How does Paxlovid (nirmatrelvir/ritonavir) affect International Normalized Ratio (INR) in patients taking warfarin?

Paxlovid's Effect on INR in Patients Taking Warfarin

Paxlovid (nirmatrelvir/ritonavir) can significantly increase INR values in patients taking warfarin due to ritonavir's strong inhibition of CYP3A4 and P-glycoprotein, requiring close monitoring and potential warfarin dose adjustment. 1

Mechanism of Interaction

Paxlovid affects warfarin metabolism through multiple pathways:

• Ritonavir component:

  • Strong inhibitor of CYP3A4 enzymes
  • Inhibits P-glycoprotein transporter protein
  • Paradoxically, also induces CYP2C9 and CYP1A2, which can increase clearance of the more potent S-isomer of warfarin 2

• Nirmatrelvir component:

  • Functions as both substrate and inhibitor of CYP3A enzymes
  • Affects P-glycoprotein transporter protein 1

Clinical Impact on INR

The interaction between Paxlovid and warfarin presents a complex situation:

• Paradoxically, antiretroviral regimens containing ritonavir often require higher doses of warfarin to maintain therapeutic INR values 2
• This is contrary to what might be expected from a CYP3A4 inhibitor, and is attributed to ritonavir's simultaneous induction of CYP2C9 and CYP1A2 2
• The effect can vary between patients based on genetic variations in CYP2C9 and VKORC1 enzymes 3

Monitoring Recommendations

When initiating Paxlovid in patients on warfarin:

1. Check baseline INR before starting Paxlovid
2. Monitor INR within 2-3 days of initiating Paxlovid therapy
3. Continue frequent INR monitoring throughout Paxlovid treatment course
4. Extend monitoring for 2-4 weeks after Paxlovid discontinuation, as enzyme effects may persist 2

Management Strategies

To manage this drug interaction effectively:

• Consider temporary warfarin dose adjustment (typically 25-33% reduction or increase based on the specific patient response)
• Maintain close communication between healthcare providers managing the patient's anticoagulation
• Be vigilant for signs of bleeding or thrombotic events
• Avoid other medications that may further affect warfarin metabolism during Paxlovid treatment

Risk Factors for Adverse Outcomes

Patients at higher risk for complications from this interaction include:

• Elderly patients (>75 years)
• Those with renal or hepatic impairment
• Patients with history of bleeding disorders
• Those on multiple medications with potential interactions
• Patients with unstable INR values prior to Paxlovid initiation 2, 3

Clinical Implications

• The risk of bleeding increases exponentially when INR exceeds 4.5-5.0 4, 5
• Even patients with therapeutic INR values can experience bleeding complications if other factors are present 6
• Surgical procedures may need to be delayed if INR becomes elevated 7

This interaction highlights the importance of vigilant monitoring and proactive management when prescribing Paxlovid to patients on warfarin therapy to prevent potentially serious bleeding complications.