Basingstoke, Winchester & Southampton District Prescribing Committee Shared Care Guideline: Leflunomide Name of patient treated under this guideline: This shared care guideline has been produced to support the seamless transfer of prescribing and patient monitoring from secondary to primary care, and provides an information resource to support clinicians providing care to the patient. It does not replace discussion about sharing care on an individual patient basis. This guideline was prepared using information available at the time of preparation, but users should always refer to the manufacturer s current edition of the Summary of Product Characteristics (http://www.emc.medicines.org.uk ) or http://www.rheumatology.org.uk/ for more details. http://www.westhampshireccg.nhs.uk/documents/cat_view/84-medicines/87-shared-care-guidelines 1.0 Status of Leflunomide Leflunomide is an amber drug using our local traffic light system. This means that treatment will usually be initiated in secondary care and may be transferred to primary care if appropriate. The key principle is that the GP is provided with information and given the opportunity to accept (or decline) prescribing responsibility before the transfer occurs. In accepting prescribing responsibility the GP also accepts responsibility for undertaking the activities outlined in this shared care guideline in section 7.0 below, which may include monitoring. 2.0 Licensed Indications Leflunomide is a disease-modifying anti-rheumatic drug. It is licensed for patients over 18 years of age with active rheumatoid arthritis. Start with a dose of 10mg or 20mg daily, depending on the activity of the disease. The recommended maintenance dose for rheumatoid arthritis is 10mg to 20mg once daily. If a 20mg dose is prescribed, please prescribe 1 x 20mg tablet instead of 2 x 10mg tablets ( ). It is also licensed for patients over 18 years of age with active psoriatic arthritis. In psoriatic arthritis the recommended dose is 20mg daily. A loading dose is not usually given for either rheumatoid arthritis or psoriatic arthritis. There is no dose adjustment recommended in patients with mild renal insufficiency. The therapeutic effect usually starts after 4 to 6 weeks of treatment and improvement may continue for 4 to 6 months. 3.0 Referral Criteria Consultants will consider leflunomide as a therapy for patients attending their clinics with the indications described in section 2. 4.0 Patient Selection As above.
5.0 Safety Issues 5.1 Contraindications (see BNF or SPC) Leflunomide is contraindicated in: Patients with hypersensitivity to leflunomide (especially previous Stevens-Johnson syndrome, toxic epidermal necrolysis, erythema multiforme), peanut or soya or to any of the excipients in the tablets. Patients with impairment of liver function. Patients with moderate to severe renal insufficiency. Hypertension which is uncontrolled or difficult to control. Patients with serious infections or severe immunodeficiency states. Patients with severe hypoproteinaemia e.g. nephrotic syndrome. Patients with tuberculin reactivity must be carefully monitored because of the risk of tuberculosis reactivation. Patients with significantly impaired bone marrow function or significant anaemia, leucopenia, neutropenia or thrombocytopenia due to cause other than rheumatoid arthritis. Recent or concurrent treatment with hepatotoxic or haematotoxic DMARDs may result in an increased risk of serious adverse reactions. Pregnancy The active metabolite of leflunomide is suspected to cause serious birth defects when administered during pregnancy. Leflunomide must not be given to pregnant women or to women of childbearing potential who are not using reliable contraception. Pregnancy must be excluded before start of treatment with leflunomide. Women of childbearing potential have to use effective contraception during and up to 2 years after treatment (see waiting period below) or follow washout procedure (see below for details). The patient must be advised that if there is any delay in onset of menses or any other reason to suspect pregnancy, they must notify their physician immediately. The Consultant Rheumatologist must also be notified of a suspected pregnancy immediately. For women receiving leflunomide treatment and who wish to become pregnant, one of the following procedures is recommended in order to ascertain that the foetus