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OCTOBER 2015

DELHI PSYCHIATRY JOURNAL Vol. 18 No. 2

Drug Review

Suvorexant: A Dual Orexin Receptor Antagonist for the Management of Insomnia Satyakam Mohapatra, Neelmadhav Rath Mental Health Institute, S.C.B. Medical College, Cuttack, Odisha Contact: Satyakam Mohapatra, Email: [email protected]

Introduction A variety of treatment options are available for insomnia. The most commonly used pharmacological interventions are benzodiazepines (BZDs), non-BZD gamma-amino-butyric acid (GABA)–acting hypnotics, sedating antidepressants, melatonin agonists, and antihistamines. Diminished efficacy and frequently noticed side effects (residual daytime sleepiness, cognitive impairment, confusion, dizziness, impaired motor coordination, physical and psychological dependence) limit the use of these treatment options for many patients. So drug with different mechanism of action is of great clinical interest. Suvorexant is a selective dual orexin receptor antagonist (DORA) for the treatment of insomnia. The drug (originally known as MK-4305) has completed phase III trials and was approved for use by the U.S. Food & Drug Administration on August 13, 2014 for the treatment of adult patients with primary insomnia.1 Mechanism of action The orexin (hypocretin) neuropeptide signaling system is a central promoter of wakefulness and are involved in regulating the sleep–wake cycle2 . The actions of orexin A (hypocretin-1) and orexin B (hypocretin-2) are mediated through two receptors, orexin 1 receptor (OX1R or HCRTR1) and orexin 2 receptor (OXR2 or HCRTR2). Suvorexant exerts its therapeutic effect in insomnia through antagonism of orexin receptors. Blocking the binding of wake-promoting neuropeptides orexin A and orexin B to receptors orexin receptor type 1 and orexin receptor type 2 is thought to suppress wake drive in persons experiencing insomnia, thus helping them fall asleep faster and stay asleep

longer. Suvorexant’s mechanism of action differs from that of most current sleep therapeutics.2,3 The latter drugs that are GABA-A receptor modulators plays a role in sleep, wakefulness, memory, and locomotor function leading to their untoward side effects. Suvorexant improves sleep onset and sleep maintenance. Unlike benzodiazapines, suvorexant does not have any addictive qualities as it does not increase dopaminergic tone. This unique alternative suvorexant has a favorable tolerability and limited side-effect profile.3 Pharmacokinetics Time to reach maximum blood levels (Tmax) of suvorexant is nearly 1 to 2 hours if fasted and 3 hours if fed. The half-life is approximately 12.2 hours on average (range 8–19 hours). Steady-state plasma concentrations occur in about three days with daily administration. For a dose of 10 mg, the mean absolute bioavailability is 82%. It is extensively (99%) bound to plasma proteins. It is metabolised predominantly by hepatic CYP3A4. Suvorexant is eliminated primarily via inactive metabolites in the feces; there is no renal elimination.4 Clinical results The US FDA approval was primarily based on data from two 3-months, phase III, randomized, double-blind, placebo controlled, parallel-group, efficacy trials,5,6 a 12-month, long-term, safety trial (which also included a discontinuation phase)7and a 4-week, phase IIB trial,8 all of which were conducted in patients with primary insomnia. In both phase III trials5,6 suvorexant 15 mg or 20 mg was superior to placebo for sleep latency and sleep maintenanceas assessed both objectively by polysomnography and subjectively by patient-

Delhi Psychiatry Journal 2015; 18:(2) © Delhi Psychiatric Society

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estimated sleep latency. In these trials, suvorexant was also evaluated at doses of 30 mg and 40 mg and were found to have similar efficacy to lower doses, but significantly more adverse reactions were reported at the higher doses. In the 1-month crossover study,8 non-elderly adults (age 18-64 years, mean age 44 years) were treated with placebo (n = 249) and suvorexant at a dose of 10 mg (n = 62), 20 mg (n = 61), or up to 80 mg. Suvorexant 10 mg and 20 mg were superior to placebo for sleep latency and sleep maintenance, as assessed objectively by polysomnography. The efficacy of suvorexant was also supported by data from another study7in adult (including elderly) patients. Once-daily suvorexant 30 mg (elderly patients) or 40 mg (non-elderly adults) improved subjective total sleep time (sTST), and subjective time to sleep onset (sTSO) by a significantly greater extent than placebo at 1, 2, 3 and 4 weeks. Discontinuation of suvorexant after 1 year was generally well tolerated, with no evidence of withdrawal or tolerance7;the return of symptoms was not indicative of rebound insomnia.5,6,9 No signs of physical dependence were reported with prolonged use of suvorexant.10

OCTOBER 2015

at higher than the recommended dose, or if coadministered with other central nervous system depressants or other drugs that increase blood levels of suvorexant.8 Cognitive and behavioral changes such as amnesia, anxiety, hallucinations have been reported. Alcohol and other central nervous system depressants may increase the risk of such behaviors. Discontinuation of suvorexant should be strongly considered for patients who report any complex sleep behaviour (e.g., preparing and eating food, making phone calls, or having sex). Worsening depression or suicidal thoughts have been reported. No clinically important rebound or withdrawal was observed following suvorexant discontinuation4. No signs of physical dependence were reported with prolonged use of suvorexant.10 Precautions

Suvorexant is used for the treatment of insomnia, characterized by difficulties with sleep onset and/or sleep maintenance. It can be used both for primary insomnia and as adjuvant in different psychiatric conditions with insomnia.

