Succeeding Under Pressure

Educational Objectives • Describe the pathophysiology and unmet burdens of narcolepsy with a focus on cardiovascular and cardiometabolic risks • Discuss recently published evidence and practical prescribing considerations for the pharmacologic treatment of adult and pediatric patients with narcolepsy

• Tailor multimodal therapeutic plans for narcolepsy based on longterm treatment goals including sleep quality and stability, sodiumassociated negative clinical outcomes, comorbidities, and shared decision making with patients

NARCOLEPSY

An Overview of Disease Presentation and Diagnosis

Narcolepsy – A Brief History First case reports were published in the late nineteenth century by Karl Friedrich Otto Westphal (1877) and Jean-Baptiste-Édouard Gélineau (1880).

1880 1902 1935

1953 1960 1964 1977 1998 2014

2026

Gelineau coined “narcolepsy.”

Dement opened the first narcolepsy clinic at Stanford.

Lӧwenfeld coined the term “cataplexy.”

Carskadon, working with William Dement, developed the MSLT.

Aserinsky and Kleitman first observed REM sleep; Dement, the “Father of Sleep Medicine” proved its deep connection to dreaming and charted the human sleep cycle.

de Lecea and Sakurai independently discovered the hypocretin (orexin) gene; Mignot established that massive loss of hypocretin-producing neurons caused narcolepsy.

Vogel discovered that disordered REM sleep played a role in narcolepsy.

ICSD listed narcolepsy with and without cataplexy as separate disorders.

ICSD, International Classification of Sleep Disorders; MSLT, multiple sleep latency test; REM, rapid eye movement. Mignot EJM. Immunol Res. 2014;58(2):315-339; Todman D. ISPUB. 2013:9(2). https://ispub.com/IJN/9/2/7361.

Dr. William Dement

The “Father of Sleep Medicine”

Dr. Dement (July 29, 1928 – June 17, 2020), one of my mentors, founded the worlds FIRST sleep center in 1970 at Stanford University and the first Sleep Fellowship training program, where I was fortunate to attend and work with Dr. Dement from 1991-1992.

Epidemiology • ~3 million globally1

• ~200,000 in the US1

• Most cases present at adolescence or young adulthood – but any age can be affected2

• In 10%-15% of cases, symptoms present before age 10 years2

1. Narcolepsy Network. Fast Facts. https://narcolepsynetwork.org/about-narcolepsy/narcolepsy-fast-facts/; 2. Latorre D, et al. Semin Immunopathol. 2022; 44(5):611-623.

Narcolepsy is Commonly Misdiagnosed Top 5 misdiagnoses, regardless of age of onset, based on a narcolepsy registry1

Rate

Depression

31.3%

Anxiety disorder

16.3%

ADHD

16.2%

Insomnia

14.4%

Hypersomnia

14.3%

Nearly 60% of patients receive ≥1 misdiagnosis before obtaining a correct diagnosis,2 often waiting up to 15 years.3 ADHD, attention deficit/hyperactivity disorder.

1. Ohayon MM, et al. Neurology. 2019;92(15 suppl):3.6-37; 2. Carter LP, et al. Postgrad Med. 2014;126(3):216-24; 3. Thorpy MJ, Krieger AC. Sleep Med. 2014;15(5):502-507.

Narcolepsy and Common Comorbidities Top 5 coexisting conditions, regardless of age of onset, based on a narcolepsy registry

Rate

Depression

34.0%

Anxiety disorder

27.1%

Obstructive sleep apnea (OSA)

24-51%

Hypersomnia

9.9%

ADHD

9.6%

Patients with narcolepsy may have various comorbidities.

Ohayon MM, et al. Neurology. 2019;92(15 suppl):3.6-37; Sansa G, et al. Sleep Med. 2010;11:93-95; Miano S, et al. Sleep Med X. 2024:8:100126.

How Is Narcolepsy Defined?

International Classification of Sleep Disorders (ICSD)-3-Text Revision (TR) In addition to EDSa, ICSD-3-TR relies on the following objective data1-3 NT1

NT2

The presence of at least one of the following: 1. Cataplexy (as defined under Essential Features) and either:

REM sleep dysregulation as described in criteria a) and each of the following: 1. Absence of cataplexy 2. CSF hypocretin not measured or >110 pg/mL or >⅓ of mean control values 3. Hypersomnolence and/or MSLT findings not better explained by other causes

a) Mean sleep latency of ≤8 minutes and two or more SOREMPs on MSLT b) A SOREMP (≤15 minutes of sleep onset) on nocturnal PSG

2. CSF hypocretin ≤110 pg/mL (using a Stanford reference sample) or <⅓ of mean values obtained in normal subjects with the same standardized assay

Limitations of ICSD-3 TR criteria include variability in clinical presentation of cataplexy, multiple and/or invasive CSF diagnostic tests, and lack of normative diagnostic test data (eg, MSLT).2 aDaily periods of an irrepressible need to sleep or daytime lapses into sleep occurring for at least 3 months. CSF, cerebrospinal fluid; PSG, polysomnography;

SOREMPs, sleep onset REM periods. 1. American Academy of Sleep Medicine. International Classification of Sleep Disorders Third Edition, Text Revision. Darien, IL. AASM; 2023; 2. Ruoff C, Rye D. Curr Med Res Opin. 2016;32(10):1611-1622; 3. Berro LF, et al. Sleep Sci. 2014;7(1):3-4.

