Pitolisant is an oral histamine-3 (H3) receptor antagonist/inverse agonist, the first in its class. Pitolisant is indicated for the treatment of excessive daytime sleepiness (EDS) or cataplexy in adult patients with narcolepsy. The efficacy of pitolisant for the treatment of EDS was established in 2 placebo-controlled, active control trials of 8 weeks duration. In both trials, pitolisant-treated patients had significantly improved EDS during activities of daily living as measured using the least-squares mean final Epworth Sleepiness Scale (ESS) vs. ESS scores for patients receiving placebo. During studies for cataplexy, treated patients had a significant change in the geometric mean number of cataplexy attacks per week from baseline vs. placebo. The drug may cause QT prolongation and it is contraindicated in patients with severe hepatic impairment.
General Administration Information
For storage information, see the specific product information within the How Supplied section.
Route-Specific Administration
Oral Administration
-Administer each dose in the morning upon patient wakening.
-If a dose is missed, skip the missed dose and administer the next dose the following day in the morning upon wakening.
In placebo-controlled trials of pitolisant in patients with narcolepsy with and without cataplexy, nausea was a common adverse reaction that occurred in 6% of pitolisant-treated patients compared to 3% of placebo-treated patients. Other gastrointestinal adverse reactions that occurred more frequently with pitolisant treatment than placebo treatment include abdominal pain including abdominal discomfort (3%), decreased appetite (3%), and xerostomia (2%). Weight gain has been observed during postmarketing experience.
The In placebo-controlled trials of pitolisant in patients with narcolepsy with and without cataplexy, insomnia (inclusive of initial and middle insomnia, insomnia, and poor quality sleep) was a common adverse reaction that occurred in 6% of pitolisant-treated patients compared to 2% of placebo-treated patients. Anxiety (inclusive of nervousness, stress, stress at work, and anxiety) occurred in 5% of pitolisant-treated patients compared to 1% of placebo-treated patients. Hallucinations (inclusive of visual hallucination, hypnagogic hallucination, and hallucinations) occurred in 3% of pitolisant-treated patients compared to no placebo-treated patients. Sleep disturbances (inclusive of dyssomnia, sleep disorder, sleep paralysis, and sleep talking) occurred in 3% of pitolisant-treated patients compared to 2% of placebo-treated patients. Other adverse reactions that occurred more frequently with pitolisant treatment than placebo treatment include irritability (3%) and cataplexy (2%). Abnormal behavior, abnormal dreams, anhedonia, bipolar disorder, depression, depressed mood, nightmares, unspecified sleep disorder, suicide attempt, and suicidal ideation have been observed during postmarketing experience.
In placebo-controlled trials of pitolisant in patients with narcolepsy with and without cataplexy, headache was a common adverse reaction that occurred in 18% of pitolisant-treated patients compared to 15% of placebo-treated patients. Cluster headache, migraine, headache, premenstrual headache, and tension headaches were observed. Epilepsy and seizures have been observed during postmarketing experience.
In placebo-controlled trials of pitolisant in patients with narcolepsy with and without cataplexy, musculoskeletal pain (inclusive of arthralgia, back pain, carpal tunnel syndrome, limb discomfort, myalgia, neck pain, osteoarthritis, musculoskeletal pain, extremity pain, and sciatica) occurred in 5% of pitolisant-treated patients and at incidences higher than with placebo.
Increases in heart rate and sinus tachycardia were observed during placebo-controlled clinical trials in 5% of pitolisant-treated patients. Pitolisant prolongs the QT interval. A QTc increase of 4.2 msec occurred at the highest recommended dosage of pitolisant (35.6 mg daily). Exposures 3.8-fold higher than that achieved at the highest recommended dose increased mean QTc 16 msec. Avoid the use of pitolisant in patients with conditions that may increase the risk of QT prolongation, such as known congenital long QT syndrome or a history of cardiac arrhythmias, as well as other circumstances that may increase the risk of the occurrence of torsade de pointes or sudden death. The risk of QT prolongation may be greater in patients with renal or hepatic impairment due to a decrease in drug elimination with a subsequent increase in drug exposure.
In placebo-controlled trials of pitolisant in patients with narcolepsy with and without cataplexy, upper respiratory tract infections, (inclusive of pharyngitis, rhinitis, sinusitis, upper respiratory tract inflammation, upper respiratory tract infection, and viral upper respiratory tract infection) occurred in 5% of pitolisant-treated patients and at rates higher than with placebo.
In placebo-controlled trials of pitolisant in patients with narcolepsy with and without cataplexy, rash (inclusive of eczema or atopic dermatitis, rash, erythema migrans, and urticaria) occurred in 2% of pitolisant-treated patients and at incidence rates higher than with placebo. Hypersensitivity (anaphylaxis, anaphylactoid reactions) and pruritus have been observed during postmarketing experience.
Fatigue has been observed during postmarketing experience with pitolisant.
Pitolisant is contraindicated in patients with known hypersensitivity to pitolisant or any component of the formulation. Anaphylaxis has been reported with use of the drug.
Pitolisant is contraindicated in patients with severe hepatic impairment (Child-Pugh C). Pitolisant has not been studied in this population. Pitolisant is extensively metabolized by the liver, and a significant increase in drug exposure occurs in patients with moderate hepatic disease (Child-Pugh B). Specific dosage adjustments are available for patients with moderate hepatic impairment. Monitor hepatic function in patients and adjust the dosage as necessary. No dosage adjustment is recommended in patients with mild hepatic impairment (Child-Pugh A). Dosage reduction is recommended in patients known to be CYP2D6 poor metabolizers (CYP2D6 PMs) because these patients have higher pitolisant concentrations than normal CYP2D6 metabolizers.
Pitolisant use is not recommended in patients with end-stage renal disease (i.e., renal failure; eGFR less than 15 mL/minute/1.73 m2), as pitolisant has not been studied in this population. Specific dosage adjustments are available for patients with moderate (eGFR 30 to 59 mL/minute/1.73 m2) or severe renal impairment (eGFR 15 to 29 mL/minute/1.73 m2). No dosage adjustment is needed for patients with mild renal impairment.
Pitolisant prolongs the QT interval. Avoid the use of pitolisant in patients with known QT prolongation, receiving medications known to prolong the QT interval, with a history of cardiac arrhythmias, or who have other conditions that may increase the risk of the occurrence of torsade de pointes or sudden death (including symptomatic bradycardia, hypokalemia or hypomagnesemia, and the presence of congenital prolongation of the QT interval such as congenital long QT syndrome). Use pitolisant with caution in patients with conditions that may increase the risk of QT prolongation including bradycardia, AV block, heart failure, stress-related cardiomyopathy, myocardial infarction, stroke, hypocalcemia, or in patients receiving medications known to cause electrolyte imbalances. Females, geriatric patients, patients with sleep deprivation, pheochromocytoma, sickle cell disease, hypothyroidism, hyperparathyroidism, hypothermia, systemic inflammation (e.g., human immunodeficiency virus (HIV) infection, fever, and some autoimmune diseases including rheumatoid arthritis, systemic lupus erythematosus (SLE), and celiac disease) and patients undergoing apheresis procedures (e.g., plasmapheresis [plasma exchange], cytapheresis) may also be at increased risk for QT prolongation. The risk of QT prolongation may be greater in patients with renal or hepatic impairment due to a decrease in drug elimination with a subsequent increase in drug exposure. A QTc increase of 4.2 milliseconds occurred at the highest recommended dosage of pitolisant (35.6 mg daily). Exposures 3.8-fold higher than that achieved at the highest recommended dose increased mean QTc 16 milliseconds.
There are no adequate data on the developmental risk associated with pitolisant use during human pregnancy. Available case reports from clinical trials and postmarketing reports with pitolisant 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 or greater and 4 times or greater the maximum recommended human dose (MRHD) of 35.6 mg based on mg/square meter body surface area, respectively. The no observed adverse effect dose for maternal toxicity and embryofetal development were 2 and 4 times the MRHD based on body surface area, respectively. There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to pitolisant during pregnancy. To enroll or obtain information, patients can call 1-800-833-7460. The effects of pitolisant during labor and obstetric delivery are unknown.
Contraception requirements are suggested for pitolisant. Pitolisant may reduce the effectiveness of hormonal contraceptives. Female 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 discontinuing treatment.
Use pitolisant with caution during lactation; 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 breastfed infant from pitolisant or the underlying maternal condition. Pitolisant was found to pass into breast milk at low levels in an open-label study of 8 healthy lactating women who were 11 to 96 weeks postpartum. The concentration of pitolisant was evaluated in breast milk samples collected over 24 hours and serum samples were collected over 120 hours after a single dose of 35.6 mg of pitolisant was administered. Approximately 50% of the amount of pitolisant measured in breast milk occurred during the first 4 hours post dose. Based on the study, the mean infant dose was 0.009 mg/day, less than 1% of the maternal weight-adjusted dose. There are no data on the effects of pitolisant on the breastfed infant or the effect of pitolisant on milk production.
The safety and efficacy of pitolisant in infants, children, and adolescents have not been established.
For the treatment of excessive daytime sleepiness or cataplexy in patients with narcolepsy:
Oral dosage:
Adults: Initially, 8.9 mg PO once daily in the morning upon awakening for 1 week. Then, increase dosage to 17.8 mg PO once daily for 1 week. After that, the dose may be adjusted based on efficacy response and tolerability. Max: 35.6 mg/day PO; limit to 17.8 mg/day PO in CYP2D6 poor metabolizers. Up to 8 weeks may be necessary for clinical response. ADJUSTMENTS: Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.
Maximum Dosage Limits:
-Adults
35.6 mg/day PO.
-Geriatric
35.6 mg/day PO.
-Adolescents
Safety and efficacy have not been established.
-Children
Safety and efficacy have not been established.
-Infants
Safety and efficacy have not been established.
Patients with Hepatic Impairment Dosing
Mild hepatic impairment (Child-Pugh A): No dosage adjustment needed. Monitor hepatic function.
Moderate hepatic impairment (Child-Pugh B): Initially, 8.9 mg once daily. Increase after 2 weeks to a maximum of 17.8 mg once daily. Monitor hepatic function.
Severe hepatic impairment (Child-Pugh C): Use is contraindicated.
Patients with Renal Impairment Dosing
eGFR 60 mL/minute/1.73 m2 or more (Mild renal impairment): No dose adjustment needed.
eGFR 15 to 59 mL/minute/1.73 m2 (Moderate to Severe renal impairment): 8.9 mg PO once daily initially, then increase dose after 1 week to a maximum of 17.8 mg PO once daily.
eGFR less than 15 mL/minute/1.73 m2: Use is not recommended in end-stage renal disease (ESRD); no studies are available in these patients.
*non-FDA-approved indication
Acetaminophen; Aspirin; Diphenhydramine: (Major) Avoid coadministration of pitolisant with diphenhydramine as the effect of pitolisant may be decreased. Pitolisant increases histamine concentrations in the brain; therefore, H1-receptor antagonists like diphenhydramine, may reduce pitolisant efficacy.
Acetaminophen; Caffeine; Pyrilamine: (Major) Avoid coadministration of pitolisant with pyrilamine as the effect of pitolisant may be decreased. Pitolisant increases histamine concentrations in the brain; therefore, H1-receptor antagonists like pyrilamine, may reduce pitolisant efficacy.
Acetaminophen; Chlorpheniramine: (Major) Avoid coadministration of pitolisant with chlorpheniramine as the effect of pitolisant may be decreased. Pitolisant increases histamine concentrations in the brain; therefore, H1-receptor antagonists like chlorpheniramine, may reduce pitolisant efficacy.
Acetaminophen; Chlorpheniramine; Dextromethorphan: (Major) Avoid coadministration of pitolisant with chlorpheniramine as the effect of pitolisant may be decreased. Pitolisant increases histamine concentrations in the brain; therefore, H1-receptor antagonists like chlorpheniramine, may reduce pitolisant efficacy.
Acetaminophen; Chlorpheniramine; Dextromethorphan; Phenylephrine: (Major) Avoid coadministration of pitolisant with chlorpheniramine as the effect of pitolisant may be decreased. Pitolisant increases histamine concentrations in the brain; therefore, H1-receptor antagonists like chlorpheniramine, may reduce pitolisant efficacy.
Acetaminophen; Chlorpheniramine; Dextromethorphan; Pseudoephedrine: (Major) Avoid coadministration of pitolisant with chlorpheniramine as the effect of pitolisant may be decreased. Pitolisant increases histamine concentrations in the brain; therefore, H1-receptor antagonists like chlorpheniramine, may reduce pitolisant efficacy.
Acetaminophen; Chlorpheniramine; Phenylephrine : (Major) Avoid coadministration of pitolisant with chlorpheniramine as the effect of pitolisant may be decreased. Pitolisant increases histamine concentrations in the brain; therefore, H1-receptor antagonists like chlorpheniramine, may reduce pitolisant efficacy.
Acetaminophen; Dextromethorphan; Doxylamine: (Major) Avoid coadministration of pitolisant with doxylamine as the effect of pitolisant may be decreased. Pitolisant increases histamine concentrations in the brain; therefore, H1-receptor antagonists like doxylamine, may reduce pitolisant efficacy.
