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* In 2000, Orphan Medical submitted a New Drug Application (NDA) to the FDA<ref>{{cite web|url= http://xyrem.com/learn/|title= http://xyrem.com/learn/}}</ref> and Xyrem was granted Priority Review.<ref>{{cite web|url= http://xyrem.com/learn/|title= http://xyrem.com/learn/}}</ref> Priority Review is an expedited review process given to products that offer a major advance in treatment or treatment where no adequate therapy exists.<ref>{{cite web|url= http://www.fda.gov/forconsumers/byaudience/forpatientadvocates/speedingaccesstoimportantnewtherapies/ucm128291.htm#priorityreview|title= FDA.gov}}</ref>
* In 2000, Orphan Medical submitted a New Drug Application (NDA) to the FDA<ref>{{cite web|url= http://xyrem.com/learn/|title= http://xyrem.com/learn/}}</ref> and Xyrem was granted Priority Review.<ref>{{cite web|url= http://xyrem.com/learn/|title= http://xyrem.com/learn/}}</ref> Priority Review is an expedited review process given to products that offer a major advance in treatment or treatment where no adequate therapy exists.<ref>{{cite web|url= http://www.fda.gov/forconsumers/byaudience/forpatientadvocates/speedingaccesstoimportantnewtherapies/ucm128291.htm#priorityreview|title= FDA.gov}}</ref>


* In 2002, after several years of clinical trials and review, Xyrem received approval from the FDA for the treatment of [[cataplexy]] in patients with [[narcolepsy]].<ref>{{cite web|url= http://www.accessdata.fda.gov/drugsatfda_docs/appletter/2002/21196ltr.pdf |title= FDA Approval Letter for Xyrem; Indication: Cataplexy associated with narcolepsy; 17 Jul 2002}}</ref>
* In 2002, Xyrem received approval from the FDA for the treatment of [[cataplexy]] in patients with [[narcolepsy]].<ref>{{cite web|url= http://www.accessdata.fda.gov/drugsatfda_docs/appletter/2002/21196ltr.pdf |title= FDA Approval Letter for Xyrem; Indication: Cataplexy associated with narcolepsy; 17 Jul 2002}}</ref>


* 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 [[Excessive daytime sleepiness|EDS]] in patients with [[narcolepsy]].<ref>{{cite web|url= http://www.accessdata.fda.gov/drugsatfda_docs/appletter/2005/021196s005ltr.pdf |title= FDA Approval Letter for Xyrem; Indication: EDS (Excessive Daytime Sleepiness) associated with narcolepsy; 18 Nov 2005}}</ref> 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 treatment of [[cataplexy]] in adult patients with [[narcolepsy]] by the [[European Medicines Agency]] for the [[European Union]] (EU) and the Swiss Agency, [[Swissmedic]], for Therapeutic Products.<ref>{{cite web|url= http://www.aasmnet.org/jcsm/ViewAbstract.aspx?pid=27549 |title= 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}}</ref>
* 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 [[Excessive daytime sleepiness|EDS]] in patients with [[narcolepsy]].<ref>{{cite web|url= http://www.accessdata.fda.gov/drugsatfda_docs/appletter/2005/021196s005ltr.pdf |title= FDA Approval Letter for Xyrem; Indication: EDS (Excessive Daytime Sleepiness) associated with narcolepsy; 18 Nov 2005}}</ref> 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 treatment of [[cataplexy]] in adult patients with [[narcolepsy]] by the [[European Medicines Agency]] for the [[European Union]] (EU) and the Swiss Agency, [[Swissmedic]], for Therapeutic Products.<ref>{{cite web|url= http://www.aasmnet.org/jcsm/ViewAbstract.aspx?pid=27549 |title= 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}}</ref>
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* In 2006, Xyrem received an expanded indication for [[narcolepsy]] with [[cataplexy]] in the [[EU]].<ref>{{cite web|url= http://www.aasmnet.org/jcsm/ViewAbstract.aspx?pid=27549 |title= 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}}</ref>
* In 2006, Xyrem received an expanded indication for [[narcolepsy]] with [[cataplexy]] in the [[EU]].<ref>{{cite web|url= http://www.aasmnet.org/jcsm/ViewAbstract.aspx?pid=27549 |title= 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}}</ref>


