siponimod fumaric acid: clinical use

Prescribing considerations

• Specialist initiation and supervision are required.
• Establish CYP2C9 genotype before prescribing; exposure and suitability are genotype-dependent.
• Review cardiac history, resting pulse, ECG and interacting rate-lowering treatments before initiation.
• Exclude severe active infection and consider prior or overlapping immunosuppression.
• Confirm varicella immunity or vaccination history.
• Assess pregnancy potential, contraception and pregnancy-test status where relevant.
• Use caution with diabetes, uveitis, retinal disease, uncontrolled hypertension, significant liver disease and limited evidence in older adults.

Contraindications and cautions

• CYP2C9*3*3 genotype
• Pregnancy or childbearing potential without effective contraception
• Immunodeficiency syndrome
• Previous progressive multifocal leukoencephalopathy or cryptococcal meningitis
• Active malignancy
• Severe hepatic impairment
• Recent myocardial infarction, unstable angina, stroke, transient ischaemic attack or specified severe/decompensated heart failure
• Specified advanced atrioventricular, sinoatrial or sick-sinus conduction disorders without a pacemaker
• Hypersensitivity to siponimod, peanut, soya or another excipient

Monitoring

• Full blood count and absolute lymphocyte count at baseline and during treatment
• Liver transaminases and bilirubin at baseline; repeat if clinically indicated
• Blood pressure regularly
• Ophthalmological assessment after initiation and whenever visual symptoms occur; assess higher-risk patients before treatment
• Baseline and periodic skin examination, with continued sun protection advice
• ECG and first-exposure observation for patients with specified cardiac risk factors
• Clinical surveillance for infection, PML, neurological deterioration and disease activity after stopping

Clinical pharmacology

Siponimod is a selective S1P1/S1P5 receptor modulator. Functional antagonism of lymphocyte S1P1 receptors reversibly sequesters lymphocytes in lymphoid tissue, reducing T-cell recirculation into the central nervous system. It crosses the blood–brain barrier and is metabolised predominantly by polymorphic CYP2C9, with a smaller CYP3A4 contribution.

Formulation and product differences

• Film-coated tablet presentations are colour- and marking-differentiated, and a starter-pack presentation supports gradual initiation.
• All tablet presentations contain lactose monohydrate and soya lecithin and must be swallowed whole.

Tablet

Route: Oral

Strengths: 0.25 mg, 1 mg, 2 mg