4. Drug-Drug Interactions

Patient profiles will be assessed to identify those drug regimens, which may result in clinically significant drug-drug interactions. Major drug-drug interactions considered clinically significant for DOACs are summarized in Table 11. 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.

Table 11. DOAC Drug-Drug Interactions1-7
Target Drug Interacting Drug Interaction Recommendation Clinical Significance Level#
dabigatran P-gp inhibitors (e.g., amiodarone, clarithromycin) increases dabigatran exposure and bleeding risk
  • Non-valvular AF:
    • avoid use with CrCl less than 30 mL/min; reduce dose to 75 mg twice daily with CrCl 30-50 mL/min (dronedarone, systemic ketoconazole only)
  • Treatment and prevention of DVT and PE:
    • avoid use with CrCl less than 50 mL/min
  • Prevention of DVT and PE after hip replacement surgery:
    • avoid use with CrCl less than 50 mL/min; separate by several hours with CrCl greater than 50 mL/min
 dabigatran, major; itraconazole, contraindicated (DrugReax) 2 – major (CP)
dabigatran, edoxaban P-gp inducers (e.g., rifampin) reduces serum dabigatran, edoxaban serum levels and increases thrombosis risk avoid concurrent use major (DrugReax) 2 – major (CP)
DOACs anticoagulants, NSAIDs, aspirin, antiplatelet agents, fibrinolytics increases bleeding risk avoid concurrent use; if adjunctive administration necessary, use cautiously and monitor closely for signs/ symptoms of bleeding major (DrugReax) anticoagulants, 2 – major; fibrinolytics, 1 – severe (CP)
DOACs defibrotide enhances DOAC pharmacologic effects, increasing bleeding risk avoid concurrent use contraindicated (DrugReax) 1 – severe (CP)
DOACs selective serotonin reuptake inhibitors (SSRIs)/ serotonin norepinephrine reuptake inhibitors (SNRIs) may increase bleeding risk avoid concurrent use; if adjunctive administration necessary, use cautiously and monitor closely for signs/ symptoms of bleeding major (DrugReax) 2 – major (CP)
DOACs orlistat may increase INR due to decreased vitamin K absorption if adjunctive administration necessary, use cautiously and monitor closely for changes in coagulation factors major (DrugReax) 3 – moderate (CP)
rivaroxaban, apixaban dual P-gp and CYP3A4 inhibitors   (e. g., ritonavir, ketoconazole) increases serum rivaroxaban, apixaban levels, which increases bleeding risk avoid concurrent use; reduce dose of apixaban by 50%; avoid use in patients receiving apixaban 2.5 mg twice daily major (DrugReax) 2 – major (CP)
rivaroxaban, apixaban dual P-gp and CYP3A4 inducers (e.g., rifampin, phenytoin, carbamazepine) decreases rivaroxaban exposure by 50%; rifampin decreases apixaban exposure by 50%; increases thrombosis risk avoid concurrent use major (DrugReax) 2 – major (CP)