Xarelto - Drug Monograph

Introduction

Xarelto (rivaroxaban) is an oral anticoagulant medication belonging to the class of direct factor Xa inhibitors. Developed by Bayer and Janssen Pharmaceuticals, it was first approved by the FDA in 2011. Xarelto represents a significant advancement in anticoagulation therapy, offering several advantages over traditional vitamin K antagonists, including predictable pharmacokinetics, fixed dosing, and no requirement for routine coagulation monitoring.

Mechanism of Action

Rivaroxaban selectively and competitively inhibits factor Xa (both free and clot-bound), which is a key component in the coagulation cascade. By blocking factor Xa, the drug prevents the conversion of prothrombin to thrombin, thereby reducing thrombus formation. Unlike indirect factor Xa inhibitors that require antithrombin III as a cofactor, rivaroxaban directly inhibits factor Xa without requiring any cofactors.

Indications

• Reduction of risk of stroke and systemic embolism in nonvalvular atrial fibrillation
• Treatment of deep vein thrombosis (DVT)
• Treatment of pulmonary embolism (PE)
• Reduction in risk of recurrence of DVT and/or PE
• Prophylaxis of DVT following hip or knee replacement surgery
• Reduction of risk of major cardiovascular events in patients with coronary artery disease or peripheral artery disease
• Prophylaxis of venous thromboembolism in acutely ill medical patients at risk for thromboembolic complications

Dosage and Administration

• Atrial fibrillation: 20 mg once daily with evening meal
• DVT/PE treatment: 15 mg twice daily with food for first 21 days, then 20 mg once daily with food
• DVT/PE prophylaxis after hip/knee surgery: 10 mg once daily
• CAD/PAD: 2.5 mg twice daily with or without food

• Renal impairment: Dose adjustment required for CrCl <50 mL/min in AFib patients (15 mg daily)
• Hepatic impairment: Avoid in patients with moderate-to-severe hepatic impairment
• Elderly: Consider renal function for dosing adjustments

Pharmacokinetics

• Absorption: Rapid oral absorption with 80-100% bioavailability when taken with food
• Distribution: Volume of distribution approximately 50 L; 92-95% plasma protein bound
• Metabolism: Primarily metabolized via CYP3A4/5 and CYP2J2 isoenzymes
• Elimination: Renal elimination (66%, with 36% as unchanged drug) and fecal excretion (28%)
• Half-life: 5-9 hours in healthy young subjects, 11-13 hours in elderly patients

Contraindications

• Active pathological bleeding
• Severe hypersensitivity reaction to rivaroxaban
• Patients with mechanical heart valves (not studied in clinical trials)
• Triple positive antiphospholipid syndrome (increased thrombotic risk)

Warnings and Precautions

• Increased risk of thrombotic events with premature discontinuation: Implement bridging strategy if discontinuation necessary
• Spinal/epidural hematoma risk: May occur with neuraxial anesthesia or spinal puncture
• Risk of bleeding: Can cause serious and fatal bleeding
• Renal impairment: Increased exposure and bleeding risk in patients with CrCl <30 mL/min
• Pregnancy: Not recommended; limited human data available
• Labor and delivery: Safety not established

Drug Interactions

• Ketoconazole, itraconazole, ritonavir: Avoid concomitant use
• Clarithromycin, erythromycin: Use with caution

• Rifampin, carbamazepine, phenytoin: May decrease rivaroxaban levels

• Increased bleeding risk when used with warfarin, aspirin, clopidogrel, NSAIDs

Adverse Effects

• Bleeding complications (various types)
• Nausea
• Pruritus
• Pain in extremities
• Elevated transaminases

• Major bleeding events
• Spinal/epidural hematoma
• Thrombocytopenia (rare)
• Severe hypersensitivity reactions

Monitoring Parameters

• Signs and symptoms of bleeding
• Renal function (serum creatinine at baseline and periodically)
• Hemoglobin/hematocrit
• Liver function tests
• Compliance with dosing instructions
• Signs of thrombotic events if discontinued

Patient Education

• Take exactly as prescribed with food for higher dose formulations
• Do not discontinue without consulting healthcare provider
• Report any signs of bleeding (unusual bruising, blood in urine/stool)
• Inform all healthcare providers about Xarelto use before any procedures
• Use reliable contraception if sexually active and of childbearing potential
• Report any planned surgeries or dental procedures
• Be aware of increased fall risk and take appropriate precautions

References

1. Patel MR, et al. Rivaroxaban versus Warfarin in Nonvalvular Atrial Fibrillation. N Engl J Med. 2011;365(10):883-891. 2. Xarelto [package insert]. Titusville, NJ: Janssen Pharmaceuticals; 2023. 3. Weitz JI, et al. Rivaroxaban or Aspirin for Extended Treatment of Venous Thromboembolism. N Engl J Med. 2017;376(13):1211-1222. 4. Eikelboom JW, et al. Rivaroxaban with or without Aspirin in Stable Cardiovascular Disease. N Engl J Med. 2017;377(14):1319-1330. 5. FDA-approved labeling for Xarelto. Accessed through DailyMed. 6. Steffel J, et al. 2021 European Heart Rhythm Association Practical Guide on the Use of Non-Vitamin K Antagonist Oral Anticoagulants in Patients with Atrial Fibrillation. Europace. 2021;23(10):1612-1676.