Clinical Symptom Presentations & Variability • EDS is typically the first and primary presenting symptom • Cataplexy develops after EDS in most cases. Only rarely does it present as the first symptom before EDS

Key Symptoms • EDS (including sleep attacks, involuntary napping, automatic behavior) • Concentration and memory deficits

• Fatigue (including lack of energy) • Cataplexy (partial and complete) • Further symptoms • Disrupted nocturnal sleep

Further Symptoms • Nightmares, vivid dreaming, enactment of dreams • Sleep paralysis • Sleep-related hallucinations (visual, auditory, tactile)

• Overweight, weight gain at disease onset • Autonomic disturbances

Frequently Associated Conditions • Sleep disorders (restless legs syndrome, sleep apnea, parasomnias) • Depression, anxiety EDS, excessive daytime sleepiness.

Latorre D, et al. Semin Immunopathol. 2022;44(5):611-623.

• Attention-deficit hyperactivity disorder • Headaches, migraine

24-Hour PSG Recordings

Normal vs Narcolepsy Hypnogram Normal

REM Sleep

Sleep Stage

W R N1 N2 NS 1800

2000

2200

2400

0200

0400

0600

0800

1000

1200

1400

1600

1000

1200

1400

1600

Time Narcolepsy

REM Sleep

Sleep Stage

W R N1 N2 NS 1800

2000

2200

2400

0200

0400

0600

0800

Time

A Pentad of Symptoms Associated with REM Sleep Physiology • EDS (100%) • Sleep disruption (~30%-95%) • Hypnagogic and/or hypnopompic hallucinations (~33%-80%) • Sleep paralysis (~25%-50%) • Cataplexy

Narcolepsy Link. https://www.narcolepsylink.com/screening-and-diagnosis/narcolepsy-differential-diagnosis/.

Degeneration of Hypocretin and Locus Coeruleus Deficiency • Postmortem analysis of 11 brains with NT1

Control

NT1

Control

NT1

Neuromelanin and norepinephrine cell loss in the locus coeruleus of narcolepsy with cataplexy patients

Individuals with NT1 also have an average 46% loss in the number and an 18% increase in the size of brainstem norepinephrine neurons in the LC. LC, locus coeruleus.

Thannickal TC, et al. Nat Commun. 2026. https://doi.org/10.1038/s41467-026-70899-x.

The Patient Perspective A Qualitative Study

EDS

Cataplexy

• Described as “microsleeps” or “shutting off”

• Causes embarrassment when occurring publicly • Influenced by factors such as the weather, seasons, or menstruation

• Commonly triggered by positive emotions or situations, including sexual intercourse • Emotions are suppressed to prevent episodes, leading to misinterpretations by others as drunkenness

Nocturnal Sleep Disturbances • Include vivid dreams, nightmares, sleep paralysis, hallucinations • All lead to negative emotional experiences

Overall, narcolepsy symptoms significantly impacted patients’ emotional well-being.

Hlodak J, et al. Sleep Breath.2025;29(4):231.

The Patient Perspective

Self-Reported Concerns Regarding Cognition “When I was in grad school, I would read a chapter three times, but I still didn’t know what it said.”

“My meds affect the way I respond to things because my brain feels overworked sometimes from being awake, so my thinking is almost never entirely clear.”

“Even when I’m wellrested and taking all my meds, studying is harder than before I had narcolepsy.”

“My meds keep me from falling asleep at work, but I spend much of the day in a fog.”

“My memory is affected severely by my narcolepsy, which sometimes gives off the impression that I don’t care or don’t pay attention, but I just can’t remember.”

“I have to double-check if I sent that email.”

“I can’t multitask because the task at hand takes so much effort.”

Overall, narcolepsy symptoms significantly impacted patients’ emotional well-being.

Cano CA, et al. Sleep. 2024;47(9):zsae150.

Differential Diagnosis for Hypersomnolence ❑ Fragmentation of Sleep • Obstructive sleep apnea/upper airway resistance syndrome • Periodic leg movement disorder • Environmental causes • Chronic pain

❑ Lack of Total Sleep • Insufficient sleep syndrome • Insomnia

❑ Central Nervous System • NT1 • NT2 • Idiopathic hypersomnia (IH) • Kleine-Levin Syndrome

❑ Other Causes • Substance-induced sleep disorder • Psychiatric or medical disorders • Circadian rhythm sleep-wake disorders

Slowik JM, et al. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2026. https://www.ncbi.nlm.nih.gov/books/NBK459236/.

