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Narcolepsy Alert: Newer Pharmacologic Options and Pharmacist Implications

INTRODUCTION

Hypersomnias are disorders in which patients persistently experience episodes of excessive daytime sleepiness (EDS) or prolonged nighttime sleep. The International Classification of Sleep Disorders, third edition (ICSD-3), describes eight central disorders of hypersomnolence: narcolepsy type 1 (NT1), narcolepsy type 2 (NT2), idiopathic hypersomnia, Kleine-Levin syndrome, hypersomnia due to a medical disorder, hypersomnia due to a medication or substance, hypersomnia associated with a psychiatric disorder, and insufficient sleep syndrome.1,2 This activity focuses on the pharmacological treatments available for NT1 and NT2 and on the role of pharmacists in the management of narcolepsy.

Clinical Case #1

JS is a 17-year-old female whose past medical and surgical history only includes a tonsillectomy at age 6 years. She has no history of behavioral or learning challenges but is now having difficulty staying awake during class and other sedentary activities, which raised concern among her teachers and parents. She states that on the average school day she goes to bed at approximately 10:00 pm and wakes up at 6:30 am. She feels refreshed and alert when she wakes up each morning but becomes very sleepy during by the time her first class period begins. JS denies depression, limb weakness or paralysis, or facial drooping. She is not experiencing any unusual experiences at sleep onset or awakening. Despite being a member of the school’s soccer team and eating a balanced diet, JS has gained approximately 12 pounds over the past 6 months. She does not take any prescription medications but does admit to taking 2 to 3 nonprescription caffeine tablets daily for the past 2 months to help ease her tiredness with limited efficacy.

What symptoms of narcolepsy does JS present with?

Diagnostic Criteria, Symptomatology, and Underlying Causes

The ICSD-3 diagnostic criteria for narcolepsy (summarized in Table 1) requires that patients experience a daily irrepressible need to sleep or actual lapses into sleep during the day for at least 3 months.1 Within the ICSD-3, the American Academy of Sleep Medicine further distinguishes 2 types of narcolepsy based on deficiency of hypocretin (also known as orexin), a neuropeptide involved in regulation of arousal and wakefulness.

Table 1. Clinical Criteria for Narcolepsy Type 1 and Type 21,3,30
Clinical Criteria Narcolepsy Type 1 Narcolepsy Type 2
Chronic EDS > 3 months ✓ ✓
≥ 2 SOREM periods on MSLT or
1 SOREM period on PSG and ≥1 SOREM
period on MSLT 		✓ ✓
Mean sleep latency < 8 min on MSLT or PSG ✓ ✓
Exclusion of other causes for EDS ✓ ✓
Cataplexy ✓
CSF hypocretin < 110 pg/mL ✓
CSF, cerebrospinal fluid; EDS, excessive daytime sleepiness; MSLT, multiple sleep latency test; PSG, polysomnography; SOREM, sleep onset rapid eye movement

NT1 is narcolepsy with hypocretin deficiency (less than 110 pg/mL in cerebrospinal fluid or 1/3 of the mean value of healthy subjects) and/or cataplexy (a sudden loss of muscle tone while awake in response to certain stimuli). NT2 is narcolepsy without hypocretin deficiency or cataplexy. While cataplexy is always associated with NT1, a subset of patients with NT1 may not demonstrate cataplexy at time of diagnosis.1,3

In the absence of known hypocretin deficiency, providers use results from the multiple sleep latency test (MSLT) to diagnose narcolepsy. Results must reflect one of the following to diagnose narcolepsy1,3,4:

  • a mean sleep latency of less than 8 minutes and 2 or more periods of sleep-onset rapid eye movement periods (SOREMP) on MSLT
  • SOREMP on a polysomnogram (PSG) coupled with at least one SOREMP on the MSLT

An irreversible loss of hypocretin neurons results in the low or nonexistent hypocretin levels found in NT1.3,4 NT2 does not present as a specific phenotype, which can complicate diagnosis.4

The narcolepsy pentad describes a set of 5 symptoms present in persons with NT15-7:

  1. Excessive daytime sleepiness (EDS)
  2. Sleep fragmentation, particularly rapid eye movement (REM) sleep
  3. Cataplexy (only for NT1)
  4. Sleep-related hallucinations
  5. Sleep paralysis

Persons with NT2 may have all of the narcolepsy pentad symptoms except cataplexy.7 EDS—an irresistible urge to sleep during the day that often occurs in monotonous situations or periods of inactivity—is the hallmark symptom present in all cases of narcolepsy.4,8 Fragmented sleep typically manifests with pathological REM sleep patterns and inability to stay asleep for extended periods that subsequently impact daytime wakefulness.7,9

Cataplexy is a differentiating symptom between NT1 and NT2.10 Persons with NT1 may experience cataplexy in different ways: negative, active, or mixed. Negative cataplexy may present as knee buckling, collapsing to the ground, or head drop. Active cataplexy may present as facial, perioral, or tongue movements. Patients with mixed cataplexy may present with mouth opening, tongue protrusion, or eyelid drooping.6

Sleep-associated hallucinations can involve visual, auditory, and/or tactile aspects and may occur as a person is falling asleep (hypnagogic hallucination) or while waking up (hypnopompic hallucination).11,12 Sleep paralysis, as implied in the term, refers to the inability to move or speak during the sleep/wake cycle and patients may feel unable to breathe.13 Figure 1 summarizes narcolepsy symptoms and the differences between NT1 and NT2.