Acetaminophen; Diphenhydramine: (Major) Avoid coadministration of pitolisant with diphenhydramine as the effect of pitolisant may be decreased. Pitolisant increases histamine concentrations in the brain; therefore, H1-receptor antagonists like diphenhydramine, may reduce pitolisant efficacy.
Acetaminophen; Pamabrom; Pyrilamine: (Major) Avoid coadministration of pitolisant with pyrilamine as the effect of pitolisant may be decreased. Pitolisant increases histamine concentrations in the brain; therefore, H1-receptor antagonists like pyrilamine, may reduce pitolisant efficacy.
Acrivastine; Pseudoephedrine: (Major) Avoid coadministration of pitolisant with acrivastine as the effect of pitolisant may be decreased. Pitolisant increases histamine concentrations in the brain; therefore, H1-receptor antagonists like acrivastine, may reduce pitolisant efficacy.
Adagrasib: (Major) Concomitant use of adagrasib and pitolisant increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Alfuzosin: (Major) Avoid coadministration of pitolisant with alfuzosin as concurrent use may increase the risk of QT prolongation. Pitolisant prolongs the QT interval. Alfuzosin may prolong the QT interval in a dose-dependent manner.
Amiodarone: (Major) Concomitant use of amiodarone and pitolisant increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. Due to the extremely long half-life of amiodarone, a drug interaction is possible for days to weeks after drug discontinuation.
Amisulpride: (Major) Avoid coadministration of pitolisant with amisulpride as concurrent use may increase the risk of QT prolongation. If concomitant therapy is unavoidable, monitor ECGs. Amisulpride causes dose- and concentration- dependent QT prolongation.
Amitriptyline: (Major) Avoid coadministration of pitolisant with tricyclic antidepressants (TCAs) as the effect of pitolisant may be decreased; concurrent use may also increase the risk of QT prolongation. Pitolisant increases histamine concentrations in the brain; therefore, H1-receptor antagonists like TCAs, may reduce pitolisant efficacy. Pitolisant prolongs the QT interval. TCAs share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations).
Amoxicillin; Clarithromycin; Omeprazole: (Major) Avoid coadministration of pitolisant with clarithromycin as concurrent use may increase the risk of QT prolongation. Pitolisant prolongs the QT interval. Clarithromycin is associated with an established risk for QT prolongation and torsade de pointes (TdP).
Anagrelide: (Major) Avoid coadministration of pitolisant with anagrelide as concurrent use may increase the risk of QT prolongation. Pitolisant prolongs the QT interval. Torsade de pointes (TdP) and ventricular tachycardia have been reported with anagrelide. In addition, dose-related increases in mean QTc and heart rate were observed in healthy subjects.
Apalutamide: (Major) Monitor for loss of pitolisant efficacy after initiation of apalutamide. Increase to double the original daily dose of pitolisant over 7 days in patients stable on 8.9 mg or 17.8 mg once daily (i.e., 17.8 mg or 35.6 mg, respectively). Decrease the pitolisant dose by half if apalutamide is discontinued. Pitolisant is a CYP3A4 substrate; apalutamide is a strong CYP3A4 inducer. Coadministration of strong CYP3A4 inducers decreases pitolisant exposure by 50%.
Apomorphine: (Major) Avoid coadministration of pitolisant with apomorphine since concurrent use may increase the risk of QT prolongation. Pitolisant prolongs the QT interval. Dose-related QTc prolongation is associated with therapeutic apomorphine exposure.
Aripiprazole: (Major) Concomitant use of pitolisant and aripiprazole increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Arsenic Trioxide: (Major) Avoid coadministration of pitolisant with arsenic trioxide as concurrent use may increase the risk of QT prolongation. If concomitant drug use is unavoidable, frequently monitor electrocardiograms. Pitolisant prolongs the QT interval. Torsade de pointes (TdP), QT interval prolongation, and complete atrioventricular block have been reported with arsenic trioxide use.
Artemether; Lumefantrine: (Major) Avoid coadministration of pitolisant with artemether; lumefantrine as concurrent use may increase the risk of QT prolongation. Consider ECG monitoring if pitolisant must be used with or after artemether; lumefantrine treatment. Pitolisant prolongs the QT interval. Artemether; lumefantrine is associated with prolongation of the QT interval.
Asenapine: (Major) Avoid coadministration of pitolisant with asenapine as concurrent use may increase the risk of QT prolongation. Pitolisant prolongs the QT interval. Asenapine has been associated with QT prolongation.
Atogepant: (Major) Avoid use of atogepant and pitolisant when atogepant is used for chronic migraine. Use an atogepant dose of 30 or 60 mg PO once daily for episodic migraine if coadministered with pitolisant. Concurrent use may decrease atogepant exposure and reduce efficacy. Atogepant is a CYP3A substrate and pitolisant is a weak CYP3A inducer. Coadministration with a weak CYP3A inducer resulted in a 25% reduction in atogepant overall exposure and a 24% reduction in atogepant peak concentration.
Atomoxetine: (Major) Concomitant use of pitolisant and atomoxetine increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Azelastine: (Major) Avoid coadministration of pitolisant with azelastine as the effect of pitolisant may be decreased. Pitolisant increases histamine concentrations in the brain; therefore, H1-receptor antagonists like azelastine, may reduce pitolisant efficacy.
Azelastine; Fluticasone: (Major) Avoid coadministration of pitolisant with azelastine as the effect of pitolisant may be decreased. Pitolisant increases histamine concentrations in the brain; therefore, H1-receptor antagonists like azelastine, may reduce pitolisant efficacy.
Azithromycin: (Major) Concomitant use of pitolisant and azithromycin increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Bedaquiline: (Major) Avoid coadministration of pitolisant with bedaquiline as concurrent use may increase the risk of QT prolongation. Monitor ECGs if coadministration is necessary. Discontinue bedaquiline if evidence of serious ventricular arrhythmia or QTcF interval greater than 500 ms. Both bedaquiline and pitolisant prolong the QT interval.
Bismuth Subcitrate Potassium; Metronidazole; Tetracycline: (Major) Concomitant use of metronidazole and pitolisant increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Bismuth Subsalicylate; Metronidazole; Tetracycline: (Major) Concomitant use of metronidazole and pitolisant increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Brompheniramine: (Major) Avoid coadministration of pitolisant with brompheniramine as the effect of pitolisant may be decreased. Pitolisant increases histamine concentrations in the brain; therefore, H1-receptor antagonists like brompheniramine, may reduce pitolisant efficacy.
Brompheniramine; Dextromethorphan; Phenylephrine: (Major) Avoid coadministration of pitolisant with brompheniramine as the effect of pitolisant may be decreased. Pitolisant increases histamine concentrations in the brain; therefore, H1-receptor antagonists like brompheniramine, may reduce pitolisant efficacy.
Brompheniramine; Phenylephrine: (Major) Avoid coadministration of pitolisant with brompheniramine as the effect of pitolisant may be decreased. Pitolisant increases histamine concentrations in the brain; therefore, H1-receptor antagonists like brompheniramine, may reduce pitolisant efficacy.
Brompheniramine; Pseudoephedrine: (Major) Avoid coadministration of pitolisant with brompheniramine as the effect of pitolisant may be decreased. Pitolisant increases histamine concentrations in the brain; therefore, H1-receptor antagonists like brompheniramine, may reduce pitolisant efficacy.
Brompheniramine; Pseudoephedrine; Dextromethorphan: (Major) Avoid coadministration of pitolisant with brompheniramine as the effect of pitolisant may be decreased. Pitolisant increases histamine concentrations in the brain; therefore, H1-receptor antagonists like brompheniramine, may reduce pitolisant efficacy.
Buprenorphine: (Major) Concomitant use of pitolisant and buprenophine increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Buprenorphine; Naloxone: (Major) Concomitant use of pitolisant and buprenophine increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Bupropion: (Major) Initiate pitolisant at 8.9 mg once daily in patients taking bupropion; increase pitolisant after 7 days to a maximum dosage of 17.8 mg once daily. If bupropion is initiated in a patient on a stable dose of pitolisant, reduce the pitolisant dose by half. Pitolisant is a CYP2D6 substrate; bupropion is a strong CYP2D6 inhibitor. Coadministration of strong CYP2D6 inhibitors increases pitolisant exposure by 2.2-fold.
Bupropion; Naltrexone: (Major) Initiate pitolisant at 8.9 mg once daily in patients taking bupropion; increase pitolisant after 7 days to a maximum dosage of 17.8 mg once daily. If bupropion is initiated in a patient on a stable dose of pitolisant, reduce the pitolisant dose by half. Pitolisant is a CYP2D6 substrate; bupropion is a strong CYP2D6 inhibitor. Coadministration of strong CYP2D6 inhibitors increases pitolisant exposure by 2.2-fold.
Cabotegravir; Rilpivirine: (Major) Avoid coadministration of pitolisant with rilpivirine as concurrent use may increase the risk of QT prolongation. Pitolisant prolongs the QT interval. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation.
Carbamazepine: (Major) Monitor for loss of pitolisant efficacy after initiation of carbamazepine. Increase to double the original daily dose of pitolisant over 7 days in patients stable on 8.9 mg or 17.8 mg once daily (i.e., 17.8 mg or 35.6 mg, respectively). Decrease the pitolisant dose by half if carbamazepine is discontinued. Pitolisant is a CYP3A4 substrate; carbamazepine is a strong CYP3A4 inducer. Coadministration of strong CYP3A4 inducers decreases pitolisant exposure by 50%.
Carbinoxamine: (Major) Avoid coadministration of pitolisant with carbinoxamine as the effect of pitolisant may be decreased. Pitolisant increases histamine concentrations in the brain; therefore, H1-receptor antagonists like carbinoxamine, may reduce pitolisant efficacy.
Ceritinib: (Major) Avoid coadministration of pitolisant with ceritinib as concurrent use may increase the risk of QT prolongation. If concomitant use is unavoidable, periodically monitor ECGs and electrolytes; an interruption of ceritinib therapy, dose reduction, or discontinuation of therapy may be necessary if QT prolongation occurs. Ceritinib causes concentration-dependent QT prolongation. Pitolisant also prolongs the QT interval.
Chlophedianol; Dexbrompheniramine: (Major) Avoid coadministration of pitolisant with dexbrompheniramine as the effect of pitolisant may be decreased. Pitolisant increases histamine concentrations in the brain; therefore, H1-receptor antagonists like dexbrompheniramine, may reduce pitolisant efficacy.
Chlophedianol; Dexchlorpheniramine; Pseudoephedrine: (Major) Avoid coadministration of pitolisant with dexchlorpheniramine as the effect of pitolisant may be decreased. Pitolisant increases histamine concentrations in the brain; therefore, H1-receptor antagonists like dexchlorpheniramine, may reduce pitolisant efficacy.
Chlorcyclizine: (Major) Avoid coadministration of pitolisant with chlorcyclizine as the effect of pitolisant may be decreased. Pitolisant increases histamine concentrations in the brain; therefore, H1-receptor antagonists like chlorcyclizine, may reduce pitolisant efficacy.
Chlordiazepoxide; Amitriptyline: (Major) Avoid coadministration of pitolisant with tricyclic antidepressants (TCAs) as the effect of pitolisant may be decreased; concurrent use may also increase the risk of QT prolongation. Pitolisant increases histamine concentrations in the brain; therefore, H1-receptor antagonists like TCAs, may reduce pitolisant efficacy. Pitolisant prolongs the QT interval. TCAs share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations).
Chloroquine: (Major) Avoid coadministration of chloroquine with pitolisant due to the increased risk of QT prolongation. If use together is necessary, obtain an ECG at baseline to assess initial QT interval and determine frequency of subsequent ECG monitoring, avoid any non-essential QT prolonging drugs, and correct electrolyte imbalances. Chloroquine is associated with an increased risk of QT prolongation and torsade de pointes (TdP); the risk of QT prolongation is increased with higher chloroquine doses. Pitolisant also prolongs the QT interval.
Chlorpheniramine: (Major) Avoid coadministration of pitolisant with chlorpheniramine as the effect of pitolisant may be decreased. Pitolisant increases histamine concentrations in the brain; therefore, H1-receptor antagonists like chlorpheniramine, may reduce pitolisant efficacy.
Chlorpheniramine; Codeine: (Major) Avoid coadministration of pitolisant with chlorpheniramine as the effect of pitolisant may be decreased. Pitolisant increases histamine concentrations in the brain; therefore, H1-receptor antagonists like chlorpheniramine, may reduce pitolisant efficacy.
Chlorpheniramine; Dextromethorphan: (Major) Avoid coadministration of pitolisant with chlorpheniramine as the effect of pitolisant may be decreased. Pitolisant increases histamine concentrations in the brain; therefore, H1-receptor antagonists like chlorpheniramine, may reduce pitolisant efficacy.
Chlorpheniramine; Dextromethorphan; Phenylephrine: (Major) Avoid coadministration of pitolisant with chlorpheniramine as the effect of pitolisant may be decreased. Pitolisant increases histamine concentrations in the brain; therefore, H1-receptor antagonists like chlorpheniramine, may reduce pitolisant efficacy.
