Rivaroxaban

Suggestions for Peri-Procedural Management of Rivaroxaban

CrCl T 1/2

Time of last dose of rivaroxaban prior to procedure

(peri-procedural bridging is generally not required)

    Standard Risk of Bleeding

High Risk of Bleeding1

(major surgery, spinal puncture or placement of spinal/epidural catheter, and other situations in which complete hemostasis is required)

1 ASRA 4th edition 2018: hold 72 hours for all patients prior to neuraxial procedures, without regard for influence of renal function on half-life and clearance

> 80 ml/min         8.3 hrs       at least 24 hours at least 48 hours
50-79 ml/min 8.7 hrs   
30-49 ml/min 9 hrs
15-29 ml/min 9.5 hrs
< 15 ml/min unknown consider measuring drug activity with rivaroxaban assay to determine absence of drug effect

 

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

Suggestions for Conversion To/From Rivaroxaban

CONVERSION UW MEDICINE RECOMMENDATION
From warfarin to rivaroxaban

Stop warfarin and start rivaroxaban when INR < lower limit of therapeutic range

(manufacturer recommends stop warfarin and start rivaroxaban when INR < 3)

From rivaroxaban to warfarin

 

(NOTE: rivaroxaban is not intended to be used as a short term "bridge" to warfarin.  These recommendations refer to transitioning patients who are taking rivaroxaban on a long term basis and are switching to warfarin instead)

Start warfarin and stop rivaroxaban 3 days later

OR IF continuous, uninterruped anticoagulation is necessary:

a) stop rivaroxaban

b) begin both parenteral anticoagulation (LMWH or UFH) and warfarin at the time the next dose of rivaroxaban would have been given

c) stop the parenteral anticoagulant when INR reaches an acceptable range

From LMWH/ fondaparinux to rivaroxaban

Stop parenteral anticoagulant and administer rivaroxaban 0-2 hours before the next dose of parenteral drug  would have been given

From IV heparin to rivaroxaban Administer first dose of rivaroxaban at the same time as discontinuation of IV heparin infusion
from 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
From rivaroxaban to apixaban, dabigatran or edoxaban

stop rivaroxaban and begin the other agentat the time that the next scheduled dose of rivaroxaban would have been given

 

 

 

Rivaroxaban - Dosing and Renal Function Effects

The presence of chronic kidney disease is an independent risk factor for increased bleeding events, including hemorrhagic stroke. Please carefully consider the risks and benefits of any oral anticoagulant prior to initiating therapy.

 

CrCl FDA Recommended Dose for Atrial Fibrillation FDA Recommended Dose for VTE Prevention in Ortho Surgery FDA Recommended Dose for VTE Treatment AUC T 1/2
> 80 ml/min 20mg daily 10mg daily 15mg bid for 21 days, then 20mg daily for remainder of treatment course - 8.3 hrs
50-80 ml/min 1.4 x increase 8.7 hrs
30-49 ml/min

CrCl 15-49 ml/min:     15mg daily

CrCl < 15ml/min:         avoid use

UWMedicine: RESTRICTED IF CrCl < 30 ml/min, consider alternative therapy

1.5 x increase 9 hrs
<30 ml/min

CrCl < 30ml/min: avoid use

UWMedicine: RESTRICTED IF CrCl < 30 ml/min, consider alternative therapy

CrCl< 30ml/min: avoid use

UWMedicine: RESTRICTED IF  CrCl < 30 ml/min, consider alternative therapy

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.

General information and Dosing

Rivaroxaban

An oral direct factor Xa inhibitor approved for:

  • Stroke prevention in atrial fibrillation (20 mg daily, or 15 mg daily in patients with CrCl 15-50 ml/min)
  • Treatment of DVT/PE (15 mg bid for 21 days, then 20 mg daily)
  • Prevention of DVT/PE following total hip or knee replacement (10 mg daily)

Relevant Clinical Trials

Atrial Fibrillation

DVT/PE Treatment

Hip Replacement

Knee Replacement

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 now an FDA approved reversal agent for apixaban, see andexanet alfa and Guidelines For Reversal of Anticoagulants.

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:  PCC (Kcentra) and andexanet alfa when this product becomes available

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