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Hosp Pharm 2015;50(1):059–071 2015 © Thomas Land Publishers, Inc. www.hospital-pharmacy.com doi: 10.1310/hpj5001-059 Formulary Drug Reviews Suvorexant

Dennis J. Cada, PharmD, FASHP, FASCP (Editor)*; Terri L. Levien, PharmD†; and Danial E. Baker, PharmD, FASHP, FASCP‡

Each month, subscribers to The Formulary Monograph Service receive 5 to 6 well-documented monographs on drugs that are newly released or are in late phase 3 trials. The monographs are targeted to Pharmacy & Therapeutics Committees. Subscribers also receive monthly 1-page summary monographs on agents that are useful for agendas and pharmacy/nursing in-services. A comprehensive target drug utilization evaluation/medication use evaluation (DUE/MUE) is also provided each month. With a subscription, the monographs are sent in print and are also avail- able on-line. Monographs can be customized to meet the needs of a facility. A drug class review is now published monthly with The Formulary Monograph Service. Through the cooperation of The Formulary, Hospital Pharmacy publishes selected reviews in this column. For more informa- tion about The Formulary Monograph Service, call The Formulary at 800-322-4349. The January 2015 monograph topics are ledipasvir/sofosbuvir, eliglustat, naloxegol, pembrolizumab, and dula- glutide injection. The Safety MUE is on ledipasvir/sofosbuvir.

Generic Name: Suvorexant and are involved with the regulation of arousal and Proprietary Name: Belsomra (Merck) wakefulness. Suvorexant is able to block the effects Approval Rating: 1S of the compounds and promote sleep.8-10 In Therapeutic Class: antagonists; animal models, suvorexant dose-dependently reduced and , locomotor activity and promoted sleep.9 In healthy nonbarbiturate human subjects, suvorexant was associated with a Similar Drugs: None dose-dependent increase in sleepiness and decrease in Sound- and Look-Alike alertness.11 Names: Serevent Suvorexant appears to have a lack of effect on sleep neurophysiology. Minimal electroencepha- INDICATIONS lographic changes were observed during rapid eye Suvorexant is indicated for the treatment of movement (REM) and non-REM sleep following the , which is characterized by difficulties with administration of suvorexant to patients with pri- and/or sleep maintenance.1 The US Food mary insomnia and to healthy volunteers.12,13 and Drug Administration (FDA)–approved indica- tions for the hypnotics are com- pared in Table 1.2-7 Following oral administration, the median

time-to-peak concentration (Tmax) is 2 hours (range, CLINICAL PHARMACOLOGY 30 minutes to 6 hours).1,13 Mean absolute bioavail- Suvorexant is a dual orexin , ability of the 10 mg dose is 82%. Exposure increases binding the orexin-1 and orexin-2 receptors. Endog- in a slightly less than dose-proportional manner enous orexin A and B bind to the orexin receptors over the range of 10 to 80 mg because of reduced

*Founder and Contributing Editor, The Formulary; †Clinical Professor, College of Pharmacy, Washington State University; ‡Director, Drug Information Center, and Professor of Pharmacy Practice, College of Pharmacy, Washington State University Spokane, PO Box 1495, Spokane, Washington 99210-1495. The authors indicate no relationships that could be perceived as a conflict of interest.

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Table 1. US Food and Drug Administration–approved indications for nonbenzodiazepine hypnotics 1-7 Agent Class Indications Treatment of insomnia Treatment of insomnia Treatment of insomnia characterized by characterized by characterized by difficulty with sleep difficulties with sleep difficulties with sleep onset onset and/or sleep maintenance maintenance Suvorexant Orexin receptor X antagonist Tricyclic X receptor X receptor X agonist Benzodiazepine receptor X agonist extended Benzodiazepine receptor X release agonist Zolpidem Benzodiazepine receptor X immediate release agonist

absorption at higher doses.1 Ingestion with a high-fat COMPARATIVE EFFICACY 1 meal resulted in delayed Tmax. Suvorexant is highly Indication: Insomnia plasma-protein bound (greater than 99%).1 Suvorexant is primarily eliminated via cyto- Guidelines chrome P450 (CYP-450) 3A metabolism, with less Guideline: Clinical guideline for the evaluation and elimination via CYP2C19 metabolism. The primary management of chronic insomnia in adults metabolite, hydroxy-suvorexant, is not active.1 Reference: Schutte-Rodin S, et al, 200814 The mean terminal elimination half-life is approxi- Comments: Selection of a pharmacotherapy should 1,11,13 mately 12 hours. The primary route of elimina- be guided by the symptom pattern, treatment goals, 1 tion is through the feces. Its volume of distribution past treatment responses, patient preferences, cost, 1 is 49 L. availability of other treatments, comorbid condi- Suvorexant exposure is higher in females than in tions, contraindications, concurrent medication males, with the area under the curve (AUC) increased interactions, and adverse effects. The recommended 17% and the peak concentration (C ) increased max initial medication trials should be with short- to 9%.1 Suvorexant clearance is inversely related to intermediate-acting benzodiazepine receptor ago- body mass index (BMI). In obese patients, the AUC nists ( or benzodiazepine receptor is increased 31% and Cmax is increased 17% com- pared with subjects with a normal BMI. In obese such as zolpidem, eszopiclone, zaleplon, and ) or ramelteon. If the initial agent females, the AUC and Cmax are increased 46% and 25% compared with nonobese females.1 Suvorex- is not effective, then an alternate short- to inter- ant half-life was increased in subjects with moder- mediate-acting benzodiazepine receptor agonist ate hepatic impairment (19 vs 15 hours); however, or ramelteon should be tried. Sedating antidepres- exposure did not differ.1 Suvorexant exposure did sants, especially when used in the management of not differ between subjects with severe renal impair- comorbid depression or anxiety, may be tried next; ment and healthy matched controls.1 Age and race do examples of these agents include , ami- not appear to have any clinically important effect on triptyline, doxepin, and . The next step suvorexant pharmacokinetics.1 can be combined use of a sedating antidepressant