Chlorpheniramine; Dextromethorphan; Pseudoephedrine: (Major) Avoid coadministration of pitolisant with chlorpheniramine as the effect of pitolisant may be decreased. Pitolisant increases histamine concentrations in the brain; therefore, H1-receptor antagonists like chlorpheniramine, may reduce pitolisant efficacy.
Chlorpheniramine; Hydrocodone: (Major) Avoid coadministration of pitolisant with chlorpheniramine as the effect of pitolisant may be decreased. Pitolisant increases histamine concentrations in the brain; therefore, H1-receptor antagonists like chlorpheniramine, may reduce pitolisant efficacy.
Chlorpheniramine; Ibuprofen; Pseudoephedrine: (Major) Avoid coadministration of pitolisant with chlorpheniramine as the effect of pitolisant may be decreased. Pitolisant increases histamine concentrations in the brain; therefore, H1-receptor antagonists like chlorpheniramine, may reduce pitolisant efficacy.
Chlorpheniramine; Phenylephrine: (Major) Avoid coadministration of pitolisant with chlorpheniramine as the effect of pitolisant may be decreased. Pitolisant increases histamine concentrations in the brain; therefore, H1-receptor antagonists like chlorpheniramine, may reduce pitolisant efficacy.
Chlorpheniramine; Pseudoephedrine: (Major) Avoid coadministration of pitolisant with chlorpheniramine as the effect of pitolisant may be decreased. Pitolisant increases histamine concentrations in the brain; therefore, H1-receptor antagonists like chlorpheniramine, may reduce pitolisant efficacy.
Chlorpromazine: (Major) Avoid coadministration of pitolisant with chlorpromazine as concurrent use may increase the risk of QT prolongation. Pitolisant prolongs the QT interval. Chlorpromazine, a phenothiazine, is associated with an established risk of QT prolongation and torsade de pointes (TdP).
Ciprofloxacin: (Major) Concomitant use of pitolisant and ciprofloxacin increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Cisapride: (Contraindicated) Coadministration of cisapride with pitolisant is contraindicated due to the potential for QT prolongation and torsade de pointes (TdP). QT prolongation and ventricular arrhythmias, including TdP and death, have been reported with cisapride. Pitolisant prolongs the QT interval.
Citalopram: (Major) Concomitant use of pitolisant and citalopram increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Clarithromycin: (Major) Avoid coadministration of pitolisant with clarithromycin as concurrent use may increase the risk of QT prolongation. Pitolisant prolongs the QT interval. Clarithromycin is associated with an established risk for QT prolongation and torsade de pointes (TdP).
Clemastine: (Major) Avoid coadministration of pitolisant with clemastine as the effect of pitolisant may be decreased. Pitolisant increases histamine concentrations in the brain; therefore, H1-receptor antagonists like clemastine, may reduce pitolisant efficacy.
Clofazimine: (Major) Concomitant use of clofazimine and pitolisant increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Clomipramine: (Major) Avoid coadministration of pitolisant with tricyclic antidepressants (TCAs) as the effect of pitolisant may be decreased; concurrent use may also increase the risk of QT prolongation. Pitolisant increases histamine concentrations in the brain; therefore, H1-receptor antagonists like TCAs, may reduce pitolisant efficacy. Pitolisant prolongs the QT interval. TCAs share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations).
Clozapine: (Major) Avoid coadministration of pitolisant with clozapine as concurrent use may increase the risk of QT prolongation. Pitolisant prolongs the QT interval. Treatment with clozapine has been associated with QT prolongation, torsade de pointes (TdP), cardiac arrest, and sudden death.
Codeine; Phenylephrine; Promethazine: (Major) Avoid coadministration of pitolisant with promethazine as the effect of pitolisant may be decreased; concurrent use may also increase the risk of QT prolongation. Pitolisant increases histamine concentrations in the brain; therefore, H1-receptor antagonists like promethazine, may reduce pitolisant efficacy. Pitolisant prolongs the QT interval. Promethazine, a phenothiazine, is associated with a possible risk for QT prolongation.
Codeine; Promethazine: (Major) Avoid coadministration of pitolisant with promethazine as the effect of pitolisant may be decreased; concurrent use may also increase the risk of QT prolongation. Pitolisant increases histamine concentrations in the brain; therefore, H1-receptor antagonists like promethazine, may reduce pitolisant efficacy. Pitolisant prolongs the QT interval. Promethazine, a phenothiazine, is associated with a possible risk for QT prolongation.
Crizotinib: (Major) Avoid coadministration of crizotinib with pitolisant due to the risk of QT prolongation. If concomitant use is unavoidable, monitor ECGs for QT prolongation and monitor electrolytes. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib if QT prolongation occurs. Crizotinib can cause concentration-dependent QT prolongation. Pitolisant also prolongs the QT interval.
Cyproheptadine: (Major) Avoid coadministration of pitolisant with cyproheptadine as the effect of pitolisant may be decreased. Pitolisant increases histamine concentrations in the brain; therefore, H1-receptor antagonists like cyproheptadine, may reduce pitolisant efficacy.
Dacomitinib: (Major) Initiate pitolisant at 8.9 mg once daily in patients taking dacomitinib; increase pitolisant after 7 days to a maximum dosage of 17.8 mg once daily. If dacomitinib is initiated in a patient on a stable dose of pitolisant, reduce the pitolisant dose by half. Pitolisant is a CYP2D6 substrate; dacomitinib is a strong CYP2D6 inhibitor. Coadministration of strong CYP2D6 inhibitors increases pitolisant exposure by 2.2-fold.
Dasatinib: (Major) Avoid coadministration of pitolisant with dasatinib as concurrent use may increase the risk of QT prolongation. Pitolisant prolongs the QT interval. In vitro studies have shown that dasatinib has the potential to prolong the QT interval.
Degarelix: (Major) Avoid coadministration of pitolisant with degarelix as concurrent use may increase the risk of QT prolongation. Pitolisant prolongs the QT interval. Androgen deprivation therapy (i.e., degarelix) may prolong the QT/QTc interval.
Desflurane: (Major) Avoid coadministration of pitolisant with halogenated anesthetics as concurrent use may increase the risk of QT prolongation. Pitolisant prolongs the QT interval. Halogenated anesthetics can also prolong the QT interval.
Desipramine: (Major) Avoid coadministration of pitolisant with tricyclic antidepressants (TCAs) as the effect of pitolisant may be decreased; concurrent use may also increase the risk of QT prolongation. Pitolisant increases histamine concentrations in the brain; therefore, H1-receptor antagonists like TCAs, may reduce pitolisant efficacy. Pitolisant prolongs the QT interval. TCAs share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations).
Desogestrel; Ethinyl Estradiol: (Major) Advise patients to use an alternative, non-hormonal contraceptive during and for at least 21 days after discontinuation of pitolisant. Pitolisant is a weak CYP3A4 inducer and may decrease the plasma exposure of hormonal contraceptives resulting in decreased efficacy.
Deutetrabenazine: (Major) Avoid coadministration of pitolisant with deutetrabenazine as concurrent use may increase the risk of QT prolongation. Pitolisant prolongs the QT interval. Deutetrabenazine may prolong the QT interval, but the degree of QT prolongation is not clinically significant when deutetrabenazine is administered within the recommended dosage range.
Dexbrompheniramine: (Major) Avoid coadministration of pitolisant with dexbrompheniramine as the effect of pitolisant may be decreased. Pitolisant increases histamine concentrations in the brain; therefore, H1-receptor antagonists like dexbrompheniramine, may reduce pitolisant efficacy.
Dexbrompheniramine; Pseudoephedrine: (Major) Avoid coadministration of pitolisant with dexbrompheniramine as the effect of pitolisant may be decreased. Pitolisant increases histamine concentrations in the brain; therefore, H1-receptor antagonists like dexbrompheniramine, may reduce pitolisant efficacy.
Dexchlorpheniramine: (Major) Avoid coadministration of pitolisant with dexchlorpheniramine as the effect of pitolisant may be decreased. Pitolisant increases histamine concentrations in the brain; therefore, H1-receptor antagonists like dexchlorpheniramine, may reduce pitolisant efficacy.
Dexchlorpheniramine; Dextromethorphan; Pseudoephedrine: (Major) Avoid coadministration of pitolisant with dexchlorpheniramine as the effect of pitolisant may be decreased. Pitolisant increases histamine concentrations in the brain; therefore, H1-receptor antagonists like dexchlorpheniramine, may reduce pitolisant efficacy.
Dexmedetomidine: (Major) Concomitant use of dexmedetomidine and pitolisant increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Dextromethorphan; Bupropion: (Major) Initiate pitolisant at 8.9 mg once daily in patients taking bupropion; increase pitolisant after 7 days to a maximum dosage of 17.8 mg once daily. If bupropion is initiated in a patient on a stable dose of pitolisant, reduce the pitolisant dose by half. Pitolisant is a CYP2D6 substrate; bupropion is a strong CYP2D6 inhibitor. Coadministration of strong CYP2D6 inhibitors increases pitolisant exposure by 2.2-fold.
Dextromethorphan; Diphenhydramine; Phenylephrine: (Major) Avoid coadministration of pitolisant with diphenhydramine as the effect of pitolisant may be decreased. Pitolisant increases histamine concentrations in the brain; therefore, H1-receptor antagonists like diphenhydramine, may reduce pitolisant efficacy.
Dextromethorphan; Quinidine: (Major) Avoid coadministration of pitolisant and quinidine as concurrent use may increase the risk of QT prolongation. When administered as quinidine; dextromethorphan, coadministration with pitolisant is contraindicated. If concurrent use is unavoidable, initiate pitolisant at 8.9 mg once daily in patients taking quinidine; increase pitolisant after 7 days to a maximum dosage of 17.8 mg once daily. If quinidine is initiated in a patient on a stable dose of pitolisant, reduce the pitolisant dose by half. Pitolisant is a CYP2D6 substrate that prolongs the QT interval; quinidine is a strong CYP2D6 inhibitor that has been associated with QT prolongation and torsade de pointes. Coadministration of strong CYP2D6 inhibitors increases pitolisant exposure by 2.2-fold.
Dienogest; Estradiol valerate: (Major) Advise patients to use an alternative, non-hormonal contraceptive during and for at least 21 days after discontinuation of pitolisant. Pitolisant is a weak CYP3A4 inducer and may decrease the plasma exposure of hormonal contraceptives resulting in decreased efficacy.
Dimenhydrinate: (Major) Avoid coadministration of pitolisant with dimenhydrinate as the effect of pitolisant may be decreased. Pitolisant increases histamine concentrations in the brain; therefore, H1-receptor antagonists like dimenhydrinate, may reduce pitolisant efficacy.
Diphenhydramine: (Major) Avoid coadministration of pitolisant with diphenhydramine as the effect of pitolisant may be decreased. Pitolisant increases histamine concentrations in the brain; therefore, H1-receptor antagonists like diphenhydramine, may reduce pitolisant efficacy.
Diphenhydramine; Ibuprofen: (Major) Avoid coadministration of pitolisant with diphenhydramine as the effect of pitolisant may be decreased. Pitolisant increases histamine concentrations in the brain; therefore, H1-receptor antagonists like diphenhydramine, may reduce pitolisant efficacy.
Diphenhydramine; Naproxen: (Major) Avoid coadministration of pitolisant with diphenhydramine as the effect of pitolisant may be decreased. Pitolisant increases histamine concentrations in the brain; therefore, H1-receptor antagonists like diphenhydramine, may reduce pitolisant efficacy.
Diphenhydramine; Phenylephrine: (Major) Avoid coadministration of pitolisant with diphenhydramine as the effect of pitolisant may be decreased. Pitolisant increases histamine concentrations in the brain; therefore, H1-receptor antagonists like diphenhydramine, may reduce pitolisant efficacy.
Disopyramide: (Major) Avoid coadministration of pitolisant with disopyramide as concurrent use may increase the risk of QT prolongation. Pitolisant prolongs the QT interval. Disopyramide administration is associated with QT prolongation and torsade de pointes (TdP).
Dofetilide: (Major) Coadministration of dofetilide and pitolisant is not recommended as concurrent use may increase the risk of QT prolongation. Dofetilide, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and TdP. Pitolisant also prolongs the QT interval.
Dolasetron: (Major) Avoid coadministration of pitolisant with dolasetron as concurrent use may increase the risk of QT prolongation. Pitolisant prolongs the QT interval. Dolasetron has been associated with a dose-dependent prolongation in the QT, PR, and QRS intervals on an electrocardiogram.
Dolutegravir; Rilpivirine: (Major) Avoid coadministration of pitolisant with rilpivirine as concurrent use may increase the risk of QT prolongation. Pitolisant prolongs the QT interval. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation.
Donepezil: (Major) Avoid coadministration of pitolisant with donepezil as concurrent use may increase the risk of QT prolongation. Pitolisant prolongs the QT interval. Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy.
Donepezil; Memantine: (Major) Avoid coadministration of pitolisant with donepezil as concurrent use may increase the risk of QT prolongation. Pitolisant prolongs the QT interval. Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy.
