The cost utility of pitolisant as narcolepsy treatment.

OBJECTIVES: The cost-effectiveness of available pharmacological treatments for narcolepsy is largely unknown. Available pharmacological treatments are associated with tolerability, abuse, and adherence issues. Pitolisant is the first inverse agonist of the histamine H3 receptor to be prescribed for the treatment of narcolepsy with and without cataplexy. Studies suggest that pitolisant is both as effective as previously introduced drugs and is associated with fewer adverse effects. The objective in this study was to estimate the cost-effectiveness of pitolisant as monotherapy, and pitolisant as an adjunctive treatment to modafinil, compared with standard treatment. MATERIALS & METHODS: Calculations were performed using a Markov model with a 50-year time horizon. Healthcare utilization and quality-adjusted life years (QALYs) for each treatment alternative were calculated assuming no treatment effect on survival. Probabilistic sensitivity analyses were performed for treatment effectiveness and healthcare cost parameters. RESULTS: The cost per additional quality-adjusted life year was estimated at SEK 356 337 (10 SEK ≈ 1 Euro) for pitolisant monotherapy, and at SEK 491 128 for pitolisant as an adjunctive treatment, as compared to standard treatment. The cost-effectiveness measure was demonstrated to be particularly sensitive to the assumptions made concerning indirect effects on total healthcare utilization and the pitolisant treatment cost. CONCLUSIONS: The incremental cost-effectiveness ratios were below the unofficial willingness-to-pay threshold at SEK 500 000. The estimated costs per additional QALY obtained here are likely to overestimate the true cost-effectiveness ratio since significant potential indirect effects-pertaining both to labor-market and household-related productivity-of treatment are not taken into account.

In-field assessment of sodium oxybate effect in pediatric type 1 narcolepsy: an actigraphic study.

Study Objectives: Sodium oxybate (SXB) is a GABAergic agent widely used as off-label treatment in pediatric type 1 narcolepsy (NT1). Here, we aimed at analyzing by wrist actigraphy the sleep/wake profile of NT1 children and adolescents in drug-naïve condition and after 1 year of SXB treatment. As secondary aim, we investigated changes on sleepiness, cataplexy, and children's anthropometric profile after 1 year of SXB treatment. Methods: Twenty-four drug-naïve NT1 children underwent 7 days of actigraphy during the school week. Information on sleepiness, narcolepsy symptoms, and anthropometric features were collected during the same week with questionnaires and semistructured clinical interview. Children started SXB treatment and underwent a second evaluation encompassing actigraphy, clinical interview, questionnaires, and anthropometric assessment after 1 year of stable treatment. Results: Actigraphy effectively documented an improvement of nocturnal sleep quality and duration coupled with a reduction of diurnal total sleep time, nap frequency, and duration at 1 year follow-up. Reduction of sleepiness, cataplexy frequency and severity, and weight loss, mainly in obese and overweight NT1 children, were also observed at the 1 year follow-up. Conclusions: Actigraphy objectively documented changes in nocturnal sleep quality and diurnal napping behavior after 1 year of SXB treatment, thus representing a valid approach to ecologically assess SXB treatment effect on NT1 children's sleep/wake profile. NT1 symptoms severity and children's anthropometric features also changed as expected. Actigraphy offers the possibility to longitudinally follow up children and has potential to become a key tool to tailor treatment in pediatric patients.

The cost-utility of sodium oxybate as narcolepsy treatment.

AIMS AND OBJECTIVES: Based on class-I studies, sodium oxybate is regarded as a first-line treatment for both EDS and cataplexy. The cost-effectiveness of sodium oxybate is largely unknown, though. In this study, we estimate the cost-effectiveness of sodium oxybate as treatment for patients with narcolepsy as compared to standard treatment, by calculating incremental cost-effectiveness ratios (cost per quality-adjusted life year, QALY) for patients in a Swedish setting. MATERIALS AND METHODS: Calculations were performed using a Markov model with a 10-year time horizon. The study population consisted of adult patients treated for narcolepsy with cataplexy. Healthcare utilization and quality-adjusted life years (QALYs) for each treatment alternative were calculated assuming no treatment effect on survival. Sensitivity analyses were performed for treatment effectiveness and healthcare cost parameters. RESULTS: The cost per additional quality-adjusted life year was estimated at SEK 563,481. The cost-effectiveness measure was demonstrated to be particularly sensitive to the duration of the relative quality-of-life improvements accruing to patients treated with sodium oxybate. CONCLUSIONS: The estimated cost per additional QALY for the sodium oxybate treatment alternative compared with standard treatment was estimated above the informal Swedish willingness-to-pay threshold (SEK 500,000). The estimated cost per additional QALY obtained here is likely to overestimate the true cost-effectiveness ratio as potentially beneficial effects on productivity of treatment with sodium oxybate were not included (due to lack of data).

