histamine H3 antagonist/agonist
Treatment of excessive daytime sleepiness or cataplexy in patients with narcolepsy.
Acts as a histamine-3 (H3) receptor antagonist/reverse agonist. Exact mechanism by which it minimizes excessive daytime sleepiness in narcolepsy unknown.
Reduced perception of falling asleep during daily life activities.
Absorption: 90% absorbed following oral administration.
Distribution: Extensively distributed to tissues.
Protein Binding: 91–96%.
Metabolism and Excretion: Primarily metabolized by the liver by the CYP2D6 isoenzyme, and to a lesser extent by the CYP3A4 isoenzyme; the CYP2D6 enzyme system exhibits genetic polymorphism (~7% of population may be poor metabolizers and may have significantly ↑ pitolisant concentrations and an ↑ risk of adverse effects).Primarily excreted in urine (90%; <2% as unchanged drug), with only 2% excreted in feces.
Half-life: 20 hr.
TIME/ACTION PROFILE (plasma concentrations)
|PO||unknown||2–5 hr||24 hr|
- Severe hepatic impairment
- End-stage renal disease
- QT interval prolongation, congenital QT interval prolongation, history of cardiac arrhythmias, symptomatic bradycardia, hypokalemia, or hypomagnesemia
- Concurrent use with QT interval prolonging medications.
Use Cautiously in:
- Moderate or severe renal impairment (↓ dose)
- Mild or moderate hepatic impairment (↓ dose in moderate hepatic impairment)
- Poor CYP2D6 metabolizer (↑ risk for adverse reactions; ↓ dose);
- OB: Use during pregnancy only if potential maternal benefit justifies potential fetal risk;
- Lactation: Use while breastfeeding only if potential maternal benefit justifies potential risk to infant;
- Pedi: Safety and effectiveness not established in children;
- Geri: Should start therapy in older adults at lower end of dosing range.
Adverse Reactions/Side Effects
CNS: headache, anxiety, hallucinations, insomnia, irritability, sleep disturbances
CV: QT INTERVAL PROLONGATION, tachycardia
GI: abdominal pain, dry mouth, nausea
Metabolic: cataplexy, ↓ appetite
Resp: upper respiratory tract infection
Misc: HYPERSENSITIVITY REACTIONS (including anaphylaxis)
* CAPITALS indicate life-threatening.
Underline indicate most frequent.
- QT interval prolonging medications, including amiodarone, chlorpromazine, disopyramide, dofetilide, moxifloxacin, procainamide, quinidine, sotalol, thioridazine, or ziprasidone may ↑ risk of QT interval prolongation and torsade de points; avoid concurrent use.
- Strong CYP2D6 inhibitors, including bupropion, fluoxetine, or paroxetine may ↑ levels and risk of toxicity; ↓ pitolisant dose.
- Strong CYP3A4 inducers, including carbamazepine, phenytoin, or rifampin, may ↓ levels and effectiveness; ↑ pitolisant dose.
- May ↓ levels and effectiveness of CYP3A4 substrates, including cyclosporine, hormonal contraceptives, or midazolam ; use alternative non-hormonal contraceptive during therapy and for ≥21 days after discontinuing therapy.
- Centrally-acting H1 antagonists, including clomipramine, diphenhydramine, imipramine, mirtazapine, or promethazine may ↓ effectiveness; avoid concurrent use.
PO (Adults): 8.9 mg once daily in the morning upon awakening for 1 wk, then ↑ to 17.8 mg once daily in the morning upon awakening for 1 wk; may then ↑ to 35.6 mg once daily in the morning upon awakening. Concurrent use of strong CYP2D6 inhibitors (initiation of therapy)– 8.9 mg once daily in the morning upon awakening for 1 wk, then ↑ to 17.8 mg once daily in the morning upon awakening (max dose = 17.8 mg/day). Concurrent use of strong CYP2D6 inhibitors (stabilized on therapy)– ↓ pitolisant dose by 50%. Concurrent use with strong CYP3A4 inducers– If stable on 8.9 mg once daily, ↑ to 17.8 mg once daily over 7 days; if stable on 17.8 mg once daily, ↑ to 35.6 mg once daily over 7 days. Poor CYP2D6 metabolizers– 8.9 mg once daily in the morning upon awakening for 1 wk, then ↑ to 17.8 mg once daily in the morning upon awakening (max dose = 17.8 mg/day).
PO (Adults): Moderate hepatic impairment (Child-Pugh B)– 8.9 mg once daily in the morning upon awakening for 2 wk, then ↑ to 17.8 mg once daily in the morning upon awakening (max dose = 17.8 mg/day).
PO (Adults): CCr 15–59 mL/min/1.73 m2 – 8.9 mg once daily in the morning upon awakening for 1 wk, then ↑ to 17.8 mg once daily in the morning upon awakening (max dose = 17.8 mg/day).
Tablets: 4.45 mg, 17.8 mg
- Monitor for symptoms of daytime sleepiness during therapy.
Assess ECG before starting therapy to determine whether patient has a prolonged QT interval. Monitor patients with hepatic or renal impairment for increased QTc. May require dose modification.
- PO Administer once daily in the morning upon awakening.
- Instruct patient to take pitolisant as directed. If a dose is missed, omit and take next dose the next day in the morning.
Advise patient to notify health care professional if signs and symptoms on QTc interval prolongation (feel faint, lose consciousness, heart palpitations) occur.
- Instruct patient to notify health care professional of all Rx or OTC medications, vitamins, or herbal products being taken and to consult health care professional before taking other Rx, OTC, herbal products.
- Rep: Advise patient to notify health care professional if pregnancy is planned or suspected or if breastfeeding. Inform patient that pitolisant may reduce effectiveness of hormonal contraceptives; advise patients using hormonal contraceptives to use a nonhormonal method of contraception during therapy and for at least 21 days after last dose of pitolisant. Encourage patients who become pregnant while taking pitolisant to enroll in the pregnancy exposure registry that monitors pregnancy outcomes in women who are exposed to pitolisant during pregnancy. To enroll or obtain information from the registry, patients can call 1-800-833-7460.
Decrease in daytime sleepiness or cataplexy in adults with narcolepsy.