Lower-sodium oxybate (LXB) is an oxybate medication approved to treat cataplexy or excessive daytime sleepiness (EDS) in patients with narcolepsy 7 years of age and older in the United States. LXB was developed as an alternative to sodium oxybate (SXB), because the incidence of cardiovascular comorbidities is higher in patients with narcolepsy and there is an elevated cardiovascular risk associated with high sodium consumption. LXB has a unique formulation of calcium, magnesium, potassium, and sodium ions, containing 92% less sodium than SXB. Whereas the active oxybate moiety is the same for LXB and SXB, their pharmacokinetic profiles are not bioequivalent; therefore, a phase 3 trial in participants with narcolepsy was conducted for LXB. This review summarizes the background on oxybate as a therapeutic agent and its potential mechanism of action on the gamma-aminobutyric acid type B (GABAB) receptor at noradrenergic and dopaminergic neurons, as well as at thalamocortical neurons. The rationale leading to the development of LXB as a lower-sodium alternative to SXB and the key efficacy and safety data supporting its approval for both adult and pediatric patients with narcolepsy are also discussed. LXB was approved in August 2021 in the United States for the treatment of idiopathic hypersomnia in adults. Potential future developments in the field of oxybate medications may include novel formulations and expanded indications for other diseases.

Department of Neurology 1st Faculty of Medicine Charles University and General University Hospital Prague Czech Republic

Department of Neurology Albert Einstein College of Medicine Bronx NY USA

Helsinki Sleep Clinic Terveystalo Healthcare and Department of Clinical Neurosciences University of Helsinki Helsinki Finland

Sleep and Wake Disorders Centre Department of Neurology Gui de Chauliac Hospital Montpellier France

Sleep Disorders Center Department of Neurology Cleveland Clinic Cleveland OH USA

University of Montpellier INSERM Institute Neuroscience Montpellier Montpellier France

University of South Carolina School of Medicine Columbia SC USA

Zobrazit více v PubMed

Maski K, Trotti LM, Kotagal S, et al. Treatment of central disorders of hypersomnolence: an American Academy of Sleep Medicine clinical practice guideline. J Clin Sleep Med. 2021;17(9):1881–1893. doi:10.5664/jcsm.9328 PubMed DOI PMC

Bassetti CLA, Kallweit U, Vignatelli L, et al. European guideline and expert statements on the management of narcolepsy in adults and children. J Sleep Res. 2021;30(6):e13387. doi:10.1111/jsr.13387 PubMed DOI

Caputo F, Del Re A, Brambilla R, et al. Sodium oxybate in maintaining alcohol abstinence in alcoholic patients according to Lesch typologies: a pilot study. J Psychopharmacol. 2014;28(1):23–30. doi:10.1177/0269881113504015 PubMed DOI

Xyrem® (sodium oxybate) oral solution, CIII [prescribing information]. Palo Alto, CA: Jazz Pharmaceuticals, Inc.; 2020.

Billiard M, Bassetti C, Dauvilliers Y, et al. EFNS guidelines on management of narcolepsy. Eur J Neurol. 2006;13(10):1035–1048. doi:10.1111/j.1468-1331.2006.01473.x PubMed DOI

Wang YG, Swick TJ, Carter LP, Thorpy MJ, Benowitz NL. Safety overview of postmarketing and clinical experience of sodium oxybate (Xyrem): abuse, misuse, dependence, and diversion. J Clin Sleep Med. 2009;5(4):365–371. doi:10.5664/jcsm.27549 PubMed DOI PMC

Xyrem [summary of product characteristics]. Brussels, Belgium: UCB Pharma; 2021.