The European Medicines Agency review of pitolisant for treatment of narcolepsy: summary of the scientific assessment by the Committee for Medicinal Products for Human Use.

On 31 March 2016, the European Commission issued a decision for a marketing authorisation valid throughout the European Union (EU) for pitolisant (Wakix) for the treatment of narcolepsy with or without cataplexy in adults. Pitolisant is an antagonist/inverse agonist of the human histamine H3 receptor. The dose should be selected using an up-titration scheme depending on individual patient response and tolerance and should not exceed 36 mg/day. The main evidence of efficacy of pitolisant was based on two Phase III clinical trials. The improvement on excessive daytime sleepiness was shown against placebo in the Harmony I study (-3.33 points; 95% confidence interval (CI) [-5.83; -0.83]; p = 0.024) and in Harmony CTP (-3.41 points; 95% CI [-4.95; -1.87]; p < 0.0001). The daily cataplexy rate in Harmony I improved against placebo with a rate ratio (rR) of 0.38 whilst in the Harmony CTP the ratio of improvement on weekly cataplexy rate against placebo was 0.512. The most commonly reported adverse reactions were headache, insomnia and nausea. This article summarizes the scientific review leading to approval of pitolisant in the EU. The assessment report and product information are available on the European Medicines Agency website (http://www.ema.europa.eu).

The Burden of Narcolepsy Disease (BOND) study: health-care utilization and cost findings.

OBJECTIVES: The aim of this study was to characterize health-care utilization, costs, and productivity in a large population of patients diagnosed with narcolepsy in the United States. METHODS: This retrospective, observational study using data from the Truven Health Analytics MarketScan Research Databases assessed 5 years of claims data (2006-2010) to compare health-care utilization patterns, productivity, and associated costs among narcolepsy patients (identified by International Classification of Diseases, Ninth Revision (ICD9) narcolepsy diagnosis codes) versus matched controls. A total of 9312 narcolepsy patients (>18 years of age, continuously insured between 2006 and 2010) and 46,559 matched controls were identified. RESULTS: Compared with controls, narcolepsy subjects had approximately twofold higher annual rates of inpatient admissions (0.15 vs. 0.08), emergency department (ED) visits w/o admission (0.34 vs. 0.17), hospital outpatient (OP) visits (2.8 vs. 1.4), other OP services (7.0 vs. 3.2), and physician visits (11.1 vs. 5.6; all p<0.0001). The rate of total annual drug transactions was doubled in narcolepsy versus controls (26.4 vs. 13.3; p<0.0001), including a 337% and 72% higher usage rate of narcolepsy drugs and non-narcolepsy drugs, respectively (both p<0.0001). Mean yearly costs were significantly higher in narcolepsy compared with controls for medical services ($8346 vs. $4147; p<0.0001) and drugs ($3356 vs. $1114; p<0.0001). CONCLUSIONS: Narcolepsy was found to be associated with substantial personal and economic burdens, as indicated by significantly higher rates of health-care utilization and medical costs in this large US group of narcolepsy patients.

Safety profile of modafinil across a range of prescribing indications, including off-label use, in a primary care setting in England: results of a modified prescription-event monitoring study.

