Trust Guideline. for. Shared Care Guidelines for the Use of Leflunomide (Arava )

A guideline recommended for use Trust Guideline for Shared Care Guidelines for the Use of Leflunomide (Arava ) In: By: For: East and North Herts NHS Trust (ENHT) East and North Herts PCT/ENHCCG Consultants in East and North Herts NHS Trust, GPs in ENHCCG and those elsewhere who share the care of patients with specialists at the ENHT, and Pharmacists Adult patients in East and North Herts NHS Trust and Primary Care Organisations (PCOs) Key Words: Written by: Supported by: Approved by: Leflunomide, rheumatoid arthritis, psoriatic arthritis, Arava Sharon Pearson (Rheumatology Specialist Nurse) Fiona Sinclair (General Practitioner and Chair of Herts Primary Care Medicines Management Committee [PCMMG]) TPC Sub-Committee Dr Spencer Ellis (Consultant Rheumatologist) Therapeutics Policy Committee Aide Viljoen (Chair) March 2013 Ratified by: Clinical Guidelines Steering Group Dr Diane Harvey (Chair) September 2015 Guideline issued: September 2013 To be reviewed before: September 2015 To be reviewed by: Guideline supersedes: Location of archived copy: Chief Pharmacist Not applicable Archive section of Pharmacy Intranet page and Clinical Governance U: Drive CGSG Guideline Registration No. 137 Version No. 01 Authors: Sharon Pearson and Fiona Sinclair Date of issue: September 2013 Page 1 of 11

Index Part One Shared Care Responsibilities Page No. 1. Hospital Specialist Responsibilities 3 2. General Practitioner Responsibilities 3 3. Patient Responsibilities 4 4. Contact Details 4 Part Two Supporting Information 1. Background 5 2. Indication 5 3. Dosage and Administration 5 4. Cost 5 5. Absolute Contra-indications 6 6. Pregnancy, Contraception and Breastfeeding 6 7. Monitoring 7 8. Common Side-Effects 7 9. Rare but Serious Side-Effects 8 10. Drug Interactions 8 11. Washout Regime 8 Appendix 1 9 Side Effects and Actions to be Taken Dissemination and Access This Guideline can only be considered valid when viewed via the East & North Hertfordshire NHS Trust Knowledge Centre. If this document is printed in hard copy, or saved at another location, you must check that it matches the version on the Knowledge Centre. Equality Impact Assessment This Guideline, and its impact upon equality, has been reviewed in line with the Trust s Equality Scheme and no detriment was identified. Authors: Sharon Pearson and Fiona Sinclair Date of issue: September 2013 Page 2 of 11

Part One - Shared Care Guideline for Leflunomide (Arava ) 1. Rheumatology Consultant / Rheumatology Specialist Nurse Responsibilities: Advise the patient and GP to arrange immunisation with one-off Pneumovax before starting leflunomide (Arava ), as immunisation is more effective prior to immunesuppression. Advise yearly flu vaccine with the first dose 2 weeks prior to starting immunesuppression if this coincides with the flu vaccination season (October to March). Supply the first month s prescription of leflunomide (Arava ). Write to the GP with a copy of the shared care guidelines requesting shared care after the patient has been commenced on leflunomide (Arava ). Provide regular clinic follow up review. Continue to monitor blood results and provide copies to the GPs. Alter the dose of leflunomide (Arava ), and other relevant medications, as required. Inform the GP of any changes in treatment. Provide advice during working hours via the Rheumatology Advice Line 01438 285624. 2. General Practitioner Responsibilities: Respond promptly to the request to enter into a shared care agreement If declining to enter into a shared care agreement explain why they are not in a position to take on shared care for leflunomide (Arava ). Notify the Rheumatology Department of any concerns about health or symptoms that might be related to leflunomide (Arava ) treatment. Follow the guidance in Appendix 1 Guideline re where urgent action is needed. Ensure leflunomide (Arava ) is entered in the electronic patient record, to aid checking for contraindications and drug interactions eg as a medication, even if the practice will not be issuing the prescriptions. Check blood test results prior to issuing prescriptions. Decline to issue a prescription if blood tests results are not available. Authors: Sharon Pearson and Fiona Sinclair Date of issue: September 2013 Page 3 of 11

3. Patient Responsibilities: Read the written information provided at the initial visit, and seek clarification of any points of the treatment that are unclear. Inform the specialist, GP or community pharmacist dispensing their prescriptions of any other medication being taken including over-the-counter medication. Report any concerns, adverse effects or warning symptoms to the specialist or GP whilst taking leflunomide (Arava ). Use reliable contraception during leflunomide (Arava ) treatment if patient or partner is of child-bearing age. Take up the offer of immunisation as advised by the specialist and GP, or actively decline. Take the leflunomide (Arava ) as prescribed 4. Contact Details: Specialist Designation Contact number Dr Binder Consultant Rheumatologist 01438 284128 Dr Axon Consultant Rheumatologist 01438 285399 Dr Ellis Consultant Rheumatologist 01438 284473 Dr Wijeyekoon Consultant Rheumatologist 01438 286120 Rheumatology advice-line Rheumatology Nurse Specialist 01438 285624 Annual Review advice-line Rheumatology Nurse Practitioner 01438 284672 http://www.enhertsrheumatology.co.uk Authors: Sharon Pearson and Fiona Sinclair Date of issue: September 2013 Page 4 of 11

