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Interaction studies have only been performed in adults.
Anticoagulants and platelet aggregation agents: Concomitant use of PRADAXA with treatment that interfere with hemostasis or coagulation increases bleeding risk (see Bleeding under Precautions). The following treatments are not recommended concomitantly with PRADAXA: unfractionated heparins and heparin derivatives, low molecular weight heparins (LMWH), fondaparinux, desirudin, thrombolytic agents, GPIIb/IIIa receptor antagonists, clopidogrel, ticlopidine, dextran, sulfinpyrazone and vitamin K antagonists. It should be noted that unfractionated heparin can be administered at doses necessary to maintain a patent central venous or arterial catheter.
Interactions linked to dabigatran etexilate and dabigatran metabolic profile: Dabigatran etexilate and dabigatran are not metabolised by the cytochrome P450 system and have no in vitro effects on human cytochrome P450 enzymes. Therefore, related medicinal product interactions are not expected with dabigatran (see "Pharmacology: Pharmacokinetics: Special populations under Actions").
NSAIDs: NSAIDs given for short-term perioperative analgesia have been shown not to be associated with increased bleeding risk when given in conjunction with dabigatran etexilate. With chronic use in the RE-LY study, NSAIDs increased the risk of bleeding by approximately 50 % on both dabigatran etexilate and warfarin. Therefore, due to the risk of haemorrhage, notably with NSAIDs with elimination halflives >12 hours, close observation for signs of bleeding is recommended.
P-glycoprotein interactions: P-glycoprotein inhibitors: Dabigatran etexilate is a substrate for the efflux transporter P-gp. Concomitant administration of P-gp inhibitors (such as amiodarone, verapamil, quinidine, systemic ketoconazole, dronedarone, ticagrelor and clarithromycin) is expected to result in increased dabigatran plasma concentrations.
Concomitant administration of systemic ketoconazole is contraindicated.
Primary prevention of venous thromboembolic events in adult patients who have undergone elective total hip replacement surgery or total knee replacement surgery: For the concomitant use of P-gp inhibitors and dosing of PRADAXA in the indication, see "Dosage & Administration" and "Pharmacology: Pharmacokinetics: Special populations under Actions".
Prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation: Treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE), and prevention of recurrent DVT, and PE in adults (DVT/PE): For the P-gp inhibitors listed previously, no dose adjustments are required for PRADAXA in this indication.
Amiodarone is an inhibitor of the efflux transporter P-glycoprotein and dabigatran etexilate a substrate of this transporter. Dabigatran exposure in healthy subjects was increased by 1.6 fold (+60 %) in the presence of amiodarone (see "Pharmacology: Pharmacokinetics: Special populations under Actions"). In view of the long half-life of amiodarone the potential for drug interaction may exist for weeks after discontinuation of amiodarone.
Prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation: In patients in the RE-LY trial concentrations were increased by no more than 14% and no increased risk of bleeding was observed.
Verapamil: When PRADAXA (150mg) was coadministered with oral verapamil, the Cmax and AUC of dabigatran were increased but the magnitude of this change differs, depending on timing of administration and formulation of verapamil (see "Pharmacology: Pharmacokinetics: Special populations under Actions").
Prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation: In patients in the RE-LY trial concentrations were increased by no more than 21% and no increased risk of bleeding was observed.
Quinidine: Dabigatran exposure in healthy subjects was increased by 1.5 fold (+53 %) in the presence of quinidine (see "Pharmacology: Pharmacokinetics: Special populations under Actions").
Clarithromycin: Dabigatan exposure in healthy subjects was increased by about 19% in the presence of clarithromycine without any clinical safety concern (see "Pharmacology: Pharmacokinetics: Special populations under Actions").
Ketoconazole: Dabigatran exposure was increased by 2.5 fold (+150%) after single and multiple doses of systemic ketoconazole (see "Contraindications" and "Pharmacology: Pharmacokinetics: Special populations under Actions").
Dronedarone: Dabigatran exposure was increased by 2.1 fold (+114%) after single or 2.4 fold (+136%) after multiple doses of dronedarone, respectively (see "Pharmacology: Pharmacokinetics: Special populations under Actions").
Ticagrelor: Dabigatran exposure in healthy subjects was increased by 1.46 fold (+ 46%) in the presence of ticagrelor at steady state or by 1.73 fold (+73%) when a loading dose of ticagrelor was administered simultaneously with a single dose of 75 mg dabigatran etexilate.
Dabigatran steady state exposure in healthy subjects was increased by 1.26 fold (+ 26 %) in the presence of ticagrelor at steady state or by 1.49 fold (+49%) when a loading dose of ticagrelor was administered simultaneously with 110 mg dabigatran etexilate. The increase in exposure was less pronounced when the180 mg ticagrelor loading dose was given two hours after dabigatran intake (+27%).
P-glycoprotein substrate: Digoxin: In a study performed with 24 healthy subjects, when PRADAXA was coadministered with digoxin, no changes on digoxin and no clinical relevant changes on dabigatran exposure have been observed (see "Pharmacology: Pharmacokinetics: Special populations under Actions").
P-glycoprotein inducers: After 7 days of treatment with 600 mg rifampicin qd total dabigatran AUC0-∞ and Cmax were reduced by 67%and 66% compared to the reference treatment, respectively.
The concomitant use with P-gp inducers (e.g., rifampicin, St. John´s wort (Hypericum perforatum), carbamazepine, or phenytoin) reduces exposure to dabigatran and should be avoided (see "Precautions" and "Pharmacology: Pharmacokinetics: Special populations under Actions").
