording is unchanged (“insomnia characterized by difficulties with sleep onset and/or sleep maintenance”); use in this population is therefore on-label and supported by PI-incorporated evidence. Adverse-event rates in this trial are reflected in the Side Effects section.
Delirium prevention in hospitalized older adults — Several Japanese RCTs and observational analyses suggest a reduction in delirium incidence when suvorexant is used prophylactically in at-risk inpatients (Hatta 2020). Findings in mixed and ICU populations have been more variable. Evidence quality: low to moderate.
Insomnia in substance-use recovery — Small early-phase studies in opioid and alcohol use disorder; not established. Evidence quality: very low.
Dosing
The labeled approach is to use the lowest effective dose. Recommended starting dose is 10 mg taken within 30 minutes of going to bed, only when at least 7 hours of sleep opportunity remain before activities requiring full alertness. The 10 mg dose may be increased to a maximum of 20 mg once daily if 10 mg is well tolerated but ineffective. Because suvorexant exposure is higher in women and in patients with high BMI, dose escalation should be especially conservative in obese women. Concurrent CYP3A inhibitors materially change the exposure–effect relationship and dictate specific dose ceilings.
| Clinical Scenario | Starting Dose | Maintenance Dose | Maximum Dose | Notes |
|---|---|---|---|---|
| Adult insomnia (sleep onset and/or maintenance) — primary indication | 10 mg PO | 10–20 mg nightly | 20 mg/day | Take within 30 min of bed; ≥7 h before planned awakening May increase to 20 mg if 10 mg well tolerated but ineffective |
| Older adults (≥65 years) | 10 mg PO | 10–20 mg nightly | 20 mg/day | Same recommended dosing as younger adults 15 mg was the dose used in pivotal elderly trial arms; counsel on falls and next-day driving |
| Mild-to-moderate Alzheimer disease (labeled population) | 10 mg PO | 10–20 mg nightly | 20 mg/day | Same recommended dosing In the AD trial, 77% of patients were uptitrated from 10 mg to 20 mg after 2 weeks |
| Obese women (BMI ≥30) | 10 mg PO | 10 mg nightly | 10–20 mg/day | Cautious escalation AUC ~46% and Cmax ~25% higher than non-obese women |
| Concomitant moderate CYP3A inhibitor (e.g., diltiazem, verapamil, erythromycin, fluconazole, ciprofloxacin) | 5 mg PO | 5–10 mg nightly | 10 mg/day | May increase to 10 mg only if needed Avoid grapefruit juice on dosing nights |
| Concomitant strong CYP3A inhibitor (e.g., ketoconazole, itraconazole, clarithromycin, ritonavir, nefazodone) | Not recommended | Use alternative hypnotic Substantial increase in exposure expected | ||
| Concomitant strong CYP3A inducer (e.g., rifampin, carbamazepine, phenytoin) | Efficacy may be reduced | Choose a non-CYP3A-dependent hypnotic if appropriate | ||
| Mild–moderate hepatic impairment (Child-Pugh A–B) | 10 mg PO | 10 mg nightly | 20 mg/day | No formal dose adjustment Apparent terminal t½ ~19 h in moderate impairment vs ~15 h healthy |
| Severe hepatic impairment (Child-Pugh C) | Not recommended | — | — | Not studied; avoid use |
| Renal impairment (any severity, including severe) | 10 mg PO | 10–20 mg nightly | 20 mg/day | No dose adjustment required |
| Pediatric (<18 years) | Not established | — | — | Safety and effectiveness not established |
Suvorexant has a half-life of approximately 12 hours, longer than most short-acting hypnotics. The FDA label is explicit that suvorexant should not be administered unless ≥7 hours remain before required awakening, and that the 20 mg dose carries a labeled caution against next-day driving. Patients waking earlier than planned, on-call clinicians, and shift workers are not appropriate candidates.
If insomnia fails to remit after 7–10 days of treatment, the FDA label advises re-evaluation for an underlying psychiatric or medical disorder rather than continued empiric treatment.
