Issues for surgery
For suppression of transplant rejection – risk of rejection if omitted.
Risk of post-operative infection if continued (see Further information).
Risk of QT-interval prolongation if continued (see Interactions with common anaesthetic agents and Interactions with other common medicines used in the perioperative period).
Advice in the perioperative period
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.
Emergency surgery
Continue – inform the patient’s relevant specialist at the earliest opportunity.
Post-operative advice
Restart treatment in the immediate post-operative period when next dose due. 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.
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.
Interactions with common anaesthetic agents
QT-interval prolongation
See also Interactions with other common medicines used in the perioperative period.
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.
Anaesthetic agents that may be used in the perioperative period that are known to, or predicted to, prolong the QT-interval include:
- desflurane, isoflurane, sevoflurane*
- thiopental (theoretical)**
*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).
Interactions with other common medicines used in the perioperative period
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 include:
- ciprofloxacin*
- clarithromycin* / **
- domperidone – avoid
- droperidol *
- erythromycin (particularly intravenous)*/**
- granisetron*
- haloperidol*
- loperamide – increased risk with high doses*
- ondansetron*
- prochlorperazine*
*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
See also QT-interval prolongation above.
There has been one isolated case where metoclopramide might have increased tacrolimus concentrations, although other factors may have contributed. The clinical relevance of this remains unclear. Monitor for adverse effects if metoclopramide is used concomitantly with tacrolimus.
Corticosteroids
Corticosteroids may cause hypokalaemia, increasing the risk of torsades de pointes, which might be additive with the effects of tacrolimus. Monitor potassium levels closely.
Antimicrobials
See also QT-interval prolongation above.
There are a number of interactions between tacrolimus and antibacterials that increase the risk of nephrotoxicity, and in some cases hyperkalaemia. Tacrolimus plasma levels and effects (e.g. on renal function) should be monitored closely if concomitant use of these antibacterials is required:
- aminoglycosides (e.g. gentamicin, tobramycin)
- cephalosporins
- macrolides (e.g. clarithromycin)
- sulfonamides (e.g. co-trimoxazole and trimethoprim)
- vancomycin
Macrolides (e.g. clarithromycin) and ciprofloxacin may increase the risk of QT-interval prolongation when used concomitantly with tacrolimus – see QT-interval prolongation above.
Antacids and proton pump inhibitors (PPIs)
PPIs might increase tacrolimus concentrations – monitor tacrolimus plasma levels and effects (e.g. on renal function) where a PPI is used for a prolonged period in the perioperative period. In addition, PPIs can cause hypomagnesaemia, which might be additive with the magnesium-lowering effect of tacrolimus. Consider monitoring magnesium concentrations before and during treatment if a PPI is used long-term with 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).
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 sepsis. Patients should be monitored for neutropenia. Patients may not present with the typical signs and symptoms of infections (i.e. fever, leucocytosis). Microbiology advice may need to be sought when infections develop.
Prescribing guidance
Tacrolimus
MHRA/CHM advice: Oral tacrolimus product: prescribe and dispense by brand name only, to minimise the risk of inadvertent switching between products, which has been associated with reports of toxicity and graft rejection (June 2012):
- 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.
Plasma level monitoring
Plasma levels of 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 surgery.
References
Baxter K, Preston CL (eds), Stockley’s Drug Interactions (online) London: Pharmaceutical Press. http://www.medicinescomplete.com [Accessed on 7th April 2019]
Brusich KT, Acan I. Anesthetic Considerations in Transplant Recipients for Nontransplant Surgery. Organ Donation and Transplantation – Current Status and Future Challenges. 2018. Accessed via www.intechopen.com 08/08/19
Joint Formulary Committee. British National Formulary (online) London: BMJ Group and Pharmaceutical Press. http://www.medicinescomplete.com [Accessed on 12th March 2019]
Tacrolimus. In: Brayfield A (Ed), Martindale: The Complete Drug Reference. London: The Royal Pharmaceutical Society of Great Britain. http://www.medicinescomplete.com [Accessed 30th March 2019]