Is it safe to use Paxlovid (nirmatrelvir/ritonavir) and Eliquis (apixaban) together?

Paxlovid and Eliquis: Significant Drug Interaction Requiring Intervention

Co-administration of Paxlovid (nirmatrelvir/ritonavir) with Eliquis (apixaban) creates a clinically significant drug interaction that substantially increases bleeding risk and requires either dose reduction of apixaban, temporary switching to an alternative anticoagulant, or enhanced monitoring. 1

Mechanism of Interaction

The ritonavir component of Paxlovid is a potent CYP3A4 inhibitor that dramatically slows the metabolism of apixaban, which is a substrate of both CYP3A4 and P-glycoprotein (P-gp). 1, 2 This dual inhibition leads to:

• Increased apixaban blood levels that can exceed safe therapeutic ranges 1
• Elevated bleeding risk particularly in patients with additional risk factors 1
• Prolonged drug exposure due to ritonavir's pharmacokinetic enhancement effect 3, 2

Ritonavir affects approximately 60% of available medications through CYP3A4 inhibition, making it a significant source of drug-drug interactions. 2

Management Strategies

Option 1: Temporary Anticoagulant Switch (Preferred)

Consider switching to low molecular weight heparin (LMWH) during the 5-day Paxlovid treatment course. 1 This approach:

• Eliminates the drug interaction entirely
• Provides reliable anticoagulation without dose adjustment concerns
• Can be resumed to apixaban after Paxlovid completion

Option 2: Apixaban Dose Reduction

If continuing apixaban is necessary, reduce the dose by 25% during Paxlovid therapy. 4 This strategy:

• Mitigates but does not eliminate the interaction risk
• Requires careful calculation based on current apixaban dosing (standard 5 mg twice daily would become approximately 3.75 mg twice daily, though this creates practical dosing challenges with available tablet strengths)
• Demands heightened monitoring for bleeding complications 1

Option 3: Enhanced Monitoring Without Dose Change

If neither switching nor dose reduction is feasible:

• Monitor closely for bleeding signs and symptoms throughout the 5-day Paxlovid course and for 2-3 days after completion 1
• This is the least preferred option given the predictable pharmacokinetic interaction

High-Risk Patient Populations

Exercise particular caution in patients with: 1

• Renal impairment (reduced drug clearance compounds the interaction)
• Advanced age (>75 years)
• Low body weight (<60 kg)
• Concurrent antiplatelet therapy
• History of bleeding disorders
• Recent surgery or trauma

Patient Education Requirements

Instruct patients to immediately report: 1

• Unusual bruising or bleeding
• Blood in urine or stool (red, black, or tarry stools)
• Prolonged bleeding from cuts
• Severe headache or dizziness
• Coughing up blood or vomit that looks like coffee grounds

Alternative DOAC Considerations

Edoxaban represents the safest DOAC option with Paxlovid if switching anticoagulants is considered, as it demonstrates minimal clinically significant interactions and never requires dose adjustment with ritonavir-containing regimens. 4, 1 However, switching between DOACs requires careful timing and bridging considerations based on renal function and thromboembolic risk.

Clinical Pitfalls to Avoid

• Do not assume standard apixaban dosing is safe during Paxlovid therapy—the interaction is predictable and significant 1, 2
• Do not rely solely on patient symptoms to detect interaction—proactive management is essential 1
• Do not forget to resume standard anticoagulation after the 5-day Paxlovid course if temporary adjustments were made
• Do not overlook the 2-3 day washout period after Paxlovid completion, as ritonavir effects persist beyond the treatment course 2