Introduction
Xywav® (calcium, magnesium, potassium, and sodium oxybates) oral solution is a central nervous system depressant approved for the treatment of cataplexy or excessive daytime sleepiness (EDS) in patients 7 years of age and older with narcolepsy. It is also indicated for the treatment of idiopathic hypersomnia (IH) in adults. Xywav represents an evolution of sodium oxybate therapy with significantly reduced sodium content, addressing cardiovascular concerns associated with high sodium intake.
Mechanism of Action
Xywav's active moiety is oxybate, which is the sodium salt of gamma-hydroxybutyrate (GHB). The precise mechanism by which Xywav exerts its therapeutic effects is not fully understood but is believed to involve agonist activity at GABA-B receptors and possibly GHB-specific receptors. This activity appears to consolidate sleep and improve sleep architecture by increasing slow-wave sleep and reducing nighttime awakenings in patients with narcolepsy. The improved sleep quality subsequently reduces symptoms of cataplexy and excessive daytime sleepiness.
Indications
- Treatment of cataplexy in patients 7 years of age and older with narcolepsy
- Treatment of excessive daytime sleepiness (EDS) in patients 7 years of age and older with narcolepsy
- Treatment of idiopathic hypersomnia (IH) in adults
Dosage and Administration
Initial Titration:- Narcolepsy (adults): 4.5 g per night orally divided into two doses
- Narcolepsy (pediatric 7-17 years): Based on body weight (0.5-0.75 g/kg)
- Idiopathic hypersomnia: 4.5 g per night orally divided into two doses
- First dose at bedtime while in bed
- Second dose taken 2.5-4 hours later
- Must be taken while fasting (at least 2 hours after food)
- May increase by 1.5 g/night every 1-2 weeks
- Maximum dose: 9 g/night for narcolepsy (adults), 6 g/night for IH
- Pediatric maximum: 9 g/night or 0.1 g/kg, whichever is less
- Hepatic impairment: Use with caution, consider dose reduction
- Renal impairment: Not studied in severe impairment (avoid use)
- Geriatric: Use with caution due to increased sensitivity
Pharmacokinetics
Absorption: Rapidly absorbed with peak concentrations reached within 0.5-1.25 hours. Bioavailability is approximately 25% due to first-pass metabolism. Distribution: Rapidly distributes throughout the body with an apparent volume of distribution of 190-384 mL/kg. Minimal protein binding. Metabolism: Primarily metabolized via the Krebs cycle to carbon dioxide and water, with minor metabolism by β-oxidation. No cytochrome P450 involvement. Elimination: Elimination half-life is 0.5-1 hour. Excreted primarily as carbon dioxide via respiration, with less than 5% excreted unchanged in urine.Contraindications
- Concomitant use with sedative/hypnotic agents
- Patients with succinic semialdehyde dehydrogenase deficiency
- History of substance use disorder
- Hypersensitivity to any component of the formulation
Warnings and Precautions
Boxed Warning:- Central nervous system depression
- Abuse and misuse potential
- Respiratory depression
- Sleepwalking and parasomnias: May cause complex sleep-related behaviors
- Depression and suicidality: Monitor for emergence or worsening of depression
- Respiratory depression: Risk increased in patients with compromised respiratory function
- Sodium content: Contains less sodium than sodium oxybate (approximately 1,080 mg less per maximum dose)
Drug Interactions
Major Interactions:- Alcohol: Additive CNS depression (contraindicated)
- Sedative-hypnotics: Additive CNS depression (contraindicated)
- Opioids: Increased risk of respiratory depression
- Valproic acid: May increase oxybate levels
- SSRIs/TCAs: Possible additive effects on sleep architecture
- Stimulants: May alter efficacy of Xywav
Adverse Effects
Common (≥5%):- Nausea (21%)
- Headache (19%)
- Dizziness (14%)
- Anxiety (8%)
- Vomiting (7%)
- Fatigue (7%)
- Respiratory depression
- Psychiatric symptoms (psychosis, paranoia)
- Sleepwalking with injury
- Depression and suicidal ideation
- Seizures
Monitoring Parameters
- Respiratory rate and oxygen saturation (especially in at-risk patients)
- Mental status and mood changes
- Sleep behaviors and parasomnias
- Electrolytes (particularly in patients on restricted diets)
- Blood pressure and cardiovascular status
- Efficacy measures: Epworth Sleepiness Scale, cataplexy frequency
- Signs of misuse or diversion
Patient Education
- Take while in bed and remain in bed after dosing
- Prepare both doses before bedtime
- Take second dose 2.5-4 hours after first dose
- Avoid alcohol and other CNS depressants
- Do not operate machinery for at least 6 hours after dosing
- Report any sleepwalking episodes or unusual behaviors
- Use caution when rising from bed during the night
- Store securely to prevent accidental ingestion or misuse
- Keep all follow-up appointments with healthcare provider
- Report any mood changes or suicidal thoughts immediately
References
1. Xywav® [package insert]. Palo Alto, CA: Jazz Pharmaceuticals, Inc.; 2023. 2. FDA Approval: Xywav (calcium, magnesium, potassium, and sodium oxybates) oral solution. FDA.gov. 2020. 3. Bogan RK, et al. Effect of oral JZP-258 on oxybate-associated sodium intake in narcolepsy: SLEEP 2021. 4. Dauvilliers Y, et al. Safety and efficacy of lower-sodium oxybate in narcolepsy: a phase 3, double-blind, placebo-controlled study. Lancet Neurol. 2021. 5. Jazz Pharmaceuticals. Xywav REMS Program. 2023. 6. American Academy of Sleep Medicine. International Classification of Sleep Disorders. 3rd ed. 2014.