Reported Medication Errors Associated With Methotrexate

Abstract and Introduction

Purpose: Medication errors reported to FDA as adverse events in which methotrexate was identified as a possible contributor were studied.
Methods: All adverse-event reports submitted to FDA between November 1997 and December 2001 indicating potential medication errors involving methotrexate were analyzed to determine the indication for use, the type of error, and the point in the medication-use process where the error occurred.
Results: A total of 106 cases of reported medication errors associated with methotrexate were identified, including errors resulting in 25 deaths (24%) and 48 other serious outcomes (45%). The most common types of errors involved confusion about the once-weekly dosage schedule (30%) and other dosage errors (22%). The most frequently involved indication for use was rheumatoid arthritis (42%). Of the errors, 39 (37%) were attributable to the prescriber, 21 (20%) to the patient, 20 (19%) to dispensing, and 18 (17%) to administration by a health care professional.
Conclusion: A review of medication errors involving methotrexate revealed that errors occurred during all phases of use, often resulted from confusion about dosage, and often caused death or other serious adverse effects.

Methotrexate is a folic acid antagonist used in the treatment of many medical conditions, including rheumatoid arthritis,^[1] psoriasis,^[2] and ectopic pregnancy.^[3] It has also been proven effective against several forms of cancer, including acute lymphoblastic leukemia,^[1] osteosarcoma,^[4] and non-Hodgkin's lymphoma.^[5] Doses of methotrexate (as the sodium salt) for rheumatoid arthritis can be as low as 2.5 mg, while 15 g/m² can be used (along with leucovorin rescue therapy) for osteosarcoma—a 10,000-fold difference. Scheduling of doses also varies widely, from cyclical protocols for cancer chemotherapy to weekly for rheumatoid arthritis and sarcoidosis.^[6,7] Adding to this complexity, methotrexate can be administered orally, intravenously, intramuscularly, or intrathecally.

Since folic acid plays a major role in cell division, its inhibition is associated with major toxicity to blood cells, the oral mucosa, hepatocytes, and lung and fetal tissue. Severe blood-cell toxicity is usually manifested as anemia, leucopenia, or thrombocytopenia and has been reported in up to 36% of lymphoma patients receiving methotrexate.^[7] Oral ulceration, which can occur at the lower end of the methotrexate dosage spectrum, was seen in 11 of 29 patients treated for rheumatoid arthritis.^[8] Methotrexate-related hepatotoxicity, which has occurred in 10% of sarcoidosis patients,^[7] is not well correlated with liver-function test findings; biopsy is the only accurate method of assessing liver status. Pneumonitis, which is related to the cumulative dose, was reported in a literature review to occur in 5% of patients undergoing long-term therapy.^[9] Methotrexate is such a potent teratogen that the manufacturer recommends that both male and female partners avoid exposure during pregnancy.^[10]

Frequent serious medication errors involving methotrexate have been reported, and some patients have died.^[11,12,13] The errors have involved some aspect of the dosage regimen. Three recent fatal cases illustrate the hazards of failing to observe the weekly dosage schedule for rheumatoid arthritis. In one of these cases, a patient misunderstood the directions for use and took methotrexate 2.5 mg every 12 hours for six consecutive days instead of 2.5 mg every 12 hours for three doses each week.^[14] In the second case, a patient misread the directions on a prescription bottle and took 10 mg every morning instead of every Monday.^[14] In the third case, a physician prescribed methotrexate 15 mg daily instead of weekly, and the patient received nine doses.^[15]

Errors like these have been reported to organizations like the Institute for Safe Medication Practices (ISMP) and the United States Pharmacopeia, which in turn automatically notify FDA.^[16] To evaluate the overall risk posed by methotrexate, errors need to be viewed in aggregate, along with their associated causes, to determine the most effective prevention strategies.

We studied medication errors reported to FDA as adverse events in which methotrexate was identified as a possible contributor.

Am J Health Syst Pharm. 2004;61(13) © 2004 American Society of Health-System Pharmacists

Cite this: Reported Medication Errors Associated With Methotrexate - Medscape - Jul 01, 2004.