Safety of fingolimod in patients with relapsing remitting multiple sclerosis: A descriptive analysis of data from the EudraVigilance database

The most prevalent disease course of Multiple Sclerosis (MS) is relapsing remitting multiple sclerosis (RRMS). Fingolimod ( Gilenya ® ) was the first oral disease-modifying therapy to RRMS. Patients affected by MS require long-term treatment, making the ongoing evaluation of the safety profile of fingolimod imperative. The aim of this study was to analyze the post-marketing pharmacovigilance data of fingolimod in Europe. Data of 12-year period (1 January 2011 – 19 June 2023) were obtained from EudraVigilance, and a descriptive analysis using drug-reaction pairs was performed. A total of 22,957 reports were collected. The most reported adverse events (AEs) were related to nervous system disorders SOC ( multiple sclerosis relapse n = 2271; 3.51%, headache n = 921; 1.42%, central nervous system lesion n = 893; 1,38%, dizziness 769; 1,19%, hypoaesthesia 487; 0.75% and multiple sclerosis 449; 0.69%), followed by investigations ( lymphocyte count decreased n = 1648; 2.55%, white blood cell count decreased n = 833; 1.29%), blood and lymphatic system disorder ( lymphopenia n = 1146; 1.77%), and general disorders and administration site condition ( fatigue n = 1106; 1.71%, gait disturbance 564; 0.87%). A percentage of 23.00% of serious adverse events (SAEs), among the most reported were multiple sclerosis relapse ( n = 2271; 15.27%), macular oedema ( n = 793; 5.33%), bradycardia ( n = 678; 4.56%), leukopenia ( n = 533; 3.58%), and multiple sclerosis ( n = 449; 3.02%). Most of AEs were non-serious, some SAEs related to cardiac, ophthalmic and infectious disorders emerged: their prevalence, along with the alignment of reported AEs with existing literature, supports the overall safety of fingolimod. Considering the rare and long-term ADRs that may arise in patients chronically treated for MS, continuous pharmacovigilance remains essential.


Introduction
Multiple sclerosis (MS) is a chronic inflammatory demyelinating and neurodegenerative disorder of the central nervous system (CNS) [1].According to the Atlas of MS, the most extensive worldwide study of the epidemiology of MS, it is estimated that >2.9 million individuals are affected by MS globally.>1 million (1.188.216) of them are living in the European countries, where 1 in every 700 people is affected by MS [2].The disease affects woman 3 times more than men, suggesting that different aspects are likely to be influencing it such as hormonal [3] and genetic [4].Most people are diagnosed between the ages of 20 and 50, although MS can occur in young children and older adults [2].
The most prevalent disease course in multiple sclerosis is relapsing remitting multiple sclerosis (RRMS), affecting roughly 85% of patients with MS and characterized by episodes of new or worsening neurological symptoms [5].Among these, the most common early symptoms include trouble seeing, sensitivity to heat, numbness, especially in the feet, weakness, fatigue, difficulty thinking clearly, depression, needing to urinate urgently, trouble with balance, and lack of coordination.However, the symptoms and the course of MS can vary significantly Abbreviations: ADR, Adverse Drug Reaction; CHMP, The Committee for Medicinal Products for Human Use; CNS, Central Nervous System; DMT, Diseasemodifying therapy; EEA, European Economic Area; EMA, European Medicines Agency; EU, European Union; EV, EudraVigilance; FDA, United States Food and Drug Administration agency; HR, Heart Rate; ICSR, Individual Case Safety Report; MedDRA, Medical Dictionary for Regulatory Activities; MS, Multiple Sclerosis; PRAC, The Pharmacovigilance Risk Assessment Committee; PT, Preferred Term; RRMS, Relapsing-Remittent Multiple Sclerosis; SAE, Serious Adverse Event; SOC, System Organ Class; SPC or SmPC, Summary of the Product Characteristic.from person to person.These relapses are followed by periods of partial or complete recovery.
There are several disease-modifying therapies (DMTs) with different mechanisms of action available for RRMS.They do not provide a cure for MS, but they can decrease the frequency and severity of relapses experienced by patients.
The advent of fingolimod (Gilenya®) was a new therapeutic approach to RRMS.Fingolimod is the first oral DMT for RRMS approved by US Food and Drug Administration (FDA) in September 2010 and by European Medicine Agency (EMA) in March 2011.It acts as a sphingosine 1-phosphate receptor modulator, exerting its therapeutic effects by blocking the capacity of lymphocytes to egress from lymph nodes, causing a redistribution, rather than depletion, of lymphocytes [6].The drug's safety and efficacy in reducing relapse rates and delaying disability progression has been well-documented from three large, randomized, double-blind, multicenter, pivotal Phase III clinical trials and their extensions, earning it a prominent position in the armamentarium against MS [7][8][9][10][11][12][13][14].However, given the chronic use of the drug, these studies anyway have a limited duration.Patients affected by MS require long-term treatment, making the ongoing evaluation of the safety profile of DMTs imperative.In this regard, pharmacovigilance plays a vital role in identifying and assessing potential adverse events associated with the use of fingolimod in a real-world setting.
Therefore, the aim of this study was to analyze the post-marketing pharmacovigilance data of fingolimod in Europe.Our findings contribute to the existing knowledge about fingolimod's safety, supporting healthcare professionals in making informed decisions and optimizing patient care in the treatment of MS.

