In the Wake of Progress: Improving Clinical and Pharmacoeconomic Outcomes in the Management of Narcolepsy

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1 Continuing Education In the Wake of Progress: Improving Clinical and Pharmacoeconomic Outcomes in the Management of Narcolepsy Continuing Education Faculty John M. Dopp, PharmD, MS Associate Professor School of Pharmacy University of Wisconsin-Madison Clinical Pharmacist Wisconsin Sleep Center Madison, WI This activity is supported by an educational grant from Jazz Pharmaceuticals, Inc. Educational Objectives After completing this continuing education program, the participant should be able to: 1. Describe the clinical symptoms, diagnostic criteria, and pathophysiology of narcolepsy. 2 Discuss which health (eg, morbidity/mortality), economic, and social burdens may be increased in narcoleptic patients. 3. Identify the goals of narcolepsy management and distinguish the different features of the various medications used to treat narcolepsy symptoms. 4. Develop a treatment and monitoring plan for the drug therapy management and symptom control of narcolepsy. 5. Summarize important aspects of appropriate and timely narcolepsy diagnosis, and multidisciplinary strategies for selection of appropriate and cost-effective therapy. Target Audience The intended audience for this activity consists of medical directors, pharmacy directors, pharmacy benefit managers, and other managed care professionals who are involved with the treatment of patients with narcolepsy. Type of activity: Knowledge Release date: February 6, 2015 Expiration date: February 6, 2017 Estimated time to complete activity: 2.0 hours Fee: This lesson is offered free at Pharmacy Times Office of Continuing Professional Education is accredited by the Accreditation Council for Pharmacy Education (ACPE) as a provider of continuing pharmacy education. This activity is approved for 2.0 contact hours (0.20 CEUs) under the ACPE universal activity number H01-P. The activity is available for CE credit through February 6, Disclosures The following contributors have no relevant financial relationships with commercial interests to disclose: Faculty John M. Dopp, PharmD, MS Pharmacy Times Office of Continuing Professional Education Planning staff David Heckard; Steve Lin, PharmD, RPh; Donna Fausak; and Nathalie Harden The American Journal of Pharmacy Benefits Planning staff Nicole Beagin An anonymous peer reviewer was part of the content validation and conflict resolution. The peer reviewer has no relevant financial relationships with commercial interests to disclose. Instructions for earning credit 1. Begin the activity by reading the article in its entirety. 2. Go to and click on the activity to access and complete the posttest and activity evaluation form. 3. To receive a Statement of Credit, participants must complete the online evaluation and posttest with a score of 70% or better before the activity expires. 4. After successful completion and submission of the online posttest and activity evaluation your credit will be uploaded to CPE Monitor. You may view your credit within 48 hours at Vol. 7, No. 1 The American Journal of Pharmacy Benefits 45

2 n Dopp Overview Narcolepsy is a sleep disorder characterized by excessive daytime sleepiness (EDS) and abnormal manifestations of rapid eye movement (REM) sleep. 1 Cataplexy, hallucinations, and sleep paralysis are the abnormal REM sleep manifestations most frequently described by narcoleptic patients. Narcolepsy is associated with significant morbidity, 2,3 mortality, 4 and reduced quality of life 5, and has a significant social 6,7 and economic 8,9 impact on patients and the healthcare system. 10 Opportunities exist to improve narcolepsy management, patient health, and quality of life, and to reduce the burden of narcolepsy on patients and society. 1 Epidemiology Narcolepsy is relatively rare compared with other sleep disorders such as insomnia or restless legs syndrome. Over 30 studies have investigated the prevalence of narcolepsy in populations around the world. Prevalence studies performed using intensive patient evaluations or clinical evaluations estimate the prevalence of narcolepsy to be between 0.025% and 0.05% (or 25 to 50 per 100,000 population). 11 Around the world, consistent prevalence of narcolepsy with cataplexy has been found using in-depth questionnaires (26 per 100,000, per 100,000, per 100, ) and medical records (36 per 100,000). 15 Actual prevalence is likely higher since it is widely agreed that narcolepsy is underdiagnosed around the world. 16 It is estimated that 60% to 70% of narcoleptic patients will have cataplexy accompanying their EDS. 17,18 Pathophysiology Narcolepsy is an acquired rather than an inherited disorder, although both genetic and environmental factors play a role in predisposition and development of the disease. Disease onset has a bimodal distribution with the first peak onset occurring during adolescence (second and third decades of life) and the second peak of onset in patients early 30s. 19 The pathophysiology of narcolepsy with and without cataplexy are believed to be different. Narcolepsy with cataplexy is almost always associated with a deficiency of hypocretin (orexin) in the cerebrospinal fluid (CSF) of patients. Hypocretin is a hypothalamic neuropeptide responsible for promoting wakefulness and regulating REM sleep. In patients with narcolepsy and cataplexy, there is a strong association with the human leukocyte antigen (HLA) DQB1*0602, 20 indicating an autoimmune attack on hypocretin neurons. The general theory is that certain individuals are predisposed to an autoimmune attack of the hypocretin neurons that is likely initiated by environmental conditions (ie, toxins, hormone changes, stress) and may also be infective in nature. The autoimmune attack on hypocretin neurons results in irreversible loss of hypocretin and its wake-promoting and REM-modulating effects. Pathophysiology of patients without cataplexy is less certain, although similar changes may be involved. Narcoleptic patients without cataplexy may have normal CSF hypocretin concentrations. It is unknown if this represents heterogeneous disease or incomplete loss of hypocretin neurons following autoimmune attack. 