is not exposed to toxic concentrations of the active metabolite of leflunomide (target concentration below 0.02mg/L) Waiting period The plasma levels of the active metabolite of leflunomide can be expected to be above 0.02mg/L for a prolonged period. The concentration may be expected to decrease below 0.02mg/L about 2 years after stopping treatment with leflunomide. After a 2-year waiting period, the active metabolite plasma concentration is measured for the first time. Thereafter, the plasma concentration must be determined again after an interval of at least 14 days. If both plasma concentrations are below 0.02mg/L no teratogenic risk is to be expected. Washout procedure After stopping treatment with leflunomide, either colestyramine (8g administered three times a day) or activated powdered charcoal (50g administered four times a day) should be taken for a period of 11 days. Following either washout procedure, plasma concentration of the active metabolite of leflunomide should be
measured. The plasma concentration must then be determined again after an interval of at least 14 days. A waiting period of one-and-a-half months between the first occurrence of a plasma concentration below 0.02 mg/l and fertilisation is required. Women of childbearing potential should be told that a waiting period of 2 years after treatment discontinuation is required before they may become pregnant. If a waiting period of up to approximately 2 years under reliable contraception is considered unpractical, prophylactic institution of a washout procedure is advisable. Both colestyramine and activated powdered charcoal may influence the absorption of oestrogens and progestogens such that reliable contraception with oral contraceptives may not be guaranteed during the washout procedure. Use of alternative contraceptive methods is recommended. Procreation (recommendations for men) Male patients should be aware of the possible male-mediated foetal toxicity. Reliable contraception during treatment with leflunomide should also be guaranteed. To minimise any possible risk, men wishing to father a child should consider discontinuing use of leflunomide and taking colestyramine 8g three times daily for 11 days or 50g activated powdered charcoal four times daily for 11 days. In either case, the plasma concentration of the active metabolite of leflunomide must be measured. Thereafter, the plasma concentration must be determined again after an interval of at least 14 days. If both plasma concentrations are below 0.02mg/L, and after a waiting period of at least 3 months, the risk of foetal toxicity is very low. Women must not breast-feed while they are receiving leflunomide. 5.2 Cautions (see BNF or SPC) Leflunomide should be discontinued if any persistent abnormality of liver function is detected. Alcohol avoid. 5.3 Common Side Effects (See BNF or SPC) The supervising consultant must be notified immediately about any serious side effect. The active metabolite of leflunomide has a long half-life (usually 1-4 weeks). Serious adverse effects to leflunomide might occur even if the treatment with leflunomide has been stopped. Therefore, when such toxicities (e.g. pancytopenia) occur the washout procedure must be followed to accelerate the elimination of leflunomide. Concurrent or recent treatment with hepatotoxic or haematotoxic drugs may increase adverse effects. Infections Haematological Immune system disorders Metabolism and nutrition disorders Nervous system Cardiovascular Leflunomide may increase susceptibility to infections, including opportunistic infections. In the event that severe, uncontrolled infections occur, it may be necessary to interrupt leflunomide treatment and administer a washout procedure. Check FBC. Anaemia and mild thrombocytopenia (platelets < 100 x 10 9 /L) are uncommon. Leucopenia (leucocytes <2 X109/L) or pancytopenia are rare, but treatment should be stopped if these occur. Mild allergic reactions. Very rarely: severe anaphylactic/anaphylactoid reactions, Anorexia and 10% body weight loss. CPK increased. Hypokalaemia, hyperlipidaemia, hypophosphataemia. Headache (may respond to dose reduction), dizziness and paraesthesia. Anxiety is uncommon. Increase in blood pressure (usually mild). BP increases tend to affect those with pre-existing hypertension and may require additional antihypertensive therapy or cessation of treatment if uncontrolled.
