PONVORY

MS Agents
Sphingosine 1-phosphate receptor modulator

Ponesimod tablets should be swallowed whole.
May be administered with or without food.

bradycardia / Rapid / 5.8-5.8
AV block / Early / 3.4-3.4
hyperkalemia / Delayed / 0-2.0
seizures / Delayed / 1.4-1.4
macular edema / Delayed / 1.1-1.1
hypertensive crisis / Early / Incidence not known
progressive multifocal leukoencephalopathy / Delayed / Incidence not known
immune reconstitution syndrome / Delayed / Incidence not known
visual impairment / Early / Incidence not known
skin cancer / Delayed / Incidence not known
new primary malignancy / Delayed / Incidence not known
multiple sclerosis exacerbation / Delayed / Incidence not known

elevated hepatic enzymes / Delayed / 23.0-23.0
hypertension / Early / 10.1-10.1
cystitis / Delayed / 6.0-6.0
dyspnea / Early / 5.0-5.0
hypercholesterolemia / Delayed / 2.0-2.0
chest pain (unspecified) / Early / 2.0
migraine / Early / 2.0
depression / Delayed / 2.0
peripheral edema / Delayed / 2.0
QT prolongation / Rapid / Incidence not known
lymphopenia / Delayed / Incidence not known
encephalopathy / Delayed / Incidence not known
jaundice / Delayed / Incidence not known

infection / Delayed / 54.2-54.2
dizziness / Early / 5.0-5.0
cough / Delayed / 4.0-4.0
drowsiness / Early / 3.0-3.0
vertigo / Early / 2.0-2.0
fever / Early / 2.0-2.0
rhinitis / Early / 2.0
sinusitis / Delayed / 2.0
insomnia / Early / 2.0
dyspepsia / Early / 2.0
xerostomia / Early / 2.0
fatigue / Early / 2.0
back pain / Delayed / 2.0

PONVORY

Rx

Oral sphingosine 1-phosphate receptor modulator
Used in adult patients for the treatment of relapsing forms of multiple sclerosis
Patients with certain cardiac conditions should not receive this drug

Mild hepatic impairment (Child-Pugh class A): No dosage adjustments are needed.
Moderate or severe hepatic impairment (Child-Pugh class B or C): Use is not recommended.

No dosage adjustments are needed.

