Safety Of Fingolimod Research Articles

The effectiveness of fingolimod in a Portuguese real-world population

IntroductionFingolimod is an oral treatment for Relapsing-Remitting Multiple Sclerosis (RRMS) with established efficacy in clinical trials. Post-marketing studies are important to assess its effectiveness in real-world populations. ObjectivesTo report the effectiveness and safety of fingolimod in a real-world population. MethodsA retrospective study of patients with RRMS treated with fingolimod for at least six months. The demographic characteristics, Annualized Relapse Rate (ARR), Expanded Disability Status Score (EDSS), previous treatments and Adverse Events (AE) were analysed. Results104 patients were included, with a mean treatment duration of 21.06 months. First-line disease modifying therapy failure patients (n=56) had an ARR decrease of 68.53% (1.43 vs. 0.45, p<0.001), 66.07% of them were relapse-free, EDSS significantly decreased (2.5 vs. 2.0, p<0.001) and 91.07% showed no disability progression. In patients previously treated with natalizumab as a second-line drug mainly switched due to safety concerns (n=41), although the differences were not statistically significant, both the ARR and EDSS increased in 41.46% and 19.51% of patients, respectively. In treatment-naive patients (n=7) the ARR decreased 94.90% (1.57 vs. 0.08, p=0.027) and there was no disability progression. 56.7% of all patients experienced AE not considered serious in any of the cases. ConclusionIn this population, fingolimod was an effective treatment after first-line treatment failure, decreasing both the ARR and EDSS, and may be an effective option after natalizumab.

Efficacy and Safety of Fingolimod in an Unselected Patient Population

BackgroundFingolimod is a first in class oral compound approved for the treatment of relapsing-remitting multiple sclerosis (RR-MS). The aim of this study was to evaluate clinical and neuroradiological responses to fingolimod as well as the safety and tolerability in RR-MS patients in clinical practice. In addition, a panel of pro-inflammatory serum cytokines was explored as potential biomarker for treatment response.MethodsWe conducted a retrospective, non-randomized, open-label, observational study in 105 patients with RR-MS and measured cytokines in longitudinal serum samples.ResultsCompared to the year before fingolimod start the annualized relapse rate was reduced by 44%. Also, the percentage of patients with a worsening of the EDSS decreased. Accordingly, the fraction of patients with no evidence of disease activity (no relapse, stable EDSS, no new active lesions in MRI) increased from 11% to 38%. The efficacy and safety were comparable between highly active patients or patients with relevant comorbidities and our general patient population.ConclusionsThe efficacy in reducing relapses was comparable to that observed in the phase III trials. In our cohort fingolimod was safe and efficacious irrespective of comorbidities and previous treatment.

Fingolimod: efectividad y seguridad en la práctica clínica habitual. Estudio observacional, retrospectivo y multicéntrico en Galicia

Introduction. The effectiveness and safety of fingolimod in patients with relapsing-remitting multiple sclerosis (RRMS) have been proven in clinical trials. Yet,due to their limitations,it is important to know how it behaves under everyday clinical practice conditions. Hence,the aim of this study is to evaluate the effectiveness and safety of fingolimod after 12 months’ usage in clinical practice in Galicia. Patients and methods. We conducted a retrospective,multi-centre study (n = 8) of patients with RRMS who were treated with one or more doses of fingolimod,0.5 mg/day. Effectiveness was assessed -annualised relapse rate (ARR),changes in the score on the Expanded Disability Status Scale (EDSS),percentage of patients free from relapses,free from progression of disability and free from activity in resonance-for the total number of patients and according to previous treatment. Safety was assessed based on the percentage of patients who withdrew and presented adverse side effects. Results. After 12 months’ use,fingolimod reduced the ARR by 87% (1.7 to 0.23; p < 0.0001) and,consequently,81% of patients were free from relapses. The score was reduced by 9%. In all,91% of patients were free from progression of disability and 72% were free from resonance activity. No signs of disease activity were found in 43% of the patients. Most of the benefits of fingolimod differed depending on previous treatment. About a third of the patients reported adverse side effects,but only 2% of them withdrew for this reason. Conclusions. In clinical practice,most of the results on the effectiveness of the clinical trials conducted with fingolimod were observed during the first 12 months of treatment. A better safety profile was observed than that reported in the clinical trials.

