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Belsomra

Generic Name: Suvorexant
Class: Anxiolytics, Sedatives, and Hypnotics; Miscellaneous
Chemical Name: [(7R) - 4 - (5 - Chloro - 2 - benzoxazolyl)hexahydro - 7 - methyl - 1H - 1,4 - diazepin - 1 - yl][5 - methyl - 2 - (2H - 1,2,3 - triazol - 2 - yl)phenyl] - methanone
Molecular Formula: C23H23ClN6O2
CAS Number: 1030377-33-3

Introduction

Hypnotic; dual orexin-1 and orexin-2 receptor antagonist.1 6 7

Uses for Belsomra

Insomnia

Management of insomnia characterized by difficulty with sleep onset and/or sleep maintenance.1 3 6

Decreases sleep latency and improves sleep maintenance in patients with primary insomnia receiving therapy for up to 3 months.1 3 4 Generally safe and well tolerated and reportedly effective with nightly use for up to 1 year.5

Belsomra Dosage and Administration

Administration

Oral Administration

Administer no more than once per night, within 30 minutes of bedtime.1

May administer without regard to meals; however, administration with or immediately after a meal decreases rate of absorption and may delay onset of effect.1

Use only if ≥7 hours remain before planned time of awakening.1

Dosage

Use smallest effective dosage.1

Concomitant use with certain drugs (e.g., CNS depressants, CYP3A inhibitors) is not recommended or may require dosage adjustment.1 (See Interactions.)

Adults

Insomnia
Oral

10 mg once daily.1 If 10 mg is well tolerated but ineffective, may increase dosage but do not exceed 20 mg once daily.1

Prescribing Limits

Adults

Insomnia
Oral

Maximum 20 mg once daily.1

Special Populations

Hepatic Impairment

No dosage adjustment necessary in patients with mild to moderate hepatic impairment.1

Not adequately studied in patients with severe hepatic impairment; use not recommended.1

Renal Impairment

Dosage adjustment not necessary.1

Geriatric Patients

Dosage adjustment not necessary based solely on age.1 10

Gender

Dosage adjustment generally not necessary based solely on gender; use caution when increasing dosage in obese women (body mass index [BMI] >30 kg/m2).1 (See Absorption: Special Populations, under Pharmacokinetics.)

Cautions for Belsomra

Contraindications

  • Narcolepsy.1 (See Actions and also see Narcolepsy-like Events under Cautions.)

Warnings/Precautions

CNS Depressant Effects and Next-day Impairment

CNS depressant; may impair daytime wakefulness even when used as prescribed.1

May impair ability to drive a motor vehicle and may increase risk of falling asleep while driving.1 Patients receiving the 20-mg dose should avoid driving or engaging in other activities that require complete mental alertness the day after use.1 Driving impairment also possible in patients receiving lower dosages.1 (See Advice to Patients.) If daytime somnolence develops in patients who drive, discontinue drug or decrease dosage.1

Risk of next-day impairment is increased if drug is administered with less than a full night of sleep remaining, if a higher than recommended dose is administered, or if used concomitantly with other CNS depressants or with drugs capable of increasing suvorexant concentrations.1 (See Interactions.)

Monitor patients for excessive somnolence and CNS depression; 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.1

Concomitant use with other CNS depressants (e.g., alcohol, benzodiazepines, opiates, tricyclic antidepressants) increases the risk of CNS depression.1 (See Interactions.)

Adequate Patient Evaluation

Insomnia may be a manifestation of an underlying physical and/or psychiatric disorder; carefully evaluate patient before providing symptomatic treatment.1

Failure of insomnia to remit after 7–10 days of treatment, worsening of insomnia, or emergence of new abnormal thinking or behavior may indicate the presence of an underlying psychiatric, physical, and/or medical condition that requires evaluation.1

Abnormal Thinking and Behavioral Changes

Abnormal thinking and behavioral changes (e.g., amnesia, anxiety, hallucinations, other neuropsychiatric symptoms) reported in patients receiving hypnotic agents.1

Complex behaviors such as sleep-driving (i.e., driving while not fully awake after taking a hypnotic agent), preparing and eating food, making phone calls, or having sex with no memory of the event also reported in patients receiving hypnotic agents.1

