Dosing & Uses
Dosage Forms & Strengths
tablet
- 0.25mg
- 2mg
Multiple Sclerosis
Indicated for relapsing forms of multiple sclerosis (MS), to include clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease
Patients with CYP2C9 genotypes *1/*1, *1/*2, or *2/*2
- Initiate with a 5-day titration
- Maintenance dose (Day 6): 2 mg PO qDay
- Use a starter pack for patients who will be titrated to the 2-mg maintenance dosage
- Do not use starter pack for patients who will be titrated to the 1-mg maintenance dosage
Titration for the 2-mg/day maintenance dose
- Day 1: 0.25 mg (1 x 0.25 mg) PO
- Day 2: 0.25 mg (1 x 0.25 mg) PO
- Day 3: 0.50 mg (2 x 0.25 mg) PO
- Day 4: 0.75 mg (3 x 0.25 mg) PO
- Day 5: 1.25 mg (5 x 0.25 mg) PO
- Day 6 and thereafter: 2 mg (1 x 2 mg) PO qDay
Patients with CYP2C9 genotypes *1/*3 or *2/*3
- Initiate with a 4-day titration
- Maintenance dose (Day 5): 1 mg PO qDay
- Do not use the starter pack for patients who will be titrated to the 1-mg maintenance dosage
Titration for 1-mg/day maintenance dose
- Day 1: 0.25 mg (1 x 0.25 mg) PO
- Day 2: 0.25 mg (1 x 0.25 mg) PO
- Day 3 0.50 mg (2 x 0.25 mg) PO
- Day 4: 0.75 mg (3 x 0.25 mg) PO
- Day 5 and thereafter: 1 mg (4 x 0.25 mg) PO qDay
Reinitiation after treatment interruption
- After completing initial titration, if maintenance treatment is interrupted for 4 or more consecutive daily doses, reinitiate treatment with Day 1 of the titration regimen
- Also complete first-dose monitoring in patients for whom it is recommended
Dosage Modifications
Renal impairment
- No dosage adjustment necessary
- End-stage renal disease or patients on hemodialysis: Not studied; owing to high plasma protein binding (>99.9%) of siponimod, hemodialysis is not expected to alter the total and unbound siponimod concentration and no dose adjustments are anticipated based on these considerations
Hepatic impairment
- No dosage adjustment necessary
- Increased unbound siponimod AUC observed with moderate and severe hepatic impairment is not expected to be clinically significant
Dosing Considerations
Before initiating treatment
- Test for CYP2C9 variants to determine CYP2C9 genotype; an FDA-cleared or FDA-approved test for detecting CYP2C9 variants to direct the use of siponimod is not currently available
- Test for antibodies to varicella-zoster virus (VZV); VZV vaccination of antibody-negative patients is recommended prior to commencing treatment
- Determine whether patients are taking drugs that could slow heart rate or atrioventricular (AV) conduction
- If patients are taking or have a history of taking antineoplastic, immunosuppressive, or immune-modulating therapies, consider possible unintended additive immunosuppressive effects before initiating treatment
- Ophthalmic examination, including evaluation of the fundus, including the macula
- Electrocardiogram (ECG)
- Recent CBC count
- Recent (eg, within last 6 months) transaminase and bilirubin levels
First-dose monitoring in patients with certain preexisting cardiac conditions
- Because initiating treatment results in a decrease in heart rate (HR), recommend first-dose 6-hr monitoring for patients with sinus bradycardia (HR <55 bpm), first- or second-degree (Mobitz type I) AV block, or a history of myocardial infarction or heart failure
If any of the following abnormalities are present after 6 hr (even in the absence of symptoms):
- HR 6 hr postdose <45 bpm or is at the lowest value postdose
- ECG 6 hr postdose shows new-onset second-degree or higher AV block
- Monitor until the abnormality resolves
- If postdose symptomatic bradycardia, bradyarrhythmia, or conduction related symptoms occur, or if ECG 6 hr postdose shows new-onset second-degree or higher AV block or QTc ≥500 msec, initiate appropriate management; monitor ECG and symptoms until resolved if no pharmacological treatment is required
- If pharmacological treatment is required, monitor overnight and repeat 6-hr monitoring after second dose
- Consult with a cardiologist for patients with preexisting heart and cerebrovascular conditions, a prolonged QTc interval before dosing or during the 6-hr observation, at additional risk for QT prolongation, or on concurrent therapy with QT-prolonging drugs with a known risk of torsades de pointes or drugs that slow heart rate or AV conduction
Safety and efficacy not established
Interactions
Interaction Checker
No Results

Contraindicated
Serious - Use Alternative
Significant - Monitor Closely
Minor

Adverse Effects
>10%
Headache (15%)
Hypertension (13%)
Transaminase increased (11%)
Falls (11%)
1-10%
Peripheral edema (8%)
Nausea (7%)
Dizziness (7%)
Diarrhea (6%)
Bradycardia (6%)
Pain in extremity (6%)
Vascular events (eg, ischemic strokes, pulmonary embolisms, myocardial infarctions) (3%)
Seizures (1.7%)
Frequency Not Defined
Malignancies (eg, melanoma in situ)
Dose-dependent reductions in forced expiratory volume over 1 sec (FEV1)
Warnings
Contraindications
A CYP2C9*3/*3 genotype
In the last 6 months experienced myocardial infarction, unstable angina, stroke, transient ischemic attack (TIA), decompensated heart failure requiring hospitalization, or Class III or IV heart failure