Figure 1. Symptoms of Narcolepsy5-7

Prevalence and Burden of Disease

Affecting fewer than 200,000 people in the United States (U.S.), narcolepsy is considered a rare disease. Estimates on the annual incidence rates of narcolepsy in the U.S. range from 1.37 to 7.67 per 100,000 person-years.14,15 Prevalence estimates suggest 20 to 200 cases per 100,000 persons globally and roughly 30 per 100,000 persons in Europe, Canada, and the U.S.16 Recent studies analyzing U.S. medical or prescription claims databases found that 38.9 to 79.4 per 100,000 persons are diagnosed with narcolepsy.15,17 One of the studies delineated the prevalence between NT1 (14.0 per 100,000 persons) and NT2 (65.4 per 100,000 persons) and also observed greater prevalence and incidence in females compared to males.15

Narcolepsy can be a devastating condition for patients and their families. Reduced quality of life and comorbidities can severely impact the physical, psychological, and socioeconomic well-being of patients with narcolepsy. Delays in diagnosis that can span up to 10 years also compound narcolepsy’s impact on quality of life.5,6,18,19 A range of comorbidities are associated with narcolepsy. The most common class of comorbidities, affecting up to 40% of patients with narcolepsy, involve sleep disturbances: sleep apnea, restless leg syndrome, or periodic limb movement disorder.18 Psychiatric comorbidities (e.g., anxiety, depression) are also pervasive, as are obesity and endocrine disorders (e.g., metabolic disorder).18,20-22

Persons with narcolepsy experience increased direct and indirect healthcare expenses as a result of symptoms and comorbidities. For example, in a claims database study, persons with narcolepsy experienced increased health care costs compared to a control group at rates 2-fold higher for medical expenses ($8,346 versus $4,147, p < 0.0001) and 3-fold higher for prescription drug costs ($3,356 versus $1,114, p < 0.0001).22 Other studies reflected similar 2-fold higher medical costs where annual direct costs for those with and without narcolepsy were $11,702 and $5,261, respectively (p < 0.0001).23

The burden of illness stretches beyond comorbidities and increased health care costs. Persons with narcolepsy experience decreased health-related quality of life, increased long-term disability, and increased absenteeism and presenteeism.24-26 Researchers have also observed an association between narcolepsy and increased excess mortality.27

Pathophysiology

Two important milestones in understanding the pathophysiology of narcolepsy have facilitated progress in therapy development. First, researchers identified that genes HLA-DR2 and HLA-DQB1 are associated with susceptibility to develop narcolepsy. Second, they elucidated the role of hypocretin in narcolepsy.28,29 While variants of HLA-DR2, HLA-DQB1, and other genes are associated with susceptibility to develop narcolepsy (specifically NT1), there does not appear to be a clear pattern of inheritability.7 This genetic association coupled with hypocretin cell loss suggests that NT1 may be an autoimmune disorder, but a full understanding of the mechanism is not clear.

The prevailing theory of narcolepsy pathophysiology focuses on an autoimmune condition with a genetic basis precipitated by an environmental trigger, such as a bacterial or viral infection.30 This is based in part on a monozygotic twin concordance rate of 25% to 31% and the finding that only 2% of persons diagnosed with narcolepsy have a family member with the disorder.7,30-32 NT2 pathophysiology is less clear, and some researchers have suggested that NT2 is an early manifestation of NT1.33 A schematic of the proposed immunological basis for narcolepsy illustrates a disrupted blood brain barrier allowing immune and inflammatory cells to penetrate the central nervous system (CNS), leading to destruction of hypocretin neurons and disease progression (Figure 2).30

Figure 2. Narcolepsy Disease Mechanism and Progression30
Abbreviations: HCRT, hypocretin neuropeptide precursor; NT, narcoleptic; NT1, narcolepsy type 1; NT2, narcolepsy type 2

Figure reproduced with permission from Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/) from Latorre D, Federica S, Bassetti CLA, Kallweit U. Narcolepsy: a model interaction between immune system, nervous system, and sleep-wake regulation. Semin Immunopathol. 2022. doi:10.1007/S00281-022-00933-9 with no change to figure and a change in caption.