Doxepin: (Major) Avoid coadministration of pitolisant with tricyclic antidepressants (TCAs) as the effect of pitolisant may be decreased; concurrent use may also increase the risk of QT prolongation. Pitolisant increases histamine concentrations in the brain; therefore, H1-receptor antagonists like TCAs, may reduce pitolisant efficacy. Pitolisant prolongs the QT interval. TCAs share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations).
Doxylamine: (Major) Avoid coadministration of pitolisant with doxylamine as the effect of pitolisant may be decreased. Pitolisant increases histamine concentrations in the brain; therefore, H1-receptor antagonists like doxylamine, may reduce pitolisant efficacy.
Doxylamine; Pyridoxine: (Major) Avoid coadministration of pitolisant with doxylamine as the effect of pitolisant may be decreased. Pitolisant increases histamine concentrations in the brain; therefore, H1-receptor antagonists like doxylamine, may reduce pitolisant efficacy.
Dronedarone: (Contraindicated) Coadministration of dronedarone with pitolisant is contraindicated due to the potential for QT prolongation and torsade de pointes (TdP). Pitolisant prolongs the QT interval. Dronedarone administration is associated with a dose-related increase in the QTc interval. The increase in QTc is approximately 10 milliseconds at doses of 400 mg twice daily (the FDA-approved dose) and up to 25 milliseconds at doses of 1,600 mg twice daily. Although there are no studies examining the effects of dronedarone in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation.
Droperidol: (Major) Avoid coadministration of pitolisant with droperidol as concurrent use may increase the risk of QT prolongation. If coadministration cannot be avoided, use extreme caution; initiate droperidol at a low dose and increase the dose as needed to achieve the desired effect. Droperidol administration is associated with an established risk for QT prolongation and torsade de pointes (TdP). Some cases have occurred in patients with no known risk factors for QT prolongation and some cases have been. Pitolisant also prolongs the QT interval.
Drospirenone: (Major) Advise patients to use an alternative, non-hormonal contraceptive during and for at least 21 days after discontinuation of pitolisant. Pitolisant is a weak CYP3A4 inducer and may decrease the plasma exposure of hormonal contraceptives resulting in decreased efficacy.
Drospirenone; Estetrol: (Major) Advise patients to use an alternative, non-hormonal contraceptive during and for at least 21 days after discontinuation of pitolisant. Pitolisant is a weak CYP3A4 inducer and may decrease the plasma exposure of hormonal contraceptives resulting in decreased efficacy.
Drospirenone; Estradiol: (Major) Advise patients to use an alternative, non-hormonal contraceptive during and for at least 21 days after discontinuation of pitolisant. Pitolisant is a weak CYP3A4 inducer and may decrease the plasma exposure of hormonal contraceptives resulting in decreased efficacy.
Drospirenone; Ethinyl Estradiol: (Major) Advise patients to use an alternative, non-hormonal contraceptive during and for at least 21 days after discontinuation of pitolisant. Pitolisant is a weak CYP3A4 inducer and may decrease the plasma exposure of hormonal contraceptives resulting in decreased efficacy.
Drospirenone; Ethinyl Estradiol; Levomefolate: (Major) Advise patients to use an alternative, non-hormonal contraceptive during and for at least 21 days after discontinuation of pitolisant. Pitolisant is a weak CYP3A4 inducer and may decrease the plasma exposure of hormonal contraceptives resulting in decreased efficacy.
Efavirenz: (Major) Avoid coadministration of pitolisant with efavirenz as concurrent use may increase the risk of QT prolongation. Pitolisant prolongs the QT interval. QTc prolongation has been observed with the use of efavirenz.
Efavirenz; Emtricitabine; Tenofovir Disoproxil Fumarate: (Major) Avoid coadministration of pitolisant with efavirenz as concurrent use may increase the risk of QT prolongation. Pitolisant prolongs the QT interval. QTc prolongation has been observed with the use of efavirenz.
Efavirenz; Lamivudine; Tenofovir Disoproxil Fumarate: (Major) Avoid coadministration of pitolisant with efavirenz as concurrent use may increase the risk of QT prolongation. Pitolisant prolongs the QT interval. QTc prolongation has been observed with the use of efavirenz.
Elagolix; Estradiol; Norethindrone acetate: (Major) Advise patients to use an alternative, non-hormonal contraceptive during and for at least 21 days after discontinuation of pitolisant. Pitolisant is a weak CYP3A4 inducer and may decrease the plasma exposure of hormonal contraceptives resulting in decreased efficacy.
Eliglustat: (Major) Avoid coadministration of pitolisant with eliglustat as concurrent use may increase the risk of QT prolongation. Pitolisant prolongs the QT interval. Eliglustat is predicted to cause PR, QRS, and/or QT prolongation at significantly elevated plasma concentrations.
Emtricitabine; Rilpivirine; Tenofovir alafenamide: (Major) Avoid coadministration of pitolisant with rilpivirine as concurrent use may increase the risk of QT prolongation. Pitolisant prolongs the QT interval. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation.
Emtricitabine; Rilpivirine; Tenofovir Disoproxil Fumarate: (Major) Avoid coadministration of pitolisant with rilpivirine as concurrent use may increase the risk of QT prolongation. Pitolisant prolongs the QT interval. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation.
Encorafenib: (Major) Avoid concurrent use of encorafenib with pitolisant due to the risk for decreased pitolisant exposure and efficacy and additive risk for QT/QTc prolongation and torsade de pointes (TdP). If concomitant use is necessary, monitor for loss of pitolisant efficacy after initiation of encorafenib and increase pitolisant to double its original daily dose over seven days in patients stable on 8.9 mg or 17.8 mg once daily (i.e., 17.8 mg or 35.6 mg, respectively). Decrease the pitolisant dose by one-half if encorafenib is discontinued. Additionally, consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring. Pitolisant is a CYP3A substrate, encorafenib is a strong CYP3A inducer, and both medications have been associated with QT/QTc prolongation. Coadministration of strong CYP3A inducers decreases pitolisant exposure by 50%.
Entrectinib: (Major) Avoid coadministration of pitolisant with entrectinib as concurrent use may increase the risk of QT prolongation. Entrectinib has been associated with QT prolongation. Pitolisant also prolongs the QT interval.
Enzalutamide: (Major) Monitor for loss of pitolisant efficacy after initiation of enzalutamide. Increase to double the original daily dose of pitolisant over 7 days in patients stable on 8.9 mg or 17.8 mg once daily (i.e., 17.8 mg or 35.6 mg, respectively). Decrease the pitolisant dose by half if enzalutamide is discontinued. Pitolisant is a CYP3A4 substrate; enzalutamide is a strong CYP3A4 inducer. Coadministration of strong CYP3A4 inducers decreases pitolisant exposure by 50%.
Eribulin: (Major) Avoid coadministration of pitolisant with eribulin as concurrent use may increase the risk of QT prolongation. If coadministration is necessary, monitor ECG. Eribulin has been associated with QT prolongation. Pitolisant also prolongs the QT interval.
Erythromycin: (Major) Concomitant use of pitolisant and erythromycin increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Escitalopram: (Major) Concomitant use of pitolisant and escitalopram increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Estradiol; Levonorgestrel: (Major) Advise patients to use an alternative, non-hormonal contraceptive during and for at least 21 days after discontinuation of pitolisant. Pitolisant is a weak CYP3A4 inducer and may decrease the plasma exposure of hormonal contraceptives resulting in decreased efficacy.
Estradiol; Norethindrone: (Major) Advise patients to use an alternative, non-hormonal contraceptive during and for at least 21 days after discontinuation of pitolisant. Pitolisant is a weak CYP3A4 inducer and may decrease the plasma exposure of hormonal contraceptives resulting in decreased efficacy.
Estradiol; Norgestimate: (Major) Advise patients to use an alternative, non-hormonal contraceptive during and for at least 21 days after discontinuation of pitolisant. Pitolisant is a weak CYP3A4 inducer and may decrease the plasma exposure of hormonal contraceptives resulting in decreased efficacy.
Ethinyl Estradiol; Norelgestromin: (Major) Advise patients to use an alternative, non-hormonal contraceptive during and for at least 21 days after discontinuation of pitolisant. Pitolisant is a weak CYP3A4 inducer and may decrease the plasma exposure of hormonal contraceptives resulting in decreased efficacy.
Ethinyl Estradiol; Norethindrone Acetate: (Major) Advise patients to use an alternative, non-hormonal contraceptive during and for at least 21 days after discontinuation of pitolisant. Pitolisant is a weak CYP3A4 inducer and may decrease the plasma exposure of hormonal contraceptives resulting in decreased efficacy.
Ethinyl Estradiol; Norgestrel: (Major) Advise patients to use an alternative, non-hormonal contraceptive during and for at least 21 days after discontinuation of pitolisant. Pitolisant is a weak CYP3A4 inducer and may decrease the plasma exposure of hormonal contraceptives resulting in decreased efficacy.
Ethynodiol Diacetate; Ethinyl Estradiol: (Major) Advise patients to use an alternative, non-hormonal contraceptive during and for at least 21 days after discontinuation of pitolisant. Pitolisant is a weak CYP3A4 inducer and may decrease the plasma exposure of hormonal contraceptives resulting in decreased efficacy.
Etonogestrel: (Major) Advise patients to use an alternative, non-hormonal contraceptive during and for at least 21 days after discontinuation of pitolisant. Pitolisant is a weak CYP3A4 inducer and may decrease the plasma exposure of hormonal contraceptives resulting in decreased efficacy.
Etonogestrel; Ethinyl Estradiol: (Major) Advise patients to use an alternative, non-hormonal contraceptive during and for at least 21 days after discontinuation of pitolisant. Pitolisant is a weak CYP3A4 inducer and may decrease the plasma exposure of hormonal contraceptives resulting in decreased efficacy.
Etrasimod: (Major) Concomitant use of etrasimod and pitolisant increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. Etrasimod has a limited effect on the QT/QTc interval at therapeutic doses but may cause bradycardia and atrioventricular conduction delays which may increase the risk for TdP in patients with a prolonged QT/QTc interval.
Fexinidazole: (Major) Concomitant use of fexinidazole and pitolisant increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Fingolimod: (Major) Avoid coadministration of pitolisant with fingolimod as concurrent use may increase the risk of QT prolongation. Pitolisant prolongs the QT interval. Fingolimod initiation results in decreased heart rate and may prolong the QT interval. Fingolimod has not been studied in patients treated with drugs that prolong the QT interval, but drugs that prolong the QT interval have been associated with cases of TdP in patients with bradycardia.
Flecainide: (Major) Concomitant use of pitolisant and flecainide increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Fluconazole: (Major) Concomitant use of pitolisant and fluconazole increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Fluoxetine: (Major) Avoid coadministration of pitolisant and fluoxetine as concurrent use may increase the risk of QT prolongation. If concurrent use is unavoidable, initiate pitolisant at 8.9 mg once daily; increase pitolisant after 7 days to a maximum dosage of 17.8 mg once daily. If fluoxetine is initiated in a patient on a stable dose of pitolisant, reduce the pitolisant dose by half. Pitolisant is a CYP2D6 substrate that prolongs the QT interval; fluoxetine is a strong CYP2D6 inhibitor that has been associated with QT prolongation and torsade de pointes. Coadministration of strong CYP2D6 inhibitors increases pitolisant exposure by 2.2-fold.
Fluphenazine: (Minor) Fluphenazine is associated with a possible risk for QT prolongation. Theoretically, fluphenazine may increase the risk of QT prolongation if coadministered with other drugs that have a risk of QT prolongation, such as pitolisant.
Fluvoxamine: (Major) Avoid coadministration of pitolisant with fluvoxamine as concurrent use may increase the risk of QT prolongation. Pitolisant prolongs the QT interval. QT prolongation and torsade de pointes (TdP) has been reported during fluvoxamine postmarketing use.
Foscarnet: (Major) Avoid coadministration of pitolisant with foscarnet as concurrent use may increase the risk of QT prolongation. Pitolisant prolongs the QT interval. Both QT prolongation and torsade de pointes (TdP) have been reported during postmarketing use of foscarnet.
Fosphenytoin: (Major) Monitor for loss of pitolisant efficacy after initiation of fosphenytoin. Increase to double the original daily dose of pitolisant over 7 days in patients stable on 8.9 mg or 17.8 mg once daily (i.e., 17.8 mg or 35.6 mg, respectively). Decrease the pitolisant dose by half if fosphenytoin is discontinued. Pitolisant is a CYP3A4 substrate; fosphenytoin is a strong CYP3A4 inducer. Coadministration of strong CYP3A4 inducers decreases pitolisant exposure by 50%.
Fostemsavir: (Major) Avoid coadministration of pitolisant with fostemsavir as concurrent use may increase the risk of QT prolongation. Pitolisant prolongs the QT interval. Supratherapeutic doses of fostemsavir (2,400 mg twice daily, four times the recommended daily dose) have been shown to cause QT prolongation. Fostemsavir causes dose-dependent QT prolongation.
