Pitolisant hydrochloride, a selective competitive antagonist and inverse agonist at the histamine H3 receptor, is a wakefulness-promoting agent.1, 4, 6, 7
Pitolisant hydrochloride is used in the treatment of excessive daytime sleepiness or cataplexy in adults with narcolepsy.1, 2, 3 Pitolisant hydrochloride is also used in the treatment of excessive daytime sleepiness in pediatric patients ≥6 years of age with narcolepsy.1 Pitolisant has been designated an orphan drug by FDA for use in the treatment of narcolepsy.9
Efficacy of pitolisant in reducing excessive daytime sleepiness associated with narcolepsy was established in 2 randomized, double-blind, placebo- and active (modafinil)-controlled studies (HARMONY I and HARMONY I-bis) in adults who met International Classification of Sleep Disorders, Second Edition (ICSD-2) criteria for narcolepsy, with or without cataplexy, and had a baseline Epworth Sleepiness Scale (ESS) score of 14 or higher.1, 2, 3 The ESS is an 8-item questionnaire by which patients rate their perceived likelihood of falling asleep during usual daily life activities; the maximum total score is 24.1, 2 Approximately 75-80% of patients in the 2 studies had a history of cataplexy.1, 2 Both studies included a 3-week dosage-titration phase followed by a 5-week stable-dosage phase.1, 2, 3 The designs of the 2 studies differed mainly in pitolisant dosage and randomization ratio.2 In HARMONY I, patients were randomized in a 1:1:1 ratio to receive pitolisant (initial dosage of 8.9 mg once daily, increased at weekly intervals during the dosage-titration phase to 17.8 or 35.6 mg daily based on response and tolerability), modafinil (initial dosage of 100 mg once daily, increased at weekly intervals during the dosage-titration phase to 200 or 400 mg daily based on response and tolerability), or placebo;1, 2, 3 61% of pitolisant-treated patients achieved a stable dosage of 35.6 mg daily.1 In HARMONY I-bis, patients were randomized in a 2:2:1 ratio to receive pitolisant (initial dosage of 4.45 mg daily, increased at weekly intervals during the dosage-titration phase to 8.9 or 17.8 mg daily based on response and tolerability), modafinil (initial dosage of 100 mg once daily, increased at weekly intervals during the dosage-titration phase to 200 or 400 mg daily based on response and tolerability), or placebo;1, 2 76% of pitolisant-treated patients achieved a stable dosage of 17.8 mg daily.1 In both studies, pitolisant was associated with greater improvements in wakefulness, as measured by the ESS, compared with placebo from baseline to week 8.1, 2, 3 Subgroup analysis suggested that sex did not affect response to pitolisant.1
Efficacy of pitolisant for the treatment of cataplexy associated with narcolepsy in adults was established in 2 randomized, double-blind, placebo-controlled studies (HARMONY I and HARMONY-CTP).1, 3, 14 Adults were eligible for HARMONY-CTP if they met the ICSD-2 criteria for narcolepsy with cataplexy with at least 3 cataplexy attacks per week and a baseline ESS score of 12 or higher.1, 14 Patients in HARMONY-CTP, along with the 81% of patients with cataplexy in HARMONY-1, were assessed based on the change in the mean number of cataplexy attacks per week.1, 3, 14 Patients in HARMONY-CTP were randomized 1:1 to receive either pitolisant or placebo over a 7-week treatment period.1, 14 The first 3 weeks consisted of a dosage-titration phase; this was followed by a 4-week stable-dosage phase.1, 14 The initial dosage of pitolisant was 4.45 mg once daily; during the second week, this was increased to 8.9 mg once daily.1, 14 The dosage could then be decreased, stay the same, or increased to a maximum of 35.6 mg over the next 2 weeks, depending on tolerability and clinical response;1, 14 65% of pitolisant-treated patients achieved a stable dosage of 35.6 mg daily.1 In both HARMONY-CTP and the subgroup of patients with cataplexy in HARMONY-1, pitolisant was associated with significantly greater improvements in the change of the mean number of cataplexy attacks per week compared with placebo.1, 3, 14 Subgroup analysis suggested that sex did not affect response to pitolisant.1
