Introduction
Mayzent (siponimod) is an oral sphingosine-1-phosphate (S1P) receptor modulator approved by the FDA in 2019 for the treatment of relapsing forms of multiple sclerosis (MS), including clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease. It represents a significant advancement in MS therapy, particularly for patients with secondary progressive MS who have active disease.
Mechanism of Action
Siponimod acts as a sphingosine-1-phosphate receptor modulator that binds with high affinity to S1P receptors 1 and 5. The drug prevents lymphocytes from egressing lymph nodes, reducing the number of peripheral lymphocytes available to migrate into the central nervous system. This mechanism limits the inflammatory damage to neurons and helps preserve neurological function. Unlike some other S1P receptor modulators, siponimod does not require phosphorylation for activation.
Indications
- Treatment of relapsing forms of multiple sclerosis in adults, including clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease
- Reduction in frequency of clinical exacerbations
- Delay in accumulation of physical disability
Dosage and Administration
Initial titration: 0.25 mg once daily on days 1 and 2; 0.5 mg once daily on day 3; 0.75 mg once daily on day 4; 1.25 mg once daily on day 5 Maintenance dose: 2 mg once daily starting on day 6 Special populations:- CYP2C91/3 or 2/3 genotypes: Maximum dose 1 mg daily
- CYP2C93/3 genotype: Contraindicated
- Hepatic impairment (Child-Pugh B): Maximum dose 1 mg daily
- Severe hepatic impairment (Child-Pugh C): Not recommended
- Renal impairment: No dosage adjustment necessary
Pharmacokinetics
Absorption: Rapidly absorbed with Tmax of 4 hours; bioavailability approximately 84% Distribution: Volume of distribution 124 L; >99.9% protein bound Metabolism: Primarily via CYP2C9 and to a lesser extent CYP3A4 Elimination: Half-life approximately 30 hours; excreted primarily in feces (61%) and urine (30%)Contraindications
- Patients with CYP2C93/3 genotype
- Recent (within 6 months) myocardial infarction, unstable angina, stroke, TIA, or decompensated heart failure requiring hospitalization
- Presence of Mobitz type II second-degree or third-degree AV block or sick sinus syndrome without pacemaker
- Severe untreated sleep apnea
- Hypersensitivity to siponimod or any component
Warnings and Precautions
Cardiac effects: May cause bradycardia and AV conduction delays. Requires first-dose monitoring for patients with certain cardiac conditions Infections: Increased risk of infections including herpes zoster, cryptococcal infections, and PML Macular edema: Regular ophthalmologic evaluations recommended Liver injury: Monitor liver enzymes before treatment and periodically during therapy Fetal risk: Women of childbearing potential should use effective contraception Respiratory effects: May cause decreased pulmonary function Hypertension: Monitor blood pressure during treatment Cutaneous malignancies: Regular skin examinations recommendedDrug Interactions
Strong CYP2C9 inhibitors: Contraindicated (e.g., gemfibrozil) Moderate CYP2C9 inhibitors: Use with caution (e.g., fluconazole) Immunosuppressants: Increased risk of additive immunosuppression Live vaccines: Avoid concurrent administration Beta-blockers: May potentiate bradycardia Class Ia/III antiarrhythmics: Increased risk of torsades de pointes QT-prolonging drugs: Use with cautionAdverse Effects
Common (≥10%): Headache (15%), hypertension (13%), transaminase increased (11%) Less common (1-10%): Bradycardia, macular edema, infections, dizziness, diarrhea, peripheral edema Serious: Infections (including herpes zoster and cryptococcal meningitis), progressive multifocal leukoencephalopathy, AV block, bradycardia, liver injury, macular edema, respiratory effects, cutaneous malignanciesMonitoring Parameters
- CYP2C9 genotype testing before initiation
- ECG and blood pressure monitoring during first-dose observation
- Complete blood count with differential
- Liver function tests (baseline and periodically)
- Ophthalmologic evaluation (baseline and at 3-4 months after initiation)
- Skin examination for suspicious lesions
- Signs and symptoms of infection
- Pulmonary function tests if respiratory symptoms develop
- Neurological status regularly
Patient Education
- Report any signs of infection (fever, cough, unusual fatigue) immediately
- Notify healthcare provider of heart rate <50 bpm, dizziness, or fatigue
- Report visual changes promptly
- Use effective contraception during treatment and for 10 days after discontinuation
- Avoid live vaccines during and for 4 weeks after treatment
- Regular skin self-examinations and professional skin checks
- Carry identification indicating MS treatment with Mayzent
- Do not stop medication abruptly without medical supervision
- Inform all healthcare providers about Mayzent therapy before any new treatments
References
1. Kappos L, Bar-Or A, Cree BAC, et al. Siponimod versus placebo in secondary progressive multiple sclerosis (EXPAND): a double-blind, randomised, phase 3 study. Lancet. 2018;391(10127):1263-1273. 2. Mayzent [package insert]. East Hanover, NJ: Novartis Pharmaceuticals Corporation; 2021. 3. Gergely P, Nuesslein-Hildesheim B, Guerini D, et al. The selective sphingosine 1-phosphate receptor modulator BAF312 redirects lymphocyte distribution and has species-specific effects on heart rate. Br J Pharmacol. 2012;167(5):1035-1047. 4. Scott FL, Clemons B, Brooks J, et al. Ozanimod (RPC1063) is a potent sphingosine-1-phosphate receptor-1 (S1P1) and receptor-5 (S1P5) agonist with autoimmune disease-modifying activity. Br J Pharmacol. 2016;173(11):1778-1792. 5. US Food and Drug Administration. FDA approves new oral drug to treat multiple sclerosis. March 2019. 6. National Multiple Sclerosis Society. Medications. Accessed January 2023.