Pharmacy Matters: Severe Harm and Deaths Associated with Incidents Involving Low-Dose Methotrexate Vol 40 No 6 - Nov 2015 | Nov. 10, 2015 Pharmacy Matters

This article appeared in the Institute for Safe Medication Practices (ISMP) Canada Safety Bulletin on September 30, 2015.

For patients with the autoimmune disease rheumatoid arthritis (RA), oral or parenteral methotrexate is the preferred disease-modifying antirheumatic drug with respect to efficacy and safety, unless it is specifically contraindicated.[1][2] In contrast to dosing for antineoplastic indications, methotrexate for RA is administered once weekly as low-dose therapy.[3] ISMP Canada has received multiple reports of severe harm or death in patients taking methotrexate for RA and other autoimmune diseases. The findings and recommendations from selected recent case reports are shared here to highlight system-based opportunities to improve safety.

Medication Incidents

Incident 1: A patient with renal dysfunction and hypoalbuminemia was experiencing worsening RA symptoms. To address these symptoms, the patient doubled his weekly methotrexate dose from 10mg to 20mg, a change that happened to coincide with the end of a treatment course of amoxicillin for an infection. The next day, the rheumatologist started another disease-modifying antirheumatic drug, leflunomide. Within a week, the patient presented to hospital with pancytopenia, and despite aggressive treatment, he died. The patient’s baseline risk factors for methotrexate toxicity, the intentional doubling of the methotrexate dose by the patient without the prescriber’s knowledge, and drug interactions related to the concomitant use of amoxicillin and leflunomide all contributed to the development of severe toxic effects.

Incident 2: An elderly patient with RA was admitted to hospital for treatment of a fracture caused by a fall. While in hospital, the patient’s weekly dose of methotrexate 20mg was continued and diclofenac was started. The patient developed renal failure (possibly precipitated by diclofenac use) and pancytopenia and subsequently died. It was later determined that the known severe interaction between methotrexate and diclofenac was not addressed when the second drug was initiated, possibly because of the lack of interaction specificity (i.e., presence of numerous alerts including non-critical interactions) when the order was initially entered and there was an incorrect assumption that the patient had been taking diclofenac in the community. The patient died as a result of methotrexate toxicity.

Incident 3: Methotrexate 15mg once weekly was prescribed for treatment of an autoimmune disorder in an elderly patient. The community pharmacy dispensed a 3-month quantity of medication, but gave instructions to take 15mg (6 x 2.5 mg tablets) once daily. The error was discovered during pharmacist counselling when the patient requested a refill 3 weeks later. The error resulted in severe harm, which led to a long hospital stay, including treatment with the antidote folinic acid.

Background

For the treatment of RA, low-dose methotrexate is recommended, typically with doses up to 25mg weekly.[1] Some of the most common toxic effects with a low-dose regimen are gastrointestinal, hematological, and hepatic.[4] Severe adverse effects are more common with the higher doses of methotrexate used for antineoplastic indications. However, hematological toxicity is reported to occur in up to 3% of patients treated with long-term, low-dose methotrexate for RA and other autoimmune disorders[5] and severe adverse events, such as myelosuppression, pulmonary complications, central nervous system toxicity, hepatotoxicity, and mucositis, have led to hospital admissions and even death.[6] RA prescribing guidelines recommend that a complete blood count (CBC) be obtained and liver enzyme and creatinine levels measured before methotrexate is initiated.[1]'[2] In addition, it is recommended that measurement of these parameters be repeated at regular intervals for the duration of therapy[2] and that practitioners address any rapid, unusual changes in these parameters, as well as any consistent upward or downward trends.[7]

Hypoalbuminemia, renal dysfunction, and certain concomitant medications, including nonsteroidal anti-inflammatory drugs and proton pump inhibitors, all increase a patient’s risk of developing toxic effects from methotrexate.[6] Interacting medications are often prescribed with methotrexate and can be used together safely, provided regular monitoring is taking place. To reduce gastrointestinal and hepatic toxic effects, folate supplementation may be recommended for patients who are receiving low-dose methotrexate.[8]

The US Institute for Safe Medication Practices (ISMP) has identified methotrexate as a high-alert medication[9] in the community setting, even when used for non-oncologic purposes such as RA. As with all high-alert medications, there is a heightened risk of significant patient harm when this drug is used in error. ISMP Canada has previously published concerns about inadvertent daily, rather than weekly, administration of methotrexate.[10]’[11] When a dosing error is discovered, it is important that the patient receive immediate medical attention. Although serum levels of methotrexate can be measured, they are not an accurate predictor of either the degree of toxicity or the outcome for the patient, because of the drug’s pharmacokinetic and pharmacodynamic properties.[6]'[12]

Recommendations

The following considerations are suggested to reduce the risk of incidents similar to those described above.

