Pitolisant (Monograph)

Brand name: Wakix
Drug class: Wakefulness-promoting Agents
Chemical name: 1-[3-[3-(4-chlorophenyl)propoxy]propyl]piperidine monohydrochloride
Molecular formula: C₁₇H₂₆ClNO•HCl.
CAS number: 903576-44-3

Medically reviewed by Drugs.com on Nov 6, 2023. Written by ASHP.

Introduction

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

Uses for Pitolisant

Narcolepsy

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

Pitolisant Dosage and Administration

Administration

Oral Administration

Administer orally once daily in the morning upon awakening.

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

Dosage

Available as pitolisant hydrochloride; dosage expressed in terms of pitolisant. Dosage also has been expressed in terms of the salt; 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.

Adults

Narcolepsy

Oral

Recommended dosage range: 17.8–35.6 mg once daily. 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. During week 3, may increase dosage to maximum of 35.6 mg once daily.

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

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

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

Prescribing Limits

Adults

Narcolepsy

Oral

Maximum, 35.6 mg once daily.

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

Special Populations

Hepatic Impairment

Mild hepatic impairment: Dosage adjustment not required.

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

Severe hepatic impairment: Contraindicated. (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.

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

Geriatric Patients

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

Cautions for Pitolisant

Contraindications

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

Warnings/Precautions

QT-Interval Prolongation

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

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). (See Interactions.)

Patients with hepatic or renal impairment may be at increased risk for QT-interval prolongation because of potentially higher pitolisant concentrations. (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. Teratogenicity, embryofetal toxicity, and adverse developmental effects observed in animal studies.

Pregnancy registry at 800-833-7460.

Pitolisant may reduce efficacy of hormonal contraceptives. (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.

Lactation

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

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.

Pediatric Use

Safety and efficacy not established in pediatric patients. Systemic exposure may be greater in pediatric patients than in adults. (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.

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

Hepatic Impairment

Pitolisant is extensively metabolized in the liver.

Mild hepatic impairment (Child-Pugh class A): Systemic exposure not substantially altered.

Moderate hepatic impairment (Child-Pugh class B): Increased systemic exposure. Dosage adjustment required. (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. (See QT-Interval Prolongation under Cautions.) Appropriately monitor patients with either mild or moderate hepatic impairment, including monitoring for QT-interval prolongation.

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

Renal Impairment

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

Moderate renal impairment (eGFR 30–59 mL/minute per 1.73 m²): Systemic exposure based on total pitolisant concentrations is increased; exposure based on free drug concentrations is similar to that in individuals with normal renal function. Clinical trials in narcolepsy included only a limited number of patients with moderate renal impairment. Dosage adjustment recommended. (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. Clinical trials in narcolepsy included no patients with severe renal impairment. Dosage adjustment recommended. (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. (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.

Pharmacogenomics and Effects of CYP2D6 Polymorphism

Poor CYP2D6 metabolizers: Increased systemic exposure. Dosage adjustment recommended in known poor CYP2D6 metabolizers. (See Absorption: Special Populations, under Pharmacokinetics and also see Dosage under Dosage and Administration.)

Common Adverse Effects

Insomnia, nausea, anxiety.

Drug Interactions

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

Drugs Affecting Hepatic Microsomal Enzymes

Potent CYP2D6 inhibitors: Increased AUC of pitolisant. 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. In patients already receiving a stable pitolisant dosage, reduce pitolisant dosage by one-half when initiating a potent CYP2D6 inhibitor.

Potent CYP3A4 inhibitors: No effect on pharmacokinetics of pitolisant.

Potent CYP3A4 inducers: Decreased AUC of pitolisant. 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. If a potent CYP3A4 inducer is discontinued, reduce pitolisant dosage by one-half.

Drugs Metabolized by Hepatic Microsomal Enzymes

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

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

Drugs that Prolong the QT Interval

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

Specific Drugs

Pitolisant Pharmacokinetics

Absorption

Bioavailability

Oral bioavailability is approximately 90%.

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

Food

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

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. (See Interactions.)

Mild hepatic impairment (Child-Pugh class A): Systemic exposure not substantially altered.

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

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.

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.

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.

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.

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.

Distribution

Extent

Not known whether pitolisant distributes into human milk.

Plasma Protein Binding

Approximately 91–96% bound to serum proteins.

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. None of these metabolites are pharmacologically active.

Elimination Route

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

Half-life

Median half-life is approximately 20 hours.

Special Populations

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

Stability

Storage

Oral

Tablets

20–25°C (may be exposed to 15–30°C).

Actions

• Selective competitive antagonist and inverse agonist at the histamine H₃ receptor. 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).

• 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. 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.

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

• 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.

• Appears to have minimal potential for abuse.

Advice to Patients

• Advise patients to consult their clinician immediately if they feel faint, lose consciousness, or have heart palpitations. Importance of patients informing clinicians that they are taking pitolisant before initiating therapy with any new drug.

• 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.

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

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

• Importance of informing patients of other important precautionary information. (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.

Reload page with references included

Frequently asked questions

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

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