Esomeprazole and Methotrexate Injection: Interaction Details
AI-assisted, pharmacist-reviewed · Source data updated Aug 8, 2026 · Sources: FDA labeling, DDInter 2.0, cited literature
Methotrexate Injection
Esomeprazole
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 and prolonged plasma concentration of methotrexate and its metabolite
Interaction Deep Dive
Although no formal drug interaction studies have been conducted with methotrexate and proton pump inhibitors (PPIs), case reports, population pharmacokinetic studies, and a retrospective cohort study suggest that concomitant use of methotrexate (primarily high doses) and PPIs such as esomeprazole may result in delayed elimination of methotrexate and increased methotrexate and/or hydroxymethotrexate concentrations with potential for methotrexate toxicity31. A retrospective cohort study (n=79) revealed a 6.7-fold increased risk of delayed methotrexate elimination with concomitant use of a PPI in patients with cancer who received high-dose IV methotrexate 2. Consider a temporary withdrawal of the PPI in high-dose methotrexate therapy 3. and closely monitor methotrexate levels and signs of toxicity in patients receiving concomitant high-dose methotrexate and PPIs.
Why it happens (mechanism)
Decreased renal elimination of methotrexate by esomeprazole
Literature reports
1 report — tap to read
a) A retrospective, non-interventional cohort study (n=79) revealed a 6.7-fold increased risk of delayed methotrexate elimination with concomitant use of a proton pump inhibitor. Patients with various types of cancer (mean age, 48.8 years; range, 16 to 76 years) received cycles of high-dose IV methotrexate (greater than 1 g/m(2)). Cycles with avoidable causes for delayed methotrexate elimination were excluded from analysis. Delayed methotrexate elimination was defined as plasma methotrexate concentrations greater than 15, 1.5, and/or 0.15 mcmol/L at 24, 48, and 72 hours, respectively. Of 197 cycles, delayed methotrexate elimination was noted in 16% (32/197) of cycles. Of the cycles with delayed methotrexate elimination, concomitant use of a proton pump inhibitor (pantoprazole, lansoprazole, omeprazole, or esomeprazole) was significantly greater compared with cycles without delayed methotrexate elimination (53.1% vs 15%; p less than 0.001; odds ratio 6.66; 95% confidence interval, 3.13 to 14.17). Plasma methotrexate concentrations were significantly greater at each time point (24, 48, and 72 hours) in patients with delayed elimination compared with patients without delayed elimination (p less than 0.01) 2.
Common questions
Can I take Esomeprazole and Methotrexate Injection together?
Increased and prolonged plasma concentration of methotrexate and its metabolite Always confirm with your pharmacist or prescriber before making any change.
How serious is the Esomeprazole and Methotrexate Injection interaction?
It is rated major. Potentially serious — often needs a change or close monitoring.
How quickly could this interaction happen?
The documented onset is "unspecified". The timing of this interaction is not well characterized.
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 Esomeprazole or Methotrexate Injection 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 (3)
- Product Information: methotrexate intramuscular intravenous intra-arterial injection, methotrexate intramuscular intravenous intra-arterial injection. Hospira, Inc. (per FDA), Lake Forest, IL, 2011.
- Santucci R, Leveque D, Kemmel V, et al: Severe intoxication with methotrexate possibly associated with concomitant use of proton pump inhibitors. Anticancer Res 2010; 30(3):963-965.
- Product Information: ESOMEPRAZOLE STRONTIUM oral delayed-release capsules, esomeprazole strontium oral delayed-release capsules. Amneal Pharmaceuticals (per FDA), Glasgow, KY, 2013. DailyMed
Keep reading about Methotrexate Injection
Keep reading about Esomeprazole
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