Oxfordshire
Clinical Commissioning Group
LEFLUNOMIDE FOR USE IN RHEUMATOLOGY & PAEDIATRIC RHEUMATOLOGY
Shared Care Protocol
This protocol provides prescribing and monitoring guidance for leflunomide therapy. It
should be read in conjunction with the Summary of Product Characteristics (SPC) available on
www.medicines.org.uk/emc, the BNF and Shared Care Protocol Responsibilities.
BACKGROUND FOR USE
Leflunomide is a disease modifying antirheumatic drug (DMARD). It should only be initiated by a
rheumatologist. Its uses in this shared care protocol in adults include:


Rheumatoid arthritis (licensed). It can be used as monotherapy or in combination with another
DMARD4.
Psoriatic arthritis (licensed).
Its uses in this shared care protocol in paediatrics include:
 Treatment of inflammatory disorders including Juvenile Idiopathic Arthritis, psoriatic arthritis,
non bacterial osteomyelitis and uveitis.
The optimum therapeutic dose of DMARDs should be achieved to minimise disease progression and
joint erosions. Leflunomide is typically used to treat patients who are unable to tolerate methotrexate.
It can also be used simultaneously with other medications including methotrexate and sulphasalazine
to gain optimum control of disease if monotherapy is ineffective. Studies of children and young people
aged 3 to 18 years have shown leflunomide to be a safe and effective alternative to methotrexate,
resulting in substantial improvements in joint mobility and function in children with Juvenile Idiopathic
Arthritis (Foeldvari & Wierk, 2010; Silverman et al 2005a; Silverman et al, 2005b).
Since lefluomide is only licensed for adults over 18 years and is not included within the BNF
for children leflunomide should only be initiated by and under the direction of a consultant
paediatric rheumatologist, or a rheumatologist with an interest in paediatric rheumatology.
The first dose should be prescribed by the initiating specialist, and be prescribed by them until the
dose is stable and/or the GP formally agrees to shared care (as stated in the shared care
responsibilities document).
For all renal patients, supply of this medication will be provided in secondary care.
CONTRAINDICATIONS AND PRECAUTIONS
Contraindications
Vaccination with LIVE
vaccines
Chickenpox/shingles
Patients receiving leflunomide must NOT receive immunisation with LIVE
vaccines. Inactivated polio is available although sub-optimal response may
be seen. Remember, for paediatrics Fluenz Tetra® (nasal ‘flu vaccine) is live
so should not be used.
Patients suffering from chickenpox or active skin lesions in shingles, withhold
leflunomide and inform rheumatologist. For those with exposure to
chickenpox or shingles and no history of infection/vaccination, passive
immunisation with VZIG should be carried out.
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Conception and
Pregnancy
Breastfeeding
Impaired liver function
due to any cause
Moderate to severe
renal impairment
Precautions
Infection
Alcohol
Pulmonary infiltration
/reactions
Leflunomide is teratogenic and must not be given to women of child bearing
potential unless reliable contraception is used. Women planning to have
children should either discontinue the drug for 2 years prior to conception or
have rapid removal of its active metabolite by following the washout
procedure. Blood concentrations should be checked prior to planning
pregnancy (see washout procedure). Men should also receive the washout
procedure and use effective contraception for 3 months after stopping
leflunomide prior to planning to conceive.
Avoid
Avoid
Avoid
Vigilance required in detection and treatment.
Limit alcohol intake to 4 - 8 units per week.
Acute allergic reactions can occur. Added risk when used in combination with
methotrexate. Patients should be made aware of this rare complication.
DOSAGE
Adults
 Typical dosage is 10 - 20 mg daily.
 There is no dose adjustment in patients over 65 years of age or those with mild renal
insufficiency.
 A dose of 10 mg daily is usually recommended if leflunomide is used in combination with
another potentially hepatotoxic DMARD, e.g. methotrexate.
 Leflunomide has an elimination half life of several weeks. In cases of significant adverse
reactions, ‘washout’ procedure to speed elimination may be necessary.
 Time to response is 8 to 12 weeks. Symptoms may further improve after several months.
Paediatrics
 Leflunomide is prescribed according to weight:
o <10kg – 5mg once a day
o 10-40kg – 10mg once a day
o >40kg – 20mg once a day
 Benefit is seen after 6 to 8 weeks and improvement may continue over a further 4 to 6
months.
