UMEM Educational Pearls

Nirmatrelvir-ritonavir (Paxlovid™) is a combination of two protease inhibitors used for the treatment of mild-moderate symptomatic COVID-19. Nirmatrelvir inhibits the SARS-CoV2 main protease, and ritonavir inhibits metabolism of nirmatrelvir, acting as a “booster” to increase nirmatrelvir concentrations. 

The EPIC-HR trial, which included non-hospitalized adults with mild-moderate COVID-19 who were unvaccinated and at risk of progressing to severe disease, showed an 89% reduction in COVID-19-related hospitalization or 28-day all-cause mortality in patients treated with nirmatrelvir-ritonavir compared to placebo. The efficacy rates in this trial were similar to remdesivir (87% relative risk reduction), and greater than molnupiravir (31% relative risk reduction), two alternative agents used for treatment of mild-moderate COVID-19. However, these three agents have never been directly compared. Nirmatrelvir-ritonavir was initially approved by the FDA under Emergency Use Authorization (EUA), but is now fully FDA-approved as of May 2023. 

Which patients benefit?

• Mild – moderate COVID-19 symptoms
  • ED or outpatients
  • Hospitalized patients who are admitted for reasons other than COVID-19
• Not requiring supplemental oxygen above baseline needs
• Presenting within 5-7 days of symptom onset
• Risk factor(s) for progression to severe disease
  • Age > 65
  • Comorbidities such as diabetes, chronic lung disease, asthma, malignancy, etc.
  • Immunocompromise

Drug-Drug Interactions:

• Ritonavir strongly inhibits the CYP3A4 enzyme, which may significantly increase serum concentrations of medications metabolized by CYP3A4. Several common medications are metabolized by this enzyme and concomitant use may pose serious risk of toxicity.
• In many cases, drug-drug interactions can be managed safely with close monitoring or dose adjustments. Some may require use of alternative COVID-19 therapies such as remdesivir or molnupiravir.

Dosing:

• eGFR 60 mL/min or above: Nirmatrelvir 300 mg (2 tabs) + ritonavir 100 mg (1 tab) twice daily for 5 days
• eGFR >30 - <60 mL/min: Nirmatrelvir 150 mg (1 tab) + ritonavir 100 mg (1 tab) twice daily for 5 days
• eGFR <30 mL/min: Use is not recommended per the manufacturer, but retrospective studies have shown that reduced dosing is well-tolerated.

Common side effects:

• Diarrhea (3%)
• Altered sense of taste (5%)

Bottom Line: Paxlovid is appropriate for patients with symptomatic mild-moderate COVID-19 with risk factors for progression to severe disease. Ask your pharmacist for assistance evaluating drug-drug interactions!

References

• Ritonavir-boosted nirmatrelvir (Paxlovid™) [package insert]. New York, NY. Pfizer Inc. 2023.
• COVID-19 Treatment Guidelines Panel. Coronavirus Disease 2019 (COVID-19) Treatment Guidelines. National Institutes of Health. Available at https://www.covid19treatmentguidelines.nih.gov/. Accessed 11 Jan 2024.
• Hammond J, Leister-Tebbe H, Gardner A, Abreu P et al. Oral nirmatrelvir for high-risk non-hospitalized adults with COVID-19. N Engl J Med. 2022; 386:1397-1408
• Gottlieb RL, Vaca CE, Paredes R et al. Early remdesivir to prevent progression to severe COVID-19 in outpatients. N Engl J Med. 2022;386(4):305-315.
• Jayk Bernal A, Gomes da Silva MM, Musungaie DB et al. Molnupiravir for oral treatment of COVID-19 in nonhospitalized patients. N Engl J Med. 2022;386(6):509-520.
• Chan GCK, Lui GCY, Wong CNS, et al. Safety profile and clinical and virological outcomes of nirmatrelvir-ritonavir treatment in patients with advanced chronic kidney disease and coronavirus disease 2019 (COVID-19). Clin Infect Dis. 2023; 77(10):1406-1412.
• Hiremath S, Blake PG, Yeung A, et al. Early experience with modified dose nirmatrelvir/ritonavir in dialysis patients with coronavirus disease 2019. Clin J Am Soc Nephrol. 2023;18(4):485-490.

Additional resources:

• List of underlying medical conditions associated with risk of severe COVID-19: https://www.cdc.gov/coronavirus/2019-ncov/hcp/clinical-care/underlyingconditions.html
• Liverpool COVID-19 drug interaction resource: https://www.covid19-druginteractions.org/checker 
• UMMS COVID-19 guidance (Sanford Guide): https://webedition.sanfordguide.com/en/sanford-guide-online/disease-clinical-condition/coronavirus#autotoc-item-autotoc-1