BACKGROUND: Modafinil (Provigil) was marketed in the UK in 1998 to promote wakefulness in the treatment of narcolepsy. In April 2004, the licence was extended to include chronic pathological conditions; 2 years later, the prescription of modafinil was restricted to patients with shift work sleep disorder, narcolepsy and obstructive sleep apnoea/hypopnoea syndrome. Following a recent review of the safety data, the licence has been further restricted to only treat patients with narcolepsy. The review highlighted the degree of off-label usage of modafinil, including patients with multiple sclerosis. OBJECTIVE: The aim of this study was to examine the safety profile of modafinil in real-world clinical usage and across a range of prescribing indications, including multiple sclerosis. METHODS: The study was conducted using the observational cohort technique of Modified Prescription-Event Monitoring. Patients were identified from dispensed prescriptions issued by primary care physicians from July 2004 to August 2005. Patient demographics and information on prescribing behaviour were included in the questionnaire sent to the prescribing general practitioner (GP) 6 months after the initial prescription for each patient. The questionnaire sought data on any events that patient may have experienced during that time, reasons for stopping treatment with modafinil, adverse drug reactions (ADRs), potential interaction with contraceptives, and pregnancies. Incidence densities (IDs) were calculated for all events, and stratified according to indication and dose. Specific events were evaluated by requesting further information. RESULTS: Of the 4,023 questionnaires sent to GPs, 2,416 were returned (response rate 60.1 %). Of these, only those patients issued modafinil after April 2004 (with the associated broadening of the indications for treatment) were included in the study, resulting in a final cohort of 1,096 patients: 497 (45.3 %) male, median age of 52 years (interquartile range [IQR] 41-63), and 599 (54.7 %) female, median age of 47 years (IQR 38-57). Nine patients were aged 16 years or younger; no serious skin reactions were reported in this group. Thirty-four percent of the cohort had an indication of multiple sclerosis. In this study, the majority of the clinical events that were most frequently reported as ADRs or reasons for stopping or that occurred in month 1 have been previously documented with modafinil. The results of the study show that less than half of the women of child-bearing potential were established on a recommended contraceptive programme; three women became pregnant whilst taking modafinil and the oral contraceptive pill. Stratification of IDs by dose revealed certain additional events occurred during month 1 of treatment at the higher dose only. Assessment of individual cases of cardiac, psychiatric and skin events indicated causal associations with modafinil. CONCLUSIONS: This study provides important additional safety data on the use of modafinil in patients in 'real-world' use, including those for whom the prescribing indication is outside the terms of licence, as per recent changes to the licensed indications for treatment. In addition to safety data, our study provides useful utilization data. Results from this study indicate that a significant number of women of child-bearing potential had not been commenced on appropriate contraceptive programmes prior to starting modafinil. There were three pregnancies that occurred whilst taking contraception, highlighting the necessity of ensuring effective contraceptive cover for women during and after stopping treatment with modafinil. Analysis of the data showed that the majority of events reported as ADRs or reasons for stopping and ranked events during the first month of treatment had been previously documented with the use of modafinil. Stratification of events according to dose revealed a number of events that occurred at the higher dose only, including serious events such as psychosis. The targeted events for which causality assessments were undertaken confirmed the potential of modafinil to induce certain types of events in individual patients, including cardiac and psychiatric events.

Assessment of brain activity during memory encoding in a narcolepsy patient on and off modafinil using normative fMRI data.

We present behavioral and functional magnetic resonance imaging (fMRI) findings of a 20-year-old female with narcolepsy who completed a standardized fMRI-adapted face memory task both 'off' and 'on' modafinil compared to a normative sample (N = 38). The patient showed poor recognition performance off modafinil (z = -2.03) but intact performance on modafinil (z = 0.78). fMRI results showed atypical activation during memory encoding off modafinil, with frontal lobe hypoactivity, but hippocampal hyperactivity, whereas all brain regions showed more normalized activation on modafinil. Results from this limited study suggest hippocampal and frontal alterations in individuals with narcolepsy. Further, the results suggest the hypothesis that modafinil may affect brain activation in some people with narcolepsy.

The economic consequences of narcolepsy.

