AHFS Class:

• Wakefulness-promoting Agents 28:20.80

Generic Name(s):

• Pitolisant Hydrochloride

Chemical Name:

• 1-[3-[3-(4-chlorophenyl)propoxy]propyl]piperidine monohydrochloride

Molecular Formula:

• C₁₇H₂₆ClNO•HCl.

Pitolisant hydrochloride, a selective competitive antagonist and inverse agonist at the histamine H₃ receptor, is a wakefulness-promoting agent.1,4,6,7

Narcolepsy

Pitolisant hydrochloride is used in the symptomatic treatment of narcolepsy to improve wakefulness in patients with excessive daytime sleepiness.1,2,3 Pitolisant has been designated an orphan drug by FDA for use in the treatment of narcolepsy.9 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

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 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

Administration

Pitolisant hydrochloride is administered orally once daily in the morning upon awakening.1 If a dose of pitolisant is missed, the regular dosing schedule should be resumed the following day.1

Dosage

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

Narcolepsy

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 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

In patients who are known to be poor metabolizers of cytochrome P-450 (CYP) isoenzyme 2D6 substrates, pitolisant should be initiated at a dosage of 8.9 mg once daily and increased after 7 days to a maximum dosage of 17.8 mg once daily.1 (See Pharmacogenomics and Effects of CYP2D6 Polymorphism under Warnings/Precautions: Specific Populations, in Cautions.)

Dosage adjustments also are required when pitolisant is used concomitantly with potent CYP2D6 inhibitors or potent CYP3A4 inducers.1 (See Drug Interactions: Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes.)

Special Populations

In patients with moderate 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 Dosage adjustment is not required in patients with mild hepatic impairment.1 The drug is contraindicated in patients with severe hepatic impairment.1 (See Hepatic Impairment under Warnings/Precautions: Specific Populations, in Cautions.)

In patients with moderate or severe renal impairment, pitolisant should be initiated at a dosage of 8.9 mg once daily and increased after 7 days to a maximum dosage of 17.8 mg once daily.1 Use of pitolisant in patients with end-stage renal disease is not recommended.1 (See Renal Impairment under Warnings/Precautions: Specific Populations, in Cautions.)

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 the elderly should be considered.1 (See Geriatric Use under Warnings/Precautions: Specific Populations, in Cautions.)

Contraindications

Pitolisant is contraindicated in patients with severe hepatic impairment.1 (See Hepatic Impairment under Warnings/Precautions: Specific Populations, in Cautions.)

Warnings/Precautions

Prolongation of QT Interval

Pitolisant prolongs the QT interval.1 The mean increase in corrected QT (QT_c) 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 (See Drug Interactions: Drugs that Prolong the QT Interval.)

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 (See Dosage and Administration: Special Populations.)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 (See Specific Populations under Cautions: Warnings/Precautions.)

Specific Populations

Pregnancy

Available case reports from clinical trials and postmarketing experience are insufficient to determine pitolisant-associated risks of major birth defects, spontaneous abortion, 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 (See CYP3A4 Substrates under Drug Interactions: Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes.)

Lactation

It is not known whether pitolisant is distributed into human milk, affects breast-fed infants, or affects milk production.1 Pitolisant is distributed into milk in rats; when radiolabeled pitolisant was administered to lactating rats, the level of radioactivity was approximately 1-3 times higher in milk than in plasma from 0.25-6 hours following administration.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 child from the drug or from the underlying maternal condition.1

Pediatric Use

Safety and efficacy of pitolisant have not been established in pediatric patients.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 twofold in adolescents 12-17 years of age and threefold in children 7-11 years of age compared with adults.1

Geriatric Use

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 the elderly also should be considered.1

Hepatic Impairment

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 (See Prolongation of QT Interval under Cautions: Warnings/Precautions.) 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 (See Dosage and Administration: Special Populations.)

Pitolisant is contraindicated in patients with severe hepatic impairment (Child-Pugh class C); data are lacking in this patient population.1

Renal Impairment

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 moderate or severe renal impairment (estimated glomerular filtration rate [eGFR] 15-59 mL/minute per 1.73 m²).1 (See Dosage and Administration: Special Populations.)

