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CLINICAL GUIDELINE

Use of Disease Modifying Treatments (DMTs) in Adults with Relapsing Remitting Multiple Sclerosis (RR-MS)

Adapted from:

West of Scotland Regional Multiple Sclerosis Service / NHS GGC Relapsing Remitting Multiple Sclerosis (RR-MS) Clinical Management Guideline

Version Number: 2.0

Date Approved: October 2019

Date of Next Review: October 2021

Authors: Dr Uwe Spelmeyer – Consultant Neurologist

Lynda Kearney – Lead Multiple Sclerosis Specialist Nurse

Duncan Wilson – Senior Clinical Pharmacist

Approval Group: NHS Fife Managed Service Drug and Therapeutics Committee (MSDTC)

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Contents Page

Item Title Page

Clinical management algorithm for DMTs in RR-MS 3

1. Background 4

2. Disease Modifying Treatments

Interferon beta-1a

Peginterferon beta 1a

Glatiramer acetate

Teriflunomide

Dimethyl fumarate

Natalizumab

Fingolimod

Alemtuzumab

Cladribine

Ocrelizumab

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3. Pregnancy & Breastfeeding – the use of DMTs 13

4. References 15

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Consider:

a. reduce the dose temporarily

if dimethyl fumarate.

b. switch to a different first-line DMT.

c. discontinue treatment and observe.

Switch to Natalizumab or Fingolimod or

Cladribine or Ocrelizumab or [Alemtuzumab]

(if not previously tried)

Consider 3rd line treatment

e.g. Bone marrow transplant

Clinical management algorithm for disease modifying treatments (DMT) in relapsing remitting Multiple Sclerosis (RR-MS)

NHS Fife Multiple Sclerosis Service Version 1.0 Date written: June 2019

Frequent/significant relapses

+ significant residual deficit

Failure to tolerate first line

DMT

Patient fulfils the ABN criteria (2001) for treatment of MS with Beta-

interferon or Glatiramer acetate[3]

(i.e. 2 clinically significant relapses in

the last 2 years and ambulant with maximum EDSS 6.5*) plus the SMC accepted indications for Teriflunomide, Dimethyl fumarate,

[Alemtuzumab]** or Ocrelizumab**

Rapidly evolving severe RR-MS (defined as 2 relapses, whether on treatment or not, in one year, and one

or more gadolinium-enhancing lesions on MRI or a significant increase in T2-lesion load compared with a

previous MRI)

Start immunomodulation with first-line DMT (Beta-interferon (B-IFN),

Glatiramer acetate (GA)***, Teriflunomide[4]

, Dimethyl fumarate[5]

or

[Alemtuzumab]**[6]

or Ocrelizumab**[11]

Natalizumab[7]

Ocrelizumab, [Alemtuzumab], Fingolimod, Cladribine[9]

Relapsing Remitting Multiple Sclerosis (RR-MS) as defined by McDonald criteria (2001, 2010 and 2017)[1],[2],[10]

Monitor patients 6 monthly for relapses, disease progression and side effects

Failure to tolerate treatment, continues to relapse or is JC Virus

positive and on Natalizumab >2years or increasing JCV titer

* with an EDSS of 6.5 or less, meaning that you must be able to walk at least 10 metres with or without assistance.

** although unlikely to be first line choice unless rapidly evolving severe relapsing remitting MS. For RRMS (that is not RES), [alemtuzumab] or

ocrelizumab are an options that may be considered. However, they should only be used when the patient and MS specialists accept the specific risks associated with the treatment and the burden of monitoring; [alemtuzumab] will only be used in exceptional circumstances in accordance with the 2019 MHRA guidance

[12].

*** Choice of beta-interferon preparation or glatiramer-acetate is based on MS specialist opinion and patient preference. In the absence of clear clinical imperative to select a particular agent, cost should be an important consideration. Consideration should be given to discontinuing disease modifying treatment when patients disability is greater than 6.5 on EDSS for > 6 mths.

JC Virus negative JC Virus positive

Monitor patients 6 monthly for relapses, disease progression and side effects. Re-baseline MRI at 4-6 mths depending on the treatment and

perform annual MRI to look for new asymptomatic activity.

