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  • CLASSES

    MS Agents
    Sphingosine 1-phosphate receptor modulator

    DEA CLASS

    Rx

    DESCRIPTION

    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

    COMMON BRAND NAMES

    MAYZENT

    HOW SUPPLIED

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

    DOSAGE & INDICATIONS

    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]

    MAXIMUM DOSAGE

    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.

    DOSING CONSIDERATIONS

    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.

    ADMINISTRATION

    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]

    STORAGE

    MAYZENT:
    - Do not refrigerate once opened
    - May be stored at room temperature not exceeding 77 degrees F for up to 3 months
    - See package insert for detailed storage information
    - Store in a cool, dry place
    - Store in original container
    - Store opened (in use) product at room temperature 68 to 77 degrees F
    - Store unopened containers in refrigerator (36 to 46 degrees F)

    CONTRAINDICATIONS / PRECAUTIONS

    General Information

    Siponimod is contraindicated in patients who have a CYP2C9*3/*3 genotype because substantially elevated drug concentrations may occur.[64031]

    Acquired immunodeficiency syndrome (AIDS), chemotherapy, corticosteroid therapy, fungal infection, herpes infection, immunosuppression, infection, leukemia, lymphoma, vaccination, viral infection

    Siponimod may increase the risk for infections due to a reduction in peripheral lymphocyte count because of reversible sequestration of lymphocytes in lymphoid tissues; life-threatening and fatal reactions have occurred in association with its use. Prior to treatment initiation, review results of a recent CBC (i.e., within 6 months or after discontinuation of prior therapy). Delay treatment initiation in patients with severe active infection until resolution. Treatment suspension may be considered during a serious infection. Continue observation for infection 3 to 4 weeks after drug discontinuation because of residual pharmacodynamic effects. Siponimod may be inappropriate for use by patients with immunosuppression, leukemia, lymphoma, human immunodeficiency virus infection (HIV), or acquired immunodeficiency syndrome (AIDS). Herpes zoster, herpes infection, bronchitis, sinusitis, upper respiratory infection, and fungal infection (dermal) were more common in siponimod-treated patients during placebo-controlled trials. Rare cases of cryptococcal meningitis (CM) have been reported with siponimod. Cases of fatal CM and disseminated cryptococcal infections have been reported with fingolimod, another sphingosine 1-phosphate receptor modulator. Patients with signs or symptoms of CM should undergo prompt evaluation and treatment if CM is diagnosed. Discontinue siponimod until a cryptococcal infection has been excluded. Cases of herpes viral infection, including 1 case of reactivation of varicella-zoster virus (VZV) leading to varicella zoster meningitis, have been reported with siponimod. Test patients without a confirmed history of chickenpox or documentation of a full course of vaccination against VZV for antibodies to VZV prior to treatment initiation. Vaccinate antibody-negative patients prior to treatment initiation. Postpone siponimod initiation for 1 month after vaccination to allow the full effect of vaccination to occur. Avoid vaccination with live vaccines during treatment and for 4 weeks after stopping treatment due to potential immunosuppression and increased risk of infection during siponimod therapy. Vaccinations may be less effective if given during siponimod treatment.[64031] 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. Further, concomitant use of siponimod with immunosuppressive or immune-modulating therapies, including corticosteroid therapy or chemotherapy, would be expected to increase the risk of immunosuppression. Consider the duration and mode of action of drugs with prolonged immune effects to avoid unintended immunosuppressive effects when initiating siponimod.[64031]

    Angina, apheresis, AV block, bradycardia, cardiac arrest, cardiomyopathy, celiac disease, cerebrovascular disease, females, fever, geriatric, heart failure, human immunodeficiency virus (HIV) infection, hyperparathyroidism, hypocalcemia, hypokalemia, hypomagnesemia, hypothermia, hypothyroidism, long QT syndrome, myocardial infarction, pheochromocytoma, QT prolongation, rheumatoid arthritis, sick sinus syndrome, sickle cell disease, sleep apnea, sleep deprivation, stroke, syncope, systemic lupus erythematosus (SLE)

