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12:50 – 1:50 PM Disclosures This session is supported by an independent educational grant from Eisai Inc. Managing Sleep Maintenance in Older Adults The following relationships exist related to this presentation: ► Russell P. Rosenberg, PhD: Advisory Board for Harmony Biosciences, LLC and Jazz Pharmaceuticals, Inc. Consultant for Bose Corporation and Eisai Inc. Contracted Research for SPEAKER Eisai Inc.; Fitbit, Inc.; Idorsia Pharmaceuticals Ltd; Johnson & Johnson; and Merck & Co., Inc. Russell P. Rosenberg, PhD Services Provided for Promotional Purposes (not for CME/CE Services) for Jazz Pharmaceuticals, Inc.

Off-Label/Investigational Discussion ► In accordance with pmiCME policy, faculty have been asked to disclose discussion of unlabeled or unapproved use(s) of drugs or devices during the course of their presentations.

ASK QUESTIONS USING OUR NEW SOCIAL Q&A FEATURE! Learning Objectives Navigate to www.midwest.cnf.io • Describe current challenges associated with managing sleep maintenance insomnia, especially in older and elderly patients • Utilize currently available and emerging treatments to manage sleep Ask a maintenance insomnia, including those that avoid residual next-day Question effects, especially in older and elderly populations

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Syllabi/slides for this program are a supplement to the live CME session and are not intended for other purposes. Agenda

• Defining insomnia • Impact of sleep maintenance insomnia • Sleep maintenance insomnia: • Current management approaches and unmet needs in older adults • Novel and emerging agents • Practical management approaches Pre-Activity

Little Difference in Diagnostic Criteria

DSM-5 Diagnostic Criteria ICSD-3 Diagnostic Criteria

A. A predominant complaint of dissatisfaction with sleep quantity or A. The patient reports, or the caregiver observes, one or more of the quality, associated with one (or more) of the following symptoms: following: 1. Difficulty initiating sleep 1. Difficulty initiating sleep 2. Difficulty maintaining sleep – frequent awakenings or problems 2. Difficulty maintaining sleep returning to sleep after awakenings 3. Waking earlier than desired 3. Early-morning awakening with inability to return to sleep 4. Resistance to going to bed on appropriate schedule B. Causes clinically significant distress or impairment in social, 5. Difficulty sleeping without parent or caregiver intervention occupational, educational, academic, behavioral, or other important B. The patient reports, or the caregiver observes, one or more of the areas of functioning following related to nighttime sleep difficulty: C. Occurs at least 3 nights per week 1. Fatigue/malaise D. Present for at least 3 months 2. Attention, concentration, or memory impairment E. Occurs despite adequate opportunity for sleep 3. Impaired social, family, occupational, or academic performance Defining Insomnia F. Not better explained by/does not occur exclusively during the course of 4. Mood disturbance/irritability another sleep-wake disorder (eg, narcolepsy, a breathing-related sleep 5. Daytime sleepiness disorder, a circadian rhythm sleep-wake disorder, a parasomnia) 6. Behavioral problems (eg, hyperactivity, impulsivity, aggression) G. Not due to coexisting mental disorders and medical conditions 7. Reduced motivation, energy, initiative H. Not attributable to the physiological effects of a substance (eg, a drug 8. Proneness for errors/accidents of abuse, a medication) 9. Concerns about dissatisfaction with sleep C. Cannot be explained purely by inadequate opportunity or inadequate circumstances for sleep American Psychiatric Association. (2013). Diagnostic and statistical D. Occur at least 3 times per week manual of mental disorders (5th ed.); World Health Organization. (1992).; E. Present for at least 3 months American Academy of Sleep Medicine (2014). The International F. Cannot be explained by another sleep disorder Classification of Sleep Disorders, Third Edition (ICSD-3).

Syllabi/slides for this program are a supplement to the live CME session and are not intended for other purposes. Insomnia Occurs When the Wake-sleep Insomnia is Characterized by Problems in Circuit is Disrupted Initiating and Maintaining Sleep Integrated Factors Sleep onset insomnia Sleep maintenance insomnia Homeostatic Drive • Difficulty falling asleep • Difficulty staying asleep and/or Circadian Rhythms • More common in younger difficulty getting back to sleep adults after middle-of-the-night waking Allostatic Signaling • More common in older/elderly Sleep Wake adults

• Early morning awakening GABA Orexin galanin Activates Inhibit wake- wake- promoting promoting neurons neurons

Fiorentino L, et al. J Clin Psychol. 2010;66(11):1161-1174. Saper CB, et al. Nature, 2005;437(7063):1257-1263.

