Sequencing of Disease Modifying Treatments in Multiple Sclerosis - Belinda Weller
Teaching Course 1 Disease modifying treatment - …...Teaching Course 1 Disease modifying treatment...
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Teaching Course 1
Disease modifying treatment
Chairs: R.J. Fox (Cleveland, US) L. Kappos (Basel, CH)
1 New MS treatments and updates on established treatments R.J. Fox (Cleveland, US)
2 Assessing and mitigating risks: the right treatment for the right patient S. Vukusic (Lyon, FR)
3 Defining what is working: choosing a therapeutic strategy L. Kappos (Basel, CH)
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New MS Treatments and
Updates on Established Treatments
Robert J. Fox, MD Staff Neurologist, Mellen Center for Multiple Sclerosis
Vice-Chair for Research, Neurological Institute Cleveland Clinic, Cleveland, OH, USA
Disclosures: Dr. Fox receives personal consulting fees from Actelion, Biogen, Genentech, Novartis, Mallinckrodt, MedDay, Teva, and Xenoport; serves on clinical trial steering committees for Biogen Idec and Novartis; serves on the Scientific Advisory Board for MedDay; and serves on the editorial boards of Neurology and Multiple Sclerosis Journal.
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Introduction
Prior to a few years ago, initial long-term treatment of MS usually involved an
injectable therapy (interferon-β1 or glatiramer acetate). In a mostly unpredictable fashion,
some patients would display complete control of disease, whereas others would continue
to have disease activity as measured by a combination of clinical relapses and new
lesions on MRI. Searches for accurate predictive biomarkers have been largely
unsuccessful, and so clinicians have had very limited tools to personalize treatment
choices to maximize efficacy.
The development of natalizumab heralded the era of highly effective anti-
inflammatory therapies. With such high efficacy, predictors of treatment response are
generally unnecessary. The high efficacy of natalizumab, however, also came with a
price – the risk of progressive multi-focal leukoencephalopathy (PML). A potentially
fatal brain infection, PML was initially estimated to occur at a rate of approximately
1:1000 in patients treated with natalizumab over 18 months. Mitoxantrone is another
potent MS therapy with significant risks of cardiac injury and lymphoproliferative
disorders including leukemia, and so this therapy is now infrequently used.
In the last several years, three oral therapies have become clinically available –
fingolimod, teriflunomide, and dimethyl fumarate. All three therapies have relatively
good efficacy and tolerability, and reasonable safety profiles. With more than ten
approved therapies currently available, and more pending regulatory review, the choice
of MS therapy has become increasingly challenging.
Currently, there are no established guidelines for choosing an initial long-term
MS disease modifying therapy for relapsing MS. Like with other medical therapies, the
choice of treatment should be guided by the balance of efficacy and risk, along with
patient tolerability and convenience. Several new therapies have become available, which
expand the available treatment options. In addition, the high cost of MS disease
modifying therapies necessitates incorporation of local payer policies into choice of
therapy.
Efficacy
With the exception of the recent oral therapies, there have been few head-to-head
trials of different MS disease modifying (DMT) therapies. For the injectable therapies
(interferon-β; glatiramer acetate), many clinicians feel that their efficacy across patient
populations is more similar than different.1 However, the population-based efficacy
studies should not be blindly applied to individual patients, as one patient may respond to
one injectable therapy after insufficiently responding to another therapy. Given their
similar population-based efficacies, choice of injectable therapy should probably be
driven predominantly by expected side-effect profile, patient choice, and clinician
familiarity with the particular injectable therapy.
The development of oral therapies appears to bring with them a general increase
in efficacy and tolerability. Fingolimod and dimethyl fumarate (DMF) both reduce
annualized relapse rates by about 50% and MRI measures of active inflammation by 71-
90%.2 In head-to-head studies against injectable therapies, both were found to be superior
in reducing relapses and/or MRI disease activity, although the comparison in the DMF
study was post-hoc. Teriflunomide also reduces annualized relapse rate and MRI
measures of disease activity, with what appears to be similar efficacy to injectable
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therapies. Direct, head-to-head studies are needed to clarify how the efficacy compares
between these three oral disease modifying therapies. Similar to studies of injectable
therapies, clinical practice-based studies comparing fingolimod and DMF suggest that
their efficacy is more similar than different.3
There are different approaches to MS therapy choice, including gradual escalation
(i.e. start with the safest therapy, and then gradually escalate intensity, if needed) and
maximal efficacy (i.e. start with the strongest therapy, and then consider decreasing
intensity of therapy later). The optimal approach to most effectively manage MS over
several decades is not yet known.
