MYCOPHENOLATE MOFETIL In Renal Transplantation (prior to August 2004) and lupus nephritis/vasculitis

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1 Patient name Date of Birth DOCUMENT TO BE FILED IN NOTES AND SCANNED INTO ELECTRONIC RECORDS INTRODUCTION Mycophenolate Mofetil (Cellcept ) * is currently used first line as part of the triple immunosuppressant regimen with Ciclosporin (Neoral ) and Prednisolone at Barts and the London NHS Trust. Mycophenolate Mofetil is a reversible inhibitor of inosine monophosphate dehydrogenase and thus inhibits purine synthesis, with potent cytostatic effects on both T- and B-lymphocytes. It has been used mainly as the morpholinoethyl derivative, Mycophenolate Mofetil. It is given with other immunosuppressants, for the prevention of graft rejection, and has also been tried in various diseases with an auto-immune or immunemediated inflammatory component. Recipients who are not able to tolerate Mycophenolate Mofetil may be transferred on to Azathioprine. However Mycophenolate Mofetil will not be administered concomitantly with Azathioprine. In some circumstances recipients may be initiated on, or transferred on to Sirolimus (+/- Ciclosporin) or Tacrolimus. Although the later combination of Mycophenolate Mofetil with Tacrolimus is not covered within the Cellcept SPC, we routinely use this combination. Other formulations of Mycophenolate may become available which have different molar equivalent strengths (e.g. enteric coated Mycophenolate sodium or Myfortic ). Unless otherwise stated Barts and The London NHS Trust patients always take Mycophenolate Mofetil (Cellcept ). If and when Myfortic is approved for use at Barts and The London NHS Trust, ALL prescribing will be continued in the hospital setting. At the point of discharge the patient will be issued a one month supply of all medications. The shared-care will commence as soon as the supply needs renewing. The patient will continue to be seen in the transplant clinic at regular intervals. A second indication is for lupus nephritis or vasculitis. This is an unlicensed indication; however it has been used routinely for this group of patients for a number of years, based on extensive evidence. It is initiated first line on the recommendation of the Consultant Nephrologist, as well as in patients intolerant to cyclophosphamide i.e. bone marrow suppression, infertility or malignancy. The shared care guidelines for transplant only relate to those patients transplanted prior to August 2004, (Currently allocated monies for the repatriation of immunosuppressants only includes funding for newly transplanted patients not existing transplant patients prior to the above date) * ; the black triangle symbol identifies newly licensed medicines that are monitored intensively by MHRA/CSM. ALL suspected adverse drug reactions should be reported. 1

2 DOSE AND ADMINISTRATION Mycophenolate Mofetil (Cellcept ) Starting and maintenance dosage for renal transplantation: The adult dose is 1g twice daily (except for Afro- Caribbean 1.5gm/bd 1 ). Patients may be on a lower dose if they have not tolerated the higher dose. Gastro-intestinal adverse-effects may be limited by splitting doses (e.g. 500mg four times daily). If a patient is taking Mycophenolate Mofetil; Reduce the Mycophenolate Mofetil by 50% on initiation of Sirolimus. Lupus/vasculitis nephritis: The adult dose is 1g twice daily; patients may be on a lower dose if they have not tolerated the higher dose. 2 1) (Dosage supported in: Neylan J et al. Immunosuppressive therapy in high risk transplant patients: Dosedependent efficacy of Mycophenolate Mofetil in African American renal allograft recipients. Transplantation; 15 November 1997; Vol 64(9); This is a licensed dosage in the Cellcept SPC for the indications of hepatic and cardiac transplantation, but not for the indication of renal transplantation). 2) Dosage supported in: Dooley et al. Mycophenylate mofetil: What role in the treatment of lupuslupus (2006)15, ADVERSE EFFECTS This monitoring will not usually require additional routine appointments unless a problem is anticipated. Gastrointestinal upset is the most common side effect (e.g. nausea, vomiting, abdominal discomfort, diarrhoea or constipation). If severe or persistent, refer back to the renal physician. Anaemia, leucopenia and thrombocytopenia are most likely to be discovered in the transplant clinic. Opportunistic infections such as cytomegalovirus, herpes zoster/varicella or recurrent herpes simplex should be referred back to the renal physician if suspected. Patients should try to avoid contact with people who have active chickenpox or shingles. Life threatening infections relating to immunosuppression, including meningitis, infectious endocarditis, tuberculosis and atypical mycobacterial infection. See the summary of product characteristics (SPC) for other adverse effects. Other Drug Monitoring issues Suspected non-compliance with immunosuppression is serious and can lead to loss of the graft. The patient should be referred to the renal physician urgently. Pregnancy and breast feeding are manufacturer s contra-indications for Mycophenolate Mofetil. Patients discovered or planning to become pregnant should be started on folic acid 400micrograms daily and referred to their renal physician at the earliest opportunity. The combined oral contraceptive is a suitable option for renal transplant recipients, and is supported in the SPC. Drug Interactions The patient s renal function should be taken into consideration when co-prescribing for renal transplant patients. Mycophenolate Mofetil rapidly undergoes complete pre-systemic absorption to Mycophenolic Acid (MPA), which in turn is metabolised to MPA glucuronide. This then undergoes extensive enterohepatic recirculation; drugs which may interfere with this pathway should be avoided. 2