Patients with high disease activity or patient with disease activity despite treatment with a DMT. Patients should have had at least one relapse in the previous year while

on previous therapy, and have at least nine T2- hyperintense lesions in cranial magnetic resonance imaging (MRI) or at least one new or 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.

Infrequent/mild relapses

No/minimal residual deficit

Consider continuing with

present DMT or switching

to an alternative first line

DMT

Consider switch to an

alternative first line DMT

and monitor

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1. Background

In the individual patient, multiple sclerosis (MS) remains a fundamentally unpredictable condition.

There are many factors that influence prognosis and disease course, including sex, relapse frequency,

type of relapse, age, MRI lesion load and spinal cord involvement. However, for most patients, MS

results in a gradual accumulation of fixed neurological disability over time. There is an increasing

tendency to use treatment earlier and more aggressively in those people deemed to have a worse

outlook.

DMTs clearly impact significantly on MS, and the Association of British Neurologists (ABN) recommends

starting treatment as early as possible in eligible patients. Treatment decisions can be complex for both

patient and neurologist. Common practice is shared discussions of the treatment options and decision

making where possible; in NHS Fife this takes place in the Consultant lead MS clinic, where on the basis

of clinical characteristics of the individual patient a choice of suitable drugs is discussed; further

discussions then take place in the MS Nurse led clinics at Cameron, Victoria or Queen Margaret

Hospitals; the decision is shared with the patient in most cases, taking into account clinical

characteristics of the patients MS and patients choice. We regard it of importance for the patient to

understand the aim of treatment, the risks associated with treatment and the burden of monitoring.

All of the licensed DMTs for MS reduce relapse rate and MRI lesion accumulation in RR-MS, to varying

extents. The ABN suggests that the DMTs can be divided into two broad classes: drugs of moderate

efficacy (average relapse reduction in 30–50% range) and drugs of high efficacy (average relapse

reduction substantially more than 50%).

Patient and clinician engagement in the choice of therapy is important to ensure adherence to the treatment and monitoring schedules. Several clinical factors should be taken into account when deciding on the most appropriate DMT for MS. These include:

Disease history

Disease activity pattern

Disability accrued from incomplete recovery from relapses

JC virus status

MRI lesion load

MRI lesion distribution

MRI activity

Side effects of treatment

Type of relapses (sensory or motor)

The following patient specific factors should also be taken into account:

Age

Gender

Lifestyle and Demographics

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2. Disease Modifying Treatments (DMTs)

All DMTs listed below for the management of multiple sclerosis should only be prescribed by an

identified specialist neurologist in the disease-modifying clinic. All monitoring is conducted by

secondary care or contracted out to a specific manufacturer commissioned phlebotomy service as part

of a homecare arrangement. Establishment of commercial /homecare services must be done in

conjunction with NHS Fife Pharmacy.

DMT Brand Administration NHS Fife Formulary

Homecare Risk of developing PML

Interferon beta-1a

Avonex® intramuscular Very low

Peginterferon beta 1a

Plegridy® subcutaneous Very low

Glatiramer acetate

Copaxone® subcutaneous Very low

Teriflunomide Aubagio® oral Very low

Dimethyl fumarate

Tecfidera® oral Low

Natalizumab Tysabri® IV infusion High

Fingolimod Gilenya® oral Low

Alemtuzumab Lemtrada® IV infusion Very low

Cladribine Mavenclad® oral Very low

Ocrelizumab Ocrevus® IV infusion Very low

Table 1. Summary of DMTs

For further details please refer to the individual summary of product characteristics (SPCs) available

from www.medicines.org.uk.

NICE: Beta interferons and glatiramer acetate for treating multiple sclerosis [TA527], June 2018

Interferon beta-1a (Beta-interferon)

Brand: Avonex®

Route: intramuscular

Dose & frequency: 30 micrograms weekly

SMC: * Rebif® and Betaferon® are not recommended for use within NHS Scotland.