Safety / Risk Mitigation
In parallel to developing more effective MS disease modifying therapies has been
progress mitigating the risks of treatment complications. Risk mitigation strategies
identify the risk of therapies based on individual patient characteristics. Some risk
characteristics are identified in phase III trials, but others are recognized only after post-
marketing phase IV studies and general clinical use. Further complicating treatment
choices, some risk factors are not static but can change over time, which secondarily
change the risk-benefit profile of a treatment for an individual patient. Through risk
stratification, clinicians can now personalize treatment.4
Progressive multifocal leukencephalopathy (PML) is a rare serious risk of several
MS therapies. The risk of PML was originally estimated to be about 1:1000 over 18
months in all patients using natalizumab. Risk stratification has allowed that estimate to
be tailored to individual patient characteristics, and so now PML varies between 1:X and
1:XX, depending upon several factors. Age may be a risk factor for PML related to DMF
and fingolimod, since cases of PML with those therapies have developed in patients older
than the population in which those therapies are generally used.5
Risk assessment and mitigation is discussed in detail in the next talk.
New Therapies
Two new therapies have received recent regulatory approval, and a third is
pending regulatory approval. These therapies are increasing the treatment options
available for patients with relapsing forms of MS. Effective therapies for progressive MS
remain elusive.
Alemtuzumab.
CD52 is an anonymous surface protein expressed by T-cells, B-cells, monocytes,
and eosinophils. Alemtuzumab is a monoclonal antibody that targets CD52, and
administration leads to rapid, profound, and prolonged lymphocyte depletion, with
gradual reconstitution of cells with altered cell profile and function. Previously approved
for CLL, it was approved for relapsing forms of MS in 2014.
Alemtuzumab is given by slow intravenous infusion daily for five days; then after
one year, treatment is repeated daily for 3 days. Premedication with histamine blockers
(both H1 and H2) and corticosteroids reduces infusion reactions. Antiviral prophylaxis
reduces the incidence of herpetic infections. Monitoring for 2 hours post infusion helps
identify and manage infusion reactions.
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Phase 3 trials of alemtuzumab have found that it reduces ARR by 50-54% relative
to interferon, and reduces progression of disability by 30-42%.6,7
Side-effects include an
increased rate of nasopharyngitis, UTI, and herpes viral infections. There is an increased
rate of humoral-mediated autoimmune reactions (i.e. thyroiditis, thrombocytopenia, anti-
glomerular membrane disorder, and agranulocytosis). There may also be an increased
rate of some rare cancers.
Risk mitigation strategies include antihistamines and corticosteroids for infusion
reactions, antiviral prophylaxis for herpetic viral infections, and blood and urine
monitoring for signs of humoral autoimmune reactions. Because of its risks,
alemtuzumab not generally considered as a first-line treatment option for MS.
Daclizumab.
The Interleukin(IL)-2 receptor is a heterotrimetric complex with 3 transmembrane
subunits. Several of the subunits are shared with other IL receptors. The IL-2 receptor
appears to function in the proliferation and differentiation of immune cells, including T-
cells, B-cells, and NK cells; elimination of self-reactive T-cells; and maintenance of T-
regulatory cells. Daclizumab is a humanized (90% human; 10% mouse) monoclonal
antibody which binds to the IL-2R alpha chain, blocking IL-2 binding and signaling.
Without IL-2 receptor signaling, T-cell and B-cell activation by IL-2 is hinhibited, and
IL-2 receptor expression is down-regulated on activated T-cells. Daclizumab is an old
therapy, having been approved as Zenepax in 1997 (FDA) and 1999 (EMEA) for
prevention of renal allograft rejection. It is the third monoclonal antibody to receive
regulatory approval, and is the first humanized and first against a cytokine receptor. For
MS, daclizumab is given as a monthly subcutaneous injection.
