What is the interaction between Paxlovid (nirmatrelvir/ritonavir) and apixaban?

Paxlovid and Apixaban Interaction: Management Recommendations

Paxlovid (nirmatrelvir/ritonavir) significantly increases apixaban blood levels due to strong CYP3A4 and P-gp inhibition, requiring a 50% dose reduction of apixaban when co-administration is necessary. 1

Mechanism of Interaction

• Apixaban is metabolized primarily through CYP3A4 enzymes and is a substrate for P-glycoprotein (P-gp) transport proteins 2
• Ritonavir, a component of Paxlovid, is a strong inhibitor of both CYP3A4 and P-gp transporters 1, 3
• This dual inhibition leads to increased plasma concentrations of apixaban, which can significantly increase bleeding risk 2
• The effect is more pronounced with combined P-gp and strong CYP3A4 inhibitors compared to P-gp inhibitors that only moderately inhibit CYP3A4 2

Clinical Implications

• Increased apixaban exposure (higher Cmax and AUC) leads to an elevated risk of bleeding complications 2
• The FDA drug label specifically notes that combined P-gp and strong CYP3A inhibitors like ritonavir increase blood levels of apixaban and increase bleeding risk 1
• Retrospective studies examining similar strong CYP3A4 and P-gp inhibitors (like clarithromycin) with apixaban found higher incidence of hospitalization for major bleeding compared to P-gp inhibitors alone 2
• Real-world evidence identifies anticoagulants including apixaban among the top drugs expected to cause drug-drug interactions with nirmatrelvir/ritonavir 4

Management Recommendations

For patients on standard apixaban dose (5 mg twice daily):

• Reduce apixaban dose by 50% (to 2.5 mg twice daily) when co-administered with Paxlovid 2, 1
• Monitor closely for signs of bleeding during the co-administration period 2, 1
• Resume standard apixaban dosing after completing the Paxlovid course (typically 5 days) 1

For patients already on reduced apixaban dose (2.5 mg twice daily):

• Concomitant use is not recommended as further dose reduction is not established 2, 1
• Consider alternative COVID-19 treatment options if possible 1
• If Paxlovid is deemed necessary, temporary switching to an alternative anticoagulant with less interaction potential may be warranted 2

Monitoring Recommendations

• Closely observe for signs of bleeding during co-administration 2, 1
• Be vigilant for unexpected bruising, prolonged bleeding from cuts, nosebleeds, bleeding gums, blood in urine or stool, and unusual headache 1
• The interaction effect persists throughout the Paxlovid treatment course (typically 5 days) 1, 3
• Return to the standard apixaban dosing regimen after completing Paxlovid 1

Special Considerations

• Patients with additional risk factors for bleeding (advanced age, renal impairment, concomitant antiplatelet therapy) may require even more careful monitoring 2
• The interaction is more significant than with moderate CYP3A4 inhibitors, where empiric dose reduction is not typically recommended 2
• Pharmacokinetic studies specifically examining Paxlovid-apixaban interaction in high-risk populations are limited 2, 3

This interaction represents a significant clinical concern requiring proactive management to minimize bleeding risk while maintaining therapeutic anticoagulation during COVID-19 treatment.