Pharmacology of Suvorexant
Mechanism of Action
Suvorexant is a highly selective antagonist at both orexin receptor subtypes, OX1R and OX2R. The orexin (hypocretin) system, with peptidergic neurons in the lateral hypothalamus projecting widely to monoaminergic and cholinergic wake-promoting nuclei, is a key driver of arousal and wakefulness. By blocking the binding of orexin A and orexin B at OX1R and OX2R, suvorexant suppresses wake drive rather than augmenting sleep drive — a fundamentally different mechanism from GABAergic hypnotics. The clinical signature of this mechanism is the labeled signal for narcolepsy-spectrum events (sleep paralysis, hypnagogic/hypnopompic hallucinations, and cataplexy-like leg weakness) in some patients. Loss of orexin neurons is the pathological substrate of human narcolepsy with cataplexy, which is why narcolepsy is the only labeled contraindication.
ADME Profile
| Parameter | Value | Clinical Implication |
|---|---|---|
| Absorption | Median Tmax ~2 h fasted (range 0.5–6 h); absolute oral bioavailability ~82% at 10 mg; less-than-proportional exposure increase across 10–80 mg due to reduced absorption at higher doses | Time to effect delayed if taken with or soon after a meal (Tmax delayed ~1.5 h with high-fat meal); take on an empty stomach for fastest onset |
| Distribution | Vd ~49 L; protein binding >99% (albumin and α1-acid glycoprotein); not preferentially distributed to red blood cells | High protein binding; clinically meaningful displacement interactions are unlikely. Hemodialysis is not expected to remove drug in overdose |
| Metabolism | Hepatic; CYP3A is the major enzyme, with minor contribution from CYP2C19. Major circulating metabolite (hydroxy-suvorexant) is not pharmacologically active | CYP3A is the dominant determinant of drug interactions — strong CYP3A inhibitors are not recommended; moderate inhibitors require dose reduction |
| Elimination | ~66% feces, ~23% urine (as metabolites); steady-state by day 3; t½ ~12 h; accumulation 1- to 2-fold with daily dosing | Half-life is meaningfully longer than older hypnotics — adequate sleep opportunity (≥7 h) is essential. No renal dose adjustment |
Side Effects
The most common adverse event in pivotal trials of suvorexant 15 mg or 20 mg was somnolence (7% vs 3% on placebo). Other common events including headache, dizziness, dry mouth, abnormal dreams, and cough occurred at incidences within 1–2 percentage points of placebo. Most CNS adverse events show a clear dose response, and the labeled narcolepsy-spectrum events (sleep paralysis, hypnagogic/hypnopompic hallucinations, cataplexy-like leg weakness) — although uncommon — are mechanistically distinctive and increase with dose. Suvorexant is a Schedule IV controlled substance, and abuse-liability studies in recreational polydrug users showed subjective ratings comparable to zolpidem.
| Adverse Effect | Incidence | Clinical Note |
|---|---|---|
| None reported at this frequency | — | No adverse event reached ≥10% incidence on suvorexant 15 mg or 20 mg in pivotal placebo-controlled trials |
| Adverse Effect | Incidence | Clinical Note |
|---|---|---|
| Somnolence (next-day) | 7% | Placebo 3%; dose-related (2% at 10 mg → 5% at 20 mg → 12% at 40 mg). Higher in women (8%) than men (3%) |
| Headache | 7% | Placebo 6%; usually mild and self-limiting |
| Dizziness | 3% | Placebo 2%; counsel older adults to rise slowly if waking overnight |
| Diarrhea | 2% | Placebo 1% |
| Dry mouth | 2% | Placebo 1% |
| Upper respiratory tract infection | 2% | Placebo 1%; clinical significance unclear |
| Abnormal dreams | 2% | Placebo 1%; usually not bothersome but warrant inquiry on follow-up |
| Cough | 2% | Placebo 1% |
| Adverse Effect | Incidence | Clinical Note |
|---|---|---|
| Somnolence | 4% | Placebo 1%; lower absolute rate than non-AD trials, possibly reflecting shorter exposure |
| Dry mouth | 2% | Placebo 1% |
| Falls | 2% | Placebo 0%; assess gait stability and fall risk before dose escalation in dementia |
| Adverse Effect | Estimated Frequency | Typical Onset | Required Action |
|---|---|---|---|
| Daytime impairment / impaired driving | Dose-related; documented at 20 mg in healthy non-elderly volunteers | Morning after dose | Counsel against next-day driving at 20 mg dose; reduce dose or discontinue if daytime somnolence develops |
| Complex sleep behaviors (sleep-driving, sleep-eating, phone calls, sex with amnesia) | Reported with hypnotics including suvorexant | Any time during therapy | Strongly consider permanent discontinuation after any episode; risk increased by alcohol and other CNS depressants |
| Worsening depression and emergence of suicidal ideation | Dose-dependent increase in suicidal ideation by questionnaire in trials | Variable | Immediately evaluate any new behavioral signs or suicidal ideation; prescribe smallest feasible quantity in patients with depression |