Materials and methods
In this retrospective observational study data were obtained from EudraVigilance (EV), the European Union's post-marketing surveillance database, using the online interface adrreports.eu[15].EV is a public spontaneous reporting system maintained by the European Medicines Agency on behalf of the European Union (EU), which receives Individual Case Safety Reports (ICSRs) concerning suspected adverse drug reactions within the European Economic Area (EEA) [16].
We performed our analysis on 12-year period, between 1st of January 2011 and 19th of June 2023.We retrieved all reports related to fingolimod reported as suspected drug.
The reports extracted were distinguished by a unique EU Local Number.These reports were all spontaneous and contained information on the, primary source qualification (healthcare professional or nonhealthcare professional), EV gateway receipt date, patient sex (female, male, or not specified) and age group p (0-1 month, 2 months to 2 years, 3-11 years, 12-17 years, 18-64 years, 65-85 years, >85 years, or not specified), MedDRA preferred terms (PT), seriousness criteria, and suspect and concomitant drugs.To facilitate global regulatory information sharing for human medical products, all adverse drug reactions (ADRs) are classified using a specific standardized medical terminology -the Medical Dictionary for Regulatory Activities (MedDRA).MedDRA employs a structured five-tiered multi-axial hierarchy, offering increasing levels of specificity as one descends it.At the highest level of hierarchy there are 27 System Organ Classes (SOC).These SOCs incorporate High Level Group Terms (HLGTs) and High Level Terms (HLTs) at the lower levels.Moving down the hierarchy, there are Preferred Terms (PTs), each member of this level is a distinct descriptor (single medical concept) for a symptom, sign, disease diagnosis, therapeutic indication, investigation, surgical or medical procedure, and medical social or family history characteristic.Lastly, one or more Lower Level Terms (LLTs) correspond to each PT; the LLTs are effectively entry terms that include synonyms and lexical variants [17].One or more symptoms can be reported for each EV report.We analyzed all the reports related to the fingolimod (Gilenya®) performing a descriptive analysis using drugreaction pairs, meaning that each individual report may include, for instance, one suspected drug and three distinct adverse events, resulting in the generation of three drug-event pairs.In the event of two suspected drugs, six drug-event pairs are generated, and so forth.The notoriety of the suspected adverse drug reactions was ascertained by checking if the most frequently reported ADRs were listed in the corresponding Summary of the Product Characteristics (SPC) [6].An adverse event (AE) was categorized as serious based on EudraVigilance Important Medical Event (IME) term list (MedDRA version 26.1) [18].
The manuscript does not contain clinical studies or patient data.For this type of study, ethics committee approval and formal consent are not required.