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with a benzodiazepine receptor agonist or ramelt- • Change from baseline in wake time after sleep eon. Antiepilepsy medications (eg, , onset (WASO) at night 1 (high dose vs placebo): tiagabine) and atypical (eg, quetiap- reduced 38.4 minutes with suvorexant relative ine, ) should only be used in patients to placebo (P < .001). with comorbid insomnia who may benefit from the • Change from baseline in WASO at month primary action of the drugs as well as from their ­1 (high dose vs placebo): reduced 26.3 minutes sedating effects. Nonprescription with suvorexant relative to placebo (P < .001). and antihistamine/analgesic agents and herbal and • Change from baseline in WASO at month nutritional supplements are not recommended for ­3 (high dose vs placebo): reduced 22.9 minutes the treatment of chronic insomnia due to the lack with suvorexant relative to placebo (P < .001). of efficacy and safety data. Older approved agents • Change from baseline in subjective time to sleep for insomnia, such as and chloral onset (TSO) at week 1 (high dose vs placebo): hydrate, are also not recommended. The guideline reduced 5.7 minutes with suvorexant relative to advises that therapy should be supple- placebo (P = .0061). mented with behavioral and cognitive therapies • Change from baseline in subjective TSO at when possible, along with patient education. month 1 (high dose vs placebo): reduced 7.4 minutes with suvorexant relative to placebo Studies ­(P = .003). Drug: Suvorexant vs Placebo • Change from baseline in subjective TSO at Reference: Connor K, et al, 2012 (Study P028)15,16 month 3 (high dose vs placebo): reduced 8.4 minutes with suvorexant relative to placebo Study Design: Randomized, double-blind, placebo- (P < .001). controlled, multicenter study • Change from baseline in latency to onset of per- Study Funding: Merck sistent sleep on night 1 (high dose vs placebo): Patients: 1,022 patients with primary insom- reduced 10.3 minutes with suvorexant relative nia; 1,021 received at least 1 dose of the study to placebo (P < .001). medication. Mean age of patients was 56 years • Change from baseline in latency to onset of per- (range, 18 to 87 years), with 42% elderly (65 sistent sleep at month 1 (high dose vs placebo): years and older); 62.4% were female; 65.1% reduced 11.2 minutes with suvorexant relative of patients were White, 25.8% were Asian, and to placebo (P < .001). 5.7% were Black; and 35% were from Europe, • Change from baseline in latency to onset of per- 33.9% were from North America, and 24.2% sistent sleep at month 3 (high dose vs placebo): were from Japan. reduced 9.4 minutes with suvorexant relative to Intervention: Suvorexant 20 mg (15 mg for patients placebo (P < .001). 65 years and older), 40 mg (30 mg for patients 65 Secondary Endpoint(s): years and older), or placebo for 3 months, with an • Change from baseline in subjective TST at week optional 3-month double-blind extension and a 1 (low dose vs placebo): 13.6 minutes greater 1-week double-blind run-out at the conclusion of with suvorexant (P < .001). treatment. • Change from baseline in subjective TST at Results month 1 (low dose vs placebo): 16.3 minutes Primary Endpoint(s): greater with suvorexant (P < .001). • Change from baseline in subjective total sleep • Change from baseline in subjective TST at time (TST) at week 1 (high dose vs placebo): month 3 (low dose vs placebo): 10.7 minutes 21.4 minutes greater with suvorexant (P < .001). greater with suvorexant (P = .017). • Change from baseline in subjective TST at • Change from baseline in WASO at night 1 (low month 1 (high dose vs placebo): 19.6 minutes dose vs placebo): reduced 32.5 minutes with greater with suvorexant (P < .001). suvorexant relative to placebo (P < .001). • Change from baseline in subjective TST at • Change from baseline in WASO at month 1 month 3 (high dose vs placebo): 19.7 minutes (low dose vs placebo): reduced 26.4 minutes greater with suvorexant (P < .001). with suvorexant relative to placebo (P < .001).

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• Change from baseline in WASO at month 3 (low and 30.2% were from Europe and 48% were from dose vs placebo): reduced 16.6 minutes relative North America. to placebo (P < .001). Intervention: Suvorexant 20 mg (15 mg for patients • Change from baseline in subjective TSO at week 65 years and older), 40 mg (30 mg for patients­ 1 (low dose vs placebo): reduced 5.6 minutes 65 years and older), or placebo for 3 months, with with suvorexant relative to placebo (P = .016). an optional 3-month double-blind extension and a • Change from baseline in subjective TSO 1-week double-blind run-out at the conclusion of at month 1 (low dose vs placebo): reduced treatment. 5.4 minutes with suvorexant relative to placebo Results ­(P = .052). Primary Endpoint(s): • Change from baseline in subjective TSO • Change from baseline in subjective TST at week at month 3 (low dose vs placebo): reduced 1 (high dose vs placebo): 26.4 minutes greater ­5.2 minutes with suvorexant relative to placebo with suvorexant than placebo (P < .001). ­(P = .04). • Change from baseline in subjective TST at • Change from baseline in latency to onset of per- month 1 (high dose vs placebo): 26.3 minutes sistent sleep on night 1 (low dose vs placebo): greater with suvorexant than placebo (P < .001). reduced 9.6 minutes with suvorexant relative to placebo (P < .001). • Change from baseline in subjective TST at • Change from baseline in latency to onset of per- month 3 (high dose vs placebo): 25.1 minutes sistent sleep at month 1 (low dose vs placebo): greater with suvorexant than placebo (P < .001). reduced 10.3 minutes with suvorexant relative • Change from baseline in WASO at night 1 (high to placebo (P < .001). dose vs placebo): reduced 42 minutes with suvorexant relative to placebo (P < .001). • Change from baseline in latency to onset of per- • Change from baseline in WASO at month sistent sleep at month 3 (low dose vs placebo): 1 (high dose vs placebo): reduced 29.4 minutes reduced 8.1 minutes with suvorexant relative to with suvorexant relative to placebo (P < .001). placebo (P = .0061). • Change from baseline in WASO at month Comments: Adherence with the prescribed study ­3 (high dose vs placebo): reduced 29.4 minutes medication was 98% in all treatment groups. Dif- with suvorexant relative to placebo (P < .001). ferences between the 20 or 15 mg dose and placebo • Change from baseline in subjective TSO at week were smaller than differences between the 40 or 1 (high dose vs placebo): reduced 13.1 minutes 30 mg dose and placebo, although most remained with suvorexant relative to placebo (P < .001). significant. No clinically important rebound or • Change from baseline in subjective TSO at withdrawal was observed by the investigators fol- month 1 (high dose vs placebo): reduced 12.8 lowing discontinuation of suvorexant therapy. Dis- minutes with suvorexant relative to placebo continuations due to adverse effects occurred in ­(P < .001). 3.9% of patients receiving high-dose suvorexant, • Change from baseline in subjective TSO at 2.4% of those receiving low-dose suvorexant, and month 3 (high dose vs placebo): reduced 13.2 5.5% of those receiving placebo. minutes with suvorexant relative to placebo Limitations: Presented only as a meeting abstract ­(P < .001). and in the FDA briefing document. • Change from baseline in latency to onset of per- sistent sleep on night 1 (high dose vs placebo): 16-18 Reference: Ivgy-May N, et al, 2012 (Study P029) reduced 21.7 minutes with suvorexant relative Study Design: Randomized, double-blind, placebo- to placebo (P < .001). controlled, multicenter study • Change from baseline in latency to onset of per- Study Funding: Merck sistent sleep at month 1 (high dose vs placebo): Patients: 1,019 patients with primary insomnia; reduced 12.1 minutes with suvorexant relative 1,009 received at least 1 dose of the study medi- to placebo (P < .001). cation. Mean age of patients was 56 years (range, • Change from baseline in latency to onset of per- 18 to 86 years), with 41% elderly (65 years or sistent sleep at month 3 (high dose vs placebo): older); 66.5% were female; 80.2% of patients were reduced 3.6 minutes with suvorexant relative to White, 7.7% were Asian, and 4.5% were Black; placebo (P = .27).

