Transplant Anti-Rejection Medication


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).


  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.

  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.


  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: -

  • 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 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 mycophenolic acid (MPA) exposure have been seen with a number of antibacterials3, 4; the effect appears to be additive2. In some cases, this is due to antibacterials interfering with the enterohepatic ciriculation.4, 5, 6.

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
Concomitant use of mercaptopurine with the following can increase the risk of myelosuppression3, 4: -

  • 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 avoid1, 2, 8. 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 needed1. This combination should be 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 required1, 4, 9, 10: -

  • 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 above under QT-interval Prolongation.

Antacids and Proton Pump Inhibitors (PPIs)

MMF
Decreased MPA exposure has been observed when PPIs have been administered with MMF5, 6, 7; 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 seen5, 7. 

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
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 sirolimus2.

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 period4, 10. 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 tacrolimus4.

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
Sirolimus is associated with a 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 patients11, 12, 13.

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)1:

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 strengths1.

Mycophenolate
MPA (as sodium salt) and MMF have different pharmacokinetic profiles5. Unnecessary switching between manufacturer’s products should be avoided – ensure that the patient is maintained on the same brand1, 5.

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


  1. Joint Formulary Committee. British National Formulary (online) London: BMJ Group and Pharmaceutical Press. http://www.medicinescomplete.com [Accessed on 12th March 2019]
  2. 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]
  3. 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]
  4. Baxter K, Preston CL (eds), Stockley’s Drug Interactions (online) London: Pharmaceutical Press. http://www.medicinescomplete.com  [Accessed on 7th April 2019]
  5. 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]
  6. 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]
  7. 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]
  8. 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]
  9. 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]
  10. 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
  11. 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
  12. 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
  13. 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