Methotrexate - PPI Interaction

FDA	Use caution when administering high-dose methotrexate to patients receiving proton pump inhibitor (PPI) therapy. Concomitant use of some PPIs with methotrexate (primarily at high dose), may elevate and prolong serum levels of methotrexate and/or its metabolite hydroxymethotrexate, possibly leading to methotrexate toxicities.  Delayed methotrexate elimination was observed when high-dose methotrexate was co-administered with PPIs, but was not observed when methotrexate was co-administered with ranitidine.  No formal drug interaction studies of methotrexate with ranitidine have been conducted.
Lexicomp	Severity :Moderate  (clinical significance pf the interaction may be lower with typically lower methotrexate dose ) Mechanism :MTX is actively secreted in distal renal tubule with hydrogen ions produced via hydrogen/potassium ATPase pump, PPI by inhibiting renal elimication of hydrogen ion may inhibit MTX elimination. Management: Monitor increased MTX toxicity (mucositis, myalgias, etc)
BC Cancer Agency Cancer Drug Manual	Management of concomitant use Monitor for methotrexate toxicity for high-dose methotrexate - consider discontinuing PPI one day prior to methotrexate consider an H2 antagonist (e.g., ranitidine) instead of PPI
Bezabeh et al, 2012	The majority of the reported cases occurred with the administration of high-dose methotrexate. Although the product label describes high-dose therapy as 12 g/m2 as a 4-hour infusion, doses ≥500 mg/m2 are frequently cited as “high dose” in the literature, and the majority of the above case reports and series were reported from patients receiving doses of 300 mg/m2 to 12 g/m2. It appears the risk is greatest in the high-dose setting; however, there were also cases of patients taking a PPI and experiencing toxicity at doses as low as 15 mg of methotrexate per week. Clinicians should consider substituting H2 blockers for PPIs when acid suppression is clinically indicated during methotrexate therapy.

Reference: 

1. http://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm284421.htm
2. http://www.bccancer.bc.ca/drug-database-site/Drug%20Index/Methotrexate_monograph_1Feb2016.pdf
3. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3336837/
4. Lexicomp