Siponimod
Multiple sclerosis disease-modifying therapies
Multiple sclerosis disease-modifying therapies
An oral S1P receptor modulator for relapsing and active secondary progressive MS. A CYP2C9 gene test decides whether and how it can be used.
Quick facts
- Group
- Multiple sclerosis disease-modifying therapies
- Target
- Sphingosine-1-phosphate receptor 1 (S1PR1)
- Used for
- Relapsing forms of multiple sclerosis
- Key effects
- Headache and dizziness · Pain in the arms or legs
- Monitor
- CYP2C9 genotype before starting · Blood count
- ATC
- L04AE03
No doses: the clinician sets them by the current guideline.
Mechanism of action
The figure shows siponimod bound to the human S1P1 receptor coupled to its Gi protein.
Siponimod acts directly on the S1P1 and S1P5 receptors. It behaves as a functional antagonist of S1P1: the receptor is internalized and degraded, lymphocytes cannot follow the S1P signal to leave the lymph nodes, and fewer of them enter the central nervous system.
- Siponimod binds S1P1 (and S1P5)
- S1P1 is internalized and degraded
- Lymphocytes remain in lymph nodes
- Fewer relapses and slower disability
Indications
- Relapsing forms of multiple sclerosis, including clinically isolated syndrome, relapsing-remitting and active secondary progressive disease Multiple sclerosis →
Adverse effects
Common
- Headache and dizziness
- Pain in the arms or legs
- Diarrhoea
- Raised blood pressure
Contraindications
- CYP2C9*3/*3 genotype
- Heart attack, unstable angina, stroke, TIA or heart failure in the previous 6 months
- Some heart rhythm disorders without a pacemaker
Key interactions
- Moderate or strong CYP2C9/CYP3A4 inducers (rifampicin, carbamazepine)
- Lower siponimod levels; the combination is not recommended
- Moderate or strong inhibitors (fluconazole)
- Higher siponimod levels; the combination is not recommended
- Medicines that slow the heart
- More bradycardia
- Live vaccines
- Avoided from 1 week before starting until 1 month after the last dose unless the treating team advises otherwise
What is monitored
- CYP2C9 genotype before starting
- ECG before the first dose and 6 hours after it
- Blood count, liver tests, eye (macula) and skin checks
- Blood pressure
- Varicella immunity
Administration and safety
- Oral tablet raised over the first days
- The first dose is given in a health facility, with an ECG before it and 6 hours after it
Pregnancy and breastfeeding
Effective contraception is used during treatment and for at least 10 days after the last dose.
Nursing care
- Confirm the CYP2C9 test result before the first dose
- Check pulse and ECG at the start
- Teach sun protection and skin self-checks
- Teach the signs of infection and of PML (one-sided weakness, confusion)
- Advise contraception during treatment and for 10 days after the last dose
Pharmacokinetics
- Absorption
- Oral, with good bioavailability
- Metabolism
- By CYP2C9, a highly polymorphic enzyme, and then CYP3A4
- Elimination
- Mainly in bile and faeces
Test yourself
Think of the answer, then tap the question to see it.
Which genetic test is done before siponimod?
CYP2C9 genotyping.
Which CYP2C9 genotype contraindicates siponimod?
Homozygous CYP2C9*3/*3.
Which form of MS is siponimod notable for treating among S1P modulators?
Active secondary progressive multiple sclerosis.
Connections
← Back to the class: Multiple sclerosis disease-modifying therapies
Educational content on how drugs work; not a prescribing guide and no substitute for a health professional's advice. No doses are given.
Sources: Siponimod: MedlinePlus Drug Information (MedlinePlus (U.S. National Library of Medicine), 2026); ATCDDD - ATC/DDD Index (WHO Collaborating Centre for Drug Statistics Methodology, 2026); RCSB PDB - 7EVY: Cryo-EM structure of siponimod -bound Sphingosine-1-phosphate receptor 1 in complex with Gi protein (RCSB Protein Data Bank, 2026).
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Representative model, for educational purposes only.