Rivaroxaban

  • A new oral direct factor Xa inhibitor approved for stroke prevention in atrial fibrillation (20mg daily/15mg daily in patients with Clcr 15-50) and for prevention of DVT/PE in patients undergoing total hip or knee replacement (10mg daily)
Relevant Clinical Trials

Atrial Fibrillation

Hip Replacement

Knee Replacement

Medication Guide
Patient Education Documentation
  • Coming soon
Effect of Renal Function on Rivaroxaban Pharmacokinetics

 

Clcr

Recommended
Dose In AF

Recommended Dose in Ortho Surgery

AUC

T 1/2

> 80 ml/min

 

20mg qday

 

10mg daily

-

8.3 hrs

50 – 80 ml/min

1.4 x increase

8.7 hrs

30 – 50 ml/min

Clcr 15-50 ml/min:
15mg daily

Clcr< 15 ml/min:
Avoid use

1.5 x increase

9.0 hrs

<  30 ml/min

 

Clcr < 30:
Avoid use

 

1.6 x increase

 

9.5 hrs

Kubitza D et al. Effects of renal impairment on the pharmacokinetics, pharmacodynamics and safety of rivaroxaban, an oral, direct Factor Xa inhibitor. B J Clin Pharmacol 2010; 70:703-12.

 

Suggestions for Conversion To/From Rivaroxaban

 

warfarin to rivaroxaban

stop warfarin and start rivaroxaban when INR < 2

rivaroxaban to warfarin

start warfarin and stop rivaroxaban 3 days later

LMWH/ fondaparinux to rivaroxaban

stop parenteral anticoagulant and administer rivaroxaban 0-2 hours before next parenteral dose would have been given

IV heparin to rivaroxaban

administer first dose of rivaroxaban at time of discontinuation
of IV heparin infusion

rivaroxaban to parenteral anticoagulant

Stop rivaroxaban and administer first dose of parenteral anticoagulant at the time the next dose of rivaroxaban would have been given

 

Suggestions for Peri-Procedural Management of Rivaroxaban

 

Time of last dose of rivaroxaban
before procedure

Standard Risk of Bleeding

High Risk of Bleeding
(major surgery, spinal puncture or placement of spinal/epidural catheter, and other situations in which complete hemostasis may be required)

 

24 hrs

 

24-48 hours

 

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
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.

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

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

Known or Probable Effect

US PI Recommendation

Suggested  Management Guidelines

Combined P-gp inhibitor and CYP3A4 inhibitor

amiodarone, atazanavir azithromycin, boceprevir, clarithromycin, conivaptan, cyclosporine, darunavir, delavirdine, diltiazem, dronedarone, erythromycin, fluconazole, fosamprenavir,imatinib,indinavir,
itraconazole,ketoconazole, lapativirb, mifepristone,nefazodone, nelfinavir, posaconazole, quinidine, ranolazine, ritonavir, saquinavir, tamoxifen, telaprevir, telithromycin, verapamil, voriconazole

Significant increase in rivaroxaban concentration

1.  Avoid use of P-gp/strong CYP3A4 inhibitors (eg: ketoconazole, intraconazole, ritonavir, conivaptan) . 

2.  Use P-gp/moderate CYP3A4 inhibitors (eg:  amiodarone, azithromycin, diltiazem, dronedarone, erythromycin, felodipine, , quinidine, ranolazine, verapamil) with caution in patients with renal impairment

3. No precautions necessary for use of clarithromycin and erythromycin in patients receiving rivaroxaban specifically for DVT prophylaxis

Avoid use

Risk higher in pts with renal impairment

Combined P-gp inducer and 3A4 inducer

barbiturates, carbamazepine, phenytoin, rifampin, St Johns wort

Significant reduction in rivaroxaban concentration

Avoid use of P-gp/strong CYP3A4 inducers (eg: carbamazepine, phenytoin, rifampin, St Johns wort)

Avoid use

Other inducers of P-gp

doxorubicin, prazosin, tipranavir, trazodone, vinblastine

Significant reduction in rivaroxaban concentration

Not specifically addressed

Avoid use

Other inducers of CYP3A4

bosentan, efavirenz, etravirine, fosphenytoin, nafcillin, nevirapine, oxarbazepine, primidone, rifabutin, rifapentine

Significant reduction in rivaroxaban concentration

Not specifically addressed

Avoid use

 

 

Therapeutic Monitoring

 

Rivaroxaban is not intended to be monitored using routine coagulation testing. Its fixed dosing is not intended to be adjusted on the basis of any coagulation laboratory parameter. In certain clinical situations in which the absence of anticoagulant effect induced by rivaroxaban needs to be assured, prothrombin time (PT) and partial thromboplastin time (PTT) can be evaluated and should be normal.

These settings include:

  • to assure appropriate rivaroxaban clearance prior to invasive procedures
  • to assure appropriate rivaroxaban clearance prior to thrombolytic therapy for acute ischemic stroke

NOTE: there is no reliable correlation between elevated PT/PTT and therapeutic effect

Hillarp A et al. Effects of oral direct factor Xa inhibitor rivaroxaban on commonly used coagulation assays. J Thromb Haemost 2011; 9:133-9.

 

Suggestions for Reversal and Management of Bleeding

 

There is NO REVERSAL AGENT OR ANTIDOTE for rivaroxaban. Very limited data, primarily non-human, are available to guide management of bleeding.

Mild Bleeding

  • delay next dose or discontinue therapy

Moderate to Severe Bleeding

  • symptomatic treatment
  • mechanical compression
  • surgical intervention
  • fluid replacement and hemodynamic support
  • blood product transfusion
  • oral charcoal (if rivaroxaban administered < 2 hrs prior)
  • NOTE: not dialyzable

Life Threatening Bleeding

  • measures above
  • charcoal filtration
  • last resort: rVIIa or PCC

Eerenberg ES et al. Reversal of rivaroxaban and dabigatran by prothrombin complex concentrate: a randomized, placebo-controlled, crossover study in healthy subjects. Circulation 2011; 124: 1573-9.