Contents
Dosing
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 | (reference) | 8.3 hrs |
| 50-80 ml/min | 40% 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 |
50% 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
Note: Manufacturer labeling states to avoid use if CrCl < 15ml/min. Patients with CrCl < 30 ml/min were excluded from clinical trials and there are limited post-approval data published for this population. UWMedicine: RESTRICTED IF CrCl < 30 ml/min, consider alternative therapy |
60% increase | 9.5 hrs |
Indications
An oral direct factor Xa inhibitor approved for:
1) Stroke prevention in atrial fibrillation (20 mg daily, or 15 mg daily in patients with CrCl 15-50 ml/min)
2) Treatment of DVT/PE (15 mg bid for 21 days, then 20 mg daily)
3) Long term prevention of DVT/PE after initial 6 months of treatment (10 mg daily)
4) Prevention of DVT/PE following total hip or knee replacement (10 mg daily)
5) Prevention of DVT/PE (31-39 days) in acutely ill medical patients (10 mg daily)
6) Reduction of major cardiovascular events in coronary artery disease or perpheral artery disease (2.5 mg twice daily)
Drug Interactions
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 metabolism 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 (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, phenobarbital3, 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 |
1based 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.
2based on probable effects on rivaroxaban, taking into consideration known characteristics of the precipitant drug according to human in vivo data
3avoid rivaroxaban use in patients on long-term phenobarbital; the UW Medicine Phenobarbital Protocol for Alcohol Withdrawal Syndrome is a short course, lessening the risk of inducing rivaroxaban metabolism as it typically takes at least 5-7 days to produce maximal induction
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, uninterrupted 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 agent at the time that the next scheduled dose of rivaroxaban would have been given |
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 | Bleeding High Risk of Bleeding (major surgery, spinal puncture or placement of spinal/epidural catheter, and other situations in which complete hemostasis is required)
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 hrs | At least 48 hrs |
| 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 | |
Therapeutic Monitoring
Rivaroxaban is not intended to be monitored using routine coagulation testing. 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
Learn more about Rivaroxaban Assay (RIVAR1)
NOTE: There is no reliable correlation between elevated PT/PTT and therapeutic effect (Source)
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
Management Plan
The direct oral anticoagulants (DOACs; apixaban, betrixaban, dabigatran, edoxaban, rivaroxaban) do not require the specialized long-term monitoring and management services provided by the UW Medicine Anticoagulation Clinics. UW Medicine Anticoagulation Services provides the following on a consultative basis:
1) consults to providers regarding DOAC drug selection, dosing, drug interactions, and peri-procedural issues
2) support and instructions to patients and providers for switching patients among the various oral agents
3) DOAC patient education, both telephonic and in person
Guidelines for long-term management of DOACs, developed by UW Medicine Anticoagulation Services and intended to be used by MDs/RNs/MAs in primary or specialty care clinics, are available below.
Guidelines for DOAC Management
Patient Education
Patient education materials, specific to each DOAC and developed by UW Medicine Anticoagulation Services, are available on this website in the Patient Education tab.
Relevant Clinical Trials
Stroke Prevention in Atrial Fibrillation
DVT/PE Treatment
- EINSTEIN Investigators. Oral rivaroxaban for symptomatic venous thromboembolism. New Engl J Med 2010; 363(26):2499-2510. (EINSTEIN DVT)
- EINSTEIN-PE Investigators. Oral rivaroxaban for the treatment of symptomatic pulmonary embolism. New Eng J Med 2012; 366(14):1287-1297. (EINSTEIN PE)
Hip Replacement
- Eriksson BI, et al. Rivaroxaban versus enoxaparin for thromboprophylaxis after hip arthroplasty. New Engl J Med 2008; 358(26):2765-2775. (RECORD1)
- Kakkar AK, et al (2008). Extended duration rivaroxaban versus short term enoxaparin for the prevention of venous thromboembolism after total hip arthroplasty: a double-blind, randomised controlled trial. Lancet 2008; 372(9632):31-39. (RECORD2)
Knee Replacement
- Lassen MR, et al. Rivaroxaban versus enoxaparin for thromboprophylaxis after total knee arthroplasty. New Engl J Med 2008; 358(26):2776-2786. (RECORD3)
- Turpie AG, et al. Rivaroxaban versus enoxaparin for thromboprophylaxis after total knee replacement arthroplasty (RECORD4): a randomized trial. Lancet 2009; 373(9676):1673-1680. (RECORD4)
DVT/PE Prevention
Chronic CAD/PAD