Sleep-wake Circuit Pathophysiology

Ventrolateral Upper pons Locus coeruleus Hypothalamus preoptic nucleus pedunculopontine How do I identify patients with laterodorsal Acetylcholine tegmental nuclei Dopamine insomnia and does pattern GABA Histamine Orexin galanin Norepinephrine matter? Acetylcholine Serotonin

Hypothalamus Thalamus Cerebral Cortex Brain Stem Cerebral Cortex Which ones might also have Sleep Wake OSA?

Saper CB, et al. Nature, 2005;437(7063):1257-1263.

Syllabi/slides for this program are a supplement to the live CME session and are not intended for other purposes. Prevalence of Insomnia and Psychiatric Comorbidity Insomnia and Its Related Symptoms Across Four Primary Diagnoses • Population- and clinic- • 98% of elderly individuals • 62% of individuals with based studies: high rates of with symptoms of sleep maintenance • 400 treatment-seeking outpatients psychiatric comorbidities in depression or anxiety had insomnia also had a • Depressive, bipolar affective, anxiety, and schizophrenia spectrum patients with chronic impaired sleep psychiatric comorbidity disorders insomnia • Anxiety more frequently • Depression (50%) • Early waking and associated with waking-up • GAD (23%) • DSM-5 Insomnia by Brief Insomnia Questionnaire hypersomnia was during the night • SAD (14%) associated with a 2- to • 31.8% had DSM-5 insomnia disorder 3-fold increased risk of • Panic disorder (12%) bipolar disorder

Insomnia and psychiatric Sleep maintenance insomnia Insomnia and psychiatric comorbidities are common in commonly occurs with comorbidities are common1-4 the elderly5 depression or anxiety6

GAD, generalized anxiety disorder; SAD, social anxiety disorder 1. Ohayon MM, et al. J Psychiatr Res. 2003;37(1):9-15. 2. Breslau N, et al. Biol Psychiatry. 1996;39(6):411-418. 3. Chang PP, et al. Am J Epidemiol. 1997;146(2):105-114. 4. Geoffroy PA, et al. J Affect Disord. 2018;226:132-141. 5. Press Y, et al. Aging Clin Exp Res. Seow LSE, et al. J Clin Sleep Med. 2018;14(2):237-244. 2018;30(7):755-765. 6. Bolge SC, et al. Popul Health Manag. 2010;13(1):15-20.

Significant Impact of Insomnia in the Elderly

• 93.9% reported difficulty • Increased risk of falls • More emergency room staying asleep visits • Decreased EQ-5D scores • 65.1% reported early • More provider visits morning awakenings • Impaired functional status • More days hospitalized • 68.9% reported difficulty • Impaired cognitive falling asleep function Impact of Sleep • Wake after sleep onset Maintenance Insomnia 62.5 ± 41.5 min

Quality of Life and Health-system Sleep Quality1 Functioning2-7 Burden8

1. Sidani S, et al. Clin Nurs Res. 2018 Oct 15. [Epub ahead of print] 2. Ensrud KE, et al. J Am Geriatr Soc. 2009;57(11):2085-2093. 3. Stone KL, et al. J Am Geriatr Soc. 2014;62(2):299-305. 4. Stone KL, et al. Arch Intern Med. 2008;168(16):1768-1775. 5. Lubetkin EI, et al. Sleep Health. 2018;4(2):182-187. 6. Spira AP, et al. J Gerontol Series B Psychol Sci Social Sci. 2014;69(Suppl 1):S35-S41. 7. Bernstein JPK, et al. Neuropschology. 2018;32(2):220-229. 8. Bolge SC, et al. Popul Health Manag. 2010;13(1):15-20.

Syllabi/slides for this program are a supplement to the live CME session and are not intended for other purposes. Comorbid Conditions Can Contribute to or Challenges to Treating Insomnia in the Elderly Worsen Because of Insomnia Lack of treatments to manage sleep maintenance insomnia 1 Mood without undue daytime consequences and adverse events Disorders Physical Dementia Disability Elderly patients more likely to have impaired drug metabolism2 Restless CV Disease Legs Syndrome Elderly patients more likely to be on multiple medications that may interact with currently available insomnia treatments2

Snoring/ Pain Insomnia Apnea Elderly patients are more prone to accidents due to sleep medications and hypersomnolence2

Adapted from: Gulia KK, et al. Psychogeriatrics. 2018;18(3):155-165. 1. Bolge SC, et al. Popul Health Manag. 2010;13(1):15-20. 2. Gooneratne NS, et al. Clin Geriatr Med. 2014;30(3):591-627. Image: www.presentationgo.com.

