BELSOMRA®

(suvorexant) tablets, for oral use, C-IV

Mechanism of Action

BELSOMRA is a highly selective antagonist for orexin receptors

Orexin Neurons
  • Orexin is a central promoter of wakefulness. It reinforces the activity of other wake-promoting neurotransmitters.1
  • Blocking orexin receptors is thought to suppress wake drive.
  • The therapeutic effect of BELSOMRA in insomnia is presumed to be through antagonism of orexin receptors.
  • BELSOMRA has no appreciable binding affinity at acetylcholine, dopamine, gamma-aminobutyric acid (GABA), histamine, melatonin, noradrenaline, opiate, or serotonin receptors.2,3
  • Antagonism of orexin receptors may also underlie potential adverse effects such as signs of narcolepsy/cataplexy. Genetic mutations in the orexin system in animals result in hereditary narcolepsy; loss of orexin neurons has been reported in humans with narcolepsy.

Video: Learn more about BELSOMRA and the brain’s wake and sleep systems

This is BELSOMRA. BELSOMRA is the only insomnia therapy to target the orexin pathway. BELSOMRA is indicated for the treatment of insomnia characterized by difficulties with sleep onset and/or sleep maintenance. BELSOMRA is contraindicated in patients with narcolepsy. BELSOMRA contains suvorexant, a Schedule IV controlled substance. BELSOMRA can impair daytime wakefulness. Central nervous system (CNS) depressant effects can last for up to several days after discontinuation. In the brain’s wake/sleep circuitry, 2 systems work together to regulate wake and sleep.(1) These systems receive many inputs including from the body’s circadian drive (its natural 24-hour rhythm) and homeostatic drive (which gauges the body’s need for sleep).(1) Under regular conditions, sleep occurs when wake-promoting signaling begins to diminish, the sleep system sends out inhibitory neurotransmitters to block the wake system, and the sleep system takes over, allowing a transition to sleep.(1,2) Many factors contribute to insomnia.(1,3) Science suggests that when insomnia occurs, wakepromoting signaling overrides sleep-promoting signaling in the brain.(1,3) BELSOMRA can impair driving skills and may increase the risk of falling asleep while driving. Caution patients taking BELSOMRA 20 mg against next-day driving and other activities requiring full mental alertness. Coadministration with other CNS depressants increases the risk of CNS depression. Patients should be advised not to consume alcohol in combination with BELSOMRA due to additive effects. Dosage adjustments of BELSOMRA and of other concomitant CNS depressants may be necessary when administered together because of potentially additive effects. The use of BELSOMRA with other drugs to treat insomnia is not recommended. The risk of next-day impairment, including impaired driving, is increased if BELSOMRA is taken with less than a full night of sleep remaining, if a higher than recommended dose is taken, if coadministered with other CNS depressants, or if coadministered with other drugs that increase blood levels of BELSOMRA. Patients should be cautioned against driving and other activities requiring complete mental alertness if taken in these circumstances. Wake-promoting signaling involves many neurotransmitters.1 These include serotonin, dopamine, noradrenaline, histamine, acetylcholine, and orexin.(1) Orexin is a central promoter of wakefulness and reinforces the activity of other wake-promoting neurotransmitters.(4) Orexin neurons are localized in the hypothalamus and project to the cerebral cortex.(5) BELSOMRA is a highly selective antagonist for orexin receptors. Blocking orexin receptors is thought to suppress wake drive. The therapeutic effect of BELSOMRA in insomnia is presumed to be through antagonism of orexin receptors. BELSOMRA has no appreciable binding affinity at acetylcholine, dopamine, GABA, histamine, melatonin, noradrenaline, opiate, or serotonin receptors.