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* Extavia® is less convenient for patients due to the alternate day dosing and is therefore not

recommend in NHS Fife

MoA: reduces blood brain barrier disruption and modulates T-cell, B-cell and cytokine functions

Side effects: injection site reactions, flu-like symptoms, elevated liver enzymes, decreased white cell

count, low mood and leg stiffness

Monitoring:

FBC and LFTs = at week 2, months 1, 2, 6 then every 6 months

Comments:

Neutralising antibodies (NAb) are not tested within NHS Fife as they provide no additional

clinical information

Peginterferon beta 1a

Brand: Plegridy®

Route: subcutaneous

Dose & frequency: 63 micrograms at dose 1 (on day 0), increasing to 94 micrograms at dose 2 (on day

14), reaching the full dose of 125 micrograms by dose 3 (on day 28) and continuing with the full dose

(125 micrograms) every 2 weeks thereafter

SMC: is accepted for use within NHS Scotland

MoA: reduces blood brain barrier disruption and modulates T-cell, B-cell and cytokine functions

Side effects: injection site reactions, flu-like symptoms, elevated liver enzymes, decreased white cell

count, low mood and leg stiffness

Monitoring:

FBC and LFTs = at week 2, months 1, 2, 6 then every 6 months

Comments:

Neutralising antibodies (NAb) are not tested within NHS Fife as they provide no additional

clinical information

Glatiramer acetate

Brand: Copaxone®

Route: subcutaneous

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Dose & frequency: 20mg once daily, alternatively 40mg three times a week (with at least 48 hours)

apart

SMC: accepted for use within NHS Scotland.

MoA: stimulating regulatory T-cells

Side effects: injection site reactions, lipoatrophy, chest pain, palpitations, and anxiety

Monitoring: no routine blood tests are required

Teriflunomide

Brand: Aubagio®

Route: oral

Dose & frequency: 14 mg once daily

SMC: is accepted for restricted use within NHS Scotland for the treatment of adults with relapsing

remitting multiple sclerosis (MS). SMC restriction:

as an alternative to treatment with interferon beta or glatiramer acetate. Teriflunomide is not

expected to be used for the treatment of patients with highly active disease.

NICE: Teriflunomide for treating relapsing–remitting multiple sclerosis [TA303], June 2014

MoA: inhibits dihydroorotate dehydrogenase, an enzyme required for pyrimidine synthesis in

proliferating cells

Side effects: elevated liver transaminases, liver toxicity, hypertension, nausea, diarrhoea, alopecia, and

interstitial lung inflammation

Monitoring:

FBC and LFTs = every 2 weeks for 6 months and then every two months

Comments:

Long half life (~19 days) due to enterohepatic recirculation and takes an average of 8 months

(or up to 2 years) to eliminate after stopping treatment

Dimethyl fumarate

Brand: Tecfidera®

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Route: oral

Dose & frequency: starting dose is 120 mg twice a day. After 7 days, the dose should be increased to

the recommended maintenance dose of 240 mg twice a day.

SMC: is accepted for use within NHS Scotland

NICE: Dimethyl fumarate for treating relapsing‑remitting multiple sclerosis [TA320], August 2014

MoA: promotes a shift of the cytokine secretion pattern from pro-inflammatory cytokine to anti-

inflammatory cytokines

Side effects: flushing and hot flushes, GI adverse effects (abdominal pain, diarrhoea, nausea and

vomiting). Elevated hepatic transaminases, decreased lymphocyte count.

Monitoring:

FBC, U&E’s, urinalysis and LFTs = at week 2, month 1, 3 and 6 then every 6 months

Natalizumab

Brand: Tysabri®

Route: intravenous (IV) infusion

Dose & frequency: 300mg every 4 weeks

SMC: accepted for restricted use within NHS Scotland as single disease modifying therapy in highly

active relapsing remitting multiple sclerosis (RRMS) only in patients with rapidly evolving severe RRMS

defined by two or more disabling relapses in one year and with one or more gadolinium-enhancing

lesions on brain magnetic resonance imaging (MRI) or a significant increase in T2 lesion load compared

with a previous MRI.