21 A small study suggests that patients without cataplexy who have low CSF hypocretin have shorter mean REM sleep latency, younger age at onset, and associations with HLA-DR2. 22 Triggers for Cataplexy Cataplexy occurs periodically in narcoleptic patients and is triggered by strong, acute emotional stimuli. Different stimuli can trigger cataplexy within an individual patient, but the most common triggers include surprise, anger, laughter, fear, stress, and excitement. During cateplectic attacks, patients partially lose skeletal muscle control, resulting in muscle weakness and inability to respond. Patients remain conscious of themselves and their surroundings during cataplectic spells that can last a few seconds to a minute or longer. Diagnosis Narcolepsy is diagnosed using a combination of clinical symptoms and objective sleep testing. Symptoms of daytime sleepiness can be assessed subjectively using questionnaires such as the Epworth Sleepiness Scale. 23 Daytime sleepiness along with symptom reports of cataplexy, sleep paralysis, and hallucinations make a strong diagnostic case for narcolepsy, and make up the classic tetrad of narcolepsy symptoms. Objective testing for narcolepsy includes an overnight polysomnographic study followed by a daytime multiple sleep latency test (MSLT). The overnight sleep study is performed to rule out any other sleep pathologies (eg, obstructive sleep apnea, periodic limb movements of sleep) that could result in EDS. The following day, subjects are given the opportunity to sleep for 20 minutes every 2 hours for 4 to 5 nap periods. A short sleep latency (<8 minutes) and the presence of REM sleep during at least 2 nap periods is diagnostic for narcolepsy. 24 Testing of HLA genetic markers is not performed routinely in a clinical setting, but a positive HLA DQB1*0602 test is found in 95% of patients with narcolepsy and cataplexy, and in 40% of patients with narcolepsy without 46 The American Journal of Pharmacy Benefits January/February

3 In the Wake of Progress: Improving Clinical and Pharmacoeconomic Outcomes in the Management of Narcolepsy Table 1. International Classification of Sleep Disorders Narcolepsy Diagnostic Criteria Type 1 Narcolepsy Type 2 Narcolepsy a A. Excessive daytime sleepiness >3 months AND A. Excessive daytime sleepiness >3 months AND B. The presence of 1 or both of the following: B. Mean sleep latency <8 minutes and 2 sleep onset REM periods during MSLT b 1. Cataplexy and mean sleep latency 8 minutes and 2 sleep onset REM periods during MSLT b 2. CSF hypocretin-1 concentrations 110 pg/ml c CSF indicates cerebrospinal fluid; MSLT, multiple sleep latency test; REM, rapid eye movement. a Conditions A-E must be met for diagnosis of type 2 narcolepsy. b One sleep onset REM period may be from preceding night s sleep study. c Or one-third the baseline normal levels of hypocretin-1. C. No cataplexy D. CSF hypocretin-1 concentrations >110 pg/ml or hypocretin-1 not measured E. Symptoms not caused by other sleep disorders, medical condition or substances cataplexy. 20,25 However, this HLA test is also found in 18% to 35% of the general population without narcolepsy or cataplexy, limiting the use of HLA testing as a confirmatory test for the diagnosis of narcolepsy. 20 Cerebrospinal fluid hypocretin concentrations can also be used to help confirm a narcolepsy diagnosis; concentrations <110 pg/ ml (measured using a Stanford University technique) positively predict narcolepsy. 26,27 The new International Classification of Sleep Disorders (ICSD-3) separates narcolepsy into type 1 and type 2, and includes use of CSF hypocretin-1 concentrations for diagnosis in type 1 narcolepsy. 24 Criteria for determination of type 1 or 2 diagnosis can be found in Table 1. In addition to daytime sleepiness and cataplexy, narcoleptic patients may experience hallucinations and/or sleep paralysis. Sleep paralysis is a frightening phenomenon in which an individual awakens and cannot move or respond to the environment. Sleep paralysis may also occur in individuals without narcolepsy, so by itself, is not diagnostic. Hallucinations also occur at the sleep-wake transition (either waking [hypnopompic] or falling asleep [hypnagogic]) and may be an extremely vivid auditory or visual experiences. Lastly, individuals with narcolepsy may have disrupted nighttime sleep with frequent awakenings and a short REM sleep latency. Clinical and Social Burden of Narcolepsy Morbidity and mortality. Narcolepsy has a significantly negative effect on quality of life, and narcoleptic patients also experience increased morbidity and mortality. A factual analysis of morbidity and mortality was performed using the Danish National Patient Registry before and after a narcolepsy diagnosis. 