Presence of Mobitz type II second- or third-degree AV block or sick sinus syndrome, unless patient has a functioning pacemaker
Cautions
Macular edema reported; majority of cases occurred within the first 4 months of therapy
Dose-dependent reductions in absolute FEV1 observed as early as 3 months after treatment initiation
Elevated transaminases may occur; exercise caution when treating patients with a history of significant liver disease
Incidence of hypertension reported in clinical trials in patients treated with siponimod was slightly higher than those treated with placebo; monitor blood pressure during treatment and manage appropriately
Based on animal studies, fetal harm may occur (see Pregnancy)
Rare cases of posterior reversible encephalopathy syndrome reported in patients receiving a sphingosine 1-phosphate (S1P) receptor modulator; such events have not been reported for siponimod-treated patients in the development program
Severe disease exacerbation, including disease rebound, rarely reported after discontinuing S1P receptor modulator
After discontinuing, siponimod remains in the blood for up to 10 days; starting other therapies during this interval results in concomitant exposure to siponimod
May cause a decline in pulmonary function; assess pulmonary function (eg, spirometry) if clinically indicated
Bradyarrhythmia and AV conduction delays
- Since initiation of treatment results in a transient decrease in HR and AV conduction delays, use an up-titration scheme to reach maintenance dosage
- After first titration dose, decrease in HR starts within 1 hr, and on Day 1 declines at ~3-4 hr; with continued up-titration, further HR decreases are seen on subsequent days, with maximal decrease from Day 1-baseline reached on Day 5-6; with continued dosing, HR starts increasing after Day 6 and reaches placebo levels within 10 days after treatment initiation
- The resting heart rate under stable dose of beta-blocker should be considered before introducing therapy
Not studied in patients who had:
- In the last 6 months experienced myocardial infarction, unstable angina, stroke, TIA, or decompensated heart failure requiring hospitalization
- New York Heart Association Class II-IV heart failure
- Cardiac conduction or rhythm disorders (eg, complete left bundle-branch block, sinus arrest, sinoatrial block, symptomatic bradycardia, sick sinus syndrome, Mobitz type II second-degree AV-block, or higher-grade AV block [either history or observed at screening]), unless patient has a functioning pacemaker
- Significant QT prolongation (QTc >500 msec)
- Arrhythmias requiring treatment with Class Ia or Class III antiarrhythmic drugs
- If such patients are considered for treatment, consult with cardiologist
Infections
- Dose-dependent reduction in peripheral lymphocyte count to 20-30% of baseline values may occur because of reversible sequestration of lymphocytes in lymphoid tissues; therefore, increased risk of infections; life-threatening and rare fatal infections have occurred
- Delay treatment initiation in patients with severe active infection until resolution
- Infection risk may persist for up to 3-4 weeks after discontinuing because of residual pharmacodynamic effects (eg, decreased lymphocyte count); continue monitoring
- Appropriately diagnose and treat symptomatic patients with infection while on therapy; consider suspending treatment if a patient develops a serious infection
- Cases of fatal cryptococcal meningitis (CM) and disseminated cryptococcal infections reported with another S1P receptor modulator
- Rare cases of CM have also occurred
- Herpes viral infection, including 1 case of reactivation of VZV infection leading to varicella- zoster meningitis, reported in clinical trialshave
- Progressive multifocal leukoencephalopathy is an opportunistic viral infection of the brain caused by the JC virus that typically only occurs in patients who are immunocompromised, and that usually leads to death or severe disability
Drug interactions overview
- When switching from drugs with prolonged immune effects, consider half-life and mode of action of these drugs to avoid unintended additive immunosuppressive effects and to minimize risk of disease reactivation when initiating treatment
- Initiating siponimod after treatment with alemtuzumab is not recommended
- Siponimod can generally be started immediately after discontinuation of beta-interferon or glatiramer acetate
- Owing to the potential additive HR effects, should not be initiated in patients who are concurrently treated with QT-prolonging drugs with known arrhythmogenic properties, Class 1a or III antiarrhythmics, HR-lowering calcium channel blockers (eg, verapamil, diltiazem), or other drugs that may decrease HR (eg, ivabradine, digoxin)
- Use caution when initiating treatment in patients concomitantly using a beta-blocker because of the additive effects on lowering HR; consider temporary interruption of the beta-blocker prior to initiation of treatment; beta-blocker treatment can be initiated in patients receiving stable doses of siponimod