Results
A total of 22,979 ICSRs were collected: 22,957 reports (99.9%)referred to the branded product (Gilenya®) and a tiny portion of reports (0.09%) were related to generic fingolimods (22 to Fingolimod Mylan and 3 to Fingolimod Accord).Date of issue of marketing authorization valid throughout the European Union was 18/08/2021 for Fingolimod Mylan and 26/06/2020 for Fingolimod Accord.Fig. 1 describes the trend of reports over time.In 2012, there were more reports than in any other year, followed by 2018.Since 2018, there has been a gradual decline in reports each year, reaching its lowest point in (excluding the first 6 months of 2023).Most reports, 19,855 (86.5%), were submitted by healthcare professionals, compared to 3102 (13.5%) from non-healthcare individuals.The trend of reports over the years, broken down by type of reporter, is depicted in Fig. 2. The proportions of reports from females were higher than from males 16,074 (70.0%) vs 5259 (22.9%), respectively.However, in 1624 (7.1%) of reports the information about the sex was missing.Most of the reports, 12,558 (54.7%), referred to patients aged 18-64 years.Among these reports, 9318 (40.6%) were related to females, 3117 (13.6%) to males, and in 123 (0.5%) cases the information on sex was missing.Additionally, in 9839 (42.9%) of the reports, information about the patient's age was omitted.A tiny number of reports 312 (1.4%) pertained to women aged 65-85 years, while for the rest of the groups, the reports were below 1%.Tables 1 summarizes the characteristics of each report by patients' sex (female, male, and not specified) and age range (0-17 years, 18-64 years, 65-85 years, over 85 years, and not specified).

Discussion
The results of our study, based on data collected from the EudraVigilance database, provide valuable insights into the safety profile of fingolimod (Gilenya®).
The temporal trend of reports showed a peak in 2012, followed by another notable increase in 2018, which might be explained by the EMA approval of fingolimod in this year for the treatment of children 10-17 years old with RRMS.However, since 2018, there has been a consistent decline in the number of reports each year, reaching a nadir in 2022 (excluding the first half of 2023).The spike in reporting in 2012 may first be because the drug was recently introduced to the market and early post-marketing periods often witness an increased focus on safety surveillance.Additionally, in early 2012 EMA conducted a review of the cardiovascular safety of Gilenya® following the concerns over the effects of the medicine on the heart after the first dose, concluding that the benefits of the medicine continue to outweigh the risks [19].A similar explanation could be given for the notable increase in the number of reports in 2018 following the scientific conclusions of the Pharmacovigilance Risk Assessment Committee (PRAC) and the Committee for Medicinal Products for Human Use (CHMP) in October 2017: "the contra-indications section of the SmPC should be updated to include cardiac underlying conditions; a warning should be added to sections 4.4 and 4.8 of the SmPC to alert prescribers of the possible occurrence of Merkel cell carcinoma, SCC and MM, including cautions regarding exposure to sunlight without protection, regarding concomitant phototherapy with UV-B-radiation or PUVA-photochemotherapy and specific screening of the skin to be performed every six to 12 months; a warning should be included in section 4.4 of the SmPC to inform of the consequences of the immunosuppressive effect and that increased risks appear to be related to long term treatment with fingolimod and in patients that have history of immunosuppressive treatments or other risk factors that could increase this risk (for example, sun exposure, known active infections or malignancies)" [20].Therefore, enhanced monitoring, possibly due to these safety concerns, might have led to increased reporting during these specific periods.The tendency of the number of reports to decrease could also be explained by the Weber effect, which constitutes a peak in adverse event reporting of a drug at the end of second year after regulatory approval followed by a continuous decline thereafter.One possible reason for this effect is a decrease in the reporting of minor or insignificant reactions over time.The consistent decline in the number of reports each year may be indicative of a decreasing trend in either the incidence of adverse events or the reporting over time.
Most ICSRs were submitted by healthcare professionals (86.5%), emphasizing the sustained engagement and continued commitment to pharmacovigilance of those directly involved in patient care.As per Directive 2010/84/EU of the European Parliament and of the Council of 15 December 2010, healthcare professionals are asked to report for all medicines products any suspected adverse reactions via the national reporting system.European Union rules in relation to pharmacovigilance should continue to rely on the crucial role of healthcare professionals in monitoring the safety of medicinal products and should take account of the fact that patients are also well placed to report suspected adverse reactions to medicinal products.Reports from nonhealthcare individuals accounted for 13.5%.This important difference may be due to the fact that healthcare professionals are better trained and informed about reporting suspected adverse reactions, have a background that may facilitate the recognition of a possible adverse reaction.In addition, they are the main interlocutors for patients in the event of a potential adverse reaction occurring.
Analysis by sex revealed a higher proportion of reports concerning females (70.0%) compared to males (22.9%).This is consistent with the known prevalence of multiple sclerosis, a primary indication for fingolimod, which is 3 times more common among women than men [21].The distribution of reports by age group showed a prevalence in the 18-64 years category (54.7%), this also aligns with the typical age of multiple sclerosis onset [2].Moreover, fingolimod's use in pediatrics with RRMS was approved later (at the end of 2018), while in elder population, it should be used with caution due to insufficient data on safety and efficacy, which may explain the lower number of reports from both these groups.