    Siponimod initiation may result in decreased heart rate or atrioventricular conduction delays, most often manifested as first- or second-degree (Mobitz type 1) AV block. Siponimod may also produce QT prolongation. Siponimod is contraindicated for use by patients who have experienced myocardial infarction, unstable angina, stroke, transient ischemic attack, decompensated heart failure requiring hospitalization, or Class 3 or 4 heart failure within the last 6 months. Siponimod is also contraindicated for use in patients with Mobitz type 2 second-degree AV block, third-degree AV block, or sick sinus syndrome unless the patient has a functioning pacemaker. Siponimod has not been studied in these patient populations. Siponimod has not been studied in patients with Class 2 heart failure, complete left bundle branch block, sinus arrest or sino-atrial block, symptomatic bradycardia, significant QT prolongation (QTc greater than 500 milliseconds), or those with arrhythmias requiring treatment with Class 1a or Class 3 anti-arrhythmic drugs. Since significant bradycardia may be poorly tolerated in patients with certain forms of cardiac disease, siponimod is not recommended for use in patients with a history of cardiac arrest, cerebrovascular disease or stroke, uncontrolled high blood pressure, or severe untreated sleep apnea. Consult a cardiologist prior to treatment initiation if siponimod is considered for use in patients with significant QT prolongation (QTc greater than 500 milliseconds), patients with arrhythmias requiring treatment with Class 1a or Class 3 anti-arrhythmic drugs, patients with ischemic heart disease, heart failure, a history of cardiac arrest or myocardial infarction, cerebrovascular disease, uncontrolled high blood pressure, severe untreated sleep apnea, or patients with a history of second-degree Mobitz type 2 or higher AV block, sick-sinus syndrome, or sino-atrial heart block. Use of siponimod in patients with recurrent syncope or symptomatic bradycardia should be based on overall benefit-risk assessment, and a cardiologist should be consulted before use. Obtain an ECG in all patients to determine if preexisting cardiovascular conditions are present. Perform first-dose monitoring and ECG testing according to established product label recommendations in patients with sinus bradycardia (heart rate less than 55 beats per minute), first- or second-degree AV block, or a history of myocardial infarction or heart failure with onset more than 6 months before initiation. Use siponimod with caution in patients with conditions that may increase the risk of QT prolongation including congenital long QT syndrome, bradycardia, stress-related cardiomyopathy, hypomagnesemia, hypokalemia, hypocalcemia, or in patients receiving medications known to prolong the QT interval or cause electrolyte imbalances. Females, geriatric patients, patients with sleep deprivation, pheochromocytoma, sickle cell disease, hypothyroidism, hyperparathyroidism, hypothermia, systemic inflammation (e.g., human immunodeficiency virus (HIV) infection, fever, and some autoimmune diseases including rheumatoid arthritis, systemic lupus erythematosus (SLE), and celiac disease) and patients undergoing apheresis procedures (e.g., plasmapheresis [plasma exchange], cytapheresis) may also be at increased risk for QT prolongation. Concomitant use of other drugs that decrease heart rate with siponimod may produce severe bradycardia and heart block. For patients taking a stable dose of a beta-blocker with a resting heart rate of more than 50 beats per minute, siponimod may be initiated. If the resting heart rate is 50 beats per minute or less, interrupt beta-blocker treatment until a heart rate of more than 50 is reached, which allows for siponimod initiation. Reinitiate beta-blocker treatment when the siponimod target maintenance dosage is reached. Consultation with a cardiologist is recommended before siponimod initiation for patients taking other drugs known to affect heart rate.[28432] [28457] [56592] [64031]

    Diabetes mellitus, uveitis, visual disturbance

    Siponimod increases the risk of macular edema. Perform an examination of the fundus including the macula in all patients before starting treatment and again at any time after a patient reports visual disturbance while on siponimod therapy. Patients with a history of uveitis and patients with diabetes mellitus are at increased risk of macular edema during siponimod receipt. The incidence of macular edema was approximately 10% in patients with a history of uveitis or diabetes as compared with 2% in patients without a history of uveitis or diabetes. Regular follow-up ophthalmologic evaluations during siponimod receipt are advised for patients with diabetes mellitus or a history of uveitis.[64031]

    Hypertension

    Cautious use of siponimod is warranted in patients who have hypertension throughout treatment. Patients with uncontrolled high blood pressure need a cardiac evaluation by an appropriately trained physician prior to siponimod initiation. These patients may poorly tolerate siponimod-induced bradycardia or may experience serious rhythm disturbances after the first dose. If treated with siponimod, monitor these patients overnight with continuous electrocardiogram (ECG) in a medical facility after the first dose. Blood pressure elevation may occur with siponimod use in any patient. Regularly monitor the blood pressure of any patient during siponimod receipt.[64031]

