Pitolisant (Monograph)

Brand name: Wakix
Drug class: Wakefulness-promoting Agents

Medically reviewed by Drugs.com on Apr 10, 2025. Written by ASHP.

Introduction

Selective competitive antagonist and inverse agonist at the histamine H₃ receptor; a wakefulness-promoting agent.^{1 4 6 7}

Uses for Pitolisant

Narcolepsy

Treatment of excessive daytime sleepiness or cataplexy in adults with narcolepsy and in pediatric patients ≥6 years of age with narcolepsy.^{1 2 3 14 15} (designated an orphan drug by FDA for treatment of narcolepsy).⁹

The American Academy of Sleep Medicine (AASM) provides a strong recommendation for use of pitolisant for the treatment of adults with narcolepsy (versus no treatment).⁵⁷ The AASM does not discuss use of pitolisant for pediatric patients; however, these guidelines were published prior to its FDA approval for this patient population.⁵⁷

Pitolisant Dosage and Administration

General

Patient Monitoring

• Monitor patients with hepatic or renal impairment for QT-interval prolongation.¹

Administration

Oral Administration

Administer orally once daily in the morning upon awakening.¹

If a dose is missed, take the next dose the following day in the morning upon awakening.¹

Dosage

Available as pitolisant hydrochloride; dosage expressed in terms of pitolisant.¹ Dosage also has been expressed in terms of the salt;^{2 3} 4.45 mg of pitolisant is equivalent to 5 mg of pitolisant hydrochloride, and 17.8 mg of pitolisant is equivalent to 20 mg of pitolisant hydrochloride.¹

Pediatric Patients

Narcolepsy

Oral

Pediatric patients ≥6 years of age weighing <40 kg: Initially, 4.45 mg once daily for 1 week, followed by 8.9 mg (two 4.45-mg tablets) once daily during week 2.¹ During week 3, may increase dosage to maximum of 17.8 mg once daily.¹

Pediatric patients ≥6 years of age weighing ≥40 kg: Initially, 4.45 mg once daily for 1 week, followed by 8.9 mg (two 4.45-mg tablets) once daily during week 2.¹ During week 3, may increase dosage to 17.8 mg once daily and further increase dosage during week 4 to maximum of 35.6 mg (two 17.8-mg tablets) once daily.¹

Adjust dosage based on tolerability.¹ Up to 8 weeks may be required for some patients to achieve a clinical response.¹

Adults

Narcolepsy

Oral

Recommended dosage range: 17.8–35.6 mg once daily.¹ Initially, 8.9 mg (two 4.45-mg tablets) once daily for 1 week, followed by 17.8 mg (one 17.8-mg tablet) once daily during week 2.¹ During week 3, may increase dosage to maximum of 35.6 mg (two 17.8-mg tablets) once daily.¹

Adjust dosage based on tolerability.¹ Up to 8 weeks may be required for some patients to achieve a clinical response.¹

Dosage Modifications for Concomitant Use with Potent CYP2D6 Inhibitors and Potent CYP3A4 Inducers

Adults receiving potent CYP2D6 inhibitors: Initiate pitolisant at 8.9 mg once daily and increase after 7 days to maximum recommended dosage of 17.8 mg once daily.¹

Pediatric patients ≥6 years of age weighing <40 kg receiving potent CYP2D6 inhibitors: Initiate pitolisant at 4.45 mg once daily and increase after 7 days to maximum recommended dosage of 8.9 mg once daily.¹

Pediatric patients ≥6 years of age weighing ≥40 kg receiving potent CYP2D6 inhibitors: Initiate pitolisant at 4.45 mg once daily and increase after 7 days to 8.9 mg once daily.¹ After another 7 days, may increase to a maximum recommended dosage of 17.8 mg once daily.¹

In adult and pediatric patients receiving a stable dosage of pitolisant, reduce the dosage of pitolisant by one-half when initiating a potent CYP2D6 inhibitor.¹

