Regulatory Decision Summary for Wakix

Wakix (pitolisant) is currently approved in Canada for the treatment of excessive daytime sleepiness (EDS) or cataplexy in patients with narcolepsy in adults and in pediatric patients (aged 6 years and older and weighing at least 30 kilograms [kg]).

The sponsor submitted a Supplemental New Drug Submission, based on two pivotal Phase 3 studies, to propose the addition of the indication for the Treatment of EDS in adult patients with obstructive sleep apnea (OSA), with or without concomitant continuous positive airway pressure (CPAP).

The proposed indication was revised to indicate clearly that Wakix does not treat the underlying cause of OSA and does not replace primary treatment.

The final approved supplement to the current indication is:

Wakix is indicated for the treatment of EDS in adult patients with obstructive sleep apnea (OSA), accepting or refusing concomitant continuous positive airway pressure (CPAP) as a primary treatment.

Wakix is not indicated to treat the underlying airway obstruction in patients with OSA and is not a substitute for primary OSA therapy. Primary OSA therapy for the underlying airway obstruction should be maintained continued during treatment with Wakix.

With this Supplemental New Drug Submission the sponsor sought approval of an additional indication and patient population for the drug product Wakix (5 and 20 milligram [mg] pitolisant tablets).

Obstructive sleep apnea (OSA) is a common sleep disorder associated with comorbidities. Primary treatments such as continuous positive airway pressure (CPAP) are important to improve patients’ sleep and may also decrease comorbidities, but adherence may be difficult. Patients complain of remaining excessive daytime sleepiness (EDS), with or without CPAP. EDS can be debilitating and affect patients’ daily function.

Two pivotal Phase 3 studies demonstrated improvement in the Epworth Sleepiness Scale (ESS) in OSA patients that either adhered to CPAP therapy (Study P-09-08), or refused CPAP therapy (Study P-09-09). A third supportive Phase 3 study confirmed the effect of Wakix. The studies were well-designed and well-conducted.

Since Wakix does not address the underlying cause of OSA, the proposed indication statement was revised to clearly enunciate that it does not replace primary treatment.

The adverse effects reported in the Phase 3 studies were generally consistent with the adverse effects previously observed in narcolepsy studies (in the original NDS). The most common adverse events reported in pitolisant-treated patients, at an incidence greater than placebo were insomnia (8.8% versus [vs.] 4.0%), nausea (3.2% vs. 1.3%) and abdominal pain (2.6% vs. 1.3%). Headache, which was the most frequently reported adverse event, had a higher incidence in the placebo group (13.9%) compared to the pitolisant group (13.5%), without reaching statistical significance.

OSA is associated with cardiovascular comorbidities. Wakix labelling includes warnings regarding QT prolongation and an adverse event of QT prolongation on electrocardiogram was reported in laboratory values. Yet, no obvious signal of increased cardiovascular risk was detected in the Phase 3 studies in support of use of Wakix in OSA patients.

Amphetamine-like withdrawal symptoms may include symptoms such as dysphoria, insomnia / hypersomnia or psychomotor agitation. Patients were assessed at the conclusion of the studies (either at the end of the double-blind phase or after the open label phase), where no patients met the criteria for amphetamine-like withdrawal symptoms, however, the ESS scores were suggestive of a possible rebound effect. The adverse event of withdrawal syndrome was added to the post-market adverse reactions section of the Product Monograph based on two reports in the Periodic Safety Update (PSUR).

Wakix demonstrated efficacy in OSA patients in the pivotal Phase 3 studies. Adverse effects, risks, and uncertainties were properly addressed in the labelling. The Product Monograph was updated to expand the indication as follows:

The treatment of EDS in adult patients with obstructive sleep apnea (OSA), accepting or refusing concomitant continuous positive airway pressure (CPAP) as a primary treatment.

Wakix is not indicated to treat the underlying airway obstruction in patients with OSA and is not a substitute for primary OSA therapy. Primary OSA therapy for the underlying airway obstruction should be continued during treatment with Wakix.

Overall, the benefit-harm-uncertainty profile was favorable for Wakix when used according to the recommended indications in the approved Product Monograph. Therefore, a Notice of Compliance was recommended.

For further details about Wakix, please refer to the Product Monograph, approved by Health Canada and available through the Drug Product Database.