Differential Diagnosis Obstructive Sleep Apnea

How common is coexisting Narcolepsy and OSA?

Prevalence of OSA in narcolepsy ranges from 24.8% to 51.4%

Miano S, et al. Sleep Med X. 2024:8:100126.

Proportion of All Narcolepsy Cases Diagnosis Distribution

Symptom

NT1

NT2

Hypnagogic/hypnopompic hallucinations

80%, structured interview 46%, chart review

40%, structured interview 25%, chart review

Sleep paralysis

59%, structured interview 56%, chart review

28%, structured interview 19%, chart review

1. Barateau L, et al. Sleep Med. 2024;124:510-521; 2. Dauvilliers, Barateau et al., 2020; 3. Jiang RY, et al. J Clin Med. 2025;14(9):3217.

Proportion of All Narcolepsy Cases Then vs Now

Era

NT1

NT2

50%-90%

10%-50%

70%

30%

2020s, population-based studies6

45% (19.1K/100K)

55% (23.3K/100K)

2023, US general population survey,7 %(n)

33% (12.6K/100K)

67% (25.1K/100K)

2020–2023, US insurance claims;8 %(n)

23% (15.5K/100K)

77% (51.1K/100K)

2025, single-center clinical cohort;9 %(n)

17% (52/304)

83% (252/304)

Early 2000s1-4 20154,5

1. Silber MH, et al. Sleep. 2002;25(2):197-202; 2.Ohayon MM, et al. Neurology. 2002;58(12):1826-1833; 3. Hublin C, et al. Sleep. 1994;17(8 suppl):S7–S12; 4.

Dauvilliers Y, et al. Neurology. 2001;57(11):2029-2033; 5. Thorpy MJ, Dauvilliers Y. Sleep Med. 2015;16(1):9-18; 6. Ohayon MM, et al. Psychiatry Res. 2025;347:116390; 7. Ohayon MM, et al. Sleep Med X. 2023:6:100095; 8. Ghosh S, et al. Sleep Adv. 2026;7(2):43:1-10; 9. Jiang RY, et al. J Clin Med. 2025;14(9):3217.

Differential Diagnosis

Central (Primary) Disorders of Hypersomnolence NT1

NT2

IH

EDS

EDS

EDS

Cataplexy

No cataplexy

No cataplexy

Low or no orexin

Absence of low orexin

Absence of low orexin

More frequent sleep paralysis

Less frequent sleep paralysis

Not associated with sleep paralysis

More frequent hallucinations

Less frequent hallucinations

Not associated with hallucinations

Greatly associated with REM

Less associated REM

Not associated with REM

The differentiation between NT1, NT2 and IH rests on the degree of linkage to REM sleep pathology.

Slowik JM, et al. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2026. https://www.ncbi.nlm.nih.gov/books/NBK459236/; Trotti LM. Sleep Med Clin. 2017;12(3):331–344.

Patient Evaluation and Diagnostic Workup Clinical evaluation

Discuss confounding factors

1) NPSG; HSAT cannot be used

• Review of Symptoms (ROS)

• Sleep schedule prior to the study; may need to adjust prior to MSLT • Antidepressant use may inhibit REM; if depression worsens while medication is temporarily interrupted, then resume medication • Withhold stimulants for 2 weeks, with a minimum of 4 days

• A minimum of 6 hours total sleep time • Check for short REM onset (<15 min) • Looks for evidence of other sleep disorders

– EDS ≥3 months, cataplexy, sleep paralysis, and hallucinations

• Validated tools, eg, Epworth Sleepiness Scale • Assess other causes of EDS, eg, medical conditions (hypothyroidism, insufficient sleep syndrome), or other sleep disorders, (OSA, PLMS) • Medication side-effects

Additional tests • CSF hypocretin-1 test; levels ≤110 pg/mL confirm type 1 • HLA typing; genetic test for DQB1*0602 to support type 1 diagnosis

2) MSLT • Performed the day after PSG • Series of 5 scheduled naps, every 2 hours • Patient is given a 20-minute opportunity to fall asleep • If patient falls asleep, they are allowed 15 minutes to transition into REM sleep • Measure mean sleep latency and check for SOREMPs • Urine drug screen is best in the afternoon, not at the beginning

The MSLT is the gold standard for diagnosing narcolepsy, but its utility is limited by poor reproducibility and high false-negative rates.2 HSAT, home sleep apnea test; NPSG, nocturnal PSG; PLMS, periodic limb movements of sleep testing. Ruoff C, Rye D. Curr Med Res Opin.

2016;32(10):1611-1622; American Academy of Sleep Medicine. International Classification of Sleep Disorders Third Edition, Text Revision. Darien, IL. AASM; 2023; Berro LF, et al. Sleep Sci. 2014;7(1):3-4.

