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Home , Sodium oxybate

Submitted by: Deborah Profant, PhD Associate Director, [email protected]

Xyrem® (Sodium Oxybate) Oral Solution Executive Summary for Medicaid

Narcolepsy Overview

Narcolepsy is a chronic neurologic disorder that involves dysregulation of the sleep/wake cycle.1 Narcolepsy is associated with a pentad of symptoms – excessive daytime sleepiness (EDS), (sudden transient loss of muscle tone), hypnogogic/hypnopompic hallucinations (hallucinations upon falling asleep/awakening), sleep paralysis and disrupted nighttime sleep (DNS, associated with fragmented sleep resulting from awakenings).2 It is a rare disorder and the prevalence in the United States ranges between 30.6 and 56.3 per 100,000 persons.3-5

Xyrem Overview

Xyrem is a central nervous system indicated for the treatment of cataplexy or EDS in patients 7 years and older with narcolepsy.6 The of Xyrem in the treatment of narcolepsy is unknown; however, it is hypothesized that its therapeutic effects on cataplexy and EDS are mediated by GABAB actions at noradrenergic and dopaminergic neurons, as well as at thalamocortical neurons.

The American Academy of Sleep Medicine has designated Xyrem as a standard of care for treatment of EDS, cataplexy, and disrupted sleep in narcolepsy.7 Xyrem is the only medication approved by the FDA to treat both EDS and cataplexy in narcolepsy, and the only FDA approved medication for the treatment of cataplexy. Xyrem is contraindicated in combination with or and in patients with succinic semialdehyde dehydrogenase deficiency.6

The recommended dosage range for Xyrem in adults is 6 g to 9 g per night orally, while in pediatric patients the recommended starting dosage, titration regimen, and maximum total nightly dosage are based on body weight.6 Xyrem is only available through a restricted program called the Xyrem REMS Program and both prescribers and patients must enroll.

Xyrem – Efficacy and Safety in Adult Patients

The effectiveness of Xyrem in reducing the frequency of cataplexy attacks was established in two, randomized, double-blind, placebo-controlled, multicenter, parallel-group trials in adult patients with narcolepsy with cataplexy – Trials N1 with 136 patients and N2 with 55.6

In Trial N1, Xyrem 6 g and 9 g/night resulted in statistically significant reductions in the frequency of cataplexy attacks (P <0.05 and P <0.005 vs placebo, respectively).6 Trial N2, was a randomized withdrawal trial and patients randomized to placebo after discontinuing long-term open-label Xyrem experienced a significant increase in cataplexy attacks, providing evidence of the continued efficacy of Xyrem after long-term use. Most patients, 80-85% in each trial, were receiving concomitant central nervous system (CNS) .

The effectiveness of Xyrem in improving excessive daytime sleepiness was also established in two 8- week, randomized, double-blind, placebo-controlled, multicenter, parallel-group trials in adult patients with narcolepsy with moderate to severe excessive daytime sleepiness – Trial N3 with 228 patients and Trial N4 with 222 patients.6

In Trial N3, statistically significant improvements were seen in EDS as measured by the Epworth Sleepiness Scale score and Clinical Global Impression of Change at Week 8 with Xyrem 6 g and 9 g/night versus placebo (P <0.001 vs placebo).6 A statistically significant improvement in the change in the Maintenance of Wakefulness Test score from baseline at Week 8 was seen in the Xyrem and Xyrem plus groups compared with the placebo group (P <0.001 vs placebo for both groups) was observed in Trial N4. A post-hoc analysis of Trial N4 was conducted to characterize the effect of Xyrem, modafinil and their combination on DNS.2 The results of this analysis showed that Xyrem alone or in combination with modafinil significantly consolidated sleep (improved DNS) and improved patient-reported sleep quality when compared to placebo (P≤0.05).

