Research

Original Investigation

Varicella-Zoster Virus Infections in Patients Treated

With Fingolimod
Risk Assessment and Consensus Recommendations
for Management
Ann M. Arvin, MD; Jerry S. Wolinsky, MD; Ludwig Kappos, MD, PhD; Michele I. Morris, MD; Anthony T. Reder, MD; Carlo Tornatore, MD, PhD;
Anne Gershon, MD; Michael Gershon, MD; Myron J. Levin, MD; Mauritz Bezuidenhoudt, MSc; Norman Putzki, MD

Editorial page 10
IMPORTANCE Varicella-zoster virus (VZV) infections increasingly are reported in patients with Author Audio Interview at
multiple sclerosis (MS) and constitute an area of significant concern, especially with the jamaneurology.com
advent of more disease-modifying treatments in MS that affect T-cell–mediated immunity.
Supplemental content at
jamaneurology.com
OBJECTIVE To assess the incidence, risk factors, and clinical characteristics of VZV infections
in fingolimod-treated patients and provide recommendations for prevention and
management.

DESIGN, SETTING, AND PARTICIPANTS Rates of VZV infections in fingolimod clinical trials are
based on pooled data from the completed controlled phases 2 and 3 studies (3916
participants) and ongoing uncontrolled extension phases (3553 participants). Male and
female patients aged 18 through 55 years (18-60 years for the phase 2 studies) and diagnosed
as having relapsing-remitting MS were eligible to participate in these studies. In the
postmarketing setting, reporting rates since 2010 were evaluated.

INTERVENTIONS In clinical trials, patients received fingolimod at a dosage of 0.5 or 1.25 mg/d,
interferon beta-1a, or placebo. In the postmarketing setting, all patients received fingolimod,
0.5 mg/d (total exposure of 54 000 patient-years at the time of analysis).

MAIN OUTCOMES AND MEASURES Calculation of the incidence rate of VZV infection per 1000
patient-years was based on the reporting of adverse events in the trials and the
postmarketing setting.

RESULTS Overall, in clinical trials, VZV rates of infection were low but higher with fingolimod
compared with placebo (11 vs 6 per 1000 patient-years). A similar rate was confirmed in the
ongoing extension studies. Rates reported in the postmarketing settings were comparable (7
per 1000 patient-years) and remained stable over time. Disproportionality in reporting
herpes zoster infection was higher for patients receiving fingolimod compared with those
receiving other disease-modifying treatments (empirical Bayes geometric mean, 2.57 [90%
CI, 2.26-2.91]); the proportion of serious herpes zoster infections was not higher than the
proportion for other treatments (empirical Bayes geometric mean, 1.88 [90% CI, 0.87-3.70]).
Corticosteroid treatment for relapses might be a risk factor for VZV reactivation.

CONCLUSIONS AND RELEVANCE Rates of VZV infections in clinical trials were low with
fingolimod, 0.5 mg/d, but higher than in placebo recipients. Rates reported in the
postmarketing setting are comparable. We found no sign of risk accumulation with longer
exposure. Serious or complicated cases of herpes zoster were uncommon. We recommend
establishing the patient’s VZV immune status before initiating fingolimod therapy and
Author Affiliations: Author
immunization for patients susceptible to primary VZV infection. Routine antiviral prophylaxis
affiliations are listed at the end of this
is not needed, but using concomitant pulsed corticosteroid therapy beyond 3 to 5 days article.
requires an individual risk-benefit assessment. Vigilance to identify early VZV symptoms is Corresponding Author: Norman
important to allow timely antiviral treatment. Putzki, MD, Novartis Pharma AG,
Fabrikstrasse 12-2.03.38, CH-4002
JAMA Neurol. 2015;72(1):31-39. doi:10.1001/jamaneurol.2014.3065 Basel, Switzerland (norman.putzki
Published online November 24, 2014. @novartis.com).

