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Suvorexant

Pronunciation

(soo voe REX ant)

Index Terms

  • MK4305

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Tablet, Oral:

Belsomra: 5 mg

Belsomra: 10 mg [contains fd&c blue #1 aluminum lake]

Belsomra: 15 mg, 20 mg

Brand Names: U.S.

  • Belsomra

Pharmacologic Category

  • Hypnotic, Miscellaneous
  • Orexin Receptor Antagonist

Pharmacology

Suvorexant blocks the binding of wake-promoting neuropeptides orexin A and orexin B to receptors OX1R and OX2R, which is thought to suppress wake drive. Antagonism of orexin receptors may also underlie potential adverse effects such as signs of narcolepsy/cataplexy.

Absorption

Decreased at higher doses

Distribution

Vd: ~49 L

Metabolism

Primarily hepatic by CYP3A with a minor contribution from CYP2C19; the hydroxy-suvorexant metabolite is inactive.

Excretion

Feces (~66%); urine (~23%)

Onset of Action

~30 minutes

Time to Peak

2 hours (range: 30 minutes to 6 hours); Delayed approximately 1.5 hours when administered with a meal.

Half-Life Elimination

~12 hours; Half-life terminal: ~15 hours (healthy subjects, range: 10 to 22 hours), ~19 hours (moderate hepatic disease, range: 11 to 49 hours)

Protein Binding

>99%

Special Populations: Hepatic Function Impairment

The apparent terminal half-life of suvorexant increased from ~15 hours (range: 10 to 22 hours) in healthy subjects to ~19 hours (range: 11 to 49 hours) in patients with moderate hepatic insufficiency.

Special Populations: Gender

In females, the area under the curve (AUC) and maximum plasma concentration (Cmax) increased by 17% and 9%, respectively, following administration of suvorexant 40 mg. The average concentration 9 hours after dosing is 5% higher for females across the dose range studied (10 to 40 mg).

Special Populations Note

Obesity: The AUC and Cmax increases by 31% and 17%, respectively. The average concentration ~9 hours after a 20 mg dose is 15% higher in obese patients (BMI >30 kg/m2) relative to those with a normal BMI (BMI ≤25 kg/m2). In obese females, the AUC and Cmax increase by 46% and 25%, respectively.

Use: Labeled Indications

Insomnia: Treatment of insomnia characterized by difficulties with sleep onset and/or sleep maintenance.

Contraindications

Narcolepsy

Dosing: Adult

Insomnia: Oral: Note: Use the lowest effective dose for the patient. Usual dose: 10 mg once daily within 30 minutes of bedtime; may increase to a maximum of 20 mg once daily if the 10 mg dose is well tolerated but not effective. Maximum daily dose: 20 mg

Dosage adjustment for concomitant therapy:

Moderate CYP3A inhibitors (eg, amprenavir, aprepitant, atazanavir, ciprofloxacin, diltiazem, erythromycin, fluconazole, fosamprenavir, grapefruit juice, imatinib, verapamil): Usual dose: 5 mg once daily; maximum daily dose: 10 mg

Strong CYP3A inhibitors (eg, ketoconazole, itraconazole, posaconazole, clarithromycin, nefazodone, ritonavir, saquinavir, nelfinavir, indinavir, boceprevir, telaprevir, telithromycin, conivaptan): Use of suvorexant is not recommended.

CNS depressants: Dosage adjustment of suvorexant and/or the other CNS depressant may be necessary.

Dosing: Geriatric

Refer to adult dosing.

Dosing: Renal Impairment

No dosage adjustment necessary.

Dosing: Hepatic Impairment

Mild or moderate impairment: No dosage adjustment necessary.

Severe impairment: Use is not recommended (has not been studied).

Dosing: Obesity

Consider the increased risk of exposure-related adverse effects in obese women before increasing the dose.

Administration

Oral: Administer within 30 minutes of bedtime with at least 7 hours remaining before planned time of awakening. Onset is delayed with food; do not administer with or immediately after a meal.

Dietary Considerations

For faster sleep onset, do no administer with (or immediately after) a meal.

Storage

Store at 20°C to 25°C (68°F to 77°F); excursions are permitted between 15°C and 30°C (59°F and 86°F). Protect from light and moisture.