NICE: Natalizumab for the treatment of adults with highly active relapsing–remitting multiple

sclerosis [TA127], August 2007

MoA: humanised monoclonal antibody that targets alpha-4, preventing migration of immune cells

across the blood brain barrier into the CNS

Side effects: infusion related hypersensitivity reactions, raised LFTs, reduced white cell count and

increased risk of infection

Monitoring:

FBC = monthly

LFTs = 3 monthly

MRI brain scans:

JC virus negative = annually

JC virus positive = as often as 3-6 monthly, depending on the duration of treatment, the

JC Virus antibody titre and the patient’s previous use of immunosuppressive agents

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Comments:

Patients who are JC virus positive (particularly those who have a high antibody titre) and who

have been taking natalizumab for more than 2 years are at high risk of developing progressive

multifocal leuko-encephalopathy (PML).

Fingolimod

Brand: Gilenya®

Route: oral

Dose & frequency: 500 micrograms once daily

SMC: accepted for restricted use within NHS Scotland for patients with:

High disease activity despite treatment with at least one disease modifying therapy.

Rapidly evolving severe relapsing remitting multiple sclerosis.

NICE: Fingolimod for the treatment of highly active relapsing–remitting multiple sclerosis [TA254],

April 2012

MoA: sphygosine-1-phosphate receptor modulator – interfering with mechanism that lymphocytes use

to exit lymph nodes, meaning lymphocytes cannot enter the CNS to initiate MS lesions

MHRA Drug Safety Update, Sept 2019:

Contraindicated during pregnancy and in women of childbearing potential not using effective

contraception. Fingolimod is associated with an increased risk of major congenital malformations

including cardiac, renal, and musculoskeletal defects, when used in pregnancy.

advise women that fingolimod increases the risk of congenital abnormalities and provide them

with the new pregnancy-specific patient reminder card

exclude pregnancy before starting fingolimod and repeat pregnancy testing at suitable

intervals during treatment (depending on contraceptive used and personal)

ensure that an effective form of contraception is used during treatment and for 2 months after

discontinuation.

Side effects: elevated liver transaminases, macular oedema, reduced white cell count, bradycardia,

increased risk of infection

Monitoring:

First dose monitoring: first dose is taken with continuous cardiac monitoring for at least 6

hours following the dose

Pregnancy testing - MHRA Drug Safety Update (March 2019) provides guidance to prescribers

for medicines with teratogenic potential on the frequency of pregnancy testing needed to

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avoid exposure in pregnancy during treatment, depending on the chosen contraceptive

method

Regular monitoring:

FBC, LFTs = week 2, month 1, 2, 3, 6, 9 and 12 then every 6 months.

Eye examinations at month 3

Comments:

Concomitant bradycardia inducing drugs are contraindicated (e.g. digoxin, beta-blockers,

ivabradine, etc)

There is a possibility of return of disease activity (rebound) after fingolimod discontinuation.

Refer to the Summary of Product Characteristics (SPC) for further guidance on stopping

therapy.

Alemtuzumab

Brand: Lemtrada®

Route: intravenous (IV) infusion

Dose & frequency:

First treatment course: 12 mg/day on 5 consecutive days

Second treatment course: 12 mg/day on 3 consecutive days administered 12 months after the

first treatment course.

Two additional treatment courses, as needed, may be considered after this point. Further clinical

director approval is to be sought if these additional treatment courses are required.

SMC: is accepted for use within NHS Scotland for adult patients with relapsing-remitting multiple

sclerosis (RR-MS) with active disease defined by clinical or imaging features.

NICE: Alemtuzumab for treating relapsing‑remitting multiple sclerosis [TA312], May 2014

MHRA Drug Safety Update, May 2019:

Restricted indication for new patients: alemtuzumab for multiple sclerosis should only be started in

adults with either:

RR-MS that is highly active despite an adequate course of treatment with at least 2 other

disease-modifying therapies

highly active RR-MS if all other disease modifying therapies are contraindicated or otherwise

unsuitable

Side effects: infusion related hypersensitivity, autoimmune conditions, lowered blood cell counts, and

infection

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MoA: humanised monoclonal antibody that targets the surface molecule of CD52 on T-lymphocytes, B-

lymphocytes, monocytes and other immune cells. Results in depletion of T-and B-lymphocytes for

extended periods.

