MAYZENT

MS Agents
Sphingosine 1-phosphate receptor modulator

Oral Administration Oral Solid Formulations

Take without regard to meals.
Storage: Store tablets in the starter pack for up to 1 week at room temperature in the original container after opening the blister. Store tablets in bottles for up to 1 month at room temperature after opening the bottles.[64031]

Severe

macular edema / Delayed / 1.8-10.0
bradycardia / Rapid / 6.0-6.0
AV block / Early / 1.7-5.1
pulmonary embolism / Delayed / 3.0-3.0
myocardial infarction / Delayed / 3.0-3.0
stroke / Early / 3.0-3.0
seizures / Delayed / 1.7-1.7
skin cancer / Delayed / 0.2-1.1
progressive multifocal leukoencephalopathy / Delayed / Incidence not known
immune reconstitution syndrome / Delayed / Incidence not known
multiple sclerosis exacerbation / Delayed / Incidence not known
new primary malignancy / Delayed / Incidence not known

Moderate

hypertension / Early / 13.0-13.0
elevated hepatic enzymes / Delayed / 11.0-11.0
peripheral edema / Delayed / 8.0-8.0
fluid retention / Delayed / 8.0-8.0
lymphopenia / Delayed / 0-5.0
QT prolongation / Rapid / Incidence not known
meningitis / Delayed / Incidence not known
dyspnea / Early / Incidence not known
encephalopathy / Delayed / Incidence not known

Mild

infection / Delayed / 49.0-49.0
headache / Early / 15.0-15.0
dizziness / Early / 7.0-7.0
nausea / Early / 7.0-7.0
diarrhea / Early / 6.0-6.0
tremor / Early / 0-5.0
asthenia / Delayed / 0-5.0
sinusitis / Delayed / 2.9-2.9

MAYZENT

Rx

Oral sphingosine 1-phosphate receptor modulator
Used for treatment of relapsing forms of multiple sclerosis in adults
May cause transient bradycardia and atrioventricular conduction delays, particularly during initiation

For the treatment of relapsing forms of multiple sclerosis, including clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease. Oral dosage in patients with *1/*1, *1/*2, or *2/*2 CYP2C9 genotypes Adults

Initiate treatment using a titration regimen. Give 0.25 mg PO once on days 1 and 2, 0.5 mg PO (two 0.25 mg tablets) once on day 3, 0.75 mg PO (three 0.25 mg tablets) once on day 4, and 1.25 mg PO (five 0.25 mg tablets) once on day 5. Begin maintenance dose of 2 mg PO once daily on day 6. First dose monitoring is recommended in patients with bradycardia (heart rate less than 55 beats per minute), first or second degree (Mobitz type 1) AV block, or a history of myocardial infarction or heart failure. If 1 titration is missed for more than 24 hours, reinitiate with day 1 of the titration regimen. If maintenance treatment is interrupted for 4 or more consecutive days, reinitiate treatment with the titration regimen and complete first dose monitoring when needed.[64031]

Oral dosage in patients with *1/*3 or *2/*3 CYP2C9 genotypes Adults

Initiate treatment using a titration regimen. Give 0.25 mg PO once on days 1 and 2, 0.5 mg PO (two 0.25 mg tablets) once on day 3, and 0.75 mg PO (three 0.25 mg tablets) once on day 4. Begin maintenance dose of 1 mg PO once daily on day 5. First dose monitoring is recommended in patients with bradycardia (heart rate less than 55 beats per minute), first or second degree (Mobitz type 1) AV block, or a history of myocardial infarction or heart failure. If 1 titration is missed for more than 24 hours, reinitiate with day 1 of the titration regimen. If maintenance treatment is interrupted for 4 or more consecutive days, reinitiate treatment with the titration regimen and complete first dose monitoring when needed.[64031]

Hepatic Impairment

Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no dosage adjustments are needed.

Renal Impairment

Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed.

