Shared Care
Guideline
Leflunomide
For the treatment of:
Inflammatory arthritis in adults ( 16 years old)
For the latest information on interactions and adverse affects, always consult the
latest version of the Summary of Product Characteristics (SmPC), which can be
found at: www.medicines.org.uk
These guidelines are based on the monitoring criteria of the British Society of Rheumatology,
published in the following reference:
Chakravarty, K., McDonald, H., Pullar, T. et al. (2008) BSR/BHPR guideline for diseasemodifying anti-rheumatic drug (DMARD) therapy in consultation with the British Association of
Dermatologists. Rheumatology 47(6), 924-925.
Authors: Dr Kelsey M Jordan (Consultant Rheumatologist, BSUH NHS Trust)
Dr Stewart E Glaspole (Pharmacist, BSUH NHS Trust/BHCPCT)
LFL SCG
Document status Final/Draft: Final 13 Jan 2009
Date of next review if final: 13 Jan 2010
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Drug Name
Leflunomide 10mg, 20mg and 100mg tablets (Arava®)
Indications for use within the protocol
Leflunomide is indicated for the treatment of adult patients with:

active rheumatoid arthritis as a "disease-modifying antirheumatic drug"
(DMARD)

active psoriatic arthritis
Pharmacology
Leflunomide reversibly inhibits dihydroorotate dehydrogenase (DHODH), the rate
limiting step in the de novo synthesis of pyrimidines, thus interfering with DNA
synthesis, repair, and cellular replication. The precise mechanism of action in
rheumatoid arthritis is unknown. It may affect immune function and clarification of its
effect on immune activity and the relation of this to rheumatoid immunopathogenesis
await further studies.
Dosage and administration

Leflunomide is taken in tablet form at 20mg /day (dose can be reduced to
10mg daily if poorly tolerated).
Loading dose
100mg once daily for 3 days may be used to speed up the onset of effect.
Unacceptable gastrointestinal (GI) side effects such as diarrhoea may occur when a
loading dose is given and this is often omitted in routine practice. A loading dose is
not recommended when used as part of combination therapy.
Contra-indications

Pregnancy, breast-feeding and women of child bearing potential not using
reliable contraception.
NOTE: Both men and women receiving leflunomide must use contraception
throughout the treatment period, and for at least two years in women (3 months for
men) after discontinuing treatment. Alternatively, a washout procedure can be
undertaken – see monitoring below). Blood concentrations should be measured for
the first time after the recommended waiting time and repeated after at least 14 days
to ensure levels are below 0.02 mg/l before pregnancy occurs.

Live Vaccines (oral polio, measles, mumps, rubella, BCG, oral typhoid, yellow
fever) must not be administered whilst taking leflunomide.

Moderate to severe renal insufficiency

Severe hypoproteinaemia or impaired liver function
LFL SCG
Document status Final/Draft: Final 13 Jan 2009
Date of next review if final: 13 Jan 2010
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Additional cautions
Patients receiving leflunomide must not receive immunization with live vaccines.
Inactivated polio is available although suboptimal response may be seen.

Annual flu vaccination is recommended

When the patient has had close contact with chicken pox or shingles seek
secondary care advice using the contact details below
Monitoring
The British Society for Rheumatology (BSR) recommends precise monitoring to be
carried out for this drug. The requirements are summarised in the following table.
a. Pre-treatment
assessment
b. Ongoing Monitoring
Additional monitoring
not required but useful

FBC, U&E, LFTs.

Blood pressure: If >140/90 on two consecutive
readings 2 weeks apart treat hypertension before
commencing the drug.

Weight: to allow assessment of weight loss: this may
be attributable to leflunomide.

These tests will be carried out by the initiating
hospital specialist.

FBC, LFTs every month for 6 months and, if stable, 2
monthly thereafter.

Blood checks should be continued long-term, at least
once a month, if co-prescribed with another
immunosuppressant or potentially hepatotoxic agent.

