Dabigatran Drug Interaction Potential

 

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

Pharmacokinetic Interactions
The absorption of the pro-drug dabigatran etexilate is mediated by P-glycoprotein (P-gp). P-gp inhibitors can increase the absorption of dabigatran etexilate, ultimately increasing both AUC and Cmax of dabigatran, the active drug. Conversely, P-gp inducers can reduce the absorption of dabigatran etexilate, ultimately decreasing AUC and Cmax of dabigatran, the active drug.

Based on the observation that in the RE-LY trial, patients with moderate renal impairment exhibited a 2.3-fold increase in dabigatran compared to patients with normal renal function, the FDA has stated that “any interaction that will result in an increase in the exposure to dabigatran greater than 2.5-fold (or greater than 150%) will require a dose/regimen adjustment”. However, it is possible that changes in exposure that are lower than this threshold may cause clinically significant changes. Therefore, caution is advised with the concurrent use of dabigatran and all P-gp inhibitors and inducers.

Based on observations with verapamil it is possible that administration of dabigatran etexilate two hours prior to any P-gp inhibitor may reduce or eliminate the impact of the interaction, but there is insufficient evidence at this time to make this conclusion definitively.  Using this strategy with P-gp inducers is not likely to minimize the impact of drug interactions.

Drug Class Examples (based on human in vivo data1) Known or Probable Effect US PI Recommendation Suggested Management Guidelines
P-gp Inhibitors

alfentanil, amiodarone**, atorvastatin, azithromycin, carvedilol, clarithromycin**, cobicistat, conivaptan,  cyclosporine,  diltiazem,  dronedarone**, duloxetine, erythromycin, fenofibrate, grapefruit juice, indinavir, itraconazole, ivacaftor*, ketoconazole**, lapatinib, ledipasvir, lomitapide,  lovastatin, mefloquine, nelfinavir, nicardipine, nifedipine*, ponatinib posaconazole, propafenone, quinidine**, ranolazine*, ritonivir, saquinavir, simvastatin, sunitinib, tacrolimus, tamoxifen, telaprevir, telithromycin, ticagrelor**, tolvaptan*, verapamil**

 

* weak P-gp inhibitor

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

Variable increase in dabigatran concentrations

AF: Consider dose reduction to 75mg twice daily if administered with dronedarone or ketoconazole in pts with CrCl 30-50 ml/min.

AF: Avoid use with any P-gp inhibitor in patients with severe renal impairment (CrCl < 30 ml/min)

 

VTE: Avoid use with any P-gp inhibitor in pts with CrCl < 50ml/min

AVOID USE with cyclosporine, dronedarone, itraconazole, ketoconazole, or tacrolimus

 

AVOID USE with any P-gp inhibitor in patients with moderate to severe renal impairment (CrCl < 50 ml/min) or in any patient aged > 75 years.

 

When concomitant use of a P-gp inhibitor cannot be avoided, administer dabigatran at least 2 hours before P-gp inhibitor

P-gp inducers

carbamazepine, dexamethasone, fosphenytoin, phenytoin, rifampin*, St. John's wort,  tipranavir

 

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

Significant reduction in dabigatran concentration

Effect may persist for several weeks following discontinuation of inducers of P-pg.

 

Avoid use AVOID USE
Antacids H2 antagonists, proton pump inhibitors Modest reduction in dabigatran concentration None When practical, administer dabigatran at least 2 hours before antacids

(1)  based on human in vivo data, in Cytochrome 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 daibgatran, taking into consideratoin known characteristics of the precipitant drug according to human in vivo data