David N. Neubauer, MD

Lemborexant, FDA-approved for the treatment of insomnia, has demonstrated efficacy in improving both sleep onset and sleep maintenance.¹ This novel compound is now the second approved insomnia medication classed as a dual orexin receptor antagonist (Table 1). This targeted mechanism of action aims to enhance sleep while limiting the adverse effects associated with traditional hypnotics.

Clinical implications

Insomnia symptoms affect approximately one-third of the general population at least occasionally. Approximately 10% of individuals meet DSM-5 criteria for insomnia disorder, which require nighttime sleep difficulty and daytime consequences persisting for a minimum of 3 months.² The prevalence is considerably higher in patients with chronic medical disorders and comorbid psychiatric conditions, especially mood, anxiety, substance use, and stress- and trauma-related disorders. Clinical guidelines for treating insomnia disorder typically recommend cognitive-behavioral therapy for insomnia as a first choice and FDA-approved insomnia medications as secondary options.³

Currently approved insomnia medi­cations fall into 4 distinct pharmaco­dynamics categories.⁴ Benzodiazepine receptor agonist hypnotics include 5 medications with classic benzodiazepine structures (estazolam, flurazepam, quazepam, temazepam, and triazolam) and 3 compounds (eszopiclone, zaleplon, and zolpidem) with alternate structures but similar mechanisms of action. There is 1 melatonin receptor agonist (ramelteon) and 1 histamine receptor antagonist (low-dose doxepin). Joining suvorexant (approved in 2014), lemborexant is the second dual orexin receptor antagonist.

The orexin (also called hypocretin) system was first described in 1998 and its fundamental role in promoting and coordinating wakefulness was quickly established.⁵ A relatively small number of hypothalamic neurons located in the lateral and perifornical regions produce 2 similar orexin neuropeptides (orexin A and orexin B) with widespread distributions, notably reinforcing the wake-promoting activity of histamine, acetylcholine, dopamine, serotonin, and norepinephrine. Consistent with the typical sleep-wake cycle, orexin release is limited during the nighttime. The orexin neuropeptides interact with 2 G-protein-coupled orexin receptors (OX1R, OX2R).

Animal studies showed that impairment in orexin system activity was associated with symptoms characteristic of narcolepsy, including cataplexy and excessive sleep episodes. Soon after, it was found that humans diagnosed with narcolepsy with cataplexy had markedly low CSF orexin levels.⁶ This recognition that excessively sleepy people with narcolepsy had a profound decrease in orexin production led to the hypothesis that pharmacologically decreasing orexin activity might be sleep-enhancing for insomnia patients, who presumably are excessively aroused. Numerous compounds soon were evaluated for their potential as orexin receptor antagonists. The efficacy of treating insomnia with a dual orexin receptor antagonist in humans was first reported in 2007 with almorexant, a compound that remains investigational.⁷ Research continues to investigate both single and dual orexin antagonist molecules for insomnia and other potential indications.

How it works

Unlike most hypnotics, which have widespread CNS depressant effects, lemborexant has a more targeted action in promoting sleep by suppressing the wake drive supported by the orexin system.⁸ Lemborexant is highly selective for the OX1R and OX2R orexin receptors, where it functions as a competitive antagonist. It is hypothesized that by modulating orexin activity with a receptor antagonist, excessive arousal associated with insomnia can be reduced, thus improving nighttime sleep. The pharmacokinetic properties allow benefits for both sleep onset and maintenance.

Pharmacokinetics

Lemborexant is available in immediate-release tablets with a peak concentration time (T_max) of approximately 1 to 3 hours after ingestion. When taken after a high-fat and high-calorie meal, there is a delay in the T_max, a decrease in the maximum plasma concentration (C_max), and an increase in the concentration area under the curve (AUC_0-inf).¹

Continue to: Metabolism is primarily through...

Metabolism is primarily through the cytochrome P450 (CYP) 3A4 pathway, and to a lesser extent through CYP3A5. Concomitant use with moderate or strong CYP3A inhibitors or inducers should be avoided, while use with weak CYP3A inhibitors should be limited to the 5-mg dose of lemborexant.

Lemborexant has the potential to induce the metabolism of CYP2B6 substrates, such as bupropion and methadone, possibly leading to reduced efficacy for these medications. Accordingly, the clinical responses to any CYP2B6 substrates should be monitored and dosage adjustments considered.

Concomitant use of lemborexant with alcohol should be avoided because there may be increased impairment in postural stability and memory, in part due to increases in the medication’s C_max and AUC, as well as the direct effects of alcohol.

Efficacy

In randomized, placebo-controlled trials, lemborexant demonstrated both objective and subjective evidence of clinically significant benefits for sleep onset and sleep maintenance in patients diagnosed with insomnia disorder.¹ The 2 pivotal efficacy studies were:

• Sunrise 1, a 4-week trial with older adults that included laboratory polysomnography (PSG) studies (objective) and patient-reported sleep measures (subjective) on selected nights⁹
• Sunrise 2, a 6-month trial assessing patient-reported sleep characteristics in adults and older adults.¹⁰

Sunrise 1 was performed with older adults with insomnia who were randomized to groups with nightly use of lemborexant, 5 mg (n = 266), lemborexant, 10 mg (n = 269), zolpidem extended-release, 6.25 mg, as an active comparator (n = 263), or placebo (n = 208).⁹ The age range was 55 to 88 years with a median age of 63 years. Most patients (86.4%) were women. Because this study focused on the assessment of efficacy for treating sleep maintenance difficulty, the inclusion criteria required a subjective report of experiencing a wake time after sleep onset (sWASO) of at least 60 minutes for 3 or more nights per week over the previous 4 weeks. The zolpidem extended-release 6.25 mg comparison was chosen because it has an indication for sleep maintenance insomnia with this recommended dose for older adults.

Continue to: Laboratory PSG monitoring...

Laboratory PSG monitoring was performed for 2 consecutive nights at baseline (before treatment), the first 2 treatment nights, and the final 2 treatment nights (Nights 29 and 30). The primary study endpoint was the change in latency to persistent sleep (LPS) from baseline to the final 2 nights for the lemborexant doses compared with placebo. Additional PSG-based endpoints were similar comparisons for sleep efficiency (percent time asleep during the 8-hour laboratory recording period) and objective wake after sleep onset (WASO) compared with placebo, and WASO during the second half of the night (WASO2H) compared with zolpidem. Patients completed Insomnia Severity Index (ISI) questionnaires at baseline and the end of the treatment to compare disease severity. Subjective assessments were done daily with electronic diary entries that included sleep onset latency (sSOL), sWASO, and subjective sleep efficiency.

In comparison with placebo, both lemborexant doses were associated with significantly improved PSG measures of LPS, WASO, and sleep efficiency during nights 1 and 2 that were maintained through Nights 29 and 30 (Table 2^1,9). The lemborexant doses also demonstrated significant improvements in WASO2H compared with zolpidem and placebo on the first 2 and final 2 treatment nights. Analyses of the subjective assessments (sSOL, sWASO, and sleep efficiency) compared the baseline with means for the first and the last treatment weeks. At both lemborexant doses, the sSOL was significantly reduced during the first and last weeks compared with placebo and zolpidem. Subjective sleep efficiency was significantly improved at both time points for the lemborexant doses, though these were not significantly different from the zolpidem values. The sWASO values were significantly decreased for both lemborexant doses at both time points compared with placebo. During the first treatment week, both lemborexant doses did not differ significantly from zolpidem in the sWASO change from baseline; however, at the final treatment week, the zolpidem value was significantly improved compared with lemborexant, 5 mg, but not significantly different from lemborexant, 10 mg. The ISI change from baseline to the end of the treatment period showed significant improvement for the lemborexant doses and zolpidem extended-release compared with placebo.

In the Sunrise 2 study, patients who met the criteria for insomnia disorder (age range 18 to 88, mean 55; 68% female) were randomized to groups taking nightly doses of lemborexant, 5 mg (n = 323), lemborexant, 10 mg (n = 323), or placebo (n = 325) for 6 months.¹⁰ Inclusion criteria required an sSOL of at least 30 minutes and/or a sWASO of at least 60 minutes 3 times a week or more during the previous 4 weeks. Efficacy was assessed with daily electronic diary entries, with analyses of change from baseline for sSOL (primary endpoint, baseline to end of 6-month study period), sWASO, and patient-reported sleep efficiency (sSEF). Subjective total sleep time (sTST) represented the estimated time asleep during the time in bed. Additional diary assessments related to sleep quality and morning alertness. All of these subjective assessments were compared as 7-day means for the first week of treatment and the last week of each treatment month.

The superiority of lemborexant, 5 mg and 10 mg, compared with placebo was demonstrated by significant improvements in sSOL, sSEF, sWASO, and sTST during the initial week of the treatment period that remained significant at the end of the 6-month placebo-controlled period (Table 3^1,10). At the end of 6 months, there were significantly more sleep-onset responders and sleep-maintenance responders among patients taking lemborexant compared with those taking placebo. Sleep-onset responders were patients with a baseline sSOL >30 minutes and a mean sSOL ≤20 minutes at the end of the study. Sleep-maintenance responders were participants with a baseline sWASO >60 minutes who at the end of the study had a mean sWASO ≤60 minutes that included a reduction of at least 10 minutes.

Following the 6-month placebo-controlled treatment period, the Sunrise 2 study continued for an additional 6 months of nightly active treatment for continued safety and efficacy assessment. Patients assigned to lemborexant, 5 mg or 10 mg, during the initial period continued on those doses. Those in the placebo group were randomized to either of the 2 lemborexant doses.

