Safety Concerns Persist for Low-Dose Methotrexate

Patient Safety Monitor Insider

December 9, 2015

Despite warnings issued since 1996, ISMP continues to receive reports of severe harm and death caused by errors and drug interactions involving low-dose methotrexate.

For patients with severe, disabling rheumatoid arthritis (RA), oral methotrexate is often the preferred disease-modifying antirheumatic drug, unless it is specifically contraindicated (Bykerk et al., 2012; Saag et al., 2008; Singh et al., 2012). compared to dosing for antineoplastic indications, methotrexate for RA is administered once weekly as low-dose therapy (Sing et al., 2012). According to official prescribing information, the recommended starting dose is a single oral dose of 7.5 mg once weekly or divided oral doses of 2.5 mg every 12 hours for three doses per week. The dosing schedule may be adjusted to achieve optimal response, with doses up to about 25 mg weekly.

Since early 1996 and as recently as May 2015, harmful or fatal errors with low-dose oral methotrexate have been reported to ISMP and published in more than 50 of our newsletters. Most errors involved accidental daily dosing of oral methotrexate that was intended for weekly administration. In 2004, we published a study of methotrexate errors over a 4-year period that resulted in 25 deaths and 48 serious outcomes, many due to daily dosing (Moore, Walsh, & Cohen, 2004). Our sister organization, ISMP Canada, has also received multiple reports of severe harm or death in patients taking low-dose methotrexate for RA and other autoimmune diseases.

Two of the three recent incidents highlighted in the September 30, 2015, ISMP Canada Safety Bulletin involved patients who were taking no more than 20 mg of methotrexate weekly, yet they died of severe methotrexate toxic effects due to other risk factors, including drug interactions that increased the serum concentration of methotrexate. The third event is very similar to many other methotrexate errors, with patients taking the medication daily instead of weekly. The findings and recommendations from these three selected recent cases reported to ISMP Canada are shared here to highlight system-based opportunities to further improve safety with low-dose methotrexate therapy.

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