For sleep maintenance insomnia, which treatment(s) Current Management do I try first and why? Approaches for Sleep Maintenance Insomnia

Syllabi/slides for this program are a supplement to the live CME session and are not intended for other purposes. Components of Cognitive Behavioral Using Brief CBTi in Primary Care Therapy (CBT-I)

• Sleep hygiene: essential but not effective alone • Start with review of sleep hygiene • Cognitive therapy • Common sense recommendations-usual suspects • Stimulus control • Avoid light (computer/phone screens) • Sleep restriction • Don’t watch the clock • No news is good news • Relaxation/mindfulness therapies. (calm.com) • Morning exercise • Stimulus Control: associate the bed with sleep Delivery Systems • Get out of bed after about 15 minutes • Mental health specialists • Try again when sleepy or about 20 minutes • Nurses and PAs • Repeat • Online options (sleepio, shuti) Manber R, et al. Sleep. 2008;31(4):489-495.

Current Landscape for Pharmacologic Treatment of Insomnia What if my patient cannot adhere to CBTi • • Non-benzodiazepines or just wants a medication for sleep • Atypical maintenance insomnia? • Sedating • Orexin antagonists • OTCs • Herbal remedies

OTCs, over the counter medications

Syllabi/slides for this program are a supplement to the live CME session and are not intended for other purposes. Over-the-Counter Agents for the Treatment of Occasional Disturbed Sleep or Transient Insomnia 2019 Beers Criteria – American Geriatrics Society

Benzodiazepines • H1 antagonists or AVOID MODERATE EVIDENCE STRONG RECOMENDATION • Short & intermediate acting: Older adults have increased sensitivity to benzodiazepines and decreased metabolism , , , of long-acting agents; in general, all benzodiazepines increase risk of • or valerian/hops , , cognitive impairment, delirium, falls, fractures, and motor vehicle crashes in older adults Long-acting: , (alone or in May be appropriate for seizure disorders, rapid eye movement sleep disorders, Review of the literature: January 2003 to July 2014 combination with or clidinium), withdrawal, ethanol withdrawal, severe generalized anxiety disorder, , , , and periprocedural anesthesia • A review of randomized controlled studies over the past 12 years suggests commonly used OTC sleep-aid agents, especially and Non-benzodiazepines and Benzodiazepine Receptor Agonist valerian, lack robust clinical evidence supporting efficacy and safety. AVOID MODERATE EVIDENCE STRONG RECOMENDATION , , Benzodiazepine receptor agonists have adverse events similar to those of benzodiazepines in older adults (eg, delirium, falls, fractures); increased emergency department visits and hospitalizations; motor vehicle crashes; minimal improvement in sleep latency and duration

Culpepper L, et al. Prim Care Companion CNS Disord. 2015;17(6):eCollection 2015. American Geriatrics Society 2019 Beers Criteria Update Expert Panel. J Am Geriatr Soc. 2019;64(4):674-694.

Recommended Treatments for Insomnia – AASM Guidelines 2017 No Differences Between Tiagabine Eszopiclone Benzodiazepines and Zaleplon Valerian Zolpidem Diphenhydramine Temazepam Non-benzodiazepines on Risk of Triazolam Melatonin Trazadone Adverse Events in Elderly Patients Tryptophan

Recommended for Recommended for Recommended sleep onset or sleep onset sleep maintenance Not recommended maintenance insomnia insomnia insomnia

Sateia MJ, et al. J Clin Sleep Med. 2017;13(2):307-349.

Syllabi/slides for this program are a supplement to the live CME session and are not intended for other purposes. Dual Antagonists (DORAs)

In vitro binding assays suggest that:2 Suvorexant and Suvorexant  Novel and Emerging Blocking orexin * affinity for orexin-1 receptors is thought selectively and receptor Agents for Sleep to suppress wake competitively bind Lemborexant  1 drive to orexin-1 and affinity for orexin-2 Maintenance Insomnia orexin-2 receptors receptor

Clinical Effects Receptor Binding Receptor Affinity 1. Bennett T, et al. P T. 2014;39(4):264-266. 2. Beuckmann CT, et al. J Pharmacol Exp Ther. 2017;362(2):287-295. *Lemborexant is currently under FDA review for the treatment of insomnia. A Prescription Drug User Fee Act date is set for December 27, 2019.

