AHFS Class:

• Orexin Receptor Antagonists 28:24.40

Generic Name(s):

• Suvorexant

Chemical Name:

• [(7 R )-4-(5-Chloro-2-benzoxazolyl)hexahydro-7-methyl-1 H -1,4-diazepin-1-yl][5-methyl-2-(2 H -1,2,3-triazol-2-yl)phenyl]-methanone

Molecular Formula:

• C₂₃H₂₃ClN₆O₂

Suvorexant, an orexin receptor antagonist, is a hypnotic agent.1,6,7

Insomnia

Suvorexant is used for the treatment of insomnia characterized by difficulty with sleep onset and/or sleep maintenance.1,3,6 In controlled clinical studies, suvorexant improved sleep onset and sleep maintenance compared with placebo.1,3,4

Efficacy of suvorexant in the management of insomnia was established in 2 multicenter, randomized, double-blind, placebo-controlled, parallel-group studies of 3 months' duration (studies 1 and 2) and supported by a 1-month multicenter, randomized, double-blind, placebo-controlled, crossover study (study 3) in patients who met DSM-IV-TR criteria for primary insomnia.1,3,4,6

In studies 1 and 2, which were similar in design, a total of 1260 patients received suvorexant (at doses of 20 mg in patients 18-64 years of age [mean age: 46 years] and 15 mg in patients 65 years of age and older [mean age: 71 years]) or placebo.1,3 Patients with sleep disorders other than primary insomnia, confounding neurologic disorders, current major affective or psychotic psychiatric illnesses, substance abuse, or unstable medical conditions were excluded.3 In both studies, suvorexant was superior to placebo on measures of sleep maintenance, as assessed by polysomnographic wake time after sleep onset (WASO) during the first night of use and at 1 and 3 months and as assessed subjectively as patient-reported total sleep time (sTST) during the first week of use and at 1 and 3 months.1,3 Suvorexant also was superior to placebo for decreasing sleep latency, as assessed by polysomnographic latency to persistent sleep (LPS) during the first night of use, at 1 month, and at 3 months (in study 1 only) and patient-reported time to sleep onset (sTSO) during the first week of use, at 1 month (in study 2 only), and at 3 months.1,3

In these studies, the efficacy and safety of suvorexant at doses of 30 mg (in patients ≥65 years of age) and 40 mg (in patients 18-64 years of age) also were evaluated; while also effective in decreasing sleep latency and improving sleep maintenance, the higher doses were associated with substantially more adverse effects.1,3

Study 3 included patients 18-64 years of age.1,4 In this study, 249 patients received placebo and 123 patients received suvorexant 10 or 20 mg; doses up to 80 mg also were studied.1,4 During the first night of use and at week 4 of treatment, suvorexant doses of 10 and 20 mg were superior to placebo on polysomnographic measures of sleep latency and sleep maintenance (i.e., LPS and WASO).1,4,9

Suvorexant also was evaluated in a long-term safety study in 781 patients with primary insomnia.5,6 Although the study was designed to primarily assess safety of suvorexant, results indicate that the higher doses used in the study (40 mg in patients <65 years of age and 30 mg in patients ≥65 years of age) were superior to placebo based on subjective measures of sleep latency and sleep maintenance (i.e., sTSO and sTST) at 1 month, and efficacy was maintained for periods of up to 12 months.5,6,7

General

Pretreatment Screening

• Because sleep disturbances may be a manifestation of a physical and/or psychiatric disorder, symptomatic treatment of insomnia should be initiated only after careful evaluation of the patient.1

Patient Monitoring

• Monitor for somnolence and CNS depressant effects.1

Administration

Suvorexant is administered orally no more than once per night, within 30 minutes of bedtime and at least 7 hours before the planned time of awakening.1

Although suvorexant may be administered without regard to meals, administration with or immediately after a meal decreases the rate of drug absorption and may delay the onset of effect.1 (See Description.)

