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Making methotrexate safer

With a disproportionate number of adverse incidents relating to methotrexate treatment in Ireland, more must be done to eradicate error. Dr Diarmuid Quinlan and Dr Paul Ryan describe why a collective approach is the best way

Ireland has an unenviable reputation. We have four times more adverse incidents with patients taking methotrexate than in the UK.1Perhaps Irish people are uniquely susceptible to the side-effects of methotrexate; much more likely is that something is dangerously amiss with our patient safety systems and culture.

Errors can, and do, arise in prescribing, dispensing, administration and monitoring. We need a shared solution to this patient safety issue: patient empowerment is crucial, as patient safety is everyone’s responsibility. The consultants initiating methotrexate, the GPs writing the prescriptions, the pharmacists dispensing; we must sing from the same hymn sheet. We need to promote and ensure safe use of methotrexate at each and every patient contact.


In excess of 11,000 people in Ireland take methotrexate.1 That’s a lot of methotrexate prescribing and dispensing. Some 80% of patients take methotrexate for rheumatological disease, whereas most of the remainder are dermatological indications.1

Is there a commensurate monitoring and safety system in place? The cold statistics suggest we are failing our patients in this regard. Is this a case of familiarity breeding contempt? We know that monitoring of lithium is seriously deficient in Ireland, with just one third of patients taking lithium appropriately monitored.2 Is this a symptom of a deeper malaise, as yet undocumented, pertaining to other potentially toxic medications – warfarin, “the biologics”, combined oral contraception, NSAIDs to name a few.

NICE guidelines issued in September 2012 outline the responsibilities of doctors prescribing methotrexate.3 The simplicity of these recommendations belies their importance. Ignore them at your (patients’) peril. Methotrexate is simply one potentially toxic medicine. Many patients experience immunosuppression with chemotherapy. Still more commence novel immune suppressing medications.

NICE published a clinical guideline in September 2012, addressing neutropenia in patients taking immune suppressing medicines.The clinical difficulty is compounded if these patients are simultaneously taking oral corticosteroids, when signs and symptoms of sepsis may be few or absent. The median onset of methotrexate-induced toxicity is 17 months:5 just when you thought it was safe…

Common errors

Errors in methotrexate can and do arise with frightening regularity. There are clear roles and responsibilities for everyone involved. Almost 40% of Irish patients take 10mg tablets, compared to just 8% in the UK.1 Many of these patients take both 2.5mg and 10mg tablets.1 If you wanted to design a safe patient journey you wouldn’t start here… However, pharmacists are addressing the safety issues around methotrexate. My local pharmacy stocks methotrexate 2.5mg tablets only.

Methotrexate is locked in the safe, to help maintain awareness of the potential toxicity and the need for great caution in dispensing methotrexate; we physicians have a lot to learn from our proactive pharmacy colleagues. In Ireland an average of two children, under five years of age, accidentally ingest methotrexate every year.1 These small children take an average dose of 17.5mg. That’s a lot of methotrexate for a small child! Failure to discontinue methotrexate is a common cause of methotrexate toxicity, especially in unwell patients admitted to hospital.1

Fixing the problem

An audit of methotrexate monitoring in my practice in 2008 showed lots of scope for improvement. We are currently repeating this audit but on a much more ambitious scale. We have engaged with each of the groups involved in methotrexate, and written to our local rheumatology, dermatology and other consultants to highlight the systemic failings in safe use of methotrexate.

Our local pharmacists have engaged enthusiastically:

  • The 10mg tablets are not stocked; patients are dispensed 2.5mg tablets regardless of the dose. 
  • Pharmacists also encourage patients to attend for regular blood testing.
  • Pharmacists remind patients of the importance of taking methotrexate once weekly, on a specific day of the week. 
  • They ensure folic acid is dispensed and taken appropriately.
  • Crucially, they now inform patients of the signs and symptoms of methotrexate toxicity and what action to take if such signs/symptoms arise.

The law is frighteningly simple. Responsibility rests with the doctor who signs the prescription. Your signature... you’re responsible. No wiggle room! So what can you do?

Informed consent

Start with informed consent, and informed means informed. Patient empowerment is vital to ensure a safe methotrexate journey. Ensure the patient is aware of the risks and benefits of methotrexate. Have you documented this? Did you have this conversation once, many moons ago, or is it a regular discussion? What about a footnote to the methotrexate script: this could advise of the signs and symptoms of methotrexate toxicity, and the need to act urgently should these arise. A computer-generated template makes this fast and easy. Recommend that 2.5mg tablets only are to be dispensed, and how many to take; also, specify the day of the week.

Regular blood tests

Link patient blood testing to prescribing. This ensures a robust system to ensure regular monitoring. No test, no script, no exceptions. The BNF has recommendations about the recommended blood testing intervals.6


We have developed a simple patient alert leaflet. We print it on bright yellow A4 paper for instant recognition. It folds nicely to a credit card size for ease of storage and retrieval by the patient.

Extra vaccinations

Patients taking immunosuppressants are immunocompromised! Consider the uptake of flu and pneumococcal vaccines. The next edition of the national immunisation guidelines will specifically address the area of immunosuppressed patients.

Assess alcohol intake

Methotrexate and alcohol are both effective hepatotoxins. Patient education, including assessment of alcohol intake, is part of the recommended clinical assessment for methotrexate toxicity.7 Have you had that discussion yet?

We are all responsible

Methotrexate toxicity represents a real and ongoing threat to our patients, and we all have a role in addressing this. A shared responsibility exists to address our responsibilities to patients and patient empowerment is central to the safe use of methotrexate. Once you start down this road you might subsequently consider lithium, warfarin, DMARDs, to name a few.

Start today and build a safe methotrexate culture in your practice. It is good for patients and good for doctors... a win-win situation.

In summary

  • 11,000 patients take methotrexate; Ireland has four times the error rate of the UK.
  • Irish Medicines Board advice from April 2012; ignore it at your (patients’) peril.
  • No blood test: no prescription (no exception) 
  • Specify 2.5mg tablets; tablet strength confusion is lethal. 
  • Specify the day of the week; inadvertent daily consumption is lethal.
  • Educate patients on the symptoms of methotrexate toxicity.
  • Act urgently if neutropenic sepsis is suspected.
  1. Safe treatment with oral methotrexate, a shared responsibility demanding a shared solution, ISMN, Networking for safety in cancer care, 7 Oct 2011 
  2. An audit in general adult psychiatric service, Ir Med J, 103 (4) :123-4 (2010) 
  3. Irish Medicines Board, Drug Safety Newsletter, 47th edition, April 2012 
  4. Neutropenic sepsis; prevention and management of neutropenic sepsis in cancer patients (September 2012) 
  5. Grove M L, Hassell A B, Hay E M et al, Adverse reactions to disease-modifying anti-rheumatic drugs in clinical practice, Q J Med 94309–319.319 (2001)
  6. BNF (September 2012) 
  7. Visser et al, Multinational evidence based recommendations for the use of methotrexate in rheumatic disorders with a focus on Rheumatoid arthritis, Ann Rheum Disease 68;1086-1093 (2009)
Dr Diarmuid Quinlan is a GP and Dr Paul Ryan is an intern and qualified pharmacist, both based in Cork.
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