Key points

Advice

The content of this evidence summary was up-to-date in March 2017. See summaries of product characteristics (SPC), British national formulary (BNF) or the MHRA or NICE websites for up-to-date information.

Regulatory status: New medicine. Pitolisant is a histamine H3‑receptor antagonist/inverse agonist that is licensed for the treatment of narcolepsy with or without cataplexy in adults. It was launched in the UK in September 2016.

Overview

Narcolepsy is a rare, disabling long‑term brain disorder that can result in excessive daytime sleepiness, sleep attacks, cataplexy, sleep paralysis, excessive dreaming and disturbed nocturnal sleep.

This evidence summary reviewed 2 small randomised controlled trials (RCTs) of pitolisant 5–40 mg per day in adults with narcolepsy with or without cataplexy. Compared with placebo, pitolisant improved excessive daytime sleepiness, improved time awake in a darkened room and reduced the weekly cataplexy rate. Pitolisant was also compared with modafinil in a non-inferiority analysis (an analysis designed to test if it was not worse than modafinil for improving excessive daytime sleepiness by a pre-specified amount). Non-inferiority to modafinil was not shown.

The long‑term safety data for pitolisant in people with narcolepsy are limited. Narcolepsy is an orphan disease, and clinical studies included small numbers of people for a short duration of time. In the 2 RCTs reviewed in this evidence summary, the most common adverse events in the pitolisant groups were headache, insomnia, abdominal discomfort, nausea, irritability and anxiety. No participants in the pitolisant groups had withdrawal syndrome during the withdrawal phase.

Pitolisant is the first of a new class of medicine licensed to treat narcolepsy with or without cataplexy, and is an additional option that could be used in this rare condition. Other medicines licensed for use in narcolepsy include the central nervous system stimulants, modafinil and dexamfetamine, and the central nervous system depressant, sodium oxybate.

A summary to inform local decision-making is shown in table 1.

Table 1 Summary of the evidence on effectiveness, safety, patient factors and resource implications

Effectiveness

Pitolisant 10 mg to 40 mg per day^a was statistically and clinically superior to placebo for improving excessive daytime sleepiness measured by the Epworth Sleepiness Scale (ESS). The mean difference was −3.0 points; 95% confidence interval (CI) −5.6 to −0.4, p=0.024 (HARMONY I [Dauvilliers et al. 2013], 8‑week duration, n=95).
Pitolisant 10 mg to 40 mg per day^a was not shown to be non-inferior to modafinil 100 mg to 400 mg per day for excessive daytime sleepiness measured by the ESS. The mean difference was 0.12 points; 95% CI −2.5 to 2.7, p=0.250, which was outside the non-inferiority margin of 2 points (HARMONY I, 8-week duration, n=95).
For time awake in a darkened room, pitolisant 10–40 mg per day^a was statistically superior to placebo by a factor of 1.47 (95% CI 1.01 to 2.14, p=0.044) and there was no statistically significant difference compared with modafinil 100 mg to 400 mg per day (0.77; 95% CI 0.52 to 1.13, p=0.173) measured by the maintenance of wakefulness test. There was an increase from a baseline of 7.4 minutes to 9.7 minutes in the pitolisant group, and 8.8 minutes to 15.1 minutes in the modafinil group (HARMONY I, 8‑week duration, n=95).
For attention level, there was no statistically significant difference between pitolisant 10 mg to 40 mg per day^a and placebo, or pitolisant 10 mg to 40 mg per day^a and modafinil 100 mg to 400 mg per day for the sustained attention to response task total score (HARMONY I, 8‑week duration, n=95).
Pitolisant 5 mg to 40 mg per day^a reduced the weekly cataplexy rate by about half compared with placebo (rate ratio 0.51; 95% CI 0.44 to 0.60, p<0.0001); from a baseline of 9.15 to 2.27 attacks per week in the pitolisant group, and 7.31 to 4.52 attacks per week in the placebo group (HARMONY-CTP [Szakacs et al. 2017], 7‑week duration, n=106).

Safety

Pitolisant is contraindicated in severe hepatic impairment and should be administered with caution in people with moderate hepatic impairment or renal impairment, a history of psychiatric disorders, acid related gastric disorders or taking concomitant gastric irritants, severe obesity or anorexia, severe epilepsy, cardiac disease, taking concomitant QT‑prolonging medicines or CYP2D6 inhibitors (pitolisant summary of product characteristics [SPC]).
Women of childbearing potential have to use effective contraception during treatment and for at least 21 days after discontinuation. Pitolisant may reduce the effectiveness of hormonal contraceptives and alternative methods of contraceptives should be used (pitolisant SPC).
The most serious adverse drug reactions are abnormal weight decrease (0.09%) and spontaneous abortion (0.09%; pitolisant SPC).

Patient factors

Pitolisant tablets should be used at the lowest effective dose, depending on individual response and tolerance (dose range 4.5 mg to 36 mg per day^a). It is estimated that about one third of people will be maintained on 18 mg per day and two thirds of people will require 36 mg per day.
Pitolisant is taken as a single dose in the morning during breakfast.
The most frequent adverse drug reactions are insomnia (8.4%), headache (7.7%), nausea (4.8%), anxiety (2.1%), irritability (1.8%), dizziness (1.4%), depression (1.3%), tremor (1.2%), sleep disorders (1.1%), fatigue (1.1%), vomiting (1.0%), vertigo (1.0%), dyspepsia (1.0%), weight increase (0.9%), and upper abdominal pain (0.9%; pitolisant SPC).

Resource implications

The cost of 30 days treatment with pitolisant at a dose of 4.5 mg to 36 mg once daily is £310.00 to £620.00 (MIMS, February 2017, excluding VAT).
The cost of 30 days treatment with other medicines used for narcolepsy is £6.06 to £318.24 for stimulants such as modafinil, dexamfetamine or methylphenidate and £540.00 to £1,080.00 for sodium oxybate (Drug Tariff, February 2017, excluding VAT).

^a In the RCTs, pitolisant was given as pitolisant hydrochloride 5 mg to 40 mg, which is equivalent to a pitolisant dose of 4.5 mg to 36 mg.