3 Antacids with magnesium and aluminium hydroxides reduce the absorption of Mycophenolate Mofetil. Cholestyramine: should not be taken at the same time of day as they will impair the absorption of Mycophenolate Mofetil. NSAIDs (and other nephrotoxic drugs) should be used with extreme caution. Note: Simvastatin should not be prescribed for hyperlipidaemia in renal transplant patients due to the increased risk of rhabdomyolysis with some immunosuppressants. To avoid any complications, all patients should be prescribed atorvastatin. Appendix 1 of the BNF is a useful guide to whether any drug is likely to cause a problem. If there is a clinical need to use such drugs then this is best undertaken in consultation with the renal clinic with careful monitoring. CAUTIONS Malignancies; Patients receiving immunosuppressive regimens involving combinations of drugs, including Mycophenolate Mofetil, are at increased risk of developing lymphomas and other malignancies, particularly of the skin. The risk appears to be related to the intensity and duration of immunosuppression rather than to the use of any specific agent. As general advice to minimise the risk for skin cancer, exposure to sunlight and UV light should be limited by wearing protective clothing and using a sunscreen with a high protection factor. Active serious digestive system disease; Mycophenolate Mofetil has been associated with an increased incidence of digestive system adverse events, including infrequent cases of gastrointestinal tract ulceration, haemorrhage and perforation. Vaccinations; Patients should be advised that during treatment with Mycophenolate Mofetil vaccinations may be less effective and the use of live attenuated vaccines should be not be given. However the Influenza vaccination may be of value. Prescribers should refer to national guidelines for influenza vaccination. Genetic deficiencies; Mycophenolate Mofetil is an IMPDH (inosine monophosphate dehydrogenase) inhibitor. On theoretical grounds therefore it should be avoided in patients with rare hereditary deficiency of hypoxanthine-guanine phosphoribosyl-transferase (HGPRT) such as Lesch-Nyhan and Kelley-Seegmiller syndrome. CONTRAINDICATIONS Hypersensitivity to Mycophenolate Mofetil or mycophenolic acid. Mycophenolate Mofetil is contraindicated in women who are pregnant or breastfeeding. 3