| Sleep paralysis (inability to move/speak during sleep–wake transitions) | Uncommon; dose-related | Sleep–wake transitions | Reassure if isolated and brief; consider dose reduction or discontinuation if recurrent or distressing |
| Hypnagogic / hypnopompic hallucinations | Uncommon; dose-related | Falling asleep or waking | Counsel proactively about the nature of these events; consider dose reduction or discontinuation if recurrent |
| Cataplexy-like symptoms (transient leg weakness, day or night) | Uncommon; dose-related; not necessarily emotion-triggered | Variable | Consider dose reduction or discontinuation; assess fall risk in older adults and patients with dementia |
| Respiratory depression in compromised patients | Cannot be excluded in OSA or COPD per PI | Variable | Not studied in severe OSA or severe COPD; consider risks before prescribing in these populations and in combination with opioids |
| Abuse and dependence (Schedule IV) | Subjective effects similar to zolpidem in recreational drug users | Variable | Screen substance-use history; monitor for misuse; prescribe limited quantities in at-risk patients |
Driving studies in healthy adults documented impaired Standard Deviation of Lane Position with the 20 mg dose, with a small minority of subjects (4 non-elderly women) prematurely terminating the driving test due to somnolence. The FDA label specifically cautions patients on the 20 mg dose against next-day driving and other activities requiring full mental alertness. Counsel every patient — including those on 10 mg — to allow at least 8 hours between dose and driving and to discontinue or step down if morning impairment develops.
Drug Interactions
Suvorexant is a CYP3A substrate, and CYP3A inhibitor / inducer interactions are the dominant pharmacokinetic concerns. Suvorexant itself is a weak intestinal P-glycoprotein inhibitor with a small effect on digoxin exposure. Pharmacodynamic additivity with alcohol and other CNS depressants is the dominant non-PK concern. Paroxetine showed no clinically meaningful PK or PD interaction in a dedicated study.
Per the FDA label, dedicated PK/PD studies showed no clinically meaningful interactions when suvorexant was co-administered with paroxetine, midazolam (CYP3A substrate), warfarin, or oral contraceptives. Suvorexant is unlikely to cause clinically significant inhibition of CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, or CYP2D6.
Monitoring
The FDA label does not specify routine laboratory monitoring for suvorexant. Clinical follow-up should focus on therapeutic response, daytime function, dose-related neuropsychiatric and narcolepsy-spectrum events, and — because suvorexant is a controlled substance — appropriate use and abuse-screening.
-
Sleep response
Reassess at 7–10 days, then periodically
Routine Track sleep latency, wake after sleep onset, total sleep time, and daytime function. Per the FDA label, failure of insomnia to remit after 7–10 days should prompt re-evaluation for an underlying psychiatric or medical disorder. -
Daytime somnolence and driving
Each follow-up visit
Routine Specifically inquire about morning grogginess, near-misses while driving, and difficulty concentrating. Reduce to 10 mg or discontinue if daytime impairment develops. -
Mood and suicidal ideation
Each follow-up visit
Routine A dose-dependent increase in suicidal ideation by questionnaire was observed in trials. PHQ-9 with item 9 review or C-SSRS is appropriate, particularly in patients with prior depression. -
Complex sleep behaviors
Each follow-up visit
Routine Ask directly about sleep-walking, sleep-eating, sleep-driving, and unrecalled night-time activity. Strongly consider permanent discontinuation after any episode. -
Narcolepsy-spectrum events
Each follow-up visit
Routine Inquire specifically about sleep paralysis, vivid hallucinations on falling asleep or waking, and transient leg weakness. Dose reduction or discontinuation if recurrent. -
Falls and balance (older adults, dementia)
Each follow-up visit
Routine Falls were reported in 2% of suvorexant-treated patients in the AD trial vs 0% on placebo. Assess gait stability, especially before dose escalation in dementia or frail older adults. -
Substance-use risk
Baseline; ongoing as indicated
Routine Suvorexant is a Schedule IV controlled substance. Screen for prior alcohol or sedative misuse before initiation; monitor for early refill requests or dose escalation. -
Respiratory status
Baseline if compromised
Trigger-based In patients with OSA or COPD, weigh hypnotic need against potential respiratory effects. Suvorexant has not been studied in severe OSA or severe COPD. -
Digoxin levels
When co-administered
Trigger-based Per the FDA label, monitor digoxin concentrations when co-administered with suvorexant.