Adverse event analysis
Regarding each type of ADR, our study confirmed the well-known MS drug-related safety issues.The predominant suspected adverse events were associated with the SOC of nervous system disorders: multiple sclerosis relapse, headache, central nervous system lesions, dizziness, hypoaesthesia and multiple sclerosis.Among these, the most reported SAE, multiple sclerosis relapse, emerged in the previous clinical trials.This reported suspected SAE led to different interpretations.It can be argued that it is simply a writing mistake of the reporters, with multiple sclerosis relapse being the target disease for the drug in study rather than an adverse event.From another side, it cannot be excluded that the mention of the target disease in the field of adverse reactions may be understood as a statement of the disease progression due to therapeutic ineffectiveness (the PT related to drug ineffective has been reported 456 times, 1%, in our study).In addition, multiple sclerosis relapse can represent a rebound upon cessation.It is interesting to note from a systematic review with frequentist network meta-analysis that, although numerous studies described SAEs, they were not reported in a standardized manner regarding the inclusion or exclusion of multiple sclerosis relapse as a SAE [22].In particular, multiple sclerosis relapse was considered a SAE in ASSESS and FREEDOMS trials.In the ASSESS trial it was reported by at least 1% of participants, while in the FREEDOMS trial, it was among the most common SAEs [7,23].In a meta-analysis that included studies excluding multiple sclerosis relapse as a SAE, no differences were found in the rate of SAEs for fingolimod versus placebo.In addition, they conducted a sensitivity analysis that revealed that the inclusion of multiple sclerosis relapse as a SAE had only a small impact on the obtained results [24].Other notable most frequently reported suspected AEs were related to investigations SOC (lymphocyte count decreased, white blood cell count decreased, heart rate decreased, gamma-glutamyltransferase increased, alanine aminotransferase increased, hepatic enzyme increased, aspartate aminotransferase increased, blood pressure increased), blood and lymphatic system disorders (lymphopenia, leukopenia), and general disorders (fatigue, gait disturbance, asthenia, pyrexia, pain).Suspected cardiac AEs (bradycardia and atrioventricular block second degree), ophthalmic AEs (macular oedema, vision blurred and visual impairment), AEs related to infections (herpes zoster and urinary tract infections), and other (nausea, dyspnoea, depression, fall, chest pain, back pain, diarrhoea, hypertension and cough) also emerged.Importantly, most of these AEs were non-serious and were listed in the SPC or documented in existing literature or research studies.Comparison of extracted PTs with the IME list identified 14,870 SAEs, constituting 23.00% of the total.Among these, multiple sclerosis relapse, macular edema, bradycardia, leukopenia, and multiple sclerosis were the most frequently reported SAEs.Our results are consistent with those become known from clinical trials: the incidence of reported AEs was similar in all groups in FREEDOMS and TRANSFORMS and the AEs occurring in >10% of patients in the fingolimod groups included back pain, diarrhoea, fatigue, gastrointestinal disturbance, headache and upper respiratory tract infections [7,8].Furthermore, they are in line with those of a multicenter double-blinded study spanning 18 countries, where a comprehensive analysis revealed that 6% of the participants experienced lymphopenia and 1% presented bradycardia.Notably, serious complications occurred in 25% of the patients, with macular edema reported in 2%.Nearly all patients (96%) reported at least one adverse effect associated with fingolimod, with the most common being nasopharyngitis (≥5%), followed by headache and urinary tract infections.Other observed events encompassed falls, hypertension, elevated liver enzyme levels, back pain, upper respiratory tract infections, arthralgia, constipation, influenza, cough, fatigue, nausea, pain in limbs, dizziness, pyrexia, upper abdominal pain, depression, and insomnia.Cardiac complications, occurring in <1% of the population, included second-degree atrioventricular block, myocardial infarction, myocardial ischemia, angina pectoris, and secondary hypertension.Isolated cases of cystoid macular edema, herpes zoster, and dyspnea were also documented [25].Moreover, our results are in line with the meta-analysis in which fingolimod demonstrated an acceptable safety profile [26].