2 Jennum et al found that both prior to and after narcolepsy diagnosis, patients experienced increased endocrine, nutritional, metabolic, nervous system, musculoskeletal, and other morbidity compared with control subjects. 2 Narcoleptics had a higher risk of obesity, sleep apnea and other sleep disorders, chronic obstructive pulmonary disease, back pain, arthritis, other nonspecific neurological disorders, and other diseases. Authors found a trend (hazard ratio 0.8; P =.07) for increased mortality after 12 years in narcoleptic patients. 2 A different analysis of the same patient registry found that narcoleptic patients have higher medication use. 7 A mortality study was performed using US patients from the Symphony Health Solutions Source Lx database to calculate standardized mortality ratios for patients with and without narcolepsy, and those rates were also compared with those of the general US population. 4 Mortality rates were consistently 1.5-fold higher relative to individuals without narcolepsy across all age groups over a 3-year period. 4 However, since it was not possible to determine the cause of death for subjects, possible confounding factors could not be accounted for. Collectively, data suggest that narcolepsy is associated with increased mortality risk. Associated comorbidities. Studies have shown that narcolepsy is associated with increased risk of psychiatric and other medical conditions. Individuals with narcolepsy are more likely to have hypercholesterolemia, digestive diseases, heart disease, upper respiratory tract diseases, and hypertension. 3 Narcoleptic patients are at high risk of psychiatric disorders, including: major depressive disorder, social anxiety disorder, generalized anxiety disorder, bipolar disorder, obsessive compulsive disorder, and a number of others. 3 Social impact. Narcolepsy is also associated with impairments in social functioning and health-related quality of life. 5,7 Narcoleptic patients and their partners utilize more social services and have lower employment rates compared to those without narcolepsy. 5 Narcoleptic patients may also have impairments at work, poor driving records, and other social difficulties. 6 Risk of motor Vol. 7, No. 1 The American Journal of Pharmacy Benefits 47

4 n Dopp vehicle accidents are also higher for individuals with narcolepsy, 28,29 and these risks may be greater than accident risks for patients with obstructive sleep apnea. 30 Economic Burden of Narcolepsy Patient burdens. The clinical symptoms of narcolepsy seem likely to influence earning potential and healthcare expenses. Early analysis of the economic burden faced by narcoleptics found that total annual costs for narcolepsy were high, and contributed significantly to early retirement and unemployment. 8 A subsequent study using the Danish National Patient Registry was also used for an analysis of economic consequences of narcolepsy. 9 Both direct and indirect health costs were calculated, including labor supply and social transfer payments (eg, income from state sources like pensions, subsistence allowances, social security, social assistance). Compared with control subjects, patients with narcolepsy had higher health contact rates, medication use, expenses, and unemployment rates. 9 When employed, individuals with narcolepsy had reduced income levels compared with control subjects. Annual total direct and indirect costs for narcoleptics were almost 10 times higher than for control subjects. Individuals with narcolepsy had annual mean excess health-related costs of $10,224. Thus, individuals with narcolepsy suffer significant economic consequences, earning less money, having higher unemployment, and having greater health-related expenses. Healthcare utilization. Without a doubt, individuals with narcolepsy have significant healthcare utilization and economic costs. Healthcare utilization and costs were recently investigated in the Burden of Narcolepsy Disease (BOND) study. 10 Researchers analyzed 5 years of claims data for narcoleptic and control patients, and found profound increases in healthcare utilization for narcolepsy. Narcoleptics had 2-fold higher annual rates of inpatient admissions, emergency department visits, hospital outpatient visits, other outpatient visits, and physician visits. 10 Individuals with narcolepsy had greater number of prescription drug transactions, including both narcolepsy medications and non-narcolepsy medications. Average yearly costs for medical services ($8346 vs $4147; P <.00001) and medications ($3356 vs $1114; P <.00001) were higher for narcoleptics than for control patients. Analysis of the Danish National Patient Registry also showed excess (sum of direct and indirect healthcare) costs for individuals with narcolepsy versus control subjects. 