What is the dosing regimen for Xywav (calcium, magnesium, potassium, and sodium oxybates) in treating narcolepsy?

Xywav vs. Xyrem: Key Differences and Dosing

Xywav (lower-sodium oxybate) and Xyrem (sodium oxybate) contain the same active moiety but differ critically in sodium content—Xywav contains 92% less sodium than Xyrem, which is clinically meaningful for reducing cardiovascular morbidity in narcolepsy patients who already face increased cardiovascular risk. 1, 2

Sodium Content Comparison

• Xyrem adds 1100-1640 mg of sodium to daily dietary intake at recommended adult doses (6-9 g/night), which significantly increases blood pressure and cardiovascular risk 1
• Xywav achieves the same therapeutic effect with 92% less sodium by substituting calcium, magnesium, and potassium ions for most of the sodium content 1, 3
• The FDA recognizes Xywav's lower sodium content as clinically meaningful in reducing cardiovascular morbidity compared to Xyrem in the narcolepsy population 2

Dosing Regimen for Xywav

Adult Dosing

• Starting dose: 4.5 g per night divided into two equal doses (2.25 g at bedtime and 2.25 g taken 2.5-4 hours later) 4
• Titration: Increase by 1.5 g per night at weekly intervals (0.75 g added to each dose) 4
• Recommended dosage range: 6-9 g per night 4
• Maximum dose: 9 g per night (doses higher than this have not been studied and should not be administered) 4

Pediatric Dosing (≥7 years)

The dosing is weight-based 4:

• 20-30 kg: Start ≤1 g per dose (≤2 g total nightly), increase by 0.5 g per dose weekly, maximum 3 g per dose (6 g total nightly) 4
• 30-45 kg: Start ≤1.5 g per dose (≤3 g total nightly), increase by 0.5 g per dose weekly, maximum 3.75 g per dose (7.5 g total nightly) 4
• ≥45 kg: Start ≤2.25 g per dose (≤4.5 g total nightly), increase by 0.75 g per dose weekly, maximum 4.5 g per dose (9 g total nightly) 4

Administration Instructions

• Prepare both doses before bedtime by diluting each dose with approximately ¼ cup (60 mL) of water in pharmacy-provided containers 4
• Take the first dose at least 2 hours after eating to optimize absorption 4
• Take each dose while in bed and lie down immediately after dosing 4
• The second dose must be taken 2.5-4 hours after the first dose 4

Therapeutic Equivalence

• Xywav and Xyrem demonstrate bioequivalence with slight pharmacokinetic differences that do not affect clinical efficacy 1, 3
• Both medications effectively treat cataplexy, excessive daytime sleepiness, and disrupted nocturnal sleep in narcolepsy 5, 3
• In the SEGUE study, 93% of patients switching gram-per-gram from Xyrem to Xywav reported the transition was "easy," and 79% preferred Xywav, primarily due to lower sodium content 2
• Mean Epworth Sleepiness Scale scores remained stable during the switch (9.4 at baseline on Xyrem vs. 8.8 after switching to Xywav), demonstrating maintained effectiveness 2

Critical Safety Considerations

Both medications carry identical FDA black box warnings 5, 4:

• CNS depression and respiratory depression risk: Both are Schedule III controlled substances (sodium salt of GHB) 5, 4
• Available only through REMS programs using certified pharmacies 5, 4
• Common adverse effects: Nausea, dizziness, nocturnal enuresis, headache, chest discomfort, sleep disturbances, and confusion 5, 3
• Contraindicated with sedative hypnotics, alcohol, or in patients with succinic semialdehyde dehydrogenase deficiency 4

Hepatic Impairment Dosing

For patients with hepatic impairment, start with one-half of the original dosage per night, divided into two doses 4

Clinical Preference

Given equivalent efficacy and safety profiles, Xywav should be preferentially prescribed over Xyrem due to its substantially lower sodium content and associated reduction in cardiovascular risk, particularly important since narcolepsy patients already face elevated cardiovascular morbidity 1, 2