Section 04 · Monograph

Siponimod

Reviewed Nov 2026FDA label

MayzentS1P receptor modulator

Indications

Treatment of relapsing forms of multiple sclerosis (MS) in adults, to include clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive diseaseFDA-labeled

Siponimod is a sphingosine 1-phosphate (S1P) receptor modulator that selectively binds S1P receptor subtypes 1 and 5
Binding to S1P1 on lymphocytes causes internalization of the receptor, blocking lymphocyte egress from lymph nodes and reducing circulating lymphocyte counts available to migrate to the CNS
S1P1 binding on cardiac myocytes (particularly atrial cells) activates G-protein-coupled inwardly rectifying potassium channels, producing the transient heart-rate-lowering effect seen with treatment initiation
S1P5 binding on oligodendrocytes may have additional CNS effects, though clinical significance is not established
Siponimod pharmacokinetics are strongly influenced by CYP2C9 genotype because it is predominantly metabolized via CYP2C9 (~79%) and CYP3A4 (~18%)

CYP2C9 genotype testing is required before initiating therapy to determine dosing
CYP2C9*1/*1, *1/*2, or *2/*2 (normal/extensive metabolizers): titrate over 5 days (Day 1–2: 0.25 mg; Day 3: 0.5 mg; Day 4: 0.75 mg; Day 5: 1.25 mg) to a maintenance dose of 2 mg once daily starting Day 6
CYP2C9*1/*3 or *2/*3 (intermediate metabolizers): titrate over 4 days (Day 1–2: 0.25 mg; Day 3: 0.5 mg; Day 4: 0.75 mg) to a reduced maintenance dose of 1 mg once daily starting Day 5
CYP2C9*3/*3 (poor metabolizers): MAYZENT is contraindicated — do not use at any dose
First-dose (6-hour) cardiac monitoring recommended for patients with sinus bradycardia (HR <55 bpm), first- or second-degree Mobitz type I AV block, or history of myocardial infarction or heart failure
If titration is interrupted for ≥4 consecutive days, treatment must be reinitiated with a new titration

Patients with a CYP2C9*3/*3 genotype (poor metabolizers)
Myocardial infarction, unstable angina, stroke, TIA, decompensated heart failure requiring hospitalization, or Class III/IV heart failure within the last 6 months
Mobitz type II second-degree AV block, third-degree AV block, or sick sinus syndrome, unless patient has a functioning pacemaker
Known hypersensitivity to siponimod or any excipient

Concomitant use with drugs causing moderate CYP2C9 and moderate-or-strong CYP3A4 inhibition simultaneously is not recommended (risk of markedly increased siponimod exposure)
In CYP2C9*1/*3 and *2/*3 (intermediate metabolizer) patients, concomitant moderate or strong CYP3A4 inducers are not recommended due to loss of efficacy
Beta-blockers and other heart-rate/AV-conduction-lowering drugs may have additive bradycardic effects; caution advised, may require temporary interruption of beta-blocker before initiation
Live attenuated vaccines should be avoided during treatment and for up to 4 weeks after discontinuation
Class Ia and Class III anti-arrhythmic drugs — use with caution given AV-conduction effects

CYP2C9 genotype testing before first dose to determine eligibility and titration/maintenance dose
First-dose 6-hour observation with hourly HR/BP monitoring in patients with specified cardiac risk factors
Baseline ECG, complete blood count, and liver function tests before initiation
Baseline ophthalmic (fundus) exam and follow-up if visual symptoms occur; higher-risk patients (diabetes, uveitis) warrant more frequent exams
Periodic liver function monitoring during treatment
Blood pressure monitoring during treatment
Monitor for signs/symptoms of infection and for symptoms suggestive of PML; withhold drug if PML is suspected
Varicella zoster antibody status assessment prior to initiation

Can cause fetal harm; animal studies demonstrated embryotoxicity, fetotoxicity, and teratogenicity
Women of childbearing potential must use effective contraception during treatment and for at least 10 days after stopping siponimod
No human data on presence of siponimod in breast milk; animal studies show excretion into milk — weigh maternal benefit against potential infant risk