Screening Tools

As mentioned, providers use the MSLT to establish narcolepsy diagnosis. The MSLT uses a set of 5 scheduled naps to measure a subject’s propensity to fall asleep during the day (i.e., EDS).34,35 Through the MSLT, clinicians calculate a patient’s mean sleep latency where shorter latency corresponds to greater EDS.35 The MSLT also measures SOREMPs. A mean latency less than 8 minutes and 2 or more SOREMPs during the MSLT indicates narcolepsy.1,35 It is important that patients taper off of any medication with the potential to suppress REM sleep about 2 weeks before the MSLT, as they could potentially interact with the test. Medications with long half-lives may require a washout period up to 6 weeks.35

To measure the ability to stay awake, clinicians use the Maintenance of Wakefulness Test (MWT). The MWT is also helpful for evaluating the effectiveness of pharmacological or non-pharmacological interventions in treating narcolepsy and other sleep disorders.35,36

Clinicians also use inventory/questionnaire-type tools alongside the MSLT and MWT to screen patients for narcolepsy. Researchers have described 5 major tools for screening and diagnosis of narcolepsy.10 The Epworth Sleepiness Scale (ESS)—the most commonly used and validated patient assessment tool—has 8 questions with scores ranging from 0-24. It has demonstrated high sensitivity and specificity for EDS but is not specific for narcolepsy.10 The Ullanlinna Narcolepsy Scale is an 11-item questionnaire which includes questions related to cataplexy to differentiate narcolepsy from other sleep disorders. The Stanford Sleep Inventory is a very comprehensive questionnaire; although, with 146 items in 9 sections, the tool is not commonly used in clinical practice. Using a subset of the Stanford Sleep Inventory, the Cataplexy Emotional Trigger Questionnaire focuses on differentiating cataplexy caused by narcolepsy from cataplexy caused by other conditions. With the fewest number of questions, the Swiss Narcolepsy Scale is a 5-item questionnaire to screen for EDS and cataplexy with sensitivity and specificity comparable to other tools.10

NARCOLEPSY PHARMACOTHERAPY

Clinical Case #2

TB is a 25-year-old male who was first diagnosed with NT2 at age 15 years. He was initially prescribed dextroamphetamine for his narcolepsy, but his provider transitioned him to modafinil at age 21 years when his EDS became uncontrolled despite medication adherence and good sleep hygiene. Since that time, his EDS has been controlled at a level deemed acceptable. Today, he presents with complaints of episodes where he loses control of muscle tone on both sides of his body including some facial and eyelid drooping. He began to notice the symptoms about 2 months ago. The episodes were initially brief and he did not seek care. However, about 3 weeks ago, he presented to the emergency room with concerns that he might be experiencing a stroke. It was determined that he was not having a stroke, and he was diagnosed with cataplexy.

What is the best treatment regimen for TB at this time?

Older Therapies

No curative treatments exist for narcolepsy, so pharmacological interventions focus on symptomatic treatment, particularly EDS and cataplexy. Prior to development of specific drugs for narcolepsy, providers used tricyclic antidepressants, selective serotonin reuptake inhibitors (SSRIs), and serotonin-norepinephrine-reuptake inhibitors (SNRIs) off-label for cataplexy, sleep paralysis, and REM sleep abnormalities. This was based on expert consensus rather than clinical trial data.37 Commonly used drugs in these classes include citalopram, clomipramine, duloxetine, escitalopram, fluoxetine, fluvoxamine, selegiline, and venlafaxine. Recent American Academy of Sleep Medicine (AASM) guidelines do not recommend these therapies’ use.38

Two stimulants–dextroamphetamine and methylphenidate– are U.S. Food and Drug Administration (FDA) approved for narcolepsy.39,40 The most recent AASM guidelines conditionally recommend dextroamphetamine and methylphenidate while acknowledging that the quality of evidence for their use was very low.38 Notably, dextroamphetamine and methylphenidate are Schedule II controlled substances, and both drugs carry Boxed Warnings regarding on their high potential for abuse.39,40

Providers have also historically used hypnosedatives–including benzodiazepines and non-benzodiazepines–off-label to treat poor sleep associated with narcolepsy.9 Outdated guidelines from the European Federation of Neurological Societies recommended the use of hypnosedatives, but those guidelines were developed before approval of newer, more effective agents.41 Hypnosedatives have fallen out of use in narcolepsy, and current guidelines from AASM and European societies do not recommend their use.38,42

Pitolisant

With a unique mechanism of action, pitolisant is a first-in-class drug for the treatment of EDS or cataplexy in adults with narcolepsy.43 Pitolisant acts as a presynaptic antagonist/inverse agonist at histamine H3 receptors (H3R) to increase histamine synthesis and release.44-46 At nonhistaminergic neurons, pitolisant also acts to promote the release of other neurotransmitters (i.e., acetylcholine, dopamine, norepinephrine, serotonin) leading to improved REM sleep and reduced cataplexy.46