Phase 3 trials of daclizumab found that it reduced ARR by 45% compared with
IFNβ.8,9
There was also a 54% reduction in new or enlarging T2 lesions, although no
difference in disability progression compared with IFNβ.9 Side-effects include a slightly
increased rate of infections, including nasopharyngitis; elevated liver enzymes; and
cutaneous reactions. Eczema is very common, although most patients require no specific
treatment. More severe rashes can be appear like psoriasis, although biopsies show
features of eczematous dermatitis.10,11
Summary: Daclizumab has good efficacy and the convenience of monthly SQ
administration. Disadvantages include safety concerns, particularly liver injury and skin
reactions; and monthly liver monitoring. The principal indication appears to be relapsing
MS patients who have failed several other MS therapies.
Ocrelizumab.
CD20 is a 297 amino acid membrane-associated phosphoprotein expressed on
pre-B-cells and B-cells, but not on stem cells or plasma cells. CD20 is not shed and does
not cause substantial international when bound. Several anti-CD20 antibodies have
developed by a variety of manufacturers. To varying degrees, they all selectively deplete
B cells bearing the CD20 surface marker via antibody-dependent cellular cytotoxicity,
complement-dependent cytotoxicity, and apoptosis.
Rituximab is an anti-CD20 monoclonal antibody that causes rapid and profound
depletion of B-cells. A phase II trial in RRMS found that rituximab treated was
RJ Fox, New MS Treatments and Updates on Established Treatments Page 5 of 6
associated with a 91% reduction in enhancing lesions, and a 56% reduction in ARR. The
manufacturer then decided to further develop a more humanized antiCD20 antibody
ocrelizumab in MS. Phase III trials of ocrelizumab in relapsing MS found that it was
associated with a 46% reduction in ARR, and 40% reduction in sustained progression of
disability.12
A phase III trial of ocrelizumab in young patients with early-stage PPMS
found that it slowed the progression of disability by 24%, although the majority of the
benefit was observed in the first 12 weeks of the trial.13
Additionally, patients with
gadolinium enhancing lesions were more likely to demonstrate slowed progression of
disability compared to those without gadolinium enhancing lesions.14
Side-effects of rituximab and ocrelizumab include infusion reactions;
nasopharyngitis, sinusitis, bladder infections. Both relapsing and progressive MS studies
observed an increased incidence of cancers, although overall rate was low and cancer is
not a signal reported from other trials of ocrelizumab in autoimmune disorders (i.e.
systemic lupus and rheumatoid arthritis).
Placement of New Therapies
The appropriate placement of these new therapies in the MS treatment algorithm
is not yet established. Due to their side-effect profile, alemtuzumab and daclizumab are
typically relegated to patients who have sub-optimally responded or not tolerated two or
more MS therapies. The optimal location of ocrelizumab in the treatment algorithm is not
yet clear, although some argue that its side-effect profile makes it a reasonable first-line
therapy.
Patient Preference
Patients are an important partner in the choice of MS therapies. Several aspects of
therapy can influence patient preference, including expected side-effects, expected
benefit of the therapy, and expected course of the disease if left untreated. Tolerance to
risk can impact patient preference for therapy, and risk tolerance varies greatly across the
MS patient population.
Payor Influence
MS disease modifying therapies are very expensive, which make local health
system policies regarding MS therapy coverage an important factor in the choice of MS
therapy. Different systems have taken different approaches to managing these costs, and
payer policies will impact a clinician’s ability to utilize different therapies.
Conclusion
There are many MS therapies available for treatment of RRMS. Contemporary
developments with current therapies focus on management of risk, including risk
stratification and risk minimization. New therapies available or expected to be available
in the future include alemtuzumab, daclizumab, and ocrelizumab. Each of these therapies
has its own benefit and risk profile. The optimal sequencing of MS therapies has yet to be
established.
References:
RJ Fox, New MS Treatments and Updates on Established Treatments Page 6 of 6
1. Fox RJ, Arnold DL. Seeing injectable MS therapies differently: they are more
similar than different. Neurology 2009;72:1972-3.
2. Phillips JT, Fox RJ. BG-12 in multiple sclerosis. Semin Neurol 2013;33:56-65.
3. Hersh CM, Love TE, Cohn S, et al. Comparative efficacy and discontinuation of
dimethyl fumarate and fingolimod in clinical practice at 12-month follow-up. Multiple
Sclerosis and Related Disorders 2016;In Press Accepted manuscript.
