Active COVID-19, Clinical Pathway — All Settings

Nirmatrelvir-ritonavir (Paxlovid™)


Nirmatrelvir-ritonavir (Paxlovid) is an oral antiviral drug combination with activity against SARS-CoV-2. Nirmatrelvir is a protease inhibitor, which acts to inhibit viral replication by cleaving viral polyproteins involved in replication. Ritonavir is co-administered, and “boosts” the activity of nirmatrelvir by inhibiting metabolism of nirmatrelvir via CYP3A4, thus increasing the concentration of nirmatrelvir to levels required for therapeutic effect. Paxlovid has similar antiviral activity against the alpha, beta, gamma, and lambda variants; data are limited evaluating its activity against omicron, but early in vitro data suggest it is active against omicron.

The efficacy of Paxlovid was evaluated in the EPIC-HR   study, which compared Paxlovid administered by mouth for 5 days to placebo in adults ≥ 18 years with mild or moderate SARS-CoV-2 infection and one or more risk factors for progression to severe disease. All participants were outpatients, all were unvaccinated, and they were randomized within 5 days of symptom onset. The primary outcome of COVID-19 related hospitalization or all-cause mortality at day 28 occurred in 0.8% of the Paxlovid group and 6.3% of the placebo group, yielding a relative risk reduction of approximately 89%. Based on these data, the FDA issued an Emergency Use Authorization (EUA) for Paxlovid on 12/22/2021. Notably, no children < 18 years old were included in this study, and there are no pediatric pharmacokinetic data for nirmatrelvir, although ritonavir has been used extensively in children with other viral infections (including HIV). Further, children generally experience a milder course of illness than high-risk adults, so it is likely that children will derive less benefit from Paxlovid than adults.


Paxlovid can be considered for the treatment of mild COVID-19 infection in patients who meet criteria set forth in the FDA EUA, summarized below. Please also review the Therapies by Illness Severity table. Providers should carefully consider the risk/benefit ratio of Paxlovid before prescribing, noting that there are no pediatric safety or efficacy data for this drug. Please see healthcare provider fact sheet   for additional details and review prescribing steps below.


  • Age ≥ 12 years AND ≥ 40 kg (not available and not recommended for younger children) AND
  • Positive SARS-CoV-2 PCR or antigen test AND
  • Outpatient with mild-moderate symptoms AND
  • Within 5 days of symptom onset (but as soon as possible after symptom onset) AND
  • Able to swallow pills (tabs cannot be crushed) AND
  • High risk for progression to severe disease (see “Risk Stratification” below) AND
  • No significant drug-drug interactions listed as contraindications (review the healthcare provider fact sheet  , see below for additional resources)


  • Hospitalized due to severe or critical COVID-19 (note that if a patient is hospitalized during the 5 days of treatment, treatment can be completed using home supply per the healthcare provider’s discretion)
  • Renal impairment with GFR < 30 mL/min
  • Severe hepatic impairment (Child-Pugh Class C)

Risk stratification

Pediatric data informing risk stratification to identify children at highest risk of severe disease are limited. The table below summarizes pediatric patients who appear at highest risk for severe disease, particularly if they are unvaccinated or not expected to develop protective immunity from SARS-CoV-2 vaccination due to an immunocompromising condition. We recommend prioritizing these patients for use of Paxlovid. In addition, Paxlovid may be considered in all individuals classified as high-risk for severe disease by the CDC   .

Risk Strata Recommendation
  • Consider Paxlovid if no contraindication, review Prescribing Considerations
  • Paxlovid not routinely recommended, but use is permitted under the EUA
  • 1 Fully vaccinated is defined as an immunocompetent patient ≥ 14 days after the second dose of either mRNA vaccine against COVID-19 OR a single dose of the Johnson and Johnson vaccine

Adverse events

Key common adverse events include dysgeusia (6%), diarrhea (3%), hypertension (1%), and myalgia (1%). Severe adverse events include extremely rare reports of hepatotoxicity with ritonavir. There may also be a risk of promoting resistance to protease inhibitors in patients with undiagnosed or uncontrolled HIV due to the ritonavir component.

