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Issues for surgery

For suppression of transplant rejection – risk of rejection if omitted (see Ciclosporin (Transplant Anti-transplant Rejection) drug monograph).

Risk of perioperative flare in disease activity if omitted.

Risk of post-operative infection if continued.

Advice in the perioperative period

Monitoring of renal and hepatic function, blood pressure, and serum electrolytes (especially potassium and magnesium) is recommended perioperatively.

Elective surgery 

Rheumatology indications 

Continue.

Individualised decisions should be made for procedures considered to have a high risk of infection and should be balanced against the risk of disease flare (see Further information). The surgical team and the patient’s rheumatologist should be involved in the planning.

Steroid exposure should be minimised prior to surgical procedures, and increases in steroid dose to prevent adrenal insufficiency are not routinely required.

Other indications (e.g. dermatology, ulcerative colitis)

The decision to continue should be made on an individual patient basis in conjunction with the surgical team and the patient’s specialist.

If the decision is made to stop ciclosporin prior to surgery, it should be stopped 2 weeks pre-operatively.

Emergency surgery 

The patient should be closely monitored for signs of infection following emergency surgery.

Post-operative advice

For high-risk surgical procedures or where there are patient factors that may increase surgical infection risk, i.e. age and / or co-morbidity, consider withholding ciclosporin dose in the immediate post-operative period except where used for prevention of transplant rejection (see Ciclosporin (Transplant Anti-transplant Rejection) drug monograph).

If discontinued, restart once wound healing is satisfactory.

NB: if the patient cannot take their oral ciclosporin post-operatively, consideration should be given to using intravenous (IV) ciclosporin. It is important to note that the oral and IV doses of ciclosporin are not equivalent. IV ciclosporin should only be prescribed by, or in close collaboration with, a physician with experience of immunosuppressive therapy and/or organ transplantation.

Where ciclosporin is continued, close monitoring of renal function is important so that inadvertent drug accumulation does not occur.

Interactions with common anaesthetic agents

Neuromuscular blocking drugs (NMBDs)

There is evidence that the neuromuscular blocking effects of atracurium, pancuronium and vecuronium may be increased in some patients treated with ciclosporin. The general importance is unclear but be alert for an increase in the effects of neuromuscular blockade in any patient receiving ciclosporin.

Interactions with other common medicines used in the perioperative period

CYP3A4 / P-glycoprotein inhibition/induction

Ciclosporin is an inhibitor of CYP3A4, the multidrug efflux transporter P-glycoprotein (P-gp) and organic anion transporter proteins (OATP), hence there will be interactions with medicines that are also substrates of these enzymes and/or transporters. There is potential for serious interactions resulting in decreased or increased ciclosporin levels. Care should be taken when prescribing any new medicine that may affect CYP3A4 and/or P-gp regulation. Consult current product literature.

Octreotide

Concomitant use of octreotide with ciclosporin decreases oral absorption of ciclosporin. It is recommended that a 50% increase in the ciclosporin dose or a switch to intravenous administration could be necessary.

Non-steroidal anti-inflammatory drugs (NSAIDs)

Ciclosporin and NSAIDs can increase the risk of nephrotoxicity and hyperkalaemia.

Monitor renal and hepatic function if concomitant treatment with a NSAID is inititated.

Diclofenac

Concomitant use of diclofenac and ciclosporin has been found to result in a significant increase in the bioavailability of diclofenac, with the possible consequence of reversible renal function impairment.

Nephrotoxicity

Care should be taken when using ciclosporin together with other active substrates that exhibit nephrotoxic synergy:

• aminoglycosides (e.g. gentamicin)
• NSAIDs (also see NSAIDs above)
• H2-receptor antagonists (interaction not supported by evidence but bear in mind if case of unexpected response)
• vancomycin

Close monitoring of renal function is advised – if significant impairment of renal function occurs, the dosage of the co-administered medical product should be reduced or alternative treatment considered.

Antimicrobials 

See also Nephrotoxicity above.

Reports of increased ciclosporin concentrations, and potential toxicity, has been reported with the following:

• macrolides (e.g. clarithromycin)
• co-trimoxazole (in kidney transplant patients)
• tigecycline
• trimethoprim

Bear the interaction in mind with concomitant use of other antimicrobials if there is an unexplained change in ciclosporin concentrations or nephrotoxicity occurs.

Whilst single surgical prophylactic doses should not pose a problem, continued post-operative treatment may require close monitoring of ciclosporin concentrations and/or effects (e.g. renal function). Consult current product literature.

Hyperkalaemia

Both ciclosporin and low molecular weight heparin (LMWH)/unfractionated heparin (UFH) can increase the risk of hyperkalaemia.

Further information

MHRA/CHM Advice: Ciclosporin must be prescribed and dispensed by brand name (December 2009)

With systemic use, patients should be stabilised on a particular brand of oral ciclosporin because switching between formulations without close monitoring may lead to clinically important changes in blood-ciclosporin concentration.

Rheumatoid arthritis (RA) flare

RA flares develop in 10-20% of patients undergoing surgery and have a potential to impact adversely on post-operative recovery. In addition, active RA increases infection risk, further complicating decisions regarding DMARD interruption.

References

Ledingham J, Gullick N, Irving K et al. Rheumatology Guidelines. The British Society of Rheumatology and British Health Professionals in Rheumatology. BSR and BHPR guideline for the prescription and monitoring of non-biologic disease-modifying anti-rheumatic drugs. Rheumatology. 2017; 56(6):865-68 and online supplementary information www.rheumatology.oxfordjournals.org [Accessed on 2nd June 2019]

Ciclosporin. In: Brayfield A (Ed), Martindale: The Complete Drug Reference. London: The Royal Pharmaceutical Society of Great Britain. http://www.medicinescomplete.com [Accessed 18th May 2019]

Baxter K, Preston CL (eds), Stockley’s Drug Interactions (online) London: Pharmaceutical Press. http://www.medicinescomplete.com [Accessed on 3rd June 2019]

Summary of Product Characteristics – Neoral® (ciclosporin) Soft Gelatin Capsules. Accord-UK Ltd. Accessed via www.medicines.org.uk 02/06/2019 [date of revision of the text October 2017]

Joint Formulary Committee. British National Formulary (online) London: BMJ Group and Pharmaceutical Press http://www.medicinescomplete.com [Accessed on 2nd June 2019]