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Secondary Endpoint(s): receiving high-dose suvorexant, 4.2% of patients • Change from baseline in subjective TST at week receiving low-dose suvorexant, and 4.4% of 1 (low dose vs placebo): 16.8 minutes greater patients receiving placebo. with suvorexant than placebo (P < .001). The 2 pivotal efficacy studies were P028 and P029. • Change from baseline in subjective TST at Both studies were similar in design and provided month 1 (low dose vs placebo): 20.9 minutes 3-month treatment data for the primary efficacy greater with suvorexant than placebo (P < .001). assessment. Both P028 and P029 showed that the • Change from baseline in subjective TST at high-dose suvorexant was better than placebo in month 3 (low dose vs placebo): 22.1 minutes sleep maintenance and sleep onset throughout the greater with suvorexant than placebo (P < .001). study. The lower dose group was not the primary • Change from baseline in WASO at night 1 (low focus of the study but did show some efficacy on dose vs placebo): reduced 37 minutes with sleep maintenance and inconsistent improvements suvorexant relative to placebo (P < .001). in sleep onset.16 • Change from baseline in WASO at month ­1 (low dose vs placebo): reduced 24.1 minutes Limitations: Presented only as a meeting abstract with suvorexant relative to placebo (P < .001). and in the FDA briefing document. • Change from baseline in WASO at month Reference: Michelson D, et al, 2014 (Study ­3 (low dose vs placebo): reduced 31.1 minutes P009)16,19-22 with suvorexant relative to placebo (P < .001). Study Design: Randomized, double-blind, placebo- • Change from baseline in subjective TSO at week controlled, 12-month, multicenter study 1 (low dose vs placebo): reduced 7.5 minutes Study Funding: Merck with suvorexant relative to placebo (P = .006). • Change from baseline in subjective TSO Patients: 781 patients with primary insomnia; per- at month 1 (low dose vs placebo): reduced cent younger than 65 years (approximately 41%) ­6.9 minutes with suvorexant relative to placebo and 65 years and older (59%) were similar in both (P = .05). groups. • Change from baseline in subjective TSO Intervention: Patients were randomly assigned to at month 3 (low dose vs placebo): reduced suvorexant (n = 522) or placebo (n = 259) nightly ­7.6 minutes with suvorexant relative to placebo for 12 months using a 2:1 ratio. The dose of (P = .04). suvorexant was 40 mg for patients 18 to 64 years • Change from baseline in latency to onset of per- of age and 30 mg for patients 65 years and older. sistent sleep on night 1 (low dose vs placebo): After 12 months, patients treated with suvorex- reduced 12.4 minutes with suvorexant relative ant were re-randomized to either suvorexant or to placebo (P = .004). placebo for 2 months, whereas those originally • Change from baseline in latency to onset of per- assigned the placebo remained on placebo for this sistent sleep at month 1 (low dose vs placebo): 2-month period. reduced 7.8 minutes with suvorexant relative to Results placebo (P = .03). Primary Endpoint(s): • Change from baseline in latency to onset of per- • Safety and tolerability: Over 1 year, 69.5% of sistent sleep at month 3 (low dose vs placebo): patients treated with suvorexant and 63.6% reduced 0.3 minutes with suvorexant relative to treated with placebo experienced an adverse placebo (P = .93). event. Serious adverse events were reported in Comments: Adherence with the prescribed study 5.2% of patients treated with suvorexant and medication as 98% in all treatment groups. Dif- 6.6% treated with placebo. was the ferences between the 20 or 15 mg dose and pla- most common adverse event, reported in 13.2% cebo were smaller than differences between the of patients treated with suvorexant compared 40 or 30 mg dose and placebo. No clinically with 2.7% treated with placebo. Other adverse important rebound or withdrawal was observed events that occurred more frequently with by the investigators following discontinuation suvorexant than placebo were fatigue and dry of suvorexant therapy. Discontinuations due mouth. Discontinuation due to adverse events to adverse effects occurred in 4.8% of patients occurred in 11.7% in the suvorexant group

