Rivaroxaban - Drug Monograph

Introduction

Rivaroxaban (brand name Xarelto®) is an oral anticoagulant belonging to the class of direct factor Xa inhibitors. It was first approved by the FDA in 2011 and 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 free and clot-bound factor Xa, a key serine protease in the coagulation cascade. By inhibiting factor Xa, rivaroxaban prevents the conversion of prothrombin to thrombin, thereby reducing thrombin generation and ultimately preventing fibrin clot formation. Unlike indirect factor Xa inhibitors, rivaroxaban does not require antithrombin III as a cofactor.

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 of risk of recurrence of DVT and PE
• Prophylaxis of DVT following hip or knee replacement surgery
• Reduction of risk of major cardiovascular events in patients with chronic coronary artery disease or peripheral artery disease

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 replacement: 10 mg once daily
• Chronic coronary artery disease/peripheral artery disease: 2.5 mg twice daily with or without food

• Renal impairment: Dose adjustment required for CrCl 15-50 mL/min
• Hepatic impairment: Not recommended in patients with moderate-to-severe impairment
• Elderly: Consider renal function when dosing

Pharmacokinetics

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

Contraindications

• Active pathological bleeding
• Severe hypersensitivity reaction to rivaroxaban
• Patients with mechanical heart valves
• Moderate-to-severe hepatic impairment (Child-Pugh B and C)
• Concomitant use with strong CYP3A4 and P-gp inhibitors in patients with renal impairment (CrCl <30 mL/min)

Warnings and Precautions

• Risk of bleeding: Increased risk of serious and potentially fatal bleeding
• Spinal/epidural hematoma risk with neuraxial anesthesia
• Premature discontinuation increases thrombotic risk
• Renal impairment: Increased exposure and bleeding risk
• Pregnancy: Use only if potential benefit justifies potential risk to fetus
• Laboratory test interference: Affects PT, INR, and aPTT

Drug Interactions

• Strong CYP3A4 and P-gp inhibitors (ketoconazole, ritonavir): Increase rivaroxaban exposure
• Strong CYP3A4 inducers (rifampin, carbamazepine): Decrease rivaroxaban exposure
• Anticoagulants, antiplatelets, NSAIDs: Increased bleeding risk

Adverse Effects

• Bleeding complications (major and minor)
• Nausea
• Elevated transaminases
• Pruritus
• Back pain

• Major bleeding events
• Spinal/epidural hematoma
• Hepatotoxicity
• Hypersensitivity reactions

Monitoring Parameters

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

Patient Education

• Take exactly as prescribed with food (for 15 mg and 20 mg doses)
• Do not discontinue without consulting healthcare provider
• Report any signs of bleeding (unusual bruising, blood in urine/stool)
• Inform all healthcare providers about rivaroxaban use before any procedures
• Use reliable contraception if of childbearing potential
• Avoid activities with high risk of injury/bleeding
• Seek immediate medical attention for trauma or signs of stroke

References

1. FDA. Xarelto (rivaroxaban) prescribing information. 2023. 2. Patel MR, et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med. 2011;365(10):883-891. 3. EINSTEIN Investigators. Oral rivaroxaban for symptomatic venous thromboembolism. N Engl J Med. 2010;363(26):2499-2510. 4. Weitz JI, et al. Rivaroxaban in patients with thrombotic antiphospholipid syndrome. N Engl J Med. 2023;388(4):319-328. 5. January CT, et al. 2019 AHA/ACC/HRS focused update of the 2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation. J Am Coll Cardiol. 2019;74(1):104-132.