55.   The approval letter for Sunosi says: “Your application for Sunosi was not referred to an FDA advisory committee because the efficacy and safety data were readily interpretable and not controversial, and there was experience with other drugs in this class.”

  56.   Michelle G. Baladi et al., “Characterization of the Neurochemical and Behavioral Effects of Solriamfetol (JZP-110), a Selective Dopamine and Norepinephrine Reuptake Inhibitor,” Journal of Pharmacology and Experimental Therapeutics 366 (2018): 367–76.

  57.   Lee Hye-seon, “SK Biopharmaceutical’s Sleepiness Drug Initially Aimed to Treat Depression,” Korea Biomedical Review, August 22, 2019, https://koreabiomed.com/news/articleView.html?idxno=6320.

  58.   Perri Panula, “Histamine Receptors, Agonists, and Antagonists in Health and Disease,” Handbook of Clinical Neurology 180 (2021): 377–87.

  59.   Zoltan Szakacs et al., “Safety and Efficacy of Pitolisant on Cataplexy in Patients with Narcolepsy: A Randomised, Double-Blind, Placebo-Controlled Trial,” Lancet Neurology 16 (2017): 200–7.

  60.   Smaranda Leu-Semenscu et al., “Effects of Pitolisant, a Histamine H3 Inverse Agonist, in Drug-Resistant Idiopathic and Symptomatic Hypersomnia: A Chart Review,” Sleep Medicine 15 (2014): 681–87.

  61.   Food and Drug Administration, NDA 211150, Pitolisant clinical review, https://www.accessdata.fda.gov/drugsatfda_docs/nda/2019/211150Orig1s000MedR.pdf.

  62.   U.S. National Library of Medicine, “A Study of Safety and Efficacy of BTD-001 in Treatment of Patients with Idiopathic Hypersomnia (IH) or Narcolepsy Type 2,” https://clinicaltrials.gov/ct2/show/NCT02512588, last update 2019.

  63.   U.S. National Library of Medicine, “A Study of Oral BTD-001 in Adults with Idiopathic Hypersomnia (ARISE2),” https://clinicaltrials.gov/ct2/show/NCT03542851, last update 2020.

  64.   Ping Sheng et al., “Efficacy of Modafinil on Fatigue and Excessive Daytime Sleepiness Associated with Neurological Disorders: A Systematic Review and Meta-Analysis,” PLOS One 8 (2013): e81802.

  15. KNOCK YOURSELF OUT

    1.   U.S. National Library of Medicine, “A Multicenter Study of the Efficacy and Safety of JZP-258 in the Treatment of Idiopathic Hypersomnia (IH) with an Open-label Safety Extension,” https://clinicaltrials.gov/ct2/show/NCT03533114.

    2.   Gunjan Junnarkar et al., “Development of a Lower–Sodium Oxybate Formulation for the Treatment of Patients with Narcolepsy and Idiopathic Hypersomnia,” Expert Opinion in Drug Discovery (2021).

    3.   Jazz Pharmaceuticals, 2020 Annual Report, 5.

    4.   Julie Vienne et al., “Differential Effects of Sodium Oxybate and Baclofen on EEG, Sleep, Neurobehavioral Performance, and Memory,” Sleep 35 (2012): 1071–83.

    5.   Food and Drug Administration, Xyrem label, revised October 2018, https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/021196s030lbl.pdf.

    6.   Malene Landbo Børresen et al., “Sodium Oxybate (Xyrem) Treatment in Severely Sleep-Deprived Child with Epstein-Barr Virus Encephalitis with Lesion of Sleep-Wake Regulation System: A Case Report,” Sleep Medicine 62 (2019): 29–31.

    7.   Lynn M. Trotti, “Conventional (and Not-So-Conventional) Treatments for Idiopathic Hypersomnia,” 2018 Hypersomnia Conference, YouTube video posted August 2, 2019, 21–24 minutes, https://www.youtube.com/watch?v=kADh5rCzlRU.