Continue to: Safety studies and adverse reactions

Safety studies and adverse reactions

Potential medication effects on middle-of-the-night and next-morning postural stability (body sway measured with an ataxiameter) and cognitive performance, as well as middle-of-the-night auditory awakening threshold, were assessed in a randomized, 4-way crossover study of 56 healthy older adults (women age ≥55 [77.8%], men age ≥65) given a single bedtime dose of placebo, lemborexant, 5 mg, lemborexant, 10 mg, and zolpidem extended-release, 6.25 mg, on separate nights.¹¹ The results were compared with data from a baseline night with the same measures performed prior to the randomization. The middle-of-the-night assessments were done approximately 4 hours after the dose and the next-morning measures were done after 8 hours in bed. The auditory threshold analysis showed no significant differences among the 4 study nights. Compared with placebo, the middle-of-the-night postural stability was significantly worse for both lemborexant doses and zolpidem; however, the zolpidem effect was significantly worse than with either lemborexant dose. The next-morning postural stability measures showed no significant difference from placebo for the lemborexant doses, but zolpidem continued to show a significantly worsened result. The cognitive performance assessment battery provided 4 domain factor scores (power of attention, continuity of attention, quality of memory, and speed of memory retrieval). The middle-of-the-night battery showed no significant difference between lemborexant, 5 mg, and placebo in any domain, while both lemborexant, 10 mg, and zolpidem showed worse performance on some of the attention and/or memory tests. The next-morning cognitive assessment revealed no significant differences from placebo for the treatments.

Respiratory safety was examined in a placebo-controlled, 2-period crossover study of 38 patients diagnosed with mild obstructive sleep apnea who received lemborexant, 10 mg, or placebo nightly during each 8-day period.¹² Neither the apnea-hypopnea index nor the mean oxygen saturation during the lemborexant nights were significantly different from the placebo nights.

The most common adverse reaction during the month-long Sunrise 1 study and the first 30 days of the Sunrise 2 study was somnolence or fatigue, which occurred in 1% receiving placebo, 7% receiving lemborexant, 5 mg, and 10% receiving lemborexant, 10 mg. Headache was reported by 3.5% receiving placebo, 5.9% receiving lemborexant, 5 mg, and 4.5% receiving lemborexant, 10 mg. Nightmare or abnormal dreams occurred with 0.9% receiving placebo, 0.9% receiving lemborexant, 5 mg, and 2.2% receiving lemborexant, 10 mg.¹

Unique clinical issues

Because investigations of individuals who abused sedatives for recreational purposes showed lemborexant had a likeability rating similar to zolpidem and significantly greater than placebo, the US Drug Enforcement Agency has categorized lemborexant as a Schedule IV controlled substance. Research has not shown evidence of physical dependence or withdrawal signs or symptoms upon discontinuation of lemborexant.¹

Contraindications

Narcolepsy is the only contraindication to the use of lemborexant.¹ Narcolepsy is associated with a decrease in the orexin-producing neurons in the hypothalamus, presumably causing the excessive sleepiness, sleep paralysis, hypnagogic hallucinations, and cataplexy characteristic of the disorder. Hypothetically, an orexin antagonist medication could exacerbate these symptoms.

Continue to: Dosing

Lemborexant should be taken no more than once per night immediately before going to bed and with at least 7 hours remaining before the planned time of awakening.¹ The recommended starting dose is 5 mg. The dosage may be increased to a maximum of 10 mg if the initial dose is well tolerated but insufficiently effective. Patients with moderate hepatic impairment or who are concomitantly taking weak CYP3A inhibitors should receive a maximum of 5 mg once nightly. Lemborexant should be avoided in patients with severe hepatic impairment and in those taking moderate or strong CYP3A inhibitors or inducers.

Orexin receptor antagonists do not share cross-tolerance with other hypnotics; this should be taken into consideration when switching to lemborexant. Abruptly stopping a benzodiazepine receptor agonist hypnotic may lead to rebound insomnia and thus may confound the interpretation of the clinical response when starting lemborexant.

Patients prescribed lemborexant should be educated about possible impairment in alertness and motor coordination, especially with the 10-mg dose, which may affect next-morning driving in sensitive individuals.¹³ Caution is advised with doses >5 mg in patients age ≥65 due to possible somnolence and a higher risk of falls.¹

Bottom Line

Lemborexant is a dual orexin receptor antagonist indicated for the treatment of insomnia characterized by difficulties with sleep onset and/or sleep maintenance. It promotes sleep by suppressing the wake drive supported by the orexin system. In randomized, placebo-controlled trials, lemborexant demonstrated objective and subjective evidence of clinically significant benefits for sleep onset and sleep maintenance.

Related Resource

• Sateia MJ, Buysse DJ, Krystal AD, et al. Clinical practice guideline for the pharmacologic treatment of chronic insomnia in adults: an American Academy of Sleep Medicine clinical practice guideline. J Clin Sleep Med. 2017;13(2):307-349.

Drug Brand Names

Bupropion • Wellbutrin
Doxepin • Silenor
Eszopiclone • Lunesta
Lemborexant • Dayvigo
Methadone • Methadose, Dolophine
Quazepam • Doral
Ramelteon • Rozerem
Suvorexant • Belsomra
Temazepam • Restoril
Triazolam • Halcion
Zaleplon • Sonata
Zolpidem • Ambien, Intermezzo

Lemborexant, FDA-approved for the treatment of insomnia, has demonstrated efficacy in improving both sleep onset and sleep maintenance.¹ This novel compound is now the second approved insomnia medication classed as a dual orexin receptor antagonist (Table 1). This targeted mechanism of action aims to enhance sleep while limiting the adverse effects associated with traditional hypnotics.

Clinical implications

Insomnia symptoms affect approximately one-third of the general population at least occasionally. Approximately 10% of individuals meet DSM-5 criteria for insomnia disorder, which require nighttime sleep difficulty and daytime consequences persisting for a minimum of 3 months.² The prevalence is considerably higher in patients with chronic medical disorders and comorbid psychiatric conditions, especially mood, anxiety, substance use, and stress- and trauma-related disorders. Clinical guidelines for treating insomnia disorder typically recommend cognitive-behavioral therapy for insomnia as a first choice and FDA-approved insomnia medications as secondary options.³

Currently approved insomnia medi­cations fall into 4 distinct pharmaco­dynamics categories.⁴ Benzodiazepine receptor agonist hypnotics include 5 medications with classic benzodiazepine structures (estazolam, flurazepam, quazepam, temazepam, and triazolam) and 3 compounds (eszopiclone, zaleplon, and zolpidem) with alternate structures but similar mechanisms of action. There is 1 melatonin receptor agonist (ramelteon) and 1 histamine receptor antagonist (low-dose doxepin). Joining suvorexant (approved in 2014), lemborexant is the second dual orexin receptor antagonist.

The orexin (also called hypocretin) system was first described in 1998 and its fundamental role in promoting and coordinating wakefulness was quickly established.⁵ A relatively small number of hypothalamic neurons located in the lateral and perifornical regions produce 2 similar orexin neuropeptides (orexin A and orexin B) with widespread distributions, notably reinforcing the wake-promoting activity of histamine, acetylcholine, dopamine, serotonin, and norepinephrine. Consistent with the typical sleep-wake cycle, orexin release is limited during the nighttime. The orexin neuropeptides interact with 2 G-protein-coupled orexin receptors (OX1R, OX2R).

Animal studies showed that impairment in orexin system activity was associated with symptoms characteristic of narcolepsy, including cataplexy and excessive sleep episodes. Soon after, it was found that humans diagnosed with narcolepsy with cataplexy had markedly low CSF orexin levels.⁶ This recognition that excessively sleepy people with narcolepsy had a profound decrease in orexin production led to the hypothesis that pharmacologically decreasing orexin activity might be sleep-enhancing for insomnia patients, who presumably are excessively aroused. Numerous compounds soon were evaluated for their potential as orexin receptor antagonists. The efficacy of treating insomnia with a dual orexin receptor antagonist in humans was first reported in 2007 with almorexant, a compound that remains investigational.⁷ Research continues to investigate both single and dual orexin antagonist molecules for insomnia and other potential indications.

How it works

Unlike most hypnotics, which have widespread CNS depressant effects, lemborexant has a more targeted action in promoting sleep by suppressing the wake drive supported by the orexin system.⁸ Lemborexant is highly selective for the OX1R and OX2R orexin receptors, where it functions as a competitive antagonist. It is hypothesized that by modulating orexin activity with a receptor antagonist, excessive arousal associated with insomnia can be reduced, thus improving nighttime sleep. The pharmacokinetic properties allow benefits for both sleep onset and maintenance.

Pharmacokinetics

Lemborexant is available in immediate-release tablets with a peak concentration time (T_max) of approximately 1 to 3 hours after ingestion. When taken after a high-fat and high-calorie meal, there is a delay in the T_max, a decrease in the maximum plasma concentration (C_max), and an increase in the concentration area under the curve (AUC_0-inf).¹

Continue to: Metabolism is primarily through...

Metabolism is primarily through the cytochrome P450 (CYP) 3A4 pathway, and to a lesser extent through CYP3A5. Concomitant use with moderate or strong CYP3A inhibitors or inducers should be avoided, while use with weak CYP3A inhibitors should be limited to the 5-mg dose of lemborexant.

Lemborexant has the potential to induce the metabolism of CYP2B6 substrates, such as bupropion and methadone, possibly leading to reduced efficacy for these medications. Accordingly, the clinical responses to any CYP2B6 substrates should be monitored and dosage adjustments considered.

Concomitant use of lemborexant with alcohol should be avoided because there may be increased impairment in postural stability and memory, in part due to increases in the medication’s C_max and AUC, as well as the direct effects of alcohol.

