Monday, August 29, 2016

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

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