Complex behaviors may occur in hypnotic agent-naive or -experienced patients.1

Concomitant use of alcohol and other CNS depressants may increase the risk of complex behaviors.1

Strongly consider discontinuing drug in patients who report any complex sleep behavior.1

Worsening of Depression and Suicidality Risk

Dose-dependent increase in suicidal ideation observed in clinical studies.1

Worsening of depression and suicidal thoughts and actions (including completed suicides) reported in primarily depressed patients receiving sedative and hypnotic agents.1 Suicidal tendencies may be present; intentional overdosage more frequent in such patients.1 Protective measures may be required.1 Prescribe and dispense drug in the smallest feasible quantity.1

Evaluate patient immediately if emergence of suicidality or any new behavioral abnormalities occurs.1

Patients with Compromised Respiratory Function

If used in patients with compromised respiratory function, consider possible effects on respiratory function.1 Respiratory depressant effects in patients with mild to moderate obstructive sleep apnea (OSA) or COPD cannot be excluded; not studied in patients with severe OSA or COPD.1

No respiratory depressant effect observed in healthy individuals with normal respiratory function after single doses up to 150 mg.1

Narcolepsy-like Events

Sleep paralysis (inability to move or speak for up to several minutes during sleep-wake transition) and hypnagogic/hypnopompic hallucinations reported.1 3 4 5

Dosage-dependent, mild cataplexy-like symptoms (e.g., leg weakness lasting from seconds to a few minutes) may occur at night and/or during the day; may not be associated with an identified triggering event (e.g., laughter, surprise).1 (See Advice to Patients.)

Abuse Potential and Dependence

Abuse potential of high suvorexant doses (40–150 mg) appears to be similar to that of high zolpidem tartrate doses (15–30 mg).1 Patients with a history of drug or alcohol abuse or addiction are at increased risk of abuse and addiction; use only with careful surveillance in such patients.1

Discontinuance following chronic administration did not produce withdrawal symptoms or clear evidence of rebound insomnia.1 Does not appear to produce physical dependence.1

Specific Populations

Pregnancy

Category C.1

Lactation

Distributed into milk in rats; not known whether distributed into human milk.1 Use with caution.1

Pediatric Use

Safety and efficacy not established in pediatric patients.1

Geriatric Use

At recommended dosages, no overall differences in safety or efficacy relative to younger adults.1

Balance impairment observed when geriatric individuals were awakened 90 minutes after a 30-mg dose; no memory impairment observed when awakened 4 hours after the dose.1 9

Hepatic Impairment

Dosage adjustment not necessary in patients with mild or moderate hepatic impairment.1

Not adequately studied in patients with severe hepatic impairment; use not recommended.1

Renal Impairment

Dosage adjustment not necessary in patients with renal impairment.1

Gender

Somnolence, headache, abnormal dreams, dry mouth, cough, and upper respiratory infection are at least twice as common in women as in men.1

Systemic exposure and peak plasma concentration are higher in women compared with men.1 (See Absorption: Special Populations, under Pharmacokinetics and also see Gender under Dosage and Administration.)

Obesity

Systemic exposure and peak plasma concentration are higher in obese patients (BMI >30 kg/m2) compared with nonoverweight patients (BMI ≤25 kg/m2).1 (See Absorption: Special Populations, under Pharmacokinetics and also see Gender under Dosage and Administration.)

Common Adverse Effects

Somnolence,1 3 headache,1 3 dizziness,1 3 abnormal dreams,1 3 cough,1 3 diarrhea,1 3 dry mouth,1 3 upper respiratory tract infection.1 3

Interactions for Belsomra

Metabolized principally by CYP3A and, to a lesser extent, by CYP2C19.1

May potentially inhibit CYP3A and intestinal P-glycoprotein (P-gp).1 Does not appear to inhibit CYP1A2, 2B6, 2C8, 2C9, 2C19, or 2D6.1

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: Potential increased exposure to suvorexant.1 Avoid concomitant use with a potent CYP3A inhibitor.1 If used concomitantly with a moderate CYP3A inhibitor, recommended initial suvorexant dose is 5 mg; may increase dosage if necessary, but generally do not exceed 10 mg once daily.1

