Administration of a proton pump inhibitor with intravenous methotrexate may result in elevated serum levels of methotrexate, with toxic consequences, according to a statement issued on Dec. 21 by the Food and Drug Administration.

Case reports and published pharmacokinetic studies "suggest" that concomitant use of proton pump inhibitors (PPIs) with methotrexate, primarily high dose methotrexate, "may elevate and prolong serum levels of methotrexate and/or its metabolite hydroxymethotrexate, possibly leading to methotrexate toxicities," the statement says.

In two cases, elimination of methotrexate was delayed when it was administered with a PPI but not when it was administered with ranitidine, the statement says. However, no formal drug interaction studies of methotrexate and ranitidine have been conducted, the statement adds. Ranitidine, a histamine H2-receptor antagonist used for similar indications as PPIs, is marketed as Zantac and is available in generic formulations.

The FDA is recommending that clinicians "use caution when administering high-dose methotrexate to patients receiving proton pump inhibitor therapy," and this information has been added to the warnings section of the label for methotrexate.

Methotrexate, classified as an antimetabolite, is approved to treat neoplastic diseases, severe psoriasis, and rheumatoid arthritis. PPIs are widely used drugs used to treat several conditions, including gastroesophageal reflux disease. The PPIs available in the United States include omeprazole (Prilosec), esomeprazole (Nexium), lansoprazole (Prevacid), and pantoprazole (Protonix), as well as several generic and over-the-counter formulations. The FDA statement did not say that the warning is being added to the PPI labels.

Serious adverse events associated with these and other drugs should be reported to the FDA’s MedWatch program at 800-332-1088.

12/21/11