Important disclaimers and disclosures:

The management of COVID-19 is rapidly evolving, and guidelines change based on newly released evidence. It is highly important for clinicians to stay up to date on the latest recommendations and guidelines.

While generic names are preferred to avoid commercial bias, ritonavir-boosted nirmatrelvir may be referred to Paxlovid as it is the more commonly known name.

The author of this article does not have any financial relationships with any manufacturer or distributor of any COVID-19 related treatments.

As of May 2022, there are 4 therapeutics authorized or approved for outpatient management of mild to moderate COVID-19: ritonavir-boosted nirvatrelvir (Paxlovid), molnupiravir (Lagevrio), bebtelovimab and remdesivir (Veklury).

NIH guidelines Clinical Management Summary | COVID-19 Treatment Guidelines (nih.gov) list ritonavir-boosted nirmatrelvir (Paxlovid) and remdesivir (Veklury) as preferred therapies with bebtelovimab and molnupiravir (Lagevrio) as alternative therapies only when neither of the preferred therapies are available, feasible to use or clinically appropriate. Remdesivir (Veklury) is impractical for most Urgent Care centers because it requires intravenous infusion for 3 days.

Even though CDC and NIH have recommended that Paxlovid be used first line in the outpatient management of mild to moderate COVID-19 in high-risk patients, providers have been hesitant to prescribe Paxlovid. An informal survey of local providers suggests multiple reasons including unfamiliarity with the medication, concern about prescribing a new medication that is not FDA-approved, concern about patient renal function, concern about drug-drug interactions and patient hesitancy.

Paxlovid is a combination medication consisting of nirmatrelvir and ritonavir. Nirmatrelvir is a viral protease inhibitor that has anti-viral activity against SARS-CoV-2 by interfering with replication. Ritonavir does not have anti-SARS-CoV-2 activity and acts solely to block the metabolism of nirmatrevir thus maintaining therapeutic levels of nirmatrevir. Because ritonavir is a potent Cy450 3A4 inhibitor any therapeutics that relies on Cy450 3A4 for metabolism may be adversely affected.

Paxlovid should be considered in the outpatient setting in adults and children 12 years and older and weigh 40 kgs or more who present within 5 days of onset and have mild to moderate COVID-19 infection. Paxlovid is not authorized for prophylaxis or post-exposure prophylaxis. Paxlovid is also contraindicated in patients with a creatinine clearance less than 30mL/min, end-stage liver disease, or patients who are on medications with a significant drug-drug interaction.

A step-by step flowchart may help ease provider hesitancy and provide an approach for providers

Step 1: Is the patient eligible under the emergency use authorization (EUA)?

Date of onset of symptoms

Confirmation of positive COVID-19 test

Patient has mild to moderate disease

Patient is at high risk for progression to severe disease

Paxlovid must be started within 5 days of symptom onset. If symptom duration is over 5 days but within 7 days, MAB infusion/bebtelovimab may be considered. A positive COVID-19 test needs to be documented. A patient-attested positive home test is acceptable and will meet this requirement. Common risk factors include obesity, age, smoking, and concurrent chronic illness. Underlying Medical Conditions Associated with Higher Risk for Severe COVID-19: Information for Healthcare Professionals | CDC

Does being overweight (BMI ≥25 kg/m2, but <30 kg/m2) qualify? Overweight is associated as suggestive of higher risk for severe COVID, thus a patient who is overweight is at increased risk for serious disease

Step 2: Document and review the risks and benefits of Paxlovid

Does the patient consent to treatment?

If patient opts to proceed with Paxlovid then print out and give the fact-sheet to the patient PAXLOVID Fact Sheet for Patients and Caregivers (pfizer.com)

Step 3: Assess for renal impairment

Paxlovid is contraindicated if the CrCl is < 30mL/min. Paxlovid is prescribed at a reduced dose if CrCl is between 30-60mL/min and a “renal dose” pack is available. The reduced renal dose is 150mg of nirmatrelvir versus 300mg of nirmatrelvir.

Serum creatinine is advised within 1 year if patient is at risk for chronic kidney disease (CKD) or has a history of chronic kidney disease.

Step 4: Assess for severe hepatic disease

Paxlovid is contraindicated in Child-Pugh score class C.

Step 5: Update patient medication list

Review drug-drug interactions

This is the potentially the most time-consuming step. Unfortunately, patients who are at the highest risk of progression to severe disease are also likely to be on multiple medications. There are several drug-drug interaction checkers on the internet. A helpful strategy is to familiarize yourself with a list of common contraindicated medications (i.e., phenytoin, amiodarone, apixaban (Eliquis), etc.) versus medications that have interactions and need only to be held while on Paxlovid (e.g., statin class medications)

Online resources include: Liverpool COVID-19 Interactions (covid19-druginteractions.org), Paxlovid Drug-Drug Interactions | COVID-19 Treatment Guidelines (nih.gov)

Step 6: Find an authorized pharmacy

Initially, Paxlovid was only available at limited pharmacies and health care centers. More recently, Paxlovid availability has become more widespread. Nevertheless, do not assume the patient’s regular pharmacy is a distributor of Paxlovid. ASPR has an excellent website that provides updated availability of COVID-19 therapeutics COVID-19 Therapeutics Locator (arcgis.com)

Step 7: Discharge instructions

Counsel patient on recommended CDC isolation and stay-at-home protocols

Counsel patient on the limitations of Paxlovid

Counsel patient on red flag signs that warrant return to clinic or going to the Emergency Department

While Paxlovid use reduces risk of progression to severe disease in high-risk patients, Paxlovid is not a cure. Paxlovid treatment does not shorten the recommended isolation and stay-at-home guidelines. Providers should also be aware of Paxlovid rebound, which is a phenomenon where a patient initially reports improvement after starting Paxlovid only to have recurrent symptoms after the Paxlovid is completed. Retreatment with Paxlovid or other therapy for Covid is not recommended or required for outpatients with rebound symptoms. 

Not every COVID-19 patient will benefit from Paxlovid treatment. Always consider the individual patient situation, weigh the benefit versus risk, and utilize shared decision-making process.