Navigating Paxlovid Interactions With Anticoagulants

The introduction of nirmatrelvir/ritonavir (Paxlovid; Pfizer) marked a significant advancement in the fight against COVID-19. Ritonavir boosts plasma concentrations of nirmatrelvir by potently and irreversibly inhibiting CYP3A4. Because the onset of ritonavir’s inhibitory effect is rapid, even short courses of nirmatrelvir/ritonavir treatment can cause clinically relevant drug-drug interactions.¹

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Dabigatran (Pradaxa; Boehringer Ingelheim) targets thrombin (Factor IIa) in the anticoagulation cascade, irreversibly binding to the thrombin molecule and preventing thrombin-mediated activation of coagulation factors.² Evidence for clinical recommendations surrounding concomitant dabigatran and nirmatrelvir/ritonavir usage seems mixed. Depending on patient kidney function and indication for dabigatran, the concomitant use of the medication with nirmatrelvir/ritonavir may be acceptable with appropriate adjustments.

For patients with non-valvular atrial fibrillation, it is recommended to avoid using dabigatran with drugs containing ritonavir if their creatinine clearance (CrCl) is 15 to 30 ml/min. When treating or reducing the risk of deep venous thrombosis and pulmonary embolism in adult patients, it is also advised to avoid taking dabigatran with drugs containing ritonavir if their CrCl is less than 50 ml/min. When a patient’s CrCl is 50 ml/min or more, taking dabigatran and drugs containing ritonavir should be kept separate by several hours.³ The EU however, still does not recommend the concomitant use of dabigatran and nirmatrelvir/ritonavir due to lack of evidence concerning patient safety.⁴

Apixaban (Eliquis; Bristol-Myers Squibb) is a direct inhibitor of Factor Xa in the anticoagulation cascade, and a substrate of CYP3A4. Concomitant use with nirmatrelvir/ritonavir may increase the risk of bleeding in patients. A recent case study in New Jersey of a patient with atrial fibrillation warranting stroke prophylaxis found that dose-reduced apixaban is a safe and a viable choice, while concurrently receiving ritonavir-boosted highly active antiretroviral therapy.⁵ As such, the FDA recommends a 50% reduction for apixaban patients receiving 5 mg or 10 mg twice daily doses.⁶ If patients are already taking 2.5 mg twice daily, the coadministration of apixaban and drugs containing ritonavir should be avoided.⁷ In the EU, the use of apixaban is not recommended in patients who are receiving concomitant treatment with drugs containing ritonavir.⁸

Like apixaban, rivaroxaban (Xarelto; Janssen Pharmaceutical Companies) also directly inhibits Factor Xa. A nonrandomized, open-label study conducted in Germany found that the coadministration of ritonavir and rivaroxaban resulted in a statistically and potentially clinically significant increase in rivaroxaban AUC.⁹ Similarly, in a recent physiologically-based pharmacokinetic modeling study, the simulated coadministration of ritonavir with rivaroxaban was shown to increase rivaroxaban AUC and increase the risk of major bleeding, with higher risk in patients with renal impairment.¹⁰ Current COVID-19 treatment guidelines in the United States suggest withholding rivaroxaban during nirmatrelvir/ritonavir treatment and for 2 to 3 more days following discontinuation if possible, and considering alternate COVID-19 therapy if temporarily withholding rivaroxaban is not clinically reasonable.¹¹ The EU also does not recommend the use of rivaroxaban in patients who are receiving concomitant systemic treatment with ritonavir due to increased risk of bleeding.¹²

For patients on dabigatran, closely monitoring renal function and adjusting the dose accordingly can mitigate potential risks. In cases with patients taking apixaban, while the EU aligns with a more conservative strategy, adhering to the FDA’s recommendation of a 50% anticoagulant dose reduction during concurrent nirmatrelvir/ritonavir therapy seems prudent. The use of rivaroxaban should be withheld entirely during nirmatrelvir/ritonavir treatment so as to prioritize patient safety. The key takeaway is the necessity for a personalized, evidence-based approach that best reflects the needs of the patient and ensures the highest standards of care.

About the Authors

Evan Shockey is a PharmD candidate at the University of Maryland School of Pharmacy in Baltimore

Louis Ledan, PharmD, is a pharmacist at an ambulatory care pharmacy in Washington, DC.

REFERENCES

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