Dosage

The smallest effective dosage of suvorexant should be used.1

For the management of insomnia, the recommended adult dosage of suvorexant is 10 mg no more than once per night.1 If the 10-mg dose is well tolerated but not effective, dosage may be increased but should not exceed 20 mg once per night.1

Dosage Adjustment for Concomitant Therapy

When used concomitantly with a moderate cytochrome P-450 (CYP) 3A inhibitor, the recommended dosage of suvorexant is 5 mg no more than once per night; the dosage should generally not exceed 10 mg once per night.1 Concomitant use of strong CYP3A inhibitors is not recommended.1

When used concomitantly with other CNS depressants, dosage adjustment of suvorexant or the other CNS depressant may be necessary because of potential additive effects.1

Special Populations

Hepatic Impairment

No dosage adjustment is necessary in patients with mild to moderate hepatic impairment; however, suvorexant has not been adequately studied in patients with severe hepatic impairment and is not recommended for use in such patients.1

Renal Impairment

No dosage adjustment is necessary in patients with renal impairment.1

Geriatric Patients

Adjustment of suvorexant dosage in geriatric patients is not necessary based solely on age.1,10

Obese Patients and Women

Systemic exposure to suvorexant is increased in obese patients (BMI > 30 kg/m²) compared with nonobese patients, and in women compared with men.1 The manufacturer states that the increased risk of exposure-related adverse effects should be considered before increasing the dosage of suvorexant, particularly in obese women.1

Contraindications

• Patients with narcolepsy.1

Warnings/Precautions

CNS Depressant Effects and Daytime Impairment

Suvorexant, like other hypnotic agents, has CNS depressant effects and may impair daytime wakefulness even when used as prescribed.1 Patients receiving suvorexant should be monitored for somnolence and CNS depressant effects; however, impairment may occur in the absence of symptoms and may not be reliably detected by ordinary clinical examination (i.e., formal psychomotor testing may be required).1 CNS depressant effects may persist for up to several days after discontinuance of suvorexant.1 CNS depression may increase the risk of falls, particularly in geriatric patients.1

Suvorexant may impair the ability to drive a motor vehicle and may increase the risk of falling asleep while driving.1 In clinical trials in healthy adults, administration of suvorexant at bedtime (15 or 30 mg in individuals ≥65 years of age and 20 or 40 mg in individuals <65 years of age) was associated with next-morning impairment of driving performance in individuals receiving a single 20- or 40-mg dose.1 In these trials, 5 individuals (1 geriatric and 4 younger women) discontinued their driving tests prematurely because of somnolence.1 Therefore, although tolerance or adaptation to some depressant effects may develop with daily use, patients receiving the 20-mg dose should be cautioned against driving or engaging in other activities that require complete mental alertness the day after use.1 Patients receiving lower doses of the drug also should be advised of the risk of driving impairment.1 If daytime somnolence develops in patients who drive, suvorexant should be discontinued or the dosage decreased.1

Concomitant use of suvorexant with other CNS depressants (e.g., alcohol, benzodiazepines, opiates, tricyclic antidepressants) increases the risk of CNS depression.1 Dosage adjustment of suvorexant and/or other CNS depressants may be necessary if the drugs are used concomitantly.1 Concomitant use of suvorexant with alcohol or other drugs to treat insomnia is not recommended.1

The risk of daytime impairment is increased if suvorexant is administered with less than a full night of sleep remaining, if a higher than recommended dose of suvorexant is administered, or when suvorexant is used concomitantly with other CNS depressants or with drugs capable of increasing suvorexant concentrations.1

Worsening of Depression and Suicidal Ideation

In clinical studies, a dose-dependent increase in suicidal ideation was observed in patients receiving suvorexant.1

Worsening of depression and suicidal thoughts and actions (including completed suicides) have been reported in primarily depressed patients receiving sedative and hypnotic agents.1 Suicidal tendencies may be present, and protective measures may be required.1 Intentional overdosage is more common in this patient population, and the least amount of drug feasible should be prescribed and dispensed at any one time to avoid such intentional overdosage.1 Patients should be immediately evaluated if emergence of suicidality or any new behavioral abnormalities occurs during suvorexant therapy.1

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 following use of hypnotic agents, including suvorexant.1 Patients usually did not remember experiencing these complex sleep behaviors.1

These events can occur in hypnotic agent-naive as well as in hypnotic agent-experienced patients.1 These behaviors can occur following the first dose or at any time during treatment with suvorexant, with or without concomitant use of alcohol or other CNS depressants.1 Suvorexant should be discontinued immediately if a complex sleep behavior occurs.1

Sleep Paralysis, Hypnagogic/Hypnopompic Hallucinations, Cataplexy-Like Symptoms

Sleep paralysis (an inability to move or speak for up to several minutes during sleep-wake transition) and hypnagogic/hypnopompic hallucinations, including vivid and disturbing perceptions, may occur in patients taking suvorexant.1 In addition, dose-related symptoms similar to mild cataplexy (e.g., leg weakness lasting from seconds to a few minutes) may occur either at night and/or during the day and may not be associated with an identified triggering event (e.g., laughter or surprise).1 The risk of symptoms similar to mild cataplexy can increase with dose.1 Patients should be informed of the possibility of these effects.1

