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Pitolisant

Class: Wakefulness-promoting Agents
Chemical Name: 1-[3-[3-(4-chlorophenyl)propoxy]propyl]piperidine monohydrochloride
Molecular Formula: C17H26ClNO•HCl.
CAS Number: 903576-44-3
Brands: Wakix

Medically reviewed by Drugs.com. Last updated on Nov 16, 2020.

Introduction

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

Uses for Pitolisant

Narcolepsy

Symptomatic treatment of narcolepsy to improve wakefulness in patients with excessive daytime sleepiness1 2 3 (designated an orphan drug by FDA for treatment of narcolepsy).9

Pitolisant Dosage and Administration

Administration

Oral Administration

Administer orally once daily in the morning upon awakening.1

If a dose is missed, resume the regular dosing schedule the following day.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

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 once daily.1

Known poor CYP2D6 metabolizers: Initially, 8.9 mg once daily; increase after 7 days to maximum dosage of 17.8 mg 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

Concomitant use with potent CYP2D6 inhibitors or potent CYP3A4 inducers: Dosage adjustment required.1 (See Drugs Affecting Hepatic Microsomal Enzymes under Interactions.)

Prescribing Limits

Adults

Narcolepsy
Oral

Maximum, 35.6 mg once daily.1

Known poor CYP2D6 metabolizers: Maximum, 17.8 mg once daily.1

Special Populations

Hepatic Impairment

Mild hepatic impairment: Dosage adjustment not required.1

Moderate hepatic impairment: Initially, 8.9 mg once daily; increase after 14 days to maximum dosage of 17.8 mg once daily.1

Severe hepatic impairment: Contraindicated.1 (See Hepatic Impairment under Cautions.)

Renal Impairment

Moderate or severe renal impairment: Initially, 8.9 mg once daily; increase after 7 days to maximum dosage of 17.8 mg once daily.1

End-stage renal disease: Use not recommended.1 (See Renal Impairment under Cautions.)

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 the elderly.1

Cautions for Pitolisant

Contraindications

  • Severe hepatic impairment.1 (See Hepatic Impairment under Cautions.)

Warnings/Precautions

QT-Interval Prolongation

Pitolisant prolongs the QT interval.1 Mean increase in corrected QT (QTc) 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 (See Interactions.)

Patients with hepatic or renal impairment may be at increased risk for QT-interval prolongation because of potentially higher pitolisant concentrations.1 (See Specific Populations under Cautions and also see Special Populations under Dosage and Administration.)

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 observed in animal studies.1

Pregnancy registry at 800-833-7460.1

Pitolisant may reduce efficacy of hormonal contraceptives.1 (See Specific Drugs under Interactions.) 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

Lactation

Not known whether pitolisant distributes into human milk, affects breast-fed infants, or affects milk production.1 Pitolisant distributes into milk in rats (concentrations approximately 1–3 times higher in milk than in plasma from 0.25–6 hours following administration).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 child from the drug or from the underlying maternal condition.1

Pediatric Use

Safety and efficacy not established in pediatric patients.1 Systemic exposure may be greater in pediatric patients than in adults.1 (See Absorption: Special Populations, under Pharmacokinetics.)

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 the elderly.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 (See Hepatic Impairment under Dosage and Administration and also see Absorption: Special Populations, under Pharmacokinetics.)

Patients with hepatic impairment may be at increased risk for QT-interval prolongation because of higher drug concentrations.1 (See QT-Interval Prolongation under Cautions.) 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 (See Renal Impairment under Dosage and Administration.)

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 (See Renal Impairment under Dosage and Administration.)

Patients with renal impairment may be at increased risk for, and should be monitored for, QT-interval prolongation because of higher drug concentrations.1 (See QT-Interval Prolongation under Cautions.)

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 (See Absorption: Special Populations, under Pharmacokinetics and also see Dosage under Dosage and Administration.)

