Fingolimod in the treatment algorithm of relapsing remitting multiple sclerosis: a statement of the Central and East European (CEE) MS Expert Group
Wien Med Wochenschr
Fingolimod in the treatment algorithm of relapsing remitting multiple sclerosis: a statement of the Central and East European (CEE) MS Expert Group
Franz Fazekas 0 1 2
0 Schlüsselwörter: Multiple Sklerose , Behandlung, Immunmodulation, Immunsuppression, Fingolimod
1 F. Fazekas, MD () Department of Neurology, Medical University of Graz , Auenbruggerplatz 22, 8036 Graz , Austria
2 Members of “The Central and East European (CEE) MS Expert Group” are listed as follows: Austria: Berger Thomas, Univ.-Klinik für Neurologie, Innsbruck; Fazekas Franz, Univ.- Klinik für Neurologie, Graz (Chair); Kraus Jörg, Univ.-Klinik für Neurologie, Salzburg; Vass Karl, Univ.-Klinik für Neurologie, Wien. Bulgaria: Milanov Ivan, University Hospital „Saint Naum“, Neurology Clinic , Sofia; Traykov Latchezar , University Hospital Alexandrovska, Neurology Clinic, Sofia. Cyprus: Kyriakides Theodoros, Cyprus Institute of Neurology and Genetics, Nicosia; Panayiotou Panayiotis, Aretaieio Private Hospital, Nicosia. Czech Republic: Havrdová Eva, Department of Neurology, Prague (Chair); Taláb Radomír, Department of Neurology, Hradec Kralove. Hungary: Jakab Gábor, Department of Neurology, Budapest; Komoly Samuel, Department of Neurology, Pécs. Malta: Vella Norbert, Department of Neurology, Msida MSD. Slovakia: Kurcˇa Egon, Department of Neurology , Martin; Lisý
Zusammenfassung Fingolimod ist das erste oral verabreichbare Medikament zur Behandlung der Multiplen Sklerose. Es ist der erste Sphingosin 1-phosphat Rezeptor Modulator seiner Klasse, der sich an Sphingosin 1-phosphat Rezeptoren auf Lymphozyten bindet und über Abregulation den Austritt von Lymphozyten aus dem lymphatischen Gewebe in die Blutbahn verhindert. Dieser Mechanismus reduziert das Einwandern potentiell autoagressiver Lymphozyten in das Zentralnervensystem. Zwei große Phase-III-Studien mit Fingolimod haben überlegene Wirksamkeit dieser Substanz in zwei Dosierungen gegenüber Plazebo sowie wöchentlicher intramuskulärer Injektion von Interferon beta-1a gezeigt. Zu den möglichen Nebenwirkungen des Medikamentes gehört eine transiente Bradykardie nach der ersten Dosis Fingolimod einschließlich möglicher AV-Blockierung, weshalb über einen Zeitraum von 6 Stunden nach der ersten Verabreichung Pulsrate und Blutdruck monitiert werden sollen. Während der Behandlung müssen spezifische Infektionen, erhöhte Leberenzyme und ophthalmologische Veränderungen Beachtung finden. Dieser Artikel gibt Empfehlungen zum Einsatz von Fingolimod einschließlich der notwendigen Sicherheitsaspekte während der Behandlung mit diesem Medikament.
Fingolimod im Behandlungsalgorithmus der schubförmigen Multiplen Sklerose; Eine Stellungnahme der mittel- und osteuropäischen MS ExpertInnengruppe
Summary Fingolimod is the first oral treatment of
multiple sclerosis. It is the first-in-class sphingosine
1-phosphate receptor modulator that binds to
sphingosine 1-phophate receptors on lymphocytes and via
downregulation of the receptor prevents lymphocyte
egress from lymphoid tissues into the circulation. This
mechanism reduces the infiltration of potentially
autoaggressive lymphocytes into the central nervous system.
Two large phase III studies with fingolimod have shown
superior efficacy of the drug in two dosages compared to
placebo and to weekly intramuscular injections of
Interferon beta-1a. Among possible side effects of the drug is
a transient bradycardia after the first dose of fingolimod
including possible AV blockade and therefore
monitoring of pulse rate and blood pressure for 6 h following
the first application is needed. During treatment,
attention has to be given to specific infections, elevated liver
enzymes, and ophthalmologic changes.
Recommendations on the use of fingolimod including safety aspects
are given in this article.
Established therapies for MS
Interferon beta and glatiramer acetate (GA)
Multiple sclerosis (MS) is a chronic autoimmune
inflammatory disease of the central nervous system (CNS)
diagnosed mainly in the third or fourth decade of life. Its
course is characterized by inflammation, demyelination,
and axonal loss even in the early stages of the disease.
