Note: International considerations: Tablet strengths are listed as 4.5 mg and 18 mg in international product labeling, whereas US products are listed as 4.45 mg and 17.8 mg.
Narcolepsy (excessive daytime sleepiness/cataplexy): Oral: Initial: 8.9 mg once daily for 1 week, then increase to 17.8 mg once daily for 1 week; may further increase dose based on response and tolerability during week 3 to a maximum dose of 35.6 mg once daily.
Missed dose: If morning dose is missed, administer the next dose the following morning upon awakening.
Dosage adjustment for known CYP2D6 poor metabolizers: Initial (treatment-naïve): 8.9 mg once daily; may further increase dose based on response and tolerability after 1 week to a maximum dose of 17.8 mg once daily.
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
eGFR ≥60 mL/minute/1.73 m2: There are no dosage adjustments provided in the manufacturer's labeling.
eGFR 15 to <60 mL/minute/1.73 m2: Initial: 8.9 mg once daily for 1 week, then increase to a maximum dose of 17.8 mg once daily.
eGFR <15 mL/minute/1.73 m2 (end-stage renal disease): Use is not recommended.
Mild hepatic impairment (Child-Pugh class A): No dosage adjustment necessary.
Moderate hepatic impairment (Child-Pugh class B): Initial: 8.9 mg once daily for 2 weeks, then increase to a maximum dose of 17.8 mg once daily.
Severe hepatic impairment (Child-Pugh class C): Use is contraindicated; has not been studied.
Refer to adult dosing.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Tablet, Oral, as hydrochloride:
Wakix: 4.45 mg, 17.8 mg
No
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Tablet, Oral:
Wakix: 5 mg, 20 mg
Oral: Administer once daily upon awakening.
Narcolepsy: Treatment of cataplexy or excessive daytime sleepiness in adults with narcolepsy.
Pitolisant may be confused with Pitocin
Wakix may be confused with Lasix
Pitolisant may be confused with Pitogin brand name for oxytocin [Indonesia].
Wakix: Brand name for pitolisant [US] may be confused with Walix brand name for oxaprozin [Italy] or Warix brand name for podofilox [Switzerland].
The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified.
>10%: Nervous system: Headache (18%)
1% to 10%:
Cardiovascular: Increased heart rate (3%)
Dermatologic: Skin rash (2%)
Gastrointestinal: Abdominal pain (3%), decreased appetite (3%), nausea (6%), xerostomia (2%)
Nervous system: Anxiety (5%), cataplexy (2%), hallucination (3%), insomnia (6%), irritability (3%), sleep disturbance (3%)
Neuromuscular & skeletal: Musculoskeletal pain (5%)
Respiratory: Upper respiratory tract infection (5%)
Frequency not defined:
Cardiovascular: Prolonged QT interval on ECG, tachycardia
Nervous system: Migraine, sleep paralysis, sleep talking
Postmarketing:
Dermatologic: Pruritus
Endocrine & metabolic: Weight gain
Hypersensitivity: Anaphylaxis, hypersensitivity reaction
Nervous system: Abnormal behavior, abnormal dreams, bipolar mood disorder, depressed mood, depression, epilepsy, fatigue, lack of emotion (anhedonia), nightmares, sleep disorder, suicidal ideation, suicidal tendencies
Hypersensitivity to pitolisant or any component of the formulation; severe hepatic impairment.
Canadian labeling: Additional contraindications (not in the US labeling): Breastfeeding.
Concerns related to adverse effects:
• Cardiovascular: May prolong the QT interval; avoid use in patients with known QT prolongation or concomitant use with other agents known to prolong the QT interval. Risk may be greater in patients with hepatic or renal impairment. Avoid use in patients with a known history of cardiac arrhythmias or circumstances that may increase the risk of torsades de pointes or sudden death (eg, symptomatic bradycardia, hypokalemia, hypomagnesemia, congenital prolongation of the QT interval).
Disease-related concerns:
• Hepatic impairment: Use with caution in patients with hepatic impairment; may require dose adjustment. Use is contraindicated in severe hepatic impairment (Child-Pugh class C).
• Renal impairment: Use with caution in patients with renal impairment; dose adjustment required. Use is not recommended in patients with end-stage renal disease (eGFR <15 mL/minute/1.73 m2).
