Rivaroxaban Drug Monograph

Rivaroxaban (Xarelto®)

National Drug Monograph

June 2012

VA Pharmacy Benefits Management Services,
Medical Advisory Panel, and VISN Pharmacist Executives

The purpose of VA PBM Services drug monographs is to provide a comprehensive drug review for making formulary decisions. These documents will be updated when new clinical data warrant additional formulary discussion. Documents will be placed in the Archive section when the information is deemed to be no longer current.

Executive Summary:

  • Rivaroxaban is an oral, direct factor Xa inhibitor that is FDA approvedfor the 1) prophylaxis of venous thromboembolism (VTE) in patients undergoing total hip replacement (THR) or total knee replacement (TKR) surgery and 2) prevention of stroke and systemic embolism in patients with nonvalvular atrial fibrillation (AF).
  • VTE prophylaxis dosing: The recommended dose of rivaroxaban is 10 mg orally once daily without regard to food. Treatment should be initiated at least 6-10 hours after surgery and once hemostasis has been established. The recommended duration of treatment is 35 days for THR and 12 days for TKR. Rivaroxaban should be avoided in patients with a CrCl <30 ml/min.
  • Stroke prevention in AF dosing: The recommended dose of rivaroxaban is 20 mg orally once daily taken with the evening meal for patients with a creatinine clearance (CrCl) of >50 ml/min. A reduced dose of 15 mg orally once daily with the evening meal is recommended for patients with a CrCl of 30-50 ml/min. Patients with a CrCl <30 were excluded from clinical trials, though a 15 mg orally once daily dose is available for patients with a CrCl of 15-30 ml/min based on pharmacokinetic data. Rivaroxaban should be avoided when CrCl <15ml/min. Note: Rivaroxaban exhibits dose-dependent bioavailability; higher doses which are used for AF should be taken with food to enhance absorption.
  • Efficacy and Bleeding in DVT Prophylaxis: TheRECORD clinical development program included four phase 3, double-blind, randomized, controlledtrials that studiedover 12,000 patients for the use of rivaroxaban vs. enoxaparin for the prevention of VTE in patients undergoing THR (RECORD 1 and 2) or TKR (RECORD 3 and 4) surgery. The studies each differed in design but shared the same primary and secondary endpoints. Of note, the FDA did not include RECORD 4 in support of the VTE prophylaxis indication for rivaroxaban because of significant concerns with study conduct, oversight, and data collection.

Overall, rivaroxaban was shown to be superior to enoxaparin for the primary composite endpoint of any DVT (asymptomatic and symptomatic), non-fatal PE, or all-cause mortality in patients undergoing THR or TKR. Secondary endpoints of major VTE and symptomatic VTE were also lower with rivaroxaban in some of the trials. A pooled analysis of the RECORD 1-3 studies supports the favorable efficacy with rivaroxaban compared to enoxaparin for the composite endpoint of symptomatic VTE and all-cause mortality at 2 weeks (0.4% vs. 0.8%, respectively; p=0.005). Rates of major bleeding and clinically relevant bleeding tended to be higher with rivaroxaban based on results from a pooled analysis of RECORD 1-4, though event rates overall were low (0.4% vs. 0.2%; p=0.076). A similar trend of more bleeding events with rivaroxaban was observed when RECORD 4 data were excluded. In the elderly population, efficacy and bleeding endpoints tended to be higher in both treatment arms, and the results were directionally similar to those found in the overall population.

  • Efficacy and Bleeding in Stroke Prevention in AF: The effect of rivaroxaban on the reduction of the risk of stroke or systemic embolism in patients with nonvalvular AF was compared to adjusted-dose warfarin in the phase 3, randomized, double-blind, non-inferiority ROCKET AF trial. A total of 14,264 patients with a moderate-to-high risk of stroke (mean CHADS2 score of 3.5) were included and treated for a median duration of 590 days. Over half of the population had a history of prior transient ischemic attack (TIA) or stroke, and about 40% of patients were 75 years or older. Of note, the mean time in therapeutic range (TTR) for warfarin patients was 55%, which is lower than TTRs reported in recent, major trials.

