Appendix III. PROTOCOLS FOR INDIVIDUAL IMMUNOSUPPRESSIVE AGENTS Basiliximab (Simulect)

Transcription

1 Appendix III PROTOCOLS FOR INDIVIDUAL IMMUNOSUPPRESSIVE AGENTS Basiliximab (Simulect) Indication All patients receiving kidney and/or pancreas transplant Dose 20mg given 2 hours prior to transplantation 20mg given on day 4 post transplant (The first dose must not be administered unless it is absolutely certain that the patient will receive the graft.) Reconstitution 1. 5ml water for injection (provided) should be added to the vial containing the Basiliximab powder. 2. Shake the vial gently to dissolve the powder 3. The solution should be used immediately. (It can be stored for 24hours in the fridge or 4 hours at room temperature.) Administration There are two possible routes of administration 1. Intravenous bolus injection 2. Intravenous infusion over minutes. (Final volume of at least 50ml using sodium chloride 0.9% or dextrose 5%.) Compatibility Basiliximab should not be mixed with other medicines/substances and should always be given through a separate infusion line. Adverse Effects Severe acute hypersensitivity reactions have been observed both on initial exposure and re- exposure to basiliximab. These include anaphylactoid- type reactions. If severe hypersensitivity reaction occurs, therapy with basiliximab must be permanently discontinued and no further dose administered. Side Effects Basiliximab does not appear to add to the background of side effects seen in organ transplantation patients as a consequence of their underlying disease and concurrent administration of immunosuppressants. 54

2 PREDNISOLONE Prednisolone is normally reduced according to the following schedule: 20 mg x 1 month started on day 2 15 mg x 1 month 10 mg x 1 month 5 mg x thereafter At 3 months to remain on minimum of 5 mg or 7.5 mg if >75 kg in weight. To remain on maintenance dose until the end of the first year and then review. At one year, cessation of Prednisolone should be considered (See steroid withdrawal protocol) NB caution should be exercised in patients with an increased risk of rejection. All patients to receive Ranitidine (150 mgs od) along with Prednisolone. This schedule may be altered if rejection occurs. Increased Risk for Steroid withdrawal : Level of HLA mismatching, particularly HLA- DR and DQ > 2 transplants highly sensitised patients Rejection episodes > 1 or more acute rejection episodes Banff grade > II Proteinuria Late acute rejection ie occurring after 6 months. In this case, steroid withdrawal is not recommended and, if indicated, should only be undertaken after renal biopsy has confirmed no ongoing inflammation or rejection. Steroid withdrawal Steroid withdrawal should be discussed with the patient and they should be informed of the risk of rejection. The steroids should be withdrawn according to the following schedule: Decrease by 1 mg per month till 0mg The patient requires monthly blood for creatinine 55

3 Steroid induced osteoporosis All patients should receive additional elemental calcium, this may be as one or two tablets per day depending on dietary intake. If GFR > 50 mls/min Calcichew D3 Forte should be used. If GFR < 50 mls/min Alfacalcidol and Calcichew should be used. HRT should be used in individuals at risk of osteoporosis (unless patient has a contra indication to HRT ) All patients should be given advice on diet, weight, exercise, smoking cessation, skin surveillance. 56

4 TACROLIMUS (PROGRAF/ADVAGRAF) Current indication As the lead agent in standard triple therapy for all patients. Dosage mg/kg/day in 2 divided doses (normally between 2 mg and 5 mg bd). Preparation Tacrolimus is available as 0.5 mg (cream), 1 mg (white) and 5 mg (greyish red) capsules. The brand is Prograf. In addition, the once a day preparation Advagraf is now also available. Prograf will be used in the initial post- operative period in most patients. Patients can be switched to Advagraf once stable levels have been achieved. Administration Oral route in most instances (well absorbed even in those with NG tubes). It is administered at 10 am and 10 pm. The capsules are taken on an empty stomach either 1 hour before or 2-3 hours after meals. Contents of the capsule can be suspended in water for NG administration. One fifth of the oral dose can be given as a continuous IV infusion in saline via non PVC bags/tubing if absolutely necessary. Levels Whole blood trough levels to be checked on Mondays, Wednesdays and Fridays. The target level for the first six months is 10 ng/ml (range 8-12 ng/ml) and 5-10 ng/ml after six months. In adult kidney transplant patients steady state may be reached 2-3 days after starting therapy or changing dose. 57

