What is the recommended treatment regimen for Paxlovid (nirmatrelvir/ritonavir) in patients with COVID-19?

Paxlovid (Nirmatrelvir/Ritonavir) Treatment Regimen for COVID-19

Paxlovid should be administered as 300 mg nirmatrelvir (two 150 mg tablets) with 100 mg ritonavir (one 100 mg tablet) taken together orally twice daily for 5 days, initiated within 5 days of symptom onset in high-risk patients with mild-to-moderate COVID-19. 1

Standard Dosing Protocol

• Initiate treatment as soon as possible after COVID-19 diagnosis and within 5 days of symptom onset 1
• Administer orally with or without food 1
• Take all three tablets together at approximately the same time each day 1
• Complete the full 5-day course 1
• Nirmatrelvir must always be co-administered with ritonavir—never give nirmatrelvir alone 1

Dose Adjustments for Renal Impairment

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

• 150 mg nirmatrelvir (one tablet) with 100 mg ritonavir (one tablet) twice daily for all 5 days 1

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

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

Hepatic Impairment

• Paxlovid is not recommended in patients with severe hepatic impairment (Child-Pugh Class C) 1
• No dose adjustment needed for mild to moderate hepatic impairment 1

Patient Selection Criteria

High-risk patients who benefit most include: 2, 3

• Age ≥65 years (absolute risk reduction for hospitalization is much greater in this group) 3
• Immunocompromised status, including hematological malignancies 2
• Multiple comorbidities: diabetes, cardiovascular disease, chronic lung disease 2
• Both vaccinated and unvaccinated patients benefit (similar absolute risk reduction for hospitalization) 3

Clinical Efficacy

• Reduces hospitalization risk by 39% (95% CI 36-41%) with absolute risk reduction of 0.9 percentage points 2, 3
• Reduces mortality by 61% (95% CI 55-67%) with absolute risk reduction of 0.2 percentage points 2, 3
• Hospitalization or emergency department encounters during days 5-15 after treatment occur in <1% of treated patients 4
• Significantly shortens nucleic acid shedding time (3.26 vs 7.75 days compared to standard treatment) 5

Critical Drug Interaction Management

MANDATORY pre-prescription screening: 2, 6

• Review ALL medications using the Liverpool COVID-19 drug interaction tool before prescribing 2
• Ritonavir is a potent CYP3A4 inhibitor causing potentially severe, life-threatening, or fatal drug interactions 1, 6
• Contraindicated with drugs highly dependent on CYP3A4 clearance where elevated concentrations cause serious reactions 1
• Contraindicated with potent CYP3A inducers that may reduce nirmatrelvir/ritonavir levels and cause treatment failure 1

Common management strategies for drug interactions: 6

• Temporarily pause the interacting comedication during the 5-day treatment course 6
• For medications that cannot be stopped (e.g., nucleoside antivirals for hepatitis B), continue them to avoid viral reactivation 2
• Provide counseling about potential interaction risks when pausing is not feasible 6

Special Populations

Pregnant and breastfeeding patients:

• Consider nirmatrelvir/ritonavir despite limited data, as benefits likely outweigh risks in high-risk patients 2

Patients with hepatitis B:

• Do not stop nucleoside antivirals during COVID-19 treatment to avoid HBV reactivation 2
• Screen for HBsAg if systemic corticosteroids or tocilizumab are used ≥7 days 2

Immunocompromised patients and those with hematological malignancies:

• Nirmatrelvir/ritonavir is recommended for mild COVID-19 (graded CIIt by ECIL guidelines) 7
• These patients are at particularly high risk for progression and should be prioritized for treatment 2

Common Pitfalls to Avoid

• Missing the 5-day treatment window: Emphasize early testing and rapid treatment initiation 2
• Failing to screen for drug interactions: This is the most critical safety concern and can result in life-threatening events 2, 1
• Prescribing without checking renal function: Dose adjustment is mandatory for renal impairment 1
• Administering nirmatrelvir without ritonavir: The drugs must be co-administered 1

Adverse Events

• Most common adverse reactions (≥1%): dysgeusia (altered taste) and diarrhea 1
• Nirmatrelvir/ritonavir probably has little or no effect on treatment-emergent adverse events overall (RR 0.95% CI 0.82-1.10) 8
• Treatment-related adverse events like dysgeusia and diarrhea are increased (RR 2.06,95% CI 1.44-2.95) but are generally mild 8
• Discontinuation due to adverse events is actually decreased compared to placebo (RR 0.49,95% CI 0.30-0.80) 8
• Serious adverse events are reduced (RR 0.24,95% CI 0.15-0.41) 8

Hypersensitivity Reactions

• Anaphylaxis, toxic epidermal necrolysis, Stevens-Johnson syndrome, and other hypersensitivity reactions have been reported 1
• Immediately discontinue Paxlovid and initiate appropriate supportive care if clinically significant hypersensitivity occurs 1
• Contraindicated in patients with history of clinically significant hypersensitivity to nirmatrelvir or ritonavir 1

Limitations of Use

• Not approved for pre-exposure or post-exposure prophylaxis for prevention of COVID-19 1
• Evidence for moderate to severe COVID-19 in hospitalized patients is very low certainty and insufficient to support use 8
• No evidence supports use for preventing SARS-CoV-2 infection 8