COVID-19 has an initial phase of viral replication and a significant inflammatory response in moderate illness. This inflammation can lead to poor outcomes, including hospitalization, invasive ventilation, and death. However, treatments that target SARS-CoV-2 replication, if administered before the inflammatory phase of COVID-19, can improve outcomes. Nirmatrelvir works by binding to the SARS-CoV-2 3CL protease, which ultimately causes viral replication to stop. Ritonavir is a potent CYP3A4 inhibitor. It is not active against SARS-CoV-2 but is administered as a "boosting agent" to slow the metabolism of nirmatrelvir, thus increasing concentrations of nirmatrelvir.# What is the benefit of nirmatrelvir/ritonavir for COVID 19?
No peer-reviewed studies are available for analysis. However, the drug was approved based on data from the unpublished EPIC-HR study 1 which was done in unvaccinated, high-risk patients prior to circulation of the Omicron variant.
Based on regulatory submissions, nirmatrelvir/ritonavir reduces hospitalization in adult outpatients (with laboratoryproven SARS-CoV-2 infection, who were not on supplemental oxygen, and who were within 5 days of symptom onset).
With Health Canada's approval of nirmatrelvir/ritonavir, the Ontario Science Advisory Table has made a conditional recommendation that nirmatrelvir/ritonavir be used in COVID-19 patients who are not on supplemental oxygen but are at high risk of progression to moderate or severe  This recommendation is based on incomplete data. It will be revised with the publication of peer-reviewed data.
Nirmatrelvir/ritonavir is a highly e ective outpatient therapy based on available data, but there is uncertainty about e ect magnitude in target populations and high certainty for harm with ritonavir if drug interactions are not mitigated.
Nirmatrelvir/ritonavir should be o ered preferentially to patients with mild COVID-19 at higher risk of severe disease or complications from COVID-19:
In times of drug shortage, nirmatrelvir/ritonavir should be o ered preferentially to patients with mild disease at highest risk of severe disease or complications from COVID-19:
Nirmatrelvir/ritonavir should be deployed preferentially to regions where there are barriers to intravenous administration of other recommended outpatient therapies (i.e., sotrovimab, remdesivir Ritonavir is a potent inhibitor of CYP3A4 isoenzyme and various drug transporters (e.g., P-glycoprotein).
Ritonavir and nirmatrelvir are both CYP3A4 substrates.
Nirmatrelvir/ritonavir is contraindicated in patients taking drugs that are:
If the patient is taking or has taken a CYP3A4 enzyme inducer in the last 28 days (e.g., certain anticonvulsants, antineoplastics, a rifamycin, St. John's wort): Do NOT prescribe nirmatrelvir/ ritonavir.
If the patient takes an interacting drug with a long plasma half-life and narrow therapeutic window (e.g., certain antiarrhythmics, antipsychotics, antineoplastics), the interacting drug will persist in the body after the last dose and may still interact with nirmatrelvir/ritonavir: Do NOT prescribe nirmatrelvir/ritonavir even if the interacting drug can be held.
If the patient takes an interacting drug that can be held, hold the medication starting the first day of nirmatrelvir/ritonavir therapy, and resume 2 days after the last dose of nirmatrelvir/ritonavir treatment.
A specialist prescriber or pharmacist may be able to help adjust the dose or dosing interval, replace the drug with an alternative agent, manage side e ects, and guide therapeutic drug monitoring.
Page 2 of 3 Paxlovid consists of 2 drugs packaged together: Each carton contains 5 blister cards. One blister card is used each day. The full course of treatment is 5 days. eGFR 30 to 59 mL/min: The dose is 1 each of nirmatrelvir 150 mg and ritonavir 100 mg, with both tablets taken together orally BID x 5 days. eGFR <30 mL/min: Nirmatrelvir/ritonavir is not recommended.
Severe hepatic impairment (Child-Pugh Class C): Nirmatrelvir/ritonavir is not recommended.  

# Special Dosing Considerations:
Take 2 pink tablets of nirmatrelvir and 1 white tablet of ritonavir (3 tablets total) together at the same time, once in the morning and once in the evening for 5 days (i.e., 6 tablets per day).
Nirmatrelvir (pink) 150 mg tablet Ritonavir (white) 100 mg tablet

# What if my patient is taking therapy for human immunodeficiency virus (HIV)?
Patients taking ritonavir or cobicistat for HIV therapy should continue their complete antiretroviral regimen at usual dosing while taking nirmatrelvir/ritonavir.
Nirmatrelvir/ritonavir may be taken with or without food. What side effects should I be aware of?
Common side e ects of nirmatrelvir/ritonavir are generally mild and can include dysgeusia (taste disturbance), diarrhea, hypertension, myalgia, vomiting and headache.
Not many people have taken this drug, and it is still being studied -so it is possible that all the side e ects are not yet known, or that rare, but serious side e ects may happen. Continue with standard dosing. Drug interaction not likely to be clinically relevant Although mentioned in the monograph, interaction is not anticipated (e.g., minimal impact on certain metabolic pathways, wide therapeutic index, and short course of nirmatrelvir/ritonavir therapy).
Try to avoid coadministering due to risk of serious toxicity. Ideally, only start nirmatrelvir/ritonavir if drug can be safely held or replaced. In some instances, dose-adjustment is possible (refer to product monograph).
Additional information may be found in the prescribing monograph:  or the University of Liverpool COVID-19 drug interaction checker: /.
This is not an exhaustive list. Consultation with a pharmacist who can get a complete medication, recreational, and natural health product history from the patient is recommended prior to prescribing nirmatrelvir/ritonavir.