Methotrexate toxicity in the setting of oral therapeutic errors: a multicenter retrospective study

Methotrexate, a dihydrofolate reductase inhibitor with immunosuppressive and disease-modifying effects, is typically dosed orally once weekly. Misunderstanding instructions can lead to daily instead of weekly dosing. This study characterizes thresholds for toxicity from unintentional daily ingestion in adults.

This was a multi-center retrospective cohort study using records from six regional poison centers between January 1, 2000 and January 24, 2023. Inclusion criteria were adults ≥18 years of age with a therapeutic error of oral methotrexate administration more frequently than weekly. We defined organ system dysfunction as any cytopenia, severe mucositis/stomatitis, severe dermatologic manifestations, renal dysfunction, or elevated aminotransferase activity. The primary outcome was the threshold cumulative dose and duration associated with any organ system dysfunction.

We screened 139 cases and after exclusion, 54 cases remained. Median age was 64 years (IQR 57-70) and 70% of cases were female. There were 51 cases (95%) prescribed methotrexate weekly, and 50 (93%) instead took methotrexate daily. Median duration and dose of methotrexate was six days (IQR 4-9 days) and 66 mg (IQR 45-108 mg), respectively. End organ dysfunction occurred in 31 (57%) cases, 29 (94%) of which had mucositis and 16 (52%) had any cytopenia. There were two deaths. No patient developed organ system dysfunction if methotrexate was taken for less than three consecutive days, or a total dose of <37.5 mg.

Despite relatively low doses and duration of methotrexate exposure, patients commonly developed significant end organ toxicity. These thresholds provide additional data to develop triage and management guidelines. Healthcare providers should counsel patients on appropriate dosing. Limitations include use of voluntarily reported poison center data.

Daily methotrexate administration may result in severe organ dysfunction after relatively low dose and duration therapeutic errors.