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Sodium oxybate

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This article pertains to the prescription medication Xyrem, for information about its active ingredient, please see gamma-Hydroxybutyric acid
Sodium oxybate
Clinical data
License data
Routes of
administration		Oral
ATC code
  • none
Legal status
Legal status
Pharmacokinetic data
Bioavailability25%
Protein binding1%
Elimination half-life0.5 to 1 hour.
ExcretionAlmost entirely by biotransformation to carbon dioxide, which is then eliminated by expiration
Identifiers
  • Sodium 4-hydroxybutanoate
CAS Number
PubChem CID
PubChem SID
ChemSpider
KEGG
CompTox Dashboard (EPA)
ECHA InfoCard100.007.231 Edit this at Wikidata
Chemical and physical data
FormulaC4H7NaO3
Molar mass126.09 grams/mole g·mol−1
3D model (JSmol)
  • [Na+].[O-]C(=O)CCCO
  • InChI=1S/C4H8O3.Na/c5-3-1-2-4(6)7;/h5H,1-3H2,(H,6,7);/q;+1/p-1 checkY
  • Key:XYGBKMMCQDZQOZ-UHFFFAOYSA-M checkY
 ☒NcheckY (what is this?)  (verify)

Xyrem (sodium oxybate) is a prescription medication manufactured by Jazz Pharmaceuticals, and is approved by the U.S. Food and Drug Administration (FDA) for the treatment of cataplexy associated with narcolepsy[2] and Excessive Daytime Sleepiness (EDS) associated with narcolepsy.[3] Sodium oxybate is the sodium salt of γ-hydroxybutyric acid. The American Academy of Sleep Medicine (AASM) recommends Xyrem as a standard of care for the treatment of cataplexy, daytime sleepiness, and disrupted sleep due to narcolepsy in its Practice Parameters for the Treatment of Narcolepsy and other Hypersomnias of Central Origin. These recommendations are based upon careful review of the medical literature, and the designation "standard" of care "reflects a high degree of clinical certainty" based on strong empirical evidence.[4]

Xyrem is a prescription medication used to treat narcolepsy, which is a rare medical condition that has been documented worldwide, with a prevalence ranging from 0.002% in Israel to 0.18% in Japan. Prevalence in the US is approximately 0.05%. The pentad of clinical symptoms includes: Excessive Daytime Sleepiness (EDS), cataplexy, hypnagogic hallucinations, sleep paralysis, and fragmented sleep. EDS and cataplexy are the most common daytime symptoms of narcolepsy.[5]

Development

Xyrem is designated as an orphan drug, which is a pharmaceutical agent that has been developed specifically to treat a rare medical condition, the condition itself being referred to as an orphan disease.[6] The assignment of orphan status to a disease and to any drugs developed to treat it is a matter of public policy in many countries, and has resulted in medical breakthroughs that may not have otherwise been achieved due to the economics of drug research and development.[7] In the last 20 years efforts have been made to encourage companies to develop orphan drugs. The Orphan Drug Act in the US (1983) was succeeded by similar legislation in Japan (1985), Australia (1997), and the European Community (2000).[8]

The development of Xyrem (sodium oxybate) oral solution as a prescription medication was initiated by the Office of Orphan Products Development (OOPD).[9] The OOPD is a department of the FDA dedicated to promoting the development of products that demonstrate promise for the diagnosis and/or treatment of rare diseases or conditions.[10]

