This column was prepared by the Institute for Safe Medication Practices (ISMP), an ECRI affiliate. 

Methotrexate is a folic acid antagonist that was originally approved to treat a variety of cancers. Used for oncologic indications, methotrexate is administered in cyclical frequencies and in variable doses based on body surface area and the type of cancer being treated. The labeled indications for methotrexate later expanded to include the treatment of non-oncologic conditions, including psoriasis and rheumatoid arthritis. For most non-oncologic indications (eg, rheumatoid arthritis), a low dose of methotrexate is administered weekly – for example, 7.5 mg per week when initiating treatment for rheumatoid arthritis.

Accidental daily dosing of oral methotrexate has occurred all too frequently. This type of wrong frequency error has originated in all stages of the medication-use process, from prescribing to self-administration. These errors have resulted in serious methotrexate overdoses that led to mouth sores, stomatitis, serious skin lesions, liver failure, renal failure, myelosuppression, gastrointestinal bleeding, life-threatening pulmonary symptoms, and death.  

Methotrexate Errors 

The death of a patient reported in the media is a stark reminder of the harm that can occur. A patient had been admitted to a rehabilitation facility following a fall at home. A prescription for methotrexate 20 mg daily was sent to the pharmacy instead of a prescription for methotrexate 20 mg weekly. The pharmacy dispensing system allowed the pharmacist to bypass a high-dose alert. As a result, the patient received 20 mg of methotrexate daily for a week (a total of 100 mg). The patient became ill and died about a week later. Now, both the prescriber and pharmacist are facing criminal charges.

Since 1996, errors with daily oral methotrexate for non-oncologic use have been reported to ISMP and published in dozens of ISMP Medication Safety Alert! newsletters. For example, in one case, methotrexate 15 mg once weekly was prescribed for treatment of an autoimmune disorder in an elderly patient. The community pharmacy dispensed a three-month quantity of medication but provided instructions on the label to take 15 mg (six 2.5 mg tablets) once daily. The error was discovered three weeks later during patient counseling with a pharmacist when the patient requested a refill. The error resulted in severe harm, which led to a long hospital stay and treatment with the rescue agent leucovorin calcium. 

Safe Practice Recommendations

Most of these wrong frequency errors with methotrexate can be prevented by implementing known risk-reduction strategies. It is time for technology vendors, regulators, standards-setting organizations, health care organizations, and practitioners to make the system improvements outlined in Best Practice #3 in the ISMP Medication Safety Best Practices for Community Pharmacy, including: 

  • Use a weekly dosage regimen default for oral methotrexate in electronic systems when medication orders are entered. 
  • Require verification and entry of an appropriate oncologic indication in order entry systems for daily orders. Ideally, computer systems would require a hard-stop verification of an appropriate oncologic indication for all daily oral methotrexate orders. 
  • Create a forcing function (eg, electronic stop in the sales register that requires intervention and acknowledgement by a pharmacist) to ensure that every oral methotrexate prescription is reviewed with the patient or a family member when a prescription is presented or refills are processed. 
  • Provide specific patient and/or family education for all oral methotrexate prescriptions. 

To learn more about how to identify medication safety risks before they cause harm, consider attending an ISMP Medication Safety Intensive workshop designed for those working in community and specialty pharmacies. For more details about the program, please visit the ISMP workshop web page.