Patients with Compromised Respiratory Function

Effects of suvorexant on respiratory function should be considered if the drug is used in patients with compromised respiratory function.1

In a randomized, placebo-controlled crossover study in 26 patients with mild to moderate obstructive sleep apnea (OSA), suvorexant 40 mg given nightly was associated with a small increase in the average number of episodes of apnea and hypopnea per hour of sleep (mean apnea/hypopnea index [AHI]11 treatment difference of 2.7 for suvorexant compared with placebo) after 4 nights of use; however, substantial interindividual and intraindividual variation was observed and clinically meaningful respiratory depressant effects in patients with OSA cannot be excluded.1,9 Effects of suvorexant on respiratory function in patients with severe OSA have not been established.1

In a randomized, placebo-controlled crossover study in 25 patients with mild to moderate chronic obstructive pulmonary disease (COPD), suvorexant (30 mg in geriatric individuals and 40 mg in nongeriatric individuals) had no effect on oxygen saturation after 1 and 4 nights of use.1 However, substantial interindividual and intraindividual variation was observed and clinically meaningful respiratory depressant effects in patients with COPD cannot be excluded.1 Effects of suvorexant on respiratory function in patients with severe COPD have not been established.1

Single suvorexant doses of up to 150 mg did not have a respiratory depressant effect as measured by oxygen saturation in healthy individuals with normal respiratory function.1

Adequate Patient Evaluation

Because sleep disturbances may be a manifestation of a physical and/or psychiatric disorder, symptomatic treatment of insomnia should be initiated only after careful evaluation of the patient.1 Failure of insomnia to remit after 7-10 days of suvorexant therapy, worsening of insomnia, or emergence of new cognitive or behavioral abnormalities may indicate the presence of an underlying psychiatric, physical, and/or medical condition requiring evaluation.1

Abuse Potential and Dependence

Suvorexant is a schedule IV controlled substance (C-IV).1,8

In an abuse-potential study conducted in recreational drug users, administration of higher than recommended doses of suvorexant (40-150 mg) produced subjective responses (e.g., “drug liking”) similar to those produced by higher doses of zolpidem tartrate (15-30 mg),13 a schedule IV (C-IV) hypnotic agent.1 Because patients with a history of drug or alcohol abuse or addiction are at increased risk for abuse of and addiction to suvorexant, such patients should be monitored carefully when receiving the drug.1

In clinical studies of 3 months' duration, there was no clear evidence of rebound insomnia following discontinuance of suvorexant.1 In addition, clinical studies of the drug provided no evidence of physical dependence with prolonged use, and no withdrawal symptoms were reported following drug discontinuance.1

Specific Populations

Pregnancy

There are no adequate data on the use of suvorexant in pregnant women to evaluate the risk of adverse developmental effects or adverse maternal or fetal outcomes.1

In animal reproduction studies, decreased maternal weight gain was observed at dosages resulting in 30 and 28 times the exposures achieved with the maximum recommended human dosage in rats and rabbits, respectively.1 Decreased fetal weight was observed in rats at dose exposure levels ≥86 times the maximum recommended human dosage.1

In rats administered suvorexant during pregnancy and lactation, no adverse fetal or developmental effects were observed at dosages resulting in up to 25 times the exposures achieved with the maximum recommended human dosage.1 In rabbits administered suvorexant during pregnancy, no adverse fetal toxicities were observed at dosages resulting in up to 28 times the exposures achieved with the maximum recommended human dosage.1

Lactation

Suvorexant and a hydroxyl metabolite are distributed into milk in rats; it is not known whether the drug is distributed into human milk.1 The effects of the drug on the breast-fed infant or on milk production also are unknown.1 Consider the developmental and health benefits of breast-feeding along with the mother's clinical need for the drug and any potential adverse effects on the breast-fed infant from the drug or from the underlying maternal condition.1

The manufacturer states that infants exposed to suvorexant through breast milk should be monitored for excessive sedation.1

Pediatric Use

Safety and efficacy of suvorexant have not been established in pediatric patients.1

Geriatric Use

In clinical studies, 46% of patients who received suvorexant were ≥65 years of age, while 9% were ≥75 years of age.1 No substantial differences in safety and efficacy relative to younger adults were observed at recommended dosages of the drug.1

