Apixaban Drug Interaction Potential

Pharmacodynamic Interactions

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

Pharmacokinetic Interactions

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

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

3. Agents that interfere with both P-gp and CYP3A4 are likely to cause more significant interactions with apixaban 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 Recommendations

UW Medicine

Suggested Management Guidelines 2

Combined P-gp inhibitor and strong inhibitor of CYP3A4

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

* cited  as example in US PI

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

Significant increase in apixaban concentration

Reduce apixaban dose to 2.5mg twice daily. 

In patients already taking 2.5mg twice daily, avoid coadministration

AVOID USE

Combined P-gp inhibitor and/or moderate CYP3A4 inhibitor

amiodarone, azithromycin, chloramphenicol, cimetidine, clarithromycin*, cyclosporine, diltiazem*, dronedarone, erythromycin, felodipine, fluconazole, grapefruit, lapatinib, mifepristone, nicardipine, quinidine, ranolazine, tamoxifen,  ticagrelor, verapamil

 

* pharmacokinetic data cited in US PI

Moderate increase in apixaban concentrations in patients with normal renal function.

Potentially significant increase in apixaban concentrations in patients with severe renal insufficiency

No dose adjustment recommended

USE WITH CAUTION in patients with normal renal function.

 

AVOID USE in patients with severe renal insufficiency (CrCl < 30ml/min), age > 80 yrs, or low body weight (< 60 kg)

Combined P-gp inducer and strong CYP3A4 inducer

carbamazepine*, dexamethadone,  rifampin**, St Johns wort*

* cited as example in US PI

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

Significant reduction in apixaban concentration

Effect may persist for several weeks after discontinuation of stong 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, oxcarbazepine, 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 Cytochrome P450 Enzymes and Transports 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 apixaban, taking into consideration known characteristics of the precipitant drug according to human in vivo data