  • In 1994, the OOPD petitioned a pharmaceutical company called Orphan Medical to investigate sodium oxybate as a potential treatment for narcolepsy.[9]
  • In 1996, Orphan Medical submitted an Investigational New Drug Application (IND) to the FDA and began Phase I, II, and III clinical trials to investigate the safety and efficacy of sodium oxybate.[9]
  • In 2000, Orphan Medical submitted a New Drug Application (NDA) to the FDA for Xyrem.[9] Xyrem was granted "Priority Review",[9] which is an expedited review process given to products that offer a major advance in treatment or treatment where no adequate therapy exists.[11]
  • In 2002, Xyrem received approval from the FDA for the treatment of cataplexy in patients with narcolepsy.[2]
  • In 2005, Xyrem was acquired by Jazz Pharmaceuticals when they purchased Orphan Medical. Later that year, Xyrem was granted a second indication by the FDA for the treatment of EDS in patients with narcolepsy.[3] Also that year Xyrem was approved for the treatment of cataplexy in patients with narcolepsy by Health Canada's Therapeutic Products Directorate, and for the same indication in adult patients by the European Medicines Agency for the European Union (EU) and the Swiss Agency for Therapeutic Products, Swissmedic.[5]
  • In 2006, Xyrem received an expanded indication for narcolepsy with cataplexy in the EU.[5]
  • In 2010, Jazz Pharmaceuticals completed two Phase III clinical trials investigating sodium oxybate for the treatment of fibromyalgia. Fibromyalgia is a complex musculoskeletal disorder clinically characterized by widespread pain usually accompanied by fatigue, insomnia, and dyscognition. The company submitted a New Drug Application (NDA) to the FDA; approval was refused in October.[12]

There are also ongoing tests to see if Xyrem could prove helpful with other medical conditions, such as Parkinson's disease, chronic fatigue syndrome (ME), schizophrenia,[13] binge eating,[14] essential tremor and other non-Parkinson's movement disorders.[15]

Mechanism of action

Main article: gamma-hydroxybutyric acid § Pharmacology

Cost

Orphan drugs by their nature are very specialized and have relatively few patients to spread the costs associated with bringing them to market. The average cost of a specialty drug in the US is $2,875 per month or $34,500 annually,[16] however drug prices vary by country.

In European Union (EU) countries, the government either provides national health insurance (as in the UK and Italy) or strictly regulates quasi-private social insurance funds (as in Germany, France, and the Netherlands). These government agencies are the sole purchaser (or regulator) of medical goods and services and have the power to set prices.[17] The cost of pharmaceuticals, including Xyrem, tend to be lower in these countries.[17]

In the US, the cost of Xyrem is $975 (180 mL bottle, 500 mg/mL)[18] and the effective dose range is 6–9 grams per night which equates to $1,950–2,925 per month. Xyrem is covered by most insurance plans including Medicare and Medicaid and approximately 90% of Xyrem patients have a flat monthly co-pay. 75% of Xyrem insurance copays are less than $50 and 42% are less than $25 for a one-month supply. The manufacturer offers a coupon program for the small number of patients with larger co-pays. Some insurance companies may require physicians to fill out an insurance form called a Prior Authorization as part of the prescribing process. Additionally, the manufacturer offers a Patient Assistance Program to patients that do not have insurance and are unable to afford their Xyrem prescription. Approximately 8% of Xyrem patients currently participate in this program and receive their prescription for free.[19]

Existing US Patents on Xyrem prevent other companies from manufacturing it as a drug. Xyrem is protected by US Patents 6472431,[20] and 6780889[21] which are set to expire in 2019 and 2022, respectively.

Distribution

A number of measures have been put in place by Xyrem's manufacture to ensure that it is used safely and appropriately. Xyrem requires a prescription and can only be obtained through a restricted distribution program, called the "Xyrem Success Program". This restricted distribution program is required by the FDA as part of a Risk Management Program (RMP) to manage product safety and prevent abuse.[22]

The program involves many risk management components, such as:

  • Physician education
  • Registration
  • Patient education
  • Detailed patient surveillance

The program includes a single centralized pharmacy with a toll-free number.

Initial dosages are set by the prescribing physician. Each bottle of Xyrem is shipped with a graduated syringe (measured in grams) and two dosing cups. Each night, the patient mixes two doses with 60 ml of water (sometimes substituted with a calorie-free beverage to cover the unpleasant taste of the medication). The first dose is taken at bedtime, and the second is taken 2.5 to 4 hours later.