31

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 Research Original Investigation
V
aricella-zoster virus (VZV) is a neurotropic, epidermo-
tropic, and lymphotropic α-herpesvirus that infects more
than 90% of people worldwide.1 Primary infection with
VZV (varicella) is usually acquired in childhood or early adoles-
cence, and infection in adults is rare and often more severe than
in children. Fatal cases with multiple-organ diseases, such as
pneumonia, hepatitis, and coagulopathy, are significantly more
common in healthy adults than in children. Respiratory muco-
sal epithelial cells are presumed to be the first site of infection.
The T cells become infected with VZV in the tonsils and re-
gional lymph nodes and then transport virions to the skin, where
VZV replication results in the typical vesicular lesions of vari-
cella. Varicella-zoster virus gains access to cranial and dorsal root
ganglia and likely to autonomic ganglia by T-cell viremia and
by retrograde transport from skin lesions through the afferent
fibers of the sensory nervous system. Similar to herpes sim-
plex virus types 1 and 2, VZV then establishes life-long latency
in the sensory ganglia.1 Antibodies and T cells specific to VZV
are induced during primary infection and typically protect
against symptomatic reinfections after new exposure in immu-
nocompetent and most immunocompromised individuals. Vari-
cella-zoster virus antibodies are likely to provide a first line of
defense against a new respiratory mucosal inoculation of the
virus, whereas VZV-specific T-cell responses are the major host
defense against symptomatic reactivation of latent VZV, which
results in herpes zoster (HZ), commonly termed shingles.1 In in-
dividuals unable to produce VZV IgG antibodies, T-cell immu-
nity is sufficient to protect against a second episode.2 Varicella-
zoster virus antibodies do not protect against HZ, regardless of
the levels detected in the serum.3 After mid-adulthood, T-cell–
mediated immunity declines with increasing age, and a signifi-
cant decrease in VZV-specific early effectors and cytokine-
producing CD4 + and CD8 + T cells increases the risk for
reactivation of latent virus and the incidence of HZ.4
The available literature on the incidence of clinically symp-
tomatic VZV infections or HZ in patients with multiple sclero-
sis (MS) is limited. Herpes zoster has been reported in pa-
tients who receive disease-modifying treatments (DMTs) for
MS, such as natalizumab, alemtuzumab, and fingolimod.5-10
Fingolimod, 0.5 mg/d (Gilenya [FTY720]; Novartis Pharma
AG), has shown superior efficacy to the approved first-line treat-
ment, interferon beta-1a, and placebo in three phase 3 studies8-10
and is currently approved as a once-daily oral therapy for re-
lapsing forms of MS. The therapeutic effects of fingolimod are
mediated via the modulation of sphingosine 1-phosphate (S1P)
receptors by fingolimod phosphate, a phosphorylated active
moiety of fingolimod. In vivo, fingolimod-phosphate binds as
an analogue of S1P to S1P receptor 1 (S1P1) receptors on lympho-
cytes to trigger receptor internalization and degradation. This
process leads to the inhibition of S1P signaling and the selec-
tive retention of CCR7+ lymphocytes in the lymphoid organs.
As a consequence, predominant levels of CD4-naive T cells and
central memory T cells (TCM), but not effector memory T cells
(TEM), are reduced in the circulation.11,12
The recently approved MS DMTs all lead to distinct altera-
tions of immune surveillance.13-15 Infections with VZV may be
seen more frequently with the more efficacious DMTs in clini-
cal practice, and increased vigilance is warranted. Preven-
32 JAMA Neurology January 2015 Volume 72, Number 1
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Varicella-Zoster Virus Infections in MS
tion and management of VZV infections, predominantly HZ
in adults with MS receiving DMTs, is a topic of clinical
relevance.
Methods
Patient Population
We based our analyses on the pooled data from the double-
blind phases of 6 completed phase 2 and 3 studies (3916 par-
ticipants) of fingolimod in MS and from any ongoing exten-
sion phases of these studies as of August 31, 2012 (3553
participants) (clinicaltrials.gov identifiers: NCT00333138,
N C T 0 0 2 3 5 43 0 , N C T 0 0 2 8 9 9 7 8 , N C T 0 03 4 0 83 4 , a n d
NCT00355134).8-10,16 Institutional review board approval was
obtained at all sites, and participants provided written in-
formed consent, as detailed previously.8-10,16 Male and fe-
male patients aged 18 through 55 years (18-60 years for the
phase 2 studies) and diagnosed with relapsing-remitting MS
were eligible to participate in these studies. Details of the study
population have been presented elsewhere.8-10,16 Serologic test-
ing using an enzyme-linked immunoassay for VZV IgG anti-
bodies was introduced as a protocol amendment during the
pivotal phase 3 studies. All patients with positive test results
after randomization continued the study. For patients with
negative test results after randomization, increased vigilance
for infections was implemented. Patients who were found to
be seronegative for antibodies before randomization were not
included in these studies.
Assessments and Analysis
Calculation of the incidence rate of VZV infections was based
on the reporting of adverse events in the respective trials. The
incidence is reported per 1000 patient-years, which was de-
fined as the sum of days all patients in each treatment group
received the study drug divided by 365.25 days. The number
and percentage of patients with VZV infection was summa-
rized for patients who received concomitant systemic corti-
costeroid dosages of no more than 1000 mg/d for the treat-
ment of relapses. For the postmarketing incidence of VZV
infection, we conducted a search of the US Food and Drug Ad-
ministration Adverse Event Reporting System database to iden-
tify spontaneously reported adverse events consisting of
HZ.17,18 The search included reported frequency and propor-
tion of HZ infection for all drugs, including fingolimod and
other DMTs for MS, from January 1, 1994, through June 30,
2012. Point estimates of the disproportionality in reporting fin-
golimod vs other DMTs for MS were assessed using the ad-
justed value of a ratio of observed to expected reports (em-
pirical Bayes geometric mean [EBGM]). The lower limit of a 90%