Leflunomide is taken in tablet form and should be swallowed whole. Tablets are available as 10mg
and 20mg doses.
PRE-TREATMENT ASSESSMENT BY RHEUMATOLOGIST
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FBC, LFT, U&Es and CRP.
Blood pressure for adults, if >140/90 on two consecutive readings, two weeks apart, refer
back to GP for treatment of hypertension before commencing leflunomide. Children: record
baseline BP
Weight (to allow assessment of weight loss which may be attributable to leflunomide).
Exclude possibility of pregnancy
A baseline chest X-Ray is not required unless pre-existing fibrotic or interstitial lung disease.
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ONGOING MONITORING SCHEDULE
FBC, U&Es, CRP, LFTs, BP, weight: Monitor fortnightly for 3 months. After that monitor monthly until
stable, then reduce to every two months on specialist’s advice. The monitoring interval needs to be
reduced to monthly if leflunomide is used in combination with other potentially hepatotoxic agents,
e.g. methotrexate.
ACTIONS TO BE TAKEN
Adults
Side effects ADULTS
WBC < 3.5 X 10^9/l
Neutrophils <2 X 0^9/l
Platelets <150 X 10^9/l
Liver function > 2 fold rise in
AST/ALT (from upper limit of
reference range)
Actions ADULTS
Stop leflunomide and repeat WBC. If repeat count is
normal continue, if abnormal discuss with specialist
team.
Stop leflunomide and repeat WBC. If repeat count is
normal continue, if abnormal discuss with specialist
team.
Strict monitoring of LFT’s is essential due to
hepatotoxicity. Caution is necessary when used
concomitantly with other hepatotoxic medication
e.g. methotrexate, or if evidence current or recent
hepatitis B or C infection.
If on 20mg/day reduce dose to 10mg/day. Recheck
weekly until normalised and maintain at 10mg/day.
If ALT/AST remains elevated withhold until
discussed with specialist rheumatology team. If
persistent consider washout
AST/ALT > 3 fold rise from
upper limit of reference range
Stop drug.
Re-check LFTs within 72 hours. If persistent
consider washout.
Renal Impairment. i.e. eGFR
<30 mls minute
Reduce dose by 50%
Increase frequency of monitoring
Hypertension
If B/P > 140/90 Treat according to NICE guidance.
If B/P remains uncontrolled, discontinue drug.
Discuss with specialist team any patient not
responding to treatment.
Consider dose reduction with or without
antihistamines. If severe stop and consider washout
procedure,
Immediate FBC and withhold until result of FBC
available
Is not uncommon, usually settles, but if severe may
require reduction in dose/discontinuation of the drug
with or without washout procedure.
If greater than 10% with no identified cause, reduce
or discontinue with or without washout.
If severe consider dosage reduction
Most cases are mild/ moderate and resolve during
treatment. If severe consider dosage reduction
Discuss with specialist team.
.
Rash or severe mouth ulcers
Severe sore throat, abnormal
bruising
GI upset/nausea, diarrhoea
Weight loss
Headache
Alopecia
Tenosynovitis and rarely
tendon rupture.
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Paediatric
Side Effect PAEDIATRIC
WBC < 4 X 10^ 9 /l
Neutrophils <1.5 X10^9/l
Actions PAEDIATRIC
Withhold, repeat WBC, if normal continue, otherwise discuss with
paediatric rheumatology team
Withhold until discussed with paediatric rheumatology team
Platelets <150 X10^9/l
Withhold until discussed with paediatric rheumatology team
Liver function. ALT or AST
>120
Withhold until discussed with paediatric rheumatology team.
Transaminase increase 3 X normal is common within 2 days of
drug administration and may be attributable to an asymptomatic
viral infection. Consider rechecking ALT at trough level. (i.e 0-2
days prior to injection)
Check folate. GGT, TSH B12. If B12 or folate low, start
appropriate supplementation.
See Appendix A for normal blood pressures in children.
Recheck any blood pressures above 90th centile in 1 week.
If above 95th centile for 3 consecutive weeks then discuss with
paediatric rheumatology team.
Look for alternative causes. Withhold until discussed with
paediatric rheumatology team. Re-challenge with lower dose once
symptoms settle.
Withhold until discussed with rheumatologist
MCV > 105 fl
Hypertension
Rash or severe oral ulceration
Unexplained fall in Albumin
Diarrhoea
Significant reduction in renal
function
Weight loss
Alopecia
Monitor to ensure caused by leflunomide and not gastroenteritis.