- During and for up to 1 month after discontinuation of treatment, vaccinations may be less effective; therefore, withhold treatment 1 week prior to and for 4 weeks after vaccination
- Avoid use with live-attenuated vaccines during and for up to 4 weeks after treatment owing to the potential risk of infection
- Because of a significant increase in exposure to siponimod, coadministration with moderate CYP2C9 plus moderate/strong CYP3A4 inhibitors is not recommended; exercise caution if concomitantly used alone with moderate CYP2C9 inhibitors
- Because of a significant decrease in siponimod exposure, coadministration with moderate CYP2C9 plus moderate/strong CYP3A4 inducers is not recommended for all patients; exercise caution if coadministered alone with moderate CYP2C9 inducers; concurrent use of siponimod and moderate (eg, modafinil, efavirenz) or strong CYP3A4 inducers is not recommended for patients with CYP2C9*1/*3 and*2/*3 genotype
Pregnancy
Pregnancy
There are no adequate data on the developmental risk associated with the use in pregnant women
Animal data
- Based on animal data and its mechanism of action, fetal harm may occur when administered to a pregnant woman
- Reproductive and developmental studies in pregnant rats and rabbits have demonstrated drug-induced embryotoxicity and fetotoxicity in rats and rabbits and teratogenicity in rats
- Increased incidences of postimplantation loss and fetal abnormalities (external, urogenital, and skeletal) in rats and of embryofetal deaths, abortions, and fetal variations (skeletal and visceral) in rabbits observed following prenatal exposure to siponimod starting at a dose 2 times the exposure in humans at the highest recommended dose of 2 mg/day
Contraception
- Before initiating treatment, counsel women of childbearing potential on the potential risks to the fetus
- Advise on effective contraception during treatment
- Since it takes ~10 days to eliminate drug from the body after discontinuation, potential risks to the fetus may persist and women should use effective contraception during this period
Lactation
Unknown if distributed in human breast milk
A study in lactating rats has shown excretion of siponimod and/or its metabolites in milk
Consider the developmental and health benefits of breastfeeding along with the mother’s clinical need for the drug, and any potential adverse effects on the breastfed infant from the drug or from the underlying maternal condition
Pregnancy Categories
A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.
B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk. C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done. D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk. X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist. NA: Information not available.Pharmacology
Mechanism of Action
Sphingosine-1-phosphate (S1P) receptor modulator
Binds with high affinity to S1P receptors 1 and 5; blocks lymphocyte egress from lymph nodes, reducing the number of lymphocytes in peripheral blood
Mechanism by which siponimod exerts therapeutic effects in MS is unknown, but may involve reduction of lymphocyte migration into the central nervous system
Absorption
Peak plasma time: 4 hr
Peak plasma concentration: 30.4 ng/mL (2 mg/day over 10 days)
AUC: 558 ng·hr/mL (2mg/day over 10 days)
Steady-state reached after ~ 6 days
Oral bioavailability: ~84%
Siponimod absorption is extensive (≥70%)
Distribution
Vd: 124 L
Animal studies show that siponimod readily crosses the blood-brain barrier
Protein bound: >99.9%
Metabolism
Extensively metabolized, mainly via CYP2C9 (79.3%), followed by CYP3A4 (18.5%)
Pharmacological activity of the main metabolites M3 and M17 is not expected to contribute to the clinical effect and safety of siponimod in humans
Elimination
Clearance: 3.11 L/hr
Half-life: ~30 hr
Eliminated from the systemic circulation mainly due to metabolism, and subsequent biliary/fecal excretion; unchanged siponimod was not detected in urine
Pharmacogenomics
CYP2C9 genotype
- Before initiating treatment, test patients to determine CYP2C9 genotype
- Contraindicated in patients homozygous for CYP2C9*3 (eg, CYP2C9*3/*3 genotype)
- Dosage adjustment recommended in patients with CYP2C9 *1/*3 or *2/*3 genotype because of an increase in exposure to siponimod
Administration
Oral Administration
Administer with or without food
Missed dose
- During titration: If 1 titration dose is missed for >24 hr, treatment needs to be reinitiated with Day 1 of the titration regimen
During maintenance
- If 1 dose missed after initial dose titration, take as soon as possible
- Dosing interrupted for ≥4 consecutive daily doses: Reinitiate treatment with Day 1 of the titration regimen
Storage
Unopened bottles: Refrigerate at 2-8°C (36-46°F)
After opening
- Starter pack: Store at room temperature (20-25°C [68-77°F]) for up to 1 week after opening
- Bottles (0.25- or 2-mg tablets): Store at room temperature (20-25°C [68-77°F]) for up to 1 month after opening
Images
Patient Handout
Formulary
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