Acebutolol: (Moderate) Monitor for decreases in heart rate if concomitant use of ponesimod and beta-blockers is necessary. Consider a temporary interruption in beta-blocker therapy before initiating ponesimod in patients with a resting heart rate less than or equal to 55 bpm. Beta-blocker treatment can be initiated in patients receiving stable doses of ponesimod. Concomitant use of another beta-blocker with ponesimod resulted in a mean decrease in heart rate of 12.4 bpm after the first dose of ponesimod and 7.4 bpm after beginning maintenance ponesimod.
Adagrasib: (Major) Concomitant use of adagrasib and ponesimod 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. Ponesimod 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.
Albuterol; Budesonide: (Moderate) Monitor for signs and symptoms of infection. Additive immune suppression may result from concomitant use of ponesimod and high-dose corticosteroid therapy which may extend the duration or severity of immune suppression. High-dose corticosteroid therapy is generally defined as a dose of at least 20 mg/day of prednisone or equivalent (or 2 mg/kg/day for patients weighing less than 10 kg) for at least 14 consecutive days.
Alemtuzumab: (Major) Initiating treatment with ponesimod after alemtuzumab treatment is not recommended due to the characteristics and duration of the immunosuppressive effects of alemtuzumab.
Alfuzosin: (Major) In general, do not initiate ponesimod in patients taking alfuzosin 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. Alfuzosin may prolong the QT interval in a dose-dependent manner.
Amiodarone: (Major) In general, do not initiate ponesimod in patients taking amiodarone 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. Amiodarone, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and TdP. Although the frequency of TdP is less with amiodarone than with other Class III agents, amiodarone is still associated with a risk of TdP. Due to the extremely long half-life of amiodarone, a drug interaction is possible for days to weeks after discontinuation of amiodarone.
Amisulpride: (Major) In general, do not initiate ponesimod in patients taking amisulpride 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. Amisulpride causes dose- and concentration-dependent QT prolongation.
Amobarbital: (Major) Avoid concurrent use of ponesimod and barbiturates and monitor for decreased ponesimod efficacy if use is necessary. Ponesimod is a CYP3A substrate and barbiturates are strong CYP3A inducers that may decrease ponesimod exposure. Additionally, phenobarbital is known to also induce UGT1A1; ponesimod is also an UGT1A1 substrate.
Amoxicillin; Clarithromycin; Omeprazole: (Major) In general, do not initiate ponesimod in patients taking clarithromycin 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. Clarithromycin is associated with an established risk for QT prolongation and TdP.
Anagrelide: (Major) In general, do not initiate ponesimod in patients taking anagrelide 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. 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) Avoid concurrent use of ponesimod and apalutamide and monitor for decreased ponesimod efficacy if use is necessary. Ponesimod is a CYP3A substrate and apalutamide is a strong CYP3A inducer that may decrease ponesimod exposure.
Apomorphine: (Major) In general, do not initiate ponesimod in patients taking apomorphine 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. Dose-related QTc prolongation is associated with therapeutic apomorphine exposure.
Aripiprazole: (Major) In general, do not initiate ponesimod in patients taking aripiprazole 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. QT prolongation has occurred during therapeutic use of aripiprazole and following overdose.
Arsenic Trioxide: (Major) Avoid concomitant use of arsenic trioxide and ponesimod due to the risk of additive bradycardia, QT prolongation, and torsade de pointes (TdP); additive immunosuppression may also occur which may extend the duration or severity of immune suppression. If concomitant drug use is unavoidable, frequently monitor ECGs and for signs and symptoms of infection. Torsade de pointes (TdP), QT interval prolongation, and complete atrioventricular block have been reported with arsenic trioxide use. 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.
Artemether; Lumefantrine: (Major) In general, do not initiate ponesimod in patients taking artemether; lumefantrine due to the risk of additive bradycardia, QT prolongation, and torsade de pointes (TdP). If treatment initiation is considered, seek advice from a cardiologist and consider ECG monitoring. 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. Artemether; lumefantrine is associated with prolongation of the QT interval.
Asenapine: (Major) In general, do not initiate ponesimod in patients taking asenapine 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. Asenapine has been associated with QT prolongation.
Aspirin, ASA; Butalbital; Caffeine: (Major) Avoid concurrent use of ponesimod and barbiturates and monitor for decreased ponesimod efficacy if use is necessary. Ponesimod is a CYP3A substrate and barbiturates are strong CYP3A inducers that may decrease ponesimod exposure. Additionally, phenobarbital is known to also induce UGT1A1; ponesimod is also an UGT1A1 substrate.
Atenolol: (Moderate) Monitor for decreases in heart rate if concomitant use of ponesimod and beta-blockers is necessary. Consider a temporary interruption in beta-blocker therapy before initiating ponesimod in patients with a resting heart rate less than or equal to 55 bpm. Beta-blocker treatment can be initiated in patients receiving stable doses of ponesimod. Concomitant use of another beta-blocker with ponesimod resulted in a mean decrease in heart rate of 12.4 bpm after the first dose of ponesimod and 7.4 bpm after beginning maintenance ponesimod.
Atenolol; Chlorthalidone: (Moderate) Monitor for decreases in heart rate if concomitant use of ponesimod and beta-blockers is necessary. Consider a temporary interruption in beta-blocker therapy before initiating ponesimod in patients with a resting heart rate less than or equal to 55 bpm. Beta-blocker treatment can be initiated in patients receiving stable doses of ponesimod. Concomitant use of another beta-blocker with ponesimod resulted in a mean decrease in heart rate of 12.4 bpm after the first dose of ponesimod and 7.4 bpm after beginning maintenance ponesimod.
Atomoxetine: (Major) In general, do not initiate ponesimod in patients taking atomoxetine 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. QT prolongation has occurred during therapeutic use of atomoxetine and following overdose.
Azithromycin: (Major) Avoid coadministration of azithromycin with ponesimod 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. QT prolongation and torsade de pointes (TdP) have been spontaneously reported during azithromycin postmarketing surveillance. 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.
Bacillus Calmette-Guerin Vaccine, BCG: (Contraindicated) Avoid vaccines containing live virus (live attenuated vaccines) during treatment with ponesimod. If a live attenuated vaccine is required, administer at least 1 month (4 weeks) before initiation of ponesimod. The use of live attenuated vaccines may carry the risk of infection and should therefore be avoided during ponesimod treatment and for 1 to 2 weeks after discontinuation of ponesimod. During treatment, and for up to 1 to 2 weeks after discontinuation of ponesimod, vaccinations may also be less effective.
Barbiturates: (Major) Avoid concurrent use of ponesimod and barbiturates and monitor for decreased ponesimod efficacy if use is necessary. Ponesimod is a CYP3A substrate and barbiturates are strong CYP3A inducers that may decrease ponesimod exposure. Additionally, phenobarbital is known to also induce UGT1A1; ponesimod is also an UGT1A1 substrate.
Bedaquiline: (Major) In general, do not initiate ponesimod in patients taking bedaquiline 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.
Beta-blockers (without QT/QTc prolongation): (Moderate) Monitor for decreases in heart rate if concomitant use of ponesimod and beta-blockers is necessary. Consider a temporary interruption in beta-blocker therapy before initiating ponesimod in patients with a resting heart rate less than or equal to 55 bpm. Beta-blocker treatment can be initiated in patients receiving stable doses of ponesimod. Concomitant use of another beta-blocker with ponesimod resulted in a mean decrease in heart rate of 12.4 bpm after the first dose of ponesimod and 7.4 bpm after beginning maintenance ponesimod.
Betamethasone: (Moderate) Monitor for signs and symptoms of infection. Additive immune suppression may result from concomitant use of ponesimod and high-dose corticosteroid therapy which may extend the duration or severity of immune suppression. High-dose corticosteroid therapy is generally defined as a dose of at least 20 mg/day of prednisone or equivalent (or 2 mg/kg/day for patients weighing less than 10 kg) for at least 14 consecutive days.
Betaxolol: (Moderate) Monitor for decreases in heart rate if concomitant use of ponesimod and beta-blockers is necessary. Consider a temporary interruption in beta-blocker therapy before initiating ponesimod in patients with a resting heart rate less than or equal to 55 bpm. Beta-blocker treatment can be initiated in patients receiving stable doses of ponesimod. Concomitant use of another beta-blocker with ponesimod resulted in a mean decrease in heart rate of 12.4 bpm after the first dose of ponesimod and 7.4 bpm after beginning maintenance ponesimod.
Bismuth Subcitrate Potassium; Metronidazole; Tetracycline: (Major) Concomitant use of metronidazole and ponesimod 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. Ponesimod 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.
Bismuth Subsalicylate; Metronidazole; Tetracycline: (Major) Concomitant use of metronidazole and ponesimod 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. Ponesimod 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.
Bisoprolol: (Moderate) Monitor for decreases in heart rate if concomitant use of ponesimod and beta-blockers is necessary. Consider a temporary interruption in beta-blocker therapy before initiating ponesimod in patients with a resting heart rate less than or equal to 55 bpm. Beta-blocker treatment can be initiated in patients receiving stable doses of ponesimod. Concomitant use of another beta-blocker with ponesimod resulted in a mean decrease in heart rate of 12.4 bpm after the first dose of ponesimod and 7.4 bpm after beginning maintenance ponesimod.
Bisoprolol; Hydrochlorothiazide, HCTZ: (Moderate) Monitor for decreases in heart rate if concomitant use of ponesimod and beta-blockers is necessary. Consider a temporary interruption in beta-blocker therapy before initiating ponesimod in patients with a resting heart rate less than or equal to 55 bpm. Beta-blocker treatment can be initiated in patients receiving stable doses of ponesimod. Concomitant use of another beta-blocker with ponesimod resulted in a mean decrease in heart rate of 12.4 bpm after the first dose of ponesimod and 7.4 bpm after beginning maintenance ponesimod.
Brimonidine; Timolol: (Moderate) Monitor for decreases in heart rate if concomitant use of ponesimod and beta-blockers is necessary. Consider a temporary interruption in beta-blocker therapy before initiating ponesimod in patients with a resting heart rate less than or equal to 55 bpm. Beta-blocker treatment can be initiated in patients receiving stable doses of ponesimod. Concomitant use of another beta-blocker with ponesimod resulted in a mean decrease in heart rate of 12.4 bpm after the first dose of ponesimod and 7.4 bpm after beginning maintenance ponesimod.
Budesonide: (Moderate) Monitor for signs and symptoms of infection. Additive immune suppression may result from concomitant use of ponesimod and high-dose corticosteroid therapy which may extend the duration or severity of immune suppression. High-dose corticosteroid therapy is generally defined as a dose of at least 20 mg/day of prednisone or equivalent (or 2 mg/kg/day for patients weighing less than 10 kg) for at least 14 consecutive days.
Budesonide; Formoterol: (Moderate) Monitor for signs and symptoms of infection. Additive immune suppression may result from concomitant use of ponesimod and high-dose corticosteroid therapy which may extend the duration or severity of immune suppression. High-dose corticosteroid therapy is generally defined as a dose of at least 20 mg/day of prednisone or equivalent (or 2 mg/kg/day for patients weighing less than 10 kg) for at least 14 consecutive days.
Budesonide; Glycopyrrolate; Formoterol: (Moderate) Monitor for signs and symptoms of infection. Additive immune suppression may result from concomitant use of ponesimod and high-dose corticosteroid therapy which may extend the duration or severity of immune suppression. High-dose corticosteroid therapy is generally defined as a dose of at least 20 mg/day of prednisone or equivalent (or 2 mg/kg/day for patients weighing less than 10 kg) for at least 14 consecutive days.
Buprenorphine: (Major) In general, do not initiate ponesimod in patients taking buprenorphine 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. Buprenorphine has been associated with QT prolongation and has a possible risk of TdP.
Buprenorphine; Naloxone: (Major) In general, do not initiate ponesimod in patients taking buprenorphine 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. Buprenorphine has been associated with QT prolongation and has a possible risk of TdP.
Butabarbital: (Major) Avoid concurrent use of ponesimod and barbiturates and monitor for decreased ponesimod efficacy if use is necessary. Ponesimod is a CYP3A substrate and barbiturates are strong CYP3A inducers that may decrease ponesimod exposure. Additionally, phenobarbital is known to also induce UGT1A1; ponesimod is also an UGT1A1 substrate.
Butalbital; Acetaminophen: (Major) Avoid concurrent use of ponesimod and barbiturates and monitor for decreased ponesimod efficacy if use is necessary. Ponesimod is a CYP3A substrate and barbiturates are strong CYP3A inducers that may decrease ponesimod exposure. Additionally, phenobarbital is known to also induce UGT1A1; ponesimod is also an UGT1A1 substrate.
Butalbital; Acetaminophen; Caffeine: (Major) Avoid concurrent use of ponesimod and barbiturates and monitor for decreased ponesimod efficacy if use is necessary. Ponesimod is a CYP3A substrate and barbiturates are strong CYP3A inducers that may decrease ponesimod exposure. Additionally, phenobarbital is known to also induce UGT1A1; ponesimod is also an UGT1A1 substrate.