Efficacy

In randomized, placebo-controlled trials, lemborexant demonstrated both objective and subjective evidence of clinically significant benefits for sleep onset and sleep maintenance in patients diagnosed with insomnia disorder.¹ The 2 pivotal efficacy studies were:

• Sunrise 1, a 4-week trial with older adults that included laboratory polysomnography (PSG) studies (objective) and patient-reported sleep measures (subjective) on selected nights⁹
• Sunrise 2, a 6-month trial assessing patient-reported sleep characteristics in adults and older adults.¹⁰

Sunrise 1 was performed with older adults with insomnia who were randomized to groups with nightly use of lemborexant, 5 mg (n = 266), lemborexant, 10 mg (n = 269), zolpidem extended-release, 6.25 mg, as an active comparator (n = 263), or placebo (n = 208).⁹ The age range was 55 to 88 years with a median age of 63 years. Most patients (86.4%) were women. Because this study focused on the assessment of efficacy for treating sleep maintenance difficulty, the inclusion criteria required a subjective report of experiencing a wake time after sleep onset (sWASO) of at least 60 minutes for 3 or more nights per week over the previous 4 weeks. The zolpidem extended-release 6.25 mg comparison was chosen because it has an indication for sleep maintenance insomnia with this recommended dose for older adults.

Continue to: Laboratory PSG monitoring...

Laboratory PSG monitoring was performed for 2 consecutive nights at baseline (before treatment), the first 2 treatment nights, and the final 2 treatment nights (Nights 29 and 30). The primary study endpoint was the change in latency to persistent sleep (LPS) from baseline to the final 2 nights for the lemborexant doses compared with placebo. Additional PSG-based endpoints were similar comparisons for sleep efficiency (percent time asleep during the 8-hour laboratory recording period) and objective wake after sleep onset (WASO) compared with placebo, and WASO during the second half of the night (WASO2H) compared with zolpidem. Patients completed Insomnia Severity Index (ISI) questionnaires at baseline and the end of the treatment to compare disease severity. Subjective assessments were done daily with electronic diary entries that included sleep onset latency (sSOL), sWASO, and subjective sleep efficiency.

In comparison with placebo, both lemborexant doses were associated with significantly improved PSG measures of LPS, WASO, and sleep efficiency during nights 1 and 2 that were maintained through Nights 29 and 30 (Table 2^1,9). The lemborexant doses also demonstrated significant improvements in WASO2H compared with zolpidem and placebo on the first 2 and final 2 treatment nights. Analyses of the subjective assessments (sSOL, sWASO, and sleep efficiency) compared the baseline with means for the first and the last treatment weeks. At both lemborexant doses, the sSOL was significantly reduced during the first and last weeks compared with placebo and zolpidem. Subjective sleep efficiency was significantly improved at both time points for the lemborexant doses, though these were not significantly different from the zolpidem values. The sWASO values were significantly decreased for both lemborexant doses at both time points compared with placebo. During the first treatment week, both lemborexant doses did not differ significantly from zolpidem in the sWASO change from baseline; however, at the final treatment week, the zolpidem value was significantly improved compared with lemborexant, 5 mg, but not significantly different from lemborexant, 10 mg. The ISI change from baseline to the end of the treatment period showed significant improvement for the lemborexant doses and zolpidem extended-release compared with placebo.

In the Sunrise 2 study, patients who met the criteria for insomnia disorder (age range 18 to 88, mean 55; 68% female) were randomized to groups taking nightly doses of lemborexant, 5 mg (n = 323), lemborexant, 10 mg (n = 323), or placebo (n = 325) for 6 months.¹⁰ Inclusion criteria required an sSOL of at least 30 minutes and/or a sWASO of at least 60 minutes 3 times a week or more during the previous 4 weeks. Efficacy was assessed with daily electronic diary entries, with analyses of change from baseline for sSOL (primary endpoint, baseline to end of 6-month study period), sWASO, and patient-reported sleep efficiency (sSEF). Subjective total sleep time (sTST) represented the estimated time asleep during the time in bed. Additional diary assessments related to sleep quality and morning alertness. All of these subjective assessments were compared as 7-day means for the first week of treatment and the last week of each treatment month.

The superiority of lemborexant, 5 mg and 10 mg, compared with placebo was demonstrated by significant improvements in sSOL, sSEF, sWASO, and sTST during the initial week of the treatment period that remained significant at the end of the 6-month placebo-controlled period (Table 3^1,10). At the end of 6 months, there were significantly more sleep-onset responders and sleep-maintenance responders among patients taking lemborexant compared with those taking placebo. Sleep-onset responders were patients with a baseline sSOL >30 minutes and a mean sSOL ≤20 minutes at the end of the study. Sleep-maintenance responders were participants with a baseline sWASO >60 minutes who at the end of the study had a mean sWASO ≤60 minutes that included a reduction of at least 10 minutes.

Following the 6-month placebo-controlled treatment period, the Sunrise 2 study continued for an additional 6 months of nightly active treatment for continued safety and efficacy assessment. Patients assigned to lemborexant, 5 mg or 10 mg, during the initial period continued on those doses. Those in the placebo group were randomized to either of the 2 lemborexant doses.

Continue to: Safety studies and adverse reactions

Safety studies and adverse reactions

Potential medication effects on middle-of-the-night and next-morning postural stability (body sway measured with an ataxiameter) and cognitive performance, as well as middle-of-the-night auditory awakening threshold, were assessed in a randomized, 4-way crossover study of 56 healthy older adults (women age ≥55 [77.8%], men age ≥65) given a single bedtime dose of placebo, lemborexant, 5 mg, lemborexant, 10 mg, and zolpidem extended-release, 6.25 mg, on separate nights.¹¹ The results were compared with data from a baseline night with the same measures performed prior to the randomization. The middle-of-the-night assessments were done approximately 4 hours after the dose and the next-morning measures were done after 8 hours in bed. The auditory threshold analysis showed no significant differences among the 4 study nights. Compared with placebo, the middle-of-the-night postural stability was significantly worse for both lemborexant doses and zolpidem; however, the zolpidem effect was significantly worse than with either lemborexant dose. The next-morning postural stability measures showed no significant difference from placebo for the lemborexant doses, but zolpidem continued to show a significantly worsened result. The cognitive performance assessment battery provided 4 domain factor scores (power of attention, continuity of attention, quality of memory, and speed of memory retrieval). The middle-of-the-night battery showed no significant difference between lemborexant, 5 mg, and placebo in any domain, while both lemborexant, 10 mg, and zolpidem showed worse performance on some of the attention and/or memory tests. The next-morning cognitive assessment revealed no significant differences from placebo for the treatments.

Respiratory safety was examined in a placebo-controlled, 2-period crossover study of 38 patients diagnosed with mild obstructive sleep apnea who received lemborexant, 10 mg, or placebo nightly during each 8-day period.¹² Neither the apnea-hypopnea index nor the mean oxygen saturation during the lemborexant nights were significantly different from the placebo nights.

The most common adverse reaction during the month-long Sunrise 1 study and the first 30 days of the Sunrise 2 study was somnolence or fatigue, which occurred in 1% receiving placebo, 7% receiving lemborexant, 5 mg, and 10% receiving lemborexant, 10 mg. Headache was reported by 3.5% receiving placebo, 5.9% receiving lemborexant, 5 mg, and 4.5% receiving lemborexant, 10 mg. Nightmare or abnormal dreams occurred with 0.9% receiving placebo, 0.9% receiving lemborexant, 5 mg, and 2.2% receiving lemborexant, 10 mg.¹

Unique clinical issues

Because investigations of individuals who abused sedatives for recreational purposes showed lemborexant had a likeability rating similar to zolpidem and significantly greater than placebo, the US Drug Enforcement Agency has categorized lemborexant as a Schedule IV controlled substance. Research has not shown evidence of physical dependence or withdrawal signs or symptoms upon discontinuation of lemborexant.¹

Contraindications

Narcolepsy is the only contraindication to the use of lemborexant.¹ Narcolepsy is associated with a decrease in the orexin-producing neurons in the hypothalamus, presumably causing the excessive sleepiness, sleep paralysis, hypnagogic hallucinations, and cataplexy characteristic of the disorder. Hypothetically, an orexin antagonist medication could exacerbate these symptoms.

Continue to: Dosing

Lemborexant should be taken no more than once per night immediately before going to bed and with at least 7 hours remaining before the planned time of awakening.¹ The recommended starting dose is 5 mg. The dosage may be increased to a maximum of 10 mg if the initial dose is well tolerated but insufficiently effective. Patients with moderate hepatic impairment or who are concomitantly taking weak CYP3A inhibitors should receive a maximum of 5 mg once nightly. Lemborexant should be avoided in patients with severe hepatic impairment and in those taking moderate or strong CYP3A inhibitors or inducers.

Orexin receptor antagonists do not share cross-tolerance with other hypnotics; this should be taken into consideration when switching to lemborexant. Abruptly stopping a benzodiazepine receptor agonist hypnotic may lead to rebound insomnia and thus may confound the interpretation of the clinical response when starting lemborexant.

Patients prescribed lemborexant should be educated about possible impairment in alertness and motor coordination, especially with the 10-mg dose, which may affect next-morning driving in sensitive individuals.¹³ Caution is advised with doses >5 mg in patients age ≥65 due to possible somnolence and a higher risk of falls.¹

Bottom Line

Lemborexant is a dual orexin receptor antagonist indicated for the treatment of insomnia characterized by difficulties with sleep onset and/or sleep maintenance. It promotes sleep by suppressing the wake drive supported by the orexin system. In randomized, placebo-controlled trials, lemborexant demonstrated objective and subjective evidence of clinically significant benefits for sleep onset and sleep maintenance.

Related Resource

• Sateia MJ, Buysse DJ, Krystal AD, et al. Clinical practice guideline for the pharmacologic treatment of chronic insomnia in adults: an American Academy of Sleep Medicine clinical practice guideline. J Clin Sleep Med. 2017;13(2):307-349.

