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Wakix

Generic Name: Pitolisant Hydrochloride
Class: Wakefulness-promoting Agents
Chemical Name: 1-[3-[3-(4-chlorophenyl)propoxy]propyl]piperidine
Molecular Formula: C17H26ClNO
CAS Number: 362665-56-3

Medically reviewed by Drugs.com. Last updated on Sep 16, 2019.

Introduction

Pitolisant hydrochloride is a wakefulness-promoting agent.

Uses for Wakix

Pitolisant hydrochloride has the following uses:

Pitolisant hydrochloride is a histamine-3 (H3) receptor antagonist/inverse agonist indicated for the treatment of excessive daytime sleepiness (EDS) in adult patients with narcolepsy.1

Wakix Dosage and Administration

General

Pitolisant hydrochloride is available in the following dosage form(s) and strength(s):

Tablets: 4.45 mg and 17.8 mg.1

Dosage

It is essential that the manufacturer's labeling be consulted for more detailed information on dosage and administration of this drug. Dosage summary:

Adults

Administer once daily in the morning upon wakening.1

The recommended dosage range is 17.8 mg to 35.6 mg daily.1 Titrate dosage as follows:

  • Week 1: Initiate with 8.9 mg once daily1

  • Week 2: Increase dosage to 17.8 mg once daily1

  • Week 3: May increase to the maximum recommended dosage of 35.6 mg once daily1

Hepatic Impairment

Moderate hepatic impairment: Initial dosage is 8.9 mg once daily. Titrate to a maximum dosage of 17.8 mg once daily after 14 days.1

Renal Impairment

Moderate and severe impairment: Initial dosage is 8.9 mg once daily. Titrate to maximum dosage of 17.8 mg once daily after 7 days.1

End-stage renal disease (ESRD): Not recommended.1

Poor Metabolizers of CYP2D6

Maximum recommended dosage is 17.8 mg once daily.1

Cautions for Wakix

Contraindications

Pitolisant hydrochloride is contraindicated in patients with severe hepatic impairment.1

Warnings/Precautions

QT Interval Prolongation

Pitolisant hydrochloride prolongs the QT interval. The use of pitolisant hydrochloride should be avoided in patients with known QT prolongation or in combination with other drugs known to prolong the QT interval. Pitolisant hydrochloride should also be avoided in patients with a history of cardiac arrhythmias, as well as other circumstances that may increase the risk of the occurrence of torsades de pointes or sudden death, including symptomatic bradycardia, hypokalemia or hypomagnesemia, and the presence of congenital prolongation of the QT interval. The risk of QT prolongation may be greater in patients with hepatic or renal impairment due to higher concentrations of pitolisant. Monitor patients with hepatic or renal impairment for increased QTc. Dosage modification is recommended in patients with moderate hepatic impairment and moderate or severe renal impairment. Pitolisant hydrochloride is contraindicated in patients with severe hepatic impairment. Pitolisant hydrochloride is not recommended in patients with end-stage renal disease (ESRD). 1

Specific Populations

Pregnancy

Pregnancy Exposure Registry: There is a pregnancy exposure registry that monitors pregnancy outcomes in women who are exposed to pitolisant hydrochloride during pregnancy. Patients should be encouraged to enroll in the pitolisant hydrochloride pregnancy registry if they become pregnant. To enroll or obtain information from the registry, patients can call 1-800-833-7460.1

Risk Summary: Available case reports from clinical trials and postmarketing reports with pitolisant hydrochloride use in pregnant women have not determined a drug-associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes. In animal reproductive studies, administration of pitolisant during organogenesis caused maternal and embryofetal toxicity in rats and rabbits at doses ≥13 and >4 times the maximum recommended human dose (MRHD) of 35.6 mg based on mg/m2 body surface area, respectively. Oral administration of pitolisant to female rats during pregnancy and lactation adversely affected maternal and fetal health and produced developmental delay at doses ≥13 times the MRHD, based on mg/m2 body surface area and increased the incidence of major malformations at 22 times the MRHD.1