U.S. Xyrem Multicenter Study Group. A randomized, double blind, placebo-controlled multicenter trial comparing the effects of three doses of orally administered sodium oxybate with placebo for the treatment of narcolepsy. Sleep. 2002;25(1):42–49. PubMed

U.S. Xyrem Multicenter Study Group. A 12-month, open-label, multicenter extension trial of orally administered sodium oxybate for the treatment of narcolepsy. Sleep. 2003;26(1):31–35. PubMed

U.S. Xyrem Multicenter Study Group. Sodium oxybate demonstrates long-term efficacy for the treatment of cataplexy in patients with narcolepsy. Sleep Med. 2004;5(2):119–123. doi:10.1016/j.sleep.2003.11.002 PubMed DOI

Xyrem International Study Group. A double-blind, placebo-controlled study demonstrates sodium oxybate is effective for the treatment of excessive daytime sleepiness in narcolepsy. J Clin Sleep Med. 2005;1(4):391–397. doi:10.5664/jcsm.26368 PubMed DOI

Black J, Houghton WC. Sodium oxybate improves excessive daytime sleepiness in narcolepsy. Sleep. 2006;29(7):939–946. doi:10.1093/sleep/29.7.939 PubMed DOI

Strunc MJ, Black J, Lillaney P, et al. The Xyrem(®) (sodium oxybate) Risk Evaluation and Mitigation Strategy (REMS) Program in the USA: results from 2016 to 2017. Drugs Real World Outcomes. 2021;8(1):15–28. doi:10.1007/s40801-020-00223-6 PubMed DOI PMC

Carter LP, Pardi D, Gorsline J, Griffiths RR. Illicit gamma-hydroxybutyrate (GHB) and pharmaceutical sodium oxybate (Xyrem): differences in characteristics and misuse. Drug Alcohol Depend. 2009;104(1–2):1–10. doi:10.1016/j.drugalcdep.2009.04.012 PubMed DOI PMC

George J, Majeed W, Mackenzie IS, Macdonald TM, Wei L. Association between cardiovascular events and sodium-containing effervescent, dispersible, and soluble drugs: nested case-control study. BMJ. 2013;347:f6954. doi:10.1136/bmj.f6954 PubMed DOI PMC

Wei L, Mackenzie IS, MacDonald TM, George J. Cardiovascular risk associated with sodium-containing medicines. Expert Opin Drug Saf. 2014;13(11):1515–1523. doi:10.1517/14740338.2014.970163 PubMed DOI

Whelton PK, Appel LJ, Sacco RL, et al. Sodium, blood pressure, and cardiovascular disease: further evidence supporting the American Heart Association sodium reduction recommendations. Circulation. 2012;126(24):2880–2889. doi:10.1161/CIR.0b013e318279acbf PubMed DOI

Clinical superiority findings; 2021. Available from: https://www.fda.gov/industry/designating-orphan-product-drugs-and-biological-products/clinical-superiority-findings. Accessed July 9, 2021.

Food and Drug Administration. Voluntary sodium reduction goals: target mean and upper bound concentrations for sodium in commercially processed, packaged, and prepared foods: guidance for industry; 2021. Available from: https://www.fda.gov/media/98264/download. Accessed December 8, 2021.

Chen C, Jenkins J, Zomorodi K, Skowronski R. Pharmacokinetics, bioavailability, and bioequivalence of lower-sodium oxybate in healthy participants in 2 open-label, randomized, crossover studies. Clin Transl Sci. 2021;14(6):2278–2287. doi:10.1111/cts.13087 PubMed DOI PMC

Bogan RK, Thorpy MJ, Dauvilliers Y, et al. Efficacy and safety of calcium, magnesium, potassium, and sodium oxybates (lower-sodium oxybate [LXB]; JZP-258) in a placebo-controlled, double-blind, randomized withdrawal study in adults with narcolepsy with cataplexy. Sleep. 2021;44(3):zsaa206. doi:10.1093/sleep/zsaa206 PubMed DOI PMC

Morse AM, Chen C, Wang YG, Skowronski RJ, Plazzi G. Evidence to support dose regimens for lower-sodium oxybate in pediatric patients with narcolepsy: phase 3 clinical data, pharmacokinetic (PK) data, and population PK modeling [oral presentation]. Paper presented at: Biennial Congress of the International Pediatric Sleep Association; February 5–6, 2021; 2021.

Xywav® (calcium, magnesium, potassium, and sodium oxybates) oral solution, CIII [prescribing information]. Palo Alto, CA: Jazz Pharmaceuticals, Inc.; 2021.

Kothare SV, Kaleyias J. Pharmacotherapy of narcolepsy: focus on sodium oxybate. Clin Med Insights Ther. 2010;2:37–52.