Safety and efficacy of fingolimod in clinical practice: The experience of an academic center in the Middle East

BackgroundFew published studies addressed real-world clinical experience with fingolimod especially in the Middle East region. ObjectiveTo review our clinical experience with fingolimod at a specialized academic MS center in Lebanon. MethodsAll patients treated with fingolimod at the MS Center between October 2011 and January 2015 were retrospectively identified. ResultsA total of 122 patients were included. The first dose observation was uneventful in 98.8% of patients. Annualized relapse rate decreased from 1.16 pre-treatment to 0.29 post-treatment representing a relative risk reduction of 75% (p<0.0001). The proportion of patients with no new T2 or enhancing lesions was 66.3%. Seventy-six (62.3%) patients experienced adverse events with lymphopenia, increase liver enzymes, urinary tract infections and fatigue being the most common. ConclusionOur cohort confirms the effectiveness and safety of fingolimod in a real world setting.

OP69 – 2651: Safety and effect of fingolimod on no evidence of disease activity (NEDA-4) in young adult patients with relapsing-remitting multiple sclerosis

Objective To evaluate the safety and effect of fingolimod 0.5 mg on NEDA-4 in young adult RRMS patients. NEDA-4 is a combined 4-part measure (no new/enlarging T2 lesions; no confirmed relapses; no 6-month confirmed disability progression; annualized rate of brain atrophy Methods Post-hoc analysis of NEDA-4 was conducted in the combined FREEDOMS/FREEDOMS II (2-year studies versus placebo), and in TRANSFORMS (1-year study versus intramuscular interferon-beta-1a, IFN). NEDA-4 was analyzed by logistic regression model (adjusted for treatment, age at baseline, treatment-by-age interaction). Proportion of patients with NEDA-4 and odds ratios (OR) versus controls were estimated for ages ≤30 years and >30 years. Safety in patients ≤30 years was evaluated from AEs reported on fingolimod (N=1364) and placebo (N=966) using combined data from all fingolimod phase II/III RRMS studies. Results In young adults (≤30 years) from FREEDOMS/FREEDOMS II, 24/153 (15.7%) had NEDA-4 on fingolimod versus 4/141 (2.8%) on placebo (OR=6.37, p 30 years. The fingolimod AE profile in young adults was consistent with the known profile of fingolimod in the overall population. Conclusion Young adults were approximately 3–6 times more likely to achieve NEDA-4 on fingolimod versus controls. Efficacy and safety of fingolimod in young patients will be further investigated in the PARADIGMS study (fingolimod versus IFN in pediatric MS), currently recruiting worldwide.

Efficacy and safety of Fingolimod: the French Grand-Est Cohort (P3.249)

Efficacy and safety of Fingolimod: the French Grand-Est Cohort (P3.249)

Second-Line Therapy with Fingolimod for Relapsing-Remitting Multiple Sclerosis in Clinical Practice: The Effect of Previous Exposure to Natalizumab

Background: To evaluate efficacy and safety of fingolimod for relapsing-remitting multiple sclerosis, particularly in patients previously exposed to natalizumab. Method: Prospective observational single-centre second-line cohort study. Results: Among 71 patients treated with fingolimod 0.5 mg/day for a mean duration of 21.75 w 12.60 months, the annualized relapse rate was 0.66 (C.I. 95% 0.27-1.05) with a significant difference between 26 patients with prior natalizumab exposure (1.15; C.I. 95% 0.12-2.17) and 45 not exposed (0.38; C.I. 95% 0.18-0.57; p = 0.002). In a multivariate negative regression model, only previous exposure to natalizumab (p = 0.049) and duration of fingolimod treatment (p < 0.001) significantly correlated with the annualized relapse rate. Previous exposure to natalizumab (p = 0.028) and duration of treatment with fingolimod (p < 0.001) were confirmed by restricting the analysis to the first 12 months of treatment with fingolimod, but were no longer statistically significant by analysing only patients (n = 51) with at least 12 months of treatment with fingolimod (0.32; C.I. 95% 0.08-0.55 vs. 0.22; C.I. 95% 0.11-0.32; p = NS). No differences were observed in neuroradiological outcomes and disability progression in patients exposed to natalizumab and not exposed. The rate of discontinuation due to adverse events was 11.3%, with no differences between the two groups. Conclusions: Our study confirms efficacy and side effects of fingolimod in a second-line clinical practice cohort. Prior natalizumab exposure and duration of treatment with fingolimod are independent predictors of annualized relapse rate during the first 12 months of treatment with fingolimod, but not in the long-term, and may be influenced by the 3 months washout period between the two drugs. i 2014 S. Karger AG, Basel