5 Contra- indications Tacrolimus is contra- indicated in pregnancy. As it is not known to what extent Tacrolimus may influence the efficacy of oral contraceptives it is generally recommended that other forms of contraception be used. Side Effects The most frequent side effects seen with Tacrolimus include : abnormal kidney function (similar to Ciclosporin) tremor headache paraesthesia Less common side effects are: diarrhoea hypertension hyperglycaemia hyperkalemia hypomagnesaemia visual and neurological disturbances (affected patients should not drive or operate machinery) hypertrophic cardiomyopathy ( in paediatric patients with trough levels >25 mg/ml). Interactions Potential interactions due to effects on hepatic microsomal enzymes. Tacrolimus is extensively metabolised via the hepatic microsomal cytochrome P450 3A4 isoenzyme. Concomitant use of substances known to inhibit or induce cytochrome P450 3A4 (CYP3A4) may affect the metabolism of tacrolimus. Therefore: Inhibitors of CYP3A4 may decrease metabolism of tacrolimus and thus increase tacrolimus blood levels, e.g. clotrimazole diltiazem fluconazole * nicardipine ketoconazole * danazol 58

6 itraconazole * erthromycin * clarithromycin * voriconazole grapefruit juice (naringenin) ethinyl oestradiol omeprazole nifedipine Inducers of CYP3A4 may increase metabolism of tacrolimus and thus decrease blood levels, e.g. rifampicin * phenobarbitol phenytoin * *Drugs marked with an asterisk will require a dose adjustment of Tacrolimus in nearly all patients. Other listed drugs may require dose adjustment only in individual cases. Tacrolimus itself has a powerful inhibitory effect on CYP3A4. Thus concomitant use of tacrolimus with drugs metabolised by CYP3A4 dependant pathways may affect the metabolism of such drugs. For this reason Ciclosporin A should not be co- prescribed with tacrolimus. Patients switched from Ciclosporin to Tacrolimus should receive the first tacrolimus dose at least 24 hours after the last Ciclosporin dose. Interactions due to cumulative toxicity/synergistic effects Concurrent use of tacrolimus with drugs known to have nephrotoxic or neurotoxic effects may increase the degree of toxicity. Enhanced nephrotoxicity has been observed with co- administration of: Ciclosporin A Amphotericin B Ibuprofen Sirolimus (Rapamune) As tacrolimus may cause hyperkalemia, high potassium intake or potassium sparing diuretics should be avoided. Interactions due to plasma protein binding of Tacrolimus Tacrolimus is extensively bound (>98%) to plasma proteins so competition with other highly protein bound drugs may result in displacement of either drug. This 59

7 displacement may not be reflected in the blood levels of Tacrolimus or other drugs. Therefore, dosage adjustment may not be needed unless clinical signs and symptoms suggest otherwise. Other interactions Vaccinations may be less effective and the use of live attenuated vaccines should be avoided. Administration of Tacrolimus with a meal of moderate fat content reduces the oral bioavailability of the drug. Complimentary medicines may cause a variety of interactions (See page 45). This is not a comprehensive list of potential interactions with Tacrolimus. For further information please ask a member of staff or consult the transplant unit pharmacist. 60

8 CICLOSPORIN Current Indication No longer a first line agent but some transplant patients will still have Neoral (previous formulation Sandimmun but nearly all patients are on Neoral) as the lead agent in their immunosuppression regime. Dose Starting dose is 8 mg/kg/day in 2 divided doses. Preparation Ciclosporin is available 10 mg (yellow / white), 25 mg (blue / grey), 50 mg (yellow / white) and 100 mg (blue / grey) capsules and as a 100 mg/ml oral solution. Different generic preparations of ciclosporin may vary in bioavailability and should not be considered interchangeable. Within NHS Lothian the formulation in use for solid organ transplantation is Neoral. As ciclosporin is a drug with a narrow therapeutic index drug it is vital that patients are not switched between formulations. Therefore care must be taken to prescribe and dispense ciclosporin by BRAND name to avoid potential toxicity or potential graft rejection. Administration Oral route in most instances. It is administered usually at 10 am and 10 pm. Oral solution should be diluted immediately before taking. May be diluted in orange juice or squash, apple juice or water (not grapefruit juice - see interactions). Needs to be stirred well. Measuring device should not come into contact within the dilutent. One third of the oral dose can be given as a slow intravenous infusion in normal saline or dextrose 5% over 2-6 hours if absolutely necessary. 61

