What is the recommended treatment with Paxlovid (nirmatrelvir/ritonavir) for a high-risk patient with confirmed COVID-19 and potentially impaired renal function?

Paxlovid Treatment for High-Risk COVID-19 Patients with Renal Impairment

For high-risk patients with confirmed COVID-19 and renal impairment, Paxlovid should be prescribed with mandatory dose reduction based on kidney function: use the standard dose (300 mg nirmatrelvir/100 mg ritonavir twice daily) for normal or mild renal impairment, reduce to 150 mg nirmatrelvir/100 mg ritonavir twice daily for moderate impairment (eGFR 30-59 mL/min), and further reduce to a single daily dose (300 mg/100 mg on day 1, then 150 mg/100 mg once daily on days 2-5) for severe impairment including dialysis patients. 1

Patient Selection and Risk Stratification

• Strongly recommend Paxlovid for high-risk patients with non-severe COVID-19, as WHO guidelines provide high-certainty evidence of important reduction in hospitalization and moderate certainty of survival benefit 2

• High-risk criteria include: age ≥65 years, immunocompromised status (including hematological malignancies, transplant recipients), unvaccinated or vaccine non-responders, and multiple comorbidities 3, 4

• Real-world effectiveness demonstrates 39% relative risk reduction in hospitalization and 61% relative risk reduction in death, with benefits observed in both vaccinated and unvaccinated patients 5

Critical Timing Requirements

• Initiate treatment as soon as possible after diagnosis and within 5 days of symptom onset for optimal effectiveness 1

• Treatment beyond 5 days significantly reduces effectiveness and should be avoided 4

Renal Dosing Algorithm

For patients with normal renal function or mild impairment (eGFR ≥60 mL/min):

• Standard dose: 300 mg nirmatrelvir (two 150 mg tablets) with 100 mg ritonavir (one 100 mg tablet) twice daily for 5 days 1

For patients with moderate renal impairment (eGFR 30-59 mL/min):

• Reduced dose: 150 mg nirmatrelvir (one 150 mg tablet) with 100 mg ritonavir (one 100 mg tablet) twice daily for all 5 days 1
• This dose reduction is based on pharmacokinetic data showing 187% increased nirmatrelvir exposure in moderate renal impairment 6

For patients with severe renal impairment (eGFR <30 mL/min) including hemodialysis:

• Day 1: 300 mg nirmatrelvir (two 150 mg tablets) with 100 mg ritonavir (one 100 mg tablet) once daily 1
• Days 2-5: 150 mg nirmatrelvir (one 150 mg tablet) with 100 mg ritonavir (one 100 mg tablet) once daily 1
• On hemodialysis days, administer after dialysis 1
• This adjustment accounts for 304% increased nirmatrelvir exposure and 80% decreased renal clearance in severe impairment 6

Mandatory Drug Interaction Assessment

Before prescribing, you must check for drug-drug interactions using the Liverpool COVID-19 Drug Interaction Tool 3, 7

• Ritonavir is a potent CYP3A4 inhibitor causing numerous clinically significant interactions that can result in severe, life-threatening, or fatal events 1

• Contraindicated medications include drugs highly dependent on CYP3A for clearance where elevated concentrations cause serious harm 1

• Options for managing interactions are limited to: temporarily pausing the comedication for 5 days, adjusting doses of interacting drugs, or counseling patients about additional risks 8

• Ritonavir causes interactions during active treatment and possibly for several days after completion 3

Monitoring During Treatment

• Reassess renal function during treatment if clinical deterioration occurs, as COVID-19 itself can cause acute kidney injury 3

• Monitor for common adverse effects including dysgeusia and diarrhea, which may be more pronounced with higher drug levels in renal impairment 3

• Monitor for signs of hypersensitivity reactions including anaphylaxis, toxic epidermal necrolysis, and Stevens-Johnson syndrome; immediately discontinue if these occur 1

• If baseline hepatic abnormalities exist, monitor hepatic function as hepatotoxicity has been reported with ritonavir 1

Critical Contraindications

• History of clinically significant hypersensitivity to nirmatrelvir or ritonavir 1

• Co-administration with potent CYP3A inducers that would significantly reduce nirmatrelvir/ritonavir concentrations and risk treatment failure 1

• Severe hepatic impairment (Child-Pugh Class C) is a contraindication 1

Alternative Therapies When Paxlovid Cannot Be Used

• Remdesivir is the preferred alternative, particularly for patients with problematic drug interactions, pregnancy, or severe hepatic impairment 4

• Molnupiravir is a less effective oral option when Paxlovid is unavailable or contraindicated, though WHO guidelines indicate Paxlovid is superior based on greater reduction in hospitalization 2, 4

Common Pitfalls to Avoid

• Do not prescribe Paxlovid to low-risk patients without risk factors for severe disease, as benefits are trivial and do not justify risks of drug interactions 2, 4

• Do not delay treatment while waiting for complete medication reconciliation; rapidly assess for absolute contraindications and proceed if safe 8

• Do not use standard dosing in patients with moderate or severe renal impairment, as this leads to excessive drug accumulation 6

• Do not withhold Paxlovid due to concerns about viral rebound; no hospitalizations or deaths have been reported among outpatients experiencing rebound, and rebound rates are similar between treated and untreated patients 9