Clinical Guidance for Cladribine 2015

1. Barts Health NHS Trust: Newham University Hospital, The London Chest Hospital,
The Royal London Hospital, St Bartholomew’s Hospital and Whipps Cross Hospital.
BartsMS Patient Information Sheet Cladribine, drafted by Drs Monica Marta & Niall MacDougall, reviewed & edited by
Drs Klaus Schmierer, Sharmilee Gnananpavan, Benjamin Turner and Professor Gavin Giovannoni, 22 October 2015.
Scheduled review October 2016
BartsMS Patient Information Sheet
Cladribine for treatment of people with multiple sclerosis
Introduction
You have been given this information sheet as your neurologist would like to offer you Cladribine as a
treatment of your MS. Please read this information and then discuss any questions you may have
with your neurologist and/or MS Specialist Nurse.
Background
Cladribine has been used over many years as a therapy for people with MS (pwMS)1,2
. Cladribine
works through suppression of a specific proportion of the immune system, the lymphocytes (white
blood cells). There is plenty of evidence that this type of cells is important in MS, and that lowering
the number of lymphocytes circulating in the blood can be beneficial for pwMS. Clinical trials have
shown that Cladribine is an effective and generally safe treatment for pwMS1-6
. Despite this
favourable evidence, however, Cladribine has so far only been licensed for pwMS in Russia and
Australia, whilst this is not the case for the UK, EU, or the USA. Cladribine does have a license, since
1993, for treatment of people with ‘hairy cell leukaemia’. For further information on licensing, see
‘About unlicensed medicines’ below.
In clinical trials for relapsing MS, Cladribine has been shown to significantly reduce the number of
relapses3-5
and the rate of disease progression3,4
. After 96 weeks observation and following two
courses of treatment, 45% of pwMS on Cladribine showed no signs of disease activity (no relapses, no
disease deterioration and no new manifestations on MRI brain) compared to only 12% of pwMS who
were given a placebo4
. There is also, albeit as yet inconclusive, evidence that Cladribine may be useful
in pwMS who have progressive forms of MS1,2,6
.
How does Cladribine work?
Cladribine lowers the number of a sub-group (lymphocytes) of the white cells in the blood, thereby
partially suppressing the immune system. As MS has many features of an auto-immune disease,
where the immune system attacks the brain, Cladribine may reduce the damage caused by MS
through its effect on lymphocytes.
How is Cladribine given?
Cladribine can be given by infusion in a vein or as subcutaneous injection (injection under the skin).
There is also an oral version of (Cladribine tablets; Movectro), however these tablets are currently not
available. At Barts Health, we therefore use Cladribine subcutaneous injections. These injections are
usually very well tolerated, and usually do not cause any injection site reactions. Should this
nevertheless occur, please inform your care team immediately.

2. Barts Health NHS Trust: Newham University Hospital, The London Chest Hospital,
The Royal London Hospital, St Bartholomew’s Hospital and Whipps Cross Hospital.
BartsMS Patient Information Sheet Cladribine, drafted by Drs Monica Marta & Niall MacDougall, reviewed & edited by
Drs Klaus Schmierer, Sharmilee Gnananpavan, Benjamin Turner and Professor Gavin Giovannoni, 22 October 2015.
Scheduled review October 2016
During the 1st
week of treatment we administer Cladribine on days 1, 2 and 3. Four weeks later we
check your lymphocyte count in the blood to decide whether you should be given another 1, 2, 3 or –
rarely – no further injection(s) in week 5. The reason for this dosing scheme is that by checking your
lymphocytes at week 4 we try to avoid suppressing this cell type any further than what is considered a
safe level (i.e. a lymphocyte count no lower than 0.5 x 109
/L)).
We will then check your white cell counts after another 4 weeks, and then every 3 months until your
2nd
treatment cycle is due, which is regularly one year after the 1st
injection of Cladribine. Your
lymphocytes will then be re-checked, and the 2nd
course of treatment given in the same way as the
1st
. Following this 2nd
course of Cladribine treatment a further course will only be given if signs of new
disease activity are emerging (relapses, significant deterioration without relapse, or new lesions on
MRI).
What side effects does Cladribine have?
Cladribine has a number of possible side effects. Most of these side effects have been described in
people receiving Cladribine for treatment of leukaemia, and we have therefore attached to this
information sheet the summary of product characteristics of Cladribine (Litak) when used in people
with Leukaemia (Appendix 1).
N = 430N = 435