Butalbital; Acetaminophen; Caffeine; Codeine: (Major) Avoid concurrent use of ponesimod and barbiturates and monitor for decreased ponesimod efficacy if use is necessary. Ponesimod is a CYP3A substrate and barbiturates are strong CYP3A inducers that may decrease ponesimod exposure. Additionally, phenobarbital is known to also induce UGT1A1; ponesimod is also an UGT1A1 substrate.
Butalbital; Aspirin; Caffeine; Codeine: (Major) Avoid concurrent use of ponesimod and barbiturates and monitor for decreased ponesimod efficacy if use is necessary. Ponesimod is a CYP3A substrate and barbiturates are strong CYP3A inducers that may decrease ponesimod exposure. Additionally, phenobarbital is known to also induce UGT1A1; ponesimod is also an UGT1A1 substrate.
Cabotegravir; Rilpivirine: (Major) In general, do not initiate ponesimod in patients taking rilpivirine 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. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation.
Carbamazepine: (Major) Avoid concurrent use of ponesimod and carbamazepine and monitor for decreased ponesimod efficacy if use is necessary. Ponesimod is a CYP3A and an UGT1A1 substrate and carbamazepine is a strong CYP3A inducer and an UGT1A1 inducer that may decrease ponesimod exposure.
Carteolol: (Moderate) Monitor for decreases in heart rate if concomitant use of ponesimod and beta-blockers is necessary. Consider a temporary interruption in beta-blocker therapy before initiating ponesimod in patients with a resting heart rate less than or equal to 55 bpm. Beta-blocker treatment can be initiated in patients receiving stable doses of ponesimod. Concomitant use of another beta-blocker with ponesimod resulted in a mean decrease in heart rate of 12.4 bpm after the first dose of ponesimod and 7.4 bpm after beginning maintenance ponesimod.
Carvedilol: (Moderate) Monitor for decreases in heart rate if concomitant use of ponesimod and beta-blockers is necessary. Consider a temporary interruption in beta-blocker therapy before initiating ponesimod in patients with a resting heart rate less than or equal to 55 bpm. Beta-blocker treatment can be initiated in patients receiving stable doses of ponesimod. Concomitant use of another beta-blocker with ponesimod resulted in a mean decrease in heart rate of 12.4 bpm after the first dose of ponesimod and 7.4 bpm after beginning maintenance ponesimod.
Ceritinib: (Major) Avoid concomitant use of ponesimod and ceritinib due to the risk of severe bradycardia and heart block, QT prolongation, and torsade de pointes (TdP); additive immunosuppression may also occur which may extend the duration or severity of immune suppression. If concomitant use is unavoidable, monitor ECGs, electrolytes, and for signs and symptoms of infection; an interruption of ceritinib therapy, dose reduction, or discontinuation of therapy may be necessary if QT prolongation occurs. Ceritinib causes concentration-dependent QT prolongation. 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.
Chloroquine: (Major) Avoid coadministration of chloroquine with ponesimod due to the increased risk of QT prolongation and torsade de pointes (TdP). 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 TdP; the risk of QT prolongation is increased with higher chloroquine doses. 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.
Chlorpromazine: (Major) In general, do not initiate ponesimod in patients taking chlorpromazine 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. Chlorpromazine is associated with an established risk of QT prolongation and TdP.
Chlorthalidone; Clonidine: (Major) Avoid concomitant use of ponesimod and medications that may decrease heart rate such as clonidine due to the risk for severe bradycardia and heart block. Consider consultation from a cardiologist if concomitant use is necessary.
Cholera Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the live cholera vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to cholera bacteria after receiving the vaccine.
Ciprofloxacin: (Major) Concomitant use of ciprofloxacin and ponesimod 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. Ponesimod 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.
Cisapride: (Contraindicated) Coadministration of cisapride with ponesimod is contraindicated due to the risk for additive QT prolongation and torsade de pointes (TdP). QT prolongation and ventricular arrhythmias, including TdP and death, have been reported with cisapride. 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.
Citalopram: (Major) In general, do not initiate ponesimod in patients taking citalopram 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.
Clarithromycin: (Major) In general, do not initiate ponesimod in patients taking clarithromycin 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. Clarithromycin is associated with an established risk for QT prolongation and TdP.
Clofazimine: (Major) Concomitant use of clofazimine and ponesimod 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. Ponesimod 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.
Clonidine: (Major) Avoid concomitant use of ponesimod and medications that may decrease heart rate such as clonidine due to the risk for severe bradycardia and heart block. Consider consultation from a cardiologist if concomitant use is necessary.
Clozapine: (Major) In general, do not initiate ponesimod in patients taking clozapine 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. Treatment with clozapine has been associated with QT prolongation, TdP, cardiac arrest, and sudden death.
Codeine; Phenylephrine; Promethazine: (Major) In general, do not initiate ponesimod in patients taking promethazine 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. Promethazine is associated with a possible risk for QT prolongation.
Codeine; Promethazine: (Major) In general, do not initiate ponesimod in patients taking promethazine 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. Promethazine is associated with a possible risk for QT prolongation.
Corticosteroids (systemic): (Moderate) Monitor for signs and symptoms of infection. Additive immune suppression may result from concomitant use of ponesimod and high-dose corticosteroid therapy which may extend the duration or severity of immune suppression. High-dose corticosteroid therapy is generally defined as a dose of at least 20 mg/day of prednisone or equivalent (or 2 mg/kg/day for patients weighing less than 10 kg) for at least 14 consecutive days.
Cortisone: (Moderate) Monitor for signs and symptoms of infection. Additive immune suppression may result from concomitant use of ponesimod and high-dose corticosteroid therapy which may extend the duration or severity of immune suppression. High-dose corticosteroid therapy is generally defined as a dose of at least 20 mg/day of prednisone or equivalent (or 2 mg/kg/day for patients weighing less than 10 kg) for at least 14 consecutive days.
Crizotinib: (Major) Avoid concomitant use of ponesimod and crizotinib due to the risk of severe bradycardia and heart block, QT prolongation, and torsade de pointes (TdP); additive immunosuppression may also occur which may extend the duration or severity of immune suppression. If concomitant use is unavoidable, monitor ECGs, electrolytes, and for signs and symptoms of infection; 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. 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.
Dasatinib: (Major) In general, do not initiate ponesimod in patients taking dasatinib due to the risk of additive bradycardia, QT prolongation, and torsade de pointes (TdP); additive immunosuppression may also occur which may extend the duration or severity of immune suppression. If treatment initiation is considered, seek advice from a cardiologist and monitor for signs and symptoms of infection. 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. In vitro studies have shown that dasatinib has the potential to prolong the QT interval.
Deflazacort: (Moderate) Monitor for signs and symptoms of infection. Additive immune suppression may result from concomitant use of ponesimod and high-dose corticosteroid therapy which may extend the duration or severity of immune suppression. High-dose corticosteroid therapy is generally defined as a dose of at least 20 mg/day of prednisone or equivalent (or 2 mg/kg/day for patients weighing less than 10 kg) for at least 14 consecutive days.
Degarelix: (Major) In general, do not initiate ponesimod in patients taking degarelix 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. Androgen deprivation therapy (i.e., degarelix) may prolong the QT/QTc interval.
Desflurane: (Major) In general, do not initiate ponesimod in patients taking halogenated anesthetics 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. Halogenated anesthetics can prolong the QT interval.
Deutetrabenazine: (Major) In general, do not initiate ponesimod in patients taking deutetrabenazine 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. 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.
Dexamethasone: (Moderate) Monitor for signs and symptoms of infection. Additive immune suppression may result from concomitant use of ponesimod and high-dose corticosteroid therapy which may extend the duration or severity of immune suppression. High-dose corticosteroid therapy is generally defined as a dose of at least 20 mg/day of prednisone or equivalent (or 2 mg/kg/day for patients weighing less than 10 kg) for at least 14 consecutive days.
Dexmedetomidine: (Major) Concomitant use of dexmedetomidine and ponesimod 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. Ponesimod 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.
Dextromethorphan; Quinidine: (Major) In general, do not initiate ponesimod in patients taking quinidine 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. Quinidine administration is associated with QT prolongation and TdP.
Digoxin: (Major) Avoid concomitant use of ponesimod and medications that may decrease heart rate such as digoxin due to the risk for severe bradycardia and heart block. Consider consultation from a cardiologist if concomitant use is necessary.
Diltiazem: (Major) Avoid concomitant use of ponesimod and medications that may decrease heart rate such as diltiazem due to the risk for severe bradycardia and heart block. Consider consultation from a cardiologist if concomitant use is necessary.
Disopyramide: (Major) In general, do not initiate ponesimod in patients taking disopyramide 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. Disopyramide administration is associated with QT prolongation and TdP.
Dofetilide: (Major) In general, do not initiate ponesimod in patients taking dofetilide 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. Dofetilide, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and TdP.
Dolasetron: (Major) In general, do not initiate ponesimod in patients taking dolasetron 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. Dolasetron has been associated with a dose-dependent prolongation in the QT, PR, and QRS intervals on an electrocardiogram.
Dolutegravir; Rilpivirine: (Major) In general, do not initiate ponesimod in patients taking rilpivirine 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. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation.
Donepezil: (Major) In general, do not initiate ponesimod in patients taking donepezil 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. Case reports indicate that QT prolongation and TdP can occur during donepezil therapy.
Donepezil; Memantine: (Major) In general, do not initiate ponesimod in patients taking donepezil 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. Case reports indicate that QT prolongation and TdP can occur during donepezil therapy.
Dorzolamide; Timolol: (Moderate) Monitor for decreases in heart rate if concomitant use of ponesimod and beta-blockers is necessary. Consider a temporary interruption in beta-blocker therapy before initiating ponesimod in patients with a resting heart rate less than or equal to 55 bpm. Beta-blocker treatment can be initiated in patients receiving stable doses of ponesimod. Concomitant use of another beta-blocker with ponesimod resulted in a mean decrease in heart rate of 12.4 bpm after the first dose of ponesimod and 7.4 bpm after beginning maintenance ponesimod.
Dronedarone: (Contraindicated) Coadministration of dronedarone with ponesimod is contraindicated due to the risk for additive QT prolongation and torsade de pointes (TdP). 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. 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.
Droperidol: (Major) Avoid coadministration of droperidol with ponesimod due to the risk of additive bradycardia, QT prolongation, and torsade de pointes (TdP). If coadministration cannot be avoided, seek advice from a cardiologist and initiate droperidol at a low dose. Droperidol administration is associated with an established risk for QT prolongation and TdP. Some cases have occurred in patients with no known risk factors for QT prolongation and some cases have been fatal. 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.
Efavirenz: (Major) In general, do not initiate ponesimod in patients taking efavirenz 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. QTc prolongation has been observed with the use of efavirenz.
Efavirenz; Emtricitabine; Tenofovir Disoproxil Fumarate: (Major) In general, do not initiate ponesimod in patients taking efavirenz 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. QTc prolongation has been observed with the use of efavirenz.
Efavirenz; Lamivudine; Tenofovir Disoproxil Fumarate: (Major) In general, do not initiate ponesimod in patients taking efavirenz 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. QTc prolongation has been observed with the use of efavirenz.
Eliglustat: (Major) In general, do not initiate ponesimod in patients taking eliglustat 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. Eliglustat is predicted to cause PR, QRS, and/or QT prolongation at significantly elevated plasma concentrations.
Emtricitabine; Rilpivirine; Tenofovir alafenamide: (Major) In general, do not initiate ponesimod in patients taking rilpivirine 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. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation.
Emtricitabine; Rilpivirine; Tenofovir Disoproxil Fumarate: (Major) In general, do not initiate ponesimod in patients taking rilpivirine 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. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation.
Encorafenib: (Major) Avoid coadministration of encorafenib and ponesimod due to the risk of additive bradycardia, QT prolongation, and torsade de pointes (TdP); additive immunosuppression may also occur which may extend the duration or severity of immune suppression. If concurrent use cannot be avoided, monitor ECGs, electrolytes, and for signs and symptoms of infection; correct hypokalemia and hypomagnesemia prior to treatment. Encorafenib has been associated with dose-dependent QT prolongation. 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.
