Xyrem (sodium oxybate) Fact Sheet

August 6, 2008

Indications

XYREM® (sodium oxybate) oral solution was approved by the U.S. Food and Drug Administration (FDA) in July 2002 for the treatment of cataplexy in patients with narcolepsy. In November 2005, the FDA also approved XYREM for the treatment of excessive daytime sleepiness (EDS) in patients with narcolepsy. In XYREM clinical trials, approximately 80 percent of patients maintained concomitant stimulant use.

Cataplexy is a sudden bilateral loss of voluntary muscle tone, usually triggered by strong emotions such as laughter, surprise, fear, or anger.¹ Cataplectic episodes resemble the loss of muscle tone that occurs with the normal dreaming stage of sleep called rapid eye movement (REM).2 During normal REM sleep, the muscles become immobile or paralyzed as a protection against acting out one's dreams. (2,3,4)

Excessive Daytime sleepiness (EDS) refers to a propensity to fall asleep, nod, or doze easily in relaxed or sedentary situations, or a need to exert extra effort to avoid sleepiness in these situations. Unwanted sleepiness may also manifest as sleep attacks (irresistible urges to sleep) occurring not only during monotonous situations conducive to sleep, but also in situations where the patient is actively engaged in a task.¹

All narcolepsy patients (100 percent) experience EDS and an estimated 60-100 percent experience cataplexy, making them the two most common daytime symptoms of this chronic and debilitating neurological sleep disorder.4,5 XYREM is the only product to be FDA-approved for the treatment of both EDS and cataplexy. XYREM is not approved for the treatment of any of other symptoms of narcolepsy. In December 2007, the American Academy of Sleep Medicine (AASM) defined XYREM as a standard of care for the treatment of EDS and cataplexy associated with narcolepsy.6

As there is no known cure for narcolepsy, current therapy focuses on the management of symptoms to enable patients to have the fullest personal and professional lives possible. Pharmacologic therapy is directed at alleviating the most prominent symptoms, and is typically initiated at low doses to avoid potential side effects.3,7 There are currently no FDA-approved agents for the management of sleep paralysis and hypnagogic hallucinations.

Product Description

XYREM is a formulation of gamma-hydroxybutyrate, an endogenous neurotransmitter and metabolite of GABA. It has complex effects on several neurotransmitter systems. While the precise mechanism of XYREM is unknown, the effects may be mediated in part through interaction with GABAB and GHB receptors.8

Sodium oxybate, the active ingredient in XYREM, is a salt of gamma-hydroxybutyrate (GHB), a powerful, rapidly acting central nervous system depressant.8 XYREM is a Schedule III drug under the Controlled Substances Act. Non-medical uses of sodium oxybate are classified as Schedule I under the Controlled Substances Act.9 XYREM is only distributed through the XYREM Success Program®, a patient and physician support program developed with the FDA and clinicians specializing in narcolepsy treatment. The XYREM Success Program promotes safe and responsible use of XYREM and helps minimize the potential for abuse and diversion.9

Efficacy

Approval of XYREM for the treatment of EDS and cataplexy in narcolepsy is based on four multi-center, randomized, double-blind, placebo-controlled, parallel-group trials.9 Numerous other studies have also evaluated the use of XYREM in patients with narcolepsy.

Excessive Daytime Sleepiness (EDS) Efficacy
XYREM significantly increases daytime wakefulness in narcolepsy. In an eight-week study, patients taking XYREM, 9 grams/night, showed a median 37 percent reduction from baseline in levels of daytime sleepiness at endpoint as assessed by the Epworth Sleepiness Scale (ESS). The ESS is a patient questionnaire that evaluates the extent of sleepiness in everyday situations;9 patients taking XYREM had ESS scores closer to the normal range at end point as compared to patients taking placebo.10 Results from another eight-week study also indicate that XYREM, either as a monotherapy or in combination with modafinil, improves both objective and subjective measures of EDS in patients with narcolepsy beyond baseline modafinil treatment. These results were significant when compared with placebo.11

Cataplexy Efficacy
In a four-week study the median frequency of weekly cataplexy attacks at endpoint decreased 49 percent from baseline in patients treated with XYREM 6 grams/night and 69 percent from baseline in patients treated with XYREM 9 grams/night, compared with a decrease of 28 percent in patients treated with placebo.12 The greatest reduction in cataplexy occurred over the first two weeks of treatment and continued through the four-week period.

Long-term Efficacy
XYREM also demonstrated continued efficacy in the treatment of cataplexy after long-term use in a study with patients with an average of 21 months (range: 7 to 44 months) of XYREM treatment.9,13 During the two week double-blind phase, abrupt cessation of long-term XYREM therapy resulted in a gradual increase in cataplexy attacks from baseline in placebo patients (P<0.001); no median change was observed in patients continuing with XYREM.13 The gradual increase in cataplexy observed in this trial contrasts with reports of acute rebound cataplexy known to occur following the abrupt withdrawal of antidepressant medications when used for the treatment of cataplexy. In addition, patients withdrawn from XYREM did not experience other overt symptoms characteristic of an acute withdrawal (abstinence) syndrome.9,13

Dosing

XYREM should be taken at bedtime, while in bed, a minimum of two hours after eating. The recommended starting dose for XYREM is 4.5 grams/night divided into two equal doses of 2.25 grams. In clinical trials, the effective dose range of XYREM was 6 to 9 grams/night. XYREM should be titrated to effect in increments of 1.5 grams/night at one or two week intervals to a maximum of 9 grams/night.9 It is important to use XYREM as prescribed.

