NOTE:
For methotrexate use in the treatment of neoplastic disease see Chemotherapy drug record.
Issues for surgery
For rheumatology, dermatology and inflammatory bowel disease (IBD) conditions – risk of perioperative flare in disease activity if omitted.
Risk of post-operative infection if continued (see Further information).
Advice in the perioperative period
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 for elective surgery.
Steroid exposure should be minimised prior to surgical procedures and increases in steroid dose to prevent adrenal insufficiency are not routinely required.
Dermatology indications
Continue.
Where patients are due to undergo major surgery and have co-morbidities such as diabetes, which may alter infection risk, the decision to continue must be made on an individual patient basis. The surgical team and the patient’s dermatologist should be involved in the planning.
IBD indications (e.g. Crohn’s disease)
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 methotrexate 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 methotrexate dose in the immediate post-operative period if it is due.
If discontinued, restart once wound healing is satisfactory.
Where methotrexate is continued, close monitoring of renal function is important so that inadvertent drug accumulation does not occur.
Interactions with common anaesthetic agents
Nitrous oxide
Nitrous oxide potentially increases the risk of methotrexate toxicity when given with methotrexate and concomitant use should be avoided.
Interactions with other common medicines used in the perioperative period
Non-steroidal anti-inflammatory drugs (NSAIDs)
NSAIDs and methotrexate can increase the risk of nephrotoxicity.
Increased methotrexate toxicity, sometimes life-threatening, has been seen in a few patients concurrently treated with some NSAIDs. The risk is lowest with low-dose methotrexate. This monograph does not cover high-dose chemotherapy for neoplastic indications.
Methotrexate and NSAIDs are frequently used together in the treatment of rheumatoid arthritis and provided this is done with caution, in low doses, and patients are appropriately monitored, concurrent use need not be avoided.
Antimicrobials
There are a number of antimicrobials that may be used in the perioperative period that interact with methotrexate (risks include hepatotoxicity, methotrexate toxicity, myelosuppression). Consult product literature where necessary.
Methotrexate toxicity
Methotrexate toxicity, due to reduced clearance, can occur with the following antimicrobials:
- penicillins – serious interactions are uncommon, but risk factors are as yet unknown
- ciprofloxacin – avoid
- trimethoprim – avoid (also see Myelosuppression below)
Whilst single surgical prophylactic doses of penicillins should not pose a problem, continued post-operative treatment would require close monitoring.
Myelosuppression
Myelosuppression can occur with the following antimicrobials:
- sulfonamides (e.g. sulfamethoxazole contained in co-trimoxazole) – avoid
- trimethoprim – avoid (also see Methotrexate toxicity above)
Proton pump inhibitors (PPIs)
PPIs decrease clearance of methotrexate and the risk seems greatest with high-dose methotrexate. Routine monitoring should be adequate to detect any toxicity. H2-receptor antagonists might be a suitable alternative6.
Paracetamol
In clinical practice, hepatotoxicity may be seen with concomitant use of methotrexate and paracetamol, although this appears to be a rare interaction – monitor.
Further information
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.
Methotrexate prescribing
Note that for rheumatology and dermatology indications, the dose of methotrexate is a weekly dose – it is important that the prescription clearly shows the dose and frequency of methotrexate administration.
Patients on subcutaneous weekly methotrexate injections should have their medication prescribed by brand name to avoid inadvertent switching to a device that they are not trained to use.
Infection risk
Some data suggests that not all DMARDs carry the same infection risk. Methotrexate use in the perioperative period (orthopaedic surgery) has been studied in two controlled trials. In these studies there was no evidence to suggest an adverse impact on wound health or an increase in post-operative complications. In these studies, methotrexate doses were typically low (< 15mg/week) and co-morbidities were not considered. There have also been a number of observational studies that have not found any association between DMARD interruption and infection risk or evidence of any adverse effect when methotrexate is continued perioperatively. No studies have looked at peri- / post-operative complications in patients receiving low-dose methotrexate for dermatological indications, or in patients following general surgery.
References
Baxter K, Preston CL (eds), Stockley’s Drug Interactions (online) London: Pharmaceutical Press. http://www.medicinescomplete.com [Accessed on 26th May 2019]
Joint Formulary Committee. British National Formulary (online) London: BMJ Group and Pharmaceutical Press http://www.medicinescomplete.com [Accessed on 26th May 2019]
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 26th May 2019]
Methotrexate. In: Brayfield A (Ed), Martindale: The Complete Drug Reference. London: The Royal Pharmaceutical Society of Great Britain. http://www.medicinescomplete.com [Accessed 26th May 2019]
Summary of Product Characteristics – Methotrexate 2.5mg Tablets. Hospira UK Ltd. Accessed via www.medicines.org.uk 26/05/2019 [date of revision of the text January 2019]
Warren RB, Weatherhead SC, Smith CH et al. British Association of Dermatologists’ guidelines for the safe and effective prescribing of methotrexate for skin disease. British Journal of Dermatology. 2016; 175:23-44