Entrectinib: (Major) In general, do not initiate ponesimod in patients taking entrectinib due to the risk of additive bradycardia, QT prolongation, and torsade de pointes (TdP); additive immunosuppression may also occur which may extend the duration or severity of immune suppression. If treatment initiation is considered, seek advice from a cardiologist and monitor for signs and symptoms of infection. 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. Entrectinib has been associated with QT prolongation.
Enzalutamide: (Major) Avoid concurrent use of ponesimod and enzalutamide and monitor for decreased ponesimod efficacy if use is necessary. Ponesimod is a CYP3A substrate and enzalutamide is a strong CYP3A inducer that may decrease ponesimod exposure.
Eribulin: (Major) In general, do not initiate ponesimod in patients taking eribulin due to the risk of additive bradycardia, QT prolongation, and torsade de pointes (TdP); additive immunosuppression may also occur which may extend the duration or severity of immune suppression. If treatment initiation is considered, monitor ECGs and for signs and symptoms of infection. 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. Eribulin has been associated with QT prolongation.
Erythromycin: (Major) In general, do not initiate ponesimod in patients taking erythromycin 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. Erythromycin is associated with QT prolongation and TdP.
Escitalopram: (Major) In general, do not initiate ponesimod in patients taking escitalopram 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. Escitalopram has been associated with a risk of QT prolongation and torsade de pointes (TdP).
Esmolol: (Moderate) Monitor for decreases in heart rate if concomitant use of ponesimod and beta-blockers is necessary. Consider a temporary interruption in beta-blocker therapy before initiating ponesimod in patients with a resting heart rate less than or equal to 55 bpm. Beta-blocker treatment can be initiated in patients receiving stable doses of ponesimod. Concomitant use of another beta-blocker with ponesimod resulted in a mean decrease in heart rate of 12.4 bpm after the first dose of ponesimod and 7.4 bpm after beginning maintenance ponesimod.
Etravirine: (Major) Avoid concurrent use of ponesimod and etravirine and monitor for decreased ponesimod efficacy if use is necessary. Ponesimod is an UGT1A1 substrate and etravirine is an UGT1A1 inducer that may decrease ponesimod exposure.
Flecainide: (Major) In general, do not initiate ponesimod in patients taking flecainide 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. Flecainide is a Class IC antiarrhythmic associated with a possible risk for QT prolongation and/or TdP; flecainide increases the QT interval, but largely due to prolongation of the QRS interval. Although causality for TdP has not been established for flecainide, patients receiving concurrent drugs that have the potential for QT prolongation may have an increased risk of developing proarrhythmias.
Fluconazole: (Major) In general, do not initiate ponesimod in patients taking fluconazole 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. Fluconazole has been associated with QT prolongation and rare cases of TdP.
Fludrocortisone: (Moderate) Monitor for signs and symptoms of infection. Additive immune suppression may result from concomitant use of ponesimod and high-dose corticosteroid therapy which may extend the duration or severity of immune suppression. High-dose corticosteroid therapy is generally defined as a dose of at least 20 mg/day of prednisone or equivalent (or 2 mg/kg/day for patients weighing less than 10 kg) for at least 14 consecutive days.
Fluoxetine: (Major) In general, do not initiate ponesimod in patients taking fluoxetine 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. Fluoxetine is associated with QT prolongation and TdP.
Fluphenazine: (Minor) Concurrent use of ponesimod and fluphenazine may increase the risk of additive bradycardia, QT prolongation, and torsade de pointes (TdP). 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. 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.
Fluvoxamine: (Major) In general, do not initiate ponesimod in patients taking fluvoxamine 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. Fluvoxamine is associated with QT prolongation and TdP.
Foscarnet: (Major) In general, do not initiate ponesimod in patients taking foscarnet 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. Both QT prolongation and TdP have been reported during postmarketing use of foscarnet.
Fosphenytoin: (Major) Avoid concurrent use of ponesimod and fosphenytoin and monitor for decreased ponesimod efficacy if use is necessary. Ponesimod is a CYP3A and an UGT1A1 substrate and fosphenytoin is a strong CYP3A inducer and an UGT1A1 inducer that may decrease ponesimod exposure.
Fostemsavir: (Major) In general, do not initiate ponesimod in patients taking fostemsavir 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. 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) In general, do not initiate ponesimod in patients taking gemifloxacin 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. 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) In general, do not initiate ponesimod in patients taking gemtuzumab due to the risk of additive bradycardia, QT prolongation, and torsade de pointes (TdP); additive immunosuppression may also occur which may extend the duration or severity of immune suppression. If treatment initiation is considered, obtain an ECG and serum electrolytes prior to the start of gemtuzumab and as needed during treatment; monitor for signs and symptoms of infection. 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. Although QT interval prolongation has not been reported with gemtuzumab, it has been reported with other drugs that contain calicheamicin.
Gilteritinib: (Major) In general, do not initiate ponesimod in patients taking gilteritinib due to the risk of additive bradycardia, QT prolongation, and torsade de pointes (TdP); additive immunosuppression may also occur which may extend the duration or severity of immune suppression. If treatment initiation is considered, seek advice from a cardiologist and monitor for signs and symptoms of infection. 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. Gilteritinib has been associated with QT prolongation.
Glasdegib: (Major) Avoid coadministration of glasdegib and ponesimod due to the risk of additive bradycardia, Q T prolongation, and torsade de pointes (TdP); additive immunosuppression may also occur which may extend the duration or severity of immune suppression. If coadministration cannot be avoided, monitor patients for increased risk of QT prolongation with increased frequency of ECG monitoring and monitor for signs and symptoms of infection. Glasdegib therapy may result in QT prolongation and ventricular arrhythmias including ventricular fibrillation and ventricular tachycardia. 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.
Goserelin: (Major) In general, do not initiate ponesimod in patients taking goserelin 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. Androgen deprivation therapy (i.e., goserelin) may prolong the QT/QTc interval.
Granisetron: (Major) In general, do not initiate ponesimod in patients taking granisetron 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. Granisetron has been associated with QT prolongation.
Halogenated Anesthetics: (Major) In general, do not initiate ponesimod in patients taking halogenated anesthetics 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. Halogenated anesthetics can prolong the QT interval.
Haloperidol: (Major) In general, do not initiate ponesimod in patients taking haloperidol 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. QT prolongation and 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) In general, do not initiate ponesimod in patients taking histrelin 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. Androgen deprivation therapy (i.e., histrelin) may prolong the QT/QTc interval.
Hydrocortisone: (Moderate) Monitor for signs and symptoms of infection. Additive immune suppression may result from concomitant use of ponesimod and high-dose corticosteroid therapy which may extend the duration or severity of immune suppression. High-dose corticosteroid therapy is generally defined as a dose of at least 20 mg/day of prednisone or equivalent (or 2 mg/kg/day for patients weighing less than 10 kg) for at least 14 consecutive days.
Hydroxychloroquine: (Major) Avoid coadministration of hydroxychloroquine and ponesimod due to the risk of increased 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. Hydroxychloroquine prolongs the QT interval. 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 torsade de pointes in patients with bradycardia.
Hydroxyzine: (Major) In general, do not initiate ponesimod in patients taking hydroxyzine 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. Postmarketing data indicate that hydroxyzine causes QT prolongation and TdP.
Ibutilide: (Major) In general, do not initiate ponesimod in patients taking ibutilide 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. Ibutilide administration can cause QT prolongation and 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) In general, do not initiate ponesimod in patients taking iloperidone 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. Iloperidone has been associated with QT prolongation.
Inotuzumab Ozogamicin: (Major) Avoid coadministration of inotuzumab and ponesimod due to the risk of additive bradycardia, QT prolongation, and torsade de pointes (TdP); additive immunosuppression may also occur which may extend the duration or severity of immune suppression. If coadministration is unavoidable, obtain ECGs and electrolytes prior to the start of treatment and periodically during treatment and monitor for signs and symptoms of infection. Inotuzumab has been associated with QT interval prolongation. 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.
Intranasal Influenza Vaccine: (Contraindicated) Avoid vaccines containing live virus (live attenuated vaccines) during treatment with ponesimod. If a live attenuated vaccine is required, administer at least 1 month (4 weeks) before initiation of ponesimod. The use of live attenuated vaccines may carry the risk of infection and should therefore be avoided during ponesimod treatment and for 1 to 2 weeks after discontinuation of ponesimod. During treatment, and for up to 1 to 2 weeks after discontinuation of ponesimod, vaccinations may also be less effective.
Isoflurane: (Major) In general, do not initiate ponesimod in patients taking halogenated anesthetics 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. Halogenated anesthetics can prolong the QT interval.
Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Major) Avoid concurrent use of ponesimod and rifampin and monitor for decreased ponesimod efficacy if use is necessary. Ponesimod is a CYP3A and an UGT1A1 substrate and rifampin is a strong CYP3A inducer and an UGT1A1 inducer that may decrease ponesimod exposure.
Isoniazid, INH; Rifampin: (Major) Avoid concurrent use of ponesimod and rifampin and monitor for decreased ponesimod efficacy if use is necessary. Ponesimod is a CYP3A and an UGT1A1 substrate and rifampin is a strong CYP3A inducer and an UGT1A1 inducer that may decrease ponesimod exposure.
Itraconazole: (Major) In general, do not initiate ponesimod in patients taking itraconazole 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. Itraconazole has been associated with prolongation of the QT interval.
Ivabradine: (Major) Avoid concomitant use of ponesimod and medications that may decrease heart rate such as ivabradine due to the risk for severe bradycardia and heart block. Consider consultation from a cardiologist if concomitant use is necessary.
Ivosidenib: (Major) Avoid coadministration of ivosidenib with ponesimod if possible due to the risk of additive bradycardia, QT prolongation, and torsade de pointes (TdP); additive immunosuppression may also occur which may extend the duration or severity of immune suppression. If concomitant use is unavoidable, monitor ECGs, electrolytes, and for signs and symptoms of infection; 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. 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.
Ketoconazole: (Contraindicated) Avoid concomitant use of ketoconazole and ponesimod due to an increased risk for torsade de pointes (TdP) and QT/QTc prolongation. Ponesimod 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.
Labetalol: (Moderate) Monitor for decreases in heart rate if concomitant use of ponesimod and beta-blockers is necessary. Consider a temporary interruption in beta-blocker therapy before initiating ponesimod in patients with a resting heart rate less than or equal to 55 bpm. Beta-blocker treatment can be initiated in patients receiving stable doses of ponesimod. Concomitant use of another beta-blocker with ponesimod resulted in a mean decrease in heart rate of 12.4 bpm after the first dose of ponesimod and 7.4 bpm after beginning maintenance ponesimod.
Lansoprazole; Amoxicillin; Clarithromycin: (Major) In general, do not initiate ponesimod in patients taking clarithromycin 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. Clarithromycin is associated with an established risk for QT prolongation and TdP.
Lapatinib: (Major) In general, do not initiate ponesimod in patients taking lapatinib due to the risk of additive bradycardia, QT prolongation, and torsade de pointes (TdP); additive immunosuppression may also occur which may extend the duration or severity of immune suppression. If treatment initiation is considered, seek advice from a cardiologist and monitor for signs and symptoms of infection. 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. Lapatinib has been associated with concentration-dependent QT prolongation; ventricular arrhythmias and TdP have been reported in postmarketing experience with lapatinib.
Lasmiditan: (Major) Avoid concomitant use of ponesimod and medications that may decrease heart rate such as lasmiditan due to the risk for severe bradycardia and heart block. Consider consultation from a cardiologist if concomitant use is necessary.
Lefamulin: (Major) Avoid coadministration of lefamulin with ponesimod as concurrent use may increase the risk of QT prolongation. If coadministration cannot be avoided, ECG monitoring is recommended 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. 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 torsade de pointes in patients with bradycardia.
Lenvatinib: (Major) In general, do not initiate ponesimod in patients taking lenvatinib 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. Prolongation of the QT interval has been reported with lenvatinib therapy.
