Trimethoprim and Methotrexate Interaction
Drug interaction information between Trimethoprim and Methotrexate.
Trimethoprim and Methotrexate have a documented minor interaction in FDA labeling.
FDA drug labeling documents a minor-severity interaction between Trimethoprim and Methotrexate. This page displays the available source-record category and label text. The category is not an individual risk estimate or medication-combination direction.
How They Interact
Trimethoprim can push methotrexate off the proteins it normally sticks to in the blood and slow down how fast the kidneys remove it. This leads to higher levels of methotrexate in the body.
FDA Label Information
Sulfonamides can also displace methotrexate from plasma protein binding sites and can compete with the renal transport of methotrexate, thus increasing free methotrexate concentrations.
Trimethoprim Also Interacts With
- Theophylline major
- Prenatal Multivitamin moderate
- Spironolactone moderate
- Spironolactone (Acne) moderate
- Metformin minor
Methotrexate Also Interacts With
- Celecoxib moderate
- Diflunisal moderate
- Indomethacin moderate
- Mefenamic Acid moderate
- Meloxicam moderate
Frequently Asked Questions
What SPL severity band is on file for Trimethoprim + Methotrexate?
Compiled FDA labeling labels this pair minor. That is a source-record field, not an individual medication-combination decision.
Which drug in this pair has the larger labeled-interaction portfolio?
Methotrexate has 38 labeled pairs on file vs Trimethoprim's 22. In the minor band specifically: Trimethoprim has 18 (also Metformin, Glipizide, Warfarin, Pioglitazone); Methotrexate has 26 (also Aspirin, Folic Acid, Probenecid, Phenytoin).
What mechanism field is on file for Trimethoprim and Methotrexate?
Trimethoprim can push methotrexate off the proteins it normally sticks to in the blood and slow down how fast the kidneys remove it. This leads to higher levels of methotrexate in the body.
Trimethoprim carries more major-labeled pairs than Methotrexate
SPL source-record counts only. This page's band is minor · classes on file: Trimethoprim (Dihydrofolate Reductase Inhibitor); Methotrexate (Disease-Modifying Antirheumatic Drug (DMARD)).
Trimethoprim has 1 major-labeled pair vs Methotrexate's 0. This page itself is in the minor band, not the major band.
1 major · 3 moderate · 18 minor · 22 total
- Other minor peers for Trimethoprim
- Metformin
- Glipizide
- Warfarin
- Pioglitazone
0 major · 12 moderate · 26 minor · 38 total
- Other minor peers for Methotrexate
- Aspirin
- Folic Acid
- Probenecid
- Phenytoin
Sources: FDA Drug Labels (SPL) via openFDA (2026). This is for informational purposes only and is not medical advice. This registry does not provide individual medication-combination directions.
Read our methodology - how this data is sourced, computed, and verified.