Eliquis Drug Interactions

Inhibitors of CYP3A4 and P-gp: Co-administration of apixaban with ketoconazole (400 mg once a day), a strong inhibitor of both CYP3A4 and P-gp, led to a 2-fold increase in mean apixaban AUC and a 1.6-fold increase in mean apixaban C_max. No dose adjustment for apixaban is required with concomitant ketoconazole therapy, however apixaban should be used with caution in patients receiving concomitant systemic treatment with azole-antimycotics such as ketoconazole or other strong inhibitors of both CYP3A4 and P-gp (see Precautions).
Active substances moderately inhibiting the apixaban elimination pathways, CYP3A4 and/or P-gp, are expected to increase apixaban plasma concentrations to a lesser extent. Diltiazem (360 mg once a day), for instance, considered a moderate CYP3A4 and a weak P-gp inhibitor, led to a 1.4-fold increase in mean apixaban AUC and a 1.3-fold increase in C_max. Naproxen (500 mg, single dose), an inhibitor of P-gp but not an inhibitor of CYP3A4, led to a 1.5-fold and 1.6-fold increase in mean apixaban AUC and C_max, respectively. No dose adjustment for apixaban is required when co-administered with less potent inhibitors of CYP3A4 and/or P-gp.
Inducers of CYP3A4 and P-gp: Co-administration of apixaban with rifampin, a strong inducer of both CYP3A4 and P-gp, led to an approximate 54% and 42% decrease in mean apixaban AUC and C_max, respectively. The concomitant use of apixaban with other strong CYP3A4 and P-gp inducers (e.g., phenytoin, carbamazepine, phenobarbital or St. John's Wort) may also lead to reduced apixaban plasma concentrations. No dose adjustment for apixaban is required during concomitant therapy with such agents, however in patients receiving strong inducers of both CYP3A4 and P-gp apixaban should be used with caution for the prevention of VTE in elective hip or knee replacement surgery and for the prevention of stroke in patients with NVAF.
Anticoagulants: After combined administration of enoxaparin (40 mg single dose) with apixaban (5 mg single dose), an additive effect on anti-Factor Xa activity was observed.
Due to an increased bleeding risk, care is to be taken if patients are treated concomitantly with any other anticoagulants (see Precautions).
Platelet aggregation inhibitors and NSAIDs: Pharmacokinetic or pharmacodynamic interactions were not evident when apixaban was co-administered with acetylsalicylic acid 325 mg once a day.
Apixaban co-administered with clopidogrel (75 mg once a day) or with the combination of clopidogrel 75 mg and acetylsalicylic acid 162 mg once daily did not show a relevant increase in bleeding time, platelet aggregation, or clotting tests (PT, INR, and aPTT) compared to administration of the antiplatelet agents without apixaban.
Naproxen (500 mg), an inhibitor of P-gp, led to a 1.5-fold and 1.6-fold increase in mean apixaban AUC and C_max, respectively. Corresponding increases in clotting tests were observed for apixaban. No changes were observed in the effect of naproxen on arachidonic acid-induced platelet aggregation and no clinically relevant prolongation of bleeding time was observed after concomitant administration of apixaban and naproxen.
Despite these findings, there may be individuals with a more pronounced pharmacodynamic response when antiplatelet agents are co-administered with apixaban. Care is to be taken if patients are treated concomitantly with NSAIDs (including acetylsalicylic acid) and/or platelet aggregation inhibitors because these medicinal products typically increase the bleeding risk (see Precautions).
Agents associated with serious bleeding are not recommended concomitantly with Eliquis, such as: thrombolytic agents, GPIIb/IIIa receptor antagonists, thienopyridines (e.g., clopidogrel), dipyridamole, dextran and sulfinpyrazone.
Other concomitant therapies: No clinically significant pharmacokinetic or pharmacodynamic interactions were observed when apixaban was co-administered with atenolol or famotidine. Co-administration of apixaban 10 mg with atenolol 100 mg did not have a clinically relevant effect on the pharmacokinetics of apixaban. Following administration of the two drugs together, mean apixaban AUC and C_max were 15% and 18% lower than when administered alone. The administration of apixaban 10 mg with famotidine 40 mg had no effect on apixaban AUC or C_max.
Laboratory parameters: Clotting tests (eg, PT, INR and aPTT) are affected as expected by the mechanism of action of apixaban. Changes observed in these clotting tests at the expected therapeutic dose are small and subject to a high degree of variability (see Pharmacology: Pharmacodynamics under Actions).
Paediatric population: Interaction studies have only been performed in adults.
Effect of apixaban on other drugs: In vitro apixaban studies showed no inhibitory effect on the activity of CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2D6 or CYP3A4 (IC50 >45 µM) and weak inhibitory effect on the activity of CYP2C19 (IC50 >20 µM) at concentrations that are significantly greater than peak plasma concentrations observed in patients. Apixaban did not induce CYP1A2, CYP2B6, CYP3A4/5 at a concentration up to 20 µM. Therefore, apixaban is not expected to alter the metabolic clearance of co-administered drugs that are metabolized by these enzymes. Apixaban is not a significant inhibitor of P-gp.
In studies conducted in healthy subjects, as described, apixaban did not meaningfully alter the pharmacokinetics of digoxin, naproxen or atenolol.
Digoxin: Co-administration of apixaban (20 mg once a day) and digoxin (0.25 mg once a day), a P-gp substrate, did not affect digoxin AUC or C_max. Therefore, apixaban does not inhibit P-gp mediated substrate transport.
Naproxen: Co-administration of single doses of apixaban (10 mg) and naproxen (500 mg), a commonly used NSAID, did not have any effect on the naproxen AUC or C_max.
Atenolol: Co-administration of a single dose of apixaban (10 mg) and atenolol (100 mg), a common beta-blocker, did not alter the pharmacokinetics of atenolol.
Activated charcoal: Administration of activated charcoal reduces apixaban exposure (see Overdosage).