At doses up to 40 mg daily, pitolisant was found to improve EDS compared to placebo, but the Harmony I trial found it was not non-inferior to modafinil.44,47 In the Harmony Ibis trial, lower doses of pitolisant (4.5 mg or 18 mg daily) did not demonstrate non-inferiority to modafinil and showed efficacy compared to placebo for secondary endpoints of EDS.44,48 Researchers observed contrasting effects on cataplexy between the 2 studies, possibly as a result of dose differences. The drug showed efficacy in reducing cataplexy in the Harmony I trial compared to placebo but showed increased cataplexy in the Harmony Ibis trial.44 Subsequent clinical trials of higher pitolisant doses (up to 40 mg) consistently showed improvements in cataplexy over placebo.44 Pitolisant also shows efficacy in reducing hallucinations, sleep paralysis, and sleep attacks when administered alone or with other agents.49

Pitolisant is administered orally once daily in the morning with dosing gradually titrated up over 3 weeks (8.9 mg daily week 1, 17.8 mg daily week 2, up to 35.6 mg daily if needed week 3 and beyond).43 With low abuse potential, pitolisant is the only medication recommended for narcolepsy that is not scheduled as a controlled substance.46 A lower maximum dose of pitolisant (17.8 mg daily) is recommended for moderate hepatic impairment, moderate/severe renal impairment, and poor cytochrome P450 (CYP)2D6 metabolizers, but pitolisant is not recommended for patients with end stage renal disease.43

As pitolisant is metabolized by CYP2D6 and CYP3A4, providers should avoid concomitant use with strong CYP2D6 inhibitors (increased pitolisant exposure) and strong CYP3A4 inducers (decreased pitolisant exposure). Pitolisant may also reduce the effectiveness of sensitive CYP3A4 substrates, including hormonal contraceptives. Patients using pitolisant and hormonal contraceptives should use other non-hormonal forms of contraception during and for at least 21 days after discontinuing pitolisant treatment.43 An additional precaution for pitolisant is the risk of QT interval prolongation, which may be greater in those with liver or kidney impairment.43

Solriamfetol

Solriamfetol is a selective dopamine and norepinephrine reuptake inhibitor indicated for EDS associated with narcolepsy or obstructive sleep apnea.50-52 The pivotal efficacy trial for solriamfetol in narcolepsy determined that 150 mg or 300 mg once daily significantly improved measures of EDS compared to placebo. Solriamfetol cohorts showed significant reductions in ESS scores (–5.4 ± 0.7 standard error for 150 mg, –6.4 ± 0.7 for 300 mg) compared to placebo (–1.6 ± 0.7, p < 0.0001). Least square mean changes from baseline on MWT sleep latency were also improved by 9.8 min ± 1.3 for 150 mg solriamfetol, 12.3 min ± 1.4 for 300 mg solriamfetol, and 2.1 min ± 1.3 for placebo (p < 0.0001).52

Initial solriamfetol dosing for narcolepsy is 75 mg orally daily in the morning, which can be increased as needed in intervals of 3 days or longer to a maximum of 150 mg daily. Dose reduction is recommended in renal impairment. For moderate impairment, a starting dose of 37.5 mg is recommended, which may be increased after at least 7 days to a maximum of 75 mg. In severe impairment, the recommended starting and maximum dose is 37.5 mg, and solriamfetol is not recommended in end stage renal disease.50

Cautioned use is recommended for dopaminergic drugs and other drugs that may increase blood pressure and/or heart rate. In addition, solriamfetol is contraindicated with monoamine oxidase inhibitors.50 Because of its impact on the heart, solriamfetol should be avoided in patients with serious and/or unstable cardiovascular disease, including arrhythmias.50 Solriamfetol is a Schedule IV controlled substance. Providers should monitor patients closely for psychiatric symptoms such as irritability or anxiety. If psychiatric symptoms appear or are exacerbated in patients with a baseline history of psychiatric disease, providers should consider dose reduction or therapy discontinuation.50

Modafinil and Armodafinil

Modafinil and its R-enantiomer, armodafinil, are selective dopamine reuptake inhibitors approved for treating EDS in patients with narcolepsy, obstructive sleep apnea, or shift work disorder.53,54 Modafinil and armodafinil, however, have no effect on cataplexy.55 Both are Schedule IV controlled substances and are dosed orally once daily in the morning.