    Multiple sclerosis exacerbation

    Monitor patients for severe multiple sclerosis exacerbation after siponimod discontinuation.[64031] Rare cases of severe disability increases with multiple new lesions on MRI have been observed after discontinuation of fingolimod, another sphingosine 1-phosphate receptor modulator. Disability increases typically within 12 weeks, although cases up to 24 weeks after treatment have been reported. The disability was more severe than typical multiple sclerosis relapses, as several patients who were able to walk without assistance while taking fingolimod progressed to needing wheelchairs or became bedbound. Most patients did not return to the functional status they had before fingolimod discontinuation, and permanent disease worsening occurred in some cases. Advise patients of the potential risk of an exacerbation of their multiple sclerosis when siponimod is discontinued, and to seek immediate medical attention if they experience new or worsened symptoms of multiple sclerosis. If an increase in disability occurs, test for new or enhancing lesions on MRI and begin appropriate treatment if clinically indicated.[63770] [64031]

    Asthma, chronic obstructive pulmonary disease (COPD), pulmonary disease, respiratory insufficiency

    Cautious use of siponimod is warranted for patients with respiratory insufficiency or pulmonary disease, including asthma or chronic obstructive pulmonary disease (COPD). Siponimod may cause reductions in forced expiratory volume over 1 second (FEV1) as early as 3 months after treatment initiation. Spirometric evaluation of respiratory function should be performed during siponimod treatment if clinically indicated. The decline in the absolute FEV1 decline from baseline compared to placebo was 88 mL at 2 years during a controlled trial. The mean difference between siponimod-treated patients and placebo-treated patients in percent predicted FEV1 at 2 years was 2.8%. It is unknown if changes in FEV1 are reversible after treatment discontinuation. FEV1 changes are similar between adults with multiple sclerosis who have mild to moderate asthma or COPD compared with the overall population.[64031]

    Hepatic disease

    Elevations of liver enzymes may occur in patients receiving siponimod; recent (i.e., within the last 6 months) transaminase and bilirubin concentrations should be assessed before siponimod therapy is initiated. Monitor liver function tests (LFTs) and bilirubin in patients who develop symptoms suggestive of hepatic dysfunction, such as unexplained nausea, vomiting, abdominal pain, fatigue, anorexia, jaundice and/or dark urine. Discontinue siponimod if significant liver injury is confirmed. Patients with pre-existing hepatic disease or hepatic impairment may be at increased risk of developing elevated LFTs when taking the drug. In clinical trials in adults, elevation of liver transaminases to 3-fold and 5-fold the upper limit of normal (ULN) occurred in 5.6% and 1.4% of siponimod recipients vs. 1.5% and 0.5% of patients on placebo, respectively. AST or ALT increased 8- to 10-fold in 0.5% and 0.2% of siponimod-treated patients, respectively, compared to no placebo-treated patients. The majority of elevations occurred within 6 months. During clinical trials, siponimod was discontinued if LFT elevation exceeded 3-times the ULN and the patient showed signs of hepatic dysfunction. Serum transaminase concentrations returned to normal approximately 1 month after discontinuation of the drug.[64031]

    Encephalopathy, progressive multifocal leukoencephalopathy

    Progressive multifocal leukoencephalopathy (PML) may occur with siponimod. PML has not been observed in siponimod-treated patients; however, PML has been reported with fingolimod, another sphingosine 1-phosphate receptor modulator, and other multiple sclerosis therapies. PML can be fatal, instruct patients to notify their healthcare provider immediately if they notice new or worsening neurological signs or symptoms such as ataxia, visual changes, or confusion. Similarly, suspect PML in any patient presenting with neurological symptoms; discontinue siponimod at the first sign or symptom of PML and perform a clinical evaluation. Consider MRI monitoring for signs that may be consistent with PML. MRI findings suggestive of PML and detection of JC virus (JCV) DNA in the CSF in the absence of clinical signs and symptoms of PML have been reported in patients treated with other multiple sclerosis medications; many cases progressed to symptomatic PML. Promptly investigate any suspicious findings to allow for early diagnosis. There have also been rare cases of posterior reversible encephalopathy syndrome (PRES) reported in patients receiving fingolimod. Symptoms reported included sudden onset of severe headache, altered mental status, visual disturbances, and seizure. Symptoms of PRES are usually reversible but may evolve into ischemic stroke or cerebral hemorrhage. A delay in diagnosis and treatment may lead to permanent neurological sequelae. If PRES is suspected, discontinue siponimod and perform a clinical evaluation.[60067] [64031]

    Contraception requirements, pregnancy, reproductive risk

    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. 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. Discuss contraception requirements with the patient. 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.[64031]