CI of the EBGM above the threshold of 2.0 is considered to in-
dicate a potential signal that deserves further investigation.
All these analyses were undertaken using the following pre-
ferred terms from the Medical Dictionary for Regulatory Ac-
tivities, version 15.119: herpes zoster, herpes zoster dissemi-
nated, herpes zoster infection neurological, herpes zoster
multidermatomal, herpes zoster ophthalmic, herpes zoster oti-
cus, and postherpetic neuralgia.
jamaneurology.com
 Varicella-Zoster Virus Infections in MS
Table 1. Incidence Rate of HZ Events per 1000 Patient-years by Severity in Clinical Trials and Extensionsa
No. of Cases Reported (Patient-year Rateb)
Double-blind Controlled Studiesc
Fingolimod, 1.25 mg/d Fingolimod, 0.5 mg/d
HZ Event (1661 Patient-years) (1716 Patient-years)
Skin involvement
≤2 Contiguous dermatomes 17 (10.2) 18 (10.4)
Bilateral or >2 contiguous 3 (1.8) 0 0
dermatomes
Disseminatede 1 (0.6) 0 0
Ophthalmic 0 1 (0.5)
Oticus 0 0
Encephalitis 0 0
Abbreviation: HZ, herpes zoster.
a
Diagnosis of HZ is based on clinical symptoms and investigating physicians’
judgment. Data cutoff was August 31, 2012.
b
Calculated by the following formula: No. of cases/(patient-year × 1000).
Patient-years were defined as the sum of the number of days receiving the
study drug for all patients in each treatment group divided 365.25 days.
c
Treatment time in the double-blind phase of the completed clinical trials is 3
months (vaccination study), 6 months (phase 2 study), and 24 months
(FREEDOMS [FTY720 Research Evaluating Effects of Daily Oral therapy in
Multiple Sclerosis]8 and FREEDOMS II10) for placebo; 3 months (vaccination
Results
Fingolimod Clinical Studies Data
Although the overall incidence of VZV infection was low, the in-
cidence was higher in fingolimod recipients (11 per 1000 patient-
years) compared with placebo recipients (6 per 1000 patient-
years) in the MS randomized clinical trials. More cases occurred
during the first 6 months of fingolimod treatment. Uncompli-
cated cutaneous HZ involving a single dermatome or 2 adja-
cent dermatomes was the most common presentation of HZ
across all treatment groups (Table 1). No increase in incidence
was observed for up to 7 years in the extension studies, and the
profile of patients who developed HZ did not differ from that
of patients without HZ with respect to age, duration of fingoli-
mod treatment, other treatments, or previous DMT use.
Two fatal cases of VZV infection were reported in pa-
tients treated with fingolimod. In a clinical trial, a patient who
had received fingolimod, 1.25 mg/d, for 10 months died of dis-
seminated VZV primary infection (reported in May 2008).9 The
second fatal case was VZV reactivation (reported in April 2013)
that occurred in a patient who was seropositive for VZV anti-
bodies before initiating fingolimod therapy, 0.5 mg/d, for 6
months in a postmarketing observational study (the prior DMT
was natalizumab, and the washout period was approxi-
mately 3 months) (Novartis Pharma AG; annual Periodic Safety
Update Report to US Food and Drug Administration; submit-
ted on October 18, 2013 [data not available in the public do-
main]). Both cases received approximately 10 days of con-
comitant corticosteroid therapy. Details of the cases are given
in the eAppendix in the Supplement.
After this second case was reported, integrated analysis of
the data was conducted to assess the potential impact of con-
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Original Investigation Research
Double-blind Controlled Studies
and Long-term Extensionsd
Placebo Fingolimod, 1.25 mg/d
(1305 Switched to 0.5 mg/d Fingolimod, 0.5 mg/d
Patient-years) (4402 Patient-years) (4136 Patient-years)
7 (5.3) 41 (9.3) 49 (11.8)
6 (1.3) 2 (0.4)
1 (0.2) 0
0 5 (1.1) 4 (0.9)
0 1 (0.2) 0
0 0 0
study), 12 months (TRANSFORMS [Trial Assessing Injectable Interferon versus
FTY720 Oral in Relapsing-Remitting Multiple Sclerosis]9; only fingolimod arms
included), and 24 months (FREEDOMS8 and FREEDOMS II10) for fingolimod.
d
Treatment time in the double-blind and extension phases of the clinical trials
was as long as 4 years for fingolimod, 0.5 mg/d (FREEDOMS,8 TRANSFORMS,9
and FREEDOMS II10 extension studies), and as long as 7 years for fingolimod,
1.25 mg/d, switched to 0.5 mg/d (phase 2 extension study).
e
Indicates presence of bilateral lesions or lesions affecting more than 2
contiguous dermatomes (cutaneous dissemination) or in other organs than
the skin.
comitant administration of corticosteroids as a risk factor for VZV
infection or severity in patients receiving fingolimod. No appar-
ent relationship between HZ and systemic corticosteroid use for
fingolimod (all dosages) or placebo was noted. Of 41 cases in the
fingolimod arm, only 5 occurred during or within 30 days of con-
comitant corticosteroid use (Table 2). However, corticosteroid
use was limited to a maximum of 5 days per the protocol.
Postmarketing Data
Reporting Rate of VZV Infections
As of February 28, 2013, a total of 60 873 patients had received
fingolimod therapy in the postmarketing setting, which con-
stituted approximately 54 000 patient-years of drug expo-
sure. The reporting rate of HZ infection is 7 per 1000 patient-
years and has remained stable since the launch of fingolimod
in 2010 (Figure 1). These incidence rates are slightly lower than
those observed in the clinical trials.8-10,16 In a separate analysis
performed using databases that report spontaneous adverse
events to identify any disproportionate reporting of an ad-
verse event,17,18 higher rates of HZ were observed for fingoli-
mod (EBGM, 2.57 [90% CI, 2.26-2.91]) compared with all other
DMTs for MS (Novartis Pharma AG; annual Periodic Safety Up-
date Report to US Food and Drug Administration; submitted on
October 18, 2013 [data not available in the public domain]).
Severity
Serious or complicated cases of HZ were uncommon. The in-
volvement of more than 2 dermatomes was reported in 27 of
339 HZ cases (8.0%). The overall incidence rate of compli-
cated HZ is estimated at 1 per 1000 patient-years.17,18 The dis-
proportionate reporting assessment showed that the propor-
tion of serious HZ infections during fingolimod treatment is
not higher (lower confidence limit, <2) compared with those
JAMA Neurology January 2015 Volume 72, Number 1 33
 Research Original Investigation Varicella-Zoster Virus Infections in MS