Saytzeff A. [On the reduction of succinyl chloride]. Justus Liebigs Ann Chem. 1874;171(2):258–290. doi:10.1002/jlac.18741710216 DOI

Gamma-hydroxybutyric acid (GHB) critical review report; 2012. Available from: https://www.who.int/medicines/areas/quality_safety/4.1GHBcritical_review.pdf. Accessed January 19, 2022.

Laborit H. Sodium 4-hydroxybutyrate. Int J Neuropharmacol. 1964;3:433–451. doi:10.1016/0028-3908(64)90074-7 PubMed DOI

Bertharion C, Laborit H. [Stereotactic study of the potentials evoked by sodium 4-hydroxybutyrate. Agressologie. 1962;3:489–496. French.

Danon-Boileau H, Lavitry S, Lab P, Levy E, Ruffiot S, Laborit H. [Utilization in psychiatry of gamma-OH]. Presse Med. 1962;70:2205–2207. French. PubMed

Rinaldi F, Puca FM, Mastrosimone F, Memoli G. [On the use of gamma-hydroxybutyrate of sodium in psychiatric therapy]. Acta Neurol (Napoli). 1967;22(1):21–41. Italian. PubMed

Broughton R, Mamelak M. The treatment of narcolepsy-cataplexy with nocturnal gamma-hydroxybutyrate. Can J Neurol Sci. 1979;6(1):1–6. doi:10.1017/S0317167100119304 PubMed DOI

Guiraud J, Addolorato G, Aubin HJ, et al. Treating alcohol dependence with an abuse and misuse deterrent formulation of sodium oxybate: results of a randomised, double-blind, placebo-controlled study. Eur Neuropsychopharmacol. 2021;52:18–30. doi:10.1016/j.euroneuro.2021.06.003 PubMed DOI

Plazzi G, Ruoff C, Lecendreux M, et al. 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;2(7):483–494. doi:10.1016/S2352-4642(18)30133-0 PubMed DOI

Dauvilliers Y, Arnulf I, Foldvary-Schaefer N, et al. Efficacy and safety of lower-sodium oxybate in adults with idiopathic hypersomnia: a phase 3, placebo-controlled, double-blind, randomized withdrawal study. Lancet Neurol. 2022;21(1):53–65. PubMed

Venzi M, Di Giovanni G, Crunelli V. A critical evaluation of the gamma-hydroxybutyrate (GHB) model of absence seizures. CNS Neurosci Ther. 2015;21(2):123–140. doi:10.1111/cns.12337 PubMed DOI PMC

GHB drug fact sheet; 2020. Available from: https://www.dea.gov/factsheets/ghb-gamma-hydroxybutyric-acid. Accessed April 27, 2021.

Drug scheduling; 2019. Available from: https://www.dea.gov/drug-scheduling. Accessed May 23, 2019.

Fuller DE, Hornfeldt CS, Kelloway JS, Stahl PJ, Anderson TF. The Xyrem risk management program. Drug Saf. 2004;27(5):293–306. doi:10.2165/00002018-200427050-00002 PubMed DOI

Silber MH, Krahn LE, Olson EJ, Pankratz VS. The epidemiology of narcolepsy in Olmsted County, Minnesota: a population-based study. Sleep. 2002;25(2):197–202. doi:10.1093/sleep/25.2.197 PubMed DOI

Longstreth WT Jr, Ton TG, Koepsell T, Gersuk VH, Hendrickson A, Velde S. Prevalence of narcolepsy in King County, Washington, USA. Sleep Med. 2009;10(4):422–426. doi:10.1016/j.sleep.2008.05.009 PubMed DOI PMC

Vignatelli L, Antelmi E, Ceretelli I, et al. Red flags for early referral of people with symptoms suggestive of narcolepsy: a report from a national multidisciplinary panel. Neurol Sci. 2019;40(3):447–456. doi:10.1007/s10072-018-3666-x PubMed DOI PMC

Dauvilliers Y, Arnulf I, Mignot E. Narcolepsy with cataplexy. Lancet. 2007;369(9560):499–511. doi:10.1016/S0140-6736(07)60237-2 PubMed DOI

Narcolepsy Type 2. The International Classification of Sleep Disorders. 3rd ed. Darien, IL: American Academy of Sleep Medicine; 2014.