Patients take modafinil 200 mg daily for narcolepsy, and dose reductions are recommended for geriatric patients (unspecified lower dose) and patients with severe hepatic impairment (50% normal dose).53 Some studies have shown initiating modafinil at 100 mg in the morning and titrating up to 200 mg in 2 divided doses (morning and early afternoon), with the possibility of further titration to 400 mg in divided doses (morning and early afternoon) after several weeks may have benefit on late-day sleepiness.33,56,57 Patients have tolerated daily doses up to 400 mg, but there is no strong evidence to support increased efficacy for doses exceeding 200 mg per day.58The recommended daily dose of armodafinil is 150 mg or 250 mg with unspecified dose reductions for geriatric patients and patients with severe hepatic impairment.54

Both modafinil and armodafinil carry warnings about the potential risks of

  • Stevens-Johnson syndrome
  • toxic epidermal necrolysis
  • drug reaction with eosinophilia and systemic symptoms (also known asmulti-organ hypersensitivity reactions)
  • angioedema and anaphylaxis reactions
  • persistent sleepiness
  • development of psychiatric symptoms

Both drugs also caution use in patients with known cardiovascular disease and history of psychosis, depression, mania, or tic disorders.53,54 Drug interactions with modafinil and armodafinil include decreased efficacy of hormonal contraceptives (including oral, depot, or implantable), reduction of cyclosporine blood levels, and increased exposure of CYP2C19 substrates.33,53,54 Due to the interaction with hormonal contraceptives and the potential for teratogenic effects, patients with pregnancy potential taking these medications should be counseled to utilize an alternative effective medicinal and/or barrier contraceptive.53,54

Oxybates

The oxybates are salts of gamma-hydroxybutyrate (GHB) approved for the treatment of both EDS and cataplexy in patients aged 7 years or older with narcolepsy.59,60 The calcium-magnesium-potassium-sodium salts product is also approved for the treatment of idiopathic hypersomnia in adults.59 GHB is the core chemical constituent of sodium oxybate (SXB) and the lower sodium product, calcium-magnesium-potassium-sodium oxybates (LXB). The oxybates appear to exert their effects via gamma-aminobutyric acid type B (GABAB) receptor stimulation in noradrenergic, dopamine (DA), and thalamocortical neurons.61 Given its potential for abuse, GHB is classified as a Schedule I controlled substance, while the FDA-approved formulations (SXB and LXB) are classified as Schedule III controlled substances with Boxed Warnings for CNS depression, abuse/misuse, and restricted access.59-61 Recognizing the high potential for abuse and diversion, FDA required a Risk Evaluation and Mitigation Strategy (REMS) program for all oxybates and only approved pharmacies can dispense these drugs.62,63

SXB was the original FDA-approved oxybate product. The high sodium content (1640 mg sodium per 9 g maximum SXB dose) caused concern for use in patients with hypertension, kidney disease, and/or heart failure. LXB has 131 mg sodium per 9 g maximum dose.64,65 The recommended initial adult dose of SXB is 4.5 g nightly in 2 divided doses at bedtime and 2 to 4.5 hours later. Patients then titrate the dose by 1.5 g (in divided doses) per night on a weekly basis to a recommended maintenance dose of 6 to 9 g nightly.60 Patients or caregivers should prepare both doses at the same time prior to bedtime due to the patient’s inherent drowsy state the time of the second nightly dose, and patients should take SXB on an empty stomach.60

Adult patients can administer LXB in the same dose and manner as SXB (i.e., 2 divided doses) or as a single nightly dose. The initial single dose of LXB for adults is 3 g or less, which can be titrated up to effect (up to 1.5 g per night per week) with a maximum 6 g single nightly dose.59 SXB and LXB dosing is weight-based for pediatric patients aged 7 years and older.59,60 SXB and LXB significantly interact with divalproex sodium whereby the initial SXB or LXB dose should be reduced by 20% or greater.59,60 All patients with hepatic impairment regardless of age should start SXB and LXB at half of the original dose per night in divided doses.59,60

SXB and LXB are contraindicated for use in combination with sedative hypnotics or alcohol (due to CNS suppressive effects).59,60,65 GHB dehydrogenase metabolizes the oxybates to form succinic semialdehyde, which is further metabolized to succinic acid by succinic semialdehyde dehydrogenase. Therefore, these drugs are also contraindicated in patients with succinic semialdehyde dehydrogenase deficiency.59,60,65 Both products carry warnings regarding parasomnias, depression, suicidality, respiratory depression, sleep-disordered breathing, and behavioral/psychiatric reactions.59,60

Investigational and Emerging Therapies

Challenges in dose administration of SXB has prompted investigation into an alternative, once-nightly formulation of SXB. This product, FT218, is formulated as an extended-release oral suspension to simplify dosing. FT218 has received tentative FDA approval (pending expiration of a patent) and the drug product will require a REMS program for distribution and use similar to SXB and LXB.66-68 While SXB and LXB are indicated for the treatment of EDS, FT218 is expected to have indications for EDS and cataplexy. In a Phase III clinical trial of FT218, the drug showed improvements to both sleep latency, ESS scores, and weekly number of cataplexy attacks compared to placebo.69