(7,8) Antagonism of orexin receptors may also underlie potential adverse effects such as signs of narcolepsy/ cataplexy. Genetic mutations in the orexin system in animals result in hereditary narcolepsy; loss of orexin neurons has been reported in humans with narcolepsy. Reevaluate patients for comorbid conditions if insomnia persists after 7 to 10 days of treatment. A variety of cognitive and behavioral changes (eg, amnesia, anxiety, hallucinations, and other neuropsychiatric symptoms) have been reported with the use of hypnotics such as BELSOMRA. Complex behaviors such as “sleep-driving” (ie, driving while not fully awake after taking a hypnotic) and other complex behaviors (eg, preparing and eating food, making phone calls, or having sex), with amnesia for the event, have been reported in association with the use of hypnotics. Discontinuation of BELSOMRA should be strongly considered for these patients. The use of alcohol and other CNS depressants may increase the risk of such behaviors. These events can occur in hypnotic-naïve as well as hypnotic-experienced persons. Discontinuation of BELSOMRA should be strongly considered for patients who report any complex sleep behavior. BELSOMRA is the only orexin receptor antagonist for the treatment of insomnia. It selectively blocks orexin receptors, which is thought to inhibit wake drive. In clinical studies, a dose-dependent increase in suicidal ideation was observed in patients taking BELSOMRA, as assessed by questionnaire. Immediately evaluate patients with suicidal ideation or any new onset behavioral changes. Suicidal tendencies may be present and intentional overdose is more common in this group of patients. Intentional overdose is more common in this group of patients; therefore, the lowest number of tablets that is feasible should be prescribed for the patient at any one time. The effect of BELSOMRA on respiratory function should be considered. Sleep paralysis, hypnagogic/hypnopompic hallucinations, and cataplexy-like symptoms can occur. The risk of cataplexy-like symptoms increases with the dose of BELSOMRA. BELSOMRA is not recommended for patients with severe hepatic impairment or those taking a strong CYP3A inhibitor. In clinical studies, the most common adverse reaction (reported in 5% or more of patients treated with 15 mg or 20 mg of BELSOMRA and at least twice the placebo rate) was somnolence (BELSOMRA 7%, placebo 3%). The recommended dose of BELSOMRA is 5 mg in patients receiving moderate CYP3A inhibitors. Digoxin levels should be monitored, as slight increases were seen with coadministration of BELSOMRA. BELSOMRA…the only orexin receptor antagonist indicated for the treatment of insomnia characterized by difficulties with sleep onset and/or sleep maintenance. Before prescribing BELSOMRA, please read the accompanying Prescribing Information. The Medication Guide is also available. Select Links to access. References: 1. Saper CB, Scammell TE, Lu J. Hypothalamic regulation of sleep and circadian rhythms. Nature. 2005;437(7063):1257−1263. 2. Saper CB, Fuller PM, Pedersen NP, et al. Sleep state switching. Neuron. 2010;68(6):1023–1042. 3. Nofzinger EA, Buysse DJ, Germain A, et al. Functional neuroimaging evidence for hyperarousal in insomnia. Am J Psychiatry. 2004;161(11):2126−2129. 4. Sakurai T. The neural circuit of orexin (hypocretin): maintaining sleep and wakefulness. Nat Rev Neurosci. 2007;8(3):171–181. 5. Marcus JN, Elmquist JK. Orexin projections and localization of orexin receptors. In: Nishino S, Sakurai T, eds. The Orexin/Hypocretin System: Physiology and Pathophysiology. Totowa, NJ: Humana Press; 2006:21–43. 6. Gotter AL, Winrow CJ, Brunner J, et al. The duration of sleep promoting efficacy by dual orexin receptor antagonists is dependent upon receptor occupancy threshold. BMC Neurosci. 2013;14(90):1–16. 7. Winrow CJ, Gotter AL, Cox CD, et al. Promotion of sleep by suvorexant—a novel dual orexin receptor antagonist. J Neurogenet. 2011;25(1–2):52–61. 8. Data available on request from Merck Professional Services-DAP, WP1, PO Box 4, West Point, PA 19486-0004. Please specify information package NEUR-1129586-0000.

References 

1. Sakurai T. The neural circuit of orexin (hypocretin): maintaining sleep and wakefulness. Nat Rev Neurosci. 2007;8(3):171–181. 