7 The documented increases in healthcare costs and utilization mean that timely and accurate diagnosis and early, effective therapy for narcolepsy are essential in order to improve patient care and control costs. Management of Narcolepsy The treatment goals of narcolepsy are: 1) reduce EDS; 2) reduce frequency and severity of cataplexy, sleep paralysis, and hallucinations; and 3) improve and consolidate nighttime sleep disruption. Both pharmacologic and nonpharmacologic therapies are used to optimize care of patients and reduce disease burden. Nonpharmacologic therapy includes implementation of appropriate sleep hygiene and strategic nap opportunities during the day. On occasion, workplace or school accommodations may also be necessary to provide flexibility for the patient to be productive and functional. Treatment of excessive daytime sleepiness. The cornerstone of therapy for EDS includes traditional central nervous system stimulants (methylphenidate and amphetamines) and the wake-promoting agents modafinil and armodafinil. Current practice parameters from the American Academy of Sleep Medicine recommend modafinil and sodium oxybate as standard therapies, traditional CNS stimulants as guideline therapies, and selegiline as an option therapy for treatment of EDS (Table 2). 31 Amphetamines and methylphenidate have long been recognized as effective treatments for EDS. However, compared with modafinil, these agents do not have as much high-quality evidence supporting their use. The guidelines mention that this discrepancy is likely a result of amphetamine drugs and methylphenidate being largely available generically without the manufacturers motivation to fund welldesigned studies. In contrast, sodium oxybate and modafinil have not been available generically, and manufacturers had significant impetus to fund and conduct clinical trials and obtain FDA indications for their products. Pemoline was used in the early days of narcolepsy treatment, but is associated with severe liver toxicity and is no longer available in the United States. Armodafinil is the active (R)-isomer, whereas modafinil is a racemic mixture of (L)- and (R)-modafinil. Armodafinil was not available when the AASM Practice parameters were published, but has shown efficacy similar to modafinil in randomized controlled trials. 32,33 The relative effectiveness of medications for the treatment of EDS in narcolepsy has not been evaluated in direct head-to-head study comparisons. Interestingly, however, the comparative effectiveness of available therapies has been estimated using combined MSLT and maintenance of wakefulness (MWT) data from various studies. Mittler and Hajdukovic estimate the percent of normal wakefulness obtained during therapy with a variety of agents. Their analysis suggests that no medications brought patients to normal levels of wakefulness, but methylphenidate and 48 The American Journal of Pharmacy Benefits January/February

5 In the Wake of Progress: Improving Clinical and Pharmacoeconomic Outcomes in the Management of Narcolepsy dextroamphetamine produced the largest gains in wakefulness at an estimated 70% of normal. 34 These findings agree with a general clinical consensus derived from years of successful treatment of patients with narcolepsy. Dextroamphetamine, regular release amphetamine/dextroamphetamine, and immediate-release methylphenidate are FDA indicated for the treatment of narcolepsy, and other amphetamines have demonstrated similar efficacy. Modafinil and armodafinil have been extensively investigated for the treatment of narcolepsy, and consistently reduce daytime sleepiness in randomized controlled trials. The exact mechanism of action of modafinil/armodafinil is unknown, but is different from other CNS stimulants and is thought to involve stimulation of wake pathways in the hypothalamus. Modafinil has advantages over traditional stimulants in ease of prescribing since it is a C-IV substance 6 months of refills are allowed. Modafinil also has significantly fewer side effects and has better tolerability than CNS stimulants. Modafinil may be dosed once in the morning, or twice daily with a dose upon awakening and a second dose around lunchtime; it can also be used in combination with traditional CNS stimulants, but if clinicians choose dual therapy, careful monitoring for adverse effects needs to be performed. Patients with relatively refractory daytime sleepiness may experience less success with modafinil if switched from amphetamines/methylphenidate. Armodafinil may have a longer duration of action than regular modafinil since serum concentrations remain high later in the day compared with modafinil dosing. 1 No direct studies have evaluated armodafinil against regular racemic modafinil. Sodium oxybate is the sodium salt of gamma hydroxybutyrate that is FDA approved for treatment of EDS and cataplexy in narcolepsy. In studies, sodium oxybate produces significant reductions in daytime sleepiness. Although most studies have studied nighttime dosing of sodium oxybate used in combination with daytime CNS stimulants, 2 studies demonstrated reduced daytime sleepiness with sodium oxybate monotherapy. 35,36 Sodium oxybate is a tightly controlled schedule III medication that can only be obtained directly from the manufacturer as part of the Xyrem Success Program. Sodium oxybate is a potent sedative medication that consolidates REM sleep, increases slow wave sleep, and appears to bind to both gamma-aminobutyric acid-b and sodium oxybate specific receptors. However, its exact mechanism of action is not entirely understood. The recommended starting dose of sodium oxybate is 2.25 grams twice nightly. The first dose should be taken at bedtime, and the second dose 2.5 to 4 hours later; doses of sodium oxybate may be slowly Table 2. American Academy of Sleep Medicine Practice Parameter Recommendations for Drug Therapy of Excessive Daytime Sleepiness 31 Standard Guideline Option Modafinil Sodium Oxybate Methylphenidate Dextroamphetamine Amphetamine Methamphetamine Selegiline up-titrated (over 6 to 8 weeks) to a maximum dose of 4.5 grams twice nightly. The 2 doses of sodium oxybate should be prepared prior to bedtime, and the prescribed amount of medication is mixed in approximately 60 ml of water. Patients frequently need to set an alarm to ensure that they take the second dose in a timely manner. Patients are instructed to be in bed while taking both doses to reduce the risk of falls or other complications. Full benefit from therapy may not appear for 2 to 3 months, especially regarding effects on daytime wakefulness. 