Leuprolide: (Major) In general, do not initiate ponesimod in patients taking leuprolide 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. Androgen deprivation therapy (i.e., leuprolide) may prolong the QT/QTc interval.
Leuprolide; Norethindrone: (Major) In general, do not initiate ponesimod in patients taking leuprolide 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. Androgen deprivation therapy (i.e., leuprolide) may prolong the QT/QTc interval.
Levobunolol: (Moderate) Monitor for decreases in heart rate if concomitant use of ponesimod and beta-blockers is necessary. Consider a temporary interruption in beta-blocker therapy before initiating ponesimod in patients with a resting heart rate less than or equal to 55 bpm. Beta-blocker treatment can be initiated in patients receiving stable doses of ponesimod. Concomitant use of another beta-blocker with ponesimod resulted in a mean decrease in heart rate of 12.4 bpm after the first dose of ponesimod and 7.4 bpm after beginning maintenance ponesimod.
Levofloxacin: (Major) Concomitant use of levofloxacin and ponesimod 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. Ponesimod 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.
Levoketoconazole: (Contraindicated) Avoid concomitant use of ketoconazole and ponesimod due to an increased risk for torsade de pointes (TdP) and QT/QTc prolongation. Ponesimod 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.
Lithium: (Major) In general, do not initiate ponesimod in patients taking lithium 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. Lithium has been associated with QT prolongation.
Live Vaccines: (Contraindicated) Avoid vaccines containing live virus (live attenuated vaccines) during treatment with ponesimod. If a live attenuated vaccine is required, administer at least 1 month (4 weeks) before initiation of ponesimod. The use of live attenuated vaccines may carry the risk of infection and should therefore be avoided during ponesimod treatment and for 1 to 2 weeks after discontinuation of ponesimod. During treatment, and for up to 1 to 2 weeks after discontinuation of ponesimod, vaccinations may also be less effective.
Lofexidine: (Major) In general, do not initiate ponesimod in patients taking lofexidine 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. Lofexidine has been associated with QT prolongation.
Loperamide: (Major) In general, do not initiate ponesimod in patients taking loperamide 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. At high doses, loperamide has been associated with serious cardiac toxicities, including syncope, ventricular tachycardia, QT prolongation, TdP, and cardiac arrest.
Loperamide; Simethicone: (Major) In general, do not initiate ponesimod in patients taking loperamide 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. At high doses, loperamide has been associated with serious cardiac toxicities, including syncope, ventricular tachycardia, QT prolongation, TdP, and cardiac arrest.
Lopinavir; Ritonavir: (Major) Avoid coadministration of lopinavir with ponesimod 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. Lopinavir is associated with QT prolongation. 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 torsade de pointes in patients with bradycardia. (Major) Avoid concurrent use of ponesimod and ritonavir and monitor for decreased ponesimod efficacy if use is necessary. Ponesimod is an UGT1A1 substrate and ritonavir is an UGT1A1 inducer that may decrease ponesimod exposure.
Lumacaftor; Ivacaftor: (Major) Avoid concurrent use of ponesimod and lumacaftor; ivacaftor and monitor for decreased ponesimod efficacy if use is necessary. Ponesimod is a CYP3A substrate and lumacaftor; ivacaftor is a strong CYP3A inducer that may decrease ponesimod exposure.
Lumacaftor; Ivacaftor: (Major) Avoid concurrent use of ponesimod and lumacaftor; ivacaftor and monitor for decreased ponesimod efficacy if use is necessary. Ponesimod is a CYP3A substrate and lumacaftor; ivacaftor is a strong CYP3A inducer that may decrease ponesimod exposure.
Macimorelin: (Major) Avoid concurrent administration of macimorelin with drugs that prolong the QT interval, such as ponesimod. 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. 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 torsade de pointes in patients with bradycardia.
Maprotiline: (Major) In general, do not initiate ponesimod in patients taking maprotiline 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. Cases of long QT syndrome and 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.
Measles Virus; Mumps Virus; Rubella Virus; Varicella Virus Vaccine, Live: (Contraindicated) Avoid vaccines containing live virus (live attenuated vaccines) during treatment with ponesimod. If a live attenuated vaccine is required, administer at least 1 month (4 weeks) before initiation of ponesimod. The use of live attenuated vaccines may carry the risk of infection and should therefore be avoided during ponesimod treatment and for 1 to 2 weeks after discontinuation of ponesimod. During treatment, and for up to 1 to 2 weeks after discontinuation of ponesimod, vaccinations may also be less effective.
Measles/Mumps/Rubella Vaccines, MMR: (Contraindicated) Avoid vaccines containing live virus (live attenuated vaccines) during treatment with ponesimod. If a live attenuated vaccine is required, administer at least 1 month (4 weeks) before initiation of ponesimod. The use of live attenuated vaccines may carry the risk of infection and should therefore be avoided during ponesimod treatment and for 1 to 2 weeks after discontinuation of ponesimod. During treatment, and for up to 1 to 2 weeks after discontinuation of ponesimod, vaccinations may also be less effective.
Mefloquine: (Major) In general, do not initiate ponesimod in patients taking mefloquine 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. There is evidence that the use of halofantrine after mefloquine causes a significant lengthening of the QTc interval. Mefloquine alone has not been reported to cause QT prolongation.
Methadone: (Major) In general, do not initiate ponesimod in patients taking methadone 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. Methadone is associated with an increased risk for QT prolongation and torsade de pointes (TdP), especially at higher doses (> 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.
Methohexital: (Major) Avoid concurrent use of ponesimod and barbiturates and monitor for decreased ponesimod efficacy if use is necessary. Ponesimod is a CYP3A substrate and barbiturates are strong CYP3A inducers that may decrease ponesimod exposure. Additionally, phenobarbital is known to also induce UGT1A1; ponesimod is also an UGT1A1 substrate.
Methylprednisolone: (Moderate) Monitor for signs and symptoms of infection. Additive immune suppression may result from concomitant use of ponesimod and high-dose corticosteroid therapy which may extend the duration or severity of immune suppression. High-dose corticosteroid therapy is generally defined as a dose of at least 20 mg/day of prednisone or equivalent (or 2 mg/kg/day for patients weighing less than 10 kg) for at least 14 consecutive days.
Metoprolol: (Moderate) Monitor for decreases in heart rate if concomitant use of ponesimod and beta-blockers is necessary. Consider a temporary interruption in beta-blocker therapy before initiating ponesimod in patients with a resting heart rate less than or equal to 55 bpm. Beta-blocker treatment can be initiated in patients receiving stable doses of ponesimod. Concomitant use of another beta-blocker with ponesimod resulted in a mean decrease in heart rate of 12.4 bpm after the first dose of ponesimod and 7.4 bpm after beginning maintenance ponesimod.
Metoprolol; Hydrochlorothiazide, HCTZ: (Moderate) Monitor for decreases in heart rate if concomitant use of ponesimod and beta-blockers is necessary. Consider a temporary interruption in beta-blocker therapy before initiating ponesimod in patients with a resting heart rate less than or equal to 55 bpm. Beta-blocker treatment can be initiated in patients receiving stable doses of ponesimod. Concomitant use of another beta-blocker with ponesimod resulted in a mean decrease in heart rate of 12.4 bpm after the first dose of ponesimod and 7.4 bpm after beginning maintenance ponesimod.
Metronidazole: (Major) Concomitant use of metronidazole and ponesimod 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. Ponesimod 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.
Midostaurin: (Major) In general, do not initiate ponesimod in patients taking midostaurin due to the risk of additive bradycardia, QT prolongation, and torsade de pointes (TdP); additive immunosuppression may also occur which may extend the duration or severity of immune suppression. If treatment initiation is considered, monitor ECGs and for signs and symptoms of infection. 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. QT prolongation was reported in patients who received midostaurin in clinical trials.
Mifepristone: (Major) In general, do not initiate ponesimod in patients taking mifepristone 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. Mifepristone is associated with dose-related prolongation of the QT interval.
Mirtazapine: (Major) In general, do not initiate ponesimod in patients taking mirtazapine 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. Mirtazapine has been associated with dose-dependent prolongation of the QT interval; TdP has been reported postmarketing primarily in overdose or in patients with other risk factors for QT prolongation.
Mitapivat: (Major) Avoid concurrent use of ponesimod and mitapivat and monitor for decreased ponesimod efficacy if use is necessary. Ponesimod is a UGT1A1 substrate and mitapivat is a UGT1A1 inducer that may decrease ponesimod exposure.
Mitotane: (Major) Avoid concurrent use of ponesimod and mitotane and monitor for decreased ponesimod efficacy if use is necessary. Ponesimod is a CYP3A substrate and mitotane is a strong CYP3A inducer that may decrease ponesimod exposure.
Mobocertinib: (Major) Concomitant use of mobocertinib and ponesimod 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. Ponesimod 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.
Moxifloxacin: (Major) In general, do not initiate ponesimod in patients taking moxifloxacin 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. 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.
Nadolol: (Moderate) Monitor for decreases in heart rate if concomitant use of ponesimod and beta-blockers is necessary. Consider a temporary interruption in beta-blocker therapy before initiating ponesimod in patients with a resting heart rate less than or equal to 55 bpm. Beta-blocker treatment can be initiated in patients receiving stable doses of ponesimod. Concomitant use of another beta-blocker with ponesimod resulted in a mean decrease in heart rate of 12.4 bpm after the first dose of ponesimod and 7.4 bpm after beginning maintenance ponesimod.
Nebivolol: (Moderate) Monitor for decreases in heart rate if concomitant use of ponesimod and beta-blockers is necessary. Consider a temporary interruption in beta-blocker therapy before initiating ponesimod in patients with a resting heart rate less than or equal to 55 bpm. Beta-blocker treatment can be initiated in patients receiving stable doses of ponesimod. Concomitant use of another beta-blocker with ponesimod resulted in a mean decrease in heart rate of 12.4 bpm after the first dose of ponesimod and 7.4 bpm after beginning maintenance ponesimod.
Nebivolol; Valsartan: (Moderate) Monitor for decreases in heart rate if concomitant use of ponesimod and beta-blockers is necessary. Consider a temporary interruption in beta-blocker therapy before initiating ponesimod in patients with a resting heart rate less than or equal to 55 bpm. Beta-blocker treatment can be initiated in patients receiving stable doses of ponesimod. Concomitant use of another beta-blocker with ponesimod resulted in a mean decrease in heart rate of 12.4 bpm after the first dose of ponesimod and 7.4 bpm after beginning maintenance ponesimod.
Nilotinib: (Major) In general, do not initiate ponesimod in patients taking nilotinib due to the risk of additive bradycardia, QT prolongation, and torsade de pointes (TdP); additive immunosuppression may also occur which may extend the duration or severity of immune suppression. If treatment initiation is considered, seek advice from a cardiologist and monitor for signs and symptoms of infection. 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. Sudden death and QT interval prolongation have occurred in patients who received nilotinib therapy.
Nirmatrelvir; Ritonavir: (Major) Avoid concurrent use of ponesimod and ritonavir and monitor for decreased ponesimod efficacy if use is necessary. Ponesimod is an UGT1A1 substrate and ritonavir is an UGT1A1 inducer that may decrease ponesimod exposure.
Ofloxacin: (Major) Concomitant use of ofloxacin and ponesimod 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. Ponesimod 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.
Olanzapine: (Major) In general, do not initiate ponesimod in patients taking olanzapine 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. Limited date, including some case reports suggest that olanzapine may be associated with a significant prolongation of the QTc interval.
Olanzapine; Fluoxetine: (Major) In general, do not initiate ponesimod in patients taking fluoxetine 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. Fluoxetine is associated with QT prolongation and TdP. (Major) In general, do not initiate ponesimod in patients taking olanzapine 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. Limited date, including some case reports suggest that olanzapine may be associated with a significant prolongation of the QTc interval.
Olanzapine; Samidorphan: (Major) In general, do not initiate ponesimod in patients taking olanzapine 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. Limited date, including some case reports suggest that olanzapine may be associated with a significant prolongation of the QTc interval.
Ondansetron: (Major) In general, do not initiate ponesimod in patients taking ondansetron 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. Ondansetron has been associated with a dose-related increase in the QT interval and postmarketing reports of TdP.
Osilodrostat: (Major) In general, do not initiate ponesimod in patients taking osilodrostat 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. Osilodrostat is associated with dose-dependent QT prolongation.
Osimertinib: (Major) Avoid coadministration of ponesimod with osimertinib if possible due to the risk of additive bradycardia, QT prolongation, and torsade de pointes (TdP); additive immunosuppression may also occur which may extend the duration or severity of immune suppression. If concomitant use is unavoidable, periodically monitor ECGs, electrolytes, and for signs and symptoms of infection; 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. 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.