Respiratory Gastrointestinal Liver Skin Muscular skeletal Interstitial lung disease is rare, leflunomide should be discontinued. Nausea, vomiting, diarrhoea (these may respond to dose reduction), oral mucosal disorders (e.g. mouth ulceration) and abdominal pain. Taste disturbances are uncommon. Elevations of liver function tests may occur, especially ALT, less often GGT, ALP, bilirubin. Hepatotoxicity usually occurs within 6 months of starting therapy and is more likely in patients with existing liver damage or those taking other hepatotoxic drugs or alcohol. Alopecia, eczema and dry skin, rash (including maculopapular rash), pruritus. Very rare: Stevens-Johnson syndrome or toxic epidermal necrolysis - discontinue and initiate washout procedure Ulcerative stomatitis discontinue leflunomide. Tenosynovitis, asthenia Side effects should be discussed with the supervising consultant In patients with pre-existing anaemia, leucopenia and/or thrombocytopenia as well as in patients with impaired bone marrow function or those at risk of bone marrow suppression, the risk of haematological disorders is increased. If such effects occur, including pancytopenia, leflunomide and any concomitant myelosuppressive therapy must be discontinued and a leflunomide washout procedure initiated. 5.4 Interactions Due to the long half life of the active metabolite of leflunomide, drug interactions may occur after leflunomide has been stopped. Drug Colestyramine Activated powdered charcoal Effect Rapid and significant decrease in plasma level of active metabolite of leflunomide avoid unless drug elimination desired (i.e. treating toxicity). Tolbutamide Phenytoin Warfarin Rifampicin Increases levels of phenytoin, warfarin and tolbutamide (drugs metabolised by CYP2C9). Increase peak levels of active metabolite of leflunomide. Note: 1) Live Vaccines - Vaccination with live attenuated vaccines is not recommended. The long half-life of leflunomide should be considered when contemplating administration of a live attenuated vaccine in a patient who has recently stopped leflunomide. 2) Alcohol - Due to a potential for additive hepatotoxic effects, it is recommended that alcohol consumption be avoided during treatment with leflunomide. 3) If a patient is already receiving NSAIDs and/or corticosteroids these may be continued after starting leflunomide.
5.5 Pre-treatment Assessment Full blood count (including differential white blood cell count and platelets), urea, electrolytes and liver function tests (ALT). Urine analysis for blood and protein. Blood pressure on 2 occasions 2 weeks apart. If > 140/90 treat before starting leflunomide. Body weight Patient given relevant information, leaflets and advice. Pregnancy excluded. 5.6 Routine Safety Monitoring Monitoring to be undertaken by the prescriber unless agreed otherwise. NB These are guidelines only, which may be overridden at the discretion of the consultant. Results outside recommendations should be discussed with the consultant along with trends raising concerns. See BSR Recommendations If leflunomide is co-prescribed with another hepatotoxic or haematotoxic drug closer monitoring of LFT s and FBC is recommend Parameter & frequency Full blood count, including differential white blood cell count and platelets, must be checked before initiation and every 4 weeks for the first 6 months of treatment and every 8 weeks thereafter. Liver function tests. ALT must be checked before initiation and every 4 weeks during the first 6 months of treatment and every 8 weeks thereafter. For ALT elevations between 2- and 3-fold the upper limit of normal, dose reduction from 20mg to 10mg may be considered and monitoring must be performed weekly. If ALT elevations of more than 2-fold the upper limit of normal persist (after dose reduction) or if ALT elevations of more than 3-fold the upper limit of normal are present, leflunomide must be discontinued and washout procedures initiated (refer to SPC for details). It is recommended that monitoring of liver enzymes be maintained after discontinuation of leflunomide treatment, until liver enzyme levels have normalised. Skin reactions. Rare cases of Stevens Johnson syndrome or toxic epidermal necrolysis have been reported. As soon as skin and/or mucosal reactions are observed which raise suspicion of such severe reactions, leflunomide must be discontinued and washout procedure initiated immediately. Infections. In severe infection, it may be necessary to interrupt treatment and administer a washout procedure. Blood pressure must be checked before initiation and then every 2 months. Treat BP if > 140/90. Hypoproteinaemia. Plasma levels of the active metabolite of leflunomide are enhanced. ESR and CRP. As agreed with the consultant. A rapidly increasing or decreasing trend in any values should prompt caution and extra vigilance.
