Introduction
Wakix (pitolisant) is a first-in-class selective histamine H₃ receptor antagonist/inverse agonist approved by the FDA in 2019 for the treatment of excessive daytime sleepiness (EDS) or cataplexy in adults with narcolepsy. Unlike traditional stimulants used for narcolepsy, Wakix represents a novel therapeutic approach with a different mechanism of action and favorable safety profile.
Mechanism of Action
Pitolisant works through dual mechanisms as a selective histamine H₃ receptor antagonist and inverse agonist. By blocking presynaptic H₃ autoreceptors, it increases the synthesis and release of histamine in the brain. Additionally, it enhances the release of other wake-promoting neurotransmitters including dopamine, norepinephrine, and acetylcholine in the cortex. This unique mechanism promotes wakefulness without direct stimulant effects on monoamine systems.
Indications
- Treatment of excessive daytime sleepiness in adults with narcolepsy
- Treatment of cataplexy in adults with narcolepsy
Dosage and Administration
Initial dose: 8.9 mg once daily upon waking Titration: Increase to 17.8 mg daily after 7 days Maximum dose: 35.6 mg daily (may be increased after 7 more days if needed) Administration: Take within 30 minutes of waking with or without food Special populations:- Renal impairment: No dosage adjustment needed for mild to moderate impairment; use caution in severe impairment
- Hepatic impairment: Contraindicated in severe hepatic impairment
- Geriatric patients: Use caution
- Pediatric patients: Safety and effectiveness not established
Pharmacokinetics
Absorption: Rapidly absorbed with Tmax of 3.5 hours; bioavailability approximately 90% Distribution: Volume of distribution ~100 L; protein binding 91-96% Metabolism: Primarily hepatic via CYP3A4 and secondarily via CYP2D6 Elimination: Half-life approximately 20 hours; excreted primarily in urine (90%) and feces (2.3%)Contraindications
- Severe hepatic impairment
- Known hypersensitivity to pitolisant or any component of the formulation
- Concomitant use with strong CYP3A4 inhibitors
- Concomitant use with drugs that prolong QT interval
Warnings and Precautions
QT Prolongation: Dose-dependent QT interval prolongation observed; avoid in patients with known QT prolongation or risk factors Hepatic Impairment: Not recommended in moderate hepatic impairment; contraindicated in severe impairment Pregnancy: Limited data; use only if potential benefit justifies potential risk Lactation: Not recommended during breastfeeding Abuse Potential: No evidence of abuse potential in clinical studiesDrug Interactions
Strong CYP3A4 inhibitors (e.g., ketoconazole, clarithromycin): Contraindicated - significantly increase pitolisant exposure Moderate CYP3A4 inhibitors (e.g., fluconazole, diltiazem): Reduce Wakix dose by 50% CYP3A4 inducers (e.g., rifampin, carbamazepine): May decrease pitolisant efficacy QT-prolonging drugs: Avoid concomitant use Oral contraceptives: May decrease efficacy of hormonal contraceptivesAdverse Effects
Most common (≥5%):- Insomnia (6%)
- Nausea (6%)
- Anxiety (5%)
- Headache (5%)
- Irritability (5%)
- QT interval prolongation
- Severe hepatic impairment
- Hypersensitivity reactions
Monitoring Parameters
- Efficacy assessment: Epworth Sleepiness Scale, cataplexy frequency
- ECG monitoring: Baseline and periodic assessment of QT interval
- Liver function tests: Baseline and periodic monitoring
- Mental status: Monitor for anxiety, depression, or irritability
- Weight: Monitor for changes
- Blood pressure and heart rate
Patient Education
- Take medication upon waking, with or without food
- Do not crush or break tablets
- Inform healthcare provider of all medications being taken
- Report any palpitations, dizziness, or fainting
- Use effective non-hormonal contraception during treatment
- Avoid activities requiring mental alertness until drug effects are known
- Report any mood changes, anxiety, or irritability
- Regular follow-up appointments are essential
References
1. FDA Prescribing Information: Wakix (pitolisant) tablets. August 2019. 2. Dauvilliers Y, et al. Pitolisant versus placebo or modafinil in patients with narcolepsy: a double-blind, randomised trial. Lancet Neurol. 2013;12(11):1068-1075. 3. Setnikar I, et al. Assessment of the abuse potential of pitolisant, a selective H3-receptor antagonist/inverse agonist, in comparison with modafinil and placebo in recreational stimulant users. J Psychopharmacol. 2017;31(7):896-908. 4. Syed YY. Pitolisant: First Global Approval. Drugs. 2016;76(13):1313-1318. 5. Thorpy MJ, et al. Pitolisant for the treatment of excessive daytime sleepiness in narcolepsy: A randomized clinical trial. JAMA Neurol. 2019;76(4):444-452.