Methotrexate is an immunosuppressant medication used in the treatment of autoimmune diseases and some type of cancers. It acts by competitively inhibiting the dihydrofolate reductase (DHFR), a key enzyme involved in the synthesis of DNA, RNA, thymidylates, and proteins. Different regulatory bodies issued alerts on the safety concerns of medication errors and fatal overdose occurrences associated with noncompliant dosing frequencies of methotrexate use. Despite of implementing various risk minimizing measures, health authorities are still receiving case reports pertaining to these safety concerns. A brief summary of significant information from different national health authorities is presented here to further disseminate this into public comprising both health care professionals and patients for a better patient safety.

Potential medication error and accidental (unintentional) overdose:

Methotrexate is used for intended indications in once in a weekly dosing schedule. Due to unawareness, polypharmacy, and lack of education- patients are prone to intake of more than recommended dosage of methotrexate (more than 1 dose in a week) which in turn lead to unintended overdose of drug.

Methotrexate overdose can cause serious adverse effects like hematopoietic disorders which included leukopenia, thrombocytopenia, anaemia, and pancytopenia and gastrointestinal reactions like mucositis, stomatitis, oral ulceration, gastrointestinal ulceration, and gastrointestinal bleeding. Methotrexate overdose can even lead to fatal outcome with the events such as sepsis or septic shock, renal failure, and aplastic anaemia.

In 2006, National Patient Safety Agency (NPSA) issued a patient safety alert to address this potential inadvertent overdose and for improving oral dosing compliance with methotrexate medication. In contrast, Health authority of UK, Medicines and Healthcare products Regulatory Agency (MHRA) has been receiving case reports pertaining to this safety concern via yellow care scheme. From 2006 to 30-Jul-2020, MHRA received 11 cases of methotrexate overdose which included 4 serious case reports.

Risk minimizing measures (RMM):

In 22 Aug 2019, European Medicines Agency (EMA), published below measures for minimizing the risk of potential medication errors (at the level of prescription, dispensing, and patient’s compliance with oral dosing frequency) and serious, fatal overdose concerns.

  1. Restricting the persons who can prescribe methotrexate. i.e., health care professional only with adequate knowledge of benefit-risk profile of methotrexate in the context of individual patient’s medical condition can prescribe this medicine.
  2. Clear warnings about overdose/dosing frequency on package information leaflets which is more prominent.
  3. Providing educational materials for patients and healthcare professionals to strengthen the awareness of this potential safety concerns which are preventable with knowledge and minimizing measures.
  4. Providing methotrexate tablets in blister packs instead of bottles (or tubes) for assisting patient’s compliance in dosing frequency.

A Direct Healthcare Professional Communication (DHPC) has issued by Pfizer on 13 Jan 2020 to disseminate this significant safety information to all the marketing authorization holders of methotrexate to address these safety concerns and for implementing risk minimizing measures.

Important information for Healthcare professionals & Patients:

  • Methotrexate is intended to use only “once in a week dosing”.
  • Consider about the ‘day’ of week in which dose was administered. Follow the consistent day for every week.
  • Be aware of significant safety concerns for methotrexate overdose and be compliant with dosing frequency.
  • Read the prescribing information documents and package information leaflets for the required instructions on usage, precautions, and warnings.
  • Be aware of signs and symptoms of methotrexate overdose and inform to your respective health care professional on immediate basis for a suspected overdose.
  • Be responsible and report and any unusual adverse experiences associated with methotrexate and any other medicinal product to your respective national health authority.
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