P029 - Efficacy and safety of fingolimod treatment in multiple sclerosis: The clinical experience of the AUBMC Multiple Sclerosis Center in Lebanon

Background Fingolimod is the first oral disease-modifying therapy (DMT) approved by the US Food and Drug Administration (FDA) in September 2010 and by the European Medicines Agency (EMA) in March 2011 for the treatment of relapsing-remitting multiple sclerosis (RRMS). The available efficacy and safety data of fingolimod derives from the two completed Phase III clinical trials, FREEDOMS and TRANSFORMS which demonstrated a reduction in the relapse-rate, disability progression and gadolinium-enhancing lesions compared to placebo and intramuscular interferon beta 1a. However, there are still no or few data about the real-world efficacy and safety of fingolimod, at least after one year of treatment in the Middle East region. Objective To describe our clinical experience with fingolimod looking at different outcomes including efficacy, tolerability and safety in multiple sclerosis (MS) patients presenting to our MS Center. Methods MS patients who were treated with fingolimod and visited our AUBMC-MS Center from October 2011 to December 2013 were identified. Demographics, MS disease related variables, first-dose and follow up recorded adverse events and efficacy outcomes were extracted from our medical charts. Main efficacy outcomes were the annualized relapse rate (ARR), the disability progression (EDSS) and the magnetic resonance imaging (MRI) activity. Results Eighty seven RRMS patients who were prescribed fingolimod were included in the analysis. Fifty eight were women and 29 men. Mean disease duration was 6.8±6.1 years and mean EDSS at fingolimod initiation was 2.33±1.4. Eight patients received fingolimod between 3 and 5 months, 26 patients received treatment between 6 and 11 months, 32 patients between 12 and 23 months, and 21 patients >24 months. First dose observation was uneventful in all patients. Within a period of 14.9±8 months, treatment was discontinued in 21 patients (24.4%) due to progression of the disease to secondary progressive MS (n=6), lack of efficacy (n=10), pregnancy (n=1), recurrent infections (n=1), varicella zoster virus (VZV) radiculitis (n=1), and patients' personal decision (n=2). ARR in the year previous to fingolimod treatment was 1.31 and decreased to 0.26 during the overall treatment period. In patients treated with fingolimod for <12 months (n=53), 60.4% were free from EDSS progression and 62.3% were free from MRI activity. Conclusion In our study patients, fingolimod was safe, well tolerated and effective in reducing disease activity and progression of disability. Fingolimod is the first oral disease-modifying therapy (DMT) approved by the US Food and Drug Administration (FDA) in September 2010 and by the European Medicines Agency (EMA) in March 2011 for the treatment of relapsing-remitting multiple sclerosis (RRMS). The available efficacy and safety data of fingolimod derives from the two completed Phase III clinical trials, FREEDOMS and TRANSFORMS which demonstrated a reduction in the relapse-rate, disability progression and gadolinium-enhancing lesions compared to placebo and intramuscular interferon beta 1a. However, there are still no or few data about the real-world efficacy and safety of fingolimod, at least after one year of treatment in the Middle East region. To describe our clinical experience with fingolimod looking at different outcomes including efficacy, tolerability and safety in multiple sclerosis (MS) patients presenting to our MS Center. MS patients who were treated with fingolimod and visited our AUBMC-MS Center from October 2011 to December 2013 were identified. Demographics, MS disease related variables, first-dose and follow up recorded adverse events and efficacy outcomes were extracted from our medical charts. Main efficacy outcomes were the annualized relapse rate (ARR), the disability progression (EDSS) and the magnetic resonance imaging (MRI) activity. Eighty seven RRMS patients who were prescribed fingolimod were included in the analysis. Fifty eight were women and 29 men. Mean disease duration was 6.8±6.1 years and mean EDSS at fingolimod initiation was 2.33±1.4. Eight patients received fingolimod between 3 and 5 months, 26 patients received treatment between 6 and 11 months, 32 patients between 12 and 23 months, and 21 patients >24 months. First dose observation was uneventful in all patients. Within a period of 14.9±8 months, treatment was discontinued in 21 patients (24.4%) due to progression of the disease to secondary progressive MS (n=6), lack of efficacy (n=10), pregnancy (n=1), recurrent infections (n=1), varicella zoster virus (VZV) radiculitis (n=1), and patients' personal decision (n=2). ARR in the year previous to fingolimod treatment was 1.31 and decreased to 0.26 during the overall treatment period. In patients treated with fingolimod for <12 months (n=53), 60.4% were free from EDSS progression and 62.3% were free from MRI activity. In our study patients, fingolimod was safe, well tolerated and effective in reducing disease activity and progression of disability.