U&E's 6-12 monthly (more frequently if there is any
reason to suspect deteriorating renal function)

Blood pressure and weight should be checked at each
monitoring visit.
ESR and/or CRP every three months
LFL SCG
Document status Final/Draft: Final 13 Jan 2009
Date of next review if final: 13 Jan 2010
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Actions to be taken
WBC<3.5 x 109/L
Withhold until discussed with specialist team.
9
Withhold until discussed with specialist team.
Platelets<150 x 10 /L
Withhold until discussed with specialist team.
AST and/or ALT between two and
three times the upper limit of
reference range
If the current dose is more than 10mg daily
reduce the dose to 10mg daily and recheck
weekly until normalised. If the AST & ALT is
returning to normal, leave on 10mg a day. If
LFTs remain elevated withdraw the drug and
discuss with the specialist team.
AST and/or ALT more than three
times the upper limit of reference
range
Recheck LFTs within 72 h, if still more than
three times the reference range: stop drug,
consider washout and discuss with the
specialist team.
Rash or itch
Consider dosage reduction with or without
antihistamines; if severe, stop drug, consider
washout and discuss with the specialist team.
Hair loss
Consider dosage reduction; if severe, stop
drug, consider washout and discuss with the
specialist team.
Abnormal bruising or severe sore
throat
Check FBC immediately and withhold until
results are available.
Hypertension
If BP>140/90 treat in line with NICE guidance.
Neutrophils<2.0 x 10 /L
9
If BP remains uncontrolled, stop leflunomide
and consider washout
Headache
If severe, consider dosage reduction. If
headaches persist, stop and consider washout
GI upset (nausea, diarrhoea)
If loading dose has been used, give
symptomatic treatment. If steady state has
been reached, give symptomatic treatment and
consider dosage reduction. If symptoms are
severe or persistent, stop and consider
washout
Weight loss
Monitor carefully. If >10% weight loss with no
other cause identified, reduce dosage or stop
and consider washout
Breathlessness
If increasing shortness of breath occurs, stop
leflunomide and consider washout
Washout procedure
Cholestyramine 8 g is administered 3 times daily. Alternatively, 50 g of activated
powdered charcoal is administered 4 times daily. Duration of a complete washout is
usually 11 days. The duration may be modified depending on clinical or laboratory
variables.
LFL SCG
Document status Final/Draft: Final 13 Jan 2009
Date of next review if final: 13 Jan 2010
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Undesirable effects

Common - nausea, anorexia, oral ulceration, minor hair thinning, abdominal
discomfort, diarrhoea, headaches, hypertension

Uncommon - rash, bone marrow suppression, causing thrombocytopenia,
neutropenia, and rarely anaemia. Patients should be warned to report a sore
throat and abnormal bleeding/bruising

Hepatotoxicity. Rare cases of severe liver injury (some with fatal outcome) have
been reported during treatment with leflunomide. There is potential for increased
toxicity if co-prescribed with methotrexate and if there is evidence of recent coinfection with hepatitis B and C virus

Pulmonary toxicity. Acute pneumonitis or chronic pulmonary fibrosis may occur.
This is not dose related. It presents with dry cough, dyspnoea and often fever.
Pregnancy and Lactation

Leflunomide is teratogenic and there is a theoretical risk of sperm mutation in
males, therefore leflunomide should not be used during pregnancy.

Women planning to have children should either discontinue the drug 2 yrs prior to
conception or have a rapid removal of its active metabolite by following the
washout procedure.

Men should use effective contraception for 3 months after stopping leflunomide.

Leflunomide is excreted into breast milk in low concentrations and should be
avoided
Blood concentrations should be checked prior to planned pregnancy
especially if within 2 years of stopping leflunomide or following wash out. Any
pregnancy within 2 yrs of discontinuation of leflunomide should be discussed
with rheumatologist if drug washout has not been performed. Notify
pharmaceutical company in the event of pregnancy while on leflunomide.
Interactions
Leflunomide can interact with many drugs and has a very long half-life (2 weeks) and
therefore potential interactions may take time to become clinically apparent on
discontinuation and requires close monitoring:

Interacts with warfarin and increases the International normal ratio (INR)

Enhances the effects of phenytoin and tolbutamide

Please check the SmPC and/or BNF for the full list of interactions
LFL SCG
Document status Final/Draft: Final 13 Jan 2009
Date of next review if final: 13 Jan 2010
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Consultant / hospital responsibilities

Identify those patients who will benefit from treatment with leflunomide

Undertake pre-treatment monitoring as detailed above

Inform the GP of the reasons for initiating leflunomide.