Safety

Xyrem has been safely used by patients with narcolepsy for more than seven years.[5] A recent analysis evaluated the postmarketing safety of Xyrem (Wang et al. 2009), including rates of abuse, dependence, and withdrawal, using a conservative application of the Diagnostic and Statistical Manual of Mental Disorders, 4th Edition (DSM-IV) criteria to all worldwide Xyrem adverse event cases containing reporting terminology related to abuse or misuse.[5] The analysis included cases reported to the manufacture from market introduction in 2002 through March 2008. Using the DSM-IV criteria, the analysis found the following rates of abuse, dependence, and withdrawal of the approximately 26,000 patients who used Xyrem during this period:

  • Abuse – 10 cases (0.04%)
  • Dependence – 4 cases (0.016%)
  • Withdrawal symptoms after discontinuation – 8 cases (0.031%; including 3 of the previous 4 dependence cases)

The analysis also found 2 confirmed cases (0.008%) of sodium oxybate–facilitated sexual assault; in both cases the women knew that they were taking sodium oxybate. In addition, there were 21 deaths (0.08%) in patients receiving sodium oxybate treatment, with 1 death known to be related to sodium oxybate, and 3 cases (0.01%) of traffic accidents involving drivers taking sodium oxybate. The extremely low rates of abuse, dependence, withdrawal, and assault found in this analysis suggest that after seven years of commercial availability, Xyrem use is largely appropriate and confined to patients with legitimate therapeutic needs.[5]

In the US, Xyrem is classified as a Schedule III controlled substance for medicinal use under the Controlled Substances Act, with illicit use subject to Schedule I penalties. Examples of other schedule III products in the US include vicodin, tylenol with codeine, and testosterone.[23] In Canada and the European Union (EU), it is classified as a Schedule III and a Schedule IV controlled substance, respectively.[5]

Adverse effects

Xyrem is generally well-tolerated by most patients. The most common side effects reported in clinical trials include nausea, dizziness, headache, vomiting, sleepiness, and bed-wetting.[24][25] Some patients treated with Xyrem have also experienced moderate to significant weight loss. This may be due to the fact that Xyrem improves sleep architecture and increases the length of deep sleep stages, resulting in increased production of human growth hormone (GH) and changes in energy metabolism.[26]

Use by athletes

Xyrem has been instrumental in allowing cyclist Franck Bouyer to resume his career and is the only treatment for narcolepsy approved by the World Anti-Doping Agency.[27]

