The European Medicines Agency (EMA) approved pitolisant (Wakix®, Bioprojet Pharma, Paris, France) in 2016 for the treatment of the rare disease narcolepsy with or without cataplexy. As we enter 2019, neurologists now have several years of experience with pitolisant and that experience reinforces that pitolisant is a safe and effective therapy for narcolepsy and cataplexy. Pitolisant is also being used in pediatric patients experimentally in in the EU and off-label in the United States and the safety profile in children appears to be consistent with that seen in adults.
According to a 2018 review article by Romigi et al, at the time of writing, the clinical program for pitolisant involved 1,385 subjects (291 healthy controls and 1,094 patients, of whom 342 were diagnosed with narcolepsy, while the remaining 742 patients were being treated for different indications). Approximately 20% of these patients had been treated with pitolisant for longer than a year. In the case of patients being treated for narcolepsy, the percentage of patients treated with pitolisant (52.3%) reported at least one adverse event (AE), a number which was slightly higher than that seen in the group being treated by placebo (41.1%) and similar to a different active drug (modafinil, 55.1%). The most common AEs with pitolisant were headache (16%), insomnia (7.9%), and nausea (5.6%). There have been no documented serious adverse events with pitolisant except for one case of severe nausea. According to its package insert the most commonly observed adverse events (≥5%) associated with the use of modafinil are headache, nausea, nervousness, rhinitis, diarrhea, back pain, anxiety, insomnia, dizziness, and dyspepsia. The other drug frequently prescribed to treat narcolepsy and cataplexy is Sodium oxybate, which has a black box warning for central nervous system depression and misuse and abuse.
Termination of pitolisant was not associated with withdrawal syndrome. In addition, animal studies indicate that pitolisant is not associated with any potential for abuse or dependence. Researchers acknowledge, however, that since pitolisant has been found to enhance memory performance there is a risk that patients may divert pitolisant to improve intellectual performance. In contrast, modafinil is listed in Schedule IV of the Controlled Substances Act due to its abuse potential and sodium oxybate is listed as a Schedule III controlled substance for similar reasons.
A 2018 meta-analysis compared the safety and efficacy of multiple treatments of narcolepsy as documented in 14 randomized control trials. The investigators found that, when compared to other treatments for narcolepsy and/or cataplexy, pitolisant had the highest benefit/risk ratio. The investigator calculated the ratio of efficacy to safety and found that pitolisant at 40 mg/day had the best score at 0.53 (95% confidence interval [CI], 0.10 – 0.95), followed by modafinil (score of 0.29, 95% CI, 0.09-0.49), and sodium oxybate at 9 grams/day (score of 0.22, 95% CI, -0.13-0.57). These scores reflect the fact that while pitolisant’s efficacy was like sodium oxybate and modafinil, its safety profile was far superior.
Pediatric experience with pitolisant, while it exists, remains limited. Preliminary results of a trial of 24 children in the EU with narcolepsy were presented in 2016 at the 23rd Congress of the European Sleep Research Society. Those results indicate that the 18 mg single dose is tolerable in the patients aged 6-18. Research presented at the 2018 Foundation for Prader-Willi Research (FPWR) annual research symposium in Las Vegas described the US experience of pediatric patients with Prader-Willi Syndrome (PWS) who obtained pitolisant from the EU via personal importation allowed at the FDA’s discretion. The researchers reported that pitolisant was well-tolerated in doses up to 36 mg/day in patients aged 2 years to 15 years.
Lehert, P and B Falissard. Multiple treatment comparison in narcolepsy: a network meta-analysis. Sleep. 41 (12). December 2018.
Pullen, LC, M Picone, LJ Tan, et al. Cognitive Improvements in Children with Prader-Willi Syndrome Following Pitolisant Treatment. 2018 Foundation for Prader-Willi Research (FPWR) Annual Research Symposium. Abstract.
Romigi, A, G Vitrani, T Lo Giudice, et al. Profile of pitolisant in the management of narcolepsy: design, development, and place in therapy. Drug Des Devel Ther. 2018; 12: 2665–2675.
Szakacs Z, Y Dauvilliers, V Mikhaylov, et al. Safety and efficacy of pitolisant on cataplexy in patients with narcolepsy: a randomised, double-blind, placebo-controlled trial. Lancet Neurol. 2017;16(3):200-207.