The US Food and Drug Administration (FDA) has approved an expanded indication for sodium oxybate (Xyrem, Jazz Pharmaceuticals) oral solution for treating symptoms associated with pediatric narcolepsy.
The manufacturer's supplemental new drug application (NDA) was for revising the labeling to include an indication for the treatment of excessive daytime sleepiness (EDS) or cataplexy in patients aged 7 to 17 years with narcolepsy. Cataplexy is the sudden weakening or paralysis of muscles when a patient feels strong emotions.
The central nervous system depressant was previously indicated for these conditions in adult patients only. The FDA's new thumbs up of sodium oxybate "marks the first medicine approved to treat [these symptoms] in children and adolescents with narcolepsy ages seven and older," the manufacturer reported in a press release.
"Narcolepsy is often misunderstood, misrepresented, misdiagnosed, and underdiagnosed, especially in children," Claire Crisp, executive director of Wake Up Narcolepsy, said in the same release. This expanded approval "is a significant step forward for the narcolepsy community as work to elevate awareness of the condition in children and ensure patients, both pediatric and adult, have meaningful treatment options available," added Crisp, who is also the mother of a child with narcolepsy.
The drug was first approved by the FDA in 2002 to treat cataplexy in adults with narcolepsy. As reported by Medscape Medical News, the agency expanded approval in November 2005 to include treatment for EDS in these adult patients.
In July 2018, preliminary results from the multisite, phase 2/3 EXPRESS study, which assessed use of sodium oxybate for the treatment of these symptoms in pediatric patients with narcolepsy, were published in the Lancet Child and Adolescent Health.
In addition, the manufacturer presented oral and poster presentations of EXPRESS results showing efficacy and long-term safety at the SLEEP 2018 annual meeting.
The primary efficacy endpoint was change in weekly number of cataplexy attacks from baseline to end of the double-blind period. Change in EDS during the same period was a key secondary outcome. An open-label safety period of up to 47 weeks followed, for a total study duration of up to 1 year. The participants who were randomly assigned to receive placebo experienced a greater increase in weekly cataplexy attacks compared with those who received sodium oxybate (median increase in attacks, 12.7 per week vs 0.3 per week; P < .0001).
"The safety profile...in children and adolescents in this study was similar to that reported in adults, and no new safety concerns were identified following the use of Xyrem for up to one year," the company reports.
Plazzi G, Ruoff C, Lecendreux M, Dauvilliers Y, Rosen CL, Black J, Parvataneni R, Guinta D, Wang YG, Mignot E. Treatment of paediatric narcolepsy with sodium oxybate: a double-blind, placebo-controlled, randomised-withdrawal multicentre study and open-label investigation. Lancet Child Adolesc Health. 2018 Jul;2(7):483-494.
Narcolepsy is a lifelong neurological disorder with onset commonly in childhood or adolescence. No drugs are indicated for cataplexy and excessive daytime sleepiness in paediatric patients with narcolepsy. Sodium oxybate is approved for use in adult patients with excessive daytime sleepiness or cataplexy, or both, in narcolepsy. We aimed to examine the safety and efficacy of sodium oxybate oral solution treatment in children and adolescents who have narcolepsy with cataplexy.
This was a prospective, double-blind, placebo-controlled, randomised-withdrawal, multisite study and open-label investigation done at 30 sites in five countries (USA, Finland, France, Italy, and the Netherlands). Eligible participants were aged 7-16 years at screening, had narcolepsy with cataplexy, and were either being treated with sodium oxybate or were sodium oxybate-naive at entry. Sodium oxybate-naive participants were titrated to an optimal dose. Participants were randomly assigned (1:1) with a dynamic randomisation algorithm to receive placebo or to remain on sodium oxybate for 2 weeks; they then entered an open-label sodium oxybate treatment period for a total study duration of up to 1 year. Random assignment to placebo was discontinued if early efficacy was shown in the preplanned interim analysis of the primary efficacy endpoint, which was change in weekly number of cataplexy attacks. Participants entering the study after the interim analysis would then be assigned to receive open-label sodium oxybate for 2 weeks. The primary analysis of efficacy and safety included data collected until the cutoff date of Feb 10, 2017. The efficacy population consisted of all participants randomly assigned to receive an intervention who completed at least 5 days of dosing in the double-blind treatment period, and the safety population consisted of all participants who took the study drug, including open-label sodium oxybate. This study is registered with ClinicalTrials.gov, number NCT02221869.
Between Oct 1, 2014, and Feb 10, 2017, we enrolled 106 participants, and 104 took the study drug (the safety population). 96 (92%) of these participants completed the stable-dose period, of whom 63 participants (the efficacy population) were randomly assigned to receive sodium oxybate (n=31) or placebo (n=32) for 2 weeks. A preplanned interim analysis of the primary endpoint showed efficacy (p=0·0002), resulting in discontinuation of the placebo arm following guidance from the data safety monitoring board; 33 participants then received sodium oxybate on an open-label basis during the double-blind period. Participants who were randomly assigned to receive placebo and who were withdrawn from sodium oxybate (32 [51%] of 63 patients) had increased weekly cataplexy attacks (median increase of 12·7 attacks per week [Q1, Q3=3·4, 19·8]) when compared with those randomly assigned to continue treatment with sodium oxybate (median increase of 0·3 attacks per week [-1·0, 2·5]; p<0·0001). Commonly reported (>5%) adverse events were enuresis (15 [21%] of 72 sodium oxybate-naive participants vs four [13%] of 32 participants taking sodium oxybate at study entry), nausea (16 [22%] vs two [6%]), vomiting (15 [21%] vs two [6%]), headache (13 [18%] vs four [13%]), decreased weight (11 [15%] vs one [3%]), decreased appetite (eight [11%] vs none), nasopharyngitis (seven [10%] vs none), and dizziness (five [7%] vs 1 [3%]). Two serious adverse events (one event of severe acute psychosis and one event of moderate suicidal ideation) were reported, and both were considered to be related to the study drug. There were no reported deaths.
These results support the clinical efficacy of sodium oxybate for the treatment of both excessive daytime sleepiness and cataplexy in narcolepsy in children. The safety profile of sodium oxybate was consistent with that observed in adult patients.