When should Paxlovid (nirmatrelvir/ritonavir) be prescribed for COVID-19?

When to Prescribe Paxlovid for COVID-19

Prescribe Paxlovid (nirmatrelvir/ritonavir) to adults with confirmed mild-to-moderate COVID-19 who are at high risk for progression to severe disease, initiating treatment within 5 days of symptom onset. 1, 2, 3

Patient Selection Criteria

Timing Requirements

• Treatment must begin within 5 days of symptom onset to be effective 1, 3
• Initiate as soon as possible after COVID-19 diagnosis is confirmed 3
• The antiviral window is critical—early viral replication peaks occur at day 4 in mild cases and day 8 in moderate-severe cases, making early intervention essential 1

High-Risk Populations Who Should Receive Paxlovid

Prescribe to patients with at least one of the following risk factors 2:

• Age ≥65 years (absolute risk reduction for hospitalization is substantially greater in this group) 4
• Immunosuppression or immunocompromised status (including organ transplant recipients) 2
• Hematological malignancies or history of hematopoietic cell transplantation 2
• Underlying chronic medical conditions (cardiovascular disease, diabetes, chronic kidney disease, chronic lung disease, neurological conditions) 5

Vaccination Status Does Not Exclude Treatment

• Paxlovid remains effective even in vaccinated patients, including those with ≥3 mRNA vaccine doses (adjusted hazard ratio 0.50 for hospitalization) 6
• The absolute risk reduction for hospitalization is similar between vaccinated and unvaccinated patients 4
• Both Paxlovid and vaccination provide independent protective effects 5

Contraindications and Precautions

Absolute Contraindications 3

• History of clinically significant hypersensitivity to nirmatrelvir or ritonavir
• eGFR <30 mL/min/1.73 m² (requires dose adjustment; see below)
• ALT ≥5 times upper limit of normal
• Severe hepatic impairment (Child-Pugh Class C)
• Concomitant use of drugs highly dependent on CYP3A for clearance where elevated concentrations cause serious/life-threatening reactions
• Concomitant use of potent CYP3A inducers

Critical Drug Interaction Assessment

Before prescribing, you must review ALL patient medications for potential interactions with ritonavir, a strong CYP3A inhibitor 3. This is the most common prescribing pitfall and can result in severe, life-threatening adverse events 3.

Dosing Regimen

Standard Dosing (eGFR ≥60 mL/min) 3

• 300 mg nirmatrelvir (two 150 mg tablets) + 100 mg ritonavir (one 100 mg tablet)
• Administer twice daily for 5 days
• Take all 3 tablets together at approximately the same time each day
• Can be taken with or without food

Dose Adjustments for Renal Impairment 3

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

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

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

• Day 1: 300 mg nirmatrelvir + 100 mg ritonavir ONCE
• Days 2-5: 150 mg nirmatrelvir + 100 mg ritonavir once daily
• On hemodialysis days, administer after dialysis 3

Expected Clinical Benefits

Effectiveness Data

• Reduces hospitalization risk by 39-49% in real-world settings 6, 4
• Reduces mortality risk by 61% (absolute risk reduction 0.2 percentage points) 4
• Absolute risk reduction for hospitalization is 0.9 percentage points overall 4
• Greatest benefit in patients ≥65 years compared to younger age groups 4
• More effective in immunosuppressed patients and those with cardiovascular or neurological disease 5

Important Limitation

Paxlovid is NOT effective in already-hospitalized patients with severe disease—a multicenter RCT showed no mortality benefit (4.92% vs 6.06%, p=0.39) when given to hospitalized patients 7. This underscores that Paxlovid works by preventing progression, not treating established severe disease.

Monitoring Requirements

Before Starting Treatment 8

• Assess hepatic function (ALT/AST)
• Assess renal function (eGFR)
• Check prothrombin time
• Complete medication reconciliation for drug interactions

During Treatment 3

• Discontinue if ALT increases to >10 times upper limit of normal
• Discontinue if ALT elevation accompanied by signs/symptoms of liver inflammation
• Monitor for hypersensitivity reactions (anaphylaxis, Stevens-Johnson syndrome, toxic epidermal necrolysis)

Common Pitfalls to Avoid

1. Delaying treatment beyond 5 days of symptom onset—efficacy is lost 3
2. Failing to screen for drug interactions before prescribing—this is the FDA's boxed warning 3
3. Withholding from vaccinated patients—they still benefit significantly 6, 4
4. Prescribing to already-hospitalized severe patients—no proven benefit in this population 7
5. Not adjusting dose for renal impairment—can lead to toxicity 3

Alternative Therapies When Paxlovid Unavailable or Contraindicated

• Remdesivir (3-day course for outpatients) 8, 2
• Molnupiravir (less effective than Paxlovid but acceptable alternative) 1, 2
• High-titer convalescent plasma (particularly for immunocompromised patients) 2

Health Equity Considerations

Real-world data reveals disparities in Paxlovid prescribing, with lower treatment rates among Black and Hispanic/Latino patients and those in socially vulnerable communities 4. Active efforts to ensure equitable access are essential, as the medication's benefits are not being uniformly distributed 4.