Initiate and prescribe the medication. Decide on the dose and duration of therapy
and subsequent dosage adjustments

Ensure that patients understand the nature and possible complications of
leflunomide and their role in reporting adverse effects promptly

Agree to discuss promptly with the GP questions regarding treatment with
leflunomide and review patients promptly if requested by the GP

Provide the patient with monitoring blood forms whilst on treatment with copies of
results sent to the GP (unless the GP chooses to take responsibility for both
prescribing and monitoring)

Undertake responsibility to act on pathology lab results (unless the GP chooses
to take responsibility)

Review efficacy of treatment at regular intervals and ensure any drug treatment
changes are communicated to the GP

Communicate any changes in frequency of pathology testing to the GP

Provide access to back up and support facilities

Report any adverse events to the CSM

Evaluate any adverse events reported by the GP.
GP/Primary care responsibilities
It is the GP’s responsibility to:

Return the shared care agreement letter to the consultant to indicate agreement
with this guideline. If for any reason the GP is unhappy with the arrangements
they should contact the appropriate hospital specialist

Prescribe leflunomide at the dose recommended by the hospital specialist. Any
decision to alter or discontinue treatment should be taken after discussion with
the hospital specialist

Check for possible drug interactions when newly prescribing or stopping
concurrent medication (see interaction section)

Report any suspected or actual adverse drug reactions to the hospital specialist
and the CSM

Undertake an urgent full blood count to check for leucopenia in patients
developing significant infection, or multiple mouth ulcers
LFL SCG
Document status Final/Draft: Final 13 Jan 2009
Date of next review if final: 13 Jan 2010
Page 6 of 10
Patient responsibilities
It is the patient’s responsibility to:

