4. Drug-Drug Interactions

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Patient profiles are 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 of contraindicated or those considered life threatening which have not yet been classified will be reviewed.

Table 11. DOAC Drug-Drug Interactions¹
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	major
dabigatran, edoxaban	P-gp inducers (e.g., rifampin)	reduces serum dabigatran, edoxaban serum levels and increases thrombosis risk	avoid concurrent use	major
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	anticoagulants: major fibrinolytics: Contraindicated with apixaban
DOACs	defibrotide	enhances DOAC pharmacologic effects, increasing bleeding risk	avoid concurrent use	contraindicated
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	moderate
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	moderate
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
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