Drug Interactions

Alcohol (Ethyl): May enhance the CNS depressant effect of Suvorexant. Avoid combination

Azelastine (Nasal): CNS Depressants may enhance the CNS depressant effect of Azelastine (Nasal). Avoid combination

Blonanserin: CNS Depressants may enhance the CNS depressant effect of Blonanserin. Consider therapy modification

Bosentan: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Brimonidine (Topical): May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Buprenorphine: CNS Depressants may enhance the CNS depressant effect of Buprenorphine. Management: Consider reduced doses of other CNS depressants, and avoiding such drugs in patients at high risk of buprenorphine overuse/self-injection. Initiate buprenorphine patches (Butrans brand) at 5 mcg/hr in adults when used with other CNS depressants. Consider therapy modification

Cannabis: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Chlorphenesin Carbamate: May enhance the adverse/toxic effect of CNS Depressants. Monitor therapy

CNS Depressants: May enhance the CNS depressant effect of Suvorexant. Management: Dose reduction of suvorexant and/or any other CNS depressant may be necessary. Use of suvorexant with alcohol is not recommended, and the use of suvorexant with any other drug to treat insomnia is not recommended. Consider therapy modification

Conivaptan: May increase the serum concentration of CYP3A4 Substrates. Avoid combination

CYP3A4 Inducers (Moderate): May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

CYP3A4 Inducers (Strong): May decrease the serum concentration of Suvorexant. Avoid combination

CYP3A4 Inhibitors (Moderate): May increase the serum concentration of Suvorexant. Consider therapy modification

CYP3A4 Inhibitors (Strong): May increase the serum concentration of Suvorexant. Avoid combination

Dabrafenib: May decrease the serum concentration of CYP3A4 Substrates. Management: Seek alternatives to the CYP3A4 substrate when possible. If concomitant therapy cannot be avoided, monitor clinical effects of the substrate closely (particularly therapeutic effects). Consider therapy modification

Dasatinib: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

Deferasirox: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Dimethindene (Systemic): May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Dronabinol: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Droperidol: May enhance the CNS depressant effect of CNS Depressants. Management: Consider dose reductions of droperidol or of other CNS agents (e.g., opioids, barbiturates) with concomitant use. Consider therapy modification

Flunitrazepam: CNS Depressants may enhance the CNS depressant effect of Flunitrazepam. Consider therapy modification

Fosaprepitant: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

Fusidic Acid (Systemic): May increase the serum concentration of CYP3A4 Substrates. Avoid combination

HYDROcodone: CNS Depressants may enhance the CNS depressant effect of HYDROcodone. Management: Avoid concomitant use of hydrocodone and benzodiazepines or other CNS depressants when possible. These agents should only be combined if alternative treatment options are inadequate. If combined, limit the dosages and duration of each drug. Consider therapy modification

Idelalisib: May increase the serum concentration of CYP3A4 Substrates. Avoid combination

Ivacaftor: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

Kava Kava: May enhance the adverse/toxic effect of CNS Depressants. Monitor therapy

Lofexidine: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Luliconazole: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

Magnesium Sulfate: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Methotrimeprazine: May enhance the CNS depressant effect of CNS Depressants. CNS Depressants may enhance the CNS depressant effect of Methotrimeprazine. Management: Reduce adult dose of CNS depressant agents by 50% with initiation of concomitant methotrimeprazine therapy. Further CNS depressant dosage adjustments should be initiated only after clinically effective methotrimeprazine dose is established. Consider therapy modification

MetyroSINE: CNS Depressants may enhance the sedative effect of MetyroSINE. Monitor therapy

Minocycline: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Nabilone: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Orphenadrine: CNS Depressants may enhance the CNS depressant effect of Orphenadrine. Avoid combination

OxyCODONE: CNS Depressants may enhance the CNS depressant effect of OxyCODONE. Management: Avoid concomitant use of oxycodone and benzodiazepines or other CNS depressants when possible. These agents should only be combined if alternative treatment options are inadequate. If combined, limit the dosages and duration of each drug. Consider therapy modification

Palbociclib: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

Paraldehyde: CNS Depressants may enhance the CNS depressant effect of Paraldehyde. Avoid combination

Perampanel: May enhance the CNS depressant effect of CNS Depressants. Management: Patients taking perampanel with any other drug that has CNS depressant activities should avoid complex and high-risk activities, particularly those such as driving that require alertness and coordination, until they have experience using the combination. Consider therapy modification

Piribedil [INT]: CNS Depressants may enhance the CNS depressant effect of Piribedil [INT]. Monitor therapy

Pramipexole: CNS Depressants may enhance the sedative effect of Pramipexole. Monitor therapy

ROPINIRole: CNS Depressants may enhance the sedative effect of ROPINIRole. Monitor therapy

Rotigotine: CNS Depressants may enhance the sedative effect of Rotigotine. Monitor therapy

Rufinamide: May enhance the adverse/toxic effect of CNS Depressants. Specifically, sleepiness and dizziness may be enhanced. Monitor therapy

Selective Serotonin Reuptake Inhibitors: CNS Depressants may enhance the adverse/toxic effect of Selective Serotonin Reuptake Inhibitors. Specifically, the risk of psychomotor impairment may be enhanced. Monitor therapy

Siltuximab: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Simeprevir: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

Sodium Oxybate: Hypnotics (Nonbenzodiazepine) may enhance the CNS depressant effect of Sodium Oxybate. Avoid combination

St John's Wort: May decrease the serum concentration of CYP3A4 Substrates. Management: Consider an alternative for one of the interacting drugs. Some combinations may be specifically contraindicated. Consult appropriate manufacturer labeling. Consider therapy modification