Drug Brand Names

Bupropion • Wellbutrin
Doxepin • Silenor
Eszopiclone • Lunesta
Lemborexant • Dayvigo
Methadone • Methadose, Dolophine
Quazepam • Doral
Ramelteon • Rozerem
Suvorexant • Belsomra
Temazepam • Restoril
Triazolam • Halcion
Zaleplon • Sonata
Zolpidem • Ambien, Intermezzo

Lemborexant, FDA-approved for the treatment of insomnia, has demonstrated efficacy in improving both sleep onset and sleep maintenance.¹ This novel compound is now the second approved insomnia medication classed as a dual orexin receptor antagonist (Table 1). This targeted mechanism of action aims to enhance sleep while limiting the adverse effects associated with traditional hypnotics.

Clinical implications

Insomnia symptoms affect approximately one-third of the general population at least occasionally. Approximately 10% of individuals meet DSM-5 criteria for insomnia disorder, which require nighttime sleep difficulty and daytime consequences persisting for a minimum of 3 months.² The prevalence is considerably higher in patients with chronic medical disorders and comorbid psychiatric conditions, especially mood, anxiety, substance use, and stress- and trauma-related disorders. Clinical guidelines for treating insomnia disorder typically recommend cognitive-behavioral therapy for insomnia as a first choice and FDA-approved insomnia medications as secondary options.³

Currently approved insomnia medi­cations fall into 4 distinct pharmaco­dynamics categories.⁴ Benzodiazepine receptor agonist hypnotics include 5 medications with classic benzodiazepine structures (estazolam, flurazepam, quazepam, temazepam, and triazolam) and 3 compounds (eszopiclone, zaleplon, and zolpidem) with alternate structures but similar mechanisms of action. There is 1 melatonin receptor agonist (ramelteon) and 1 histamine receptor antagonist (low-dose doxepin). Joining suvorexant (approved in 2014), lemborexant is the second dual orexin receptor antagonist.

The orexin (also called hypocretin) system was first described in 1998 and its fundamental role in promoting and coordinating wakefulness was quickly established.⁵ A relatively small number of hypothalamic neurons located in the lateral and perifornical regions produce 2 similar orexin neuropeptides (orexin A and orexin B) with widespread distributions, notably reinforcing the wake-promoting activity of histamine, acetylcholine, dopamine, serotonin, and norepinephrine. Consistent with the typical sleep-wake cycle, orexin release is limited during the nighttime. The orexin neuropeptides interact with 2 G-protein-coupled orexin receptors (OX1R, OX2R).

Animal studies showed that impairment in orexin system activity was associated with symptoms characteristic of narcolepsy, including cataplexy and excessive sleep episodes. Soon after, it was found that humans diagnosed with narcolepsy with cataplexy had markedly low CSF orexin levels.⁶ This recognition that excessively sleepy people with narcolepsy had a profound decrease in orexin production led to the hypothesis that pharmacologically decreasing orexin activity might be sleep-enhancing for insomnia patients, who presumably are excessively aroused. Numerous compounds soon were evaluated for their potential as orexin receptor antagonists. The efficacy of treating insomnia with a dual orexin receptor antagonist in humans was first reported in 2007 with almorexant, a compound that remains investigational.⁷ Research continues to investigate both single and dual orexin antagonist molecules for insomnia and other potential indications.

How it works

Unlike most hypnotics, which have widespread CNS depressant effects, lemborexant has a more targeted action in promoting sleep by suppressing the wake drive supported by the orexin system.⁸ Lemborexant is highly selective for the OX1R and OX2R orexin receptors, where it functions as a competitive antagonist. It is hypothesized that by modulating orexin activity with a receptor antagonist, excessive arousal associated with insomnia can be reduced, thus improving nighttime sleep. The pharmacokinetic properties allow benefits for both sleep onset and maintenance.

Pharmacokinetics

Lemborexant is available in immediate-release tablets with a peak concentration time (T_max) of approximately 1 to 3 hours after ingestion. When taken after a high-fat and high-calorie meal, there is a delay in the T_max, a decrease in the maximum plasma concentration (C_max), and an increase in the concentration area under the curve (AUC_0-inf).¹

Continue to: Metabolism is primarily through...

Metabolism is primarily through the cytochrome P450 (CYP) 3A4 pathway, and to a lesser extent through CYP3A5. Concomitant use with moderate or strong CYP3A inhibitors or inducers should be avoided, while use with weak CYP3A inhibitors should be limited to the 5-mg dose of lemborexant.

Lemborexant has the potential to induce the metabolism of CYP2B6 substrates, such as bupropion and methadone, possibly leading to reduced efficacy for these medications. Accordingly, the clinical responses to any CYP2B6 substrates should be monitored and dosage adjustments considered.

Concomitant use of lemborexant with alcohol should be avoided because there may be increased impairment in postural stability and memory, in part due to increases in the medication’s C_max and AUC, as well as the direct effects of alcohol.

Efficacy

In randomized, placebo-controlled trials, lemborexant demonstrated both objective and subjective evidence of clinically significant benefits for sleep onset and sleep maintenance in patients diagnosed with insomnia disorder.¹ The 2 pivotal efficacy studies were:

• Sunrise 1, a 4-week trial with older adults that included laboratory polysomnography (PSG) studies (objective) and patient-reported sleep measures (subjective) on selected nights⁹
• Sunrise 2, a 6-month trial assessing patient-reported sleep characteristics in adults and older adults.¹⁰

Sunrise 1 was performed with older adults with insomnia who were randomized to groups with nightly use of lemborexant, 5 mg (n = 266), lemborexant, 10 mg (n = 269), zolpidem extended-release, 6.25 mg, as an active comparator (n = 263), or placebo (n = 208).⁹ The age range was 55 to 88 years with a median age of 63 years. Most patients (86.4%) were women. Because this study focused on the assessment of efficacy for treating sleep maintenance difficulty, the inclusion criteria required a subjective report of experiencing a wake time after sleep onset (sWASO) of at least 60 minutes for 3 or more nights per week over the previous 4 weeks. The zolpidem extended-release 6.25 mg comparison was chosen because it has an indication for sleep maintenance insomnia with this recommended dose for older adults.

Continue to: Laboratory PSG monitoring...

Laboratory PSG monitoring was performed for 2 consecutive nights at baseline (before treatment), the first 2 treatment nights, and the final 2 treatment nights (Nights 29 and 30). The primary study endpoint was the change in latency to persistent sleep (LPS) from baseline to the final 2 nights for the lemborexant doses compared with placebo. Additional PSG-based endpoints were similar comparisons for sleep efficiency (percent time asleep during the 8-hour laboratory recording period) and objective wake after sleep onset (WASO) compared with placebo, and WASO during the second half of the night (WASO2H) compared with zolpidem. Patients completed Insomnia Severity Index (ISI) questionnaires at baseline and the end of the treatment to compare disease severity. Subjective assessments were done daily with electronic diary entries that included sleep onset latency (sSOL), sWASO, and subjective sleep efficiency.

In comparison with placebo, both lemborexant doses were associated with significantly improved PSG measures of LPS, WASO, and sleep efficiency during nights 1 and 2 that were maintained through Nights 29 and 30 (Table 2^1,9). The lemborexant doses also demonstrated significant improvements in WASO2H compared with zolpidem and placebo on the first 2 and final 2 treatment nights. Analyses of the subjective assessments (sSOL, sWASO, and sleep efficiency) compared the baseline with means for the first and the last treatment weeks. At both lemborexant doses, the sSOL was significantly reduced during the first and last weeks compared with placebo and zolpidem. Subjective sleep efficiency was significantly improved at both time points for the lemborexant doses, though these were not significantly different from the zolpidem values. The sWASO values were significantly decreased for both lemborexant doses at both time points compared with placebo. During the first treatment week, both lemborexant doses did not differ significantly from zolpidem in the sWASO change from baseline; however, at the final treatment week, the zolpidem value was significantly improved compared with lemborexant, 5 mg, but not significantly different from lemborexant, 10 mg. The ISI change from baseline to the end of the treatment period showed significant improvement for the lemborexant doses and zolpidem extended-release compared with placebo.

In the Sunrise 2 study, patients who met the criteria for insomnia disorder (age range 18 to 88, mean 55; 68% female) were randomized to groups taking nightly doses of lemborexant, 5 mg (n = 323), lemborexant, 10 mg (n = 323), or placebo (n = 325) for 6 months.¹⁰ Inclusion criteria required an sSOL of at least 30 minutes and/or a sWASO of at least 60 minutes 3 times a week or more during the previous 4 weeks. Efficacy was assessed with daily electronic diary entries, with analyses of change from baseline for sSOL (primary endpoint, baseline to end of 6-month study period), sWASO, and patient-reported sleep efficiency (sSEF). Subjective total sleep time (sTST) represented the estimated time asleep during the time in bed. Additional diary assessments related to sleep quality and morning alertness. All of these subjective assessments were compared as 7-day means for the first week of treatment and the last week of each treatment month.

The superiority of lemborexant, 5 mg and 10 mg, compared with placebo was demonstrated by significant improvements in sSOL, sSEF, sWASO, and sTST during the initial week of the treatment period that remained significant at the end of the 6-month placebo-controlled period (Table 3^1,10). At the end of 6 months, there were significantly more sleep-onset responders and sleep-maintenance responders among patients taking lemborexant compared with those taking placebo. Sleep-onset responders were patients with a baseline sSOL >30 minutes and a mean sSOL ≤20 minutes at the end of the study. Sleep-maintenance responders were participants with a baseline sWASO >60 minutes who at the end of the study had a mean sWASO ≤60 minutes that included a reduction of at least 10 minutes.

Following the 6-month placebo-controlled treatment period, the Sunrise 2 study continued for an additional 6 months of nightly active treatment for continued safety and efficacy assessment. Patients assigned to lemborexant, 5 mg or 10 mg, during the initial period continued on those doses. Those in the placebo group were randomized to either of the 2 lemborexant doses.