Acebutolol: (Moderate) Monitor for significant bradycardia with coadministration of siponimod and beta-blockers, as additive lowering effects on heart rate may occur; temporary interruption of beta-blocker treatment may be necessary prior to siponimod initiation. Beta-blocker treatment can be initiated in patients receiving stable doses of siponimod.
Adagrasib: (Major) Avoid concomitant use of adagrasib and siponimod due to the potential for increased siponimod exposure and additive risk for QT/QTc prolongation and torsade de pointes (TdP). Siponimod is a CYP2C9 and CYP3A substrate, adagrasib is a dual moderate CYP2C9 and strong CYP3A inhibitor, and both medications have been associated with QT interval prolongation.
Alemtuzumab: (Major) Initiating treatment with siponimod after alemtuzumab treatment is not recommended due to the characteristics and duration of the immunosuppresive effects of alemtuzumab.
Alfuzosin: (Major) In general, do not initiate treatment with siponimod in patients receiving alfuzosin due to the potential for QT prolongation. Consult a cardiologist regarding appropriate monitoring if siponimod use is required. Siponimod therapy prolonged the QT interval at recommended doses in a clinical study. Based on electrophysiology studies performed by the manufacturer, alfuzosin may prolong the QT interval in a dose-dependent manner.
Amiodarone: (Major) Concomitant use of siponimod and amiodarone is not recommended due to a significant increase in siponimod exposure. Additionally, both drugs are associated with QT prolongation. Due to the extremely long half-life of amiodarone, a drug interaction is possible for days to weeks after discontinuation of amiodarone. Siponimod is a CYP2C9 and CYP3A4 substrate; amiodarone is a moderate CYP2C9/CYP3A4 dual inhibitor. Coadministration with another moderate CYP2C9/CYP3A4 dual inhibitor led to a 2-fold increase in the exposure of siponimod.
Amisulpride: (Major) In general, do not initiate treatment with siponimod in patients receiving amisulpride due to the potential for QT prolongation. Consult a cardiologist regarding appropriate monitoring if siponimod use is required. Siponimod therapy prolonged the QT interval at recommended doses in a clinical study. Amisulpride causes dose- and concentration- dependent QT prolongation.
Amoxicillin; Clarithromycin; Omeprazole: (Major) In general, do not initiate treatment with siponimod in patients receiving clarithromycin due to the potential for QT prolongation. Consult a cardiologist regarding appropriate monitoring if siponimod use is required. Siponimod therapy prolonged the QT interval at recommended doses in a clinical study. Clarithromycin has also been associated with prolongation of the QT interval. Additionally, concomitant use of siponimod and clarithromycin may increase siponimod exposure. If the patient is also receiving a drug regimen containing a moderate CYP2C9 inhibitor, use of siponimod is not recommended due to a significant increase in siponimod exposure. Siponimod is a CYP2C9 and CYP3A4 substrate; clarithromycin is a strong CYP3A4 inhibitor. Coadministration with a moderate CYP2C9/CYP3A4 dual inhibitor led to a 2-fold increase in the exposure of siponimod.
Anagrelide: (Major) Do not use anagrelide with other drugs that prolong the QT interval, such as siponimod. Siponimod therapy prolonged the QT interval at recommended doses in a clinical study. Torsade de pointes and ventricular tachycardia have been reported with anagrelide; dose-related increases in mean QTc and heart rate were observed in healthy subjects.
Anthrax Vaccine: (Moderate) Administer all non-live vaccines at least 2 weeks before siponimod initiation, whenever possible. Vaccines may be less effective if given during siponimod treatment. Patients should be considered unimmunized if vaccinated within a 14-day period before starting immunosuppresive therapy or during immunosuppressive therapy, and should they be revaccinated at least 3 months after therapy is discontinued if immune competence is restored.
Apalutamide: (Moderate) Concomitant use of siponimod and apalutamide is not recommended for patients with CYP2C9*1/*3 and *2/*3 genotypes due to a significant decrease in siponimod exposure. Use of siponimod with apalutamide is not recommended in any patient if they are also receiving a moderate CYP2C9 inducer. Siponimod is a CYP2C9 and CYP3A4 substrate; apalutamide is a strong CYP3A4 inducer. Coadministration with a moderate CYP2C9/strong CYP3A4 dual inducer decreased siponimod exposure by 57%.
Apomorphine: (Major) In general, do not initiate treatment with siponimod in patients receiving apomorphine due to the potential for QT prolongation. Dose-related QTc prolongation is associated with therapeutic apomorphine exposure. Consult a cardiologist regarding appropriate monitoring if siponimod use is required. Siponimod therapy prolonged the QT interval at recommended doses in a clinical study.
Aprepitant, Fosaprepitant: (Moderate) Concomitant use of siponimod and aprepitant, fosaprepitant may increase siponimod exposure. If the patient is also receiving a drug regimen containing a moderate CYP2C9 inhibitor, use of siponimod is not recommended due to a significant increase in siponimod exposure. Siponimod is a CYP2C9 and CYP3A4 substrate. When administered as a 3 day oral regimen, aprepitant is a moderate inhibitor of CYP3A4. Single oral and IV doses have not been shown to alter concentrations of CYP3A4 substrates. Coadministration with a moderate CYP2C9/CYP3A4 dual inhibitor led to a 2-fold increase in the exposure of siponimod.
Aripiprazole: (Major) Concomitant use of siponimod and aripiprazole increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Arsenic Trioxide: (Major) Avoid concomitant use of arsenic trioxide with other drugs that may cause QT interval prolongation, such as siponimod. Consult a cardiologist regarding appropriate monitoring if siponimod use is required. Siponimod therapy prolonged the QT interval at recommended doses in a clinical study. Torsade de pointes, QT interval prolongation, and complete atrioventricular block have been reported with arsenic trioxide use.
Artemether; Lumefantrine: (Major) Avoid coadministration of siponimod and artemether; lumefantrine due to the potential for additive QT prolongation. Consult a cardiologist regarding appropriate monitoring if siponimod use is required. Siponimod therapy prolonged the QT interval at recommended doses in a clinical study. Artemether; lumefantrine is associated with QT interval prolongation.
Asciminib: (Moderate) Concomitant use of siponimod and asciminib 200 mg twice daily may increase siponimod exposure. If the patient is also receiving a drug regimen containing a moderate or strong CYP3A inhibitor, use of siponimod is not recommended due to a significant increase in siponimod exposure. Siponimod is a CYP2C9 and CYP3A substrate; asciminib 200 mg twice daily is a moderate CYP2C9 inhibitor. Coadministration with a moderate CYP2C9/CYP3A dual inhibitor led to a 2-fold increase in the AUC of siponimod. An interaction is not expected with asciminib doses less than 200 mg twice daily.
Asenapine: (Major) Avoid coadministration of siponimod and asenapine due to the potential for additive QT prolongation. Consult a cardiologist regarding appropriate monitoring if siponimod use is required. Siponimod therapy prolonged the QT interval at recommended doses in a clinical study. Asenapine is associated with QT interval prolongation.
Aspirin, ASA; Butalbital; Caffeine: (Moderate) Concomitant use of siponimod and butalbital is not recommended for patients with CYP2C9*1/*3 and *2/*3 genotypes due to a significant decrease in siponimod exposure. Use of siponimod with butalbital is not recommended in any patient if they are also receiving a strong CYP3A4 inducer. Siponimod is a CYP2C9 and CYP3A4 substrate; butalbital is a moderate CYP2C9 and CYP3A4 inducer. Across CYP2C9 genotypes, coadministration of a moderate CYP3A4 inducer reduced siponimod exposure by up to 52%, according to in silico evaluation. Coadministration with a moderate CYP2C9/strong CYP3A4 dual inducer decreased siponimod exposure by 57% in CY2C9*1/*1 subjects.
Atazanavir: (Moderate) Concomitant use of siponimod and atazanavir may increase siponimod exposure. If the patient is also receiving a drug regimen containing a moderate CYP2C9 inhibitor, use of siponimod is not recommended due to a significant increase in siponimod exposure. Siponimod is a CYP2C9 and CYP3A4 substrate; atazanavir is a strong CYP3A4 inhibitor. Coadministration with a moderate CYP2C9/CYP3A4 dual inhibitor led to a 2-fold increase in the exposure of siponimod.
Atazanavir; Cobicistat: (Moderate) Concomitant use of siponimod and atazanavir may increase siponimod exposure. If the patient is also receiving a drug regimen containing a moderate CYP2C9 inhibitor, use of siponimod is not recommended due to a significant increase in siponimod exposure. Siponimod is a CYP2C9 and CYP3A4 substrate; atazanavir is a strong CYP3A4 inhibitor. Coadministration with a moderate CYP2C9/CYP3A4 dual inhibitor led to a 2-fold increase in the exposure of siponimod. (Moderate) Concomitant use of siponimod and cobicistat may increase siponimod exposure. If the patient is also receiving a drug regimen containing a moderate CYP2C9 inhibitor, use of siponimod is not recommended due to a significant increase in siponimod exposure. Siponimod is a CYP2C9 and CYP3A4 substrate; cobicistat is a strong CYP3A4 inhibitor. Coadministration with a moderate CYP2C9/CYP3A4 dual inhibitor led to a 2-fold increase in the exposure of siponimod.
Atenolol: (Moderate) Monitor for significant bradycardia with coadministration of siponimod and beta-blockers, as additive lowering effects on heart rate may occur; temporary interruption of beta-blocker treatment may be necessary prior to siponimod initiation. Beta-blocker treatment can be initiated in patients receiving stable doses of siponimod.
Atenolol; Chlorthalidone: (Moderate) Monitor for significant bradycardia with coadministration of siponimod and beta-blockers, as additive lowering effects on heart rate may occur; temporary interruption of beta-blocker treatment may be necessary prior to siponimod initiation. Beta-blocker treatment can be initiated in patients receiving stable doses of siponimod.
Atomoxetine: (Major) Concomitant use of siponimod and atomoxetine increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Azithromycin: (Major) Concomitant use of siponimod and azithromycin increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Bacillus Calmette-Guerin Vaccine, BCG: (Major) Avoid the use of live vaccines during treatment with siponomid and for 4 weeks after stopping treatment due to the risk of secondary infection. Additionally, vaccines may be less effective if administered during siponimod treatment and for 4 weeks after siponimod treatment discontinuation.
Bedaquiline: (Major) In general, do not initiate treatment with siponimod in patients receiving bedaquiline due to the potential for QT prolongation. Consult a cardiologist regarding appropriate monitoring if siponimod use is required. Siponimod therapy prolonged the QT interval at recommended doses in a clinical study. Bedaquiline has been reported to prolong the QT interval.
Berotralstat: (Moderate) Concomitant use of siponimod and berotralstat may increase siponimod exposure. If the patient is also receiving a drug regimen containing a moderate CYP2C9 inhibitor, use of siponimod is not recommended due to a significant increase in siponimod exposure. Siponimod is a CYP2C9 and CYP3A4 substrate; berotralstat is a moderate CYP3A4 inhibitor. Coadministration with a moderate CYP2C9/CYP3A4 dual inhibitor led to a 2-fold increase in the AUC of siponimod.
Beta-adrenergic blockers: (Moderate) Monitor for significant bradycardia with coadministration of siponimod and beta-blockers, as additive lowering effects on heart rate may occur; temporary interruption of beta-blocker treatment may be necessary prior to siponimod initiation. Beta-blocker treatment can be initiated in patients receiving stable doses of siponimod.
Betamethasone: (Moderate) Monitor patients carefully for signs and symptoms of infection during coadministration of siponimod and betamethasone. Concomitant use may increase the risk of immunosuppression. Siponimod has not been studied in combination with other immunosuppressive therapies used for the treatment of multiple sclerosis, including immunosuppressant doses of corticosteroids.
Betaxolol: (Moderate) Monitor for significant bradycardia with coadministration of siponimod and beta-blockers, as additive lowering effects on heart rate may occur; temporary interruption of beta-blocker treatment may be necessary prior to siponimod initiation. Beta-blocker treatment can be initiated in patients receiving stable doses of siponimod.
Bexarotene: (Moderate) Concomitant use of siponimod and bexarotene is not recommended for patients with CYP2C9*1/*3 and *2/*3 genotypes due to a significant decrease in siponimod exposure. Siponimod is a CYP2C9 and CYP3A4 substrate; bexarotene is a moderate CYP3A4 inducer. Across different CYP2C9 genotypes, a moderate CYP3A4 inducer decreased the exposure of siponimod by up to 52% according to in silico evaluation.
Bismuth Subcitrate Potassium; Metronidazole; Tetracycline: (Major) Concomitant use of metronidazole and siponimod increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Bismuth Subsalicylate; Metronidazole; Tetracycline: (Major) Concomitant use of metronidazole and siponimod 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.
Bisoprolol: (Moderate) Monitor for significant bradycardia with coadministration of siponimod and beta-blockers, as additive lowering effects on heart rate may occur; temporary interruption of beta-blocker treatment may be necessary prior to siponimod initiation. Beta-blocker treatment can be initiated in patients receiving stable doses of siponimod.
Bisoprolol; Hydrochlorothiazide, HCTZ: (Moderate) Monitor for significant bradycardia with coadministration of siponimod and beta-blockers, as additive lowering effects on heart rate may occur; temporary interruption of beta-blocker treatment may be necessary prior to siponimod initiation. Beta-blocker treatment can be initiated in patients receiving stable doses of siponimod.
Bosentan: (Moderate) Concomitant use of siponimod and bosentan is not recommended for patients with CYP2C9*1/*3 and *2/*3 genotypes due to a significant decrease in siponimod exposure. Use of siponimod with bosentan is not recommended in any patient if they are also receiving a strong CYP3A4 inducer. Siponimod is a CYP2C9 and CYP3A4 substrate; bosentan is a moderate CYP2C9 and CYP3A4 inducer. Across CYP2C9 genotypes, coadministration of a moderate CYP3A4 inducer reduced siponimod exposure by up to 52%, according to in silico evaluation. Coadministration with a moderate CYP2C9/strong CYP3A4 dual inducer decreased siponimod exposure by 57% in CY2C9*1/*1 subjects.
Brimonidine; Timolol: (Moderate) Monitor for significant bradycardia with coadministration of siponimod and beta-blockers, as additive lowering effects on heart rate may occur; temporary interruption of beta-blocker treatment may be necessary prior to siponimod initiation. Beta-blocker treatment can be initiated in patients receiving stable doses of siponimod.
Buprenorphine: (Major) Concomitant use of siponimod and buprenorphine increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Buprenorphine; Naloxone: (Major) Concomitant use of siponimod and buprenorphine 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.
Butalbital; Acetaminophen: (Moderate) Concomitant use of siponimod and butalbital is not recommended for patients with CYP2C9*1/*3 and *2/*3 genotypes due to a significant decrease in siponimod exposure. Use of siponimod with butalbital is not recommended in any patient if they are also receiving a strong CYP3A4 inducer. Siponimod is a CYP2C9 and CYP3A4 substrate; butalbital is a moderate CYP2C9 and CYP3A4 inducer. Across CYP2C9 genotypes, coadministration of a moderate CYP3A4 inducer reduced siponimod exposure by up to 52%, according to in silico evaluation. Coadministration with a moderate CYP2C9/strong CYP3A4 dual inducer decreased siponimod exposure by 57% in CY2C9*1/*1 subjects.
Butalbital; Acetaminophen; Caffeine: (Moderate) Concomitant use of siponimod and butalbital is not recommended for patients with CYP2C9*1/*3 and *2/*3 genotypes due to a significant decrease in siponimod exposure. Use of siponimod with butalbital is not recommended in any patient if they are also receiving a strong CYP3A4 inducer. Siponimod is a CYP2C9 and CYP3A4 substrate; butalbital is a moderate CYP2C9 and CYP3A4 inducer. Across CYP2C9 genotypes, coadministration of a moderate CYP3A4 inducer reduced siponimod exposure by up to 52%, according to in silico evaluation. Coadministration with a moderate CYP2C9/strong CYP3A4 dual inducer decreased siponimod exposure by 57% in CY2C9*1/*1 subjects.
Butalbital; Acetaminophen; Caffeine; Codeine: (Moderate) Concomitant use of siponimod and butalbital is not recommended for patients with CYP2C9*1/*3 and *2/*3 genotypes due to a significant decrease in siponimod exposure. Use of siponimod with butalbital is not recommended in any patient if they are also receiving a strong CYP3A4 inducer. Siponimod is a CYP2C9 and CYP3A4 substrate; butalbital is a moderate CYP2C9 and CYP3A4 inducer. Across CYP2C9 genotypes, coadministration of a moderate CYP3A4 inducer reduced siponimod exposure by up to 52%, according to in silico evaluation. Coadministration with a moderate CYP2C9/strong CYP3A4 dual inducer decreased siponimod exposure by 57% in CY2C9*1/*1 subjects.
Butalbital; Aspirin; Caffeine; Codeine: (Moderate) Concomitant use of siponimod and butalbital is not recommended for patients with CYP2C9*1/*3 and *2/*3 genotypes due to a significant decrease in siponimod exposure. Use of siponimod with butalbital is not recommended in any patient if they are also receiving a strong CYP3A4 inducer. Siponimod is a CYP2C9 and CYP3A4 substrate; butalbital is a moderate CYP2C9 and CYP3A4 inducer. Across CYP2C9 genotypes, coadministration of a moderate CYP3A4 inducer reduced siponimod exposure by up to 52%, according to in silico evaluation. Coadministration with a moderate CYP2C9/strong CYP3A4 dual inducer decreased siponimod exposure by 57% in CY2C9*1/*1 subjects.
Cabotegravir; Rilpivirine: (Major) In general, do not initiate treatment with siponimod in patients receiving rilpivirine due to the potential for QT prolongation. Consult a cardiologist regarding appropriate monitoring if siponimod use is required. Siponimod therapy prolonged the QT interval at recommended doses in a clinical study. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation.
Carbamazepine: (Major) Concomitant use of siponimod and carbamazepine is not recommended due to a significant decrease in siponimod exposure. Siponimod is a CYP2C9 and CYP3A4 substrate; carbamazepine is a moderate CYP2C9/strong CYP3A4 dual inducer. Coadministration with another moderate CYP2C9/strong CYP3A4 dual inducer decreased siponimod exposure by 57%.
Carteolol: (Moderate) Monitor for significant bradycardia with coadministration of siponimod and beta-blockers, as additive lowering effects on heart rate may occur; temporary interruption of beta-blocker treatment may be necessary prior to siponimod initiation. Beta-blocker treatment can be initiated in patients receiving stable doses of siponimod.
Carvedilol: (Moderate) Monitor for significant bradycardia with coadministration of siponimod and beta-blockers, as additive lowering effects on heart rate may occur; temporary interruption of beta-blocker treatment may be necessary prior to siponimod initiation. Beta-blocker treatment can be initiated in patients receiving stable doses of siponimod.
Cenobamate: (Moderate) Concomitant use of siponimod and cenobamate is not recommended for patients with CYP2C9*1/*3 and *2/*3 genotypes due to a significant decrease in siponimod exposure. Siponimod is a CYP2C9 and CYP3A4 substrate; cenobamate is a moderate CYP3A4 inducer. Across different CYP2C9 genotypes, a moderate CYP3A4 inducer decreased the exposure of siponimod by up to 52% according to in silico evaluation.
Ceritinib: (Major) In general, do not initiate treatment with siponimod in patients receiving ceritinib due to the potential for QT prolongation. Consult a cardiologist regarding appropriate monitoring if siponimod use is required. Siponimod therapy prolonged the QT interval at recommended doses in a clinical study. Ceritinib causes concentration-dependent prolongation of the QT interval. Additionally, concomitant use of siponimod and ceritinib may increase siponimod exposure. If the patient is also receiving a drug regimen containing a moderate CYP2C9 inhibitor, use of siponimod is not recommended due to a significant increase in siponimod exposure. Siponimod is a CYP2C9 and CYP3A4 substrate; ceritinib is a strong CYP3A4 inhibitor and a weak CYP2C9 inhibitor. Coadministration with a moderate CYP2C9/CYP3A4 dual inhibitor led to a 2-fold increase in the exposure of siponimod.
Chloramphenicol: (Moderate) Concomitant use of siponimod and chloramphenicol may increase siponimod exposure. If the patient is also receiving a drug regimen containing a moderate CYP2C9 inhibitor, use of siponimod is not recommended due to a significant increase in siponimod exposure. Siponimod is a CYP2C9 and CYP3A4 substrate; chloramphenicol is a strong CYP3A4 inhibitor. Coadministration with a moderate CYP2C9/CYP3A4 dual inhibitor led to a 2-fold increase in the exposure of siponimod.
Chloroquine: (Major) Avoid coadministration of chloroquine with siponimod due to the increased risk of QT prolongation. If use together is necessary, obtain an ECG at baseline to assess initial QT interval and determine frequency of subsequent ECG monitoring, avoid any non-essential QT prolonging drugs, and correct electrolyte imbalances. Chloroquine is associated with an increased risk of QT prolongation and torsade de pointes (TdP); the risk of QT prolongation is increased with higher chloroquine doses. Siponimod therapy prolonged the QT interval at recommended doses in a clinical study.
Chlorpromazine: (Major) In general, do not initiate treatment with siponimod in patients receiving chlorpromazine due to the potential for QT prolongation. Consult a cardiologist regarding appropriate monitoring if siponimod use is required. Siponimod therapy prolonged the QT interval at recommended doses in a clinical study. Chlorpromazine, a phenothiazine, is associated with an established risk of QT prolongation and torsade de pointes.
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) In general, do not initiate treatment with siponimod in patients receiving ciprofloxacin due to the potential for QT prolongation. Consult a cardiologist regarding appropriate monitoring if siponimod use is required. Siponimod therapy prolonged the QT interval at recommended doses in a clinical study. Ciprofloxacin has also been associated with prolongation of the QT interval. Additionally, concomitant use of siponimod and ciprofloxacin may increase siponimod exposure. If the patient is also receiving a drug regimen containing a moderate CYP2C9 inhibitor, use of siponimod is not recommended due to a significant increase in siponimod exposure. Siponimod is a CYP2C9 and CYP3A4 substrate; ciprofloxacin is a moderate CYP3A4 inhibitor. Coadministration with a moderate CYP2C9/CYP3A4 dual inhibitor led to a 2-fold increase in the exposure of siponimod.
Cisapride: (Contraindicated) Concomitant use of siponimod and cisapride is contraindicated due to the potential for additive QT prolongation. Siponimod therapy prolonged the QT interval at recommended doses in a clinical study. QT prolongation and ventricular arrhythmias, including TdP and death, have been reported with cisapride.
Citalopram: (Major) Concomitant use of siponimod and citalopram increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Clarithromycin: (Major) In general, do not initiate treatment with siponimod in patients receiving clarithromycin due to the potential for QT prolongation. Consult a cardiologist regarding appropriate monitoring if siponimod use is required. Siponimod therapy prolonged the QT interval at recommended doses in a clinical study. Clarithromycin has also been associated with prolongation of the QT interval. Additionally, concomitant use of siponimod and clarithromycin may increase siponimod exposure. If the patient is also receiving a drug regimen containing a moderate CYP2C9 inhibitor, use of siponimod is not recommended due to a significant increase in siponimod exposure. Siponimod is a CYP2C9 and CYP3A4 substrate; clarithromycin is a strong CYP3A4 inhibitor. Coadministration with a moderate CYP2C9/CYP3A4 dual inhibitor led to a 2-fold increase in the exposure of siponimod.
Clofazimine: (Major) Concomitant use of clofazimine and siponimod 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.
Clozapine: (Major) In general, do not initiate treatment with siponimod in patients receiving clozapine due to the potential for QT prolongation. Consult a cardiologist regarding appropriate monitoring if siponimod use is required. Siponimod therapy prolonged the QT interval at recommended doses in a clinical study. Treatment with clozapine has been associated with QT prolongation, torsade de pointes, cardiac arrest, and sudden death.
Cobicistat: (Moderate) Concomitant use of siponimod and cobicistat may increase siponimod exposure. If the patient is also receiving a drug regimen containing a moderate CYP2C9 inhibitor, use of siponimod is not recommended due to a significant increase in siponimod exposure. Siponimod is a CYP2C9 and CYP3A4 substrate; cobicistat is a strong CYP3A4 inhibitor. Coadministration with a moderate CYP2C9/CYP3A4 dual inhibitor led to a 2-fold increase in the exposure of siponimod.
Codeine; Phenylephrine; Promethazine: (Major) Concomitant use of siponimod and promethazine 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.
Codeine; Promethazine: (Major) Concomitant use of siponimod and promethazine 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.
Conivaptan: (Moderate) Concomitant use of siponimod and conivaptan may increase siponimod exposure. If the patient is also receiving a drug regimen containing a moderate CYP2C9 inhibitor, use of siponimod is not recommended due to a significant increase in siponimod exposure. Siponimod is a CYP2C9 and CYP3A substrate; conivaptan is a moderate CYP3A inhibitor. Coadministration with a moderate CYP2C9/CYP3A dual inhibitor led to a 2-fold increase in the overall exposure of siponimod.
Cortisone: (Moderate) Monitor patients carefully for signs and symptoms of infection during coadministration of siponimod and cortisone. Concomitant use may increase the risk of immunosuppression. Siponimod has not been studied in combination with other immunosuppressive therapies used for the treatment of multiple sclerosis, including immunosuppressant doses of corticosteroids.
Crizotinib: (Major) In general, do not initiate treatment with siponimod in patients receiving crizotinib due to the potential for QT prolongation. Consult a cardiologist regarding appropriate monitoring if siponimod use is required. Siponimod therapy prolonged the QT interval at recommended doses in a clinical study. Crizotinib has also been associated with prolongation of the QT interval. Additionally, concomitant use of siponimod and crizotinib may increase siponimod exposure. If the patient is also receiving a drug regimen containing a moderate CYP2C9 inhibitor, use of siponimod is not recommended due to a significant increase in siponimod exposure. Siponimod is a CYP2C9 and CYP3A4 substrate; crizotinib is a moderate CYP3A4 inhibitor. Coadministration with a moderate CYP2C9/CYP3A4 dual inhibitor led to a 2-fold increase in the exposure of siponimod.