Accumulation of these pathological processes is
responsible for the clinical disease progression and the patients’
prognosis. MS affects with an average incidence rate of
100 in 100,000 approximately 490,000 individuals in the
European Union [
]. Although the exact etiology of MS is
still unknown, the current concept derived from animal
initiation of an altered immune response in a genetically
susceptible individual. The pathophysiology is complex
as in other inflammatory and neurodegenerative diseases
resulting in unpredictable and variable clinical outcomes.
Most patients initially present with the relapsing–
remitting form of MS (RRMS) and may progress to the
secondary progressive (SP) form with or without
superimposed relapses after variable intervals of time [
RRMS patients suffer from episodes of objective
neurologic dysfunction for a period of at least 24 h but in
most patients these deficits last for weeks to months or
remain permanent in some cases [
]. Frequent relapses
in the first 2 years of the disease and shorter interattack
intervals in this period predict shorter times to reach
defined disability endpoints and a shorter time interval
to develop SPMS [
]. Disease-modifying drugs (DMDs)
can reduce the relapse rate and delay the time of disease
progression if treatment is started early [
In the last decade, scientific progress in immunology
and the discovery of new therapeutic targets for the
treatment of MS boosted development programs of new
therapeutic agents as well as for drugs already in the market
for other indications. These treatment strategies included
efforts towards selective
immunomodulation/immunosuppression such as that obtained with fingolimod.
This article reflects the outcome of an experts’ meeting
involving clinical neurologists experienced in research
and treatment of MS from eight European countries to
discuss the clinical benefit/risk profile of the first
approved oral treatment for MS, fingolimod (Gilenya™), to
suggest the position of this new therapy within the current
treatment algorithm and to make recommendations for
selection and management of patients.
Over more than 15 years, the first-line treatment of RRMS
predominantly consisted of four DMDs: Interferon (IFN)
beta-1b (Betaferon® 250 µg s.c. every other day), IFN
beta-1a (Avonex® 30 µg i.m. once a week), IFN beta-1a
(Rebif® 22 µg or 44 µg s.c. three times a week), and GA
(Copaxone® 20 mg s.c. once a day).
These agents have been approved by the European
Medicines Agency (EMA) for the treatment of patients
with RRMS after successful class I-randomized
placebocontrolled trials [
]. Further studies in patients who
have had a single attack of demyelination (clinical
isolated syndrome, CIS), and who were considered to be at
high risk for clinically definite MS, led to the approval for
Avonex®, Betaferon® , and Copaxone® in this early stage
of MS [
]. Following one positive trial, Betaferon®
received approval from the EMA also for the treatment
of patients with SPMS and superimposed relapses .
The benefit/risk profile of these DMDs was positively
assessed on their efficacy to significantly reduce disease
activity by reducing the number of relapses and the
occurrence of new and enhancing lesions detected by
magnetic resonance imaging (MRI) and delaying
relapse-related progression of disability compared to placebo.
Studies in CIS and data from natural history studies have
led to a consensus to consider treatment at least as soon
as the diagnosis of MS is established or after a CIS if there
is a high risk to develop clinically definite MS.
The moderate efficacy of the DMDs is accompanied by
a safety profile with mild to moderate frequent adverse
events. For IFN beta products, these comprise of
injection site reactions/pain and the post injection flu-like
syndrome for 12–24 h which are often transient and
subside after the first 6 weeks, and of rare local skin necrosis.
With GA injection, site reactions include erythema, pain,
and lipoatrophy and the rare post injection systemic
reaction, which includes vasodilatation, chest tightness, and
shortness of breath lasting 5–15 min, which may occur
once during treatment in about 20 % of patients [
Besides lack of therapeutic efficacy and the
inconvenience of side effects, particularly in the first months
of treatment, the fact that all first-line DMDs have to be
applied by injection limits adherence to long-term
treatment with these drugs.
Complete adherence to the dose regimen was found
in 75 % of 2,648 patients with average treatment
duration of 31 months in a multicenter observational study
]. Patients and physicians received paper
questionnaires regarding adherence to the prescribed treatment
regimen. Adherence was defined as not missing a single
injection within 4 weeks before the study. The most
common reasons for nonadherence were forgetting to
administer the injection and other injection-related reasons.
Another recently published study assessed the impact of
adherence to DMDs on clinical and economic outcomes
in a cohort of 2,446 patients [
]. Adherence was
assessed in this study using the medication possession ratio
(MPR) derived from the administrative claims database.