Evaluation of OSA with Persistent EDS Follow-up evaluation

1) NPSG on OSA treatment, ie, PAP

• Compliant with OSA treatment; no signs of insufficient treatment • EDS (ESS ≥10) • Reassess for RLS or signs of PLMS • Medication side-effects

• A minimum of 6 hours total sleep time • Check for short REM onset (<15 min) • If PAP settings are not optimal, adjust

Additional tests • CSF hypocretin-1 test; levels ≤110 pg/mL confirm type 1 • HLA typing; genetic test for DQB1*0602 to support type 1 diagnosis

2) MSLT on OSA treatment, ie, PAP • Performed the day after PSG • Series of 5 scheduled naps, every 2 hours • Patient is given a 20-minute opportunity to fall asleep • If patient falls asleep, they are allowed 15 minutes to transition into REM sleep • Measure mean sleep latency and check for SOREMPs • Urine drug screen is best in the afternoon, not at the beginning

The MSLT is the gold standard for diagnosing narcolepsy, but it is under utilized by most sleep centers and without a MSLT, an objective noninvasive narcolepsy diagnosis can not be obtained. 2 PAP, positive airway pressure; RLS, restless leg syndrome. Ruoff C, Rye D. Curr Med Res Opin. 2016;32(10):1611-1622; American Academy of Sleep Medicine.

International Classification of Sleep Disorders Third Edition, Text Revision. Darien, IL. AASM; 2023; Berro LF, et al. Sleep Sci. 2014;7(1):3-4.

Understanding Test Results • NPSG – Short REM latency counts as a MSLT REM nap – May show OSA, which may require treatment, or PLMS – REM without atonia is also a common finding

• MSLT – Measures average mean sleep onset latency (MSOL), classically less than 8 minutes – If over 8 minutes, assess factors that can hinder results, eg, stress, anxiety, environmental factors – Entering REM sleep on at least 2 naps – REM may not be as profound as that on NPSG • EMG reduction with EEG changes (saw tooth waves), in the setting of less obvious indicators of REM EEG, electroencephalogram; EMG, electromyogram.

De-identified Example

NARCOLEPSY AND CARDIOVASCULAR AND CARDIOMETABOLIC RISK

Let’s Recap: CV-BOND A Real-world Evidence Study

Unadjusted Incidence per 1000 Person-Years

• Retrospective cohort study of claims data revealed the risk of NEW-ONSET CARDIOVASCULAR EVENTS was higher with narcolepsy vs controls 25 20

Narcolepsy P<0.05

P<0.05

P<0.05

P<0.05

15

P<0.05

ns

P<0.05

17.7

13.3

11.8

10 5

P<0.05

Matched non-narcolepsy

4.3

5.0 2.2

5.7 3.2

8.9

6.9 3.4

3.7

1.9

1.5

8.0

1.4

0 Any stroke

Afib

Heart failure

Ischemic stroke

MACE

MI

Stroke, Afib, or edema

CVD

Consider cardiovascular risk in patients with narcolepsy when weighing treatment options.

Afib, atrial fibrillation; CV-BOND, Cardiovascular Burden of Narcolepsy Disease; CVD, cardiovascular disease; MACE, major adverse cardiovascular events; MI, myocardial infarction.

Ben-Joseph RH, et al. Sleep. 2023;46(10):zsad161.

CV Health in Children With Narcolepsy Risk of hypertension, hyperlipidemia, diabetes, and nonalcoholic fatty liver disease/nonalcoholic steatohepatitis among patients with vs without narcolepsy in propensity score–matched subgroup

Hypertension Subgroups

No. of events/no. of patients

Incidence per 100 person-years

Adjusted hazard ratio

With

Without

With

Without

Main analysis

2508/22293

4910/63709

4.51

3.22

1.44 (1.34-1.54)

Age, ≤25 years

269/8243

321/21023

1.33

0.68

2.01 (1.60-2.53)

0.5

Hyperlipidemia Subgroups

No. of events/no. of patients

Incidence per 100 person-years

2

4

Adjusted hazard ratio

With

Without

With

Without

Main analysis

3213/22293

6353/63709

6.02

4.28

1.48 (1.39-1.57)

Age, ≤25 years

382/8243

424/21023

1.91

0.90

1.84 (1.53-2.23)

0.5

Kaufman CN, et al. J Am Heart Assoc. 2025;14(12):e039899.

