pitolisant

General Information

Pitolisant (Wakix) is a wake-promoting medication indicated for excessive daytime sleepiness (EDS) and cataplexy in adult patients with narcolepsy (label).

It is a histamine H3 receptor inverse agonist/antagonist and is not a controlled substance. Medication selection often balances misuse risk, psychiatric comorbidity, and monitoring feasibility (label/clinical).

QT prolongation risk is clinically central; higher exposures (CYP2D6 poor metabolizers, strong CYP2D6 inhibitors, hepatic impairment, and interacting regimens) increase risk, so dose limits and interaction review are key safeguards (label).

Pitolisant may reduce effectiveness of hormonal contraceptives (CYP3A4 induction); non-hormonal contraception is recommended during therapy and for 21 days after discontinuation (label).

The pitolisant compare view, evidence feed, and print page support review of non-stimulant strategies and monitoring considerations.

Pitolisant offers a non-scheduled wake-promoting option for narcolepsy, but QT-focused safety management (dose limits, interaction review, and attention to hepatic impairment and CYP2D6 status) is a required trade-off and commonly shapes patient selection (label/clinical).

Mechanism of Action

Refer to the Glossary entry on Neurotransmitters for background on receptor systems involved in serious mental illness.

Pitolisant is a histamine H3 receptor inverse agonist/antagonist, increasing histaminergic signaling in the brain and promoting wakefulness (label/clinical).

Compared with stimulant reuptake inhibitors, pitolisant is often framed as a non-scheduled option, but insomnia and anxiety can still occur and require monitoring, particularly in serious mental illness (clinical).

• Histamine H3 receptor inverse agonism/antagonism (wake-promoting mechanism).

Metabolism and Pharmacokinetics

• Pitolisant is primarily metabolized by CYP2D6 and to a lesser extent by CYP3A4; metabolites are not pharmacologically active (label).
• After a single dose, median half-life is ~20 hours (range ~7.5–24.2 hours). Renal clearance accounts for <2% of total clearance (label).
• CYP2D6 poor metabolizers and strong CYP2D6 inhibitors increase exposure; dose adjustments and maximum dosage limits are required to reduce QT risk (label).

Dosing and Administration

• Adults: titrate weekly—8.9 mg once daily in the morning (week 1), 17.8 mg once daily (week 2), and may increase to 35.6 mg once daily (week 3) based on response and tolerability (label).
• Morning dosing is emphasized; late-day dosing increases insomnia risk (label/clinical).
• Strong CYP2D6 inhibitors or known CYP2D6 poor metabolizers: maximum recommended dosage is 17.8 mg once daily (label).
• Hepatic impairment requires careful selection; pitolisant is contraindicated in severe hepatic impairment and requires dosage modification in moderate hepatic impairment (label).

Monitoring & Labs

• QT risk review (history, co-medications, exposure-increasing interactions) (label/clinical).
• Mood and psychiatric symptom monitoring (anxiety, agitation, mania/psychosis) (clinical).
• Sleep disruption monitoring (insomnia, circadian effects) (clinical).
• Drug interaction review (CYP2D6 inhibitors; CYP3A4 inducers; contraception) (label).
• Hepatic function status review for dosing safety (label).

Adverse Effects

Interactions

• Strong CYP2D6 inhibitors increase exposure (about 2.2-fold); reduce dose and cap at 17.8 mg once daily (label).
• Strong CYP3A4 inducers decrease exposure (about 50%); assess for loss of efficacy and adjust dosing per label (label/clinical).
• Pitolisant may reduce effectiveness of sensitive CYP3A4 substrates, including hormonal contraceptives; use non-hormonal contraception during therapy and for 21 days after discontinuation (label).
• Avoidance of other QT-prolonging agents when possible is a common risk management strategy, especially in polypharmacy (label/clinical).

Other Useful Information

• Evidence syntheses and guidelines support wake-promoting agents for excessive daytime sleepiness in central hypersomnolence disorders; choice is individualized based on symptom profile, comorbidity, and monitoring feasibility (AASM/clinical).
• In serious mental illness, clinicians often monitor closely for insomnia, anxiety, and mood destabilization when adding wake-promoting agents, and prioritize nonpharmacologic contributors to sleepiness when present (clinical).

References

1. WAKIX (pitolisant) tablets prescribing information — DailyMed (2025)
2. Treatment of central disorders of hypersomnolence: an American Academy of Sleep Medicine clinical practice guideline — Journal of Clinical Sleep Medicine (2021)
3. Treatment OF Central Disorders OF Hypersomnolence: AN American Academy OF Sleep Medicine Systematic Review, Meta Analysis, AND Grade Assessment — Journal of Clinical Sleep Medicine (2021)
4. Pitolisant versus placebo or modafinil in patients with narcolepsy — Lancet Neurology (2013)