P035 - Long-term safety of fingolimod: Interim evaluation of data from the longterms trial

Background/objective Multiple sclerosis patients participating in the fingolimod phase 2/3 core and extension studies were eligible to transfer to LONGTERMS, an open-label, multicentre, single-arm, long-term safety and tolerability study. Here, we compared the long-term fingolimod (0.5 mg dose) safety data in the LONGTERMS study (up to data cut-off), with shorter-term (1–2 years) safety data pooled from the randomized controlled trials. Design/methods In this study, patients from two cohorts (Core Cohort, CC; LONGTERMS cohort, LC) were compared. Patients in CC [ n =1212; median (range) exposure: 1.6 (0.01–2.4) years] were pooled from the fingolimod 0.5 mg arms of the core phase 2/3 trials. Patients in LC [ n =1655; median (range) exposure: 3.7 (0.01–7.4)] included CC and phase 2/3 core comparator patients transitioned to fingolimod 0.5 mg in their extensions. Incidence rates (number of patients experiencing ?1 event/100 patient-years) were determined for adverse events (AEs) of special interest. Results The incidence rates for AEs of special interest were similar or lower in LC compared with CC, for: infections (LC, 68.3; CC, 91.0), skin cancer and other malignant neoplasms (LC, 0.7 and 0.4; CC, 1.3 and 0.4), thromboembolic events (LC, 0.9; CC, 1.0), hypertension (LC, 3.6; CC, 5.5), respiratory conditions (LC, 1.2; CC, 1.5) and reactivation of viral infections (LC, 5.3; CC, 5.9). Conclusion With long-term use of fingolimod (median: 3.7 years), incidence rates for AEs of special interest were comparable with those in controlled studies. There were no new safety signals detected with the long-term use of fingolimod.

80.: Cardiac effects of high-dose fingolimod ingestion

Fingolimod is associated with first dose transient atrioventricular conduction defects mandating cardiac monitoring at initiation. This side effect is not seen with chronic use. Theoretically, overdose of fingolimod should not lead to cardiac side effects, but there are very few reports. We present a case and review the literature of fingolimod overdoses. We report an intentional overdose of 21 mg of fingolimod in a patient with relapsing remitting multiple sclerosis and depression. We retrospectively reviewed the clinical notes of our patient and searched for any similar reports in the literature. At the time of initial assessment and during the subsequent observation period of approximately 4 h, no cardiovascular symptoms, signs or atrioventricular conduction delay were noted. Though there has been a recent report of cardiac side effects noticed after intentional fingolimod overdose, in our patient no such side effects were observed. This highlights the relative safety of fingolimod and that the adverse effects can be variable. We expect further reports of effects of overdoses of this drug with more widespread use.