4 Post transplant outpatient management: MONITORING STANDARDS FOR AT BARTS AND THE LONDON NHS TRUST Up to 6 weeks Week 6 12 At 3 months 3x clinics/week (Monday, Wednesday, and Friday) 2x clinics/week (Tuesday and Friday) 1x clinic/week (Wednesday) Maximum interval between clinics: 3 6 months every 2 weeks 6 9 months every 3 weeks 9 12 months every 4 weeks 1 2 years every 2 months > 2 years every 3 months If very stable, after 6 months, can alternate bloods only with clinic Monitoring FBC (+differential) U+E s (+calcium and phosphate) LFT s Dipstick MSU Blood pressure Weight Random Cholesterol Random Glucose Frequency Each clinic appointment Note: For lupus patients, the above monitoring should be carried out at three month intervals. ACTION AND ADVICE Problem Sickness if the patient is unable to take medication or has diarrhoea If a patient reports any other serious adverse events to you, or if you notice any other blood result abnormalities Development of opportunistic infections Such as Cytomegalovirus and herpes zoster/varicella or recurrent herpes simplex. Action/advice Please contact the Transplant clinic or renal Pharmacists (Out of hours the Renal registrar on-call). Please contact the Transplant clinic or renal Pharmacists (Out of hours the Renal registrar on-call). Please ask the patient to ring the transplant clinic and make an urgent appointment to be seen by a doctor The patient s further therapy should be discussed with the patient s specialist. 4

5 SHARED CARE Sharing of care assumes a partnership between the specialist, GP and the patient. The intention to share care should be explained to the patient and accepted by them. Patients are under regular follow-up and this provides an opportunity to discuss drug therapy. The doctor who prescribes the medication has the clinical responsibility for the drug and the consequences of its use. Intrinsic in the shared care agreement is that the prescribing doctor should be appropriately supported by a system of communication and co-operation in the management of patients. SHARED CARE RESPONSIBILITIES Consultant 1. Initiate treatment and prescribe until the GP formally agrees to share care (as a minimum, supply the first month treatment or until patient is stabilised). 2. Send a letter to the GP requesting shared care for this patient. 3. Clinical and laboratory supervision of the patient by routine clinic follow-up on a regular basis. 4. Send a letter to the GP after each clinic attendance and inpatient stay (maximum of one letter/week irrespective of number of clinic visits within a week) ensuring current dose, most recent blood results and frequency of monitoring are stated. 5. Evaluation of any reported adverse effects by GP or patient. 6. Advise GP on review, duration or discontinuation of treatment where necessary. 7. Inform GP of patients who do not attend clinic appointments. 8. Inform GP, by letter, of clinic visits and action taken for management of patient. 9. Ensure that back up advice is available at all times. General Practitioner 1. Prescribe Mycophenolate Mofetil as Cellcept. 2. Identify adverse effects and treat or report to renal physician where appropriate. 3. Alert transplant unit to any identified non-compliance with immunosuppressants 4. Avoid drug interactions. 5. Avoid live vaccines. 6. If the GP has concerns over the prescribing of Mycophenolate Mofetil, they should contact the renal physician as soon as possible. 7. Conversion to alternative immunosuppressants should only be attempted by the Consultant Nephrologist. Patient 1. Report any adverse effects to their GP and/or specialist whilst taking Cellcept 2. Ensure they have a clear understanding of their treatment. 3. Report any changes in disease symptoms to GP and/or specialist whilst taking Cellcept. 4. Alert GP and/or specialist of any changes of circumstance which could affect management of disease e.g. plans for pregnancy whilst taking Cellcept. PCT 1. To provide feedback to trusts via Trust Medicines Committee. 2. To support GPs to make the decision whether or not to accept clinical responsibility for prescribing. 3. To support trusts in resolving issues that may arise as a result of shared care. 5

6 COST Mycophenolate Mofetil (Cellcept ) 250mg caps x mg tabs x 50 1g/5ml suspension x 175ml 0.88 /Capsule 1.75 /Tablet /175ml (Prices taken from emims May 2005) CONTACT NUMBERS FOR ADVICE AND SUPPORT Transplant clinical nurse specialists ext. 3204/2934 Renal Consultants office via switchboard: Dr. Martin Raftery. Registrar on-call out of hours Georgina Glass (Senior Directorate Pharmacist) Reena Popat (Senior Renal Pharmacist) ext. 7368, 7367 Air call via switchboard Bleep Via switchboard Bleep 1328 Medicines Information (for drug information related queries) ext Virology (Vaccine advice) Prescribing Adviser, Tower Hamlet PCT