4. Ontaneda D, Fox RJ. Multiple sclerosis treatment: risk mitigation. Continuum
(Minneap Minn) 2013;19:1092-9.
5. Ontaneda D, Fox RJ, Brosseau MSG, Stobbe G, Wundes A. Natalizumab-related
PML 2 weeks after negative anti-JCV antibody assay / Author response. Neurology
2016;87:957-8.
6. Coles AJ, Twyman CL, Arnold DL, et al. Alemtuzumab for patients with
relapsing multiple sclerosis after disease-modifying therapy: a randomised controlled
phase 3 trial. Lancet 2012;380:1829-39.
7. Cohen JA, Coles AJ, Arnold DL, et al. Alemtuzumab versus interferon beta 1a as
first-line treatment for patients with relapsing-remitting multiple sclerosis: a randomised
controlled phase 3 trial. Lancet 2012;380:1819-28.
8. Gold R, Giovannoni G, Selmaj K, et al. Daclizumab high-yield process in
relapsing-remitting multiple sclerosis (SELECT): a randomised, double-blind, placebo-
controlled trial. Lancet 2013;381:2167-75.
9. Kappos L, Wiendl H, Selmaj K, et al. Daclizumab HYP versus Interferon Beta-1a
in Relapsing Multiple Sclerosis. N Engl J Med 2015;373:1418-28.
10. Oh J, Saidha S, Cortese I, et al. Daclizumab-induced adverse events in multiple
organ systems in multiple sclerosis. Neurology 2014;82:984-8.
11. Cortese I, Ohayon J, Fenton K, et al. Cutaneous adverse events in multiple
sclerosis patients treated with daclizumab. Neurology 2016;86:847-55.
12. Hauser SL, Comi GC, Hartung H, et al. Efficacy and safety of Ocrelizumab in
relapsing multiple sclerosis - results of the interferon-beta-1a-controlled, double-blind,
Phase III OPERA I and II studies. In: European Committee for treatment and Research in
Multiple Sclerosis (ECTRIMS); 2015; Barcelona, Spain; 2015. p. PS190.
13. Montalban X, Hemmer B, Rammohan K, et al. Efficacy and safety of ocrelizumab
in primary progressive multiple sclerosis - results of the placebo-controlled, double-blind,
Phase III ORATORIO study. In: European Committee for Treatment and Research in
Multiple Sclerosis (ECTRIMS) 2015; Barcelona, Spain; 2015. p. PS 228.
14. Wolinski JS. Efficacy of ocrelizumab in patients with Primary Progressive
Multiple Sclerosis with and without T1 gadolinium-enhancing lesions at baseline in a
Phase III, placebo-controlled trial. In: The Americas Committee for Treatment and
Research in Multiple Sclerosis (ACTRIMS); 2016; New Orleans, LA; 2016.
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Assessing and mitigating risks –
The right treatment for the right patient
ECTRIMS Teaching Course #1 “Disease Modifying Treatment”
Wednesday October 14th, 2016
Sandra VUKUSIC, MD PhD1-4
1 Service de Neurologie A and Fondation Eugène Devic EDMUS contre la Sclérose en Plaques,
Hôpital Neurologique Pierre Wertheimer, Hospices Civils de Lyon, Lyon, F-6977, France; 2 Centre des Neurosciences de Lyon, INSERM 1028 et CNRS UMR5292, Equipe Neuro-oncologie et
Neuro-inflammation, Lyon, F-69003, France; 3 Université de Lyon, Lyon, F-69003, France;
4 Université Lyon 1, Lyon, F-69003, France;
Correspondance to: Prof. Sandra VUKUSIC – Service de Neurologie A – Hôpital Neurologique Pierre Wertheimer 59 boulevard Pinel – 69677 BRON cedex – France e-mail: [email protected] Tel: +33 4 72 35 75 22 – Fax: +33 4 72 35 75 25 Financial Disclosure Statement
Dr. Vukusic has received consulting and lecturing fees, travel grants and research support from Bayer-
Schering, Biogen Idec, Genzyme, Novartis, Merck Serono, Roche, Sanofi Aventis and Teva Pharma.
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If there is still no cure for MS, disease-modifying treatments (DMTs) have become available since the
early 1990s. Interferon beta and glatiramer acetate first demonstrated efficacy in preventing the
recurrence of relapses, and, to some extent, in delaying disability accumulation. If not so convenient in
daily life, because of sub-cutaneous or intramuscular administration and injection-related adverse
effects, data on their long term safety is up to now very reassuring. In particular, there is no more
concern on their risk of increasing cancer or opportunistic infections.