Gemifloxacin: (Major) Avoid coadministration of pitolisant with gemifloxacin as concurrent use may increase the risk of QT prolongation. Pitolisant prolongs the QT interval. Gemifloxacin may prolong the QT interval in some patients. The maximal change in the QTc interval occurs approximately 5 to 10 hours following oral administration of gemifloxacin. The likelihood of QTc prolongation may increase with increasing dose of the drug; therefore, the recommended dose should not be exceeded especially in patients with renal or hepatic impairment where the Cmax and AUC are slightly higher.
Gemtuzumab Ozogamicin: (Major) Avoid coadministration of pitolisant with gemtuzumab ozogamicin as concurrent use may increase the risk of QT prolongation. If these agents are used together, obtain an ECG and serum electrolytes prior to the start of gemtuzumab and as needed during treatment. Pitolisant prolongs the QT interval. Although QT interval prolongation has not been reported with gemtuzumab, it has been reported with other drugs that contain calicheamicin.
Gilteritinib: (Major) Avoid coadministration of pitolisant with gilteritinib as concurrent use may increase the risk of QT prolongation. Pitolisant prolongs the QT interval. Gilteritinib has also been associated with QT prolongation.
Glasdegib: (Major) Avoid coadministration of glasdegib with pitolisant due to the potential for additive QT prolongation. If coadministration cannot be avoided, monitor patients for increased risk of QT prolongation with increased frequency of ECG monitoring. Glasdegib therapy may result in QT prolongation and ventricular arrhythmias including ventricular fibrillation and ventricular tachycardia. Pitolisant also prolongs the QT interval.
Goserelin: (Major) Avoid coadministration of pitolisant with goserelin as concurrent use may increase the risk of QT prolongation. Pitolisant prolongs the QT interval. Androgen deprivation therapy (i.e., goserelin) may also prolong the QT/QTc interval.
Granisetron: (Major) Avoid coadministration of pitolisant with granisetron as concurrent use may increase the risk of QT prolongation. Pitolisant prolongs the QT interval. Granisetron has been associated with QT prolongation.
Halogenated Anesthetics: (Major) Avoid coadministration of pitolisant with halogenated anesthetics as concurrent use may increase the risk of QT prolongation. Pitolisant prolongs the QT interval. Halogenated anesthetics can also prolong the QT interval.
Haloperidol: (Major) Avoid coadministration of pitolisant with haloperidol as concurrent use may increase the risk of QT prolongation. Pitolisant prolongs the QT interval. QT prolongation and torsade de pointes (TdP) have been observed during haloperidol treatment. Excessive doses (particularly in the overdose setting) or IV administration of haloperidol may be associated with a higher risk of QT prolongation.
Histrelin: (Major) Avoid coadministration of pitolisant with histrelin as concurrent use may increase the risk of QT prolongation. Pitolisant prolongs the QT interval. Androgen deprivation therapy (i.e., histrelin) may prolong the QT/QTc interval.
Hydroxychloroquine: (Major) Concomitant use of pitolisant and hydroxychloroquine increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Hydroxyzine: (Major) Avoid coadministration of pitolisant with hydroxyzine as the effect of pitolisant may be decreased; concurrent use may also increase the risk of QT prolongation. Pitolisant increases histamine concentrations in the brain; therefore, H1-receptor antagonists like hydroxyzine, may reduce pitolisant efficacy. Pitolisant prolongs the QT interval. Postmarketing data indicate that hydroxyzine causes QT prolongation and torsade de pointes (TdP).
Ibutilide: (Major) Avoid coadministration of pitolisant with ibutilide as concurrent use may increase the risk of QT prolongation. Pitolisant prolongs the QT interval. Ibutilide administration can cause QT prolongation and torsade de pointes (TdP); proarrhythmic events should be anticipated. The potential for proarrhythmic events with ibutilide increases with the coadministration of other drugs that prolong the QT interval.
Iloperidone: (Major) Avoid coadministration of pitolisant with iloperidone as concurrent use may increase the risk of QT prolongation. Pitolisant prolongs the QT interval. Iloperidone has also been associated with QT prolongation.
Imipramine: (Major) Avoid coadministration of pitolisant with tricyclic antidepressants (TCAs) as the effect of pitolisant may be decreased; concurrent use may also increase the risk of QT prolongation. Pitolisant increases histamine concentrations in the brain; therefore, H1-receptor antagonists like TCAs, may reduce pitolisant efficacy. Pitolisant prolongs the QT interval. TCAs share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations).
Inotuzumab Ozogamicin: (Major) Avoid coadministration of inotuzumab with pitolisant due to the potential for additive QT prolongation and torsade de pointes. If coadministration cannot be avoided, monitor ECG before and during treatment. Inotuzumab has been associated with QT interval prolongation. Pitolisant also prolongs the QT interval.
Isoflurane: (Major) Avoid coadministration of pitolisant with halogenated anesthetics as concurrent use may increase the risk of QT prolongation. Pitolisant prolongs the QT interval. Halogenated anesthetics can also prolong the QT interval.
Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Major) Monitor for loss of pitolisant efficacy after initiation of rifampin. Increase to double the original daily dose of pitolisant over 7 days in patients stable on 8.9 mg or 17.8 mg once daily (i.e., 17.8 mg or 35.6 mg, respectively). Decrease the pitolisant dose by half if rifampin is discontinued. Pitolisant is a CYP3A4 substrate; rifampin is a strong CYP3A4 inducer. Coadministration of rifampin decreased pitolisant exposure by 50%.
Isoniazid, INH; Rifampin: (Major) Monitor for loss of pitolisant efficacy after initiation of rifampin. Increase to double the original daily dose of pitolisant over 7 days in patients stable on 8.9 mg or 17.8 mg once daily (i.e., 17.8 mg or 35.6 mg, respectively). Decrease the pitolisant dose by half if rifampin is discontinued. Pitolisant is a CYP3A4 substrate; rifampin is a strong CYP3A4 inducer. Coadministration of rifampin decreased pitolisant exposure by 50%.
Itraconazole: (Major) Avoid coadministration of pitolisant with itraconazole as concurrent use may increase the risk of QT prolongation. Pitolisant prolongs the QT interval. Itraconazole has been associated with prolongation of the QT interval.
Ivosidenib: (Major) Avoid coadministration of ivosidenib with pitolisant due to an increased risk of QT prolongation. If concomitant use is unavoidable, monitor ECGs for QTc prolongation and monitor electrolytes; correct any electrolyte abnormalities as clinically appropriate. An interruption of therapy and dose reduction of ivosidenib may be necessary if QT prolongation occurs. Prolongation of the QTc interval and ventricular arrhythmias have been reported in patients treated with ivosidenib. Pitolisant prolongs the QT interval.
Ketoconazole: (Contraindicated) Avoid concomitant use of ketoconazole and pitolisant due to an increased risk for torsade de pointes (TdP) and QT/QTc prolongation.
Lansoprazole; Amoxicillin; Clarithromycin: (Major) Avoid coadministration of pitolisant with clarithromycin as concurrent use may increase the risk of QT prolongation. Pitolisant prolongs the QT interval. Clarithromycin is associated with an established risk for QT prolongation and torsade de pointes (TdP).
Lapatinib: (Major) Avoid coadministration of pitolisant with lapatinib as concurrent use may increase the risk of QT prolongation. If concomitant use is necessary, monitor for evidence of QT prolongation. Pitolisant prolongs the QT interval. Lapatinib has been associated with concentration-dependent QT prolongation; ventricular arrhythmias and torsade de pointes (TdP) have been reported in postmarketing experience with lapatinib.
Lefamulin: (Major) Avoid coadministration of lefamulin with pitolisant as concurrent use may increase the risk of QT prolongation. If coadministration cannot be avoided, monitor ECG during treatment. Lefamulin has a concentration dependent QTc prolongation effect. The pharmacodynamic interaction potential to prolong the QT interval of the electrocardiogram between lefamulin and other drugs that effect cardiac conduction is unknown. Pitolisant prolongs the QT interval.
Lenvatinib: (Major) Avoid coadministration of pitolisant with lenvatinib as concurrent use may increase the risk of QT prolongation. Pitolisant prolongs the QT interval. Prolongation of the QT interval has also been reported with lenvatinib therapy.
Leuprolide: (Major) Avoid coadministration of pitolisant with leuprolide as concurrent use may increase the risk of QT prolongation. Pitolisant prolongs the QT interval. Androgen deprivation therapy (i.e., leuprolide) may prolong the QT/QTc interval.
Leuprolide; Norethindrone: (Major) Advise patients to use an alternative, non-hormonal contraceptive during and for at least 21 days after discontinuation of pitolisant. Pitolisant is a weak CYP3A4 inducer and may decrease the plasma exposure of hormonal contraceptives resulting in decreased efficacy. (Major) Avoid coadministration of pitolisant with leuprolide as concurrent use may increase the risk of QT prolongation. Pitolisant prolongs the QT interval. Androgen deprivation therapy (i.e., leuprolide) may prolong the QT/QTc interval.
Levofloxacin: (Major) Concomitant use of pitolisant and levofloxacin increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Levoketoconazole: (Contraindicated) Avoid concomitant use of ketoconazole and pitolisant due to an increased risk for torsade de pointes (TdP) and QT/QTc prolongation.
Levonorgestrel: (Major) Advise patients to use an alternative, non-hormonal contraceptive during and for at least 21 days after discontinuation of pitolisant. Pitolisant is a weak CYP3A4 inducer and may decrease the plasma exposure of hormonal contraceptives resulting in decreased efficacy.
Levonorgestrel; Ethinyl Estradiol: (Major) Advise patients to use an alternative, non-hormonal contraceptive during and for at least 21 days after discontinuation of pitolisant. Pitolisant is a weak CYP3A4 inducer and may decrease the plasma exposure of hormonal contraceptives resulting in decreased efficacy.
Levonorgestrel; Ethinyl Estradiol; Ferrous Bisglycinate: (Major) Advise patients to use an alternative, non-hormonal contraceptive during and for at least 21 days after discontinuation of pitolisant. Pitolisant is a weak CYP3A4 inducer and may decrease the plasma exposure of hormonal contraceptives resulting in decreased efficacy.
Levonorgestrel; Ethinyl Estradiol; Ferrous Fumarate: (Major) Advise patients to use an alternative, non-hormonal contraceptive during and for at least 21 days after discontinuation of pitolisant. Pitolisant is a weak CYP3A4 inducer and may decrease the plasma exposure of hormonal contraceptives resulting in decreased efficacy.
Lithium: (Major) Concomitant use of pitolisant and lithium increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Lofexidine: (Major) Avoid coadministration of pitolisant with lofexidine as concurrent use may increase the risk of QT prolongation. If coadministration cannot be avoided, ECG monitoring is recommended during treatment. Both pitolisant and lofexidine prolong the QT interval.
Loperamide: (Major) Avoid coadministration of pitolisant with loperamide as concurrent use may increase the risk of QT prolongation. Pitolisant prolongs the QT interval. At high doses, loperamide has been associated with serious cardiac toxicities, including syncope, ventricular tachycardia, QT prolongation, torsade de pointes (TdP), and cardiac arrest.
Loperamide; Simethicone: (Major) Avoid coadministration of pitolisant with loperamide as concurrent use may increase the risk of QT prolongation. Pitolisant prolongs the QT interval. At high doses, loperamide has been associated with serious cardiac toxicities, including syncope, ventricular tachycardia, QT prolongation, torsade de pointes (TdP), and cardiac arrest.
Lopinavir; Ritonavir: (Major) Avoid coadministration of lopinavir with pitolisant due to the potential for additive QT prolongation. If use together is necessary, obtain a baseline ECG to assess initial QT interval and determine frequency of subsequent ECG monitoring, avoid any non-essential QT prolonging drugs, and correct electrolyte imbalances. Both drugs have been associated with QT prolongation. (Moderate) Monitor for decreased efficacy of ritonavir if coadministered with pitolisant. Concurrent use may decrease the plasma concentrations of ritonavir leading to a reduction of antiretroviral efficacy and the potential development of viral resistance. Ritonavir is a CYP3A substrate and pitolisant is a weak CYP3A inducer.
Lumacaftor; Ivacaftor: (Major) Monitor for loss of pitolisant efficacy after initiation of lumacaftor; ivacaftor. Increase to double the original daily dose of pitolisant over 7 days in patients stable on 8.9 mg or 17.8 mg once daily (i.e., 17.8 mg or 35.6 mg, respectively). Decrease the pitolisant dose by half if lumacaftor; ivacaftor is discontinued. Pitolisant is a CYP3A4 substrate; lumacaftor; ivacaftor is a strong CYP3A4 inducer. Coadministration of strong CYP3A4 inducers decreases pitolisant exposure by 50%.
Lumacaftor; Ivacaftor: (Major) Monitor for loss of pitolisant efficacy after initiation of lumacaftor; ivacaftor. Increase to double the original daily dose of pitolisant over 7 days in patients stable on 8.9 mg or 17.8 mg once daily (i.e., 17.8 mg or 35.6 mg, respectively). Decrease the pitolisant dose by half if lumacaftor; ivacaftor is discontinued. Pitolisant is a CYP3A4 substrate; lumacaftor; ivacaftor is a strong CYP3A4 inducer. Coadministration of strong CYP3A4 inducers decreases pitolisant exposure by 50%.