2. Winrow CJ, Gotter AL, Cox CD, et al. Promotion of sleep by suvorexant—a novel dual orexin receptor antagonist. J Neurogenet. 2011;25(1–2):52–61. 

3. Data available on request from Merck Professional Services-DAP, WP1, PO Box 4, West Point, PA 19486-0004. Please specify information package NEUR-1129586-0000.

Indication

BELSOMRA is indicated for the treatment of insomnia characterized by difficulties with sleep onset and/or sleep maintenance.

Selected Safety Information

Contraindications

  • BELSOMRA is contraindicated in patients with narcolepsy.
  • BELSOMRA contains suvorexant, a Schedule IV controlled substance.

Warnings and Precautions

  • BELSOMRA is a central nervous system (CNS) depressant and can impair daytime wakefulness even when used as prescribed. Prescribers should monitor for somnolence and CNS depressant effects, but impairment can occur in the absence of symptoms, and may not be reliably detected by ordinary clinical exam. CNS depressant effects may persist in some patients for up to several days after discontinuing BELSOMRA.
  • BELSOMRA can impair driving skills and may increase the risk of falling asleep while driving. Discontinue or decrease the dose in patients who drive if daytime somnolence develops. Caution patients taking BELSOMRA 20 mg against next-day driving and other activities requiring full mental alertness. Caution patients taking lower doses of BELSOMRA as well, because there is individual variation in sensitivity to BELSOMRA.
  • Coadministration with other CNS depressants (eg, benzodiazepines, opioids, tricyclic antidepressants, alcohol) increases the risk of CNS depression. Patients should be advised not to consume alcohol in combination with BELSOMRA due to additive effects. Dosage adjustments of BELSOMRA and of other concomitant CNS depressants may be necessary when administered together because of potentially additive effects. The use of BELSOMRA with other drugs to treat insomnia is not recommended.
  • The risk of next-day impairment, including impaired driving, is increased if BELSOMRA is taken with less than a full night of sleep remaining, if a higher than recommended dose is taken, if coadministered with other CNS depressants, or if coadministered with other drugs that increase blood levels of BELSOMRA. Patients should be cautioned against driving and other activities requiring complete mental alertness if taken in these circumstances.
  • Symptomatic treatment of insomnia should be initiated only after careful evaluation of the patient. Reevaluate for comorbid conditions if insomnia persists after 7 to 10 days of treatment.
  • A variety of cognitive and behavioral changes (eg, amnesia, anxiety, hallucinations, and other neuropsychiatric symptoms) have been reported with the use of hypnotics such as BELSOMRA. Complex behaviors such as “sleep-driving” (ie, driving while not fully awake after taking a hypnotic) and other complex behaviors (eg, preparing and eating food, making phone calls, or having sex), with amnesia for the event, have been reported in association with the use of hypnotics. Discontinuation of BELSOMRA should be strongly considered for these patients. The use of alcohol and other CNS depressants may increase the risk of such behaviors. These events can occur in hypnotic-naïve as well as hypnotic-experienced persons. Discontinuation of BELSOMRA should be strongly considered for patients who report any complex sleep behavior.
  • In clinical studies, a dose-dependent increase in suicidal ideation was observed in patients taking BELSOMRA, as assessed by questionnaire. Immediately evaluate patients with suicidal ideation or any new onset behavioral changes. In primarily depressed patients treated with sedative-hypnotics, worsening of depression or suicidal thinking, including suicidal thoughts and actions (including completed suicide), have been reported. Suicidal tendencies may be present in such patients and protective measures may be required. Intentional overdose is more common in this group of patients; therefore, the lowest number of tablets that is feasible should be prescribed for the patient at any one time.
  • The effect of BELSOMRA on respiratory function should be considered if prescribed to patients with compromised respiratory function.
  • Sleep paralysis, an inability to move or speak for up to several minutes during sleep-wake transitions, and hypnagogic/hypnopompic hallucinations, including vivid perceptions by the patient, can occur with use of BELSOMRA.
  • Symptoms similar to mild cataplexy can occur, with risk increasing with the dose of BELSOMRA. Such symptoms can 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 an identified triggering event (eg, laughter or surprise).

