Different Doses of Fingolimod in Relapsing-Remitting Multiple Sclerosis: A Systematic Review and Meta-Analysis of Randomized Controlled Trials

Abstract

Background: The efficacy and safety of fingolimod for relapsing-remitting multiple sclerosis (RRMS) had been well verified in several large randomized controlled trials (RCTs) during the past decade. However, there are fewer systematic comparisons of different doses of fingolimod and whether the dose of 0.5 mg/d is the optimal one still remains to be solved.Objective: The objective of this systematic review was to evaluate the efficacy and safety of the four existing doses of fingolimod in the treatment of RRMS, especially the dose of 0.5 mg/d.Methods: MEDLINE, EMBASE, Cochrane Library, and clinicaltrials.gov were searched for RCTs which were performed to evaluate different doses of fingolimod and the corresponding control (placebo or DMTs) up to October 2020. Review Manager 5.3 software was used to assess the data. The risk ratio (RR) and mean difference (MD) was analyzed and calculated with a random effect model.Results: We pooled 7184 patients from 11 RCTs. Fingolimod 0.5 mg/d was superior to control group in all eight efficacy outcomes including annualized relapse rate (ARR) (MD −0.22, 95%CI −0.29 to −0.14, p < 0.00001) but surprisingly showed a higher risk of basal-cell carcinoma (RR 4.40, 95%CI 1.58 to 12.24, p = 0.004). Although 1.25 mg/d is more than twice the dose of 0.5 mg/d, the effect size was almost similar between them. Dose of 5 mg/d obtained an unsatisfactory efficacy while showing a greater risk of adverse events than other three doses (RR 1.17, 95%CI 1.05 to 1.30, p = 0.003). Additionally, fingolimod 0.25 mg/d not only showed a better performance in delaying the disease progress of magnetic resonance imaging (MRI), but also achieved a certain degree of patient treatment satisfaction.Conclusion: At present, 0.5 mg/d remains to be the optimal dose of fingolimod for RRMS patients but trials of a lower dose are still of great clinical significance and should be paid more attentions.

Risk for Cardiovascular Adverse Events Associated With Sphingosine-1-Phosphate Receptor Modulators in Patients With Multiple Sclerosis: Insights From a Pooled Analysis of 15 Randomised Controlled Trials

“…Our stratified analyses demonstrated that S1PRMs did not have dose-dependent effects. One meta-analysis ( 46 ) published in 2021 that evaluated the efficacy and safety of different doses of fingolimod by examining 11 RCTs found that fingolimod 0.5 mg/d showed a significantly higher risk for overall AEs (RR, 1.25; 95% CI, 1.01–1.54), but no significant difference was found between the 0.5 mg/d fingolimod group and the control treatment group in serious AEs including bradycardia (RR, 2.97; 95% CI, 0.75–11.72) and atrioventricular block (RR, 2.03; 95% CI, 0.45–9.25). In our study, regardless of AE severity, fingolimod 0.5 mg/d and 1.25 mg/d were associated with a significant high risk for bradyarrhythmia consisting of bradycardia and atrioventricular block without a statistically significant difference (P interaction = 0.360).…”

Cost-effectiveness analysis of rituximab versus natalizumab in patients with relapsing remitting multiple sclerosis

“…The DNMC included the costs of traveling to other cities and accommodation as well as the meals consumed by the patient and his/ her family, and the nursing home care expenses determined by asking the patients. The human capital approach was used for IC calculation [ 48 – 50 ].…”

Immunomodulatory drug fingolimod (FTY720) restricts the growth of opportunistic yeast Candida albicans in vitro and in a mouse candidiasis model

“…Administration of FTY720 at 1.25 mg/day in healthy adults–above which has proved unbeneficial for people with MS [ 7 ]–results in a maximum blood concentration (C max ) of 10.2 (±2.7) ng/mL at steady-state [ 9 ]; this concentration is 25000 times lower than its MIC 99 for C . albicans .…”

“…While being associated with beneficial outcomes and reasonable tolerability among people with immune-mediated conditions such as MS [ 5 , 6 ], safety and toxicity studies have shown both dose-dependent and time-dependent adverse effects associated with FTY720 [ 7 ]. The time-dependent adverse effects have been opportunistic infections, reactivation of latent viruses, malignancies, etc.…”

“…The time-dependent adverse effects have been opportunistic infections, reactivation of latent viruses, malignancies, etc. ; these are mostly deemed to be due to chronic immunosuppression [ 7 ]. Among the dose-dependent adverse effects, the most common has been cardiotoxicity [ 5 , 6 ].…”