In clinical trials, the most common adverse reactions in adults, with an incidence of 5% or more and at least twice the incidence with placebo, were nausea, dizziness, vomiting, somnolence, enuresis, and tremor.6 Of the 398 patients with narcolepsy treated with Xyrem, 10.3% of patients discontinued because of adverse reactions compared with 2.8% of patients receiving placebo. The most common adverse reaction leading to discontinuation was nausea (2.8%). The majority of adverse reactions leading to discontinuation began during the first few weeks of treatment.

Xyrem – Efficacy and Safety in Pediatric Patients

The effectiveness of Xyrem in the treatment of cataplexy and excessive daytime sleepiness in pediatric patients 7 years of age and older with narcolepsy was established in a double-blind, placebo-controlled, randomized-withdrawal study (Trial N5) in which 106 pediatric patients were enrolled.6 Patients entered the study either on a stable dose of Xyrem or were Xyrem-naïve. The dose of Xyrem, in Xyrem naïve patients, was initiated and titrated based on body weight over a period of up to 10 weeks. Results from this study showed that withdrawal of Xyrem and subsequent treatment with placebo resulted in a statistically significant (P<0.0001) increase in weekly cataplexy attacks and statistically significant, (P=0.0004) worsening of excessive daytime sleepiness when compared with patients who remained on Xyrem.

The most common adverse reactions in pediatric patients, occurring at an incidence ≥5%, were enuresis, nausea, headache, vomiting, weight decreased, decreased appetite, and dizziness.6 In Trial N5, 5 of 104 patients reported adverse reactions that led to withdrawal from the study (hallucination, tactile; suicidal ideation; weight decreased; sleep apnea syndrome; and affect lability).

Xyrem – Additional Information6

Drug Interactions Xyrem should not be used in combination with alcohol or sedative hypnotics. Use of other CNS may potentiate the CNS-depressant effects of Xyrem. Concomitant use of Xyrem with divalproex sodium resulted in a 25% mean increase in systemic exposure to Xyrem (AUC ratio range of 0.8 to 1.7) and in a greater impairment on some tests of attention and working memory. An initial Xyrem dose reduction of at least 20% is recommended if divalproex sodium is prescribed to patients

already taking Xyrem. Prescribers are advised to monitor patient response closely and adjust dose accordingly if concomitant use of Xyrem and divalproex sodium is warranted.

Pregnancy There are no adequate and well-controlled studies in pregnant women. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. The background risk of major birth defects and miscarriage for the indicated population is unknown.

Dependence and Tolerance There have been case reports of withdrawal, ranging from mild to severe, following discontinuation of illicit use of GHB at frequent repeated doses (18 g to 250 g per day) in excess of the therapeutic dosage range. Tolerance to Xyrem has not been systematically studied in controlled clinical trials. There have been some case reports of symptoms of tolerance developing after illicit use at dosages far in excess of the recommended Xyrem regimen.

Place in Therapy

XYREM is approved by the US FDA to treat cataplexy and EDS in patients 7 years and older with narcolepsy (XYREM [package insert] 2018).7 The American Academy of Sleep Medicine has designated XYREM as a standard of care for treatment of excessive daytime sleepiness, cataplexy, and disrupted nighttime sleep in narcolepsy. The American Academy of Sleep Medicine has designated XYREM as an option for treatment of hypnagogic hallucinations and sleep paralysis.7 XYREM is not indicated to treat disrupted nighttime sleep, hypnagogic hallucinations or sleep paralysis.6

Most treatments for narcolepsy target the associated symptom of EDS.8 FDA approved treatments for EDS in narcolepsy include stimulants (e.g., ), wakefulness-promoting agents (modafinil and ), a and (), a histamine-3 antagonist/inverse agonist (pitolisant) and a CNS depressant (sodium oxybate).8,9,10-14,6)