Patients with MPR ≥ 80 % were regarded as adherent. A
total of 59.6 % of the patients were adherent to their
treatment. Adherence was associated with better clinical and
economic outcomes including lower risks for MS-related
hospitalization, MS relapses, and less MS-related
medical costs. In an adherence study comparing data from
retrospective self-reports, medication diaries and
electronic monitoring of needle disposal, Bruce found that
nearly one-fifth of the patients missed more than 20 %
of the injections and concludes that studies using
selfreports and diaries may underestimate poor adherence
Mitoxantrone and natalizumab
Two other drugs have been approved in Europe for
treatment of MS-patients. Since 2003 mitoxantrone, a
synthetic anthracenedione with cytotoxic and
immunosuppressive effects is labelled in some European
countries for patients with SPMS and an EDSS of 3–6, and for
patients with active relapsing progressive MS despite
treatment with first-line DMDs. A randomized
placebocontrolled trial resulted in a significant effect on relapse
rate and disease progression [
]. In a non-randomized
subgroup of the study, mitoxantrone did not reduce
Gadolinium positive (Gd+) MRI scans compared to
placebo but resulted in positive trends of secondary MRI
outcome measures [
]. Similar to other cytotoxic drugs,
mitoxantrone may induce nausea, vomiting, the risk of
infections, secondary leukemia [
], amenorrhea, and
infertility. Due to its cardiotoxicity, the mitoxantrone use
in MS patients is limited to a total cumulative dose of
Natalizumab was authorized for the treatment of MS
patients in June 2006. It is the first monoclonal antibody
used in MS. This antibody is directed against the α4
subunit of α4β1 integrin. It is believed that natalizumab acts
by blocking the entry of immune cells into the CNS via
the interference of the adherence of leukocytes to
endothelial vascular cell adhesion molecule (VCAM)-1 [
Natalizumab reduced the risk of disability progression
over two years by 42 % and the relapse rate by 68 % at
one year and 69 % after two years. The accumulation of
new or enlarging hyperintense lesions detected by
T2weighted MRI was reduced by 82 % at two years and the
number of Gd+ MRI lesions by 92 % [
A second Phase III study compared the combination
of natalizumab with intramuscular INF beta-1a with INF
beta-1a monotherapy. The annualized relapse rate was
reduced by 54 % with the combination compared to the
INF beta-1a only treatment [
]. In this study, the
administration of natalizumab had to be suspended during
the open-label follow-up study when two cases of
progressive multifocal leukoencephalopathy (PML) were
identified. PML is a rare and potentially fatal disease of
the brain caused by the JC Virus (JCV).
The European Commission granted a marketing
authorization in 2006 for second-line treatment of patients
with RRMS or for patients with highly active disease. At
the time of approval, the risk of developing PML was
estimated to be 1/1,000 patients. The last assessment
report from EMA in 2010 stated that the risk of
developing PML increases after 24 months of treatment and
with prior immunosuppressive treatment [
]. The EMA
has recently approved the inclusion of anti-JCV antibody
status as an additional factor to assess the individual risk
of a patient for developing PML before and during
treatment with natalizumab. Beside this very rare adverse
effect, the safety profile of natalizumab includes some
infusion reactions (23.1 % of patients), hypersensitivity
reactions (4 % patients), other opportunistic infections,
and liver damage. Persistent neutralizing antibodies to
natalizumab interfering with the drug’s efficacy were
found in 6 % of patients [
Approved DMDs are associated with poor adherence,
suboptimal therapeutic response and frequent mild to
moderate side effects. The use of mitoxantrone in SPMS
and progressive relapsing MS is limited due to its
doserelated toxicity. Natalizumab, while a potent and effective
drug, on clinical and paraclinical parameters of disease
activity, is associated with rare cases of the
opportunistic CNS infection PML. All these medications have to be
given either as a self-injection or as infusion [
Therefore much attention has been paid by the MS community
to clinical programs with oral treatment including
fingolimod, cladribine, fumaric acid, teriflunomide,
laquinimod, and others [
] which may serve to overcome
some of these limitations and to increase adherence.
Fingolimod (Gilenya®) has been approved by health
authorities in the United States and Australia as a first-line
treatment for relapsing forms of MS and in Russia,
Switzerland, and United Arab Emirates for RRMS.
In January 2011, Fingolimod received a positive
opinion from the Committee for Medicinal Products for
Human Use (CHMP), a prerequisite for the approval
by the European authority. The European Commission
granted a marketing authorization valid throughout the
European Union for Gilenya® on 17 March 2011. The
recommended indication defined by the CHMP is that
fingolimod is indicated as single disease-modifying
therapy in highly active RRMS for the following adult patient
• Patients with high disease activity despite treatment
with a beta-interferon.
These patients may be defined as those who have
failed to respond to a full adequate course (normally
at least 1 year of treatment) of beta-interferon.
Fig. 1 Mode of action of
S1P1. Lymphocytes remain
in lymphoid tissue. (Modified
ents should have had at least one relapse in the
previous year while on therapy, and have at least nine
T2hyperintensive lesions on cranial MRI or at least one
Gadolinium-enhancing lesion. A “non-responder”
could also be defined as a patient with an unchanged
or increased relapse rate or ongoing severe relapses,
as compared to the previous year.
• Patients with rapidly evolving severe RRMS defined by
2 or more disabling relapses in 1 year, and with one or
more Gadolinium enhancing lesions on brain MRI or
a significant increase in T2 lesion load as compared to
a recent MRI.