BACKGROUND: Narcolepsy is a chronic neurodegenerative disorder with a typical onset in childhood or early adulthood. Narcolepsy may have serious negative effects on health-, social-, education-, and work-related issues for people with narcolepsy and for their families. The disease may, thus, present a significant socioeconomic burden, but no studies to date have addressed the indirect and direct costs of narcolepsy. METHODS: Using records from the Danish National Patient Registry (1998-2005), we identified 459 Danish patients with the diagnosis of narcolepsy. Using a ratio of 1 patient record to 4 control subjects' records, we then compared the information of patients with narcolepsy with that of 1836 records from age- and sex-matched, randomly chosen citizens in the Danish Civil Registration System Statistics. We calculated the annual direct and indirect health costs, including labor supply and social transfer payments (which include income derived from state coffers, such as subsistence allowances, pensions, social security, social assistance, public personal support for education, etc.). Direct costs included frequencies and costs of hospitalizations and weighted outpatient use, according to diagnosis-related groups, and specific outpatient costs based on data from The Danish Ministry of Health. The use of and costs of drugs were based on data from the Danish Medicines Agency. The frequencies and costs from primary sectors were based on data from The National Health Security. Indirect costs were based on income data derived from data from the Coherent Social Statistics. RESULTS: Patients with narcolepsy had significantly higher rates of health-related contact and medication use and higher expenses, as compared with control subjects. They also had higher unemployment rates. The income level of patients with narcolepsy who were employed was lower than that of employed control subjects. The annual total direct and indirect costs were euro 11,654 (euro = Eurodollars) for patients with narcolepsy and euro 1430 for control subjects (p < 0.001), corresponding to an annual mean excess health-related cost of euro 10,223 for each patient with narcolepsy. In addition, the patients with narcolepsy received an annual social transfer income of euro 2588. CONCLUSION: The study confirms that narcolepsy has major socioeconomic consequences for the individual patient and for society. Early diagnosis and treatment could potentially reduce disease burden, which would have a significant socioeconomic impact.

Precipitating pharmakologies and capital entrapments: narcolepsy and the strange cases of Provigil and Xyrem.

Since the mid-1990s, Americans have been made more aware of chronic sleep deprivation and sleep disorders exacerbated by dominant temporal regimes of work, school, and family life, primarily through increased medical and media attention. Concomitantly, Americans have turned to medical treatments and pharmaceutical cocktails to achieve normalcy rather than attending to the social and cultural causes of sleep sickness. This turn toward pharmaceuticalization is aided in part by the proliferation of medical disorders and the pharmaceuticals marketed to treat them (e.g., "excessive daytime sleepiness" requires treatment once reserved for narcoleptics). These cocktails have explicit and implicit components: the former consist of pharmaceuticals, the latter of capital dependencies, including ties to medical insurance companies, stable employment, and familial networks. In this article, I examine the proliferation of pharmaceutical cocktails through the concept of the pharmakon-something simultaneously remedy and cause-to illuminate the causes and effects of such pharmaceutical regimens in contemporary American society, specifically those relating to sleepiness. Specific cases of this struggle between chemical dependence and normalcy are offered from my ethnographic work with patients who suffer from sleep disorders.

Armodafinil: a new treatment for excessive sleepiness.

BACKGROUND: Armodafinil is a wake-promoting agent developed by Cephalon that was approved in mid-2007 for the treatment of excessive sleepiness associated with narcolepsy, obstructive sleep apnea and shift work disorder. It is the R-enantiomer of the compound modafinil. Like modafinil, the mechanism of action for armodafinil is not fully characterized. OBJECTIVE: To determine what data are available to support the potential use of armodafinil in clinical settings. METHODS: There are limited data on armodafinil available in the public domain, particularly in regard to chemistry and pharmacokinetics/dynamics. Data were reviewed from refereed journals, scientific presentations, and published labeling. RESULTS/CONCLUSION: Clinical trials demonstrated efficacy and safety profiles that were similar to those of the parent compound with wake promotion sustained throughout the day. The longer duration of effect has the potential for improved patient response and compliance but this will require further study. The primary commercial challenge may be the future availability of generic modafinil.

Medico-legal assessment of disability in narcolepsy: an interobserver reliability study.

