Methotrexate once-weekly for autoimmune diseases: new measures to reduce risk of fatal overdose due to inadvertent daily instead of weekly dosing
In autoimmune conditions and some cancer therapies, methotrexate should be taken once a week; however, we continue to receive reports of inadvertent overdose due to more frequent dosing (including daily administration). New measures have been implemented to prompt healthcare professionals to record the day of the week for intake and to remind patients of the dosing schedule and the risks of overdose.
Advice for healthcare professionals:
Advice for prescribers:
- before prescribing methotrexate, make sure that the patient is able to understand and comply with once-weekly dosing
- consider the patient’s overall polypharmacy burden when deciding which formulation prescribe, especially for a patient with a high pill burden
- decide with the patient which day of the week they will take their methotrexate and note this day down in full on the prescription
- inform the patient and their caregivers of the potentially fatal risk of accidental overdose if methotrexate is taken more frequently than once a week; specifically, that it should not be taken daily
- advise patients of the need to promptly seek medical advice if they think they have taken too much
Advice for dispensers:
- remind the patient of the once-weekly dosing and risks of potentially fatal overdose if they take more than has been directed
- where applicable, write the day of the week for intake in full in the space provided on the outer package
- demonstrate the Patient Card included with the methotrexate packet and encourage patients to:
- write the day of the week for intake on the patient card
- carry it with them to alert any healthcare professionals they consult who are not familiar with their methotrexate treatment about their dosing schedule (for example, on hospital admission, change of care)
Review of medication errors with once-weekly methotrexate
In autoimmune conditions (and less commonly, in some cancer therapy regimens), methotrexate should be taken once a week. Measures (including a patient safety alert in 2006) have previously been put in place to minimise the risk of inadvertent overdose due to more frequent dosing of methotrexate, however a small number of reports continue to be received.
Since 1 Jan 2006 and up to 30 July 2020, we are aware of 11 Yellow Card reports of serious toxicity associated with inadvertent daily dosing of once-weekly methotrexate in the UK, with 4 of these serious reports received since January 2016.
Overdose of methotrexate can lead to serious adverse effects such as haematopoietic disorders (leukopenia, thrombocytopenia, anaemia, and pancytopenia) and gastrointestinal reactions (mucositis, stomatitis, oral ulceration, gastrointestinal ulceration, and gastrointestinal bleeding).
Some reports of overdose have been fatal. In these fatal cases, events such as sepsis or septic shock, renal failure, and aplastic anaemia were reported.
A European review of these types of medication error has looked at the root causes of these errors and set out several recommendations to minimise the likelihood of them occurring. A letter has been sent to prescribers and pharmacists involved in provision of methotrexate for autoimmune diseases.
Key recommendations
Prescribing advice
Medication errors that lead to taking more than the intended dose (including daily instead of once-weekly dosing) have been identified at all steps in the treatment pathway, including prescribing and dispensing of methotrexate, transfer of care (for example, hospital admission and discharge), and communicating with patients.
Methotrexate should only be prescribed by healthcare professionals who are fully aware of the benefits and risks of treatment and who have all necessary prescribing competence.
Healthcare professionals should take into consideration a patient’s overall polypharmacy burden when prescribing an oral formulation once-weekly and ensure that the patient is able to comply with once-weekly dosing when prescribing methotrexate. They should inform patients of the risks associated with taking methotrexate more frequently than prescribed, and specifically, that it should not be taken daily.
Patients should be advised to seek urgent medical attention if they think they have taken too much methotrexate.
Changes to the instructions and packs
The product information and outer and inner packaging of all methotrexate products for once-weekly dosing will carry a warning about the dosing schedule and the consequences of dosing errors.
The outer package warning will also include a space for the dispenser to write the day of the week for intake. Advice on dividing the once-weekly dose is being removed from the product information since this was identified as a source of confusion that could lead to medication error.
For methotrexate tablets, availability in bottle and tube packaging will be phased out over a period of 4 years.
Patient card and educational materials
Oral methotrexate products with indications requiring once-weekly dosing will come with a (July 2020), which will prompt patients to take methotrexate once a week and to record the day of the week for intake. It will also help patients to identify the signs and symptoms of overdose.
Instruct patients to carry the card with them in their purse or wallet and to use it to alert any healthcare professionals they consult who are not familiar with their methotrexate treatment about their once-weekly dosing schedule (for example, on hospital admission, change of care).
(July 2020) for healthcare professionals will also be made available for oral products with indications requiring once-weekly dosing. These materials should be used in conjunction with local guidance materials if available.
Background
Methotrexate is authorised for two different therapeutic areas, each of them with a different administration schedule:
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For the treatment of cancer in which regimens vary and can require daily administration of methotrexate
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For the treatment of autoimmune diseases including rheumatoid arthritis, psoriasis and Crohn’s disease, which require once-weekly use
Report on a Yellow Card
Suspected adverse reactions and any medication error that results in patient harm should be reported to the MHRA through the Yellow Card scheme.
You can report suspected side effects electronically via:
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the free Yellow Card app; download now from the Apple App Store or PlayStore
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some clinical IT systems (EMIS/SystmOne/Vision/MiDatabank) for healthcare professionals
Article citation: Drug Safety Update volume 14, issue 2: September 2020: 3.
Post-publication note
In order to facilitate the safety measures outlined above, IT systems used in the prescribing and dispensing process should be updated as necessary to allow healthcare professionals to adhere to the guidance.