Potent inducers of CYP3A: Potential decreased exposure to and efficacy of suvorexant, but do not exceed maximum recommended suvorexant dosage (20 mg once daily).1

Specific Drugs and Foods

Drug or Food

Interaction

Comments

Anticonvulsants (carbamazepine, phenytoin)

Possible substantial decrease in suvorexant exposure1

Hypnotic efficacy may be decreased, but do not exceed maximum recommended suvorexant dosage (20 mg once daily)1

Antifungals, azole (fluconazole, itraconazole, ketoconazole, posaconazole)

Possible increased suvorexant exposure; increase may be substantial with potent CYP3A inhibitors1

Ketoconazole (400 mg daily): Suvorexant AUC increased approximately threefold1 10

Itraconazole, ketoconazole, posaconazole: Concomitant use not recommended1

Fluconazole: Initial suvorexant dose of 5 mg; may increase if necessary, but generally do not exceed 10 mg once daily1

Aprepitant

Possible increased suvorexant exposure1

Initial suvorexant dose of 5 mg; may increase if necessary, but generally do not exceed 10 mg once daily1

Calcium-channel blocking agents (diltiazem, verapamil)

Possible increased suvorexant exposure1

Diltiazem: Suvorexant AUC increased approximately twofold1 10

Initial suvorexant dose of 5 mg; may increase if necessary, but generally do not exceed 10 mg once daily1

Ciprofloxacin

Possible increased suvorexant exposure1

Initial suvorexant dose of 5 mg; may increase if necessary, but generally do not exceed 10 mg once daily1

CNS depressants (e.g., alcohol, benzodiazepines, opiates, tricyclic antidepressants)

Possible additive CNS depression1

Alcohol: Additive psychomotor impairment1

Alcohol: Avoid concomitant use (see Advice to Patients)1

Other hypnotics: Concomitant use not recommended1

Other CNS depressants: Dosage reduction of suvorexant and/or other CNS depressant may be necessary1

Conivaptan

Possible substantial increase in suvorexant exposure1

Concomitant use not recommended1

Digoxin

Slightly increased digoxin concentrations and AUC due to P-gp inhibition1 10

Monitor digoxin concentrations1

Grapefruit juice

Possible increased suvorexant exposure1

If used concomitantly, initial suvorexant dose of 5 mg; may increase if necessary, but generally do not exceed 10 mg once daily1

HCV protease inhibitors (boceprevir)

Possible substantial increase in suvorexant exposure1

Concomitant use not recommended1

HIV protease inhibitors (atazanavir, fosamprenavir, indinavir, nelfinavir, ritonavir, saquinavir)

Possible increased suvorexant exposure; increase may be substantial with potent CYP3A inhibitors1

Indinavir, nelfinavir, ritonavir, saquinavir: Concomitant use not recommended1

Atazanavir, fosamprenavir: Initial suvorexant dose of 5 mg; may increase if necessary, but generally do not exceed 10 mg once daily1

Imatinib

Possible increased suvorexant exposure1

Initial suvorexant dose of 5 mg; may increase if necessary, but generally do not exceed 10 mg once daily1

Macrolide antibiotics (clarithromycin, erythromycin, telithromycin)

Possible increased suvorexant exposure; increase may be substantial with potent CYP3A inhibitors1

Clarithromycin, telithromycin: Concomitant use not recommended1

Erythromycin: Initial suvorexant dose of 5 mg; may increase if necessary, but generally do not exceed 10 mg once daily1

Midazolam

No clinically important effect on midazolam pharmacokinetics1 10

No dosage adjustment necessary1

Nefazodone

Possible substantial increase in suvorexant exposure1

Concomitant use not recommended1

Oral contraceptives

Oral contraceptive containing ethinyl estradiol and norgestimate: No clinically important effect on pharmacokinetics of hormonal components1 10

No dosage adjustment necessary1

Paroxetine

No clinically important effect on pharmacokinetics or pharmacodynamics (psychomotor performance) of suvorexant (single 40-mg dose) or paroxetine (20 mg daily)1 10

