What is the recommended treatment and dosage of Mayzent (siponimod) for secondary progressive multiple sclerosis (SPMS)?

Mayzent (Siponimod) for Secondary Progressive Multiple Sclerosis

Recommended Treatment and Dosage

Mayzent (siponimod) is indicated for adults with active secondary progressive MS at a maintenance dose of 2 mg once daily (or 1 mg for specific CYP2C9 genotypes), following mandatory dose titration over 6 days. 1

Specific Indication Requirements

• Active disease is required: Treatment is approved specifically for SPMS patients with evidence of relapses or MRI features of inflammatory activity 1, 2
• The FDA indication covers relapsing forms of MS including clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease 1
• European approval is more restrictive, requiring documented active disease 2

Dosing Protocol

Initial Titration (Mandatory)

• All patients must undergo 6-day dose titration before reaching maintenance dose 1
• Titration schedule starts at 0.25 mg and increases gradually to the target maintenance dose 1
• Tablets must be swallowed whole; do not split, crush, or chew 1

Maintenance Dosing

• Standard maintenance dose: 2 mg once daily for most patients 1, 3
• Reduced maintenance dose: 1 mg once daily for patients with CYP2C9*1/*3 or *2/*3 genotype 1
• Contraindicated in patients with CYP2C9*3/*3 genotype 1

Pre-Treatment Requirements

Mandatory Assessments Before Initiation

• CYP2C9 genotyping to determine appropriate dosing and identify contraindications 1
• Complete blood count (CBC) to assess baseline lymphocyte levels 1
• Liver enzyme testing before treatment initiation 1
• Ophthalmologic evaluation including fundus and macula examination 1
• Cardiac evaluation for patients with specific risk factors (see below) 1

Cardiac Monitoring Requirements

First-dose monitoring is recommended for patients with: 1

• Sinus bradycardia
• First-degree or second-degree (Mobitz type I) atrioventricular block
• History of myocardial infarction or heart failure

Absolute cardiac contraindications include: 1

• Myocardial infarction, unstable angina, stroke, TIA, or decompensated heart failure requiring hospitalization in the last 6 months
• Class III/IV heart failure
• Mobitz type II second-degree AV block, third-degree AV block, or sick sinus syndrome (unless patient has functioning pacemaker)

Clinical Efficacy Data

Disability Progression Outcomes

• 21% relative risk reduction in 3-month confirmed disability progression versus placebo (HR 0.79,95% CI 0.65-0.95; p=0.013) 3
• Benefits observed across age subgroups, with 31-38% risk reduction in 3-month CDP and 27-43% risk reduction in 6-month CDP in active SPMS patients 4
• Efficacy maintained during up to 5 years of treatment in open-label extension studies 2

Patient Population in Pivotal Trial

• Mean time since first MS symptoms: 16.8 years 3
• Mean time since conversion to SPMS: 3.8 years 3
• 64% had not relapsed in previous 2 years, but all had active disease features 3
• 56% required walking assistance at baseline 3

Safety Profile and Monitoring

Common Adverse Events (>10% incidence)

• Headache 1
• Hypertension 1
• Transaminase increases 1

Adverse Events of Special Interest

Cardiovascular effects: 1, 3

• Transient decrease in heart rate at treatment initiation (mitigated by dose titration)
• Bradycardia and bradyarrhythmia
• Mean increase of 2.47 bpm at 6 hours post-first dose in most patients 5

Infectious complications: 1, 3

• Increased infection risk due to lymphopenia
• Varicella zoster reactivation
• No increased risk of progressive multifocal leukoencephalopathy (PML) observed, but withhold at first sign 1

Ophthalmologic: 1

• Macular edema (higher risk in patients with diabetes mellitus or uveitis)
• Requires baseline and periodic fundus examinations

Hepatic: 1, 3

• Increased liver transaminases
• Monitor liver enzymes; discontinue if significant liver injury occurs

Other: 1, 3

• Lymphopenia
• Hypertension (monitor blood pressure during treatment)
• Cutaneous malignancies (perform skin examinations)
• Convulsions

Ongoing Monitoring Requirements

• Blood pressure monitoring throughout treatment 1
• Periodic ophthalmologic examinations and any time vision changes occur 1
• Pulmonary function assessment if clinically indicated 1
• Skin examinations prior to or shortly after treatment start and periodically thereafter 1

Drug Interactions and Contraindications

Vaccination Considerations

• Avoid live-attenuated vaccines during treatment and for up to 4 weeks after stopping siponimod 1
• Complete age-appropriate immunizations at least 4 weeks before treatment initiation 1

CYP Inhibitor Interactions

• Concomitant use with moderate CYP2C9 and moderate or strong CYP3A4 inhibitors is not recommended due to increased siponimod exposure 1

Cardiac Drug Interactions

• Obtain cardiology consultation before concomitant use with other drugs that decrease heart rate (e.g., beta-blockers) 1

Switching from Other DMTs

• Conversion from other disease-modifying therapies was generally well tolerated in the EXCHANGE study 5
• Patients switching from fingolimod (another S1P modulator) may transition immediately to siponimod maintenance dose without dose titration and without effects on heart rate 5
• For other DMTs, follow standard 6-day titration protocol 5

Pregnancy and Contraception

• Women of childbearing potential must use effective contraception during treatment and for 10 days after stopping Mayzent 1
• Siponimod poses fetal risk 1

Treatment Duration

• Median treatment duration in pivotal trial was 18 months 2
• Safety and efficacy data available for up to 5 years of continuous treatment 2
• Treatment should continue as long as clinical benefit is observed and tolerability is maintained 2