Pitolisant exposure reduced by 50% with concomitant use of potent CYP3A4 inducers; monitor for loss of pitolisant efficacy upon initiation of potent CYP3A4 inducer.¹ In adult and pediatric patients receiving a stable pitolisant dosage of 8.9 mg or 17.8 mg once daily, upon initiation of a potent CYP3A4 inducer, double the pitolisant daily dosage (i.e., to 17.8 mg or 35.6 mg, respectively) over 7 days.¹ If a potent CYP3A4 inducer is discontinued, reduce the pitolisant dosage by 50%.¹

Special Populations

Hepatic Impairment

Mild hepatic impairment: Dosage adjustment not required.¹

Adults with moderate hepatic impairment (Child-Pugh class B): Initially, 8.9 mg once daily; increase after 14 days to maximum dosage of 17.8 mg once daily.¹

Pediatric patients ≥6 years of age with moderate hepatic impairment weighing <40 kg: Initially, 4.45 mg once daily; increase after 14 days to maximum dosage of 8.9 mg once daily.¹

Pediatric patients ≥6 years of age with moderate hepatic impairment weighing ≥40 kg: Initially, 4.45 mg once daily; increase after 14 days to 8.9 mg once daily.¹ Dosage may be further increased after another 14 days to maximum dosage of 17.8 mg once daily.¹

Severe hepatic impairment: Contraindicated.¹

Renal Impairment

Adults with eGFR <60 mL/minute per 1.73 m²: Initially, 8.9 mg once daily; increase after 7 days to maximum dosage of 17.8 mg once daily.¹

Pediatric patients ≥6 years of age with eGFR <60 mL/minute per 1.73 m² (based on Schwartz equation) weighing <40 kg: Initially, 4.45 mg once daily; increase after 7 days to 8.9 mg once daily.¹

Pediatric patients ≥6 years of age with eGFR <60 mL/minute per 1.73 m² (based on Schwartz equation) weighing ≥40 kg: Initially, 4.45 mg once daily; increase after 7 days to 8.9 mg once daily.¹ Dosage may be further increased after 7 days to maximum dosage of 17.8 mg once daily.¹

End-stage renal disease (eGFR <15 mL/minute per 1.73 m²): Use not recommended.¹

Geriatric Patients

In general, select dosage carefully, usually initiating therapy at the low end of the dosage range.¹ Consider the greater frequency of decreased hepatic, renal, and/or cardiac function and of concomitant disease and drug therapy observed in geriatric patients.¹

CYP2D6 Poor Metabolizers

Adults who are known poor metabolizers of CYP2D6: Initiate pitolisant at 8.9 mg once daily and increase after 7 days to maximum dosage of 17.8 mg once daily.¹

Pediatric patients weighing <40 kg who are known poor metabolizers of CYP2D6: Initiate pitolisant at 4.45 mg once daily and increase after 7 days to maximum dosage of 8.9 mg once daily.¹

Pediatric patients weighing ≥40 kg who are known poor metabolizers of CYP2D6: Initiate pitolisant at 4.45 mg once daily and increase after 7 days to 8.9 mg once daily.¹ May be further increased after another 7 days to maximum dosage of 17.8 mg once daily.¹

Cautions for Pitolisant

Contraindications

• Severe hepatic impairment.¹

• Hypersensitivity to the drug or any component of the formulation.¹

Warnings/Precautions

QT-Interval Prolongation

Pitolisant prolongs the QT interval.¹ Mean increase in corrected QT (QT_c) interval: 4.2 msec at highest recommended dosage (35.6 mg daily) and 16 msec at exposure levels that were 3.8 times higher than those achieved at highest recommended dosage.¹

Avoid use in patients with known QT-interval prolongation or a history of cardiac arrhythmias; patients receiving other drugs known to prolong the QT interval; and those with other conditions that may increase the risk for torsades de pointes or sudden death (e.g., symptomatic bradycardia, hypokalemia or hypomagnesemia, congenital prolongation of the QT interval).¹