Lumateperone: (Major) Avoid coadministration of lumateperone and pitolisant as concurrent use may decrease lumateperone exposure which may reduce efficacy. Lumateperone is a CYP3A substrate; pitolisant is a weak CYP3A inducer.
Macimorelin: (Major) Avoid concurrent administration of macimorelin with drugs that prolong the QT interval, such as pitolisant. Use of these drugs together may increase the risk of developing torsade de pointes-type ventricular tachycardia. Sufficient washout time of drugs that are known to prolong the QT interval prior to administration of macimorelin is recommended. Treatment with macimorelin has been associated with an increase in the corrected QT (QTc) interval.
Maprotiline: (Major) Avoid coadministration of pitolisant with maprotiline as concurrent use may increase the risk of QT prolongation. Pitolisant prolongs the QT interval. Maprotiline has been reported to prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). Cases of long QT syndrome and torsade de pointes (TdP) tachycardia have been described with maprotiline use, but rarely occur when the drug is used alone in normal prescribed doses and in the absence of other known risk factors for QT prolongation. Limited data are available regarding the safety of maprotiline in combination with other QT-prolonging drugs.
Meclizine: (Major) Avoid coadministration of pitolisant with meclizine as the effect of pitolisant may be decreased. Pitolisant increases histamine concentrations in the brain; therefore, H1-receptor antagonists like meclizine, may reduce pitolisant efficacy.
Mefloquine: (Minor) Coadministration of pitolisant and mefloquine may increase the risk of QT prolongation. Pitolisant prolongs the QT interval. There is evidence that the use of halofantrine after mefloquine causes a significant lengthening of the QTc interval; however, mefloquine alone has not been reported to cause QT prolongation.
Methadone: (Major) Avoid coadministration of pitolisant with methadone as concurrent use may increase the risk of QT prolongation. Pitolisant prolongs the QT interval. Methadone is considered to be associated with an increased risk for QT prolongation and torsade de pointes (TdP), especially at higher doses (more than 200 mg/day but averaging approximately 400 mg/day in adult patients). Most cases involve patients being treated for pain with large, multiple daily doses of methadone, although cases have been reported in patients receiving doses commonly used for maintenance treatment of opioid addiction.
Metronidazole: (Major) Concomitant use of metronidazole and pitolisant increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Midostaurin: (Major) Avoid coadministration of pitolisant with midostaurin as concurrent use may increase the risk of QT prolongation. If coadministration is necessary, consider interval assessments of QT by EKG. Pitolisant prolongs the QT interval. QT prolongation was reported in patients who received midostaurin in clinical trials.
Mifepristone: (Major) Concomitant use of pitolisant and mifepristone increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Mirtazapine: (Major) Avoid coadministration of pitolisant with mirtazapine as the effect of pitolisant may be decreased; concurrent use may also increase the risk of QT prolongation. Pitolisant increases histamine concentrations in the brain; therefore, H1-receptor antagonists like mirtazapine, may reduce pitolisant efficacy. Pitolisant prolongs the QT interval. Mirtazapine has been associated with dose-dependent prolongation of the QT interval. Torsade de pointes (TdP) has been reported postmarketing, primarily in overdose or in patients with other risk factors for QT prolongation.
Mitotane: (Major) Monitor for loss of pitolisant efficacy after initiation of mitotane. Increase to double the original daily dose of pitolisant over 7 days in patients stable on 8.9 mg or 17.8 mg once daily (i.e., 17.8 mg or 35.6 mg, respectively). Decrease the pitolisant dose by half if mitotane is discontinued. Pitolisant is a CYP3A4 substrate; mitotane is a strong CYP3A4 inducer. Coadministration of strong CYP3A4 inducers decreases pitolisant exposure by 50%.
Mobocertinib: (Major) Concomitant use of mobocertinib and pitolisant increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Moxifloxacin: (Major) Avoid coadministration of moxifloxacin with pitolisant as concurrent use may increase the risk of QT prolongation and torsade de pointes (TdP). Quinolones have been associated with a risk of QT prolongation. Although extremely rare, TdP has been reported during postmarketing surveillance of moxifloxacin. These reports generally involved patients with concurrent medical conditions or concomitant medications that may have been contributory. Pitolisant prolongs the QT interval.
Nanoparticle Albumin-Bound Sirolimus: (Moderate) Monitor for reduced sirolimus efficacy if sirolimus is coadministered with pitolisant. Concomitant use may decrease sirolimus exposure. Sirolimus is a CYP3A substrate and pitolisant is a weak CYP3A inducer.
Nilotinib: (Major) Avoid coadministration of pitolisant with nilotinib as concurrent use may increase the risk of QT prolongation. Pitolisant prolongs the QT interval. Sudden death and QT interval prolongation have occurred in patients who received nilotinib therapy.
Nirmatrelvir; Ritonavir: (Moderate) Monitor for a diminished response to nirmatrelvir if concomitant use of pitolisant is necessary. Concomitant use of nirmatrelvir and pitolisant may reduce the therapeutic effect of nirmatrelvir. Nirmatrelvir is a CYP3A substrate and pitolisant is a weak CYP3A inducer. (Moderate) Monitor for decreased efficacy of ritonavir if coadministered with pitolisant. Concurrent use may decrease the plasma concentrations of ritonavir leading to a reduction of antiretroviral efficacy and the potential development of viral resistance. Ritonavir is a CYP3A substrate and pitolisant is a weak CYP3A inducer.
Non-oral combination contraceptives: (Major) Advise patients to use an alternative, non-hormonal contraceptive during and for at least 21 days after discontinuation of pitolisant. Pitolisant is a weak CYP3A4 inducer and may decrease the plasma exposure of hormonal contraceptives resulting in decreased efficacy.
Norethindrone Acetate; Ethinyl Estradiol; Ferrous fumarate: (Major) Advise patients to use an alternative, non-hormonal contraceptive during and for at least 21 days after discontinuation of pitolisant. Pitolisant is a weak CYP3A4 inducer and may decrease the plasma exposure of hormonal contraceptives resulting in decreased efficacy.
Norethindrone: (Major) Advise patients to use an alternative, non-hormonal contraceptive during and for at least 21 days after discontinuation of pitolisant. Pitolisant is a weak CYP3A4 inducer and may decrease the plasma exposure of hormonal contraceptives resulting in decreased efficacy.
Norethindrone; Ethinyl Estradiol: (Major) Advise patients to use an alternative, non-hormonal contraceptive during and for at least 21 days after discontinuation of pitolisant. Pitolisant is a weak CYP3A4 inducer and may decrease the plasma exposure of hormonal contraceptives resulting in decreased efficacy.
Norethindrone; Ethinyl Estradiol; Ferrous fumarate: (Major) Advise patients to use an alternative, non-hormonal contraceptive during and for at least 21 days after discontinuation of pitolisant. Pitolisant is a weak CYP3A4 inducer and may decrease the plasma exposure of hormonal contraceptives resulting in decreased efficacy.
Norgestimate; Ethinyl Estradiol: (Major) Advise patients to use an alternative, non-hormonal contraceptive during and for at least 21 days after discontinuation of pitolisant. Pitolisant is a weak CYP3A4 inducer and may decrease the plasma exposure of hormonal contraceptives resulting in decreased efficacy.
Norgestrel: (Major) Advise patients to use an alternative, non-hormonal contraceptive during and for at least 21 days after discontinuation of pitolisant. Pitolisant is a weak CYP3A4 inducer and may decrease the plasma exposure of hormonal contraceptives resulting in decreased efficacy.
Nortriptyline: (Major) Avoid coadministration of pitolisant with tricyclic antidepressants (TCAs) as the effect of pitolisant may be decreased; concurrent use may also increase the risk of QT prolongation. Pitolisant increases histamine concentrations in the brain; therefore, H1-receptor antagonists like TCAs, may reduce pitolisant efficacy. Pitolisant prolongs the QT interval. TCAs share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations).
Ofloxacin: (Major) Concomitant use of pitolisant and ofloxacin increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Olanzapine: (Major) Avoid coadministration of pitolisant with olanzapine as concurrent use may increase the risk of QT prolongation. Pitolisant prolongs the QT interval. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval.
Olanzapine; Fluoxetine: (Major) Avoid coadministration of pitolisant and fluoxetine as concurrent use may increase the risk of QT prolongation. If concurrent use is unavoidable, initiate pitolisant at 8.9 mg once daily; increase pitolisant after 7 days to a maximum dosage of 17.8 mg once daily. If fluoxetine is initiated in a patient on a stable dose of pitolisant, reduce the pitolisant dose by half. Pitolisant is a CYP2D6 substrate that prolongs the QT interval; fluoxetine is a strong CYP2D6 inhibitor that has been associated with QT prolongation and torsade de pointes. Coadministration of strong CYP2D6 inhibitors increases pitolisant exposure by 2.2-fold. (Major) Avoid coadministration of pitolisant with olanzapine as concurrent use may increase the risk of QT prolongation. Pitolisant prolongs the QT interval. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval.
Olanzapine; Samidorphan: (Major) Avoid coadministration of pitolisant with olanzapine as concurrent use may increase the risk of QT prolongation. Pitolisant prolongs the QT interval. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval.
Ondansetron: (Major) Concomitant use of pitolisant and ondansetron increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. Do not exceed 16 mg of IV ondansetron in a single dose; the degree of QT prolongation associated with ondansetron significantly increases above this dose.
Oral Contraceptives: (Major) Advise patients to use an alternative, non-hormonal contraceptive during and for at least 21 days after discontinuation of pitolisant. Pitolisant is a weak CYP3A4 inducer and may decrease the plasma exposure of hormonal contraceptives resulting in decreased efficacy.
Osilodrostat: (Major) Avoid coadministration of pitolisant with osilodrostat as concurrent use may increase the risk of QT prolongation. If concomitant use is necessary, monitor ECGs. Pitolisant prolongs the QT interval. Osilodrostat is associated with dose-dependent QT prolongation.
Osimertinib: (Major) Avoid coadministration of pitolisant with osimertinib due to the risk of QT prolongation and torsade de pointes (TdP). If concomitant use is unavoidable, periodically monitor ECGs for QT prolongation and monitor electrolytes; an interruption of osimertinib therapy with dose reduction or discontinuation may be necessary if QT prolongation occurs. Concentration-dependent QTc prolongation occurred during clinical trials of osimertinib. Pitolisant prolongs the QT interval.
Oxaliplatin: (Major) Avoid coadministration of pitolisant with oxaliplatin as concurrent use may increase the risk of QT prolongation. Pitolisant prolongs the QT interval. QT prolongation and ventricular arrhythmias including fatal torsade de pointes have also been reported with oxaliplatin use in postmarketing experience.
Ozanimod: (Major) In general, do not initiate ozanimod in patients taking pitolisant due to the risk of additive bradycardia, QT prolongation, and torsade de pointes (TdP). If treatment initiation is considered, seek advice from a cardiologist. Ozanimod initiation may result in a transient decrease in heart rate and atrioventricular conduction delays. Ozanimod has not been studied in patients taking concurrent QT prolonging drugs; however, QT prolonging drugs have been associated with TdP in patients with bradycardia. Pitolisant prolongs the QT interval.
Pacritinib: (Major) Concomitant use of pacritinib and pitolisant increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Paliperidone: (Major) Avoid coadministration of paliperidone with pitolisant due to the potential for additive QT prolongation and risk of torsade de pointes (TdP). Paliperidone has been associated with QT prolongation; torsade de pointes and ventricular fibrillation have been reported in the setting of overdose. Pitolisant prolongs the QT interval.
Panobinostat: (Major) Avoid coadministration of pitolisant with panobinostat as concurrent use may increase the risk of QT prolongation. Pitolisant prolongs the QT interval. QT prolongation has been reported with panobinostat.
Paroxetine: (Major) Initiate pitolisant at 8.9 mg once daily in patients taking paroxetine; increase pitolisant after 7 days to a maximum dosage of 17.8 mg once daily. If paroxetine is initiated in a patient on a stable dose of pitolisant, reduce the pitolisant dose by half. Pitolisant is a CYP2D6 substrate; paroxetine is a strong CYP2D6 inhibitor. Coadministration of paroxetine increased pitolisant exposure by 2.2-fold.
Pasireotide: (Major) Avoid coadministration of pitolisant with pasireotide as concurrent use may increase the risk of QT prolongation. Pitolisant prolongs the QT interval. QT prolongation has occurred with pasireotide at therapeutic and supra-therapeutic doses.
Pazopanib: (Major) Avoid coadministration of pitolisant with pazopanib as concurrent use may increase the risk of QT prolongation. If coadministration is necessary, closely monitor the patient for QT interval prolongation. Pitolisant prolongs the QT interval. Pazopanib has also been reported to prolong the QT interval.
Pentamidine: (Major) Avoid coadministration of pitolisant with pentamidine as concurrent use may increase the risk of QT prolongation. Pitolisant prolongs the QT interval. Systemic pentamidine has been associated with QT prolongation.
Perphenazine: (Minor) Perphenazine is associated with a possible risk for QT prolongation. Theoretically, perphenazine may increase the risk of QT prolongation if coadministered with other drugs that have a risk of QT prolongation, such as pitolisant.
