The Xyrem?? Risk Management Program

Abstract

Sodium oxybate, also known as gamma-hydroxybutyric acid (GHB), was discovered in 1960 and has been described both as a therapeutic agent with high medical value and, more recently, a substance of abuse. The naturally occurring form of this drug is found in various body tissues but has been studied most extensively in the CNS where its possible function as a neurotransmitter continues to be studied. Sodium oxybate has been approved in different countries for such varied uses as general anaesthesia, the treatment of alcohol withdrawal and addiction, and, most recently, cataplexy associated with narcolepsy. During the 1980s, easy access to GHB-containing products led to various unapproved uses, including weight loss, bodybuilding and the treatment of sleeplessness, sometimes with serious long-term effects. The availability of these unapproved and unregulated forms of the drug led to GHB and its analogues being popularised as substances of abuse and subsequent notoriety as agents used in drug-facilitated sexual assault, or 'date rape', eventually leading to the prohibition of GHB sales in the US. Legal efforts to control the sale and distribution of GHB and its analogues nearly prevented the clinical development of sodium oxybate for narcolepsy in the US. However, following extensive discussions with a variety of interested parties, a satisfactory solution was devised, including legislative action and the development of the Xyrem Risk Management Program. Amendments to the US Controlled Substances Act made GHB a schedule I drug, but also contained provisions that allow US FDA-approved products to be placed under schedule III. This unique, bifurcated schedule for sodium oxybate/GHB allowed the clinical development of sodium oxybate to proceed and, in July 2002, it was approved by the FDA as an orphan drug for the treatment of cataplexy in patients with narcolepsy as Xyrem(sodium oxybate) oral solution. To promote the safe use of sodium oxybate, as well as alleviate concerns over possible diversion and abuse following product approval, a proprietary restricted drug distribution system was created, called the Xyrem Success Program. Components of the programme include a centralised distribution and dispensing system, a physician and patient registry, compulsory educational materials for patients and physicians, a specially trained pharmacy staff, a method for tracking prescription shipments, and an initial post-marketing surveillance programme. The system has created a unique opportunity to provide both physician and patient education and ongoing patient counselling, promoting greater drug safety and enhanced patient compliance.

Determination of gamma-hydroxybutyric acid in dried blood spots using a simple GC-MS method with direct “on spot” derivatization

“…Although it has been abandoned as anaesthetic agent in most countries because of side effects such as seizures and coma, it is still registered in Germany (Somsanit®). The sodium salt of GHB, known under the international drug name sodium oxybate, has a role in the treatment of narcolepsy with cataplexy (Xyrem®) and of opiate and alcohol withdrawal (Alcover®) [7][8][9][10][11].…”

Pharmacotherapy of Narcolepsy: Focus on Sodium Oxybate

“…39 Abuse, addiction, withdrawal syndrome, and overdoses have been documented with GHB, which led to its 1990's ban and placement as a Schedule I agent under the Controlled Substances Act. 40,41 Concerns regarding the history of abuse of GHB were taken into consideration by the Food and Drug Administration (FDA) and the manufacturer in the development of sodium oxybate. 40,41 Sodium oxybate (γ-hydroxybutyrate; Xyrem ® ) was approved in 2002 by the Food and Drug Administration as an orphan drug for the management of narcolepsy.…”

Feasibility of Following up Gamma-Hydroxybutyric Acid Concentrations in Sodium Oxybate (Xyrem®)-Treated Narcoleptic Patients Using Dried Blood Spot Sampling at Home

“…It has been demonstrated that GHB administration in narcoleptic patients with cataplexy increases slow-wave sleep duration, improves EDS and reduces the number of awakenings at night. [4][5][6] Therefore, sodium oxybate has been approved in 2002 by the US Food and Drug Administration (FDA) for the treatment of cataplexy in narcolepsy patients, and subsequently in 2005 for the treatment of EDS in narcolepsy patients. Also, in 2005, the European Medicines Agency (EMA) approved sodium oxybate for the treatment of narcolepsy with cataplexy.…”

“…The first dose should be taken at bedtime and the second 2.5-4 h later. [4][5][6] Intraand interindividual variation in clinical effect has been seen with sodium oxybate; however, it is not known whether this correlates with variation in obtained GHB concentrations. Therefore, the dried blood spot (DBS) sampling technique, stated to be easy and minimally invasive, may be useful to obtain patient samples in a non-hospital-based setting.…”