Neurological safety of fingolimod: An updated review

Abstract

Fingolimod (FTY) is the first oral medication approved for treatment of relapsing–remitting multiple sclerosis (RRMS). Its effectiveness and safety were confirmed in several phase III clinical trials, but proper evaluation of safety in the real patient population requires long‐term post‐marketing monitoring. Since the approval of FTY for RRMS in Japan in 2011, it has been administered to approximately 5000 MS patients, and there have been side‐effect reports from 1750 patients. Major events included infectious diseases, hepatobiliary disorders, nervous system disorders and cardiac disorders. In the present review, we focus especially on central nervous system adverse events. The topics covered are: (i) clinical utility of FTY; (ii) safety profile; (iii) post‐marketing adverse events in Japan; (iv) white matter (tumefactive) lesions; (v) rebound after FTY withdrawal; (vi) relationship between FTY and progressive multifocal leukoencephalopathy; (vii) FTY and progressive multifocal leukoencephalopathy‐related immune reconstitution inflammatory syndrome; and (viii) neuromyelitis optica and leukoencephalopathy.

Fingolimod Rebound: A Review of the Clinical Experience and Management Considerations

“…When they occur, the timing of severe relapses after stopping fingolimod appears somewhat predictable, with events occurring approximately within 2-4 months after stopping fingolimod [47]. A review of the initial case reports noted that the relapses occurred between 4 and 16 weeks after stopping fingolimod [42].…”

Clinical effectiveness and safety of fingolimod in relapsing remitting multiple sclerosis in Western Iran

“…A heightened risk of infections secondary to reduced circulating lymphocytes by fingolimod also occurs. 1 According to previous pivotal clinical trials comparing fingolimod with a placebo 4 or intramuscular interferon, 5 fingolimod had superior efficacy in the annual relapse rate and produced brain magnetic resonance imaging outcomes with generally mild and tolerable side effects. The drug was approved by Food and Drug Administration )FDA( as a first-line DMD and by European Medicines Agency )EMA( as a second-line DMD.…”

Severe rebound relapse of multiple sclerosis after switching from fingolimod to dimethyl fumarate

“…As DMF has shown a better risk–benefit profile than fingolimod and equivalent efficacy, the number of cases where fingolimod is switched to another disease‐modifying drug (DMD) has gradually been increasing. Recent reports have highlighted the possible risk of rebound disease activity after withdrawal of fingolimod, but the consequence of switching to DMF remains unclear . Here, we report a case of relapsing–remitting MS with severe rebound after fingolimod was switched to DMF.…”

“…Fingolimod exerts an immunosuppressive effect by sequestering lymphocytes into lymph nodes through sphingosine‐1‐phosphate receptor signaling . As a result, lymphopenia and infection are the major adverse effects of fingolimod . Meanwhile, DMF acts by affecting hydroxycarboxylic acid receptor 2 signaling, which results in immunomodulatory effects without significant immunosuppression, and confers cytoprotective effects through the nuclear factor erythroid 2‐related factor 2 pathway .…”

“…Additionally, DMF has shown equivalent therapeutic efficacy as fingolimod, thereby increasing the number of relapsing–remitting MS cases in which fingolimod is switched to DMF . In contrast, cases of severe MS rebound after fingolimod withdrawal have recently been reported . A recent study also reported that 10 of 19 Japanese MS patients who switched fingolimod to DMF showed clinical or radiological exacerbation, and three of these 10 patients developed multifocal tumefactive lesions .…”