Aspirin Rectal and Methotrexate: Interaction Details
AI-assisted, pharmacist-reviewed · Source data updated Jul 11, 2026 · Sources: FDA labeling, DDInter 2.0, cited literature
Aspirin Rectal
Methotrexate
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
Increased methotrexate exposure, an increased risk of methotrexate toxicity, reduced active metabolite formation and possibly reduced methotrexate efficacy
Interaction Deep Dive
Coadministration of methotrexate with aspirin (a salicylate and an NSAID) may increase methotrexate exposure, which may increase the risk of methotrexate severe adverse reactions2. Aspirin may enhance the toxicity of methotrexate by displacing it from its plasma protein binding sites and/or reducing its renal clearance 1. In some cases, the coadministration of methotrexate with aspirin may also subsequently reduce active metabolite formation, which may reduce the clinical effectiveness of methotrexate. If coadministration cannot be avoided, monitor closely for methotrexate adverse reactions 2. Concomitant aspirin and methotrexate therapy has been reported to result in increased methotrexate toxicity 34.
Why it happens (mechanism)
Reduced methotrexate absorption; reduced renal clearance of methotrexate; protein binging displacement
Literature reports
3 reports — tap to read
a) Concomitant aspirin and methotrexate therapy has been reported to result in increased methotrexate toxicity 34.
b) The pharmacokinetics of low dose methotrexate were evaluated in 12 rheumatoid arthritis patients in the presence and absence of chronically dosed aspirin or sulindac. The patients all had been receiving methotrexate for at least 1 year and had been on a steady dose for at least 2 months prior to the study. The study was a 3-way crossover design with patients receiving either aspirin 45 to 50 mg/kg/day in 3 doses per day for 16 days, sulindac 200 mg every 12 hours for 16 days, or no nonsteroidal antiinflammatory treatment. On day 14 methotrexate 10 mg/m(2) was administered by intravenous bolus and plasma levels were obtained. No difference in methotrexate clearance was found with any of the 3 treatments. However, the area under the time curve for the active metabolite 7-OH-methotrexate was increased, meaning the body was exposed to the metabolite for a longer period of time with the sulindac treatment and to a greater extent with aspirin treatment. The implications of this metabolite in rheumatoid arthritis treatment are not completely understood, but it is believed to have some cytotoxic activity and to be capable of inducing renal damage. Until the significance of 7-OH-methotrexate's activity and the effect of prolonged exposure to it are known, the use of these nonsteroidal antiinflammatory agents, especially aspirin, should be used with caution in combination with methotrexate 5.
c) A similar study of low-dose intravenous methotrexate (10 mg) and oral aspirin (3900 mg/day) found that the unbound fraction of methotrexate was higher and the systemic and renal clearance of methotrexate were lower with concomitant aspirin than methotrexate alone in 15 rheumatoid arthritis patients. Single-dose methotrexate disposition was evaluated both prior to and following one week of aspirin therapy. Hematologic, renal, and hepatic toxicity was not seen in any of the study patients 6.
Common questions
Can I take Aspirin Rectal and Methotrexate together?
Increased methotrexate exposure, an increased risk of methotrexate toxicity, reduced active metabolite formation and possibly reduced methotrexate efficacy Always confirm with your pharmacist or prescriber before making any change.
How serious is the Aspirin Rectal and Methotrexate interaction?
It is rated major. Potentially serious — often needs a change or close monitoring.
How quickly could this interaction happen?
The documented onset is "rapid". Effects can appear quickly, often within about 24 hours of combining the drugs.
How strong is the evidence for this interaction?
The evidence is graded "probable". Good supporting evidence, though not definitively proven.
From our Q&A
Real reader questions about these medications, each personally answered by our pharmacist:
Questions for your pharmacist
- Does my dose of Aspirin Rectal or Methotrexate 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)
- Product Information: CARISOPRODOL, ASPIRIN, CODEINE PHOSPHATE oral tablets, carisoprodol, aspirin, codeine phosphate oral tablets. Ingenus Pharmaceuticals LLC (per DailyMed), Orlando, FL, 2021. DailyMed
- Product Information: JYLAMVO oral solution, methotrexate oral solution. Shorla Oncology Inc (per FDA), Cambridge, MA, 2024. DailyMed
- Mandel NA: The synergistic effect of salicylates on methotrexate toxicity. Plast Reconstr Surg 1976; 57:733. PubMed
- Baker H: Intermittent high dose oral methotrexate therapy in psoriasis. Br J Dermatol 1970; 82:65. DOI
- Furst DE, Herman RA, Koehnke R, et al: Effect of aspirin and sulindac on methotrexate clearance. J Pharm Sci 1990; 79:782-786. PubMed
- Stewart CF, Fleming RA, Germain BF, et al: Aspirin alters methotrexate disposition in rheumatoid arthritis patients. Arthritis Rheum 1991; 34:1514-1520. DOI
Keep reading about Aspirin Rectal
Keep reading about Methotrexate
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