Shared Care Guidelines In partnership with Acute Trust & PCTs SIROLIMUS In renal transplant August 2016 Page 0 of 12 SirolimusRenalTransplantGUI201609V2.0FINAL Table of Contents Introduction 2 Licensing 2 Referral 2 Initiation and maintenance of therapy 3 Administration 3 Supply 3 Prescribing 3 Adverse effects 4 Contraindication 4 Drug interactions 4 Monitoring 5 Area of responsibility for the sharing of care 5 Responsibilities of the Hospital 6 Responsibilities of the GP 6 Overdose 6 Availability of Consultant and senior hospital staff 7 Additional sources of advice 7 Key points summary Sirolimus inhibits both B and T cell activation leading to suppression of immune and rejection responses. The pharmacological action of sirolimus appears to differ to that of tacrolimus and ciclosporin. Tablets should be protected from light Oral solution should be kept in the fridge but may be kept at room temperature for up to 24 hours if necessary Oral solution should be mixed with at least 60ml water or orange juice immediately before taking, refill container with at least 120ml and drink immediately to ensure total dose received. Do not mix with any other liquids Page 1 of 12 SirolimusRenalTransplantGUI201609V2.0FINAL Introduction Mid Essex Hospitals Services NHS Trust (MEHT) and the local PCTs have agreed that sirolimus is suitable for shared-care: Prescribing status RED: For all new patients prescribing to remain with secondary care. Prescribing status AMBER: SHARED CARE for existing patients only The objectives of these guidelines are: To provide impartial information to GPs and community pharmacists who may not have previous experience of this drug To define the procedure for referral of the patient from the hospital to the GP To define the aspects of care for which the hospital and GP are responsible To define the support available from the hospital To establish lines of communication between GPs, Consultants and senior hospital staff Contributors to these guidelines are: Dr A Ali Dr S Abeygunasekara Dr AY Chan Sarah Cox Renal Pharmacist Author: Clare Drain, Medicines Information & Education & Training manager Licensing Sirolimus is licensed for immunosuppression in cases of ciclosporin or tacrolimus nephrotoxicity and for primary immunosuppression in kidney allograft recipients with low to medium immunological risk. Referral of patients The patient will be assessed by a specialist, and the decision to commence sirolimus therapy made. Once stable the specialist will invite the GP to undertake shared care. Page 2 of 12 SirolimusRenalTransplantGUI201609V2.0FINAL Initiation and maintenance of therapy Medication history is checked to ensure there are no contra-indications to sirolimus therapy Blood levels of sirolimus will be monitored Full blood counts and coagulation tests (including U&Es) Liver function tests Initial cholesterol level monitoring Administration/dosage Sirolimus should be taken at the same time each day in relation to food. Sirolimus may be added to immunosuppressive therapy after 2-3 months. Initial dosing should start orally at a daily dose of 8mg loading dose followed by 4mg once a day. The dose should then be individualized over the next 2-3 months aiming for a sirolimus drug trough level of 5-12ng/ml. Ciclosporin doses should be tapered during this time to obtain a trough level of 150- 400mg/ml. In the maintenance phase ciclosporin is progressively discontinued over 4-8 weeks and sirolimus dose is increased to give a drug trough level of 12-20ng/ml. Concurrent dosing with corticosteroids is required at this stage. Sirolimus is often swapped with ciclosporin or tacrolimus in cases of nephrotoxicity and there is no tapering of Ciclosporin dose. Supply Sirolimus is available as Rapamune® tablets from Wyeth. Prescribing Sirolimus is classified on the traffic light system as an Amber1 medication which means that it should only be prescribed under a shared care protocol with additional biochemical monitoring on a level 1 basis as per local enhanced service. Initiation of sirolimus treatment will be made by the hospital. The hospital will perform the relevant tests before treatment is started and will supply the first three months of medication. Once the patient is considered to be stable the specialists will write to the GP asking for agreement to take over the responsibility for prescribing, detailing dose information and monitoring requirements. Sirolimus is prescribable on FP10. Page 3 of 12 SirolimusRenalTransplantGUI201609V2.0FINAL Adverse effects Very common Lymphocele, peripheral oedema, hypertension, headache, abdominal pain, diarrhoea, constipation, nausea, anaemia, thrombocytopenia, hypercholesterolaemia, hypertriglyceridaemia, hypophosphateaemia, hyperglycaemia, hypokalaemia, increased