Oxaliplatin: (Major) In general, do not initiate ponesimod in patients taking oxaliplatin due to the risk of additive bradycardia, QT prolongation, and torsade de pointes (TdP); additive immunosuppression may also occur which may extend the duration or severity of immune suppression. If concomitant use is unavoidable, monitor ECGs, electrolytes, and for signs and symptoms of infection. 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. QT prolongation and ventricular arrhythmias, including fatal TdP, have been reported with oxaliplatin use in postmarketing experience.
Pacritinib: (Major) Concomitant use of pacritinib and ponesimod 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. Ponesimod 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.
Paliperidone: (Major) In general, do not initiate ponesimod in patients taking paliperidone 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. Paliperidone has been associated with QT prolongation; torsade de pointes and ventricular fibrillation have been reported in the setting of overdose.
Panobinostat: (Major) In general, do not initiate ponesimod in patients taking panobinostat 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. QT prolongation has been reported with panobinostat.
Pasireotide: (Major) In general, do not initiate ponesimod in patients taking pasireotide 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. QT prolongation has occurred with pasireotide at therapeutic and supra-therapeutic doses.
Pazopanib: (Major) Avoid coadministration of pazopanib and ponesimod due to the risk of additive bradycardia, QT prolongation, and torsade de pointes (TdP); additive immunosuppression may also occur which may extend the duration or severity of immune suppression. If concomitant use is unavoidable, monitor ECGs, electrolytes, and for signs and symptoms of infection; correct hypokalemia, hypomagnesemia, and hypocalcemia. Pazopanib has been associated with QT prolongation. 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.
Pentamidine: (Major) In general, do not initiate ponesimod in patients taking pentamidine 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. Systemic pentamidine has been associated with QT prolongation.
Pentobarbital: (Major) Avoid concurrent use of ponesimod and barbiturates and monitor for decreased ponesimod efficacy if use is necessary. Ponesimod is a CYP3A substrate and barbiturates are strong CYP3A inducers that may decrease ponesimod exposure. Additionally, phenobarbital is known to also induce UGT1A1; ponesimod is also an UGT1A1 substrate.
Perphenazine: (Minor) Concomitant use of ponesimod and perphenazine may increase 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. 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.
Perphenazine; Amitriptyline: (Minor) Concomitant use of ponesimod and perphenazine may increase 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. 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.
Phenobarbital: (Major) Avoid concurrent use of ponesimod and barbiturates and monitor for decreased ponesimod efficacy if use is necessary. Ponesimod is a CYP3A substrate and barbiturates are strong CYP3A inducers that may decrease ponesimod exposure. Additionally, phenobarbital is known to also induce UGT1A1; ponesimod is also an UGT1A1 substrate.
Phenobarbital; Hyoscyamine; Atropine; Scopolamine: (Major) Avoid concurrent use of ponesimod and barbiturates and monitor for decreased ponesimod efficacy if use is necessary. Ponesimod is a CYP3A substrate and barbiturates are strong CYP3A inducers that may decrease ponesimod exposure. Additionally, phenobarbital is known to also induce UGT1A1; ponesimod is also an UGT1A1 substrate.
Phenytoin: (Major) Avoid concurrent use of ponesimod and phenytoin and monitor for decreased ponesimod efficacy if use is necessary. Ponesimod is a CYP3A and an UGT1A1 substrate and phenytoin is a strong CYP3A inducer and an UGT1A1 inducer that may decrease ponesimod exposure.
Pimavanserin: (Major) In general, do not initiate ponesimod in patients taking pimavanserin 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. Pimavanserin prolongs the QT interval.
Pimozide: (Contraindicated) Coadministration of pimozide with ponesimod is contraindicated due to the risk for additive QT prolongation and torsade de pointes (TdP). Pimozide is associated with a well-established risk of QT prolongation and TdP. 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.
Pindolol: (Moderate) Monitor for decreases in heart rate if concomitant use of ponesimod and beta-blockers is necessary. Consider a temporary interruption in beta-blocker therapy before initiating ponesimod in patients with a resting heart rate less than or equal to 55 bpm. Beta-blocker treatment can be initiated in patients receiving stable doses of ponesimod. Concomitant use of another beta-blocker with ponesimod resulted in a mean decrease in heart rate of 12.4 bpm after the first dose of ponesimod and 7.4 bpm after beginning maintenance ponesimod.
Pitolisant: (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) In general, do not initiate ponesimod in patients taking posaconazole 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. Posaconazole has been associated with prolongation of the QT interval as well as rare cases of TdP.
Prednisolone: (Moderate) Monitor for signs and symptoms of infection. Additive immune suppression may result from concomitant use of ponesimod and high-dose corticosteroid therapy which may extend the duration or severity of immune suppression. High-dose corticosteroid therapy is generally defined as a dose of at least 20 mg/day of prednisone or equivalent (or 2 mg/kg/day for patients weighing less than 10 kg) for at least 14 consecutive days.
Prednisone: (Moderate) Monitor for signs and symptoms of infection. Additive immune suppression may result from concomitant use of ponesimod and high-dose corticosteroid therapy which may extend the duration or severity of immune suppression. High-dose corticosteroid therapy is generally defined as a dose of at least 20 mg/day of prednisone or equivalent (or 2 mg/kg/day for patients weighing less than 10 kg) for at least 14 consecutive days.
Primaquine: (Major) In general, do not initiate ponesimod in patients taking primaquine 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. Primaquine has been associated with QT interval prolongation.
Primidone: (Major) Avoid concurrent use of ponesimod and barbiturates and monitor for decreased ponesimod efficacy if use is necessary. Ponesimod is a CYP3A substrate and barbiturates are strong CYP3A inducers that may decrease ponesimod exposure. Additionally, phenobarbital is known to also induce UGT1A1; ponesimod is also an UGT1A1 substrate.
Procainamide: (Major) In general, do not initiate ponesimod in patients taking procainamide 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. Procainamide is associated with a well-established risk of QT prolongation and TdP.
Prochlorperazine: (Minor) Concomitant use of ponesimod and prochlorperazine may increase the risk of additive bradycardia, QT prolongation, and torsade de pointes (TdP). 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. 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.
Promethazine: (Major) In general, do not initiate ponesimod in patients taking promethazine 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. Promethazine is associated with a possible risk for QT prolongation.
Promethazine; Dextromethorphan: (Major) In general, do not initiate ponesimod in patients taking promethazine 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. Promethazine is associated with a possible risk for QT prolongation.
Promethazine; Phenylephrine: (Major) In general, do not initiate ponesimod in patients taking promethazine 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. Promethazine is associated with a possible risk for QT prolongation.
Propafenone: (Major) In general, do not initiate ponesimod in patients taking propafenone 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. Propafenone is a Class IC antiarrhythmic which increases the QT interval, but largely due to prolongation of the QRS interval.
Propranolol: (Moderate) Monitor for decreases in heart rate if concomitant use of ponesimod and beta-blockers is necessary. Consider a temporary interruption in beta-blocker therapy before initiating ponesimod in patients with a resting heart rate less than or equal to 55 bpm. Beta-blocker treatment can be initiated in patients receiving stable doses of ponesimod. Concomitant use of another beta-blocker with ponesimod resulted in a mean decrease in heart rate of 12.4 bpm after the first dose of ponesimod and 7.4 bpm after beginning maintenance ponesimod.
Propranolol; Hydrochlorothiazide, HCTZ: (Moderate) Monitor for decreases in heart rate if concomitant use of ponesimod and beta-blockers is necessary. Consider a temporary interruption in beta-blocker therapy before initiating ponesimod in patients with a resting heart rate less than or equal to 55 bpm. Beta-blocker treatment can be initiated in patients receiving stable doses of ponesimod. Concomitant use of another beta-blocker with ponesimod resulted in a mean decrease in heart rate of 12.4 bpm after the first dose of ponesimod and 7.4 bpm after beginning maintenance ponesimod.
Quetiapine: (Major) In general, do not initiate ponesimod in patients taking quetiapine 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. Quetiapine has been associated with a significant prolongation of the QTc interval in rare instances.
Quinidine: (Major) In general, do not initiate ponesimod in patients taking quinidine 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. Quinidine administration is associated with QT prolongation and TdP.
Quinine: (Major) In general, do not initiate ponesimod in patients taking quinine 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. Quinine has been associated with QT prolongation and rare cases of TdP.
Quizartinib: (Major) Concomitant use of quizartinib and ponesimod 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. Ponesimod 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.
Ranolazine: (Major) In general, do not initiate ponesimod in patients taking ranolazine 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. Ranolazine is associated with dose- and plasma concentration-related increases in the QTc interval.
Relugolix: (Major) In general, do not initiate ponesimod in patients taking relugolix 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. Androgen deprivation therapy (i.e., relugolix) may prolong the QT/QTc interval.
Relugolix; Estradiol; Norethindrone acetate: (Major) In general, do not initiate ponesimod in patients taking relugolix 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. Androgen deprivation therapy (i.e., relugolix) may prolong the QT/QTc interval.
Ribociclib: (Major) In general, do not initiate ponesimod in patients taking ribociclib due to the risk of additive bradycardia, QT prolongation, and torsade de pointes (TdP); additive immunosuppression may also occur which may extend the duration or severity of immune suppression. If treatment initiation is considered, seek advice from a cardiologist and monitor for signs and symptoms of infection. 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. Ribociclib has been shown to prolong the QT interval in a concentration-dependent manner; the ribociclib ECG changes occurred within the first4 weeks of treatment and were reversible with dose interruption.
Ribociclib; Letrozole: (Major) In general, do not initiate ponesimod in patients taking ribociclib due to the risk of additive bradycardia, QT prolongation, and torsade de pointes (TdP); additive immunosuppression may also occur which may extend the duration or severity of immune suppression. If treatment initiation is considered, seek advice from a cardiologist and monitor for signs and symptoms of infection. 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. Ribociclib has been shown to prolong the QT interval in a concentration-dependent manner; the ribociclib ECG changes occurred within the first4 weeks of treatment and were reversible with dose interruption.
Rifampin: (Major) Avoid concurrent use of ponesimod and rifampin and monitor for decreased ponesimod efficacy if use is necessary. Ponesimod is a CYP3A and an UGT1A1 substrate and rifampin is a strong CYP3A inducer and an UGT1A1 inducer that may decrease ponesimod exposure.
Rifapentine: (Major) Avoid concurrent use of ponesimod and rifapentine and monitor for decreased ponesimod efficacy if use is necessary. Ponesimod is a CYP3A substrate and rifapentine is a strong CYP3A inducer that may decrease ponesimod exposure.
Rilpivirine: (Major) In general, do not initiate ponesimod in patients taking rilpivirine 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. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation.
Risperidone: (Major) In general, do not initiate ponesimod in patients taking risperidone 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. Risperidone has been associated with a possible risk for QT prolongation and TdP, primarily in the overdose setting.
Ritonavir: (Major) Avoid concurrent use of ponesimod and ritonavir and monitor for decreased ponesimod efficacy if use is necessary. Ponesimod is an UGT1A1 substrate and ritonavir is an UGT1A1 inducer that may decrease ponesimod exposure.
Romidepsin: (Major) In general, do not initiate ponesimod in patients taking romidepsin due to the risk of additive bradycardia, QT prolongation, and torsade de pointes (TdP); additive immunosuppression may also occur which may extend the duration or severity of immune suppression. If concomitant use is unavoidable, monitor ECGs, electrolytes, and for signs and symptoms of infection. 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. Romidepsin has been reported to prolong the QT interval.
Rotavirus Vaccine: (Contraindicated) Avoid vaccines containing live virus (live attenuated vaccines) during treatment with ponesimod. If a live attenuated vaccine is required, administer at least 1 month (4 weeks) before initiation of ponesimod. The use of live attenuated vaccines may carry the risk of infection and should therefore be avoided during ponesimod treatment and for 1 to 2 weeks after discontinuation of ponesimod. During treatment, and for up to 1 to 2 weeks after discontinuation of ponesimod, vaccinations may also be less effective.
Saquinavir: (Major) Avoid coadministration of saquinavir boosted with ritonavir with ponesimod due to the risk of additive QT prolongation. If no acceptable alternative therapy is available, perform a baseline ECG prior to initiation of concomitant therapy and carefully follow monitoring recommendations. 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). 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.
