Xyrem - Drug Monograph

Introduction

Xyrem (sodium oxybate) is a central nervous system depressant approved by the FDA for the treatment of cataplexy and excessive daytime sleepiness in patients with narcolepsy. It is the sodium salt of gamma-hydroxybutyrate (GHB) and is classified as a Schedule III controlled substance in the United States due to its potential for abuse and dependence.

Mechanism of Action

Xyrem's exact mechanism of action in narcolepsy is not fully understood. It is believed to work through agonist activity at GABA-B receptors and possibly through effects on dopamine neurotransmission. The drug consolidates sleep and improves sleep architecture by increasing slow-wave sleep and REM sleep, which may explain its efficacy in reducing cataplexy attacks and improving daytime sleepiness.

Indications

• Treatment of cataplexy in patients 7 years of age and older with narcolepsy
• Treatment of excessive daytime sleepiness in patients 7 years of age and older with narcolepsy

Dosage and Administration

• First dose at bedtime
• Second dose taken 2.5-4 hours later

• Renal impairment: Use with caution in patients with renal insufficiency
• Hepatic impairment: Not studied; use with caution
• Geriatric patients: Use with caution due to increased sensitivity
• Pediatric patients: Dosing based on weight (0.5-0.75 g/kg body weight per night)

• Must be diluted with approximately ¼ cup of water
• Administer while in bed
• Avoid food within 2 hours of administration

Pharmacokinetics

Contraindications

• Concomitant use with sedative-hypnotic agents
• Patients with succinic semialdehyde dehydrogenase deficiency
• History of substance use disorder
• Hypersensitivity to sodium oxybate or any component of the formulation

Warnings and Precautions

• Central nervous system depression
• Abuse and misuse potential
• Respiratory depression

• Sleepwalking and other parasomnias
• Depression and suicidal ideation
• Sodium content (approximately 1.5 g per gram of sodium oxybate)
• Syncope and seizures

Drug Interactions

• Alcohol: Profound additive CNS depression
• Sedative-hypnotics: Increased risk of respiratory depression
• Opioids: Potentiation of CNS and respiratory depression
• Valproic acid: May increase levels of GHB

Adverse Effects

• Nausea (17%)
• Dizziness (11%)
• Headache (10%)
• Somnolence (7%)
• Vomiting (6%)

• Respiratory depression
• Confusion
• Depression
• Psychotic symptoms
• Enuresis
• Sleepwalking

Monitoring Parameters

• Respiratory rate and oxygen saturation (especially during initiation)
• Mental status changes
• Depression screening
• Sodium levels in patients on sodium-restricted diets
• Signs of abuse or diversion
• Sleep behaviors
• Efficacy parameters: Cataplexy frequency, daytime sleepiness measures

Patient Education

• Take while in bed due to rapid onset
• Prepare both doses before bedtime
• Avoid alcohol and other CNS depressants
• Do not operate machinery for at least 6 hours after dosing
• Report any sleepwalking or unusual behaviors
• Use reliable contraception
• Store securely to prevent misuse
• Never share medication with others
• Keep all follow-up appointments

References

1. Xyrem® (sodium oxybate) prescribing information. Jazz Pharmaceuticals, Inc. 2021. 2. 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. 3. Mamelak M, Black J, Montplaisir J, et al. A pilot study on the effects of sodium oxybate on sleep architecture and daytime alertness in narcolepsy. Sleep. 2004;27(7):1327-1334. 4. FDA. Xyrem REMS Program. Accessed January 2023. 5. Boscolo-Berto R, Viel G, Montagnese S, et al. Narcolepsy and effectiveness of gamma-hydroxybutyrate (GHB): a systematic review and meta-analysis of randomized controlled trials. Sleep Med Rev. 2012;16(5):431-443.