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compared with 8.5% in the placebo group. Sui- • Three or more withdrawal symptoms on the cidal ideation occurred in 4 patients treated with Tyrer Withdrawal Symptom Questionnaire on suvorexant and none treated with placebo. Other any of the first 3 nights after discontinuation predefined events of clinical interest included were reported in no more than 3.2% of patients somnambulism (1 event), hypnagogic halluci- in any treatment group, with no difference nation (3 events), hypnopompic hallucination between treatments. ­(1 event), and sleep paralysis (2 events), all of Comments: Insomnia symptoms returned within which occurred in suvorexant-treated patients. ­1 week of discontinuation of suvorexant therapy. Excessive daytime sleepiness was reported in Limitations: Study doses were higher than the 2.5% of suvorexant-treated patients and 0.8% of FDA-approved doses. The 1-year phase of the study placebo-treated patients. Motor vehicle accidents was completed by 62% of the patients randomly or citations were reported in 6% of suvorexant- assigned to receive suvorexant and 63% assigned treated patients and 4% of placebo recipients. to receive placebo. Secondary Endpoint(s): • Mean change from baseline in self-reported Reference: Herring WJ, et al, 2012; Belsomra pre- 1,16,23 TST after 1 month of treatment: 22.7 minutes scribing information, 2014 (Study P006) greater with suvorexant than with placebo Study Design: Randomized, double-blind, double- (95% CI, 16.4% to 29%; P < .001). dummy, placebo-controlled, multicenter, crossover • Mean change from baseline in self-reported study TSO after 1 month of treatment: 9.5 minutes Study Funding: Merck Research Laboratories sooner with suvorexant than with placebo Patients: 249 patients 18 to 64 years of age (mean, (95% CI, −14.6 to −4.5; P < .001). 44 years) with primary insomnia, polysomnogra- Other Endpoint(s): phy assessed with latency to persistent sleep of at • Mean change from baseline in self-reported least 20 minutes, and a mean wake time after sleep WASO after 1 month of treatment: 9 minutes onset of at least 60 minutes. At baseline, mean sleep less with suvorexant than with placebo (95% efficiency was 66%, mean TST was 316 minutes, CI, −13.8 to −4.1; P < .001). average WASO was 101 minutes, and mean latency • Mean change from baseline in self-reported to persistent sleep was 69 minutes. Of the patients, TST, TSO, and WASO at each month over 12 59% were women and 70% were White; 87% were months: suvorexant results were reported to from the United States and 13% were from Japan. be maintained over the 12-month evaluation Intervention: Suvorexant 10, 20, 40, or 80 mg period (P < .05). nightly for 4 weeks and placebo nightly for 4 weeks. • Suvorexant was better than placebo at month Results 1 and 12 for several diary measures (WASO, Primary Endpoint(s): quality of sleep, and refreshed feeling on wak- • Sleep efficiency (TST divided by time in bed ing; all Ps < .05) but not for the measure of in minutes) on night 1: increased with each number of awakenings. Suvorexant was better suvorexant dose relative to placebo (5.2% with than placebo at month 1 and 12 for all rating the 10 mg dose, P ≤ .01; 7.6% with the 20 mg scale endpoints (Insomnia Severity Index, Cli- dose, P ≤ .001; 10.8% with the 40 mg dose, nician Global Impression of Severity, Patient P ≤ .001; 12.9% with the 80 mg dose, P ≤ .001). Global Impression of Severity, Clinical Global • Sleep efficiency at the end of week 4: increased Impression of Improvement, and Patient Global with each suvorexant dose relative to placebo Impression of Improvement; all Ps < .05). No (4.7% with the 10 mg dose, P ≤ .01; 10.4% difference between treatments was observed with the 20 mg dose, P ≤ .001; 7.8% with the in the measure of mood (Quick Inventory of 40 mg dose, P ≤ .001; and 7.6% with the 80 mg Depressive Symptomatology). dose, P ≤ .001). • Rebound insomnia measures were not significantly Secondary Endpoint(s): worse among patients switched from suvorexant • WASO on night 1: reduced with each suvorex- to placebo compared with those remaining on ant dose relative to placebo (−21.2 minutes with placebo; however, the proportion of patients with the 10 mg dose, −24.7 minutes with the 20 mg rebound insomnia was greater numerically in the dose, −33.9 minutes with the 40 mg dose, −36.8 group discontinued from suvorexant. minutes with the 40 mg dose; all Ps ≤ .001).

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• WASO at the end of week 4: reduced with each when taken as recommended. It can impair driving suvorexant dose relative to placebo (−21.4 min- skills and may increase the risk of falling asleep while utes with the 10 mg dose, −28.1 minutes with driving. Impaired driving ability was seen in some the 20 mg dose, −33.2 minutes with the 40 mg patients taking a 20 mg dose. Patients taking the 20 mg dose, −28.9 minutes with the 40 mg dose; all dose should be advised against next-day driving and ­Ps ≤ .001). other activities requiring full mental alertness. Caution • Latency to persistent sleep on night 1: reduced is also advised in patients taking lower doses. The risk with the suvorexant 40 and 80 mg doses rela- of next-day impairment is increased if suvorexant is tive to placebo (−23.1 minutes with the 40 mg taken with less than a full night of sleep remaining, if dose, −25.4 minutes with the 80 mg dose; both a higher than recommended dose is taken, if it is coad- Ps ≤ .001). ministered with other CNS medications or • Latency to persistent sleep at the end of week 4: , or if it is coadministered with other drugs that reduced only with the suvorexant 20 mg dose increase blood levels of suvorexant.1 relative to placebo (−22.3 minutes, P ≤ .001). In studies of the residual effects of single and Other Endpoint(s): repeated evening doses of suvorexant 15 and 30 mg • TST on night 1: increased with each suvorex- in 24 healthy elderly subjects and 20 and 40 mg in 28 ant dose relative to placebo (25.1 minutes with nonelderly subjects on highway driving, suvorexant the 10 mg dose, P ≤ .01; 36.2 minutes with the was not associated with clinically important mean ­20 mg dose, P ≤ .001; 52.4 minutes with the 40 changes in the standard deviation of lateral position, mg dose, P ≤ .001; 61.9 minutes with the 80 mg a measure of “weaving” in a highway driving test, dose, P ≤ .001). conducted the next morning; however, impaired driv- • TST at the end of week 4: increased with each ing performance was observed in some subjects. In suvorexant dose relative to placebo (22.3 min- addition, 5 subjects (4 nonelderly subjects on suvorex- utes with the 10 mg dose, P ≤ .01; 49.9 minutes ant and 1 elderly subject on placebo) prematurely with the 20 mg dose, P ≤ .001; 36.8 minutes stopped their driving tests due to somnolence.1,24 with the 40 mg dose, P ≤ .001; 36.6 minutes Next-day impairment of memory and balance were with the 80 mg dose, P ≤ .001). not observed in 3 studies but were observed in a • Number of awakenings: reduced only with the fourth study in healthy nonelderly subjects exposed 80 mg dose on night 1 (−3.3, P ≤ .001). to suvorexant at bedtime.1 • Residual effects were not consistently observed Underlying physical and/or psychiatric disorders using the Digit Symbol Copy Test and Digit should be considered prior to initiating therapy for a Symbol Substitution Test. sleep disturbance. Failure of insomnia to remit after Limitations: The study had 95% power to detect ­7 to 10 days of therapy may indicate the presence of a 40-minute difference in TST (an 8.3% change in an underlying disorder that should be evaluated.1 sleep efficiency) and 93% power to detect a clinically Cognitive and behavioral changes, including relevant difference in WASO but only 64% power to amnesia, anxiety, hallucinations, and other neuro- detect a clinically relevant difference in latency to psychiatric symptoms, have been reported with the persistent sleep. Study duration was short. Elderly use of hypnotics such as suvorexant. Complex behav- patients were excluded from the study population. iors such as “sleep-driving” have also been reported. The use of alcohol and other CNS may increase the risk of these behaviors. Discontinuation CONTRAINDICATIONS, WARNINGS, AND of therapy should be strongly considered in patients PRECAUTIONS who report any complex sleep behavior.1 Contraindications A dose-dependent increase in suicidal ideation was Suvorexant is contraindicated in patients with observed in patients taking suvorexant in clinical trials. .1 Table 2 summarizes the contraindications, Patients with suicidal ideation or any new behavioral warnings, and precautions for the nonbenzodiazepine sign or symptom should be immediately evaluated.1 hypnotics used in the treatment of insomnia. Suvorexant has not been studied in patients with severe obstructive sleep apnea or severe chronic Warnings and Precautions obstructive pulmonary disease (COPD). In patients Suvorexant is a central nervous system (CNS) with mild to moderate obstructive sleep apnea and depressant and may impair daytime wakefulness even mild to moderate COPD, significant respiratory