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.1

Animal Data: Pitolisant was administered orally to pregnant rats during the period of organogenesis at doses of 30, 52, 90 and 110 mg/kg/day, which are approximately 7, 13, 22 and 27 times the MRHD, based on mg/m2 body surface area, respectively. Maternal toxicity occurred at >22 times the MRHD and included decreases in body weight, food consumption and convulsions. At these maternally toxic doses, no adverse effects on embryofetal development were noted and the no-observed-adverse-effect-level for embryofetal toxicity is 27 times the MRHD based on mg/m2 body surface area.1

Pitolisant was administered intramuscularly to pregnant rabbits during the period of organogenesis at doses of 4, 8, and 16 mg/kg/day, which are approximately 2, 4 and 8 times the MRHD, based on mg/m2 body surface area, respectively. Maternal toxicity occurred at ≥4 times the MRHD and included significant body weight loss and decreased food consumption. Mortality (1 animal) and convulsions (2 animals) occurred at 8 times the MRHD. At the maternally toxic dose (8 times the MRHD), the incidence of pre-implantation loss and abortions increased with a consequent decrease in both the number of implantations and live fetuses. Pitolisant was not teratogenic at doses up to 8 times the MRHD; however, delayed skeletal development (incomplete ossification and supernumerary ribs) was observed. The no-observed-adverse-effect-level for maternal toxicity and embryofetal development is 2 and 4 times the MRHD based on mg/m2 body surface area, respectively.1

Pitolisant was administered orally to pregnant rats from gestation day 7 through lactation day 20 post-partum at doses of 30, 52, and 90 mg/kg/day, which are 7, 13 and 22 times the MRHD, based on mg/m2 body surface area, respectively. Maternal toxicity included death, CNS signs including convulsions, and significant decrease in body weight and food consumption at 22 times the MRHD based on mg/m2 body surface area. At the maternally toxic dose (22 times the MRHD), fetal toxicity included stillbirths, postnatal pup mortality (due to lack of milk and/or failure to nurse), and decreased pup length and weight. A single female at the mid dose (13 times the MRHD) also failed to produce milk resulting in pup mortality. At the maternally toxic dose (22 times the MRHD), pitolisant was teratogenic causing major malformations (cleft palate, abnormal limb flexure). F1 toxicity included delay in postnatal development (decrease in body weight and length, delay in incisor eruption, and delay in testes descent), which occurred at ≥13 times the MRHD; however, there was no effect on sexual maturation or reproductive capacity of the F1 generation. The no-observed-adverse-effect-level for developmental toxicity is approximately 7 times the MRHD, based on mg/m2 body surface area.1

Lactation

Risk Summary: There are no data on the presence of pitolisant in human milk, the effects on the breastfed infant, or the effect of this drug on milk production.1

Pitolisant is present in the milk of lactating rats. When a drug is present in animal milk, it is likely that the drug will be present in human milk. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for pitolisant hydrochloride and any potential adverse effects on the breastfed child from pitolisant hydrochloride or from the underlying maternal condition.1

Data: Radiolabeled [14C]-pitolisant (30 mg/kg, free base; 8 times the MRHD based on mg/m2) was administered to female rats during lactation on day 14 post-partum. Radioactivity in milk was first measured at 0.25 hours post-administration and reached a maximum by 6 hours post-administration. The level of radioactivity tended to be higher in milk compared to plasma, ranging from approximately 1 to 3 times higher in milk than plasma from 0.25 to 6 hours post-administration.1

Females and Males of Reproductive Potential

Pitolisant hydrochloride may reduce the effectiveness of hormonal contraceptives. Patients using hormonal contraception should be advised to use an alternative non-hormonal contraceptive method during treatment with pitolisant hydrochloride and for at least 21 days after discontinuing treatment.1

Pediatric Use

The safety and effectiveness of pitolisant hydrochloride in pediatric patients have not been established.1

Limited pharmacokinetic data from 24 pediatric patients with narcolepsy (ages 7 to <18 years) receiving a single dose of pitolisant hydrochloride suggest that pediatric patients have higher exposure to pitolisant than adults. The exposure (Cmax and AUC) of pitolisant was 2-fold higher in pediatric patients 12 to <18 years and 3-fold higher in pediatric patients 7 to <12 years compared to adults.1

Geriatric Use

Limited pharmacokinetic data are available in healthy elderly subjects. A pharmacokinetic study that compared 12 elderly subjects (age 68 to 82 years) to 12 healthy adults (age 18 to 45 years) did not reveal any significant differences in drug exposure.1

