Siponimod

FDA label

Read the full label on DailyMed ↗

Titration Mandatory initiation titration: Day 1 0.25 mg, Day 2 0.25 mg, Day 3 0.5 mg, Day 4 0.75 mg (then Day 5 1.25 mg for the 2-mg regimen); if any titration dose is missed >24 h, restart from Day 1

Renal Undefined

Hepatic No specific dose adjustment stated; obtain transaminases/bilirubin (within 6 months) before initiation and closely monitor patients with severe hepatic impairment

Interruption of ≥4 consecutive daily doses after initial titration → reinitiate from Day 1 titration, repeating first-dose monitoring where recommended

Instructions

• Before first dose: CYP2C9 genotype (required), ECG, recent CBC, LFTs, baseline fundus/macula exam, skin exam, VZV antibody test (vaccinate seronegative patients before starting), review immunosuppressant history
• Administer tablets whole; do not split, crush, or chew
• First-dose 6-hour monitoring (hourly pulse/BP, ECG at end) if sinus bradycardia (HR <55 bpm), first- or second-degree Mobitz I AV block, or history of MI or heart failure; extend monitoring for HR <45 bpm, nadir at 6 h, or new AV block
• Cardiologist consultation before use with QT-prolonging or heart-rate-slowing drugs or in preexisting cardiac/cerebrovascular disease

Contraindications

• CYP2C9*3/*3 genotype (substantially elevated siponimod levels)
• In the last 6 months: MI, unstable angina, stroke, TIA, decompensated heart failure requiring hospitalization, or Class III/IV heart failure
• Mobitz type II second-degree or third-degree AV block, or sick sinus syndrome, unless a functioning pacemaker is present

Cautions

• Infections (herpes zoster/VZV meningoencephalitis, cryptococcal meningitis, fatal cases) — CBC before starting; delay start in active infection; vigilance continues 3–4 wk after stopping
• Progressive multifocal leukoencephalopathy — withhold at first sign/symptom
• Macular edema — baseline and periodic fundus exams; diabetes and uveitis increase risk
• Bradyarrhythmia/AV conduction delays — transient HR decrease at initiation; titration required; caution with beta-blockers and other HR-lowering drugs
• Decline in pulmonary function — spirometry if clinically indicated
• Liver injury — LFTs before initiation; discontinue if significant injury
• Cutaneous malignancies — baseline and periodic skin exams
• Increased blood pressure — monitor during treatment
• Fetal risk — effective contraception during and 10 days after stopping
• Posterior reversible encephalopathy syndrome
• Additive immunosuppression with prior/concomitant immune therapies
• Severe increase in disability after stopping; immune effects persist 3–4 weeks after discontinuation

Adverse reactions

• Most common (>10%): headache, hypertension, transaminase increases
• Also more common than placebo: herpes zoster/herpes infections, bradycardia at initiation, macular edema, lymphopenia (dose-dependent reduction to 20–30% of baseline)

Pregnancy Can cause fetal harm (embryotoxicity/teratogenicity in rats and rabbits at ≥2× human exposure); effective contraception during and 10 days after stopping; pregnancy safety study — report exposures to Novartis

Lactation No human data; rat milk excretion shown — weigh benefits of breastfeeding against risk to infant