Table 2. Incidence Rate of HZ Events per 1000 Patient-years by Corticosteroid Use in Controlled Clinical Trialsa

No. of Patients With Event/No. of Patients Treated With Corticosteroids (%)

Fingolimod, 1.25 mg/d Fingolimod, 0.5 mg/d Placebo
VZV-Related Adverse Event (n = 1313) (n = 1212) (n = 866)
Yes
Within 30 d of the last dose of corticosteroidb 3/445 (0.7) 2/387 (0.5) 0
Outside 30-d corticosteroid window 10/445 (2.2) 9/387 (2.3) 4/460 (0.9)
No 432/445 (97.1) 376/387 (97.2) 456/460 (99.1)
b
Abbreviations: HZ, herpes zoster; VZV, varicella-zoster virus. Includes 500 to 1000 mg of intravenous methylprednisolone daily for 3 to 5
a
Treatment time in the double-blind phase of clinical trials was 6 months days with or without a subsequent tapering dosage of oral corticosteroids
(phase 2 study) and 24 months (FREEDOMS8 and FREEDOMS II10) for placebo (most often prednisone) for 1 to 3 weeks. Specific decisions as to dosage,
and 12 months (TRANSFORMS9; only fingolimod arms included) and 24 duration of treatment, and whether a taper is used are based on the type of
months (FREEDOMS8 and FREEDOMS II10) for fingolimod. relapse and the clinicians’ judgment.

subjects.20-23 In an age-adjusted retrospective analysis of claims

Figure 1. Cumulative Reporting of Varicella-Zoster Virus (VZV) Infections
in the Postmarketing Setting databases, HZ incidence was approximately twice as high in
patients with MS as in the general population (6 per 1000 pa-
10 tient-years) (Novartis Pharma AG; annual Periodic Safety Up-
date Report to US Food and Drug Administration; submitted
on October 18, 2013 [data not available in the public do-
8
main]). The observed rate of HZ was higher in patients receiv-
1000 Patient-years of Exposure
Observed Reporting Rate per

ing fingolimod compared with those receiving placebo in the

6
4 ting, reporting rates were lower than those of clinical trials, and
2
VZV only
VZV + herpes unspecified
0 exposure data, validation of clinical details, and potential bi-
September 1, 2011, to March 1, 2012, to
February 29, 2012 August 31, 2012
Herpes unspecified indicates VZV infection with further information regarding
the infection type and/or severity not specified in the spontaneous report. Error
bars indicate 90% CIs.
for other MS DMTs (EBGM, 1.88 [90% CI, 0.87-3.70]) (Novar-
tis Pharma AG; annual Periodic Safety Update Report to US Food
and Drug Administration; submitted on October 18, 2013 [data
not available in the public domain]). Noncutaneous manifes-
tations were uncommon. The reporting rate of visceral dis-
semination was less than 0.1 per 1000 patient-years. Only a few
cases of recurrent nonserious dermatomal HZ cases have been
reported to date (Novartis Pharma AG; annual Periodic Safety
Update Report to US Food and Drug Administration; submit-
ted on October 18, 2013 [data not available in the public do-
main]).
Discussion
Although it is unclear whether patients with MS have in-
creased susceptibility to HZ, several population-based epide-
miological and case-control studies suggest that they might
be at greater risk for HZ compared with healthy control
clinical trials. The rates were similar and remained stable for
patients continuing to receive fingolimod during the long-
term extensions for up to 7 years. In the postmarketing set-
no increase in the cumulative reporting rate since 2010 was ob-
served (exposure, 54 000 patient-years as of February 28, 2013).
However, the postmarketing reporting of spontaneous ad-
verse events has limitations, such as underreporting, lack of
September 1, 2012, to
ases (eg, stimulated reporting).24 Effective risk mitigation, such
February 28, 2013 as VZV immunization recommended by the fingolimod label,
may affect the actual risk. Comparison of the fingolimod ex-
perience with that of other DMTs is difficult owing to study
differences in patient characteristics, reporting of HZ occur-
rence, and concomitant medications (Figure 2).6,7,25-29 Based
on reports of adverse events, HZ was documented more of-
ten with fingolimod than with other DMTs, such as interferon
beta, but the proportion of complicated HZ cases was not higher
(reporting rate, 1 per 1000 patient-years in the postmarketing
setting). We acknowledge that the analysis of HZ severity is
based on limited case numbers and the reported 90% CI is wide
(0.80-3.70). Disproportionality analysis methods other than
EBGM are available but were not applied for this analysis.30
These reporting rates may be influenced by increasing aware-
ness about VZV infections over time and by recommenda-
tions in the product information and educational materials (for
Gilenya) and may be confounded by differences in MS dis-
ease characteristics and previous DMT exposure.
To control VZV reactivation, T-cell immunity is critical.
Central memory T cells are intermediate memory T cells that
do not yet display effector function. However, TCMs are the
basis for long-term immunity and form the reactive memory,
rapidly proliferating and giving rise to TEMs on strong anti-
gen challenge. In the case of VZV infections, fingolimod may
reduce the recirculation of specific CD4+ TCMs by retaining

