Pharmacology Update

Xyrem—A New Drug for Cataplexy

By William T. Elliott, MD, FACP, and James Chan, PharmD, PhD

The FDA has approved sodium oxybate for the treatment of patients with cataplexy associated with narcolepsy. Originally marketed as a dietary supplement, sodium oxybate is also known as gamma hydroxybutyrate or GHB. The drug is notorious as a street drug, popular among young adults due to its ability to cause relaxation and euphoria,1 and has been dubbed the "date rape drug" by the press. Still, sodium oxybate has been anxiously awaited by the 20,000-50,000 narcoleptic patients who suffer from cataplexy. To assure appropriate prescribing, sodium oxybate will be distributed directly to the patient from one central pharmacy. It will be marketed under the name of Xyrem by Orphan Medical Inc.

Indications

Sodium oxybate is indicated for the treatment of cataplexy in patients with narcolepsy. It is contraindicated in patients currently being treated with sedative-hypnotics.2

Dosage

The recommended dose is 2.25 g at bedtime and again 2.5-4 hours later. The dose may be increased to 9 g/d in increments of 1.5 g/d after 2 weeks. The first dose should be taken while in bed and the second dose while sitting in bed. Each dose of sodium oxybate is diluted with 2 ounces (60 mL) of water. It should be taken on an empty stomach as food significantly reduces bioavailability. The effective dose is 6-9 g/d with 9 g being most effective. Doses greater than 9 g/d should not be taken.2 Patients should not engage in any activity requiring alertness for at least 6 hours after taking this drug. Concomitant use of alcohol and other sedatives should be avoided.

Sodium oxybate is supplied as 500 mg/mL in a 180 mL bottle including a measuring syringe and dosing cups. Diluted preparations should be taken within 24 hours.

Potential Advantages

Sodium oxybate has been shown to reduce the frequency of cataplexy attacks. Patients with a mean of 23.5 cataplexy attacks per week at baseline had a median reduction of 16 attacks per week with the 9 g/d dose and a reduction of 10 attacks per week with the 6 g/d dose.2,3 In patients with a low frequency of cataplexy, (4/week) attacks were eliminated.2 The frequency of inadvertent naps/sleep attacks and nighttime awakening were significantly improved with the 9 g dose.3

Potential Disadvantages

Sodium oxybate has significant abuse potential. It has been used as a recreational drug for about a decade. It produces relaxation and euphoria and has become popular as "liquid ectasy" and as a "date rape" drug.1 Common side effects (vs placebo) include dizziness (32% vs 6%), nausea (15-34% vs 6%), and incontinence (6-14% vs 0%). The drug has also been associated with depression, confusion, and other neuropsychiatric events.2 Abuse can lead to serious CNS side effects (eg, seizures, respiratory depression) that have resulted in coma and death as well as drug dependence and withdrawal symptoms.2

Comments

The efficacy of sodium oxybate was studied in 2 randomized, double-blind, placebo-controlled, 4-week studies involving a total of 185 patients. Eighty to 85% of these were being treated with CNS stimulants. Sodium oxybate (mainly the 9 g dose) was shown to significantly reduce cataplexy episodes. In more severe cases (mean of 23.5 attacks/week), the frequency was reduced by about two thirds. Attacks were eliminated in less severe cases (4 attacks/week). In addition, daytime sleepiness, inadvertent daytime naps/sleep attacks, and nighttime awakenings were also improved.2,3 The mechanism of action is unclear but some postulate that it may serve as a neurotransmitter/neuromodulator and improve the restorative nature of nocturnal sleep. Sodium oxybate is and has been used as a recreational drug and carries with it a significant risk for abuse. The drug is available only through restricted distribution from a central pharmacy and will not be available in retail pharmacies. As condition for approval, the FDA required numerous risk management components. These include restricted distribution, a medication guide, documentation and verification of prescriber and patient education, maintenance of patient and prescriber registries, specific prescription handling and shipment directions, and a post marketing evaluation program. Prescribers and patients may call a toll free number for information on sodium oxybate (1-877-67-XYREM). Sodium oxybate solution is a Schedule III, federally controlled substance.

Clinical Implications

Narcolepsy is a lifelong disorder affecting about 120,000 people or about 1-2/2000 in the United States.4 It is characterized by excessive daytime sleepiness, cataplexy, sleep paralysis, hypnagogic hallucinations, and sleep disturbance with serious personal, social, and economic implications. Cataplexy, which affects up to about 40% of these individuals, is a sudden loss of skeletal muscle tone (often dropping of the jaw) without loss of consciousness. These are often triggered by bursts of laughter, elation, embarrassment, anger, or sexual arousal. Defects in the orexin (hypocretin) A and B system have been hypothesized as the cause of this disorder.5 Narcolepsy is generally managed with CNS stimulants (eg, amphetamines, methylphenidate, modafinil). While these are effective in improving daytime sleepiness, they do not affect cataplexy. Antidepressants, primarily tricyclic antidepressants, are the current standard treatment for cataplexy. There are, however, currently no published comparative studies between sodium oxybate and antidepressants. Sodium oxybate does offer an effective alternative.

References

1. Kam PC, Yoong FF. Anaesthesia. 1998;53:1195-1198.

2. Xyrem Product. Labeling May 2002. Orphan Medical Inc.

3. Anonymous. Sleep. 2002;25(1):42-49.

4. FDA Talk Paper. July 17, 2002. (www.fda.gov/bbs/topics/ANSWER/2002/ANS01157.html).

5. Beuckmann CT, Yanagisawa M. J Mol Med. 2002; 80(6):329-342.

Dr. Elliott is Chair, Formulary Committee, Northern California Kaiser Permanente; Asst. Clinical Professor of Medicine, University of California-San Francisco. Dr. Chan is Pharmacy Quality and Outcomes Manager, Kaiser Permanente, Oakland, CA. Both are Associate Editors of Internal Medicine Alert.