Substrate of CYP2D6 (major), CYP3A4 (major); Note: Assignment of Major/Minor substrate status based on clinically relevant drug interaction potential
Ajmaline: May increase the serum concentration of CYP2D6 Substrates (High risk with Inhibitors). Risk C: Monitor therapy
Antihistamines: May diminish the therapeutic effect of Pitolisant. Risk X: Avoid combination
Artemether and Lumefantrine: May increase the serum concentration of CYP2D6 Substrates (High risk with Inhibitors). Risk C: Monitor therapy
CYP2D6 Inhibitors (Moderate): May increase the serum concentration of Pitolisant. Risk C: Monitor therapy
CYP2D6 Inhibitors (Strong): May increase the serum concentration of Pitolisant. Management: Reduce the pitolisant dose by 50% if a strong CYP2D6 inhibitor is initiated. For patients receiving strong CYP2D6 inhibitors, initiate pitolisant at 8.9 mg once daily and increase after 7 days to a maximum of 17.8 mg once daily. Risk D: Consider therapy modification
CYP3A4 Inducers (Strong): May decrease the serum concentration of Pitolisant. Management: If on a stable pitolisant dose of 8.9 mg or 17.8 mg/day and starting a strong CYP3A4 inducer, double the pitolisant dose over 7 days (ie, to either 17.8 mg/day or 35.6 mg/day, respectively). Reduce pitolisant dose by 50% when the inducer is discontinued. Risk D: Consider therapy modification
Erdafitinib: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Risk C: Monitor therapy
Haloperidol: QT-prolonging Agents (Indeterminate Risk - Avoid) may enhance the QTc-prolonging effect of Haloperidol. Risk C: Monitor therapy
Hormonal Contraceptives: Pitolisant may decrease the serum concentration of Hormonal Contraceptives. Management: Patients using hormonal contraception should be advised to use an alternative non-hormonal contraceptive method during treatment with pitolisant and for at least 21 days after discontinuation of pitolisant treatment. Risk D: Consider therapy modification
Ivosidenib: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Risk C: Monitor therapy
Levoketoconazole: QT-prolonging Agents (Indeterminate Risk - Avoid) may enhance the QTc-prolonging effect of Levoketoconazole. Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor therapy
Mirtazapine: May diminish the therapeutic effect of Pitolisant. Risk X: Avoid combination
Peginterferon Alfa-2b: May decrease the serum concentration of CYP2D6 Substrates (High risk with Inhibitors). Peginterferon Alfa-2b may increase the serum concentration of CYP2D6 Substrates (High risk with Inhibitors). Risk C: Monitor therapy
Promethazine: May diminish the therapeutic effect of Pitolisant. Risk X: Avoid combination
QT-prolonging Agents (Highest Risk): QT-prolonging Agents (Indeterminate Risk - Avoid) may enhance the QTc-prolonging effect of QT-prolonging Agents (Highest Risk). Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor therapy
Tricyclic Antidepressants: May diminish the therapeutic effect of Pitolisant. Risk X: Avoid combination
Pitolisant may reduce the effectiveness of hormonal contraceptives. Females of reproductive potential should be advised to use an alternative nonhormonal contraceptive method during treatment and for ≥21 days after the last dose of pitolisant.
Adverse events were observed in some animal reproduction studies.
Data collection to monitor pregnancy and infant outcomes following exposure to pitolisant is ongoing. Patients exposed to pitolisant during pregnancy are encouraged to enroll in the Pregnancy Registry (1-800-833-7460).
It is not known if pitolisant is present in breast milk
According to the manufacturer, the decision to breastfeed during therapy should consider the risk of infant exposure, the benefits of breastfeeding to the infant, and benefits of treatment to the mother.
Renal and hepatic function (at baseline and as clinically indicated)
The mechanism of action of pitolisant is unclear, but may be mediated through its activity as an antagonist/inverse agonist at histamine-3 receptors.
Onset: In the treatment of narcolepsy, it may take up to 8 weeks for patients to achieve a clinical response.
Absorption: ~90%
Distribution: Vd: 700 L (5 to 10 L/kg)
Protein binding: 91% to 96%
Metabolism: Metabolized by CYP2D6 and to a lesser extent by CYP3A4 to inactive metabolites
Half-life elimination: ~20 hours (7.5 to 24.2 hours)
Time to peak: Tmax: 3.5 hours (2 to 5 hours)
Excretion: Urine: ~90% (<2% as unchanged drug); feces: 2.3%
Tablets (Wakix Oral)
4.45 mg (per each): $136.10
17.8 mg (per each): $272.20
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