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 Varicella-Zoster Virus Infections in MS Original Investigation Research

Figure 2. Incidence of Varicella-Zoster Virus (VZV) Infections in Fingolimod Trials and Comparison With Other
Treatments and Conditions

Fingolimod Clinical Trials and Extensions

Interferon-beta
Placebo
Controlled Trials Fingolimod, 0.5 mg/d
Fingolimod, 1.25 mg/d
Controlled Trials +
Extensions

0 5 10 15 20 25 30 35 40 45 50 55 60 65 70 75
Incidence Rate per 1000 Patient-years
Natalizumab Placebo-Controlled Studies25 of MS

Natalizumab

Placebo

0 5 10 15 20 25 30 35 40 45 50 55 60 65 70 75
Incidence Rate per 1000 Patient-years

DEFINE,26 CONFIRM,27 and Phase 228

Dimethyl Fumarate,
240 mg TID

Dimethyl Fumarate, Vertical dashed lines at 3.7 and 5.6

240 mg BID per 1000 patient-years are
background rates in the general
Placebo
population and patients with multiple
sclerosis (MS) that one would expect
in a population of the same age
0 5 10 15 20 25 30 35 40 45 50 55 60 65 70 75 distribution as the patients treated in
Incidence Rate per 1000 Patient-years fingolimod clinical trials. Because the
incidence of VZV varies with age, the
REFLEX29
background rates were adjusted to
Rituximab the age of the patient population
enrolled in fingolimod clinical trials.
The shaded area throughout the
0 5 10 15 20 25 30 35 40 45 50 55 60 65 70 75
graph represents the incidence rate in
controlled clinical trials for
Incidence Rate per 1000 Patient-years
fingolimod, 0.5 mg/d.6-8,10,16,25-29
Error bars indicate 90% CIs.
CARE-MS I7 and CARE-MS II6 BID indicates twice daily; CARE,
Interferon-beta CARE-MS I Comparison of Alemtuzumab and
CARE-MS II Rebif Efficacy in Multiple Sclerosis;
CARE-MS I CONFIRM, Comparator and an Oral
Alemtuzumab,
12 mg/d CARE-MS II Fumarate in RRMS; DEFINE,
Determination of the Efficacy and
Alemtuzumab, CARE-MS II
Safety of Oral Fumarate in
24 mg/d
Relapsing-Remitting Multiple
Sclerosis (RRMS); RA, rheumatic
0 5 10 15 20 25 30 35 40 45 50 55 60 65 70 75 arthritis; REFLEX, Randomized
Incidence Rate per 1000 Patient-years Evaluation of Long-term Efficacy of
Rituximab in RA; TID, thrice daily.

them in the lymph nodes, thereby preventing their wider dis-
tribution to the sites of VZV replication, such as the skin (and
possibly the ganglia). As a consequence, the generation of
TEMs from TCMs would be restricted to tissues that harbor
sufficient numbers of TCMs, which may reduce VZV-specific
immune control and may be especially problematic as a
result of confounding factors, such as immune suppression
by corticosteroid use. In contrast, antiviral CD8 T-cell immu-
nity would be largely preserved during treatment with fingo-
limod because CD8 T-cell immunity predominantly results
from CCR7-linked TEMs that are not retained in the lymph
nodes by the drug.11,12
Studies showing intact T-cell immune responses to non-
specific and specific stimuli during fingolimod treatment sug-
gest that the pharmacodynamic effect of fingolimod leading
to the ubiquitous reduction of circulating TCMs may not be re-
sponsible for increased HZ incidence.12 However, informa-
tion about the effects on VZV-specific T-cell responses is lim-
ited at present.31 Varicella-zoster virus–specific T cells are
normally present at low frequencies, and the occurrence of HZ
infection in individuals without underlying disease is associ-
ated with a rapid and substantial increase in these cells.32 Vari-
cella-zoster virus–specific T cells have multiple functions, in-
cluding production of key cytokines that orchestrate local