Mode of action
Fingolimod is the first orally bioavailable sphingosine
1-phosphate (S1P) receptor modulator. S1P is
derived from sphingosine, phosphorylated by ubiquitously
appearing sphingosine-kinases. S1P binds to five
cellsurface high-affinity G-protein-coupled receptors, the
S1P1–5. Distribution and signalling function varies
between the subtypes. S1P1–3 are mainly distributed in the
immune system, CNS and cardiovascular organs, S1P4 in
lymphoid tissue and S1P5 in CNS white matter [
S1P and its receptors regulate circulation of
lymphocytes between blood and lymphoid organs depending on
specific requirements of the immune system and
accomplished by enzymes that regulate sphingolipid
metabolism and partly by a concentration gradient between
lymphoid organs and blood [
Specifically S1P1 on lymphocytes regulates homing
and egress of lymphocytes in and from lymphoid organs.
The active phosphorylated form of fingolimod binds with
high affinity to S1P1 and to a less extent to S1P3–5. For the
treatment of MS, the most important consequence of the
down-regulation (internalization) of S1P1 is that
T-lymphocytes, including potentially auto-aggressive T cells,
remain retained in lymph nodes and their number in the
circulation is considerably reduced (Fig. 1).
Experimental and clinical data indicate that
fingolimod retains naïve T cells and central memory T cells
(TCMs) including Th17 cells in lymphoid tissue. The
proinflammatory Th17 cells may have a central role in CNS
]. In a small prospective observational
study, fingolimod reduced the number of Th17 (IL17
producing cells) by > 90 % [
]. The retention of lymphocytes
does not lead to an enlargement of lymph nodes since
normally only 2 % of the total number of these cells
circulate in the blood.
Fingolimod crosses the blood–brain barrier and the
oral formulation can result in biologically active
concentration in the CNS. It is likely that the drug interacts
directly with S1P receptors on neurons, oligodendrocytes,
astrocytes, and their progenitor cells. In rodent
experimental autoimmune encephalomyelitis models,
fingolimod has demonstrated prophylactic and therapeutic
efficacy, reversing central inflammation, favouring
preservation of the integrity of the blood–brain barrier, and
inducing structural and functional restoration of the CNS
]. Ongoing preclinical and
clinical studies are looking at whether the direct interaction
with S1P receptors in the CNS contributes to the clinical
efficacy of the drug and can provide a clinically relevant
reduction of neurodegenerative processes or initiate
repair mechanisms in MS patients .
Efficacy in clinical trials
Clinical efficacy and safety of Fingolimod have been
evaluated in an extensive development program which has
been already reviewed elsewhere [
]. In short, the
phase II study program consisted of a six-months
placebo-controlled core study of 281 patients with
relapsing MS and a six-months extension switching placebo
patients to active treatment which showed a significant
reduction in the detection of new MS lesions on MRI and
of clinical disease activity for both daily doses of 1.25 or
5.0 mg of fingolimod [
]. In the subsequent follow-up
of these patients, all patients receiving fingolimod 5.0 mg
were switched to 1.25 mg during months 15–24 with no
indication that lowering the dose from 5.0 to 1.25 mg
was associated with a reduction of efficacy [
consistent therapeutic effect was also confirmed after 36
The phase III program consisted of two large trials, the
placebo-controlled FREEDOMS (FTY Research
Evaluating Effects of Daily Oral therapy in Multiple Sclerosis)
and the TRANSFORMS (Trial Assessing Injectable
Interferon versus FTY720 Oral in Relapsing–Remitting
Multiple Sclerosis) studies.
In FREEDOMS, which included a total of 1,272 RRMS
patients, all clinical and MRI efficacy endpoints
significantly favoured both active-treated groups over placebo
with no difference in efficacy between the two
fingolimod doses after 24 months [
]. The annualized relapse
rate (ARR) was 0.18 with 0.5 mg of fingolimod, 0.16 with
1.25 mg fingolimod, and 0.4 with placebo (p < 0.001 for
both fingolimod doses versus placebo). Fingolimod
reduced the risk of disability progression, confirmed after
3 months, over the 24-months period (hazard ratios were
0.70 for the 0.5 mg dose and 0.68 for the 1.25 mg dose;
p = 0.02 vs placebo, for both comparisons). The
cumulative probability of disability progression (confirmed after
3 months) was 17.7 % for fingolimod 0.5 mg, 16.6 % for
fingolimod 1.25 mg, and 24.1 % for placebo. The risk of
disability progression confirmed after 6 months was also
reduced with both doses of fingolimod over the study
period. EDSS scores and MSFC z-scores remained stable
or improved slightly in the active treatment groups and
worsened in the placebo group. Both fingolimod doses
were also superior to placebo with regard to
MRI-related measures. Actively treated patients had significantly
fewer Gd+ lesions than patients on placebo (mean 0.2 vs
1.1) and significantly fewer new or enlarged lesions on
T2-weighted MRI scans at 24 months (mean 2.5 vs 9.8).