1

1

2

4

CV Health in Children With Narcolepsy Risk of hypertension, hyperlipidemia, diabetes, and nonalcoholic fatty liver disease/nonalcoholic steatohepatitis among patients with vs without narcolepsy in propensity score–matched subgroup Diabetes Subgroups

No. of events/no. of patients

Incidence per 100 person-years

Adjusted hazard ratio

With

Without

With

Without

Main analysis

753/22293

1345/63709

1.25

0.83

1.61 (1.40-1.83)

Age, ≤25 years

112/8243

112/21023

0.55

0.24

2.37 (1.66-3.37)

Nonalcoholic fatty liver disease/Nonalcoholic steatohepatitis Subgroups

No. of events/no. of patients

Incidence per 100 person-years

0.5

1

2

Adjusted hazard ratio

With

Without

With

Without

Main analysis

257/22293

460/63709

0.42

0.28

1.49 (1.19-1.86)

Age, ≤25 years

42/8243

45/21023

0.20

0.09

1.84 (1.53-2.23) 0.5

1

2

Consequently, all patients with narcolepsy should be monitored for cardiovascular disease development throughout the course of their condition.

Kaufman CN, et al. J Am Heart Assoc. 2025;14(12):e039899.

4

4

Negative Clinical Outcomes (NCOs) in Narcolepsy Real-world study to quantify the risk of NCOs in narcolepsy • NCOs were defined as cardiovascular,a cardiometabolic (edema), and renal (kidney failure, chronic kidney disease, proteinuria) conditions • Narcolepsy patients, n=29,317, vs non-narcolepsy controls n=146,585 – Any NCO, HR – Hypertension, HR – MACE, HR – Edema, HR – Renal NCOs, HR

1.79 1.72 1.90 2.12 1.77

Individuals with narcolepsy had an increased risk of NCOs relative to those without narcolepsy. aHypertension, stroke, transient ischemic attack, heart failure, major adverse cardiovascular event (MACE; ie, heart failure, stroke, myocardial infarction, unstable

angina, or coronary revascularization procedures).

Markt SC, et al. World Sleep 2025. Singapore. https://ws2025.abstractserver.com/program/#/details/presentations/2915.

Cardiovascular Risks in Narcolepsy Expert Consensus Recommendations

1

Recognize the risk of hypertension and cardiovascular/cardiometabolic disease in patients with narcolepsy

A. Consider that narcolepsy has been linked to increased cardiovascular/cardiometabolic risk B. Recognize that patients with narcolepsy may have other sleep disorders, which may also increase risk C. In patients with narcolepsy without existing cardiovascular/cardiometabolic disease, annually monitor BP, weight, and waist circumference D. Implement guideline recommendations for screening lipids and glycated hemoglobin A1c E. In the setting of conditions such as hypertension, family history of premature cardiovascular disease, diabetes, glucose intolerance, obesity, metabolic syndrome, and OSA, initiate earlier or more frequent monitoring as clinically indicated

Kwon Y, et al. J Am Heart Assoc. 2024;13(16):e035168.

Cardiovascular Risks in Narcolepsy Expert Consensus Recommendations

2

Reduce the risk of hypertension and cardiovascular/cardiometabolic disease in patients with narcolepsy

A. Educate patients on the association between narcolepsy and cardiovascular/cardiometabolic comorbidities B. Counsel and monitor patients on the AHA's “Life's Essential 8” and implement other lifestyle changes (eg, exercise, food choices/timing, reduced sodium intake, smoking cessation) to decrease risk C. Sleep clinicians should evaluate/treat comorbid risk factors/conditions in collaboration with primary care, cardiology, endocrinology, sleep medicine, and other relevant specialties D. Evaluate for and treat comorbid OSA E. Tailor narcolepsy drug therapy based on the risk for hypertension and cardiovascular disease

AHA, American Heart Association.

Kwon Y, et al. J Am Heart Assoc. 2024;13(16):e035168.

Cardiovascular Risks in Narcolepsy Expert Consensus Recommendations

3

Reduce sodium intake to lower the risk of hypertension and cardiovascular disease in patients with narcolepsy

A. Educate patients that high sodium intake from diet or medications can increase the risk of HTN and CVD B. Advise patients that reductions in sodium intake may lower their BP and cardiovascular risk C. Provide dietary educational materials (eg, AHA guidelines, DASH diet, WHO recommendations) to aid in reducing sodium intake D. Advise patients to use a salt substitute (if not contraindicated) and implement a low‐sodium diet

BP, blood pressure; DASH, Dietary Approaches to Stop Hypertension; HTN, hypertension; WHO, World Health Organization.

Kwon Y, et al. J Am Heart Assoc. 2024;13(16):e035168.

Daily Sodium Intake

• Americans consume >3300 mg/day of sodium1 • WHO recommends ≤2000 mg/day2 • AHA recommends an ideal limit closer to 1500 mg/day3 • US study reported 89% of adults exceed dietary sodium intake of 2300 mg/day and 92% - 94% of children consume excess sodium4 • WHO reports an estimated 1.7 million deaths each year are associated with consuming too much sodium (2023)2

Milligrams of Sodium

WHO & AHA Recommendations 3500 3000 2500 2000 1500 1000 500 0

American adult daily consumption (>3300 mg) Recommended maximum level (2000 mg) Recommended daily level (1500 mg) Adult needed daily level (180 mg)

How does this affect treatment selection?