Sleep Onset – Polysomnography Latency to Sleep Maintenance – Polysomnography Wake Onset of Persistent Sleep After Sleep Onset Suvorexant – Pooled Analysis of Phase 3 Studies1 Lemborexant SUNRISE-12 Suvorexant – Pooled Analysis of Phase 3 Studies1 Lemborexant SUNRISE-12

10 10 0 0 NIGHT 1 MONTH 1 MONTH 3 NIGHTS 1/2 NIGHTS 29/30 5 -10 5 -10 P<.05 vs PBO

0 P<.001 -20 P<.01 vs PBO 0 -20 P<.001 NIGHT 1 MONTH 1 MONTH 3 NIGHTS 1/2 NIGHTS 29/30 P<.01 vs PBO P<.05 vs PBO P=NS P=NS -5 -30 -5 P<.01 vs PBO -30 P<.001 P<.01 vs PBO P<.01 P<.001 -10 -40 P<.01 vs PBO P<.005 P<.05 vs PBO P<.001 -10 P<.005 P<.05 vs PBO -40 -15 -50 -15 -50 P<.01 vs PBO P<.001 -20 P<.001 -60 -20 -60 Suvorexant 15 mg Suvorexant 30 mg Lemborexant 5 mg Lemborexant 10 mg Zolpidem 6.25 mg Suvorexant 15 mg Suvorexant 30 mg Lemborexant 5 mg Lemborexant 10 mg Zolpidem 6.25 mg

Difference between DORA and placebo or zolpidem in least squares mean change from baseline in Difference between DORA and placebo or zolpidem in least squares mean change from baseline in elderly patients (≥65 years) with insomnia elderly patients (≥65 years) with insomnia

1. Herring WJ, et al. Am J Geriatr Psychiatry. 2017;25(7):791-802. 2. Rosenberg R, et al. Presented at 24th Congress of the European 1. Herring WJ, et al. Am J Geriatr Psychiatry. 2017;25(7):791-802. 2. Rosenberg R, et al. Presented at 24th Congress of the Sleep Research Society, 25-28 September 2018, Basel Switzerland. P163. European Sleep Research Society, 25-28 September 2018, Basel Switzerland. P163.

Syllabi/slides for this program are a supplement to the live CME session and are not intended for other purposes. Sleep Maintenance – Polysomnography Wake Most Common AEs in Elderly Subjects: >3% of After Sleep Onset in the Second Half of the Night Elderly Subjects in Any Active Treatment Group

Lemborexant SUNRISE-11 Pooled Analysis of 0 SUNRISE-1 NIGHTS 1/2 NIGHTS 29/30 Phase 3 Studies Suvorexant Suvorexant Lemborexant Lemborexant -10 P<.05 vs PBO Placebo Zolpidem Placebo 15 mg 30 mg 5 mg 10 mg P<.01 vs PBO -20 Headache 6.9% 5.6% 3.2% 4.1% 2.6% 3.4% 4.3% P <0.01 vsP <.01PBO vs PBO -30 Somnolence 5.4% 8.8% 3.2% 2.6% 3.7% 1.1% 1.0% P<.01 vs PBO -40 P<.01 vs PBO Nasopharyngitis 3.5% 2.9% 4.1% — — — — Fatigue 1.5% 3.8% 1.7% — — — — -50 P<.01 vs PBO Upper respiratory 3.0% 2.6% 1.3% — — — — -60 tract infection Lemborexant 5 mg Lemborexant 10 mg Zolpidem 6.25 mg Dizziness 4.0% 2.2% 4.9% — ——— Diarrhea 4.0% 2.2% 1.5% — — — Difference between DORA and placebo or zolpidem in least squares mean change from baseline in elderly patients (≥65 years) with insomnia AEs, adverse events 1. Rosenberg R, et al. Presented at 24th Congress of the European Sleep Research Society, 25-28 September 2018, Basel Switzerland. 1. Herring JW, et al. Am J Geriatr Psychiatry. 2017;25(7):791-802. 2. Rosenberg R, et al. Presented at 24th Congress of the P163. European Sleep Research Society, 25-28 September 2018, Basel Switzerland. P163.

