If not otherwise specifically described, close clinical surveillance (looking for signs of bleeding or anaemia) is required when dabigatran is co-administered with strong P-gp inhibitors. A coagulation test helps to identify patients with an increased bleeding risk due to increased dabigatran exposure (see sections 4.2, 4.4 and 5.1).

Systemic ketoconazole, cyclosporine, itraconazole and tacrolimus are contraindicated (see section 4.3). Caution should be exercised with other strong P-gp inhibitors (e.g. amiodarone, quinidine or verapamil) (see sections 4.2 and 4.4).

Ketoconazole: Ketoconazole increased total dabigatran AUC0- and Cmax values by 138 % and 135 %, respectively, after a single dose of 400 mg , and 153 % and 149 %, respectively, after multiple dosing of 400 mg ketoconazole once daily. The time to peak, terminal half-life and mean residence time were not affected by ketoconazole (see section 4.4). Concomitant treatment with systemic ketoconazole is contraindicated (see section 4.3).

Amiodarone: When Pradaxa was co-administered with a single oral dose of 600 mg amiodarone, the extent and rate of absorption of amiodarone and its active metabolite DEA were essentially unchanged. The dabigatran AUC and Cmax were increased by about 60 % and 50 %, respectively. The mechanism of the interaction has not been completely clarified. In view of the long half-life of amiodarone the potential for drug interaction may exist for weeks after discontinuation of amiodarone (see sections 4.2 and 4.4).

Patients treated for prevention of VTEs after hip or knee replacement surgery, dosing should be reduced to 150 mg taken once daily as 2 capsules of 75 mg Pradaxa if they receive concomitantly dabigatran etexilate and amiodarone (see section 4.2). Close clinical surveillance is recommended when dabigatran etexilate is combined with amiodarone and particularly in the occurrence of bleeding, notably in patients having a mild to moderate renal impairment.

Quinidine: Quinidine was given as 200 mg dose every 2nd hour up to a total dose of 1000 mg. Dabigatran etexilate was given twice daily over 3 consecutive days, on the 3rd day either with or without quinidine. Dabigatran AUC,ss and Cmax,ss were increased on average by 53 % and 56 %, respectively with concomitant quinidine (see sections 4.2 and 4.4).

Patients treated for prevention of VTEs after hip or knee replacement surgery, dosing should be reduced to 150 mg taken once daily as 2 capsules of 75 mg Pradaxa if they receive concomitantly dabigatran etexilate and quinidine (see section 4.2). Close clinical surveillance is recommended when dabigatran etexilate is combined with quinidine and particularly in the occurrence of bleeding, notably in patients having a mild to moderate renal impairment.

Verapamil: When dabigatran etexilate (150 mg) was co-administered with oral verapamil, the Cmax and AUC of dabigatran were increased but magnitude of this change differs depending on timing of administration and formulation of verapamil (see sections 4.2 and 4.4).

The greatest elevation of dabigatran exposure was observed with the first dose of an immediate release formulation of verapamil administered one hour prior to dabigatran etexilate intake (increase of Cmax by about 180 % and AUC by about 150 %). The effect was p