Cyclosporine: (Moderate) Concomitant use of siponimod and cyclosporine may increase siponimod exposure. If the patient is also receiving a drug regimen containing a moderate CYP2C9 inhibitor, use of siponimod is not recommended due to a significant increase in siponimod exposure. Siponimod is a CYP2C9 and CYP3A4 substrate; cyclosporine is a moderate CYP3A4 inhibitor. Coadministration with a moderate CYP2C9/CYP3A4 dual inhibitor led to a 2-fold increase in the exposure of siponimod.
Dabrafenib: (Moderate) Concomitant use of siponimod and dabrafenib is not recommended for patients with CYP2C9*1/*3 and *2/*3 genotypes due to a significant decrease in siponimod exposure. Siponimod is a CYP2C9 and CYP3A4 substrate; dabrafenib is a moderate CYP3A4 inducer. Across different CYP2C9 genotypes, a moderate CYP3A4 inducer decreased the exposure of siponimod by up to 52% according to in silico evaluation.
Danazol: (Moderate) Concomitant use of siponimod and danazol may increase siponimod exposure. If the patient is also receiving a drug regimen containing a moderate CYP2C9 inhibitor, use of siponimod is not recommended due to a significant increase in siponimod exposure. Siponimod is a CYP2C9 and CYP3A4 substrate; danazol is a moderate CYP3A4 inhibitor. Coadministration with a moderate CYP2C9/CYP3A4 dual inhibitor led to a 2-fold increase in the exposure of siponimod.
Darunavir: (Moderate) Concomitant use of siponimod and darunavir may increase siponimod exposure. If the patient is also receiving a drug regimen containing a moderate CYP2C9 inhibitor, use of siponimod is not recommended due to a significant increase in siponimod exposure. Siponimod is a CYP2C9 and CYP3A4 substrate; darunavir is a strong CYP3A4 inhibitor. Coadministration with a moderate CYP2C9/CYP3A4 dual inhibitor led to a 2-fold increase in the exposure of siponimod.
Darunavir; Cobicistat: (Moderate) Concomitant use of siponimod and cobicistat may increase siponimod exposure. If the patient is also receiving a drug regimen containing a moderate CYP2C9 inhibitor, use of siponimod is not recommended due to a significant increase in siponimod exposure. Siponimod is a CYP2C9 and CYP3A4 substrate; cobicistat is a strong CYP3A4 inhibitor. Coadministration with a moderate CYP2C9/CYP3A4 dual inhibitor led to a 2-fold increase in the exposure of siponimod. (Moderate) Concomitant use of siponimod and darunavir may increase siponimod exposure. If the patient is also receiving a drug regimen containing a moderate CYP2C9 inhibitor, use of siponimod is not recommended due to a significant increase in siponimod exposure. Siponimod is a CYP2C9 and CYP3A4 substrate; darunavir is a strong CYP3A4 inhibitor. Coadministration with a moderate CYP2C9/CYP3A4 dual inhibitor led to a 2-fold increase in the exposure of siponimod.
Darunavir; Cobicistat; Emtricitabine; Tenofovir alafenamide: (Moderate) Concomitant use of siponimod and cobicistat may increase siponimod exposure. If the patient is also receiving a drug regimen containing a moderate CYP2C9 inhibitor, use of siponimod is not recommended due to a significant increase in siponimod exposure. Siponimod is a CYP2C9 and CYP3A4 substrate; cobicistat is a strong CYP3A4 inhibitor. Coadministration with a moderate CYP2C9/CYP3A4 dual inhibitor led to a 2-fold increase in the exposure of siponimod. (Moderate) Concomitant use of siponimod and darunavir may increase siponimod exposure. If the patient is also receiving a drug regimen containing a moderate CYP2C9 inhibitor, use of siponimod is not recommended due to a significant increase in siponimod exposure. Siponimod is a CYP2C9 and CYP3A4 substrate; darunavir is a strong CYP3A4 inhibitor. Coadministration with a moderate CYP2C9/CYP3A4 dual inhibitor led to a 2-fold increase in the exposure of siponimod.
Dasatinib: (Major) In general, do not initiate treatment with siponimod in patients receiving dasatinib due to the potential for QT prolongation. Consult a cardiologist regarding appropriate monitoring if siponimod use is required. Siponimod therapy prolonged the QT interval at recommended doses in a clinical study. In vitro studies have shown that dasatinib has the potential to prolong the QT interval.
Deflazacort: (Moderate) Monitor patients carefully for signs and symptoms of infection during coadministration of siponimod and deflazacort. Concomitant use may increase the risk of immunosuppression. Siponimod has not been studied in combination with other immunosuppressive therapies used for the treatment of multiple sclerosis, including immunosuppressant doses of corticosteroids.
Degarelix: (Major) In general, do not initiate treatment with siponimod in patients receiving degarelix due to the potential for QT prolongation. Consult a cardiologist regarding appropriate monitoring if siponimod use is required. Siponimod therapy prolonged the QT interval at recommended doses in a clinical study. Androgen deprivation therapy (i.e., degarelix) may also prolong the QT/QTc interval.
Delavirdine: (Major) Concomitant use of siponimod and delavirdine is not recommended due to a significant increase in siponimod exposure. Siponimod is a CYP2C9 and CYP3A4 substrate; delavirdine is a moderate CYP2C9/strong CYP3A4 dual inhibitor. Coadministration with a moderate CYP2C9/CYP3A4 dual inhibitor led to a 2-fold increase in the exposure of siponimod.
Desflurane: (Major) In general, do not initiate treatment with siponimod in patients receiving halogenated anesthetics due to the potential for QT prolongation. Consult a cardiologist regarding appropriate monitoring if siponimod use is required. Siponimod therapy prolonged the QT interval at recommended doses in a clinical study. Halogenated anesthetics can prolong the QT interval.
Deutetrabenazine: (Major) In general, do not initiate treatment with siponimod in patients receiving deutetrabenazine due to the potential for QT prolongation. Consult a cardiologist regarding appropriate monitoring if siponimod use is required. Siponimod therapy prolonged the QT interval at recommended doses in a clinical study. 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.
Dexmedetomidine: (Major) Concomitant use of dexmedetomidine and siponimod increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Dextromethorphan; Quinidine: (Major) In general, do not initiate treatment with siponimod in patients receiving quinidine due to the potential for QT prolongation. Consult a cardiologist regarding appropriate monitoring if siponimod use is required. Siponimod therapy prolonged the QT interval at recommended doses in a clinical study. Quinidine administration is associated with QT prolongation and torsade de pointes.
Digoxin: (Major) In general, do not initiate treatment with siponimod in patients receiving digoxin due to the potential for additive effects on heart rate. Consult a cardiologist regarding appropriate monitoring if siponimod use is required.
Diltiazem: (Major) In general, do not initiate treatment with siponimod in patients receiving diltiazem due to the potential for additive effects on heart rate. Consult a cardiologist regarding appropriate monitoring if siponimod use is required. Additionally, concomitant use of siponimod and diltiazem may increase siponimod exposure. If the patient is also receiving a drug regimen containing a moderate CYP2C9 inhibitor, use of siponimod is not recommended due to a significant increase in siponimod exposure. Siponimod is a CYP2C9 and CYP3A4 substrate; diltiazem is a moderate CYP3A4 inhibitor. Coadministration with a moderate CYP2C9/CYP3A4 dual inhibitor led to a 2-fold increase in the exposure of siponimod.
Diphtheria Toxoid, Tetanus Toxoid, Acellular Pertussis Vaccine, DTaP; Haemophilus influenzae type b Conjugate Vaccine; Hepatitis B Vaccine, Recombinant; Inactivated Poliovirus Vaccine, IPV: (Moderate) Administer all non-live vaccines at least 2 weeks before siponimod initiation, whenever possible. Vaccines may be less effective if given during siponimod treatment. Patients should be considered unimmunized if vaccinated within a 14-day period before starting immunosuppresive therapy or during immunosuppressive therapy, and should they be revaccinated at least 3 months after therapy is discontinued if immune competence is restored.
Diphtheria Toxoid, Tetanus Toxoid, Acellular Pertussis Vaccine, DTaP; Haemophilus influenzae type b Conjugate Vaccine; Inactivated Poliovirus Vaccine, IPV: (Moderate) Administer all non-live vaccines at least 2 weeks before siponimod initiation, whenever possible. Vaccines may be less effective if given during siponimod treatment. Patients should be considered unimmunized if vaccinated within a 14-day period before starting immunosuppresive therapy or during immunosuppressive therapy, and should they be revaccinated at least 3 months after therapy is discontinued if immune competence is restored.
Diphtheria Toxoid, Tetanus Toxoid, Acellular Pertussis Vaccine, DTaP; Hepatitis B Vaccine, Recombinant; Inactivated Poliovirus Vaccine, IPV : (Moderate) Administer all non-live vaccines at least 2 weeks before siponimod initiation, whenever possible. Vaccines may be less effective if given during siponimod treatment. Patients should be considered unimmunized if vaccinated within a 14-day period before starting immunosuppresive therapy or during immunosuppressive therapy, and should they be revaccinated at least 3 months after therapy is discontinued if immune competence is restored.
Diphtheria Toxoid, Tetanus Toxoid, Acellular Pertussis Vaccine, DTaP; Inactivated Poliovirus Vaccine, IPV: (Moderate) Administer all non-live vaccines at least 2 weeks before siponimod initiation, whenever possible. Vaccines may be less effective if given during siponimod treatment. Patients should be considered unimmunized if vaccinated within a 14-day period before starting immunosuppresive therapy or during immunosuppressive therapy, and should they be revaccinated at least 3 months after therapy is discontinued if immune competence is restored.
Diphtheria Toxoid; Tetanus Toxoid Adsorbed, DT, Td: (Moderate) Administer all non-live vaccines at least 2 weeks before siponimod initiation, whenever possible. Vaccines may be less effective if given during siponimod treatment. Patients should be considered unimmunized if vaccinated within a 14-day period before starting immunosuppresive therapy or during immunosuppressive therapy, and should they be revaccinated at least 3 months after therapy is discontinued if immune competence is restored.
Diphtheria/Tetanus Toxoids; Pertussis Vaccine: (Moderate) Administer all non-live vaccines at least 2 weeks before siponimod initiation, whenever possible. Vaccines may be less effective if given during siponimod treatment. Patients should be considered unimmunized if vaccinated within a 14-day period before starting immunosuppresive therapy or during immunosuppressive therapy, and should they be revaccinated at least 3 months after therapy is discontinued if immune competence is restored.
Disopyramide: (Major) In general, do not initiate treatment with siponimod in patients receiving disopyramide due to the potential for QT prolongation. Consult a cardiologist regarding appropriate monitoring if siponimod use is required. Siponimod therapy prolonged the QT interval at recommended doses in a clinical study. Disopyramide administration is associated with QT prolongation and torsade de pointes.
Dofetilide: (Major) Coadministration of dofetilide and siponimod is not recommended as concurrent use may increase the risk of QT prolongation. If coadministration cannot be avoided, consult a cardiologist regarding appropriate monitoring. Dofetilide, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and torsade de pointes (TdP). Siponimod therapy prolonged the QT interval at recommended doses in a clinical study.
Dolasetron: (Major) In general, do not initiate treatment with siponimod in patients receiving dolasetron due to the potential for QT prolongation. Consult a cardiologist regarding appropriate monitoring if siponimod use is required. Siponimod therapy prolonged the QT interval at recommended doses in a clinical study. 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 treatment with siponimod in patients receiving rilpivirine due to the potential for QT prolongation. Consult a cardiologist regarding appropriate monitoring if siponimod use is required. Siponimod therapy prolonged the QT interval at recommended doses in a clinical study. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation.
Donepezil: (Major) In general, do not initiate treatment with siponimod in patients receiving donepezil due to the potential for QT prolongation. Consult a cardiologist regarding appropriate monitoring if siponimod use is required. Siponimod therapy prolonged the QT interval at recommended doses in a clinical study. Case reports indicate that QT prolongation and torsade de pointes can occur during donepezil therapy.
Donepezil; Memantine: (Major) In general, do not initiate treatment with siponimod in patients receiving donepezil due to the potential for QT prolongation. Consult a cardiologist regarding appropriate monitoring if siponimod use is required. Siponimod therapy prolonged the QT interval at recommended doses in a clinical study. Case reports indicate that QT prolongation and torsade de pointes can occur during donepezil therapy.
Dorzolamide; Timolol: (Moderate) Monitor for significant bradycardia with coadministration of siponimod and beta-blockers, as additive lowering effects on heart rate may occur; temporary interruption of beta-blocker treatment may be necessary prior to siponimod initiation. Beta-blocker treatment can be initiated in patients receiving stable doses of siponimod.
Dronedarone: (Contraindicated) Coadministration of dronedarone with siponimod is contraindicated due to the risk of QT prolongation; increased exposure to siponimod is also possible. Siponimod therapy prolonged the QT interval at recommended doses in a clinical study. 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 1600 mg twice daily. Siponimod is a CYP2C9 and CYP3A4 substrate; dronedarone is a moderate CYP3A4 inhibitor. Coadministration with a moderate CYP2C9/CYP3A4 dual inhibitor led to a 2-fold increase in the exposure of siponimod.
Droperidol: (Major) Avoid coadministration of siponimod and droperidol due to the potential for additive QT prolongation. Consult a cardiologist regarding appropriate monitoring if siponimod use is required. Siponimod therapy prolonged the QT interval at recommended doses in a clinical study. Droperidol administration is associated with an established risk for QT prolongation and torsade de pointes. Some cases have occurred in patients with no known risk factors for QT prolongation and some cases have been fatal.
Duvelisib: (Moderate) Concomitant use of siponimod and duvelisib may increase siponimod exposure. If the patient is also receiving a drug regimen containing a moderate CYP2C9 inhibitor, use of siponimod is not recommended due to a significant increase in siponimod exposure. Siponimod is a CYP2C9 and CYP3A4 substrate; duvelisib is a moderate CYP3A4 inhibitor. Coadministration with a moderate CYP2C9/CYP3A4 dual inhibitor led to a 2-fold increase in the exposure of siponimod.
Efavirenz: (Major) In general, do not initiate treatment with siponimod in patients receiving efavirenz due to the potential for QT prolongation. Consult a cardiologist regarding appropriate monitoring if siponimod use is required. Siponimod therapy prolonged the QT interval at recommended doses in a clinical study. Efavirenz has also been associated with prolongation of the QT interval. Additionally, concomitant use of siponimod and efavirenz is not recommended for patients with CYP2C9*1/*3 and *2/*3 genotypes due to a significant decrease in siponimod exposure. Siponimod is a CYP2C9 and CYP3A4 substrate; efavirenz is a moderate CYP3A4 inducer. Across different CYP2C9 genotypes, efavirenz decreased the exposure of siponimod by up to 52% according to in silico evaluation.
Efavirenz; Emtricitabine; Tenofovir Disoproxil Fumarate: (Major) In general, do not initiate treatment with siponimod in patients receiving efavirenz due to the potential for QT prolongation. Consult a cardiologist regarding appropriate monitoring if siponimod use is required. Siponimod therapy prolonged the QT interval at recommended doses in a clinical study. Efavirenz has also been associated with prolongation of the QT interval. Additionally, concomitant use of siponimod and efavirenz is not recommended for patients with CYP2C9*1/*3 and *2/*3 genotypes due to a significant decrease in siponimod exposure. Siponimod is a CYP2C9 and CYP3A4 substrate; efavirenz is a moderate CYP3A4 inducer. Across different CYP2C9 genotypes, efavirenz decreased the exposure of siponimod by up to 52% according to in silico evaluation.
Efavirenz; Lamivudine; Tenofovir Disoproxil Fumarate: (Major) In general, do not initiate treatment with siponimod in patients receiving efavirenz due to the potential for QT prolongation. Consult a cardiologist regarding appropriate monitoring if siponimod use is required. Siponimod therapy prolonged the QT interval at recommended doses in a clinical study. Efavirenz has also been associated with prolongation of the QT interval. Additionally, concomitant use of siponimod and efavirenz is not recommended for patients with CYP2C9*1/*3 and *2/*3 genotypes due to a significant decrease in siponimod exposure. Siponimod is a CYP2C9 and CYP3A4 substrate; efavirenz is a moderate CYP3A4 inducer. Across different CYP2C9 genotypes, efavirenz decreased the exposure of siponimod by up to 52% according to in silico evaluation.
Elagolix: (Moderate) Concomitant use of siponimod and elagolix is not recommended for patients with CYP2C9*1/*3 and *2/*3 genotypes due to a significant decrease in siponimod exposure. Siponimod is a CYP2C9 and CYP3A4 substrate; elagolix is a moderate CYP3A4 inducer. Across different CYP2C9 genotypes, a moderate CYP3A4 inducer decreased the exposure of siponimod by up to 52% according to in silico evaluation.
Elagolix; Estradiol; Norethindrone acetate: (Moderate) Concomitant use of siponimod and elagolix is not recommended for patients with CYP2C9*1/*3 and *2/*3 genotypes due to a significant decrease in siponimod exposure. Siponimod is a CYP2C9 and CYP3A4 substrate; elagolix is a moderate CYP3A4 inducer. Across different CYP2C9 genotypes, a moderate CYP3A4 inducer decreased the exposure of siponimod by up to 52% according to in silico evaluation.
Eliglustat: (Major) In general, do not initiate treatment with siponimod in patients receiving eliglustat due to the potential for QT prolongation. Consult a cardiologist regarding appropriate monitoring if siponimod use is required. Siponimod therapy prolonged the QT interval at recommended doses in a clinical study. Eliglustat is predicted to cause PR, QRS, and/or QT prolongation at significantly elevated plasma concentrations.
Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Alafenamide: (Moderate) Concomitant use of siponimod and cobicistat may increase siponimod exposure. If the patient is also receiving a drug regimen containing a moderate CYP2C9 inhibitor, use of siponimod is not recommended due to a significant increase in siponimod exposure. Siponimod is a CYP2C9 and CYP3A4 substrate; cobicistat is a strong CYP3A4 inhibitor. Coadministration with a moderate CYP2C9/CYP3A4 dual inhibitor led to a 2-fold increase in the exposure of siponimod.
Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Disoproxil Fumarate: (Moderate) Concomitant use of siponimod and cobicistat may increase siponimod exposure. If the patient is also receiving a drug regimen containing a moderate CYP2C9 inhibitor, use of siponimod is not recommended due to a significant increase in siponimod exposure. Siponimod is a CYP2C9 and CYP3A4 substrate; cobicistat is a strong CYP3A4 inhibitor. Coadministration with a moderate CYP2C9/CYP3A4 dual inhibitor led to a 2-fold increase in the exposure of siponimod.
Emtricitabine; Rilpivirine; Tenofovir alafenamide: (Major) In general, do not initiate treatment with siponimod in patients receiving rilpivirine due to the potential for QT prolongation. Consult a cardiologist regarding appropriate monitoring if siponimod use is required. Siponimod therapy prolonged the QT interval at recommended doses in a clinical study. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation.
Emtricitabine; Rilpivirine; Tenofovir Disoproxil Fumarate: (Major) In general, do not initiate treatment with siponimod in patients receiving rilpivirine due to the potential for QT prolongation. Consult a cardiologist regarding appropriate monitoring if siponimod use is required. Siponimod therapy prolonged the QT interval at recommended doses in a clinical study. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation.
Encorafenib: (Major) Avoid coadministration of encorafenib and siponimod due to the potential for additive QT prolongation. Consult a cardiologist regarding appropriate monitoring if siponimod use is required. Siponimod therapy prolonged the QT interval at recommended doses in a clinical study. Encorafenib has been associated with dose-dependent QT prolongation.
Entrectinib: (Major) Avoid coadministration of entrectinib with siponimod due to the risk of QT prolongation. If coadministration cannot be avoided, consult a cardiologist regarding appropriate monitoring. Entrectinib has been associated with QT prolongation. Siponimod therapy prolonged the QT interval at recommended doses in a clinical study.
Enzalutamide: (Major) Concomitant use of siponimod and enzalutamide is not recommended due to a significant decrease in siponimod exposure. Siponimod is a CYP2C9 and CYP3A4 substrate; enzalutamide is a moderate CYP2C9/strong CYP3A4 dual inducer. Coadministration with another moderate CYP2C9/strong CYP3A4 dual inducer decreased siponimod exposure by 57%.
Eribulin: (Major) In general, do not initiate treatment with siponimod in patients receiving eribulin due to the potential for QT prolongation. Consult a cardiologist regarding appropriate monitoring if siponimod use is required. Siponimod therapy prolonged the QT interval at recommended doses in a clinical study. Eribulin has been associated with QT prolongation.
Erythromycin: (Major) In general, do not initiate treatment with siponimod in patients receiving erythromycin due to the potential for QT prolongation. Consult a cardiologist regarding appropriate monitoring if siponimod use is required. Siponimod therapy prolonged the QT interval at recommended doses in a clinical study. Erythromycin has also been associated with prolongation of the QT interval. Additionally, concomitant use of siponimod and erythromycin may increase siponimod exposure. If the patient is also receiving a drug regimen containing a moderate CYP2C9 inhibitor, use of siponimod is not recommended due to a significant increase in siponimod exposure. Siponimod is a CYP2C9 and CYP3A4 substrate; erythromycin is a moderate CYP3A4 inhibitor. Coadministration with a moderate CYP2C9/CYP3A4 dual inhibitor led to a 2-fold increase in the exposure of siponimod.
Escitalopram: (Major) Concomitant use of siponimod and escitalopram increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Eslicarbazepine: (Moderate) Concomitant use of siponimod and eslicarbazepine is not recommended for patients with CYP2C9*1/*3 and *2/*3 genotypes due to a significant decrease in siponimod exposure. Siponimod is a CYP2C9 and CYP3A4 substrate; eslicarbazepine is a moderate CYP3A4 inducer. Across different CYP2C9 genotypes, a moderate CYP3A4 inducer decreased the exposure of siponimod by up to 52% according to in silico evaluation.
Esmolol: (Moderate) Monitor for significant bradycardia with coadministration of siponimod and beta-blockers, as additive lowering effects on heart rate may occur; temporary interruption of beta-blocker treatment may be necessary prior to siponimod initiation. Beta-blocker treatment can be initiated in patients receiving stable doses of siponimod.
Etravirine: (Moderate) Concomitant use of siponimod and etravirine is not recommended for patients with CYP2C9*1/*3 and *2/*3 genotypes due to a significant decrease in siponimod exposure. Siponimod is a CYP2C9 and CYP3A substrate; etravirine is a moderate CYP3A inducer. Across different CYP2C9 genotypes, a moderate CYP3A inducer decreased the exposure of siponimod by up to 52% according to in silico evaluation.
Fedratinib: (Moderate) Concomitant use of siponimod and fedratinib may increase siponimod exposure. If the patient is also receiving a drug regimen containing a moderate CYP2C9 inhibitor, use of siponimod is not recommended due to a significant increase in siponimod exposure. Siponimod is a CYP2C9 and CYP3A4 substrate; fedratinib is a moderate CYP3A4 inhibitor. Coadministration with a moderate CYP2C9/CYP3A4 dual inhibitor led to a 2-fold increase in the AUC of siponimod.
Fingolimod: (Major) In general, do not initiate treatment with siponimod in patients receiving fingolimod due to the potential for QT prolongation. Consult a cardiologist regarding appropriate monitoring if siponimod use is required. Siponimod therapy prolonged the QT interval at recommended doses in a clinical study. Fingolimod treatment results in decreased heart rate and may prolong the QT interval. Fingolimod has not been studied in patients treated with drugs that prolong the QT interval, but drugs that prolong the QT interval have been associated with cases of torsade de pointes in patients with bradycardia.
Flecainide: (Major) Concomitant use of siponimod and flecainide increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Fluconazole: (Major) In general, do not initiate treatment with siponimod in patients receiving fluconazole due to the potential for QT prolongation. Consult a cardiologist regarding appropriate monitoring if siponimod use is required. Siponimod therapy prolonged the QT interval at recommended doses in a clinical study. Fluconazole has been associated with QT prolongation and rare cases of torsade de pointes. Additionally, increased exposure to siponimod is also possible. Siponimod is a CYP2C9 and CYP3A4 substrate; fluconazole is a moderate CYP2C9/CYP3A4 dual inhibitor. Coadministration with fluconazole led to a 2-fold increase in the exposure of siponimod in CYP2C9*1/*1 healthy volunteers. Across different CYP2C9 genotypes, fluconazole led to a 2- to4-fold increase in the exposure of siponimod, according to in silico evaluation.
Fluorouracil, 5-FU: (Moderate) Concomitant use of siponimod and fluorouracil may increase siponimod exposure. If the patient is also receiving a drug regimen containing a moderate or strong CYP3A4 inhibitor, use of siponimod is not recommended due to a significant increase in siponimod exposure. Siponimod is a CYP2C9 and CYP3A4 substrate; fluorouracil is a moderate CYP2C9 inhibitor. Coadministration with a moderate CYP2C9/CYP3A4 dual inhibitor led to a 2-fold increase in the exposure of siponimod.
Fluoxetine: (Major) Concomitant use of siponimod and fluoxetine 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.
Fluphenazine: (Minor) In general, do not initiate treatment with siponimod in patients receiving fluphenazine due to the potential for QT prolongation. Consult a cardiologist regarding appropriate monitoring if siponimod use is required. Siponimod therapy prolonged the QT interval at recommended doses in a clinical study. Fluphenazine is associated with a possible risk for QT prolongation.
Fluvoxamine: (Major) In general, do not initiate treatment with siponimod in patients receiving fluvoxamine due to the potential for QT prolongation. Consult a cardiologist regarding appropriate monitoring if siponimod use is required. Siponimod therapy prolonged the QT interval at recommended doses in a clinical study. QT prolongation and torsade de pointes have been reported during fluvoxamine postmarketing use. Additionally, concomitant use of siponimod and fluvoxamine may increase siponimod exposure. If the patient is also receiving a drug regimen containing a moderate CYP2C9 inhibitor, use of siponimod is not recommended due to a significant increase in siponimod exposure. Siponimod is a CYP2C9 and CYP3A4 substrate; fluvoxamine is a moderate CYP3A4 inhibitor. Coadministration