Contraindications & Cautions
Absolute Contraindications (per FDA Label)
- Narcolepsy — the only labeled contraindication. Orexin antagonism could exacerbate the underlying loss of orexin signaling that produces the disorder.
Not Recommended / Specialist Input Suggested
- Concomitant strong CYP3A inhibitors — co-administration is not recommended due to substantial increase in suvorexant exposure.
- Severe hepatic impairment (Child-Pugh C) — not studied; the FDA label states suvorexant is not recommended.
- Active major depression with suicidal ideation — a dose-dependent increase in suicidal ideation was observed in pivotal trials. Prescribe the lowest feasible quantity per label.
- Pediatric patients — safety and effectiveness have not been established.
Use with Caution
- Severe obstructive sleep apnea or severe COPD — not studied in these populations; respiratory effects cannot be excluded. Weigh risk–benefit individually.
- Mild-to-moderate respiratory disease — clinically meaningful respiratory effects cannot be excluded.
- Older adults — falls and confusion are more clinically meaningful; the 15 mg dose was used in pivotal elderly trial arms.
- Mild-to-moderate Alzheimer disease — labeled population data exist; falls were reported in 2% (vs 0% placebo). Assess gait and supervision needs.
- Obese patients, particularly obese women — exposure is meaningfully higher; cautious dose escalation. AUC is approximately 46% higher in obese women vs non-obese women.
- Concomitant moderate CYP3A inhibitors — start at 5 mg, max 10 mg.
- History of substance use disorder — Schedule IV; abuse-liability comparable to zolpidem in recreational users.
- Patients who cannot guarantee 7 hours of sleep opportunity — risk of next-day impairment is materially increased.
- Pregnancy and lactation — postmarketing data are insufficient to establish drug-associated risk; animal studies show decreased fetal weight at high doses. Suvorexant and its metabolite are present in human breast milk at low concentrations (relative infant dose <1%); monitor breastfed infants for somnolence and feeding problems.
In April 2019, the FDA required a Boxed Warning on eszopiclone, zaleplon, and zolpidem for rare but serious complex sleep behaviors (sleep-driving, sleep-walking, sleep-eating, and others) that have resulted in injuries and deaths. Suvorexant was not included in the 2019 Boxed Warning, but its FDA label states that complex sleep behaviors have been reported with suvorexant and that discontinuation should be strongly considered for any patient who reports such an episode. The risk is increased by alcohol and other CNS depressants. Counsel every patient on this risk before the first dose.
Patient Counselling
Purpose of Therapy
Suvorexant is approved for adults with insomnia involving difficulty falling asleep, staying asleep, or both. It works differently from older sleeping pills: rather than enhancing the brain’s sleep-promoting signals, it blocks the brain’s own wake-promoting signals (orexin). Suvorexant is a federally controlled substance because it can be misused; keep it in a secure place and do not share it. Cognitive behavioural therapy for insomnia (CBT-I) is the recommended first-line treatment for chronic insomnia and should ideally be offered or continued alongside any drug therapy.
How to Take It
Take one tablet within 30 minutes of going to bed, and only when you can stay in bed for at least 7 hours before being active again. The recommended starting dose is 10 mg; the maximum is 20 mg per night. Take it on an empty stomach for fastest effect — taking it with or shortly after a meal will delay how quickly it begins working. Do not drink alcohol on evenings you take suvorexant.
Sources
- U.S. Food and Drug Administration. Belsomra (suvorexant) prescribing information — supplement s006 (February 2020 label update incorporating Alzheimer disease findings; initial approval August 2014). accessdata.fda.gov Authoritative US label — primary source for indications, dosing, contraindications, interactions, and incidence figures cited throughout this monograph.
- DailyMed (NIH). BELSOMRA (suvorexant) tablet, film coated — current label. dailymed.nlm.nih.gov Searchable, regularly updated mirror of the FDA-approved labeling, including the PLLR-format Pregnancy and Lactation sections.
