Apixaban Atlanta Medicare Drug Interactions

Inhibitors of CYP3A4 and P-gp: Coadministration 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 which are not considered strong inhibitors of both CYP3A4 and P-gp, (eg., amiodarone, diltiazem, naproxen, quinidine, verapamil) are expected to increase apixaban plasma concentration 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: Coadministration of apixaban with rifampicin, 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 medicinal products for the prevention of VTE following elective hip or knee replacement surgery or for the prevention of stroke or systemic embolism in non-valvular atrial fibrillation patients, however strong inducers of both CYP3A4 and P-gp apixaban should be co-administered with caution.
For the treatment of DVT and PE, concomitant therapy with strong inducers of both CYP3A4 and P-gp is not recommended (see Precautions). For the prevention of recurrent DVT and PE, strong inducers of both CYP3A4 and P-gp should be co-administered with caution (see Precautions).
Anticoagulants, platelet aggregation inhibitors, and NSAIDs: 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.
Pharmacokinetic or pharmacodynamic interactions were not evident in healthy subjects when apixaban was co-administered with ASA 325 mg once a day.
Apixaban co-administered with clopidogrel (75 mg once a day) or with the combination of clopidogrel 75 mg and ASA 162 mg once daily, or with prasugrel (60 mg followed by 10 mg once daily) in Phase I studies did not show a relevant increase in bleeding time, or further inhibition of platelet aggregation, compared to administration of the antiplatelet agents without apixaban. Increases in clotting tests (PT, INR, and aPTT) were consistent with the effects of apixaban alone.
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, in healthy subjects, 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, Apixaban should be used with caution when co-administered with NSAIDs (including ASA) because these medicinal products typically increase the bleeding risk.
Agents associated with serious bleeding are not recommended concomitantly with apixaban, such as: unfractionated heparins and heparin derivatives (including low molecular weight heparins (LMWH)), FXa inhibiting oligosaccharides (e.g., fondaparinux), direct thrombin II inhibitors (e.g., desirudin), thrombolytic agents, GPIIb/IIIa receptor antagonists, dipyridamole, dextran, sulfinpyrazone, vitamin K antagonists, and other oral anticoagulants. It should be noted that unfractionated heparin can be administered at doses necessary to maintain a patent central venous or arterial catheter (see Precautions).
In patients with atrial fibrillation and a condition that warrants mono or dual antiplatelet therapy, a careful assessment of the potential benefits against the potential risks should be made before combining this therapy with apixaban (see Precautions).
Other concomitant therapies: No clinically significant pharmacokinetic or pharmacodynamic interactions were observed when apixaban was co-administered with atenolol or famotidine. Coadministration 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 medicinal products 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.
Effect of apixaban on other medicinal products: 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 medicinal products that are metabolised by these enzymes. Apixaban is not a significant inhibitor of P-gp.
In studies conducted in healthy subjects, as described as follows, apixaban did not meaningfully alter the pharmacokinetics of digoxin, naproxen, or atenolol.
Digoxin: Coadministration 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: Coadministration 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: Coadministration of a single dose of apixaban (10 mg) and atenolol (100 mg), a common beta-blocker, did not alter the pharmacokinetics of atenolol.
Laboratory parameters: Clotting tests (e.g., PT, INR, and aPTT) are affected as expected by the mechanism of action of apixaban (see Pharmacology: Pharmacodynamics under Actions). Changes observed in these clotting tests at the expected therapeutic dose are small and subject to high degree of variability (see Pharmacology: Pharmacodynamics under Actions).
Pediatric population: Interaction studies have only been performed in adults.