Azathioprine, Ciclosporin, Mycophenolate mofetil, Sirolimus, Tacrolimus |
Issues for Surgery |
For suppression of transplant rejection – risk of rejection if omitted. For rheumatology, dermatology and inflammatory bowel disease (IBD) conditions – risk of perioperative flare in disease activity if omitted (see individual drug monographs for Immunosuppressant, Disease-Modifying Antirheumatic Drug - DMARD). Risk of post-operative infection if continued (see Further Information). For tacrolimus – risk of QT-interval prolongation if continued (see Interaction(s) with Common Anaesthetic Agents and Interaction(s) with other Common Medicines used in the Perioperative Period). |
Advice in the Perioperative period |
For mycophenolate or tacrolimus - ensure that the patient is maintained on a specific manufacturer’s product (see Further Information). Elective Surgery Continue – the patient’s relevant specialist should be involved in the planning for surgery. EXCEPT:
Emergency Surgery Continue – inform the patient’s relevant specialist at the earliest opportunity. EXCEPT:
Post-operative Advice Restart treatment in the immediate post-operative period when next dose due (EXCEPT sirolimus – see below). If the patient cannot take their usual oral medication post-operatively, their relevant specialist must be consulted for advice on an alternative medication, dose, route and frequency. If stopped pre-operatively sirolimus should not be re-started until adequate wound healing has taken place – consult with the patient’s specialist to ensure a management plan is in place. Monitor for signs of infection. Monitor renal function and electrolytes. If renal function deteriorates post-operatively, the patient’s specialist should be consulted. Due to the nature of these agents and the potential interactions that can occur, consult product literature prior to starting any medicines in the post-operative period. |
Interaction(s) with Common Anaesthetic Agents |
For azathioprine – see Azathioprine monograph For ciclosporin – see Ciclosporin monograph For mycophenolate (MMF), sirolimus and tacrolimus – none1, 2, 3, 4, 5, 6, 7, 8, 9. QT-Interval Prolongation (see also Interaction(s) with other Common Medicines used in the Perioperative Period) Anaesthetic agents that may be used in the perioperative period that are known to, or predicted to, prolong the QT-interval include4: -
*monitor ECG if concurrent use unavoidable; if risk factors for QT-prolongation are also present (increasing age, female sex, cardiac disease, and some metabolic disturbances e.g. hypokalaemia) use greater caution **monitor ECG with concurrent use if risk factors for QT-prolongation are also present (increasing age, female sex, cardiac disease, and some metabolic disturbances e.g. hypokalaemia). |
Interaction(s) with other Common Medicines used in the Perioperative Period |
For azathioprine – see Azathioprine monograph For ciclosporin – see Ciclosporin monograph QT-Interval Prolongation Tacrolimus has been associated with QT-interval prolongation or torsades de pointes. Care should be taken with concomitant use of medicines that can also prolong the QT-interval. These include4: -
*monitor ECG with concurrent use, particularly if risk factors for QT-interval prolongation also present (increasing age, female sex, cardiac disease, and some metabolic disturbances e.g. hypokalaemia) ** monitor plasma concentrations and effects (e.g. on renal function) of tacrolimus if these medications are started or stopped, adjusting the tacrolimus dose as necessary. Antiemetics (for patients taking tacrolimus see also under QT-Interval Prolongation above) The UK and US manufacturers state that metoclopramide might increase sirolimus concentrations1, 8. There has been one isolated case where metoclopramide might have increased tacrolimus concentrations, although other factors may have contributed4. The clinical relevance of this remains unclear4. Monitor for adverse effects if metoclopramide is used concomitantly with sirolimus or tacrolimus. Corticosteroids Surgical stress, corticosteroids and MMF may contribute to gastrointestinal ulcers, so consideration should be given to providing stress ulcer prophylaxis for transplanted patients10, but see below under Antacids and Proton Pump Inhibitors (PPIs). Corticosteroids may cause hypokalaemia, increasing the risk of torsades de pointes, which might be additive with the effects of tacrolimus. Monitor potassium levels closely4. Antimicrobials (for patients taking tacrolimus also see under QT-Interval