Efficacy and safety of fingolimod in Hispanic patients with multiple sclerosis: pooled clinical trial analyses.

The disease characteristics of multiple sclerosis (MS) appear to differ between Hispanic and Caucasian patients, with Hispanic patients having a younger age at onset, and a higher prevalence of optic nerve and spinal cord involvement. Fingolimod, the first-in-class oral sphingosine 1-phosphate receptor modulator approved for the treatment of relapsing MS, has been shown to significantly reduce annualized relapse rates (ARRs), lesion-based magnetic resonance imaging (MRI) activity, confirmed disability, and brain volume loss, compared with placebo or intramuscular interferon beta-1a (IFNβ-1a IM) in randomized, double-blind, controlled clinical studies. Here, the efficacy and safety profile of fingolimod in Hispanic patients was compared to that observed in the overall study populations. This was a post hoc analysis of relapses and safety data for Hispanic patients with relapsing-remitting MS (RRMS) randomized to receive daily fingolimod 0.5 mg, weekly IFNβ-1a IM (30 mg) or placebo, in the phase 3, controlled FREEDOMS, FREEDOMS II, and TRANSFORMS fingolimod studies. The ARR was estimated for each treatment group; only relapses that were confirmed by an independent examining neurologist were included in these analyses. Safety assessments included the incidence of adverse events and serious adverse events. Eligible Hispanic patients aged 18-55 years (n=181) had been treated as follows: fingolimod 0.5 mg (n=89), IFNβ-1a IM (n=65), and placebo (n=27). Hispanic patients treated with fingolimod for up to 2 years had lower ARRs (ARR: 0.22, 95% confidence interval [CI]: 0.14-0.35) than those receiving placebo (ARR: 0.46, 95% CI: 0.24-0.88) or IFNβ-1a IM (ARR: 0.34, 95% CI: 0.18-0.63), with relative reductions of 52% and 35%, respectively. A transient decrease in heart rate that started to attenuate 6 h after fingolimod administration was observed, consistent with the well-characterized pharmacologic effect following fingolimod treatment initiation. No cases of symptomatic bradycardia were reported in Hispanic patients. The incidence of first-degree atrioventricular block was low and similar across all treatment groups (3.1-4.5%). The safety profile of fingolimod in Hispanic patients was consistent with that reported in the overall population of each study. Overall, this study demonstrates that fingolimod is efficacious and well tolerated in Hispanic patients with RRMS.

Fingolimod for multiple sclerosis: a review for the specialist nurse.

The availability of treatments for multiple sclerosis (MS) has increased substantially over the past decade. Once-daily fingolimod 0.5mg capsules (Gilenya, Novartis Pharma) were approved in the European Union in March 2011 as the first oral disease-modifying therapy for patients with relapsing MS. This review summarises the efficacy and safety of fingolimod, and discusses practical considerations for MS specialist nurses. Fingolimod has demonstrated efficacy in the treatment of relapsing-remitting MS, as assessed by relapse measures, inflammatory disease activity and brain volume loss. Evaluation of its safety profile suggests a need for monitoring procedures for specific adverse events, including transient, mostly asymptomatic, reductions in heart rate, blood pressure increases, macular oedema and liver enzyme elevations. The MS nurse is likely to be involved in monitoring treatment initiation, providing support in the case of adverse events and promoting patient adherence to the prescribed treatment regimen.

Efficacy And Safety Of Fingolimod In Hispanic Patients: Pooled Data From Three Phase 3 Clinical Trials (P2.208)

Efficacy And Safety Of Fingolimod In Hispanic Patients: Pooled Data From Three Phase 3 Clinical Trials (P2.208)

Safety and efficacy of fingolimod in patients with relapsing-remitting multiple sclerosis (FREEDOMS II): a double-blind, randomised, placebo-controlled, phase 3 trial