Efficacy of pitolisant in reducing excessive daytime sleepiness associated with narcolepsy in pediatric patients ≥6 years of age was established in a randomized, double-blind, placebo-controlled study.1, 15 Patients 6-17 years of age were eligible if they met the ICSD, Third Edition (ICSD-3) criteria for narcolepsy, with or without cataplexy, and had a Pediatric Daytime Sleepiness Scale (PDSS) score ≥15.1, 15 Patients were randomized in a 2:1 ratio to receive pitolisant (initial dosage of 4.45 mg once daily, increased at weekly intervals during the dosage-titration phase to a maximum of 17.8 mg [week 3] for patients weighing <40 kg or 35.6 mg [week 4] for patients weighing ≥40 kg based on response and tolerability) or placebo; 69% of patients weighing <40 kg reached a stable dosage of 17.8 mg and 72% of patients weighing ≥40 kg reached a stable dosage of 35.6 mg.1 The mean age of participants in this study was 12.9 years and 55% of patients were male;15 82% of patients had a history of cataplexy.1 Pitolisant was associated with significantly greater improvements in wakefulness, as measured by the PDSS, compared with placebo from baseline to the end of treatment.1, 15
Narcolepsy is a neurologic sleep disorder characterized by chronic excessive daytime sleepiness, short sleep latency, and sleep-onset rapid eye movement (REM) periods.4, 5 Other manifestations may include cataplexy (sudden and transient loss of muscle tone during wakefulness), disrupted nocturnal sleep, hypnagogic hallucinations, and/or sleep paralysis.4, 5
The American Academy of Sleep Medicine (AASM) provides a strong recommendation for the use of several agents (including modafinil, pitolisant, sodium oxybate, and solriamfetol) for the treatment of adults with narcolepsy (versus no treatment).57 A conditional recommendation is given for armodafinil, dextroamphetamine, and methylphenidate.57
The AASM provides a conditional recommendation for the use of modafinil or sodium oxybate for the treatment of narcolepsy in pediatric patients.57 The AASM does not discuss the use of pitolisant for pediatric patients; however these guidelines were published prior to its FDA approval for this patient population.57
Pitolisant hydrochloride is administered orally once daily in the morning upon awakening.1 If a dose of pitolisant is missed, the next dose should be taken the following day in the morning upon awakening.1
Store at 20-25ºC (may be exposed to 15-30ºC).1
Dosage of pitolisant hydrochloride is expressed in terms of pitolisant.1 Dosage of the drug 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
The recommend initial dosage of pitolisant in pediatric patients ≥6 years of age with narcolepsy is 4.45 mg administered once daily upon awakening.1 The pitolisant dosage may be increased after 1 week to 8.9 mg (two 4.45-mg tablets) once daily during week 2, and further increased to 17.8 mg (one 17.8-mg tablet) once daily during week 3, which is the maximum dosage for pediatric patients weighing <40 kg.1 During week 4, pediatric patients weighing ≥40 kg may undergo an additional dosage increase to the maximum dosage of 35.6 mg (two 17.8-mg tablets) once daily.1 Dosage may be adjusted based on tolerability.1 Up to 8 weeks may be required for some patients to achieve a clinical response.1
The recommended dosage range of pitolisant in adults with narcolepsy is 17.8-35.6 mg administered once daily upon awakening.1 Pitolisant therapy should be initiated at a dosage of 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, dosage may be increased to the maximum recommended dosage of 35.6 mg (two 17.8-mg tablets) once daily.1 Dosage may be adjusted 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
In adults receiving a potent cytochrome P-450 (CYP) 2D6 inhibitor, pitolisant should be initiated at a dosage of 8.9 mg once daily and increased after 7 days to a maximum recommended dosage of 17.8 mg once daily.1
In pediatric patients ≥6 years of age weighing <40 kg receiving a potent CYP2D6 inhibitor, pitolisant should be initiated at a dosage of 4.45 mg once daily and increased after 7 days to a maximum recommended dosage of 8.9 mg once daily.1
In pediatric patients ≥6 years of age weighing ≥40 kg receiving a potent CYP2D6 inhibitor, pitolisant should be initiated at a dosage of 4.45 mg once daily and increased after 7 days to 8.9 mg once daily.1 After another 7 days, the pitolisant dosage may be increased to a maximum recommended dosage of 17.8 mg once daily.1
In adult and pediatric patients receiving a stable dosage of pitolisant, dosage of pitolisant should be reduced by one-half when therapy with a potent CYP2D6 inhibitor is initiated.1
