Sodium oxybate

Sodium Oxybate Chemical Structure

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 and Excessive Daytime Sleepiness (EDS) associated with narcolepsy . The American Academy of Sleep Medicine (AASM) recently recognized 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. Sodium oxybate, the active ingredient in the solution, is also known as γ-Hydroxybutyric acid (GHB) or 4-hydroxybutanoic acid.

Overview

Xyrem is 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.

Xyrem is 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: EDS, cataplexy, hypnagogic hallucinations, sleep paralysis, and fragmented sleep. EDS and cataplexy are the most common daytime symptoms of narcolepsy.

The development of Xyrem (sodium oxybate) oral solution as a prescription medication was initiated by the Office of Orphan Products Development (OOPD). 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.

In 1994 the OOPD petitioned a pharmaceutical company called Orphan Medical to investigate sodium oxybate as a potential treatment for narcolepsy. Orphan Medical conducted Phase I, II, and III clinical trials to investigate the safety and efficacy of sodium oxybate and in 2000 submitted a New Drug Application (NDA) to the FDA.

The FDA granted Xyrem Priority Review, which is an expedited review process given to products that offer a major advance in treatment or treatment where no adequate therapy exists.

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.

In 2005, Xyrem was acquired by Jazz Pharmaceuticals and was granted a second indication by the FDA for the treatment of EDS in patients with narcolepsy. 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.

In 2006, Xyrem received an expanded indication for narcolepsy with cataplexy in the EU.

Jazz Pharmaceuticals has recently 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.

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.

Xyrem is also the only drug to be on two drug schedules at once under U.S. law: GHB is on schedule I, meaning that it is considered a highly dangerous and addictive drug with no medical uses, but GHB marketed as Xyrem and prescribed for specific conditions is on schedule III, which includes many drugs considered safe when used properly. This is unusual because the schedule system is built around the assumption that a drug's risks are due to the chemical itself, without reference to the user or the circumstances of its use. However, the government cites pragmatic reasons for the distinction: recreational drugs are often of unknown origin, may contain contaminants, and are difficult to take at a precise dose, while the same substance in prescription form is easier to use as intended. The involvement of a doctor also helps reduce the risk of dependency or of recreational, rather than medical use. This is similar to the justification for offering Marinol under schedule III, while marijuana is schedule I, but it differs in that pharmaceutical THC (referred to as Marinol or dronabinol) is a pure version of one of the many active chemicals in marijuana, whereas GHB and Xyrem are chemically identical. The law is inconsistent in this regard, as other drugs such as amphetamine and fentanyl fall under a single schedule, regardless of whether they are in pharmaceutical form or have been illicitly synthesized for recreational use.

In 2007, the makers of Xyrem, Orphan Medical, which is now part of Jazz Pharmaceuticals, pleaded guilty to a felony charge of marketing Xyrem for unapproved uses. These off-label uses included treatments for conditions such as fatigue, pain, and psychiatric disorders.

Cost

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.

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

Xyrem Safety

Xyrem has been safely used by patients with narcolepsy for more than seven years. 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. 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.

Xyrem Success Program

Xyrem is available by prescription only 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.

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.

See also

• Narcolepsy
• Cataplexy
• Excessive daytime sleepiness
• Gamma-hydroxybutyric acid

External links

• Xyrem Official Website Jazz Pharmaceuticals
• Xyrem Package Insert
• WebMD - Xyrem