Background

The American Academy of Sleep Medicine (AASM) guidelines for chronic insomnia recommend the use of short-intermediate acting benzodiazepine-receptor agonists, the melatonin receptor agonist ramelteon, sedating antidepressants if comorbid depression/anxiety, and other sedating agents when also needed for the medication's primary indication.¹ Over-the-counter antihistamines and herbal supplements are not recommended due to relative lack of efficacy and safety data. Since the publication of the AASM guideline in 2008, two new drugs have been approved by the FDA for sleep disorders: tasimelteon in January 2014 and suvorexant in August 2014.

Tasimelteon

Tasimelteon is a melatonin (MT₁/MT₂) receptor agonist that is indicated for Non-24-Hour Sleep-Wake Syndrome (Non-24), a disorder in which circadian rhythm becomes unsynchronized with the 24-hour day-night cycle.^2,3 Non-24 is most common in totally blind patients, with an estimated US prevalence of 65-95 thousand patients. Tasimelteon is dosed 20 mg prior to bedtime at the same time each night. Tasimelteon is an orphan drug with a wholesale acquisition cost (WAC) of $270/capsule.⁴ Cardiovascular side effects were not reported in tasimelteon clinical trials, and there are no documented significant drug interactions with common cardiology drugs. Given the rarity of Non-24, most cardiology practitioners are unlikely to encounter this drug.

Suvorexant Indication and Dosing

Suvorexant is a dual orexin (OX₁R/OX₂R) receptor antagonist (DORA) that is indicated for the treatment of insomnia characterized by difficulties with sleep onset and/or sleep maintenance.^5,6 Suvorexant comes in 5, 10, 15, and 20 mg tablets and is classified as a C-IV controlled substance. The recommended starting dose is 10 mg, taken no more than once per night and within 30 minutes of going to bed, with at least 7 hours remaining before planned awakening. If well-tolerated but ineffective, the dose may be increased to a maximum of 20 mg daily.

In patients taking concomitant moderate CYP3A inhibitors (e.g., diltiazem, verapamil), the starting dose is 5 mg daily and should not exceed 10 mg daily. It should not be used with strong CYP3A inhibitors (e.g., ritonavir). Because suvorexant concentration is increased in women vs. men (5% higher nine hours after dosing) and increased in obese vs. non-obese patients (15% higher nine hours after dosing), obese females may need to have a lower maximum dose due to a 46% increase in exposure compared to non-obese females.

If taken with or soon after a meal, the onset time of suvorexant may be delayed.

Suvorexant Pharmacology

Orexigenic neurons are located in the lateral hypothalamic area and are a central promoter of wakefulness.^5,7 Suvorexant blocks the wake-promoting neuropeptides orexin A and orexin B from binding to OX₁R and OX₂R receptors, inhibiting activation of wake-promoting neurons and facilitating the transition from an awake to a sleep state.

Orexin antagonism may also increase the risk of narcolepsy/cataplexy adverse effects, since orexin genetic mutations in animals result in hereditary narcolepsy, and human narcolepsy is associated with orexin deficiency.

Animal studies have indicated that orexin is involved in cardiovascular regulation.^8,9 Intrathecal injections of exogenous orexin A in rats led to dose-dependent increase in arterial blood pressure and heart rate, with attenuation of effects upon administration of an orexin antagonist. Orexin knock out mice had lower resting blood pressure and did not have increased blood pressure in response to social stress but maintained a cardiovascular response to physical stress. In humans, there have been conflicting reports of increased or decreased sympathetic tone in patients with narcolepsy.¹⁰

Suvorexant Efficacy

The evidence which led to FDA approval came from two three-month randomized, double-blind, placebo-controlled, parallel-group Phase 3 trials in non-elderly (18-64 years) and elderly (≥65 years) patients with primary insomnia, and one two-period (four weeks per period) randomized, double-blind, placebo-controlled crossover Phase 2b study in non-elderly patients with primary insomnia.^5,7,11,12

