What is the efficacy and prescribing recommendations for Paxlovid (nirmatrelvir and ritonavir) in adults with confirmed COVID-19, particularly those with underlying health conditions such as diabetes, hypertension, or respiratory diseases, and impaired renal function?

Paxlovid Efficacy and Prescribing Recommendations

Effectiveness

Paxlovid (nirmatrelvir/ritonavir) demonstrates substantial clinical benefit in high-risk COVID-19 patients, with real-world data showing a 39% reduction in hospitalization risk and 61% reduction in mortality. 1

Key Efficacy Outcomes

• Hospitalization reduction: Meta-analysis shows significant reduction (RR = 0.53; 95% CI: 0.24-0.69, p < 0.001) in hospitalization rates compared to no treatment 2
• Mortality benefit: All-cause mortality significantly reduced (RR = 0.36; 95% CI: 0.27-0.50, p < 0.001) 2
• Combined endpoint: Hospitalization or death reduced by 50% (RR = 0.50; 95% CI: 0.37-0.67, p < 0.001) 2
• ICU admissions: Reduced by 55% (RR = 0.45; 95% CI: 0.27-0.73, p = 0.001) 2
• Hospital length of stay: Shortened by approximately 1.1 days (WMD = -1.11; 95% CI, -1.81, -0.41) 2

The benefits remain consistent across vaccinated and unvaccinated populations and against Omicron subvariants through August 2023. 1

Prescribing Recommendations

Patient Selection Criteria

Prescribe Paxlovid ONLY to patients with confirmed mild-to-moderate COVID-19 who are at HIGH risk for progression to severe disease, within 5 days of symptom onset. 3, 1, 4

High-Risk Criteria (Treat These Patients):

• Age ≥65 years 1, 5
• Unvaccinated or vaccine non-responders 1, 5
• Immunocompromised status, including hematological malignancies 1, 6, 5
• Multiple comorbidities: diabetes, cardiovascular disease, chronic lung disease, chronic kidney disease, obesity 1, 6
• Radiographic evidence of pneumonia 1

Low-Risk Patients (DO NOT Treat):

Do not prescribe Paxlovid to low-risk patients without risk factors for severe disease, as potential risks of drug interactions and adverse effects outweigh trivial benefits. 1, 6

Dosing Regimen

Standard Dosing (Normal Renal Function):

• 300 mg nirmatrelvir (two 150 mg tablets) with 100 mg ritonavir (one 100 mg tablet) taken together twice daily for 5 days 4
• Administer orally with or without food 4
• Take at approximately the same time each day 4

Renal Impairment Dosing:

Moderate renal impairment (eGFR 30-59 mL/min):

• 150 mg nirmatrelvir (one tablet) with 100 mg ritonavir (one tablet) twice daily for 5 days 4

Severe renal impairment (eGFR <30 mL/min) including hemodialysis:

• 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 4
• On hemodialysis days, administer after dialysis 4

Evidence supports nirmatrelvir-ritonavir use in advanced kidney disease (eGFR <30 mL/min), showing lower all-cause mortality (HR: 0.624,95% CI: 0.455-0.857) and hospitalization (HR: 0.782,95% CI: 0.64-0.954) compared to molnupiravir. 7

Timing Requirements

Initiate treatment as soon as possible after COVID-19 diagnosis and MUST be within 5 days of symptom onset. 3, 1, 4 Delaying beyond 5 days significantly reduces effectiveness. 1

Critical Contraindications and Warnings

Absolute Contraindications:

• History of clinically significant hypersensitivity to nirmatrelvir or ritonavir 4
• Co-administration with drugs highly dependent on CYP3A for clearance where elevated concentrations cause serious/life-threatening reactions 4
• Co-administration with potent CYP3A inducers 4
• Severe hepatic impairment (Child-Pugh Class C) 4

Drug Interaction Management (CRITICAL):

BEFORE prescribing Paxlovid, you MUST review ALL patient medications to assess drug-drug interactions with ritonavir, a strong CYP3A inhibitor, which can cause potentially severe, life-threatening, or fatal events. 4, 6

• Use the Liverpool COVID-19 drug interaction tool to screen all medications 6
• Determine if concomitant medications require dose adjustment, temporary interruption, or additional monitoring 4
• Common problematic interactions include: statins, anticoagulants, immunosuppressants, antiarrhythmics, and sedatives 4
• Do NOT stop nucleoside antivirals in patients with hepatitis B during COVID-19 treatment to avoid HBV reactivation 6

Special Populations

Pregnant and breastfeeding patients: May consider Paxlovid use through shared decision-making about potential risks versus benefits, though data are limited. 1, 6 Remdesivir is the preferred alternative in pregnancy. 1

HIV-positive patients: Paxlovid use may lead to HIV-1 developing resistance to HIV protease inhibitors in individuals with uncontrolled or undiagnosed HIV-1 infection. 4

Alternative Therapies When Paxlovid Contraindicated

Remdesivir is the preferred alternative, particularly for patients with problematic drug interactions with ritonavir, pregnant patients, and children—administered as a 3-day IV course. 1, 6, 5

Molnupiravir is a less effective oral option when Paxlovid is unavailable or contraindicated, though inferior to nirmatrelvir/ritonavir in indirect comparisons. 3, 1, 6

Common Pitfalls to Avoid

• Missing the 5-day treatment window: Emphasize early testing and rapid treatment initiation 6
• Failing to screen for drug interactions: This is the most critical safety concern and can result in life-threatening events 6, 4
• Prescribing to low-risk patients: No benefit justifies the interaction risks 1, 6
• Incorrect dosing in renal impairment: Must adjust dose based on eGFR 4
• Using as prophylaxis: Paxlovid is NOT approved for pre-exposure or post-exposure prophylaxis 4

Adverse Events

Most common adverse reactions (incidence ≥1%) are dysgeusia (altered taste) and diarrhea, which are generally mild to moderate in severity. 4, 8 Serious hypersensitivity reactions including anaphylaxis, toxic epidermal necrolysis, and Stevens-Johnson syndrome have been reported—discontinue immediately if these occur. 4