Since 2005, MS treatment has been entering a new era, with arrival of drugs that are more effective,
but at the cost of rare but severe risks, as opportunistic infections, cancers or other auto-immune
diseases. Natalizumab, first monoclonal antibody marketed for MS, is responsible for cases of
Progressive Multifocal Leukoencephalopathy (PML) in around 3 persons per 1000 treated for more
than two years. Other drugs are or will become available, with concerns on their safety that cannot be
ruled out by clinical trials only. This is the case for oral drugs, like fingolimod, dimethylfumarate and
teriflunomide and for other monoclonal antibodies (alemtuzumab, rituximab, ocrelizumab,
daclizumab…) or IV immunosuppressants (mitoxantrone).
Year 2005 was also a crucial time-point in drug surveillance. In response to several affairs leading to
the withdrawal of drugs due to unexpected side effects discovered after dissemination on the market,
drug regulation agencies modified their mainly passive pharmacovigilance strategy and imposed the
concept of a mandatory pro-active approach to post-marketing surveillance, through the Risk
Management Plans (RMPs) in Europe and Risk Evaluation and Mitigation Strategies (REMs) in the
United States.
The widening of the DMT arsenal for MS, the introduction of the notion of life-threatening risks
balanced with greater efficacy, as well as the new legal framework, have modified neurological
practice: 1. towards patients, who deserve to be informed about the benefits and the risks of the
different drugs that may be proposed to them; 2. towards neurologist colleagues, who may need a
shared decision process, with expert MS centres or concertation meetings; and 3. towards regulation
agencies and industrials, with a more active implication in post-marketing surveillance of new drugs.
From a drug’s life…
At the time of marketing authorization, relatively limited information is known about the safety of a
drug. This is due to many facts, directly related to the design of clinical trials: 1- the limited number of
subjects (hundreds to 1-2 thousands), compared to the much larger number of patients in which it
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might be used in daily practice; 2- the restricted population evaluated in trials in term of age, gender
and ethnicity, but also in terms of co-morbidities and associated treatments; 3- the restricted
conditions of use, strictly defined by the study protocol; 4- the relatively short duration of follow-up.
Pre-marketing studies are therefore insufficient to detect rare adverse events (<1/1000), especially in
populations that are not or insufficiently studied in clinical trials. The number of patients treated in real
life settings, not selected by restrictive per-protocol inclusion and exclusion criteria and exposed for
years to the drugs, might then reveal soon or late unexpected and sometimes severe adverse events.
Pharmacovigilance aims at detecting such events, but it still might be difficult to define whether they
are above the threshold of events happening within the general population, not in relation with the
drug.
A Risk Management Plan is defined as “a set of pharmacovigilance activities and interventions
designed to identify, characterize, prevent or minimize risks relating to medicinal products, including
the assessment of the effectiveness of those interventions” (EMEA/CHMP/96268/2005). This strategy
introduces new activities - as detection, evaluation, minimization, communication - to set “a proactive
and systematic approach, always challenged with benefits, in order to optimize the benefit/risk balance
of the drug, all along its life”. The aim of this risk management system is “to ensure that the benefits of
a particular medicine exceed the risks by the greatest achievable margin for the individual patient and
for the target population as a whole”. The EU-RMP contains two parts, describing risk detection
(Safety Specifications and pharmacovigilance plan), and risk minimization activities (including an
evaluation of the need for risk minimization activities and a risk minimization plan).
Three levels of risks are defined: 1-important identified risks (safety issues that could impact the
benefit/risk balance, with a causative association with the drug, established by temporal relation or
biological plausibility for example), 2-important potential risks (safety issues that could be related to
the drug but need to be confirmed) and 3-important missing information (safety concerns for which no
or insufficient information is available at the time of authorization, for example at-risk populations).
