What is the recommended treatment protocol for COVID-19 using Paxlovid (nirmatrelvir/ritonavir)?

Paxlovid Treatment Protocol for COVID-19

Primary Recommendation

Consider nirmatrelvir/ritonavir (Paxlovid) for symptomatic 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

Patient Selection Criteria

Eligible Patients

• Confirmed COVID-19 with mild-to-moderate disease (not requiring supplemental oxygen) 2, 3
• Symptom onset within 5 days - treatment must begin in this window as viral replication peaks at day 4 in mild cases 3
• High-risk features including:
  • Age ≥65 years 4
  • Immunocompromised status or immunosuppression 2, 3
  • Hematological malignancies or history of hematopoietic cell transplantation 2, 3
  • Multiple comorbidities 5
  • Organ transplant recipients 3

Absolute Contraindications

• History of clinically significant hypersensitivity to nirmatrelvir or ritonavir 3, 6
• eGFR <30 mL/min/1.73 m² (requires dose modification, see below) 6
• ALT ≥5 times upper limit of normal 3, 6
• Severe hepatic impairment (Child-Pugh Class C) 6
• Concomitant use of drugs highly dependent on CYP3A for clearance where elevated concentrations cause serious/life-threatening reactions 6, 7
• Co-administration with potent CYP3A inducers 6

Dosing Protocol

Standard Dosing (eGFR ≥60 mL/min)

• 300 mg nirmatrelvir (two 150 mg tablets) + 100 mg ritonavir (one 100 mg tablet) 3, 6
• Twice daily for 5 days 3, 6
• Can be taken with or without food 3, 6
• Administer at approximately the same time each day 6

Dose Adjustments for Renal Impairment

Moderate renal impairment (eGFR 30-59 mL/min): 6

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

Severe renal impairment (eGFR <30 mL/min, including hemodialysis): 6

• Day 1: 300 mg nirmatrelvir (two tablets) + 100 mg ritonavir (one tablet) once
• Days 2-5: 150 mg nirmatrelvir (one tablet) + 100 mg ritonavir (one tablet) once daily
• On hemodialysis days, administer after dialysis 6

Pre-Treatment Assessment

Before initiating Paxlovid, complete the following: 3

• Assess hepatic function (ALT, AST)
• Assess renal function (eGFR)
• Check prothrombin time
• Complete medication reconciliation for drug-drug interactions with CYP3A substrates 7

Monitoring During Treatment

• Monitor for hypersensitivity reactions including anaphylaxis, toxic epidermal necrolysis, and Stevens-Johnson syndrome 3, 6
• Discontinue immediately if ALT increases to >10 times upper limit of normal or if ALT elevation is accompanied by signs/symptoms of liver inflammation 3
• Watch for dysgeusia and diarrhea (most common adverse reactions) 6

Critical Drug Interaction Management

Ritonavir is a potent CYP3A4 inhibitor that can cause severe, life-threatening, or fatal drug interactions even with a 5-day course 6, 7. Management options are limited to:

• Preemptive pausing of comedications metabolized by CYP3A 7
• Symptom-driven pausing of interacting drugs 7
• Patient counseling about additional risks 7

Common pitfall: Failing to review all medications before prescribing - this is mandatory given ritonavir's potent CYP3A inhibition 6, 7

Clinical Effectiveness Evidence

The most recent high-quality real-world evidence demonstrates: 4

• 39% relative risk reduction in hospitalization (95% CI 36-41%; absolute risk reduction 0.9 percentage points)
• 61% relative risk reduction in death (95% CI 55-67%; absolute risk reduction 0.2 percentage points)
• Effectiveness maintained in vaccinated patients 4
• Greatest absolute benefit in patients ≥65 years 4

Important caveat: One study in hospitalized patients with severe comorbidities showed no mortality benefit, but this population differs from the approved indication of mild-to-moderate outpatient disease 8

Alternative Therapies When Paxlovid Contraindicated

• Remdesivir for outpatients when Paxlovid unavailable or contraindicated 5, 3
• Molnupiravir as a less effective alternative (6.8% vs 9.7% hospitalization/death rate) 1, 5, 3
• High-titer convalescent plasma particularly for immunocompromised patients 5, 3

Special Considerations

HIV-1 resistance risk: Paxlovid may lead to HIV-1 protease inhibitor resistance in individuals with uncontrolled or undiagnosed HIV-1 infection 6

Elderly patients: Those >65 years have significantly higher plasma concentrations (odds ratio 11.2 for excessive levels) and warrant closer monitoring, though they also derive the greatest absolute benefit 9, 4

Not approved for: Pre-exposure or post-exposure prophylaxis 6