Even Low-Dose Methotrexate Can Cause Harm or Death If Taken Daily or With Certain Other Medicines

Published November 4, 2024

Methotrexate is a medicine used to treat certain types of cancer. Doctors also prescribe methotrexate to treat other conditions such as severe rheumatoid arthritis and psoriasis (a skin condition). However, the dose and frequency of taking the medicine are different based on the condition being treated. For example, when used to treat cancer, methotrexate is often taken daily for 5 days or more at a higher dose. When used to treat rheumatoid arthritis or psoriasis, methotrexate is usually taken just once or twice a week at a lower dose. People often begin by taking a single 7.5 mg tablet once a week, or three 2.5 mg tablets per week, each taken 12 hours apart. The doctor may increase the weekly dose up to about 25 mg if needed. But if you take methotrexate every day by accident, you could be harmed. There are reports of this type of error probably because most people are more familiar with taking medicines every day rather than once a week. Some of these errors have even resulted in death.

Since early 1996, harmful or fatal errors with low-dose oral methotrexate have been reported to the Institute for Safe Medication Practices (ISMP). One example of an event involved an elderly woman with rheumatoid arthritis. Her doctor had prescribed 15 mg of methotrexate once every week. The pharmacy provided the woman with a 3-month supply of the medicine. Unfortunately, the directions on the prescription bottle were wrong. The label instructed the woman to take 15 mg daily instead of weekly. The woman took the medicine daily until the 3-month supply was finished. The error was discovered when the woman tried to refill the prescription just 3weeks after first filling it. She developed severe toxic effects and had to be treated in the hospital for several weeks.

Serious harm or death can also happen when taking methotrexate along with some other medicines. Examples include prescription and over-the-counter (OTC) pain medicines called nonsteroidal anti-inflammatory drugs (NSAIDs), such as Motrin or Advil (ibuprofen); medicines used to treat stomach acid associated with gastric reflux or stomach ulcers; and certain antibiotics. A serious reaction can occur because these medicines increase the toxic effects of methotrexate. When one medicine affects another medicine, it is called a drug-drug interaction. Two fatal events caused by drug-drug interactions with low-dose methotrexate were reported.

In the first case, an elderly man with kidney disease doubled his weekly methotrexate dose from 10 mg to 20 mg without his doctor’s approval because his rheumatoid arthritis symptoms were getting worse. The man was also taking the antibiotic amoxicillin to treat an infection. The next day, his doctor also gave him a prescription for leflunomide, another medicine to treat rheumatoid arthritis. Within a week, the man was hospitalized with a very low blood count. Despite all efforts to treat him, the man died. His kidney disease, doubling of the methotrexate dose without his doctor’s knowledge, and the drug interactions from taking amoxicillin and leflunomide together with methotrexate all contributed to his death.

In the other case, an elderly man with rheumatoid arthritis was hospitalized with a fractured leg caused by a fall. While in the hospital, his weekly dose of methotrexate 20 mg was continued. He was also receiving the pain medicine, diclofenac, as needed every 6 hours. Diclofenac is an NSAID, much like Advil and Motrin but only available with a prescription. The man’s doctor, pharmacists, and nurses failed to address the potentially serious drug-drug interaction that occurs when taking diclofenac and methotrexate together. The man developed kidney failure and extremely low blood counts, and died.

Even when low-dose methotrexate is taken correctly, severe side effects can occur that can lead to hospitalization or death. Methotrexate primarily affects the blood cell counts causing them to become low. If blood cell counts are not regularly checked, people can quickly become very sick and possibly die. Some of the more common side effects include nausea, vomiting, and diarrhea. The medicine can also cause stomach, kidney, liver, brain, and spinal cord problems. Because the kidneys and liver help eliminate methotrexate from the body, kidney or liver problems may increase the risk of developing serious side effects even when taking low-dose methotrexate. But when methotrexate is taken daily or with certain medicines that cause serious drug interactions, these life-threatening side effects may become difficult or impossible to treat.

‍Here’s what you can do: To avoid mistakes or serious drug-drug interactions with oral methotrexate, consider the following:

When receiving a prescription

• Ask your doctor to put the reason for your medicine on all prescriptions. You might take a medicine like methotrexate daily if you have cancer, but weekly if you have arthritis. If the pharmacist knows your condition, they will make sure the directions for taking your medicine are correct. Since 2020, the US Food and Drug Administration (FDA) recommends single weekly doses of methotrexate for non-cancer conditions. Therefore, your doctor should instruct you to take the weekly dose at one time (e.g., every Tuesday at8:00 am).
• Provide your doctor with a list of all the medicines you currently take. Be sure to include medicines and supplements that you purchase OTC (without a prescription).
• Never leave the doctor’s office unless you clearly understand how to take your medicine.
• Ask your doctor about a follow up monitoring plan for you that specifies a clear schedule of tests that you will need before and while taking methotrexate.

When dropping off a prescription

• Pick the day(s) of the week that you will be taking your medicine, and ask your pharmacist to include that in the instructions. Avoid Monday, it could be misread as “morning."
• Ask for large print on the prescription label if you have poor eyesight.
• Provide your pharmacist with a list of all the medicines you take. Be sure to include medicines and supplements that you purchase OTC (without a prescription).
• If insurance permits, fill prescriptions with just a 4-week supply, not a 3-monthsupply.

When picking up your prescription

• Ask the pharmacist to go over the directions for taking the medicine. Be sure it agrees with what the doctor told you.
• Repeat back the instructions to the pharmacist so they can be sure you understand when to take the medicine and the harm that can be caused by taking the medicine more often than you should.
• Read the information leaflet that comes with the medicine when you get home, before taking the medicine.

When taking your medicine

• Never take any extra doses of methotrexate. It is not a medicine that can be used “as needed” for symptom control.
• Know your monitoring plan and never skip appointments for laboratory and X-ray tests. Some of these tests may be frequent (e.g., every 2-4 weeks) at first, but may be less frequent over time.
• Be alert to any signs of serious side effects and report them to your doctor right away. Such side effects might include fever, sore throat, mouth ulcers, abdominal pain, jaundice (yellowing of the skin or eyes), new or increased shortness of breath, chest pain, dry cough, diarrhea, nausea, or vomiting. Toxicity from methotrexate can progress rapidly and may not be fully reversible; it can potentially be fatal.
• Ask your doctor before taking OTC or prescription NSAIDs (e.g., Motrin, Advil, or generic ibuprofen). Many times, these other medicines can be safely taken with methotrexate. However, it is important to check blood cell counts, and liver and kidney function.
• Ask your doctor before receiving immunizations (live vaccines may need to be avoided).
• Let your doctor know if you must take an antibiotic to treat an infection.
• Let your doctor know if you have an active infection, a decrease in appetite, or have been in contact with someone who has chicken pox or shingles infection.
• Do not drink alcohol while taking methotrexate.
• If you realize you have been taking too much of the medicine, seek immediate medical attention.
• For more information, read the free ISMP information leaflet on oral methotrexate.

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