Cardiac disorders
Observational studies in real-world settings have shown that individuals with multiple sclerosis (MS) face an elevated risk of developing cardiovascular diseases [27].Among the most frequently reported cardiac events, 678 (1.05%) cases of bradycardia and 382 (0.59%) of atrioventricular block second degree have been reported in EV.Both events are serious and linked to fingolimod due to sphingosine in the cardiovascular system.Initiating the treatment, for instance, leads to a temporal decrease in heart rate (HR) and may also be connected to a delay in atrioventricular conduction [28,29].Our results reflect the data from existing literature.In clinical trials bradycardia and second-degree AV block were reported in 1.4% and 0.1%, respectively, of patients upon treatment initiation with fingolimod 0,5 mg [7,9].Further post marketing studies (FIRST and START) provided evidence that the first dose of fingolimod was associated with a transient, mostly asymptomatic bradycardia, and that AV-conduction abnormalities are infrequent and recover spontaneously which is consistent with other studies [30,31,32].Moreover, in another study, although the occurrence of bradycardia was rare in the overall study population, it was found that bradycardia occurred more often in patients treated with beta or calcium channel blockers [30].However, despite the seriousness of the event, a review found that patient who had no previous cardiac disorders had no clinical consequences after experiencing prolonged symptomatic bradycardia and slowing down of atrioventricular conduction associated with fingolimod treatment [33].
Fingolimod appears well tolerated in regard to the cardiovascular profile and our data contribute to confirm the existing findings in the real-world and clinical trials for the cardiovascular AEs [32,34,35].

Hepatic events
The well-known AEs regarding the elevation of liver enzymes were among the most frequently reported in our research: gamma-glutamyl transferase increased 604 (0.93%), alanine aminotransferase increased 600 (0.93%), hepatic enzyme increased 443 (0.69%), and aspartate aminotransferase increased 391 (0.60%).A meta-analysis showed that the most common laboratory abnormality was an increase in alanine aminotransferase levels and, in general, the elevation in liver enzyme levels was not associated with clinical symptoms in all included trials [26].In accordance with our results, increases in alanine aminotransferase and bilirubin levels without symptoms were primarily observed in the initial month of fingolimod treatment during clinical trials.Following the discontinuation of treatment, the enzymes reverted to their normal levels within six months [34,35].

Ophthalmic events
Adverse events affecting the eye, among the most reported, included 3 events reported in SPC of fingolimod: macular oedema with 793 cases (1.23%), vision blurred 520 (0.80%) and visual impairment 505 (0.78%).The latter 2 events could be related to macular oedema since blurry vision and vision that gets worse are the main symptoms of this condition.Macular oedema is a SAE, that has been reported in clinical trials with or without visual symptoms in 0.5% patients, most of the cases occurred in the first 3-4 months of treatment, and the majority recovered after treatment interruption without the need of macular oedema treatment [36].In addition, the risk of developing this condition is increased in patients with diabetes mellitus or uveitis.The mechanism of macular oedema development is likely related to effects of S1P pathway activation on vascular permeability [37].A literature revision revealed that the incidence of this event in all considered studies was 0.32% [32].Hence, it is advisable to undergo an ophthalmological assessment 3-4 months after starting the treatment, followed by periodic evaluations [38].

Infections
Fingolimod is an immunomodulatory drug, so increased susceptibility to infection is an expected consequence.Our data showed among the most frequently reported AEs herpes zoster 689 (1.07%) and urinary tract infections 358 (0.55%).For these AEs the overall incidence of infections and serious infections was similar to placebo in clinical trials, with the only type of infections with slightly higher incidence than placebo being the lower respiratory tract infections [34].The reviewed studies by Fonseca confirmed this infection profile, nevertheless, in support of our data the researcher highlights the incidence in all studies of reactivation of chronic viral infections (0.79%) and herpes zoster infections (0.25% versus 3.1% reported in clinical trials [34]) [32].In the extension of the FREEDOMS and TRANSFORMS studies, herpes virus infections were reported in 9%-12.1% and in 10.1%-15% across the treatment groups, respectively [10,11].In addition, one case of herpes zoster infection developed after 39 months of fingolimod exposure in clinical trial extension studies [39].Nevertheless, from a meta-analysis, the occurrence of infectious events was not high [26], which was also in accordance with the open-label study conducted in Italy [40].Hence, individuals treated with fingolimod should be informed about the potential elevated susceptibility to infections and should consider discontinuing the treatment in the event of a severe infection.

