UK Clinical Pharmacy Association

Azathioprine - as Transplant anti-rejection medication

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 Immunosuppressants and DMARD drug records).

Risk of post-operative infection if continued (see Further information).

For tacrolimus – 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

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:

  • Sirolimus – consult with the patient’s relevant specialist at the earliest opportunity when planning for surgery so that a management plan can be made (see Further information)

Emergency surgery 

Continue – inform the patient’s relevant specialist at the earliest opportunity.

Except:

  • Sirolimus – consult with the patient’s relevant specialist before next dose due to discuss management (see Further information)

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.

Interactions with common anaesthetic agents

See also Azathioprine-as Immunosuppressant & DMARD drug record

See also Ciclosporin-Systemic drug record

For mycophenolate (MMF), sirolimus and tacrolimus – none.

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

See also Azathioprine-as Immunosuppressant & DMARD drug record

See also Ciclosporin-Systemic drug record

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

For patients taking tacrolimus see also QT-interval prolongation above.

The UK and US manufacturers state that metoclopramide might increase sirolimus concentrations. 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 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 patients. See also Antacids and proton pump inhibitors (PPIs) below.

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

For patients taking tacrolimus see also QT-interval prolongation above.

Mycophenolate (MMF)

Reductions in mycophenolic acid (MPA) exposure have been seen with a number of antibacterials; the effect appears to be additive. In some cases, this is due to antibacterials interfering with the enterohepatic circulation.

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-amoxiclav. 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 MMF. 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 MMF.

Myelosuppression

Concomitant use of mercaptopurine with the following can increase the risk of myelosuppression:

  • co-trimoxazole
  • linezolid
  • trimethoprim

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

Clarithromycin (due to inhibition of cytochrome P450 isoenzyme CYP3A4) and erythromycin are predicted to increase the concentration of sirolimus – manufacturer advises avoid. If concurrent use is unavoidable, increase the frequency of monitoring sirolimus concentrations and effects (e.g. on renal function), and adjust the sirolimus dose as needed. This combination should not be used without prior consultation with the patient’s relevant specialist.

Tacrolimus

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)

MMF

Decreased MPA exposure has been observed when PPIs have been administered with MMF; however, the available information is conflicting. When comparing rates of transplant rejection or rate of graft loss between MMF patients taking PPIs vs. MMF patients not taking PPIs, no significant differences were seen. 

Mycophenolate has been associated with an increased incidence of digestive system adverse effects, including infrequent cases of gastrointestinal tract ulceration, haemorrhage and perforation. Surgical stress and potential use of corticosteroids further increase this risk – see 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 MMF; however, the reductions in peak plasma concentrations of MPA were considered unlikely to be clinically significant. 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 recommended.

Sirolimus

PPIs can cause hypomagnesaemia, which might be additive with the magnesium-lowering effects of sirolimus. Consider monitoring magnesium concentrations before and during treatment if a PPI is used long-term with sirolimus.

Tacrolimus

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.

Sirolimus

Sirolimus is associated with an increased incidence of infections and impaired wound healing in both renal and liver transplant recipients immediately after transplantation, which is probably further complicated by the use of corticosteroids in these groups of patients.

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.

Sirolimus

The 500 microgram (mcg) tablet is not bioequivalent to the 1mg and 2mg tablets. Multiples of 500mcg tablets should not be used as a substitute for other tablet strengths.

Mycophenolate

MPA (as sodium salt) and MMF have different pharmacokinetic profiles. Unnecessary switching between manufacturer’s products should be avoided – ensure that the patient is maintained on the same brand.

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 surgery.

Sirolimus whole blood trough concentrations should be monitored. Close monitoring is required if there is concomitant treatment with potent inducers or inhibitors of sirolimus metabolism. Contact specialists for advice where necessary.

References

Joint Formulary Committee. British National Formulary (online) London: BMJ Group and Pharmaceutical Press. http://www.medicinescomplete.com [Accessed on 12th March 2019]

Sirolimus. 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]

Mycophenolate. 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]

Baxter K, Preston CL (eds), Stockley’s Drug Interactions (online) London: Pharmaceutical Press. http://www.medicinescomplete.com [Accessed on 7th April 2019]

Summary of Product Characteristics – Cellcept® (mycophenolate mofetil) 500mg Film-Coated Tablets. Roche Products Limited. Accessed via www.medicines.org.uk 04/08/2019 [date of revision of the text March 2018]

Summary of Product Characteristics – Myfortic® (Mycophenolic acid as mycophenolate sodium) 360 mg gastro-resistant tablets. Novartis Pharmaceuticals UK Ltd. Accessed via www.medicines.org.uk 04/08/2019 [date of revision of the text August 2018]

Summary of Product Characteristics – Mycophenolate Mofetil 500 mg Film-coated Tablets. Mylan. Accessed via www.medicines.org.uk 04/08/2019 [date of revision of the text December 2017]

Summary of Product Characteristics – Rapamune® (sirolimus) 2mg coated tablets. Pfizer Limited. Accessed via www.medicines.org.uk 04/08/2019 [date of revision of the text June 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]

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

Troppmann C, Pierce JL, Ghandi MM et al. Higher surgical wound complication rates with sirolimus immunosuppression after kidney transplantation: a matched-pair pilot study. Transplantation. 2003; 76(2):426-9

Grim S, Slover CM, Sankary H et al. Risk Factors for Wound Healing Complications in Sirolimus-Treated Renal Transplant Recipients. Transplantation Proceedings. 2006; 38(10):3520-3

Fisher A, Seguel JM, de la Torre AN et al. Effect of Sirolimus on Infection Incidence in Liver Transplant Recipients. Liver Transplantation. 2004; 10(2):193-198