What are the latest treatment options for narcolepsy with cataplexy?

Latest Treatments for Narcolepsy with Cataplexy

First-Line Treatment

Sodium oxybate (Xywav/Xyrem) is the primary treatment for narcolepsy with cataplexy, as it is the only medication that effectively treats both cataplexy and excessive daytime sleepiness simultaneously. 1

Sodium Oxybate Administration and Efficacy

• Administer as a liquid in two equally divided doses: the first at bedtime and the second 2.5-4 hours later 1
• Demonstrated clinically significant improvements in cataplexy attacks, excessive daytime sleepiness, and overall disease severity based on 6 RCTs and 6 observational studies 1
• In adults, the 9g nightly dose showed a median increase of >10 minutes on the Maintenance of Wakefulness Test (p<0.001) and significant dose-related decreases in Epworth Sleepiness Scale scores at 6g and 9g doses 2
• In pediatric patients (ages 7-16), withdrawal from sodium oxybate resulted in a median increase of 12.7 cataplexy attacks per week compared to 0.3 attacks in those continuing treatment (p<0.0001) 3

Lower-Sodium Formulation (Xywav)

• A newer formulation containing 92% less sodium than traditional sodium oxybate (Xyrem) is now available, reducing daily sodium intake by 1100-1640 mg 4
• This lower-sodium oxybate provides equivalent efficacy while reducing cardiovascular risks associated with excess sodium consumption 4
• Approved for narcolepsy in patients 7 years and older, and also for idiopathic hypersomnia in adults 4

Critical Safety Warnings for Sodium Oxybate

• FDA black box warning: central nervous system depressant that may cause respiratory depression; use with extreme caution in patients with any respiratory conditions 1, 5
• Schedule III controlled substance (sodium salt of gamma hydroxybutyrate/GHB) available only through REMS program using certified pharmacies 1, 5
• Common adverse events include nausea, dizziness, nocturnal enuresis, headache, chest discomfort, sleep disturbances, and confusion 1
• In pediatric patients, enuresis (21%), nausea (22%), vomiting (21%), headache (18%), and decreased weight (15%) were most common 3
• Rare but serious effects include central sleep apnea, depression, and suicidality 1
• Avoid combination with alcohol or other sedating medications due to respiratory depression risk 1

Second-Line Treatment: Pitolisant

• Pitolisant (Wakix) is a histamine-3-receptor inverse agonist effective for both cataplexy and excessive daytime sleepiness 1, 6, 7
• Major advantage: not a controlled substance by the US Drug Enforcement Administration, making it an attractive alternative when controlled substance prescribing is problematic 1
• In adult trials, demonstrated statistically significant improvement of -3.1 points on ESS compared to placebo (95% CI: -5.73, -0.46) 7
• For cataplexy, showed a rate ratio of 0.51 (95% CI: 0.44,0.60) for weekly cataplexy attacks versus placebo 7
• In pediatric patients (6-17 years), showed improvement of -3.41 points on PDSS total score compared to placebo (95% CI: -5.52, -1.31) 7
• Dosing: initiated at 4.45 mg once daily, can be increased to 17.8 mg for patients <40 kg or 35.6 mg for patients ≥40 kg 7
• Important caveat: reduces efficacy of hormonal contraceptives; advise patients to use alternative contraception methods 7
• May prolong QT interval; patients should report faintness, loss of consciousness, or palpitations immediately 7

Combination Therapy Algorithm

When excessive daytime sleepiness remains inadequately controlled on sodium oxybate monotherapy:

• Add either pitolisant or an amphetamine (dextroamphetamine or methylphenidate) to sodium oxybate 1
• Pitolisant is preferred for combination therapy as it is not a controlled substance and has direct anticataplectic effects 1
• If using amphetamines with sodium oxybate, exercise extreme caution due to opposing CNS effects (amphetamines are stimulants, sodium oxybate is a depressant) 1
• Monitor heart rate and blood pressure closely when combining amphetamines with sodium oxybate, as amphetamines increase both parameters 1
• Critical distinction: amphetamines (dextroamphetamine, methylphenidate), modafinil, armodafinil, and solriamfetol treat excessive daytime sleepiness but do NOT directly treat cataplexy 1, 8

Medications That Do NOT Treat Cataplexy

• Solriamfetol, armodafinil, modafinil, dextroamphetamine, and methylphenidate are recommended for excessive daytime sleepiness only 1
• These agents should not be relied upon for cataplexy control 1

Non-Pharmacological Management

• Maintain good sleep hygiene and regular sleep-wake schedules to help control cataplexy 1
• Avoid shift work and on-call schedules as occupational considerations 1
• Workplace accommodations and cognitive-behavioral therapy remain essential adjuncts regardless of medication regimen 1

Monitoring Requirements

• Assess cataplexy frequency and severity regularly to evaluate treatment efficacy 1
• Monitor for medication side effects, particularly respiratory depression, enuresis, nausea, and headache with sodium oxybate 1, 5
• Watch for cataplexy exacerbation if any medication affecting adrenergic systems is initiated, as loss of hypocretin-producing neurons suggests adrenergic systems are downstream mediators of cataplexy pathology 1, 6
• For elderly patients on sodium oxybate, careful monitoring is required due to potential adverse effects 5

Special Populations

• Pregnant or breastfeeding patients: avoid combination therapy as all medications may cause fetal harm based on animal data 1
• Patients with significant cardiovascular disease: require individualized risk-benefit assessment, particularly when considering combination therapy 1
• Patients with history of substance abuse: use sodium oxybate with caution due to potential for misuse 5

Referral Considerations

• Primary care physicians should refer patients to a sleep specialist when narcolepsy with cataplexy is suspected for proper diagnosis and treatment initiation 1