Methotrexate and Rabeprazole: Interaction Details
AI-assisted, pharmacist-reviewed · Source data updated Aug 8, 2026 · Sources: FDA labeling, DDInter 2.0, cited literature
Methotrexate
Rabeprazole
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 risk of methotrexate toxicity
Interaction Deep Dive
Although not studied specifically with rabeprazole1, concomitant administration of methotrexate and some proton pump inhibitors (pantoprazole, lansoprazole, omeprazole, or esomeprazole) resulted in a 6.7-fold increased risk of delayed methotrexate elimination in a retrospective study of 79 cancer patients. Of cycles with delayed methotrexate elimination, 53.1% had a concomitantly administered proton pump inhibitor. In addition, 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) 3. Use caution when administering high-dose methotrexate to patients receiving proton pump inhibitors 1. During high-dose methotrexate administration, consider temporarily stopping rabeprazole therapy 2. Closely monitor patients for signs and symptoms of methotrexate toxicity.
Why it happens (mechanism)
Decreased renal elimination of methotrexate by rabeprazole
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) 3.
Common questions
Can I take Methotrexate and Rabeprazole together?
Increased risk of methotrexate toxicity Always confirm with your pharmacist or prescriber before making any change.
How serious is the Methotrexate and Rabeprazole 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 "theoretical". Predicted from the drugs' pharmacology; not yet confirmed in people.
From our Q&A
Real reader questions about these medications, each personally answered by our pharmacist:
Questions for your pharmacist
- Does my dose of Methotrexate or Rabeprazole 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.
- Product Information: ACIPHEX(R) oral delayed-release tablets, rabeprazole sodium oral delayed-release tablets. Eisai Inc. (per FDA), Woodcliff Lake, NJ, 2012. DailyMed
- 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.
Keep reading about Methotrexate
Keep reading about Rabeprazole
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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