Suvorexant

Indications

• FDA-approved for the treatment of insomnia characterized by difficulties with sleep onset, sleep maintenance, or both, in adults.
• Efficacy was maintained over 3-month randomized trials, so it is suitable for longer courses than the traditional short-term hypnotics.
• The American Academy of Sleep Medicine gives a weak recommendation for suvorexant in sleep maintenance insomnia.
• Off-label interest in delirium prevention in hospitalized older adults exists, with small trials suggesting reduced incidence.
• It is an option when benzodiazepines and Z-drugs are undesirable, though it remains a schedule IV controlled substance.
• Contraindicated in narcolepsy, since orexin signaling is already deficient in that disorder and further blockade worsens it.

Mechanism of action

• Dual orexin receptor antagonist blocking OX1R and OX2R, the receptors for the wake-promoting neuropeptides orexin A and orexin B.
• Rather than enhancing GABAergic sedation, it removes the arousal signal from lateral hypothalamic orexin neurons to monoaminergic nuclei.
• Because it targets wakefulness rather than global CNS depression, sleep architecture is largely preserved with increases in REM sleep.
• Loss of orexin signaling is the lesion in narcolepsy, which explains both the contraindication and the sleep paralysis and cataplexy-like effects.
• Absence of GABA-A activity means no muscle relaxation, no anticonvulsant effect, and less amnesia than benzodiazepine hypnotics.

Pharmacokinetics

• Absorbed with peak levels near 2 hours and bioavailability about 82 percent; a high-fat meal delays the peak by roughly 1.5 hours.
• Elimination half-life is about 12 hours, long enough that next-day residual effects are the main dose-limiting problem.
• Metabolized almost entirely by CYP3A4 with a minor CYP2C19 contribution; the major circulating metabolite is inactive.
• Exposure is higher in obese patients and particularly in obese women, who should be watched closely for next-day sedation.
• No adjustment is needed for renal impairment or mild to moderate hepatic impairment; severe hepatic disease has not been studied.

Dosing

• Adults: 10 mg PO once nightly within 30 minutes of going to bed, with at least 7 hours remaining before planned awakening.
• If 10 mg is tolerated but not effective, the dose may be increased to 15 or 20 mg, which is the labeled maximum.
• With a moderate CYP3A4 inhibitor such as diltiazem, verapamil or fluconazole, use 5 mg nightly and do not exceed 10 mg.
• Not recommended with strong CYP3A4 inhibitors such as ketoconazole, itraconazole, clarithromycin or ritonavir.
• Take no more than one dose per night, and avoid dosing with or soon after a meal since food delays the onset of effect.
• No taper is required, and rebound insomnia after discontinuation is minimal compared with benzodiazepines and Z-drugs.

Adverse effects

• Somnolence in about 7 percent versus 3 percent on placebo, headache 7 percent, dizziness 3 percent and abnormal dreams.
• Next-day driving impairment demonstrated at 20 mg in both men and women, with the effect present even when patients feel alert.
• Sleep paralysis, hypnagogic and hypnopompic hallucinations, and mild cataplexy-like leg weakness reflecting orexin blockade.
• Complex sleep behaviors including sleepwalking have been reported, and the drug should be stopped if any such episode occurs.
• Worsening of depression and suicidal ideation, reported more often at 20 mg; assess mood before and during treatment.
• Respiratory depression risk in patients with compromised respiratory function, and additive impairment with alcohol and opioids.

Monitoring

• Assess next-morning alertness and driving safety, particularly at 15 and 20 mg, and in obese patients where exposure is higher.
• Ask about sleep paralysis, hallucinations on falling asleep, leg weakness and any complex sleep behaviors at follow-up visits.
• Screen for depression and suicidal ideation before starting and at each visit, since worsening mood has been reported.
• Evaluate for obstructive sleep apnea and COPD before use, since respiratory effects in those groups are incompletely characterized.
• Check the prescription monitoring program before prescribing this schedule IV agent and reassess ongoing need periodically.

Interactions

• Strong CYP3A4 inhibitors are not recommended for co-administration; moderate inhibitors require the reduced 5 mg starting dose.
• Strong CYP3A4 inducers such as rifampin, carbamazepine and St. John's wort substantially reduce exposure and may abolish benefit.
• Additive sedation and respiratory depression with opioids, alcohol, benzodiazepines, gabapentinoids and sedating antihistamines.
• Contraindicated in narcolepsy; use caution in obstructive sleep apnea, severe COPD and any condition compromising respiration.
• Suvorexant is a weak inhibitor of intestinal P-glycoprotein and can modestly raise digoxin levels, so monitor digoxin concentrations.

Special populations

• Pregnancy: human data are insufficient; a pregnancy exposure registry exists and the drug should be used only if clearly needed.
• Lactation: it is not known whether suvorexant passes into human milk; monitor the nursing infant for sedation and poor feeding.
• Pediatrics: safety and effectiveness under age 18 are not established and use is not recommended in that age group.
• Older adults: not among the agents the AGS Beers Criteria flag for avoidance, but next-day sedation and fall risk still apply.
• Hepatic and renal impairment: no adjustment for renal disease or mild to moderate hepatic disease; not studied in severe hepatic disease.

Clinical pearls

• Blocks the wake signal instead of sedating, so sleep architecture is largely preserved.
• Absolutely contraindicated in narcolepsy, where orexin signaling is already lost.
• Next-day driving is measurably impaired at 20 mg even when the patient reports feeling fine.