When no concerns have arisen in pre-marketing clinical trials, spontaneous reporting through the
pharmacovigilance system may be sufficient. However, additional activities may be needed. There is a
wide range of designs for post-authorization studies. Some of them have already been used in MS:
prescription event monitoring in the TOUCH program in the United States or exposure registries in
Europe. Exposure registries may also be dedicated to the study of a particular population, the most
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common situation being exposure during pregnancy. Table 1 provides a comparison of characteristics
of different study designs aiming at evaluating the safety of a drug. In some countries, where MS
specific databases exist, neurologists actively contribute to the post-marketing surveillance through the
national MS registries, which offer the possibility to study not only the effectiveness and risks of a
given drug, but also the interplay with the use of other drugs. This is of particular interest as this data
is usually missing in clinical trials.
For interferons and glatiramer acetate in the late 90s, surveillance was limited to pharmacovigilance
reporting. Mitoxantrone received FDA approval in 2000 and sometimes later in European countries for
aggressive MS. Rapidly, regulatory agencies issued an alert about the dose-cumulative potential of
cardiotoxicity and, in some countries, about the risk of leukaemia. Cardiac and haematologic
surveillance were recommended but not mandatory and were not collected in a post-marketing study.
No RMP was requested from the manufacturer as approval was given before 2005. This point has to
be underlined, as some may think that new drugs are more dangerous than oldest ones, only because
of the particular surveillance they are committed to.
We present here in Table 2 an overview of MS drugs risk mitigation recommendations by the
European Medicine Agency.
…to a patient’s centered decision process
As neurologists, we have to transpose those data collected through the drug’s life into information that
will help us evaluate the benefit/risk balance in a patient’s life. That means taking into account many
other parameters:
- related to the patient: extreme ages (no or poor data in younger and older ones), co-medications,
comorbidities, desire of pregnancy
- related to MS course: risk of starting a treatment, risk of not starting a treatment, risk of stopping a
treatment (especially for those were a rebound can be feared)
- related to the successive use of drugs in an individual patient, that can have similar adverse events,
as infections and cancer. The most striking situation today is the risk of PML when stopping
natalizumab because of the presence of risk factors. What is the best timing to switch to avoid a
potential rebound? To avoid the risk of starting a new drug when PML is already developing (13% of
PML cases are diagnosed after natalizumab cessation)? To avoid a cumulative risk when using other
drugs that have a prolonged impact on the immune defence?
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Table 1
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Table 2
Drug Identified risks EMA Risk mitigation recommendations
Interferons bêta
Hepatic dysfunction Liver enzymes if clinical signs
Hematological abnormalities Complete Blood Count (no details)
Depression Patient information
Clinical vigilance
Thrombotic microangiopathy Clinical vigilance
Pregnancy Limited information - might be an increased risk of aborption
Initiation is contraindicated during pregnancy
Benefits on MS course should be weighted against possible increased risk of
spontaneous aborption
RMP No
Drug Identified risks EMA Risk mitigation recommendations
Glatiramer acetate
No No
Pregnancy Limited informartion - no signal
Insufficient animal data
Contraindicated during pregnancy
RMP No
Drug Identified risks EMA Risk mitigation recommendations
Fingolimod
Bradyarrythmia ECG - Blood pressure prior to initiation
6-hour monitoring at first dose and re-introduction
Infections Complete Blood Cell Count
prior to initiation, at Month 3 and yearly or if signs of infection thereafter
stop if lymphocytes <0,2.109/l
VZV vaccine prior to initiation
if seronegative or no confirmed history of chickenpox
PML Baseline MRI
MRI follow-up according to local recommendations
Macular oedema Ophtalmologic evaluation at month 3-4 or anytime if visual symptoms
Hepatic dysfunction Liver function (no details)
prior to initiation, at month 1, 3, 6, 9 and 12 and periodically thereafter
Elevated blood pressure Clinical vigilance
Basal cell carcinoma Dermatological evaluation
prior to initiation and yearly thereafter
Pregnancy Limited informartion
Reproductive toxicity in animals
Contraindicated during pregnancy
Active contraception - Stop FTY 2 months prior to conception
RMP Restricted indication "Highly active RRMS"
Physician information pack
- SPC
- Checklist prior to prescription