Drug-drug interactions

Paxlovid has many drug-drug interactions due to strong inhibition of CYP3A by ritonavir, which can lead to life-threatening toxicities due to elevated concentrations of other drugs metabolized by CYP3A. In addition, both nirmatrelvir and ritonavir are substrates of CYP3A, so if administered with or immediately after drugs that are strong inducers of CYP3A, levels of nirmatrelvir and ritonavir may be reduced. Prescribing clinicians must review the patient’s medication list to ensure possible interactions are evaluated prior to prescribing Paxlovid. Depending on the drug-drug interaction, Paxlovid may be contraindicated, or managing the drug interaction through dose adjustment, use of alternative medications, increased monitoring, and/or temporary withholding of the concomitant medication may be options. These decisions should be made in collaboration with any relevant subspecialists and/or clinical pharmacy. Helpful resources for evaluating drug interactions include: NIH Guideline on Paxlovid drug interactions  , FDA information on drug interactions, and the Liverpool COVID-19 drug interactions tool  . Prescribers may also contact the on call clinical pharmacist using Epic secure chat.

Prescribing Steps

Any provider may prescribe Paxlovid in the outpatient setting. Outpatient retail pharmacies are responsible for ordering and stocking Paxlovid. As of 4/15/22, the CHOP outpatient pharmacy does stock Paxlovid.

  1. Review the eligibility criteria above and the information in the healthcare provider fact sheet   to ensure the patient is eligible to receive Paxlovid under the EUA.
  2. Review the patient’s medication list and evaluate for drug interactions.
  3. The CHOP outpatient pharmacy has a limited supply of Paxlovid. Prescriptions may be sent directly to the outpatient pharmacy through Epic and prescribers will be notified if there is no supply. Prescribers may also review this website   to identify a pharmacy supplying Paxlovid.
  4. Discuss the risks and benefits of Paxlovid with the patient/family and provide the Fact Sheet for Patients and Parents/Caregivers   to the patient/family. A paper copy or electronic copy may be provided.
  5. Obtain verbal informed consent AND document this discussion using the smartphrase: .PAXLOVIDEUA. Prescribers must utilize this documentation.
  6. Counsel patients taking oral contraceptives should abstain from sex while taking Paxlovid and through one menstrual cycle after stopping Paxlovid.
  7. Order Paxlovid using Epic order. You will need to specify the dose, based on renal function, as indicated in “Dosing and Administration” below. You will also need to indicate a “do not dispense after” date, which should be dated 5 days after the patient’s symptom onset to align with the EUA criteria for use. Finally, you must answer all questions to ensure the regulatory steps for prescribing Paxlovid are adhered to.
  8. Prescribers must report all medication errors and adverse events (death, serious adverse events1) considered potentially related to Paxlovid within 7 days of the event to FDA MedWatch  . It is the responsibility of the person prescribing Paxlovid to report these errors and adverse events.

1Serious adverse events include any of the following occurring while receiving Paxlovid: death, life-threatening event, event resulting in hospitalization or prolongation of existing hospitalization, persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions, a congenital anomaly/birth defect, a medical or surgical intervention to prevent death, a life-threatening event, hospitalization, disability, or congenital anomaly.

Dosing and Administration

Nirmatrelvir and ritonavir are copackaged as 2 tablets of nirmatrelvir and 1 tablet of ritonavir per dose. Ritonavir must be co-administered with nirmatrelvir. Failure to co-administer the ritonavir will lead to inadequate serum levels of nirmatrelvir.

Category Dose/Duration Dose Adjustment
Adults ≥ 12 years and ≥ 40 kg
  • Nirmatrelvir 300 mg (2 x 150 mg tablets) and ritonavir 100 mg (1 x 100 mg tablet), with all three tablets taken together twice daily x 5 days.
  • Note that nirmatrelvir or ritonavir tablets cannot be crushed.
  • Both drugs must be taken together, for all of the doses, and for the full 5 days.
  • If a dose is missed and it is within 8 hours of the time the dose is due, take the dose as soon as possible and resume the usual dosing schedule. If the dose is missed by more than 8 hours, skip the missed dose and resume at the next scheduled time.
  • Renal failure:
  • GFR ≥ 60 - < 90: no adjustment
  • GFR ≥ 30 - < 60: nirmatrelvir 150 mg (1 x 150 mg tablet) and 100 mg ritonavir (1 x 100 mg tablet) together twice daily x 5 days
  • GFR < 30: not recommended
  • Hepatic failure:
  • Not recommended for patients with severe hepatic impairment (Child-Pugh Class C); use with caution in mild or moderate (Child-Pugh Class A or B) hepatic impairment.