What is the appropriate treatment and dosage of Xyrem (sodium oxybate) for a patient with narcolepsy, considering its potential for abuse and side effects?

Xyrem (Sodium Oxybate) for Narcolepsy: Treatment Protocol

Primary Recommendation

Sodium oxybate is the first-line treatment for narcolepsy with cataplexy in adults, as it is the only medication proven to treat both excessive daytime sleepiness and cataplexy simultaneously, with strong evidence supporting its efficacy. 1, 2

Dosing Protocol

Adult Patients with Narcolepsy

• Starting dose: 4.5 g per night, divided into two equal doses of 2.25 g at bedtime and 2.25 g taken 2.5-4 hours later 3
• Titration: Increase by up to 1.5 g per night per week (0.75 g per dose) based on efficacy and tolerability 3
• Target dose range: 6-9 g per night 3
• Maximum dose: 9 g per night (doses above this have not been studied and should not be administered) 3
• Some patients achieve better responses with unequal doses at bedtime versus the second dose 3

Pediatric Patients (7 years and older)

Weight-based dosing is mandatory for pediatric patients: 3

• 20-30 kg: Start ≤1 g per dose, maximum weekly increase 0.5 g per dose, maximum total 6 g/night (3 g per dose) 3
• 30-45 kg: Start ≤1.5 g per dose, maximum weekly increase 0.5 g per dose, maximum total 7.5 g/night (3.75 g per dose) 3
• ≥45 kg: Start ≤2.25 g per dose, maximum weekly increase 0.75 g per dose, maximum total 9 g/night (4.5 g per dose) 3
• For patients <20 kg, insufficient data exists for specific recommendations, but lower starting doses and slower titration should be considered if used 3

Critical Safety Warnings

Black Box Warning

Sodium oxybate carries an FDA black box warning as a CNS depressant that may cause respiratory depression and death, particularly when combined with alcohol or other sedating medications. 2, 3

Controlled Substance Status

• Sodium oxybate is a Schedule III controlled substance (the sodium salt of GHB, which is Schedule I) 1, 3
• Available ONLY through REMS program using certified specialty pharmacies 1, 2, 3
• High abuse potential due to rapid onset of sedation and amnestic properties, especially when combined with alcohol 3

Respiratory Complications

• Central sleep apnea and clinically significant oxygen desaturation (≤55%) can occur in both adult and pediatric patients 3
• In patients with pre-existing obstructive sleep apnea, one of four patients with moderate-to-severe OSA had significant worsening of apnea/hypopnea index 3
• Three patients (6%) in OSA studies experienced clinically significant oxygen desaturation, with one requiring withdrawal 3
• Prescribers must be aware that sleep-disordered breathing is more prevalent in obese patients, men, postmenopausal women not on hormone replacement, and narcolepsy patients 3

Psychiatric Risks

• Depression and suicidal ideation can occur with sodium oxybate treatment 3
• In adult narcolepsy trials (n=781), two suicides and two attempted suicides occurred, including three patients with previous depressive psychiatric disorder 3
• Depression was reported in 7% of patients, with <1% discontinuing due to depression 3
• In pediatric trials (n=104), one patient experienced suicidal ideation and two reported depression 3

Common Adverse Effects

Most frequently reported adverse events include: 1, 2

• Nausea, dizziness, and headache
• Nocturnal enuresis (bedwetting)
• Weight loss and decreased appetite
• Vomiting and nasopharyngitis
• Chest discomfort, sleep disturbances, and confusion

In pediatric patients specifically: weight loss, enuresis, nausea, vomiting, headache, decreased appetite, and dizziness were most common 1

Absolute Contraindications

• Concurrent use with alcohol or other CNS depressants is absolutely contraindicated due to risk of respiratory depression, seizures, decreased consciousness, coma, and death 3
• Pregnancy and breastfeeding represent high-risk situations, as animal data suggests fetal harm with insufficient human data 1, 2

Monitoring Requirements

Initial Evaluation

• Confirm narcolepsy diagnosis (type 1 with cataplexy or type 2) 4
• Screen for history of substance abuse due to high abuse potential 3
• Assess for pre-existing respiratory conditions, particularly obstructive sleep apnea 3
• Screen for depression and suicidal ideation 3
• Document baseline cataplexy frequency and Epworth Sleepiness Scale scores 4