    Breast-feeding

    There are no data on the presence of siponimod in human milk, the effects on the breast-fed infant, or the effects on milk production. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally ingested drug, healthcare providers are encouraged to report the adverse effect to the FDA.[64031]

    Skin cancer, sunlight (UV) exposure

    Limit sunlight (UV) exposure during siponimod therapy due to an increased risk for skin cancer with long-term use of sphingosine 1-phosphate (S1P) receptor modulators. Patients should wear protective clothing and use a sunscreen with high protection factor. The risk of basal cell carcinoma was increased in patients treated with siponimod during a clinical trial. Cases of squamous cell carcinoma and malignant melanoma were also reported. Periodic skin examination is recommended for all patients, particularly those with risk factors for skin cancer. Providers and patients are advised to monitor for suspicious skin lesions. If a suspicious skin lesion is observed, it should be promptly evaluated. Concomitant phototherapy with UV-B radiation or PUVA-photochemotherapy is not recommended in patients taking siponimod.

    ADVERSE REACTIONS

    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
    progressive multifocal leukoencephalopathy / Delayed / Incidence not known
    multiple sclerosis exacerbation / Delayed / Incidence not known
    skin cancer / 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
    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

    DRUG INTERACTIONS

    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.
    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) In general, do not initiate treatment with siponimod in patients receiving aripiprazole 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 during therapeutic use of aripiprazole and following overdose.
    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.
    Aspirin, ASA; Butalbital; 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.
    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) In general, do not initiate treatment with siponimod in patients receiving atomoxetine 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 during therapeutic use of atomoxetine and following overdose.
    Azithromycin: (Major) Avoid coadministration of azithromycin 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. QT prolongation and torsade de pointes (TdP) have been spontaneously reported during azithromycin postmarketing surveillance. Siponimod therapy prolonged the QT interval at recommended doses in a clinical study.
    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.
    Belladonna Alkaloids; Ergotamine; 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%.
    Bendroflumethiazide; 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.
    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) In general, do not initiate treatment with siponimod in patients receiving buprenorphine 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. Buprenorphine has been associated with QT prolongation and has a possible risk of torsade de pointes. FDA-approved labeling for some buprenorphine products recommend avoiding use with Class 1A and Class III antiarrhythmic medications while other labels recommend avoiding use with any drug that has the potential to prolong the QT interval.
    Buprenorphine; Naloxone: (Major) In general, do not initiate treatment with siponimod in patients receiving buprenorphine 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. Buprenorphine has been associated with QT prolongation and has a possible risk of torsade de pointes. FDA-approved labeling for some buprenorphine products recommend avoiding use with Class 1A and Class III antiarrhythmic medications while other labels recommend avoiding use with any drug that has the potential to prolong the QT interval.
    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.
    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) Avoid coadministration of siponimod and citalopram 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. Citalopram causes dose-dependent QT interval prolongation.
    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) In general, do not initiate treatment with siponimod in patients receiving clofazimine 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 in patients receiving clofazimine in combination with QT prolonging medications.
    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) In general, do not initiate treatment with siponimod in patients receiving promethazine 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. Promethazine, a phenothiazine, is associated with a possible risk for QT prolongation.
    Codeine; Promethazine: (Major) In general, do not initiate treatment with siponimod in patients receiving promethazine 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. Promethazine, a phenothiazine, is associated with a possible risk for QT prolongation.
    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.
    Dasabuvir; Ombitasvir; Paritaprevir; 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.
    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.
    Dexamethasone: (Moderate) Concomitant use of siponimod and dexamethasone 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; dexamethasone 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. Additonally, monitor patients carefully for signs and symptoms of infection if coadministration is necessary, as 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.
    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.
    Diphtheria/Tetanus Toxoids; Pertussis Vaccine; 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.
    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: (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.
    Enflurane: (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.
    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.
    Erythromycin; Sulfisoxazole: (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) In general, do not initiate treatment with siponimod in patients receiving escitalopram 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. Escitalopram is associated with a risk of QT prolongation and torsade de pointes.
    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 may alter 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; etravirine is a moderate CYP2C9 inhibitor and a moderate CYP3A4 inducer. The net effect on siponimod exposure is unknown. Coadministration with a moderate CYP2C9/CYP3A4 dual inhibitor led to a 2-fold increase in the exposure of siponimod, while across different CYP2C9 genotypes, a moderate CYP3A4 inducer reduced siponimod exposure by up to 52%, according to in silico evaluation.