Part Two Supporting Information 1. BACKGROUND Rheumatoid Arthritis (1,2,3) Rheumatoid arthritis (RA) is the most common chronic inflammatory joint disease affecting 0.5 1% of the population. It is believed that RA is triggered by exposure of an immunogenetically susceptible host to an arthritogenic antigen. A continuing auto-immune reaction ultimately leads to joint destruction. The present aim of treatment is to control joint inflammation as early as possible after diagnosis. This should lead to pain reduction and maintain the range of joint movement, minimise loss of function, prevent deformity and keep patients mobile and independent. Several factors have influenced the change in practice, which advocates the earlier use of disease modifying antirheumatic drugs (DMARDs). The rate of occurrence of bony erosions is greatest during the first two years of RA and there is evidence that earlier use of DMARDs slows radiological progression and improves function. The toxicity of DMARDs is similar to NSAIDs, particularly during the early stages of RA when patients general health is good and newer DMARDs eg methotrexate, are less toxic and more effective than those previously available. 2. Indications Leflunomide (Arava ) is a disease-modifying anti-arthritic drug (DMARD) licensed for the use in treatment of adult patients with moderate to severe rheumatoid arthritis and active psoriatic arthritis. Leflunomide (Arava ) is an immunomodulatory agent used for patients who have failed on other available DMARDs including sulphasalazine and methotrexate. It is known to retard structural damage and provide early clinical benefit. Leflunomide can be used in combination with methotrexate, with extra vigilance in the first few months, blood monitoring 4 weekly, due to the increased risk of hepatic reactions and bone marrow toxicity. Leflunomide has a good safety record with few serious adverse effects. Most side effects occur within the first three months. Leflunomide is immunosuppressive and can increase the risk of opportunistic and other infections. Leflunomide can take up to twelve weeks to take effect and even six months for full benefit. Due to the long half-life there is no point in stopping therapy during inter-current infection unless sepsis is identified, when the washout procedure may be advised. 3. Dosage and Administration: (4) 10 mg to 20 mg once daily (orally) with or after food. 4. Cost for 30 days: (6) (Prices from Drug Tariff March 2013) Leflunomide 10 mg (white) 30 tablet pack 39.18 20 mg (yellow) 30 tablet pack 44.74 Authors: Sharon Pearson and Fiona Sinclair Date of issue: September 2013 Page 5 of 11

5. Absolute Contra-indications: (4) Significant immune, hepatic or renal impairment. On-going infections. Use with caution in patients with a history of TB. Not recommended for use in patients under 18 years Pregnancy and breast feeding. The active metabolite is teratogenic. 6. Pregnancy, Contraception and Breastfeeding Exclude pregnancy and breast feeding prior to commencing treatment. Effective contraception is essential for both men and women during treatment and for at least two years after treatment in women and three months in men if the washout procedure is not performed 5 Leflunomide is teratogenic and there is a theoretical risk of sperm mutation in males. Women planning to have children should either discontinue leflunomide 2 years prior to conception or have a rapid removal of its active metabolite following the washout procedure. Leflunomide is excreted into breast milk in low concentrations and should be avoided. Blood concentrations should be checked prior to pl anning pr egnancy especiall y if w ithin 2 year s of st opping leflunomide or follow ing w ash out. An y pregnancy w ithin 2 years of discontinuation of leflunomide should be discussed w ith rheumatologist if drug w ashout has not been performed. Notif y pharmaceut ical company in the event of pr egnancy w hile on leflunomide. Authors: Sharon Pearson and Fiona Sinclair Date of issue: September 2013 Page 6 of 11

7. Monitoring: British Society for Rheumatology (BSR) guidelines: NB These differ from those in the Summary of Product Characteristics 4 a. Baseline assessment b. On-going Monitoring Additional monitoring (for disease activity) FBC, U&E, LFTs. Pregnancy test for women child bearing age. Blood pressure: If >140/90 on two consecutive readings, 2 weeks apart, treat hypertension in line with NICE guidance before commencing the drug. Weight: to allow assessment of weight loss as 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 such as methotrexate. U&Es 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 within secondary care. ESR and/or CRP every three months 8. Common Side-Effects: (See Appendix 1 for more details) If a dose reduction is indicated below, contact the rheumatology advice line to discuss. Since leflunomide has a very long half-life, have a low threshold for deferring treatment until advice is received. Blood pressure: can cause mild increase especially with pre-existing hypertension. If >140/90 treat in line with NICE guidance. Gastrointestinal: o Diarrhoea - most common side effect. Usually self-limiting, but if persistent discuss with Rheumatology Consultant to consider reducing leflunomide dose and/or using loperamide. o Nausea - usually self-limiting but if persists Rheumatology Team will reduce leflunomide dose or advise trying an antiemetic. Rash: Usually mild. Try reducing leflunomide dose but if it persists, stop the drug. Mild elevation of LFT s (1-3 fold rise in ALT/AST whichever is included in LFT bundle): reduce leflunomide dose; (20 mg to 10 mg daily or 10 mg to defer) according to liver function abnormality. If liver function abnormality persists, discontinue treatment and consider washout procedure. Alopecia: Usually mild and self-limiting. Dose reduction may be of benefit. Other common side-effects include: anorexia, mouth ulceration, weight loss (usually insignificant), headache, dizziness, tenosynovitis, eczema and dry skin. Authors: Sharon Pearson and Fiona Sinclair Date of issue: September 2013 Page 7 of 11

