Evidence-Based Recommendations on the Use of Nirmatrelvir/Ritonavir (Paxlovid) for Adults in Ontario

Abstract

Nirmatrelvir and ritonavir are two co-administered antiviral medications, marketed under the name Paxlovid in Canada, for the treatment of SARS-CoV-2 infection. Nirmatrelvir is an inhibitor of SARS-CoV-2 3CL-like protease that prevents polyprotein cleavage of proteins necessary for SARS-CoV-2 genome replication. Nirmatrelvir has been studied in combination with ritonavir, a medication that has no known activity against SARS-CoV-2 but slows the metabolism of nirmatrelvir by inhibiting hepatic enzymes, thus “boosting” concentrations of nirmatrelvir. Nirmatrelvir/ritonavir is currently approved in Canada for the treatment of mild COVID-19 (termed “mild to moderate” with Health Canada’s terminology) in those who are at high risk for progression to severe or critical COVID-19 illness. It is not approved for the treatment of patients requiring hospitalization due to COVID-19, nor for pre- or post-exposure prophylaxis for the prevention of SARS-CoV-2 infection. As of the date of publication of this Science Brief, there is one peer-reviewed publication comparing nirmatrelvir/ritonavir against placebo. Nirmatrelvir/ritonavir reduces the incidence of hospitalization and/or death in patients with mild COVID-19 with risk factors for progression to moderate or critical illness, with fewer treatment-emergent serious adverse events relative to placebo. The panel noted a marginal benefit in individuals at low risk of hospitalization, and the high certainty of harm with nirmatrelvir/ritonavir if known drug-drug interactions are not mitigated. Critically Ill Patients (On High-Flow Oxygen, Mechanical Ventilation, or Extracorporeal Membrane Oxygenation (ECMO)) Nirmatrelvir/ritonavir is not recommended for critically ill patients with COVID-19. Moderately Ill Patients (On Low-Flow Oxygen) Nirmatrelvir/ritonavir is not recommended for moderately ill patients with COVID-19. Mildly Ill Patients (Not Requiring Supplemental Oxygen) Nirmatrelvir/ritonavir is recommended at a dose of 300 mg nirmatrelvir (two 150 mg tablets) with 100 mg ritonavir (one 100 mg tablet), with all three tablets taken together orally twice daily for five days. Patients must be at higher risk of severe disease from COVID-19 and present within five days of symptom onset. Risk factors for progression to moderate or critical COVID-19 are outlined in “Methods used for this Science Brief” below, and include immunocompromised individuals, and individuals whose combination of age, vaccination history, and risk factors put them at increased risk of progression to severe disease. Other treatment options that may be available to these higher risk patients include sotrovimab, remdesivir, fluvoxamine, and budesonide. Clinicians should consider patient-specific factors including (but not limited to) drug-drug interactions, renal function, duration of COVID-19 symptoms, ability to administer intravenous versus oral drugs, strength of evidence, situational context, and drug supply in decision-making regarding choice of therapy (see Therapeutic Management of Adult Patients with COVID-19 summary for additional details). If eligible patients with mild COVID-19 who began treatment with nirmatrelvir/ritonavir progress to moderate COVID-19 during their treatment course, they may complete their treatment course at the discretion of the treating physician. Implementation Considerations It is recommended that oral antiviral therapy be administered to non-hospitalized individuals across Ontario using a hybrid network that includes, but is not limited to, mobile integrated healthcare services, community paramedicine, virtual/remote assessment, and outpatient clinics. Special Populations Pharmacist consultation is important to mitigate any significant drug-drug interactions (including natural products). Nirmatrelvir/ritonavir is contraindicated in patients taking certain medications that have the potential for serious or life-threatening reactions at high concentrations and are highly dependent on CYP3A4-mediated metabolism; and in patients taking certain medications that are CYP3A-inducing, as these may significantly decrease concentrations of nirmatrelvir/ritonavir, decreasing its efficacy as a COVID-19 treatment (see Tables 1-4 in the “Considerations” section below, and the guidance document “Nirmatrelvir/ritonavir (Paxlovid): What prescribers and pharmacists need to know”). For complex interactions, consultation with a pharmacist experienced in managing ritonavir-related interactions may be helpful. In patients with moderate renal impairment (eGFR ≥30 to