What is the recommended treatment regimen for COVID-19 using Nirmatrelvir (Paxlovid)?

Recommended Treatment Regimen for COVID-19 Using Nirmatrelvir (Paxlovid)

Nirmatrelvir-ritonavir combination therapy should be considered to treat symptomatic patients with confirmed mild to moderate COVID-19 in the outpatient setting who are within 5 days of symptom onset and at high risk for progressing to severe disease. 1

Dosage and Administration

• Standard dosage: 300 mg nirmatrelvir (two 150 mg tablets) with 100 mg ritonavir (one 100 mg tablet), with all 3 tablets taken together twice daily for 5 days 2
• Treatment should be initiated as soon as possible after diagnosis of COVID-19 and within 5 days of symptom onset for optimal effectiveness 2
• Administer orally with or without food at approximately the same time each day 2

Dose Adjustments for Special Populations

• Moderate renal impairment (eGFR ≥30 to <60 mL/min): 150 mg nirmatrelvir (one tablet) with 100 mg ritonavir (one tablet) twice daily for 5 days 2
• Severe renal impairment (eGFR <30 mL/min):
  • Day 1: 300 mg nirmatrelvir (two tablets) with 100 mg ritonavir (one tablet) once
  • Days 2-5: 150 mg nirmatrelvir (one tablet) with 100 mg ritonavir (one tablet) once daily 2
• Severe hepatic impairment: Not recommended in patients with Child-Pugh Class C 2

Patient Selection Criteria

• Treatment is specifically indicated for patients at high risk for progression to severe COVID-19 1, 3
• Not recommended for low-risk patients without risk factors for severe disease, as potential risks may outweigh benefits 3
• Treatment must be initiated within 5 days of symptom onset for optimal effectiveness 1, 3

Clinical Evidence Supporting Use

• Nirmatrelvir-ritonavir has demonstrated significant reduction in:
  • All-cause mortality (reduction shown in 4 studies) 1
  • COVID-19 mortality (reduction shown in 1 study) 1
  • COVID-19 hospital admission (reduction shown in 2 studies) 1
• The EPIC-HR trial showed an 89.1% relative risk reduction in COVID-19-related hospitalization or death when treatment was initiated within 3 days of symptom onset 4
• Recent evidence from a 2025 study demonstrated that nirmatrelvir-ritonavir reduced the 28-day risk of all-cause mortality by 86% in critically ill patients 5

Important Precautions and Contraindications

• Drug interactions: Significant drug interactions may occur due to ritonavir, a strong CYP3A inhibitor 2
  • Review all medications taken by the patient prior to prescribing
  • Determine if concomitant medications require dose adjustment, interruption, or additional monitoring 2
• Contraindications:
  • History of clinically significant hypersensitivity reactions to nirmatrelvir or ritonavir
  • Co-administration with drugs highly dependent on CYP3A for clearance
  • Co-administration with potent CYP3A inducers 2

Common Adverse Effects

• Most common adverse reactions (incidence ≥1% and greater than placebo):
  • Dysgeusia (altered taste) - reported in 5.8% of patients 2, 6
  • Diarrhea - reported in 2.1-3.1% of patients 2, 6

Clinical Pearls and Pitfalls

• Nirmatrelvir-ritonavir is generally considered more efficacious than molnupiravir for reducing hospitalization in high-risk patients 7
• Delaying treatment beyond 5 days of symptom onset significantly reduces effectiveness 3
• For patients with drug interactions or contraindications to nirmatrelvir-ritonavir, alternative options include molnupiravir or remdesivir 8, 7
• HIV-1 drug resistance may develop in individuals with uncontrolled or undiagnosed HIV-1 infection 2
• Hepatotoxicity: Monitor for hepatic transaminase elevations, clinical hepatitis, and jaundice 2

By following this treatment regimen and carefully selecting appropriate patients, nirmatrelvir-ritonavir can significantly reduce the risk of progression to severe COVID-19, hospitalization, and death in high-risk individuals.