Patients with hepatic or renal impairment may be at increased risk for QT-interval prolongation because of potentially higher pitolisant concentrations.¹

Specific Populations

Pregnancy

Available case reports from clinical trials and postmarketing experience have not determined a pitolisant-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes.¹ Teratogenicity, embryofetal toxicity, and adverse developmental effects observed in animal studies.¹

Pregnancy registry at 800-833-7460.¹

Pitolisant may reduce efficacy of hormonal contraceptives.¹ Women using a hormonal contraceptive should use an alternative nonhormonal contraceptive method during pitolisant therapy and for at least 21 days after discontinuance of the drug.¹

Lactation

Pitolisant transfers into the breast milk in low quantities.¹ Approximately 50% of the dose is collected in breast milk within 4 hours post dose.¹ Following a single oral dose of 35.6 mg in lactating women, the relative infant dose (RID) is <1% of the maternal weight-adjusted dose and the mean infant dosage is 0.009 mg/day.¹ Not known whether pitolisant affects breast-fed infants or affects milk production.¹

Consider the developmental and health benefits of breast-feeding along with the mother’s clinical need for pitolisant and any potential adverse effects on the breast-fed infant from the drug or from the underlying maternal condition.¹

Females and Males of Reproductive Potential

Women using a hormonal contraceptive should use an alternative nonhormonal contraceptive method during pitolisant therapy and for ≥21 days after discontinuance of the drug.¹

Pediatric Use

Safety and efficacy established for excessive daytime sleepiness in pediatric patients ≥6 years of age with narcolepsy.¹ Safety and efficacy for excessive daytime sleepiness not established in pediatric patients <6 years of age with narcolepsy.¹ Safety and efficacy for cataplexy not established in pediatric patients with narcolepsy.¹ Systemic exposure may be greater in pediatric patients than in adults.¹

Geriatric Use

No clinically important differences in safety, efficacy, or drug exposure observed between geriatric patients and younger adults; however, the possibility of greater sensitivity cannot be ruled out.¹

In general, select dosage carefully, usually initiating therapy at the low end of the dosage range.¹ Consider the greater frequency of decreased hepatic, renal, and/or cardiac function and of concomitant disease and drug therapy observed in geriatric patients.¹

Hepatic Impairment

Pitolisant is extensively metabolized in the liver.¹

Mild hepatic impairment (Child-Pugh class A): Systemic exposure not substantially altered.^{1 8}

Moderate hepatic impairment (Child-Pugh class B): Increased systemic exposure.^{1 8} Dosage adjustment required.¹

Patients with hepatic impairment may be at increased risk for QT-interval prolongation because of higher drug concentrations.¹ Appropriately monitor patients with either mild or moderate hepatic impairment, including monitoring for QT-interval prolongation.¹

Severe hepatic impairment (Child-Pugh class C): Contraindicated; data are lacking.¹

Renal Impairment

Mild renal impairment (eGFR 60–89 mL/minute per 1.73 m²): Systemic exposure based on total pitolisant concentrations is increased;^{1 8} exposure based on free drug concentrations is similar to that in individuals with normal renal function.⁸ In clinical trials in narcolepsy, drug dosage and frequency of adverse effects in patients with mild renal impairment were similar to those in patients with normal renal function.⁸

Moderate renal impairment (eGFR 30–59 mL/minute per 1.73 m²): Systemic exposure based on total pitolisant concentrations is increased;^{1 8} exposure based on free drug concentrations is similar to that in individuals with normal renal function.⁸ Clinical trials in narcolepsy included only a limited number of patients with moderate renal impairment.⁸ Dosage adjustment recommended.¹

Severe renal impairment (eGFR 15–29 mL/minute per 1.73 m²): Systemic exposure based on total or free pitolisant concentrations is increased.^{1 8} Clinical trials in narcolepsy included no patients with severe renal impairment.⁸ Dosage adjustment recommended.¹