37 Selegiline is an irreversible monoamine oxidase-b inhibitor that is metabolized into L-amphetamine and L- methamphetamine. 34 If doses are kept below 10 mg per day, selegiline retains specificity for MAO-B, but these low doses have not been shown to be effective for narcolepsy. 38 Doses that have successfully reduced daytime sleepiness are 20 mg to 40 mg. 39,40 However, at higher doses, selegiline should not be used in combination with other CNS stimulants or antidepressants, and a low tyramine diet should be followed due to the risk of serotonin syndrome and hypertensive crisis. Treatment of Cataplexy, Hallucinations, and Sleep Paralysis CNS stimulants increase norepinephrine release and as a result, appear to reduce cataplexy and sleep paralysis. Care should be taken if a patient is switched from amphetamines or methylphenidate to modafinil, as cataplexy and other REM sleep abnormalities may worsen. Modafinil and armodafinil are not effective at treating cataplexy and REM sleep abnormalities. In patients with severe cataplexy, CNS stimulants alone are usually not sufficient to control symptoms, and concomitant REM suppressing antidepressants or sodium oxybate should be added. Antidepressants (nonsedating tricyclic antidepressants, selective serotonin reuptake inhibitors, and venlafaxine) have historically been the first-line agents for treatment of cataplexy (rated as guideline by the AASM practice parameters), sleep paralysis, and hallucinations (rated as option for both) (Table 3). 31 By increasing noradrenergic signaling in the locus coeruleus, they reverse the effect of Vol. 7, No. 1 The American Journal of Pharmacy Benefits 49

6 n Dopp Table 3. American Academy of Sleep Medicine Practice Parameter Recommendations for Drug Therapy of Cataplexy, Hypnogogic Hallucinations, and Sleep Paralysis 31 Standard Cataplexy Sodium oxybate Guideline Cataplexy Tricyclic antidepressants SSRIs Venlafaxine Option Cataplexy Selegiline Hallucinations and sleep paralysis Sodium oxybate Tricyclic antidepressants SSRIs Venlafaxine SSRI indicates selective serotonin reuptake inhibitor. decreased adrenergic firing occurring during natural REM sleep. 41 Antidepressants are relatively affordable, well tolerated, and adequately effective for symptom control if doses are increased until maximum doses are reached or until control of cataplexy, hallucinations, and sleep paralysis is obtained. Severity and frequency of cataplectic attacks can be evaluated by instructing patients to keep a record of cataplexy events should they occur. Selegiline also has some anti-cataplectic (rated as option ) (Table 3) activity, and similar to its use for treatment of sleepiness, doses greater than 10 mg per day provide the best efficacy. 30 Sodium oxybate may be the most effective medication for treatment of cataplexy (rated as standard ), sleep paralysis, and hallucinations (rated as option for both) (Table 3). 30 It is unknown how sodium oxybate exerts its strong daytime anticataplectic effects, especially given that it is dosed at bedtime and during the night. Tolerability and Monitoring Although traditional CNS stimulants produce the largest improvements in daytime sleepiness, they also have the potential for adverse effects that are significant and possibly serious. Common adverse effects include increased blood pressure, tachycardia, nervousness, insomnia, headache, tremors, and xerostomia. Contraindications to amphetamine use include cardiovascular disease, history of substance abuse, glaucoma, and moderate to severe hypertension. Prudent monitoring should include blood pressure, heart rate, and assessment of cardiovascular status prior to therapy and periodically during therapy. Caution should be used in patients with concomitant epilepsy, as some studies suggest that amphetamines may lower the seizure threshold. Methylphenidate increases the risk of bleeding when used with warfarin, so frequent INR monitoring should be performed when these medications are used concomitantly. Modafinil and armodafinil have fewer central and peripheral adverse effects compared with traditional CNS stimulants and should be the therapies of choice for narcoleptic patients with cardiovascular comorbidities. Common side effects of modafinil and armodafinil include headache, nausea, anxiety, nervousness, dizziness, and palpitations. When used chronically, modafinil and armodafinil induce cytochrome P450 3A4 enzymes. 42 The most significant impact of CYP 3A4 induction is that modafinil may render hormonal contraceptives less effective. 42 Patients taking modafinil with hormonal contraceptives should be counseled to use back-up forms of birth control, and consideration should be given to a change in stimulant therapy. Sodium oxybate is a potent sedative that should not be combined with other sedating medications, including alcohol due to risk of respiratory depression, hypotension, and over-sedation. 