Limits and strengths
The spontaneous reporting system remains a cornerstone of pharmacovigilance since it allows the early detection of possible safety signals and the continuous monitoring and evaluation of potential safety issues in relation to reported ADRs [41].Especially, it is crucial to identify rare or long-term ADRs that may not have been captured during the limited duration and controlled settings of premarketing clinical trials [42][43][44].Spontaneous reporting system is an important tool for identifying previously unknown ADRs and emerging safety issues.Furthermore, post marketing data encompass a broader patient population compared to those involved in strictly controlled clinical trials settings, including, for instance, those with co-morbidities, concomitant medications, and vulnerable groups.This allows the system to reflect data on general population, real-world clinical practice, and patient experiences.However, pharmacovigilance studies based on spontaneous reporting system, such as this present one, have some limitations.First, the lack of the number of patients exposed to a particular drug, which does not allow for the accurate calculation of incidence rates, or determining the true risk associated with the use of a specific medication.Secondly, the information contained in the reports may be incomplete and inaccurate, affecting the quality and completeness of the reported data, and then the reliability and validity of the data.In addition, the lack of comprehensive information on the patient's medical history, the usage of concomitant medications, and other relevant factors make it difficult to assess a causal relationship between the medication and reported ADR.Finally, and above all, the system is affected by the underreporting, owing to various factors such as lack of awareness, uncertainty about causality, lack of time or perception that reporting is burdensome [45][46][47][48].For instance, despite being the third most frequently reported AE, lymphopenia represented only 1.77% of the events.This may be under-represented in our pharmacovigilance data despite being reported as a common adverse reaction in SPC.This includes considerations like the expected nature of this adverse reaction and possibly lower reporting frequency due to its known occurrence.Additionally, lymphopenia is often monitored and managed as a part of routine clinical practice, leading healthcare professionals to prioritize the reporting of more unexpected or severe suspected adverse events.Furthermore, routine monitoring of blood counts in patients on fingolimod might lead to early detection and management of lymphopenia, reducing the perceived need for formal adverse event reporting.The incompleteness and variability in reporting require cautious interpretation of the data.To overcome these limitations, it is crucial to integrate studies based on spontaneous reporting with other pharmacovigilance methods, such as signal detection algorithms, disproportionality analyses, and additional observational or experimental studies.These complementary approaches can provide a more comprehensive understanding of the safety profile of a drug and minimize the impact of limitations.
Overall, the results we analyzed showed that most of AEs were nonserious and they align with the established safety profile of fingolimod and are reinforced by the extended studies PANGAEA and LONGTERMS, wherein no novel safety concerns were identified [49,50].In support of these observations, in a review, it has been indicated that certain AEs were dose-dependent, including elevated alanine aminotransferase levels, cardiac abnormalities, and macular oedema, thus recommending the use of a lower dose [33].However, some serious adverse events related to cardiac, ophthalmic and infectious disorders emerged.The same events have already justified the decision of the EMA to approve fingolimod (Gilenya®) as a second-line treatment for patients with MS not responsive to first-line therapy, or those with rapidly evolving course.

Conclusions
Ensuring safety during long-term disease-modifying therapy (DMT) for multiple sclerosis (MS) is a crucial consideration.Despite its limitations, pharmacovigilance data remains a valuable tool for postmarketing surveillance.It complements clinical trial data by capturing real-world experiences and long-term safety information.Real-world evidence (RWE) is essential to acquire insights into the extended safety profile, enabling evidence-based decision-making and elevating the standard of patient care.In conclusion, our study contributes to the ongoing evaluation of the safety of the branded fingolimod Gilenya® in real-world settings.The prevalence of non-serious AEs, along with the alignment of reported adverse events with the summary of the product characteristic and the existing literature, supports the overall safety of fingolimod in the treatment of relapsing multiple sclerosis.Considering the rare and long-term ADRs that may arise in patients chronically treated for MS, continuous pharmacovigilance remains essential to monitor and ensure the ongoing safety of this treatment.

Table 1 -
Number of ICSRs by age group and sex.

Table 4 -
Most reported suspected adverse events (AEs) in EudraVigilance for fingolimod Gilenya® related to women in the age group 18-64 years.