Patients with renal impairment may be at increased risk for, and should be monitored for, QT-interval prolongation because of higher drug concentrations.¹

End-stage renal disease (eGFR <15 mL/minute per 1.73 m²): Use not recommended; effect on drug's pharmacokinetics is unknown.¹

Pharmacogenomics and Effects of CYP2D6 Polymorphism

Poor CYP2D6 metabolizers: Increased systemic exposure.¹ Dosage adjustment recommended in known poor CYP2D6 metabolizers.¹

Common Adverse Effects

Adults: Insomnia, nausea, anxiety.¹

Pediatric patients: Headache, insomnia.¹

Drug Interactions

Metabolized mainly by CYP2D6 and to a lesser extent by CYP3A4.¹ Borderline or weak inducer of CYP3A4.¹

Drugs Affecting Hepatic Microsomal Enzymes

Potent CYP2D6 inhibitors: Increased pitolisant exposure.¹ In adults receiving potent CYP2D6 inhibitors, initiate pitolisant at dosage of 8.9 mg once daily; increase after 7 days to maximum recommended dosage of 17.8 mg once daily.¹ In pediatric patients ≥6 years of age weighing <40 kg receiving potent CYP2D6 inhibitors, initiate pitolisant at dosage of 4.45 mg once daily; increase after 7 days to maximum recommended dosage of 8.9 mg once daily.¹ In pediatric patients ≥6 years of age weighing ≥40 kg receiving potent CYP2D6 inhibitors, initiate pitolisant at dosage of 4.45 mg once daily; increase after 7 days to 8.9 mg once daily.¹ After another 7 days, dosage may be further increased to maximum recommended dosage of 17.8 mg once daily.¹ In adult and pediatric patients already receiving a stable pitolisant dosage, reduce pitolisant dosage by one-half when initiating a potent CYP2D6 inhibitor.¹

Potent CYP3A4 inhibitors: No substantial effect on pharmacokinetics of pitolisant.¹

Potent CYP3A4 inducers: Decreased AUC of pitolisant.^{1 8} Monitor for loss of pitolisant efficacy following initiation of a potent CYP3A4 inducer; in adult and pediatric patients stable on a pitolisant dosage of 8.9 or 17.8 mg once daily, increase dosage to 17.8 or 35.6 mg daily, respectively, over 7 days.¹ If a potent CYP3A4 inducer is discontinued, reduce pitolisant dosage by one-half.¹

Drugs Metabolized by Hepatic Microsomal Enzymes

CYP3A4 substrates: Possible reduced efficacy of the CYP3A4 substrate drug.¹

CYP2B6 substrates: No change in exposure to sensitive CYP2B6 substrate.¹

Drugs that Prolong the QT Interval

Possible additive QT-interval prolongation and increased risk of cardiac arrhythmia.¹ Avoid concomitant use.¹

Specific Drugs

Pitolisant Pharmacokinetics

Absorption

Bioavailability

Oral bioavailability is approximately 90%.¹

Peak plasma concentrations are achieved at a median of 3.5 hours (range: 2–5 hours) after oral administration; peak plasma concentrations and AUC are proportional to dose.¹ Steady state achieved in 7 days.¹

Food

Administration with a high-fat meal does not substantially alter pharmacokinetics of pitolisant.¹

Special Populations

Poor CYP2D6 metabolizers: AUC increased by approximately 2.4-fold compared with normal metabolizers; magnitude of effect is similar to that observed with concomitant use of pitolisant and CYP2D6 inhibitors.¹

Mild hepatic impairment (Child-Pugh class A): Systemic exposure not substantially altered.^{1 8}

Moderate hepatic impairment (Child-Pugh class B): AUC increased by 140% compared with individuals with normal hepatic function.⁸

Mild renal impairment (eGFR 60–89 mL/minute per 1.73 m²): Systemic exposure based on total pitolisant concentrations is increased approximately twofold; exposure based on free drug concentrations is similar to that in individuals with normal renal function.⁸