Safety

The safety and tolerability profile of XYREM has been established in placebo-controlled and open-label clinical trials involving 717 patients.9 XYREM has been used by more than 25,000 patients commercially, during the past five-and-a-half years. For additional safety data, see the full prescribing information, including boxed warnings.

In clinical trials, the most commonly observed adverse events with XYREM were nausea, dizziness, headache, vomiting, sleepiness, bed-wetting, and nasopharyngitis. Patients should talk with their doctors to discuss possible side effects.

XYREM is contraindicated in patients being treated with sedative hypnotic agents and in patients with succinic semialdehyde dehdrogenase deficiency.9

In drug interaction studies in healthy adults there were no pharmacokinetic interactions between XYREM and three drugs commonly used in patients with narcolepsy (zolpidem tartrate, protriptyline HCl, and modafinil). Pharmacodynamic interactions cannot be ruled out.9

XYREM is marketed by Jazz Pharmaceuticals, Inc.

!WARNING: Central nervous system depressant with abuse potential. Should not be used with alcohol or other CNS depressants. Sodium oxybate is GHB, a known drug of abuse. Abuse has been associated with some important central nervous system (CNS) adverse events (including death). Even at recommended doses, use has been associated with confusion, depression and other neuropsychiatric events. Reports of respiratory depression occurred in clinical trials. Almost all of the patients who received sodium oxybate during clinical trials were receiving CNS stimulants. Important CNS adverse events associated with abuse of GHB include seizure, respiratory depression and profound decreases in level of consciousness, with instances of coma and death. For events that occurred outside of clinical trials, in people taking GHB for recreational purposes, the circumstances surrounding the events are often unclear (e.g., dose of GHB taken, the nature and amount of alcohol or any concomitant drugs). Xyrem is available through the Xyrem Success Program, using a centralized pharmacy 1-866-XYREM88 ® (1-866-997-3688). The Success Program provides educational materials to the prescriber and the patient explaining the risks and proper use of sodium oxybate, and the required prescription form. Once it is documented that the patient has read and/or understood the materials, the drug will be shipped to the patient. The Xyrem Success Program also recommends patient follow-up every 3 months. Physicians are expected to report all serious adverse events to the manufacturer. (See WARNINGS).

1 Mahmood M, Black J. Narcolepsy-cataplexy: how does recent understanding help in evaluation and treatment. Curr Treat Options Neurol. 2005;7:363-371.
2 National Institute of Neurological Disorders and Stroke. Narcolepsy Fact Sheet. NIH Publication No. 03-1637. March 2005.
3 Guilleminault C, Fromherz S. Narcolepsy: Diagnosis and Management. In: Kryger MH, Roth T, Dement WC, eds. Principles and Practice of Sleep Medicine. 4th Ed. Philadelphia, Pa: Elsevier Saunders; 2005:780-790.
4 Bassetti C, Aldrich MS. Narcolepsy. Neurol Clin. 1996;14:545-571.
5 Czeisler CA, Winkleman JW, Richardson GS. Sleep Disorders: Chapter 27 in Harrison’s Principles of Internal Medicine. 16th ed. New York, NY: McGraw-Hill;2005.
6 Morgenthaler TI, Kapur VK, Brown T, Swick TJ, Alessi C, Aurora RN, Boehlecke B, Chesson AL, Friedman L, Maganti R, Owens J, Pancer J, Zak R; Standards of Practice Committee of the AASM. Practice param¬eters for the treatment of narcolepsy and other hypersomnias of central origin. SLEEP. 2007;30(12):1705-1711.
7 Overeem S, Mignot E, van Dijk JG, Lammers GJ. Narcolepsy: clinical features, new pathophysiologic insights, and future perspectives. J Clin Neurophysiol. 2001;18:78-105.
8 Pardi D, Black J. Gamma-Hydroxybutyrate/sodium oxybate: neurobiology, and impact on sleep and wakefulness. CNS Drugs. 2006;20(12):993-1018.
9 XYREM® (sodium oxybate) [prescribing information]. Palo Alto, Calif : Jazz Pharmaceuticals; 2005.
10 The International Xyrem® Study Group. A double-blind, placebo controlled study demonstrates sodium oxybate is effective for the treatment of excessive daytime sleepiness in narcolepsy. J Clin Sleep Med. 2005;1(4):391-397.
11 Black J, Houghton WC. Sodium oxybate improves excessive daytime sleepiness in narcolepsy. Sleep. 2006; 29:939-946.
12 The US Xyrem® Multicenter Study Group. A randomized, double blind, placebo-controlled multicenter trial comparing the effects of three doses of orally administered sodium oxybate with placebo for the treatment of narcolepsy. Sleep. 2002;25(1):42-49. 13 The US Xyrem® Multicenter Study Group. Sodium oxybate demonstrates long-term efficacy for the treatment of cataplexy in patients with narcolepsy. Sleep Med. 2004;5:119-123.