Impairment because of narcolepsy strongly limits job performance, but there are no standard criteria to assess disability in people with narcolepsy and a scale of disease severity is still lacking. We explored: (1) the interobserver reliability among Italian Medical Commissions making disability and handicap benefit decisions for people with narcolepsy, searching for correlations between the recognized disability degree and patients' features; (2) the willingness to report patients to the driving licence authority and (3) possible sources of variance in judgement. Fifteen narcoleptic patients were examined by four Medical Commissions in simulated sessions. Raw agreement and interobserver reliability among Commissions were calculated for disability and handicap benefit decisions and for driving licence decisions. Levels of judgement differed on percentage of disability (P < 0.001), severity of handicap (P = 0.0007) and the need to inform the driving licence authority (P = 0.032). Interobserver reliability ranged from Kappa = -0.10 to 0.35 for disability benefit decision and from Kappa = -0.26 to 0.36 for handicap benefit decision. The raw agreement on driving licence decision ranged from 73% to 100% (Kappa not calculable). Spearman's correlation between percentages of disability and patients' features showed correlations with age, daytime naps, sleepiness, cataplexy and quality of life. This first interobserver reliability study on social benefit decisions for narcolepsy shows the difficulty of reaching an agreement in this field, mainly because of variance in interpretation of the assessment criteria. The minimum set of indicators of disease severity correlating with patients' self assessments encourages a disability classification of narcolepsy.

Excessive daytime sleepiness and sleep disturbances in patients with neurological diseases: epidemiology and management.

Up to 12% of the general population experience excessive daytime sleepiness (EDS), with increasing prevalence in the elderly. EDS may lead to cognitive impairment, resulting in inattentiveness, poor memory, mood disorders and an increased risk of accidents. As a result, quality of life is reduced in most patients with EDS as well as in their caregiving spouses. There are a variety of causes leading to EDS, including CNS pathology, neurological dysfunction, associated sleep disorders with insufficient or fragmented sleep, and drug therapy. Since EDS accompanies many neurological disorders, such as neurodegenerative and neuromuscular diseases, neurologists should be familiar with the diagnosis, its major causes and with treatment options. The main focus of this article is on movement disorders, neuromuscular diseases, multiple sclerosis, dementia, cerebrovascular diseases, head and brain trauma, pain and epilepsy. General management strategies for EDS in all these neurological diseases include sleep hygiene aspects such as extensions of noctural time in bed and frequent naps during the day. Pharmacological treatment is generally achieved with stimulants such as amphetamine, methylphenidate and pemoline, or newer compounds such as modafinil.

Narcolepsy in the older adult: epidemiology, diagnosis and management.

Narcolepsy is a disorder of impaired expression of wakefulness and rapid-eye-movement (REM) sleep. This manifests as excessive daytime sleepiness and expression of individual physiological correlates of REM sleep that include cataplexy and sleep paralysis (REM sleep atonia intruding into wakefulness), impaired maintenance of REM sleep atonia (e.g. REM sleep behaviour disorder [RBD]), and dream imagery intruding into wakefulness (e.g. hypnagogic and hypnopompic hallucinations). Excessive sleepiness typically begins in the second or third decade followed by expression of auxiliary symptoms. Only cataplexy exhibits a high specificity for diagnosis of narcolepsy. While the natural history is poorly defined, narcolepsy appears to be lifelong but not progressive. Mild disease severity, misdiagnoses or long delays in cataplexy expression often cause long intervals between symptom onset, presentation and diagnosis. Only 15-30% of narcoleptic individuals are ever diagnosed or treated, and nearly half first present for diagnosis after the age of 40 years. Attention to periodic leg movements (PLM), sleep apnoea and RBD is particularly important in the management of the older narcoleptic patient, in whom these conditions are more likely to occur. Diagnosis requires nocturnal polysomnography (NPSG) followed by multiple sleep latency testing (MSLT). The NPSG of a narcoleptic patient may be totally normal, or demonstrate the patient has a short nocturnal REM sleep latency, exhibits unexplained arousals or PLM. The MSLT diagnostic criteria for narcolepsy include short sleep latencies (<8 minutes) and at least two naps with sleep-onset REM sleep. Treatment includes counselling as to the chronic nature of narcolepsy, the potential for developing further symptoms reflective of REM sleep dyscontrol, and the hazards associated with driving and operating machinery. Elderly narcoleptic patients, despite age-related decrements in sleep quality, are generally less sleepy and less likely to evidence REM sleep dyscontrol. Nonpharmacological management also includes maintenance of a strict wake-sleep schedule, good sleep hygiene, the benefits of afternoon naps and a programme of regular exercise. Thereafter, treatment is highly individualised, depending on the severity of daytime sleepiness, cataplexy and sleep disruption. Wake-promoting agents include the traditional psychostimulants. More recently, treatment with the 'activating' antidepressants and the novel wake-promoting agent modafinil has been advocated. Cataplexy is especially responsive to antidepressants which enhance synaptic levels of noradrenaline (norepinephrine) and/or serotonin. Obstructive sleep apnoea and PLMs are more common in narcolepsy and should be suspected when previously well controlled older narcolepsy patients exhibit a worsening of symptoms. The discovery that narcolepsy/cataplexy results from the absence of neuroexcitatory properties of the hypothalamic hypocretin-peptidergic system will significantly advance understanding and treatment of the symptom complex in the future.