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18_hpj5001059_071.indd 65 24/12/14 12:21 PM Formulary Drug Reviews X X X X X X X X X X X 1-7 Zolpidem extended- release X X X X X X X X X X X Zolpidem X X X X X X X X X X Zaleplon X X X X X X X X X X Ramelteon X X X X X X X X X X X Eszopiclone X X X X X X X X X Doxepin X X X X X X X X Suvorexant Contraindications, warnings, and precautions for the nonbenzodiazepine sedative hypnotics used in treatment of insomnia CNS = central nervous system. Use in elderly and/or debilitated Withdrawal effects Withdrawal Changes in testosterone and levels Severe hepatic impairment Sleep paralysis, hypnagogic hallucinations, hypnagogic hallucinations, Sleep paralysis, cataplexy-like symptoms Severe anaphylactic and anaphylactoid reactions Compromised respiratory function Worsening of depression/suicidal ideation Worsening Abnormal thinking and behavioral changes Evaluation for comorbid diagnoses Daytime or next-day impairment Concomitant fluvoxamine Concurrent monoamine oxidase inhibitor or use within 2 weeks Untreated narrow-angle glaucoma or severe urinary retention and precautions Warnings CNS depressant effects Note: Contraindications Narcolepsy Hypersensitivity/angioedema/anaphylaxis Table 2. Table

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effects were not observed; however, side inter- and headache (7%); dizziness (3%); and abnormal intraindividual effects were observed, such that clini- dreams, cough, diarrhea, dry mouth, and upper respi- cally important respiratory effects could not be ruled ratory tract infection (all 2%).1 Somnolence occurred out. The effects of suvorexant on respiratory function more frequently in females than males (8% vs 3%), as should be considered if used in a patient with com- did headache, abnormal dreams, dry mouth, cough, promised respiratory function.1 and upper respiratory tract infection.1 Sleep paralysis, an inability to move or speak for up to several minutes during sleep-wake transitions, DRUG INTERACTIONS and hypnagogic/hypnopompic hallucinations, includ- Caution is advised if suvorexant is coadminis- ing vivid and disturbing perceptions by the patient, tered with other CNS depressant medications. Con- can occur with the use of suvorexant. These poten- current alcohol ingestion should be avoided.1 tial adverse events should be discussed with patients Coadministration of suvorexant with strong when prescribing suvorexant. Symptoms similar to CYP3A inhibitors (eg, , , mild cataplexy can also occur, including leg weakness posaconazole, , , , lasting up to a few minutes occurring both at night saquinavir, nelfinavir, , boceprevir, telapre- 1 and during the day. vir, telithromycin, ) is not recommended. Suvorexant is undergoing Drug Enforcement A reduced dose of suvorexant 5 mg is recommended Administration (DEA) review to determine the con- in patients receiving moderate CYP3A inhibitors (eg, 25 trolled substances schedule. Abuse increases the risk amprenavir, aprepitant, atazanavir, ciprofloxacin, dil- of somnolence, daytime sleepiness, decreased reaction tiazem, , fluconazole, fosamprenavir, time, and impaired driving skills. In abuse liability grapefruit juice, imatinib, ). The dose can be studies, suvorexant produced effects similar to zolpi- increased to 10 mg if necessary.1 dem on subjective ratings of “drug liking” and other Suvorexant exposure is substantially reduced, measures of subjective drug effects. No evidence of potentially resulting in reduced efficacy, if suvorex- physical dependence was observed in studies with ant is administered with strong CYP3A inducers (eg, prolonged use, and no withdrawal symptoms have rifampin, carbamazepine, phenytoin).1 1 been reported after suvorexant discontinuation. Slightly increased digoxin levels were observed The safety and effectiveness of suvorexant have with digoxin and suvorexant coadministration 1 not been established in pediatric patients. because of inhibition of intestinal P-glycoprotein. Suvorexant is in Category C. It should Digoxin concentrations should be monitored with be used in pregnancy only if the potential benefit jus- coadministration.1 tifies the potential risk to the fetus. In animal mod- Clinically important interactions were not els, suvorexant use in pregnancy was associated with observed between suvorexant and , war- decreased fetal body weight, but there was no evi- farin, or a combined ethinyl /norgestimate 1 dence of teratogenicity. oral contraceptive.1 Suvorexant and the hydroxyl-suvorexant metab- olite were excreted in rat milk and in higher concen- RECOMMENDED MONITORING trations than were observed in maternal plasma. It is No specific laboratory monitoring has been not known whether suvorexant is secreted in human reported in clinical trials. Patients should be assessed milk; however, caution is advised if suvorexant is for response and adverse events. administered to a breast-feeding woman.1 Cautions with the use of nonbenzodiazepine DOSING sedative hypnotics in special populations are summa- The recommended dose is 10 mg taken no rized in Table 3. more than once per night and within 30 minutes of going to bed when at least 7 hours remain before ADVERSE REACTIONS the planned time of awakening. The time to effect The most common adverse reaction associated may be delayed if taken with food or shortly after with suvorexant is somnolence (reported in 7% of a meal. If the 10 mg dose is well tolerated but not patients treated with suvorexant vs 3% of patients effective, the dose may be increased. The maximum treated with placebo).1 Other adverse effects reported dose is 20 mg once daily. The lowest effective dose in at least 2% of suvorexant-treated patients included should be used.1

