Effects of pitolisant, a histamine H3 inverse agonist, in drug-resistant idiopathic and symptomatic hypersomnia: a chart review

• We evaluated pitolisant in refractory idiopathic and symptomatic hypersomnia.
• A long-term favorable benefit/risk ratio was found in 23–38% of the patients.
• Side effects were gastro-intestinal problems, weight gain, headache, insomnia, anxiety.
• The good safety profile supports testing the drug more formally in patients with IH.

ObjectiveTo evaluate the benefits and risks of pitolisant (a wake-enhancing drug that increases the histamine release in the brain by blocking presynaptic H3 histamine reuptake) in patients with idiopathic (IH) and symptomatic (SH) hypersomnia plus sleepiness refractory to available stimulants (modafinil, methylphenidate, mazindol, sodium oxybate, and d-amphetamine).MethodsThrough retrospective analyses of patient files, the benefit (the score from the Epworth Sleepiness Scale [ESS], authorization renewal) and tolerance (side-effects) of pitolisant were assessed.ResultsA total of 78 patients with IH (n = 65%, 78% women) and SH (n = 13%, 54% women) received pitolisant 5–50 mg once per day over the course of five days to 37 months. The median (interquartile range) ESS scores of patients with IH decreased from 17 (15.5–18.5) to 14 (12–17). There were 36% responders (ESS fall of ⩾3). The improvement in ESS score (−1.9 ± 2.6) was different from 0 in IH without long sleep time (P < 0.002) and in IH with a long sleep time (P < 0.0001), but not in SH. Forty-four (63%) patients with IH and 12 (77%) patients with SH stopped pitolisant, mostly due to a lack of efficacy. Side-effects included gastrointestinal pain (15.4%), increased appetite and weight gain (14.1%), headache (12.8%), insomnia (11.5%), and anxiety (9%), as well as exceptional reports of depression and persistent genital arousal.ConclusionPitolisant had a long-term favorable benefit/risk ratio in 23–38% of drug-resistant patients with IH and SH, suggesting that histamine neurons can be stimulated in severe idiopathic and symptomatic hypersomnia.