What are the contraindications and precautions for Rivaroxaban (Xarelto)?

Rivaroxaban Contraindications and Precautions

Absolute Contraindications

Rivaroxaban is absolutely contraindicated in patients with active pathological bleeding, severe hypersensitivity reactions to the drug, Child-Pugh B or C hepatic impairment, and concomitant use with combined strong CYP3A4 and P-glycoprotein inhibitors. 1

Active Bleeding and Coagulopathy

• Active pathological bleeding is an absolute contraindication per FDA labeling 1
• Hepatic disease associated with coagulopathy contraindicates use, regardless of Child-Pugh classification 1
• Patients with elevated transaminases exceeding twice the upper limit of normal should not be started on rivaroxaban, particularly when laboratory signs of coagulopathy are present 2

Severe Hepatic Impairment

• Child-Pugh B and C liver cirrhosis represents an absolute contraindication 2, 1
• Active liver disease excluded patients from all clinical trials, providing no safety data for this population 2

Drug-Drug Interactions: Absolute Contraindications

• Combined strong CYP3A4 and P-glycoprotein inhibitors are contraindicated as they increase rivaroxaban exposure by approximately 2.5-fold 2, 3, 4
• Specifically contraindicated agents include:
  • Azole antifungals: ketoconazole, itraconazole, voriconazole, posaconazole 2, 3
  • HIV protease inhibitors (including ritonavir in Paxlovid) 2, 3, 4
• These dual inhibitors increase rivaroxaban AUC by 2.5-fold and peak concentrations by 1.7-fold, creating substantially elevated bleeding risk 4

Major Precautions and Dose Adjustments

Renal Impairment

Severe renal insufficiency (CrCl 15-29 mL/min) requires dose reduction from 20 mg to 15 mg once daily for atrial fibrillation, though clinical trial data supporting this range is extremely limited. 2

• Renal clearance accounts for approximately one-third of rivaroxaban elimination 2
• CrCl should always be calculated using Cockcroft-Gault formula before prescribing 2, 4
• Moderate renal impairment (CrCl 30-49 mL/min): dose reduction to 15 mg once daily recommended for atrial fibrillation 2
• Severe renal impairment (CrCl 15-29 mL/min): use with extreme caution as these patients were excluded from ROCKET AF and EINSTEIN trials 2
• Avoid use in CrCl <15 mL/min 1
• Periodic renal function monitoring is essential, particularly in elderly patients where renal function can deteriorate 2

Neuraxial Anesthesia and Spinal Procedures

Epidural or spinal hematomas can occur in patients receiving rivaroxaban who undergo neuraxial anesthesia or spinal puncture, potentially resulting in permanent paralysis. 1

• Monitor patients frequently for signs and symptoms of neurological impairment 1
• If neurological compromise is observed, urgent treatment is required 1
• Carefully weigh benefits versus risks before neuraxial intervention in anticoagulated patients 1

Drug-Drug Interactions: Use with Caution

Moderate CYP3A4 or P-glycoprotein inhibitors increase rivaroxaban exposure and require careful evaluation, particularly in patients with moderate renal impairment. 2, 3

• Drugs that inhibit only CYP3A4 or only P-glycoprotein (clarithromycin, erythromycin, verapamil) increase rivaroxaban exposure but are not absolutely contraindicated 2, 5
• Verapamil coadministration substantially increases rivaroxaban exposure across all renal function categories, requiring dose reduction to 10-15 mg daily in most patients 5
• In patients with moderate to severe renal impairment taking verapamil, reduce rivaroxaban to 10 mg daily to keep bleeding risk below 4.5% threshold 5

Strong CYP3A4 inducers decrease rivaroxaban exposure by approximately 50%, potentially reducing efficacy. 2, 3

• Use with caution: rifampicin, phenytoin, carbamazepine, phenobarbital, St. John's wort 2, 3
• These agents may compromise anticoagulant effectiveness 2

Antiplatelet Agents and NSAIDs

Concomitant use of antiplatelet agents or NSAIDs increases bleeding risk through additive mechanisms and should be avoided unless specifically indicated. 2, 6

• Aspirin <100 mg was allowed in clinical trials and increased bleeding risk similarly to warfarin 2
• Avoid triple therapy (rivaroxaban + NSAID + antiplatelet agent) as this substantially increases bleeding risk 6
• NSAIDs and antiplatelet drugs should be avoided unless specifically indicated (e.g., mechanical heart valves, acute coronary syndrome) 2

Special Populations Requiring Caution

Elderly patients (≥75-80 years), particularly those with multiple comorbidities, concomitant medications, or low body weight, require heightened vigilance despite lack of specific dose adjustments. 2, 3

• Very elderly patients with concomitant renal insufficiency were likely underrepresented in clinical trials 2
• Mean age in ROCKET AF was 73 years; real-world patients may be more complex 2
• Low body weight (<50 kg) requires caution though routine dose adjustment is not required 3

Pregnancy and Obstetric Considerations

Use rivaroxaban with caution in pregnant women due to potential for obstetric hemorrhage and/or emergent delivery. 1

Prosthetic Heart Valves and Antiphospholipid Syndrome

• Rivaroxaban use is not recommended in patients with prosthetic heart valves 1
• Not recommended in patients with triple positive antiphospholipid syndrome due to increased thrombosis risk 1

Cancer-Specific Considerations

Patients with gastric or gastroesophageal tumors are at increased risk for hemorrhage with rivaroxaban; LMWHs are preferred in this setting. 2

• Edoxaban showed excess major bleeding confined to gastrointestinal cancer patients in Hokusai VTE Cancer Study 2
• Apixaban may be safer than rivaroxaban for patients with gastric or gastroesophageal lesions 2

Premature Discontinuation Warning

Premature discontinuation of rivaroxaban increases the risk of thrombotic events; consider coverage with another anticoagulant if discontinued for reasons other than pathological bleeding or completion of therapy. 1

Monitoring Requirements

• Baseline laboratory assessment: complete blood count, PT, aPTT, serum creatinine, transaminases, bilirubin 2
• Calculate CrCl using Cockcroft-Gault formula before initiation 2, 4
• Periodic renal function monitoring, particularly in elderly and those with baseline impairment 2
• Monitor for bleeding signs, especially during concomitant use of interacting medications 4