Narcolepsy Type 1. The International Classification of Sleep Disorders. 3rd ed. Darien, IL: American Academy of Sleep Medicine; 2014.

Bassetti CLA, Adamantidis A, Burdakov D, et al. Narcolepsy - clinical spectrum, aetiopathophysiology, diagnosis and treatment. Nat Rev Neurol. 2019;15(9):519–539. doi:10.1038/s41582-019-0226-9 PubMed DOI

Fraigne JJ, Torontali ZA, Snow MB, Peever JH. REM sleep at its core - circuits, neurotransmitters, and pathophysiology. Front Neurol. 2015;6:123. doi:10.3389/fneur.2015.00123 PubMed DOI PMC

Scammell TE. Narcolepsy. N Engl J Med. 2015;373(27):2654–2662. doi:10.1056/NEJMra1500587 PubMed DOI

Saper CB, Scammell TE, Lu J. Hypothalamic regulation of sleep and circadian rhythms. Nature. 2005;437(7063):1257–1263. doi:10.1038/nature04284 PubMed DOI

Kornum BR, Knudsen S, Ollila HM, et al. Narcolepsy. Nat Rev Dis Primers. 2017;3:16100. doi:10.1038/nrdp.2016.100 PubMed DOI

Pardi D, Black J. gamma-Hydroxybutyrate/sodium oxybate: neurobiology, and impact on sleep and wakefulness. CNS Drugs. 2006;20(12):993–1018. doi:10.2165/00023210-200620120-00004 PubMed DOI

Crunelli V, Emri Z, Leresche N. Unravelling the brain targets of gamma-hydroxybutyric acid. Curr Opin Pharmacol. 2006;6(1):44–52. doi:10.1016/j.coph.2005.10.001 PubMed DOI PMC

Roth RH. Striatal dopamine and gamma-hydroxybutyrate. Pharmacol Ther B. 1976;2(1):71–88. doi:10.1016/0306-039x(76)90020-9 PubMed DOI

Spano PF, Tagliamonte A, Tagliamonte P, Gessa GL. Stimulation of brain dopamine synthesis by gamma-hydroxybutyrate. J Neurochem. 1971;18(10):1831–1836. doi:10.1111/j.1471-4159.1971.tb09588.x PubMed DOI

Howard SG, Feigenbaum JJ. Effect of gamma-hydroxybutyrate on central dopamine release in vivo. A microdialysis study in awake and anesthetized animals. Biochem Pharmacol. 1997;53(1):103–110. doi:10.1016/S0006-2952(96)00664-8 PubMed DOI

Aghajanian GK, Roth RH. Gamma-hydroxybutyrate-induced increase in brain dopamine: localization by fluorescence microscopy. J Pharmacol Exp Ther. 1970;175(1):131–138. PubMed

Hechler V, Gobaille S, Bourguignon JJ, Maitre M. Extracellular events induced by gamma-hydroxybutyrate in striatum: a microdialysis study. J Neurochem. 1991;56(3):938–944. doi:10.1111/j.1471-4159.1991.tb02012.x PubMed DOI

Roth RH, Walters JR, Aghajanian GK. Effect of impulse flow on the release and synthesis of dopamine in the rat striatum. In: Usdin E, Snyder SH, editors. Frontiers in Catecholamine Research. Proceedings of the Third International Catecholamine Symposium Held at the University of Strasbourg, Strasbourg, France May 20–25, 1973. New York, NY: Pergamon Press Inc.; 1973:567–574.

