Safer prescribing of high-risk medicines - Methotrexate: potentially fatal in overdose

A number of common sense steps can be taken by clinicians, including pharmacists, to minimise the risk of methotrexate toxicity and potential accidental overdose. Given the number of documented fatalities which have arisen from simple errors in medicine dosing frequency, the most important lesson is to emphasise that methotrexate should be taken as a weekly dose and to put in place procedures, safeguards and reminders to ensure this dosage is followed by doctors, pharmacists and patients.

Steps during patient consultation to ensure weekly administration:

• Avoid writing “as directed” on prescriptions – give the specific dose and state this in mg.
• Write the day the medicine is to be taken in full on the prescription (one case of fatality occurred when a patient interpreted “Mon” as morning, resulting in a daily as opposed to weekly dose).¹²
• Highlight differences in the appearance of 2.5 mg and 10 mg tablets, especially when a patient is transferred from one tablet size to another. Prescribe only one strength of tablet at a time in order to avoid accidental ingestion of 10 mg tablets in place of 2.5 mg tablets.¹²
• Emphasise to the patient the differences between methotrexate and folic acid – cases have occurred where the two dosing regimens were inadvertently swapped by the patient.¹¹ A simple mnemonic tool is “Methotrexate for Monday”, “Folic acid for Friday” as a means of ensuring once weekly dosing for each on different days.
• Maintain contact with the secondary care team and patient contact with rheumatology and practice nurses. Research conducted in New Zealand found significantly higher levels of patient awareness of signs and symptoms of methotrexate toxicity and awareness of weekly dosing in patients who had seen a rheumatology nurse.¹³
• If the patient has a carer, ask that they be present at consultations or that the need for accurate intake of medicines is discussed with them (with patient consent).
• In follow-up appointments specifically question patients on their medicine intake – How many tablets of methotrexate do you take? When do you take them?

Be vigilant for adverse effects, and ensure patients understand what these could be:

• Patients should be advised of key symptoms of methotrexate toxicity such as a sore throat, mouth ulcers, fever, dry persistent cough, vomiting or diarrhoea, and to report if any of these occur.
• Ensure that patient reports of adverse effects while taking methotrexate are relayed by practice staff to the patient’s usual clinician.⁹
• Practice steps to ensure weekly administration:
• Check that prescribing software automatically defaults to weekly prescriptions for methotrexate.⁹
• Flag the patient’s notes to alert other practice staff to report any potential features of methotrexate toxicity.⁹
• Consider a short education session for practice staff on methotrexate risks and symptom awareness, and put processes in place so that methotrexate adverse effects can be reported to the treating clinician.
• Be aware of failures to report for appointments by patients taking methotrexate, and double check the reasons why.

Laboratory monitoring is essential (also see Table 1):

• A full blood count, liver and renal function tests should be carried out before starting methotrexate, and repeated every two to four weeks initially, then every month to three months if results have been normal and the dose is stable.
• Ensure tests have been done within the last six weeks prior to writing repeat prescriptions.¹²
• Results showing decreased white blood cell counts or increased transaminase levels may indicate methotrexate toxicity. Discuss any abnormal results with the rheumatologist/dermatologist. See Table 1 for further details.
• Procollagen 3 (type III procollagen amino terminal propeptide, or PIIINP) may be used to monitor liver safety in patients with psoriasis. This is available as a Tier two test in the National Laboratory Test Schedule and will be arranged by a specialist. Liver biopsies may also be performed.

Check concurrent medicine and alcohol use:

• Impaired renal function can reduce the excretion of methotrexate and patients should report any use of medicines such as NSAIDs which reduce methotrexate excretion.⁵
• Alcohol intake should ideally be no more than one to two standard drinks twice per week,⁵ although many patients admit to higher amounts without developing evidence of liver problems.
• Co-trimoxazole and trimethoprim should be avoided in patients taking methotrexate due to a theoretical increase in risk of bone marrow suppression.^{5, 14}

Pharmacy steps to avoid weekly dosing errors:⁹

• Ensure that methotrexate labels state that dosing is weekly and give the day of the week, written in full, that the medicine is to be taken.
• Ensure software alerts are given appropriate attention.
• Contact the prescribing clinician with queries or to check that dosing is appropriate when there is doubt.
• Place prepared scripts for medicines with alerts in a different area to general, non-high risk, medicines so that alerts can be appropriately checked and addressed before handing medicines to patients.
• Where prescriptions are manually entered into a pharmacy computer system, double check that entry is correct. When filling repeats, refer back to original script rather than computer system to ensure any errors which may occur when entering prescription details into computer software are not perpetuated.
• Be wary of needing to order stock to fill a script for high risk medicines; as this may indicate that a prescribing error has occurred.
• Have a system for recording “near miss” events, as these can identify sources of error.

A Methotrexate Patient Guide is available from: www.saferx.co.nz/methotrexate-patient-guide.pdf

Table 1: Recommended monitoring for patients taking methotrexate, adapted from Chakravarty et al, 2008¹⁴