In a small, randomized, double-blind, placebo-controlled crossover trial in healthy geriatric individuals 65-80 years of age, administration of a single 30-mg dose of suvorexant at bedtime resulted in impairment of balance (body sway area) compared with placebo when individuals were awakened 90 minutes after the dose.1,9 In this study, memory impairment was not observed when individuals were awakened 4 hours after the dose.1,9

Because of the CNS depressant effects of suvorexant, geriatric patients in particular are at higher risk of falls.1

Hepatic Impairment

Following a single dose of suvorexant, systemic exposure to the drug in patients with moderate hepatic impairment (Child-Pugh score of 7-9) was similar to that in healthy individuals, even though the half-life of the drug was longer (19 versus 15 hours) in patients with moderate hepatic impairment; therefore, no dosage adjustment is necessary in patients with mild or moderate hepatic impairment.1 Suvorexant has not been studied in patients with severe hepatic impairment and use of the drug in such patients is not recommended.1

Renal Impairment

In a pharmacokinetic study, systemic exposure to suvorexant in patients with severe renal impairment (creatinine clearance 30 mL/minute or less) was similar to that in healthy individuals.1 Therefore, dosage adjustment is not necessary in patients with renal impairment.1

Gender

Systemic exposure to suvorexant is greater in women than in men.1 Peak plasma concentration and AUC are increased by 9 and 17%, respectively, in women compared with men following a 40-mg dose of suvorexant.1 At 9 hours after a dose, mean plasma concentrations of suvorexant are 5% higher in women than in men.1 In clinical studies, efficacy appeared to be similar in men and women; however, at doses of 15 or 20 mg, somnolence, headache, abnormal dreams, dry mouth, cough, and upper respiratory infection occurred in women at an incidence of at least twice that in men.1 Dosage adjustment generally is not necessary based solely on gender; however, caution should be used when increasing dosage in obese women.1

Obesity

Clearance of suvorexant is decreased in patients with higher body mass index (BMI).1 Peak plasma concentration and systemic exposure are 17 and 31% higher, respectively, in obese patients (BMI >30 kg/m²) compared with patients who are not overweight (BMI ≤25 kg/m²).1 Mean plasma concentrations at 9 hours after a 20-mg dose of suvorexant are 15% higher in obese patients than patients who are not overweight.1 In obese women, peak plasma concentration and AUC are increased by 25 and 46%, respectively, compared with nonobese women.1

Common Adverse Effects

The most common adverse effect of suvorexant reported in ≥5% of patients receiving the drug in clinical studies was somnolence.1,3

Suvorexant is metabolized principally by cytochrome P-450 (CYP) isoenzyme 3A and, to a lesser extent, by CYP2C19.1 In vitro studies suggest that suvorexant may potentially inhibit CYP3A isoenzymes and intestinal P-glycoprotein (P-gp).1 The drug does not appear to inhibit CYP isoenzymes 1A2, 2B6, 2C8, 2C9, 2C19, or 2D6 and is not expected to cause clinically important inhibition of organic anion-transporting polypeptide (OATP) 1B1, breast cancer resistance protein (BCRP), or organic cation transporter (OCT) 2.1

Drugs Affecting Hepatic Microsomal Enzymes

Inhibitors of CYP3A

Concomitant use of suvorexant with a potent CYP3A inhibitor (e.g., boceprevir, clarithromycin, conivaptan, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, telithromycin) is not recommended, as suvorexant exposure may be substantially increased.1,10

If suvorexant is used concomitantly with a moderate CYP3A inhibitor (e.g., aprepitant, atazanavir, ciprofloxacin, diltiazem, erythromycin, fluconazole, fosamprenavir, grapefruit juice, imatinib, verapamil), the recommended initial dose of suvorexant is 5 mg; dosage may be increased if the 5-mg dose is not effective, but generally should not exceed 10 mg once daily.1

Diltiazem

Concomitant administration of suvorexant (single 20-mg dose) and the moderate CYP3A inhibitor diltiazem hydrochloride (240 mg as an extended-release preparation daily for 6 days) increased the AUC of suvorexant by approximately twofold.1,10

Ketoconazole

Concomitant administration of suvorexant (single 4-mg dose) and the potent CYP3A inhibitor ketoconazole (400 mg daily for 11 days) increased the AUC of suvorexant by approximately threefold.1,10