Szabo ST, Gold MS, Goldberger BA, Blier P. Effects of sustained gamma-hydroxybutyrate treatments on spontaneous and evoked firing activity of locus coeruleus norepinephrine neurons. Biol Psychiatry. 2004;55(9):934–939. doi:10.1016/j.biopsych.2003.12.013 PubMed DOI

Schmidt-Mutter C, Muller C, Zwiller J, Gobaille S, Maitre M. Gamma-hydroxybutyrate and cocaine administration increases mRNA expression of dopamine D1 and D2 receptors in rat brain. Neuropsychopharmacology. 1999;21(5):662–669. doi:10.1016/S0893-133X(99)00066-4 PubMed DOI

Gottesmann C. GABA mechanisms and sleep. Neuroscience. 2002;111(2):231–239. doi:10.1016/S0306-4522(02)00034-9 PubMed DOI

Scammell TE, Arrigoni E, Lipton JO. Neural circuitry of wakefulness and sleep. Neuron. 2017;93(4):747–765. doi:10.1016/j.neuron.2017.01.014 PubMed DOI PMC

Wisor JP. Dopamine and wakefulness: pharmacology, genetics, and circuitry. Handb Exp Pharmacol. 2019;253:321–335. PubMed

Gruner JA, Marcy VR, Lin YG, Bozyczko-Coyne D, Marino MJ, Gasior M. The roles of dopamine transport inhibition and dopamine release facilitation in wake enhancement and rebound hypersomnolence induced by dopaminergic agents. Sleep. 2009;32(11):1425–1438. doi:10.1093/sleep/32.11.1425 PubMed DOI PMC

Dauvilliers Y, Tafti M, Landolt HP. Catechol-O-methyltransferase, dopamine, and sleep-wake regulation. Sleep Med Rev. 2015;22:47–53. doi:10.1016/j.smrv.2014.10.006 PubMed DOI

Burgess CR, Tse G, Gillis L, Peever JH. Dopaminergic regulation of sleep and cataplexy in a murine model of narcolepsy. Sleep. 2010;33(10):1295–1304. doi:10.1093/sleep/33.10.1295 PubMed DOI PMC

Roth RH, Doherty JD, Walters JR. Gamma-hydroxybutyrate: a role in the regulation of central dopaminergic neurons? Brain Res. 1980;189(2):556–560. doi:10.1016/0006-8993(80)90368-6 PubMed DOI

Engberg G, Nissbrandt H. gamma-Hydroxybutyric acid (GHBA) induces pacemaker activity and inhibition of substantia nigra dopamine neurons by activating GABAB-receptors. Naunyn Schmiedebergs Arch Pharmacol. 1993;348(5):491–497. doi:10.1007/BF00173208 PubMed DOI

Brown RE, Basheer R, McKenna JT, Strecker RE, McCarley RW. Control of sleep and wakefulness. Physiol Rev. 2012;92(3):1087–1187. doi:10.1152/physrev.00032.2011 PubMed DOI PMC

Schmidt C, Leibiger J, Fendt M. The norepinephrine reuptake inhibitor reboxetine is more potent in treating murine narcoleptic episodes than the serotonin reuptake inhibitor escitalopram. Behav Brain Res. 2016;308:205–210. doi:10.1016/j.bbr.2016.04.033 PubMed DOI

Barateau L, Jaussent I, Roeser J, Ciardiello C, Kilduff TS, Dauvilliers Y. Cerebrospinal fluid monoamine levels in central disorders of hypersomnolence. Sleep. 2021;44(7):zsab012. doi:10.1093/sleep/zsab012 PubMed DOI PMC

Shefner SA, Osmanovic SS. GABAA and GABAB receptors and the ionic mechanisms mediating their effects on locus coeruleus neurons. Prog Brain Res. 1991;88:187–195. PubMed

Williams SR, Turner JP, Crunelli V. Gamma-hydroxybutyrate promotes oscillatory activity of rat and cat thalamocortical neurons by a tonic GABAB, receptor-mediated hyperpolarization. Neuroscience. 1995;66(1):133–141. doi:10.1016/0306-4522(94)00604-4 PubMed DOI

Gervasi N, Monnier Z, Vincent P, et al. Pathway-specific action of gamma-hydroxybutyric acid in sensory thalamus and its relevance to absence seizures. J Neurosci. 2003;23(36):11469–11478. doi:10.1523/JNEUROSCI.23-36-11469.2003 PubMed DOI PMC

Roth T, Dauvilliers Y, Mignot E, et al. Disrupted nighttime sleep in narcolepsy. J Clin Sleep Med. 2013;9(9):955–965. doi:10.5664/jcsm.3004 PubMed DOI PMC

