suvorexant (Rx)

1-10%

Somnolence, females (8%)

Somnolence (7%)

Headache (7%)

Somnolence, males (3%)

Dizziness (3%)

Abnormal dreams (2%)

Cough (2%)

Diarrhea (2%)

Dry mouth (2%)

Upper respiratory tract infection (2%)

Postmarketing Reports

Cardiac disorders: Palpitations, tachycardia

Nervous system disorders: Psychomotor hyperactivity

Psychiatric disorders: Anxiety

Skin and subcutaneous tissue disorders: Pruritus

Contraindications

Narcolepsy

Cautions

Can impair daytime wakefulness; CNS depressant effects can last for up to several days after discontinuation

Can impair driving skills and may increase the risk of falling asleep while driving

Patients should not use suvorexant if they drank alcohol that evening or before bed; coadministration with other CNS depressants (eg, benzodiazepines, opioids, tricyclic antidepressants, alcohol) increases the risk of CNS depression

Dosage adjustments of suvorexant and concomitant CNS depressants may be necessary when administered together because of potentially additive effects

Use with other drugs to treat insomnia is not recommended

Risk of next-day impairment, including impaired driving, is increased if taken with less than a full night of sleep remaining, if a higher than the recommended dose is taken, if coadministered with other CNS depressants, or if coadministered with other drugs that increase suvorexant blood levels

Caution patients taking 20 mg to refrain from next-day driving and other activities requiring full mental alertness

Reevaluate patients for comorbid conditions if insomnia persists after 7-10 days of treatment

Cognitive and behavioral changes (eg, amnesia, anxiety, hallucinations, and other neuropsychiatric symptoms) reported with hypnotics; “sleep driving” and other complex behaviors (eg, preparing and eating food, making phone calls, or having sex), with amnesia for the event, have been reported; discontinue therapy immediately if a patient experiences a complex sleep behavior

The use of alcohol and other CNS depressants may increase the risk of cognitive changes listed above; discontinuation should be strongly considered

Dose-dependent increase in suicidal ideation was observed in patients taking suvorexant, as assessed by questionnaire; immediately evaluate patients with suicidal ideation or any new-onset behavioral changes; worsening depression or suicidal thinking, thoughts, and actions have been reported with the use of sedative-hypnotic

Consider effect on respiratory function

Risk of sleep paralysis, hypnagogic/hypnopompic hallucinations, and cataplexy-like symptoms increases with increasing doses

Not recommended for patients with severe hepatic impairment or those taking a strong CYP3A inhibitor

Pregnancy

Available data from postmarketing reports in pregnant women are insufficient to establish a drug-associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes

Animal data

• In animal reproduction studies, oral administration to pregnant rats and rabbits during period of organogenesis decreased maternal body weight and/or weight gain at doses ≥ 30 and 28 times maximum recommended human dose (MRHD) of 20 mg based on AUC in the rat and rabbit, respectively
• Treatment caused decreased fetal weight at doses ≥ 86 times MRHD based on AUC in rat and did not cause significant fetal toxicity at doses up to 28 times MRHD based on AUC in the rabbit
• The no observed adverse effect levels (NOAELs) for fetal toxicity are 25 and 28 times MRHD based on AUC in rat and rabbit, respectively
• Oral administration to pregnant rats during pregnancy and lactation caused decreased maternal and pup body weight or weight gain at approximately 48 times the MRHD based on AUC; the NOAEL for development toxicity in rat is 25 times the MRHD based on AUC

Lactation

There are no data on presence of drug in human milk, effects on breastfed infant or on milk production; drug and metabolite are present in rat milk; when drug is present in animal milk, it is likely that the drug will be present in human milk

Infants exposed to drug through breastmilk should be monitored for excessive sedation; the developmental and health benefits of breastfeeding should be considered along with mother’s clinical need for drug and any potential adverse effects on breastfed infant from drug or from 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

Orexin receptor antagonist; orexin, also called hypocretin, is a neurotransmitter that regulates arousal, wakefulness, and appetite

Blocking the binding of wake-promoting neuropeptides orexin A and orexin B to receptors OX1R and OX2R is thought to suppress wake drive

Absorption

Bioavailability: 82%

Peak plasma time: 2 hr (range 30 min to 6 hr)

Taking after a high-fat meal delays peak concentration by ~1.5 hr

Distribution

Protein bound: >99% to human serum albumin and α1-acid glycoprotein

Not preferentially distribute into RBCs

Vd: 49 L

Metabolism

Mainly eliminated by metabolism, primarily by CYP3A with a minor contribution from CYP2C19

Metabolite: hydroxy-suvorexant (not active)

Elimination

Half-life: ~12 hr

Excretion: 66% feces; 23% urine

Oral Administration

May take with or without food; however, for faster sleep onset, do not administer soon after a meal because food will delay the onset of action

If alcohol consumed in the evening or before bed, do not take suvorexant