with a moderate CYP2C9/CYP3A4 dual inhibitor led to a 2-fold increase in the exposure of siponimod.
Fosamprenavir: (Moderate) Concomitant use of siponimod and fosamprenavir may increase siponimod exposure. If the patient is also receiving a drug regimen containing a moderate CYP2C9 inhibitor, use of siponimod is not recommended due to a significant increase in siponimod exposure. Siponimod is a CYP2C9 and CYP3A substrate; fosamprenavir is a moderate CYP3A inhibitor. Coadministration with a moderate CYP2C9/CYP3A dual inhibitor led to a 2-fold increase in the AUC of siponimod.
Foscarnet: (Major) Avoid coadministration of siponimod and foscarnet due to the potential for additive QT prolongation. Consult a cardiologist regarding appropriate monitoring if siponimod use is required. Siponimod therapy prolonged the QT interval at recommended doses in a clinical study. Both QT prolongation and torsade de pointes have been reported during postmarketing use of foscarnet.
Fosphenytoin: (Major) Concomitant use of siponimod and fosphenytoin is not recommended due to a significant decrease in siponimod exposure. Siponimod is a CYP2C9 and CYP3A4 substrate; fosphenytoin is a moderate CYP2C9/strong CYP3A4 dual inducer. Coadministration with another moderate CYP2C9/strong CYP3A4 dual inducer decreased siponimod exposure by 57%.
Fostemsavir: (Major) In general, do not initiate treatment with siponimod in patients receiving fostemsavir due to the potential for QT prolongation. Consult a cardiologist regarding appropriate monitoring if siponimod use is required. Siponimod therapy prolonged the QT interval at recommended doses in a clinical study. 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 treatment with siponimod in patients receiving gemifloxacin due to the potential for QT prolongation. Consult a cardiologist regarding appropriate monitoring if siponimod use is required. Siponimod therapy prolonged the QT interval at recommended doses in a clinical study. 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 treatment with siponimod in patients receiving gemtuzumab due to the potential for QT prolongation. Consult a cardiologist regarding appropriate monitoring if siponimod use is required. Siponimod therapy prolonged the QT interval at recommended doses in a clinical study. 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 treatment with siponimod in patients receiving gilteritinib due to the potential for QT prolongation. Consult a cardiologist regarding appropriate monitoring if siponimod use is required. Siponimod therapy prolonged the QT interval at recommended doses in a clinical study. Gilteritinib has also been associated with QT prolongation.
Glasdegib: (Major) Avoid coadministration of siponimod and glasdegib due to the potential for additive QT prolongation. Consult a cardiologist regarding appropriate monitoring if siponimod use is required. Siponimod therapy prolonged the QT interval at recommended doses in a clinical study. Glasdegib therapy may result in QT prolongation and ventricular arrhythmias including ventricular fibrillation and ventricular tachycardia.
Goserelin: (Major) In general, do not initiate treatment with siponimod in patients receiving goserelin due to the potential for QT prolongation. Consult a cardiologist regarding appropriate monitoring if siponimod use is required. Siponimod therapy prolonged the QT interval at recommended doses in a clinical study. Androgen deprivation therapy (i.e., goserelin) may prolong the QT/QTc interval.
Granisetron: (Major) In general, do not initiate treatment with siponimod in patients receiving granisetron due to the potential for QT prolongation. Consult a cardiologist regarding appropriate monitoring if siponimod use is required. Siponimod therapy prolonged the QT interval at recommended doses in a clinical study. Granisetron has been associated with QT prolongation.
Grapefruit juice: (Major) Advise patients to avoid the concomitant use of siponimod and grapefruit juice due to a significant increase in siponimod exposure. Siponimod is a CYP2C9 and CYP3A4 substrate; grapefruit juice is a moderate CYP2C9/strong CYP3A4 dual inhibitor. Coadministration with a moderate CYP2C9/CYP3A4 dual inhibitor led to a 2-fold increase in the exposure of siponimod.
Haemophilus influenzae type b Conjugate Vaccine: (Moderate) Administer all non-live vaccines at least 2 weeks before siponimod initiation, whenever possible. Vaccines may be less effective if given during siponimod treatment. Patients should be considered unimmunized if vaccinated within a 14-day period before starting immunosuppresive therapy or during immunosuppressive therapy, and should they be revaccinated at least 3 months after therapy is discontinued if immune competence is restored.
Halogenated Anesthetics: (Major) In general, do not initiate treatment with siponimod in patients receiving halogenated anesthetics due to the potential for QT prolongation. Consult a cardiologist regarding appropriate monitoring if siponimod use is required. Siponimod therapy prolonged the QT interval at recommended doses in a clinical study. Halogenated anesthetics can prolong the QT interval.
Haloperidol: (Major) In general, do not initiate treatment with siponimod in patients receiving haloperidol due to the potential for QT prolongation. Consult a cardiologist regarding appropriate monitoring if siponimod use is required. Siponimod therapy prolonged the QT interval at recommended doses in a clinical study. QT prolongation and torsade de pointes 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.
Hepatitis A Vaccine, Inactivated: (Moderate) Administer all non-live vaccines at least 2 weeks before siponimod initiation, whenever possible. Vaccines may be less effective if given during siponimod treatment. Patients should be considered unimmunized if vaccinated within a 14-day period before starting immunosuppresive therapy or during immunosuppressive therapy, and should they be revaccinated at least 3 months after therapy is discontinued if immune competence is restored.
Hepatitis A Vaccine, Inactivated; Hepatitis B Vaccine, Recombinant: (Moderate) Administer all non-live vaccines at least 2 weeks before siponimod initiation, whenever possible. Vaccines may be less effective if given during siponimod treatment. Patients should be considered unimmunized if vaccinated within a 14-day period before starting immunosuppresive therapy or during immunosuppressive therapy, and should they be revaccinated at least 3 months after therapy is discontinued if immune competence is restored.
Hepatitis B Vaccine, Recombinant: (Moderate) Administer all non-live vaccines at least 2 weeks before siponimod initiation, whenever possible. Vaccines may be less effective if given during siponimod treatment. Patients should be considered unimmunized if vaccinated within a 14-day period before starting immunosuppresive therapy or during immunosuppressive therapy, and should they be revaccinated at least 3 months after therapy is discontinued if immune competence is restored.
Histrelin: (Major) In general, do not initiate treatment with siponimod in patients receiving histrelin due to the potential for QT prolongation. Consult a cardiologist regarding appropriate monitoring if siponimod use is required. Siponimod therapy prolonged the QT interval at recommended doses in a clinical study. Androgen deprivation therapy (i.e., histrelin) may prolong the QT/QTc interval.
Human Papillomavirus 9-Valent Vaccine: (Moderate) Administer all non-live vaccines at least 2 weeks before siponimod initiation, whenever possible. Vaccines may be less effective if given during siponimod treatment. Patients should be considered unimmunized if vaccinated within a 14-day period before starting immunosuppresive therapy or during immunosuppressive therapy, and should they be revaccinated at least 3 months after therapy is discontinued if immune competence is restored.
Hydrocortisone: (Moderate) Monitor patients carefully for signs and symptoms of infection during coadministration of siponimod and hydrocortisone. Concomitant use may increase the risk of immunosuppression. Siponimod has not been studied in combination with other immunosuppressive therapies used for the treatment of multiple sclerosis, including immunosuppressant doses of corticosteroids.
Hydroxychloroquine: (Major) Concomitant use of siponimod and hydroxychloroquine increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Hydroxyzine: (Major) Concomitant use of siponimod and hydroxyzine 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.
Ibutilide: (Major) In general, do not initiate treatment with siponimod in patients receiving ibutilide due to the potential for QT prolongation. Consult a cardiologist regarding appropriate monitoring if siponimod use is required. Siponimod therapy prolonged the QT interval at recommended doses in a clinical study. Ibutilide administration can cause QT prolongation and torsade de pointes; proarrhythmic events should be anticipated. The potential for proarrhythmic events with ibutilide increases with the coadministration of other drugs that prolong the QT interval.
Idelalisib: (Moderate) Concomitant use of siponimod and idelalisib may increase siponimod exposure. If the patient is also receiving a drug regimen containing a moderate CYP2C9 inhibitor, use of siponimod is not recommended due to a significant increase in siponimod exposure. Siponimod is a CYP2C9 and CYP3A4 substrate; idelalisib is a strong CYP3A4 inhibitor. Coadministration with a moderate CYP2C9/CYP3A4 dual inhibitor led to a 2-fold increase in the exposure of siponimod.
Iloperidone: (Major) Avoid coadministration of siponimod and iloperidone due to the potential for additive QT prolongation. Consult a cardiologist regarding appropriate monitoring if siponimod use is required. Siponimod therapy prolonged the QT interval at recommended doses in a clinical study. Iloperidone has been associated with QT prolongation.
Imatinib: (Moderate) Concomitant use of siponimod and imatinib may increase siponimod exposure. If the patient is also receiving a drug regimen containing a moderate CYP2C9 inhibitor, use of siponimod is not recommended due to a significant increase in siponimod exposure. Siponimod is a CYP2C9 and CYP3A4 substrate; imatinib is a moderate CYP3A4 inhibitor. Coadministration with a moderate CYP2C9/CYP3A4 dual inhibitor led to a 2-fold increase in the exposure of siponimod.
Indinavir: (Moderate) Concomitant use of siponimod and indinavir may increase siponimod exposure. If the patient is also receiving a drug regimen containing a moderate CYP2C9 inhibitor, use of siponimod is not recommended due to a significant increase in siponimod exposure. Siponimod is a CYP2C9 and CYP3A4 substrate; indinavir is a strong CYP3A4 inhibitor. Coadministration with a moderate CYP2C9/CYP3A4 dual inhibitor led to a 2-fold increase in the exposure of siponimod.
Influenza Virus Vaccine: (Moderate) Administer all non-live vaccines at least 2 weeks before siponimod initiation, whenever possible. Vaccines may be less effective if given during siponimod treatment. Patients should be considered unimmunized if vaccinated within a 14-day period before starting immunosuppresive therapy or during immunosuppressive therapy, and should they be revaccinated at least 3 months after therapy is discontinued if immune competence is restored.
Inotuzumab Ozogamicin: (Major) Avoid coadministration of siponimod and inotuzumab due to the potential for additive QT prolongation. Consult a cardiologist regarding appropriate monitoring if siponimod use is required. Siponimod therapy prolonged the QT interval at recommended doses in a clinical study. Iloperidone has been associated with QT prolongation. Inotuzumab has been associated with QT interval prolongation.
Intranasal Influenza Vaccine: (Major) Avoid the use of live vaccines during treatment with siponomid and for 4 weeks after stopping treatment due to the risk of secondary infection. Additionally, vaccines may be less effective if administered during siponimod treatment and for 4 weeks after siponimod treatment discontinuation. (Moderate) Administer all non-live vaccines at least 2 weeks before siponimod initiation, whenever possible. Vaccines may be less effective if given during siponimod treatment. Patients should be considered unimmunized if vaccinated within a 14-day period before starting immunosuppresive therapy or during immunosuppressive therapy, and should they be revaccinated at least 3 months after therapy is discontinued if immune competence is restored.
Isavuconazonium: (Moderate) Concomitant use of siponimod and isavuconazonium may increase siponimod exposure. If the patient is also receiving a drug regimen containing a moderate CYP2C9 inhibitor, use of siponimod is not recommended due to a significant increase in siponimod exposure. Siponimod is a CYP2C9 and CYP3A4 substrate; isavuconazonium is a moderate CYP3A4 inhibitor. Coadministration with a moderate CYP2C9/CYP3A4 dual inhibitor led to a 2-fold increase in the exposure of siponimod.
Isoflurane: (Major) In general, do not initiate treatment with siponimod in patients receiving halogenated anesthetics due to the potential for QT prolongation. Consult a cardiologist regarding appropriate monitoring if siponimod use is required. Siponimod therapy prolonged the QT interval at recommended doses in a clinical study. Halogenated anesthetics can prolong the QT interval.
Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Major) Concomitant use of siponimod and rifampin is not recommended due to a significant decrease in siponimod exposure. Siponimod is a CYP2C9 and CYP3A4 substrate; rifampin is a moderate CYP2C9/strong CYP3A4 dual inducer. Coadministration with rifampin decreased siponimod exposure by 57%. Across different CYP2C9 genotypes, rifampin decreased the exposure of siponimod by up to 78%.
Isoniazid, INH; Rifampin: (Major) Concomitant use of siponimod and rifampin is not recommended due to a significant decrease in siponimod exposure. Siponimod is a CYP2C9 and CYP3A4 substrate; rifampin is a moderate CYP2C9/strong CYP3A4 dual inducer. Coadministration with rifampin decreased siponimod exposure by 57%. Across different CYP2C9 genotypes, rifampin decreased the exposure of siponimod by up to 78%.
Itraconazole: (Major) In general, do not initiate treatment with siponimod in patients receiving itraconazole due to the potential for QT prolongation. Consult a cardiologist regarding appropriate monitoring if siponimod use is required. Siponimod therapy prolonged the QT interval at recommended doses in a clinical study. Itraconazole has also been associated with prolongation of the QT interval. Additionally, concomitant use of siponimod and itraconazole may increase siponimod exposure. If the patient is also receiving a drug regimen containing a moderate CYP2C9 inhibitor, use of siponimod is not recommended due to a significant increase in siponimod exposure. Siponimod is a CYP2C9 and CYP3A4 substrate; itraconazole is a strong CYP3A4 inhibitor. Coadministration with a moderate CYP2C9/CYP3A4 dual inhibitor led to a 2-fold increase in the exposure of siponimod.
Ivabradine: (Major) In general, do not initiate treatment with siponimod in patients receiving ivabradine due to the potential for additive effects on heart rate. Consult a cardiologist regarding appropriate monitoring if siponimod use is required.
Ivosidenib: (Major) Avoid coadministration of siponimod and ivosidenib due to the potential for additive QT prolongation. Consult a cardiologist regarding appropriate monitoring if siponimod use is required. Siponimod therapy prolonged the QT interval at recommended doses in a clinical study. Prolongation of the QTc interval and ventricular arrhythmias have been reported in patients treated with ivosidenib.
Japanese Encephalitis Virus Vaccine: (Moderate) Administer all non-live vaccines at least 2 weeks before siponimod initiation, whenever possible. Vaccines may be less effective if given during siponimod treatment. Patients should be considered unimmunized if vaccinated within a 14-day period before starting immunosuppresive therapy or during immunosuppressive therapy, and should they be revaccinated at least 3 months after therapy is discontinued if immune competence is restored.
Ketoconazole: (Contraindicated) Avoid concomitant use of ketoconazole and siponimod due to an increased risk for torsade de pointes (TdP) and QT/QTc prolongation. Concomitant use may also increase the exposure of siponimod, further increasing the risk for adverse effects. Siponimod is a CYP3A4 substrate and ketoconazole is a strong CYP3A4 inhibitor.
Labetalol: (Moderate) Monitor for significant bradycardia with coadministration of siponimod and beta-blockers, as additive lowering effects on heart rate may occur; temporary interruption of beta-blocker treatment may be necessary prior to siponimod initiation. Beta-blocker treatment can be initiated in patients receiving stable doses of siponimod.
Lansoprazole; Amoxicillin; Clarithromycin: (Major) In general, do not initiate treatment with siponimod in patients receiving clarithromycin due to the potential for QT prolongation. Consult a cardiologist regarding appropriate monitoring if siponimod use is required. Siponimod therapy prolonged the QT interval at recommended doses in a clinical study. Clarithromycin has also been associated with prolongation of the QT interval. Additionally, concomitant use of siponimod and clarithromycin may increase siponimod exposure. If the patient is also receiving a drug regimen containing a moderate CYP2C9 inhibitor, use of siponimod is not recommended due to a significant increase in siponimod exposure. Siponimod is a CYP2C9 and CYP3A4 substrate; clarithromycin is a strong CYP3A4 inhibitor. Coadministration with a moderate CYP2C9/CYP3A4 dual inhibitor led to a 2-fold increase in the exposure of siponimod.
Lapatinib: (Major) In general, do not initiate treatment with siponimod in patients receiving lapatinib due to the potential for QT prolongation. Consult a cardiologist regarding appropriate monitoring if siponimod use is required. Siponimod therapy prolonged the QT interval at recommended doses in a clinical study. Lapatinib has been associated with concentration-dependent QT prolongation; ventricular arrhythmias and torsade de pointes have been reported in postmarketing experience with lapatinib.
Lefamulin: (Major) Avoid coadministration of lefamulin with siponimod as concurrent use may increase the risk of QT prolongation. If coadministration cannot be avoided, monitor ECG during treatment. Lefamulin has a concentration dependent QTc prolongation effect. The pharmacodynamic interaction potential to prolong the QT interval of the electrocardiogram between lefamulin and other drugs that effect cardiac conduction is unknown. Siponimod therapy prolonged the QT interval at recommended doses in a clinical study.
Lenacapavir: (Moderate) Concomitant use of siponimod and lenacapavir may increase siponimod exposure. If the patient is also receiving a drug regimen containing a moderate CYP2C9 inhibitor, use of siponimod is not recommended due to a significant increase in siponimod exposure. Siponimod is a CYP2C9 and CYP3A substrate; lenacapavir is a moderate CYP3A inhibitor. Coadministration with a moderate CYP2C9/CYP3A dual inhibitor led to a 2-fold increase in the AUC of siponimod.
Lenvatinib: (Major) Avoid coadministration of siponimod and lenvatinib due to the potential for additive QT prolongation. Consult a cardiologist regarding appropriate monitoring if siponimod use is required. Siponimod therapy prolonged the QT interval at recommended doses in a clinical study. Prolongation of the QT interval has been reported with lenvatinib therapy.
Letermovir: (Moderate) Concomitant use of siponimod and letermovir may increase siponimod exposure. If the patient is also receiving a drug regimen containing a moderate CYP2C9 inhibitor, use of siponimod is not recommended due to a significant increase in siponimod exposure. Siponimod is a CYP2C9 and CYP3A4 substrate; letermovir is a moderate CYP3A4 inhibitor. Coadministration with a moderate CYP2C9/CYP3A4 dual inhibitor led to a 2-fold increase in the exposure of siponimod.
Leuprolide: (Major) In general, do not initiate treatment with siponimod in patients receiving leuprolide due to the potential for QT prolongation. Consult a cardiologist regarding appropriate monitoring if siponimod use is required. Siponimod therapy prolonged the QT interval at recommended doses in a clinical study. Androgen deprivation therapy (i.e., leuprolide) may prolong the QT/QTc interval.