Ninety percent of actively treated patients were free of
Gd+ lesions compared to 65 % of placebo-treated
patients. Beneficial effects of fingolimod were also noted on
the volume changes in lesions on T2- and T1-weighted
scans and brain volume reduction was significantly
smaller with fingolimod [
TRANSFORMS compared the efficacy of fingolimod
0.5 or 1.25 mg daily with that of IFN beta-1a at weekly
doses of 30 µg IM over a 12-months period in 1,292
patients with RRMS [
]. The ARR defined as the
primary efficacy endpoint was significantly lower in both
groups receiving fingolimod compared with the INF
beta-1a group (0.20 in the 1.25 mg group, 0.16 in the
0.5 mg group—Fig. 2—and 0.33 in the INF beta-1a group;
p < 0.001). Significantly more relapse-free patients were
found in the two fingolimod groups compared to INF
beta-1a-treated patients (79.8 % for 1.25 mg, and 82.6 %
for 0.5 mg vs 69.3% for INF beta-1a; p < 0.001). Confirmed
disability progression was infrequent in all study groups.
There were no significant differences in the time to
progression of disability or in the proportion of patients with
confirmed progression among the study groups. MRI
findings supported the primary clinical results. Patients in
the two fingolimod groups had significantly fewer new
or enlarged hyperintense lesions on T2-weighted images
(1.5 for 1.25 mg, 1.7 for 0.5 mg, and 2.6 for INF beta-1a) at
12 months compared to the INF beta-1a group and fewer
Gd+ lesions (0.23, 0.14 vs 0.51). The mean percent
reduction in brain volume from baseline to 12 months was
significantly lower in the two fingolimod groups than in the
INF beta-1a group [
In the TRANSFORMS extension study switching from
INF beta-1a to fingolimod led to enhanced efficacy while
continuous treatment with fingolimod over 2 years
provided a sustained treatment effect [
Safety in clinical trials
The most frequent reported adverse events in MS-studies
with fingolimod 0.5 mg were influenza viral infections,
Fig. 2 Adjusted annualized
relapse rate in the
TRANSFORMS study comparing
the efficacy of Fingolimod
with interferon-beta 1a i.m.
(Modified from [
nasopharyngitis, fatigue, back pain, diarrhea, bronchitis,
and nausea. The most common laboratory abnormalities
observed with fingolimod were lymphopenia and
abnormal liver function tests. In the FREEDOMS study,
treatment was discontinued due to adverse events in 7.5 % of
patients on fingolimod 0.5 mg, in 14.2 % of patients on
fingolimod 1.25 mg, and in 7.7 % of patients on placebo,
the rate of any serious adverse event was 10.1, 11.9, and
13.4 %, respectively [
The overall rate of infections was similar in the
fingolimod and placebo groups. Lower respiratory tract
infections were more frequent in the fingolimod groups
compared to the placebo group (9.6, 11.4 vs 6.0 %). After
the first month of the trial, the blood lymphocyte counts
were reduced by 73 % with fingolimod 0.5 mg and by 76 %
with fingolimod 1.25 mg.
After the first dose of fingolimod, heart rate
decreased with a maximum reduction of resting pulse rate of
8 bpm with fingolimod 0.5 mg and 10 bpm with
fingolimod 1.25 mg. Bradycardia was reported in nine patients
on fingolimod 0.5 mg and in 14 on fingolimod 1.25 mg.
Seven of these cases were assessed as serious adverse
events and resolved within 24 h without treatment. Two
patients from the fingolimod 0.5 mg group, six patients
from the fingolimod 1.25 mg group, and three patients
of the placebo group developed first- or second-degree
atrioventricular (AV) block. During extended treatment,
no effects on heart rate were observed.
Macular edema was reported in 7 patients of the
fingolimod 1.25 mg group. The majority of the cases were
diagnosed within the first 3 months of the study and resolved
within 6 months after discontinuation of fingolimod.
Malignant neoplasms were reported in four patients
on fingolimod 0.5 mg, four receiving fingolimod 1.25 mg,
and in ten patients of the placebo group. Eleven of these
cases were skin cancers (basal-cell carcinoma, malignant
melanoma, or Bowen’s disease), three cases in the
fingolimod 1.25 mg group, four cases in the 0.5 mg group, and
four with placebo. All were removed successfully.
The safety profile of the TRANSFORMS trial (Fig. 3) was
very similar to the FREEDOMS study with the addition of
two cases of macular edema and one case of
second-degree AV Block in the 0.5 mg fingolimod group [
Treatment considerations and recommendations
Special safety areas
Based on the pharmacodynamic properties of
fingolimod and its mode of action in MS, special safety areas
have to be mentioned and closely monitored:
• Heart rate and AV conduction at treatment initiation
• Risk of macular edema
• Liver transaminase elevation
• Reproductive toxicity
• Concomitant or prior use of immunosuppressive
Cardiac safety (see addendum)
Initiation of treatment with fingolimod results in a
transient decrease in heart rate and may induce AV
conduction delays (AV block first or second degree). This also
applies to recommencing treatment after an interruption
of more than 14 days. After the first dose, the decline in
heart rate starts within 1 h and is maximal at
approximately 4–5 h. With continued administration, heart rate
returns to baseline within 1 month. Conduction
abnormalities were usually asymptomatic, did not require
treatment, and resolved within 24 h (in the study, two
patients were treated with atropine and one patient was
treated with isoproterenol).