* In 2007, Jazz Pharmaceuticals agreed to pay $20 million to resolve parallel criminal and civil investigations relating to the illegal marketing practices of Xyrem by its wholly-owned subsidiary Orphan Medical, Inc.<ref>{{cite web|url= http://www.justice.gov/usao/nye/pr/2007/2007jul13a.html |title= Department of Justice Press Release}}</ref>
* In 2007, Jazz Pharmaceuticals agreed to pay $20 million to resolve investigations related to off-label marketing practices of Xyrem by its wholly-owned subsidiary Orphan Medical, Inc.<ref>{{cite web|url= http://www.justice.gov/usao/nye/pr/2007/2007jul13a.html |title= Department of Justice Press Release}}</ref>


* In 2010, Jazz Pharmaceuticals completed two Phase III clinical trials to investigate 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 and their review is expected to be completed in 2010.<ref>{{cite web|url= http://www.prnewswire.com/news-releases/jazz-pharmaceuticals-submits-new-drug-application-for-jzp-6-sodium-oxybate-for-the-treatment-of-fibromyalgia-79296097.html|title= http://www.prnewswire.com/news-releases/jazz-pharmaceuticals-submits-new-drug-application-for-jzp-6-sodium-oxybate-for-the-treatment-of-fibromyalgia-79296097.html}}</ref>
* In 2010, Jazz Pharmaceuticals completed two Phase III clinical trials to investigate 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 and their review is expected to be completed in 2010.<ref>{{cite web|url= http://www.prnewswire.com/news-releases/jazz-pharmaceuticals-submits-new-drug-application-for-jzp-6-sodium-oxybate-for-the-treatment-of-fibromyalgia-79296097.html|title= http://www.prnewswire.com/news-releases/jazz-pharmaceuticals-submits-new-drug-application-for-jzp-6-sodium-oxybate-for-the-treatment-of-fibromyalgia-79296097.html}}</ref>

Revision as of 02:56, 12 September 2010

Sodium Oxybate Chemical Structure[1]
This article pertains to the prescription medication Xyrem, for information about its active ingredient, please see gamma-Hydroxybutyric acid

Xyrem (sodium oxybate) oral solution 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]. 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] Sodium oxybate, the active ingredient in the solution, is also known as γ-Hydroxybutyric acid (GHB) or 4-hydroxybutanoic acid.

Overview

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]

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. 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.[6]

The development of Xyrem (sodium oxybate) oral solution as a prescription medication was initiated by the Office of Orphan Products Development (OOPD).[7] The OOPD is a department of the U.S. Food and Drug Administration (FDA) dedicated to promoting the development of products that demonstrate promise for the diagnosis and/or treatment of rare diseases or conditions.[8]

  • In 1994, the OOPD petitioned a pharmaceutical company called Orphan Medical to investigate sodium oxybate as a potential treatment for narcolepsy. Shortly there after, Orphan Medical conducted 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[10] and Xyrem was granted Priority Review.[11] Priority Review is an expedited review process given to products that offer a major advance in treatment or treatment where no adequate therapy exists.[12]
  • In 2007, Jazz Pharmaceuticals agreed to pay $20 million to resolve investigations related to off-label marketing practices of Xyrem by its wholly-owned subsidiary Orphan Medical, Inc.[17]
  • In 2010, Jazz Pharmaceuticals completed two Phase III clinical trials to investigate 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 and their review is expected to be completed in 2010.[18]

There are also ongoing tests to see if Xyrem could prove helpful with other medical conditions, such as Parkinson's, Chronic Fatigue Syndrome (ME), and Schizophrenia.[1].