Continue to: Safety studies and adverse reactions

Safety studies and adverse reactions

Potential medication effects on middle-of-the-night and next-morning postural stability (body sway measured with an ataxiameter) and cognitive performance, as well as middle-of-the-night auditory awakening threshold, were assessed in a randomized, 4-way crossover study of 56 healthy older adults (women age ≥55 [77.8%], men age ≥65) given a single bedtime dose of placebo, lemborexant, 5 mg, lemborexant, 10 mg, and zolpidem extended-release, 6.25 mg, on separate nights.¹¹ The results were compared with data from a baseline night with the same measures performed prior to the randomization. The middle-of-the-night assessments were done approximately 4 hours after the dose and the next-morning measures were done after 8 hours in bed. The auditory threshold analysis showed no significant differences among the 4 study nights. Compared with placebo, the middle-of-the-night postural stability was significantly worse for both lemborexant doses and zolpidem; however, the zolpidem effect was significantly worse than with either lemborexant dose. The next-morning postural stability measures showed no significant difference from placebo for the lemborexant doses, but zolpidem continued to show a significantly worsened result. The cognitive performance assessment battery provided 4 domain factor scores (power of attention, continuity of attention, quality of memory, and speed of memory retrieval). The middle-of-the-night battery showed no significant difference between lemborexant, 5 mg, and placebo in any domain, while both lemborexant, 10 mg, and zolpidem showed worse performance on some of the attention and/or memory tests. The next-morning cognitive assessment revealed no significant differences from placebo for the treatments.

Respiratory safety was examined in a placebo-controlled, 2-period crossover study of 38 patients diagnosed with mild obstructive sleep apnea who received lemborexant, 10 mg, or placebo nightly during each 8-day period.¹² Neither the apnea-hypopnea index nor the mean oxygen saturation during the lemborexant nights were significantly different from the placebo nights.

The most common adverse reaction during the month-long Sunrise 1 study and the first 30 days of the Sunrise 2 study was somnolence or fatigue, which occurred in 1% receiving placebo, 7% receiving lemborexant, 5 mg, and 10% receiving lemborexant, 10 mg. Headache was reported by 3.5% receiving placebo, 5.9% receiving lemborexant, 5 mg, and 4.5% receiving lemborexant, 10 mg. Nightmare or abnormal dreams occurred with 0.9% receiving placebo, 0.9% receiving lemborexant, 5 mg, and 2.2% receiving lemborexant, 10 mg.¹

Unique clinical issues

Because investigations of individuals who abused sedatives for recreational purposes showed lemborexant had a likeability rating similar to zolpidem and significantly greater than placebo, the US Drug Enforcement Agency has categorized lemborexant as a Schedule IV controlled substance. Research has not shown evidence of physical dependence or withdrawal signs or symptoms upon discontinuation of lemborexant.¹

Contraindications

Narcolepsy is the only contraindication to the use of lemborexant.¹ Narcolepsy is associated with a decrease in the orexin-producing neurons in the hypothalamus, presumably causing the excessive sleepiness, sleep paralysis, hypnagogic hallucinations, and cataplexy characteristic of the disorder. Hypothetically, an orexin antagonist medication could exacerbate these symptoms.

Continue to: Dosing

Lemborexant should be taken no more than once per night immediately before going to bed and with at least 7 hours remaining before the planned time of awakening.¹ The recommended starting dose is 5 mg. The dosage may be increased to a maximum of 10 mg if the initial dose is well tolerated but insufficiently effective. Patients with moderate hepatic impairment or who are concomitantly taking weak CYP3A inhibitors should receive a maximum of 5 mg once nightly. Lemborexant should be avoided in patients with severe hepatic impairment and in those taking moderate or strong CYP3A inhibitors or inducers.

Orexin receptor antagonists do not share cross-tolerance with other hypnotics; this should be taken into consideration when switching to lemborexant. Abruptly stopping a benzodiazepine receptor agonist hypnotic may lead to rebound insomnia and thus may confound the interpretation of the clinical response when starting lemborexant.

Patients prescribed lemborexant should be educated about possible impairment in alertness and motor coordination, especially with the 10-mg dose, which may affect next-morning driving in sensitive individuals.¹³ Caution is advised with doses >5 mg in patients age ≥65 due to possible somnolence and a higher risk of falls.¹

Bottom Line

Lemborexant is a dual orexin receptor antagonist indicated for the treatment of insomnia characterized by difficulties with sleep onset and/or sleep maintenance. It promotes sleep by suppressing the wake drive supported by the orexin system. In randomized, placebo-controlled trials, lemborexant demonstrated objective and subjective evidence of clinically significant benefits for sleep onset and sleep maintenance.

Related Resource

• Sateia MJ, Buysse DJ, Krystal AD, et al. Clinical practice guideline for the pharmacologic treatment of chronic insomnia in adults: an American Academy of Sleep Medicine clinical practice guideline. J Clin Sleep Med. 2017;13(2):307-349.

Drug Brand Names

Bupropion • Wellbutrin
Doxepin • Silenor
Eszopiclone • Lunesta
Lemborexant • Dayvigo
Methadone • Methadose, Dolophine
Quazepam • Doral
Ramelteon • Rozerem
Suvorexant • Belsomra
Temazepam • Restoril
Triazolam • Halcion
Zaleplon • Sonata
Zolpidem • Ambien, Intermezzo

Suvorexant, FDA-approved to treat insomnia, has demonstrated efficacy in helping patients with insomnia improve their ability to fall asleep and remain asleep (Table 1).¹ This first-in-class compound represents a novel mechanism of action to promoting sleep that may avoid some prob­lems associated with other hypnotics.²

Because orexin antagonists have not been used outside of clinical trials, it is too soon to tell whether suvorexant will have the ideal real-world efficacy and safety profile to make it a first-line treatment for insomnia patients, or if it will be reserved for those who have failed a trial of several other treatments.⁴

In theory, the orexin antagonist approach to treating insomnia could represent a major advance that modulates the fundamental pathology of the disorder.⁵ The syndrome of chronic insomnia encompasses not just the nighttime sleep disturbance but also an assort­ment of daytime symptoms that can include fatigue, poor concentration, irritability, and decreased school or work performance but usually not sleepiness. This constellation of nighttime and daytime symptoms could be conceptualized as a manifestation of persis­tent CNS hyperarousal. Because the orexin system promotes and reinforces arousal, per­haps an orexin antagonist that dampens the level of orexin activity will ameliorate the full spectrum of insomnia symptoms—not sim­ply sedate patients.⁶

How suvorexant works
Suvorexant is a potent and reversible dual orexin-receptor antagonist. The orexin system, first described in 1998, has a key role in promoting and stabilizing wake­fulness.⁷ Evidence suggests that people with chronic insomnia exhibit a central hyperarousal that perpetuates their sleep difficulty. Accordingly, a targeted phar­maceutical approach that reduces orexin activity should facilitate sleep onset and sleep maintenance for these patients. It is well known that the regulation of sleep and wakefulness depends on the interaction of multiple nuclei within the hypothalamus. Orexinergic neurons in the perifornical-lateral hypothalamic region project widely in the CNS and have especially dense con­nections with wake-promoting cholinergic, serotonergic, noradrenergic, and histamin­ergic neurons.⁶

A precursor prepro-orexin peptide is split into 2 orexin neurotransmitters (orexin A and orexin B). These 2 orexins bind with 2 G-protein-coupled receptors (OX1R and OX2R) that have both overlapping and distinct distributions.⁷ Suvorexant is highly selective and has similar affinity for OX1R and OX2R, functioning as an antag­onist for both.⁸ Fundamentally, suvorexant enhances sleep by dampening the arous­ing wake drive.

Pharmacokinetics
Suvorexant is available as an immediate-release tablet with pharmacokinetic prop­erties that offer benefits for sleep onset and maintenance.⁹ Ingestion under fasting conditions results in a median time to maxi­mum concentration (T_max) of approximately 2 hours, although the T_max values vary widely from patient to patient (range 30 minutes to 6 hours). Although suvorexant can be taken with food, there is a modest absorption delay after a high-fat meal, resulting in a further T_max delay of approximately 1.5 hours.

Suvorexant is primarily metabolized through the cytochrome P450 (CYP) 3A path­way, with limited contribution by CYP2C19. There are no active metabolites. The suvorex­ant blood level and risk of side effects will be higher with concomitant use of CYP3A inhibitors. The drug should not be adminis­tered with strong CYP3A inhibitors; the ini­tial dosage should be reduced with moderate CYP3A inhibitors. Concomitant use of strong CYP3A inducers can result in a low suvorex­ant level and reduced efficacy.

Suvorexant has little effect on other med­ications, although a person taking digoxin might experience intestinal P-glycoprotein inhibition with a slight rise in the digoxin level. In a patient taking both medica­tions, monitoring of the digoxin level is recommended.

The elimination half-life of suvorexant is approximately 12 hours, with a steady state in approximately 3 days. Because the half-life of suvorexant is moderately long for a sleep-promoting medication, use of the drug might be associated with residual sleepiness the morning after bedtime dosing. The risk for next-morning sleepiness or impairment should be minimized, however, when using the recommended dosages. Elimination is approximately two-thirds through feces and one-third in the urine.

Suvorexant metabolism can be affected by sex and body mass index. Females and obese people have a modestly elevated expo­sure to suvorexant, as reflected by the area under the curve and maximum concentra­tion (C_max). These patients might not require dosage adjustments unless they are obese and female, in which case they should take a lower dosage.

Age and race have not been shown to influence suvorexant metabolism to a signifi­cant degree. Patients with renal impairment and those with mild or moderate hepatic impairment do not need dosage adjust­ment. Suvorexant has not been evaluated in patients with severe hepatic impairment.