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 Research Original Investigation
Box 1. Recommendations to Mitigate Risk for VZV Infection
During Fingolimod Treatment
Varicella (Chickenpox) Vaccination: Prevention of Primary Varicella
Evidence of immunity to varicella should be sought before initiating
MS therapy.
Patients with no varicella immunity should be vaccinated (if they have
no contraindication) with 2 doses of Varivax/Varilrix separated by 4
weeks.a
In case of treatment with high-dose corticosteroids, vaccination
should be administered at least 30 days after the last corticosteroid
dose.
Live-attenuated vaccines are contraindicated during fingolimod
therapy. Varicella vaccination should not be given during fingolimod
treatment; initiation of treatment with fingolimod should be
postponed for 1 month after the second dose of vaccine.
Corticosteroid Treatment
Use of corticosteroids may increase the risk for VZV reactivation.
When possible, corticosteroid treatment for relapses should be
limited (3-5 days of intravenous methylprednisolone without
tapering) in patients receiving fingolimod.
Corticosteroid treatment with a higher dosage or for a longer
duration should be evaluated on an individual basis.
Antiviral prophylaxis is not recommended routinely but can
be considered in patients requiring prolonged or repeated
high-dose corticosteroid treatment.
Vigilance Toward Early Recognition and Treatment
of VZV Infections
In patients who have evidence of dissemination, including
symptoms of severe abdominal pain, MS therapy should be
discontinued and intravenous antiviral therapy as per the current
CDC-ACIP guidelines35 should be initiated.
Antiviral treatment in case of suspected VZV infection should be
implemented as per CDC-ACIP guidelines.
Patients receiving immunomodulatory therapies should be
educated to identify signs and symptoms of primary varicella and
recurrent HZ infections with VZV and report them promptly.
Prolonged antiviral treatment may be required for
immunocompromised patients.
Abbreviations: CDC-ACIP, Centers for Disease Control and Prevention–
Advisory Committee on Immunization Practices; HZ, herpes zoster; MS,
multiple sclerosis; VZV, varicella-zoster virus.
a
Zostavax (Merck & Co, Inc) is a live-attenuated vaccine approved for the
prevention of HZ in otherwise healthy elderly people. It contains a 14-fold
increased viral concentration compared with Varivax (Merck & Co, Inc).
Safety in the MS population is not yet established.
cell-mediated control of infection and cytotoxic effects against
infected cells.32 In a 4-week study in healthy volunteers, fin-
golimod at the 0.5 mg/d dosage had a mild to moderate inhibi-
tory effect on T-cell–dependent and T-cell–independent im-
mune responses. 33 However, the immunogenicity of the
neoantigen keyhole limpet hemocyanin was similar to the ef-
fect observed with placebo. Recall antigen responses, as as-
sessed by anti–tetanus toxoid immunogenicity and delayed-
type hypersensitivity, were not affected.33 In a smaller study
that included fingolimod-treated patients with MS and un-
treated healthy controls, humoral immune responses to in-
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Varicella-Zoster Virus Infections in MS
fluenza vaccine and the induction of circulating influenza-
specific T cells were comparable. Despite CD4+ and CD8+ T-cell
lymphopenia, the recently activated T cells may override the
dependency on S1P1 signaling for egress from the lymph nodes
by down-modulation of CCR7.34 Thus, the functionality of T
cells appears to be intact during fingolimod therapy. A recent
study31 assessed the immune responses to VZV in patients
treated with fingolimod compared with healthy controls, un-
treated patients with MS, and patients treated with other DMTs
(glatiramer acetate or interferons). The study reported that fin-
golimod treatment of patients with MS lowered VZV-specific
immunity and suggested that subclinical VZV reactivation,
demonstrated by polymerase chain reaction detection of VZV
DNA in the saliva, was higher among patients treated with fin-
golimod compared with untreated patients with MS and
healthy controls. However, patient groups were combined in
the statistical analysis, and the numbers were small. Varicella-
zoster virus DNA was not detected in blood, and none of the
fingolimod-treated patients developed clinically apparent HZ.31
Compared with CD4+ TEMs, CD8+ TEM cells are less af-
fected by fingolimod treatment and might help to control VZV
reactivation despite a drop in CD4 cell levels. Other immune
responses, such as production of interferon-γ by CD3+ T cells
and by tissue-resident T cells, may provide antiviral control that
is unaffected by fingolimod.11 In some cases, a subclinical re-
activation may trigger the recruitment of lymphocytes from
naive and TCM pools in lymph nodes to support the TEM re-
sponse and prevent clinically apparent VZV infection.
Recommendations for Management and Risk Mitigation
Three areas of risk minimization for VZV infections in pa-
tients with MS have been identified. These may also apply to
patients treated with DMTs other than fingolimod (Box 1).
Prevention of Primary VZV Infection
Any adult who has not had varicella should be vaccinated (in
the absence of contraindications) with one of the licensed live
attenuated varicella vaccines because primary VZV infection
is significantly more severe and occasionally fatal in adults. The
VZV immune status of adults should be determined at the time
of MS diagnosis 35(Box 2). However, commercially available as-
says have limited sensitivity; 10% to 15% false-negative and 8%
to 11% false-positive results often occur.36,37 Previous VZV in-
fection can also be confirmed by the assessment of the pa-
tient’s history of varicella diagnosis by a health care profes-
sional (Box 2). 35 If a patient with a history of household
exposure did not develop varicella, preexisting immunity may
be the reason. Few individuals with MS will have been given
varicella vaccine because it was only licensed in 1995 or later.
However, if the patient’s medical record shows that he or she
received 2 doses of varicella vaccine, serologic testing is not
indicated and additional doses of vaccine are not needed.
If the clinical history and serologic testing suggest that the
patient is susceptible to primary VZV infection, varicella vac-
cination should be given as listed in Box 1. Vaccination of in-
dividuals who may be in the false-negative serologic group is
not detrimental. The vaccine should not be given while the pa-
tient is receiving antiviral drugs active against VZV to avoid
jamaneurology.com
 Varicella-Zoster Virus Infections in MS Original Investigation Research