Fingolimod has shown reductions in clinical and MRI disease activity in patients with relapsing-remitting multiple sclerosis. We further assessed the efficacy and safety of fingolimod in such patients. We did this placebo-controlled, double-blind phase 3 study predominantly in the USA (101 of 117 centres). Using a computer-generated sequence, we randomly allocated eligible patients-those aged 18-55 years with relapsing-remitting multiple sclerosis-to receive fingolimod 0·5 mg, fingolimod 1·25 mg, or placebo orally once daily (1:1:1; stratified by study centre). On Nov 12, 2009, all patients assigned to fingolimod 1·25 mg were switched to the 0·5 mg dose in a blinded manner after a review of data from other phase 3 trials and recommendation from the data and safety monitoring board, but were analysed as being in the 1·25 mg group in the primary outcome analysis. Our primary endpoint was annualised relapse rate at month 24, analysed by intention to treat. Secondary endpoints included percentage brain volume change (PBVC) from baseline and time-to-disability-progression confirmed at 3 months. This trial is registered with ClinicalTrilals.gov, number NCT00355134. Between June 30, 2006, and March 4, 2009, we enrolled and randomly allocated 1083 patients: 370 to fingolimod 1·25 mg, 358 to fingolimod 0·5 mg, and 355 to placebo. Mean annualised relapse rate was 0·40 (95% CI 0·34-0·48) in patients given placebo and 0·21 (0·17-0·25) in patients given fingolimod 0·5 mg: rate ratio 0·52 (95% CI 0·40-0·66; p<0·0001), corresponding to a reduction of 48% with fingolimod 0·5 mg versus placebo. Mean PBVC was -0·86 (SD 1·22) for fingolimod 0·5 mg versus -1·28 (1·50) for placebo (treatment difference -0·41, 95% CI -0·62 to -0·20; p=0·0002). We recorded no statistically significant between-group difference in confirmed disability progression (hazard rate 0·83 with fingolimod 0·5 mg vs placebo; 95% CI 0·61-1·12; p=0·227). Fingolimod 0·5 mg caused more of the following adverse events versus placebo: lymphopenia (27 [8%] patients vs 0 patients), increased alanine aminotransferase (29 [8%] vs six [2%]), herpes zoster infection (nine [3%] vs three [1%]), hypertension (32 [9%] vs 11 [3%]), first-dose bradycardia (five [1%] vs one [<0·5%]), and first-degree atrioventricular block (17 [5%] vs seven [2%]). 53 (15%) of 358 patients given fingolimod 0·5 mg and 45 (13%) of 355 patients given placebo had serious adverse events over 24 months, which included basal-cell carcinoma (ten [3%] patients vs two [1%] patients), macular oedema (three [1%] vs two [1%]), infections (11 [3%] vs four [1%]), and neoplasms (13 [4%] vs eight [2%]). Our findings expand knowledge of the safety profile of fingolimod and strengthen evidence for its beneficial effects on relapse rates in patients with relapsing-remitting multiple sclerosis. We saw no effect of fingolimod on disability progression. Our findings substantiate the beneficial profile of fingolimod as a disease-modifying agent in the management of patients with relapsing-remitting multiple sclerosis. Novartis Pharma AG.

Pregnancy outcomes in the clinical development program of fingolimod in multiple sclerosis.

To report outcomes of pregnancies that occurred during the fingolimod clinical development program. Pregnancy outcomes from phase II, phase III, and phase IV clinical studies (with optional extensions) were reported by clinical trial investigators. Fingolimod exposure in utero was defined as fingolimod treatment at the time of conception or in the 6 weeks before conception. As of October 31, 2011, 89 pregnancies were reported in completed or ongoing clinical studies, with 74 in fingolimod treatment arms. Of 66 pregnancies with in utero exposure to fingolimod, there were 28 live births, 9 spontaneous abortions, 24 elective abortions, 4 ongoing pregnancies, and 1 pregnancy with an unknown outcome (patient lost to follow-up). Two infants were born with malformations: 1 with congenital unilateral posteromedial bowing of the tibia and 1 with acrania. Elective abortions were performed for 1 case each of tetralogy of Fallot, spontaneous intrauterine death, and failure of fetal development. There were 5 cases (7.6%; 95% confidence interval 3%-17%) of abnormal fetal development in the 66 pregnancies that had in utero exposure to fingolimod. In all 5 cases, fetal exposure to the drug took place in the first trimester of pregnancy. The number of patients becoming pregnant during fingolimod therapy remains small and does not permit firm conclusions to be drawn about fetal safety of fingolimod in humans. Given the known risks of teratogenicity in animals and the present data, women of childbearing potential should use effective contraception during fingolimod therapy and for 2 months after discontinuation.

