Siponimod

Indications

Siponimod is used for: Multiple Sclerosis

Adult Dose

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 atients 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 Hepatic impairment No dosage adjustment necessary Increased unbound siponimod AUC observed with moderate and severe hepatic impairment is not expected to be clinically significant

Child Dose

Renal Dose

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

Administration

Administer with or without food

Contra Indications

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

Precautions

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

Pregnancy-Lactation

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

Interactions

Adverse Effects

Side effects of Siponimod : >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%)

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