37 Sodium oxybate has a high sodium content, and should be used carefully in patients with cardiovascular disease, renal impairment, and hypertension. 37 Sodium oxybate is a C-III controlled substance and abuse and misuse of the medication has been reported. 37 Traditional Versus Newer Approaches The medications that in theory can treat all symptoms of narcolepsy include amphetamines, methylphenidate, sodium oxybate, and possibly selegiline. Amphetamines and methylphenidate are very effective at improving daytime sleepiness, but have rather modest effects on cataplexy, hallucinations, and sleep paralysis. A minority of narcolepsy patients find that amphetamines or methylphenidate alone effectively control all symptoms. Thus, patients frequently require a concomitant antidepressant or other therapy to help treat any accompanying cataplexy, hallucinations, and sleep paralysis. Whether taking modafinil or traditional CNS stimulants, most patients require 2 medications to treat all symptoms. A newer approach involves the use of sodium oxybate alone to treat all narcolepsy symptoms. Although used concomitantly with CNS stimulants in many studies, a few investigations have shown that sodium oxybate monotherapy (at 6-9 grams/night) will reduce daytime sleepiness while also reducing cataplexy and other symptoms. 35 Using 1 medication has advantages, but sodium oxybate is more effective at reducing daytime sleepiness when used in combination with a stimulant or modafinil. 35 It is important to note that 50 The American Journal of Pharmacy Benefits January/February

7 In the Wake of Progress: Improving Clinical and Pharmacoeconomic Outcomes in the Management of Narcolepsy the effectiveness of sodium oxybate monotherapy for daytime sleepiness has not been compared head-to-head with that of methylphenidate or amphetamines. Future of Therapy Excessive Sleepiness Histamine-3 (H-3) receptor inverse agonists and antagonists are currently being evaluated for potential treatment of EDS in narcolepsy. Histamine-3 receptor antagonists may enhance histamine signaling via disinhibition of H-3 autoreceptors and enhanced histamine concentrations in synapses. 43 The H-3 inverse agonist pitolisant was compared with modafinil and placebo in a clinical trial of narcoleptics. Pitolisant was superior to placebo but was not non-inferior to modafinil for reduction in EDS. 44 Pitolisant was well tolerated compared with modafinil, and shows strong potential as a narcolepsy medication. Animal studies have shown promising effects of thyrotropin-releasing hormone and thyrotropin-releasing hormone agonists, but human studies are needed to further evaluate their potential for use in humans. 45 Given the loss of hypocretin in narcoleptic patients, hypocretin replacement therapies are an obvious future therapeutic candidate. Hypocretin does not cross the blood-brain barrier, so its exogenous administration requires some creativity. Intranasal administration of hypocretin is possible, but human research in this area is lacking, and high doses would be necessary to exert clinical effects. 46 Intracerebroventricular administration of hypocretin would likely be effective, but drug delivery logistics would be quite challenging. Since hypocretin is a large molecule (33 amino acids), peptide agonist derivatives would be unlikely to easily cross the blood-brain barrier. To date, human studies have demonstrated reductions in REM sleep, but no significant effects on daytime sleepiness with intranasal administration. 47 Hypocretin neurons have been investigated for transplantation. Animal studies have shown some promise, but transplanted cells have low survival rates, and the host may mount an immune reaction to the cell graft. 48 Additionally, finding donor hypocretin neurons would be a difficult endeavor. Gene therapy has been proposed and successful viral delivery of a gene that expresses hypocretin has been successful in animals. 49 Hypocretin replacement strategies hold potential because they directly target the intrinsic pathophysiology of narcolepsy rather than merely provide symptomatic treatment. To date, immune-based therapies, including administration of corticosteroids, intravenous immunoglobulin, and plasmapheresis, have yielded disappointing results and have only been used with a small number of patients. 45 Future of Therapy Disrupted Nighttime Sleep Currently, sodium oxybate is a standard therapy for sleep consolidation and improvement of disrupted nighttime sleep in patients with narcolepsy. Use of other sedating medications for nighttime sleep disruption has not been systemically investigated. No controlled studies have been performed using other sedating medications; however, a published case series of temazepam for sleep disruption in narcolepsy found a mostly positive effect on daytime sleepiness. 50 As a result, future studies should evaluate the utility of various sedative hypnotics for consolidating nighttime sleep and reducing daytime sleepiness. Future therapy with sedative hypnotic agents that enhance slow wave sleep could provide benefits similar to sodium oxybate. Proposed types of agents might include novel GABA-B and GABA-A agonists, other gamma hydroxybutyrate analogues, or modifications to sodium oxybate that enhance its tolerability, ease of use, and safety. 