Fig. 3 Adverse event profile
in the TRANSFORMS study
comparing the efficacy of
interferonbeta 1a i.m. (Modified from
Recommendations (see addendum)
In patients with bradycardia (< 55 bpm), AV conduction
delays, sick sinus syndrome, ischemic heart disease or
congestive heart failure, advice from a cardiologist is
recommended before initiating treatment. Treatment
with fingolimod should not be initiated while patients
take Class Ia (e.g. quinidine, procainamide) or Class III
(e.g. amiodarone, sotalol) antiarrhythmic drugs.
Patients receiving beta-blockers or other substances
which may reduce heart rate may have an increased risk
of bradycardia because of additive effects of fingolimod
on heart rate.
All patients should be observed clinically for a period
of at least 6 h for signs and symptoms of bradycardia
following the initial administration of the drug. Should
post-dose bradycardia-related symptoms occur,
appropriate clinical management should be initiated and
observation should continue until symptoms have
resolved and the heart rate is in the normal range.
Fingolimod causes a dose-dependent reduction in
peripheral lymphocyte count to 20–30 % of baseline levels
because of the reversible sequestration of lymphocytes in
lymphoid tissues. Fingolimod may therefore increase the
risk of infections, some serious in nature. In MS studies,
the overall rate of infections (72 %) and serious
infections (2 %) with the 0.5 mg dose was similar to placebo.
However, lower respiratory tract infections, primarily
bronchitis and, to a lesser extent, pneumonia were more
common in fingolimod-treated patients.
Two fatal cases of herpes infections occurred with the
1.25 mg dose: a case of herpes simplex encephalitis in
a patient in whom initiation of acyclovir treatment was
delayed by one week, and a case of primary
disseminated varicella zoster infection in a patient not previously
exposed to varicella receiving concomitant high-dose
steroid therapy for an MS relapse. Even though fatal
infection occurred only in the high-dose group,
opportunistic infection could also happen with lower doses.
A complete blood count should be obtained before
initiation of treatment, at month 1, 3, and 6, and
periodically thereafter to check for abnormalities. An absolute
lymphocyte count of < 0.2 × 109/L should lead to
treatment interruption until recovery.
Initiation of treatment with fingolimod should be
delayed in patients with severe active infection until
Patients should be instructed to report symptoms of
infections during treatment and till 2 months after
treatment discontinuation. Diagnostic measures and
treatment for infections should be started in due time if
indicated. Suspending fingolimod treatment should be
considered during serious infections and consideration
of benefit–risk should be undertaken prior to reinitiation
Patients without a history of chickenpox or without
vaccination against varicella zoster virus (VZV) should
be tested for VZV antibodies. If negative, VZV
vaccination should be considered and treatment with
fingolimod should be postponed until full effect of vaccination
has been achieved.
Macular edema with or without visual symptoms has
been reported in 0.4 % of patients treated with
fingolimod 0.5 mg and in 1.1 % of patients with the higher dose
of 1.25 mg, predominantly in the first 3 to 4 months of
treatment. Some patients presented with blurred vision
or decreased visual acuity, but others were asymptomatic
and diagnosed at routine ophthalmological examination.
The macular edema generally improved or resolved
spontaneously after discontinuation of fingolimod treatment.
Patients with a history of uveitis and patients with
diabetes mellitus are at increased risk of macular edema. It is
recommended that MS patients with a history of uveitis
or diabetes mellitus undergo an ophthalmologic
evaluation before initiating fingolimod treatment and have
follow-up investigations during treatment.
Other patients should have an ophthalmologic
evaluation 3 to 4 months after the initiation of treatment and
at any time symptoms may occur during treatment.
It is recommended that treatment with fingolimod
should be discontinued if a patient develops macular
edema. Whether treatment should be reinitiated after
resolution of macular edema depends on the risk–benefit
evaluation of the individual patient.
During clinical trials, fingolimod 0.5 mg was associated
with a threefold or greater elevation in liver
transaminases in 8 % of treated patients compared to 2 % of the
placebo patients. The mechanism of this effect has not been
identified. The elevation of liver enzymes was generally
asymptomatic, observed after 3 to 4 months of treatment
and turned to normal within approximately 2 months
after discontinuation of fingolimod treatment.
Recent (< 6 months) transaminases and bilirubin levels
should be available before initiation of treatment with
fingolimod. Liver transaminases should be monitored at
month 1, 3 and 6, and periodically thereafter. With
repeated confirmation of liver transaminases above five times
the upper limit of normal, treatment with fingolimod
should be interrupted.