9 N.B the injection is only available in the Sandimmun brand and care should be taken if switching patients who are on the Neoral brand. Contra- indications/cautions Live vaccines are not to be given to immunocompromised patients. Neoral should be used with caution during pregnancy. Ciclosporin passes into breast milk so mothers should not breast feed their infants. Side effects The most frequent side effects seen with Ciclosporin include: abnormal kidney function hepatic dysfunction hypertrichosis gingival hypertrophy tremor gastointestinal disturbances hypertension burning sensations of hands and feet Less common side effects are: headaches rashes (possible allergic origin) weight increase oedema mild anaemia pancreatitis hyperkalaemia neuropathy hyperuricaemia reversible dysmenhorrhoea hypomagnasaemia muscle weakness, cramps or myopathy hypercholesterolaemia Interactions Potential interactions due to effects on hepatic microsomal enzymes Inhibitors of cytochrome P450 which may decrease metabolism of ciclosporin and thus increase ciclosporin blood levels include: Clarithromycin, erythromycin, nicardipine Danazol, fluconazole, ketoconazole 62

10 Oral contraception Diltiazem, verapamil Inducers of cyctochrome P450 which may increase metabolism of ciclosporin and thus decrease blood levels include: barbiturates phenytoin carbamazaepine rifampicin Interactions due to cumulative toxicity / synergistic effects Take care when using ciclosporin in combination with compounds known to have nephrotoxic effects, e.g.: aminoglycosides, ciprofloxacin, trimethoprim, amphotericin B, melphalan and NSAIDs. Concurrent administration of ciclosporin with HMG- CoA reductase inhibitors may enhance risk of rhabdomylosis. Concomitant administration of nifedipine and ciclosporin increases the rate of gingival hyperplasia when compared to that for ciclosporin alone, particularly in the presence of poor oral hygiene. Since ciclosporin may cause hyperkalemia, potassium sparing diuretics, potassium supplements and high potassium intake should be avoided. Other interactions Vaccines may be less effective and the use of live attenuated vaccines should be avoided. Owing to its possible interference with the gastrointestinal cytochrome P450 enzyme system, grapefruit or grapefruit juice should not be taken 1 hour prior to ciclosporin dosing and grapefruit juice should not be used as a dilutent for the oral solution. This is not a comprehensive list of all potential interactions with ciclosporin. For further information please ask senior members of staff or consult the transplant unit pharmacist. Levels: currently under review 63

11 MYCOPHENOLATE MOFETIL (MMF) Current indication All patients receiving a kidney and/or pancreas graft should be treated with MMF in the first instance. If they are unable to tolerate it, a switch to myfortic or azathioprine may be made. Dose 500 mg to 1g twice daily, depending on concomitant immunosuppression and renal function. MMF is best absorbed on an empty stomach, either one hour before or two hours after a meal, but gastrointestinal side effects may be alleviated by taking MMF with food and further splitting the daily dose. Mode of action MMF is rapidly hydrolysed following absorption to mycophenolic acid (MPA), the active metabolite. MPA is a potent inhibitor of inosine monophosphate dehydrogenase (IMPDH) and therefore inhibits the denovo pathway of guanosine nucleotide synthesis. B and T lymphocytes are critically dependant on the de novo pathway and so MPA inhibits B and T lymphocyte proliferation and also B- cell antibody formation. Preparation MMF is available as 250 mg capsules (blue- brown) and 500 mg tablets (lavender). The brand name is CELLCEPT. Monitoring Monitoring of MMF blood levels not needed. Contra- indications Pregnancy Side- effects 64

12 Neutropenia Gastro- intestinal bloating, cramps, diarrhoea, vomiting. Drug interactions Tacrolimus increases the AUC of MPA, the active metabolite of MMF. By 3 months past transplant the increase is such that the dose of MMF may need to be reduced with time post- transplant to maintain stable systemic exposure to MPA. Cholestyramine and antacids - may bind MMF and significantly reduce absorption. Drugs which undergo tubular secretion, e.g. Aciclovir, theoretically may impair secretion of MMF and have raised blood levels themselves during concurrent administration. Drugs which interfere with entero- hepatic recirculation may reduce the efficacy of MMF. 65

