The concomitant use of PRADAXA with treatments that act on haemostasis or coagulation including Vitamin K antagonists can markedly increase the risk of bleeding (see Precautions).
Dabigatran etexilate and dabigatran are not metabolized by the cytochrome P450 system and had no effects in vitro on human cytochrome P450 enzymes. Therefore related drug-drug interactions are not expected with dabigatran etexilate or dabigatran (see Pharmacology: Pharmacokinetics under Actions).
Anticoagulants and antiplatelet aggregation medicinal products: There is no or only limited experience with the following treatments which may increase the risk of bleeding when used concomitantly with Pradaxa: anticoagulants such as unfractionated heparin (UFH), low molecular weight heparins (LMWH), and heparin derivatives (fondaparinux, desirudin), thrombolytic medicinal products, and vitamin K antagonists, rivaroxaban or other oral anticoagulants, and platelet aggregation medicinal products such as GPIIb/IIIa receptor antagonists, ticlopidine, prasugrel, ticagrelor, dextran, and sulfinpyrazone.
From the limited data collected in the phase III study RE-LY in patients with atrial fibrillation it was observed that the concomitant use of other oral or parenteral anticoagulants increases major bleeding rates with both dabigatran etexilate and warfarin by approximately 2.5-fold, mainly related to situations when switching from one anticoagulant to another.
UFH can be administered at doses necessary to maintain a patent central venous or arterial catheter.
Clopidogrel and ASA: From the data collected in the phase III study RE-LY it was observed that the concomitant use of antiplatelets, ASA or clopidogrel approximately doubles major bleeding rates with both dabigatran etexilate and warfarin.
Clopidogrel: In a phase I study in young healthy male volunteers, the concomitant administration of dabigatran etexilate and clopidogrel resulted in no further prolongation of capillary bleeding times compared to clopidogrel monotherapy. In addition, dabigatran AUCτ,ss and Cmax,ss and the coagulation measures for dabigatran effect or the inhibition of platelet aggregation as measure of clopidogrel effect remained essentially unchanged comparing combined treatment and the respective mono-treatments. With a loading dose of 300 mg or 600 mg clopidogrel, dabigatran AUCτ,ss and Cmax,ss were increased by about 30-40% (see ASA as follows).
ASA: The effect of concomitant administration of dabigatran etexilate and ASA on the risk of bleeds was studied in patients with atrial fibrillation in a phase II study in which a randomized ASA co-administration was applied. Based on logistic regression analysis, co-administration of ASA and 150 mg dabigatran etexilate twice daily may increase the risk for any bleeding from 12% to 18% and 24% with 81 mg and 325 mg ASA, respectively.
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 half-lives >12 hours, close observation for signs of bleeding is recommended.
LMWH: The concomitant use of LMWHs, such as enoxaparin and dabigatran etexilate has not been specifically investigated. After switching from 3-day treatment of once daily 40 mg enoxaparin s.c., 24 hours after the last dose of enoxaparin the exposure to dabigatran was slightly lower than that after administration of dabigatran etexilate (single dose of 220 mg) alone. A higher anti-FXa/FIIa activity was observed after dabigatran etexilate administration with enoxaparin pre-treatment compared to that after treatment with dabigatran etexilate alone. This is considered to be due to the carry-over effect of enoxaparin treatment, and regarded as not clinically relevant. Other dabigatran related anti-coagulation tests were not changed significantly by the pre-treatment of enoxaparin.
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.
Prevention of Venous Thromboembolic Events in patients who have undergone elective total hip or total knee replacement surgery: For the concomitant use of P-gp inhibitors and dosing of PRADAXA in this indication, see Pharmacology: Pharmacokinetics under Actions and Dosage & Administration.
Prevention of stroke and SEE in adult patients with NVAF with one or more risk factors (SPAF): For the other P-gp inhibitors listed previously no dose adjustments are required for PRADAXA in this indication.
Treatment of acute deep vein thrombosis (DVT) and/or pulmonary embolism (PE) and prevention of related death: For P-gp inhibitors listed previously no dose adjustments are required for PRADAXA in this indication.
Reduction in the Risk of Recurrence of Deep Venous Thrombosis and Pulmonary Embolism: For P-gp inhibitors listed previously no dose adjustments are required for PRADAXA in this indication.
Amiodarone: Dabigatran exposure in healthy subjects was increased by 1.6 fold (+60%) in the presence of amiodarone (see Pharmacology: Pharmacokinetics under Actions).
Prevention of stroke and SEE in adult patients with NVAF with one or more risk factors (SPAF): 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 (150 mg) 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 under Actions).
Prevention of stroke and SEE in adult patients with NVAF with one or more risk factors (SPAF): 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 under Actions).
Clarithromycin: Dabigatan exposure in healthy subjects was increased by about 19% in the presence of clarithromycin without any clinical safety concern (see Pharmacology: Pharmacokinetics under Actions).
Ketoconazole: Dabigatran exposure was increased by 2.5 fold (+150%) after single and multiple doses of systemic ketoconazole (see Pharmacology: Pharmacokinetics under Actions and Contraindications).
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 under Actions).
Ticagrelor: When a single dose of 75 mg dabigatran etexilate was coadministered simultaneously with a loading dose of 180 mg ticagrelor, the dabigatran AUC and Cmax were increased by 1.73-fold and 1.95-fold (+73% and 95%), respectively. After multiple doses of ticagrelor 90 mg b.i.d. the increase of dabigatran exposure is 1.56-fold and 1.46-fold (+56% and 46%) for Cmax and AUC, respectively.
Concomitant administration of a loading dose of 180 mg ticagrelor and 110 mg dabigatran etexilate (in steady state) increased the dabigatran AUCτ,ss and Cmax,ss by 1.49-fold and 1.65-fold (+49% and 65%), respectively, compared with dabigatran etexilate given alone. When a loading dose of 180 mg ticagrelor was given 2 hours after 110 mg dabigatran etexilate (in steady state), the increase of dabigatran AUCτ,ss and Cmax,ss was reduced to 1.27-fold and 1.23-fold (+27% and 23%), respectively, compared with dabigatran etexilate given alone. This staggered intake is the recommended administration for start of ticagrelor with a loading dose.
Concomitant administration of 90 mg ticagrelor BID (maintenance dose) with 110 mg dabigatran etexilate increased the adjusted dabigatran AUCτ,ss and Cmax,ss 1.26-fold and 1.29-fold, respectively, compared with dabigatran etexilate given alone.
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 under Actions).
Co-medication with selective serotonin re-uptake inhibitors (SSRIs) or selective serotonin norepinephrine re-uptake inhibitors (SNRIs): SSRIs and SNRIs increased the risk of bleeding in RE-LY in all treatment groups.
Gastric pH: Pantoprazole: When Pradaxa was co-administered with pantoprazole, a decrease in the dabigatran area under the plasma concentration-time curve of approximately 30% was observed. Pantoprazole and other proton-pump inhibitors (PPI) were co-administered with Pradaxa in clinical trials, and concomitant PPI treatment did not appear to reduce the efficacy of Pradaxa.
Ranitidine: Ranitidine administration together with Pradaxa had no clinically relevant effect on the extent of absorption of dabigatran.
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) reduces exposure to dabigatran and should be avoided (see Pharmacology: Pharmacokinetics under Actions and Precautions).