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18_hpj5001059_071.indd 67 24/12/14 12:21 PM Formulary Drug Reviews Zolpidem Category C; consider risk versus benefit Caution Not recommended Reduce dose Respiratory depression observed; use with caution Reduce dose No dose adjustment required Increased exposure in females; reduce dose Zaleplon Category C; not recommended Not recommended Safety and effectiveness not established Reduce dose Significant effects not observed; use with caution Reduce dose in mild to moderate impairment; avoid in severe impairment No dose adjustment required No unique precautions Ramelteon Category C; consider risk versus benefit Caution Safety and effectiveness not established No unique precautions Significant effects not observed; avoid in severe obstructive sleep apnea Caution in moderate impairment; avoid in severe impairment No dosage adjustment required No unique precautions 1-7 Eszopiclone Category C; consider risk versus benefit Unknown Safety and effectiveness not established Exposure increased; reduce dose Significant effects not observed; use with caution Caution; reduce dose in severe impairment No dosage adjustment required No unique precaution Doxepin Category C; consider risk versus benefit Caution Safety and effectiveness not established Reduce dose in severe Avoid sleep apnea Reduce dose No dosage adjustment required No unique precautions

Suvorexant Category C; consider risk versus benefit Caution Safety and effectiveness not established No unique precautions Significant effects not observed; use with caution Not recommended in severe impairment No dosage adjustment required Increased exposure in females; caution with dose increase Use of nonbenzodiazepine sedative hypnotics in special populations Population Pregnancy Breast-feeding mothers Pediatric Geriatric Compromised respiratory function Hepatic impairment Renal impairment Gender Table 3. Table

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Table 4. Recommended dosage and administration for the nonbenzodiazepine sedative hypnotics1-7 Recommended dose Maximum dose Dose adjustments in special populations Suvorexant 10 mg once daily within 20 mg once daily With moderate CYP3A inhibitors, the 30 minutes of going to bed recommended dose is 5 mg and the maximum dose is 10 mg. Not recommended in patients requiring treatment with a strong CYP3A inhibitor Doxepin 3 to 6 mg within 30 minutes 6 mg/day Recommended starting dose is 3 mg in the of going to bed elderly and those with hepatic impairment Eszopiclone 1 mg immediately before bedtime 3 mg once daily Not to exceed 2 mg in the elderly or debilitated, in patients with severe hepatic impairment, or with coadministration of potent CYP3A4 inhibitors Ramelteon 8 mg within 30 minutes 8 mg per day None of going to bed Zaleplon 5 to 10 mg immediately 20 mg once daily In the elderly or debilitated, the recommended before bedtime dose is 5 mg and maximum dose is 10 mg.

In mild to moderate hepatic impairment, the recommended dose is 5 mg.

With cimetidine, the initial dose is 5 mg. Zolpidem 6.25 mg for women and 6.25 12.5 mg once daily Recommended dose is 6.25 mg for the elderly extended release or 12.5 mg for men immediately and those with hepatic impairment. before bedtime Zolpidem tablets 5 mg for women and 10 mg once daily Recommended dose is 5 mg in the elderly 5 to 10 mg for men and debilitated, and those with hepatic immediately before bedtime impairment.

Suvorexant exposure is increased in obese patients blisters of 30.1 Availability of the nonbenzodiazepine compared with nonobese patients and in women sedative hypnotics are summarized in Table 5. compared with men. The potential for increased adverse effects should be considered, particularly in DRUG SAFETY/RISK EVALUATION AND MITIGATION 1 obese women, prior to increasing the dose. STRATEGY (REMS) When used with moderate CYP3A inhibitors, the No REMS was required for suvorexant approval recommended dose of suvorexant is 5 mg, and the and no postmarketing studies were required under dose generally should not exceed 10 mg. Use with the conditions of approval.25 strong CYP3A inhibitors is not recommended.1 Suvorexant is currently under DEA review to Comparative dosages for the nonbenzodiazepine determine its controlled substance status.25 sedative hypnotics are summarized in Table 4.

PRODUCT AVAILABILITY CONCLUSION Suvorexant received FDA approval on August Suvorexant is an orexin receptor antagonist 13, 2014.25 It is available as 5, 10, 15, and 20 mg that modestly reduced the TSO, increased TST, and film-coated tablets. The tablets should be stored in reduced WASO in patients with primary insomnia. It the original package until use in order to protect offers an additional option for the therapy of insom- from light and moisture. Suvorexant tablets should nia with a unique mechanism of action. Head-to-head be stored at room temperature (20°C to 25°C [68°F studies with other treatments are lacking. The long

to 77°F]), with excursions permitted to 15°C to 30°C half-life and delayed Tmax, as well as reports of day- (59°F to 86°F).1 Suvorexant is available in unit-of-use time sleepiness, next-day impairment, sleep paralysis,

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Table 5. Product availability for the nonbenzodiazepine sedative hypnotics1-7,25-27 How available Generic available Controlled substance Suvorexant Tablets: 5, 10, 15, 20 mg No Yes, decision by the DEA is pending Doxepin Tablets: 3, 6 mg No No Eszopiclone Tablets: 1, 2, 3 mg Yes Yes, CIV Ramelteon Tablets: 8 mg No No Zaleplon Capsules: 5, 10 mg Yes Yes, CIV Zolpidem Tablets: 5, 10 mg Tablets: yes Yes, CIV Sublingual tablets: 1.75, 3.5, 5, 10 mg Sublingual tablets: no Oral spray: 5 mg/actuation Oral spray: no Zolpidem Extended-release tablets: 6.25, 12.5 mg Yes Yes, CIV extended-release Note: CIV = Schedule IV; DEA = Drug Enforcement Administration.