Leuprolide; Norethindrone: (Major) In general, do not initiate treatment with siponimod in patients receiving leuprolide due to the potential for QT prolongation. Consult a cardiologist regarding appropriate monitoring if siponimod use is required. Siponimod therapy prolonged the QT interval at recommended doses in a clinical study. Androgen deprivation therapy (i.e., leuprolide) may prolong the QT/QTc interval.
Levobunolol: (Moderate) Monitor for significant bradycardia with coadministration of siponimod and beta-blockers, as additive lowering effects on heart rate may occur; temporary interruption of beta-blocker treatment may be necessary prior to siponimod initiation. Beta-blocker treatment can be initiated in patients receiving stable doses of siponimod.
Levofloxacin: (Major) Concomitant use of siponimod and levofloxacin increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Levoketoconazole: (Contraindicated) Avoid concomitant use of ketoconazole and siponimod due to an increased risk for torsade de pointes (TdP) and QT/QTc prolongation. Concomitant use may also increase the exposure of siponimod, further increasing the risk for adverse effects. Siponimod is a CYP3A4 substrate and ketoconazole is a strong CYP3A4 inhibitor.
Lithium: (Major) Concomitant use of siponimod and lithium increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Live Vaccines: (Major) Avoid the use of live vaccines during treatment with siponomid and for 4 weeks after stopping treatment due to the risk of secondary infection. Additionally, vaccines may be less effective if administered during siponimod treatment and for 4 weeks after siponimod treatment discontinuation.
Lofexidine: (Major) In general, do not initiate treatment with siponimod in patients receiving lofexidine due to the potential for QT prolongation. Consult a cardiologist regarding appropriate monitoring if siponimod use is required. Siponimod therapy prolonged the QT interval at recommended doses in a clinical study. Lofexidine also prolongs the QT interval.
Lonafarnib: (Moderate) Concomitant use of siponimod and lonafarnib may increase siponimod exposure. If the patient is also receiving a drug regimen containing a moderate CYP2C9 inhibitor, use of siponimod is not recommended due to a significant increase in siponimod exposure. Siponimod is a CYP2C9 and CYP3A4 substrate; lonafarnib is a strong CYP3A4 inhibitor. Coadministration with a moderate CYP2C9/CYP3A4 dual inhibitor led to a 2-fold increase in the AUC of siponimod.
Loperamide: (Moderate) In general, do not initiate treatment with siponimod in patients receiving loperamide due to the potential for QT prolongation. Consult a cardiologist regarding appropriate monitoring if siponimod use is required. Siponimod therapy prolonged the QT interval at recommended doses in a clinical study. At high doses, loperamide has been associated with serious cardiac toxicities, including syncope, ventricular tachycardia, QT prolongation, torsade de pointes, and cardiac arrest.
Loperamide; Simethicone: (Moderate) In general, do not initiate treatment with siponimod in patients receiving loperamide due to the potential for QT prolongation. Consult a cardiologist regarding appropriate monitoring if siponimod use is required. Siponimod therapy prolonged the QT interval at recommended doses in a clinical study. At high doses, loperamide has been associated with serious cardiac toxicities, including syncope, ventricular tachycardia, QT prolongation, torsade de pointes, and cardiac arrest.
Lopinavir; Ritonavir: (Major) Avoid coadministration of lopinavir with siponimod 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. Consult a cardiologist. Siponimod therapy prolonged the QT interval at recommended doses in a clinical study. Lopinavir is associated with QT prolongation. (Moderate) Concomitant use of siponimod and ritonavir may increase siponimod exposure. If the patient is also receiving a drug regimen containing a moderate CYP2C9 inhibitor, use of siponimod is not recommended due to a significant increase in siponimod exposure. Siponimod is a CYP2C9 and CYP3A4 substrate; ritonavir is a strong CYP3A4 inhibitor. Coadministration with a moderate CYP2C9/CYP3A4 dual inhibitor led to a 2-fold increase in the exposure of siponimod.
Lorlatinib: (Moderate) Concomitant use of siponimod and lorlatinib is not recommended for patients with CYP2C9*1/*3 and *2/*3 genotypes due to a significant decrease in siponimod exposure. Siponimod is a CYP2C9 and CYP3A4 substrate; lorlatinib is a moderate CYP3A4 inducer. Across different CYP2C9 genotypes, a moderate CYP3A4 inducer decreased the exposure of siponimod by up to 52% according to in silico evaluation.
Lumacaftor; Ivacaftor: (Moderate) Concomitant use of siponimod and lumacaftor; ivacaftor is not recommended for patients with CYP2C9*1/*3 and *2/*3 genotypes due to a significant decrease in siponimod exposure. Use of siponimod with lumacaftor; ivacaftor is not recommended in any patient if they are also receiving a moderate CYP2C9 inducer. Siponimod is a CYP2C9 and CYP3A4 substrate; lumacaftor; ivacaftor is a strong CYP3A4 inducer. Coadministration with a moderate CYP2C9/strong CYP3A4 dual inducer decreased siponimod exposure by 57%.
Lumacaftor; Ivacaftor: (Moderate) Concomitant use of siponimod and lumacaftor; ivacaftor is not recommended for patients with CYP2C9*1/*3 and *2/*3 genotypes due to a significant decrease in siponimod exposure. Use of siponimod with lumacaftor; ivacaftor is not recommended in any patient if they are also receiving a moderate CYP2C9 inducer. Siponimod is a CYP2C9 and CYP3A4 substrate; lumacaftor; ivacaftor is a strong CYP3A4 inducer. Coadministration with a moderate CYP2C9/strong CYP3A4 dual inducer decreased siponimod exposure by 57%.
Macimorelin: (Major) Avoid concurrent administration of macimorelin with drugs that prolong the QT interval, such as siponimod. Use of these drugs together may increase the risk of developing torsade de pointes-type ventricular tachycardia. Sufficient washout time of siponimod prior to administration of macimorelin is recommended. Treatment with macimorelin has been associated with an increase in the corrected QT (QTc) interval. Siponimod therapy prolonged the QT interval at recommended doses in a clinical study.
Maprotiline: (Major) In general, do not initiate treatment with siponimod in patients receiving maprotiline due to the potential for QT prolongation. Consult a cardiologist regarding appropriate monitoring if siponimod use is required. Siponimod therapy prolonged the QT interval at recommended doses in a clinical study. Maprotiline has been reported to prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). Cases of long QT syndrome and torsade de pointes 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.
Mavacamten: (Moderate) Concomitant use of siponimod and mavacamten may decrease siponimod exposure. If the patient is also receiving a drug regimen containing a strong CYP3A inducer or for patients with CYP2C9*1/*3 and *2/*3 genotypes, use of siponimod is not recommended due to a significant decrease in siponimod exposure. Siponimod is a CYP2C9 and CYP3A substrate; mavacamten is a moderate CYP2C9 and CYP3A inducer. Coadministration with a moderate CYP2C9/strong CYP3A dual inducer decreased siponimod exposure by 57%. Across different CYP2C9 genotypes, a moderate CYP3A inducer decreased the exposure of siponimod by up to 52% according to in silico evaluation.
Measles Virus; Mumps Virus; Rubella Virus; Varicella Virus Vaccine, Live: (Major) Avoid the use of live vaccines during treatment with siponomid and for 4 weeks after stopping treatment due to the risk of secondary infection. Additionally, vaccines may be less effective if administered during siponimod treatment and for 4 weeks after siponimod treatment discontinuation.
Measles/Mumps/Rubella Vaccines, MMR: (Major) Avoid the use of live vaccines during treatment with siponomid and for 4 weeks after stopping treatment due to the risk of secondary infection. Additionally, vaccines may be less effective if administered during siponimod treatment and for 4 weeks after siponimod treatment discontinuation.
Mefloquine: (Major) In general, do not initiate treatment with siponimod in patients receiving mefloquine due to the potential for QT prolongation. Consult a cardiologist regarding appropriate monitoring if siponimod use is required. Siponimod therapy prolonged the QT interval at recommended doses in a clinical study. 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. However, due to the lack of clinical data, mefloquine should be used with caution in patients receiving drugs that prolong the QT interval.
Meningococcal Conjugate Vaccine (MCV4): (Moderate) Administer all non-live vaccines at least 2 weeks before siponimod initiation, whenever possible. Vaccines may be less effective if given during siponimod treatment. Patients should be considered unimmunized if vaccinated within a 14-day period before starting immunosuppresive therapy or during immunosuppressive therapy, and should they be revaccinated at least 3 months after therapy is discontinued if immune competence is restored.
Meningococcal Group B Vaccine (3 strain): (Moderate) Administer all non-live vaccines at least 2 weeks before siponimod initiation, whenever possible. Vaccines may be less effective if given during siponimod treatment. Patients should be considered unimmunized if vaccinated within a 14-day period before starting immunosuppresive therapy or during immunosuppressive therapy, and should they be revaccinated at least 3 months after therapy is discontinued if immune competence is restored.
Meningococcal Group B Vaccine (4 strain): (Moderate) Administer all non-live vaccines at least 2 weeks before siponimod initiation, whenever possible. Vaccines may be less effective if given during siponimod treatment. Patients should be considered unimmunized if vaccinated within a 14-day period before starting immunosuppresive therapy or during immunosuppressive therapy, and should they be revaccinated at least 3 months after therapy is discontinued if immune competence is restored.
Methadone: (Major) In general, do not initiate treatment with siponimod in patients receiving methadone due to the potential for QT prolongation. Consult a cardiologist regarding appropriate monitoring if siponimod use is required. Siponimod therapy prolonged the QT interval at recommended doses in a clinical study. Methadone is considered to be associated with an increased risk for QT prolongation and torsade de pointes, especially at higher doses (more than 200 mg/day but averaging approximately 400 mg/day in adult patients). Most cases involve patients being treated for pain with large, multiple daily doses of methadone, although cases have been reported in patients receiving doses commonly used for maintenance treatment of opioid addiction.
Methylprednisolone: (Moderate) Monitor patients carefully for signs and symptoms of infection during coadministration of siponimod and methylprednisolone. Concomitant use may increase the risk of immunosuppression. Siponimod has not been studied in combination with other immunosuppressive therapies used for the treatment of multiple sclerosis, including immunosuppressant doses of corticosteroids.
Metoprolol: (Moderate) Monitor for significant bradycardia with coadministration of siponimod and beta-blockers, as additive lowering effects on heart rate may occur; temporary interruption of beta-blocker treatment may be necessary prior to siponimod initiation. Beta-blocker treatment can be initiated in patients receiving stable doses of siponimod.
Metoprolol; Hydrochlorothiazide, HCTZ: (Moderate) Monitor for significant bradycardia with coadministration of siponimod and beta-blockers, as additive lowering effects on heart rate may occur; temporary interruption of beta-blocker treatment may be necessary prior to siponimod initiation. Beta-blocker treatment can be initiated in patients receiving stable doses of siponimod.
Metronidazole: (Major) Concomitant use of metronidazole and siponimod increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Midostaurin: (Major) In general, do not initiate treatment with siponimod in patients receiving midostaurin due to the potential for QT prolongation. Consult a cardiologist regarding appropriate monitoring if siponimod use is required. Siponimod therapy prolonged the QT interval at recommended doses in a clinical study. QT prolongation was reported in patients who received midostaurin in clinical trials.
Mifepristone: (Major) Concomitant use of siponimod and mifepristone is not recommended due to a significant increase in siponimod exposure. Additionally, both drugs are associated with QT prolongation. Siponimod is a CYP2C9 and CYP3A4 substrate; mifepristone is a moderate CYP2C9/strong CYP3A4 dual inhibitor. Coadministration with a moderate CYP2C9/CYP3A4 dual inhibitor led to a 2-fold increase in the exposure of siponimod.
Mirtazapine: (Major) Concomitant use of siponimod and mirtazapine 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.
Mitotane: (Moderate) Concomitant use of siponimod and mitotane is not recommended for patients with CYP2C9*1/*3 and *2/*3 genotypes due to a significant decrease in siponimod exposure. Use of siponimod with mitotane is not recommended in any patient if they are also receiving a moderate CYP2C9 inducer. Siponimod is a CYP2C9 and CYP3A4 substrate; mitotane is a strong CYP3A4 inducer. Coadministration with a moderate CYP2C9/strong CYP3A4 dual inducer decreased siponimod exposure by 57%.
Mobocertinib: (Major) Concomitant use of mobocertinib and siponimod 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.
Modafinil: (Moderate) Concomitant use of siponimod and modafinil is not recommended for patients with CYP2C9*1/*3 and *2/*3 genotypes due to a significant decrease in siponimod exposure. Siponimod is a CYP2C9 and CYP3A4 substrate; modafinil is a moderate CYP3A4 inducer. Across CYP2C9 genotypes, coadministration of a moderate CYP3A4 inducer reduced siponimod exposure by up to 52%, according to in silico evaluation.
Moxifloxacin: (Major) In general, do not initiate treatment with siponimod in patients receiving moxifloxacin due to the potential for QT prolongation. Consult a cardiologist regarding appropriate monitoring if siponimod use is required. Siponimod therapy prolonged the QT interval at recommended doses in a clinical study. Quinolones have been associated with a risk of QT prolongation and torsade de pointes (TdP). 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 significant bradycardia with coadministration of siponimod and beta-blockers, as additive lowering effects on heart rate may occur; temporary interruption of beta-blocker treatment may be necessary prior to siponimod initiation. Beta-blocker treatment can be initiated in patients receiving stable doses of siponimod.
Nafcillin: (Moderate) Concomitant use of siponimod and nafcillin is not recommended for patients with CYP2C9*1/*3 and *2/*3 genotypes due to a significant decrease in siponimod exposure. Siponimod is a CYP2C9 and CYP3A4 substrate; nafcillin is a moderate CYP3A4 inducer. Across different CYP2C9 genotypes, a moderate CYP3A4 inducer decreased the exposure of siponimod by up to 52% according to in silico evaluation.
Nebivolol: (Moderate) Monitor for significant bradycardia with coadministration of siponimod and beta-blockers, as additive lowering effects on heart rate may occur; temporary interruption of beta-blocker treatment may be necessary prior to siponimod initiation. Beta-blocker treatment can be initiated in patients receiving stable doses of siponimod.
Nebivolol; Valsartan: (Moderate) Monitor for significant bradycardia with coadministration of siponimod and beta-blockers, as additive lowering effects on heart rate may occur; temporary interruption of beta-blocker treatment may be necessary prior to siponimod initiation. Beta-blocker treatment can be initiated in patients receiving stable doses of siponimod.
Nefazodone: (Moderate) Concomitant use of siponimod and nefazodone may increase siponimod exposure. If the patient is also receiving a drug regimen containing a moderate CYP2C9 inhibitor, use of siponimod is not recommended due to a significant increase in siponimod exposure. Siponimod is a CYP2C9 and CYP3A4 substrate; nefazodone is a strong CYP3A4 inhibitor. Coadministration with a moderate CYP2C9/CYP3A4 dual inhibitor led to a 2-fold increase in the exposure of siponimod.
Nelfinavir: (Moderate) Concomitant use of siponimod and nelfinavir may increase siponimod exposure. If the patient is also receiving a drug regimen containing a moderate CYP2C9 inhibitor, use of siponimod is not recommended due to a significant increase in siponimod exposure. Siponimod is a CYP2C9 and CYP3A4 substrate; nelfinavir is a strong CYP3A4 inhibitor. Coadministration with a moderate CYP2C9/CYP3A4 dual inhibitor led to a 2-fold increase in the exposure of siponimod.
Netupitant, Fosnetupitant; Palonosetron: (Moderate) Concomitant use of siponimod and netupitant may increase siponimod exposure. If the patient is also receiving a drug regimen containing a moderate CYP2C9 inhibitor, use of siponimod is not recommended due to a significant increase in siponimod exposure. Siponimod is a CYP2C9 and CYP3A4 substrate; netupitant is a moderate CYP3A4 inhibitor. Coadministration with a moderate CYP2C9/CYP3A4 dual inhibitor led to a 2-fold increase in the exposure of siponimod.
Nilotinib: (Major) In general, do not initiate treatment with siponimod in patients receiving nilotinib due to the potential for QT prolongation. Consult a cardiologist regarding appropriate monitoring if siponimod use is required. Siponimod therapy prolonged the QT interval at recommended doses in a clinical study. Sudden death and QT interval prolongation have occurred in patients who received nilotinib therapy. Additionally, concomitant use of siponimod and nilotinib may increase siponimod exposure. If the patient is also receiving a drug regimen containing a moderate CYP2C9 inhibitor, use of siponimod is not recommended due to a significant increase in siponimod exposure. Siponimod is a CYP2C9 and CYP3A4 substrate; nilotinib is a moderate CYP3A4 inhibitor. Coadministration with a moderate CYP2C9/CYP3A4 dual inhibitor led to a 2-fold increase in the exposure of siponimod.
Nirmatrelvir; Ritonavir: (Moderate) Concomitant use of siponimod and ritonavir may increase siponimod exposure. If the patient is also receiving a drug regimen containing a moderate CYP2C9 inhibitor, use of siponimod is not recommended due to a significant increase in siponimod exposure. Siponimod is a CYP2C9 and CYP3A4 substrate; ritonavir is a strong CYP3A4 inhibitor. Coadministration with a moderate CYP2C9/CYP3A4 dual inhibitor led to a 2-fold increase in the exposure of siponimod.
Non-Live Vaccines: (Moderate) Administer all non-live vaccines at least 2 weeks before siponimod initiation, whenever possible. Vaccines may be less effective if given during siponimod treatment. Patients should be considered unimmunized if vaccinated within a 14-day period before starting immunosuppresive therapy or during immunosuppressive therapy, and should they be revaccinated at least 3 months after therapy is discontinued if immune competence is restored.
Ofatumumab: (Moderate) Concomitant use of ofatumumab with siponimod may increase the risk of immunosuppression. Ofatumumab has not been studied in combination with other immunosuppressive or immune modulating therapies used for the treatment of multiple sclerosis, such as siponimod. Consider the duration and mechanism of action of drugs with immunosuppressive effects when switching therapies for multiple sclerosis patients.
Ofloxacin: (Major) Concomitant use of siponimod and ofloxacin increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Olanzapine: (Major) In general, do not initiate treatment with siponimod in patients receiving olanzapine due to the potential for QT prolongation. Consult a cardiologist regarding appropriate monitoring if siponimod use is required. Siponimod therapy prolonged the QT interval at recommended doses in a clinical study. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval.
Olanzapine; Fluoxetine: (Major) Concomitant use of siponimod and fluoxetine 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. (Major) In general, do not initiate treatment with siponimod in patients receiving olanzapine due to the potential for QT prolongation. Consult a cardiologist regarding appropriate monitoring if siponimod use is required. Siponimod therapy prolonged the QT interval at recommended doses in a clinical study. Limited data, 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 treatment with siponimod in patients receiving olanzapine due to the potential for QT prolongation. Consult a cardiologist regarding appropriate monitoring if siponimod use is required. Siponimod therapy prolonged the QT interval at recommended doses in a clinical study. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval.
