Preventive Strategies against Bleeding due to Nonvitamin K Antagonist Oral Anticoagulants

Table 3

Summary of drug-drug interactions provided in the literature. When available, recommendations for dose adaptation or contraindications by the competent authorities are provided [26–28].

Molecule	Mechanism	Dabigatran	Rivaroxaban	Apixaban
Antiarrhythmics
Dronedarone	P-gp and CYP 3A4 inhibitor	AUC: +114% (400 mg: single dose)*	Minor effect (use with caution if CrCl 15–50 mL/min)***	No data yet
		AUC: +136% (400 mg: multiple doses)
Quinidine	P-gp competition	AUC: +53% (1,000 mg: single dose)**	Minor effect (use with caution if CrCl 15–50 mL/min)	No data yet
Verapamil	P-gp competition and weak CYP 3A4 inhibitor	AUC: +18% (120 mg IR: single dose taken 2 h after DE intake)**	Minor effect (use with caution if CrCl 15–50 mL/min)	No data yet
		AUC: +143% (120 mg IR: single dose, 1 h before DE intake)**
		Cmax: +12% (120 mg IR: single dose taken 2 h after DE intake)**
		Cmax: +179% (120 mg IR: single dose, 1 h before DE intake)**
Amiodarone	P-gp competition	AUC: +58% (600 mg: single dose)**	Minor effect (use with caution if CrCl 15–50 mL/min)	No clinically relevant effect
Diltiazem	P-gp and CYP 3A4 inhibitor	No effect	Minor effect (use with caution if CrCl 15–50 mL/min)	AUC: +40%
Antianginal/antihypertensive drugs
Ranolazine	P-gp and CYP 3A4 inhibitor	No data yet	Minor effect (use with caution if CrCl 15–50 mL/min)	No data yet
Felodipine	P-gp and CYP 3A4 inhibitor	No data yet	Minor effect (use with caution if CrCl 15–50 mL/min)	No data yet
Anti-inflammatory
Naproxen	P-gp competition	No data yet	AUC: +10% (500 mg)	AUC: +50%
Antihypercholesterolemiant
Atorvastatin	P-gp and CYP 3A4 substrate	AUC: +18%	No effect	No PK data yet
Antimycotic
Ketoconazole	P-gp and CYP 3A4 inhibitor	AUC: +138% (400 mg: single dose)*	Cmax: +72% (400 mg: single dose)	Cmax: +62% (400 mg od)
		AUC: +153% (400 mg: multiple doses)	AUC: +158% (400 mg: single dose)	AUC: +100% (400 mg od)
Itraconazole	P-gp and CYP 3A4 inhibitor	No data yet*	No data yet, but similar results than ketoconazole are expected	No data yet, but similar results than ketoconazole are expected
Voriconazole	P-gp and CYP 3A4 inhibitor	No data yet
Posaconazole	P-gp and CYP 3A4 inhibitor	No data yet***	No data yet
Fluconazole	CYP 3A4 inhibitor	No data yet; Supposed no effect	Cmax: +28%	No data yet
			AUC: +42%
Antibacterial
Clarithromycin	P-gp and CYP 3A4 inhibitor	Cmax: +49%		No data yet
		AUC: +60%	AUC: +54% (500 mg bid)
Azithromycin	P-gp and CYP 3A4 inhibitor	No data yet	Minor effect (use with caution if CrCl 15–50 mL/min)	No data yet
Erythromycin	P-gp and CYP 3A4 inhibitor	No data yet	AUC: +34% (500 mg tid)	No data yet
Protease inhibitors
Ritonavir	P-gp and CYP 3A4 inhibitor	No data yet***	Cmax: +55% (600 mg bid)	No PK data but strong increase
			AUC: +153% (600 mg bid)
Immunosuppressor
Cyclosporine	P-gp competition	No data yet*	AUC: +50%	No data yet
Tacrolimus	P-gp competition	No data yet*	AUC: +50%	No data yet

∗The FDA recommends reducing the dabigatran etexilate at 75 mg bid for stroke prevention in NVAF. No recommendations are given by the FDA for cyclosporine, tacrolimus, and itraconazole.
**The EMA contraindicates concomitant treatment with these drugs. EMA recommends dose reduction from 220 mg od to 150 mg od in major orthopedic surgery and from 150 mg bid to 110 mg bid in stroke prevention in patients with NVAF. No dose recommendation is provided by the FDA.
***Not recommended by the EMA.