Jazz Pharmaceuticals plc today announced that the U.S. Food and Drug Administration (FDA) approved its supplemental new drug application (sNDA) on October 26, 2018, to revise labeling for Xyrem® (sodium oxybate) oral solution, CIII, to include an indication to treat cataplexy or excessive daytime sleepiness (EDS) in patients with narcolepsy ages seven and older.
"Narcolepsy is often misunderstood, misrepresented, misdiagnosed and underdiagnosed, especially in children," said Claire Crisp, executive director of Wake Up Narcolepsy and mother of a child with narcolepsy. "This approval of Xyrem in pediatric patients is a significant step forward for the narcolepsy community as we work to elevate awareness of the condition in children and ensure patients, both pediatric and adult, have meaningful treatment options available."
"Xyrem is the only FDA-approved treatment available for excessive daytime sleepiness and cataplexy in narcolepsy for adult patients," said Jed Black, M.D., senior vice president, Sleep and CNS Medicine at Jazz Pharmaceuticals and adjunct professor, Stanford Center for Sleep Sciences and Medicine. "In a pivotal study we demonstrated both safety and efficacy of Xyrem in pediatric patients with narcolepsy. We are pleased to lead the sleep community in advancing the science and identifying meaningful treatment options for children and adolescents."
The efficacy of Xyrem for the treatment of cataplexy or EDS in pediatric patients with narcolepsy was established in the multisite Phase 2/3 EXPRESS study, which enrolled patients seven to 17 years of age with narcolepsy with cataplexy.
Participants eligible for the study could either have been taking Xyrem or be Xyrem-naïve at study entry. Xyrem-naïve participants underwent open-label titration to reach a tolerable and effective dose. Following a stable dose period, all participants underwent a two week, double-blind, randomized-withdrawal period and were randomly assigned to either remain on Xyrem at their stable dose, or to receive placebo. The primary efficacy endpoint was the change in weekly number of cataplexy attacks, from the stable-dose period (baseline) to the end of the double-blind period. The change in EDS, as assessed by the Epworth Sleepiness Scale for Children and Adolescents (ESS-CHAD), from baseline to the end of the double-blind period was a key secondary outcome measure. Following the randomized-withdrawal period, participants entered an open-label safety period for up to an additional 47 weeks, for a total study duration of up to one year.
Participants who were randomized to placebo (withdrawn from Xyrem (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 who continued treatment with Xyrem (median increase of 0·3 attacks per week [Q1, Q3 = –1·0, 2·5]; p<0·0001).
The safety profile of Xyrem 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 open-label portion of the study is still ongoing. As of February 2017 (the time of the data cut), the most common Treatment-Emergent Adverse Events (TEAEs) (>5%) were enuresis, nausea, vomiting, headache, decreased weight, decreased appetite, nasopharyngitis and dizziness. Two serious TEAEs occurred (acute psychosis which was severe and suicidal ideation which was moderate in severity).
For the data cut, safety assessments included measures of anxiety (Multidimensional Anxiety Scale for Children 10-item [MASC-10]), depressive symptoms (Children's Depression Inventory 2nd Edition Self-Report Short Version [CDI 2:SR(S)]) and suicidality (Columbia-Suicide Severity Rating Scale [C-SSRS]), in addition to TEAEs. T-scores on the MASC-10 were within the average range throughout the study in participants who were Xyrem-naïve and on-Xyrem at study entry. T-scores on the CDI 2:SR(S) were within the average range throughout the study in participants who were Xyrem-naïve and on-Xyrem at study entry; a slight downward trend was observed in mean CDI 2:SR(S) T-scores over time.
Results from the Phase 2/3 EXPRESS study were published in The Lancet Child & Adolescent Health in July 2018, and topline data was presented at APSS in June 2017 and 2018.
The Micromedex DRUGDEX® monograph for Xyrem contains a Class IIA recommendation (recommended, in most cases) for use to treat cataplexy in narcolepsy in the pediatric patient population. The Micromedex DRUGDEX® is one of several statutorily named compendia in the United States Medicaid and Medicare programs for use in the determination of prescription and non-prescription drugs.