Omeprazole; Amoxicillin; Rifabutin: (Moderate) Concomitant use of siponimod and rifabutin is not recommended for patients with CYP2C9*1/*3 and *2/*3 genotypes due to a significant decrease in siponimod exposure. Siponimod is a CYP2C9 and CYP3A4 substrate; rifabutin is a moderate CYP3A4 inducer. Across different CYP2C9 genotypes, a moderate CYP3A4 inducer decreased the exposure of siponimod by up to 52% according to in silico evaluation.
Ondansetron: (Major) Concomitant use of siponimod and ondansetron increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. Do not exceed 16 mg of IV ondansetron in a single dose; the degree of QT prolongation associated with ondansetron significantly increases above this dose.
Osilodrostat: (Major) In general, do not initiate treatment with siponimod in patients receiving osilodrostat due to the potential for QT prolongation. Consult a cardiologist regarding appropriate monitoring if siponimod use is required. Siponimod therapy prolonged the QT interval at recommended doses in a clinical study. Osilodrostat is associated with dose-dependent QT prolongation.
Osimertinib: (Major) Avoid coadministration of siponimod and osimertinib due to the potential for additive QT prolongation. Consult a cardiologist regarding appropriate monitoring if siponimod use is required. Siponimod therapy prolonged the QT interval at recommended doses in a clinical study. Concentration-dependent QTc prolongation occurred during clinical trials of osimertinib.
Oxaliplatin: (Major) In general, do not initiate treatment with siponimod in patients receiving oxaliplatin due to the potential for QT prolongation. Consult a cardiologist regarding appropriate monitoring if siponimod use is required. Siponimod therapy prolonged the QT interval at recommended doses in a clinical study. QT prolongation and ventricular arrhythmias including fatal torsade de pointes have been reported with oxaliplatin use in postmarketing experience.
Pacritinib: (Major) Concomitant use of pacritinib and siponimod increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Paliperidone: (Major) Avoid coadministration of siponimod and paliperidone due to the potential for additive QT prolongation. Consult a cardiologist regarding appropriate monitoring if siponimod use is required. Siponimod therapy prolonged the QT interval at recommended doses in a clinical study. Paliperidone has been associated with QT prolongation; torsade de pointes and ventricular fibrillation have been reported in the setting of overdose.
Panobinostat: (Major) Avoid coadministration of siponimod and panobinostat due to the potential for additive QT prolongation. Consult a cardiologist regarding appropriate monitoring if siponimod use is required. Siponimod therapy prolonged the QT interval at recommended doses in a clinical study. QT prolongation has been reported with panobinostat.
Pasireotide: (Major) In general, do not initiate treatment with siponimod in patients receiving pasireotide due to the potential for QT prolongation. Consult a cardiologist regarding appropriate monitoring if siponimod use is required. Siponimod therapy prolonged the QT interval at recommended doses in a clinical study. QT prolongation has occurred with pasireotide at therapeutic and supra-therapeutic doses.
Pazopanib: (Major) Avoid coadministration of siponimod and pazopanib due to the potential for additive QT prolongation. Consult a cardiologist regarding appropriate monitoring if siponimod use is required. Siponimod therapy prolonged the QT interval at recommended doses in a clinical study. Pazopanib has been reported to prolong the QT interval.
Pentamidine: (Major) In general, do not initiate treatment with siponimod in patients receiving pentamidine due to the potential for QT prolongation. Consult a cardiologist regarding appropriate monitoring if siponimod use is required. Siponimod therapy prolonged the QT interval at recommended doses in a clinical study. Systemic pentamidine has been associated with QT prolongation.
Pentobarbital: (Moderate) Concomitant use of siponimod and pentobarbital is not recommended for patients with CYP2C9*1/*3 and *2/*3 genotypes due to a significant decrease in siponimod exposure. Use of siponimod with pentobarbital is not recommended in any patient if they are also receiving a strong CYP3A4 inducer. Siponimod is a CYP2C9 and CYP3A4 substrate; pentobarbital is a moderate CYP2C9 and CYP3A4 inducer. Across CYP2C9 genotypes, coadministration of a moderate CYP3A4 inducer reduced siponimod exposure by up to 52%, according to in silico evaluation. Coadministration with a moderate CYP2C9/strong CYP3A4 dual inducer decreased siponimod exposure by 57% in CY2C9*1/*1 subjects.
Perphenazine: (Minor) In general, do not initiate treatment with siponimod in patients receiving perphenazine due to the potential for QT prolongation. Consult a cardiologist regarding appropriate monitoring if siponimod use is required. Siponimod therapy prolonged the QT interval at recommended doses in a clinical study. Perphenazine is associated with a possible risk for QT prolongation.
Perphenazine; Amitriptyline: (Minor) In general, do not initiate treatment with siponimod in patients receiving perphenazine due to the potential for QT prolongation. Consult a cardiologist regarding appropriate monitoring if siponimod use is required. Siponimod therapy prolonged the QT interval at recommended doses in a clinical study. Perphenazine is associated with a possible risk for QT prolongation.
Pexidartinib: (Moderate) Concomitant use of siponimod and pexidartinib is not recommended for patients with CYP2C9*1/*3 and *2/*3 genotypes due to a significant decrease in siponimod exposure. Siponimod is a CYP2C9 and CYP3A4 substrate; pexidartinib is a moderate CYP3A4 inducer. Across different CYP2C9 genotypes, a moderate CYP3A4 inducer decreased the exposure of siponimod by up to 52% according to in silico evaluation.
Phenobarbital: (Major) Concomitant use of siponimod and phenobarbital is not recommended due to a significant decrease in siponimod exposure. Siponimod is a CYP2C9 and CYP3A4 substrate; phenobarbital is a moderate CYP2C9/strong CYP3A4 dual inducer. Coadministration with another moderate CYP2C9/strong CYP3A4 dual inducer decreased siponimod exposure by 57%.
Phenobarbital; Hyoscyamine; Atropine; Scopolamine: (Major) Concomitant use of siponimod and phenobarbital is not recommended due to a significant decrease in siponimod exposure. Siponimod is a CYP2C9 and CYP3A4 substrate; phenobarbital is a moderate CYP2C9/strong CYP3A4 dual inducer. Coadministration with another moderate CYP2C9/strong CYP3A4 dual inducer decreased siponimod exposure by 57%.
Phenytoin: (Major) Concomitant use of siponimod and phenytoin is not recommended due to a significant decrease in siponimod exposure. Siponimod is a CYP2C9 and CYP3A4 substrate; phenytoin is a moderate CYP2C9/strong CYP3A4 dual inducer. Coadministration with another moderate CYP2C9/strong CYP3A4 dual inducer decreased siponimod exposure by 57%.
Pimavanserin: (Major) Avoid coadministration of siponimod and pimavanserin due to the potential for additive QT prolongation. Consult a cardiologist regarding appropriate monitoring if siponimod use is required. Siponimod therapy prolonged the QT interval at recommended doses in a clinical study. Pimavanserin may also cause QT prolongation.
Pimozide: (Contraindicated) Concomitant use of siponimod and pimozide is contraindicated due to the potential for additive QT prolongation. Siponimod therapy prolonged the QT interval at recommended doses in a clinical study. Pimozide is associated with a well-established risk of QT prolongation and torsade de pointes.
Pindolol: (Moderate) Monitor for significant bradycardia with coadministration of siponimod and beta-blockers, as additive lowering effects on heart rate may occur; temporary interruption of beta-blocker treatment may be necessary prior to siponimod initiation. Beta-blocker treatment can be initiated in patients receiving stable doses of siponimod.
Pitolisant: (Major) Avoid coadministration of pitolisant with siponimod as concurrent use may increase the risk of QT prolongation. Consult a cardiologist regarding appropriate monitoring if siponimod use is required. Siponimod therapy prolonged the QT interval at recommended doses in a clinical study. Pitolisant prolongs the QT interval.
Pneumococcal Vaccine, Polyvalent: (Moderate) Administer all non-live vaccines at least 2 weeks before siponimod initiation, whenever possible. Vaccines may be less effective if given during siponimod treatment. Patients should be considered unimmunized if vaccinated within a 14-day period before starting immunosuppresive therapy or during immunosuppressive therapy, and should they be revaccinated at least 3 months after therapy is discontinued if immune competence is restored.
Poliovirus Vaccine, Inactivated, IPV: (Moderate) Administer all non-live vaccines at least 2 weeks before siponimod initiation, whenever possible. Vaccines may be less effective if given during siponimod treatment. Patients should be considered unimmunized if vaccinated within a 14-day period before starting immunosuppresive therapy or during immunosuppressive therapy, and should they be revaccinated at least 3 months after therapy is discontinued if immune competence is restored.
Posaconazole: (Major) In general, do not initiate treatment with siponimod in patients receiving posaconazole due to the potential for QT prolongation. Consult a cardiologist regarding appropriate monitoring if siponimod use is required. Siponimod therapy prolonged the QT interval at recommended doses in a clinical study. Posaconazole has also been associated with prolongation of the QT interval. Additionally, concomitant use of siponimod and posaconazole may increase siponimod exposure. If the patient is also receiving a drug regimen containing a moderate CYP2C9 inhibitor, use of siponimod is not recommended due to a significant increase in siponimod exposure. Siponimod is a CYP2C9 and CYP3A4 substrate; posaconazole is a strong CYP3A4 inhibitor. Coadministration with a moderate CYP2C9/CYP3A4 dual inhibitor led to a 2-fold increase in the exposure of siponimod.
Prednisolone: (Moderate) Monitor patients carefully for signs and symptoms of infection during coadministration of siponimod and prednisolone. Concomitant use may increase the risk of immunosuppression. Siponimod has not been studied in combination with other immunosuppressive therapies used for the treatment of multiple sclerosis, including immunosuppressant doses of corticosteroids.
Prednisone: (Moderate) Monitor patients carefully for signs and symptoms of infection during coadministration of siponimod and prednisone. Concomitant use may increase the risk of immunosuppression. Siponimod has not been studied in combination with other immunosuppressive therapies used for the treatment of multiple sclerosis, including immunosuppressant doses of corticosteroids.
Primaquine: (Major) In general, do not initiate treatment with siponimod in patients receiving primaquine due to the potential for QT prolongation. Consult a cardiologist regarding appropriate monitoring if siponimod use is required. Siponimod therapy prolonged the QT interval at recommended doses in a clinical study. Primaquine has the potential to prolong the QT interval.
Primidone: (Major) Concomitant use of siponimod and primidone is not recommended due to a significant decrease in siponimod exposure. Siponimod is a CYP2C9 and CYP3A4 substrate; primidone is a moderate CYP2C9/strong CYP3A4 dual inducer. Coadministration with another moderate CYP2C9/strong CYP3A4 dual inducer decreased siponimod exposure by 57%.
Procainamide: (Major) In general, do not initiate treatment with siponimod in patients receiving procainamide due to the potential for QT prolongation. Consult a cardiologist regarding appropriate monitoring if siponimod use is required. Siponimod therapy prolonged the QT interval at recommended doses in a clinical study. Procainamide is associated with a well-established risk of QT prolongation and torsade de pointes.
Prochlorperazine: (Minor) In general, do not initiate treatment with siponimod in patients receiving prochlorperazine due to the potential for QT prolongation. Consult a cardiologist regarding appropriate monitoring if siponimod use is required. Siponimod therapy prolonged the QT interval at recommended doses in a clinical study. Prochlorperazine is associated with a possible risk for QT prolongation.
Promethazine: (Major) Concomitant use of siponimod and promethazine 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.
Promethazine; Dextromethorphan: (Major) Concomitant use of siponimod and promethazine 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.
Promethazine; Phenylephrine: (Major) Concomitant use of siponimod and promethazine 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.
Propafenone: (Major) Concomitant use of siponimod and propafenone 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.
Propranolol: (Moderate) Monitor for significant bradycardia with coadministration of siponimod and beta-blockers, as additive lowering effects on heart rate may occur; temporary interruption of beta-blocker treatment may be necessar y prior to siponimod initiation. Beta-blocker treatment can be initiated in patients receiving stable doses of siponimod.
Propranolol; Hydrochlorothiazide, HCTZ: (Moderate) Monitor for significant bradycardia with coadministration of siponimod and beta-blockers, as additive lowering effects on heart rate may occur; temporary interruption of beta-blocker treatment may be necessary prior to siponimod initiation. Beta-blocker treatment can be initiated in patients receiving stable doses of siponimod.
Quetiapine: (Major) Concomitant use of siponimod and quetiapine increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Quinidine: (Major) In general, do not initiate treatment with siponimod in patients receiving quinidine due to the potential for QT prolongation. Consult a cardiologist regarding appropriate monitoring if siponimod use is required. Siponimod therapy prolonged the QT interval at recommended doses in a clinical study. Quinidine administration is associated with QT prolongation and torsade de pointes.
Quinine: (Major) In general, do not initiate treatment with siponimod in patients receiving quinine due to the potential for QT prolongation and additive bradycardia. Consult a cardiologist regarding appropriate monitoring if siponimod use is required. Siponimod therapy prolonged the QT interval at recommended doses in a clinical study. Quinine has been associated with QT prolongation and rare cases of torsade de pointes (TdP). Additionally, concomitant use of siponimod and quinine may increase siponimod exposure. If the patient is also receiving a drug regimen containing a moderate CYP2C9 inhibitor, use of siponimod is not recommended due to a significant increase in siponimod exposure. Siponimod is a CYP2C9 and CYP3A4 substrate; quinine is a moderate CYP3A4 inhibitor. Coadministration with a moderate CYP2C9/CYP3A4 dual inhibitor led to a 2-fold increase in the exposure of siponimod.
Quizartinib: (Major) Concomitant use of quizartinib and siponimod 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.
Rabies Vaccine: (Moderate) Administer all non-live vaccines at least 2 weeks before siponimod initiation, whenever possible. Vaccines may be less effective if given during siponimod treatment. Patients should be considered unimmunized if vaccinated within a 14-day period before starting immunosuppresive therapy or during immunosuppressive therapy, and should they be revaccinated at least 3 months after therapy is discontinued if immune competence is restored.
Ranolazine: (Major) In general, do not initiate treatment with siponimod in patients receiving ranolazine due to the potential for QT prolongation. Consult a cardiologist regarding appropriate monitoring if siponimod use is required. Siponimod therapy prolonged the QT interval at recommended doses in a clinical study. Ranolazine is associated with dose- and plasma concentration-related increases in the QTc interval.
Relugolix: (Major) In general, do not initiate treatment with siponimod in patients receiving relugolix due to the potential for QT prolongation. Consult a cardiologist regarding appropriate monitoring if siponimod use is required. Siponimod therapy prolonged the QT interval at recommended doses in a clinical study. Androgen deprivation therapy (i.e., relugolix) may also prolong the QT/QTc interval.
Relugolix; Estradiol; Norethindrone acetate: (Major) In general, do not initiate treatment with siponimod in patients receiving relugolix due to the potential for QT prolongation. Consult a cardiologist regarding appropriate monitoring if siponimod use is required. Siponimod therapy prolonged the QT interval at recommended doses in a clinical study. Androgen deprivation therapy (i.e., relugolix) may also prolong the QT/QTc interval.
Respiratory Syncytial Virus Vaccine: (Moderate) Administer all non-live vaccines at least 2 weeks before siponimod initiation, whenever possible. Vaccines may be less effective if given during siponimod treatment. Patients should be considered unimmunized if vaccinated within a 14-day period before starting immunosuppresive therapy or during immunosuppressive therapy, and should they be revaccinated at least 3 months after therapy is discontinued if immune competence is restored.
Ribociclib: (Major) In general, do not initiate treatment with siponimod in patients receiving ribociclib due to the potential for QT prolongation. Consult a cardiologist regarding appropriate monitoring if siponimod use is required. Siponimod therapy prolonged the QT interval at recommended doses in a clinical study. Ribociclib has been shown to prolong the QT interval in a concentration-dependent manner. The ECG changes occurred within the first four weeks of treatment and were reversible with dose interruption. Additionally, concomitant use of siponimod and ribociclib may increase siponimod exposure. If the patient is also receiving a drug regimen containing a moderate CYP2C9 inhibitor, use of siponimod is not recommended due to a significant increase in siponimod exposure. Siponimod is a CYP2C9 and CYP3A4 substrate; ribociclib is a strong CYP3A4 inhibitor. Coadministration with a moderate CYP2C9/CYP3A4 dual inhibitor led to a 2-fold increase in the exposure of siponimod.
Ribociclib; Letrozole: (Major) In general, do not initiate treatment with siponimod in patients receiving ribociclib due to the potential for QT prolongation. Consult a cardiologist regarding appropriate monitoring if siponimod use is required. Siponimod therapy prolonged the QT interval at recommended doses in a clinical study. Ribociclib has been shown to prolong the QT interval in a concentration-dependent manner. The ECG changes occurred within the first four weeks of treatment and were reversible with dose interruption. Additionally, concomitant use of siponimod and ribociclib may increase siponimod exposure. If the patient is also receiving a drug regimen containing a moderate CYP2C9 inhibitor, use of siponimod is not recommended due to a significant increase in siponimod exposure. Siponimod is a CYP2C9 and CYP3A4 substrate; ribociclib is a strong CYP3A4 inhibitor. Coadministration with a moderate CYP2C9/CYP3A4 dual inhibitor led to a 2-fold increase in the exposure of siponimod.
Rifabutin: (Moderate) Concomitant use of siponimod and rifabutin is not recommended for patients with CYP2C9*1/*3 and *2/*3 genotypes due to a significant decrease in siponimod exposure. Siponimod is a CYP2C9 and CYP3A4 substrate; rifabutin is a moderate CYP3A4 inducer. Across different CYP2C9 genotypes, a moderate CYP3A4 inducer decreased the exposure of siponimod by up to 52% according to in silico evaluation.
Rifampin: (Major) Concomitant use of siponimod and rifampin is not recommended due to a significant decrease in siponimod exposure. Siponimod is a CYP2C9 and CYP3A4 substrate; rifampin is a moderate CYP2C9/strong CYP3A4 dual inducer. Coadministration with rifampin decreased siponimod exposure by 57%. Across different CYP2C9 genotypes, rifampin decreased the exposure of siponimod by up to 78%.
