1. Marion General Hospital Formulary Evaluation
Monograph
Generic Name (Trade Name): Rivaroxaban (Xarelto)
Manufacturer: Janssen Pharmaceuticals©
Dosage Forms (NDC #): oral tablet
AHFS Class: Anticoagulant
Storage: 25°C (77°F), 15°C - 30°C
Description 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 trial
14,264 patients
Methods Rivaroxaban 20mg or 15mg vs Warfarin adjusted to goal INR of 2-3
1°: composite of stroke and systemic embolism
2°: composite of stroke, systemic embolism, or death from CV causes, MI
Safety: composite of major and nonmajor clinical bleeding
Results Rivaroxaban vs. Warfarin
1°: 188 patients (1.7%) vs. 251 patients (2.2%); HR 0.79, 95%CI 0.66 to 0.96,
p<0.001
2°:
Nonmajor bleeding: 1475 patients (14.9% per year) vs. 1449 patients (14.5% per
year)
Major bleeding: 3.6% vs. 3.4%, p=0.58
ICH: (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 PE
Extension: determine benefit to risk ratio of extended use of Xarelto in DVT/PE
patients who have completed a prescribed duration of anticoagulation treatment

2. Design 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 warfarin
Extension:
• 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

3. 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 rivaroxaban
Warnings:
• 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
.
Precautions
Not 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 inhibitors
o Ketoconazole
o Ritonavir
o Clarithromycin
o Erythromycin
o Fluconazole
o *recommendation: avoid concomitant use of Xarelto and strong CYP3A4 + P-glycoprotein inhibitors.
Drugs that induce CYP3A4 and P-glycoprotein
o Rifampin
o Carbamazepine
o Phenytoin
o St. John’s Wort
o *Recommendation: avoid concomitant use of Xarelto and strong CYP3A4 + P-glycoprotein inducers
Medication Error Possibility
• None identified
Dosing and Administration
• See supplementary handout
References

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