Rivaroxaban was found to be non-inferior to warfarin for the primary composite endpoint of stroke (ischemic and hemorrhagic) or systemic embolism, with annual event rates of 1.7% with rivaroxaban vs. 2.2% with warfarin (HR 0.79; 95% CI 0.66-0.96; p <0.001 for non-inferiority). It is unclear how rivaroxaban compares to warfarin that is better controlled (e.g., higher TTR). Rivaroxaban was associated with a significantly lower risk of hemorrhagic stroke (annual rates of 0.26% vs. 0.44%; HR 0.59 95% CI 0.37-0.93; p=0.024), though ischemic stroke rates between groups were not significantly different. Based on subgroup analyses, the treatment effect of rivaroxaban was found to be consistent in patients with renal impairment (where a lower dose was studied), patients with prior TIA/stroke, and the elderly.

Overall annual rates of major and clinically relevant nonmajor bleeding were not statistically different with rivaroxaban vs. warfarin (14.9% vs. 14.5%). Significantly more patients on rivaroxaban experienced a ≥2g/dL drop in hemoglobin and received transfusions; however, there were significantly fewer critical, fatal, and intracranial bleeding events with rivaroxaban vs. warfarin. In the elderly, bleeding events were more frequent in both treatment arms, and there was a trend of more major and nonmajor clinically relevant bleeding with rivaroxaban compared to warfarin.

  • Rivaroxaban is contraindicated in patients with active pathological bleeding or severe hypersensitivity reactions to rivaroxaban. Post marketing-cases of anaphylaxis have been reported.
  • Boxed Warning - Discontinuation in patients with AF: Patients are at increased risk of thrombotic events when rivaroxaban is discontinued in the absence of alternative anticoagulation. Increased rates of stroke were observed in clinical trials in patients with AF who permanently discontinued treatment. If rivaroxaban must be discontinued for a reason other than pathological bleeding, consider administering another anticoagulant. When patients who had temporary interruptions in treatment during ROCKET AF were examined, there was a trend of more events in the rivaroxaban arm, though the number of events overall was small.
  • Boxed Warning – Spinal/Epidural Hematoma: Patients treated with rivaroxaban who are receiving neuraxial anesthesia or undergoing spinal puncture have experienced epidural or spinal hematomas that may result in long-term or permanent paralysis. Consider the benefits and risks when scheduling patients for spinal procedures and before neuraxial intervention in anticoagulated patients or those who will be anticoagulated for thromboprophylaxis.
  • The major risk with rivaroxaban treatment is bleeding. Bleeding complications were the most commonly reported adverse events. Frequencies of common non-bleeding adverse events were similar with rivaroxaban and comparators. Tolerability of rivaroxaban and comparators was similar in the four RECORD studies and in ROCKET AF, though more patients in ROCKET AF discontinued treatment due to mucosal bleeding (hematuria, gastrointestinal, gingival, nose) compared to warfarin.
  • Routine coagulation monitoring of rivaroxaban is not required based on the stable pharmacokinetic and pharmacodynamic properties of the drug. There is no known reversal agent or antidote for rivaroxaban, though the drug has a shorter duration of action compared to warfarin. Unlike warfarin, data on the optimal management of bleeding, including major and life-threatening bleeding, with rivaroxaban is lacking. General hemostatic measures should be employed.
  • Rivaroxaban is a substrate of CYP3A4/5, CYP2J2, and the P-glycoprotein (P-gp) and ATP-binding cassette G2 (ABCG2) transporters. Inhibitors or inducers may increase or decrease rivaroxaban exposure, respectively. Concomitant use of rivaroxaban with combined P-gp and strong CYP3A4 inducers and inhibitors should be avoided. Caution should be exercised when rivaroxaban is combined with weak or moderate inhibitors, particularly in patients with renal impairment, as both elimination pathways are affected.
  • Concomitant use of rivaroxaban and medications that affect hemostasis are expected to increase the risk of bleeding (aspirin, anti-platelet agents, other antithrombotic agents, fibrinolytics, NSAIDs).
  • Rivaroxaban has also been studied for VTE treatment, ACS, and VTE prophylaxis in medically ill patients. These indications remain off-label at this time.

