Beware of Erroneous Daily Oral Methotrexate Dosing!

FEBRUARY 01, 2005
Kate Kelly, PharmD, and Allen J. Vaida, PharmD, FASHP

Low-dose methotrexate therapy can be used to treat rheumatoid arthritis, asthma, psoriasis, and other inflammatory diseases. When the drug is used for these conditions, the dose is administered weekly or twice a week. Unfortunately, it is not uncommon for the Institute for Safe Medication Practices (ISMP) to receive reports of oral methotrexate overdoses, and even fatalities, due to accidental daily instead of weekly dosing.

In one case, a physician decided to add methotrexate 10 mg weekly to a psoriasis patient's daily prednisone regimen. Methotrexate 2.5 mg tablets were prescribed with instructions to "take 2 tablets on Monday morning and 2 tablets Monday at bedtime."For some reason, the pharmacy label was unclear to the patient. Because her doctor described the methotrexate as "supplemental therapy to her prednisone," the patient assumed that it was to be taken every day with her prednisone. She took 4 tablets (10 mg) daily for 1 week before being admitted to the hospital due to intolerable nausea, vomiting, and diarrhea.

Another report described a patient who was to receive 15 mg of methotrexate weekly. The prescription was written for the 2.5 mg tablets with instructions to take 3 tablets every 12 hours. Unfortunately, the physician mistakenly omitted "once weekly"on the prescription. The pharmacist who processed and dispensed the prescription spoke to the patient and told him that it seemed like a high dose for the conditions for which he was being treated. Nonetheless, the pharmacist reinforced the physician's incorrect directions. After 6 days of treatment, the patient was admitted to the hospital with rectal bleeding, mouth sores, and myalgias.

In yet another report, a patient picked up a refill of what was intended to be a 90-day supply of metoclopramide 5 mg with instructions to take 1/2 tablet (2.5 mg) 4 times daily. The vial, however, contained 360 tablets of methotrexate 2.5 mg instead. The patient did not question the change in tablet appearance. She took the medication as prescribed for several days before she developed internal and external hemorrhaging, which led to a lengthy hospitalization and numerous blood transfusions.

Methotrexate is considered a high-alert medication—a drug that bears a heightened risk of causing significant patient harm when it is used in error. For this reason, extra precautions should be taken when prescribing, dispensing, or administering methotrexate. Clearly, these reports stress the underlying need for health care practitioners to improve patient education efforts. ISMP recommends the following safeguards to reduce the risk of an error when oral methotrexate is prescribed:

  • Encourage prescribers to include a specific clinical indication (eg, rheumatoid arthritis, psoriasis) within the prescription directions. Methotrexate can be prescribed daily (generally for several days to several weeks) in some chemotherapy regimens when patients are properly monitored. It would be useful to have a dosing guide readily available wherever the drug is stored.
  • Build alerts into pharmacy computers to remind pharmacists to assess the indication and dosing frequency whenever oral methotrexate is entered. Configure the system to avoid defaulting to a daily dosing schedule.
  • Have pharmacists conduct a prospective drug utilization review before dispensing oral methotrexate. If the indication is not included, community pharmacists should speak directly with the prescriber to determine the reason for the use of methotrexate, verify the proper dosing schedule, and recommend appropriate monitoring of the patient.
  • Consider adding a label to the shelf where methotrexate is stored that reads, "METHOTREXATE is almost ALWAYS a WEEKLY dose—If the prescription reads DAILY, DOUBLECHECK!"
  • Due to the toxicity of methotrexate, limit the quantity of medication dispensed to a 1-month supply, whenever possible.
  • Dispense the drug as a dose pack (eg, Rheumatrex from Stada Pharmaceuticals), which helps reinforce the weekly dosing schedule.
  • Prepare instructions in large type size to assist elderly patients with poor eyesight.
  • Ensure that written drug information leaflets are given to patients and that they contain clear advice about the weekly dosing schedule, not a daily dosing schedule. Provide patients with clear verbal and written instructions on the prescription label that specify a particular day of the week for taking the tablet(s). Avoid choosing Monday because it could be misread as "morning."
  • Establish a system to ensure that patients receive counseling when picking up new and refilled prescriptions for methotrexate (eg, mark the bag with a red flag to alert the clerical staff that counseling is required, not optional).
  • Explain to patients or caregivers that taking extra doses is dangerous and that the medication should not be used "as needed" for symptom control. Explain what to do if a dose is missed, or advise patients to contact their physician if they miss a dose.
  • Solicit help from a responsible caregiver if the patient appears to have cognitive or sensory difficulties.
  • As a final quality control check, pharmacists should always review the drug regimen, the frequency of administration, and the tablet appearance with patients or caregivers. Have them repeat the instructions to ensure that they understand the weekly dosing schedule.

Drs. Kelly and Vaida are both with the Institute for Safe Medication Practices (ISMP). Dr. Kelly is the editor of ISMP Medication Safety Alert! Community/ Ambulatory Care Edition, and Dr. Vaida is the executive director of ISMP.

Report Medication Errors

The reports described here were received through the USP Medication Errors Reporting Program, which is presented in cooperation with the Institute for Safe Medication Practices (ISMP). ISMP is a nonprofit organization whose mission is to understand the causes of medication errors and to provide time-critical error-reduction strategies to the health care community, policy makers, and the public. Throughout this series, the underlying system causes of medication errors will be presented to help readers identify system changes that can strengthen the safety of their operation.

If you have encountered medication errors and would like to report them, you may call ISMP at 800-324-5723 (800-FAILSAFE) or USP at 800-233-7767 (800-23-ERROR). ISMP's Web address is

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The ISMP Medication Safety Alert! Community/Ambulatory Care Edition is a monthly compilation of medication-related incidents, error-prevention recommendations, news, and editorial content designed to inform and alert community pharmacy practitioners to potentially hazardous situations that may affect patient safety. Individual subscription prices are $45 per year for 12 monthly issues. Discounts are available for organizations with multiple pharmacy sites. This newsletter is delivered electronically. For more information, contact ISMP at 215-947-7797, or send an e-mail message to