Rivaroxaban Drug Interaction Potential

 

Pharmacodynamic Interactions
The concurrent use of rivaroxaban with other anticoagulants, antiplatelet agents, and nonsteroidal anti-inflammatory agents is expected to increase the risk of bleeding in comparison to use of rivaroxaban alone.

Pharmacokinetic Interactions
1.  The absorption of rivaroxaban is mediated by P-glycoprotein (P-gp). P-gp inhibitors can increase the absorption of rivaroxaban, increasing both AUC and Cmax. Conversely, P-gp inducers can reduce the absorption of rivaroxaban, decreasing AUC and Cmax.

2.  The metabolism of rivaroxaban is mediated by CYP3A4. CYP3A4 inhibitors can decrease the metabolism of rivaroxaban, increasing both AUC and Cmax. Conversely, CYP3A4 inducers can increase the metablism of rivaroxaban, decreasing AUC and Cmax

3.  Agents that interfere with both P-gp and CYP3A4 are likely to cause more significant interactions with rivaroxaban than agents that interfere with P-gp or CYP3A4 alone.

Drug Class

Examples (based on human in vivo data1)

Known or Probable Effect

US PI Recommendation

UW Medicine Suggested  Management Guidelines2

Combined P-gp inhibitor and strong CYP3A4 inhibitor

cobicistat, conivaptan, indinavir,
itraconazole, ketoconazole*, posaconazole, ritonavir*, saquinavir, telaprevir, telithromycin

 

* cited as example in US PI, with pharmacokientic data cited

Significant increase in rivaroxaban concentration

Avoid use 

AVOID USE

Risk higher in pts with renal impairment

Combined P-gp inhibitor and moderate CYP3A4 inhibitor OR strong CYP3A4 inhibitor alone

amiodarone, azithromycin, clarithromycin*, cyclosporine, diltiazem, dronedarone, erythromycin*, fluconazole*, grapefruit, lapatinib, mifepristone, nefazodone, nicardipine, ranolazine, tamoxifen, ticagrelor, verapamil, voriconazole

 

* cited as example in US PI, with pharmacokinetic data cited

Moderate increase in rivaroxaban concentration in patients with normal renal function.

Significant increase in rivaroxaban concentrations in patients with renal impairment

 

Combined P-gp and moderate 3A4 inhibitors (e.g. diltiazem, verapamil, dronedarone and erythromycin):  Avoid use if CrCl < 80 ml/min unless potential benefits outweigh the risks

USE WITH CAUTION in patients with normal renal function.

 

CONSIDER ALTERNATIVE THERAPY in patients with renal impairment (CrCl < 80ml/min)

Combined P-gp inducer and strong CYP3A4 inducer

carbamazepine*, dexamethsone,  rifampin**, St John's wort*

* cited as example in US PI

** cited as example in US PI, with pharmacokinetic data cited  

Significant reduction in rivaroxaban concentration

Effect may persist for several weeks following discontinuation of strong inducers of P-gp and/or CYP3A4

Avoid use 

AVOID USE

Inducers of P-gp

tipranavir

Not specifically addressed

AVOID USE

Strong inducers of CYP3A4

bosentan, efavirenz, etravirine, fosphenytoin, nafcillin, nevirapine, oxarbazepine, phenobarbital phenytoin*, primidone, rifabutin, rifapentine

* cited as example of combined P-gp inducer and strong CYP3A4 inducer  in US PI

Avoid use of phenytoin

AVOID USE 

(1) based on human in vivo data, in Cytorchrome P450 Enzymes and Transporters Table, from Hansten PD and Horn JR. The Top 100 Drug Interactions: A Guide to Patient Management, 2014 ed, H&H Publications, Freeland WA 2014.

(2) based on probable effects on rivaroxaban, taking into consideration known characteristics of the precipitant drug according to human in vivo data