Inducers of CYP3A

Concomitant use of suvorexant with a potent CYP3A inducer (e.g., carbamazepine, phenytoin, rifampin) may result in substantially decreased systemic exposure to suvorexant and decreased hypnotic efficacy.1 The manufacturer states that the maximum recommended dosage of 20 mg once daily should not be exceeded in patients receiving concomitant therapy with potent CYP3A inducers.1

Rifampin

Concomitant administration of suvorexant (single 40-mg dose) and the potent CYP3A inducer rifampin (600 mg daily for 17 days) resulted in a substantial (approximately 88%) decrease in the AUC of suvorexant.1,10

Drugs Metabolized by Hepatic Microsomal Enzymes

Midazolam

No clinically important changes in exposure to midazolam (a CYP3A substrate) occurred when midazolam (single oral 2-mg dose) was administered concomitantly with suvorexant (single- or multiple-dose administration of suvorexant 80 mg).1,10 No dosage adjustment is necessary when suvorexant is used concomitantly with midazolam.1

Warfarin

Concomitant administration of suvorexant (40 mg daily for 20 days) with the CYP2C9 substrate warfarin sodium (single 30-mg dose) did not affect the pharmacokinetics of R - or S -warfarin.1,10 No dosage adjustment is necessary when suvorexant is used concomitantly with warfarin.1

CNS Depressants

Concomitant use of suvorexant with other CNS depressants (e.g., alcohol, benzodiazepines, opiates, tricyclic antidepressants) may result in additive CNS depression.1 When suvorexant is used concomitantly with other CNS depressant drugs, dosage reduction of suvorexant and/or the CNS depressant may be necessary.1 Concomitant use of suvorexant with other hypnotic agents is not recommended.1

Alcohol

An additive effect on psychomotor impairment was observed following single-dose administration of suvorexant 40 mg with alcohol 0.7 g/kg; no clinically important pharmacokinetic interaction was observed.1 The manufacturer therefore recommends that suvorexant not be taken if alcohol was consumed that evening or before bedtime.1

Digoxin

Concomitant administration of suvorexant (40 mg daily for 11 days) and digoxin (single 0.5-mg dose) resulted in slight increases in digoxin peak plasma concentration and AUC (increases of 21 and 27%, respectively) via inhibition of P-gp.1,10 The manufacturer of suvorexant recommends monitoring of digoxin concentrations as clinically indicated when the drugs are used concomitantly.1

Oral Contraceptives

Concomitant administration of suvorexant (40 mg daily for 18 days) and a single dose of an oral estrogen-progestin combination contraceptive containing ethinyl estradiol 35 mcg and norgestimate 0.25 mg did not have a clinically important effect on the pharmacokinetics of ethinyl estradiol or norelgestromin, the active metabolite of norgestimate.1,10 No dosage adjustment is necessary when suvorexant is used concomitantly with ethinyl estradiol and norgestimate.1

Paroxetine

Concomitant administration of suvorexant (single 40-mg dose) and paroxetine (20 mg daily) in healthy individuals did not have a clinically important effect on the pharmacokinetics or pharmacodynamics (psychomotor performance) of either drug.1,10

Description

Suvorexant is a dual orexin-1 and orexin-2 receptor antagonist.1,6,7,12 The mechanism of action of suvorexant in the treatment of insomnia is thought to be related to antagonism of orexin receptors.1 Orexin (also known as hypocretin) receptors located in the brain promote and maintain wakefulness; these receptors are activated by the binding of orexin A and B, neuropeptides produced in the lateral hypothalamus.1,6,7 Loss of orexin-producing neurons and decreased CSF orexin concentrations have been associated with narcolepsy with cataplexy in humans,1,6,7,14,15,16 while increased orexin activity may be associated with insomnia.14,16 Suvorexant binds to orexin-1 and orexin-2 receptors and blocks the binding of orexin A and B; blockade of these receptors is thought to suppress the wake drive and promote sleep.1,6,7

Following oral administration in the fasting state, the median time to peak plasma concentration is approximately 2 hours (range: 0.5-6 hours).1 Administration of suvorexant with a high-fat meal prolongs time to peak plasma concentration by approximately 1.5 hours; peak plasma concentration and AUC are not substantially affected.1 Suvorexant is highly bound (> 99%) to plasma proteins.1 Suvorexant is metabolized by the cytochrome P-450 (CYP) microsomal enzyme system, principally by CYP3A and, to a lesser extent, by CYP2C19; the major circulating metabolite is a hydroxy derivative that is not expected to be pharmacologically active.1 The elimination half-life of suvorexant is approximately 12 hours.1 Following oral administration of radiolabeled suvorexant, approximately 66% of the dose is eliminated in feces and 23% is eliminated in urine.1