Because concomitant use of a potent CYP3A4 inducer reduces pitolisant exposure by 50%, loss of pitolisant efficacy should be assessed after initiating the potent CYP3A4 inducer.1 In both 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, the pitolisant daily dosage should be doubled (i.e., to 17.8 mg or 35.6 mg, respectively) over a 7-day period.1 When the potent CYP3A4 inducer is discontinued, the pitolisant dosage should be reduced by 50%.1
Dosage adjustment is not required in patients with mild hepatic impairment.1
In adults with moderate (Child-Pugh class B) hepatic impairment, pitolisant should be initiated at a dosage of 8.9 mg once daily and increased after 14 days to a maximum dosage of 17.8 mg once daily.1
In pediatric patients ≥6 years of age with moderate hepatic impairment who weigh <40 kg, pitolisant should be initiated at 4.45 mg once daily and increased after 14 days to a maximum recommended dosage of 8.9 mg once daily.1
In pediatric patients ≥6 years of age with moderate hepatic impairment weighing ≥40 kg, pitolisant should be initiated at 4.45 mg once daily and increased after 14 days to 8.9 mg once daily.1 The dosage may be further increased after another 14 days to the maximum recommended dosage of 17.8 mg once daily.1
Pitolisant is contraindicated in patients with severe hepatic impairment.1
In adults with an estimated glomerular filtration rate (eGFR) <60 mL/minute per 1.73 m2, pitolisant should be initiated at a dosage of 8.9 mg once daily and increased after 7 days to a maximum recommended dosage of 17.8 mg once daily.1
In pediatric patients ≥6 years of age with eGFR <60 mL/minute per 1.73 m2 (based on Schwartz equation) weighing <40 kg, pitolisant should be initiated at a dosage of 4.45 mg once daily and increased after 7 days to a maximum recommended dosage of 8.9 mg once daily.1
In pediatric patients ≥6 years of age with eGFR <60 mL/minute per 1.73 m2 (based on Schwartz equation) weighing ≥40 kg, pitolisant should be initiated at a dosage of 4.45 mg once daily and increased after 7 days to a dosage of 8.9 mg once daily.1 The dosage may be further increased after another 7 days to a maximum recommended dosage of 17.8 mg once daily.1
Use of pitolisant in end-stage renal disease (eGFR <15 mL/minute per 1.73 m2) is not recommended.1
In general, dosage for geriatric patients should be selected carefully, with therapy usually initiated at the low end of the dosage range.1 The greater frequency of decreased hepatic, renal, and/or cardiac function and of concomitant disease and drug therapy observed in geriatric patients should be considered.1
In adult patients who are known poor metabolizers of CYP2D6, pitolisant should be initiated at a dosage of 8.9 mg once daily and increased after 7 days to a maximum recommended dosage of 17.8 mg once daily.1
In pediatric patients weighing <40 kg who are known poor metabolizers of CYP2D6, pitolisant should be initiated at a dosage of 4.45 mg once daily and increased after 7 days to a maximum recommended dosage of 8.9 mg once daily.1
In pediatric patients weighing ≥40 kg who are known poor metabolizers of CYP2D6, pitolisant should be initiated at a dosage of 4.45 mg once daily and increased after 7 days to a dosage of 8.9 mg once daily.1 The pitolisant dosage may be further increased after another 7 days to a maximum recommended dosage of 17.8 mg once daily.1
Pitolisant prolongs the QT interval.1 The mean increase in corrected QT (QTc) interval was 4.2 msec at the highest recommended dosage (35.6 mg daily) and 16 msec at exposure levels that were 3.8-fold higher than those achieved at the highest recommended dosage.1
Use of pitolisant should be avoided 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, including symptomatic bradycardia, hypokalemia or hypomagnesemia, or congenital prolongation of the QT interval.1
The risk of QT-interval prolongation may be greater in patients with hepatic or renal impairment because higher concentrations of the drug may be achieved.1 Therefore, patients with hepatic or renal impairment who are receiving pitolisant therapy should be monitored for QT-interval prolongation.1 Dosage modification is recommended in patients with moderate hepatic impairment or moderate to severe renal impairment.1 Pitolisant is contraindicated in patients with severe hepatic impairment, and use of the drug in patients with end-stage renal disease is not recommended.1