Efficacy
Suvorexant showed significant evidence of improved sleep onset and sleep maintenance in patients with insomnia in clinical trials. The key efficacy clinical trials with insomnia patients included a phase-IIb dose-finding study,¹⁰ 2 similar 3-month phase-III studies,¹¹ and one 12-month phase-III safety study that incorporated efficacy outcomes.¹² All these trials included subjective sleep measures and all except for the long-term safety study also incorporated polysomnographic assess­ment. The specific sleep laboratory outcomes were latency to persistent sleep (LPS), wake after the onset of persistent sleep (WASO), total sleep time (TST), and sleep efficiency (SE). Subjective sleep outcomes were time to sleep onset (sTSO), wake after sleep onset (sWASO), and total sleep time (sTST). Other exploratory endpoints also were assessed. These efficacy and safety studies mostly were performed at dosages considerably higher than those approved by the FDA.

The dose-finding (phase-IIb) trial was conducted with non-geriatric (age 18 to 64) patients with insomnia in a random­ized, double-blind, crossover design of two 4-week periods with subjects given a nightly placebo or suvorexant (10 mg, 20 mg, 40 mg, or 80 mg).¹⁰ Each of the 4 groups included approximately 60 subjects. The 2 co-primary endpoints were SE at Night 1 and the end of Week 4; secondary endpoints were LPS and WASO. Suvorexant was associated with dos­age-related improvements in SE and WASO compared with placebo at both time points. Carryover effects from the period-1 active drug group complicated the analysis of LPS.

The phase-III efficacy and safety trials were performed with 40 mg high dosage (HD) and 20 mg low dosage (LD) groups for adults and with 30 mg HD and 15 mg LD groups for geriatric (age ≥65) patients.¹¹ Two similarly designed 3-month randomized, double-blind, placebo-controlled pivotal efficacy studies assessed objective and sub­jective sleep measures in 4 groups with non-geriatric (HD and LD) and geriatric (HD and LD) insomnia patients.

After baseline assessment, patients took nightly bedtime doses of placebo; suvorexant, 40 mg or 20 mg (non-geriatric individuals); or suvorexant, 30 mg or 15 mg (geriatric indi­viduals). All subjects kept a daily electronic diary and had polysomnographic recordings performed on Night 1, at the end of Month 1, and at the end of Month 3. Both the indi­vidual studies and combined analyses (2,030 subjects) showed that, in non-geriatric and geriatric patients, HD suvorexant resulted in significantly greater improvement in key subjective and objective measures through­out the study (Table 2,⁹ and Table 3,⁹), with the exception of a single LPS outcome in 1 study, compared with placebo. The LD dosages also demonstrated efficacy, but to a reduced extent.

Subjective sleep outcomes were assessed in a 1-year randomized, placebo-controlled trial with nightly placebo, suvorexant, 40 mg, for non-geriatric, or suvorexant, 30 mg, for geriatric insomnia patients.12 The 1-year phase was completed with 484 subjects. Key efficacy outcomes were sTST and sTSO changes from baseline during the first month of treatment. Compared with placebo, suvorexant dosages demonstrated significantly greater efficacy, improvements that were sustained throughout the year.

Clinical trials found suvorexant to be gen­erally safe and well tolerated.¹³ However, specific safety concerns led the FDA to approve the medication at dosages lower than those assessed in the phase-III studies.¹

Somnolence was the most common adverse event in clinical trials. In the phase- IIb dose-finding study, somnolence was reported in <1% in the placebo group, but was associated with suvorexant in 2% of the 10 mg group, 5% with 20 mg, 12% with 40 mg, and 11% with 80 mg.⁹ In the phase-III combined analysis of the 3-month studies, somnolence was reported by 3% in the placebo group and 7% of non-geriatric patients taking 20 mg or geriatric patients taking 15 mg. Somnolence was reported in 8% of women and 3% of men taking the 15 mg or 20 mg dosage in these stud­ies. The 1-year study was performed only with higher suvorexant dosages (30 mg and 40 mg), in comparison with placebo. In this long-term trial, somnolence was reported by 13% of subjects taking suvorexant and 3% taking placebo.

Additional safety issues in trials included excessive daytime sleepiness, impaired driv­ing, suicidal ideation, sleep paralysis, hyp­nagogic/hypnopompic hallucinations, and cataplexy-like symptoms.⁹ Occurrences of these events are rare but have been reported more often among patients taking suvorex­ant than among those taking placebo.

Unique clinical issues
The U.S. Drug Enforcement Agency has categorized suvorexant as a Schedule IV controlled substance. Although there is no evidence of physiological dependence or withdrawal symptoms with suvorexant, studies with recreational substance abusers have shown that the likeability rating is simi­lar to that of zolpidem.¹³

Contraindication
Suvorexant is contraindicated in patients with narcolepsy.⁹ The underlying pathol­ogy of narcolepsy involves a marked reduction in orexin functioning with corre­sponding excessive sleepiness and related symptoms, such as cataplexy, hypnago­gic hallucinations, and sleep paralysis. Although suvorexant has not been evalu­ated in patients with narcolepsy, the drug might, hypothetically, put patients at higher risk of the full spectrum of narco­lepsy symptoms.

There are no other contraindications for suvorexant.


Dosing
Suvorexant should be taken no more than once a night within 30 minutes of bedtime and with at least 7 hours before the planned wake time.⁹ The recommended starting dosage is 10 mg. If this dosage is well toler­ated but insufficiently effective, the dosage can be increased to a maximum of 20 mg. The 5-mg dosage is recommended for indi­viduals taking a moderate CYP3A inhibitor. Generally, patients should take the lowest effective dosage.

There are no specified limitations on the duration of suvorexant use. There is no evidence of withdrawal effects when discontinuing the medication. Patients tak­ing suvorexant should be educated about possible next-day effects that might impair driving or other activities that require full mental alertness, especially if they are tak­ing the 20-mg dosage.

Bottom Line
Suvorexant is FDA-approved for treating sleep onset and sleep maintenance insomnia. The drug is a dual orexin-receptor antagonist, which targets persistent CNS hyperarousal. In clinical trials, suvorexant improved the ability to fall asleep and remain asleep in patients with insomnia. It is generally safe and well tolerated. However, these studies evaluated dosages higher than those approved by the FDA.

Related Resources
• Jacobson LH, Callander GE, Hoyer D. Suvorexant for the treatment of insomnia. Expert Rev Clin Pharmacol. 2014; 7(6):711-730.
• Neubauer DN. New and emerging pharmacotherapeutic approaches for insomnia. Int Rev Psychiatry. 2014;26(2): 214-224.

Drug Brand Names
Doxepin • Silenor             Suvorexant • Belsomra
Digoxin • Lanoxin             Zaleplon • Sonata
Eszopiclone • Lunesta       Zolpidem • Ambien,
Ramelteon • Rozerem            Edluar, Intermezzo

Disclosure
Dr. Neubauer is a consultant to Ferring Pharmaceuticals and Vanda Pharmaceuticals.

Suvorexant, FDA-approved to treat insomnia, has demonstrated efficacy in helping patients with insomnia improve their ability to fall asleep and remain asleep (Table 1).¹ This first-in-class compound represents a novel mechanism of action to promoting sleep that may avoid some prob­lems associated with other hypnotics.²

Because orexin antagonists have not been used outside of clinical trials, it is too soon to tell whether suvorexant will have the ideal real-world efficacy and safety profile to make it a first-line treatment for insomnia patients, or if it will be reserved for those who have failed a trial of several other treatments.⁴

In theory, the orexin antagonist approach to treating insomnia could represent a major advance that modulates the fundamental pathology of the disorder.⁵ The syndrome of chronic insomnia encompasses not just the nighttime sleep disturbance but also an assort­ment of daytime symptoms that can include fatigue, poor concentration, irritability, and decreased school or work performance but usually not sleepiness. This constellation of nighttime and daytime symptoms could be conceptualized as a manifestation of persis­tent CNS hyperarousal. Because the orexin system promotes and reinforces arousal, per­haps an orexin antagonist that dampens the level of orexin activity will ameliorate the full spectrum of insomnia symptoms—not sim­ply sedate patients.⁶

How suvorexant works
Suvorexant is a potent and reversible dual orexin-receptor antagonist. The orexin system, first described in 1998, has a key role in promoting and stabilizing wake­fulness.⁷ Evidence suggests that people with chronic insomnia exhibit a central hyperarousal that perpetuates their sleep difficulty. Accordingly, a targeted phar­maceutical approach that reduces orexin activity should facilitate sleep onset and sleep maintenance for these patients. It is well known that the regulation of sleep and wakefulness depends on the interaction of multiple nuclei within the hypothalamus. Orexinergic neurons in the perifornical-lateral hypothalamic region project widely in the CNS and have especially dense con­nections with wake-promoting cholinergic, serotonergic, noradrenergic, and histamin­ergic neurons.⁶

A precursor prepro-orexin peptide is split into 2 orexin neurotransmitters (orexin A and orexin B). These 2 orexins bind with 2 G-protein-coupled receptors (OX1R and OX2R) that have both overlapping and distinct distributions.⁷ Suvorexant is highly selective and has similar affinity for OX1R and OX2R, functioning as an antag­onist for both.⁸ Fundamentally, suvorexant enhances sleep by dampening the arous­ing wake drive.

Pharmacokinetics
Suvorexant is available as an immediate-release tablet with pharmacokinetic prop­erties that offer benefits for sleep onset and maintenance.⁹ Ingestion under fasting conditions results in a median time to maxi­mum concentration (T_max) of approximately 2 hours, although the T_max values vary widely from patient to patient (range 30 minutes to 6 hours). Although suvorexant can be taken with food, there is a modest absorption delay after a high-fat meal, resulting in a further T_max delay of approximately 1.5 hours.

Suvorexant is primarily metabolized through the cytochrome P450 (CYP) 3A path­way, with limited contribution by CYP2C19. There are no active metabolites. The suvorex­ant blood level and risk of side effects will be higher with concomitant use of CYP3A inhibitors. The drug should not be adminis­tered with strong CYP3A inhibitors; the ini­tial dosage should be reduced with moderate CYP3A inhibitors. Concomitant use of strong CYP3A inducers can result in a low suvorex­ant level and reduced efficacy.