1. Centers for Disease Control and Prevention (CDC). https://www.cdc.gov/salt/about/index.html; 2. World Health Organization (WHO). https://www.who.int/news-room/fact-sheets/detail/sodium-reduction; 3. American Heart Association (AHA). https://www.heart.org/en/healthy-living/healthyeating/eat-smart/sodium/how-much-sodium-should-i-eat-per-day; 4. Ben-Joseph RH, et al. Sleep. 2023; 46(10):zsad161.

CV CONSIDERATIONS OF NARCOLEPSY TREATMENT

First…What Are the Goals of Treatment?

• Because there is no cure for narcolepsy, primary goals are to – Maximize daytime alertness – Minimize EDS – Eliminate/reduce symptoms – Improve quality of life and safety

• Pharmaceutical therapy is generally directed at treating EDS, cataplexy, and sleep fragmentation

Morse AM. Med Sci. 2019;7(12):106.

Mechanisms of Pharmacotherapies for Narcolepsy • Stimulants/wake-promoting agents – Modafinil – Armodafinil – Amphetamines – Methylphenidate (NDRI) – Solriamfetol (NDRI)

• Antidepressants – SSRIs/SNRIs – Tricyclic antidepressants

• Histamine receptor antagonist – Pitolisant

• CNS depressants – Sodium oxybate (immediate and extended release) – Low-sodium oxybate NDRI, norepinephrine - dopamine reuptake inhibitors; SNRI, serotonin-norepinephrine reuptake inhibitor; SSRI, selective serotonin reuptake inhibitor.

American Academy of Sleep Medicine (AASM) 2021 Recommendations Stimulants/Wake-Promoting Agents Intervention

Strength of Recommendation

Modafinil

• Strong • Clinical thresholds met for EDS, disease severity, and QoL • Recommended in children

Armodafinil

• Conditional • Clinical thresholds met for EDS and disease severity

Methylphenidate

• Conditional • Clinical thresholds were met for disease severity

• FDA Schedule II federally controlled substance and black box warning due to potential for abuse or dependency • Based on animal data, may cause fetal harm

• Contains a warning for serious CV events and for increased monitoring for blood pressure and heart rate

Dextroamphetamine

• Conditional • Clinical thresholds were met for EDS and cataplexy

• FDA Schedule II federally controlled substance and black box warning due to potential for abuse or dependency • Based on animal data, may cause fetal harm

• Contains a warning for individuals with heart disease, due to potential for increased risk of cardiac events and death if history of MI or angina

Solriamfetol

• Strong • Clinical thresholds were met for EDS, disease severity, and QoL

• FDA Schedule IV controlled substance; thus, has potential for abuse • Based on animal data, may cause fetal harm

• Contains a warning for increased monitoring for high blood pressure and heart rate

Risk/Warning • FDA Schedule IV federally controlled substances due to potential for abuse or dependency • 2018 annual report of ongoing pregnancy registry shows a higher rate of major congenital anomalies and other adverse reactions in children exposed to the drug in utero • May reduce the effectiveness of oral contraception

FDA, US Food and Drug Administration; QoL, quality of life. Maski K, et al. J Clin Sleep Med. 2021;17(9):1881–1893; Black J, et al. Future Cardiol. 2025;21(6):339-348.

CV Considerations

• Contains a warning for increased monitoring for CVD

AASM 2021 Recommendations (Cont.)

CNS Depressants Intervention Sodium oxybate (immediate release and extended release)

Low-sodium oxybate

Strength of Recommendation1 • Strong • Clinical thresholds met for EDS, cataplexy, and disease severity • Recommended in children • No AASM recommendations based on guideline publication date and timing of FDA-approval • Approved for pediatric patients

Risk/Warning

CV Considerations

• FDA Schedule III controlled substances only available through restricted REMS programs

• Contains a warning for high sodium content and monitoring in patients with heart failure, hypertension, or impaired renal function

• Oxybates are sodium salts of GHB (an FDA Schedule I controlled substance), abuse or misuse is associated with CNS adverse reactions • CNS depression

—

• Based on animal data, may cause fetal harm

CNS, central nervous system; GHB, γ-hydroxybutyric acid.

Maski K, et al. J Clin Sleep Med. 2021;17(9):1881–1893; Black J, et al. Future Cardiol. 2025;21(6):339-348; Xywav. Package insert. Jazz Pharmaceuticals, Inc; 2025.

Accessed September 3, 2025. https://pp.jazzpharma.com/pi/xywav.en.USPI.pdf; Xyrem. Package insert. Jazz Pharmaceuticals, Inc; 2025. Accessed September 3, 2025. https://pp.jazzpharma.com/pi/xyrem.en.USPI.pdf; Lumryz. Package insert. Avadel Pharmaceuticals, LLC; 2024. Accessed September 3, 2025. https://www.lumryzhcp.com/sites/default/files/2025-07/lumryz-prescribing-information.pdf2.