Rifapentine: (Major) Concomitant use of siponimod and rifapentine is not recommended due to a significant decrease in siponimod exposure. Siponimod is a CYP2C9 and CYP3A4 substrate; rifapentine is a moderate CYP2C9/strong CYP3A4 dual inducer. Coadministration with another moderate CYP2C9/strong CYP3A4 dual inducer decreased siponimod exposure by 57%.
Rilpivirine: (Major) In general, do not initiate treatment with siponimod in patients receiving rilpivirine due to the potential for QT prolongation. Consult a cardiologist regarding appropriate monitoring if siponimod use is required. Siponimod therapy prolonged the QT interval at recommended doses in a clinical study. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation.
Risperidone: (Major) In general, do not initiate treatment with siponimod in patients receiving risperidone due to the potential for QT prolongation. Consult a cardiologist regarding appropriate monitoring if siponimod use is required. Siponimod therapy prolonged the QT interval at recommended doses in a clinical study. Risperidone has been associated with a possible risk for QT prolongation and/or torsade de pointes (TdP). Reports of QT prolongation and TdP during risperidone therapy are noted by the manufacturer, primarily in the overdosage setting.
Ritlecitinib: (Moderate) Concomitant use of siponimod and ritlecitinib may increase siponimod exposure. If the patient is also receiving a drug regimen containing a moderate CYP2C9 inhibitor, use of siponimod is not recommended due to a significant increase in siponimod exposure. Siponimod is a CYP2C9 and CYP3A substrate; ritlecitinib is a moderate CYP3A inhibitor. Coadministration with a moderate CYP2C9/CYP3A dual inhibitor led to a 2-fold increase in the AUC of siponimod.
Ritonavir: (Moderate) Concomitant use of siponimod and ritonavir may increase siponimod exposure. If the patient is also receiving a drug regimen containing a moderate CYP2C9 inhibitor, use of siponimod is not recommended due to a significant increase in siponimod exposure. Siponimod is a CYP2C9 and CYP3A4 substrate; ritonavir is a strong CYP3A4 inhibitor. Coadministration with a moderate CYP2C9/CYP3A4 dual inhibitor led to a 2-fold increase in the exposure of siponimod.
Romidepsin: (Major) In general, do not initiate treatment with siponimod in patients receiving romidepsin due to the potential for QT prolongation. Consult a cardiologist regarding appropriate monitoring if siponimod use is required. Siponimod therapy prolonged the QT interval at recommended doses in a clinical study. Romidepsin has been reported to prolong the QT interval.
Rotavirus Vaccine: (Major) Avoid the use of live vaccines during treatment with siponomid and for 4 weeks after stopping treatment due to the risk of secondary infection. Additionally, vaccines may be less effective if administered during siponimod treatment and for 4 weeks after siponimod treatment discontinuation.
Saquinavir: (Contraindicated) Coadministration of saquinavir with siponimod is contraindicated due to the risk of QT prolongation; increased exposure to siponimod is also possible. Siponimod is a CYP2C9 and CYP3A4 substrate; saquinavir is a strong CYP3A4 inhibitor. Coadministration with a moderate CYP2C9/CYP3A4 dual inhibitor led to a 2-fold increase in the exposure of siponimod.
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: (Moderate) Concomitant use of siponimod and secobarbital is not recommended for patients with CYP2C9*1/*3 and *2/*3 genotypes due to a significant decrease in siponimod exposure. Use of siponimod with secobarbital is not recommended in any patient if they are also receiving a strong CYP3A4 inducer. Siponimod is a CYP2C9 and CYP3A4 substrate; secobarbital is a moderate CYP2C9 and CYP3A4 inducer. Across CYP2C9 genotypes, coadministration of a moderate CYP3A4 inducer reduced siponimod exposure by up to 52%, according to in silico evaluation. Coadministration with a moderate CYP2C9/strong CYP3A4 dual inducer decreased siponimod exposure by 57% in CY2C9*1/*1 subjects.
Selpercatinib: (Major) Avoid coadministration of siponimod and selpercatinib due to the potential for additive QT prolongation. Monitor ECGs more frequently for QT prolongation if coadministration is necessary. Siponimod therapy prolonged the QT interval at recommended doses in a clinical study. Concentration-dependent QT prolongation has been observed with selpercatinib therapy.
Sertraline: (Major) Concomitant use of siponimod and sertraline increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. The degree of QT prolongation associated with sertraline is not clinically significant when administered within the recommended dosage range; QT prolongation has been described at 2 times the maximum recommended dose.
Sevoflurane: (Major) In general, do not initiate treatment with siponimod in patients receiving halogenated anesthetics due to the potential for QT prolongation. Consult a cardiologist regarding appropriate monitoring if siponimod use is required. Siponimod therapy prolonged the QT interval at recommended doses in a clinical study. Halogenated anesthetics can prolong the QT interval.
Smallpox and Monkeypox Vaccine, Live, Nonreplicating: (Major) Avoid the use of live vaccines during treatment with siponomid and for 4 weeks after stopping treatment due to the risk of secondary infection. Additionally, vaccines may be less effective if administered during siponimod treatment and for 4 weeks after siponimod treatment discontinuation.
Smallpox Vaccine, Vaccinia Vaccine: (Major) Avoid the use of live vaccines during treatment with siponomid and for 4 weeks after stopping treatment due to the risk of secondary infection. Additionally, vaccines may be less effective if administered during siponimod treatment and for 4 weeks after siponimod treatment discontinuation.
Sodium Stibogluconate: (Major) Concomitant use of sodium stibogluconate and siponimod increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Solifenacin: (Major) In general, do not initiate treatment with siponimod in patients receiving solifenacin due to the potential for QT prolongation. Consult a cardiologist regarding appropriate monitoring if siponimod use is required. Siponimod therapy prolonged the QT interval at recommended doses in a clinical study. Solifenacin has been associated with dose-dependent prolongation of the QT interval. Torsade de pointes has been reported with postmarketing use, although causality was not determined.
Sorafenib: (Major) In general, do not initiate treatment with siponimod in patients receiving sorafenib due to the potential for QT prolongation. Consult a cardiologist regarding appropriate monitoring if siponimod use is required. Siponimod therapy prolonged the QT interval at recommended doses in a clinical study. Sorafenib has been associated with QT prolongation.
Sotalol: (Major) Concomitant use of sotalol and siponimod 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.
Sotorasib: (Moderate) Concomitant use of siponimod and sotorasib is not recommended for patients with CYP2C9*1/*3 and *2/*3 genotypes due to a significant decrease in siponimod exposure. Siponimod is a CYP2C9 and CYP3A4 substrate; sotorasib is a moderate CYP3A4 inducer. Across different CYP2C9 genotypes, a moderate CYP3A4 inducer decreased the exposure of siponimod by up to 52% according to in silico evaluation.
St. John's Wort, Hypericum perforatum: (Major) Concomitant use of siponimod and St. John's Wort is not recommended due to a significant decrease in siponimod exposure. Siponimod is a CYP2C9 and CYP3A4 substrate; St. John's Wort is a moderate CYP2C9/strong CYP3A4 dual inducer. Coadministration with another moderate CYP2C9/strong CYP3A4 dual inducer decreased siponimod exposure by 57%.
Sulfamethoxazole; Trimethoprim, SMX-TMP, Cotrimoxazole: (Moderate) Concomitant use of siponimod and sulfamethoxazole may increase siponimod exposure. If the patient is also receiving a drug regimen containing a moderate or strong CYP3A4 inhibitor, use of siponimod is not recommended due to a significant increase in siponimod exposure. Siponimod is a CYP2C9 and CYP3A4 substrate; sulfamethoxazole is a moderate CYP2C9 inhibitor. Coadministration with a moderate CYP2C9/CYP3A4 dual inhibitor led to a 2-fold increase in the exposure of siponimod.
Sunitinib: (Major) In general, do not initiate treatment with siponimod in patients receiving sunitinib due to the potential for QT prolongation. Consult a cardiologist regarding appropriate monitoring if siponimod use is required. Siponimod therapy prolonged the QT interval at recommended doses in a clinical study. Sunitinib can prolong the QT interval.
Tacrolimus: (Major) In general, do not initiate treatment with siponimod in patients receiving tacrolimus due to the potential for QT prolongation. Consult a cardiologist regarding appropriate monitoring if siponimod use is required. Siponimod therapy prolonged the QT interval at recommended doses in a clinical study. Tacrolimus also causes QT prolongation.
Tamoxifen: (Major) Concomitant use of tamoxifen and siponimod increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Telavancin: (Major) In general, do not initiate treatment with siponimod in patients receiving telavancin due to the potential for QT prolongation. Consult a cardiologist regarding appropriate monitoring if siponimod use is required. Siponimod therapy prolonged the QT interval at recommended doses in a clinical study. Telavancin has been associated with QT prolongation.
Tetrabenazine: (Major) Avoid coadministration of siponimod and tetrabenazine due to the potential for additive QT prolongation. Consult a cardiologist regarding appropriate monitoring if siponimod use is required. Siponimod therapy prolonged the QT interval at recommended doses in a clinical study. Tetrabenazine causes a small increase in the corrected QT interval (QTc).
Thioridazine: (Contraindicated) Concomitant use of siponimod and thioridazine is contraindicated due to the potential for additive QT prolongation. Siponimod therapy prolonged the QT interval at recommended doses in a clinical study. Thioridazine is associated with a well-established risk of QT prolongation and torsade de pointes.
Tick-Borne Encephalitis Vaccine: (Moderate) Administer all non-live vaccines at least 2 weeks before siponimod initiation, whenever possible. Vaccines may be less effective if given during siponimod treatment. Patients should be considered unimmunized if vaccinated within a 14-day period before starting immunosuppresive therapy or during immunosuppressive therapy, and should they be revaccinated at least 3 months after therapy is discontinued if immune competence is restored.
Timolol: (Moderate) Monitor for significant bradycardia with coadministration of siponimod and beta-blockers, as additive lowering effects on heart rate may occur; temporary interruption of beta-blocker treatment may be necessary prior to siponimod initiation. Beta-blocker treatment can be initiated in patients receiving stable doses of siponimod.
Tipranavir: (Moderate) Concomitant use of siponimod and tipranavir may increase siponimod exposure. If the patient is also receiving a drug regimen containing a moderate CYP2C9 inhibitor, use of siponimod is not recommended due to a significant increase in siponimod exposure. Siponimod is a CYP2C9 and CYP3A4 substrate; tipranavir is a strong CYP3A4 inhibitor. Coadministration with a moderate CYP2C9/CYP3A4 dual inhibitor led to a 2-fold increase in the exposure of siponimod.
Tolterodine: (Major) In general, do not initiate treatment with siponimod in patients receiving tolterodine due to the potential for QT prolongation. Consult a cardiologist regarding appropriate monitoring if siponimod use is required. Siponimod therapy prolonged the QT interval at recommended doses in a clinical study. Tolterodine has been associated with dose-dependent prolongation of the QT interval, especially in poor CYP2D6 metabolizers.
Toremifene: (Major) Avoid coadministration of siponimod and toremifene due to the potential for additive QT prolongation. Consult a cardiologist regarding appropriate monitoring if siponimod use is required. Siponimod therapy prolonged the QT interval at recommended doses in a clinical study. Toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner.
Trandolapril; Verapamil: (Major) In general, do not initiate treatment with siponimod in patients receiving verapamil due to the potential for additive effects on heart rate. Consult a cardiologist regarding appropriate monitoring if siponimod use is required. Additionally, concomitant use of siponimod and verapamil may increase siponimod exposure. If the patient is also receiving a drug regimen containing a moderate CYP2C9 inhibitor, use of siponimod is not recommended due to a significant increase in siponimod exposure. Siponimod is a CYP2C9 and CYP3A4 substrate; verapamil is a moderate CYP3A4 inhibitor. Coadministration with a moderate CYP2C9/CYP3A4 dual inhibitor led to a 2-fold increase in the exposure of siponimod.
Trazodone: (Major) Concomitant use of trazodone and siponomod 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.
Triamcinolone: (Moderate) Monitor patients carefully for signs and symptoms of infection during coadministration of siponimod and triamcinolone. Concomitant use may increase the risk of immunosuppression. Siponimod has not been studied in combination with other immunosuppressive therapies used for the treatment of multiple sclerosis, including immunosuppressant doses of corticosteroids.
Triclabendazole: (Major) Concomitant use of triclabendazole and siponimod 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.
Trifluoperazine: (Minor) In general, do not initiate treatment with siponimod in patients receiving trifluoperazine due to the potential for QT prolongation. Consult a cardiologist regarding appropriate monitoring if siponimod use is required. Siponimod therapy prolonged the QT interval at recommended doses in a clinical study. Trifluoperazine is associated with a possible risk for QT prolongation.
Triptorelin: (Major) In general, do not initiate treatment with siponimod in patients receiving triptorelin due to the potential for QT prolongation. Consult a cardiologist regarding appropriate monitoring if siponimod use is required. Siponimod therapy prolonged the QT interval at recommended doses in a clinical study. Androgen deprivation therapy (i.e., triptorelin) may prolong the QT/QTc interval.
Tucatinib: (Moderate) Concomitant use of siponimod and tucatinib may increase siponimod exposure. If the patient is also receiving a drug regimen containing a moderate CYP2C9 inhibitor, use of siponimod is not recommended due to a significant increase in siponimod exposure. Siponimod is a CYP2C9 and CYP3A4 substrate; tucatinib is a strong CYP3A4 inhibitor. Coadministration with a moderate CYP2C9/CYP3A4 dual inhibitor led to a 2-fold increase in the AUC of siponimod.
Typhoid Vaccine: (Major) Avoid the use of live vaccines during treatment with siponomid and for 4 weeks after stopping treatment due to the risk of secondary infection. Additionally, vaccines may be less effective if administered during siponimod treatment and for 4 weeks after siponimod treatment discontinuation.
Vandetanib: (Major) Avoid coadministration of siponimod and vandetanib due to the potential for additive QT prolongation. Consult a cardiologist regarding appropriate monitoring if siponimod use is required. Siponimod therapy prolonged the QT interval at recommended doses in a clinical study. Vandetanib can prolong the QT interval in a concentration-dependent manner; torsade de pointes and sudden death have been reported in patients receiving vandetanib.
Vardenafil: (Major) Concomitant use of vardenafil and siponimod 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.
Varicella-Zoster Virus Vaccine, Live: (Major) Avoid the use of live vaccines during treatment with siponomid and for 4 weeks after stopping treatment due to the risk of secondary infection. Additionally, vaccines may be less effective if administered during siponimod treatment and for 4 weeks after siponimod treatment discontinuation.
Vemurafenib: (Major) In general, do not initiate treatment with siponimod in patients receiving vemurafenib due to the potential for QT prolongation. Consult a cardiologist regarding appropriate monitoring if siponimod use is required. Siponimod therapy prolonged the QT interval at recommended doses in a clinical study. Vemurafenib has been associated with QT prolongation.
Venlafaxine: (Major) Concomitant use of venlafaxine and siponimod 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.
Verapamil: (Major) In general, do not initiate treatment with siponimod in patients receiving verapamil due to the potential for additive effects on heart rate. Consult a cardiologist regarding appropriate monitoring if siponimod use is required. Additionally, concomitant use of siponimod and verapamil may increase siponimod exposure. If the patient is also receiving a drug regimen containing a moderate CYP2C9 inhibitor, use of siponimod is not recommended due to a significant increase in siponimod exposure. Siponimod is a CYP2C9 and CYP3A4 substrate; verapamil is a moderate CYP3A4 inhibitor. Coadministration with a moderate CYP2C9/CYP3A4 dual inhibitor led to a 2-fold increase in the exposure of siponimod.
Voclosporin: (Major) In general, do not initiate treatment with siponimod in patients receiving voclosporin due to the potential for QT prolongation. Consult a cardiologist regarding appropriate monitoring if siponimod use is required. Siponimod therapy prolonged the QT interval at recommended doses in a clinical study. Voclosporin has been associated with QT prolongation at supratherapeutic doses.
Vonoprazan; Amoxicillin; Clarithromycin: (Major) In general, do not initiate treatment with siponimod in patients receiving clarithromycin due to the potential for QT prolongation. Consult a cardiologist regarding appropriate monitoring if siponimod use is required. Siponimod therapy prolonged the QT interval at recommended doses in a clinical study. Clarithromycin has also been associated with prolongation of the QT interval. Additionally, concomitant use of siponimod and clarithromycin may increase siponimod exposure. If the patient is also receiving a drug regimen containing a moderate CYP2C9 inhibitor, use of siponimod is not recommended due to a significant increase in siponimod exposure. Siponimod is a CYP2C9 and CYP3A4 substrate; clarithromycin is a strong CYP3A4 inhibitor. Coadministration with a moderate CYP2C9/CYP3A4 dual inhibitor led to a 2-fold increase in the exposure of siponimod.
Voriconazole: (Major) Concomitant use of siponimod and voriconazole is not recommended due to a significant increase in siponimod exposure. Additionally, both drugs are associated with QT prolongation. Siponimod is a CYP2C9 and CYP3A4 substrate; voriconazole is a moderate CYP2C9/strong CYP3A4 dual inhibitor. Coadministration with a moderate CYP2C9/CYP3A4 dual inhibitor led to a 2-fold increase in the exposure of siponimod.
Vorinostat: (Major) In general, do not initiate treatment with siponimod in patients receiving vorinostat due to the potential for QT prolongation. Consult a cardiologist regarding appropriate monitoring if siponimod use is required. Siponimod therapy prolonged the QT interval at recommended doses in a clinical study. Vorinostat therapy is associated with a risk of QT prolongation.
Voxelotor: (Moderate) Concomitant use of siponimod and voxelotor may increase siponimod exposure. If the patient is also receiving a drug regimen containing a moderate CYP2C9 inhibitor, use of siponimod is not recommended due to a significant increase in siponimod exposure. Siponimod is a CYP2C9 and CYP3A substrate; voxelotor is a moderate CYP3A inhibitor. Coadministration with a moderate CYP2C9/CYP3A dual inhibitor led to a 2-fold increase in the AUC of siponimod.
Yellow Fever Vaccine, Live: (Major) Avoid the use of live vaccines during treatment with siponomid and for 4 weeks after stopping treatment due to the risk of secondary infection. Additionally, vaccines may be less effective if administered during siponimod treatment and for 4 weeks after siponimod treatment discontinuation.
Ziprasidone: (Major) Avoid coadministration of siponimod and ziprasidone due to the potential for additive QT prolongation. Consult a cardiologist regarding appropriate monitoring if siponimod use is required. Siponimod therapy prolonged the QT interval at recommended doses in a clinical study. Clinical trial data indicate that ziprasidone causes QT prolongation; there are postmarketing reports of torsade de pointes in patients with multiple confounding factors.