Maski K, Mignot E, Plazzi G, Dauvilliers Y. Disrupted nighttime sleep and sleep instability in narcolepsy. J Clin Sleep Med. 2022;18(1):289–304. doi:10.5664/jcsm.9638 PubMed DOI PMC

Ohayon MM. Narcolepsy is complicated by high medical and psychiatric comorbidities: a comparison with the general population. Sleep Med. 2013;14(6):488–492. doi:10.1016/j.sleep.2013.03.002 PubMed DOI

Cohen A, Mandrekar J, St Louis EK, Silber MH, Kotagal S. Comorbidities in a community sample of narcolepsy. Sleep Med. 2018;43:14–18. doi:10.1016/j.sleep.2017.11.1125 PubMed DOI PMC

Black J, Reaven NL, Funk SE, et al. Medical comorbidity in narcolepsy: findings from the Burden of Narcolepsy Disease (BOND) study. Sleep Med. 2017;33:13–18. doi:10.1016/j.sleep.2016.04.004 PubMed DOI

Jennum PJ, Plazzi G, Silvani A, Surkin LA, Dauvilliers Y. Cardiovascular disorders in narcolepsy: review of associations and determinants. Sleep Med Rev. 2021;58:101440. doi:10.1016/j.smrv.2021.101440 PubMed DOI

Dahmen N, Bierbrauer J, Kasten M. Increased prevalence of obesity in narcoleptic patients and relatives. Eur Arch Psychiatry Clin Neurosci. 2001;251(2):85–89. doi:10.1007/s004060170057 PubMed DOI

Bosco A, Lopez R, Barateau L, et al. Effect of psychostimulants on blood pressure profile and endothelial function in narcolepsy. Neurology. 2018;90(6):e479–e491. doi:10.1212/WNL.0000000000004911 PubMed DOI

Grimaldi D, Calandra-Buonaura G, Provini F, et al. Abnormal sleep-cardiovascular system interaction in narcolepsy with cataplexy: effects of hypocretin deficiency in humans. Sleep. 2012;35(4):519–528. doi:10.5665/sleep.1738 PubMed DOI PMC

Vandi S, Rodolfi S, Pizza F, et al. Cardiovascular autonomic dysfunction, altered sleep architecture, and muscle overactivity during nocturnal sleep in pediatric patients with narcolepsy type 1. Sleep. 2019;42(12):zsz169. doi:10.1093/sleep/zsz169 PubMed DOI

Ohkubo T, Hozawa A, Yamaguchi J, et al. Prognostic significance of the nocturnal decline in blood pressure in individuals with and without high 24-h blood pressure: the Ohasama study. J Hypertens. 2002;20(11):2183–2189. doi:10.1097/00004872-200211000-00017 PubMed DOI

Dauvilliers Y, Jaussent I, Krams B, et al. Non-dipping blood pressure profile in narcolepsy with cataplexy. PLoS One. 2012;7(6):e38977. doi:10.1371/journal.pone.0038977 PubMed DOI PMC

National Academies of Sciences Engineering and Medicine. Dietary Reference Intakes for Sodium and Potassium. Washington, DC: The National Academies Press; 2019. PubMed

Junnarkar G, Allphin C, Profant J, et al. Development of a lower-sodium oxybate formulation for the treatment of patients with narcolepsy and idiopathic hypersomnia. Expert Opin Drug Discov. 2022;17(2):109–119. doi:10.1080/17460441.2022.1999226 PubMed DOI

Wang Q, Lin T, Allphin C, van Osdol WW, Bolger MB, Chen C. Physiologically based pharmacokinetic modeling of oxybate: the role of counter-ions in gastrointestinal absorption of oxybate [poster]. Paper presented at: Annual AAPS PharmSci 360; October 26–November 5, 2020; 2020.

Bogan RK, Foldvary-Schaefer N, Skowronski R, Chen A, Thorpy MJ. Timing and duration of treatment-emergent adverse events in a clinical trial of lower-sodium oxybate in participants with narcolepsy with cataplexy [poster 486]. Paper presented at: Annual Meeting of the Associated Professional Sleep Societies; June 10–13, 2021; 2021.