See also

References

  1. ^ "FDA-sourced list of all drugs with black box warnings (Use Download Full Results and View Query links.)". nctr-crs.fda.gov. FDA. Retrieved 22 Oct 2023.
  2. ^ a b "FDA Approval Letter for Xyrem; Indication: Cataplexy associated with narcolepsy" (PDF). US Food and Drug Administration. 2002-07-17. Retrieved 2010-10-03.
  3. ^ a b "FDA Approval Letter for Xyrem; Indication: EDS (Excessive Daytime Sleepiness) associated with narcolepsy" (PDF). US Food and Drug Administration. 2005-11-18. Retrieved 2010-10-03.
  4. ^ Morgenthaler TI, Kapur VK, Brown T, Swick TJ, Alessi C, Aurora RN, Boehlecke B, Chesson AL, Friedman L, Maganti R, Owens J, Pancer J, Zak R (December 2007). "Practice parameters for the treatment of narcolepsy and other hypersomnias of central origin". Sleep. 30 (12): 1705–11. PMC 2276123. PMID 18246980.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  5. ^ a b c d e f g Wang YG, Swick TJ, Carter LP, Thorpy MJ, Benowitz NL (2009). "Safety overview of postmarketing and clinical experience of sodium oxybate (Xyrem): abuse, misuse, dependence, and diversion". J Clin Sleep Med. 5 (4): 365–71. PMC 2725257. PMID 19968016.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  6. ^ "Office of Orphan Products Development – Orphan Drug Product Designation Database". US Food and Drug Administration. 1994-11-07. Retrieved 2010-12-01.
  7. ^ Office of Inspector General (2001-05). "The Orphan Drug Act Implementation and Impact" (PDF). US Department of Health and Human Services. {{cite web}}: Check date values in: |date= (help)
  8. ^ Aronson JK (March 2006). "Rare diseases and orphan drugs". Br J Clin Pharmacol. 61 (3): 243–5. doi:10.1111/j.1365-2125.2006.02617.x. PMC 1885017. PMID 16487216.
  9. ^ a b c d e "Learn About XYREM®". Jazz Pharmaceuticals, Inc. 2008. Retrieved 2010-10-03.
  10. ^ "Office of Orphan Products Development". US Food and Drug Administration. 2010-06-17. Retrieved 2010-10-03.
  11. ^ "Fast Track, Accelerated Approval and Priority Review". US Food and Drug Administration. Retrieved 2010-10-03.
  12. ^ The Associated Press (2010-10-12). "FDA Says No to Jazz Pharma Fibromyalgia Drug". The New York Times. Retrieved 2010-10-12.
  13. ^ "Search of: xyrem". ClinicalTrials.gov. US National Institutes of Health. Retrieved 2010-10-03.
  14. ^ McElroy SL, Guerdjikova AI, Winstanley EL, O'Melia AM, Mori N, Keck PE Jr, Hudson JISodium oxybate in the treatment of binge eating disorder: An open-label, prospective study.Int J Eat Disord. 2010 Mar 5.
  15. ^ Frucht SJ, Houghton WC, Bordelon Y, Greene PE, Louis ED. Neurology. A single-blind, open-label trial of sodium oxybate for myoclonus and essential tremor.2005 Dec 27;65(12):1967-9.
  16. ^ "Rx Watchdog Report: Brand Name Drug Prices Continue to Climb Despite Low General Inflation Rate" (PDF). AARP. 2010-03. {{cite web}}: Check date values in: |date= (help)
  17. ^ a b Danzon PM (Spring 2000). "Making sense of drug prices" (PDF). Regulation. 23 (1): 56–63.
  18. ^ "PricePoint Rx". First DataBank. Retrieved 2010-10-04.
  19. ^ "Jazz Pharmaceuticals, Inc. Q1 2010 Earnings Call Transcript". Jazz Pharmaceuticals, Inc. Retrieved 2010-10-03.
  20. ^ US patent 6472431, Cook H, Hamilton M, Danielson D, Goderstad C, Reardan D, "Microbiologically sound and stable solutions of gamma-hydroxybutyrate salt", issued 2002-10-29, assigned to Orphan Medical, Inc. 
  21. ^ US patent 6780889, Cook H, Hamilton M, Danielson D, Goderstad C, Reardan D, "Microbiologically sound and stable solutions of gamma-hydroxybutyrate salt", issued 2004-08-24, assigned to Orphan Medical, Inc. 
  22. ^ "Approval Letter for Xyrem (sodium oxybate) oral solution; Risk Management Program(RMP)Requirements" (PDF). US Food and Drug Administration. 2002-07-17.
  23. ^ "Drug Scheduling". US Drug Enforcement Administration (DEA). Retrieved 2010-10-03.
  24. ^ The XYREM Success Program® for Patients, Jazz Pharmaceuticals, Inc.
  25. ^ Owen RT. Sodium oxybate: efficacy, safety and tolerability in the treatment of narcolepsy with or without cataplexy. Drugs Today(Barc). 2008 Mar;44(3):197–204.
  26. ^ Husain AM, Ristanovic RK, Bogan RK.Weight loss in narcolepsy patients treated with sodium oxybate.Sleep Med. 2009 Jun;10(6):661–3.
  27. ^ Bouygues (25 Jan. 2009) Bouyer: "Une nouvelle expérience" (in French.) Retrieved 5 March 2010.

Further reading

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