Torapix 2.5/Torapix 5 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 Cmax.
The use of Apixaban is not recommended in patients receiving concomitant systemic treatment with strong inhibitors of both CYP3A4 and P-gp, such as azole-antimycotics (e.g., ketoconazole, itraconazole, voriconazole and posaconazole) and HIV protease inhibitors (e.g., ritonavir). Active substances which are not considered strong inhibitors of both CYP3A4 and P-gp, (eg., amiodarone, clarithromycin, diltiazem, fluconazole, naproxen, quinidine, verapamil) are expected to increase apixaban plasma concentration to a lesser extent. No dose adjustment for apixaban is required when co-administered with agents that are not strong inhibitors of both CYP3A4 and P-gp. For example, diltiazem (360 mg once a day), 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 Cmax. 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 Cmax, respectively. Clarithromycin (500 mg, twice a day), an inhibitor of P-gp and a strong inhibitor of CYP3A4, led to a 1.6-fold and 1.3-fold increase in mean apixaban AUC and Cmax 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 rifampicin, a strong inducer of both CYP3A4 and P-gp, led to an approximate 54% and 42% decrease in mean apixaban AUC and Cmax, 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, however strong inducers of both CYP3A4 and P-gp 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. For the prevention of recurrent DVT and PE, strong inducers of both CYP3A4 and P-gp should be co-administered with caution.
Interaction with other medicinal products affecting hemostasis: The concomitant use of Apixaban with antiplatelet agents increases the risk of bleeding. Care is to be taken if patients are treated concomitantly with non-steroidal anti-inflammatory drugs (NSAIDs), including acetylsalicylic acid (ASA). Other platelet aggregation inhibitors or other antithrombotic agents are not recommended concomitantly with Apixaban following surgery.
In patients with atrial fibrillation and a condition that warrants mono or dual antiplatelet therapy, a careful assessment of the potential benefits against the risks should be made before combining this therapy with Apixaban.
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 in phase 1 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 Cmax, 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 (eg, fondaparinux), direct thrombin II inhibitors (eg, 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.
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.
Effect of Apixaban on other drugs: 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 Cmax. 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 Cmax.
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.
Other concomitant therapies: No clinically significant pharmacokinetic or pharmacodynamic interactions were observed when Apixaban was co-administered with atenolol or famotidine. Co-administration of a single dose of apixaban (10 mg) with 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. Changes observed in these clotting tests at the expected therapeutic dose are small and subject to a high degree of variability.
Pediatric Population: Interaction studies have only been performed in adults.