In patients who develop symptoms suggestive of
hepatic dysfunction such as unexplained nausea, vomiting,
abdominal pain, fatigue or jaundice, the liver enzymes
should be checked and fingolimod should be
discontinued if significant liver injury is confirmed.
Patients with severe preexisting hepatic impairment
should not be treated with fingolimod.
Animal studies have shown reproductive toxicity
including fetal loss and organ defects. S1P receptors are
known to be involved in vascular formation during
Women of childbearing potential should be advised
on the potential serious risk for the fetus and the need
of effective contraception during treatment with
fingolimod. Since elimination of fingolimod takes about 2
months after the end of treatment, the potential risk for
the fetus may persist and contraception should be
continued over this time.
Before initiation of treatment in women with
childbearing potential, a negative pregnancy test result is
If a woman becomes pregnant while on
treatment with fingolimod, discontinuation of treatment is
Clinical trial data suggest that no wash-out period is
needed when switching from INF beta or GA to fingolimod if
any immune effects of such therapies have resolved. In
the clinical trials, patients were excluded if treated with
natalizumab, other monoclonal antibodies or cytotoxic
drugs in less than 6 months prior to fingolimod therapy
Natalizumab treatment should be stopped for at least 2
to 3 months before treatment initiation with fingolimod
so as to avoid the risk of cumulative immunosuppression
from the 70 % decrease in total lymphocyte count with
fingolimod. Cytotoxic drugs (e.g. mitoxantrone) should
be washed out for at least 6 months before
commencement of treatment with fingolimod.
A detailed patient management plan for treatment of
RRMS with fingolimod is provided in Table 1.
Selection and management of patients
Fingolimod 0.5 mg daily is the first oral drug for the
treatment of RRMS. At present, it is approved as a first-line
treatment for relapsing forms of MS in the United States,
in Russia, Switzerland, and in the United Arab Emirates.
In Europe, the CHMP defined the indication for
fingolimod as a disease-modifying monotherapy in highly
• For patients with high disease activity despite
treatment with an INF beta (non-responders, treatment
• For patients with rapidly evolving severe RRMS
without prior treatment.
Fig. 4 Patient evaluation
scheme in the concept of
escalating immunotherapy of
RRMS. (Modified from [
Fig. 5 Current options of
for RRMS. (Modified from
From a clinical point of view, treatment failure is defined
as continuing disease activity (in the form of relapses
supported by new or active MRI lesions) and progression
of disability. According to expert opinion this applies in a
similar manner to prior treatment with GA as to that with
INF beta. In clinical practice, unbearable side effects and
low compliance also constitute a kind of treatment
failure. Since no combinations of DMDs and
immunosuppressant or cytotoxic drugs are approved in the case of
a treatment failure and no robust clinical studies on the
efficacy of such combinations are published, the concept
of escalating immunotherapy of the Multiple Sclerosis
Therapy Consensus Group is still appropriate for this
]. The proposed algorithm for patient
evaluation and decision-making is provided in Fig. 4. In a
hierarchy of the existing approved and labelled treatments
of RRMS, fingolimod is positioned equal to natalizumab
in Europe (Fig. 5). The reason for the identically labelled
indications of the two substances in Europe may on one
hand come from their comparable efficacy in clinical and
MRI endpoints of clinical studies. On the other hand, the
potential risk of fingolimod treatment may have been
assessed with caution while long-term experience, as
with any new drug before introduction into clinical
pracA statement of the Central and East European (CEE) MS Expert Group 363
tice, is limited. Excluding the patients at risk by careful
pretreatment examination and follow-up according to
the above recommendations will contribute to the safety
of fingolimod in clinical practice and serve to maximize
patients’ benefits from the advantages of this new drug.
In conclusion, large phase III studies with fingolimod
have shown favorable efficacy compared to placebo and
to a standard treatment with INF beta-1a i.m. and an
acceptable safety profile. The position of fingolimod in
clinical practice will be influenced by issues of long-term
adherence, quality of life, and long-term safety of
patients. To ensure best use of this new treatment for patients
with RRMS, treatment should be initiated by experienced
MS-centers and monitored and documented according
to the recommendations in the six special safety areas.
The authors thank Siegfried Mayerhofer from Cytro
medical and clinical project management GmbH for medical
writing and editorial assistance for the manuscript. This
assistance and the meeting of the expert group were
funded by Novartis Pharma GmbH.
Following submission of this manuscript the EMA started
a review of the cardiovascular safety of Gilenya following
receipt of information related to an unexplained sudden
death in a patient within 24 h of taking Gilenya for the
first time in January 2012 [
]. The Agency reviewed all
available data on the heart safety of Gilenya, including 15
cases of sudden or unexplained death in patients treated
with Gilenya. It noted that most of the deaths and
cardiovascular problems had occurred in patients with a
history of cardiovascular problems or taking other
medicines. However, the data reviewed were not conclusive as
to whether Gilenya was the cause of the deaths.