Adverse Reactions

  • In clinical studies, the most common adverse reaction (reported in 5% or more of patients treated with 15 mg or 20 mg of BELSOMRA and at least twice the placebo rate) was somnolence (BELSOMRA 7%, placebo 3%).

Additional Safety Information

  • In clinical studies, during the first 3 months of treatment, the adverse reactions reported in ≥2% of patients treated with 15 mg or 20 mg of BELSOMRA and more commonly than in patients treated with placebo, were, diarrhea (BELSOMRA 2%, placebo 1%), dry mouth (2%, 1%), upper respiratory tract infection (2%, 1%), headache (7%, 6%), somnolence (7%, 3%), dizziness (3%, 2%), abnormal dreams (2%, 1%), and cough (2%, 1%).
  • At doses of 15 mg or 20 mg, the incidence of somnolence was higher in females (8%) than in males (3%). The incidence of headache, abnormal dreams, dry mouth, cough, and upper respiratory tract infection occurrence in women was at least twice that in men.

Drug Interactions

  • When BELSOMRA was coadministered with alcohol, additive psychomotor impairment was demonstrated.
  • Concomitant use of BELSOMRA with strong inhibitors of CYP3A (eg, ketoconazole, itraconazole, posaconazole, clarithromycin, nefazodone, ritonavir, saquinavir, nelfinavir, indinavir, boceprevir, telaprevir, telithromycin, conivaptan) is not recommended.
  • The recommended dose of BELSOMRA is 5 mg in subjects receiving moderate CYP3A inhibitors (eg, amprenavir, aprepitant, atazanavir, ciprofloxacin, diltiazem, erythromycin, fluconazole, fosamprenavir, grapefruit juice, imatinib, verapamil). The dose can be increased to 10 mg in these patients if necessary for efficacy.
  • The efficacy of BELSOMRA may be reduced when coadministered with strong CYP3A inducers (eg, rifampin, carbamazepine, phenytoin).
  • Slightly increased levels of digoxin were seen with coadministration of BELSOMRA. Digoxin levels should be monitored when coadministering BELSOMRA with digoxin.

Use in Specific Populations

  • No clinical studies have been conducted in pregnant women. BELSOMRA should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
  • It is not known if BELSOMRA is secreted in human milk. Use caution when administering to nursing women.
  • Safety and effectiveness of BELSOMRA in pediatric patients have not been established.

Drug Abuse and Dependence

  • BELSOMRA contains suvorexant, a Schedule IV controlled substance.
  • Because individuals with a history of abuse or addiction to alcohol or other drugs may be at increased risk for abuse and addiction to BELSOMRA, health care providers should follow such patients carefully when those patients are receiving BELSOMRA.

Dosage and Administration

  • Use the lowest dose effective for the patient.
  • The recommended dose for BELSOMRA is 10 mg, taken no more than once per night, and within 30 minutes of going to bed, with at least 7 hours remaining before the planned time of awakening. If the 10-mg dose is well tolerated but not effective, the dose can be increased. The maximum recommended dose of BELSOMRA is 20 mg once daily.
  • Exposure to BELSOMRA is increased in obese compared to non-obese patients, and in women compared to men. Particularly in obese women, the increased risk of exposure-related adverse effects should be considered before increasing the dose.
  • When BELSOMRA is combined with other CNS depressant drugs, dosage adjustment of BELSOMRA and/or the other drug(s) may be necessary because of potentially additive effects. The recommended dose of BELSOMRA is 5 mg when used with moderate CYP3A inhibitors, and the dose generally should not exceed 10 mg in these patients.
  • BELSOMRA is not recommended for use with strong CYP3A inhibitors.
  • The effect of BELSOMRA may be delayed if taken with or soon after a meal.
  • No dose adjustment is required in patients with mild and moderate hepatic impairment. BELSOMRA has not been studied in patients with severe hepatic impairment and is not recommended for these patients.

Before prescribing BELSOMRA, please read the Prescribing Information. The Medication Guide also is available.

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