Marion General Hospital Formulary EvaluationMonograph

Generic Name (Trade Name): Rivaroxaban (Xarelto)Manufacturer: Janssen Pharmaceuticals© Dosage Forms (NDC #): oral tabletAHFS Class: Anticoagulant Storage: 25°C (77°F), 15°C - 30°CDescription and Pharmacology: Rivaroxaban is an anticoagulant which inhibits Factor Xa to prevent the formation of thrombin.

Pharmacokinetics: See supplementary handout

FDA-Approved Indications1

Treatment of DVT/PE, reduction in the risk of recurrent DVT/PE after initial 6 months of treatment, postoperative DVT thromboprophylaxis, nonvalvular atrial fibrillation

Clinical Trials

Title Rivaroxaban versus Warfarin in Non-Valvular A.Fib (Rocket-AF)Objective Compare rivaroxaban with warfarin in the prevention of stroke and systemic

embolism in patients with nonvalvular atrial fibrillation who were at moderate-to-high risk for stroke

Design Multicenter,double blind, double dummy, non-inferiority trial14,264 patients

Methods Rivaroxaban 20mg or 15mg vs Warfarin adjusted to goal INR of 2-31°: composite of stroke and systemic embolism2°: composite of stroke, systemic embolism, or death from CV causes, MISafety: composite of major and nonmajor clinical bleeding

Results Rivaroxaban vs. Warfarin1°: 188 patients (1.7%) vs. 251 patients (2.2%); HR 0.79, 95%CI 0.66 to 0.96, p<0.0012°: Nonmajor bleeding: 1475 patients (14.9% per year) vs. 1449 patients (14.5% per year)Major bleeding: 3.6% vs. 3.4%, p=0.58ICH: (0.5% vs. 0.7% per year; HR, 0.67; 95% CI, 0.47 to 0.93; P=0.02).GI bleeding: 224(3.2%) vs. 154 (2.2%), p<0.001

Conclusions Rivaroxaban non-inferior to warfarin in preventing stroke or systemic embolism in nonvalvular a.fib patients who are at moderate-high risk for stroke. In addition, rates of major and nonmajor bleeding were similar among both groups. Rivaroxaban treatment arm had less intracranial and fatal bleeding. Warfarin had less GI bleeding.

Comments

Title EINSTEIN DVT/ EINSTEIN PE/ EINSTEIN extension

Objective DVT/PE: Compare safety and efficacy of Xarelto vs. standard therapy in patients with DVT or PEExtension: determine benefit to risk ratio of extended use of Xarelto in DVT/PE

patients who have completed a prescribed duration of anticoagulation treatmentDesign DVT/PE: non-inferior, randomized, open label study in patients with acute,

symptomatic DVT/PE randomized to rivaroxaban or standard therapy with enoxaparin and warfarin.

3449 patients (DVT) 4832 patients (PE)

Extension: Double-blind, superiority study in patients with confirmed DVT or PE who had 6-12 months of treatment with warfarin or rivaroxaban. Patients randomized to placebo or rivaroxaban 20mg.

1196 patients (patients from both Einstein PE/DVT studies and outside participants)

Methods DVT/PE: 1°: symptomatic, recurrent VTE (composite of DVT or nonfatal or fatal PE) Safety: composite of major and clinically relevant nonmajor bleeding Treatments:

o Study arm: Rivaroxaban 15mg BID x 3 weeks then 20mg qd for 3,6, or 12 months of treatment

o Standard therapy: Enoxaparin 1mg/kg SQ BID and warfarinExtension:

Efficacy: recurrent VTE Safety: major bleeding

Results DVT: Recurrent VTE: 2.1% vs 1.7% (HR 0.68; 95% confidence interval [CI], 0.44

to 1.04; P<0.001 for noninferiority)

Safety (first major or nonmajor clinical bleed)

o 139 patients(8.1%) vs. 138 patients (8.1%); [HR 95% CI, 0.76 to

1.22; P=0.77]PE:

Recurrent VTE: 50 patients (2.1%) vs. 44 patients (1.8%), HR 1.12 (95% confidence interval [CI], 0.75 to 1.68; P=0.003

Safety (first major or nonmajor clinical bleed): o 249 patients (10.3%) vs. 274 patients (11.4%), [HR, 0.90; 95%

CI, ]0.76 to 1.07; P=0.23}

Extension: Recurrent VTE: 8 (1.3%) vs. 42 (7.1), [HR: 0.18; 95% CI, 0.09 to 0.39;

P<0.001, RRR 82%] Major and clinically relevant nonmajor bleeding: 36(6.0%) vs. 7 (1.2%),

[HR: 5.19 95%CI, 2.3-11.7), p<0.001).

Conclusions DVT:Rivaroxaban is as effective as standard therapy in the treatment of acute DVT with comparable safety. PE:Rivaroxaban is as effective as standard therapy in the prevention of recurrent VTE with comparable bleeding rates. Extension: Purpose of extension trial was to determine the benefit to risk ratio of continuing anticoagulation therapy beyond treatment period. Rivaroxaban reduced recurrent VTE by 82%. 34 recurrent events were prevented for every 4 major bleeds. Nonmajor bleeding increased from 1.2% in placebo group to 5.4% in treatment

group. 81% of patients resumed therapy. Overall this study concluded a positive benefit to risk ratio.

Comments

Safety and Tolerability

Contraindications: active bleeding, severe hypersensitivity reaction to rivaroxabanWarnings:

Abrupt discontinuation of rivaroxaban can lead to an increase risk of thrombotic events occurring Epidural or spinal hematomas in those receiving neuraxial anesthesia or spinal puncture

.

PrecautionsNot recommended for those with prosthetic heart valves, abrupt discontinuation of medication can increase risk of

thrombotic events, monitoring is required for patients undergoing neuraxial anesthesia or spinal pucture due to risk of hematomas, concomitant use of drugs that affect hemostasis require additional monitoring, elderly patients predisposed to thrombotic and bleeding events and use should be cautioned in this population, avoid combination with dual P-glycoprotein and strong CYP3A4 inhibitors

Adverse Drug Effects

See supplementary handout

Drug Interactions

CYP3A4 and P-glycoprotein inhibitorso Ketoconazoleo Ritonaviro Clarithromycino Erythromycino Fluconazoleo *recommendation: avoid concomitant use of Xarelto and strong CYP3A4 + P-glycoprotein inhibitors.

Drugs that induce CYP3A4 and P-glycoproteino Rifampino Carbamazepineo Phenytoino St. John’s Worto *Recommendation: avoid concomitant use of Xarelto and strong CYP3A4 + P-glycoprotein inducers

Medication Error Possibility None identified

Dosing and Administration See supplementary handout

References

1. Rivaroxaban [Package Insert]. Gurabo: Janssen Ortho, LLC; 2011.