Interactions Between Methotrexate (TREXALL) and Proton Pump Inhibitors (PPIs) and Many Other Drugs

Growing evidence suggests that proton pump inhibitors (PPIs), widely used to treat ulcers and gastrointestinal reflux disease (GERD), can increase the risk of methotrexate toxicity, which can lead to serious and potentially fatal adverse reactions.

Methotrexate (TREXALL) is an old drug (first marketed in 1953) that has been used for many years to treat various types of cancers. In lower doses, this potent drug is increasingly being used to treat disorders such as rheumatoid arthritis, psoriasis and Crohn’s disease. In fact, methotrexate has become a first-line treatment for rheumatoid arthritis.

What evidence suggests a methotrexate-PPI interaction?

A recent medical research paper from Strasbourg, France, found that people who received methotrexate for cancer in addition to PPIs for acid-reduction therapy were more likely to experience delayed elimination of methotrexate from the blood. The PPIs studied include esomeprazole (NEXIUM), lansoprazole (PREVACID), omeprazole (PRILOSEC) and pantoprazole (PROTONIX).

A previous report from this same group described several people taking methotrexate who needed “rescue” therapy with a methotrexate antidote when they were given PPIs concurrently.

The authors concluded that PPIs should not be used in people receiving methotrexate for cancer.

What are the adverse outcomes of this interaction?

Excessive methotrexate blood levels can result in reduced ability of the bone marrow to make blood cells, such as white cells, red cells and platelets. A reduction in white blood cells increases the risk of infections, and lowered platelet levels increases the risk of bleeding. Methotrexate toxicity also can cause debilitating gastrointestinal toxicity, such as severe inflammation, ulcerations and bleeding in the mouth, as well as elsewhere in the gastrointestinal tract.

Does the dose of the methotrexate matter?

Most of the studies and case reports of this interaction have occurred in patients receiving large anti-cancer doses of methotrexate. Nonetheless, one cannot rule out that PPIs also may increase the risk of methotrexate toxicity in patients receiving lower doses of methotrexate for rheumatoid arthritis or other disorders. Some such cases have been reported.

Do all PPIs interact with methotrexate?

There is not enough evidence to know for sure, but it is likely that all PPIs interact similarly with methotrexate. In addition to the PPIs mentioned above, other PPIs include deslansoprazole (KAPIDEX) and rabeprazole (ACIPHEX).

Are PPIs the only drugs that cause methotrexate toxicity?

Other drugs that may increase the risk of methotrexate toxicity include NSAIDs (non-steroidal anti-inflammatory drugs) such as those listed. (See Table 2).

Other drugs listed in Table 2 include antibiotics such as co-trimoxazole (SEPTRA), some penicillins and the gout drug probenecid (PROBALAN), although more study is needed to establish the frequency and magnitude of these interactions.

What You Can Do

If you are taking high-dose methotrexate for treatment of cancer, it is critical that you keep your oncologist aware of all other medications you are taking. Some drugs that interact with methotrexate are nonprescription drugs, so they may not be subject to the usual computer screening for drug interactions. Herbal products also should only be taken upon the approval of your oncologist.

If you are taking lower-dose methotrexate for rheumatoid arthritis or other disorders, the risk of methotrexate toxicity due to drug interactions is probably lower. Nonetheless, you should take the interacting drugs only if your prescriber has carefully evaluated the risks and benefits of adding the interacting drugs, and you should be carefully monitored for evidence of methotrexate toxicity.

Consumers may report serious adverse effects with these drugs to the FDA’s MedWatch Adverse Event Reporting program either online or by regular mail, fax or phone.

• Online: https://www.accessdata.fda.gov/scripts/medwatch/medwatch-online.htm
• Regular mail: Use postage-paid, pre-addressed FDA form 3500 and mail to MedWatch, 5600 Fishers Lane, Rockville, MD 20852-9787
• Fax: (800) FDA-0178
• Phone: (800) FDA-1088

Table 1. Proton Pump Inhibitors that May Increase the Risk of Methotrexate Toxicity

Table 2. Other Drugs that May Increase the Risk of Methotrexate Toxicity