Available case reports from clinical trials and postmarketing experience with pitolisant use in pregnant women have not determined a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes.1 Teratogenicity, embryofetal toxicity, and adverse developmental effects have been observed in animal studies.1
In reproduction studies in rabbits, increased preimplantation losses and abortions were observed at a maternally toxic dosage of approximately 8 times the maximum recommended human dosage (MRHD); pitolisant was not teratogenic at dosages up to 8 times the MRHD, but delayed skeletal development (incomplete ossification, supernumerary ribs) was observed.1 In studies in rats, major malformations (cleft palate, abnormal limb flexure), stillbirths, postnatal pup mortality due to lack of milk production and/or failure to nurse, and decreased pup length and weight were observed at a maternally toxic dosage of 22 times the MRHD; delays in postnatal development (decreased body weight and length, delayed incisor eruption, delayed testes descent) were observed at dosages of 13 or more times the MRHD.1
The manufacturer has established a pregnancy registry to monitor fetal outcomes of pregnant women exposed to pitolisant.1 Women may enroll in the registry by calling 800-833-7460.1
Because pitolisant may reduce the efficacy of hormonal contraceptives, women using a hormonal contraceptive should be advised to use an alternative nonhormonal contraceptive method during pitolisant therapy and for at least 21 days after discontinuance of the drug.1
Based on data from a lactation study, pitolisant transfers into the breast milk in low quantities.1 In an open-label study of 8 lactating women, following administration of a single 35.6 mg dose of pitolisant, the mean infant dosage was calculated as 0.009 mg/day and the relative infant dose (RID) was <1% of the maternal weight-adjusted dose.1 Approximately 50% of the pitolisant dose was collected in breast milk during the first 4 hours post dose.1 It is not known whether pitolisant affects breast-fed infants or affects milk production.1
The developmental and health benefits of breast-feeding should be considered 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
Because pitolisant may reduce the efficacy of hormonal contraceptives, women using a hormonal contraceptive should be advised to use an alternative nonhormonal contraceptive method during pitolisant therapy and for at least 21 days after discontinuance of the drug.1
Safety and efficacy of pitolisant for excessive daytime sleepiness have been established in pediatric patients ≥6 years of age with narcolepsy.1 Use of pitolisant in pediatric patients is supported by 1 clinical study of 110 patients 6 to <18 years of age.1 Safety and efficacy of pitolisant for excessive daytime sleepiness have not been established in pediatric patients <6 years of age with narcolepsy.1 Safety and efficacy of pitolisant for cataplexy have not been established in pediatric patients with narcolepsy.1 Single-dose pharmacokinetic data from 24 pediatric patients with narcolepsy suggest that systemic exposure to pitolisant is greater in pediatric patients than in adults; in these patients, peak plasma concentration and area under the plasma concentration-time curve (AUC) were 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
Of the total number of patients with narcolepsy receiving pitolisant in clinical trials, 5% were 65 years of age or older.1 No clinically important differences in safety or efficacy were observed between geriatric patients and younger adults; however, the possibility of greater sensitivity of some older individuals cannot be ruled out.1 Limited pharmacokinetic data from healthy individuals did not reveal any substantial differences in pitolisant exposure between geriatric adults 68-82 years of age and younger adults 18-45 years of age.1 In general, dosage for geriatric patients should be selected carefully, usually initiating therapy at the low end of the dosage range.1 The greater frequency of decreased hepatic, renal, and/or cardiac function and of concomitant disease and drug therapy observed in geriatric patients also should be considered.1
