Oral Methotrexate Overdose Prevention

An important message from our partner Minnesota Regional Poison Center

Oral Methotrexate Overdose Prevention

Kara S. Graves, PharmD

Methotrexate was first approved for oral use in the United States in 1953.[1] Over time, it became a treatment for multiple inflammatory and oncologic treatments due to its toxicity against rapidly dividing cells.[2] It acts as a folate antimetabolite that inhibits DNA synthesis, repair, and cellular replication by inhibiting dihydrofolate reductase, thus halting purine and thymidylic acid synthesis. Due to its indiscriminate effects and potential for long-term toxicities, it has fallen out of favor as a first line treatment for conditions where newer, more targeted options have emerged. Uniquely, oral doses are generally intended to be taken once weekly, and multiple tablets are often needed to obtain the intended dose. Patients are put at risk of significant toxicity when they mistake their weekly dose as a daily dose. 

Methotrexate absorption decreases as doses increase.[3] With oral doses less than 30 mg/m2, 90% is absorbed, but at doses exceeding 80 mg/m2, less than 20% is absorbed. Consequently, if a patient ingested a large quantity of their oral methotrexate at one time, absorption would be restricted, and the patient may not experience toxicity. Therapeutic doses that are repeated daily rather than weekly, however, are more concerning as a much higher dose of methotrexate will be absorbed into the body. 

Typically, the first symptoms to manifest involve the gastrointestinal tract and nervous system.[4] Symptoms may be delayed by several days as it takes time for different cell types to undergo restricted replication, allowing multiple doses of methotrexate to build up before a patient notices toxicity. Gastrointestinal effects can include ulceration, nausea, vomiting, diarrhea, hemorrhage, glossitis, and gingivitis. Neurologic effects can include headache, drowsiness, seizure, speech impairment, cognitive dysfunction, and encephalopathy. Pancytopenia may occur and is generally delayed by 1-2 weeks. Mild hepatitis and renal failure may also occur. 

With oncologic intravenous methotrexate treatment, higher doses are prescribed, but leucovorin is given as a cellular rescue with each cycle.5 Leucovorin is a reduced form of folic acid, bypassing the methotrexate blockade, and providing cells with the cofactor they need to replicate and repair DNA. Depending on the nature of the overdose, leucovorin and hemodialysis may be indicated for treatment, along with urinary alkalinization to minimize the risk of renal failure.[4-5] 

While treatments for an overdose are important, focused attention on counseling prior to oral methotrexate initiation can prevent a mistaken overdose scenario altogether. Some potential counseling strategies include:

• Emphasize the weekly, rather than daily frequency when speaking with patients. Choose a day of the week together that the patient will take methotrexate
• Explain how many tablets will make up each weekly dose
• Prescribe 1 or 2 doses per fill (1 – 2 week supply) when the patient is starting methotrexate 
• If patients ask for an early refill after a couple days, this will likely be flagged by the filling pharmacy, starting a conversation while there is a lower risk of toxicity than if the patient had access to more doses. 
• Counsel patients to store methotrexate separately from other daily oral medications to avoid the opposite medication error, where patients take multiple tablets of another medication by mistaking the bottle for methotrexate
• Incorporate the teach-back method and have the patient explain how they will take their methotrexate before starting their first dose.

If there are any questions, concerns, or the possibility of a methotrexate overdose, call the Poison Center at 1-800-222-1222 for further information and guidance. 

1. Methotrexate Tablets [prescribing information]. U.S. Food and Drug Administration. Updated August 2020. Accessed September 18, 2025. See URL
2. Lexi-Drugs: Methotrexate. Lexicomp Online. Updated September 19, 2025. Accessed September 18, 2025. See URL
3. Wang RY. Chemotherapeutics: Methotrexate. In: Hoffman RS, Howland M, Lewin NA, Nelson LS, Goldfrank LR. eds. Goldfrank's Toxicologic Emergencies, 11. McGraw-Hill Education; 2015. See URL
4. Methotrexate. IBM Micromedex. Updated June 17, 2025. Accessed September 25, 2025. See URL
5. Howard SC, McCormick J, Pui CH, Buddington RK, Harvey RD. Preventing and managing toxicities of high-dose methotrexate. Oncologist. 2016;21(12):1471-1482. doi:10.1634/theoncologist.2015-0164