45 Role of Managed Care Professional in Optimizing Clinical and Pharmacoeconomic Outcomes in the Management of Narcolepsy Promoting accurate, early diagnosis. Narcolepsy is a medical condition with symptoms that overlap with a number of other sleep and psychiatric disorders. Excessive daytime sleepiness is common in numerous other sleep disorders, and hallucinations are typically suspected to be associated with a psychiatric diagnosis. Given the debilitating functional, social, and economic impacts associated with narcolepsy, timely diagnosis, therapy, and symptom improvement are essential to optimize clinical, economic, social, and health outcomes for the patient and for society. Clinicians have long reported that individuals with narcolepsy struggle with symptoms for significant periods of time prior to diagnosis and treatment. The most common estimate of the delay from onset of symptoms to diagnosis and treatment is 10 to 15 years. 51 Diagnosis delay is consistently reported in different countries, but varies in duration based on location. 52 Factors that are associated with delayed diagnosis include absence of cataplexy, higher body mass index, and female gender. 53 In contrast, short diagnostic delay is associated with young age at diagnosis, presence of cataplexy, and higher frequency of cataplexy attacks. 53 Other studies have produced contrasting findings, suggesting that age, gender, and presence of cataplexy may not be associated with diagnosis delay. The primary cause of delayed diagnosis is misunderstanding or lack of understanding of narcolepsy symptoms and how to triage and refer patients for appropriate testing. Pharmacists and other clinicians should Vol. 7, No. 1 The American Journal of Pharmacy Benefits 51

8 n Dopp recognize the tetrad of symptoms of narcolepsy and ask appropriate patient questions to speed accurate diagnosis. Better recognition of narcolepsy symptoms can be obtained by specialty education provided by sleep experts. Education on narcolepsy should also be accompanied by data about the comorbidities, consequences, and age of onset to help clinicians understand that narcolepsy is not merely a quality of life issue, and that adolescents and young adults are the patient age groups at highest risk. Pharmacists are in a unique position as a provider whom patients access usually once per month. Multidisciplinary medication selection. Treatment guidelines advocate that modafinil and sodium oxybate should be first-line therapies, since they have the most robust clinical studies supporting their use. However, both medications are very expensive, with sodium oxybate costing at least $65,000 per year for typical use. 54 Modafinil is now available in a generic formulation, but remains relatively costly: between $800 and $1200 per month ($9600-$14,400 per year) for generic modafinil based on prices given by retail pharmacies, although coupons and discount clubs may offer savings. The retail cost of armodafinil is estimated to be approximately $600 to $1200 per month. 55 Providers would like their decisions to be evidence based, but such high drug costs are frequently an impediment even to patients whose insurance provides coverage for these drugs save for co-payments. Many drug formularies across the United States have certain criteria patients must meet to obtain modafinil; some companies may require step therapy with methylphenidate and/or amphetamine products prior to qualifying for modafinil prior authorization. Although significantly less expensive than modafinil, amphetamines and methylphenidate have less evidence supporting their use, and are associated with increased risk of problematic adverse effects compared with modafinil. This situation creates a conundrum for practitioners and payers who wish to minimize side effects and cost while maximizing effectiveness. Many sleep practitioners advocate that all wake-promoting agents be made available on formulary, since different medications and formulations (sustained release and immediate release) often need to be trialed before finding a successful regimen. Patients frequently require a combination of sustained release and immediate release products to combat daytime sleepiness throughout the day. Pharmacists need to share their expertise with prescribers when medication selection is taking place, as their knowledge of the various amphetamine and methylphenidate sustained release products is essential to selecting the right agents for individual patients and adjusting therapy based on patient experiences and provided feedback. Careful attention should be paid to concomitant medical conditions, potential drug interactions, medication allergies/intolerances, preferred formulary recommendations, and specific features of patient symptoms and schedules. For EDS, modafinil or armodafinil can be considered as first-line therapies, but their costs are significant and they are often not effective enough for patients with severe symptoms. Amphetamines and methylphenidate successfully improve daytime sleepiness, but are associated with a greater risk of adverse effects. Pharmacy benefit managers and insurance companies should avoid restricting coverage of CNS stimulants strictly for attention deficit disorder diagnoses or for patients younger than 18 years. These restrictions are commonly encountered by sleep providers wishing to prescribe methylphenidate/amphetamines for narcoleptic patients. For the treatment of cataplexy, hallucinations, and sleep paralysis, it is prudent to attempt