Section 10 · Monograph

Pitolisant

Reviewed Nov 2026FDA label

WakixH3 receptor antagonist

Indications

Treatment of excessive daytime sleepiness (EDS) in patients 6 years of age and older with narcolepsy.FDA-labeled
Treatment of cataplexy in patients 6 years of age and older with narcolepsy.FDA-labeled
NOTE: FDA approved a supplemental NDA on February 17, 2026 expanding the cataplexy indication to pediatric patients ≥6 years old (previously, pediatric approval — granted June 2024 — covered EDS only; cataplexy was adult-only). The current label states both EDS and cataplexy indications apply to patients 6 years of age and older.FDA-labeled

Mechanism in EDS/cataplexy is not fully elucidated but is believed to be mediated through activity as an antagonist/inverse agonist at histamine H3 autoreceptors.
By blocking presynaptic H3 autoreceptors, pitolisant increases synthesis and release of histamine (a wake-promoting neurotransmitter) from histaminergic neurons in the tuberomammillary nucleus, and may also modulate release of dopamine, norepinephrine, and acetylcholine.
Distinct from stimulant/amphetamine-like agents and from sodium oxybate; not a controlled substance, and it is the only non-scheduled FDA-approved medication for narcolepsy.
The cataplexy-reducing effect is hypothesized to relate to histaminergic and noradrenergic modulation of REM-sleep-related muscle atonia circuits.

Adults: initiate at 8.9 mg once daily in the morning upon wakening; increase to 17.8 mg/day after 1 week; may increase to maximum 35.6 mg/day after another week based on response/tolerability.
Take once daily in the morning upon waking; do not administer in the afternoon or evening due to risk of insomnia.
Strong CYP2D6 inhibitors: reduce pitolisant dose by half.
Strong CYP3A4 inducers: may need to double the pitolisant dose (up to the maximum).
Missed dose: skip if remembered later in the day; do not double up.

Moderate hepatic impairment or renal impairment: reduce dose (approximately half) and slow titration; not recommended in severe renal impairment or ESRD.

Pediatric patients 6 years and older: weight-based, slower titration — Week 1: 4.45 mg/day; Week 2: 8.9 mg/day; Week 3: 17.8 mg/day (maximum for patients <40 kg); Week 4: may increase to 35.6 mg/day maximum only in patients ≥40 kg.

Known hypersensitivity to pitolisant or any of its excipients (anaphylaxis has been reported).
Severe hepatic impairment (Child-Pugh Class C) — not studied in this population.

Strong CYP2D6 inhibitors (paroxetine, fluoxetine, quinidine, bupropion): increase pitolisant exposure ~2.2-fold; reduce pitolisant dose by half.
Strong CYP3A4 inducers (rifampin, carbamazepine, phenytoin, St. John's wort): decrease pitolisant exposure by up to ~50%; may require dose increase and re-titration if the inducer is discontinued.
Sensitive CYP3A4 substrates, including hormonal contraceptives: pitolisant may induce CYP3A4 and reduce effectiveness; use alternative (non-hormonal) contraception during treatment and for at least 21 days after discontinuation.
Centrally-acting H1 antihistamines (diphenhydramine): may counteract the effect of pitolisant and reduce efficacy — avoid concomitant use.
QT-prolonging drugs: pitolisant prolongs QT interval in a dose-dependent manner; avoid use with other QT-prolonging drugs and in patients with risk factors for QT prolongation.
CYP2D6 substrates with narrow therapeutic index: pitolisant may inhibit CYP2D6 and increase exposure of these agents.

Adults, most common (≥5% and at least twice placebo): insomnia (6%), nausea (6%), anxiety (5%).
Pediatric patients (≥5% and greater than placebo): headache and insomnia.
QT interval prolongation (dose-dependent) — avoid in patients with risk factors or on other QT-prolonging drugs.
Hypersensitivity reactions including anaphylaxis.
Other reported effects: irritability, dizziness, GI upset, musculoskeletal pain, weight changes, sleep disturbances.
No signal for abuse/dependence identified in studies to date (not a controlled substance).

ECG/QT interval assessment in patients with risk factors for QT prolongation, or those on other QT-prolonging medications.
Hepatic function tests in patients with hepatic impairment; avoid in severe (Child-Pugh C) impairment.
Renal function in patients with renal impairment (dose adjustment needed).
Monitor for insomnia, anxiety, mood changes, especially during dose titration.
Assess for hypersensitivity/anaphylaxis symptoms, particularly with initial doses.
Contraceptive efficacy counseling.
In pediatric patients, monitor growth/weight and school/behavioral function periodically.

Pregnancy: Available data from case reports and a pregnancy exposure registry have not identified a drug-associated risk of major birth defects or miscarriage, but data are limited. Animal reproduction studies showed maternal and embryofetal toxicity at doses producing exposures well above the maximum recommended human dose. A pregnancy exposure registry is available (1-800-833-7460).
Lactation: Transfer of pitolisant into human breastmilk is low based on data from a lactation study — mean infant dose ~0.009 mg/day, relative infant dose <1% of the maternal weight-adjusted dose.