    8.   Smaranda Leu-Semenescu, Pauline Louis, and Isabelle Arnulf, “Benefits and Risk of Sodium Oxybate in Idiopathic Hypersomnia Versus Narcolepsy Type 1: A Chart Review,” Sleep Medicine 17 (2016): 38–44.

    9.   Henri Laborit, “Sodium 4-Hydroxybutyrate,” International Journal of Neuropharmacology 3 (1964): 433–51.

  10.   Michael E. Tunstall, “Gamma-OH in Anesthesia for Caesarean Section,” Proceedings of the Royal Society Medicine 61 (1968): 827–29.

  11.   Mortimer Mamelak, J. M. Escriu, and O. Stokan, “Sleep-Inducing Effects of Gammahydroxybutyrate,” Lancet 302 (1973): 328–29.

  12.   Roger Broughton and Mortimer Mamelak, “Gamma Hydroxy-Butyrate in the Treatment of Narcolepsy: A Preliminary Report,” Proceedings of the First International Symposium on Narcolepsy, July 1975 (Spectrum Publications).

  13.   Guilleminault cited his unsatisfactory experiences trying baclofen for people with narcolepsy. Since baclofen chemically resembles GABA, there must be another explanation for GHB’s efficacy, he argued.

  14.   Stanford researchers led by Dement saw no effect of GHB on narcolepsy in dogs. Arthur S. Foutz et al., “Monoaminergic Mechanisms and Experimental Cataplexy,” Annals of Neurology 10 (1981): 369–76.

  15.   One of the best sources on GHB’s transformation into Xyrem is a paper by a Harvard law student, written under the supervision of a former FDA chief counsel. Ariel Neuman, “GHB’s Path to Legitimacy: An Administrative and Legislative History of Xyrem,” Harvard Law School Student Papers 2004, https://dash.harvard.edu/bitstream/handle/1/9795464/Neuman.html.

  16.   Martin B. Scharf et al. “The Effects and Effectiveness of y-Hydroxybutyrate in Patients with Narcolepsy,” Journal of Clinical Psychiatry 46: 222–25 (1985).

  17.   Martin Scharf, 2020 interview.

  18.   Linda Pender, “Better Than a Lullaby,” Cincinnati Magazine, September 1984.

  19.   U.S. House of Representatives, Appropriations Committee, Subcommittee on Agriculture, Rural Development, and Related Agencies, “Agriculture, Rural Development, and Related Agencies Appropriations for 1983,” 97th Congress, part 7, 1982, p. 96, https://catalog.hathitrust.org/Record/006212564 (American Narcolepsy Association material).

  20.   Lawrence Scrima et al., “The Effects of Gamma-Hydroxybutyrate on the Sleep of Narcolepsy Patients: A Double-Blind Study,” Sleep 13 (1990): 479–90; Lawrence Scrima et al., “Efficacy of Gamma-Hydroxybutyrate Versus Placebo in Treating Narcolepsy-Cataplexy: Double-Blind Subjective Measures,” Biological Psychiatry 26 (1989): 331–43.

  21.   Jill Barshay, “One Drug, Two Faces,” Minneapolis Star-Tribune, August 6, 2000.

  22.   J. Takahara et al., “Stimulatory Effects of Gamma-Hydroxybutyric Acid on Growth Hormone and Prolactin Release in Humans,” Journal of Clinical Endocrinology and Metabolism 44 (1977): 1014–17.

  23.   Joseph J. Palamar and Perry N. Halkitis, “A Qualitative Analysis of GHB Use Among Gay Men: Reasons for Use Despite Potential Adverse Outcomes,” International Journal of Drug Policy 17 (2006): 23–28.

  24.   J. E. Dyer et al., “Epidemiologic Notes and Reports Multistate Outbreak of Poisonings Associated with Illicit Use of Gamma-Hydroxy Butyrate,” Morbidity and Mortality Weekly Report 39 (1990): 861–63.