Perphenazine; Amitriptyline: (Major) Avoid coadministration of pitolisant with tricyclic antidepressants (TCAs) as the effect of pitolisant may be decreased; concurrent use may also increase the risk of QT prolongation. Pitolisant increases histamine concentrations in the brain; therefore, H1-receptor antagonists like TCAs, may reduce pitolisant efficacy. Pitolisant prolongs the QT interval. TCAs share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). (Minor) Perphenazine is associated with a possible risk for QT prolongation. Theoretically, perphenazine may increase the risk of QT prolongation if coadministered with other drugs that have a risk of QT prolongation, such as pitolisant.
Phenobarbital: (Major) Monitor for loss of pitolisant efficacy after initiation of phenobarbital. Increase to double the original daily dose of pitolisant over 7 days in patients stable on 8.9 mg or 17.8 mg once daily (i.e., 17.8 mg or 35.6 mg, respectively). Decrease the pitolisant dose by half if phenobarbital is discontinued. Pitolisant is a CYP3A4 substrate; phenobarbital is a strong CYP3A4 inducer. Coadministration of strong CYP3A4 inducers decreases pitolisant exposure by 50%.
Phenobarbital; Hyoscyamine; Atropine; Scopolamine: (Major) Monitor for loss of pitolisant efficacy after initiation of phenobarbital. Increase to double the original daily dose of pitolisant over 7 days in patients stable on 8.9 mg or 17.8 mg once daily (i.e., 17.8 mg or 35.6 mg, respectively). Decrease the pitolisant dose by half if phenobarbital is discontinued. Pitolisant is a CYP3A4 substrate; phenobarbital is a strong CYP3A4 inducer. Coadministration of strong CYP3A4 inducers decreases pitolisant exposure by 50%.
Phenytoin: (Major) Monitor for loss of pitolisant efficacy after initiation of phenytoin. Increase to double the original daily dose of pitolisant over 7 days in patients stable on 8.9 mg or 17.8 mg once daily (i.e., 17.8 mg or 35.6 mg, respectively). Decrease the pitolisant dose by half if phenytoin is discontinued. Pitolisant is a CYP3A4 substrate; phenytoin is a strong CYP3A4 inducer. Coadministration of strong CYP3A4 inducers decreases pitolisant exposure by 50%.
Pimavanserin: (Major) Avoid coadministration of pimavanserin with pitolisant due to additive QT effects and increased risk of cardiac arrhythmia. Both pimavanserin and pitolisant prolong the QT interval.
Pimozide: (Contraindicated) Coadministration of pimozide with pitolisant is contraindicated due to the potential for QT prolongation and torsade de pointes (TdP). Pimozide is associated with a well-established risk of QT prolongation and TdP. Pitolisant prolongs the QT interval.
Ponesimod: (Major) In general, do not initiate ponesimod in patients taking pitolisant due to the risk of additive bradycardia, QT prolongation, and torsade de pointes (TdP). If treatment initiation is considered, seek advice from a cardiologist. Ponesimod initiation may result in a transient decrease in heart rate and atrioventricular conduction delays. Ponesimod has not been studied in patients taking concurrent QT prolonging drugs; however, QT prolonging drugs have been associated with TdP in patients with bradycardia. Pitolisant prolongs the QT interval.
Posaconazole: (Major) Avoid coadministration of pitolisant with posaconazole as concurrent use may increase the risk of QT prolongation. Pitolisant prolongs the QT interval. Posaconazole has been associated with prolongation of the QT interval as well as rare cases of torsade de pointes.
Primaquine: (Major) Avoid coadministration of pitolisant with primaquine as concurrent use may increase the risk of QT prolongation. Pitolisant prolongs the QT interval. Primaquine has also been associated with QT interval prolongation.
Primidone: (Major) Monitor for loss of pitolisant efficacy after initiation of primidone. Increase to double the original daily dose of pitolisant over 7 days in patients stable on 8.9 mg or 17.8 mg once daily (i.e., 17.8 mg or 35.6 mg, respectively). Decrease the pitolisant dose by half if primidone is discontinued. Pitolisant is a CYP3A4 substrate; primidone is a strong CYP3A4 inducer. Coadministration of strong CYP3A4 inducers decreases pitolisant exposure by 50%.
Procainamide: (Major) Avoid coadministration of pitolisant with procainamide as concurrent use may increase the risk of QT prolongation. Pitolisant prolongs the QT interval. Procainamide is associated with a well-established risk of QT prolongation and torsade de pointes (TdP).
Prochlorperazine: (Minor) Prochlorperazine is associated with a possible risk for QT prolongation. Theoretically, prochlorperazine may increase the risk of QT prolongation if coadministered with other drugs that have a risk of QT prolongation, such as pitolisant.
Promethazine: (Major) Avoid coadministration of pitolisant with promethazine as the effect of pitolisant may be decreased; concurrent use may also increase the risk of QT prolongation. Pitolisant increases histamine concentrations in the brain; therefore, H1-receptor antagonists like promethazine, may reduce pitolisant efficacy. Pitolisant prolongs the QT interval. Promethazine, a phenothiazine, is associated with a possible risk for QT prolongation.
Promethazine; Dextromethorphan: (Major) Avoid coadministration of pitolisant with promethazine as the effect of pitolisant may be decreased; concurrent use may also increase the risk of QT prolongation. Pitolisant increases histamine concentrations in the brain; therefore, H1-receptor antagonists like promethazine, may reduce pitolisant efficacy. Pitolisant prolongs the QT interval. Promethazine, a phenothiazine, is associated with a possible risk for QT prolongation.
Promethazine; Phenylephrine: (Major) Avoid coadministration of pitolisant with promethazine as the effect of pitolisant may be decreased; concurrent use may also increase the risk of QT prolongation. Pitolisant increases histamine concentrations in the brain; therefore, H1-receptor antagonists like promethazine, may reduce pitolisant efficacy. Pitolisant prolongs the QT interval. Promethazine, a phenothiazine, is associated with a possible risk for QT prolongation.
Propafenone: (Major) Concomitant use of propafenone and pitolisant increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Protriptyline: (Major) Avoid coadministration of pitolisant with tricyclic antidepressants (TCAs) as the effect of pitolisant may be decreased; concurrent use may also increase the risk of QT prolongation. Pitolisant increases histamine concentrations in the brain; therefore, H1-receptor antagonists like TCAs, may reduce pitolisant efficacy. Pitolisant prolongs the QT interval. TCAs share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations).
Quetiapine: (Major) Concomitant use of quetiapine and pitolisant increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Quinidine: (Major) Avoid coadministration of pitolisant and quinidine as concurrent use may increase the risk of QT prolongation. When administered as quinidine; dextromethorphan, coadministration with pitolisant is contraindicated. If concurrent use is unavoidable, initiate pitolisant at 8.9 mg once daily in patients taking quinidine; increase pitolisant after 7 days to a maximum dosage of 17.8 mg once daily. If quinidine is initiated in a patient on a stable dose of pitolisant, reduce the pitolisant dose by half. Pitolisant is a CYP2D6 substrate that prolongs the QT interval; quinidine is a strong CYP2D6 inhibitor that has been associated with QT prolongation and torsade de pointes. Coadministration of strong CYP2D6 inhibitors increases pitolisant exposure by 2.2-fold.
Quinine: (Major) Avoid coadministration of pitolisant with quinine as concurrent use may increase the risk of QT prolongation. Pitolisant prolongs the QT interval. Quinine has been associated with QT prolongation and rare cases of torsade de pointes (TdP).
Quizartinib: (Major) Concomitant use of quizartinib and pitolisant increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Ranolazine: (Major) Avoid coadministration of pitolisant with ranolazine as concurrent use may increase the risk of QT prolongation. Pitolisant prolongs the QT interval. Ranolazine is associated with dose- and plasma concentration-related increases in the QTc interval.
Relugolix: (Major) Avoid coadministration of pitolisant with relugolix as concurrent use may increase the risk of QT prolongation. Pitolisant prolongs the QT interval. Androgen deprivation therapy (i.e., relugolix) may also prolong the QT/QTc interval.
Relugolix; Estradiol; Norethindrone acetate: (Major) Advise patients to use an alternative, non-hormonal contraceptive during and for at least 21 days after discontinuation of pitolisant. Pitolisant is a weak CYP3A4 inducer and may decrease the plasma exposure of hormonal contraceptives resulting in decreased efficacy. (Major) Avoid coadministration of pitolisant with relugolix as concurrent use may increase the risk of QT prolongation. Pitolisant prolongs the QT interval. Androgen deprivation therapy (i.e., relugolix) may also prolong the QT/QTc interval.
Ribociclib: (Major) Avoid coadministration of pitolisant with ribociclib as concurrent use may increase the risk of QT prolongation. Pitolisant prolongs the QT interval. Ribociclib has been shown to prolong the QT interval in a concentration-dependent manner. The ribociclib ECG changes occurred within the first four weeks of treatment and were reversible with dose interruption.
Ribociclib; Letrozole: (Major) Avoid coadministration of pitolisant with ribociclib as concurrent use may increase the risk of QT prolongation. Pitolisant prolongs the QT interval. Ribociclib has been shown to prolong the QT interval in a concentration-dependent manner. The ribociclib ECG changes occurred within the first four weeks of treatment and were reversible with dose interruption.
Rifampin: (Major) Monitor for loss of pitolisant efficacy after initiation of rifampin. Increase to double the original daily dose of pitolisant over 7 days in patients stable on 8.9 mg or 17.8 mg once daily (i.e., 17.8 mg or 35.6 mg, respectively). Decrease the pitolisant dose by half if rifampin is discontinued. Pitolisant is a CYP3A4 substrate; rifampin is a strong CYP3A4 inducer. Coadministration of rifampin decreased pitolisant exposure by 50%.
Rifapentine: (Major) Monitor for loss of pitolisant efficacy after initiation of rifapentine. Increase to double the original daily dose of pitolisant over seven days in patients stable on 8.9 mg or 17.8 mg once daily (i.e., 17.8 mg or 35.6 mg, respectively). Decrease the pitolisant dose by one-half if rifapentine is discontinued. Pitolisant is a CYP3A4 substrate; rifapentine is a strong CYP3A4 inducer. Coadministration of strong CYP3A4 inducers decreases pitolisant exposure by 50%.
Rilpivirine: (Major) Avoid coadministration of pitolisant with rilpivirine as concurrent use may increase the risk of QT prolongation. Pitolisant prolongs the QT interval. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation.
Risperidone: (Major) Avoid coadministration of pitolisant with risperidone as concurrent use may increase the risk of QT prolongation. Pitolisant prolongs the QT interval. Risperidone has been associated with a possible risk for QT prolongation and/or TdP, primarily in the overdose setting.
Ritonavir: (Moderate) Monitor for decreased efficacy of ritonavir if coadministered with pitolisant. Concurrent use may decrease the plasma concentrations of ritonavir leading to a reduction of antiretroviral efficacy and the potential development of viral resistance. Ritonavir is a CYP3A substrate and pitolisant is a weak CYP3A inducer.
Romidepsin: (Major) Avoid coadministration of pitolisant with romidepsin as concurrent use may increase the risk of QT prolongation. If concomitant use is necessary, consider monitoring electrolytes and ECGs at baseline and periodically during treatment. Pitolisant prolongs the QT interval. Romidepsin has been reported to prolong the QT interval.
Saquinavir: (Major) Avoid coadministration of pitolisant with saquinavir/ritonavir as concurrent use may increase the risk of QT prolongation. If no acceptable alternative therapy is available, perform a baseline ECG prior to initiation of concomitant therapy and carefully follow monitoring recommendations. Pitolisant prolongs the QT interval. Saquinavir boosted with ritonavir increases the QT interval in a dose-dependent fashion, which may increase the risk for serious arrhythmias such as torsade de pointes (TdP).
Segesterone Acetate; Ethinyl Estradiol: (Major) Advise patients to use an alternative, non-hormonal contraceptive during and for at least 21 days after discontinuation of pitolisant. Pitolisant is a weak CYP3A4 inducer and may decrease the plasma exposure of hormonal contraceptives resulting in decreased efficacy.
Selpercatinib: (Major) Avoid coadministration of pitolisant with selpercatinib as concurrent use may increase the risk of QT prolongation. Monitor ECGs more frequently for QT prolongation if coadministration is necessary. Pitolisant prolongs the QT interval. Concentration-dependent QT prolongation has been observed with selpercatinib therapy.
Sertraline: (Major) Concomitant use of sertraline and pitolisant increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. The degree of QT prolongation associated with sertraline is not clinically significant when administered within the recommended dosage range; QT prolongation has been described at 2 times the maximum recommended dose.
Sevoflurane: (Major) Avoid coadministration of pitolisant with halogenated anesthetics as concurrent use may increase the risk of QT prolongation. Pitolisant prolongs the QT interval. Halogenated anesthetics can also prolong the QT interval.
Siponimod: (Major) Avoid coadministration of pitolisant with siponimod as concurrent use may increase the risk of QT prolongation. Consult a cardiologist regarding appropriate monitoring if siponimod use is required. Siponimod therapy prolonged the QT interval at recommended doses in a clinical study. Pitolisant prolongs the QT interval.