3. Barts Health NHS Trust: Newham University Hospital, The London Chest Hospital,
The Royal London Hospital, St Bartholomew’s Hospital and Whipps Cross Hospital.
BartsMS Patient Information Sheet Cladribine, drafted by Drs Monica Marta & Niall MacDougall, reviewed & edited by
Drs Klaus Schmierer, Sharmilee Gnananpavan, Benjamin Turner and Professor Gavin Giovannoni, 22 October 2015.
Scheduled review October 2016
The table above (Table 3), extracted from the pivotal phase III trial of Cladribine3
in people with
relapsing MS, gives a more realistic overview of the side effects in pwMS. Please ask one of the team if
there is anything you do not understand. Regarding the important difference in the rate of neoplasms
(benign and malignant), and particularly malignancies (0 cancers in pwMS on placebo versus 3 in
pwMS treated with Cladribine)3
, it is important to remember this difference does not enable drawing
any definite conclusion about whether there is an increased risk of cancer when taking Cladribine;
indeed current evidence does not support an increased risk of cancer with Cladribine compared to all
other (licensed) disease modifying treatments for pwMS7
.
Who should not take Cladribine?
• Anyone with known hypersensitivity to Cladribine.
• Women who are pregnant or breastfeeding.
• Anyone younger than 18 years of age.
• People with moderate or severe renal impairment (creatinine clearance ≤ 50 ml/min), or
moderate to severe hepatic impairment.
• Patients using other myelosuppressive medicinal products.
• Anyone with an active infection.
Cladribine and previous cancer
In the treatment of people with leukaemia Cladribine has been associated with the return or re-
occurrence of previously diagnosed cancers. If you have had cancer, or a potentially precancerous
condition, such as an abnormal cervical smear you should discuss this with your doctor before
treatment with Cladribine.
How does cladribine affect pregnancy and fertility?
Cladribine may cause serious birth defects when administered during pregnancy.
Women of childbearing potential must use effective contraception during treatment with Cladribine
and for 6 months after the last Cladribine dose.
Men being treated with Cladribine should not father a child for at least 6 months after the last
Cladribine dose. Men should use adequate contraception and consider cryoconservation (freezing) of
sperm prior to treatment due to a potential risk of infertility following Cladribine treatment.
How does cladribine affect breastfeeding?
We do not know if Cladribine is excreted in human milk, however theoretical considerations suggest it
may do so and as a result there is the potential for serious adverse reactions in nursing infants if they
were exposed to Cladribine. Mothers must not breast feed until 6 months after the last dose of
Cladribine.
Please inform your doctor if you have or have had:
• Liver or kidney problems

4. Barts Health NHS Trust: Newham University Hospital, The London Chest Hospital,
The Royal London Hospital, St Bartholomew’s Hospital and Whipps Cross Hospital.
BartsMS Patient Information Sheet Cladribine, drafted by Drs Monica Marta & Niall MacDougall, reviewed & edited by
Drs Klaus Schmierer, Sharmilee Gnananpavan, Benjamin Turner and Professor Gavin Giovannoni, 22 October 2015.
Scheduled review October 2016
• Infections (if you suffer from an infection, this will be treated before you start using
Cladribine).
• Any signs of infections (such as flu-like symptoms or fever) during or after
treatment
Effects on ability to drive and use machines
Cladribine may influence your ability to drive and use machines in case certain adverse reactions with
a potential impact on performance occur. Thus, we recommend you do not drive whilst being treated
with Cladribine. Possible side-effects that may impair driving ability include dizziness and drowsiness,
which may occur due to anaemia.

