Global Targeted Medication Safety Best Practice 3

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 such as psoriasis, rheumatoid arthritis, and other conditions. When used to treat disorders such as psoriasis and rheumatoid arthritis, low doses are administered weekly by the oral route. However, for some cancer types, a more frequent or higher dose is used (1). At high doses, oral methotrexate is known to be associated with serious and sometimes fatal blood dyscrasias, but similar adverse outcomes have been associated with the use of low-dose oral methotrexate when given daily.

Prescribing, transcribing, dispensing, and administration errors (including self-administration by patients) have led to daily instead of weekly dosing of oral methotrexate for non-oncological indications. Fatal dosing errors with oral methotrexate have been reported since early 1996, occurring both during hospitalization and after discharge (2-7).


The goal of this best practice is to prevent errors involving inadvertent daily dosing instead of weekly dosing of oral methotrexate for non-oncologic conditions in the ambulatory and inpatient setting.

Best Practice Description

  • a) Prescribe, dispense and administer oral methotrexate ONCE WEEKLY and specify the day of the week.
  • b) Enter a weekly dosage regimen for oral methotrexate as a default into electronic systems to prevent the accidental prescribing or dispensing of the medication for more than once-a-week administration.
  • c) Require an electronic hard stop verification of an appropriate oncologic indication for all daily oral methotrexate orders.
    • Require a pharmacist to consult prescribers for any oral methotrexate prescription indicating more than once per week dosing. The prescriber should specify the indication on the medication chart or prescription, which would alert nurses and pharmacists to any potential prescribing errors.
    • 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 an appropriate, documented oncologic diagnosis.
    • 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 these systems.
  • d) In the hospital setting, remove methotrexate from nursing units/ward stock and “after hours” cupboards.
  • e) Dispense only the needed doses in safety packaging such as a dose pack, patient pack, or calendar pack.
    • For outpatients, dispense a maximum of 1 month’s supply.
    • Always verify the patient’s dose by comparing the dose and number of tablets dispensed. Many dosing errors occur during transitions of care where the patient administers or is inadvertently given the wrong number of tablets per dose.
  • f) 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 AND verbal instructions to specifically review the dosing schedule, emphasize the danger in taking extra doses, and specify 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 consumer leaflets on oral methotrexate (e.g., free ISMP high-alert medication consumer leaflet on oral methotrexate can be found at:
  • g) 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


These selected risk-reduction strategies include constraints that can help avoid daily dosing of oral methotrexate, such as limiting the availability of methotrexate tablets by restricting quantities (e.g., dispensing blister forms as a weekly or monthly dose pack, dispensing only one dose at a time, removing methotrexate from nursing units/ward stock). The risk-reduction strategies also include high-leverage forcing functions and computerization, such as setting the default to a weekly dosage regimen for oral methotrexate in electronic systems and electronic hard-stop verification of the indication and posology of the medication. These key improvements must be accompanied by staff education, patient education and counselling, and warnings and reminders (2,8-16).

Improving oral methotrexate packaging safety

Some European Union countries (e.g., Denmark, Spain, France) and Canada have added a visual warning on oral methotrexate medication package labels about weekly dosing of this drug (e.g., “Check dose and frequency—methotrexate is usually taken once a week”) (4,6,17,18). The European Medicines Agency (EMA) is currently reviewing the risk of methotrexate dosing errors to determine required changes. Many medication safety organizations, including ISMP, ISMP-España, IMSN, Prescrire, and New Zealand’s Health Quality and Safety Commission, also recommend packaging oral methotrexate in blister forms as a weekly or monthly dose pack (or
calendar packs) to help prevent inadvertent daily dosing (4,10-15). As a result, an international safety standard for safe labeling and packaging of non-oncologic oral methotrexate is currently part of an in-progress White Paper sponsored by the IMSN and the United States Food and Drug Administration (FDA) to prevent daily use and overdose.


  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 13, 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. Ministry of Health, New South Wales (NSW). Policy Directive. High Risk Management Policy. August 2015. Download
  17. Health Canada. Good Label and Package Practice Guide for Prescription Drugs. June 30, 2016. Access
  18. Danish Medicines Agency. Latest news about medicines safety and medical devices. 2018; 3 (2) : 8.

June 2019