Methotrexate: Dosing for disaster

The Northern New England Poison Center manages several cases of methotrexate toxicity every year. While some are acute overdoses, many more are due to therapeutic error, which can lead to serious toxicity and death.

Methotrexate is prescribed in the outpatient setting in the treatment of rheumatoid arthritis, psoriasis or other autoimmune diseases. Dosing is often weekly, which can be confusing to the patient, family, caregiver or health care provider. Several cases in which significant toxicity developed were the result of the patients taking their weekly dose of methotrexate daily for several days to a month. One case resulted in a fatality. Others resulted in prolonged hospitalization and treatment.

Methotrexate is a chemotherapeutic agent that is structurally similar to folic acid. It inhibits dihydrofolate reductase. This inhibition interferes with DNA synthesis and repair, and cell reproduction. Toxicity results in the death of rapidly dividing cells throughout the body. Clinical effects of toxicity include:

  • Nausea, vomiting and diarrhea
  • Mucositis
  • Stomatitis
  • Esophagitis
  • Renal failure
  • Rash
  • Myelosuppression (leukopenia, pancytopenia, thrombocytopenia)
  • Acute lung injury
  • Tachycardia
  • Hypotension
  • Neurologic symptoms

Toxic effects can begin days to weeks after methotrexate administration. Treatment includes aggressive supportive care and use of antidotes such as leucovorin and glucarpidase.

Although the non-oncologic use of methotrexate has been on the High-Alert Medications List provided by the Institute for Safe Medication Practices for more than 15 years, errors still occur. This is a national problem and was the focus of an August 2018 ISMP Call to Action.

First, it’s important for every provider involved in the patient’s care to counsel the patient or caregiver during each encounter about appropriate use of methotrexate. The counseling should be repeated each time a patient transitions between home, hospital and nursing home/residential care.

  • Emphasize weekly, rather than daily dosing.
  • Explain the dangers of daily dosing.
  • Have the patient repeat the dosing and adverse effect information.

Support this counseling with written information.

  • Include “weekly” in the label directions and avoid vague terms such as “take as directed.”
  • Specify a day of the week other than Monday, and fully spell out the day.
  • Use a medication calendar to emphasize weekly dosing.

Limit the prescription to a 30-day supply (4 doses, rather than 30), and confirm an oncology diagnosis in any patient with an order for daily methotrexate.

Also confirm dosing whenever a patient reports adverse effects, especially rash, mucositis and/or fever, but also vague gastrointestinal, weakness or fatigue complaints.

The Northern New England Poison Center’s specialists and toxicologists are available 24 hours a day, 7 days a week to assist in the assessment and management of potential methotrexate toxicity. We can be reached by phone at 1-800-222-1222, online chat or text message by sending the word POISON to 85511.

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