hallucinations, and complex sleep behaviors within the 11. Sun H, Kennedy D, Lewis N, et al. The single dose phar- clinical trial setting are to be considered. Additional macokinetic (PK) and pharmacodynamic (PD) profiles of adverse effect data, particularly at the approved lower suvorexant (MK-4305), a dual orexin receptor antagonist, dose, are necessary to further define its place in therapy. in healthy male subjects [abstract]. Clin Pharmacol Ther. 2012;91(suppl 1):S29. REFERENCES 12. Herring WJ, Ma J, Snyder E, et al. EEG power spectral profile of the orexin receptor antagonist suvorexant (MK- 1. Belsomra (suvorexant) tablets [prescribing information]. 4305) in patients with primary insomnia and in healthy sub- Whitehouse Station, NJ: Merck & Co Inc; August 2014. jects [abstract]. Presented at: Sleep 2012: 26th Annual Meeting 2. Rozerem (ramelteon) tablets [prescribing information]. of the Associated Professional Sleep Societies; June 9-13, 2012; Deerfield, IL: Takeda Pharmaceuticals America Inc; Novem- Boston, MA. Abstract 0656. ber 2010. 13. Sun H, Kennedy WP, Wilbraham D, et al. Effects of 3. Lunesta (eszopiclone) tablets [prescribing information]. suvorexant, an orexin receptor antagonist, on sleep param- Marlborough, MA: Sunovion Pharmaceuticals Inc; May 2014. eters as measured by polysomnography in healthy men. Sleep. 2013;36(2):259-267. 4. Sonata (zaleplon) capsules [prescribing information]. New York: Pfizer Inc; May 2013. 14. Schutte-Rodin S, Broch L, Buysse D, Dorsey C, Sateia M. Clinical guideline for the evaluation and management of chronic 5. Ambien (zolpidem tartrate) tablets [prescribing informa- insomnia in adults. J Clin Sleep Med. 2008;4(5):487-504. tion]. Bridgewater, NJ: Sanofi-Aventis US LLC; July 2013. 15. Connor K, Budd K, Snavely D, et al. Efficacy and safety of 6. Ambien CR (zolpidem tartrate) extended-release tablets suvorexant, an orexin receptor antagonist, in patients with pri- [prescribing information]. Bridgewater, NJ: Sanofi-Aventis US mary insomnia: A 3-month phase 3 trial (trial #1) [abstract]. LLC; May 2013. ­J Sleep Res. 2012;21(suppl 1):97. 7. Silenor (doxepin) tablets [prescribing information]. San 16. Suvorexant (orexin receptor antagonist). Peripheral and Diego, CA: Somaxon Pharmaceuticals Inc; July 2010. Central Nervous System (PCNS) Advisory Committee brief- 8. Cox CD, Breslin MJ, Whitman DB, et al. Discovery of ing materials. US Food and Drug Administration Web site. the dual orexin receptor antagonist [(7R)-4-(5-chloro-1,3- http://www.fda.gov/downloads/AdvisoryCommittees/Commit- benzoxazol-2-yl)-7-methyl-1,4-diazepan-1-yl][5-methyl-2- teesMeetingMaterials/Drugs/PeripheralandCentralNervous- (2H-1,2,3-triazol-2-yl)phenyl]methanone (MK-4305) for the SystemDrugsAdvisoryCommittee/UCM352969.pdf. Published treatment of insomnia. J Med Chem. 2010;53(14):5320-5332. May 22, 2013. Accessed August 20, 2014. 9. Winrow CJ, Gotter AL, Cox CD, et al. Promotion of sleep 17. Ivgy-May N, Leibensperger H, Froman S, et al. Efficacy by suvorexant – A novel dual orexin receptor antagonist. J and safety of suvorexant, an orexin receptor antagonist, in Neurogenet. 2011;25(1-2):52-61. patients with primary insomnia: A 3-month phase 3 trial (trial #2) [abstract]. J Sleep Res. 2012;21(suppl 1):351-352. 10. Gatfield J, Brisbare-Roch C, Jenck F, Boss C. Orexin recep- tor antagonists: A new concept in CNS disorders? ChemMed- 18. Safety and efficacy study in primary insomnia patients – Chem. 2010;5(8):1197-1214. Study A (4305-028). ClinicalTrials.gov Web site. http://www.

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clinicaltrials.gov/ct2/show/NCT01097616?term=suvorexant&r 23. Herring WJ, Snyder E, Budd K, et al. Orexin receptor ank=1. Updated January 10, 2012. Accessed December 10, 2012. antagonism for treatment of insomnia: A randomized clinical trial of suvorexant. Neurology. 2012;79(23):2265-2274. 19. Michelson D, Snyder E, Paradis E, et al. Safety and effi- cacy of suvorexant during 1-year treatment of insomnia with 24. Vermeeren A, Vuurman E, Bautmans A, et al. Suvorex- subsequent abrupt treatment discontinuation: A phase 3 ran- ant, a dual orexin receptor antagonist, does not impair next domised, double-blind, placebo-controlled trial. Lancet Neurol. day driving performance in healthy elderly subjects [abstract]. 2014;13(5):461-471. Presented at: Sleep 2012: 26th Annual Meeting of the Asso- ciated Professional Sleep Societies; June 9-13, 2012; Boston, 20. Herring WJ, Snyder E, Paradis E, et al. Long term safety MA. Abstract 0670. and efficacy of suvorexant in patients with primary insomnia [abstract]. Presented at: Sleep. 2012: 26th Annual Meeting of 25. Unger EF. NDA approval letter: Suvorexant (NDA 204569). the Associated Professional Sleep Societies; June 9-13, 2012; US Food and Drug Administration Web site. http://www.access- Boston, MA. Abstract 0641. data.fda.gov/drugsatfda_docs/appletter/2014/204569Orig1s00 0rltr.pdf. Published August 13, 2014. Accessed August 14, 2014. 21. Herring WJ, Snyder E, Paradis E, et al. Suvorexant, an orexin receptor antagonist, in preventing symptom return 26. Sedatives and hypnotics, nonbarbiturate. Drug Facts in patients with insomnia after 1 year of treatment: A ran- and Comparisons. Facts & Comparisons [database online]. domised, double-blind, placebo-controlled study [abstract]. St. Louis, MO: Wolters Kluwer Health Inc; 2014. Accessed ­J Sleep Res. 2012;21(suppl 1):351. August 20, 2014. 22. Effects of MK-4305 (suvorexant) in patients with 27. Suvorexant. DailyMed: Current medication information. primary insomnia (MK-4305-032 AM3). ClinicalTri- US National Library of Medicine. nih.gov Web site. http://dai- als.gov Web site. http://www.clinicaltrials.gov/ct2/show/ lymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=e5b72731- NCT01021813?term=mk-4305&rank=3. Updated July 2, 1acb-45b7-9c13-290ad12d3951. Published August 2014. 2012. Accessed December 8, 2012. Accessed August 25, 2014. 

