How should Paxlovid (nirmatrelvir/ritonavir) be dosed for mild‑to‑moderate COVID‑19 in at‑risk patients, including adjustments for eGFR 30–59 mL/min/1.73 m², contraindications for eGFR < 30 mL/min/1.73 m² or severe hepatic impairment, food requirements, drug‑interaction precautions, and alternative options if contraindicated?

Paxlovid Dosing for Mild-to-Moderate COVID-19

For adults with mild-to-moderate COVID-19 at high risk for progression, prescribe nirmatrelvir 300 mg (two 150 mg tablets) with ritonavir 100 mg (one tablet) orally twice daily for 5 days, starting within 5 days of symptom onset, but reduce nirmatrelvir to 150 mg twice daily in patients with eGFR 30–59 mL/min/1.73 m², and avoid Paxlovid entirely in patients with eGFR < 30 mL/min/1.73 m² or severe hepatic impairment (Child-Pugh Class C). 1

Standard Dosing and Administration

• Administer nirmatrelvir 300 mg (two 150 mg tablets) with ritonavir 100 mg (one tablet) orally every 12 hours for 5 consecutive days. 2, 1
• Initiate treatment as soon as possible after COVID-19 diagnosis, ideally within 5 days of symptom onset—treatment beyond this window lacks efficacy data. 2, 3, 1
• Paxlovid may be taken with or without food, but should be administered at approximately the same time each day. 1

Renal Function Adjustments

Moderate Renal Impairment (eGFR 30–59 mL/min/1.73 m²)

• Reduce nirmatrelvir to 150 mg (one 150 mg tablet) while maintaining ritonavir 100 mg (one tablet) twice daily for all 5 days. 2, 1, 4
• This dose reduction is mandatory, not optional—nirmatrelvir clearance increases proportionally with creatinine clearance up to 70 mL/min/1.73 m². 4

Severe Renal Impairment (eGFR < 30 mL/min/1.73 m²)

• For patients with eGFR < 30 mL/min/1.73 m² including those on hemodialysis: Give nirmatrelvir 300 mg with ritonavir 100 mg once on Day 1, then reduce to nirmatrelvir 150 mg with ritonavir 100 mg once daily on Days 2–5. 1
• On hemodialysis days, administer Paxlovid after dialysis is completed. 1

Critical Monitoring Caveat

• Reassess renal function during treatment if clinical deterioration occurs, as COVID-19 itself can cause acute kidney injury and worsen renal function. 2

Hepatic Impairment Considerations

• Paxlovid is not recommended for patients with severe hepatic impairment (Child-Pugh Class C) because safety and pharmacokinetic data are lacking. 2, 1
• Clinical trials excluded patients with severe liver impairment; use with extreme caution in this population. 2
• Monitor for hepatotoxicity—hepatic transaminase elevations, clinical hepatitis, and jaundice have been reported with ritonavir. 3

Mandatory Pre-Treatment Drug Interaction Assessment

Before prescribing Paxlovid, systematically review all patient medications using the Liverpool COVID-19 Drug Interaction Tool—this is not optional. 2, 3, 5

Why This Matters

• Ritonavir is a potent CYP3A4 inhibitor that causes potentially life-threatening drug interactions during the 5-day treatment course and for several days after completion. 2, 1, 5
• Many commonly prescribed medications require dose adjustment, temporary discontinuation, or additional monitoring. 2, 3

Specific High-Risk Interactions

• Statins (especially simvastatin and lovastatin) may require temporary discontinuation. 3
• Immunosuppressants (tacrolimus, cyclosporine, mTOR inhibitors) require drastic dose reductions: tacrolimus should be discontinued or given as a microdose on Day 1; cyclosporine should be reduced to 20% of baseline dose. 6
• Ranolazine is absolutely contraindicated due to QT prolongation risk and torsades de pointes when plasma concentrations are elevated by CYP3A4 inhibition. 2
• Medications highly dependent on CYP3A for clearance are contraindicated if elevated concentrations cause serious or life-threatening reactions. 1

Patient Selection Criteria

High-Risk Patients Who Should Receive Paxlovid

• Age ≥65 years 3
• Immunocompromised status (including hematological malignancies, transplant recipients) 3
• Unvaccinated or vaccine non-responders 3
• Multiple chronic medical conditions 3

Patients Who Should NOT Receive Paxlovid

• Low-risk patients without risk factors for progression—benefits are trivial. 3
• Patients hospitalized primarily for non-COVID conditions who incidentally test positive. 3
• Patients with severe hepatic impairment (Child-Pugh Class C). 1
• Patients taking contraindicated medications that cannot be safely adjusted or discontinued. 1

Special Populations

Pregnancy

• Paxlovid may be offered to pregnant persons with COVID-19 to reduce disease progression, hospitalization, and death. 2, 3
• WHO Vigibase has not documented serious adverse reactions in either the pregnant individual or fetus to date. 2
• Balance the demonstrated benefit of reduced severe outcomes against theoretical fetal risks. 2

Vaccinated Patients

• Paxlovid remains effective in vaccinated populations, with similar absolute risk reduction for hospitalization compared to unvaccinated patients. 3, 7
• Absolute risk reduction for hospitalization is much greater among patients aged 65+ years than younger patients. 7

Monitoring and Adverse Effects

• Monitor for dysgeusia (altered taste) and diarrhea—these occur more frequently than with placebo but rarely necessitate discontinuation. 2, 3
• Watch for signs of drug accumulation in patients with renal impairment, which can manifest as more pronounced dysgeusia and diarrhea. 2
• Monitor for hepatotoxicity, particularly hepatic transaminase elevations. 3

Alternative Options if Paxlovid is Contraindicated

• When Paxlovid cannot be used due to drug interactions, severe renal impairment (if dosing adjustments are not feasible), or severe hepatic impairment, consider alternative COVID-19 antiviral therapies based on the patient's risk profile. 2
• Clinical judgment should guide whether treatment is appropriate in complex cases. 3

Clinical Effectiveness Data

• Paxlovid reduces the risk of hospitalization by 39% (absolute risk reduction 0.9 percentage points) and death by 61% (absolute risk reduction 0.2 percentage points) in real-world settings. 7
• Meta-analysis confirms significant reductions in hospitalization (RR 0.53), all-cause mortality (RR 0.36), ICU admission (RR 0.45), and emergency department visits (RR 0.67). 8
• Paxlovid shortens hospital length of stay and PCR negative conversion time. 8