Adult: In patients with genotype CYP2C9 *1/*1, *1/*2, or *2/*2: Initial dosage titration: 0.25 mg on days 1 and 2, 0.5 mg on day 3, 0.75 mg on day 4, and 1.25 mg on day 5. Maintenance: 2 mg beginning on day 6. In patients with genotype CYP2C9 *1/*3, *2/*3: Initial dosage titration: 0.25 mg on days 1 and 2, 0.5 mg on day 3, and 0.75 mg on day 4. Maintenance: 1 mg beginning on day 5. Alternatively, 1.25 mg may be given on day 5 (additional exposure of 0.25 mg does not impair patient safety) and maintenance doses begin on day 6. All doses are to be given once daily in the morning. Dosage recommendations may vary between countries (refer to detailed product guideline).
Administration
tab: May be taken with or without food.
Contraindications
CYP2C9 *3/*3 genotype. Recent MI, unstable angina, stroke, TIA, decompensated heart failure requiring hospitalisation, New York Heart Associated (NYHA) Class III or IV heart failure; History of Mobitz type II 2nd degree, 3rd degree atrioventricular (AV) block, sick sinus syndrome (except in patients with a pacemaker); severe active infections, cryptococcal meningitis, history of PML, active malignancy. Immunocompromised patients due to treatment (e.g. antineoplastic therapy, bone marrow transplantation), immunodeficiency syndrome. Pregnancy. Administration of live-attenuated vaccine.
Special Precautions
Patient with history of diabetes mellitus, uveitis, or underlying retinal disease; no confirmed history of varicella or no documentation of full course vaccination against varicella zoster virus; significant QT prolongation, arrhythmias requiring treatment, ischaemic heart disease, heart failure, history of cardiac arrest or MI, cerebrovascular disease, uncontrolled hypertension, history of 2nd degree Mobitz type II or higher AV block, sick-sinus syndrome, or sino-atrial heart block; history of symptomatic bradycardia or recurrent syncope, severe untreated sleep apnoea; mild to moderate asthma and chronic obstructive pulmonary disease; risk factors for skin cancer. Hepatic impairment. Lactation.
Adverse Reactions
Significant: AV conduction delays, including 1st degree AV block and 2nd degree AV block (Mobitz type I), bradycardia (primarily during treatment initiation), hepatic enzyme elevation, hypertension, macular oedema, malignancy (e.g. basal cell carcinoma, melanoma, squamous cell carcinoma, lymphoma), posterior reversible encephalopathy syndrome (PRES), progressive multifocal leukoencepalopathy (PML), QT prolongation, reduced forced expiratory volume (in the first second of expiration [FEV1]), rebound syndrome. Blood and lymphatic system disorders: Lymphopenia. Gastrointestinal disorders: Diarrhoea, nausea. General disorders and administration site conditions: Asthenia, peripheral oedema. Investigations: Increased serum alanine aminotransferase, serum aspartate aminotransferase, and serum bilirubin; decreased pulmonary function test. Musculoskeletal and connective tissue disorders: Limb pain. Nervous system disorders: Headache, dizziness, seizure, tremor. Potentially Fatal: Rarely, serious infections (e.g. cryptococcal meningitis, herpes viral infection, varicella zoster virus reactivation).
Patient Counseling Information
This drug may cause dizziness, primarily during treatment initiation; if affected, do not drive or operate machinery. Avoid exposure to sunlight, UV light, and phototherapy. Wear protective clothing and use high SPF sunscreen.
Monitoring Parameters
Determine CYP2C9 genotype before treatment initiation. Screen for latent infections (e.g. hepatitis, tuberculosis) prior to initiation of treatment; test for varicella zoster virus (VZV) antibodies if history of chickenpox or VZV vaccination status is unknown. Obtain LFT at baseline, then monitor in patients who develop symptoms of hepatic dysfunction. Monitor CBC including lymphocyte count at baseline. Monitor blood pressure during therapy; signs and symptoms of infection, PRES, PML. Obtain ECG at baseline; monitor overnight in patients with active and risk factors for QT prolongation (e.g. concomitant QT-prolonging drugs, drugs that reduce heart rate or AV conduction, pre-existing CV and cerebrovascular disease). Perform ophthalmological examination at baseline and if vision changes occur. Monitor for severe increase in disability following treatment discontinuation. Perform 1st-dose 6-hour monitoring in patients with sinus bradycardia, history of 1st or 2nd degree AV block, MI or heart failure, and monitor for signs and symptoms of bradycardia; assess heart rate, and blood pressure every 1 hour; repeat ECG after 6-hour monitoring. Repeat ECG, heart rate, and blood pressure monitoring for treatment interruption of 24 hours during initial titration regimen, or treatment interruption ≥4 consecutive days during the maintenance period.
Overdosage
Symptoms: Bradycardia. Management: Symptomatic treatment. May give atropine or isoprenaline to reverse decrease in heart rate. Monitor pulse rate, blood pressure, and ECG.
Drug Interactions
May increase the risk of infection with live-attenuated vaccines. Decreased serum concentration with carbamazepine. Additive immune effect with antineoplastics, immune-modulating, and immunosuppressive agents. Potential addictive effect on lowering heart rate with Class Ia (e.g. quinidine, procainamide), Class III (e.g. amiodarone, sotatol) antiarrhythmic agents, β-blockers (e.g. propranolol), heart-rate-lowering Ca channel blockers (e.g. verapamil, diltiazem), ivabradine, digoxin. Increased exposure with CYP2C9 and CYP3A4 inhibitors (e.g fluconazole). Decreased exposure with CYP2C9 (e.g. carbamazepine), and CYP3A4 inducers (e.g. modafinil).
Lab Interference
Siponimod causes a decrease in blood lymphocyte counts, thus peripheral blood lymphocyte counts cannot be used to evaluate the lymphocyte subset status of a patient.
Action
Description: Siponimod a sphingosine-1-phosphate (S1P) receptor modulator, binds to S1P receptor 1 and 5 thereby blocking the movement of lymphocytes out of lymph nodes. This decreases the amount of lymphocyte available to the CNS leading to reduced central inflammation. Pharmacokinetics: Absorption: Extensively absorbed from gastrointestinal tract. Bioavailability. Approx 84%. Time to peak plasma concentration: Approx 4 hours (range 2-12 hours). Distribution: Widely distributed in the body. Crosses blood-brain barrier. Volume of distribution: 124 L. Plasma protein binding: >99%. Metabolism: Extensively metabolised in the liver by CYP2C9 and CYP3A4 enzymes into inactive metabolites, M3 and M17. Excretion: Via bile and faeces as inactive metabolites. Elimination half-life: Approx 30 hours.
Chemical Structure
Siponimod Source: National Center for Biotechnology Information. PubChem Compound Summary for CID 44599207, Siponimod. https://pubchem.ncbi.nlm.nih.gov/compound/Siponimod. Accessed Sept. 27, 2021.
Storage
Unopened bottles/containers: Store between 2-8°C. Opened bottles/containers or starter pack/blister card: Store between 20-25°C. Do not refrigerate. Storage recommendation may vary among countries (refer to specific product guidelines).
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