By William Elliott, MD, FACP, and James Chan, PharmD, PhD
Dr. Elliott is Assistant Clinical Professor of Medicine, University of California, San Francisco.
Dr. Chan is Associate Clinical Professor, School of Pharmacy, University of California, San Francisco.
Drs. Elliott and Chan report no financial relationships relevant to this field of study.
The FDA has approved a first-in-class selective histamine 3 receptor antagonist/inverse agonist to treat excessive daytime sleepiness (EDS) associated with narcolepsy. Pitolisant received priority review and will be distributed as Wakix.
Pitolisant should be prescribed to treat EDS in adult patients with narcolepsy.1
The recommended dosage is 17.8 mg to 35.6 mg daily.1 The dosage should be titrated as follows: 8.9 mg once daily (week 1); 17.8 mg once daily (week 2); may increase to a maximum dose of 35.6 mg once daily (week 3).
The maximum dose is 17.8 mg for patients with hepatic impairment, renal impairment, or poor CYP2D6 metabolizers.1 Pitolisant is available as 4.45 mg and 17.8 mg tablets.
Pitolisant is the first-in-class treatment for this indication. It also is the first and only drug for this indication that is not scheduled as a controlled substance. Current FDA-approved drugs include modafinil (C-IV), armodafinil (C-IV), solriamfetol (C-IV), methylphenidate (C-II), sodium oxybate (C-III), and amphetamine (C-II).
Pitolisant prolongs the QT interval and should be avoided in patients with known QT prolongation, history of cardiac arrhythmias, or in combination with other drugs known to prolong QT interval. Reduce or avoid the dose for patients who are likely to experience increased systemic exposure to pitolisant (e.g., hepatic or renal impairment, poor CYP2D6 metabolizers, CYP2D6 inhibition). The drug may reduce the effectiveness of hormonal contraceptives (i.e., sensitive CYP3A4 substrate as pitolisant is a weak CYP34A inducer).1
The efficacy of pitolisant was evaluated in two randomized, double-blind, placebo-, and active-controlled studies that included adult subjects with narcolepsy who registered an Epworth Sleepiness Scale (ESS) score ≥ 14. ESS is based on an eight-item, self-administered questionnaire rating the subject’s perceived likelihood of falling asleep during daily activities.1 Each item was rated from 0 to 3 (maximum score, 24). Each study included an eight-week treatment period (three-week dose titration and five-week stable dose period). Subjects received pitolisant, modafinil, or placebo. In study 1 (n = 95), subjects were randomized to pitolisant (initiated at 8.9 mg daily and increased at weekly intervals to 17.8 mg or 35.6 mg based on response and tolerability), modafinil (100 mg, 200 mg, or 400 mg), or placebo.1,2 In study 2 (n = 166), pitolisant dose was initiated at 4.45 mg and increased to 8.9 mg or 17.8 mg based on response and tolerability, modafinil (200 mg daily), or placebo.1,3 The primary efficacy endpoint was the difference in mean change in ESS score between pitolisant and placebo after the eight-week treatment period. If pitolisant was statistically different to placebo, then change between pitolisant and modafinil was assessed. In both studies, pitolisant showed statistically significantly greater improvement in mean ESS score compared to placebo (17% and 12% reduction, respectively). This represented a placebo-subtracted difference of -3.1 and -2.2, with a -3 regarded as clinically relevant.2 In study 1, the improvement vs. placebo between pitolisant and modafinil appeared to differ; however, noninferiority was not established (likely due to inadequate sample size).2 Similar comparisons were not reported for study 2. In study 1, the results of a posthoc analysis suggested that the cataplexy rate was lower for pitolisant vs. placebo. Those results were supported by the results of a recent larger, placebo-controlled study (n = 106; 75% reduction in cataplexy rate vs. 38% for placebo; 49% reduction).4 The most commonly reported adverse reactions included headache, insomnia, and nausea (6-18%).
Narcolepsy is a rare, chronic, neurological disorder characterized by excessive daytime sleepiness with or without cataplexy.5,6 The latter is defined as sudden, transient loss of muscle tone triggered by emotions and accompanied by a preserved state of consciousness.6 The American Academy of Sleep Medicine and European Academy of Neurology/European Sleep Research Society/European Narcolepsy Network recommend modafinil/armodafinil as effective treatment of daytime sleepiness due to narcolepsy.5,6 The FDA recently approved solriamfetol, a selective dual dopamine norepinephrine reuptake inhibitor, for narcolepsy. Generally, these are not effective in reducing cataplexy.5,7,8 Sodium oxybate is the only drug approved in the United States and Europe for treating cataplexy and is available only through the restricted Xyrem REMS Program in the United States. Pitolisant is newly approved in the United States for narcolepsy but has been available in Europe since 2016. It is recommended as a first-line agent for narcolepsy with or without cataplexy but not currently approved in the United States for treating cataplexy. Pitolisant is an alternative to modafinil, especially since pitolisant is a nonscheduled product that may be effective in reducing cataplexy episodes and could prolong QT intervals. The cost of pitolisant has not been announced. The drug is expected to be available in the fourth quarter of 2019.
- Harmony Biosciences, LLC. Wakix Prescribing Information, August 2019. Available at: . Accessed Sept. 24, 2019.
- Dauvilliers Y, Bassetti C, Lammers GJ, et al. Pitolisant versus placebo or modafinil in patients with narcolepsy: A double-blind, randomised trial. Lancet Neurol 2013;12:1068-1075.
- ClinicalTrials.gov. Effects of BF2.649 in the treatment of excessive daytime sleepiness in narcolepsy. Available at: . Accessed Sept. 24, 2019.
- Szakacs Z, Dauvilliers Y, Mikhaylov V, et al. Safety and efficacy of pitolisant on cataplexy in patients with narcolepsy: A randomised, double-blind, placebo-controlled trial. Lancet Neurol 2017;16:200-207.
- Morgenthaler TI, Kapur VK, Brown T, et al. Practice parameters for the treatment of narcolepsy and other hypersomnias of central origin. Sleep 2007;30:1705-1711.
- Kallweit U, Bassetti CL. Pharmacological management of narcolepsy with and without cataplexy. Expert Opin Pharmacother 2017;18:809-817.
- Golicki D, Bala MM, Niewada M, Wierzbicka A. Modafinil for narcolepsy: Systematic review and meta-analysis. Med Sci Monit 2010;16:RA177-RA186.
- Thorpy MJ, Shapiro C, Mayer G, et al. A randomized study of solriamfetol for excessive sleepiness in narcolepsy. Ann Neurol 2019;85:359-370.