Husain AM, Bujanover S, Ryan R, Scheckner B, Black J, Profant J. Incidence and duration of common, early-onset adverse events occurring during 2 randomized, placebo-controlled, phase 3 studies of sodium oxybate in participants with narcolepsy. J Clin Sleep Med. 2020;16(9):1469–1474. doi:10.5664/jcsm.8530 PubMed DOI PMC

Gardener H, Rundek T, Wright CB, Elkind MS, Sacco RL. Dietary sodium and risk of stroke in the Northern Manhattan study. Stroke. 2012;43(5):1200–1205. doi:10.1161/STROKEAHA.111.641043 PubMed DOI PMC

Strazzullo P, D’Elia L, Kandala NB, Cappuccio FP. Salt intake, stroke, and cardiovascular disease: meta-analysis of prospective studies. BMJ. 2009;339:b4567. doi:10.1136/bmj.b4567 PubMed DOI PMC

Plazzi G, Ruoff C, Hassan F, et al. Clinical and patient global impression in a study of sodium oxybate in children and adolescents with narcolepsy with cataplexy [abstract P515]. J Sleep Res. 2018;27(suppl1):326.

Borgen LA, Okerholm RA, Lai A, Scharf MB. The pharmacokinetics of sodium oxybate oral solution following acute and chronic administration to narcoleptic patients. J Clin Pharmacol. 2004;44(3):253–257. doi:10.1177/0091270003262795 PubMed DOI

Chen C, Rosen CL, Ruoff C, et al. Population and noncompartmental pharmacokinetics of sodium oxybate support weight-based dosing in children and adolescents with narcolepsy with cataplexy. Clin Transl Sci. 2020;13(5):932–940. doi:10.1111/cts.12780 PubMed DOI PMC

Morgenthaler TI, Kapur VK, Brown T, et al. Practice parameters for the treatment of narcolepsy and other hypersomnias of central origin. Sleep. 2007;30(12):1705–1711. doi:10.1093/sleep/30.12.1705 PubMed DOI PMC

Maski K, Trotti LM, Kotagal S, et al. Treatment of central disorders of hypersomnolence: an American Academy of Sleep Medicine systematic review, meta-analysis, and GRADE assessment. J Clin Sleep Med. 2021;17(9):1895–1945. doi:10.5664/jcsm.9326 PubMed DOI PMC

Jazz Pharmaceuticals announces U.S. FDA approval of Xywav®(calcium, magnesium, potassium, and sodium oxybates) oral solution for idiopathic hypersomnia in adults [press release]; 2021. Available from: http://investor.jazzpharma.com/news-releases/news-release-details/jazz-pharmaceuticals-announces-us-fda-approval-xywavr-calcium. Accessed October 4, 2021.

Dauvilliers Y, Evangelista E, Barateau L, et al. Measurement of symptoms in idiopathic hypersomnia: the Idiopathic Hypersomnia Severity Scale. Neurology. 2019;92(15):e1754–e1762. doi:10.1212/WNL.0000000000007264 PubMed DOI

Avadel Pharmaceuticals announces ongoing FDA review of NDA for FT218 for patients with narcolepsy [press release]; 2021. Available from: https://www.globenewswire.com/news-release/2021/10/15/2315210/0/en/Avadel-Pharmaceuticals-Announces-Ongoing-FDA-Review-of-NDA-for-FT218-for-Patients-with-Narcolepsy.html. Accessed November 5, 2021.

Kushida CA, Shapiro CM, Roth T, et al. Once-nightly sodium oxybate (FT218) demonstrated improvement of symptoms in a phase 3 randomized clinical trial in patients with narcolepsy. Sleep. 2021. doi:10.1093/sleep/zsab200 PubMed DOI PMC

Xiang W, Xiang J-N, Canafax D. Clinical pharmacokinetics of XW10172 for once-nightly therapy in patients with narcolepsy or sleep disorders in patients with neurodegenerative diseases [poster]. Paper presented at: Annual Meeting of the Associated Professional Sleep Societies; June 10–13, 2021; 2021.