SARS-CoV-2 (COVID-19) vaccines: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine.
Secobarbital: (Major) Avoid concurrent use of ponesimod and barbiturates and monitor for decreased ponesimod efficacy if use is necessary. Ponesimod is a CYP3A substrate and barbiturates are strong CYP3A inducers that may decrease ponesimod exposure. Additionally, phenobarbital is known to also induce UGT1A1; ponesimod is also an UGT1A1 substrate.
Selpercatinib: (Major) In general, do not initiate ponesimod in patients taking selpercatinib due to the risk of additive bradycardia, QT prolongation, and torsade de pointes (TdP); additive immunosuppression may also occur which may extend the duration or severity of immune suppression. If concomitant use is unavoidable, monitor ECGs and for signs and symptoms of infection. 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. Concentration-dependent QT prolongation has been observed with selpercatinib therapy.
Sertraline: (Major) In general, do not initiate ponesimod in patients taking sertraline 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. The risk of sertraline-induced QT prolongation is generally considered to be low in clinical practice. Its effect on QTc interval is minimal (typically less than 5 msec), and the drug has been used safely in patients with cardiac disease (e.g., recent myocardial infarction, unstable angina, chronic heart failure.
Sevoflurane: (Major) In general, do not initiate ponesimod in patients taking halogenated anesthetics 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. Halogenated anesthetics can prolong the QT interval.
Smallpox and Monkeypox Vaccine, Live, Nonreplicating: (Contraindicated) Avoid vaccines containing live virus (live attenuated vaccines) during treatment with ponesimod. If a live attenuated vaccine is required, administer at least 1 month (4 weeks) before initiation of ponesimod. The use of live attenuated vaccines may carry the risk of infection and should therefore be avoided during ponesimod treatment and for 1 to 2 weeks after discontinuation of ponesimod. During treatment, and for up to 1 to 2 weeks after discontinuation of ponesimod, vaccinations may also be less effective.
Smallpox Vaccine, Vaccinia Vaccine: (Contraindicated) Avoid vaccines containing live virus (live attenuated vaccines) during treatment with ponesimod. If a live attenuated vaccine is required, administer at least 1 month (4 weeks) before initiation of ponesimod. The use of live attenuated vaccines may carry the risk of infection and should therefore be avoided during ponesimod treatment and for 1 to 2 weeks after discontinuation of ponesimod. During treatment, and for up to 1 to 2 weeks after discontinuation of ponesimod, vaccinations may also be less effective.
Sodium Stibogluconate: (Major) Concomitant use of sodium stibogluconate and ponesimod 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. Ponesimod 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.
Solifenacin: (Major) In general, do not initiate ponesimod in patients taking solifenacin 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. Solifenacin has been associated with dose-dependent prolongation of the QT interval. TdP has been reported with postmarketing use, although causality was not determined.
Sorafenib: (Major) Avoid coadministration of sorafenib with ponesimod due to the risk of additive bradycardia, QT prolongation, and torsade de pointes (TdP); additive immunosuppression may also occur which may extend the duration or severity of immune suppression. If concomitant use is unavoidable, monitor ECGs and for signs and symptoms of infection; correct electrolyte abnormalities. An interruption or discontinuation of sorafenib therapy may be necessary if QT prolongation occurs. Sorafenib is associated with QTc prolongation. 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.
Sotalol: (Major) In general, do not initiate ponesimod in patients taking sotalol 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. Sotalol administration is associated with QT prolongation and TdP. Proarrhythmic events should be anticipated after initiation of therapy and after each upward dosage adjustment.
St. John's Wort, Hypericum perforatum: (Major) Avoid concurrent use of ponesimod and St. John's Wort and monitor for decreased ponesimod efficacy if use is necessary. Ponesimod is a CYP3A substrate and St. John's Wort is a strong CYP3A inducer that may decrease ponesimod exposure.
Sunitinib: (Major) In general, do not initiate ponesimod in patients taking sunitinib due to the risk of additive bradycardia, QT prolongation, and torsade de pointes (TdP); additive immunosuppression may also occur which may extend the duration or severity of immune suppression. If treatment initiation is considered, seek advice from a cardiologist and monitor for signs and symptoms of infection. 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. Sunitinib can prolong the QT interval.
Tacrolimus: (Major) In general, do not initiate ponesimod in patients taking tacrolimus due to the risk of additive bradycardia, QT prolongation, and torsade de pointes (TdP); additive immunosuppression may also occur which may extend the duration or severity of immune suppression. If concomitant use is unavoidable, monitor ECGs, electrolytes, and for signs and symptoms of infection. 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. Tacrolimus may prolong the QT interval and cause TdP.
Tamoxifen: (Major) In general, do not initiate ponesimod in patients taking tamoxifen 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. Tamoxifen has been reported to prolong the QT interval, usually in overdose or when used in high doses. Rare case reports of QT prolongation have also been described when tamoxifen is used at lower doses.
Telavancin: (Major) In general, do not initiate ponesimod in patients taking telavancin 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. Telavancin has been associated with QT prolongation.
Tetrabenazine: (Major) In general, do not initiate ponesimod in patients taking tetrabenazine 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. Tetrabenazine causes a small increase in the corrected QT interval (QTc).
Thioridazine: (Contraindicated) Coadministration of thioridazine with ponesimod is contraindicated due to the risk for additive QT prolongation and torsade de pointes (TdP). Thioridazine is associated with a well-established risk of QT prolongation and TdP. 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.
Timolol: (Moderate) Monitor for decreases in heart rate if concomitant use of ponesimod and beta-blockers is necessary. Consider a temporary interruption in beta-blocker therapy before initiating ponesimod in patients with a resting heart rate less than or equal to 55 bpm. Beta-blocker treatment can be initiated in patients receiving stable doses of ponesimod. Concomitant use of another beta-blocker with ponesimod resulted in a mean decrease in heart rate of 12.4 bpm after the first dose of ponesimod and 7.4 bpm after beginning maintenance ponesimod.
Tolterodine: (Major) In general, do not initiate ponesimod in patients taking tolterodine 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. Tolterodine has been associated with dose-dependent prolongation of the QT interval, especially in poor CYP2D6 metabolizers.
Toremifene: (Major) Avoid coadministration of ponesimod with toremifene due to the risk of additive QT prolongation and torsade de pointes (TdP). If concomitant use is unavoidable, closely monitor ECGs for QT prolongation, monitor electrolytes, and seek advice from a cardiologist. Toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner. 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 torsade de pointes in patients with bradycardia.
Trandolapril; Verapamil: (Major) Avoid concomitant use of ponesimod and medications that may decrease heart rate such as verapamil due to the risk for severe bradycardia and heart block. Consider consultation from a cardiologist if concomitant use is necessary.
Trazodone: (Major) Concomitant use of trazodone and ponesimod 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. Ponesimod 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.
Triamcinolone: (Moderate) Monitor for signs and symptoms of infection. Additive immune suppression may result from concomitant use of ponesimod and high-dose corticosteroid therapy which may extend the duration or severity of immune suppression. High-dose corticosteroid therapy is generally defined as a dose of at least 20 mg/day of prednisone or equivalent (or 2 mg/kg/day for patients weighing less than 10 kg) for at least 14 consecutive days.
Triclabendazole: (Major) Concomitant use of triclabendazole and ponesimod 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. Ponesimod 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.
Trifluoperazine: (Minor) Concomitant use of ponesimod and trifluoperazine may increase the risk of additive bradycardia, QT prolongation, and torsade de pointes (TdP). 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. 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.
Triptorelin: (Major) In general, do not initiate ponesimod in patients taking triptorelin 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. Androgen deprivation therapy (i.e., triptorelin) may prolong the QT/QTc interval.
Typhoid Vaccine: (Contraindicated) Avoid vaccines containing live virus (live attenuated vaccines) during treatment with ponesimod. If a live attenuated vaccine is required, administer at least 1 month (4 weeks) before initiation of ponesimod. The use of live attenuated vaccines may carry the risk of infection and should therefore be avoided during ponesimod treatment and for 1 to 2 weeks after discontinuation of ponesimod. During treatment, and for up to 1 to 2 weeks after discontinuation of ponesimod, vaccinations may also be less effective.
Vandetanib: (Major) Avoid coadministration of vandetanib with ponesimod due to the risk of additive bradycardia, QT prolongation, and torsade de pointes (TdP); additive immunosuppression may also occur which may extend the duration or severity of immune suppression If concomitant use is unavoidable, monitor ECGs, electrolytes, and for signs and symptoms of infection; 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 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.
Vardenafil: (Major) In general, do not initiate ponesimod in patients taking vardenafil 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. Vardenafil is associated with QT prolongation. Both therapeutic and supratherapeutic doses of vardenafil produce an increase in QTc interval.
Varicella-Zoster Virus Vaccine, Live: (Contraindicated) Avoid vaccines containing live virus (live attenuated vaccines) during treatment with ponesimod. If a live attenuated vaccine is required, administer at least 1 month (4 weeks) before initiation of ponesimod. The use of live attenuated vaccines may carry the risk of infection and should therefore be avoided during ponesimod treatment and for 1 to 2 weeks after discontinuation of ponesimod. During treatment, and for up to 1 to 2 weeks after discontinuation of ponesimod, vaccinations may also be less effective.
Vemurafenib: (Major) In general, do not initiate ponesimod in patients taking vemurafenib due to the risk of additive bradycardia, QT prolongation, and torsade de pointes (TdP); additive immunosuppression may also occur which may extend the duration or severity of immune suppression. If treatment initiation is considered, seek advice from a cardiologist and monitor for signs and symptoms of infection. 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. Vemurafenib has been shown to prolong the QT interval in a concentration-dependent manner; the ECG changes occurred within the first month of treatment.
Venlafaxine: (Major) In general, do not initiate ponesimod in patients taking venlafaxine 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. Venlafaxine is associated with a possible risk of QT prolongation; torsade de pointes (TdP) has reported with postmarketing use.
Verapamil: (Major) Avoid concomitant use of ponesimod and medications that may decrease heart rate such as verapamil due to the risk for severe bradycardia and heart block. Consider consultation from a cardiologist if concomitant use is necessary.
Voclosporin: (Major) In general, do not initiate ponesimod in patients taking voclosporin due to the risk of additive bradycardia, QT prolongation, and torsade de pointes (TdP); additive immunosuppression may also occur which may extend the duration or severity of immune suppression. If treatment initiation is considered, seek advice from a cardiologist and monitor for signs and symptoms of infection. 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. Supratherapeutic doses of voclosporin may prolong the QT interval.
Vonoprazan; Amoxicillin; Clarithromycin: (Major) In general, do not initiate ponesimod in patients taking clarithromycin 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. Clarithromycin is associated with an established risk for QT prolongation and TdP.
Voriconazole: (Major) In general, do not initiate ponesimod in patients taking voriconazole 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. Voriconazole has been associated with QT prolongation and rare cases of TdP.
Vorinostat: (Major) In general, do not initiate ponesimod in patients taking vorinostat due to the risk of additive bradycardia, QT prolongation, and torsade de pointes (TdP); additive immunosuppression may also occur which may extend the duration or severity of immune suppression. If treatment initiation is considered, seek advice from a cardiologist and monitor for signs and symptoms of infection. 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. Vorinostat therapy is associated with a risk of QT prolongation.
Yellow Fever Vaccine, Live: (Contraindicated) Avoid vaccines containing live virus (live attenuated vaccines) during treatment with ponesimod. If a live attenuated vaccine is required, administer at least 1 month (4 weeks) before initiation of ponesimod. The use of live attenuated vaccines may carry the risk of infection and should therefore be avoided during ponesimod treatment and for 1 to 2 weeks after discontinuation of ponesimod. During treatment, and for up to 1 to 2 weeks after discontinuation of ponesimod, vaccinations may also be less effective.
Ziprasidone: (Major) In general, do not initiate ponesimod in patients taking ziprasidone 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. Clinical trial data indicate that ziprasidone causes QT prolongation; there are post marketing reports of torsade de pointes (TdP) in patients with multiple confounding factors.

