Global Targeted Medication Safety Best Practice 1

Prevent inadvertent daily dosing of oral methotrexate for non-oncologic conditions.


Methotrexate is a folate antimetabolite used in the treatment of neoplastic diseases and non-oncological conditions like psoriasis, rheumatoid arthritis, and other conditions. When used to treat disorders such as rheumatoid arthritis, the drug is administered weekly while for some cancer types, a more frequent or higher dose is used (1). At high doses, methotrexate is well known to be associated with serious and sometimes fatal blood dyscrasias, but similar reports have been associated with the use of low-dose methotrexate when given daily.

Prescribing, transcribing, dispensing, and patient errors have led to some patients receiving a daily instead of a weekly dose for non-oncological indications. Fatal dosing errors with methotrexate have been reported for many years since early 1996, occurring both during hospitalization and after discharge (2-7).


The goal of this medication safety practice is to prevent errors involving inadvertent daily instead of weekly dosing of oral methotrexate, in the ambulatory and inpatient setting.

Risk reduction strategies and key improvements

Selected error-reduction strategies include constraints such as limiting the availability of methotrexate tablets by restricting  quantities (blister forms as a weekly or monthly dose pack, dispensing only one dose at a time, removing methotrexate from nursing units/ward stock), forcing functions and computerization such as setting the weekly dosage regimen default for oral methotrexate in electronic systems, electronic hard stop verification of the indication and the posology, etc. These key improvements must be accompanied by medium and low leverage strategies such as independent double checking, reminders, warnings, and patient education and counselling (2,8-15).

Improving oral methotrexate packaging safety

Some European Union countries, such as Denmark, Spain, France, and also Canada, have added a visual warning on the medication package label (e.g., “Check dose and frequency—methotrexate is usually taken once a week”) (4,6,16,17).  While the European Medicines Agency (EMA) is currently reviewing the risk of dosing errors with methotrexate, organizations like the Institute for Safe Medication Practices (ISMP), the ISMP-España, the International Medication Safety Network (IMSN), Prescrire, and the New Zealand’s Health Quality and Safety Commission recommend that the packaging of methotrexate be provided in blister forms as a weekly or monthly dose pack (or calendar packs) (4,10-15).

The world safety standard packaging for non-oncologic methotrexate to prevent accidental daily use and overdose is currently part of a White Paper targeting International best practice for safe labelling and packaging of prescription medicines sponsored by the IMSN and the US Food and Drug Administration (FDA).

Improving medication safety practices for
preventing inadvertent daily dosing of oral methotrexate

  1. Prescribe, dispense and administer oral methotrexate ONCE WEEKLY and specify the day of the week.
  2. A weekly dosage regimen for oral methotrexate should be entered as a default into electronic systems for this drug to prevent accidental prescribing or dispensing more than once a week.
  3. Require an electronic hard stop verification of an appropriate oncologic indication for all daily oral methotrexate orders.
    1. Prescribers must be consulted by a pharmacist for any prescription for use more than once per week. Prescriber should specify the indication on the medication chart or prescription which would alert nurses and pharmacists to any potential prescribing errors (18).
    2. For manual systems and electronic order entry systems that cannot provide a hard stop, clarify all daily orders for methotrexate if the patient does not have a documented oncologic diagnosis.
    3. Where available (acute care or corporate pharmacies using information technology), work with information technology departments and software vendors to ensure that this hard stop is available. Order entry systems should be capable of this hard stop as it is an important patient safety component of their systems.
  4. Dispense only the needed doses in a safety packaging such as dose pack, patient pack or calendar pack.
    • Always verify a patient’s dose by comparing the dose and number of tablets. Many dosing errors occur during transitions of care where the patient administers or is inadvertently given the wrong number of tablets per dose.
    • In hospital setting, remove methotrexate from nursing units/ward stock and “after hours” cupboards. At discharge, dispense a maximum of one month’s supply.
  5. Provide specific patient and/or family/caregiver education for all oral methotrexate orders or new prescriptions.
    • Double-check all printed medication lists and patient education materials to ensure they indicate the correct dosage regimen for oral methotrexate prior to providing the medication to the patient.
    • Ensure that the process for providing patient education includes clear written instructions AND clear verbal instructions to specifically review the dosing schedule, emphasize the danger in taking extra doses, and specifying that the medication should never be taken “as needed” for symptom control.
    • Require the patient to repeat back the instructions to validate that the patient understands the dosing schedule and toxicities of the medication if taken more frequently than prescribed.
    • Provide all patients with a copy of  free consumer leaflets on oral methotrexate (e.g., ISMP high-alert medication consumer leaflet on oral methotrexate found here.
  6. Educate clinical staff on the safe and appropriate use of methotrexate.
    • Clinical staff involved in patient care should be able to recognize potential signs and symptoms of toxicity or intolerance of methotrexate.
    • Prescribers should order full blood counts until the patient is stabilized and every 2-3 months throughout therapy. Other laboratory tests are also necessary when monitoring patients who receive methotrexate.


  1. WHO Pharmaceuticals newsletter. Methotrexate (low-dose) - blood dyscrasias and other adverse reactions: United Kingdom. Current Problems in Pharmacovigilance Vol. 23, September 1997. Access
  2. ISMP. Beware of erroneous daily oral methotrexate dosing. ISMP Medication Safety Alert! 2002 ;7 (7) : 1-2
  3. Prescrire Editorial Staff "Weekly methotrexate: still more deaths in France in 2011" Prescrire Int 2011; 21 (123):  15.
  4. Prescrire Editorial Staff "Weekly oral methotrexate therapy: raise awareness of fatal dosing errors" Prescrire Int 2013; 22 (138): 126.
  5. ISMP 2018-2019 Targeted Medication Safety Best Practices for Hospital. Best Practice 1. December 12,2017. Access
  6. EMA reviewing risk of dosing errors with methotrexate: Review prompted by continued reports of overdose. Press release. April 14, 2018. Access
  7. Attalla M. “Signal. Methotrexate – Incorrect drug administration rate” WHO Pharmaceuticals Newsletter 2019; (1): 18.
  8. ISMP-España. Alerta especial. Errores asociados al metotrexato en el tratamiento de la artritis reumatoide. Jun 2003. Download
  9. Prescrire Editorial Staff "Oral methotrexate: preventing avoidable overdose" Prescrire Int 2007; 16 ( 90) : 150-152.
  10. Irish Medication Safety Network. Safety Alert- oral methotrexate. 2010. Access
  11. International Medication Safety Network "IMSN Position Paper on Making Medicines Naming, Labelling and Packaging Safer" October 2013; 8. Download
  12. Pharmaceutical Society of Ireland. Guidance for pharmacists on safe supply or oral methotrexate. January 2015. Download
  13. ISMP. Simple packaging change could help reduce drug diversion. ISMP Medication Safety Alert ! 2016 ; 21 (7) : 4.
  14. Health Quality & Safety Commission New Zealand "Reducing the risk of error and patient harm with low-dose oral methotrexate" Medication Safety Watch April 2016; (17): 1-2.
  15. Prescrire. Methotrexate: Room for improvement in packaging and patient information. May 2018 Access
  16. Health Canada. Good Label and Package Practice Guide for Prescription Drugs. June 30, 2016. Access
  17. Danish Medicines Agency. Latest news about medicines safety and medical devices. 2018; 3 (2) : 8.
  18. NSW Ministry of Health Policy Directive. High Risk Management Policy. August 2015. Download