Ongoing Monitoring

• Regular follow-up to assess treatment efficacy and adverse effects, particularly respiratory depression 5
• Monitor for signs of misuse or abuse (increase in dose frequency, drug-seeking behavior, feigned cataplexy) 3
• Evaluate cataplexy frequency and excessive daytime sleepiness severity at each visit 4
• Watch for depression, suicidal ideation, and behavioral changes 3
• In patients with respiratory conditions or OSA, consider polysomnography to assess for worsening sleep-disordered breathing 3

Clinical Efficacy Evidence

Sodium oxybate demonstrates clinically significant improvements across multiple narcolepsy symptoms: 1, 2

• Six randomized controlled trials and six observational studies show moderate-quality evidence for improvements in cataplexy attacks, excessive daytime sleepiness, and disease severity 2
• The 9 g dose produces median increases >10 minutes on Maintenance of Wakefulness Test (p<0.001) 6
• Dose-related decreases in Epworth Sleepiness Scale scores and inadvertent naps are significant at 6 g and 9 g doses (p<0.001) 6
• Sodium oxybate is the first drug to demonstrate efficacy for both major symptoms of narcolepsy (excessive daytime sleepiness and cataplexy) 6
• Long-term follow-up studies show persistent beneficial effects over 2 years, with complete resolution of cataplexy, sleep paralysis, and sleep-onset hallucinations 7

Special Populations

Elderly Patients

• Careful monitoring required due to potential adverse effects 5
• One case report demonstrates tolerability in an elderly man with severe OSA on CPAP therapy, though close monitoring was essential 7

Pediatric Patients

• The American Academy of Sleep Medicine provides a conditional recommendation for pediatric patients 7 years and older 1, 5
• One prospective double-blind, placebo-controlled study and three observational studies demonstrate clinically significant improvements in cataplexy, disease severity, and excessive daytime sleepiness 1
• Central sleep apnea and oxygen desaturation observed during polysomnography in pediatric patients require vigilant monitoring 3

Pregnant and Breastfeeding Patients

• Animal data suggests fetal harm, with insufficient human data to determine risk 1
• The balance of risks and harms is different for pregnant and breastfeeding patients, requiring individualized risk-benefit assessment prioritizing maternal safety and functional capacity 2

Combination Therapy Considerations

If excessive daytime sleepiness remains inadequately controlled on sodium oxybate alone, add either pitolisant or an amphetamine: 2

• When combining amphetamines with sodium oxybate, exercise extreme caution due to opposing CNS effects (amphetamines are stimulants, sodium oxybate is a CNS depressant) 2
• Monitor closely for cardiovascular effects, as amphetamines increase heart rate and blood pressure 2
• Pitolisant is the only narcolepsy treatment not scheduled as a controlled substance, making it an attractive combination option 2
• Avoid combination with alcohol or other sedating medications due to respiratory depression risk 2, 3

Alternative Treatment Options

If sodium oxybate is not tolerated or contraindicated: 2

• For patients requiring cataplexy control: Pitolisant is the preferred alternative, with moderate-quality evidence from 3 RCTs showing improvements in both excessive daytime sleepiness and cataplexy 2
• For patients with only excessive daytime sleepiness: Solriamfetol is the preferred alternative, with the strongest evidence base and high-quality evidence from 3 RCTs 2
• Traditional stimulants (dextroamphetamine, methylphenidate) and modafinil/armodafinil do NOT directly treat cataplexy 2

Insurance Authorization Strategy

• Emphasize the STRONG recommendation from the American Academy of Sleep Medicine for sodium oxybate 4
• Provide objective measures: weekly cataplexy attack frequency and Epworth Sleepiness Scale scores 4
• Document confirmed narcolepsy diagnosis and specific symptoms being treated 4
• Note that six RCTs and six observational studies demonstrate moderate-quality evidence for efficacy 4

Lower-Sodium Formulation (Xywav)

• A lower-sodium oxybate formulation (Xywav) contains 92% less sodium than traditional sodium oxybate (Xyrem) 8
• At recommended adult doses (6-9 g/night), traditional sodium oxybate increases daily sodium intake by 1100-1640 mg 8
• Xywav uses calcium, magnesium, and potassium ions in addition to minimal sodium 8
• Pharmacokinetic parameters differ slightly, but bioequivalence evaluations confirm similar efficacy and safety profiles 8
• Consider Xywav for patients with cardiovascular disease, hypertension, or those requiring sodium restriction 8