Stiripentol: May increase the serum concentration of CYP3A4 Substrates. Management: Use of stiripentol with CYP3A4 substrates that are considered to have a narrow therapeutic index should be avoided due to the increased risk for adverse effects and toxicity. Any CYP3A4 substrate used with stiripentol requires closer monitoring. Consider therapy modification

Tapentadol: May enhance the CNS depressant effect of CNS Depressants. Management: Avoid concomitant use of tapentadol and benzodiazepines or other CNS depressants when possible. These agents should only be combined if alternative treatment options are inadequate. If combined, limit the dosages and duration of each drug. Consider therapy modification

Tetrahydrocannabinol: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Thalidomide: CNS Depressants may enhance the CNS depressant effect of Thalidomide. Avoid combination

Tocilizumab: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Zolpidem: CNS Depressants may enhance the CNS depressant effect of Zolpidem. Management: Reduce the Intermezzo brand sublingual zolpidem adult dose to 1.75 mg for men who are also receiving other CNS depressants. No such dose change is recommended for women. Avoid use with other CNS depressants at bedtime; avoid use with alcohol. Consider therapy modification

Adverse Reactions

Frequency not always defined.

Central nervous system: Drowsiness (2% to 12%; dose dependent and more common in females), headache (7%; more common in females), dizziness (3%), abnormal dreams (2%; more common in females), abnormality in thinking, amnesia, anxiety, behavioral changes, central nervous system depression, drug abuse, drug dependence, exacerbation of depression, hallucination, hypnagogic hallucinations, sleep driving, suicidal ideation

Endocrine & metabolic: Increased serum cholesterol

Gastrointestinal: Diarrhea (2%), xerostomia ( 2%; more common in females)

Neuromuscular & skeletal: Lower extremity weakness, sleep paralysis

Respiratory: Cough ( 2%; more common in females), upper respiratory tract infection ( 2%; more common in females)

Warnings/Precautions

Concerns related to adverse effects:

• Abnormal thinking/behavioral changes: Hypnotics have been associated with abnormal thinking and behavior changes (eg, amnesia, anxiety, hallucinations).

• CNS depression: May cause CNS depression impairing physical and mental capabilities; patients must be cautioned about performing tasks which require mental alertness (operating machinery or driving). Suvorexant should only be administered when the patient is able to stay in bed a full night (≥7 hours) before being active again. Discontinue or decrease the dose in patients who drive if daytime somnolence occurs.

• REM sleep effects: Sleep paralysis (inability to move or speak for up to several minutes during sleep-wake transitions), hypnagogic/hypnopompic hallucinations, and mild cataplexy may occur. Cataplexy symptoms may include periods of leg weakness lasting from seconds to a few minutes, can occur both at night and during the day, and may not be associated with a triggering event (eg, laughter, surprise).

• Sleep-related activities: An increased risk for hazardous sleep-related activities such as sleep-driving; cooking and eating food, making phone calls, or having sex while asleep have also been noted. Discontinue treatment in patients who report any sleep-related episodes.

Disease-related concerns:

• Depression: Use with caution in patients with depression; worsening of depression, including suicide or suicidal ideation has been reported with the use of hypnotics. Intentional overdose may be an issue in this population. The minimum dose that will effectively treat the individual patient should be used. Prescriptions should be written for the smallest quantity consistent with good patient care.

• Drug abuse: Use with caution in patients with a history of drug dependence. Risk of abuse is increased with prolonged use of suvorexant, in patients with a history of drug abuse, or those who use suvorexant in combination with alcohol or other abused drugs.

• Hepatic impairment: Use is not recommended in patients with severe hepatic impairment (has not been studied).

• Respiratory disease: Use with caution in patients with respiratory compromise, COPD, or sleep apnea.

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Special populations:

• Female patients: Exposure is increased in females compared to males. Consider the increased risk of exposure-related adverse effects, particularly in obese females, before increasing the dose.

• Obese patients: Exposure is increased in obese compared to nonobese patients. Consider the increased risk of exposure-related adverse effects, particularly in obese females, before increasing the dose.

Other warnings/precautions:

• Appropriate use: Symptomatic treatment of insomnia should be initiated only after careful evaluation of potential causes of sleep disturbance. Failure of sleep disturbance to resolve after 7 to 10 days may indicate psychiatric and/or medical illness.

Monitoring Parameters

Daytime alertness; respiratory rate; behavior profile; tolerance, abuse, dependence

Pregnancy Risk Factor

C

Pregnancy Considerations

Adverse events have been observed in some animal reproduction studies.

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience dizziness, fatigue, or headache. Have patient report immediately to prescriber signs of depression (suicidal ideation, anxiety, emotional instability, or illogical thinking) behavioral changes, confusion, shortness of breath, hallucinations, memory impairment, difficulty moving, difficulty speaking, or muscle weakness (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience, and judgment in diagnosing, treating, and advising patients.

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