Pitolisant undergoes extensive metabolism in the liver.1 While systemic exposure to pitolisant is not substantially altered in individuals with mild hepatic impairment (Child-Pugh class A), AUC of the drug is increased by 140% and half-life is increased twofold in individuals with moderate hepatic impairment (Child-Pugh class B) compared with individuals with normal hepatic function.1, 8 Because higher concentrations of the drug may be achieved in patients with hepatic impairment, these patients may be at increased risk for QT-interval prolongation.1 Patients with either mild or moderate hepatic impairment should be monitored appropriately, including monitoring for QT-interval prolongation; dosage adjustment is required in those with moderate hepatic impairment.1
Pitolisant is contraindicated in patients with severe hepatic impairment (Child-Pugh class C); data are lacking in this patient population.1
Based on total pitolisant concentrations, systemic exposure to the drug generally is increased twofold in individuals with mild, moderate, or severe renal impairment compared with individuals with normal renal function; however, based on free drug concentrations, systemic exposure in individuals with mild or moderate renal impairment is similar to that in individuals with normal renal function, while systemic exposure is increased by slightly less than twofold in those with severe renal impairment.8 In clinical trials of pitolisant in patients with narcolepsy, drug dosage and frequency of adverse effects in patients with mild renal impairment were similar to those in patients with normal renal function; only a limited number of patients with moderate renal impairment and no patients with severe renal impairment were included in these trials.8 Dosage adjustment is recommended in patients with an estimated glomerular filtration rate (eGFR) <60 mL/minute per 1.73 m2 .1
Because higher concentrations of the drug may be achieved in patients with renal impairment, these patients may be at increased risk for, and should be monitored for, QT-interval prolongation.1
The effect of end-stage renal disease (eGFR <15 mL/minute per 1.73 m2) on the pharmacokinetics of pitolisant is unknown; therefore, use of the drug in patients with end-stage renal disease is not recommended.1
Pharmacogenomics and Effects of CYP2D6 Polymorphism
Patients who are poor metabolizers of cytochrome P-450 (CYP) isoenzyme 2D6 substrates have increased plasma concentrations of pitolisant.1 The AUC of the drug is increased by approximately 2.4-fold in poor metabolizers compared with normal metabolizers, a magnitude of effect similar to that observed with concomitant use of pitolisant and CYP2D6 inhibitors.1 Reduced dosages are recommended in patients who are known to be poor CYP2D6 metabolizers.1
Adverse effects reported in clinical trials in ≥5% of adults receiving pitolisant and at least twice as frequently with the drug as with placebo include insomnia, nausea, and anxiety.1
Adverse effects reported in ≥5% of pediatric patients receiving pitolisant and more often with the drug than with placebo include headache and insomnia.1
Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes
Pitolisant is metabolized mainly by cytochrome P-450 (CYP) isoenzyme 2D6 and to a lesser extent by CYP3A4.1 Pitolisant is a borderline or weak inducer of CYP3A4.1
Concomitant administration of pitolisant and potent CYP2D6 inhibitors (e.g., paroxetine) increases pitolisant exposure by 2.2-fold.1, 8
In adults receiving potent CYP2D6 inhibitors (e.g., paroxetine), pitolisant therapy should be initiated at a dosage of 8.9 mg once daily and increased after 7 days to a maximum recommended dosage of 17.8 mg once daily.1 In pediatric patients ≥6 years of age weighing <40 kg receiving potent CYP2D6 inhibitors, pitolisant therapy should be initiated at a dosage of 4.45 mg once daily and increased after 7 days to a maximum recommended dosage of 8.9 mg once daily.1 In pediatric patients ≥6 years of age weighing ≥40 kg receiving potent CYP2D6 inhibitors, pitolisant therapy should be initiated at a dosage of 4.45 mg once daily and increased 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 receiving a stable dosage of pitolisant, dosage of pitolisant should be reduced by one-half when therapy with a potent CYP2D6 inhibitor is initiated.1
Potent CYP3A4 inhibitors (e.g., itraconazole, ketoconazole, grapefruit juice) do not substantially alter the pharmacokinetics of pitolisant.1
