What is the recommended titration protocol for XYWAV (calcium, magnesium, potassium, and sodium oxybates) in an adult patient with narcolepsy, based on symptoms?

XYWAV Titration Protocol Based on Symptoms

For adult patients with narcolepsy, initiate XYWAV at 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), then increase by up to 1.5 g per night per week based on symptom response until reaching the target range of 6-9 g per night. 1

Initial Dosing Strategy

• Start at 4.5 g total nightly dose administered as 2.25 g at bedtime and 2.25 g taken 2.5-4 hours later 1
• Administer XYWAV at least 2 hours after eating to optimize absorption 1
• Prepare both doses prior to bedtime by diluting each dose with approximately ¼ cup of water in pharmacy-provided containers 1
• Patients must take XYWAV while in bed and lie down immediately after dosing due to rapid onset of CNS depression 1

Weekly Titration Protocol

• Increase by up to 1.5 g per night per week (e.g., add 0.75 g to each dose) based on persistent symptoms of cataplexy or excessive daytime sleepiness 1
• Continue weekly increases until symptoms are adequately controlled, intolerable adverse effects emerge, or the maximum dose of 9 g per night is reached 1
• The recommended therapeutic range is 6-9 g per night, though some patients may respond adequately at lower doses 1
• Doses higher than 9 g per night have not been studied and ordinarily should not be administered 1

Symptom-Based Dose Optimization

• For persistent cataplexy attacks: Continue weekly titration increases until cataplexy frequency is adequately reduced, as sodium oxybate demonstrates clinically significant improvements in cataplexy control 2, 3
• For persistent excessive daytime sleepiness: Titrate upward if daytime sleepiness remains problematic despite cataplexy control, as sodium oxybate effectively treats both symptoms 2, 3
• Consider unequal dosing: Some patients achieve better symptom control with unequal nightly doses (e.g., 3 g at bedtime and 4.5 g at the second dose, or vice versa) rather than equal splitting 1

Critical Safety Monitoring During Titration

• Monitor for respiratory depression at each dose increase, particularly in patients with underlying respiratory conditions, as XYWAV carries an FDA black box warning for CNS depression and respiratory compromise 2, 1
• Assess for common adverse effects including nausea (most common), dizziness, nocturnal enuresis, headache, chest discomfort, and sleep disturbances at each titration step 2, 3
• Evaluate for psychiatric symptoms including depression, suicidality, confusion, and anxiety, which require dose reduction or discontinuation if they emerge 1
• Watch for parasomnias such as sleepwalking, which may necessitate dose adjustment 1

Dose Adjustments for Specific Situations

• If adverse effects emerge: Reduce the dose by 1.5 g per night (0.75 g per dose) and maintain at the lower dose for at least one week before attempting further increases 4
• If transitioning from Xyrem: Initiate XYWAV at the same total nightly dose as Xyrem (gram for gram) and titrate as needed based on efficacy and tolerability 1
• If concomitant divalproex sodium use: Reduce the initial XYWAV dose by at least 20% due to pharmacokinetic interactions 1
• For hepatic impairment: Start at one-half the standard initial dosage (2.25 g per night divided into two 1.125 g doses) and titrate more slowly 1

Timing Considerations for Second Dose

• The second dose should be taken 2.5-4 hours after the first dose 1
• Set an alarm to ensure timely administration of the second dose, as missing or delaying the second dose may result in inadequate symptom control 1
• Patients must remain in bed for the second dose due to rapid CNS depression 1

Long-Term Monitoring

• Assess treatment response using standardized tools such as the Epworth Sleepiness Scale and cataplexy frequency logs at each follow-up visit 5
• Monitor for tolerance: The beneficial effects of sodium oxybate on cataplexy, excessive daytime sleepiness, and sleep architecture persist over time without evidence of tolerance development 4
• Evaluate for abuse potential: Although XYWAV is a Schedule III controlled substance and the sodium salt of GHB, monitor for signs of misuse, particularly in patients with substance abuse history 2, 1

Common Pitfalls to Avoid

• Inadequate titration: Do not stop titration prematurely if symptoms persist and the patient tolerates the current dose; continue weekly increases up to 9 g per night 5
• Premature discontinuation: Do not discontinue XYWAV due to initial mild adverse effects (particularly nausea), as these often resolve with continued use 5, 6
• Concurrent CNS depressants: Avoid combining XYWAV with alcohol or sedative hypnotics, as this is contraindicated due to additive CNS depression and respiratory depression risk 1
• Inadequate patient education: Ensure patients understand the REMS program requirements, as XYWAV is only available through certified pharmacies due to abuse potential 2, 1