What are the rules for prescribing Paxlovid (nirmatrelvir/ritonavir) for COVID-19 treatment?

Paxlovid (Nirmatrelvir/Ritonavir) Prescribing Rules

Paxlovid should be prescribed only for patients with confirmed mild-to-moderate COVID-19 who are at high risk for progression to severe disease, initiated within 5 days of symptom onset, after mandatory screening for drug interactions. 1, 2, 3

Patient Eligibility Criteria

Must Meet ALL of the Following:

• Confirmed COVID-19 diagnosis with mild-to-moderate symptoms (not requiring supplemental oxygen) 2, 3
• Symptom onset within the past 5 days 1, 2, 3
• High risk for progression to severe disease based on at least one of the following criteria 1, 2:
  • Unvaccinated status 1
  • Age ≥65 years 2
  • Immunosuppression 2
  • Multiple comorbidities (≥3) 2
  • Hematological disease 2
  • Radiographic evidence of pneumonia 1

Patients Who Should NOT Receive Paxlovid:

• Low-risk patients without risk factors for severe disease (the absolute benefits are trivial and risks outweigh benefits) 4, 1
• Patients beyond 5 days of symptom onset (effectiveness significantly reduced) 1
• Patients with severe hepatic impairment (Child-Pugh Class C) 3
• Patients with contraindicated drug interactions (see below) 3

Mandatory Pre-Prescription Drug Interaction Screening

Before prescribing Paxlovid, you MUST review all patient medications using a drug interaction checker, as ritonavir is a strong CYP3A inhibitor that can cause potentially life-threatening drug interactions. 1, 2, 3, 5

Absolute Contraindications (Do NOT Prescribe):

• History of clinically significant hypersensitivity to nirmatrelvir or ritonavir 3
• Concomitant use of drugs highly dependent on CYP3A for clearance where elevated concentrations cause serious/life-threatening reactions 3, 5
• Concomitant use of potent CYP3A inducers (may cause loss of virologic response) 3

Management Options for Drug Interactions:

• Temporarily pause the interacting medication during the 5-day treatment course 5
• Adjust dose of the interacting medication 3, 5
• Provide additional monitoring and patient counseling 3, 5
• If interactions cannot be safely managed, use molnupiravir as alternative 2

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 3
• Administer orally with or without food 3
• Take at approximately the same time each day 3

Dose Adjustments for Renal Impairment:

Moderate Renal Impairment (eGFR ≥30 to <60 mL/min): 3

• Days 1-5: 150 mg nirmatrelvir (one 150 mg tablet) with 100 mg ritonavir (one 100 mg tablet) twice daily

Severe Renal Impairment (eGFR <30 mL/min, including hemodialysis): 3

• Day 1: 300 mg nirmatrelvir (two 150 mg tablets) with 100 mg ritonavir (one 100 mg tablet) once
• Days 2-5: 150 mg nirmatrelvir (one 150 mg tablet) with 100 mg ritonavir (one 100 mg tablet) once daily
• On hemodialysis days, administer after dialysis 3

Timing and Administration

• Initiate treatment as soon as possible after COVID-19 diagnosis 3
• Must start within 5 days of symptom onset (delaying beyond this significantly reduces effectiveness) 1, 3
• Complete the full 5-day course even if symptoms improve 3

Monitoring During Treatment

• Assess for hypersensitivity reactions (anaphylaxis, Stevens-Johnson syndrome, toxic epidermal necrolysis can occur) 3
• Monitor hepatic function if baseline liver abnormalities are present 1, 2, 3
• Ensure patient continues isolation per public health recommendations 1, 2

Important Safety Warnings

Boxed Warning - Significant Drug Interactions:

The FDA includes a boxed warning that ritonavir may lead to greater exposure of concomitant medications, resulting in potentially severe, life-threatening, or fatal events. 3 You must weigh the benefit of reducing hospitalization and death against the risk of drug interactions for each individual patient. 3

Other Serious Risks:

• Hepatotoxicity: hepatic transaminase elevations, clinical hepatitis, and jaundice have occurred with ritonavir 3
• HIV-1 drug resistance: may develop in individuals with uncontrolled or undiagnosed HIV-1 infection 3
• Hypersensitivity reactions: immediately discontinue if anaphylaxis or serious skin reactions occur 3

Common Pitfalls to Avoid

• Do not prescribe to low-risk patients - the WHO specifically recommends against treatment in low-risk patients with non-severe COVID-19 4
• Do not skip the drug interaction review - this is mandatory and potentially life-saving 1, 2, 3
• Do not prescribe beyond 5 days of symptom onset - effectiveness drops significantly 1
• Do not combine with other antiviral therapies - there is no evidence for benefit and potential for harm 4
• Do not use for pre-exposure or post-exposure prophylaxis - Paxlovid is not approved for prevention 3

Alternative Treatment

When Paxlovid is contraindicated or unavailable due to drug interactions, molnupiravir is the recommended alternative for high-risk patients. 2 Remdesivir may be considered for specific subpopulations where nirmatrelvir/ritonavir or molnupiravir are not options (e.g., pregnant patients, children, or those with problematic drug interactions). 4

Evidence Quality Note

The American College of Physicians 2024 guidelines provide the most current recommendations, supported by high-certainty evidence that Paxlovid reduces hospitalization by 39% and death by 61% in real-world settings. 1, 2, 6 However, a 2024 New England Journal of Medicine trial found no significant benefit in time to symptom resolution in vaccinated standard-risk patients, reinforcing that treatment should be reserved for high-risk patients only. 7