  25.   Shawn Hubler and Steve Hochman, “ ‘Designer Drug’ Enters Hollywood’s Fast Lane,” Los Angeles Times, November 3 1993.

  26.   U.S. House of Representatives, Judiciary Committee, Subcommittee on Crime, “Controlled and Uncontrolled Substances Used to Commit Date Rape,” 105th Congress, July 30, 1998, p. 125, http://commdocs.house.gov/committees/judiciary/hju62309.000/hju62309_0f.htm.

  27.   Food and Drug Administration, Peripheral and Central Nervous System Drugs Advisory Committee meeting materials, June 6, 2001, https://wayback.archive-it.org/7993/20170404102834/https://www.fda.gov/ohrms/dockets/ac/01/briefing/3754b1.htm; Letter from Division Director, May 9, 2001, https://wayback.archive-it.org/7993/20170405173215/https://www.fda.gov/ohrms/dockets/ac/01/briefing/3754b1_02_section%201.pdf.

  28.   Gayle Greene, Insomniac (Berkeley: University of California Press, 2008).

  29.   Food and Drug Administration, Peripheral and Central Nervous System Drugs Advisory Committee meeting transcript, June 6, 2001, https://wayback.archive-it.org/7993/20170404102820/https://www.fda.gov/ohrms/dockets/ac/01/transcripts/3754t1.txt.

  30.   Martin B. Scharf et al., “Effect of Gamma-Hydroxybutyrate on Pain, Fatigue, and the Alpha Sleep Anomaly in Patients with Fibromyalgia,” Journal of Rheumatology 25 (1998): 1986–90.

  31.   I. Jon Russell et al., “Sodium Oxybate Relieves Pain and Improves Function in Fibromyalgia Syndrome,” Arthritis & Rheumatism 60 (2009): 299–309.

  32.   Jazz annual report from 2007, https://www.sec.gov/Archives/edgar/data/0001232524/000119312508070827/d10k.htm.

  33.   Jazz annual reports 10K, issued March 2009 and March 2010, for example: https://www.sec.gov/Archives/edgar/data/0001232524/000119312509064139/d10k.htm.

  34.   Jennifer C. Dooren, “FDA Panel Rejects Jazz Drug as Pain-Disorder Treatment,” Wall Street Journal, August 21, 2010.

  35.   Food and Drug Administration, Arthritis & Drug Safety and Risk Management Advisory Committees joint meeting transcript, August 20, 2010, https://wayback.archive-it.org/7993/20170404145710/https://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/ArthritisAdvisoryCommittee/UCM225445.pdf.

  36.   Marc I. Rosen et al., “Effects of Gamma-Hydroxybutyric Acid (GHB) in Opioid-Dependent Patients,” Journal of Substance Abuse Treatment 14 (1997): 149–54.

  37.   Food and Drug Administration, NDA 21196 Medical Review, part 4, June 15, 2001, https://www.accessdata.fda.gov/drugsatfda_docs/nda/2002/21–196_Xyrem_medr_P4.pdf.

  38.   Ronald E. Kramer, “The Administrative State and the Death of Peter Gleason, MD: An Off-Label Case Report,” Journal of Clinical Sleep Medicine 15 (2019).

  39.   “United States v. Caronia,” Harvard Law Review 127 (2012): 795–802.

  40.   Tracy Staton, “10 Big Brands Keep Pumping Out Big Bucks, with a Little Help from Price Hikes,” Fierce Biotech, May 7, 2014.

  41.   Daniel M. Hartung et al., “The Cost of Multiple Sclerosis Drugs in the US and the Pharmaceutical Industry,” Neurology 84 (May 2015): 2185–92.

  42.   Caroline Pearson, Lindsey Schapiro, and Steven D. Pearson, “The Next Generation of Rare Disease Drug Policy: Ensuring Both Innovation and Affordability,” Institute for Clinical and Economic Review white paper, 2022, https://icer.org/wp-content/uploads/2022/04/ICER-White-Paper_The-Next-Generation-of-Rare-Disease-Drug-Policy_040722.pdf.