Introduction

Rivaroxaban is an oral, direct factor Xa inhibitor that was approved in the US in 2011 for the 1) prophylaxis of venous thromboembolism (VTE) in patients undergoing total hip replacement (THR) or total knee replacement (THR) surgery and 2) prevention of stroke and systemic embolism in patients with nonvalvular atrial fibrillation (AF). The drug has been available outside of the US for VTE prophylaxis since 2008.

Routine thromboprophylaxis for orthopedic surgery including THR and TKRhas been the standard of care for more than 25 years, given the high risk of VTE associated with these surgeries. Rates of asymptomatic and symptomatic VTE with THR are about 40-60% and 2-5%, respectively, with an incidence of fatal pulmonary embolism (PE) of approximately 0.3% if no prophylaxis is used. Rates are higher with TKR, though the increased risk for symptomatic VTE following hospital discharge is shorter.[1] There has been an increased emphasis on the clinically important outcome of symptomatic VTE, though asymptomatic VTE may sometimes progress to a symptomatic event following hospital discharge. Several pharmacologic options are available in the US for VTE prophylaxis including unfractionated heparin (UFH), low molecular weight heparins (LMWH), fondaparinux, warfarin, aspirin, and rivaroxaban. As anticoagulants, these therapies are associated with an increased risk of bleeding.

Generally attributed to embolism of thrombus from the left atrium, patients with AF are at a 4-5 fold increased risk of stroke and systemic embolism compared to those without AF.[2],[3] Annual rates of stroke in patients with AF are estimated to be between 3-8%, depending on additional risk factors.2 Several clinical risk stratification schemes have been developed to assess the stroke risk in AF, including the commonly used CHADS2 score.[4]

Risk of stroke by CHADS2 score:[5]

CHADS2 Scorea / Adjusted Stroke Rate
% per yr (95% CI)
0 / 0.5
1 / 1.5
2 / 2.5
3 / 5.3
4 / 6
5 or 6 / 6.9

aThe CHADS2 score is the sum of points assigned for different risk factors. One point each is given for the following: congestive heart failure, hypertension, age ≥75 years, diabetes mellitus; two points are given for history of stroke or transient ischemic attack.

Options for oral antithrombotic treatment for the reduction of stroke and systemic embolism related to AF have traditionally included warfarin and antiplatelet agents. Several, high quality, randomized, controlled trials and meta-analyses have evaluated the effectiveness of these agents. While both warfarin and antiplatelet agents have been shown to be effective in reducing risk of stroke, warfarin has been shown to be consistently and significantly more effective than placebo or aspirin. Aspirin is associated with risk reductions of about 20% compared to placebo, whereas warfarin is associated with risk reductions of about 60-70% vs. placebo and about 50% compared to aspirin.2,[6],[7] Newly available agents in the US now include dabigatran and rivaroxaban.

The decision for use of antithrombotic therapy should be based on assessment of the individual patient’s risk of embolic event without therapy and risk of bleeding with therapy. Choice of agent (e.g., warfarin, aspirin, or other) should be based upon the absolute risks of stroke and bleeding and relative risk and benefit for a given patient.3

The purposes of this monograph are to (1) evaluate the available evidence of safety, tolerability, efficacy, cost, and other pharmaceutical issues that would be relevant to evaluating rivaroxaban for possible addition to the VA National Formulary; (2) define its role in therapy; and (3) identify parameters for its rational use in the VA.