In the two similar Phase 3 trials (Trial 1 N=1021, Trial 2 N=1009), the primary efficacy endpoints were powered for the higher 40/30 mg doses (non-elderly/elderly), rather than the lower 20/15 mg doses (non-elderly/elderly).^7,11 While there were significant differences between suvorexant and placebo in all primary endpoints with the higher doses, the FDA did not approve the 30 mg and 40 mg doses due to concerns about dose-dependent side effects such as excessive daytime sleepiness (EDS).⁷ The lower doses had variably significant or non-significant differences in the primary endpoints between suvorexant and placebo as shown in Table 1, but the FDA concluded that a lack of significant difference did not prove lack of efficacy because the trials were underpowered for the lower doses. For problems with sleep onset, suvorexant 20/15 mg decreased the time it took for patients to fall asleep by 0.3-12 minutes (LPS) or by 5-8 minutes (sTSO). For problems with sleep maintenance, suvorexant 20/15 mg decreased the amount of time a patient stayed awake after night-time awakening by 17-37 minutes (WASO) and increased the amount of time patients felt they had slept by 11-22 minutes (sTST).

Table 1: Results from Phase 3 Suvorexant Trials of Suvorexant 20/15 mg vs. Placebo¹¹

Sleep Disturbance	Endpoint	Assessment Method	Trial 1	Trial 2
			Difference Between Suvorexant 20/15 mg vs. Placebo (min)
Sleep onset	Latency to onset of persistent sleep (LPS)	Polysomnography (objective)	Week 1: -9.6 Month 1: -10.3* Month 3: -8.1	Week 1: -12.4 Month 1: -7.8 Month 3: -0.3
	Subjective time to sleep onset (sTSO)	Sleep diary (subjective)	Week 1: -5.6 Month 1: -5.4 Month 3: -5.2	Week 1: -7.5 Month 1: -6.9 Month 3: -7.6
Sleep maintenance	Wakefulness after persistent sleep onset (WASO)	Polysomnography (objective)	Week 1: -32.5* Month 1: -26.4* Month 3: -16.6*	Week 1: -37.0 Month 1: -24.1 Month 3: -31.1
	Subjective total sleep time (sTST)	Sleep diary (subjective)	Week 1: 13.6* Month 1: 16.3* Month 3: 10.7†	Week 1: 16.8 Month 1: 20.9 Month 3: 22.1

In the Phase 2b dose-ranging (suvorexant 10, 20, 40, 80 mg) polysomnography study (N=254), all doses significantly decreased wakefulness after persistent sleep onset (WASO, a sleep maintenance measure) by 21-37 minutes the first night and 21-33 minutes at week 4.¹² While the 40 mg and 80 mg doses also improved latency to onset of persistent sleep (LPS, a sleep onset measure), the 10 mg and 20 mg doses did not. However, the trial was underpowered to measure this.⁷ Of note, this was the only trial which assessed the 10 mg dose and no trial assessed the 5 mg dose. The FDA stated this trial "provided a suggestion of efficacy for the 10 mg dose," and used further post hoc and pharmacokinetic analyses to determine that the 10 mg dose was reasonable to use as a starting dose while minimizing dose-related adverse effects.

Suvorexant efficacy was comparable to results reported in zolpidem ER 12.5 mg trials: LPS 6 minutes, WASO -3 to -11 minutes, sTST 13-15 minutes.⁷ Overall, the FDA concluded the data showed clear evidence of suvorexant efficacy in sleep maintenance and weaker evidence for efficacy in sleep onset, particularly at the lower doses.

Suvorexant Safety

The most common adverse effect in trials was dose-dependent somnolence (suvorexant 7% vs. 3% placebo).⁵ Other side effects included headache, abnormal dreams, dry mouth, cough, and upper respiratory tract infection.

Suvorexant is a central nervous system depressant that may cause next-day impairment, cognitive and behavioral changes, complex behaviors associated with amnesia (e.g., "sleep-driving"), dose-dependent increase in suicidal ideation, sleep paralysis, and hypnagogic/hypnopompic hallucinations (vivid perceptual experiences during sleep onset/awakening). In addition, cataplexy-like symptoms (e.g., leg weakness) were also reported. The drug is contraindicated in patients with narcolepsy.

