Oxford Gastroenterology Unit Shared Care Protocol & Information for GPs TACROLIMUS (PROGRAF, Modigraf Adoport, Adagraf ) Prescribing Guidelines for Adult Liver Transplant Patients and autoimmune liver disease This protocol is designed to provide information relating to tacrolimus and to outline the responsibilities of the primary and secondary care teams in the prescribing of Tacrolimus in adult liver transplant patients and patients with Introduction Tacrolimus is a macrolide immunosuppressant which possesses similar but more potent immunosuppressant properties compared with ciclosporin in vitro. inhibiting both cell medicated and humoral immune responses. Its efficacy in liver transplant recipients has been evaluated in a large multicentre randomised clinical trial in liver transplantation. 1 This study confirmed its ability to reduce graft loss from rejection and defined the side effects of the drug. Therapeutic use Tacrolimus is currently licensed for primary immunosupression in allograft recipients. It has largely replaced ciclosporin as the main immunosuppressive agent following liver transplantation. Many patients are maintained on tacrolimus+/- azathiaprine +/- steroids. It is also used in a few patients with to suppress inflammation when standard therapy with prednisolone/azathiaprine+/- mycophenylate has failed. Dose and administration tacrolimus is usually started in adult liver transplant recipients at 0.1-0.2mg/kg/day administered in two divided doses (once daily if the MR preparation - Advagraf. is used) Lower doses are often used in patients to should take tacrolimus on an empty stomach (one hour before or two hours after food) and at roughly the same time each day so that trough levels are representative of the true value when they return to hospital for monitoring blood levels initial target trough levels are 5-15ng/ml. In targets are lower at 5-10ng/ml 1
patients are instructed not to take their tacrolimus on the morning of their clinic visit so that blood levels taken represent trough concentrations. the risk of rejection diminishes with time, and after six weeks the dose is usually be reduced to target blood levels of about 5ng/ml for long term maintenance. Availability Community pharmacists can obtain all tacrolimus oral preparations from local wholesalers. The concentrate for infusion is for hospital use only. Depending on the Transplant centre the brand of tacrolimus the patient is initiated on may vary. Patients must remain on the same brand they were initiated on. To avoid confusion and the potential for patients receiving the wrong formulation, it is important that all tacrolimus prescriptions specify the brand. Adverse Effects All immunosuppressive drugs are powerful and potentially toxic drugs and therefore adverse effects may be observed. There is evidence that most of the adverse drug reactions (ADR) associated with tacrolimus are reversible and respond to dose reduction. Any ADR detected must be reported to the Hepatology team. Any dose adjusts must be made in consultation with a Hepatology consultant or SpR. The following are adverse effects which are frequently observed in patients taking tacrolimus: tremor, paraesthesia and headaches are the most common side effects of tacrolimus, but are only occasionally severe enough to warrant dose reduction or discontinuation. nephrotoxicity, with increased plasma creatinine, is a dose dependent side effect of tacrolimus. Occasionally this can induce hyperkalaemia or hypertension. hyperglycaemia has been observed in some patients on tacrolimus, and is exacerbated by concomitant steroid immunosuppression. It may require treatment with oral agents or insulin. infection (bacterial, viral fungal, and protozoal) is increased in patients receiving immunosuppression therapy changes in hair growth (thinning and increased growth may occur 2
Rarer side effects include depression and abnormal behaviour have also been reported as potential side effects of tacrolimus, (Patients often experience period of reactive depression around six weeks after transplant irrespective of treatment) malignancy, specially lymphomas caused by oncogenic viruses and skin tumours, is also more common in immunosuppressed patients. Patients should be cautioned against excessive exposure to sunlight. Precautions infections. Any infection in an immunosuppressed patient may have serious consequences. Prompt investigation and treatment of suspected cases is essential. Immunosuppressed patients are also at increased risk of neoplasia. Pregnancy & breastfeeding. In