MAYZENT/Siponimod Oral Tab: 0.25mg, 1mg, 2mg

Adults

2 mg/day PO.

Geriatric

2 mg/day PO.

Adolescents

Safety and efficacy have not been established.

Children

Safety and efficacy have not been established.

Infants

Safety and efficacy have not been established.

Neonates

Safety and efficacy have not been established.

Siponimod is a sphingosine 1-phosphate receptor modulator that binds with high affinity to sphingosine 1-phosphate receptors 1 and 5. Siponimod blocks the capacity of lymphocytes to egress from lymph nodes, reducing the number of lymphocytes in peripheral blood. The mechanism by which siponimod exerts therapeutic effects in multiple sclerosis is unknown but may involve reduction of lymphocyte migration into the central nervous system.[64031]

Siponimod is administered orally. After multiple once-daily doses, concentrations increase in a dose-proportional manner. Steady-state is reached after approximately 6 days of once-daily dosing; after the dose escalation regimen over 6 days, an additional 4 days are required to reach steady-state. Siponimod distributes to body tissues with a mean volume of distribution of 124 L, and it readily crosses the blood-brain barrier. Protein binding is greater than 99.9%. Siponimod is metabolized by CYP2C9 (79.3%) and CYP3A4 (18.5%). The main metabolites, M3 and M17, are not expected to contribute to the clinical effect of the drug. The apparent systemic clearance is 3.11 L/hour, and the apparent elimination half-life is approximately 30 hours. Unchanged drug is not detected in urine.[64031]
 
Affected cytochrome P450 (CYP450) isoenzymes and drug transporters: CYP2C9, CYP3A4
Siponimod is extensively metabolized by CYP2C9 and CYP3A4.[64031]

Oral Route

Siponimod absorption is extensive, and the absolute oral bioavailability of the drug is 84%. After administration of siponimod 2 mg once-daily over 10 days, mean Cmax was 30.4 ng/mL and mean AUC was 558 hours x ng/mL. Tmax after oral administration occurs at approximately 4 hours (range 3 to 8 hours). Food intake delayed the absorption of siponimod but did not affect systemic exposure.[64031]

Pregnancy

There are no adequate data on the developmental risk associated with siponimod use during human pregnancy. Reproductive studies in animals indicate that siponimod may cause fetal harm. Discuss contraception requirements with the patient. Due to the potential reproductive risk, effective contraception is needed during therapy and for approximately 10 days after discontinuation because of the long half-life of the drug. Oral siponimod administration (0, 1, 5, or 40 mg/kg) to pregnant rats during the period of organogenesis increased incidences of fetal malformations (visceral and skeletal) and implantation loss. Plasma AUC exposure at the lowest dose tested was approximately 18 times that in humans at the recommended human dose (RHD) of 2 mg/day. In addition to rats, adverse outcomes were noted in rabbits. Increased incidences of embryolethality and fetal skeletal variations were observed. AUC exposure at the no-effect dose of 0.1 mg/kg for adverse effects was less than in humans at the RHD. Increased mortality, decreased body weight, and delayed sexual maturation were observed in the offspring of rats given oral siponimod during pregnancy and lactation. The lowest dose tested (0.05 mg/kg) was less than the RHD on a body surface area basis. There is a pregnancy exposure registry that monitors outcomes in women exposed to siponimod during pregnancy. Health care providers are encouraged to register pregnant patients, or a pregnant patient may enroll themselves in the MotherToBaby Pregnancy Study in Multiple Sclerosis study by calling 1-877-311-8972 or visiting www.mothertobaby.org/join-study.[64031]