With the efficacy of pitolisant for EDS and cataplexy, H3R inverse agonists and antagonists are promising targets for new therapeutics in narcolepsy and other neurological conditions.70 SUVN-G3031 is an orally administered H3R inverse agonist with high, selective affinity for H3R that is currently in early Phase II trials.71 Results from a Phase I dose-escalation study suggest that SUVN-G3031 is safe and well tolerated over single daily doses ranging from 0.1 mg to 20 mg.72

The norepinephrine reuptake inhibitor, reboxetine, is approved for use as an antidepressant in Europe and other countries outside of the U.S.45 Currently in Phase 3 development for narcolepsy (as AXS-12), FDA has granted orphan drug designation to AXS-12 and it remains an investigational drug without FDA approval at this time.73

Researchers are investigating a combination product, modafinil and flecainide (THN102), to treat EDS from narcolepsy and Parkinson’s disease.45,74 The combination is based on preclinical studies suggesting that flecainide enhanced the efficacy of modafinil.45 The drug’s manufacturer announced preliminary Phase II results in 2019 showing satisfactory safety and tolerability, but there was no difference in efficacy compared to modafinil alone.75

GUIDELINES AND THERAPY CONSIDERATIONS

In their updated guidelines for treating hypersomnolence disorders, AASM evaluated pharmacotherapeutics for efficacy in treating narcolepsy symptoms and their impact on quality of life and disease severity. The AASM task force provided either a “strong” recommendation or a “conditional” suggestion on the use of narcolepsy drugs available at the time of review (armodafinil, dextroamphetamine, methylphenidate, modafinil, pitolisant, SXB, and solriamfetol).38 The task force strongly recommended modafinil, pitolisant, SXB, and solriamfetol for their respective indications and disease severity. They also recommended modafinil and solriamfetol for their impact on quality of life. AASM assigned “conditional” status to armodafinil for EDS and disease severity, dextroamphetamine for EDS and cataplexy, and methylphenidate for disease severity.38 Clinicians should consult these guidelines to assist in determining the proper course of therapy for patients with narcolepsy.

Clinical Case #3

BW is a 20-year-old female who presents to the sleep clinic for a regular appointment. She was diagnosed with narcolepsy 6 years ago. The only chronic medication that BW takes is pitolisant, but she does take acetaminophen or ibuprofen as needed for an occasional headache. She is not on any other medications or supplements. Today, she mentions that she has recently become sexually active. She says that she remembers being told at her initial narcolepsy diagnosis “something about it being bad to become pregnant” while she was taking her narcolepsy regimen.

What concerns regarding contraception and/or pregnancy should be considered regarding BW?

Patient-Specific Factors

Providers must consider patient-specific factors when selecting the appropriate drug to treat narcolepsy symptoms. When prescribing for persons taking hormonal contraceptives, clinicians should be aware of drugs that can decrease the effectiveness of those contraceptives. Pitolisant, modafinil, and armodafinil each are known to induce CYP3A4, which can reduce hormonal contraceptive effectiveness, so alternative contraceptive methods are recommended.43,52,53 Minimal data exists on use of medications for narcolepsy during pregnancy. Available information suggests a potential for increased risk of teratogenic effects with modafinil, armodafinil, stimulants, and solriamfetol.39,40,49,52,53 Patients who wish to become pregnant should be advised to discuss potential management plans with their clinical care team.

The majority of narcolepsy drugs are available in tablet form. The oxybates, SXB and LXB, are unique in that they are oral solutions that patients or caregivers must dilute prior to administration. SXB and LXB are also given in divided doses 2.5 to 4 hours after an initial dose at bedtime. When considering SXB or LXB to treat EDS, clinicians should consider the ability of patients or their caregivers to accurately mix the prescribed doses and to ensure the patient can be awakened for the second divided dose. If awakening for a second dose is not feasible, LXB as a single nightly dose may be more appropriate. As an extended-release suspension, a new formulation of sodium oxybates, FT218 (with tentative FDA approval), would also alleviate the need for divided doses.

As outlined in Table 2, only 4 drugs are currently FDA approved to treat cataplexy: dextroamphetamine, LXB, pitolisant, and SXB. Until other drugs (e.g., FT218) are approved for cataplexy, treatment options are limited. Such limitations may prompt providers to prescribe other drugs off-label to treat cataplexy (e.g., tricyclic antidepressants, SSRIs, SNRIs).

Providers should also consider co-existing conditions and concomitant pharmacotherapy during narcolepsy treatment selection, paying close attention to potential drug-drug interactions (Table 2). Dose adjustments may be necessary based on a patient’s renal and/or hepatic status. With the exceptions of dextroamphetamine and methylphenidate, dose adjustments are recommended for currently approved narcolepsy drugs (Table 2). Clinicians should also give special attention to potential safety issues associated with narcolepsy drugs, many of which have been described elsewhere in this activity. Additional safety issues in relation to patient education are discussed below.

