Dosage Forms
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Tablet, Oral, as hydrochloride:
Wakix: 4.45 mg, 17.8 mg
Pharmacology
Mechanism of Action
The mechanism of action of pitolisant is unclear, but may be mediated through its activity as an antagonist/inverse agonist at histamine-3 receptors.
Pharmacokinetics/Pharmacodynamics
Absorption
~90%
Distribution
Vd: 700 L (5 to 10 L/kg)
Metabolism
Metabolized by CYP2D6 and to a lesser extent by CYP3A4 to inactive metabolites
Excretion
Urine: ~90% (<2% as unchanged drug); feces: 2.3%
Onset of Action
In the treatment of narcolepsy, it may take up to 8 weeks for patients to achieve a clinical response.
Time to Peak
Tmax: 3.5 hours (2 to 5 hours)
Half-Life Elimination
~20 hours (7.5 to 24.2 hours)
Protein Binding
91% to 96%
Use in Specific Populations
Special Populations Note
The AUC in CYP2D6 poor metabolizers is 2.4 times higher than in normal metabolizers.
Use: Labeled Indications
Narcolepsy: To improve wakefulness in adult patients with excessive daytime sleepiness associated with narcolepsy
Contraindications
Severe hepatic impairment
Dosage and Administration
Dosing: Adult
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: 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 with strong CYP3A4 inducers or strong CYP2D6 inhibitors:
Strong CYP3A4 inducer (eg, rifampin, carbamazepine, phenytoin):
If on a stable pitolisant dose and initiating strong CYP3A4 inducer: Increase pitolisant dose to double the original dose over 7 days (ie, from 8.9 mg once daily to 17.8 mg once daily, or from 17.8 mg once daily to 35.6 mg once daily). Assess for loss of pitolisant efficacy when initiating a strong CYP3A4 inducer.
If discontinuing strong CYPA4 inducer: Reduce pitolisant dose by 50%.
Strong CYP2D6 inhibitor (eg, paroxetine, fluoxetine, bupropion):
If currently on a strong CYP2D6 inhibitor and initiating pitolisant: Initial: 8.9 mg once daily for 1 week, then increase to 17.8 mg once daily (maximum dose: 17.8 mg/day).
If on a stable pitolisant dose and initiating strong CYP2D6 inhibitor: Reduce pitolisant dose by 50%.
Dosing: Geriatric
Refer to adult dosing.
Administration
Oral: Administer once daily upon awakening.
Storage
Store at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C to 30°C (59°F to 86°F).
Drug Interactions
Antihistamines: May diminish the therapeutic effect of Pitolisant. Avoid combination
CYP2D6 Inhibitors (Moderate): May increase the serum concentration of Pitolisant. 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. Consider therapy modification
CYP3A4 Inducers (Moderate): May decrease the serum concentration of Pitolisant. Monitor therapy
CYP3A4 Inducers (Strong): May decrease the serum concentration of Pitolisant. Management: For patients who are stable on pitolisant doses of 8.9 mg or 17.8 mg/day and who are also taking a strong CYP3A4 inducer, increase the pitolisant dose over 7 days to double the original dose (ie, to either 17.8 mg/day or 35.6 mg/day, respectively). Consider therapy modification
Haloperidol: QT-prolonging Agents (Indeterminate Risk - Avoid) may enhance the QTc-prolonging effect of Haloperidol. 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. Consider therapy modification
Mirtazapine: May diminish the therapeutic effect of Pitolisant. 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. Monitor therapy
Tricyclic Antidepressants: May diminish the therapeutic effect of Pitolisant. Avoid combination
Adverse Reactions
>10%: Central nervous system: Headache (18%)
1% to 10%:
Cardiovascular: Increased heart rate (3%)
Central nervous system: Insomnia (6%), anxiety (5%), hallucination (3%), irritability (3%), sleep disturbance (3%), cataplexy (2%)
Dermatologic: Skin rash (2%)
Gastrointestinal: Nausea (6%), abdominal pain (3%), decreased appetite (3%), xerostomia (2%)
Neuromuscular & skeletal: Musculoskeletal pain (5%)
Respiratory: Upper respiratory tract infection (5%)
Frequency not defined:
Cardiovascular: Prolonged QT interval on ECG, tachycardia
Central nervous system: Migraine, sleep paralysis, sleep talking
Postmarketing: Abnormal behavior, abnormal dreams, bipolar mood disorder, depressed mood, depression, epilepsy, fatigue, lack of emotion (anhedonia), nightmares, pruritus, sleep disorder, suicidal ideation, suicidal tendencies, weight gain
Warnings/Precautions
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).
Concurrent drug therapy issues:
- Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.
Monitoring Parameters
Renal and hepatic function (at baseline and as clinically indicated)
Pregnancy
Pregnancy Considerations
Adverse events were observed in some animal reproduction studies.
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.
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).
Patient Education
What is this drug used for?
- It is used to treat a lot of sleepiness during the day in patients with narcolepsy.
Frequently reported side effects of this drug
- Headache
- Trouble sleeping
- Nausea
- Anxiety
- Common cold symptoms
- Muscle pain
Other side effects of this drug: Talk with your doctor right away if you have any of these signs of:
- Fast heartbeat
- Abnormal heartbeat
- Passing out
- Signs of a significant reaction like wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat.
Note: This is not a comprehensive list of all side effects. Talk to your doctor if you have questions.
Consumer Information Use and Disclaimer: This information should not be used to decide whether or not to take this medicine or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about this medicine. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not specific medical advice and does not replace information you receive from the healthcare provider. You must talk with the healthcare provider for complete information about the risks and benefits of using this medicine.