Concomitant administration of pitolisant and potent CYP3A4 inducers decreases pitolisant exposure by approximately 50%.1
Following initiation of therapy with a potent CYP3A4 inducer (e.g., rifampicin), patients receiving pitolisant should be monitored for loss of efficacy; in adult and pediatric patients stable on a pitolisant dosage of 8.9 or 17.8 mg once daily, dosage should be increased to twice the original dosage (i.e., to 17.8 or 35.6 mg daily, respectively) over 7 days.1 If a potent CYP3A4 inducer is discontinued, pitolisant dosage should be reduced by one-half.1
Because pitolisant is a borderline or weak inducer of CYP3A4, concomitant use of pitolisant and sensitive CYP3A4 substrates (e.g., midazolam) may result in reduced efficacy of the CYP3A4 substrate drug.1 Concomitant administration of pitolisant and midazolam reduced systemic exposure to midazolam by approximately 20%.1, 8 Efficacy of hormonal contraceptives (e.g., ethinyl estradiol) may be reduced during pitolisant therapy and for 21 days following discontinuance of the drug; therefore, patients receiving hormonal contraceptives should be advised to use an alternative nonhormonal contraceptive method during pitolisant therapy and for at least 21 days following discontinuance of the drug.1
Concomitant administration of pitolisant did not substantially alter systemic exposure to the sensitive CYP2B6 substrate bupropion.1
Drugs that Prolong the QT Interval
Concomitant use of pitolisant and other drugs that are known to prolong the QT interval, including class Ia antiarrhythmics, class III antiarrhythmics, certain antipsychotics, and certain anti-infectives, may result in additive QT-interval prolongation and may increase the risk of cardiac arrhythmia.1 Concomitant use of such drugs should be avoided.1
Histamine H1-Receptor Antagonists
Because pitolisant increases histamine concentrations in the brain, histamine H1-receptor antagonists that cross the blood-brain barrier may reduce the efficacy of pitolisant.1 Therefore, concomitant use of centrally acting histamine H1-receptor antagonists should be avoided.1
Concomitant use of pitolisant and modafinil does not substantially alter the pharmacokinetics of either drug.1
Concomitant use of pitolisant and sodium oxybate does not substantially alter the pharmacokinetics of either drug.1
Pitolisant hydrochloride, a selective competitive antagonist and inverse agonist at the histamine H3 receptor, is a wakefulness-promoting agent.1, 4, 6, 7 The 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 then 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 Pitolisant binds to H3 receptors with high affinity but has no appreciable binding to other histamine receptors (H1, H2, or H4receptors).1 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 The exact mechanism by which pitolisant promotes wakefulness in adult patients with excessive daytime sleepiness associated with narcolepsy or pediatric patients 6 years of age or older with narcolepsy or cataplexy has not been fully established but is thought to be related to its activity at the histamine H3 receptor.1 Pitolisant appears to have minimal potential for abuse.2, 13
Oral bioavailability of pitolisant is approximately 90%.1 Peak plasma concentrations of the drug are achieved at a median of 3.5 hours after oral administration, and peak plasma concentrations and area under the concentration-time curve (AUC) are proportional to dose.1 Steady state is achieved by day 7.1 Administration with a high-fat meal does not substantially alter the pharmacokinetics of the drug.1 Pitolisant is approximately 91-96% bound to serum proteins.1 Pitolisant is extensively metabolized in the liver, mainly by cytochrome P-450 (CYP) isoenzyme 2D6 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 The median half-life of pitolisant is approximately 20 hours (range: 7.5-24.2 hours).1 Following oral administration of a single 17.8-mg dose of radiolabeled pitolisant, approximately 90% of the dose was excreted in urine (less than 2% as unchanged drug) and 2.3% was excreted in feces.1 Age (range: 18-82 years), sex, race or ethnicity (Caucasian or Black), and body weight (range: 48-103 kg) do not substantially affect the pharmacokinetics of the drug.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.