lactate dehydrogenase, arthralgia, acne, arthralgia, urinary tract infection. Common Abnormal healing, fever, oedema, fungal viral and bacterial infection, tachycardia, VTE, stomatitis, leucopenia, neutropenia, thrombotic thrombocytopenic purpura, abnormal liver function tests, bone necrosis, epistaxis, pneumonia, pneumonitis, skin cancer, rash, pyleonephritis, proteinuria. Uncommon Pancreatitis, lymphoma, post transplant lymphoproliferative disorder, pancytopenia, pulmonary haemorrhage. Rare Lymphodema, hypersensisitivity reactions, anaphylactic reactions, angioedma and vasculitis. Increased risk of malignancies including lymphoma, skin and other tumours appear to be linked to degree and duration of immunosuppression. The incidence is similar to other immunosuppressive agents or therapies. Patients should be counselled with regard to the risk of skin malignancy from exposure to UV light. Contraindications Hypersensitivity to the active substance or to any of the excipients. Patients allergic to peanut or soya must not take this medicine. Pregnancy – exclude before starting – if contraception is needed non-hormonal methods should be used). Breastfeeding. Precautions Monitor renal function if given in combination with ciclosporin Dose increases may be required in patients from Afro-Caribbean background Hepatic impairment – monitor drug trough levels closely. Page 4 of 12 SirolimusRenalTransplantGUI201609V2.0FINAL Drug Interactions Increased levels of sirolimus: Inhibitors of CYP3A4 decrease the metabolism and increase levels (e.g. diltiazem, verapamil, ketoconazole, voriconazole, clarithromycin) Weak inhibitors of CYP3A4 e.g. clotrimazole, fluconazole, cimetidine, danazol) Sirolimus plasma concentrations are increased by ciclosporin Decreased levels of sirolimus Inducers of CYP3A4 increase metabolism and decrease levels (e.g. rifampicin) Weak inducers of CYP3A4 (St John’s Wort, carbamazepine, phenytoin) grapefruit juice should be avoided Pharmacokinetic interactions may also be observed with gastric prokinetic agents such as cisparide and metoclopramide Live vaccines should not be administered whilst taking CICLOSPORIN Monitoring Blood levels of sirolimus Electrolytes, creatinine and urea Full blood count and coagulation values Liver function tests Cholesterol testing Area of responsibility for the sharing of care Sharing of care assumes communication between the specialist, GP and the patient. The intention to share care should be explained to the patient and accepted by them. Officially the prescribing clinician has clinical responsibility for the medication they have prescribed. Page 5 of 12 SirolimusRenalTransplantGUI201609V2.0FINAL Responsibilities of the hospital Initial tests and monitoring until patient is stable on therapy Discussion with the patient regarding benefits and side effects of treatment Provide the patient with verbal and written information prior to commencing treatment To seek the co-operation of the GP in undertaking shared care of the patient, in accordance with these guidelines and in the referral letter. The opportunity for the GP and hospital consultant to further discuss the case and shared care, if required will be highlighted To provide the patient’s GP with a full summary letter indicating dose and frequency before implementation of shared care To provide the patient and GP with blood test results Monitoring of treatment including drug levels and renal function as agreed Prompt communication with the GP of any changes in treatment (including dose adjustments) and assessments of adverse events Advice to GPs about all aspects of treatment including specifying review dates Reporting adverse events to the CSM Ensure clear arrangements for back-up, advice and support Responsibilities of the General Practitioner To prescribe maintenance therapy to patients To report any adverse events to the consultant and CSM Prompt referral to specialist if there is any change in patient’s status Reporting to and seeking advice from the specialist on any aspect of patient care which is of concern to the GP and may affect treatment To monitor overall health and well-being of the patient After stabilization to carry out blood tests, cholesterol tests (every 6 months) and monitor renal function at intervals directed by specialist Overdose Please always contact the poisons help line. UK National Poisons Information Service (directs caller to relevant local centre) - 0870 600 6266 and/or the Summary of Product Characteristics (SPC) of the sirolimus product (via www.medicines.org.uk) Page 6 of 12 SirolimusRenalTransplantGUI201609V2.0FINAL Availability of Consultant and senior hospital staff Consultant Dr A Chan 01245 514414 Consultant Dr S Abeygunasekara 01245 514414 Consultant Dr A Ali 01245