  43.   Blue Cross Blue Shield of Illinois, “Xyrem® (sodium oxybate) Prior Authorization Criteria,” accessed February 19, 2015, https://web.archive.org/web/20150219031021/https://www.bcbsil.com/provider/pdf/xyrem.pdf; State of North Carolina, “Prior Authorization Criteria” (CVS Caremark Criteria), https://files.nc.gov/ncshp/documents/files/Xyrem-Policy-254-C-03–2020.pdf.

  44.   Motley Fool, Jazz Pharmaceuticals PLC (JAZZ) Q4 2020 Earnings Call Transcript, https://www.fool.com/earnings/call-transcripts/2021/02/23/jazz-pharmaceuticals-plc-jazz-q4–2020-earnings-cal/.

  45.   Robert Langreth and Ben Elgin, “ ‘I Am Going to Die Without This’: Regulators Target a Health-Care Lifesaver,” Bloomberg Businessweek, November 21, 2017.

  46.   Jazz Pharmaceuticals Inc., “Citizen Petition,” posted by FDA, May 28, 2012, https://www.regulations.gov/document/FDA-2012-P-0499-0001.

  47.   Petra Maresova et al., “Treament Cost of Narcolepsy with Cataplexy in Central Europe,” Therapeutics and Clinical Risk Management 12 (2016): 1709–15.

  48.   Clare Dyer, “Judge Orders That Teenager with Narcolepsy Be Allowed to Try Sodium Oxybate,” BMJ 353 (2016): i3413.

  49.   Giovanni Addolorato et al., “Post-marketing and Clinical Safety Experience with Sodium Oxybate for the Treatment of Alcohol Withdrawal Syndrome and Maintenance of Abstinence in Alcohol-Dependent Subjects,” Expert Opinion on Drug Safety 19 (2020): 159–66.

  50.   Julien Guiraud et al., “Sodium Oxybate for the Maintenance of Abstinence in Alcohol-Dependent Patients: An International, Multicenter, Randomized, Double-Blind, Placebo-Controlled Trial,” Journal of Psychopharmacology 269 (2022): 2698811221104063.

  51.   European Medicines Agency, Assessment report for Alcover, October 12, 2017, https://www.ema.europa.eu/en/documents/referral/alcover-article-294-referral-assessment-report_en.pdf.

  52.   Centers for Medicare and Medicaid Services, “Jazz Pharmaceuticals Inc.,” Open Payments database, https://openpaymentsdata.cms.gov/company/100000005637.

  53.   Jazz Pharmaceuticals press release, “Jazz Pharmaceuticals Supports Narcolepsy Network Initiative to Launch the National Narcolepsy Awareness Campaign,” March 5, 2007; Jazz Pharmaceuticals press release, “Wake Up Narcolepsy and Jazz Pharmaceuticals Announce Swinging for Sleep to Raise Funds for Narcolepsy Awareness,” March 22, 2012. Jazz has supported Hypersomnia Foundation programs such as recording sessions at conferences, according to foundation board members.

  54.   From Jazz presentation on Xywav launch, October 13, 2021, p. 33.

  55.   Ed Silverman, “High Cost of Multiple Sclerosis Medicines Is Forcing Many Patients to Take ‘Drastic Actions,’ ” STAT+, January 13, 2020.

  56.   Kathleen F. Villa et al., “Changes in Medical Services and Drug Utilization and Associated Costs After Narcolepsy Diagnosis in the United States,” American Health & Drug Benefits 11 (2018): 137–45. Pharmacy costs can be calculated by subtracting medical services from total costs (medical plus pharmacy).

  57.   Y. Grace Wang et al., “Safety Overview of Postmarketing and Clinical Experience of Sodium (Xyrem): Abuse, Misuse, Dependence, and Diversion,” Journal of Clinical Sleep Medicine 4 (2009): 365–71.