Table 2. Medications Recommended for Narcolepsy Treatment in Adults39,40,43,50,53,54,59,60
Drug FDA Indication(s) Dosing and Adjustments Common AEs Clinical Pearls
Armodafinil EDS

150-250 mg once daily

Severe hepatic impairment: reduces dose recommended (none specified)

 HA, URTI, sinusitis, somnolence, insomnia, dizziness, nausea, dry mouth
  • Weak CYP3A4 inducer, weak 2C19 inhibitor
  • Do not use in patients with LVH or MV prolapse
Dextroamphetamine EDS 5-60 mg once daily or in 2-3 divided doses separated by at least 4-6 hours Decreased appetite, sweating, edginess/aggression, mood changes, dizziness, HA, sleep disturbances, hypertension, palpitations, tachycardia, blurred vision
  • Metabolized by CYP2D6 and glucuronidation
Methylphenidate EDS

10-60 mg in divided doses at breakfast and lunch

Drink ≥ 8 oz water or other fluid with each chewable tablet dose

 Dry mouth, nausea, stomach discomfort/pain, sweating, HA, loss of appetite, increased BP, tachycardia
  • High-fat foods delay and/or increase absorption of IR and chewable IR tablets
Modafinil EDS

200-400 mg once daily

Severe hepatic impairment: 50% normal dose

 Insomnia, nausea, diarrhea, HA, dry mouth, dyspepsia, nervousness, anxiety, dizziness, back pain, rhinitis
  • Moderate CYP3A4 inducer, weak CYP2C19 inhibitor
  • CrCl ≤ 20 mL/min: blood concentrations increased
  • Cirrhosis: clearance decreased 60% and steady-state concentrations doubled
  • Older adults: clearance ↓20%
  • Do not use in patients with LVH or MV prolapse
Oxybate salts (calcium, magnesium, potassium, and sodium) EDS, cataplexy, idiopathic hypersomnia

4.5-9 grams (max. once-nightly 6 grams; max. twice-nightly 9 grams)

Hepatic impairment: reduce initial total dose by 50% and take in 2 divided doses

Valproate products: Decrease oxybate salt product dose by at least 20% when initiating therapy with valproate products

 Nausea, HA, dizziness, confusion, sweating, decreased appetite, vomiting, diarrhea, nocturnal enuresis, chest discomfort, sleep-related breathing disorders, reduced appetite, anxiety
  • Similar considerations to original sodium oxybate
Pitolisant EDS, cataplexy

8.9 mg once daily week 1, 17.8 mg once daily week 2, may increase to max. 35.6 mg once daily

CYP2D6 poor metabolizers: max. 17.8 mg once daily

eGFR: 15 to < 60, max. 17.8 mg once daily; < 15: not recommended

Hepatic impairment: class B, 8.9 mg once daily for 2 weeks, then max. 17.8 mg once daily; class C, contraindicated

 HA, insomnia weight gain, nausea, anxiety, musculoskeletal pain
  • May cause QTc Prolongation
  • Potential drug interactions with: TCAs; drugs affected by CYP3A4, CYP2B6, and CYP1A2; substrates for OCT1
Sodium oxybate EDS, cataplexy

4.5-9 g in divided doses

Hepatic impairment: reduce initial total dose by 50% and take in 2 divided doses

Valproate products: Decrease oxybate salt product dose by at least 20% when initiating therapy with valproate products

 Nausea, vomiting, dizziness, nocturnal enuresis, HA, chest discomfort, sleep disturbance, confusion, sleep disordered breathing, urinary incontinence, decreased appetite, anxiety
  • Administer in bed due to rapid onset
  • High-fat meals delay and reduce absorption
  • Metabolized by the Krebs cycle to water and carbon dioxide; significant first-pass effect
  • Excreted primarily by the lungs as carbon dioxide
Solriamfetol EDS in narcolepsy or obstructive sleep apnea

75-150 mg

eGFR: 30-59, 37.5 mg once daily and titrate to max. 75 mg once daily; 15-29, 37.5 mg once daily

eGFR < 15: not recommended

 HA, decreased appetite, increased BP, tachycardia, insomnia, nausea, chest discomfort
  • Do not administer within 14 days of an MAOi
  • Half-life ≈ 7 hours; do not administer < 9 hours before bedtime
  • High fat meal delays absorption
AEs, adverse effects; BP, blood pressure; CrCl, creatinine clearance; CYP, cytochrome P450; EDS, excessive daytime sleepiness; eGFR, estimated glomerular filtration rate; FDA, U.S. Food and Drug Administration; HA, headache; IR, immediate-release; LVH, left ventricular hypertrophy; MAOi, monoamine oxidase inhibitor; max., maximum; MV, mitral valve; OCT1, organic cation transporter-1; TCAs, tricyclic antidepressants; URTI, upper respiratory tract infection

