Accidental Methotrexate Dosing Linked to Numerous Deaths

A new study finds that accidental daily use of methotrexate, a synthetic folic acid analogue used to treat rheumatoid arthritis (RA), psoriasis, and inflammatory bowel disease (IBD) has been linked to many deaths.

Researchers at the University of Sydney (Australia), the NSW Poisons Information Centre (Sydney, Australia), and other institutions conducted a retrospective review of cases in the Australian National Coronial Information System (NCIS), the Therapeutic Goods Administration Database of Adverse Event Notifications (TGA DAEN), and the Australian Poisons Information Centers (PICs) to uncover deaths resulting from accidental daily methotrexate dosing, with evidence of daily dosing on at least 3 consecutive days.


The results revealed 22 deaths linked with methotrexate identified in the NCIS, including seven cases in which erroneous daily dosing was documented. Methotrexate medication error was also listed in ten cases in the TGA DAEN, including two deaths, and the Australian PIC databases contained 92 cases. The reasons cited for the errors included patient misunderstanding and incorrect packaging of packs by pharmacists. The recorded clinical effects of daily instead of weekly doses, were consistent with those previously reported for methotrexate toxicity.

The researchers recommended that pack size could be reduced, as current Australian pack sizes can exceed a year's supply; that methotrexate could be formulated as a distinctively colored tablet to reduce the risk of medication error; and that since methotrexate and folates are often co-prescribed, the products could be packaged together. In addition, prescribing software could include warnings when methotrexate is prescribed daily, and dispensing software could include alerts if it is being dispensed too frequently. The study was published on June 6, 2016, in the Medical Journal of Australia.

“Higher or more frequent doses [than prescribed] can result in gastro-intestinal mucosal ulceration, hepatotoxicity, myelosuppression, sepsis and death,” concluded lead author Rose Cairns, PhD, of the NSW Poisons Information Centre. “Older people may be at increased risk because of a range of problems that includes confusion, memory difficulties, and age-related decline in visual acuity. Methotrexate use is likely to continue increasing as Australia's population ages, so that additional measures are needed to prevent these errors.”

Methotrexate is a cornerstone of therapy for RA and psoriasis, usually given orally once a week, but a substantial number of patients do not respond adequately or cannot tolerate the side effects of the drug, such as nausea, abdominal pain, and dyspepsia. Those patients can be given methotrexate with subcutaneous injections, which can increase the drug's bioavailability, but injection can also pose problems for patients who are afraid of needles or do not have enough manual dexterity remaining to manage needles, syringes, and vials.

Related Links:
University of Sydney
NSW Poisons Information Centre