Interactions : אינטראקציות

4.5 Interaction with other medicinal products and other forms of interaction

Edoxaban is predominantly absorbed in the upper gastrointestinal (GI) tract. Thus, medicinal products or disease conditions that increase gastric emptying and gut motility have the possibility of reducing edoxaban dissolution and absorption.

P-gp inhibitors

Edoxaban is a substrate for the efflux transporter P-gp. In pharmacokinetic (PK) studies, concomitant administration of edoxaban with the P-gp inhibitors ciclosporin, dronedarone, erythromycin, ketoconazole, quinidine, or verapamil resulted in increased plasma concentrations of edoxaban.
Concomitant use of edoxaban with ciclosporin, dronedarone, erythromycin, or ketoconazole requires dose reduction to 30 mg once daily. Concomitant use of edoxaban with quinidine, verapamil, or amiodarone does not require dose reduction based on clinical data (see section 4.2).
The use of edoxaban with other P-gp inhibitors including human immunodeficiency virus (HIV) protease inhibitors has not been studied.

Edoxaban 30 mg once daily must be administered during concomitant use with the following P-gp inhibitors:
฀     Ciclosporin: Concurrent administration of a single dose of ciclosporin 500 mg with a single dose of edoxaban 60 mg increased edoxaban AUC and maximum serum concentration (C max) by 73% and 74%, respectively.
฀     Dronedarone: Dronedarone 400 mg twice daily for 7 days with a single concomitant dose of edoxaban 60 mg on day 5 increased edoxaban AUC and Cmax by 85% and 46%, respectively. ฀     Erythromycin: Erythromycin 500 mg four times daily for 8 days with a single concomitant dose of edoxaban 60 mg on day 7 increased the edoxaban AUC and C max by 85% and 68%, respectively.
฀     Ketoconazole: Ketoconazole 400 mg once daily for 7 days with a single concomitant dose of edoxaban 60 mg on day 4, increased edoxaban AUC and Cmax by 87% and 89%, respectively. Edoxaban 60 mg once daily is recommended during concomitant use with the following P-gp inhibitors:
฀     Quinidine: Quinidine 300 mg once daily on days 1 and 4 and three times daily on days 2 and 3, with a single concomitant dose of edoxaban 60 mg on day 3, increased edoxaban AUC over 24 hours by 77% and Cmax by 85%, respectively.
฀     Verapamil: Verapamil 240 mg once daily for 11 days with a single concomitant dose of edoxaban 60 mg on day 10 increased the edoxaban AUC and Cmax by approximately 53%. ฀     Amiodarone: Co-administration of amiodarone 400 mg once daily with edoxaban 60 mg once daily increased AUC by 40% and Cmax by 66%. This was not considered clinically significant.
In ENGAGE AF-TIMI 48 study in NVAF, efficacy and safety results were similar for subjects with and without concomitant amiodarone use.
฀     Clarithromycin: Clarithromycin (500 mg twice daily) for 10 days with a single concomitant dose of edoxaban 60 mg on day 9 increased the edoxaban AUC and C max by approximately 53% and 27%, respectively.

P-gp inducers

Co-administration of edoxaban with the P-gp inducer rifampicin led to a decrease in mean edoxaban AUC and a shortened half-life, with possible decreases in its pharmacodynamic effects. The concomitant use of edoxaban with other P-gp inducers (e.g. phenytoin, carbamazepine, phenobarbital or St. John's Wort) may lead to reduced edoxaban plasma concentrations. Edoxaban should be used with caution when co-administered with P-gp inducers.

P-gp substrates

Digoxin: Edoxaban 60 mg once daily on days 1 to 14 with coadministration of multiple daily doses of digoxin 0.25 mg twice daily (days 8 and 9) and 0.25 mg once daily (days 10 to 14) increased the Cmax of edoxaban by 17%, with no significant effect on AUC or renal clearance at steady state. When the effects of edoxaban on digoxin PK were also examined, the Cmax of digoxin increased by approximately 28% and AUC by 7%. This was not considered clinically relevant. No dose modification is necessary when edoxaban is administered with digoxin.

Anticoagulants, antiplatelets, NSAIDs and SSRIs/SNRIs

Anticoagulants: Co-administration of edoxaban with other anticoagulants is contraindicated due to increased risk of bleeding (see section 4.3).

ASA: Co-administration of ASA (100 mg or 325 mg) and edoxaban increased bleeding time relative to eithermedicinal product alone. Co-administration of high dose ASA (325 mg) increased the steady state Cmax and AUC of edoxaban by 35% and 32%, respectively. The concomitant chronic use of high dose ASA (325 mg) with edoxaban is not recommended. Concomitant administration of higher doses than
100 mg ASA should only be performed under medical supervision.

In clinical studies concomitant use of ASA (low dose ≤ 100 mg/day), other antiplatelet agents, and thienopyridines was permitted and resulted in approximately a 2-fold increase in major bleeding in comparison with no concomitant use, although to a similar extent in the edoxaban and warfarin groups (see section 4.4). Co-administration of low dose ASA (≤ 100 mg) did not affect the peak or total exposure of edoxaban either after single dose or at steady-state.
Edoxaban can be co-administered with low dose ASA (≤ 100 mg/day).

Platelet inhibitors: In ENGAGE AF-TIMI 48 concomitant use of thienopyridines (e.g. clopidogrel) monotherapy was permitted and resulted in increased clinically relevant bleeding although with a lower risk of bleeding on edoxaban compared to warfarin (see section 4.4).

There is very limited experience on the use of edoxaban with dual antiplatelet therapy or fibrinolytic agents.
NSAIDs: Co-administration of naproxen and edoxaban increased bleeding time relative to either medicinal product alone. Naproxen had no effect on the Cmax and AUC of edoxaban. In clinical studies, co-administration of NSAIDs resulted in increased clinically relevant bleeding. Chronic use of NSAIDs with edoxaban is not recommended.

SSRIs/SNRIs: As with other anticoagulants the possibility may exist that patients are at increased risk of bleeding in case of concomitant use with SSRIs or SNRIs due to their reported effect on platelets (see section 4.4).

Effect of edoxaban on other medicinal products

Edoxaban increased the Cmax of concomitantly administered digoxin by 28%; however, the AUC was not affected. Edoxaban had no effect on the Cmax and AUC of quinidine.

Edoxaban decreased the Cmax and AUC of concomitantly administered verapamil by 14% and 16%, respectively.