XYREM is indicated for the treatment of cataplexy in patients 7 years and older with narcolepsy.6 Although not approved by the FDA for the treatment of cataplexy in narcolepsy, medications such as selective serotonin reuptake inhibitors (SSRIs), serotonin–norepinephrine reuptake inhibitors (SNRIs), and tricyclic (TCAs) are recommended by the American Academy of Sleep Medicine as treatments for cataplexy and are recommended as an option for hypnagogic hallucinations and sleep paralysis.7,15,16 The American Academy of Sleep Medicine also recommends hypnotics as an option for disrupted nighttime sleep.7

Rebound cataplexy, worsening of severity and frequency of cataplexy attacks above baseline levels, has been observed following abrupt discontinuation of some anticataplectics, particularly antidepressants.17 During a double-blind, placebo-controlled, randomized withdrawal study of 55 patients with narcolepsy who had been taking XYREM for 7 to 44 months prior to study entry, patients who were randomized to abruptly discontinue XYREM and take placebo experienced a gradual return of cataplexy over the two week randomized withdrawal period, and rebound cataplexy was not reported.18

References

1. Thorpy MM. Update on Therapy for Narcolepsy. Curr Treat Options Neurol 2014;17:20. 2. Dauvilliers Y, Roth T, Guinta D et al. Effect of sodium oxybate, modafinil, and their combination on disrupted nighttime sleep in narcolepsy. Sleep Med 2017; 40:53-57. 3. Silber MB, Krahn LE, Olson EJ et al. The Epidemiology of Narcolepsy in Olmsted County, Minnesota: A Population-Based Study. Sleep. 2002;25(2):197-202. 4. Longstreth WT Jr, Ton TGN, Koepsell et al. Prevalence of Narcolepsy in King Count, Washington, USA. Sleep Med. 2009;10:422-426. 5. Hess G, Mehra R, Carls G et al. US Prevalence of Narcolepsy and Other Sleep Disorders from 2013– 2016: A Retrospective, Epidemiological Study Utilizing Nationwide Claims. Poster presented at: Annual Meeting of the Association of Professional Sleep Societies (APSS); June 2-6, 2018; Baltimore, MD. Poster 335. 6. Xyrem (sodium oxybate) oral solution [prescribing information]. Jazz Pharmaceuticals, Inc.; 2018. 7. Morgenthaler TI et al. Practice parameters for the treatment of narcolepsy and other hypersomnias of central origin. Sleep. 2007;30(12):1705-1711. 8. Bhattarai J and Sumerall SW. Current and future treatment options for narcolepsy: a review. Sleep Science. 2017;10:19-27. 9. Barateau L, Lopez R, Dauvilliers Y. Treatment options for narcolepsy. CNS Drugs. 2016;30:369-379. 10. RITALIN™ (methylphenidate) tablets [prescribing information]. East Hanover, NJ: Novartis, Inc.; January 2019. 11. NUVIGIL® (armodafinil) tablets [prescribing information]. Frazer, PA: Cephalon, Inc.; May 2015. 12. PROVIGIL® (modafinil) tablets [prescribing information]. Frazer, PA: Cephalon, Inc.; November 2018. 13. SUNOSI™ (solriamfetol) tablets [prescribing information]. Palo Alto, CA: Jazz Pharmaceuticals, Inc.; June 2019. 14. WAKIX® (pitolisant) tablets [prescribing information]. Plymouth Meeting, PA: Harmony Biosciences; November 2019. 15. Thorpy MJ. Update on therapy for narcolepsy. Curr Treat Options Neurol. 2015;17:20-31. 16. Vignatelli L, D’Alessandro R, Candelise L. drugs for narcolepsy. Cochrane Database Syst Rev.2008:CD003724. 17. Ristanovic RK, Liang H, Hornfeldt CS, Lai C. Exacerbation of cataplexy following gradual withdrawal of antidepressants: Manifestation of probable protracted rebound cataplexy. Sleep Medicine. 2009;10:416-421. 18. US XYREM Multicenter Study Group. Sodium oxybate demonstrates long term efficacy for the treatment of cataplexy in patients with narcolepsy. Sleep Medicine. 2004(5);119-123.