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.
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Oral | Tablets, film-coated | 4.45 mg (of pitolisant) | Harmony Biosciences | |
17.8 mg (of pitolisant) | Wakix® | Harmony Biosciences |
AHFS® Drug Information. © Copyright, 1959-2025, Selected Revisions April 10, 2025. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, MD 20814.
1. Harmony Biosciences. Wakix® (pitolisant hydrochloride) tablets prescribing information. Plymouth Meeting, PA; 2024 Jun. [Web]
2. US Food and Drug Administration. Center for Drug Evaluation and Research. Application number 211150Orig1s000: Clinical review(s). From FDA website. [Web]
3. Dauvilliers Y, Bassetti C, Lammers GJ et al. Pitolisant versus placebo or modafinil in patients with narcolepsy: a double-blind, randomised trial. Lancet Neurol . 2013; 12:1068-75. [PubMed 24107292]
4. Thorpy MJ. Recently Approved and Upcoming Treatments for Narcolepsy. CNS Drugs . 2020; 34:9-27. [PubMed 31953791]
5. Sahni AS, Carlucci M, Malik M et al. Management Of Excessive Sleepiness In Patients With Narcolepsy And OSA: Current Challenges And Future Prospects. Nat Sci Sleep . 2019; 11:241-252. [PubMed 31695533]
6. Romigi A, Vitrani G, Lo Giudice T et al. Profile of pitolisant in the management of narcolepsy: design, development, and place in therapy. Drug Des Devel Ther . 2018; 12:2665-2675. [PubMed 30214155]
7. Schwartz JC. The histamine H3 receptor: from discovery to clinical trials with pitolisant. Br J Pharmacol . 2011; 163:713-21. [PubMed 21615387]
8. US Food and Drug Administration. Center for Drug Evaluation and Research. Application number 211150Orig1s000: Clinical pharmacology review(s). From FDA website. [Web]
9. Food and Drug Administration. FDA Application: Search Orphan Drug Designations and Approvals. Silver Spring, MD. From FDA website. [Web]
10. Abad VC, Guilleminault C. New developments in the management of narcolepsy. Nat Sci Sleep . 2017; 9:39-57. [PubMed 28424564]
11. Szabo ST, Thorpy MJ, Mayer G et al. Neurobiological and immunogenetic aspects of narcolepsy: Implications for pharmacotherapy. Sleep Med Rev . 2019; 43:23-36. [PubMed 30503715]
12. Tiligada E, Kyriakidis K, Chazot PL et al. Histamine pharmacology and new CNS drug targets. CNS Neurosci Ther . 2011; 17:620-8. [PubMed 22070192]
13. Setnik B, McDonnell M, Mills C et al. Evaluation of the abuse potential of pitolisant, a selective H3-receptor antagonist/inverse agonist, for the treatment of adult patients with narcolepsy with or without cataplexy. Sleep . 2020; 43 [PubMed 31626696]
14. Szakacs Z, Dauvilliers Y, Mikhaylov V, et al. Safety and efficacy of pitolisant on cataplexy in patients with narcolepsy: a randomised, double-blind, placebo-controlled trial. Lancet Neurol. 2017;16(3):200-207.
15. Dauvilliers Y, Lecendreux M, Lammers GJ, et al. Safety and efficacy of pitolisant in children aged 6 years or older with narcolepsy with or without cataplexy: a double-blind, randomised, placebo-controlled trial. Lancet Neurol. 2023;22(4):303-311.
57. Maski K, Trotti LM, Kotagal S, et al. Treatment of central disorders of hypersomnolence: an American Academy of Sleep Medicine Clinical Practice Guideline. J Clin Sleep Med. 2021 Sep 1;17(9):1881-1893.