4. Drug-Drug Interactions
Patient profiles will be assessed to identify those drug regimens that may result in clinically significant drug-drug interactions. Major drug-drug interactions considered clinically significant for platelet aggregation inhibitors are summarized in Table 5. Only those drug-drug interactions classified as clinical significance level 1/contraindicated or those considered life threatening which have not yet been classified will be reviewed.
| Target Drug | Interacting Drug | Interaction | Recommendation | Clinical Significance Level |
|---|---|---|---|---|
| aspirin | methotrexate (MTX) | potential for increased MTX serum levels, risk of enhanced pharmacologic/ toxic effects as NSAIDs can reduce MTX clearance | avoid concurrent aspirin use within 10 days of high-dose MTX; otherwise, use cautiously together; monitor for increased myelosuppressive, GI adverse effects; may consider using longer leucovorin rescue | major (DrugReax) 1-severe (CP) |
| cilostazol, dipyridamole | riociguat (Adempas®) | concurrent administration may result in increased hypotension risk | avoid concurrent use | contraindicated (DrugReax) dipyridamole: 1-severe; cilostazol: 3-moderate (CP) |
| cilostazol, ticagrelor, vorapaxar | itraconazole, strong CYP3A4 inhibitors | co-administration may result in elevated serum concentrations of select platelet aggregation inhibitors (PAIs) and potential bleeding complications as cilostazol, ticagrelor, and vorapaxar metabolized by CYP3A4 | avoid use; ticagrelor therapy should not be initiated for at least 2 weeks after itraconazole discontinuation; if adjunctive administration necessary, use cautiously and monitor patient closely for enhanced pharmacologic/ adverse effects, especially bleeding | ticagrelor: contraindicated; cilostazol, vorapaxar: major (DrugReax) ticagrelor: 1-severe; cilostazol, vorapaxar: 2-major (CP) |
| clopidogrel | dasabuvir/ombitasvir/paritaprevir/ritonavir (Viekira®) | adjunctive administration with clopidogrel (strong CYP2C8 inhibitor) contraindicated by manufacturer, as dasabuvir metabolized by CYP2C8, which increases risk for dasabuvir-induced QT interval prolongation; ritonavir, a CYP3A4 inhibitor, may limit clopidogrel conversion to active metabolite | avoid concurrent use | 1-severe (CP) |
| clopidogrel | omeprazole | strong CYP2C19 inhibitor (e.g. omeprazole) may result in reduced plasma concentrations of clopidogrel active metabolite and diminish antiplatelet activity | avoid concurrent use; consider alternative proton pump inhibitor (e.g. pantoprazole) | major (DrugReax) 2-major (CP) |
| PAIs | defibrotide | increased risk of hemorrhage when used adjunctively with antithrombotic/ fibrinolytic drugs like PAIs | avoid concurrent use | contraindicated (DrugReax) 1-severe (CP) |
| PAIs, including aspirin | low molecular weight heparins | potential for additive bleeding adverse effects; PAIs inhibit platelet aggregation and have increased bleeding risk, prolonged bleeding time | avoid concurrent therapy, if possible; if drug combination necessary, use cautiously, monitor for signs/symptoms of bleeding | major, moderate (DrugReax) 2-major, 3-moderate (CP) |
| PAIs, including aspirin | selective serotonin reuptake inhibitors (SSRIs)/, serotonin norepinephrine reuptake inhibitors (SNRIs) | increased bleeding risk with combined therapy; SSRIs/SNRIs deplete platelet serotonin, which may impair platelet aggregation | monitor for signs/symptoms of bleeding; may consider substituting tricyclic antidepressant for SSRI/SNRI | SSRIs –major; SNRIs-major (DrugReax) 3-moderate (CP) |
| PAIs, including aspirin | anticoagulants | combined administration may increase bleeding risk, due to additive effects | if combined therapy necessary, monitor patients closely for bleeding signs/symptoms | major (DrugReax) 2-major, 3-moderate (CP) |
| PAIs | nonsteroidal anti-inflammatory drugs (NSAIDs) | concurrent use may increase risk for bleeding especially with chronic NSAID use | monitor for signs of bleeding with concurrent use | major (DrugReax) 3-moderate (CP) |
| ticagrelor, vorapaxar | strong CYP3A inducers (e.g., rifampin) | strong inducers substantially reduce ticagrelor, vorapaxar exposure and efficacy as both are CYP3A4 substrates | avoid use | major (DrugReax) 2–major (CP) |
| ticagrelor | simvastatin, lovastatin | adjunctive use may increase lovastatin, simvastatin serum levels as ticagrelor is CYP3A4 inhibitor and lovastatin and simvastatin are metabolized by CYP3A4 | avoid lovastatin, simvastatin doses higher than 40 mg; observe for adverse effects if combined use necessary | moderate (DrugReax) 2–major (CP) |