Methotrexate


 

Immunosuppressant, Disease-Modifying Antirheumatic Drug - DMARD

 

[For methotrexate use in the treatment of neoplastic disease see Statement on Chemotherapy]


  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 infection1 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 required1.

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 basis2. 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-operatively1.

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 satisfactory1.

Where methotrexate is continued, close monitoring of renal function is important so that inadvertent drug accumulation does not occur1.


  Interaction(s) with Common Anaesthetic Agents


Nitrous Oxide

Nitrous oxide potentially increases the risk of methotrexate toxicity when given with methotrexate and concomitant use should be avoided3, 4, 5, 6.


  Interaction(s) with other Common Medicines used in the Perioperative Period


Non-Steroidal Anti-inflammatory Drugs (NSAIDs)

NSAIDs and methotrexate can increase the risk of nephrotoxicity3, 5.

Increased methotrexate toxicity, sometimes life-threatening, has been seen in a few patients concurrently treated with some NSAIDs3, 4, 5, 6. 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 monitored1, concurrent use need not be avoided5, 6.

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)3, 4, 5, 6. Consult product literature where necessary.

Methotrexate Toxicity
Methotrexate toxicity, due to reduced clearance, can occur with the following antimicrobials3, 4: -

  • penicillins – serious interactions are uncommon, but risk factors are as yet unknown
  • ciprofloxacin – avoid
  • trimethoprim – avoid (also see below under Myelosuppression)

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 antimicrobials3, 4: -

  • sulfonamides (e.g. sulfamethoxazole contained in co-trimoxazole) – avoid
  • trimethoprim – avoid (also see above under Methotrexate Toxicity)

Proton Pump Inhibitors (PPIs)

PPIs decrease clearance of methotrexate and the risk seems greatest with high-dose methotrexate3. Routine monitoring should be adequate to detect any toxicity4. H2-receptor antagonists might be a suitable alternative4, 5, 6.

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 interruption1.

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 administration3.

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 perioperatively1. No studies have looked at peri- / post-operative complications in patients receiving low-dose methotrexate for dermatological indications, or in patients following general surgery2.

 

  References


  1. 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]
  2. 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
  3. Joint Formulary Committee. British National Formulary (online) London: BMJ Group and Pharmaceutical Press http://www.medicinescomplete.com [Accessed on 26th May 2019]
  4. Baxter K, Preston CL (eds), Stockley’s Drug Interactions (online) London: Pharmaceutical Press. http://www.medicinescomplete.com [Accessed on 26th May 2019]
  5. 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]
  6. 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]