Sirolimus: (Moderate) Monitor sirolimus concentrations and adjust sirolimus dosage as appropriate during concomitant use of pitolisant. Concomitant use may decrease sirolimus exposure and efficacy. Sirolimus is a CYP3A substrate and pitolisant is a weak CYP3A inducer.
Sodium Stibogluconate: (Major) Concomitant use of sodium stibogluconate and pitolisant increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Solifenacin: (Major) Avoid coadministration of pitolisant with solifenacin as concurrent use may increase the risk of QT prolongation. Pitolisant prolongs the QT interval. Solifenacin has been associated with dose-dependent prolongation of the QT interval. Torsade de pointes (TdP) has been reported with postmarketing use, although causality was not determined.
Sorafenib: (Major) Avoid coadministration of sorafenib with pitolisant due to the risk of additive QT prolongation. Sorafenib is associated with QTc prolongation. Pitolisant also prolongs the QT interval.
Sotalol: (Major) Concomitant use of sotalol and pitolisant increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
St. John's Wort, Hypericum perforatum: (Major) Monitor for loss of pitolisant efficacy after initiation of St. John's Wort. Increase to double the original daily dose of pitolisant over 7 days in patients stable on 8.9 mg or 17.8 mg once daily (i.e., 17.8 mg or 35.6 mg, respectively). Decrease the pitolisant dose by half if St. John's Wort is discontinued. Pitolisant is a CYP3A4 substrate; St. John's Wort is a strong CYP3A4 inducer. Coadministration of strong CYP3A4 inducers decreases pitolisant exposure by 50%.
Sunitinib: (Major) Avoid coadministration of pitolisant with sunitinib as concurrent use may increase the risk of QT prolongation. If concomitant use is necessary, monitor for evidence of QT prolongation. Pitolisant prolongs the QT interval. Sunitinib can also prolong the QT interval.
Tacrolimus: (Major) Avoid coadministration of pitolisant with tacrolimus as concurrent use may increase the risk of QT prolongation. If concomitant use is necessary, consider ECG and electrolyte monitoring periodically during treatment. Pitolisant prolongs the QT interval. Tacrolimus may also prolong the QT interval and cause torsade de pointes (TdP).
Tamoxifen: (Major) Concomitant use of tamoxifen and pitolisant increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Telavancin: (Major) Avoid coadministration of pitolisant with telavancin as concurrent use may increase the risk of QT prolongation. Pitolisant prolongs the QT interval. Telavancin has been associated with QT prolongation.
Terbinafine: (Major) Initiate pitolisant at 8.9 mg once daily in patients taking terbinafine; increase pitolisant after 7 days to a maximum dosage of 17.8 mg once daily. If terbinafine is initiated in a patient on a stable dose of pitolisant, reduce the pitolisant dose by half. Pitolisant is a CYP2D6 substrate; terbinafine is a strong CYP2D6 inhibitor. Coadministration of strong CYP2D6 inhibitors increases pitolisant exposure by 2.2-fold.
Tetrabenazine: (Major) Avoid coadministration of pitolisant with tetrabenazine as concurrent use may increase the risk of QT prolongation. Pitolisant prolongs the QT interval. Tetrabenazine causes a small increase in the corrected QT interval (QTc).
Thioridazine: (Contraindicated) Coadministration of thioridazine with pitolisant is contraindicated due to the potential for QT prolongation and torsade de pointes (TdP). Thioridazine is associated with a well-established risk of QT prolongation and TdP. Pitolisant prolongs the QT interval.
Tipranavir: (Major) Initiate pitolisant at 8.9 mg once daily in patients taking tipranavir; increase pitolisant after 7 days to a maximum dosage of 17.8 mg once daily. If tipranavir is initiated in a patient on a stable dose of pitolisant, reduce the pitolisant dose by half. Pitolisant is a CYP2D6 substrate; tipranavir is a strong CYP2D6 inhibitor. Coadministration of strong CYP2D6 inhibitors increases pitolisant exposure by 2.2-fold.
Tolterodine: (Major) Avoid coadministration of pitolisant with tolterodine as concurrent use may increase the risk of QT prolongation. Pitolisant prolongs the QT interval. Tolterodine has been associated with dose-dependent prolongation of the QT interval, especially in poor CYP2D6 metabolizers.
Toremifene: (Major) Avoid coadministration of pitolisant with toremifene as concurrent use may increase the risk of QT prolongation. If concomitant use is unavoidable, closely monitor ECGs and electrolytes. Toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner. Pitolisant prolongs the QT interval.
Trazodone: (Major) Concomitant use of trazodone and pitolisant increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Triclabendazole: (Major) Concomitant use of triclabendazole and pitolisant increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Tricyclic antidepressants: (Major) Avoid coadministration of pitolisant with tricyclic antidepressants (TCAs) as the effect of pitolisant may be decreased; concurrent use may also increase the risk of QT prolongation. Pitolisant increases histamine concentrations in the brain; therefore, H1-receptor antagonists like TCAs, may reduce pitolisant efficacy. Pitolisant prolongs the QT interval. TCAs share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations).
Trifluoperazine: (Minor) Trifluoperazine is associated with a possible risk for QT prolongation. Theoretically, trifluoperazine may increase the risk of QT prolongation if coadministered with other drugs that have a risk of QT prolongation, such as pitolisant.
Trimipramine: (Major) Avoid coadministration of pitolisant with tricyclic antidepressants (TCAs) as the effect of pitolisant may be decreased; concurrent use may also increase the risk of QT prolongation. Pitolisant increases histamine concentrations in the brain; therefore, H1-receptor antagonists like TCAs, may reduce pitolisant efficacy. Pitolisant prolongs the QT interval. TCAs share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations).
Triptorelin: (Major) Avoid coadministration of pitolisant with triptorelin as concurrent use may increase the risk of QT prolongation. Pitolisant prolongs the QT interval. Androgen deprivation therapy (i.e., triptorelin) may prolong the QT/QTc interval.
Vandetanib: (Major) Avoid coadministration of vandetanib with pitolisant due to an increased risk of QT prolongation and torsade de pointes (TdP). If concomitant use is unavoidable, monitor ECGs for QT prolongation and monitor electrolytes; correct hypocalcemia, hypomagnesemia, and/or hypomagnesemia prior to vandetanib administration. An interruption of vandetanib therapy or dose reduction may be necessary for QT prolongation. Vandetanib can prolong the QT interval in a concentration-dependent manner; TdP and sudden death have been reported in patients receiving vandetanib. Pitolisant prolongs the QT interval.
Vardenafil: (Major) Concomitant use of vardenafil and pitolisant increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Vemurafenib: (Major) Avoid coadministration of pitolisant with vemurafenib as concurrent use may increase the risk of QT prolongation. If coadministration is necessary, monitor ECG. Pitolisant prolongs the QT interval. Vemurafenib has also been associated with QT prolongation.
Venlafaxine: (Major) Concomitant use of venlafaxine and pitolisant increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Voclosporin: (Major) Avoid concomitant use of pitolisant and voclosporin due to the risk of additive QT prolongation. Pitolisant prolongs the QT interval. Voclosporin has been associated with QT prolongation at supratherapeutic doses.
Vonoprazan; Amoxicillin; Clarithromycin: (Major) Avoid coadministration of pitolisant with clarithromycin as concurrent use may increase the risk of QT prolongation. Pitolisant prolongs the QT interval. Clarithromycin is associated with an established risk for QT prolongation and torsade de pointes (TdP).
Voriconazole: (Major) Avoid coadministration of pitolisant with voriconazole as concurrent use may increase the risk of QT prolongation. Pitolisant prolongs the QT interval. Voriconazole has been associated with QT prolongation and rare cases of torsade de pointes.
Vorinostat: (Major) Avoid coadministration of pitolisant with vorinostat as concurrent use may increase the risk of QT prolongation. Pitolisant prolongs the QT interval. Vorinostat therapy is also associated with a risk of QT prolongation.
Warfarin: (Moderate) Closely monitor the INR if coadministration of warfarin with pitolisant is necessary as concurrent use may decrease the exposure of warfarin leading to reduced efficacy. Pitolisant is a weak CYP3A4 inducer and the R-enantiomer of warfarin is a CYP3A4 substrate. The S-enantiomer of warfarin exhibits 2 to 5 times more anticoagulant activity than the R-enantiomer, but the R-enantiomer generally has a slower clearance.
Ziprasidone: (Major) Avoid coadministration of pitolisant with ziprasidone as concurrent use may increase the risk of QT prolongation. Pitolisant prolongs the QT interval. Clinical trial data indicate that ziprasidone causes QT prolongation; there are postmarketing reports of torsade de pointes (TdP) in patients with multiple confounding factors.
Pitolisant is a selective antagonist/inverse agonist of the histamine-3 (H3) receptor. HIstamine H3 receptors are mainly located in the brain. Activation of histaminergic neurons increases histamine release that promotes wakefulness, attention, and memory. Pitolisant regulates the release of other neurotransmitters involved in wake promotion, including dopamine, noradrenaline, and acetylcholine.
Pitolisant is administered orally. The approximate apparent volume of distribution of pitolisant is 700 L (5 to 10 L/kg). Serum protein binding is 91% to 96%. The blood to plasma ratio of pitolisant is 0.55 to 0.89. Metabolism primarily occurs by CYP2D6 and to a lesser extent by CYP3A4. Metabolites are not pharmacologically active and they are further metabolized or conjugated with glycine or glucuronic acid. Approximately 90% of a single 17.8 mg dose is excreted in urine (less than 2% unchanged) and 2.3% is excreted in the feces. The median half-life of pitolisant is approximately 20 hours (7.5 to 24.2 hours) following administration of a single 35.6 mg dose.
Affected cytochrome P450 (CYP450) isoenzymes and drug transporters: CYP2D6, CYP3A4
Pitolisant is predominately metabolized by CYP2D6 and to a lesser extent by CYP3A4. Concomitant administration of pitolisant with strong CYP2D6 inhibitors increases pitolisant exposure by 2.2-fold, and dose reductions of pitolisant are needed. Strong CYP3A4 inducers decrease exposure of pitolisant by 50%; dose adjustments may be necessary in some patients, as long as the usual maximum dosage is not exceeded. Pitolisant is a borderline/weak inducer of CYP3A4. Therefore, reduced effectiveness of sensitive CYP3A4 substrates, such as hormonal contraceptives, may occur when used concomitantly with the drug.
-Route-Specific Pharmacokinetics
Oral Route
Oral absorption of pitolisant is approximately 90%. The Cmax and AUC of pitolisant are 73 ng/mL (range: 49.2 to 126 ng/mL) and 821 ng x hour/mL (range: 518 to 1,468 ng x hour/mL), respectively, following administration of 35.6 mg once daily. The Cmax and AUC increase proportionally with the dose. The Tmax of pitolisant is 3.5 hours (range 2 to 5 hours). Steady-state is reached by day 7 of treatment. No significant differences in the pharmacokinetics of pitolisant were observed following administration with a high-fat meal.
-Special Populations
Hepatic Impairment
The AUC of pitolisant was increased by an approximate factor of 3 among 6 subjects with moderate hepatic impairment (Child-Pugh B) compared to 12 healthy subjects following receipt of a single 17.8 mg dose. The Cmax increased by an approximate factor of 1.5 of among 6 subjects with moderate hepatic impairment; however, the increase was not statistically significant. Among 6 subjects with mild hepatic impairment (Child-Pugh A) there were no significant changes in Cmax or AUC compared to healthy subjects. The effects of severe hepatic impairment (Child-Pugh C) on the pharmacokinetics of pitolisant are unknown.
Renal Impairment
The Cmax of pitolisant increased by an approximate factor of 3 among 4 subjects with severe renal impairment (eGFR 15 to 29 mL/minute/1.73 m2) compared to 12 healthy subjects following receipt of a single 17.8 mg dose. AUC increased by an approximate factor 2 of among patients with severe renal impairment. In 4 subjects with moderate renal impairment (eGFR 30 to 59 mL/minute/1.73 m2), AUC and Cmax increased by approximate factors of 2 and 1.5, respectively; the increase in Cmax was not statistically significant. In 4 subjects with mild renal impairment (eGFR 60 mL/minute/1.73 m2 or more), AUC and Cmax increased by an approximate factor of 2; the increases in AUC were not statistically significant. The effects of end-stage renal disease (eGFR less than 15 mL/minute/1.73 m2) on the pharmacokinetics of pitolisant are unknown.
Geriatric
The pharmacokinetics of pitolisant were not affected by age.
Gender Differences
The pharmacokinetics of pitolisant were not affected by gender.
Ethnic Differences
The pharmacokinetics of pitolisant were not affected by race.
Obesity
The pharmacokinetics of pitolisant were not affected by body weight (48 to 103 kg).
Other
CYP2D6 Poor Metabolizers
The Cmax and AUC of pitolisant increased approximately 2-fold among 3 CYP2D6 poor metabolizers compared to 5 CYP2D6 extensive (normal) metabolizers following receipt of pitolisant 17.8 mg for 7 days.