pitolisant

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

Excessive daytime sleepiness or cataplexy in patients with narcolepsy.

Action

Acts as a histamine-3 receptor antagonist/reverse agonist. Exact mechanism by which it minimizes excessive daytime sleepiness 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 via the CYP2D6 isoenzyme and to a lesser extent by the CYP3A4 isoenzyme;  the CYP2D6 isoenzyme 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)

Contraindication/Precautions

Contraindicated in:

• Hypersensitivity;
• Severe hepatic impairment;
• End-stage renal disease;
• QT interval prolongation, congenital QT interval prolongation, history of cardiac arrhythmias, symptomatic bradycardia, hypokalemia, or hypomagnesemia.

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

CV: QT interval prolongation, tachycardia

Derm: rash

GI: abdominal pain, dry mouth, ↓ appetite, nausea

MS: cataplexy, pain

Neuro: headache, anxiety, hallucinations, insomnia, irritability, sleep disturbances

Resp: upper respiratory tract infection

Misc: HYPERSENSITIVITY REACTIONS (including anaphylaxis)

* 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 torsades 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 nonhormonal 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

Excessive Daytime Sleepiness

PO (Adults): 8.9 mg once daily in the morning on awakening for 1 wk; then ↑ to 17.8 mg once daily in the morning on awakening for 1 wk; may then ↑ to 35.6 mg once daily in the morning on awakening.  Concurrent use of strong CYP2D6 inhibitors (initiation of therapy): 8.9 mg once daily in the morning on awakening for 1 wk; then ↑ to 17.8 mg once daily in the morning on awakening.  Concurrent use of strong CYP2D6 inhibitors (stabilized on therapy): ↓ pitolisant dose by 50%.  Concurrent use of 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 on awakening for 1 wk; then ↑ to 17.8 mg once daily in the morning on awakening.

PO (Children ≥6 yr and ≥40 kg): 4.45 mg once daily in the morning on awakening for 1 wk; then ↑ to 8.9 mg once daily in the morning on awakening for 1 wk; then ↑ to 17.8 mg once daily in the morning on awakening for 1 wk; then ↑ to 35.6 mg once daily in the morning on awakening.  Concurrent use of strong CYP2D6 inhibitors (initiation of therapy): 4.45 mg once daily in the morning on awakening for 1 wk; then ↑ to 8.9 mg once daily in the morning on awakening for 1 wk; then ↑ to 17.8 mg once daily in the morning on awakening.  Concurrent use of strong CYP2D6 inhibitors (stabilized on therapy): ↓ pitolisant dose by 50%.  Concurrent use of 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: 4.45 mg once daily in the morning on awakening for 1 wk; then ↑ to 8.9 mg once daily in the morning on awakening for 1 wk; then ↑ to 17.8 mg once daily in the morning on awakening.

PO (Children ≥6 yr and <40 kg): 4.45 mg once daily in the morning on awakening for 1 wk; then ↑ to 8.9 mg once daily in the morning on awakening for 1 wk; then ↑ to 17.8 mg once daily in the morning on awakening for 1 wk.  Concurrent use of strong CYP2D6 inhibitors (initiation of therapy): 4.45 mg once daily in the morning on awakening for 1 wk; then ↑ to 8.9 mg once daily in the morning on awakening. Concurrent use of strong CYP2D6 inhibitors (stabilized on therapy): ↓ pitolisant dose by 50%.  Concurrent use of 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: 4.45 mg once daily in the morning on awakening for 1 wk; then ↑ to 8.9 mg once daily in the morning on awakening.

Hepatic Impairment 
PO (Adults): Moderate hepatic impairment: 8.9 mg once daily in the morning on awakening for 2 wk; then ↑ to 17.8 mg once daily in the morning on awakening.

Hepatic Impairment 
PO (Children ≥6 yr and ≥40 kg): Moderate hepatic impairment: 4.45 mg once daily in the morning on awakening for 2 wk; then ↑ to 8.9 mg once daily in the morning on awakening for 2 wk; then ↑ to 17.8 mg once daily in the morning on awakening.

Hepatic Impairment 
PO (Children ≥6 yr and <40 kg): Moderate hepatic impairment: 4.45 mg once daily in the morning on awakening for 2 wk; then ↑ to 8.9 mg once daily in the morning on awakening.

Renal Impairment 
PO (Adults): CCr 15–59 mL/min/1.73 m² : 8.9 mg once daily in the morning on awakening for 1 wk; then ↑ to 17.8 mg once daily in the morning on awakening.

Renal Impairment 
PO (Children ≥6 yr and ≥40 kg): CCr 15–59 mL/min/1.73 m² : 4.45 mg once daily in the morning on awakening for 1 wk; then ↑ to 8.9 mg once daily in the morning on awakening for 1 wk; then ↑ to 17.8 mg once daily in the morning on awakening.

Renal Impairment 
PO (Children ≥6 yr <40 kg): CCr 15–59 mL/min/1.73 m² : 4.45 mg once daily in the morning on awakening for 1 wk; then ↑ to 8.9 mg once daily in the morning on awakening.

Cataplexy

PO (Adults): 8.9 mg once daily in the morning on awakening for 1 wk; then ↑ to 17.8 mg once daily in the morning on awakening for 1 wk; may then ↑ to 35.6 mg once daily in the morning on awakening.  Concurrent use of strong CYP2D6 inhibitors (initiation of therapy): 8.9 mg once daily in the morning on awakening for 1 wk; then ↑ to 17.8 mg once daily in the morning on awakening.  Concurrent use of strong CYP2D6 inhibitors (stabilized on therapy): ↓ pitolisant dose by 50%.  Concurrent use of 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 on awakening for 1 wk; then ↑ to 17.8 mg once daily in the morning on awakening.

Hepatic Impairment 
PO (Adults): Moderate hepatic impairment: 8.9 mg once daily in the morning on awakening for 2 wk; then ↑ to 17.8 mg once daily in the morning on awakening.

Renal Impairment 
PO (Adults): CCr 15–59 mL/min/1.73 m² : 8.9 mg once daily in the morning on awakening for 1 wk; then ↑ to 17.8 mg once daily in the morning on awakening.

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 QT interval prolongation. May require dose modification.

Lab Test Considerations:

Monitor baseline renal and hepatic function and as clinically indicated.

Implementation

• Do not confuse Wakix with Lasix.
• PO Administer once daily in the morning on awakening.

Patient/Family Teaching

• Explain purpose and side effects of medication to patient. Advise patient to read  Patient Information  before starting therapy. Instruct patient to take as directed. If a dose is missed, omit and take next dose the next day in the morning.
• 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, or herbal products.
• Advise patient to notify health care professional if signs and symptoms of QTc interval prolongation (feel faint, lose consciousness, heart palpitations) occur.
• Inform patient or caregiver it may take up to 8 wk to achieve a clinical response.
• Rep:  Advise patient to notify health care professional if pregnancy is planned or suspected or if breastfeeding. Inform patient that pitolisant may ↓ effectiveness of hormonal contraceptives; advise patients using hormonal contraceptives to use a nonhormonal method of contraception during therapy and for ≥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

Reduced perception of falling asleep during daily life activities.