- U.S. Food and Drug Administration. FDA Drug Safety Communication: FDA adds Boxed Warning for risk of serious injuries caused by sleepwalking with certain prescription insomnia medicines. April 30, 2019. fda.gov FDA communication clarifying that the 2019 Boxed Warning applies to eszopiclone, zaleplon, and zolpidem; suvorexant is not included.
- Merck. FDA approves BELSOMRA (suvorexant) C-IV label update to include findings from study of insomnia in patients with mild-to-moderate Alzheimer’s disease (press release, February 3, 2020). merck.com Source for the 2020 label update incorporating Alzheimer disease trial findings into the prescribing information.
- Herring WJ, Snyder E, Budd K, et al. Orexin receptor antagonism for treatment of insomnia: a randomized clinical trial of suvorexant. Neurology. 2012;79(23):2265–2274. Phase IIb randomized trial establishing dose-response and the basis for the registrational program.
- Herring WJ, Connor KM, Ivgy-May N, et al. Suvorexant in patients with insomnia: results from two 3-month randomized controlled clinical trials. Biol Psychiatry. 2016;79(2):136–148. Pivotal Phase III trials (Studies 1 and 2) supporting the FDA approval; source for efficacy data on sleep latency and sleep maintenance.
- Michelson D, Snyder E, Paradis E, et al. Safety and efficacy of suvorexant during 1-year treatment of insomnia with subsequent abrupt treatment discontinuation: a phase 3 randomised, double-blind, placebo-controlled trial. Lancet Neurol. 2014;13(5):461–471. 12-month efficacy and safety data; supports absence of physical dependence and rebound insomnia after abrupt discontinuation.
- Herring WJ, Ceesay P, Snyder E, et al. Polysomnographic assessment of suvorexant in patients with probable Alzheimer’s disease dementia and insomnia: a randomized trial. Alzheimers Dement. 2020;16(3):541–551. Randomized trial of 285 patients with mild-to-moderate Alzheimer disease; basis for the February 2020 FDA label update incorporating AD findings into the prescribing information.
- Sateia MJ, Buysse DJ, Krystal AD, Neubauer DN, Heald JL. 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(2):307–349. doi: 10.5664/jcsm.6470 AASM 2017 guideline that gives suvorexant a conditional (weak) recommendation for sleep maintenance insomnia in adults.
- Qaseem A, Kansagara D, Forciea MA, Cooke M, Denberg TD; Clinical Guidelines Committee of the American College of Physicians. Management of chronic insomnia disorder in adults: a clinical practice guideline from the American College of Physicians. Ann Intern Med. 2016;165(2):125–133. doi: 10.7326/M15-2175 ACP guideline emphasising CBT-I as first-line treatment for chronic insomnia, with pharmacotherapy reserved for patients in whom CBT-I is inadequate or unavailable.
- Cox CD, Breslin MJ, Whitman DB, et al. Discovery of the dual orexin receptor antagonist [(7R)-4-(5-chloro-1,3-benzoxazol-2-yl)-7-methyl-1,4-diazepan-1-yl][5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl]methanone (MK-4305) for the treatment of insomnia. J Med Chem. 2010;53(14):5320–5332. Discovery and characterisation of suvorexant (MK-4305) — establishes the OX1R/OX2R selectivity profile.
- Sakurai T. The neural circuit of orexin (hypocretin): maintaining sleep and wakefulness. Nat Rev Neurosci. 2007;8(3):171–181. Foundational review of orexin signalling and its role in arousal — the conceptual basis for orexin antagonism as a hypnotic strategy.
- Sun H, Kennedy WP, Wilbraham D, et al. Effects of suvorexant, an orexin receptor antagonist, on sleep parameters as measured by polysomnography in healthy men. Sleep. 2013;36(2):259–267. Polysomnographic characterisation of suvorexant pharmacodynamics in healthy adults.
- Vermeeren A, Sun H, Vuurman EFPM, et al. On-the-road driving performance the morning after bedtime use of suvorexant 20 and 40 mg: a study in non-elderly healthy volunteers. Sleep. 2015;38(11):1803–1813. On-the-road driving study underpinning the FDA caution against next-day driving at the 20 mg dose.
- Hatta K, Kishi Y, Wada K, et al. Real-world effectiveness of ramelteon and suvorexant for delirium prevention in 948 patients with delirium risk factors. J Clin Psychiatry. 2020;81(1):19m12865. Largest real-world cohort supporting the off-label use of suvorexant for delirium prevention in at-risk inpatients.