Use of fingolimod in patients with relapsing remitting multiple sclerosis in Kuwait

BackgroundPost-marketing studies are important to confirm what was established in clinical trials, and to assess the intermediate and long-term efficacy and safety. ObjectiveTo assess efficacy and safety of fingolimod in multiple sclerosis (MS) in Kuwait. MethodsWe retrospectively evaluated MS patients using the MS registries in 3 MS clinics. Relapsing remitting MS patients according to revised 2010 McDonald criteria who had been treated with fingolimod for at least 12 months were included. Primary endpoint was proportion of relapse-free patients at last follow-up. Secondary endpoints were mean change in EDSS and proportion of patients with MRI activity (gadolinium-enhancing or new/enlarging T2 lesions). Results76 patients met the inclusion criteria. Mean age and mean disease duration were 34.43 and 7.82 years respectively. Mean duration of exposure to fingolimod was 18.50 months. Proportion of relapse-free patients was 77.6% at last follow-up. Mean EDSS score significantly improved (2.93 versus 1.95; p<0.0001) while 17.1% of patients continued to have MRI activity versus 77.6% at baseline (p<0.0001). Four patients stopped fingolimod due to disease breakthrough (n=3) and lymphadenitis (n=1). ConclusionFingolimod is safe and effective in reducing clinical and radiological disease activity in relapsing remitting MS patients. Our results are comparable to reported results of phase III studies.

Nuestra experiencia con fingolimod

IntroductionMultiple Sclerosis (M.S.) is a progressive, autoimmune degenerative disease that is characterized by central nervous system neuro-inflammation. Fingolimod is a medicinal product that has been marketed in the European Union since March 2011, as the first oral treatment for very active and rapidly evolving Relapsing Remitting Multiple Sclerosis. A first dose 6 hour protocol is recommended, due to the effect of bradycardia or heart blockages. This includes monitoring the patient for 6hours after the first dose of Fingolimod, with an electrocardiogram being performed at baseline and at 6hours, as well as monitoring the heart rate and blood pressure. ObjectiveTo assess the immediate cardiac safety of Fingolimod. MethodA record was made of the electrocardiograms, the vital constants graph, and records from the MS patient register from August 2011 to October 2013, as well as those recorded prior to Fingolimod treatment (normal or abnormal electrocardiogram, or medicated or non-medicated bradycardia, prolongation of the 6h of Protocol, and interruption of treatment). ResultsA total 42 patients have started treatment with Fingolimod in our unit. Of this total, 15 patients had been treated with Natalizumab previously (reason for the change: 8 by JC Virus, 3 by hypersensitivity reaction, and inadequate response 4). Asymptomatic bradycardia was observed in 40/42 patients, with none needing treatment. A longer monitoring time was required in 5/42. Treatment was suspended with Fingolimod during follow-up in 3 patients, resumed in 2, and 1 of them re-established with Interferon beta. ConclusionThe immediate cardiac safety of Fingolimod is very good.

Effect of prior treatment status and reasons for discontinuation on the efficacy and safety of fingolimod vs. interferon β-1a intramuscular: Subgroup analyses of the Trial Assessing Injectable Interferon vs. Fingolimod Oral in Relapsing–Remitting Multiple Sclerosis (TRANSFORMS)