Computer System Administrators

• Design the computer order-entry screen for both pharmacy and physician systems to default to a weekly (rather than daily) dosage schedule for all methotrexate orders.[13]
• Require a hard stop or mandatory entry of clinical indication and duration of treatment when the clinician selects a daily schedule for methotrexate orders.
• Add an alert either at order entry or in the clinical decision support system, to indicate that serious adverse effects, including death, can result from daily administration of the methotrexate¹⁰ especially if the patient has risk factors for toxic effects or is taking concomitant interacting medications. Note that this risk can be mitigated with appropriate monitoring.
• In hospital and electronic medication record (EMR) systems, link methotrexate order entry to laboratory results (e.g., serum creatinine, CBC, liver enzymes), to prompt review of renal function and other monitoring parameters by both pharmacists and prescribers.
• Include a robust drug–drug and drug–disease interaction module for methotrexate, with links to laboratory results where possible, so prescribers and pharmacists can effectively evaluate the potential for toxic effects.
• For computer systems lacking some of the above functionalities, work with the software vendors to implement these safety features.

Prescribers

• Before initiating methotrexate therapy, obtain baseline values for monitoring parameters, including CBC, chest radiograph, and indicators of liver and kidney function, to screen for risk factors; an EMR that prompts for this information is an asset.
• Repeat CBC, liver function (especially albumin level), and serum creatinine every 2-4 weeks for 3 months after initiating methotrexate and every 8-12 weeks thereafter for patients with RA.[2]
• Screen for Hepatitis B and C and, in high-risk patients, test for HIV, as recommended in some guidelines, prior to initiating methotrexate.[1]
• Consider folate supplementation for patients starting methotrexate therapy.
• When prescribing methotrexate for weekly administration, specify a particular day of the week in the directions, to reduce the risk that the patient will receive instructions for daily use. Do not specify Monday as the day to take the weekly dose, since this might be misread as “morning”.
• Limit the prescription quantity to be dispensed to a 4-week (28-day) supply.
• Ask patients about their use of specific prescription and over-the-counter medications that could influence the risk for methotrexate toxicity.

Pharmacists

• Create a forcing function to ensure that every methotrexate prescription is reviewed with the patient or a designate when the prescription is presented.
• Ensure that every patient receives counselling and written information (e.g., the methotrexate information sheet from ISMP[14]). Ideally, pharmacy computer systems should automatically generate this information for all new and refill prescriptions.
• If folate has not been prescribed, follow up with the prescriber to suggest initiation of this supplement.
• Ensure that any drug interaction alerts generated during order entry are communicated to and resolved with the prescriber and/or the patient when indicated.
• Emphasize the need to adhere to the prescribed dose and to obtain all the monitoring tests ordered by the prescriber as scheduled.
• When possible, dispense only 4-week supply of methotrexate at a time.
• Ask the patient or caregivers about the use of specific prescription and over-the-counter medications that can influence methotrexate toxicity.

Conclusion

This bulletin highlights the importance of initial screening for risk factors and ongoing monitoring for methotrexate toxicity, even when this drug is prescribed at low doses. Methotrexate is a high-alert drug, and extra safeguards are needed whenever it is prescribed or dispensed, regardless of the dose or indication for use. Healthcare providers are urged to implement recommended system safeguards recommended for software administrators, prescribers, and pharmacists to improve the safety of low-dose methotrexate therapy.

Acknowledgements

ISMP Canada gratefully acknowledges the following individuals for their expert review of this bulletin

(in alphabetical order): Sally Bell BSc Pharm, Rheumatology Pharmacist, St. Joseph's Health Care, London, ON; James Jin RPh, Community Pharmacist, Pharmacy 101, Cobourg, ON; Susie Jin RPh CDE CPT CGP, Community Pharmacist, Pharmacy 101, Cobourg, ON; Derrick Kwan RPh BScPhm ACPR, Clinician Application Consultant, North York General Hospital, Toronto, ON; Evelyn Sutton MD FRCPC, Professor of Medicine and Medical Education, Division Head, Rheumatology, Director of Nova Scotia Arthritis Centre, Associate Dean UGME, Dalhousie University.