General

Genetic Implications:

Pronunciation:
pi-tol-i-sant

Trade Name(s)

• Wakix

Ther. Class.

central nervous system stimulants

Pharm. Class.

histamine H3 antagonist/agonist

Indications

Treatment of excessive daytime sleepiness (EDS) in patients with narcolepsy.

Action

Acts as a histamine-3 (H3) receptor antagonist/reverse agonist. Exact mechanism by which it minimizes EDS in narcolepsy unknown.

Therapeutic Effect(s):

Reduced perception of falling asleep during daily life activities.

Pharmacokinetics

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. Primarily excreted in urine (90%; <2% as unchanged drug), with only 2% excreted in feces.

Half-life: 20 hr.

TIME/ACTION PROFILE (plasma concentrations)

Contraindication/Precautions

Contraindicated in:

• 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

Derm: rash

GI: abdominal pain, dry mouth, nausea

Metabolic: cataplexy, ↓ appetite

MS: pain

Resp: upper respiratory tract infection

* CAPITALS indicate life-threatening.
Underline indicate most frequent.

Interactions

Drug-Drug

•  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.

Route/Dosage

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).

Hepatic Impairment 
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).

Renal Impairment 
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).

Availability

Tablets: 4.45 mg, 17.8 mg

Assessment

• 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.

Potential Diagnoses

• Risk for injury (Indications) 

Implementation

• PO Administer once daily in the morning upon awakening.

Patient/Family Teaching

• 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.

Evaluation/Desired Outcomes

Decrease in daytime sleepiness in adults with narcolepsy.