1. Shastay, Ann MSN, RN, AOCN

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Methotrexate, a folic acid antagonist, was originally approved to treat a variety of cancers. When used for oncologic indications, methotrexate is administered in cyclical frequencies and doses based on body surface area and the type of cancer. Methotrexate is rarely administered on a daily basis for more than 5 consecutive days, even when treating aggressive cancers. The labeled indications for methotrexate later expanded to include the treatment of nononcologic conditions (e.g., rheumatoid arthritis, psoriasis). For most nononcologic indications, a low dose of methotrexate is typically administered just once or twice weekly.


Relatively few medications are dosed weekly, so accidental daily dosing of oral methotrexate frequently occurs, resulting in methotrexate overdoses that lead to vomiting, mouth sores, stomatitis, serious skin lesions, liver failure, renal failure, severe myelosuppression, gastrointestinal bleeding, life-threatening pulmonary symptoms, and, in some cases, death.


Since 1996, harmful or fatal errors with incorrect daily dosing of oral methotrexate for nononcologic use have been reported to ISMP and published in more than 60 of our ISMP Medication Safety Alert! newsletters. Thus, oral methotrexate for nononcologic use has been included on the ISMP List of High-Alert Medications ( since the inception of the list in 2003. Although the risk of errors with oral methotrexate for nononcologic use has been known for a long time, harmful and fatal errors are still occurring today.


Medication Reconciliation and Transitions-of-Care Error

One event in which an incorrect entry for daily methotrexate on a patient's home medication list was caught during hospitalization but continued upon discharge when it was not corrected. A man with rheumatoid arthritis was admitted to a hospital with renal failure. At home, he took oral methotrexate 2.5 mg twice weekly (Monday and Wednesday). The admitting nurse began creating a list of the patient's home medications. The admitting physician noticed that methotrexate was missing from the home medication list in the patient's electronic health record and added it. However, he mistakenly documented 2.5 mg of oral methotrexate twice daily instead of twice weekly. He then made this an active order during the patient's hospitalization. Fortunately, an oncology pharmacist identified the error and corrected the order from twice daily to twice weekly. However, he did not correct the methotrexate entry on the patient's home medication list.


The patient received the correct dose before being transferred to a skilled nursing facility (SNF). Upon discharge, the physician included the erroneous methotrexate home medication entry on the list of medications to continue upon discharge, thus prescribing oral methotrexate 2.5 mg twice daily instead of twice weekly. The patient received twice daily methotrexate at the SNF for more than a week before he was rehospitalized with altered mental status, severe neutropenia, and mucositis. Sadly, he died in the hospital about a week later.


Misunderstood Instructions

Another error involved a correctly filled outpatient prescription for weekly methotrexate with an escalating dose change 2 weeks later. The patient misunderstood the instructions and took the medication daily. An 8-week supply of 2.5 mg tablets (30 tablets) had been dispensed with the following label instructions, "Take 3 tablets by mouth 1 day for 2 weeks then increase to 4 tablets by mouth 1 day per week thereafter." Despite counseling, the patient was confused by the label instructions and took 3 tablets (7.5 mg) daily for 5 days before serious symptoms led his physician to identify the error.


Look-Alike, Sound-Alike Drug Names

A mix-up involved the accidental selection of methotrexate instead of the diuretic metOLazone. Both drug names start with "m-e-t" and have overlapping tablet strengths of 2.5, 5, and 10 mg. In this case, a pharmacy technician entered a telephone prescription for oral metOLazone 2.5 mg daily, but accidentally chose methotrexate 2.5 mg daily from the drop-down menu on the screen. The computer system did not flag the methotrexate order to require verification of an appropriate oncologic indication because the dosing frequency was daily. The medication was dispensed without the pharmacist noticing the error. The patient's husband picked up the medication and was asked if he had any questions. When he had no questions, counseling was not provided. The patient took methotrexate 2.5 mg daily as directed on the label and died less than a month later.


Look-Alike Methotrexate and Folic Acid Tablets

Folic acid is sometimes prescribed with oral methotrexate to prevent folate deficiency and side effects such as mouth sores, abdominal pain, liver toxicity, hair loss, and anemia. Unfortunately, methotrexate and folic acid tablets are often similar in appearance. A patient confused daily folic acid tablets with his weekly methotrexate tablets. Both were small, yellow, and round. The patient took the methotrexate tablets 6 days a week, and then 4 folic acid tablets on the seventh day, instead of taking the folic acid tablets for 6 days and 4 methotrexate tablets on the seventh day. The patient was hospitalized with serious thrombocytopenia but survived.



Most of the wrong frequency and wrong drug errors with methotrexate could be prevented by fully implementing the Targeted Medication Safety Best Practice for Hospitals associated with methotrexate and other related risk-reduction strategies found in the ISMP Medication Safety Self Assessment(R) for High-Alert Medications.


Clarify Prescribing


* Clarify all prescriptions for oral methotrexate with "take as directed" instructions to promote clear instructions for weekly dosing.


* Be sure the number of tablets to be dispensed with a prescription for oral methotrexate is limited to a 4-week (30-day) supply; if not, contact the prescriber.


* Review all discharge orders and prescriptions for oral methotrexate to verify the dose and frequency based on the patient's diagnosis.


Patient Education


* Provide patients with a copy of the free ISMP high-alert medication consumer leaflet on oral methotrexate (found at:


* Advise patients to choose a day of the week they will take their oral methotrexate and to ask their pharmacist to include that in the instructions on the label. Remind patients to avoid "Monday," which has been misread as "Morning." This mistake has led patients to take a dose each "Morning" instead of each "Monday."


* Provide the patient with a visual calendar to clarify the weekly dosing schedule.


* Advise patients that, if available and covered by their insurance, they should ask their pharmacy to dispense oral methotrexate in a dose pack that guides them to take the proper dose weekly.


* If folic acid is prescribed along with methotrexate, educate patients about the differences between the medications, their respective administration schedules, and how to avoid mix-ups between the two tablets (e.g., keeping the methotrexate tablets in the original prescription bottle when using weekly pill organizers for daily medications).


* Educate patients about the key symptoms of methotrexate toxicity and to whom to report the symptoms.


Patient Monitoring


* If a methotrexate dosing error is discovered, ensure the patient receives immediate medical attention.