PONVORY Oral Tab: 20mg, 2-3-4-5-6-7-8-9-10mg

20 mg/day PO.

20 mg/day PO.

Safety and efficacy have not been established.

Safety and efficacy have not been established.

Safety and efficacy have not been established.

Safety and efficacy have not been established.

Ponesimod is a sphingosine 1-phosphate (S1P) receptor modulator that binds with high affinity to the S1P receptor 1. Ponesimod blocks the capacity of lymphocytes to egress from lymph nodes, reducing the number of lymphocytes in peripheral blood. The mechanism by which ponesimod exerts therapeutic effects in multiple sclerosis is unknown but may involve the reduction of lymphocyte migration into the central nervous system.

Ponesimod is administered orally. Steady state volume of distribution of ponesimod is 160 L following IV administration in healthy subjects. Plasma protein binding is greater than 99%, with the majority distributed in plasma (78.5%). Ponesimod crosses the blood brain barrier. Ponesimod is extensively metabolized to 2 inactive metabolites, M12 and M13. M13 and M12 are approximately 20% and 6% of total drug-related exposure, respectively. Unchanged ponesimod also remains in plasma. Metabolism of ponesimod to M13 occurs primarily through a combination of non-CYP450 enzymatic activities. The oxidation of ponesimod to M12 is catalyzed by multiple CYP450 enzymes (CYP2J2, CYP3A4, CYP3A5, CYP4F3A, and CYP4F12) and non-CYP450 enzymes. Ponesimod also undergoes direct glucuronidation (mainly UGT1A1 and UGT2B7). The total clearance of ponesimod is 3.8 L/hour following a single IV dose. Following a single oral administration of radiolabeled ponesimod, 57% to 80% of the dose was recovered in feces (16% as unchanged ponesimod), and 10% to 18% in urine (no unchanged ponesimod). The half-life of oral ponesimod is approximately 33 hours. The pharmacokinetics of ponesimod are similar in healthy subjects and patients with multiple sclerosis, with 25% inter-subject variability across studies.
 
Affected cytochrome P450 (CYP450) isoenzymes and drug transporters: CYP3A4, CYP3A5, CYP4F3A, CYP4F12, CYP2J2, UGT1A1, UGT2B7
Ponesimod is metabolized by multiple enzymes to form its circulating inactive metabolites (M12 and M13), without major contribution by any single enzyme. Ponesimod is metabolized by CYP2J2, CYP3A4, CYP3A5, CYP4F3A, CYP4F12 and non-CYP450 enzymes to form M12. Ponesimod is metabolized to M13 through non-CYP450 enzyme activity. Ponesimod undergoes direct glucuronidation, primarily by UGT1A1 and UGT2B7. In vitro assessments and limited clinical data indicated that concomitant use of strong CYP3A4 and UGT1A1 inducers (e.g., rifampin, phenytoin, carbamazepine) may decrease the systemic exposure of ponesimod. Coadministration of ponesimod with strong CYP3A4 inducers and UGT1A1 inducers is not recommended. Ponesimod is not a substrate of P-glycoprotein (P-gp), BCRP, OATP1B1, or OATP1B3 transporters.

There are no data on the presence of ponesimod in human milk, the effects on the breastfed infant, or the effects on milk production. It may be prudent to avoid this drug during breast-feeding until more data are available regarding infant safety. Glatiramer, interferon beta-1a, interferon beta-1b, may be potential alternatives to consider for the patient with multiple sclerosis who is breast-feeding. Consider the developmental and health benefits of breast-feeding along with the mother's clinical need for ponesimod and any potential adverse effects on the breastfed infant from ponesimod or the underlying maternal condition.