Suvorexant has little effect on other med­ications, although a person taking digoxin might experience intestinal P-glycoprotein inhibition with a slight rise in the digoxin level. In a patient taking both medica­tions, monitoring of the digoxin level is recommended.

The elimination half-life of suvorexant is approximately 12 hours, with a steady state in approximately 3 days. Because the half-life of suvorexant is moderately long for a sleep-promoting medication, use of the drug might be associated with residual sleepiness the morning after bedtime dosing. The risk for next-morning sleepiness or impairment should be minimized, however, when using the recommended dosages. Elimination is approximately two-thirds through feces and one-third in the urine.

Suvorexant metabolism can be affected by sex and body mass index. Females and obese people have a modestly elevated expo­sure to suvorexant, as reflected by the area under the curve and maximum concentra­tion (C_max). These patients might not require dosage adjustments unless they are obese and female, in which case they should take a lower dosage.

Age and race have not been shown to influence suvorexant metabolism to a signifi­cant degree. Patients with renal impairment and those with mild or moderate hepatic impairment do not need dosage adjust­ment. Suvorexant has not been evaluated in patients with severe hepatic impairment.

Efficacy
Suvorexant showed significant evidence of improved sleep onset and sleep maintenance in patients with insomnia in clinical trials. The key efficacy clinical trials with insomnia patients included a phase-IIb dose-finding study,¹⁰ 2 similar 3-month phase-III studies,¹¹ and one 12-month phase-III safety study that incorporated efficacy outcomes.¹² All these trials included subjective sleep measures and all except for the long-term safety study also incorporated polysomnographic assess­ment. The specific sleep laboratory outcomes were latency to persistent sleep (LPS), wake after the onset of persistent sleep (WASO), total sleep time (TST), and sleep efficiency (SE). Subjective sleep outcomes were time to sleep onset (sTSO), wake after sleep onset (sWASO), and total sleep time (sTST). Other exploratory endpoints also were assessed. These efficacy and safety studies mostly were performed at dosages considerably higher than those approved by the FDA.

The dose-finding (phase-IIb) trial was conducted with non-geriatric (age 18 to 64) patients with insomnia in a random­ized, double-blind, crossover design of two 4-week periods with subjects given a nightly placebo or suvorexant (10 mg, 20 mg, 40 mg, or 80 mg).¹⁰ Each of the 4 groups included approximately 60 subjects. The 2 co-primary endpoints were SE at Night 1 and the end of Week 4; secondary endpoints were LPS and WASO. Suvorexant was associated with dos­age-related improvements in SE and WASO compared with placebo at both time points. Carryover effects from the period-1 active drug group complicated the analysis of LPS.

The phase-III efficacy and safety trials were performed with 40 mg high dosage (HD) and 20 mg low dosage (LD) groups for adults and with 30 mg HD and 15 mg LD groups for geriatric (age ≥65) patients.¹¹ Two similarly designed 3-month randomized, double-blind, placebo-controlled pivotal efficacy studies assessed objective and sub­jective sleep measures in 4 groups with non-geriatric (HD and LD) and geriatric (HD and LD) insomnia patients.

After baseline assessment, patients took nightly bedtime doses of placebo; suvorexant, 40 mg or 20 mg (non-geriatric individuals); or suvorexant, 30 mg or 15 mg (geriatric indi­viduals). All subjects kept a daily electronic diary and had polysomnographic recordings performed on Night 1, at the end of Month 1, and at the end of Month 3. Both the indi­vidual studies and combined analyses (2,030 subjects) showed that, in non-geriatric and geriatric patients, HD suvorexant resulted in significantly greater improvement in key subjective and objective measures through­out the study (Table 2,⁹ and Table 3,⁹), with the exception of a single LPS outcome in 1 study, compared with placebo. The LD dosages also demonstrated efficacy, but to a reduced extent.

Subjective sleep outcomes were assessed in a 1-year randomized, placebo-controlled trial with nightly placebo, suvorexant, 40 mg, for non-geriatric, or suvorexant, 30 mg, for geriatric insomnia patients.12 The 1-year phase was completed with 484 subjects. Key efficacy outcomes were sTST and sTSO changes from baseline during the first month of treatment. Compared with placebo, suvorexant dosages demonstrated significantly greater efficacy, improvements that were sustained throughout the year.

Clinical trials found suvorexant to be gen­erally safe and well tolerated.¹³ However, specific safety concerns led the FDA to approve the medication at dosages lower than those assessed in the phase-III studies.¹

Somnolence was the most common adverse event in clinical trials. In the phase- IIb dose-finding study, somnolence was reported in <1% in the placebo group, but was associated with suvorexant in 2% of the 10 mg group, 5% with 20 mg, 12% with 40 mg, and 11% with 80 mg.⁹ In the phase-III combined analysis of the 3-month studies, somnolence was reported by 3% in the placebo group and 7% of non-geriatric patients taking 20 mg or geriatric patients taking 15 mg. Somnolence was reported in 8% of women and 3% of men taking the 15 mg or 20 mg dosage in these stud­ies. The 1-year study was performed only with higher suvorexant dosages (30 mg and 40 mg), in comparison with placebo. In this long-term trial, somnolence was reported by 13% of subjects taking suvorexant and 3% taking placebo.

Additional safety issues in trials included excessive daytime sleepiness, impaired driv­ing, suicidal ideation, sleep paralysis, hyp­nagogic/hypnopompic hallucinations, and cataplexy-like symptoms.⁹ Occurrences of these events are rare but have been reported more often among patients taking suvorex­ant than among those taking placebo.

Unique clinical issues
The U.S. Drug Enforcement Agency has categorized suvorexant as a Schedule IV controlled substance. Although there is no evidence of physiological dependence or withdrawal symptoms with suvorexant, studies with recreational substance abusers have shown that the likeability rating is simi­lar to that of zolpidem.¹³

Contraindication
Suvorexant is contraindicated in patients with narcolepsy.⁹ The underlying pathol­ogy of narcolepsy involves a marked reduction in orexin functioning with corre­sponding excessive sleepiness and related symptoms, such as cataplexy, hypnago­gic hallucinations, and sleep paralysis. Although suvorexant has not been evalu­ated in patients with narcolepsy, the drug might, hypothetically, put patients at higher risk of the full spectrum of narco­lepsy symptoms.

There are no other contraindications for suvorexant.


Dosing
Suvorexant should be taken no more than once a night within 30 minutes of bedtime and with at least 7 hours before the planned wake time.⁹ The recommended starting dosage is 10 mg. If this dosage is well toler­ated but insufficiently effective, the dosage can be increased to a maximum of 20 mg. The 5-mg dosage is recommended for indi­viduals taking a moderate CYP3A inhibitor. Generally, patients should take the lowest effective dosage.

There are no specified limitations on the duration of suvorexant use. There is no evidence of withdrawal effects when discontinuing the medication. Patients tak­ing suvorexant should be educated about possible next-day effects that might impair driving or other activities that require full mental alertness, especially if they are tak­ing the 20-mg dosage.

Bottom Line
Suvorexant is FDA-approved for treating sleep onset and sleep maintenance insomnia. The drug is a dual orexin-receptor antagonist, which targets persistent CNS hyperarousal. In clinical trials, suvorexant improved the ability to fall asleep and remain asleep in patients with insomnia. It is generally safe and well tolerated. However, these studies evaluated dosages higher than those approved by the FDA.

Related Resources
• Jacobson LH, Callander GE, Hoyer D. Suvorexant for the treatment of insomnia. Expert Rev Clin Pharmacol. 2014; 7(6):711-730.
• Neubauer DN. New and emerging pharmacotherapeutic approaches for insomnia. Int Rev Psychiatry. 2014;26(2): 214-224.

Drug Brand Names
Doxepin • Silenor             Suvorexant • Belsomra
Digoxin • Lanoxin             Zaleplon • Sonata
Eszopiclone • Lunesta       Zolpidem • Ambien,
Ramelteon • Rozerem            Edluar, Intermezzo

Disclosure
Dr. Neubauer is a consultant to Ferring Pharmaceuticals and Vanda Pharmaceuticals.

Suvorexant, FDA-approved to treat insomnia, has demonstrated efficacy in helping patients with insomnia improve their ability to fall asleep and remain asleep (Table 1).¹ This first-in-class compound represents a novel mechanism of action to promoting sleep that may avoid some prob­lems associated with other hypnotics.²

Because orexin antagonists have not been used outside of clinical trials, it is too soon to tell whether suvorexant will have the ideal real-world efficacy and safety profile to make it a first-line treatment for insomnia patients, or if it will be reserved for those who have failed a trial of several other treatments.⁴

In theory, the orexin antagonist approach to treating insomnia could represent a major advance that modulates the fundamental pathology of the disorder.⁵ The syndrome of chronic insomnia encompasses not just the nighttime sleep disturbance but also an assort­ment of daytime symptoms that can include fatigue, poor concentration, irritability, and decreased school or work performance but usually not sleepiness. This constellation of nighttime and daytime symptoms could be conceptualized as a manifestation of persis­tent CNS hyperarousal. Because the orexin system promotes and reinforces arousal, per­haps an orexin antagonist that dampens the level of orexin activity will ameliorate the full spectrum of insomnia symptoms—not sim­ply sedate patients.⁶

How suvorexant works
Suvorexant is a potent and reversible dual orexin-receptor antagonist. The orexin system, first described in 1998, has a key role in promoting and stabilizing wake­fulness.⁷ Evidence suggests that people with chronic insomnia exhibit a central hyperarousal that perpetuates their sleep difficulty. Accordingly, a targeted phar­maceutical approach that reduces orexin activity should facilitate sleep onset and sleep maintenance for these patients. It is well known that the regulation of sleep and wakefulness depends on the interaction of multiple nuclei within the hypothalamus. Orexinergic neurons in the perifornical-lateral hypothalamic region project widely in the CNS and have especially dense con­nections with wake-promoting cholinergic, serotonergic, noradrenergic, and histamin­ergic neurons.⁶

A precursor prepro-orexin peptide is split into 2 orexin neurotransmitters (orexin A and orexin B). These 2 orexins bind with 2 G-protein-coupled receptors (OX1R and OX2R) that have both overlapping and distinct distributions.⁷ Suvorexant is highly selective and has similar affinity for OX1R and OX2R, functioning as an antag­onist for both.⁸ Fundamentally, suvorexant enhances sleep by dampening the arous­ing wake drive.