- Information on Pregnancy Exposure Registry
- Patient reminder card
Prospective cohort study assessing the incidence of cardiovascular events
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Drug Identified risks EMA Risk mitigation recommendations
DimethylfumarateHepatic dysfunction Creatinine, urea, urinanalysis + ALT, AST
Renal dysfunction prior to initiation, at month 3 and 6, every 6 to 12 months thereafter
Lymphopenia Complete Blood cell Count
prior to initiation, every 3 months therafter
stop if lymphocytes <0,5.109/l persisting for more than 6 monthsPML Baseline MRI
MRI follow-up according to local recommendations
Pregnancy Limited information
Reproductive toxicity in animals
Not recommended during pregnancy
Active contraception - Benefit vs risk to be discussed individually
RMP No
Drug Identified risks EMA Risk mitigation recommendations
Teriflunomide
Hepatic dysfunction ALT, AST
prior to initiation, every 2 weeks in the first 6 months, every 8 weeks after
Hematological abnormalities Complete Blood cell Count
prior to initiation, if clinical symptoms therafter
Blood pressure Before initiation and periodically thereafter
Pregnancy Limited information in humans
Reproductive toxicity in animals
Contraindicated during pregnancy
Active contraception - Accelerated elimination procedure if desire of
pregnancy
RMP Educational programme
- SPC
- Educational material for professionals
- Educational card for patients
Pregnancy registry
Drug Identified risks EMA Risk mitigation recommendations
Natalizumab
PML Anti-JCV antibody
prior to initiation
- if negative: retest every 6 months
- if positive and low index an no prior IS: retest every 6 months after 2 years
Baseline MRI and every year
for at-risk patients
- JCV +/>2 years/prior IS
- High JCV index/>2 years
additional MRI follow-up every 3 to 6 months with abbreviated protocol
Infections Clinical vigilance
Herpes, Varicella zoster
Pregnancy Limited information - no signal (355 pregnancies)
Reproductive toxicity in animals
Benefit vs risk to be discussed individually
RMP Restricted indication "Highly active RRMS"
Physician information pack
- SPC
- Physician information
- Patient alert card
- Treatment initiation and continuation forms
- Treatment discontinuation form
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Drug Identified risks EMA Risk mitigation recommendations
Alemtuzumab
Autoimmunity
- Immune thrombocytopenic
purpuraComplete Blood cell Count
prior to initiation
monthly therafter until 48 months after the last infusion
- Nephropathies (including anti-
GBM disease)Serum creatinine, urinanalysis
prior to initiation
monthly therafter until 48 months after the last infusion
- Thyroid disorders TSH
prior to initiation
monthly therafter until 48 months after the last infusion
- Other autoimmune cytopenia Complete Blood cell Count
as above
Infusion-assicated reactions Premedication
Infections
- VZV Prophylaxis with aciclovir during 1 month after each course
- HPV HPV screening annually in female patients
Pregnancy Limited information
Reproductive toxicity in animals
Active contraception for 4 months after each course
Benefit vs risk to be discussed individually
RMP Extended indication (restricted by some national agencies)
Physician educational pack
- SPC
- Healthcare professional guide
- Prescriber check list
- Patient guide
- Patient alert card
Drug Identified risks EMA Risk mitigation recommendations
Daclizumab
Hepatic dysfunction ALT, AST, bilirubine prior to initiation
ALT, AST monthly thereafter and up to 4 months after last dose
Skin reactions Clinical vigilance
Depression Clinical vigilance
Infections Screening for active TB if past history or endemic area
Lymphopenia Complete Blood cell count
every 3 months
Pregnancy Limited information
No reproductive toxicity in animals
Benefit vs risk to be discussed individually
RMP Hepatic risk management guide
Patient card
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Drug Identified risks EMA Risk mitigation recommendations
Mitoxantrone
Myocardial toxicity Left Ejection Ventricular Fraction (LEVF)
prior to initiation, to each dose and yearly up to 5 years after the last infusion
Dose limitation <72 mg/m2
Myelosuppression Complete Blood cell Count
Acute myeloid Leukemia prior to initiation, at time and 10 days following each administration
Myelodysplastic syndrome if clinical signs
Pregnancy Genotoxic
Contraindicated during pregnancy
Active contraception for 4 months in women and 6 months in men
RMPRestricted indication "Highly active relapsing MS with no alternative
treatment"
Recently re-evaluated (June 2016) to conceal the initial national procedures
"The company will provide educational materials about the use of Novantrone
in patients with MS. The educational materials will include a guide and
checklist for healthcare professionals informing on the risks of cardiotoxicity
and leukemai…and how patients should be monitored. Patients will receive a
guide to the risks and an alert card...."