Prolongation above) Mycophenolate (MMF) Reductions in trough MPA concentrations of about 50% have been reported in renal transplant recipients in the days immediately following commencement of oral ciprofloxacin or co-amoxiclav2, 4. This effect tended to diminish with continued antibiotic use and to cease within a few days of antibiotic discontinuation. The change in pre-dose level may not accurately represent changes in overall MPA exposure. In healthy volunteers, no significant interaction was observed when MMF was concomitantly administered with norfloxacin or metronidazole separately. However, norfloxacin and metronidazole combined reduced the MPA exposure by approximately 30% following a single dose of MMF4, 5, 6, 7. Close clinical monitoring should be performed during and shortly after antibiotic treatment if the combination is used. Note that the US manufacturers consider that the combination of metronidazole and norfloxacin should not be used with MMF4. Myelosuppression
Whilst single surgical prophylactic doses of antimicrobials should not pose a problem, continued post-operative treatment may require close monitoring of LFTs and / or haematological abnormalities. Consult current product literature. Sirolimus Tacrolimus
Macrolides (e.g. clarithromycin) and ciprofloxacin may increase the risk of QT-interval prolongation when used concomitantly with tacrolimus – see above under QT-interval Prolongation. Antacids and Proton Pump Inhibitors (PPIs) MMF Mycophenolate has been associated with an increased incidence of digestive system adverse effects, including infrequent cases of gastrointestinal tract ulceration, haemorrhage and perforation5, 6, 7. Surgical stress and potential use of corticosteroids further increase this risk – see under Corticosteroids. Single doses of PPI should not pose a problem, but consider this interaction if there is a need to continue a PPI long-term post-operatively. Antacids may reduce absorption of MMF3, 4, 5, 6; however, the reductions in peak plasma concentrations of MPA were considered unlikely to be clinically significant3. UK licensed product information for MPA states that, although magnesium- or aluminium- containing antacids decrease MPA exposure and peak plasma concentration, they may be used intermittently for the treatment of occasional dyspepsia; chronic use of antacids is not recommended2, 5. Sirolimus Tacrolimus Low Molecular Weight Heparin (LMWH)/Unfractionated Heparin (UFH) Both tacrolimus and LMWH/UFH can increase the risk of hyperkalaemia, particularly if the patient is also taking other medicines that can increase plasma potassium levels (e.g. ACE inhibitors, angiotensin receptor antagonists and spironolactone/eplerenone). Non-Steroidal Anti-inflammatory Drugs (NSAIDs) NSAIDs should be avoided due to the risk of adverse interactions (including nephrotoxicity)1, 8, 10. Tacrolimus and NSAIDs can increase the risk of hyperkalaemia, particularly if the patient is also taking other medicines that can increase plasma potassium levels (e.g. ACE inhibitors, angiotensin receptor antagonists and spironolactone/eplerenone). |
Further Information |
Infection Risk Patients treated with immunosuppressants are at increased risk of opportunistic infections, fatal infections and sepsis4, 5, 6, 7. Patients should be monitored for neutropenia4, 5, 6, 7. Patients may not present with the typical signs and symptoms of infections (i.e. fever, leucocytosis). Microbiology advice may be need to be sought when infections develop10. Sirolimus Prescribing Guidance Tacrolimus To ensure maintenance of therapeutic response when a patient is stabilised on a particular brand, oral tacrolimus products should be prescribed and dispensed by brand name only. Switching between tacrolimus brands requires careful supervision and therapeutic monitoring by an appropriate specialist. Sirolimus Mycophenolate Plasma Level Monitoring Plasma levels of both ciclosporin and tacrolimus must be kept within the indicated therapeutic range. The perioperative fluctuation of the plasma level of these two drugs should be strictly monitored. There is significant reduction of drug blood level by dilution with volume infusion or cardiopulmonary bypass in cardiac surgery10. Sirolimus whole blood trough concentrations should be monitored8. Close monitoring is required if there is concomitant treatment with potent inducers or inhibitors of sirolimus metabolism2, 8. Contact specialists for advice where necessary. |
References |
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