Therefore, the EMA was of the opinion that the possible risk of
heart problems in patients taking Gilenya could be
minimized by further strengthening the existing warnings on
the cardiovascular effects of the medicine and ensuring
close monitoring of all patients as follows:
Treatment with Gilenya is not recommended [
• In patients with a history of cardiovascular or
cerebrovascular disease. However, if treatment with Gilenya
is considered necessary, advice from a cardiologist
should be sought regarding the appropriate heart
monitoring for these patients when starting treatment.
Monitoring should be at least overnight;
• In patients taking certain antiarrhythmic medicines
(medicines used to restore normal cardiac rhythm);
• In patients taking certain medicines that lower the
heart rate. However, if treatment with Gilenya is
considered necessary, advice from a cardiologist should
be sought as to whether these patients should be
switched to a different medicine that does not lower the
heart rate, or whether they should be continuously
monitored overnight by ECG after the first dose.
When starting treatment with Gilenya, doctors should:
• Before the first dose, check the patient’s blood
pressure, heart rate, as well as their heart by ECG;
• After the first dose, check the patient’s blood pressure
and heart rate every hour for 6 h;
• Doctors are recommended to continuously monitor
the patient’s heart function by ECG for 6 h after the
Doctors are recommended to extend monitoring after
the 6-h period if:
• At the end of the 6-h period, the heart rate is at its
lowest since taking the first dose. In this case, the
monitoring should be extended for at least two more hours
and until the heart rate increases again;
• Patients develop any clinically relevant heart problem
(such as bradycardia or AV block). If so, doctors are
advised to extend the monitoring period at least
overnight and until resolution.
With these risk-minimization measures in place, the
Agency concluded that the benefits of Gilenya continue
to outweigh the risk and updated the Gilenya®
prescribing information [
Conflict of interest
Thomas Berger has participated in meetings sponsored
by and received honoraria (lectures, advisory boards,
consultations) from pharmaceutical companies
marketing treatments for MS: Allergan, AOP, Baxter, Bayer
(Schering), Biogen-Idec, Biotest, CSL Behring, Merck
(Serono), Novartis, Sanofi Aventis, TEVA. His institution
has received financial support by unrestricted research
grants (Allergan, AOP, Biogen-Idec, Berlex, Bayer,
Biotest, CSL Behring, Merck Serono, Sanofi Aventis) and for
participation in clinical trials in MS sponsored by Bayer
Schering, Biogen-Idec, Merck Serono, Novartis,
Octapharma, Roche, Sanofi Aventis, Teva.
Franz Fazekas serves on scientific advisory boards
for Bayer Schering, Biogen Idec, Genzyme, Merck
Serono, Novartis, and Teva Pharmaceutical Industries
Ltd./Sanofi Aventis and has received speaker
honoraria from Biogen Idec, Merck Serono, Novartis, and
Eva Havrdová has received speaker honoraria and
payments for consulting services and clinical trials from
Biogen Idec, Bayer, Genzyme, GSK, Merck Serono, Novartis,
Tanja Hojs Fabjan declares no conflicts of interest.
Alenka Horvat Ledinek declares no conflicts of interest.
Gábor Jakab declares no conflicts of interest.
Samuel Komoly has received honoraria for talks and
payment for occasional consultancy or research
funding from TEVA, Bayer—Schering, Serono, Biogen which
manufacture immunomodulatory drugs used in MS.
Jörg Kraus received financial support for research
activities from Biogen Idec, Bayer, Genzyme,
tis, Merck Serono and Novartis. JK received personal
compensation from Biogen Idec, Bayer, Sanofi-Aventis,
Merck Serono and Novartis for lectures, advisory board
participations and consultations.
Egon Kurcˇa declares no conflicts of interest.
Theodoros Kyriakides declares no conflicts of interest.
L’ubomír Lisý declares no conflicts of interest.
Ivan Milanov declares no conflicts of interest.
Panayiotou Panayiotis declares no conflicts of interest.
Sasa Sega Jazbec declares no conflicts of interest.
Radomír Taláb declares no conflicts of interest.
Latchezar Traykov has received (500–1000 EUR or up to
1500 EUR) honoraria in advisory board fees and lecturer
fees from Novartis, Pfizer, GSK, UCB, Gedeon Richter,
Actavis, CSC Pharmaceuticals.
Turcˇáni Peter declares no conflicts of interest.
Karl Vass received honoraria for lectures and
participations at advisory boards from Allergan, BayerSchering,
Biogen Idec, MerckSerono, Novartis, SanofiAventis and
Norbert Vella has been the recipient of honoraria from
Novartis Pharma, financial support to attend meetings
from Bial, Biogen Idec, GSK, Merz and Novartis.
Open Access: This article is distributed under the terms of the
Creative Commons Attribution License which permits any use,
distribution, and reproduction in any medium, provided the
original author(s) and the source are credited.
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