Discuss with paediatric rheumatology team if continues to be a
problem.
Consider alternative causes, reduce dose following discussion
with paediatric rheumatologist.
If greater than 10% with no identified cause discuss with the
paediatric rheumatology team.
Most cases are mild/ moderate and resolve during treatment. If
severe consider dosage reduction. Usually reversible if attributable
to leflunomide
Please note that in addition to absolute values for haematological indices, a rapid fall or a consistent
downward trend in any value should prompt caution and extra vigilance. In order to monitor trends it
is recommended that all blood test results are entered in the patient held monitoring booklet.
Note:
 Annual ‘flu vaccination is recommended (warning: do not use the live paediatric nasal spray)
 Leflunomide can be withheld for 2-3 weeks without inducing a flare.
 Leflunomide should not be stopped prior to elective surgery.
WASHOUT PROCEDURE ADULTS:
This is used to aid drug elimination in case of significant adverse effect, or before starting another
DMARD or before conception (for both men and women planning a pregnancy). Refer back to
Rheumatology for washout. Stop leflunomide then use either:
 Cholestyramine 8g 3 times daily for a period of 11 days
 Or 50 g of activated charcoal 4 times daily for a period of 11 days. (aperient is recommended )
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For both men and women before conception 2 blood tests are required at least 14 days apart to
check plasma levels, which must drop below 0.02mg/l. A waiting period of one-and-a-half months
between the first plasma reading below 0.02mg/l and fertilisation is required.
WASHOUT PROCEDURE PEDIATRICS
The paediatric rheumatology team will advise if a washout procedure is required. It is recommended
that patients requiring the washout procedure should be referred back to the paediatric rheumatology
team. After stopping Leflunomide use either:
 Cholestyramine:
o 1 – 6 years 2g once daily for a period of 11 days
o 6 – 12 years 4g once daily for a period of 11 days
o 12-14 years 4 – 8g once daily for a period of 11 days
 Or Activated Charcoal:
o Activated Charcoal 1g/kg (max 50g) administered 4 times daily for a period of 11 days.
In addition 2 blood tests are required at least 14 days apart to check plasma levels, which must drop
below 0.02mg/l.
NOTABLE DRUG INTERACTIONS
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Other haematotoxic and hepatotoxic drugs, e.g. methotrexate: Reduce monitoring interval.
Warfarin: Plasma levels may be increased by leflunomide. Monitor INR of warfarin treated
patients closely.
Phenytoin: Plasma levels may be increased by leflunomide. Monitor phenytoin plasma levels
of leflunomide treated patients.
Tolbutamide: Hypoglycaemic effects may be increased by leflunomide.
Rifampicin: Increases leflunomide plasma levels.
NSAIDs may be used.
Leflunomide has an extremely long elimination half-life and interactions with these drugs may
continue for at least eight weeks after leflunomide has been discontinued.
BACK-UP INFORMATION/ADVICE
Contact Details
Oxford University Hospitals NHS Trust
Rheumatology
Rheumatology Helpline (Adult and
Paediatric)
Medicines
Information
Mylan – ad hoc
Advisory Service
(information on
plasma level
laboratory testing)
Free Plasma Level
Testing
Rheumatology Senior Registrar on
call
Tel 01865 221505
01865 737656
01865 741155, ask for SR on call via
switchboard.
+44 (0) 01707 853 000 (option 1)
Sponsored by Sanofi-Aventis. The kits and testing are provided by Eurofins
Medinet. To obtain a kit order form contact Sanofi-Aventis Medicines
Information on 0845 372 7101.
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REFERENCES
1.
2.
3.
4.
NICE Clinical Guideline 34 Hypertension, June 2006.
BNF 68. Sept 2014 – Mar 2015
Leflunomide SPC, www.medicines.org.uk/emc
NICE Clinical Guideline 79, Rheumatoid Arthritis, April 2009
Acknowledge:
Adapted from Buckinghamshire CCG Shared Care Protocols
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APPENDIX A
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(2004)The fourth report on the diagnosis, evaluation, and treatment of high blood pressure in children
and adolescents. National High Blood Pressure Education Program Working Group on High Blood
Pressure in Children and Adolescents.Pediatrics. Aug;114(2 Suppl 4th Report):p 555-76
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