common with other immunosuppressive agents, teratogenic effects have been observed in experimental animal receiving tacrolimus. The great majority of pregnancies in transplanted patients have been uneventful, and there have been case reports of successful outcomes in patients receiving tacrolimus.all patients planning a pregnancy should discuss treatment withtheir hepatologist Breastfeeding must be avoided Drug Interactions Drugs which alter tacrolimus blood levels Tacrolimus is extensively bound to plasma proteins and may interact with other drugs, which are similarly bound such as anticoagulants and antidiabetics agents, increasing free drug levels. Many drugs, including tacrolimus, are metabolised by the microsomal cytochrome P450 enzyme system in the liver. Some of these drugs inhibit P450, increasing tacrolimus in the blood to potentially toxic levels. Others induce the enzyme, promoting the degradation of tacrolimus to subtherapeutic levels. Tacrolimus itself initially inhibits the P450 system, but ultimately act as a P450 inducer. It may therefore alter the effects of other drugs which share the P450 system. Concomitant use of drugs known to affect the P450-3A system requires monitoring of tacrolimus blood levels and possible dose adjustment. Drugs which INHIBIT metabolism and therefore INCREASE tacrolimus levels: amphotercin, bromocriptine, cortisone, cimetidine, ciprofloxacin, clarithromycin, clotrimazole, dapsone, diltiazem, ergotamoine, erythromicin ethinyloestradiol, fluconazole, gestodene, itraconazole, ketoconazole, lidocaine, miconazole, midazolam, nicardipine, nifedipine, norethindrone, omeprazole, protease inhibitors, quinidine, tamoxifen, verapamil, grapefruit juice 3
Drugs which INDUCE metabolism and therefore DECREASE tacrolimus levels: barbiturates ( eg. Phenobarbitone), phenytoin, rifampicin, carbamazepine, metamizole, isoniazide It is essential to inform the hepatology team if one of the interacting drugs is newly prescribed, or stopped, so that blood levels can be monitored. Shared care of patients receiving tacrolimus Patients who receive tacrolimus to prevent rejection of a transplanted organ require regular assessment and monitoring by specialists in transplantation. A shared care arrangement involving both primary and hospital specialists is therefore essential. This protocol outlines the areas of responsibility between the hospital and the general practitioner for shared care of transplanted patients receiving tacrolimus. Most dose alterations are undertaken in the first 6 weeks with stable dosing occurring thereafter. Referral criteria Patients will be stabilised on tacrolimus in hospital before referral back to the GP. GP s will be informed of the dose and frequency of the tacrolimus regimen together with a clinical summary Responsibilities Secondary care - Hepatology team, Oxford liase with the transplant centre on initial prescription and follow up where appropriate stabilise the patient on their treatment regimen and monitor transplant graft function measure tacrolimus blood levels and advise changes of dose update patient medication card monitor efficacy of treatment regimen and side effects provide access to back up and support facilities evaluate any adverse events reported by the GP specify the brand of tacrolimus the patient is stabilised on Primary Care - General Practitioner prescribe tacrolimus maintenance therapy, according to the dosage instructions from the Hepatology Unit (Hepatology consultant or SpR only) from 6 months post transplantation and from 3 months in patients with ensure tacrolimus prescriptions specify the brand the patient is stabilised on 4
encourage patients to carry an up to date medication card check for possible drug interaction when newly prescribing or stopping concurrent medication monitor the general health of the patient and report any suspected adverse events to the Hepatology consultant or SpR Contact Numbers John Radcliffe Hospital main switchboard 01865 741166 Dr Jane Collier (consultant hepatologist) 01865 228750 or pager via JR switchboard or email jane.collier1@nhs.net.. Dr Roger Chapman (consultant hepatologist) 01865 228746 Ms Jane Phillips (hepatology clinical nurse specialist) 01865 222057 Pharmacy Medicines Information 01865 221505 Sarah Cripps (Clinical Pharmacist, Gastroenterology) 01865 741166 Bleep 1084 References 1. European FK506 Multicentre Liver Study Group. Randomised trial comparing tacrolimus (FK506) and cyclosporin in prevention of liver allograft rejection. Lancet 1994; 344: 423-428 5