Of concern to the FDA was dose-dependent increase in EDS.⁷ Suvorexant may cause a rapid switch from wakefulness to sleep while driving (microsleep episodes), increasing the risk of complete loss of vehicle control even more so than a drug like zolpidem. Because suvorexant has a long half-life (12 hours), EDS symptoms could continue for several days after drug discontinuation.

As with the benzodiazepine-receptor agonists, suvorexant has a warning regarding abuse potential (although patients with a history of substance abuse were excluded from the trials).^5,7 The FDA analysis did not find withdrawal symptoms upon abrupt suvorexant discontinuation, but data suggested rebound insomnia may occur.

Suvorexant in the Context of Cardiovascular Disease (CVD)

Although suvorexant is unlikely to increase blood pressure or heart rate given what is known about orexin pharmacology, it is unknown if suvorexant has adverse effects in CVD because patients with recent or significant CVD were excluded from the trials: acute coronary syndrome, unstable angina, congestive heart failure, cardiogenic syncope, cardiomyopathy, and any symptomatic arrhythmia.⁷

Suvorexant did not cause clinically significant prolongation of QTc.⁵ In a randomized trial (N=53), the placebo-adjusted difference for QTc remained under 10 ms with suvorexant doses up to 240 mg.

In the dose-ranging Phase 2b trial, suvorexant caused dose-dependent increases in cholesterol, but the increases seen in the approved doses (10, 20 mg) were clinically negligible (1-2 mg/dL).⁵

Suvorexant is mainly metabolized by CYP3A.⁵ CVD patients on the moderate CYP3A inhibitors diltiazem or verapamil should be started on the suvorexant 5 mg dose and not exceed 10 mg, because diltiazem was found to double suvorexant drug levels. Suvorexant also inhibits intestinal P-gp and increased digoxin concentrations by approximately 25%. Although digoxin dose does not need to be adjusted, monitoring of digoxin levels is recommended with suvorexant coadministration. Suvorexant did not significantly impact warfarin exposure, although because suvorexant also inhibits CYP3A, monitoring INR is advised since anticoagulant use was excluded from clinical trials.

Conclusion

Tasimelteon is an expensive orphan drug for a rare disease state that most cardiology practitioners are unlikely to see in practice. It is not expected to cause significant pharmacokinetic/pharmacodynamic concerns if used in a CVD patient.

Suvorexant does not offer significant efficacy or safety advantages vs. newer benzodiazepine-receptor agonists like zolpidem, and costs significantly more (Table 2). Its efficacy and safety in CVD patients is unknown, although patients on interacting drugs (diltiazem, verapamil) would need lower suvorexant doses or additional monitoring (digoxin, warfarin).