Sodium Exposure and Narcolepsy Treatment Options Medication

Sodium content per maximum recommended dose

Sodium oxybate, oral solution

1640 mg

For extended-release oral suspension

1640 mg

Calcium, magnesium, and sodium oxybates, oral solution

131 mg

• Sodium oxybate at common doses of 6 g, 7.5 g, and 9 g, equate to consuming 1100 mg, 1400 mg, and 1640 mg of sodium, respectively • Maximum AHA recommended sodium intake of 1500 mg for the entire day is consumed before any ingestion of food or drink Xywav. Package insert. Jazz Pharmaceuticals, Inc; 2025. Accessed September 3, 2025. https://pp.jazzpharma.com/pi/xywav.en.USPI.pdf; Xyrem. Package insert.

Jazz Pharmaceuticals, Inc; 2025. Accessed September 3, 2025. https://pp.jazzpharma.com/pi/xyrem.en.USPI.pdf; Lumryz. Package insert. Avadel Pharmaceuticals, LLC; 2024. Accessed September 3, 2025. https://www.lumryzhcp.com/sites/default/files/2025-07/lumryz-prescribing-information.pdf2.

Switching From Sodium Oxybate to LXB MedicationRelated Exposure

Baseline (high-sodium oxybate)

End of treatment (low-sodium oxybate)

43

43

Dosage, mean (SD)

8.0 (1.1) g/night

8.1 (1.1) g/night

Sodium content, mean (SD)

1456.5 (206.2) mg

117.8 (16.3) mg

n

Difference in sodium content of medication, mean (SD)

1338.8 (190.7) mg

24-hour Urinary Sodium Excretion (mg/day), Median (IQR)

Cardiovascular Considerations 6000 5000

4278 (3105, 5934)

4000 3000

2703 (2254, 3358)

2000 1000 0

LSM change (95% Cl): -1939 (-2364, -1514) mg/day P value (2-sided) <0.0001 Median change from baseline: -1288 mg/day

Baseline End of treatment (high-sodium oxybate) (low-sodium oxybate) n=38 n=38

Switching from SXB to LXB reduced daily treatment-related sodium intake in participants with narcolepsy and was associated with clinically meaningful BP reductions, consistent with evidence on dietary sodium effects.

CI, confidence interval; IQR, interquartile range; LSM, least squares means; LXB, low-sodium oxybate; SD, standard deviation; SXB, sodium oxybate.

White WB, et al. Hypertension. 2025;82(12):2162-2171.

Switching From Sodium Oxybate to LXB Cardiovascular Considerations LSM change (95% Cl), mm Hg Primary Endpoint

Baseline High-Sodium Oxybate (n=43)

End of Treatment Low-Sodium Oxybate (n=43)

Mean (SE), mm Hg

LSM Change (95% CI)

P value

Mm Hg

1-sided 2-sided

24-hour ambulatory SBP

132.3 (1.8)

128.2 (1.8)

-4.1 (-6.9, -1.4)

0.0019

0.0038

Daytime ambulatory SBP

139.1 (1.9)

134.1 (1.9)

-5.1 (-7.8, -2.4)

0.0003

0.0005

Office SBP

138.0 (0.9)

128.8 (1.4)

-9.2 (-11.9, -6.5)

<0.0001

<0.0001

Nighttime ambulatory SBP

116.9 (2.1)

114.9 (2.4)

-2.0 (-5.3, 1.4)

0.1265

0.2530

24-hour ambulatory DBP

77.3 (1.6)

75.0 (1.4)

-2.3 (-4.1, -0.5)

0.0118

Exploratory Daytime ambulatory DBP Endpoints Office DBP

82.7 (1.6)

79.8 (1.5)

-2.8 (-4.8, -0.9)

0.0045

85.2 (1.0)

81.4 (1.5)

-3.8 (-6.0, -1.6)

0.0014

Nighttime ambulatory DBP

65.2 (1 .8)

64.1 (1.9)

-1 .1 (-3.6, 1.5)

0.3993

Secondary Endpoints

-12

-8

-4

0

4

Greater Blood Pressure Reduction

Switching from SXB to LXB reduced daily treatment-related sodium intake in participants with narcolepsy and was associated with clinically meaningful BP reductions, consistent with evidence on dietary sodium effects.

DBP, diastolic BP; SBP, systolic BP; SE, standard error.

White WB, et al. Hypertension. 2025;82(12):2162–2171.

AASM 2021 Recommendations (Cont.)

Histamine Receptor Antagonist Intervention

Strength of Recommendation

Pitolisant

• Strong • Clinical thresholds met for EDS, cataplexy, and disease severity

Risk/Warning

CV Considerations

• Based on animal data, may cause fetal harm

• Prolongs QT interval and increases risk of arrythmia; should be avoided in patients with hepatic and renal impairment

• May reduce the effectiveness of oral contraception

Maski K, et al. J Clin Sleep Med. 2021;17(9):1881–1893; Black J, et al. Future Cardiol. 2025;21(6):339-348.