BackgroundFingolimod demonstrated superior efficacy compared with interferon β-1a intramuscular in relapsing multiple sclerosis. The impact of treatment history on fingolimod efficacy is unknown. ObjectivesThis post-hoc analysis of phase 3 TRANSFORMS data compared the efficacy and safety of fingolimod and interferon β-1a intramuscular among patient subgroups defined by prior treatment history. MethodsAnnualized relapse rate and safety of once-daily oral fingolimod 0.5mg, 1.25mg, or once-weekly interferon β-1a 30μg intramuscular for 12 months were analyzed in 1292 patients with relapsing multiple sclerosis according to prior disease-modifying therapy, reason for prior disease-modifying therapy discontinuation (adverse events or unsatisfactory therapeutic effect), and prior disease-modifying therapy duration. ResultsCompared with interferon β-1a intramuscular, fingolimod 0.5mg significantly reduced annualized relapse rate in patients who were treatment naive, received prior interferon-β treatment, discontinued prior disease-modifying therapy for unsatisfactory therapeutic effect, or had prior disease-modifying therapy duration of ≥1 year (P≤0.05, all comparisons). Similar trends were observed in patients with prior glatiramer acetate treatment. Significant reductions were also seen with fingolimod 1.25mg for treatment-naive and prior interferon-β-treated patients. ConclusionsThis analysis demonstrates superiority of fingolimod over interferon β-1a intramuscular regardless of prior (interferon-β) treatment and prior treatment efficacy and duration. ClinicalTrials.gov identifier: NCT00340834.

Impact of prior treatment status and reasons for discontinuation on the efficacy and safety of fingolimod: Subgroup analyses of the Fingolimod Research Evaluating Effects of Daily Oral Therapy in Multiple Sclerosis (FREEDOMS) study

BackgroundFingolimod is a once-daily, oral sphingosine 1-phosphate receptor modulator approved for the treatment of relapsing multiple sclerosis. ObjectiveThis post-hoc analysis of phase 3 FREEDOMS data assessed whether the effects of fingolimod are consistent among subgroups of patients defined by prior treatment history. MethodsAnnualized relapse rate and safety profile of treatment with fingolimod 0.5mg, 1.25mg, or placebo once-daily for 24 months were analyzed in 1272 relapsing multiple sclerosis patients, by subgroups based on disease-modifying therapy history (treatment-naive; prior interferon-β or glatiramer acetate), reason for discontinuation of prior disease-modifying therapy (unsatisfactory therapeutic response or adverse events), and prior disease-modifying therapy duration. ResultsBoth fingolimod doses significantly reduced annualized relapse rate in patients that received prior interferon-β or glatiramer acetate, discontinued prior disease-modifying therapy owing to unsatisfactory therapeutic effect, were treatment-naive, or had prior disease-modifying therapy duration of >1–3 years (P≤0.0301 for all comparisons vs placebo). Fingolimod 1.25mg resulted in greater reductions in annualized relapse rate in patients that discontinued prior disease-modifying therapy for adverse events or had prior disease-modifying therapy duration of ≤1 year or >3 years (P≤0.0194 vs placebo). ConclusionsFingolimod demonstrated similar efficacy in relapsing multiple sclerosis patients regardless of prior treatment history. Clinicaltrials.gov identifier: NCT00289978.

Fingolimod and cardiac risk: latest findings and clinical implications.

Fingolimod is an oral medication approved for the treatment of relapsing multiple sclerosis (MS). It is unique compared with other approved disease-modifying therapies for MS in that it is the first oral agent and it has a novel mechanism of action. In clinical trials and postmarket use, it demonstrates clear therapeutic efficacy. However, it is associated with certain risks including cardiac concerns. The recent reports of cardiac events potentially associated with the drug prompted a regulatory agencies review of the use of fingolimod for MS in the USA and Europe. After completion of their review, the US Food and Drug Administration and the European Medicines Agency concluded that its benefits outweighed the risks. However, certain recommendations were made for appropriate patient selection for fingolimod and for more cautious first-dose monitoring. We review the use of fingolimod for MS in light of the recently reported potential cardiac risks. We conclude that with appropriate patient selection and careful monitoring, it appears to have a favorable benefits/risks profile and can be a valuable treatment option for relapsing MS. Continued postmarketing surveillance and data from the extension phase of its clinical trials will be very important in understanding the long-term efficacy and safety of fingolimod and to help determine its place in the treatment algorithm for multiple sclerosis.