Omeprazole and Methotrexate: Interaction Details
AI-assisted, pharmacist-reviewed · Source data updated Aug 8, 2026 · Sources: FDA labeling, DDInter 2.0, cited literature
Methotrexate
Omeprazole
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 and an increased risk of methotrexate toxicity
Interaction Deep Dive
Case reports, population pharmacokinetic studies, and a retrospective cohort study, suggest that concomitant use of methotrexate (primarily high doses) and proton pump inhibitors (pantoprazole, omeprazole, or esomeprazole) may result in delayed elimination of methotrexate and increased methotrexate and/or hydroxymethotrexate concentrations with potential for methotrexate toxicity123. Although no pharmacokinetic studies have been performed with methotrexate and ranitidine, in 2 case reports delayed elimination of methotrexate was not observed when ranitidine was coadministered with methotrexate 1. A temporary withdrawal of omeprazole may be considered in some patients receiving high-dose methotrexate 4.
Why it happens (mechanism)
Inhibition of H+, K+-ATPase in the kidney by omeprazole blocks the active secretion of methotrexate
Literature reports
2 reports — 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.
b) A 41-year-old male received methotrexate 12 gm/m(2) for osteosarcoma, followed by leucovorin rescue. However, his methotrexate level remained elevated for several days but he experienced no manifestation of toxicity. Omeprazole (20 mg at bedtime) was discontinued, and the patient's methotrexate level rapidly declined. Three more cycles of methotrexate were administered, all with normal methotrexate clearance. Methotrexate is actively secreted in the distal nephron by the hydrogen-ion-dependent mechanism and eliminated by renal tubular excretion and glomerular filtration. Omeprazole has been reported to inhibit the hydrogen-ion transport system in the kidney in animal models. The authors postulated that omeprazole inhibited the H+, K+-ATPase in this patient, blocking the active secretion of methotrexate by the kidney and resulting in increased methotrexate levels 3.
Common questions
Can I take Omeprazole and Methotrexate together?
Increased methotrexate exposure and an increased risk of methotrexate toxicity Always confirm with your pharmacist or prescriber before making any change.
How serious is the Omeprazole 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 "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.
From our Q&A
Real reader questions about these medications, each personally answered by our pharmacist:
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- Is Sea Moss Safe To Take With Omeprazole?
- Interaction Question: Omeprazole, Spironolactone And Phentermine
- How To Dose Omeprazole And Sucralfate Together
Questions for your pharmacist
- Does my dose of Omeprazole 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 (4)
- 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.
- Reid T, Yuen A, Catolico M, et al: Impact of omeprazole on the plasma clearance of methotrexate. Cancer Chemother Pharmacol 1993; 33:82-84. PubMed
- Product Information: KONVOMEP(TM) powder for oral suspension, omeprazole sodium bicarbonate powder for oral suspension. Azurity Pharmaceuticals Inc (per manufacturer), Woburn, MA, 2022. DailyMed
Keep reading about Methotrexate
Keep reading about Omeprazole
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.
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