Monitoring:

Vital signs (including BP) = before and periodically during alemtuzumab infusion – consider

stopping the infusion and conducting additional monitoring, ECG, if any clinically significant

changes in vital signs occur

FBC, serum creatinine, urinalysis with microscopy = monthly during treatment and for 48

months after last treatment

Thyroid function tests (TFTs) = every 3 months during treatment and for 48 months after last

treatment

Liver function tests (LFTs) = every 3 months (consider discontinuing treatment in patients who

develop hepatic injury or serious immune-mediated reactions)

evaluate immediately any patients who develop early manifestations of pathologic immune

activation, and consider a diagnosis of haemophagocytic lymphohistiocytosis

Comments:

once alemtuzumab is given the effects on the immune system are persistent and cannot be

reversed

haemophagocytic lymphohistiocytosis – patients should seek immediate medical attention if

they develop unexplained fever, lymphadenopathy, bruising or rash, including if these

symptoms occur several years after treatment

patients should be pre-treated with corticosteroids immediately prior to alemtuzumab

administration on each of the first 3 days of any treatment course

oral prophylaxis (aciclovir 200mg BD – or equivalent) for herpes infection should be

administered to all patients starting on the first day of each treatment course and continuing

for a minimum of 1 month following treatment of alemtuzumab

Cladribine

Brand: Mavenclad®

Route: oral

Dose & frequency: Treatment consists of a course of tablets over two years. Each treatment course

consists of two treatment weeks, one at the beginning of the first month and one at the beginning of

the second month of the respective treatment year.

It is recommended that administration of any other oral medicinal product be separated from that of

cladribine by at least 3 hours during the limited number of days of cladribine administration.

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SMC: accepted for restricted use within NHS Scotland for the treatment of adult patients with highly

active relapsing multiple sclerosis (MS) as defined by clinical or imaging features. SMC restriction:

Patients with rapidly evolving severe relapsing-remitting MS: patients with two or more

relapses in the prior year whether on treatment or not, and at least one T1 gadolinium-

enhancing lesion.

Patients with sub-optimal therapy relapsing-remitting MS: patients with one or more relapses

in the previous year while on disease modifying therapy, and at least one T1 gadolinium-

enhancing lesion or nine T2 lesions.

NICE: Cladribine tablets for treating relapsing–remitting multiple sclerosis [TA493], December 2017

MoA: is a nucleoside analogue of deoxyadenosine and results to the selective depletion of dividing and

non-dividing T and B lymphocytes

Side effects: oral herpes, herpes zoster, TB, lymphopenia, decrease in neutrophil count

Monitoring:

Lymphocyte count must be:

Normal before initiation in year 1

At least 800 cells/mm3 before initiating in year 2

Monitored 2 and 6 months after start of treatment in each treatment year

If the lymphocyte count is below 500 cells/mm3, it should be actively monitored until

values increase again

Comments:

once caldribine is given the effects on the immune system are persistent and cannot be

reversed

Ocrelizumab

Brand: Ocrevus®

Route: intravenous (IV) infusion

Dose & frequency: The initial dose (600 mg) is administered as two 300 mg intravenous infusions on

days 1 and 15. Subsequent doses are administered as a single 600 mg intravenous infusion every 6

months.

SMC: accepted for restricted use within NHS Scotland for the treatment of adult patients with relapsing

forms of multiple sclerosis (RMS) with active disease defined by clinical or imaging features. SMC

restriction:

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Treatment of relapsing remitting multiple sclerosis (RRMS) in adults with active disease defined

by clinical or imaging features who are contra-indicated or otherwise unsuitable for

alemtuzumab.

NICE: Ocrelizumab for treating relapsing–remitting multiple sclerosis [TA533], July 2018

MoA: a recombinant humanised monoclonal antibody that selectively targets CD20-expressing B cells.

This results in antibody-dependent cellular cytolysis and complement-mediated lysis.