blocking efficacy. If a vaccine recipient develops a rash pre-

sumed to be caused by the vaccine virus, appropriate antivi-
ral therapy with acyclovir or related drugs should be initiated
promptly.38
Assessing the level of VZV T-cell–mediated immunity in
patients with MS is not possible in the clinical setting. Repeti-
tive attempts to quantitate circulating VZV IgG antibodies have
no predictive value for assessing the risk for HZ. Consistent with
the epidemiological data from the general population, more
than 95% of the adult MS population undergoing testing in the
fingolimod clinical trials was found to be seropositive for VZV
antibodies. Based on limited testing results, fingolimod had
no apparent effect on the VZV antibody status of participants
in the clinical trials.
Prevention of HZ
The risk for HZ infection is reduced in individuals without un-
derlying diseases when they are given a single-dose HZ vac-
cine (Zostavax; Merck & Co, Inc).39 However, the efficacy and
safety of this live-attenuated vaccine have not been estab-
lished in patients with MS.
Concomitant treatment with corticosteroids may in-
crease the risk for VZV reactivation. Duration of corticoste-
roid treatment for relapses in fingolimod clinical trials was
limited (3-5 days of treatment with intravenous methyl-
prednisolone without tapering). Decisions regarding dosage
and duration of corticosteroid treatment in individual pa-
tients require the physician’s judgment. Current data do not
support the general use of antiviral prophylaxis in patients re-
ceiving fingolimod given the low incidence of HZ infection.
However, antiviral prophylaxis may be considered when
prolonged or repeated high-dose corticosteroid use is deemed
necessary.
Vigilance Toward Early Symptom Recognition and
Treatment of HZ
Patients receiving fingolimod should be educated about early
symptoms and signs of varicella or HZ and the need to report
them promptly, as well as the possible increased risk when con-
comitant corticosteroids are prescribed. Antiviral treatment for
suspected VZV infection should be implemented as per the
guidelines for such treatment in immunocompromised
patients.38 The route of administration and the dose of acy-
clovir are determined by the extent of the immunosuppres-
sion and severity of infection. Because fingolimod has a half-
Box 2. Evidence of Immunity to Varicella (CDC-ACIP
Recommendations)35
Criteria for Determining Persons Who Can Be Considered Immune
to Varicella
Documentation of age-appropriate vaccination with varicella
vaccine
Laboratory evidence of immunitya or laboratory confirmation of the
disease
Birth in the United States before 1980b
Diagnosis or verification of history of varicella disease by a health care
provider
Diagnosis or verification of history of HZ by a health care provider
Abbreviations: CDC-ACIP, Centers for Disease Control and
Prevention–Advisory Committee on Immunization Practices; HZ, herpes
zoster.
a
Commercial assays may lack sensitivity for detecting vaccine-induced
immunity.
b
For health care personnel, pregnant women, and immunocompromised
persons, birth before 1980 should not be considered evidence of immunity.
life of 9 days,40 continuing its use in patients presenting with
uncomplicated HZ is reasonable because treatment interrup-
tion is unlikely to affect the recovery from HZ in response to
antiviral therapy.
Conclusions
Analysis of all available data has not identified obvious risk fac-
tors for VZV infections, such as duration of treatment, age, pre-
vious treatment, or concomitant corticosteroid use, in pa-
tients treated with fingolimod. That corticosteroids suppress
the immune system and extended corticosteroid treatment is
expected to be associated with additional risks are well
established. Therefore, the longer-term use of concomitant cor-
ticosteroids (beyond 3-5 days of high-dose intravenous
methylprednisolone for MS relapses) requires a careful risk-
benefit assessment. Proper patient education along with imple-
mentation of the recommendations and risk mitigation strat-
egies (Boxes 1 and 2) provide a systematic approach
for management of VZV infections in patients receiving
fingolimod.