On-road Driving Performance for Postural Instability in Elderly Patients Elderly Individuals

• Three studies using 20 and 40 mg doses showed no significant effects on memory or balance versus placebo • In 2 placebo-controlled studies that evaluated • Study of healthy non-elderly subjects the effects of nighttime administration of • 20 mg resulted in significant body sway versus • Immediately upon awakening: suvorexant on next-morning driving performance • Results of the present study show no statistically placebo • Body sway for lemborexant 5 mg and 10 mg group in elderly (15 mg or 30 mg), and non-elderly significant or clinically meaningful residual effects • 40 mg resulted in ↑ body sway and ↓ word recall versus placebo was not significantly different at the of single and repeated doses of lemborexant 2.5 beginning or end of treatment (20 mg or 40 mg): • Middle-of-the-night safety study (balance, memory, mg, 5 mg, and 10 mg on next-morning driving • Body sway after the first 2 doses of zolpidem was • Clinically meaningful impaired driving and psychomotor performance) in elderly patients: performance (9 hours after bedtime dosing) significantly greater versus placebo and both doses performance in some subjects • 30 mg resulted in impairment of balance of lemborexant, but not at the end of treatment • No statistically significant effect in elderly • The effects of lemborexant did not differ (measured by body sway area) at 90 minutes between adults and the elderly or between subjects versus placebo males and females • 5 subjects prematurely stopped their driving • Memory was not impaired (immediate and delayed word recall test) at 4 hours post-dose tests due to somnolence Suvorexant1 Lemborexant2 Suvorexant1 Lemborexant2

1. Belsomra [suvorexant] package insert. Merck Sharp & Dohme Corp; August 2014. 2. Vermeeren A, et al. Presented at ESRS 1. Belsomra [suvorexant] package insert. Merck Sharp & Dohme Corp; August 2014. 2. Vermeeren A, et al. Presented at ESRS 2018, poster 101. 2018, poster 101.

Syllabi/slides for this program are a supplement to the live CME session and are not intended for other purposes. Take-Aways Practice Points for Sleep Maintenance

• Sleep maintenance insomnia is commonly seen in older adults and in • Employ brief CBTi when possible psychiatric comorbidity • Consider online programs as well • Management of sleep maintenance insomnia remains an unmet need • Antihistamines not recommended due to: • All BZRAs have potential AEs that make this class not so desirable • Paucity of agents developed to treat it • Risk of residual effects associated with approved agents • Low-dose doxepin (3 to 6 mg) and orexin antagonists (suvorexant 10 to 20 mg) work well for sleep maintenance insomnia; newer drugs with this MOA • Driving impairment, postural instability, and risk of falls are critical are promising considerations in this population • Trazadone 50 to 150 mg is inexpensive yet has not been demonstrated to • Orexin antagonists show efficacy and safety with fewer side effects be effective long term • Orexin antagonists in development: postural stability and driving studies to date are promising

Generic and Brand Name Drugs Used in This Presentation

alprazolam Xanax® chlordiazepoxide Librium® clonazepam Klonopin® clorazepate Tranxene T-TAB® diazepam Valium®, Diastat® diphenhydramine Benadryl® doxepin Sinequan® escitalopram Lexapro® Post-Activity ® estazolam Prosom eszopiclone Lunesta® flurazepam Dalmane® lemborexant Development code E-2006 lorazepam Ativan® lorediplon GF-015535-00 melatonin Meladox®, Melatin®, Transzone®, Vitajoy®, various

Syllabi/slides for this program are a supplement to the live CME session and are not intended for other purposes. ASK QUESTIONS USING OUR Generic and Brand Name Drugs Used in NEW SOCIAL Q&A FEATURE! This Presentation

oxazepam Serax® Navigate to www.midwest.cnf.io piromelatine Neu-P11 quazepam Doral®, Dormalin® ramelteon Rozerem® ® suvorexant Belsomra Ask a temazepam Restoril® Question tiagabine Gabitril® Desyrel®, Oleptro® triazolam Halcion® tryptophan Aminomine® Click a valerian Valerian root Session zaleplon Sonata® Up-Vote a zaleplon-CR Investigational Question zolpidem Ambien®, Edluar®, Intermezzo®, various

Syllabi/slides for this program are a supplement to the live CME session and are not intended for other purposes.