Perils and pitfalls of methotrexate prescription

Methotrexate is a folic acid antagonist which can be used as an antineoplastic drug or as an immuno modulator. While it has a well established role in specialist oncology practice, it is increasingly being used in general medical practice for immuno modulation. Methotrexate is prescribed as a `steroid-sparing' drug for conditions in which glucocorticoids have been used to suppress inflammatory activity. These conditions include rheumatoid arthritis, asthma, psoriasis, inflammatory bowel disease, myasthenia gravis and inflammatory myositis. This list of indications continues to grow.

Methotrexate is used in an attempt to minimise the dose of long-term oral corticosteroids and reduce their adverse effects. However the somewhat atypical dose regimen for low-dose methotrexate has presented some difficulties. The toxic adverse-effect profile of methotrexate is well known. However, the weekly dosage regimen of low-dose therapy (e.g. 7.5-10 mg) has caused confusion and errors for prescribers and patients. The risk of misadventure is increased by the current tablet formulations available.¹

There have been six reports to the Adverse Drug Reactions Advisory Committee (ADRAC) of serious consequences resulting from toxic doses of methotrexate. Three of these patients died from complications of bone marrow suppression. Four of the six people were more than 70 years old and three of them misunderstood clear written instructions about taking the drug weekly, instead of daily. One patient took extra doses to relieve arthritic symptoms. Two of the cases were patients in a hospital and the methotrexate dose was incorrectly charted and/or dispensed daily, instead of weekly.

In elderly patients, other factors can contribute to the adverse outcome. Sensory and cognitive impairment may increase the chance of patient-related errors. In one of the cases cited above, there was clearly a misunderstanding of the mechanism of effect of methotrexate; it is not for symptom relief. The drug is renally cleared and may therefore accumulate in the older patient with reduced renal function.

So what can both the prescriber and `the system' do to reduce the chance of adverse effects due to errors? Common sense measures include the following:

• give clear written instructions that name a specific weekday for taking the tablet²
• prepare instructions in big print to assist people with poor eyesight
• have a clear protocol for monitoring appropriate clinical and blood parameters such as full blood count, liver and renal function tests
• take special care in those with known renal/hepatic impairment
• ensure the patient has a good understanding of how and when to take the drug and the dangers of taking too much
• explain that extra or irregular doses are dangerous
• advise the patient not to take a catch up dose if one dose is missed; the flare-up of disease is unlikely
• make a carer responsible for giving the drug if the patient appears to have cognitive or severe sensory difficulties

Most of these principles are relevant when advocating unusual or atypical regimens. The consequences of incorrect dosage can be fatal but are often preventable.³

Photomicrographs illustrating features of red cell precursors in bone marrow rendered megaloblastic by treatment with methotrexate. Normal red cell precursors on the left (slide 1) are a mixture of larger immature cells, and smaller mature forms with red cytoplasm and very dark small round nuclei. In the bone marrow of the patient affected by methotrexate on the right (slide 2), the red cell precursors are larger, tend to appear immature, and have a characteristically abnormal appearance of the nucleus. Pictures provided by Dr Frank Firkin, St Vincent's Hospital, Melbourne