What is the dosing and duration for Paxlovid (nirmatrelvir and ritonavir) and what are the contraindications and necessary medication adjustments?

Paxlovid Dosing, Duration, Contraindications, and Medication Adjustments

Standard Dosing and Duration

The standard dose of Paxlovid is nirmatrelvir 300 mg (two 150 mg tablets) plus ritonavir 100 mg (one 100 mg tablet) taken together orally twice daily for 5 days. 1

• Treatment must be initiated within 5 days of symptom onset, even if baseline symptoms are mild 1
• All three tablets should be taken together twice daily (morning and bedtime) 1
• Tablets must be swallowed whole and not chewed, broken, or crushed 1
• Can be taken with or without food 1
• Nirmatrelvir must be co-administered with ritonavir—failure to do so results in insufficient nirmatrelvir plasma levels 1
• The full 5-day course should be completed even if the patient requires hospitalization for severe COVID-19 after starting treatment 1

Renal Dose Adjustments

Dose reduction is required for patients with moderate or severe renal impairment 1:

• Mild renal impairment (eGFR ≥60 to <90 mL/min): No adjustment needed 1
• Moderate renal impairment (eGFR ≥30 to <60 mL/min): Reduce to nirmatrelvir 150 mg (one tablet) plus ritonavir 100 mg twice daily for 5 days 1
• Severe renal impairment (eGFR <30 mL/min) including hemodialysis:
  • Day 1: nirmatrelvir 300 mg (two tablets) plus ritonavir 100 mg once daily 1
  • Days 2-5: nirmatrelvir 150 mg (one tablet) plus ritonavir 100 mg once daily 1
  • On hemodialysis days, administer after dialysis 1

Hepatic Dose Adjustments

• Mild (Child-Pugh Class A) or moderate (Child-Pugh Class B) hepatic impairment: No adjustment needed 1
• Severe hepatic impairment (Child-Pugh Class C): Paxlovid is not recommended due to lack of safety and pharmacokinetic data 1

Contraindications

Paxlovid is contraindicated in patients with clinically significant hypersensitivity reactions (toxic epidermal necrolysis or Stevens-Johnson syndrome) to nirmatrelvir, ritonavir, or any product components 1

High-Risk Drug Interactions (Contraindicated or Avoid)

Ritonavir is a potent CYP3A4 inhibitor that causes numerous clinically significant drug interactions 2, 3:

• Antiarrhythmics: Avoid amiodarone, flecainide, and propafenone due to high-risk interactions 2
• Anticoagulants: Rivaroxaban is contraindicated due to increased bleeding risk 2
• Statins: Lovastatin and simvastatin should be avoided due to myopathy risk 2
• Immunosuppressants: Require major dose adjustments—tacrolimus should be discontinued or given as a microdose on day 1; cyclosporine should be reduced to 20% of initial dose; mTOR inhibitors also require adjustment 4

Critical Medication Management Considerations

Always check for drug interactions before prescribing using resources like the Liverpool COVID-19 Drug Interaction Tool 2, 5:

• The duration of interaction risk extends beyond the 5-day treatment period due to ritonavir's prolonged effects on drug metabolism and clearance 2, 5
• For patients on atorvastatin, monitor for myopathy symptoms (muscle pain, tenderness, weakness) and liver function abnormalities 2
• Consider pravastatin or fluvastatin as alternative statins during treatment if lipid-lowering therapy cannot be interrupted, as these have minimal CYP3A4 dependence 2
• Options for managing drug interactions are limited to preemptive or symptom-driven pausing of comedications or counseling about additional risks 3

Common Adverse Effects

Dysgeusia (taste disturbance) and diarrhea are the most common adverse effects 2, 5:

• Monitor for potential hepatotoxicity 2, 5
• Treatment-related adverse events like dysgeusia and diarrhea occur more frequently than placebo but are generally manageable 6
• Discontinuation due to adverse events is actually lower with Paxlovid compared to placebo 6

Missed Dose Instructions

• If missed within 8 hours: Take as soon as possible and resume normal schedule 1
• If missed by more than 8 hours: Skip the missed dose and take the next dose at regularly scheduled time—do not double dose 1

Clinical Efficacy Context

Paxlovid reduces hospitalization risk by 39% and death by 61% in high-risk patients when started within 5 days of symptom onset 7, with particular benefit in patients aged 65 years and older 7. Low-certainty evidence suggests benefit in reducing all-cause mortality and hospital admission in high-risk, unvaccinated outpatients 6.