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 DMARD 4. 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. Approved by APCO May 2015 1 of 10 Uncontrolled if printed
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 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. Approved by APCO May 2015 2 of 10 Uncontrolled if printed
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 Renal Impairment. i.e. egfr <30 mls minute Stop drug. Re-check LFTs within 72 hours. If persistent consider washout. 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. Rash or severe mouth ulcers Consider dose reduction with or without antihistamines. If severe stop and consider washout procedure, Severe sore throat, abnormal Immediate FBC and withhold until result of FBC bruising available GI upset/nausea, diarrhoea Is not uncommon, usually settles, but if severe may require reduction in dose/discontinuation of the drug with or without washout procedure. Weight loss If greater than 10% with no identified cause, reduce or discontinue with or without washout. Headache If severe consider dosage reduction Alopecia Most cases are mild/ moderate and resolve during treatment. If severe consider dosage reduction Tenosynovitis and rarely Discuss with specialist team. tendon rupture.. Approved by APCO May 2015 3 of 10 Uncontrolled if printed
Paediatric Side Effect PAEDIATRIC WBC < 4 X 10^ 9 /l Neutrophils <1.5 X10^9/l Platelets <150 X10^9/l Liver function. ALT or AST >120 MCV > 105 fl Hypertension Rash or severe oral ulceration Unexplained fall in Albumin Diarrhoea Significant reduction in renal function Weight loss Alopecia Actions PAEDIATRIC Withhold, repeat WBC, if normal continue, otherwise discuss with paediatric rheumatology team Withhold until discussed with paediatric rheumatology team Withhold until discussed with paediatric rheumatology team 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 90 th centile in 1 week. If above 95 th 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 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 ) Approved by APCO May 2015 4 of 10 Uncontrolled if printed
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 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 Rheumatology Medicines Information Mylan ad hoc Advisory Service (information on plasma level laboratory testing) Free Plasma Level Testing Oxford University Hospitals NHS Trust Rheumatology Helpline (Adult and Paediatric) Rheumatology Senior Registrar on call Tel 01865 221505 +44 (0) 01707 853 000 (option 1) 01865 737656 01865 741155, ask for SR on call via switchboard. 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. Approved by APCO May 2015 5 of 10 Uncontrolled if printed
REFERENCES 1. NICE Clinical Guideline 34 Hypertension, June 2006. 2. BNF 68. Sept 2014 Mar 2015 3. Leflunomide SPC, www.medicines.org.uk/emc 4. NICE Clinical Guideline 79, Rheumatoid Arthritis, April 2009 Acknowledge: Adapted from Buckinghamshire CCG Shared Care Protocols Approved by APCO May 2015 6 of 10 Uncontrolled if printed
APPENDIX A Approved by APCO May 2015 7 of 10 Uncontrolled if printed
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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 Approved by APCO May 2015 10 of 10 Uncontrolled if printed