Of the total number of patients with narcolepsy in clinical studies of pitolisant hydrochloride, 14 patients (5%) were ≥65 years old. No overall differences in safety or effectiveness were observed between these patients and younger patients in these clinical trials, but greater sensitivity of some older individuals cannot be ruled out. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, and cardiac function, concomitant diseases, and other drug therapy.1

Hepatic Impairment

Pitolisant hydrochloride is contraindicated in patients with severe hepatic impairment (Child-Pugh C) as it has not been studied in this population. Pitolisant hydrochloride is extensively metabolized by the liver and there is a significant increase in pitolisant hydrochloride exposure in patients with moderate hepatic impairment.1

Monitor patients with moderate hepatic impairment (Child-Pugh B) and adjust the dosage of pitolisant hydrochloride.1

Monitor patients with mild hepatic impairment (Child-Pugh A). No dosage adjustment of pitolisant hydrochloride is recommended in patients with mild hepatic impairment.1

Renal Impairment

The pharmacokinetics of pitolisant hydrochloride in patients with end-stage renal disease (ESRD) (eGFR of <15 mL/minute/1.73 m2) is unknown. Therefore, pitolisant hydrochloride is not recommended in patients with ESRD. 1

Dosage adjustment of pitolisant hydrochloride is recommended in patients with moderate (eGFR 30 to 59 mL/minute/1.73 m2) and severe (eGFR 15 to 29 mL/minute/1.73 m2) renal impairment.1

Pharmacogenomics: CYP2D6 Poor Metabolizers

Dosage reduction is recommended in patients known to be poor CYP2D6 metabolizers because these patients have higher pitolisant concentrations than normal CYP2D6 metabolizers.1

Common Adverse Effects

The most common adverse reactions (≥5% and twice placebo) for pitolisant hydrochloride were insomnia, nausea, and anxiety.1

Drug Interactions

Specific Drugs

It is essential that the manufacturer's labeling be consulted for more detailed information on interactions with this drug, including possible dosage adjustments. Interaction highlights:

  • Strong CYP2D6 Inhibitors: Maximum recommended dosage is 17.8 mg once daily.1

  • Strong CYP3A4 Inducers: Decreased exposure of pitolisant hydrochloride; consider dosage adjustment.1

  • Sensitive CYP3A4 Substrates (including hormonal contraceptives): Pitolisant hydrochloride may reduce effectiveness of sensitive CYP3A4 substrates. Use an alternative non-hormonal contraceptive method during treatment with pitolisant hydrochloride and for at least 21 days after discontinuation of treatment.1

Actions

Mechanism of Action

The mechanism of action of pitolisant in excessive daytime sleepiness (EDS) in adult patients with narcolepsy is unclear. However, its efficacy could be mediated through its activity as an antagonist/inverse agonist at histamine-3 (H3) receptors.1

Advice to Patients

Prolongation of the QT Interval

Inform patients to consult their physician immediately if they feel faint, lose consciousness, or have heart palpitations. Advise patients to inform their healthcare provider that they are taking pitolisant hydrochloride before any new drug is taken.1

Contraception

Advise patients that use of pitolisant hydrochloride may reduce the efficacy of hormonal contraceptives. Advise patients using a hormonal contraceptive to use an alternative non-hormonal contraceptive method of contraception during treatment and for at least 21 days after discontinuing treatment.1

Pregnancy

Advise patients that there is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to pitolisant hydrochloride during pregnancy.1

Concomitant Medication

Advise patients to inform their healthcare provider if they are taking, or plan to take, any prescription or over-the-counter drugs, because of the potential for interactions between pitolisant hydrochloride and other drugs.1

Additional Information

AHFSfirstRelease. For additional information 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 uses, dosage and administration, cautions, precautions, contraindications, potential drug interactions, laboratory test interferences, and acute toxicity.

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

Tablet, Film Coated

4.45 mg

Wakix

Harmony Biosciences LLC

17.8 mg

Wakix

Harmony Biosciences LLC

AHFS Drug Information. © Copyright 2020, Selected Revisions September 16, 2019. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.

References

1. Harmony Biosciences, LLC. Wakix (PITOLISANT HYDROCHLORIDE) ORAL prescribing information. 2019 Aug. http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=8daa5562-824e-476c-9652-26ceef3d4b0e