Table 2: Selected Prescription Drugs Used For Insomnia^4,13-28

Drug	Dose	Price*	Comments Relevant to CVD
Benzodiazepine-Receptor Agonist: Benzodiazepine
Temazepam capsule	Adult: 7.5-30 mg PO QHS Elderly: 7.5-30 mg PO QHS (initial dose 7.5 mg PO QHS)	$6.96/7.5 mg $0.09/15 mg $6.96/22.5 mg $0.12/30 mg	No significant drug interactions with common CVD drugs CV adverse effects, 0.5-0.9%: dyspnea, palpitations
Benzodiazepine-Receptor Agonists: Nonbenzodiazepine Hypnotics
Eszopiclone tablet	Adult: 1-3 mg PO QHS Elderly: 1-2 mg PO QHS (Initial dose 1 mg PO QHS in all patients)	$0.70/1 mg $0.70/2 mg $0.70/3 mg	Metabolized by CYP3A; monitor for increased sedation if taking moderate CYP3A inhibitors diltiazem/verapamil CV adverse effects, 0.1-0.9%: hypertension
Zaleplon capsule	Adult: 10-20 mg PO QHS Elderly: 5-10 mg PO QHS	$0.40/5 mg $0.42/10 mg	No significant drug interactions with common CVD drugs CV adverse effects, 0.1-0.9%: angina, bundle branch block, hypertension, hypotension, palpitation, syncope, tachycardia, vasodilitation
Zolpidem tablet	Adult: 5-10 mg PO QHS (Women: Initial dose 5 mg PO QHS) Elderly: 5 mg PO QHS	$0.08/5 mg $0.08/10 mg	Metabolized by CYP3A; monitor for increased sedation if taking moderate CYP3A inhibitors diltiazem/verapamil Palpitations: zolpidem 2% vs. placebo 0%
Zolpidem extended-release tablet	Adult: 6.25-12.5 mg PO QHS (Women: Initial dose 6.25 mg PO QHS) Elderly: 6.25 mg PO QHS	$4.69/6.25 mg $4.69/12.5 mg
Dual Orexin-Receptor Antagonist
Suvorexant tablet	Adult: 10-20 mg PO QHS Elderly: 10-20 mg PO QHS On moderate CYP3A inhibitor: 5-10 mg PO QHS	$8.77/5 mg $8.77/10 mg $8.77/15 mg $8.77/20 mg	Metabolized by CYP3A; use 5 mg starting dose and 10 mg max if taking moderate CYP3A inhibitors diltiazem/verapamil Monitor digoxin/INR levels if on concomitant digoxin/warfarin
Melatonin-Receptor Agonist
Ramelteon tablet	Adult: 8 mg PO QHS Elderly: 8 mg PO QHS	$9.28 mg/8 mg	No significant drug interactions with common CVD drugs No CV side effects reported in package insert label or in PubMed
Sedating Antidepressants
Doxepin capsule	Off-label use Adult: 10-50 mg PO QHS Elderly: 10-50 mg PO QHS (initial dose 10 mg PO QHS)	$0.41/10 mg $0.54/25 mg $0.77/50 mg	Metabolized by CYP2D6; quinidine may increase risk of QTc prolongation (although doxepin 6 and 50 mg doses alone unlikely to increase QTc based on trial data) Dose-related CV adverse effects: hypotension, hypertension, tachycardia, palpitations
Doxepin tablet	Adult: 6 mg PO QHS Elderly: 3-6 mg PO QHS	$9.99/3 mg $9.99/6 mg
Doxepin 10 mg/mL solution	Off-label use Adult: 6 mg PO QHS Elderly: 3-6 mg PO QHS	$0.03/3 mg $0.06/6 mg
Mirtazapine tablet	Off-label use Adult: 15 mg PO QHS Elderly: 15 mg PO QHS	$0.30/15 mg	Increased cholesterol ≥20% above upper limit of normal: mirtazapine 15% vs. placebo 7%; increased triglycerides ≥500 mg/dL: mirtazapine 6% vs. placebo 3% May increase INR slightly (mirtazapine 30 mg ↑ INR by 0.2) May decrease efficacy of clonidine
Trazodone tablet	Off-label use Adult: 50-150 mg PO QHS Elderly: 25-150 mg PO QHS (initial dose 25 mg PO QHS)	$0.05/50 mg $0.07/100 mg $0.18/150 mg	Metabolized by CYP3A; monitor for increased side effects if taking moderate CYP3A inhibitors diltiazem/verapamil Increases QTc, may be arrhythmogenic in patients with CVD, not recommended during initial recovery after MI Other CV adverse effects: hypertension, hypotension, orthostatic hypotension, syncope