Common Adverse Effects

Insomnia, nausea, anxiety.1

Interactions for Pitolisant

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 AUC of pitolisant.1 In patients receiving potent CYP2D6 inhibitors, initiate pitolisant at dosage of 8.9 mg once daily; increase after 7 days to maximum dosage of 17.8 mg once daily.1 In patients already receiving a stable pitolisant dosage, reduce pitolisant dosage by one-half when initiating a potent CYP2D6 inhibitor.1

Potent CYP3A4 inhibitors: No 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 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

Drug

Interaction

Comments

Antiarrhythmics, class Ia (e.g., disopyramide, procainamide, quinidine) or class III (e.g., amiodarone, sotalol)

Possible additive QT-interval prolongation and increased risk of cardiac arrhythmia1

Avoid concomitant use1

Anticonvulsants (e.g., carbamazepine, phenytoin)

Anticonvulsants that are potent CYP3A4 inducers: Decreased AUC of pitolisant1 8

Monitor for loss of pitolisant efficacy following initiation of anticonvulsants that are potent CYP3A4 inducers; in 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; if the anticonvulsant is discontinued, reduce pitolisant dosage by one-half1

Antifungals, azole (e.g., itraconazole, ketoconazole)

Antifungals that are potent CYP3A4 inhibitors: No effect on pharmacokinetics of pitolisant1

Anti-infectives (e.g., moxifloxacin)

Anti-infectives that prolong QT interval: Possible additive QT-interval prolongation and increased risk of cardiac arrhythmia1

Anti-infectives that prolong QT interval: Avoid concomitant use1

Antipsychotics (e.g., chlorpromazine, thioridazine, ziprasidone)

Antipsychotics that prolong QT interval: Possible additive QT-interval prolongation and increased risk of cardiac arrhythmia1

Antipsychotics that prolong QT interval: Avoid concomitant use1

Bupropion

Possible increased AUC of pitolisant; no effect on exposure to bupropion (CYP2B6 substrate)1

In patients receiving bupropion (potent CYP2D6 inhibitor), initiate pitolisant at dosage of 8.9 mg once daily; increase after 7 days to maximum dosage of 17.8 mg once daily1

In patients receiving a stable pitolisant dosage, reduce pitolisant dosage by one-half when initiating bupropion1

Cyclosporine

Possible reduced efficacy of cyclosporine (CYP3A4 substrate)1

Grapefruit juice

No effect on pharmacokinetics of pitolisant1

Histamine H1-receptor antagonists, centrally acting (e..g., clomipramine, diphenhydramine, imipramine, mirtazapine, pheniramine, promethazine)

Possible reduced efficacy of pitolisant (see Actions)1

Avoid concomitant use1

Hormonal contraceptives

Possible reduced efficacy of hormonal contraceptives (e.g., ethinyl estradiol [CYP3A4 substrate]) during pitolisant therapy and for 21 days following discontinuance of the drug1

Advise patients to use alternative nonhormonal contraceptive method during pitolisant therapy and for ≥21 days after discontinuing the drug1

Midazolam

Systemic exposure to midazolam (CYP3A4 substrate) decreased by approximately 20%1 8

Modafinil

No substantial change in pharmacokinetics of either drug1

Rifampin

Rifampin (potent CYP3A4 inducer) decreased AUC of pitolisant by approximately 50%1 8

Monitor for loss of pitolisant efficacy following initiation of rifampin; in 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; if rifampin is discontinued, reduce pitolisant dosage by one-half1

SSRIs (e.g., fluoxetine, paroxetine)

SSRIs that are potent CYP2D6 inhibitors: Increased AUC of pitolisant;1 paroxetine increased AUC of pitolisant by 2.2-fold1 8

In patients receiving an SSRI that is a potent CYP2D6 inhibitor, initiate pitolisant at dosage of 8.9 mg once daily; increase after 7 days to maximum of 17.8 mg once daily1

In patients receiving a stable pitolisant dosage, reduce pitolisant dosage by one-half when initiating the SSRI1

Sodium oxybate

No substantial change in pharmacokinetics of either drug1

Pitolisant Pharmacokinetics

Absorption

Bioavailability

Oral bioavailability is approximately 90%.1

Peak plasma concentrations are achieved at a median of 3.5 hours after oral administration; peak plasma concentrations and AUC are proportional to dose.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 (See Interactions.)