5. Barts Health NHS Trust: Newham University Hospital, The London Chest Hospital,
The Royal London Hospital, St Bartholomew’s Hospital and Whipps Cross Hospital.
BartsMS Patient Information Sheet Cladribine, drafted by Drs Monica Marta & Niall MacDougall, reviewed & edited by
Drs Klaus Schmierer, Sharmilee Gnananpavan, Benjamin Turner and Professor Gavin Giovannoni, 22 October 2015.
Scheduled review October 2016
About unlicensed (off-label) medicines8
Before a medicine can be sold in the UK, a marketing authorisation (formerly product licence) from
the MHRA is required. The MHRA will only issue a marketing authorisation if clinical trials have shown
that:
• the medicine successfully treats the condition it was developed for
• the medicine's side effects are acceptable, and
• the medicine meets high safety and quality standards
What is an unlicensed (off-label) medicine?
Prescribing a medicine licensed for condition A to treat somebody with condition B is called “off-label
prescribing”. For example, some medicines to treat depression (“condition A”) are used to treat pain
(“condition B”). A company holding the license of a medicine to treat condition A must not market
the drug for treatment of condition B (unless the medicine also has a license for condition B).
Most medicines are licensed by the Medicines and Healthcare products Regulatory Agency (MHRA) to
ensure that they provide benefit and are acceptably safe. Adverse effects from medicines can be
minor, but they can also be serious. To assess whether a medicine is acceptably safe, its benefits are
compared with the possible adverse effects it could cause. Significant and/or frequent side effects
may be acceptable for a medicine used to treat a life-threatening condition, but not in a medicine
used to treat a minor illness.
Wherever possible, doctors should prescribe medicines within their licensed indication. However, if a
doctor thinks a medicine will be effective in treating your condition despite not being licensed to treat
that condition, they may yet prescribe it.
Examples for prescribing a medicine off-label include:
• There is no available licensed medicine
• There may be a special clinical need that cannot be met by a medicine licensed for their
condition – for example, they are allergic to an ingredient, or cannot swallow tablets
• The medicine has undergone clinical trials and is waiting for approval from regulators such as
the MHRA
• Despite the availability of licensed medicine(s) your doctor thinks an off-label medicine is the
better for the treatment of your condition
• You may have agreed to receive an unlicensed medicine as part of a clinical trial
Doctors should inform you if they are prescribing a medicine to you ‘off-label’.
About licensing of Cladribine
Oral Cladribine (Movectro) is licensed in Russia and Australia for the treatment of pwMS. However,
the manufacturer (Merck) stopped supplying Movectro to these countries in 2011. In September
2015, Merck published a letter of intent to re-apply to the European Medicines Agency (EMA) for