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 (See Prolongation of QT Interval under Cautions: Warnings/Precautions.)

The effect of end-stage renal disease (eGFR less than 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 (See CYP2D6 Inhibitors under Drug Interactions: Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes.) Reduced dosages are recommended in patients who are known to be poor CYP2D6 metabolizers.1 (See Dosage and Administration: Dosage.)

Common Adverse Effects

Adverse effects reported in clinical trials in 5% or more of patients receiving pitolisant and at least twice as frequently with the drug as with placebo include insomnia, nausea, and anxiety.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

CYP2D6 Inhibitors

Concomitant administration of pitolisant and the potent CYP2D6 inhibitor paroxetine increased the area under the plasma concentration-time curve (AUC) of pitolisant by 2.2-fold.1,8

In patients receiving potent CYP2D6 inhibitors (e.g., bupropion, fluoxetine, paroxetine), pitolisant therapy should be initiated at a dosage of 8.9 mg once daily and increased after 7 days to a maximum dosage of 17.8 mg once daily.1 In patients already 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

CYP3A4 Inhibitors

Potent CYP3A4 inhibitors (e.g., itraconazole, ketoconazole, grapefruit juice) do not alter the pharmacokinetics of pitolisant.1

CYP3A4 Inducers

Concomitant administration of pitolisant and the potent CYP3A4 inducer rifampin decreased the AUC of pitolisant by approximately 50%.1,8

Following initiation of therapy with a potent CYP3A4 inducer (e.g., carbamazepine, phenytoin, rifampin), patients receiving pitolisant should be monitored for loss of efficacy; in 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., 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

CYP3A4 Substrates

Because pitolisant is a borderline or weak inducer of CYP3A4, concomitant use of pitolisant and sensitive CYP3A4 substrates (e.g., cyclosporine, hormonal contraceptives, 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

CYP2B6 Substrates

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 (e.g., disopyramide, procainamide, quinidine), class III antiarrhythmics (e..g., amiodarone, sotalol), certain antipsychotics (e.g., chlorpromazine, thioridazine, ziprasidone), and certain anti-infectives (e.g., moxifloxacin), 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 (See Description.) Therefore, concomitant use of centrally acting histamine H₁-receptor antagonists (e.g., clomipramine, diphenhydramine, imipramine, mirtazapine, pheniramine, promethazine) should be avoided.1

Modafinil

Concomitant use of pitolisant and modafinil does not substantially alter the pharmacokinetics of either drug.1

Sodium Oxybate

Concomitant use of pitolisant and sodium oxybate does not substantially alter the pharmacokinetics of either drug.1

Description

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 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 patients with excessive daytime sleepiness associated with narcolepsy 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 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.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

Advice to Patients

Advise patients to consult their clinician immediately if they feel faint, lose consciousness, or have heart palpitations.1 Importance of patients 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

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

Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.1 Importance of encouraging pregnant women who have been exposed to pitolisant to enroll in the manufacturer's pregnancy registry.1 (See Pregnancy under Warnings/Precautions: Specific Populations, in Cautions.)

Importance of informing patients of other important precautionary information.1 (See Cautions.)

Additional Information

Overview^® (see Users Guide). For additional information on this drug until a more detailed monograph is developed and published, the manufacturer's labeling should be consulted. It is essential that the manufacturer's labeling be consulted for more detailed information on usual cautions, precautions, contraindications, potential drug interactions, laboratory test interferences, and acute toxicity.

1. Harmony Biosciences. Wakix^® (pitolisant hydrochloride) tablets prescribing information. Plymouth Meeting, PA; 2019 Nov.

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][PubMedCentral]

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][PubMedCentral]

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][PubMedCentral]

7. Schwartz JC. The histamine H3 receptor: from discovery to clinical trials with pitolisant. Br J Pharmacol . 2011; 163:713-21. [PubMed 21615387][PubMedCentral]

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][PubMedCentral]

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][PubMedCentral]

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][PubMedCentral]

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][PubMedCentral]