Methotrexate Injection and Sulfisoxazole: Interaction Details
AI-assisted, pharmacist-reviewed · Source data updated Aug 8, 2026 · Sources: FDA labeling, DDInter 2.0, cited literature
Methotrexate Injection
Sulfisoxazole
No brand names on record
How we grade severity & evidence
Severity levels
- Contraindicated: These should generally not be used together.
- Major: Potentially serious — often needs a change or close monitoring.
- Moderate: Can be significant — usually manageable with monitoring.
- Minor: Usually limited clinical impact.
Evidence grades
- Established: Well documented — supported by controlled studies or strong clinical data.
- Probable: Good supporting evidence, though not definitively proven.
- Suspected: Some evidence suggests this interaction, but it is not well established.
- Possible: Limited or conflicting evidence; the interaction may occur.
- Theoretical: Predicted from the drugs' pharmacology; not yet confirmed in people.
Ratings come from the documented interaction literature and are reviewed by a pharmacist. They describe the documented risk of the combination, not what will necessarily happen to you — your dose, timing, and health picture all matter.
What happens
An increased risk of methotrexate toxicity (myelotoxicity, pancytopenia, megaloblastic anemia)
Interaction Deep Dive
A case report has demonstrated the development of hematologic toxicity in patients on methotrexate following the addition of cotrimoxazole. The antifolate mechanism of action of both these drugs may contribute to the hematologic toxicity. Sulfonamides may displace an active metabolite of methotrexate from its binding site3456.
Why it happens (mechanism)
Synergistic anti-folate effects, protein binding displacement, decreased renal tubular elimination
Literature reports
2 reports — tap to read
a) A 70-year-old woman was taking long-term, low-dose methotrexate for psoriasis 1. After diagnosing acute bronchitis, her general practitioner prescribed trimethoprim-sulfamethoxazole for her. She developed severe pancytopenia with concurrent use of methotrexate and trimethoprim-sulfamethoxazole.
b) A pharmacokinetic study found a 66% increase in systemic exposure to methotrexate when this agent was given concurrently with trimethoprim-sulfamethoxazole. Methotrexate concentrations were measured in nine children with acute lymphoblastic leukemia during methotrexate dosing alone and during coadministration with trimethoprim-sulfamethoxazole. The free methotrexate fraction increased from 37.4% to 52.2% when cotrimoxazole was added to methotrexate therapy, and free methotrexate renal clearance decreased from 12.1 to 5.6 mL/kg/min during multi-drug administration. Serum concentrations of trimethoprim-sulfamethoxazole and the percentage decrease in renal clearance of free methotrexate were closely correlated 2.
Common questions
Can I take Methotrexate Injection and Sulfisoxazole together?
An increased risk of methotrexate toxicity (myelotoxicity, pancytopenia, megaloblastic anemia) Always confirm with your pharmacist or prescriber before making any change.
How serious is the Methotrexate Injection and Sulfisoxazole interaction?
It is rated major. Potentially serious — often needs a change or close monitoring.
How quickly could this interaction happen?
The documented onset is "delayed". Effects tend to build up gradually over days to weeks.
How strong is the evidence for this interaction?
The evidence is graded "probable". Good supporting evidence, though not definitively proven.
Questions for your pharmacist
- Does my dose of Methotrexate Injection or Sulfisoxazole need adjusting while I take them together?
- What symptoms should prompt me to call you or my prescriber right away?
- Does the timing of my doses matter for this combination?
- Is there a safer alternative to one of these medications for me?
References (6)
- Liddle BJ: Methotrexate interactions (letter). Clin Exp Dermatol 1991; 16:311-312. DOI
- Ferrazzini G, Klein J, & Sulh H: Interaction between trimethoprim-sulfamethoxazole and methotrexate in children with leukemia. J Pediatr 1990; 117:823-826. PubMed
- Product Information: Methotrexate LPF(R), methotrexate. Xanodyne Pharmacal, Inc. Florence, KY, 2003. DailyMed
- Thomas MH & Gutterman LA: Methotrexate toxicity in a patient receiving trimethoprim-sulfamethoxazole. J Rheumatol 1986; 13:440-441.
- Frain JB: Methotrexate toxicity in a patient receiving trimethoprim-sulfamethoxazole. J Rheumatol 1987; 14:176-177.
- Slordal L, Sager G, & Aarbakke J: Pharmacokinetic interactions with methotrexate: is 7-hydroxy-methotrexate the culprit (letter)?. Lancet 1988; 1:591-592. PubMed
Keep reading about Methotrexate Injection
These medications also interact with supplements
Prescription drugs aren't the whole picture — herbal and dietary supplements can interact with them too. From the evidence-graded Natural Medicines database:
major · moderate · minor — check everything you take with our drug–supplement interaction checker.
Check another combination
Our instant two-drug interaction checker is almost here.
Still have questions about this combination?
Every question gets a real answer from a licensed pharmacist — free, and usually within a day.
Ask the pharmacist