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. In Canada and the EU, it is classified as a Schedule III and a Schedule IV controlled substance, respectively.[19]

Cost

Orphan drugs are typically priced much higher than drugs used to treat common conditions affecting large numbers of patients.[20] [21] Rare diseases by their nature have relatively few patients to spread the costs associated with bringing these products to market. According to First DataBank price reporting service, the current WAC (Wholesale Acquisition Cost) of Xyrem is $800 (180 mL bottle, 500 mg/mL). The effective dose range of Xyrem is 6 to 9 grams per night which equates to a Wholesale Acquisition Cost of $1,600 - $2,400 per month. Wholesale Acquisition Cost (WAC) is the manufacturer’s reported list price for a prescription pharmaceutical for sale to wholesalers.

Xyrem is covered by most insurance companies 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 manufacture offers a coupon program for the small number of patients with larger copays. Some insurance companies may require physicians to fill out an insurance form called a Prior Authorization as part of the prescribing process. Additionally, the manufacture 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.[22]

Existing US Patents on Xyrem prevent other companies from manufacturing it. Xyrem is protected by US Patients 6472431[23] and 6780889[24], which are set to expire in 2019 and 2022, respectively.

Safety

Xyrem has been safely used by patients with narcolepsy for more than seven years.[25] 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.[26] 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.[27]


Xyrem Success Program

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.[28]

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 60ml 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.

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. [29]

See also

External links

References

  1. ^ "FDA Approved Labeling (package insert) for Xyrem (sodium oxybate) oral solution" (PDF).
  2. ^ "FDA Approval Letter for Xyrem; Indication: Cataplexy associated with narcolepsy; 17 Jul 2002" (PDF).
  3. ^ "FDA Approval Letter for Xyrem; Indication: EDS (Excessive Daytime Sleepiness) associated with narcolepsy; 18 Nov 2005" (PDF).
  4. ^ "Practice Parameters for the Treatment of Narcolepsy and other Hypersomnias of Central Origin (Morgenthaler et al. Sleep. 2007;30:1705)" (PDF).
  5. ^ "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".
  6. ^ "The Orphan Drug Act Implementation and Impact" (PDF).
  7. ^ "http://xyrem.com/learn/". {{cite web}}: External link in |title= (help)
  8. ^ "FDA Office of Orphan Products Development".
  9. ^ "http://xyrem.com/learn/". {{cite web}}: External link in |title= (help)
  10. ^ "http://xyrem.com/learn/". {{cite web}}: External link in |title= (help)
  11. ^ "http://xyrem.com/learn/". {{cite web}}: External link in |title= (help)
  12. ^ "FDA.gov".
  13. ^ "FDA Approval Letter for Xyrem; Indication: Cataplexy associated with narcolepsy; 17 Jul 2002" (PDF).
  14. ^ "FDA Approval Letter for Xyrem; Indication: EDS (Excessive Daytime Sleepiness) associated with narcolepsy; 18 Nov 2005" (PDF).
  15. ^ "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".
  16. ^ "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".
  17. ^ "Department of Justice Press Release".
  18. ^ "http://www.prnewswire.com/news-releases/jazz-pharmaceuticals-submits-new-drug-application-for-jzp-6-sodium-oxybate-for-the-treatment-of-fibromyalgia-79296097.html". {{cite web}}: External link in |title= (help)
  19. ^ "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".
  20. ^ "FDA.gov".
  21. ^ "money.cnn.com".
  22. ^ "Jazz Pharmaceuticals, Inc. Q1 2010 Earnings Call Transcript". Retrieved 2010-08-06.
  23. ^ US Patent 6472431
  24. ^ US Patent 6780889
  25. ^ "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". {{cite web}}: line feed character in |title= at position 54 (help)
  26. ^ "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". {{cite web}}: line feed character in |title= at position 54 (help)
  27. ^ "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". {{cite web}}: line feed character in |title= at position 54 (help)
  28. ^ "FDA Approval Letter for Xyrem (sodium oxybate) oral solution; Risk Management Program(RMP)Requirements; 17 Jul 2002" (PDF).
  29. ^ Bouygues (25 Jan. 2009) Bouyer : "Une nouvelle expérience"(in French) accessed 5 March 2010
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