Paxlovid-Warfarin Interaction
Paxlovid (nirmatrelvir/ritonavir) can cause unpredictable bidirectional changes in warfarin levels and INR, requiring close INR monitoring if co-administration is necessary. 1
Mechanism of Interaction
The interaction between Paxlovid and warfarin is complex and bidirectional due to ritonavir's effects on multiple metabolic pathways:
- Ritonavir paradoxically induces CYP2C9 and CYP1A2, which metabolize the more potent S-isomer of warfarin, potentially decreasing its anticoagulant effect and lowering INR 2, 3
- Ritonavir simultaneously inhibits CYP3A4, which metabolizes the R-isomer of warfarin, leading to increased R-warfarin concentrations 3
- The net effect is unpredictable - pharmacokinetic modeling suggests INR may decrease during treatment, but real-world case reports document supratherapeutic INR elevations during Paxlovid therapy 3, 4
FDA-Mandated Management
The FDA drug label explicitly states: "Closely monitor international normalized ratio (INR) if co-administration with warfarin is necessary." 1
This is not a contraindication, but requires intensive monitoring due to the unpredictable nature of the interaction.
Clinical Management Algorithm
During Paxlovid Treatment (Days 1-5):
- Check INR on Day 2 of Paxlovid therapy - this is when supratherapeutic INR has been documented to occur in real-world cases 4
- Recheck INR on Day 4-5 (end of treatment course) 4
- Be prepared to adjust warfarin dose by 15-30% based on INR results, though the direction of change is unpredictable 4
Post-Paxlovid Monitoring:
- Continue INR monitoring for 2 weeks after completing Paxlovid - enzyme induction effects persist well beyond drug discontinuation 3
- INR may remain supratherapeutic for several weeks after Paxlovid completion, as documented in case reports where therapeutic INR was not achieved until one month post-treatment 4
- Rivaroxaban exposure normalizes by Day 4 post-discontinuation, but warfarin's effects are more prolonged due to its longer half-life and the persistent enzyme modulation 3
Critical Pitfalls
- COVID-19 illness itself increases INR through decreased appetite, potential organ dysfunction, and altered vitamin K metabolism - this compounds the drug interaction and makes INR changes even less predictable 4
- Outpatient monitoring is challenging because acutely ill COVID-19 patients may have difficulty presenting for INR checks and are under isolation precautions 4
- Home INR testing is valuable for this population to enable frequent monitoring without clinic visits 4
Alternative Anticoagulation Considerations
- Rivaroxaban should be avoided with Paxlovid - the FDA label states "Increased bleeding risk with rivaroxaban. Avoid concomitant use." 1
- Apixaban and dabigatran require dose adjustments based on indication and renal function when co-administered with Paxlovid 1
- If feasible, consider temporarily switching to low molecular weight heparin during the 5-day Paxlovid course to avoid complex drug interactions, particularly in high-risk patients 5
Risk Stratification
Patients at highest risk for complications from this interaction include:
- Geriatric patients with renal impairment - pharmacokinetic modeling shows more profound drug interaction effects in this population 3
- Patients with baseline supratherapeutic INR - adding Paxlovid to already elevated INR significantly increases bleeding risk 4
- Patients with severe COVID-19 illness - the disease state itself potentiates warfarin effects through multiple mechanisms 4