13 AZATHIOPRINE Current indication For use in patients who are unable to tolerate mycophenolate mofetil. Dose Initial 1-2 mg/kg once daily. Maintenance 1 mg/kg once daily. Monitoring No monitoring of drug levels is required. Preparation Azathioprine is available as 25 mg and 50 mg tablets. There are both generic and brand (Imuran) forms on the market. Administration Virtually exclusively oral although an IV preparation is available. Contra- indications Pregnancy Bone marrow dysfunction, i.e. Patients who are known to be leucopaenic or thrombocytopaenic. Reduce dose if hepatic dysfunction is present. Drug interactions Allopurinol must not be co- prescribed as an inhibition of xanthine oxidase results in potentially fatal accumulation of azathioprine and its metabolites. An alternative uricosuric- benzbromarone is available on a named patient basis. Contact transplant unit pharmacist for further details. Side Effects Bone marrow suppression - usually reversible following cessation. Cholestatis and disturbed liver function - again usually reversible. Pancreatitis Dose may require to be altered depending on WCC, ie. reduce if WCC<4.0, stop if WCC <3.0 and re- introduce at a lower doses when WCC>

14 SIROLIMUS (Rapamune ) (should not be prescribed as rapamycin) Indication As an adjunct to or substitute to a calcineurin phosphatase inhibitor for immunosuppression in patients in whom ciclosporin/tacrolimus have been implicated in allograft pathology. Contraindications Hypersensivity to Sirolimus and its derivatives. Pregnancy and breast feeding Presentation - 1mg and 2mg tablet Dosage and Administration Doses should be given on an empty stomach Day 1 8mg daily Day 2 6mg daily Day 3 onwards 2mg daily adjusted according to levels Monitoring Target range 5-15ng/ml depending on whether it is an adjunct to or substitute for a CNI. Side Effects Raised triglycerides and cholesterol Thrombocytopeania Mouth Ulceration Proteinuria Anaemia Neutropenia Diarrhoea Hypokalaemia Arthralgia Epistaxis Delayed wound healing Lymphocele Rash Oedema Infections PTLD Drug Interactions Compounds which modulate CYP3A4 activity may affect Sirolimus levels. Drugs which may increase sirolimus levels Diltiazem Bromocriptine Prokinetic agents Azole antifungals Cimetidine Protease inhibitors Macrolide antibiotics Danazol Grapefruit Drugs which may decrease Sirolimus levels: Rifampicin, Anticonvulsants 67

15 MERIEUX ANTI- THYMOCYTE IMMUNOGLOBULINS (ATG) Indication 1. Induction therapy for high immunological risk recipients (reference) 2. Treatment of vascular rejection or steroid resistant rejection (persistent biopsy proven rejection despite two courses of methylprednisolone) Contra- indications known allergy to rabbit proteins acute viral illness full anaphylactic response to the test done. Dosage and administration Thymoblobulin is usually administered through a central line but may be given peripherally if necessary. In such circumstances, 1000 units heparin should be added directly to 0.9% NaCl infusion bag to prevent superficial thrombophelebitis. The combination of thymoglobulin, heparin and hydrocortisone in 5% dextrose should be avoided as precipitation has been reported. Thymoglobulin should be administered through an in- line 0.22um filter. 68

16 1. Induction therapy (NB Basiliximab is not given if using ATG for induction) Dose: 1.5mg/kg in 250mls 0.9% NaCl to run over a minimum of 6 hours (Day 0,1,2,3,4). No test dose required Day 0: First dose administered in recovery suite after 500mg methyl prednisolone has been given via CVP line. Premedication with 1g paracetamol PO and 10mg chlorpheniramine IV to be given before thymoglobulin infusion. Day 1: As for Day 0 (following second dose of 500mg Methyl Prednisolone, with 1g paracetamol PO and 10mg chlorpheniramine IV) Day 2,3,4: Premedication of Hydrocortisone 200mg IV, paracetamol 1g PO and chlorpheniramine 10mg IV before administering thymoglobulin. Withhold dose if total WCC < 2x109/l or platelet count < 50x109/l NB: Tacrolimus, MMF prescribed as for standard immunosuppression. Omit oral prednisolone 20mg Day 2,3,4 and start day 5. 2 Treatment for acute rejection The recommended dosage of Thymoglobulin for treatment of acute renal graft rejection is 1.5 mg/kg of body weight administered daily for 7 to 14 days. Dose should be withheld when total WCC < 2x10 9 /l or platelet count < 50x10 9 /l. 69