  58.   Zsófia Németh, Bernadette Kun, and Zsolt Demetrovics, “The Involvement of Gamma-Hydroxybutyrate in Reported Sexual Assaults: A Systematic Review,” Journal of Psychopharmacology 24 (2010): 1281–87.

  59.   Deborah L. Zvosec, Stephen W. Smith, and B. J. Hall, “Three Deaths Associated with Use of Xyrem,” Sleep Medicine 10: 490–93 (2009).

  60.   Deborah L. Zvosec et al., “Rigorous Study of Xyrem/Sodium Oxybate Use Among Patients with Obstructive Sleep Apnea and Other Conditions of Compromised Respiratory Function Is Critically Needed,” Sleep Medicine 12 (2011): 103.

  61.   Food and Drug Administration, Warning Letter to Jazz Pharmaceuticals, October 11, 2011, http://wayback.archive-it.org/7993/20170112193124/http://www.fda.gov/ICECI/EnforcementActions/WarningLetters/2011/ucm275565.htm.

  62.   Y. Grace Wang et al., “Sodium Oxybate: Updates and Correction to Previously Published Safety Data,” Journal of Clinical Sleep Medicine 7 (2011): 415–16.

  63.   Food and Drug Administration, “Drug Safety Communication: Warning Against Use of Xyrem (Sodium Oxybate) with Alcohol or Drugs Causing Respiratory Depression,” December 17, 2012, https://www.fda.gov/drugs/drug-safety-and-availability/fda-drug-safety-communication-warning-against-use-xyrem-sodium-oxybate-alcohol-or-drugs-causing.

  64.   Institute for Safe Medication Practices, QuarterWatch, September 24, 2014, https://www.ismp.org/sites/default/files/attachments/2018–01/2013Q3.pdf.

  65.   Darren Scheer et al., “Prevalence and Incidence of Narcolepsy in a US Health Care Claims Database, 2008–2010,” Sleep 42 (2019): zsz091.

  66.   Jed Black et al., “The Burden of Narcolepsy Disease (BOND) Study: Health-Care Utilization and Cost Findings,” Sleep Medicine 15 (2014): 522–29.

  67.   Michael H. Silber et al., “The Epidemiology of Narcolepsy in Olmsted County, Minnesota: A Population-Based Study,” Sleep 25 (2002): 197–202; William T. Longstreth et al., “Prevalence of Narcolepsy in King County, Washington, USA,” Sleep Medicine 10 (2009): 422–26.

  68.   Heide Baumann-Vogel et al., “Narcolepsy Type 2: A Rare, yet Existing Entity,” Journal of Sleep Research (September 2020): e13203; Ester Tio et al., “The prevalence of Narcolepsy in Catalunya (Spain),” Journal of Sleep Research 27 (2018): e12640. The Catalunya study used the stringent Brighton Collaboration case definition of narcolepsy.

  69.   Bernadette Villareal et al., “Diagnosing Narcolepsy in the Active Duty Military Population,” Sleep & Breathing 25 (2021): 995–1002.

  70.   Xyrem International Study Group, “A Double-Blind, Placebo-Controlled Study Demonstrates Sodium Oxybate Is Effective for the Treatment of Excessive Daytime Sleepiness in Narcolepsy,” Journal of Clinical Sleep Medicine 1 (October 2005): 391–97.

  71.   Jed Black and William C. Houghton, “Sodium Oxybate Improves Excessive Daytime Sleepiness in Narcolepsy,” Sleep 29 (2006): 939–46.

  72.   Christian R. Baumann et al., “Challenges in Diagnosing Narcolepsy Without Cataplexy: A Consensus Statement,” Sleep 37 (2014): 1035–42.

  73.   Rye consulted for Jazz every year between 2014 and 2018, receiving more than $8,000 in 2018, according to Propublica’s Dollars for Docs database.