Remarks

• See Section 6 for help to identify patients at high risk.
• Several therapeutic options are available: see decision support tool that displays benefits and harms of nirmatrelvirritonavir, molnupiravir and remdesivir for patients at high risk of hospitalization.
• The GDG concluded that nirmatrelvir-ritonavir in general represents a superior choice to molnupiravir because it probably has a greater reduction in hospitalization and because of concerns about potential harms of molnupiravir.
• The GDG concluded that nirmatrelvir-ritonavir in general represents a superior choice to remdesivir because of the practical difficulty that arises from the intravenous administration of remdesivir.
• Clinicians should review all medications and not consider nirmatrelvir-ritonavir in patients with possible dangerous drug interactions (note: many drugs interact with nirmatrelvir-ritonavir).
• Given possible benefit and residual uncertainty regarding potential undesirable effects, clinicians should engage pregnant or breastfeeding individuals fully informed shared decision-making regarding the use of nirmatrelvir-ritonavir.
• Patients should receive nirmatrelvir-ritonavir as soon as possible after onset of symptoms, ideally within 5 days from symptom onset.

Practical info The GDG recognized that there are circumstances in which nirmatrelvir should not be used due to drug interactions that result from its combination with ritonavir. Ritonavir may increase the concentrations of drugs highly dependent on hepatic cytochrome P450 3A (CYP3A) metabolism, which include macrolide antibiotics, immune modulators, warfarin and others. These drugs may also reduce nirmatrelvir concentrations, potentially leading to a loss of virologic response. Trials excluded patients with severe kidney impairment and severe liver impairment; and clinicians should use nirmatrelvir-ritonavir with caution in such patients. Route, dosage and duration: Additional considerations are available in three summaries of practical issues (nirmatrelvirritonavir for COVID-19, administration of nirmatrelvir-ritonavir for COVID-19, safety and monitoring for patients receiving nirmatrelvir-ritonavir for COVID-19). Here follows a brief summary of key points:

• The recommended dose for nirmatrelvir-ritonavir is 300 mg (two 150 mg tablets) of nirmatrelvir and 100 mg of ritonavir every 12 hours daily for 5 days, as per the regimen evaluated in large trials informing the recommendation.
• In renal insufficiency (GFR 30–59 mL/min) the dose should be reduced to150 mg of nirmatrelvir and 100 mg of ritonavir every 12 hours daily for 5 days.
• Administration should be as early as possible in the time course of the disease. In the included studies, nirmatrelvirritonavir was administered within 5 days of symptom onset. In any patient being considered for nirmatrelvir-ritonavir use, clinicians need to give serious consideration to drug interactions. The Liverpool COVID-19 drug interaction checker may be useful in this regard [20].