Moderate renal impairment (eGFR 30–59 mL/minute per 1.73 m²): Systemic exposure based on total pitolisant concentrations is increased approximately twofold; exposure based on free drug concentrations is similar to that in individuals with normal renal function.⁸

Severe renal impairment (eGFR 15–29 mL/minute per 1.73 m²): Systemic exposure based on total pitolisant concentrations is increased approximately twofold; exposure based on free drug concentrations is increased slightly less than twofold.⁸

Pediatric patients: Single-dose data suggest that peak plasma concentration and AUC are increased at least 2-fold in adolescents 12–17 years of age and more than 3-fold in children 7–11 years of age compared with adults.¹

Age (range: 18–82 years), sex, race or ethnicity (Caucasian or Black), and body weight (range: 48–103 kg) do not substantially affect pharmacokinetics of pitolisant.¹

Distribution

Extent

Not known whether pitolisant distributes into human milk.¹

Plasma Protein Binding

Approximately 91–96% bound to serum proteins.¹

Elimination

Metabolism

Extensively metabolized in liver, mainly by CYP2D6 and to a lesser extent by CYP3A4; the resulting metabolites are further metabolized or conjugated with glycine or glucuronic acid.¹ None of these metabolites are pharmacologically active.¹

Elimination Route

Excreted in urine (approximately 90%, including <2% as unchanged drug) and feces (2.3%).¹

Half-life

Median half-life is approximately 20 hours (range: 7.5–24.2 hours).¹

Special Populations

Moderate hepatic impairment (Child-Pugh class B): Half-life increased twofold compared with individuals with normal hepatic function.⁸

Stability

Storage

Oral

Tablets

20–25°C (may be exposed to 15–30°C).¹

Actions

• Selective competitive antagonist and inverse agonist at the histamine H₃ receptor.^{1 4 6 7} Binds to histamine H₃ receptors with high affinity; does not bind appreciably to other histamine receptors (H₁, H₂, or H₄receptors).¹ Histamine H₃ receptor functions as an autoreceptor, inhibiting synthesis and release of histamine, a wakefulness-promoting neurotransmitter, and as a heteroreceptor, inhibiting release of other wakefulness-promoting neurotransmitters (e.g., acetylcholine, dopamine, norepinephrine).^{6 10 12}

• Binding of pitolisant to the histamine H₃ receptor blocks the inhibitory effect of histamine on histamine release, resulting in increased synthesis and release of histamine in the brain.^{4 7 8 11} Increased histamine binds to postsynaptic histamine H₁ receptors to activate wakefulness-promoting regions in the brain, as well as stimulate other wakefulness-promoting neuronal systems.^{4 6 8 11}

• In a murine model of narcolepsy, pitolisant enhanced wakefulness and reduced the number of direct transitions from wakefulness to rapid eye movement (REM) sleep.^{7 11}

• Exact mechanism by which pitolisant treats excessive daytime sleepiness in adults with cataplexy or in pediatric patients ≥6 years of age with narcolepsy or cataplexy not fully established; thought to be related to activity at the histamine H₃ receptor.¹

• Appears to have minimal potential for abuse.^{2 13}

Advice to Patients

• Risk of QT-interval prolongation.¹ Advise patients to consult their clinician immediately if they feel faint, lose consciousness, or have heart palpitations.¹ Stress importance of informing clinicians that they are taking pitolisant before initiating therapy with any new drug.¹

• Advise patients that pitolisant may reduce the efficacy of hormonal contraceptives and that women who are using a hormonal contraceptive should use an alternative nonhormonal contraceptive method during pitolisant therapy and for at least 21 days after discontinuance of the drug.¹

• Stress importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses.¹

• Stress importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.¹ Encourage pregnant women who have been exposed to pitolisant to enroll in the manufacturer's pregnancy registry.¹

• Inform patients of other important precautionary information.¹

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer’s labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Frequently asked questions

• How does Wakix work for narcolepsy?
• Is Wakix a controlled substance?

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