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Continuing Education Case Study Quiz

Goal—The goal of this activity is to educate pharmacists about the use of suvorexant for the treatment of patients with insomnia.

Objectives—At the completion of this activity, the reader will be able to: 1. Describe the pharmacology and pharmacokinetics of suvorexant. 2. Discuss the risks associated with the use of suvorexant. 3. Discuss the potential benefit of suvorexant for an individual patient. 4. Apply the information on the use of suvorexant to a case study.

Key Words—suvorexant, new drugs, insomnia, orexin receptor antagonist

This CE activity is co-sponsored • www.ProCE.com/HPJFDR by ProCE, Inc. and Hospital Pharmacy. • Click to access the activity page ProCE, Inc. is accredited by the Accredi- to enroll and complete the Post-Test tation Council for Pharmacy Education and Evaluation as a provider of continuing pharmacy education. ACPE Universal Activity For questions related to register- Number 0221-9999-15-001-H01-P has ing for and obtaining CE credit, contact ProCE at been assigned to this knowledge-based 630-540-2848 or [email protected]. home-study CE activity (initial release date 01-01-2015). This CE activity is approved for 1. The US Food and Drug Administration (FDA)- 1.5 contact hours (0.15 CEUs) in states that recog- approved indication for suvorexant is for the: nize ACPE providers. This CE activity is provided at a. Short-term treatment of insomnia character- no cost to participants. Completion of the evaluation ized by difficulties with sleep onset. and the post-test with a score of 70% or higher are b. Treatment of insomnia characterized by dif- required to receive CE credit. No partial credit will ficulties with sleep maintenance. be given. c. Short-term treatment of insomnia character- Faculty: Dennis J. Cada, PharmD, FASHP, FASCP ized by difficulties with sleep maintenance. (Editor), Founder and Contributing Editor, The For- d. Treatment of insomnia characterized by dif- mulary; Terri L. Levien, Pharm.D., Clinical Professor, ficulties with sleep onset and/or maintenance. College of Pharmacy, Washington State University; and Danial E. Baker, PharmD, FASHP, FASCP, Direc- 2. Suvorexant produces its sleep-promoting effects by: tor, Drug Information Center, and Professor of Phar- a. Binding the benzodiazepine receptor. macy Practice, College of Pharmacy, Washington State b. Antagonizing cholinergic receptors. University. The authors indicate no relationships that c. Binding the orexin-1 and orexin-2 receptors. could be perceived as a conflict of interest. This activ- d. Binding the . ity is self-funded by Hospital Pharmacy. Release Date: January 1, 2015 3. After oral administration of suvorexant, the time

Expiration Date: January 1, 2017 to maximum concentration (Tmax) and half-life Continuing Education for this activity is pro- (t1/2) are: cessed through the ProCE online CE Center. To a. 30 minutes, 7 hours. receive CE credit, please go to: b. 2 hours, 12 hours.

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c. 6 hours, 10 hours. 8. R.Q. should be educated about all of the fol- d. 6 hours, 14 hours. lowing effects which are warnings for the use of suvorexant EXCEPT: 4. Which of the following is a contraindication to a. Risk of withdrawal with abrupt discontinua- the use of suvorexant? tion. a. Concomitant fluvoxamine use b. Increased effects when taken with alcohol. b. Use of a monoamine oxidase inhibitor within c. Impaired next day wakefulness. 2 weeks d. Sleep paralysis. c. Narcolepsy d. Obstructive sleep apnea 9. What is the maximum approved dose for R.Q.? a. 5 mg daily 5. Suvorexant is in Pregnancy Category: b. 10 mg daily a. A. c. 15 mg daily b. B. d. 20 mg daily c. C. d. X. 10. Which medication in R.Q.’s profile has been reported to interact with suvorexant? Case History a. Fluconazole R.Q. is a 29-year-old female patient with b. Cephalexin insomnia refractory to previous treatments. She c. Both A and B reports trouble getting to sleep along with multiple d. Neither A nor B waking episodes during the night. Her previous insomnia treatments include , trazo- 11. Four weeks after starting treatment with 10 mg done, and zolpidem. Her medical history includes of suvorexant daily, R.Q. was diagnosed with a frequent urinary tract infections, for which she is urinary tract infection. Her treatment includes receiving cephalexin 250 mg daily. She has also ciprofloxacin for 3 days followed by 2 doses of received occasional fluconazole for treatment of fluconazole separated by 3 days. What dose of vaginal candidiasis, but is not currently receiving suvorexant would you recommend for her dur- antifungal treatment. She is a social drinker and ing her treatment? non-smoker. Her clinician has approached you a. Discontinue use of suvorexant about starting treatment with either suvorexant or b. Reduce dose to 5 mg daily ramelteon. c. Maintain her dose d. Increase her dose to 20 mg daily 6. How should R.Q. be counseled to take suvorexant? a. At least 1 hour prior to bedtime with a snack 12. The most common side effects associated with b. Within 30 minutes prior to bedtime on an suvorexant include: empty stomach a. Somnolence, headache, and dizziness. c. At least 10 hours prior to expected awaken- b. Headache, cough, and diarrhea. ing time c. Dry mouth, upper respiratory tract infec- d. Within 1 hour prior to bedtime on an empty tions, and headache. stomach d. Abnormal dreams, dizziness, and dry mouth.

7. What is the recommended initial dose of suvorex- 13. What characteristic of R.Q. would make you ant for R.Q.? less likely to use ramelteon? a. 5 mg a. Frequent urinary tract infections b. 10 mg b. Age less than 35 years c. 20 mg c. Frequent awakenings d. All are potential starting doses. d. Treatment refractory to trazodone

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14. What monitoring would you perform for R.Q.? 15. Suvorexant exposure is increased and a dosage a. Response and new onset depression or sui- adjustment may be recommended in each of the cidal ideation following types of patients EXCEPT: b. ALT/AST levels a. Obese patients. c. Serum creatinine b. Renal impairment. d. Complete blood count c. Female patients. d. Those receiving CYP3A inhibitors. 

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