July 20, 2015: What are the main points regarding oral methotrexate overdose?

Uses: Methotrexate is an antimetabolite used to treat various cancers, rheumatoid arthritis, psoriasis and other conditions.  The most common situation we deal with at the poison center involving methotrexate is oral overdose (both inadvertent and intentional).


Toxicity: Methotrexate is a folic acid antagonist.  It inhibits DNA synthesis, repair and cell replication.


Kinetics: Methotrexate is well absorbed orally at low doses (less than 30 mg/m2), but can be incomplete after large doses.  Time to peak with oral therapeutic doses is 1 to 2 hours. In overdose, half-life can be prolonged.  Renal failure and hepatotoxicity can delay the  metabolism and elimination of methotrexate.




GI: Nausea, vomiting, diarrhea, stomatitis, hemorrhage.


Hematologic: Leukopenia, thrombocytopenia, pancytopenia, bone marrow suppression. Hematologic effects can be delayed up to approximately 9 days after exposure.


Renal: Renal failure, nephropathy, cystitis.


Hepatic: Acute elevation of liver enzymes.




Charcoal: If the patient presents within an hour or two after ingestion, and is not symptomatic, single dose activated charcoal (aqueous) can be given.


Leucovorin: Supplies the tetrahydrofolate co-factor.  Doses equal to or greater than the ingested dose of methotrexate are given. 100 mg/m2 (IV) over 15 to 30 minutes is the typical loading   dose given.  This is followed by 10 mg/m2 (IV) every 6 hours for approximately 3 days (until the serum methotrexate level is less than 0.01mcmol/L).


Glucarpidase: not commonly used, but is indicated for the treatment of toxic concentrations greater than 1 mcmol/L, in patients with impaired renal function.  It has been used to reduce blood levels and concentrations in CSF after intrathecal overdose.  Glucarpidase catabolizes methotrexate to an inactive metabolite.  Leucovorin should not be given within 2 hours before or after a dose of glucarpidase.  Glucarpidase is available in the USA from ASD Healthcare as VORAXAZE ® via a 24 hour phone number.




Monitor serum methotrexate levels daily.  CBC with differential and platelets, BUN, creatinine, LFT’s, electrolytes.


This is a brief overview of the main points of oral methotrexate overdose.  As always, consultation with one of our toxicologists is available 24/7.



Poisoning & Drug Overdose, 6th ed., Kent R. Olson, ed.



This question prepared by:  Scott Muir, RN, CSPI (Certified Specialist in Poison Information) Tennessee Poison Center


The Tennessee Poison Center receives about 2 calls/month regarding significant methotrexate exposure/potential toxicity.  Clinically there seems to be quite a difference between acute methotrexate overdose and chronic methotrexate therapy which results in high methotrexate concentrations.  An Australian group recently presented  a number of acute methotrexate overdoses that didn’t present to the hospital for 1-2 days.  (long ways from the outback to the hospital) They all did fine.  Not so for the more chronic exposure to methotrexate./ ds


I am interested in any questions you would like answered in the Question of the Week.  Please email me with any suggestion at donna.seger@vanderbilt.edu



Donna Seger, MD

Medical Director

Tennessee Poison Center


Poison Help Hotline: 1-800-222-1222