Suvorexant falls into category C.4 There are no well-controlled studies that have been done in pregnant women. Suvorexant should be used during pregnancy only if the possible benefit outweighs the possible risk to the unborn baby. It is unknown if suvorexant is secreted in breast milk, but it is advised to stop breastfeeding during suvorexant intake. It is contraindicated in patients with narcolepsy. 4 Patients taking suvorexant should not engage in activities requiring full mental alertness (such as driving) for at least 8 hours after taking suvorexant.4 Suvorexant, as with other hypnotic agents, should be avoided in individuals with severe hepatic impairment.12 Safety and effectiveness in paediatric patients have not been established.

Dosage and administration

Drug interaction

The drug is available in 5-, 10-, 15-, and 20-mg strengths. Recommended dose is 10 mg. The maximum recommended dose of suvorexant is 20 mg once daily. It should be taken within 30 minutes of going to bed, and with at least 7 hours remaining before planned time of awakening. Time to effect may be delayed if taken with or soon after a meal.11

Suvorexant is not recommended for patients with severe hepatic impairment or those taking a strong cytochrome P450 (CYP) 3A inhibitor (clarithromycin, telithromycin, HIV protease inhibitors, ketoconazole). The recommended dose of suvorexant is 5 mg in patients receiving moderate CYP3A inhibitors (aprepitant, ciprofloxacin, diltiazem). CYP3A4 inducers (e.g., rifampin, carbamazepine, phenytoin) increase the activity of enzymes that break down Belsomra in the body. Therefore, they may decrease blood levels of Belsomra. A dose adjustment may be necessary for suvorexant to be effective. Digoxin levels should be monitored closely, as slight increases were seen

Indications

Adverse reaction The most commonly reported adverse reaction was drowsiness. It can impair daytime wakefulness and driving skills and may increase the risk of falling asleep while driving. The risk is greater if suvorexant is taken with less than a full night of sleep remaining, 2


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with coadministration of suvorexant.4,11 Conclusion Suvorexant’s mechanism of action differs from that of the benzodiazepines and nonbenzodiazepines; it has no effect on GABA. Instead of promoting sleep, it inactivates wakefulness. Adverse effects commonly observed with benzodiazepines and nonbenzodiazepines are virtually eliminated. As a result, suvorexant can be used daily on a long-term basis with no risk of rebound insomnia or physical dependence. But further studies are required to compare the safety and efficacy of suvorexant with benzodiazepines and nonbenzodiazepines hypnotics. References 1. US Food and Drug Administration. FDA approves new type of sleep drug, Belsomra. [media release]. 13 August 2014. http://www. f da . gov/N ews E vent s / N ews r oom/ P r es s Announcements/ucm409950.htm. Accessed October 7, 2014. 2. Mieda M, Sakurai T. Orexin (hypocretin) receptor agonists and antagonists for treatment of sleep disorders. Rationale for development and current status. CNS Drugs. 2013; 27(2) : 83-90. doi:10.1007/s40263-012-0036-8. 3. Briefing Materials from Peripheral and Central Nervous System Advisory Committee 2013 Available at: http://www.fda.gov/downloads/ AdvisoryCommittees/Committees Meeting Materials/Dr ugs/Per ipheral and Central Nervous System-Drugs Advisory Committee/ UCM352969.pdf. Accessed August 12, 2013. 4. Food and Drug Administration. FDA Peripheral and Central Nervous System Advisory Committee Meeting May 22, 2013. http://www. fda.gov/downloads/AdvisoryCommittees/ Committees Meeting Mater ials/Dr ugs/ Peripheral and Central Nervous System Drugs Advisory Committee/UCM354216.pdf. Accessed April 12, 2015.

5. Connor K, Budd K, Snavely D, et al. Efficacy and safety of suvorexant, an orexin receptor antagonist, in patients with primary insomnia: a 3-month phase 3 trial (trial #1) [abstract no. O324]. J Sleep Res. 2012; 21(Suppl 1) : 97. 6. Ivgy-May N, Leibensperger H, Froman S, et al. Efficacy and safety of suvorexant, an orexin receptor antagonist, in patients with primary insomnia: a 3-month phase 3 trial (trial #2) [abstract no. P988]. J Sleep Res. 2012; 21(Suppl 1) : 351–2. 7. 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(5) : 461–71. 8. Herring WJ, Snyder E, Budd K, et al. Orexin receptor antagonism for treatment of insomnia: a randomized clinical trial of suvorexant. Neurology 2012; 79(23) : 2265–74. 9. US Food and Drug Administration. Suvorexant Advisory Committee Meeting briefing document 2013. http://www.fda.gov/downloads/advisory committees/committeesmeetin materials/drugs/ peripheral and central nervous system drugs advisory committee/ucm35297.pdf. Accessed 9 Sep 2014. 10. Bennett T, Bray D, Neville MW. Suvorexant, a Dual Orexin Receptor Antagonist for the Management of Insomnia. Pharmacy and Therapeutics. 2014; 39(4) : 264-266. 11. Belsomra (suvorexant) tablets [prescribing information]. Whitehouse Station, NJ: Merck & Co Inc; August 2014. 12. FDA Advisory Committee Meeting, Briefing Document. Suvorexant Tablets Insomnia Indication, NDA 204569, May 22, 2013. Available at: www.fda.gov/downloads/Advisory Committees/Committees Meeting Materials/ Drugs/Peripheral and Central Nervous SystemDrugs Advisory Committee/UCM352970.pdf . Accessed August 14, 2013.


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