ARTICLE INFORMATION
Accepted for Publication: September 1, 2014.
Published Online: November 24, 2014.
doi:10.1001/jamaneurol.2014.3065.
Author Affiliations: Department of Pediatrics,
Stanford University School of Medicine, Stanford,
California (Arvin); Department of Neurology, The
University of Texas Health Science Center at
Houston (Wolinsky); Department of Neurology,
University Hospital Basel, Basel, Switzerland
(Kappos); Department of Infectious Diseases,
University of Miami, Miami, Florida (Morris);
Department of Neurology, University of Chicago
Medical Center, Chicago, Illinois (Reder);
Department of Neurology, MedStar Georgetown
University Hospital, Washington, DC (Tornatore);
Department of Pediatrics, Columbia University,
New York, New York (A. Gershon); Department of
Pathology and Cell Biology, Columbia University,
New York, New York (Michael Gershon);
Department of Pediatrics, University of Colorado
Anschutz Medical Campus, Aurora (Levin); Novartis
Pharma AG, Basel, Switzerland (Bezuidenhoudt,
Putzki).
Author Contributions: Mr Bezuidenhoudt and Dr
Putzki had full access to all the data in the study and
take responsibility for the integrity of the data and
the accuracy of the data analysis.
Study concept and design: Arvin, Wolinsky, Kappos,
Tornatore, M. Gershon, Levin, Putzki.
Acquisition, analysis, or interpretation of data:
Arvin, Wolinsky, Kappos, Morris, Reder, Tornatore,
A. Gershon, Levin, Bezuidenhoudt, Putzki.
Drafting of the manuscript: Arvin, Wolinsky,
Kappos, Reder, Tornatore, Levin, Bezuidenhoudt,
Putzki.
Critical revision of the manuscript for important
intellectual content: Arvin, Wolinsky, Kappos,
Morris, Reder, Tornatore, A. Gershon, M. Gershon,
Levin, Putzki.

jamaneurology.com JAMA Neurology January 2015 Volume 72, Number 1 37

Copyright 2014 American Medical Association. All rights reserved.

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 Research Original Investigation
Statistical analysis: Reder, Bezuidenhoudt, Putzki.
Study supervision: Kappos, Putzki.
Conflict of Interest Disclosures: Dr Arvin received
a consulting fee from Novartis for participation in a
workshop on herpes zoster and fingolimod and for
her work in preparing this manuscript. She
conducted this research as part of a personal
outside consulting arrangement with Novartis; the
research and research results are not in any way
associated with Stanford University. Dr Wolinsky
has received fees from Novartis as a consultant and
steering committee member for their drug
development programs in multiple sclerosis (MS).
Dr Kappos participated during the last 24 months as
principal investigator, member, or chair of the
planning and steering committees or the advisory
boards in corporate-sponsored clinical trials in MS
and other neurological diseases sponsored by
Actelion, Addex, Allozyne, Bayer HealthCare
Pharmaceuticals, Bayer Schering Pharma, Biogen
Idec, CLC Behring, GeNeuro SA, Genzyme,
GlaxoSmithKline, Lilly, Merck Serono, Mitsubishi
Pharma, Novartis, Octopharma, Ono Pharma,
Praxicon, Roche, sanofi-aventis, Santhera, Siemens,
Teva, and XenoPort and has lectured at medical
conferences or in public on various aspects of the
diagnosis and management of MS, often sponsored
by nonrestricted educational grants to the
institution from one or another of the above listed
companies. Honoraria and other payments for all
these activities have been used exclusively for
funding of research in his department. Research
and the clinical operations (nursing and patient care
services) of the MS Center in Basel have been
supported by nonrestricted grants from one or
more of these companies and by grants from the
European Union, the Swiss MS Society, the Swiss
National Research Foundation, and the Gianni
Rubatto, Novartis, and Roche Research
Foundations. Dr Morris received a consulting fee
from Novartis for the workshop. Dr Reder received
a grant for translational research consultation and is
a trialist for Novartis and most other companies and
agencies trying to cure MS. Dr Tornatore received a
consulting fee from Novartis. Dr A. Gershon has
served as a paid Novartis consultant. Dr M. Gershon
has received research grants from the National
Institutes of Health. Dr Levin received a consulting
fee from Novartis for issues that preceded
developing this manuscript, receives funds as a
consultant for Merck Research Laboratories, shares
in a patent for Zostavax, and serves on an
adjudication committee for GlaxoSmithKline for an
investigational herpes zoster vaccine. Mr
Bezuidenhoudt and Dr Putzki are employees of
Novartis Pharma AG.
Funding/Support: This study was supported by
Novartis Pharma AG, who convened the Advisory
Board and provided manuscript writing support.
Role of the Funder/Sponsor: Novartis Pharma AG
contributed to the design and conduct of these
studies and to the collection, management,
analysis, and interpretation of the data. Employees
had the opportunity to review the manuscript. The
funding source had no role in the preparation or
approval of the manuscript and decision to submit
the manuscript for publication.
Additional Contributions: Uma Kundu, MPharm,
and Hashem Salloukh, PhD, Medical
Communications, Novartis Pharma AG, provided
medical writing support, including literature search,
preparation of manuscript draft, revising the draft,
38 JAMA Neurology January 2015 Volume 72, Number 1
Copyright 2014 American Medical Association. All rights reserved.
Downloaded From: on 03/21/2018
and editing the paper for submission under author
guidance. No financial compensation was given for
this support.
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