    Ezogabine: (Major) In general, do not initiate treatment with siponimod in patients receiving ezogabine 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. Ezogabine has been associated with QT prolongation.
    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) In general, do not initiate treatment with siponimod in patients receiving flecainide 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. Flecainide is a Class IC antiarrhythmic associated with a possible risk for QT prolongation and/or torsade de pointes (TdP); flecainide increases the QT interval, but largely due to prolongation of the QRS interval. Although causality for TdP has not been established for flecainide, patients receiving concurrent drugs that have the potential for QT prolongation may have an increased risk of developing proarrhythmias.
    Fluconazole: (Major) In general, do not initiate 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) In general, do not initiate treatment with siponimod in patients receiving fluoxetine 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 in patients treated with fluoxetine.
    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 CYP3A4 substrate; fosamprenavir is a moderate/strong CYP3A4 inhibitor. Coadministration with a moderate CYP2C9/CYP3A4 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.
    Haemophilus influenzae type b Conjugate Vaccine; 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.
    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.
    Halothane: (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.
    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.
    Human Papillomavirus Bivalent 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.
    Human Papillomavirus Quadrivalent 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) Avoid coadministration of siponimod and hydroxychloroquine due to an 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. Siponimod therapy prolonged the QT interval at recommended doses in a clinical study. Hydroxychloroquine prolongs the QT interval.
    Hydroxyzine: (Major) In general, do not initiate treatment with siponimod in patients receiving hydroxyzine 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. Postmarketing data indicate that hydroxyzine causes QT prolongation and torsade de pointes.
    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: (Major) In general, do not initiate treatment with siponimod in patients receiving ketoconazole 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. Ketoconazole has also been associated with prolongation of the QT interval. Additionally, concomitant use of siponimod and ketoconazole may increase siponimod exposure. Siponimod is a CYP3A4 substrate; 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.
    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.
    Levobetaxolol: (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.
    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) In general, do not initiate treatment with siponimod in patients receiving levofloxacin 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. Levofloxacin has been associated with a risk of QT prolongation and torsade de pointes (TdP). Although extremely rare, TdP has been reported during postmarketing surveillance of levofloxacin.
    Levoketoconazole: (Major) In general, do not initiate treatment with siponimod in patients receiving ketoconazole 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. Ketoconazole has also been associated with prolongation of the QT interval. Additionally, concomitant use of siponimod and ketoconazole may increase siponimod exposure. Siponimod is a CYP3A4 substrate; ketoconazole is a strong CYP3A4 inhibitor.
    Lithium: (Major) In general, do not initiate treatment with siponimod in patients receiving lithium 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. Lithium has been associated with QT prolongation.
    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.
    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.
    Meningococcal 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.
    Meningococcal Polysaccharide Vaccine (MPSV4): (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.
    Meperidine; Promethazine: (Major) In general, do not initiate treatment with siponimod in patients receiving promethazine 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. Promethazine, a phenothiazine, is associated with a possible risk for QT prolongation.
    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) In general, do not initiate treatment with siponimod in patients receiving mirtazapine 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. Mirtazapine has been associated with dose-dependent prolongation of the QT interval. Torsade de pointes has been reported postmarketing, primarily in overdose or in patients with other risk factors for QT prolongation.
    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.
    Nevirapine: (Moderate) Concomitant use of siponimod and nevirapine 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; nevirapine is a moderate CYP3A4 inducer. Across different CYP2C9 genotypes, a moderate CYP3A4 inducer decreased the exposure of siponimod up to 52% according to in silico evaluation.
    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.
    Octreotide: (Major) In general, do not initiate treatment with siponimod in patients receiving octreotide 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. Arrhythmias, sinus bradycardia, and conduction disturbances have occurred during octreotide therapy. Since bradycardia is a risk factor for development of torsade de pointes, the potential occurrence of bradycardia during octreotide administration could theoretically increase the risk of TdP in patients receiving drugs that prolong the QT interval. Additionally, concomitant use of siponimod and octreotide 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; octreotide is a moderate CYP3A4 inhibitor. Coadministration with a moderate CYP2C9/CYP3A4 dual inhibitor led to a 2-fold increase in the exposure of siponimod.
    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) In general, do not initiate treatment with siponimod in patients receiving ofloxacin 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 ofloxacin. These reports generally involved patients with concurrent medical conditions or concomitant medications that may have been contributory.
    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) In general, do not initiate treatment with siponimod in patients receiving fluoxetine 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 in patients treated with fluoxetine. (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.
    Ombitasvir; Paritaprevir; 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.
    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) In general, do not initiate treatment with siponimod in patients receiving ondansetron 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. Ondansetron has been associated with a dose-related increase in the QT interval and postmarketing reports of torsade de pointes.