Benefits and risks of pharmacotherapy for narcolepsy.

Narcolepsy is a life-long central nervous system (CNS) syndrome characterised by excessive sleepiness, cataplexy, sleep paralysis, hypnagogic hallucinations and disturbed night-time sleep. Unsuccessfully treated narcolepsy confers increased risks on patients and on society due to the patient's increased chance of becoming involved in vehicle crashes and workplace mishaps. The syndrome may be diagnosed by a clinical history positive for cataplexy and excessive daytime sleepiness and negative for other more common sleep disorders such as sleep apnoea and sleep deprivation. Night-time polysomnography and multiple sleep latency testing are helpful in differentiating narcolepsy from other sleep problems. Recent data from canine, murine, and human forms of narcolepsy indicate that genetically or developmentally mediated deficits in the hypocretin neurotransmitter system may cause some, but not all, forms of narcolepsy. Pharmacotherapy for narcolepsy is required to control symptoms and involves the use of CNS stimulants or modafinil to control sleepiness and antidepressant medications or sodium oxybate to control cataplexy. Modafinil and sodium oxybate have been developed and approved specifically for the indication of narcolepsy based on large, double-blind, placebo-controlled, parallel group efficacy and safety studies. The efficacy of drugs in the treatment of narcolepsy is variable from patient to patient and usually associated with adverse effects that can limit patient compliance and, therefore, symptom control. Nevertheless, the benefits of pharmacotherapy are judged to outweigh the risks to the patient. The favourable benefit-risk ratio of pharmacotherapy is greater if one considers the reduced risk to society of vehicle crashes and workplace mishaps that might be precipitated by attentional lapses or sleep attacks in the untreated or under-treated patient with narcolepsy.

Health-related quality of life effects of modafinil for treatment of narcolepsy.

OBJECTIVE: To evaluate the burden of illness of narcolepsy and assess the health-related quality-of-life (HQL) effects of oral modafinil, a wake-promoting therapy for excessive daytime sleepiness associated with narcolepsy. METHODS: Subjects with narcolepsy enrolled in a nine-week, placebo-controlled, double-blind study and were randomized to placebo, modafinil 200 mg, or modafinil 400 mg. After the study, consenting subjects received modafinil in a 40-week open-label extension. A self-administered HQL questionnaire consisting of the 36-Item Short Form Health Survey (SF-36) and supplemental narcolepsy-specific scales was given to subjects at baseline, study endpoint, and several open-label timepoints. RESULTS: 481 subjects completed a baseline and double-blind endpoint HQL assessment. Compared to population norms, baseline HQL scores reflected substantial burden in vitality, social functioning, and performing usual activities. At study endpoint, subjects in the 400 mg modafinil group had significantly higher scores than placebo for 10 of the 17 HQL scales. The 400 mg modafinil group had more energy, fewer difficulties performing usual activities, fewer interferences with social activities, improved psychological well-being and higher productivity, attention and self-esteem compared to placebo subjects (p<.05). The positive treatment effects were sustained over the open-label extension. CONCLUSION: Modafinil significantly improves health-related quality of life in narcolepsy.