What is the recommended treatment and dosage of Wakix (pitolisant) for excessive daytime sleepiness in adults with narcolepsy?

Wakix (Pitolisant) for Excessive Daytime Sleepiness in Adults with Narcolepsy

Pitolisant (Wakix) is strongly recommended at a dosage of 17.8 mg to 35.6 mg once daily in the morning for the treatment of excessive daytime sleepiness in adults with narcolepsy, with a structured titration schedule to minimize side effects. 1, 2

Dosing and Administration Protocol

Standard Adult Dosing Schedule

• Week 1: Start with 8.9 mg (two 4.45 mg tablets) once daily in the morning upon waking
• Week 2: Increase to 17.8 mg (one 17.8 mg tablet) once daily
• Week 3: May increase to maximum recommended dose of 35.6 mg (two 17.8 mg tablets) once daily 2

Special Population Considerations

• Moderate hepatic impairment:

  • Start at 8.9 mg once daily
  • After 14 days, may increase to maximum of 17.8 mg once daily 2

• Renal impairment (eGFR <60 mL/min/1.73m²):

  • Start at 8.9 mg once daily
  • After 7 days, may increase to maximum of 17.8 mg once daily 2

• Poor CYP2D6 metabolizers:

  • Maximum recommended dose is 17.8 mg once daily 2

Efficacy and Mechanism of Action

Pitolisant is a histamine-3 (H3) receptor antagonist/inverse agonist that works through a novel mechanism compared to other narcolepsy treatments 3. Clinical trials demonstrate:

• Significant reduction in excessive daytime sleepiness compared to placebo (p=0.024 in HARMONY I and p<0.0001 in HARMONY CTP) 4
• Robust clinical impact with large effect sizes (Cohen's d of 0.61-0.86) 5
• Low number needed to treat (NNT) of 3-5 for excessive daytime sleepiness 5
• Effective for cataplexy with NNT of 3-4 5

Safety Profile and Monitoring

Common Side Effects

• Headache
• Insomnia
• Weight gain
• Nausea 1, 6, 7

Important Safety Considerations

• QT interval prolongation: Avoid use with other QT-prolonging drugs and in patients with risk factors for prolonged QT interval 2
• Contraindications:
  • Severe hepatic impairment
  • Known hypersensitivity to pitolisant 2
• Drug interactions:
  • Strong CYP2D6 inhibitors: Maximum dose 17.8 mg once daily
  • May reduce effectiveness of hormonal contraceptives; alternative contraception recommended during treatment and for 21 days after discontinuation 2

Treatment Response Assessment

• Clinical response may take up to 8 weeks for some patients 2
• Use the Epworth Sleepiness Scale (ESS) to track subjective sleepiness response 6
• Assess functional ability and quality of life improvements 6

Comparison to Other Narcolepsy Treatments

The American Academy of Sleep Medicine strongly recommends several medications for narcolepsy treatment 1, 6:

• Pitolisant: Effective for both excessive daytime sleepiness and cataplexy with minimal abuse potential 8
• Sodium oxybate: Most effective first-line treatment for both excessive daytime sleepiness and cataplexy, but has FDA black box warning for respiratory depression and abuse potential 1, 6
• Modafinil: Strong recommendation for excessive daytime sleepiness only 1, 6
• Solriamfetol: Strong recommendation for excessive daytime sleepiness only 1, 6

Clinical Pearls and Pitfalls

• Pitolisant is the only anti-narcoleptic medication not scheduled as a controlled substance in the USA, making it advantageous for patients with history of substance abuse 8
• May reduce effectiveness of oral contraceptives; patients should use alternative contraception methods during treatment and for 21 days after discontinuation 2
• Based on animal data, pitolisant may cause fetal harm; human data are insufficient to determine risk 1, 2
• Pitolisant offers once-daily morning dosing, improving convenience and adherence 8, 3
• If a dose is missed, patients should take the next dose the following day in the morning upon wakening rather than taking a double dose 2