4. Drug-Drug Interactions
Patient profiles will be assessed to identify those drug regimens which may result in clinically significant drug-drug interactions. Drug-drug interactions considered clinically relevant for PPIs are summarized in Table 13. Only those drug-drug interactions identified as a clinical significance of contraindicated, or those considered life-threatening which have not yet been classified will be reviewed.
| Target Drug | Interacting Drug | Interaction | Recommendation | Clinical Significance Level# |
|---|---|---|---|---|
| dexlansoprazole, esomeprazole, lansoprazole, omeprazole, rabeprazole | tacrolimus | adjunctive administration may result in increased tacrolimus serum levels especially in intermediate or poor metabolizers of CYP2C19 as tacrolimus is metabolized by CYP3A and select PPIs are substrates for CYP3A4 and CYP2C19 | avoid combination, if possible; if concurrent therapy necessary, monitor serum tacrolimus levels and observe for adverse events; adjust doses as needed | moderate |
| esomeprazole, omeprazole | cilostazol (Pletal) | adjunctive use may increase cilostazol and one of its active metabolites serum levels and enhance cilostazol pharmacologic/adverse effects as cilostazol is metabolized by CYP2C19 as esomeprazole and omeprazole are CYP2C19 inhibitors | reduce cilostazol dose by 50% when given concurrently with omeprazole or esomeprazole and monitor for enhanced cilostazol pharmacologic/ adverse effects | major |
| esomeprazole, omeprazole, rabeprazole | citalopram (Celexa) | adjunctive use may increase citalopram serum levels and enhance citalopram, pharmacologic/adverse effects (including QT interval prolongation) as citalopram is metabolized by CYP2C19 and esomeprazole and omeprazole are CYP2C19 inhibitors | citalopram dose should not exceed 20 mg/day if this drug combination is utilized, and citalopram should be discontinued in patients with persistent QTc measurements greater than 500 ms; monitor for enhanced citalopram pharmacologic/ adverse effects | moderate |
| esomeprazole | mavacamten (Camzyos) | mavacamten is a CYP2C19 substrate and esomeprazole is a moderate CYP2C19 inhibitor. Concurrent use may increase mavacamten exposure | concurrent use is contraindicated | contraindicated |
| dexlansoprazole, esomeprazole, lansoprazole, omeprazole, pantoprazole | methotrexate (MTX) | concurrent administration of select PPIs and MTX (primarily high-dose MTX) may result in elevated MTX parent and metabolite concentrations and the potential for enhanced pharmacologic and adverse effects; these PPIs reduce renal MTX elimination | use combination cautiously; monitor MTX levels and observe patients for signs/symptoms of adverse events; may use alternative PPI or H2RA that does not interact; may not occur with lower MTX doses | major |
| omeprazole | mavacamten | mavacamten is a CYP2C19 substrate and omeprazole is a weak CYP2C19 inhibitor. Concurrent use may increase mavacamten exposure | reduce mavacamten dose by 1 level in patients receiving mavacamten and starting omeprazole. Avoid initiating omeprazole in patients on stable treatment with mavacamten 2,5 mg daily. Initiate mavacamten at the recommended starting dose in patients on stable omeprazole therapy | major |
| PPIs | select azole antifungals (e.g., ketoconazole, posaconazole) | combined administration may decrease antifungal absorption and effectiveness; itraconazole, ketoconazole, and posaconazole dependent on acidic environment for favorable absorption and PPIs increase gastric pH | avoid concurrent administration, if possible; if PPI-antifungal combination necessary, may administer antifungal with acidic beverage (e.g., Coke) to increase absorption; monitor closely for continued antifungal efficacy | major |
| PPIs | clopidogrel (Plavix) | combined administration may attenuate clopidogrel effects on platelet aggregation, increase potential risk of secondary acute cardiovascular events following percutaneous coronary intervention or acute coronary syndrome; exact mechanism for interaction unknown, but PPIs may delay or minimize clopidogrel conversion to its active form by competitively inhibiting CYP2C19 | avoid combined use, if possible; H2RAs# other than cimetidine or pantoprazole (has less CYP2C19 inhibitory activity) are suitable alternatives for acid suppressive therapy in patients requiring clopidogrel | major |
| PPIs | dasatinib (Sprycel) | adjunctive administration for extended duration may result in reduced dasatinib exposure and serum levels as dasatinib dependent on acidic gastric pH for solubility and absorption | combined use not recommended; alternative acid suppressives (e.g., antacids) should be given 2 hours before or 2 hours after dasatinib dose for optimal efficacy | major |
| PPIs | erlotinib (Tarceva) | adjunctive administration may decrease erlotinib absorption and reduce effectiveness as erlotinib solubility, which is pH dependent, is reduced with PPI therapy | avoid combination, if possible; if adjunctive therapy necessary, use lowest effective PPI dose, monitor for reduced erlotinib efficacy, and adjust erlotinib dose as needed; may use alternate acid suppressive therapy (e.g., H2RAs, antacids); antacid and erlotinib doses should be separated by several hours | major |
| PPIs | mycophenolate | combined administration may result in decreased mycophenolic acid serum levels and reduced therapeutic efficacy, most likely due to decreased mycophenolate absorption with increased gastric pH | avoid combined use, if possible; if adjunctive therapy necessary, closely monitor mycophenolic acid serum levels and adjust mycophenolate doses as necessary | moderate |
| PPIs | select protease inhibitors (e.g., atazanavir, indinavir, nelfinavir) | concurrent administration may result in reduced protease inhibitor serum levels and effectiveness and increased potential for resistance, as PPIs may interfere with protease inhibitor solubility and absorption by increasing gastric pH | avoid PPI and atazanavir, indinavir, or nelfinavir combinations | contraindicated |
| PPIs | rilpivirine (Edurant) | adjunctive administration may promote rilpivirine treatment failure and potential for impaired virologic response and rilpivirine/NNRI† resistance as rilpivirine requires more acidic gastric pH for absorption | combined administration contraindicated | contraindicated |
| PPIs | other agents with solubility affected by changes in gastric pH (e.g., acalabrutinib, bosutinib, pazopanib | concomitant administration may result in reduced bioavailability and activity of agents requiring low gastric pH for solubility as PPIs increase gastric pH | avoid combination, if possible; if adjunctive therapy necessary, use lowest effective PPI dose, monitor for reduced efficacy of agents requiring low gastric pH for solubility, and adjust dose as needed; may use alternate acid suppressive therapy (e.g., H2RAs, antacids); antacid and doses for agents with solubility issues should be separated by several hours | major (DrugReax) |
| PPIs | vitamin K antagonists (e.g., warfarin) | concurrent administration may result in elevated INR^ levels and prothrombin time and enhanced anticoagulant effects; warfarin is metabolized by CYP450 (eg CYP2C19) and omeprazole is a CYP2C19 inhibitor, but mechanism for other PPIs is not well known | monitor INR levels and observe for bleeding issues/adverse effects; adjust warfarin doses as needed | moderate |
Legend:
- * CP = Clinical Pharmacology
- # histamine (H2) receptor antagonists
- † non-nucleoside reverse transcriptase inhibitor
- ^ International Normalized Ratio