THE PHARMACIST’S ROLE IN MANAGING NARCOLEPSY

Managed care and specialty pharmacists should be aware of special considerations applicable to many of the narcolepsy drugs. Newer drugs (e.g., solriamfetol) often require prior authorization for insurance approval. Some can only be dispensed from approved specialty pharmacies (e.g., LXB, pitolisant, SXB) or require REMS programs to add a layer of protection for patients (e.g., LXB, SXB).63 Some of the tactics used by payer organizations to control costs (e.g., prior authorization, step therapy) may add to treatment delays and increases in morbidity.23 Understanding the landscape of the managed care environment may be helpful in navigating hurdles and barriers to obtaining effective therapy.

Dosage and Administration Education

Oxybates require additional patient education and guidance regarding dosing and administration, much of which is covered in REMS and medication guides. Pharmacists who dispense oxybates should be prepared to educate patients about these drugs. When given in divided doses (always for SXB, optional for LXB), the patient or caregiver must prepare both doses at the same time. Pharmacists should guide patients through the proper handling of the medication container, syringe, and mixing containers. They should also emphasize dilution with ¼ cup water (supplied by the patient), review required timing between doses, and highlight strategies to ensure that the second dose can be administered properly. Since administering SXB or LXB after a meal, particularly a high-fat meal, can substantially reduce systemic exposure, pharmacists should advise patients to dose at least 2 hours after eating.

Education on solriamfetol should emphasize taking the drug upon awakening and with at least 9 hours before the patient’s planned bedtime. Reviewing the medication guide for solriamfetol will help patients understand possible adverse effects, including increased blood pressure and heart rate. For persons of child bearing potential, the solriamfetol medication guide lists contact information for the drug’s established pregnancy registry.76

Patients should take dextroamphetamine and methylphenidate in the day to avoid sleep disruptions at night, due to their stimulant mechanisms of action. Pharmacists should counsel patients to take doses before breakfast and at lunchtime.

Counseling on Medication Safety

Communication with patients regarding medication safety is crucial for narcolepsy drugs because of their effects on the CNS. A few drugs require special emphasis. When dispensing oxybates, pharmacists should be prepared to discuss a range of safety points including but not limited to

  • taking the drug while in bed because of the rapid onset of action
  • additional precautions for secure drug storage because of the risk of abuse and diversion
  • awareness of drug interactions that are contraindicated (i.e., alcohol, sedative hypnotics) or require dose-adjustment (i.e., valproic acid)
  • potential for mental health adverse effects (e.g., increased risk of suicidal ideation)
  • high salt content with sodium oxybate

Education on solriamfetol should emphasize the risk of increases in blood pressure and/or pulse. Since modafinil, armodafinil, and pitolisant increase the metabolism of hormonal contraceptives thus reducing their effectiveness, patients should be advised to use alternative forms of contraception.33,43,53,54 Pitolisant also interacts with numerous other drugs, including tricyclic antidepressants and other drugs affected by CYP isoforms (e.g., CYP3A4, CYP2B6, CYP1A2) and substrates for the organic cation transporter 1.

Addressing Adherence

Consistent adherence to narcolepsy medication therapy is suboptimal. A recent report found that 55.2% of patients with narcolepsy had good adherence (Medicines Possession Ratio [MPR] 80% or greater), 12.9% had intermediate adherence (MPR 51% to 79%), and 31.9% had poor adherence (MPR 50% or less).77 The researchers suggested that insufficient symptom control influenced adherence rates. Persons with narcolepsy may also feel stigmatized, which can impact medication adherence.9 Pharmacists’ roles as medication experts and educators can help identify medications that impact symptom control and subsequently medication therapy adherence.78

CONCLUSION

Narcolepsy is believed to be an autoimmune disorder with genetic and environmental components. Two forms of narcolepsy are recognized: NT1 with hypocretin deficiency and/or cataplexy and NT2 without hypocretin deficiency or cataplexy. Sleep study results using the MSLT and MWT aid in the diagnosis of narcolepsy. Advances in pharmacotherapy have provided clinicians with several options for treating the major symptoms associated with the condition, including EDS, sleep fragmentation, and cataplexy. New narcolepsy drug products in development aim to ease administration schedules to help promote adherence. Selection of appropriate pharmacotherapy is based on a number of factors including symptoms, concurrent pharmacotherapy, and hepatic and/or renal insufficiency, among others. Pharmacists are vital resources for patients, caregivers, and health care professionals regarding drug selection and dosage, education for proper administration, and identification of potential drug-drug interactions or other safety issues.

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