A decade of Australian methotrexate dosing errors

Cairns and colleagues1 noted in their article that eight deaths were identified as medication errors due to daily methotrexate dosing. In addition, 92 cases of methotrexate dosing errors were reported to the four Poisons Information Centres in Australia with a concerning rise in 2014–15. The authors found that low dose daily administration for 3–7 days could cause toxicity and even death.1 The toxicity of methotrexate is likely to be more dependent on the duration of exposure rather than on serum concentration.2 In a retrospective series of 28 patients, pancytopenia (79%) was found to be the most common manifestation of low dose chronic methotrexate toxicity.3 In contrast, in our study, we observed no effects with acute single dose exposures.4

We recently performed an audit of the calls referred to the clinical toxicologists at the New South Wales Poisons Information Centres (2004–2015). Ethics approval was granted by the Sydney Children’s Hospitals Network Human Research Ethics Committee (approval number LNR-2011-04-06). There were 21 chronic methotrexate poisonings — the median age was 62 years (interquartile range, 52–77) — 15 of which were reported to have symptoms indicating toxicity, with stomatitis and mucositis (30%, 7/21 patients) and neutropenia (30%, 7/21 patients) being the most commonly reported symptoms. The daily dosing reported was from 5–15 mg for 3–40 days.

Serum methotrexate concentration (n = 20) did not correlate with neutropenia (r = –0.36) or thrombocytopenia (r = 0.44).3 There was no difference in methotrexate concentration between those who died (n = 6, 0.05 ± 0.04 μg/ml) and those who survived (n = 14, 0.04 ± 0.04 μg/ml, P = 0.45). These concentrations are many fold lower than those seen in our audit of asymptomatic acute methotrexate overdose, which had a median concentration of 0.32 ± 0.08 μg/ml.4 Hence, there is no rationale to monitor methotrexate concentrations in chronic methotrexate toxicity; very low concentrations can still be associated with severe or fatal toxicity.