Pharmacokinetics
Suvorexant is available as an immediate-release tablet with pharmacokinetic prop­erties that offer benefits for sleep onset and maintenance.⁹ Ingestion under fasting conditions results in a median time to maxi­mum concentration (T_max) of approximately 2 hours, although the T_max values vary widely from patient to patient (range 30 minutes to 6 hours). Although suvorexant can be taken with food, there is a modest absorption delay after a high-fat meal, resulting in a further T_max delay of approximately 1.5 hours.

Suvorexant is primarily metabolized through the cytochrome P450 (CYP) 3A path­way, with limited contribution by CYP2C19. There are no active metabolites. The suvorex­ant blood level and risk of side effects will be higher with concomitant use of CYP3A inhibitors. The drug should not be adminis­tered with strong CYP3A inhibitors; the ini­tial dosage should be reduced with moderate CYP3A inhibitors. Concomitant use of strong CYP3A inducers can result in a low suvorex­ant level and reduced efficacy.

Suvorexant has little effect on other med­ications, although a person taking digoxin might experience intestinal P-glycoprotein inhibition with a slight rise in the digoxin level. In a patient taking both medica­tions, monitoring of the digoxin level is recommended.

The elimination half-life of suvorexant is approximately 12 hours, with a steady state in approximately 3 days. Because the half-life of suvorexant is moderately long for a sleep-promoting medication, use of the drug might be associated with residual sleepiness the morning after bedtime dosing. The risk for next-morning sleepiness or impairment should be minimized, however, when using the recommended dosages. Elimination is approximately two-thirds through feces and one-third in the urine.

Suvorexant metabolism can be affected by sex and body mass index. Females and obese people have a modestly elevated expo­sure to suvorexant, as reflected by the area under the curve and maximum concentra­tion (C_max). These patients might not require dosage adjustments unless they are obese and female, in which case they should take a lower dosage.

Age and race have not been shown to influence suvorexant metabolism to a signifi­cant degree. Patients with renal impairment and those with mild or moderate hepatic impairment do not need dosage adjust­ment. Suvorexant has not been evaluated in patients with severe hepatic impairment.

Efficacy
Suvorexant showed significant evidence of improved sleep onset and sleep maintenance in patients with insomnia in clinical trials. The key efficacy clinical trials with insomnia patients included a phase-IIb dose-finding study,¹⁰ 2 similar 3-month phase-III studies,¹¹ and one 12-month phase-III safety study that incorporated efficacy outcomes.¹² All these trials included subjective sleep measures and all except for the long-term safety study also incorporated polysomnographic assess­ment. The specific sleep laboratory outcomes were latency to persistent sleep (LPS), wake after the onset of persistent sleep (WASO), total sleep time (TST), and sleep efficiency (SE). Subjective sleep outcomes were time to sleep onset (sTSO), wake after sleep onset (sWASO), and total sleep time (sTST). Other exploratory endpoints also were assessed. These efficacy and safety studies mostly were performed at dosages considerably higher than those approved by the FDA.

The dose-finding (phase-IIb) trial was conducted with non-geriatric (age 18 to 64) patients with insomnia in a random­ized, double-blind, crossover design of two 4-week periods with subjects given a nightly placebo or suvorexant (10 mg, 20 mg, 40 mg, or 80 mg).¹⁰ Each of the 4 groups included approximately 60 subjects. The 2 co-primary endpoints were SE at Night 1 and the end of Week 4; secondary endpoints were LPS and WASO. Suvorexant was associated with dos­age-related improvements in SE and WASO compared with placebo at both time points. Carryover effects from the period-1 active drug group complicated the analysis of LPS.

The phase-III efficacy and safety trials were performed with 40 mg high dosage (HD) and 20 mg low dosage (LD) groups for adults and with 30 mg HD and 15 mg LD groups for geriatric (age ≥65) patients.¹¹ Two similarly designed 3-month randomized, double-blind, placebo-controlled pivotal efficacy studies assessed objective and sub­jective sleep measures in 4 groups with non-geriatric (HD and LD) and geriatric (HD and LD) insomnia patients.

After baseline assessment, patients took nightly bedtime doses of placebo; suvorexant, 40 mg or 20 mg (non-geriatric individuals); or suvorexant, 30 mg or 15 mg (geriatric indi­viduals). All subjects kept a daily electronic diary and had polysomnographic recordings performed on Night 1, at the end of Month 1, and at the end of Month 3. Both the indi­vidual studies and combined analyses (2,030 subjects) showed that, in non-geriatric and geriatric patients, HD suvorexant resulted in significantly greater improvement in key subjective and objective measures through­out the study (Table 2,⁹ and Table 3,⁹), with the exception of a single LPS outcome in 1 study, compared with placebo. The LD dosages also demonstrated efficacy, but to a reduced extent.

Subjective sleep outcomes were assessed in a 1-year randomized, placebo-controlled trial with nightly placebo, suvorexant, 40 mg, for non-geriatric, or suvorexant, 30 mg, for geriatric insomnia patients.12 The 1-year phase was completed with 484 subjects. Key efficacy outcomes were sTST and sTSO changes from baseline during the first month of treatment. Compared with placebo, suvorexant dosages demonstrated significantly greater efficacy, improvements that were sustained throughout the year.

Clinical trials found suvorexant to be gen­erally safe and well tolerated.¹³ However, specific safety concerns led the FDA to approve the medication at dosages lower than those assessed in the phase-III studies.¹

Somnolence was the most common adverse event in clinical trials. In the phase- IIb dose-finding study, somnolence was reported in <1% in the placebo group, but was associated with suvorexant in 2% of the 10 mg group, 5% with 20 mg, 12% with 40 mg, and 11% with 80 mg.⁹ In the phase-III combined analysis of the 3-month studies, somnolence was reported by 3% in the placebo group and 7% of non-geriatric patients taking 20 mg or geriatric patients taking 15 mg. Somnolence was reported in 8% of women and 3% of men taking the 15 mg or 20 mg dosage in these stud­ies. The 1-year study was performed only with higher suvorexant dosages (30 mg and 40 mg), in comparison with placebo. In this long-term trial, somnolence was reported by 13% of subjects taking suvorexant and 3% taking placebo.

Additional safety issues in trials included excessive daytime sleepiness, impaired driv­ing, suicidal ideation, sleep paralysis, hyp­nagogic/hypnopompic hallucinations, and cataplexy-like symptoms.⁹ Occurrences of these events are rare but have been reported more often among patients taking suvorex­ant than among those taking placebo.

Unique clinical issues
The U.S. Drug Enforcement Agency has categorized suvorexant as a Schedule IV controlled substance. Although there is no evidence of physiological dependence or withdrawal symptoms with suvorexant, studies with recreational substance abusers have shown that the likeability rating is simi­lar to that of zolpidem.¹³

Contraindication
Suvorexant is contraindicated in patients with narcolepsy.⁹ The underlying pathol­ogy of narcolepsy involves a marked reduction in orexin functioning with corre­sponding excessive sleepiness and related symptoms, such as cataplexy, hypnago­gic hallucinations, and sleep paralysis. Although suvorexant has not been evalu­ated in patients with narcolepsy, the drug might, hypothetically, put patients at higher risk of the full spectrum of narco­lepsy symptoms.

There are no other contraindications for suvorexant.


Dosing
Suvorexant should be taken no more than once a night within 30 minutes of bedtime and with at least 7 hours before the planned wake time.⁹ The recommended starting dosage is 10 mg. If this dosage is well toler­ated but insufficiently effective, the dosage can be increased to a maximum of 20 mg. The 5-mg dosage is recommended for indi­viduals taking a moderate CYP3A inhibitor. Generally, patients should take the lowest effective dosage.

There are no specified limitations on the duration of suvorexant use. There is no evidence of withdrawal effects when discontinuing the medication. Patients tak­ing suvorexant should be educated about possible next-day effects that might impair driving or other activities that require full mental alertness, especially if they are tak­ing the 20-mg dosage.

Bottom Line
Suvorexant is FDA-approved for treating sleep onset and sleep maintenance insomnia. The drug is a dual orexin-receptor antagonist, which targets persistent CNS hyperarousal. In clinical trials, suvorexant improved the ability to fall asleep and remain asleep in patients with insomnia. It is generally safe and well tolerated. However, these studies evaluated dosages higher than those approved by the FDA.

Related Resources
• Jacobson LH, Callander GE, Hoyer D. Suvorexant for the treatment of insomnia. Expert Rev Clin Pharmacol. 2014; 7(6):711-730.
• Neubauer DN. New and emerging pharmacotherapeutic approaches for insomnia. Int Rev Psychiatry. 2014;26(2): 214-224.

Drug Brand Names
Doxepin • Silenor             Suvorexant • Belsomra
Digoxin • Lanoxin             Zaleplon • Sonata
Eszopiclone • Lunesta       Zolpidem • Ambien,
Ramelteon • Rozerem            Edluar, Intermezzo

Disclosure
Dr. Neubauer is a consultant to Ferring Pharmaceuticals and Vanda Pharmaceuticals.