a trial with 1 or 2 antidepressant agents and/or selegiline prior to embarking on a trial of sodium oxybate. Although sodium oxybate may improve all narcolepsy symptoms, its cost is so high that it would be financially irresponsible to prescribe it without first conducting trials of stimulants and other medications. Cataplexy symptoms are well controlled in many patients taking antidepressants, but strong evidence documenting their effectiveness is lacking. Medication utilization and cost-effectiveness. A number of investigations suggest that individuals with narcolepsy are associated with higher medical utilization (both medications and patient visits) than those without narcolepsy. Higher medical utilization is likely a result of the narcolepsy itself and the higher rate of associated comorbidities found in narcolepsy patients. 3 Medications used to treat narcolepsy are expensive, and may be dosed more frequently than for other indications. For example, some patients require dosing up to 3 times a day, even with sustained-release stimulants. Frequent dosing requires higher monthly quantities and higher drug costs, so to reduce costs, less expensive formulations of CNS stimulants and generic products should be advocated as firstline options. Immediate-release formulations and generic products (when available) are typically less expensive than sustained release formulations and brand name products. If immediate-release formulations are effective for an individual, conversion to a sustained-release formulation can be considered in order to increase adherence and if frequent daily doses of stimulants are required. Modafinil and armodafinil are significantly more expensive than 52 The American Journal of Pharmacy Benefits January/February

9 In the Wake of Progress: Improving Clinical and Pharmacoeconomic Outcomes in the Management of Narcolepsy methylphenidate and amphetamines. Although modafinil is preferable for individuals with contraindications or cautions to use of methylphenidate/amphetamines, in otherwise healthy individuals, it remains an expensive first option for narcolepsy therapy. Based on cost, sodium oxybate should be a second- or third-line agent after therapy with less expensive alternatives has failed. For treatment of cataplexy, hallucinations, and sleep paralysis, antidepressants and/or selegiline are cost-effective first-line therapies. A trial of at least 1 of these agents prior to sodium oxybate therapy offers a relatively high likelihood of success at a reasonable cost. If success is not achieved using this strategy, sodium oxybate can be considered. When using sodium oxybate, the dose should be appropriately titrated upward (to use doses used in clinical studies) to ensure an adequate trial. One particularly revealing analysis investigated whether armodafinil, compared with modafinil, was associated with lower healthcare and medication costs. 55 In patients with EDS associated with either narcolepsy, sleep apnea, or shift work, armodafinil had lower daily average consumption (DACON) (total units dispensed divided by the prescription day supply) (1.04 vs 1.47) and reduced postindex mean medical costs compared with modafinil ($11,363 vs $13,775, respectively; P =.005). In addition, armodafinil s mean monthly drug costs were lower than modafinil s costs ($166 vs $326, respectively; P <.001). Total postindex annualized healthcare costs were also approximately $5000 lower with armodafinil compared with modafinil (P <.001). 55 A Scottish analysis looked at the cost-effectiveness of sodium oxybate for treatment of narcolepsy. The investigation found that in order to deliver a cost per quality-adjusted life-year < 20,000 (approximately $31,200), a dose of 9 grams daily would need to improve quality of life by at least 65% when added to existing therapy. 56 The author states that benefits of this magnitude are unlikely to occur across treated patients. 57 Scottish evaluations also state that manufacturer cost utility analyses of sodium oxybate versus placebo indicate that the cost per quality-adjusted life-year is around 120,000 (approximately $187,100). 58 Considering that this analysis uses placebo as a comparator, it is not especially useful for determining cost-effectiveness versus other prescribed therapies. Cost-effectiveness analysis findings have reinforced the suspicions of clinicians and payers when determining use patterns for sodium oxybate based on price. In order to be used preferentially as a first-line medication, the cost of sodium oxybate will need to decrease substantially to balance benefits and costs. Summary Narcolepsy has profound consequences for patients, including reduced quality of life and increased morbidity, mortality, and economic and social impairments. Timely symptom recognition and diagnosis is essential for identifying patients and initiating treatment. Therapy involves nonpharmacologic and pharmacologic strategies, and the goals of therapy are to reduce EDS, reduce cataplexy and REM-sleep abnormalities, and consolidate nighttime sleep. CNS stimulants, modafinil/armodafinil, nonsedating antidepressants, selegiline, and sodium oxybate are the primary agents used to control symptoms. Even with proper therapy, patients rarely achieve normal levels of wakefulness. However, future therapies are being developed that may target disease mechanisms instead of merely treat symptoms. 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