Side effects: upper respiratory tract infection, nasopharyngitis, influenza, infusion-related reactions,

neutropenia, oral herpes, herpes zoster

Monitoring:

signs and symptoms of active infection - prior to every infusion

signs and symptoms of infusion reactions - during infusion and for at least 1 hour after

completion

Comments:

the following two premedications must be administered prior to each ocrelizumab infusion to

reduce the frequency and severity of infusion-related reactions:

o 100mg intravenous methylprednisolone (or an equivalent) approximately 30 minutes

prior to each infusion

o antihistamine approximately 30-60 minutes prior to each infusion

3. Pregnancy & Breastfeeding

DMT Pregnancy Breastfeeding

Interferon beta-1a / Peginterferon beta 1a

Safe to continue until conception - previous concerns around an increased rate of spontaneous abortion have not been seen in larger registry studies

No evidence of harm to fetus

If stopped, ~3/12 to reach full efficacy post-partum

Benefits of breastfeeding outweigh any risk and should be encouraged

Glatiramer acetate Safe to continue until conception

No evidence of harm to fetus

If stopped, ~3/12 to reach full efficacy post-partum

Benefits of breastfeeding outweigh any risk and should be encouraged

Teriflunomide Contraindicated

Teratogenic in animal studies

Potential exposure in females via transfer in seminal fluid

Contraindicated

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Avoid pregnancy for 2 years after treatment course unless undergone accelerated elimination procedure

Unplanned pregnancies: accelerated elimination and high risk

Dimethyl fumarate Limited data - only continue treatment if the potential benefit justifies the potential risk to the fetus

Does not reduce the effectiveness of hormonal contraception, but note potential for GI upset

Not recommended

Natalizumab High risk of relapse / rebound if stopped

No specific pattern of birth defects

Consider treating in pregnancy; recommend last dose is week 34

Low absorption

Fingolimod Contraindicated during pregnancy in women of childbearing potential not using effective contraception

Increased risk of major congenital malformations including cardiac, renal, and musculoskeletal defects

Stop 2 months before a pregnancy is planned and consider alternative treatments

Unplanned pregnancy: stop treatment immediately and refer to an obstetrician for close monitoring during pregnancy, including ultrasound assessments

Contraindicated

Alemtuzumab Not recommended during pregnancy

Avoid pregnancy for 4/12 after treatment course

Monitor for autoimmune disease

Not recommended

Cladribine Contraindicated

Teratogenic in both ♂ and ♀

Avoid pregnancy for 6/12 after treatment course

Contraindicated

Ocrelizumab Limited data

Avoid pregnancy for 12/12 after treatment course

Unplanned pregnancy: immediately stop; high risk

Contraindicated

Table 3. Summary of DMTs in Pregnancy and Breastfeeding

Further detail is available in UK consensus on pregnancy in multiple sclerosis: ‘Association of British

Neurologists’ guidelines.

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4. References

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2. Polman C, Reingold S, Banwell B et al. Diagnostic Criteria for Multiple Sclerosis: 2010 Revisions

to the McDonald Criteria

3. Association of British Neurologists. Guidelines for the use of betainterferons and glatiramer

acetate in multiple sclerosis 2001. Available at http://theabn.org.documents/msdoc.pdf

4. Scottish Medicines Consortium. Teriflunomide (Aubagio) 2014.

5. Scottish Medicines Consortium. Dimethyl fumarate (Tecfidera) 2014.

6. Scottish Medicines Consortium. Alemtuzumab (Lemtrada) 2014 and 2019.

7. Scottish Medicines Consortium. Natalizumab (Tysabri) 2007.

8. Scottish Medicines Consortium. Fingolimod (Gilenya) 2014.

9. Scottish Medicines Consortium. Cladribine (Mavenclad) 2018.

10. Alan J Thompson et al. Diagnosis of Multiple Sclerosis: 2017 Revision of the McDonald Criteria.

Lancet Neurology Lancet Neurology 2018; 17:162-73.

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11. Scottish Medicines Consortium. Ocrelizumab (Ocrevus) - SMC 2121, 2018.

12. Medicines and Healthcare products Regulatory Agency (MHRA). Drug Safety Update -

Lemtrada (alemtuzumab) and serious cardiovascular and immune-mediated adverse reactions:

new restrictions to use and strengthened monitoring requirements. London: MHRA; 2019;

Volume 12 Issue 10, Pg2-4.

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24. Dobson R, Dassan P, Roberts M, et al. UK consensus on pregnancy in multiple sclerosis:

‘Association of British Neurologists’ guidelines Practical Neurology 2019;19:106-114.

25. Polman CH, Bertolotto A, Deisenhammer F, et al. Recommendations for clinical use of data on

neutralising antibodies to interferon-beta therapy in multiple sclerosis. Lancet Neurol. 2010

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