Report side effects to any member of the health care team

Patients are expected to attend for blood tests when required, to ensure safe and
effective ongoing treatment.
Information to the patient
The outpatient clinic will provide the patient with information about their treatment.
Information about the patient to be received by the GP from the consultant
Please refer to the shared care request letter attached. Two copies of this letter will
be sent to the GP for each patient initiated on therapy.
Patient information to be received by the consultant from the GP
In order for GPs to agree formally to this shared care protocol, it is requested that
both the shared care request letters attached be signed and one returned to the
hospital specialist requesting shared care.
Contacting the specialist team
If the patient’s Consultant is not available, one of the other Consultants or Specialist
Registrars will be able to help. Please call the Rheumatology department at RSCH
on 01273 696955 x4631/3553 or PRH on 01444 441881 x 5432/5984
Out of hours
Urgent problems should be referred to the medical team on call, contacted via RSCH
switchboard on 01273 696955 or the PRH switchboard on 01444 441881
LFL SCG
Document status Final/Draft: Final 13 Jan 2009
Date of next review if final: 13 Jan 2010
Page 7 of 10
References
1 British Society for Rheumatology. National guidelines for the monitoring of second
line drugs, 2000. www.rheumatology.org.uk
2 Sanofi-aventis summary of Product characteristics
http://emc.medicines.org.uk/emc/
assets/c/html/DisplayDoc.asp?DocumentID=7480 (24 October 2007, date last
accessed).
3 British National Formulary 48. Pharmaceutical Press, 2004.
4 Scott DL, Smolen JS, Kalden JR et al. Treatment of active rheumatoid arthritis with
leflunomide: two year follow up of a double blind, placebo controlled trial versus
sulfasalazine. Ann Rheum Dis 2001;60:913–23.
5 Kalden JR, Schattenkirchner M, So¨rensen H et al. The efficacy and safety of
leflunomide in patients with active rheumatoid arthritis: a five-year followup study.
Arthritis Rheum 2003;48:1513–20.
6 Emery P, Cannon G, Holden W, Smolen J, Strand V, Schiff M. Results from a
cohort of over 40,000 rheumatoid arthritis (RA) patients: adverse event (AE) profiles
of leflunomide (LEF), methotrexate (MTX) and other disease-modifying antirheumatic
drugs (DMARDs). Ann Rheum Dis 2002;61(Suppl. 1):42.
7 Emery P, Smolen J. Issues in rheumatoid arthritis. Lancet 1999;353:1186.
8 PSUR Periodic Safety Update Reports 6 monthly reviewers of all world wide
spontaneous adverse events reports, 2004.
9 Dougados M, Emery P, Lemmel EM et al. Efficacy and Safety of leflunomide and
predisposing factors for treatment response in patients with active rheumatoid
arthritis: RELIEF 6-month data. J Rheumatol 2003;30:2572–9.
10 Dendooven A, De Rycke L, Verhelst X, Mielants H, Veys EM, De Keyser F.
Leflunomide and methotrexate combination therapy in daily clinical practice. Ann
Rheum Dis 2006;65:833–4.
11 Hypertension: management of hypertension in adults in primary care, 2006. http://
www.nice.org.uk/guidance/CG34/guidance/pdf/English (15th February 2008, date
last accessed).
12 Saravanan V, Kelly C. Drug-related pulmonary problems in patients with
rheumatoid arthritis. Rheumatology 2006;45:787–9.
13 Ito S, Sumida T. Interstitial lung disease associated with leflunomide. Intern Med
2004;43:1103–4.
14 Kamata Y, Nara H, Kamimura T et al. Rheumatoid arthritis complicated with acute
interstitial pneumonia induced by leflunomide as an adverse reaction. Intern Med
2004;43:1201–4.
15 McCurry J. Japan deaths spark concerns over arthritis drug. Lancet
2004;363:461.
16 Takeishi M, Akiyama Y, Akiba H, Adachi D, Hirano M, Mimura T. Leflunomide
induced acute interstitial pneumonia. J Rheumatol 2005;32:1160–3.
17 Ann Rheum Dis 2000;59:841-849
LFL SCG
Document status Final/Draft: Final 13 Jan 2009
Date of next review if final: 13 Jan 2010
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Confidential shared care request
Consultant name
Consultant address
Date
GP Name
GP Address
Leflunomide in inflammatory arthritis in adults ( 16 years old)
Patient Name: Patient Hospital number: Patient Address: Patient NHS Number: Dear Dr.
Your patient has been commenced on:
Leflunomide, at a dose of:
It would be appropriate for this patient’s therapy to be shared between primary and
secondary care. The enclosed Shared Care Guideline provides additional
information to support you in this. Please sign both copies of this letter to indicate
your agreement and return one copy to my office; the other should be placed in the
patient’s notes at your practice.
Yours sincerely,
Consultant name
GP signature
Print name
LFL SCG
Document status Final/Draft: Final 13 Jan 2009
Date of next review if final: 13 Jan 2010
Page 9 of 10
Date
Confidential shared care request
Consultant name
Consultant address
Date
GP Name
GP Address
Leflunomide in inflammatory arthritis in adults ( 16 years old)
Patient Name: Patient Hospital number: Patient Address: Patient NHS Number: Dear Dr.
Your patient has been commenced on:
Leflunomide, at a dose of:
It would be appropriate for this patient’s therapy to be shared between primary and
secondary care. The enclosed Shared Care Guideline provides additional
information to support you in this. Please sign both copies of this letter to indicate
your agreement and return one copy to my office; the other should be placed in the
patient’s notes at your practice.
Yours sincerely,
Consultant name
GP signature
Print name
LFL SCG
Document status Final/Draft: Final 13 Jan 2009
Date of next review if final: 13 Jan 2010
Page 10 of 10
Date