9. Rare but Serious Side-Effects Stop treatment and seek advice via Rheumatology Advice Line and/or admit as an emergency depending on the patient s condition in the case of: Severe rash Bone marrow aplasia Severe hepatic toxicity eg Stevens Johnson syndrome WCC <3.5 x 10 9 /L, Neutrophils <2 x 10 9 /L, Platelets <150 x 10 9 /L >3 fold rise in ALT/AST Severe anaphylactic / anaphylactoid reaction Weight loss Breathlessness Progressive Mulitfocal Leukoencephalopathy (PML) if >10% with no cause identified Worsening shortness of breath (SOB) Very rare complication of all immunesuppressive agents (see BNF) 10. Drug interactions: Colestyramine reduces level of active metabolite of leflunomide, however it can be used as part of a washout procedure if required. Warfarin check INR after any change in leflunomide, as INR may be increased by leflunomide Phenytoin check levels, as these may be increased by leflunomide. Consider a reduction in tolbutamide and/or blood glucose monitoring due to risk of hypoglycaemia. Vaccination with live vaccines is contraindicated (Influenza and Pneumococcal vaccines are not live and are recommended). Increased risk of side-effects with recent or concomitant use of hepatotoxic drugs or when leflunomide is followed by such drugs without a washout period. Alcohol - should be limited to fewer than 10 units a week due to an increased risk of hepatotoxicity. Use of concomitant methotrexate may cause increased side-effects. 11. Washout Regime: (4) In the event of severe side-effects, or if pregnancy is desired, a washout can be performed using colestyramine 8g TDS OR activated powdered charcoal 50g QDS; each for 11 days. See current BNF for more information. Authors: Sharon Pearson and Fiona Sinclair Date of issue: September 2013 Page 8 of 11

Appendix 1 Side Effects and Actions to be Taken Authors: Sharon Pearson and Fiona Sinclair Date of issue: September 2013 Page 9 of 11

WBC<3.5 x 10 9 /L Side Effect/s Neutrophils<2.0 x 10 9 /L Platelets<150 x 10 9 /L AST and/or ALT between two and three times the upper limit of reference range AST and/or ALT more than three times the upper limit of reference range Rash or itch Hair loss Abnormal bruising or severe sore throat Hypertension Headache GI upset (nausea, diarrhoea) Weight loss Breathlessness Actions to be taken Withhold until discussed with Specialist Team. Withhold until discussed with Specialist Team. Withhold until discussed with Specialist Team. 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 (levels dependent) withdraw the drug and discuss with the specialist team. Recheck LFTs within 72 hours, if still more than three times the reference range: stop drug, discuss with the specialist team and consider washout. Consider dosage reduction with or without antihistamines; if severe, stop drug, discuss with the specialist team and consider washout. Consider dosage reduction; if severe, stop drug, discuss with the specialist team and consider washout. Check FBC immediately and withhold until results are available. If BP>140/90 treat in line with NICE guidance. If BP remains uncontrolled, stop leflunomide and consider washout. If severe, consider dosage reduction. If headaches persist, stop and consider washout. 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. Monitor carefully. If >10% weight loss with no other cause identified, reduce dosage or stop and consider washout. If increasing shortness of breath occurs, stop leflunomide and consider washout. Authors: Sharon Pearson and Fiona Sinclair Date of issue: September 2013 Page 10 of 11

12. References 1) British Society for Rheumatology and British Health Professionals in Rheumatology guidelines for the management of Rheumatoid arthritis (after 2 years) BSR/BHPR 2009. 2) BSR/BHPR guidelines for disease-modifying anti-rheumatic drug (DMARD) therapy in consultation with the British Association of Dermatologists, Rheumatology 2008. 3) Use of Oral Methotrexate Shared Care Guidelines for Adults, 2011. 4) Leflunomide. Summary of Product Characteristics. Sanofi 08.01.2013. 5) British National Formulary September 2012. 6) Drug Tariff March 2013 Resources: http://www.enhertsrheumatology.co.uk Authors: Sharon Pearson and Fiona Sinclair Date of issue: September 2013 Page 11 of 11