References

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4. Red Book Online. Truven Health Analytics Inc. 2015. Available at http://www.micromedexsolutions.com/home/dispatch . Last accessed 2015 May 6.
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7. FDA Center for Drug Evaluation and Research. Application number 204569Orig1s000. Medical Review(s). Available at: http://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/204569Orig1s000MedR.pdf. Last accessed 2015 Apr 29.
8. Carrive P. Orexin, orexin receptor antagonists and central cardiovascular control. Front Neurosci 2013;7:257.
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11. Herring WJ, Connor KM, Ivgy-May N, et al. Suvorexant in Patients with Insomnia: Results from Two 3-Month Randomized Controlled Clinical Trials. Biol Psychiatry 2014; S0006-3223:00762-8.
12. Herring WJ, Snyder E, Budd K, et al. Orexin receptor antagonism for treatment of insomnia: a randomized clinical trial of suvorexant. Neurology 2012;79:2265-74.
13. PL Detail-Document, Comparison of Insomnia Treatments. Pharmacist's Letter/Prescriber's Letter. July 2014 (last modified January 2015). Available at: http://pharmacistsletter.therapeuticresearch.com/pl/ArticleDD.aspx?nidchk=1&cs=PLNOPT_NDALL&s=PL&pt=2&fpt=31&dd=310211&pb=PL&searchid=51485212&segment=8092. Last accessed 2015 May 3.
14. CredibleMeds [QTc drug lists]. https://crediblemeds.org/ Last accessed 2015 May 3.
15. Drug Interations Database. Lexicomp Online. 2015. Available at http://www.crlonline.com/lco/action/home. Last accessed 2015 May 5.
16. Temazepam [package insert]. Hazelwood, MO; Mallinckrodt, Inc.; Revised March 2013.
17. Eszopiclone [package insert]. Sellersville, PA; Teva Pharmaceuticals, Inc.; Revised May 2014.
18. Zaleplon [package insert]. Morgantown, WV; Mylan Pharmaceuticals Inc.; Revised October 2013.
19. Zolpidem tartrate tablet [package insert]. Princeton, NJ; Sandoz, Inc.; Revised October 2014.
20. Zolpidem tartrate extended-release tablet [package insert]. Princeton, NJ; Sandoz, Inc.; Revised January 2015.
21. ROZEREM (ramelteon) [package insert]. Deerfield, IL; Takeda Pharmaceuticals America Inc.; Revised November 2010.
22. Doxepin hydrochloride capsules [package insert]. Morgantown, WV; Mylan Pharmaceuticals Inc.; Revised December 2012.
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24. Mansbach RS, Ludington E, Rogowski R, et al. A placebo- and active-controlled assessment of 6- and 50-mg oral doxepin on cardiac repolarization in healthy volunteers: a thorough QT evaluation. Clin Ther. 2011 Jul;33(7):851-62.
25. Doxepin hydrochloride solution [package insert]. Sellersville, PA; Teva Pharmaceuticals USA; Revised May 2014.
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27. REMERON (mirtazapine) [package insert]. Whitehouse Station, NJ; Organon (Merck & Co, Inc.); Revised August 2014.
28. Trazodone hydrochloride [package insert]. Huntsville, AL; Qualitest Pharmaceuticals; Revised July 2014.

Keywords: Acetamides, Acute Coronary Syndrome, Aged, Amnesia, Angina, Unstable, Anticoagulants, Antidepressive Agents, Anxiety, Azabicyclo Compounds, Azepines, Benzodiazepines, Benzofurans, Blood Pressure, Bundle-Branch Block, Cardiomyopathies, Cardiovascular Agents, Cataplexy, Cholesterol, Circadian Rhythm, Clonidine, Cognition, Controlled Substances, Cytochrome P-450 CYP2D6, Cytochrome P-450 CYP3A, Depression, Digoxin, Diltiazem, Double-Blind Method, Doxepin, Drug Interactions, Dyspnea, Half-Life, Hallucinations, Heart Failure, Heart Rate, Histamine Antagonists, Hypertension, Hypnotics and Sedatives, Hypotension, Orthostatic, Hypothalamic Area, Lateral, Indenes, Injections, Spinal, International Normalized Ratio, Intracellular Signaling Peptides and Proteins, Melatonin, Mianserin, Mutation, Narcolepsy, Neurons, Neuropeptides, Off-Label Use, Orphan Drug Production, ATP Binding Cassette Transporter, Subfamily B, Member 1, Pharmaceutical Preparations, Piperazines, Polysomnography, Prescription Drugs, Prevalence, Product Labeling, Pyridines, Pyrimidines, Quinidine, Rare Diseases, Receptors, GABA-A, Receptors, Melatonin, Respiratory Tract Infections, Ritonavir, Sleep Wake Disorders, Sleep Initiation and Maintenance Disorders, Sleep Paralysis, Substance Withdrawal Syndrome, Substance-Related Disorders, Suicidal Ideation, Syncope, Tablets, Tachycardia, Temazepam, Trazodone, Triazoles, Triglycerides, Verapamil, Wakefulness, Warfarin, Sleep Apnea Syndromes

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