Pharmacology/Pharmacokinetics/Pharmacodynamics[8],[9],[10]

  • Rivaroxaban is an oral,direct factor Xa inhibitor that selectively blocks the active site of Xa and does not require a co-factor. Rivaroxaban lowers the risk of blood clots by inhibiting both free and prothrombinase-bound or clot-bound factor Xa as well as downstream platelet activation.

Table 1. Pharmacokinetics of rivaroxaban and dabigatran8,9,10, [11]

Parameter / Rivaroxaban / Dabigatran
Bioavailability / 10 mg dose: 80-100% (unaffected by food)
20 mg dose: 66% (fasting; increased with food) / 3 – 7%
Cmax / 2-4 hrs / 1-2 hrs
Protein Binding / 92-95% / 35%
Metabolism / CYP3A4/5, CYP2J2, hydrolysis / Conjugation
Elimination / Renal (66%; 36% as unchanged drug) / Renal (80%)
Half-life / 5-9 hrs* / 12 – 17 hrs

*Half-life is increased to 11-13 hrs in the elderly

  • Rivaroxaban exhibits dose-dependent bioavailability. For the 10 mg dose, bioavailability is approximately 80-100% and unaffected by food. Bioavailability of the 20 mg dose is 66% in a fasting state, though exposure is increased when taken with food (mean area under the curve [AUC] and Cmax increased by 39% and 76%, respectively). It is recommended that the 15 mg and 20 mg doses be taken with the evening meal.
  • Absorption of rivaroxaban is dependent on the site of drug release in the GI tract. Administration of rivaroxaban via a feeding tube may result in reduced exposure and should be avoided.
  • Based on in vitro data, rivaroxaban does not inhibit the major cytochrome P450 enzymes CYP1A2, 2C8, 2C9, 2C19, 2D6, 2J2, and 3A4 or induce CYP1A2, 2B6, 2C19, or 3A4. Rivaroxaban exhibits a low inhibitory potential for P-glycoprotein (P-gp) and ABCG2 transporters.
  • Elderly subjects exhibit increased rivaroxaban exposure (50% higher mean AUC) and terminal half-life. Gender or extreme body weights (<50 kg or >120 kg) did not influence rivaroxaban exposure, though Japanese subjects were found to have a 50% increased exposure.
  • Results from a 10 mg, single-dose pharmacokinetic/pharmacodynamic study of rivaroxaban (n=32) in subjects with varying degrees of renal function showed increased drug exposure and pharmacodynamic effectswith declining renal function. In ROCKET AF, patients with CrCl 30-50 ml/min who received a reduced dose of rivaroxaban of 15 mg daily had similar outcomes to patients with better renal function.

Table 2. Pharmacokinetics/pharmacodynamics in renal impairment compared to normal9

Rivaroxaban Parameter
(% Increase compared to normal) / Mild
CrCl 50-79 ml/min
N=8 / Moderate
CrCl 30-49 ml/min
N=8 / Severe
CrCl 15-29 ml/min
N=8
Exposure
AUC / 44 / 52 / 64
Cmax / 28 / 12 / 26
Factor Xa inhibition
AUC / 50 / 86 / 100
Emax / 9 / 10 / 12
PT Prolongation
AUC / 33 / 116 / 144
Emax / 4 / 17 / 20

Cmax=maximum concentration; Emax=maximum effect; PT=prothrombin time

  • Results from a 10 mg, single-dose pharmacokinetic/pharmacodynamic study of rivaroxaban (n=32) in subjects with varying degrees of hepatic function (normal, mild impairment[Child-Pugh A] and moderate impairment [Child-Pugh B]) showed increased drug exposure and pharmacodynamic effects with declining hepatic function.
  • Rivaroxaban produces a predictable, dose-dependent inhibition of factor Xa activity and prolongation of prothrombin time (PT) as demonstrated in healthy subjects and in patients undergoing orthopedic surgery. Once daily dosing regimens above 5 mg showed factor Xa inhibition throughout the 24 hour dosing period. Compared with once daily dosing, twice daily dosing is associated with less fluctuation in PT.
  • At steady state, PT and aPTT are significantly prolonged 2 hours afterrivaroxaban administration. PT and aPTT return to pre-dosing levels at 12 hours after administration.

