Sodium oxybate

Side effects

The American Academy of Sleep Medicine (AASM) recommends sodium oxybate 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, and the drug has been safely used by patients with narcolepsy since 2002. A recent analysis evaluated the postmarketing safety of sodium oxybate, 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 sodium oxybate 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 sodium oxybate during this period:

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, sodium oxybate use is largely appropriate and confined to patients with legitimate therapeutic needs.

In the US, sodium oxybate 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 Tylenol with codeine, and testosterone. In Canada and the European Union (EU), it is classified as a Schedule III and a Schedule IV controlled substance, respectively. Sodium oxybate is the only treatment for narcolepsy approved by the World Anti-Doping Agency, and has been instrumental in allowing cyclist Franck Bouyer to resume his career.

On October 18, 2011, Jazz Pharmaceuticals, Inc. disclosed that it had received a Warning Letter from the FDA for specific violations during the FDA's inspection of the firm from April 27, 2011 through May 6, 2011. In the letter the FDA cited 2 specific violations: 1. Failure to develop adequate written procedures for the surveillance, receipt, evaluation, and reporting of postmarketing adverse drug experiences to FDA [21 C.F.R § 314.80(b)]. 2. Failure to submit adverse drug experience (ADE) reports that are both serious and unexpected to FDA within 15 calendar days of initial receipt of the information by the applicant [21 C.F.R. § 314.80(c)(1)(i)]. The firm also received an FDA form 483 on September 27, 2007, for similar post-marketing safety violations.

Adverse effects

Sodium oxybate 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. Some patients treated with sodium oxybate have also experienced moderate to significant weight loss. This may be due to the fact that sodium oxybate improves sleep architecture and increases the length of deep sleep stages, resulting in increased production of human growth hormone (HGH) and changes in energy metabolism. The weight loss could also be due to decreased daytime appetite (experienced by many users) and the instructions to not eat for two hours before bedtime. Serious side effects, as listed on all prescriptions of sodium oxybate, can include hallucinations, agitation, severe mental confusion, abnormal thinking, disrupted sleep, and depression.

Pregnancy considerations

The U.S. Food and Drug Administration categorizes sodium oxybate as Pregnancy Category C for all trimesters of pregnancy. Currently, there are no well-controlled studies in pregnant women. Animal studies have shown adverse effects on the fetus. In one study, rats were given oral sodium oxybate throughout pregnancy and lactation. This resulted in increased stillbirths, decreased offspring survival after birth, and decreased body weight gain. In another study, pregnant rats and pregnant rabbits were given oral sodium oxybate during organogenesis. This resulted in no evidence of adverse effects on fetal development. As such, sodium oxybate should be used in pregnancy only if the benefit outweighs the risk for the fetus.

Mechanism of action

According to the U.S. Food and Drug Administration, the precise mechanism of action for the prescription medication sodium oxybate is unknown.

However, the active metabolite of sodium oxybate, gamma-hydroxybutyric acid, is known to produce its therapeutic effects by acting as an agonist at the GABA_B receptor complex and the GHB receptor. This likely contributes to some part of sodium oxybate's therapeutic effects.

History

Sodium oxybate is designated as an orphan drug, a pharmaceutical drug developed specifically to treat an orphan disease. The development of sodium oxybate oral solution as a prescription medication was initiated by the Office of Orphan Products Development (OOPD), 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.

There are also ongoing tests to see if sodium oxybate could prove helpful with other medical conditions, such as Parkinson's disease, chronic fatigue syndrome (ME), schizophrenia, binge eating, essential tremor and other non-Parkinson's movement disorders, and chronic cluster headache.

Unapproved uses

In 2007, the makers of Xyrem, 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.

The lawsuit claimed that the manufacturers:

"In 2012, the Second Circuit Court of Appeals further expanded First Amendment commercial speech protection in the realm of pharmaceutical marketing in United States v. Caronia. The court overturned a pharmaceutical sales representative’s conviction arising from a recording of his promotion of off-label use of Xyrem (sodium oxybate) to a group of doctors. Xyrem was approved for the indication of excessive daytime sleepiness, but Caronia promoted it for insomnia and fibromyalgia. The court held that convicting the sales representative for off-label marketing that was not untruthful or misleading violated his First Amendment rights. In contrast, off-label promotion that is untruthful and misleading would be fraudulent, and thus not protected by the First Amendment."

National Health Service

NHS England authorises and pays for sodium oxybate by means of individual funding requests on the basis of exceptional circumstances. In May 2016 they were ordered by the High Court to provide funding to treat a teenager with severe narcolepsy. The judge criticised their “thoroughly bad decision” and “absurd” policy discriminating against the girl when hundreds of other NHS patients already receive the drug. The Department of Health is also paying for the treatment of people whose narcolepsy was caused by the swine flu vaccine Pandemrix in 2009-10 by means of private prescriptions outside the National Health Service.

Cost

Jazz Pharmaceuticals raised the price of Xyrem 841% earning a total of $569 million in 2013 and representing more than 50% of Jazz Pharmaceutical's revenues. In 2007 it cost $2.04; by 2014 it cost $19.40 per 1-milliliter dose. Jazz offers copay assistance to help patients access the expensive drug. According to DRX, a drug-data report published by Bloomberg, Jazz Pharmaceuticals price increase on Xyrem topped the list of price hikes in 2014.

Historically, orphan drugs cost more than other drugs and have received special treatment since the enactment of the U.S. Orphan Drug Act of 1983. However, these steep price increases of orphan and other specialty drugs has come under scrutiny. The average cost of a specialty drug in the US was $65,000 annually in June 2013 (about $5,416 a month). The price of Xyrem in the US has inflated by an average of 40% annually since it became available as a prescription.

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. The cost of pharmaceuticals, including sodium oxybate, tends to be lower in these countries.

The British Department of Health pays for the medication for 80 patients who are taking legal action over problems linked to the use of the swine flu vaccine Pandemrix at a cost of £12,000 a year. It is not universally available to patients with narcolepsy through the National Health Service.

In the US, the cost (as of Q3 2015) of Xyrem is $5,468.09 per 180 mL bottle (500 mg/mL)(a 10 to 15-day supply), compared to $576.00 (£360-390)) in the UK under the NHS. The dose range is 4.5–9 grams per night (with a therapeutic dose range of 6-9 grams per night), which equates to $6,048.60 (4.5g) to $12,097.20 (9g) per month as of February 2014; Jazz Pharmaceuticals increases its prices for Xyrem on a semi-annual basis. 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 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.

Existing US Patents on sodium oxybate prevent other companies from manufacturing it as a drug. Sodium oxybate is protected by US Patents 6472431, and 6780889 In total, sodium oxybate is protected by fifteen patents related to the product's formulation, methods of treatment, dosing regimens when taking sodium oxybate with Valproate, and Jazz Pharmaceuticals' distribution system. These patents expire from 2019 to 2033.

Distribution

A number of measures have been put in place by sodium oxybate's manufacturers to ensure that it is used safely and appropriately. For example, in the US sodium oxybate requires a prescription and can only be obtained through a restricted distribution program, called the "Xyrem REMS 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:

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

Initial dosages are set by the prescribing physician. Each bottle of sodium oxybate 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.