Withhold treatment and discuss with specialist if any of the following occurs: WCC < 3.5 x 10 9 /L Neutrophils < 2 x 10 9 /L Platelets < 150 x 10 9 /L ALT / AST > 2-3 x ULN or any persistent abnormality of liver function. Hypertension which is difficult to control with routine medication. Sore throat with oral or pharyngeal ulceration, unusual bruising, unexplained rash, severe infection, fever Check FBC and withhold therapy until results known. Deterioration in renal function Increasing shortness of breath (pulmonary infiltration / pneumonitis stop therapy and seek urgent medical treatment). 6.0 Role of Consultant To assess the suitability of the patient for leflunomide. To carry out initial investigations and safety monitoring. Monitor blood pressure and weight at each clinic appointment. To explain the possible side effects of the medication to the patient and emphasise the importance of regular monitoring To give the patient a leflunomide information sheet. To initiate therapy and maintain prescribing responsibility for at least the first month of treatment. To arrange for appropriate investigations during the first month of treatment and to keep the patient and GP informed of any abnormalities. To write to GP enclosing a copy of these shared care guideline requesting that a shared care agreement be initiated. To monitor the patient s response to leflunomide therapy (e.g. ESR/CRP) Decide when to stop therapy To advise the GP on appropriate action with respect to any of the safety monitoring results. The prescriber should carry out the safety monitoring unless otherwise agreed in writing with the other party. When the safety monitoring is carried out other than by the prescriber, the prescriber must receive a copy of all the safety monitoring results 7.0 Role of GP To accept shared care in writing as proposed. To ensure that all relevant staff within the practice are aware of the shared care guideline. To consider any side effects reported by the patient, and discuss with the consultant if action is uncertain To carry out the safety monitoring e.g. FBC, liver function tests and blood pressure and any other tests as agreed with the consultant in writing. If the GP does not wish to undertake the safety monitoring then this must be agreed in writing with the consultant. The GP must ensure under all circumstances that they receive copies of the safety monitoring before writing a prescription. To avoid or appropriately manage the drug interactions indicated in Section 5.4 and current BNF.
To provide prescriptions of the drug after the initial month. To increase the dose, if necessary, after discussion with the consultant. To refer back to the consultant if the leflunomide therapy becomes less effective. 8.0 Role of Patient To report any side effects to the GP or consultant. To report any symptoms e.g. unusual tiredness, abdominal pain or jaundice (may indicate development of liver disorders), and signs/symptoms such as paleness, tiredness, increased proneness to infections or bruising (may indicate blood disorders), or skin rash or mucous membrane lesions (may develop into severe bullous skin and mucous membrane reactions). To report any signs of infection e.g. sore throats, cough and fever. To have blood tests carried out at agreed intervals. The patient must fully understand the need for safety monitoring whilst on leflunomide. To report suspected pregnancy of the patient or partner. To have their blood pressure checked every 2 months. To avoid alcohol if possible, maximum intake 7 units per week. 9.0 Further Information University of Southampton Hospitals NHS Foundation trust (023 8077 7222) Rheumatology Consultant Dr R. Armstrong (Secretary) Ext. 6452 Specialist Nurses helpline Ext 5352 Specialist Pharmacist Caron Underhill Bleep 2407 Medicines Information 023 8079 6908/9 Hampshire Hospitals NHS Foundation Trust Royal Hampshire County Hospital ( 01962 863535) Rheumatology Consultant Dr N Buchanan Ext 4920 Dr A Cooper Ext 4919 Specialist Nurse helpline Ext 4256 Pharmacist for both sites Jo Blain Ext 4693 Medicines Information 01962 824294 Basingstoke & North Hampshire Hospital (01256 473202) Rheumatology Consultant Dr P Prouse Ext 3644 Specialist Nurse Cathy Boys Ext 3121 Medicines Information 01256 313341 Prepared by: Caron Underhill, Pharmacist - Medicine, UHS. Reviewed by: Caron Underhill, Pharmacist Medicine, UHS. (Oct 2013) Approved by DPC: Martin Stephens, Chair (Oct 2013)