6. Barts Health NHS Trust: Newham University Hospital, The London Chest Hospital,
The Royal London Hospital, St Bartholomew’s Hospital and Whipps Cross Hospital.
BartsMS Patient Information Sheet Cladribine, drafted by Drs Monica Marta & Niall MacDougall, reviewed & edited by
Drs Klaus Schmierer, Sharmilee Gnananpavan, Benjamin Turner and Professor Gavin Giovannoni, 22 October 2015.
Scheduled review October 2016
marketing authorisation of Cladribine in pwMS9
. Currently, Cladribine is not licensed in the UK, EU or
USA for treatment of pwMS.
However, Cladribine has been licensed since 1993 for the treatment of people with ‘hairy cell
leukaemia’. The reasons for refusal of a license for Cladribine as a treatment for pwMS by the EMA in
2010/11 are complex and include the concern about a possible cancer risk (as mentioned above, more
recent evidence suggests there is no increased cancer risk compared to other disease modifying
treatments for pwMS7
), the risk of lowering lymphocyte count too low, and (in 2011) insufficient
phase III clinical trial evidence of efficacy.
Will Cladribine become a licensed treatment for pwMS?
We are unable to predict whether Cladribine will be licensed in Western Europe and/or the US for
treatment of pwMS. The neurologists at BartsMS are encouraged by the evidence that Cladribine is an
effective and safe treatment for MS1-7,10
, and are working towards Cladribine becoming a licensed
drug for pwMS11-12
.
References:
1) Sipe, et al. Cladribine in treatment of chronic progressive multiple sclerosis. Lancet 1994;344:9-13.
2) Beutler, et al. The treatment of chronic progressive multiple sclerosis with cladribine. Proceedings of the National
Academy of Sciences of the United States of America 1996;93:1716-20.
3) Giovannoni, et al. A placebo-controlled trial of oral cladribine for relapsing multiple sclerosis. The New England
Journal of Medicine 2010;362:416-26.
4) Giovannoni, et al. Sustained disease-activity-free status in patients with relapsing-remitting multiple sclerosis
treated with cladribine tablets in the CLARITY study: a post-hoc and subgroup analysis. Lancet Neurol
2011;10:329-37.
5) Stelmasiak, et al. Effect of parenteral cladribine on relapse rates in patients with relapsing forms of multiple
sclerosis: results of a 2-year, double-blind, placebo-controlled, crossover study. Mult Scler J 2009;15:767-70
6) Rice GPA, et al. Cladribine and progressive MS. Clinical and MRI outcomes of a multicenter controlled trial.
Neurology 2000;54:1145–55.
7) Pakpoor, et al. No evidence for higher risk of cancer in patients with multiple sclerosis taking cladribine. Neurol
Neuroimmunol Neuroinflamm 2015;2:e158
8) http://www.gmc-uk.org/guidance/ethical_guidance/14327.asp
9) http://news.merck.de/N/0/1C517A71C016A43BC1257EBC006B50C3/$File/CladribineEng.pdf
10) Leist, et al. Effect of oral cladribine on time to conversion to clinically definite multiple sclerosis in patients with a
first demyelinating event (ORACLE MS): a phase 3 randomised trial. Lancet Neurol 2014;13:257-67.
11) http://multiple-sclerosis-research.blogspot.com/2015/12/cladribine4ms.html
12) https://twitter.com/KlausSchmierer
Appendix 1: Record of the discussion about licensed disease modifying drugs for people with
multiple sclerosis
Appendix 2: Cladribine (Litak) summary of product characteristics

7. Barts Health NHS Trust: Newham University Hospital, The London Chest Hospital,
The Royal London Hospital, St Bartholomew’s Hospital and Whipps Cross Hospital.
BartsMS Patient Information Sheet Cladribine, drafted by Drs Monica Marta & Niall MacDougall, reviewed & edited by
Drs Klaus Schmierer, Sharmilee Gnananpavan, Benjamin Turner and Professor Gavin Giovannoni, 22 October 2015.
Scheduled review October 2016
Appendix 1: Record of the discussion about licensed disease modifying drugs for people with
multiple sclerosis
Patient MRN/name:
BartsMS team member:
Record of the discussion about licensed disease modifying drugs for people with multiple sclerosis
Currently licensed disease modifying treatments for people with MS are the following:
• Interferon beta-1a (Avonex, Rebif)
• Interferon beta-1b (Betaferon, Extavia)
• Glatiramer acetate (Copaxone)
• Dimethyl fumarate (Tecfidera)
• Teriflunomide (Aubagio)
• Fingolimod (Gilenya)
• Natalizumab (Tysabri)
• Alemtuzumab (Lemtrada)
Following a discussion of the subject’s eligibility for these drugs, and their benefits and risks, please
state here the reason(s), if and as applicable, why the patient rejects treatment with any of these
medicines
State here the reason, if and as applicable, why the prescribing clinician supports treatment with
Cladribine instead of a licensed DMT