THERAPEUTIC MANAGEMENT STRATEGIES

Nonpharmacologic Strategies Behavioral Strategy Strategic Caffeine Sleep Hygiene Sleep Scheduling Cognitive Behavioral Therapy

Description Plan use of caffeine intake to promote performance and alertness Sleep-related behaviors to enhance and achieve age-appropriate number of hours of sleep Regular sleep-wake schedule Systematic application of techniques needed to evaluate and improve behavior

Scheduled Napping

Nap that is scheduled during individual’s typical height of sleep inertia

Strategic Napping

Planned nap of specific duration to promote performance and alertness

Support Groups

In person or online social communities for support

Exercise

Any cardiovascular activity for physical engagement

Mindfulness

Meditation and self-awareness

Yoga

Breath control, simple meditation, adoption of specific postures for health/relaxation

Diet

Small, frequent meals, low carbohydrate, ketogenic diet

Temperature Manipulations Morse AM. Med Sci. 2019;7(12):106.

Cold temperature environments and avoidance of hot environments

Pharmacologic Strategies by Outcome Target

EDS

Cataplexy

EDS + Cataplexy

Agent(s)

LXB

LXB

LXB

Sodium oxybate (& ER)

Sodium oxybate (& ER)

Sodium oxybate (& ER)

Pitolisant

Pitolisant

Pitolisant

Modafinil

Atomoxetine

Atomoxetine

Armodafinil

Venlafaxine

Solriamfetol

Tricyclic antidepressant

Methylphenidate

SSRI

Dextroamphetamine Atomoxetine

FDA-approved Indication Off-label

Because disrupted nighttime sleep directly feeds into daytime dysfunction, treating the night is an essential part of managing the day. Targeting both ends of the 24-hour cycle is essential to improve overall functionality.

ER, extended release.

Adapted from Morse AM. Med Sci. 2019;7(12):106.

Dose Optimization in Narcolepsy Assess

Start Low

Titrate Gradually

Monitor Response

Manage Side Effects

Maintain & Reassess

Dosing is individualized, beginning with slow titration to establish efficacy and careful monitoring to balance wakefulness with side effects.

Guidance for LXB Dose Optimization 2024 Consensus Recommendations

Introducing LXB to patients

Initiating LXB

Addressing challenges in using LXB Transitioning from sodium oxybate to LXB

✓ Should be taken ≥2 hours after eating, with the first dose taken at bedtime, while the patient is in bed ✓ For twice-nightly dosing, initiate at 4.5 g, divided into 2 equal doses, with the first dose administered at bedtime; set an alarm to awaken for second administration 4 hours later ✓ Consider once-nightly dosing (starting at ≤3 g at bedtime) and titrate to a maximum dose of 6 g if patient is unlikely to wake for second dose ✓ Dose/timing may need to be adjusted over weeks/months to achieve the optimal therapeutic effect; time to initial therapeutic effect may be up to 6 weeks; time to optimal therapeutic effect may be up to 12 weeks ✓ Follow-up should occur at least every 4 to 6 weeks after initiation and throughout the titration period; subsequent visits should occur at least every 3 months until patient is stable

Morse AM, et al. Neurol Ther. 2024;13:785-807.

LXB Dosages >9 Grams/Night DUET Study

• N=48 participants with NT1, NT2, IH • Mean total LXB dosage was 11.1 g/night • Results for completers (n=44) – Mean BL/EOT ESS scores were 11.4/8.3 • NT1 (n=26) mean BL/EOT NSS scores were 17.3/9.4 • NT2 (n=16) mean BL/EOT NSS scores were 9.7/4.3

• Common TEAEs (mostly mild/moderate) included nausea (12.5%), vomiting (12.5%), and headache (10.4%) – 3 TEAEs were severe; hypnagogic hallucinations, nausea, syncope Participants taking LXB dosages >9 g/night maintained a similar safety profile as those taking ≤9 g/night, including no respiratory safety signals.

BL, baseline; EOT, end-of-treatment; ESS, Epworth Sleepiness Scale; NSS, Narcolepsy Severity Scale; TEAE, treatment-emergent adverse event.

Simmons J, et al. Psych Congress 2025. San Diego, California. https://www.hmpgloballearningnetwork.com/node/371199.

Conclusions • Despite its immense impact on QoL, narcolepsy remains commonly misdiagnosed • Increased awareness and improved diagnostic modalities are needed to ensure timely and accurate diagnosis

• CVD remains the leading cause of mortality in the US and narcolepsy increases risk of new onset disease • While there are several pharmacotherapies available for treatment, it’s important to consider patient risk when developing management strategies