Published: 6 September 2013


Interaction: Methotrexate and Proton Pump Inhibitors

Prescriber Update 34(3):33
September 2013

Key Messages

  • Concomitant use of high-dose methotrexate and Proton Pump Inhibitors (PPIs) may delay methotrexate elimination and increase the risk of adverse reactions.
  • Prescribers should take care when high-dose methotrexate and PPIs are used together and consider temporary withdrawal of the PPI.
  • Some PPIs are available over-the-counter.
  • Prescribers should continue to follow recommendations in the current data sheets.

Concomitant use of methotrexate and proton pump inhibitors (PPIs) may increase the levels of methotrexate in the blood and lead to adverse reactions.

The risk is greatest for patients taking high-dose methotrexate. Potential adverse reactions include renal toxicity, haematologic events, mucositis and myalgia.

Methotrexate is used to treat some forms of cancer and some autoimmune diseases. PPIs (which include omeprazole, esomeprazole, pantoprazole, lansoprazole and rabeprazole) are used for the symptomatic relief of gastric reflux-like symptoms.

The potential interaction with methotrexate relates to all PPIs.

There have been several studies and case reports that have identified the potential interaction between methotrexate and PPIs1–5.

In one study (79 patients and 197 cycles of methotrexate), the co-administration of PPIs with high-dose methotrexate was a risk factor for delayed elimination of methotrexate (odds ratio 6.66, 95% confidence interval 3.13–14.17)4.

Another study (74 patients and 171 cycles of methotrexate) also found that PPI use was a risk factor for delayed elimination of methotrexate (adjusted odds ratio 2.65, 95% confidence interval 1.03–6.82) and was also a risk factor for renal and liver dysfunction5.

Most of the studies and case reports were in patients who were receiving high-dose methotrexate.

Prescribers are asked to take care when high-dose methotrexate and PPIs are used together. PPIs should be used at the lowest dose and for shortest duration possible. Prescribers could consider temporarily withdrawing the PPI.

Prescribers are also reminded that PPIs are available over-the-counter.

Medsafe are currently working with the relevant pharmaceutical companies to ensure all methotrexate and PPI data sheets contain information on this interaction.

Healthcare professionals are reminded to report any adverse events to the Centre for Adverse Reactions Monitoring (CARM).

Reporting can be done via either the Medsafe website ( or by reporting directly to CARM (

  1. Bezabeh S, Mackey AC, Kluetz P, et al. 2012. Accumulating evidence for a drug-drug interaction between methotrexate and proton pump inhibitors. Oncologist 17(4): 550–554.
  2. Ranchon F, Vantard N, Gouraud A, et al. 2011. Suspicion of drug-drug interaction between high-dose methotrexate and proton pump inhibitors: a case report — should the practice be changed? Chemotherapy 57(3): 225–229.
  3. Santucci R, Leveque D, Kemmel V, et al. 2010. Severe intoxication with methotrexate possibly associated with concomitant use of proton pump inhibitors. Anticancer Research 30(3): 963–965.
  4. Santucci R, Leveque D, Lescoute A, et al. 2010. Delayed elimination of methotrexate associated with co-administration of proton pump inhibitors. Anticancer Research 30(9): 3807–3810.
  5. Suzuki K, Doki K, Homma M, et al. 2009. Co-administration of proton pump inhibitors delays elimination of plasma methotrexate in high-dose methotrexate therapy. British Journal of Clinical Pharmacology 67(1): 44–49.
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