Rifampin

Substantially decreased suvorexant exposure1 10

Hypnotic efficacy may be decreased, but do not exceed maximum recommended suvorexant dosage (20 mg once daily)1

Warfarin

No clinically important effect on pharmacokinetics of R- or S-warfarin1 10

No dosage adjustment necessary1

Belsomra Pharmacokinetics

Absorption

Bioavailability

Peak plasma concentrations attained in approximately 2 hours (range: 0.5–6 hours) after oral administration in fasted state.1

Absolute oral bioavailability is 82%.1

Food

High-fat meal prolongs time to peak plasma concentration by approximately 1.5 hours but does not substantially affect peak plasma concentration and AUC.1

Special Populations

Peak plasma concentration, mean concentration at 9 hours postdose, and AUC are increased by 9, 5, and 17%, respectively, in women compared with men.1

In obese patients (BMI >30 kg/m2), peak plasma concentration, mean concentration at 9 hours postdose, and AUC are increased by 17, 15, and 31%, respectively, compared with nonoverweight patients (BMI <25 kg/m2).1 In obese women, peak plasma concentration and AUC are increased by 25 and 46%, respectively, compared with nonobese women.1

In patients with moderate hepatic impairment (Child-Pugh score 7–9), systemic exposure after single dose is unchanged but half-life is increased.1 (See Elimination: Special Populations, under Pharmacokinetics.)

Severe renal impairment (Clcr <30 mL/minute) does not substantially alter systemic exposure.1

Distribution

Plasma Protein Binding

>99%; binds to albumin and α1-acid glycoprotein.1

Elimination

Metabolism

Metabolized principally by CYP3A and, to a lesser extent, by CYP2C19; major circulating metabolite (hydroxy derivative) is not expected to be active.1

Elimination Route

Excreted in feces (66%) and urine (23%).1

Half-life

Approximately 12 hours.1

Special Populations

Clearance is inversely related to BMI.1 (See Absorption: Special Populations, under Pharmacokinetics.)

In patients with moderate hepatic impairment (Child-Pugh score 7–9), half-life is approximately 19 hours (versus 15 hours in healthy individuals).1

Age and race predicted to have no clinically important effect on suvorexant pharmacokinetics.1

Stability

Storage

Oral

Tablets

20–25°C (may be exposed to 15–30°C).1 Store in original package until use to protect from light and moisture.1

Actions

  • Antagonist at orexin-1 and orexin-2 receptors.1 6 7 Blockade of the actions of neuropeptides orexin A and B at these receptors is thought to suppress wake drive and promote sleep.1 6 7

  • Loss of orexin-producing neurons and the resulting absence of orexin circulating in CSF are associated with narcolepsy with cataplexy.1 6 7

Advice to Patients

  • Importance of reading the manufacturer's medication guide prior to initiating therapy and each time the prescription is refilled.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 next-day 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 abnormal thinking, behavioral changes, sleep-walking, sleep-driving, and other complex behaviors (e.g., preparing and eating food, making phone calls, having sex) while not fully awake.1 2 Importance of contacting a clinician immediately if these adverse effects occur.1 2

  • Importance of being alert to and immediately reporting emergence or worsening of depression or suicidality and any unusual changes in thoughts or behavior.1 2

  • Importance of being aware that vivid hallucinations or an inability to move or talk for several minutes (sleep paralysis) may occur while going to sleep or waking up and that temporary leg weakness (cataplexy-like symptoms) may occur during the day or night.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.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Subject to control under the Federal Controlled Substances Act of 1970 as a schedule IV (C-IV) drug.1 8

Suvorexant

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablets, film-coated

5 mg

Belsomra

Merck

10 mg

Belsomra

Merck

15 mg

Belsomra

Merck

20 mg

Belsomra

Merck

AHFS DI Essentials. © Copyright, 2016, American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814. Review Date: September 06, 2016.

References

1. Merck. Belsomra (suvorexant) tablets prescribing information. Whitehouse Station, NJ; 2014 Oct.

2. Merck. Belsomra (suvorexant) tablets medication guide. Whitehouse Station, NJ; 2014 Oct.

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.

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

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

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.

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