Is it safe to take naproxen (Nonsteroidal Anti-Inflammatory Drug) and Xarelto (rivaroxan, Factor Xa inhibitor) together?

Combining Naproxen and Xarelto: High-Risk Combination Requiring Caution

The FDA explicitly warns to avoid concurrent use of Xarelto (rivaroxaban) with NSAIDs like naproxen due to increased bleeding risk, and if combination therapy is necessary, patients must be promptly evaluated for any signs or symptoms of blood loss 1.

Bleeding Risk Magnitude

The combination of rivaroxaban and NSAIDs significantly increases bleeding risk through additive anticoagulant and antiplatelet effects:

• NSAIDs combined with anticoagulants increase gastrointestinal bleeding risk 3- to 6-fold compared to anticoagulants alone 2.
• NSAID users taking warfarin (a comparable anticoagulant) have approximately a 3-fold increase in gastrointestinal bleeding 2.
• Meta-analysis data shows concomitant rivaroxaban and NSAID use increases bleeding risk (OR 1.61; 95% CI 1.21-2.14) compared to rivaroxaban alone 3.
• Studies specifically with naproxen and rivaroxaban demonstrated significantly increased bleeding time compared to rivaroxaban alone, though the clinical significance varied among individuals 4.

When Combination Cannot Be Avoided

If the combination is medically necessary despite the risks, implement the following protocol:

Risk Assessment Before Prescribing

• Evaluate baseline bleeding risk factors: age >65 years (2-3.5-fold increased risk), prior GI bleeding (2.5-4-fold increased risk), renal impairment (CrCl 15-80 mL/min), concurrent corticosteroids (2-fold increased risk), or concurrent antiplatelet agents 2.
• Calculate creatinine clearance using Cockcroft-Gault formula - rivaroxaban should not be used with NSAIDs in patients with CrCl 15 to <80 mL/min unless potential benefit justifies the risk 1.
• Assess liver function - avoid in Child-Pugh B or C cirrhosis or transaminases >2x upper limit of normal 5.

Mandatory GI Prophylaxis

• Initiate proton pump inhibitor therapy - reduces bleeding ulcer risk by 75-85% in high-risk NSAID users 2.
• Use the lowest effective dose of naproxen for the shortest duration possible 5.

Monitoring Requirements

• Monitor for bleeding signs: unusual bruising, prolonged bleeding from cuts, black/tarry stools, blood in urine, hematemesis 5, 1.
• Consider periodic hemoglobin/hematocrit assessment, especially in high-risk patients (elderly, renal impairment, prior GI events) 5.

Critical Pitfalls to Avoid

• Never use triple therapy (rivaroxaban + NSAID + antiplatelet agent like aspirin) - this substantially increases bleeding risk beyond acceptable levels 5, 1.
• Do not overlook over-the-counter NSAID use - patients may be taking additional NSAIDs without reporting them 2.
• Avoid in patients with recent ulcer bleeding - these patients have the highest risk of recurrent bleeding 2.
• Do not assume all NSAIDs are equivalent - nonselective NSAIDs like naproxen carry higher GI bleeding risk than COX-2 selective inhibitors when combined with anticoagulants 2, 6.

Alternative Strategies

Consider safer alternatives before accepting this high-risk combination:

• Acetaminophen has low cross-reactivity with anticoagulants and should be first-line for pain management 2.
• COX-2 selective inhibitors may have lower bleeding risk than naproxen when combined with anticoagulants, though data are limited 2.
• Temporarily hold rivaroxaban if NSAID use is short-term and thromboembolic risk is low 2.