Indications for: MAYZENT
Relapsing forms of multiple sclerosis (MS), including clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease.
The efficacy of Mayzent was evaluated in a randomized, double-blind, parallel-group, placebo-controlled, time-to-event study (Study 1) in patients with secondary progressive multiple sclerosis (SPMS) who had evidence of disability progression in the prior 2 years, no evidence of relapse in 3 months prior to study enrollment, and an Expanded Disability Status Scale (EDSS) score of 3.0-6.5 at study entry (NCT 01665144). Patients were randomly assigned to receive either once daily Mayzent 2 mg or placebo, beginning with a dose titration.
The primary endpoint of the study was the time to 3-month confirmed disability progression (CDP), defined as at least a 1- point increase from baseline in EDSS (0.5-point increase for patients with baseline EDSS of 5.5 or higher) sustained for 3 months.
Results showed that treatment with Mayzent was superior to placebo in reducing the risk of confirmed disability progression by 21%, based on a time-to-event analysis (hazard ratio 0.79; P <.0134). Mayzent did not significantly delay the time to 20% deterioration in the timed 25-foot walk, compared to placebo.
Additionally, treated with Mayzent had a 55% relative reduction in annualized relapse rate, compared to patients on placebo (nominal P <.0001). The absolute reduction in the annualized relapse rate was 0.089. Although Mayzent had a significant effect on disability progression compared to placebo in patients with active SPMS (e.g., SPMS patients with an MS relapse in the 2 years prior to the study), the effect of Mayzent in patients with non-active SPMS was not statistically significant.
Determine CYP2C9 genotype before initiation. CYP2C9 genotypes (*1/*1, *1/*2, or *2/*2): initially 0.25mg once daily on Day 1 and Day 2; 0.50mg once daily on Day 3; 0.75mg once daily on Day 4; then 1.25mg once daily on Day 5. Maintenance: 2mg once daily starting on Day 6. CYP2C9 genotypes (*1/*3 or *2/*3): initially 0.25mg once daily on Day 1 and Day 2; 0.50mg once daily on Day 3; then 0.75mg once daily on Day 4. Maintenance: 1mg once daily starting on Day 5. First dose 6hr monitoring for bradycardia, other abnormalities: see full labeling. Re-initiation of therapy after interruption for ≥4 days: start with Day 1 of titration regimen.
CYP2C9 *3/*3 genotype. Recent (within the last 6 months) occurrence of: MI, unstable angina, stroke, TIA, decompensated heart failure requiring hospitalization, Class III/IV heart failure. Presence of Mobitz Type II 2nd degree or 3rd degree AV block or sick sinus syndrome, unless paced.
Increased risk of infections (may be fatal). Obtain recent CBC prior to initiation. Consider suspending therapy if serious infection develops. Active infection: do not start until infection resolved. Test for antibodies to varicella zoster virus; if negative, consider immunization before starting siponimod. Immunosuppressed. Withhold and evaluate if progressive multifocal leukoencephalopathy (PML) suspected. Risk of bradyarrhythmia, AV conduction delays: titration is required for treatment initiation. Obtain ECG prior to initiation to determine if preexisting conduction abnormalities are present. History of cardiac arrest, cerebrovascular disease, uncontrolled hypertension, severe untreated sleep apnea: not recommended; refer to cardiologist if treatment is considered. History of recurrent syncope or symptomatic bradycardia: do benefit/risk assessment; refer to cardiologist if treatment is considered. Monitor BP during treatment. Obtain recent LFTs (within 6 months) prior to initiation. Monitor for hepatic dysfunction; discontinue if significant liver injury is confirmed. History of severe liver disease. Respiratory function: perform spirometric evaluation as needed. Diabetes, history of uveitis: increased risk of macular edema. Increased risk of cutaneous malignancies (basal cell carcinoma, squamous cell carcinoma, melanoma). Perform baseline skin exam prior to or after initiation and periodically thereafter (esp. with risk factors); monitor for suspicious skin lesions and evaluate if observed. Limit exposure to sun and UV light. Do ophthalmic exam at baseline, and if any change in vision during therapy. Monitor for severe increase in disability after treatment discontinuation. Elderly. Pregnancy. Advise females of reproductive potential to use effective contraception during and for 10 days after discontinuation. Nursing mothers.
Sphingosine 1-phosphate receptor modulator.
Concomitant QT prolonging drugs (eg, quinidine, procainamide, amiodarone, sotalol): risk of torsades de pointes. Concomitant β-blockers, digoxin, ivabradine, diltiazem, verapamil during initiation may be associated with severe bradycardia or heart block. Avoid live attenuated vaccines during and for 4 weeks after discontinuing therapy; may have suboptimal response. Concomitant antineoplastic, immunosuppressant or immune-modulating therapies may increase risk of immunosuppression; use caution when switching from long-acting immunotherapies; caution for 3–4 weeks after discontinuing siponimod. Initiation after treatment with alemtuzumab: not recommended. Concomitant moderate CYP2C9 and moderate or strong CYP3A4 inhibitors: not recommended; caution with concomitant moderate CYP2C9 inhibitors. Concomitant moderate CYP2C9 and strong CYP3A4 inducers: not recommended; caution with moderate CYP2C9 inducers. For CYP2C9 *1/*3 and *2/*3 genotypes: concomitant moderate (eg, modafinil, efavirenz) or strong CYP3A4 inducers: not recommended. Concomitant phototherapy with UV-B radiation or PUVA-photochemotherapy: not recommended.
Headache, hypertension, transaminase increased, falls, edema peripheral, nausea, dizziness, diarrhea, bradycardia, pain in extremity; macular edema, decreased pulmonary function; rare: posterior reversible encephalopathy syndrome (discontinue if suspected).
The apparent elimination half-life is approximately 30 hours. Siponimod is eliminated from the systemic circulation mainly due to metabolism, and subsequent biliary/fecal excretion. Unchanged siponimod was not detected in urine.
Generic Drug Availability:
Starter Packs (0.25mg)—7, 12; Tabs (0.25mg)—28; (1mg, 2mg)—30