EMA to Review Methotrexate Overdose and Dosing Errors Save

A recent meeting (April 9-12) of the European Medicines Agency’s (EMA) Pharmacovigilance Risk Assessment Committee (PRAC) considered the problem of dosing errors with methotrexate (MTX), citing "continued reports of overdose." 

Although usually dosed at low doses,  given weekly (for rheumatoid arthritis; higher in some malignancies), the EMA has noted reports of improper MTX dosing that has lead to fatal or serious outcomes in some reports. Prompted by the Spanish medicines regulator, AEMPS, the PRAC was asked to investigate why dosing errors continue with MTX.  

There has been sporadic reports of MTX dosing errors for years, but the EMA notes that measures to reduce this risk are unclear.

Medscape reports that the PRAC will examine the evidence and make recommendations to the Committee for Medicinal Products for Human Use, on how to minimize this risk. (Citation souce:  https://wb.md/2H2Et46)

Severe toxicity from MTX may include mucosal or gastrointestinal tract ulceration, liver toxicity, bone marrow suppression, septicemia, or death.  Risk factors for MTX overdose/toxicity typically include renal insufficiency (or sudden decline in renal function), hypoalbuminemia, dosing errors (use of higher than recommended doses) and failure to use folate supplementation.

Several recent reports underscore the serious consequences of rarely seen MTX dosing errors. 

• Ajmani et al reported on 46 cases of MTX induced severe pancytopenia observed over a 19 year period. They noted a high mortality rate (13/46) and that the presenting symptoms may be high fever and severe mucositis. Common features included: oral mucositis (n = 37); fever (24); diarrhea (12), bleeding gums (5) and purpura (3). http://bit.ly/2JLjXa5 
• A study of 4 different Danish registers identified 173 errors with nearly two-thirds resulting in harm. Serious harm occurred in 15% and there were 9 deaths (5%). These involved involved incorrect daily administration (31%), dosing errors (62%) and 9% had improper \monitoring. Prescription errors involving daily rather than weekly administration, by hospital physicians, were most likely to result in serious outcomes, including deaths. http://bit.ly/2JLlxZz