Drug interactions
Methotrexate + Trimethoprim
Severity: Major
Methotrexate and Trimethoprim: major interaction.
Last updated Sources: US FDA label, NCBI (US National Library of Medicine)
For healthcare professionals — reference only. This page is a brief summary, not medical advice and not a substitute for official labeling or clinical judgement. Always verify before prescribing or dispensing.
Summary
Trimethoprim given with methotrexate can cause severe, sometimes fatal, bone marrow suppression with pancytopenia and megaloblastic changes. The risk is greatest with higher methotrexate doses, renal impairment and prolonged use.
What this interaction means in plain words
Methotrexate and Trimethoprim can interact in a way that may be serious. Using them together is sometimes necessary, but it needs a deliberate decision by the prescriber, a plan for monitoring, and clear advice on the warning signs to watch for.
Methotrexate belongs to Oncology; Trimethoprim belongs to Anti Bacterial.
Why it happens
Both drugs inhibit dihydrofolate reductase (additive antifolate effect), and trimethoprim may also reduce renal tubular secretion of methotrexate.
What to do
Avoid the combination where possible, especially with trimethoprim-sulfamethoxazole in patients on methotrexate. If unavoidable, monitor complete blood counts and renal function closely and consider folinic acid rescue.
What to ask your pharmacist
- Does the benefit of taking both outweigh the risk in my case?
- Do I need any blood test, ECG or other check while on both?
- What early warning signs should I watch for, and what should I do if they appear?
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References
- Bactrim / Bactrim DS (sulfamethoxazole and trimethoprim) tablets Prescribing Information - Drug Interactions: Methotrexate ("Avoid concurrent use"; protein-binding displacement and competition for renal transport raise free methotrexate) — FDA Label (DailyMed)
- Xatmep (methotrexate) oral solution Prescribing Information - 7 Drug Interactions (trimethoprim/sulfamethoxazole reported to increase bone marrow suppression with methotrexate) — FDA Label (DailyMed)
- Bourre-Tessier J, Haraoui B. Methotrexate drug interactions in the treatment of rheumatoid arthritis: a systematic review. J Rheumatol 2010;37:1416-21 (TMP-SMX: cytopenia risk in 1 observational study and 17 case reports) — PubMed
- Al-Quteimat OM, Al-Badaineh MA. Methotrexate and trimethoprim-sulphamethoxazole: extremely serious and life-threatening combination. J Clin Pharm Ther 2013;38:203-5 — PubMed
- Groenendal H, Rampen FH. Methotrexate and trimethoprim-sulphamethoxazole - a potentially hazardous combination (fatal pancytopenia). Clin Exp Dermatol 1990;15:358-60 — PubMed
- Pancytopenia from using trimethoprim and methotrexate (case report, trimethoprim alone). Ann Intern Med 1992;117:877 — PubMed
Other interactions of Methotrexate
- Acitretin + Methotrexate Contraindicated
- Adenovirus types 4 and 7 live + Methotrexate Contraindicated
- Influenza virus vaccine quadrivalent intranasal + Methotrexate Contraindicated
- Ketorolac + Methotrexate Contraindicated
- Measles mumps and rubella vaccine live + Methotrexate Contraindicated
- Measles mumps and rubella vaccine + Methotrexate Contraindicated
Other interactions of Trimethoprim
Frequently asked questions
Can I take Methotrexate with Trimethoprim?
MediHelp rates the interaction as major. Methotrexate and Trimethoprim can interact in a way that may be serious. Using them together is sometimes necessary, but it needs a deliberate decision by the prescriber, a plan for monitoring, and clear advice on the warning signs to watch for. Trimethoprim given with methotrexate can cause severe, sometimes fatal, bone marrow suppression with pancytopenia and megaloblastic changes. The risk is greatest with higher methotrexate doses, renal impairment and prolonged use.
How serious is the interaction between Methotrexate and Trimethoprim?
MediHelp rates it major, on a four-level scale (minor, moderate, major, contraindicated) based on published labels and references. What to do, in brief: Avoid the combination where possible, especially with trimethoprim-sulfamethoxazole in patients on methotrexate. If unavoidable, monitor complete blood counts and renal function closely and consider folinic acid rescue.
What other medicines interact with Methotrexate?
MediHelp also lists interactions of Methotrexate with, for example, Acitretin, Adenovirus types 4 and 7 live, Influenza virus vaccine quadrivalent intranasal. The full list is on the Methotrexate page.
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