Advice to Patients

• Importance of reading the manufacturer's medication guide.1
• Importance of taking suvorexant only once per night within 30 minutes of going to bed and only when able to stay in bed for ≥7 hours before being active again.1,2 Taking suvorexant with or immediately after a meal may delay its effect.1,2
• Importance of taking suvorexant only as prescribed and of not increasing the dose unless otherwise instructed by a clinician.1,2
• Importance of not taking suvorexant if alcohol has been consumed in the evening or before bedtime.1,2
• Importance of avoiding activities requiring complete mental alertness or physical coordination (e.g., driving a motor vehicle) for ≥8 hours after a dose.1
• Risk of daytime impairment.1,2 In patients receiving the 20-mg dose, importance of avoiding driving or engaging in other activities that require complete mental alertness the day after use.1
• Risk of complex sleep behaviors, including sleep-walking, sleep-driving, preparing and eating food, making phone calls, or having sex while not being fully awake.1 Importance of immediately contacting a clinician if a complex sleep behavior occurs.1
• Importance of being alert to and immediately reporting worsening depression or suicidal ideation.1,2
• Importance of informing patients and their families that sleep paralysis, hypnagogic/hypnopompic hallucinations, and mild cataplexy-like symptoms may occur.1,2
• Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.1,2
• Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements, as well as any concomitant or past illnesses (e.g., depression, substance abuse).1,2
• Importance of informing patients of other important precautionary information.1 (See Cautions.)

Additional Information

Overview^® (see Users Guide). For additional information on this drug 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 cautions, precautions, contraindications, potential drug interactions, laboratory test interferences, and acute toxicity.

1. Merck. Belsomra^® (suvorexant) tablets prescribing information. Whitehouse Station, NJ; 2020 Mar.

2. Merck. Belsomra^® (suvorexant) tablets medication guide. Whitehouse Station, NJ; 2020 Mar.

3. 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 . 2014; :. [PubMed 25526970]

4. Herring WJ, Snyder E, Budd K et al. Orexin receptor antagonism for treatment of insomnia: a randomized clinical trial of suvorexant. Neurology . 2012; 79:2265-74. [PubMed 23197752]

5. 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; 13:461-71. [PubMed 24680372]

6. Yang LP. Suvorexant: first global approval. Drugs . 2014; 74:1817-22. [PubMed 25227290]

7. Jacobson LH, Callander GE, Hoyer D. Suvorexant for the treatment of insomnia. Expert Rev Clin Pharmacol . 2014; 7:711-30. [PubMed 25318834]

8. Drug Enforcement Administration, Department of Justice. Schedules of controlled substances: placement of suvorexant into Schedule IV. 21 CFR Part 1308. Final Rule. [Docket No. DEA-381] Fed Regist. 2014; 79:51243-7.

9. US Food and Drug Administration. Center for Drug Evaluation and Research. Application number 204569Orig1s000: Medical review(s). From FDA website. [Web]

10. US Food and Drug Administration. Center for Drug Evaluation and Research. Application number 204569Orig1s000: Clinical pharmacology and biopharmaceutics review(s). From FDA website. [Web]

11. American Academy of Sleep Medicine. Obstructive sleep apnea. From AASM website. Accessed 2015 May 8. [Web]

12. Citrome L. Suvorexant for insomnia: a systematic review of the efficacy and safety profile for this newly approved hypnotic - what is the number needed to treat, number needed to harm and likelihood to be helped or harmed?. Int J Clin Pract . 2014; 68:1429-41. [PubMed 25231363]

13. Sanofi-Aventis. Ambien^® (zolpidem tartrate) tablets prescribing information. Bridgewater, NJ; 2014 Oct.

14. Wang C, Wang Q, Ji B et al. The Orexin/Receptor System: Molecular Mechanism and Therapeutic Potential for Neurological Diseases. Front Mol Neurosci . 2018; 11:220. [PubMedCentral][PubMed 30002617]

15. Janto K, Prichard JR, Pusalavidyasagar S. An Update on Dual Orexin Receptor Antagonists and Their Potential Role in Insomnia Therapeutics. J Clin Sleep Med . 2018; 14:1399-1408. [PubMedCentral][PubMed 30092886]

16. Herring WJ, Roth T, Krystal AD et al. Orexin receptor antagonists for the treatment of insomnia and potential treatment of other neuropsychiatric indications. J Sleep Res . 2019; 28:e12782. [PubMed 30338596]