17 Test dose A test dose is needed to identify those patients who will develop severe reactions including anaphylaxis. Signs of anaphylaxis are tingling in the extremities and around the mouth, swelling of the lips and larynx, bronchospasm, tenesmus, hypotension. Any reaction will normally respond to hydrocortisone 100 mg IV and chlorphenaramine 10 mg IV although 0.5 ml adrenaline 1:1000 IM may be necessary. Administration of test dose 5 mg ATG in 100 ml NaCl 0.9% infused through a peripheral vein over 1 hour. Have a hydrocortisone, chlorpheniramine and adrenaline on standby. Preparation of test dose One vial contains 25 mg ATG. Reconstitute vial contents with accompanying dilutent (5 ml water for injections), giving a solution of 5 mg ATG per ml. Take 1 ml of solution and add to 100 ml NaCl 0.9%. Observations during / after test dose Observe patient closely Monitor BP, pulse and temperature according to the following schedule: Time after test dose Frequency of observations 0-2 hrs 15 mins 2-4 hrs 30 mins thereafter hourly 70

18 First full dose Administration ATG 1.5 mg/kg in 0.9% NaCl given over 6-8 hours via a central line. Round the dose to the nearest 25 mg. Preparation Reconstitute required number of vials with 5 ml dilutent per vial. Add contents of reconstituted vials to 0.9% NaCl, allowing 50 ml per vial (250 ml bag usually appropriate). Observations Observations as for test dose. Side effects Anaphylaxis, with a drop in arterial pressure, respiratory distress, fever and urticaria may appear during or just after the infusion. Other hypersensitivity reactions include rigors (1%), fever (4%), arthralgia (1%), erythema (1%) and pruritic skin eruptions (0.5%). Symptoms are most commonly seen after the first injection and decrease during the course of treatment. Other side effects include thrombocytopenia (approx. 5%), neutropenia, serum sickness (3%) and lymphoma. Monitoring See observations. Daily: FBC and U&Es during 10 day course and for 2 weeks after 71

19 Interactions Risk of over- immunosuppression, hence the following schedule should be followed: DRUG DAY ATG Test Full * * * * * * * * * Tacrolimus/Cyclosporin Y N N N N N N Y 2 Y 2 Y 2 Y 2 Y 2 Y 2 Prednisolone Y Y Y Y Y Y Y Y Y Y Y Y Y Azathioprine/ Mycophenolate mofetil Y N N N N N N N Y Y Y Y Y PCP prophylaxis 1 Y Y Y Y Y Y Y Y Y Y Y Y N * Depending on T cell count For PCP prophylaxis use cotrimoxazole 480 mg daily, if patient allergic to co- trimoxale then the cotrimoxazole de- sensitisation protocol should be used (see page 39.) Continue if need to complete 3 month course. CMV and HSV prophylaxis using Valganciclovir for 3 months should also be used (see page33). Tacrolimus reinstated at dose of 0.05 mg / kg twice daily. Cyclosporin reinstated at dose 3 mg / kg twice daily. Ordering Mon- Fri : contact unit pharmacist. Out of hours: contact resident pharmacist, bleep 2268 Small stock held in pharmacy. Storage Both the dry powder and reconstituted solution to be stored in fridge; protect from light. 72

20 APPENDIX IV ANAESTHETIC PROTOCOL Pre- op assessment Clinical assessment including current weight and usual post- dialysis weight FBC, U&Es. Check that blood has been grouped and saved. Check immunosuppression regime has been discussed and prescribed. All patients require basiliximab pre- operatively. Fasting Patients should fast for four hours pre- op. Longer periods of fasting are neither necessary nor desirable. DVT prophylaxis The hospital policy should be followed. This includes subcutaneous heparin and compression stockings. Potassium control Many patients are chronically hyperkalaemic and tolerate this well In general, aim for [K + ] < 5.0 mmol/l - 1 Mild hyperkalaemia may be treated with dextrose/insulin but K >5.5 is an indication for dialysis. See transplant work up protocol for more detail. Pre- medication Benzodiazepine (at discretion of anaesthetist) Usual medication (except NSAIDs, diuretics and ACE - inhibitors) If gastro- oesophageal reflux, oral ranitidine. Diabetic patients Diabetics are given 10% dextrose and insulin infusion throughout the peri- operative period with hourly blood sugar measurements. Good glycaemic control should be ensured. See Inpatient protocol, page