FDA Approved Indication(s)9

1)Rivaroxaban is indicated for deep vein thrombosis (DVT) prophylaxis (which may lead to PE) in patients undergoing knee or hip replacement surgery.

2)Rivaroxaban is indicated to reduce the risk of stroke and systemic embolism in patients with nonvalvular AF. There are limited data to determine the comparative effectiveness of rivaroxaban and warfarin when warfarin therapy is well-controlled.

Potential Off-label Uses

This section is not intended to promote any off-label uses. Off-label use should be evidence-based. See VA PBM-MAP and Center for Medication Safety’s Guidance on “Off-label” Prescribing (available on the VA PBM Intranet site only).

Rivaroxaban has been studied for VTE treatment, ACS, and VTE prophylaxis in medically ill patients. Further details are provided in the Efficacy section.

Current VA National Formulary Alternatives

For VTE prophylaxis, the following agents are on VA National Formulary: aspirin, dalteparin, enoxaparin, fondaparinux, UFH, and warfarin. For stroke/systemic embolism prevention in AF, aspirin, dabigatran, and warfarin are on VA National Formulary.

Dosage and Administration9

  1. Non-valvular AF

CrCl >50 ml/min: The recommended dose of rivaroxaban is 20 mg orally once daily, taken with the evening meal.

CrCl 30-50 ml/min: The recommended dose of rivaroxaban is 15 mg once daily, taken with the evening meal.

CrCl 15-30 ml/min: Patients with CrCl of 15-30 ml/min were not studied in clinical trials. Based on pharmacokinetic data that suggests similar rivaroxaban exposure, the manufacturer recommends a dose of rivaroxaban 15 mg once daily, taken with the evening meal.

CrCl <15 ml/min: Avoid rivaroxaban.

Note: Renal function should be periodically assessed as clinically indicated and therapy adjusted accordingly. Rivaroxaban should be discontinued in patients who develop acute renal failure while receiving the drug.

Discontinuation

If rivaroxaban must be discontinued for reasons other than pathological bleeding, consider administering another anticoagulant. Discontinuing rivaroxaban in the absence of adequate alternative anticoagulation increases the risk of thrombotic events. (See Boxed Warnings)

Switching from or to warfarin

When switching from warfarin to rivaroxaban, start rivaroxaban as soon as the INR is below 3 to avoid periods of inadequate anticoagulation. There are no clinical data to guide switching from rivaroxaban to warfarin; however, it may be reasonable to discontinue rivaroxaban and start a parenteral anticoagulant and warfarin at the same time to avoid periods of inadequate anticoagulation. (See Boxed Warning in prescribing information on the increased risk of thrombotic events when rivaroxaban is discontinued)

Switching from or to anticoagulants other than warfarin

When switching from another anticoagulant to rivaroxaban, start rivaroxaban when the next dose of anticoagulant is due or at the same time of discontinuation of a continuous infusion (e.g., heparin). When switching from rivaroxaban to a parenteral anticoagulant, start therapy when the next dose of rivaroxaban would be due.

  1. DVT Prophylaxis

The recommended dose of rivaroxaban is 10 mg orally once daily without regard to food. Treatment should be initiated at least 6-10 hours after surgery once hemostasis has been established. The recommended duration of treatment is 35 days for THR and 12 days for TKR.

Renal Impairment

Patients with renal impairment are expected to experience increased exposure and pharmacodynamic effects with rivaroxaban. Patients with CrCl 30-50 ml/min should be observed closely for any signs and symptoms of bleeding. Rivaroxaban should be avoided in patients with CrCl <30 ml/min and discontinued in patients who develop acute renal failure while receiving the drug.