    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.
    Penbutolol: (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.
    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) In general, do not initiate treatment with siponimod in patients receiving promethazine 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. Promethazine, a phenothiazine, is associated with a possible risk for QT prolongation.
    Promethazine; Dextromethorphan: (Major) In general, do not initiate treatment with siponimod in patients receiving promethazine 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. Promethazine, a phenothiazine, is associated with a possible risk for QT prolongation.
    Promethazine; Phenylephrine: (Major) In general, do not initiate treatment with siponimod in patients receiving promethazine 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. Promethazine, a phenothiazine, is associated with a possible risk for QT prolongation.
    Propafenone: (Major) In general, do not initiate treatment with siponimod in patients receiving propafenone 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. Propafenone is a Class IC antiarrhythmic which increases the QT interval, but largely due to prolongation of the QRS interval.
    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 necessary 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) Avoid coadministration of siponimod and quetiapine 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. Limited data, including some case reports, suggest that quetiapine may be associated with a significant prolongation of the QTc interval in rare instances.
    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.
    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.
    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%.
    Rifaximin: (Moderate) Concomitant use of siponimod and rifaximin 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; rifaximin is a moderate CYP3A4 inducer. In patients with normal liver function, rifaximin at the recommended dosing regimen is not expected to induce CYP3A4. It is unknown whether rifaximin can have a significant effect on the pharmacokinetics of concomitant CYP3A4 substrates in patients with reduced liver function who have elevated rifaximin concentrations. Across different CYP2C9 genotypes, a moderate CYP3A4 inducer decreased the exposure of siponimod by up to 52% according to in silico evaluation.
    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.
    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.
    Rubella 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.
    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) In general, do not initiate treatment with siponimod in patients receiving sertraline 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. QTc prolongation and torsade de pointes (TdP) have been reported during postmarketing use of sertraline; most cases had confounding risk factors. The risk of sertraline-induced QT prolongation is generally considered to be low in clinical practice. Its effect on QTc interval is minimal (typically less than 5 msec), and the drug has been used safely in patients with cardiac disease (e.g., recent myocardial infarction, unstable angina, chronic heart failure).
    Sevoflurane: (Major) In general, do not initiate 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.
    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) In general, do not initiate treatment with siponimod in patients receiving sotalol 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. Sotalol administration is associated with QT prolongation and torsade de pointes. Proarrhythmic events should be anticipated after initiation of therapy and after each upward dosage adjustment.
    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) In general, do not initiate treatment with siponimod in patients receiving tamoxifen 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. Tamoxifen has been reported to prolong the QT interval, usually in overdose or when used in high doses. Rare case reports of QT prolongation have also been described when tamoxifen is used at lower doses.
    Telavancin: (Major) In general, do not initiate 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.
    Telithromycin: (Major) In general, do not initiate treatment with siponimod in patients receiving telithromycin 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. Telithromycin has also been associated with prolongation of the QT interval. Additionally, concomitant use of siponimod and telithromycin 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; telithromycin is a strong CYP3A4 inhibitor. Coadministration with a moderate CYP2C9/CYP3A4 dual inhibitor led to a 2-fold increase in the exposure of siponimod.
    Tetanus Toxoid: (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.
    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) Avoid coadministration of siponimod and trazodone 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. Trazodone can prolong the QT/QTc interval at therapeutic doses. In addition, there are postmarketing reports of torsade de pointes.
    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) In general, do not initiate treatment with siponimod in patients receiving triclabendazole 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. Transient prolongation of the mean QTc interval was noted on the ECG recordings in dogs administered triclabendazole.
    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) Avoid coadministration of siponimod and vardenafil 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. Vardenafil is associated with QT prolongation. Both therapeutic and supratherapeutic doses of vardenafil produce an increase in QTc interval.
    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) In general, do not initiate treatment with siponimod in patients receiving venlafaxine 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. Venlafaxine administration is associated with a possible risk of QT prolongation; torsade de pointes has been reported with postmarketing use.
    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.
    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.

    PREGNANCY AND LACTATION

    Pregnancy

    There are no data on the presence of siponimod in human milk, the effects on the breast-fed infant, or the effects on milk production. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally ingested drug, healthcare providers are encouraged to report the adverse effect to the FDA.[64031]

    MECHANISM OF ACTION

    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]

    PHARMACOKINETICS

    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]