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 twofold in adolescents 12–17 years of age and threefold 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.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 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 promotes wakefulness in patients with excessive daytime sleepiness associated with narcolepsy 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

  • 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 ≥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 Cautions.)

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

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.

Pitolisant Hydrochloride

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablets, film-coated

4.45 mg (of pitolisant)

Wakix

Harmony Biosciences

17.8 mg (of pitolisant)

Wakix

Harmony Biosciences

AHFS DI Essentials™. © Copyright 2021, Selected Revisions November 16, 2020. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.

References

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. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2019/211150Orig1s000MedR.pdf

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. http://www.ncbi.nlm.nih.gov/pubmed/24107292?dopt=AbstractPlus

4. Thorpy MJ. Recently Approved and Upcoming Treatments for Narcolepsy. CNS Drugs. 2020; 34:9-27. http://www.ncbi.nlm.nih.gov/pubmed/31953791?dopt=AbstractPlus http://www.pubmedcentral.nih.gov/picrender.fcgi?tool=pmcentrez&artid=PMC6982634&blobtype=pdf

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. http://www.ncbi.nlm.nih.gov/pubmed/31695533?dopt=AbstractPlus http://www.pubmedcentral.nih.gov/picrender.fcgi?tool=pmcentrez&artid=PMC6815780&blobtype=pdf

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. http://www.ncbi.nlm.nih.gov/pubmed/30214155?dopt=AbstractPlus http://www.pubmedcentral.nih.gov/picrender.fcgi?tool=pmcentrez&artid=PMC6124464&blobtype=pdf

7. Schwartz JC. The histamine H3 receptor: from discovery to clinical trials with pitolisant. Br J Pharmacol. 2011; 163:713-21. http://www.ncbi.nlm.nih.gov/pubmed/21615387?dopt=AbstractPlus http://www.pubmedcentral.nih.gov/picrender.fcgi?tool=pmcentrez&artid=PMC3111674&blobtype=pdf

8. US Food and Drug Administration. Center for Drug Evaluation and Research. Application number 211150Orig1s000: Clinical pharmacology review(s). From FDA website. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2019/211150Orig1s000ClinPharmR.pdf

9. Food and Drug Administration. FDA Application: Search Orphan Drug Designations and Approvals. Silver Spring, MD. From FDA website (http://www.accessdata.fda.gov/scripts/opdlisting/oopd/index.cfm). Accessed 2020 Jul 10.

10. Abad VC, Guilleminault C. New developments in the management of narcolepsy. Nat Sci Sleep. 2017; 9:39-57. http://www.ncbi.nlm.nih.gov/pubmed/28424564?dopt=AbstractPlus http://www.pubmedcentral.nih.gov/picrender.fcgi?tool=pmcentrez&artid=PMC5344488&blobtype=pdf

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. http://www.ncbi.nlm.nih.gov/pubmed/30503715?dopt=AbstractPlus http://www.pubmedcentral.nih.gov/picrender.fcgi?tool=pmcentrez&artid=PMC6351197&blobtype=pdf

12. Tiligada E, Kyriakidis K, Chazot PL et al. Histamine pharmacology and new CNS drug targets. CNS Neurosci Ther. 2011; 17:620-8. http://www.ncbi.nlm.nih.gov/pubmed/22070192?dopt=AbstractPlus http://www.pubmedcentral.nih.gov/picrender.fcgi?tool=pmcentrez&artid=PMC6493842&blobtype=pdf

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 http://www.ncbi.nlm.nih.gov/pubmed/31626696?dopt=AbstractPlus http://www.pubmedcentral.nih.gov/picrender.fcgi?tool=pmcentrez&artid=PMC7157189&blobtype=pdf