Nirmatrelvir/Ritonavir (PAXLOVID) for Mild-to-Moderate Illness

Nirmatrelvir/Ritonavir (PAXLOVID) for Mild-to-Moderate Illness


Prescribers MUST verify the patient's eligibility prior to prescribing nirmatrelvir/ritonavir

  • For community-based treatment, the eligibility form (see GNB Eligibility & Access to Treatment below) must be completed and sent to the pharmacy along with the prescription
  • Eligibility form is NOT required for patients admitted to hospital

Clinical Pearls

Treatment: Within 5 days of symptom onset

  • Symptom Onset: The date the case’s symptoms started would be considered ‘Day 1’.
    • E.g. If symptoms started on February 2nd, this would be the ‘Date of Symptom Onset’. February 6th would be day 5 and final day they would be eligible for treatment.

Before prescribing nirmatrelvir/ritonavir, clinicians should carefully review concomitant medications for drug interactions to reduce the risk of harm.

Drug interaction tools and resources:

Drug classes of particular concern are:

  • antiarrhythmics
  • oral anticoagulants
  • immunosuppressants
  • anticonvulsants
  • antineoplastic
  • neuropsychiatric drugs

Questions to consider:

  • Is 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.
  • Is the patient taking an interacting drug with a long plasma half-life and narrow therapeutic window (e.g., certain antiarrhythmics, antipsychotics, antineoplastics), in that 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.
  • Is the patient taking an interacting drug that can be safely held?
    • Hold the medication starting the first day of nirmatrelvir/ritonavir therapy and resume 2 to 5 days after the last dose of nirmatrelvir/ritonavir treatment depending on recommendations.
  • Is a specialist prescriber or pharmacist able to help adjust the dose or dosing interval, replace the drug with an alternative agent, manage side effects, and guide therapeutic drug monitoring?
    • Consult a local specialist or pharmacist for advice and recommendation.

Potential management strategies:

Potential management strategies to facilitate the use of nirmatrelvir/ritonavir may differ depending on the magnitude and significance of the interaction.  Options include:  

  • Dose adjustment of the concomitant medication
  • Use of an alternative to the concomitant medication
  • Increased monitoring for potential adverse reactions to the concomitant medication
  • Temporary withholding of the concomitant medication

These strategies should be considered for the 5-day duration of nirmatrelvir/ritonavir treatment and for at least 2 to 5 days after treatment completion (and for potentially longer if nirmatrelvir/ritonavir is administered with an interacting concomitant medication that has a long half-life).

Please note, the onset of inhibition is RAPID and clinically significant drug-drug interactions may occur despite the short treatment course.

The following medications should be avoided in combination with nirmatrelvir/ritonavir, they are either:

  • Contraindicated and stopping the drug does not mitigate the interaction, OR
  • Co-administration is contraindicated but management strategies are possible.

For more information please use the following tools & resources:

***Caution - the list below is only intended as a quick reference guide, and may not be complete.

Class Medication
Alpha1-adrenoreceptor antagonist alfuzosin
Analgesics meperidine, fentanyl
Antiarrhythmics amiodarone, disopyramide, dronedarone, flecainide, propafenone, quinidine
Antibacterials rifampin, rifapentine
Anticancer apalutamide, enzalutamide, neratinib, venetoclax
Anticoagulant/ antiplatelet ticagrelor, clopidogrel (significant reduction in antiplatelet activity, avoid if at very high-risk of thrombosis - review in interaction checker for more details)
Anticonvulsants carbamazepine, clonazepam, eslicarbazepine, oxcarbamazepine phenobarbital, phenytoin, primidone
Antipsychotics clozapine, lurasidone, pimozide, quetiapine
Anxiolytics/hypnotics/ sedatives alprazolam, diazepam, flurazepam, midazolam (oral), triazolam
Anti-gout colchicine
Bronchodilators salmeterol
Ergot derivatives dihydroergotamine, ergonovine, ergotamine
Gastrointestinal agents domperidone
HCV DAAs elbasvir/grazoprevir, glecaprevir/pibrentasvir
Hypotension/Heart Failure Agents aliskiren, bosentan, eplerenone, ivabradine, ranolazine
Immunosuppressants cyclosporine, sirolimus, tacrolimus, everolimus
Lipid lowering agents lovastatin, simvastatin, lomitapide
PDE5 Inhibitors sildenafil (PAH), tadalafil (PAH), vardenafil (PAH)
Herbal/Natural Health Products St John’s Wort

    -PAH - Pulmonary arterial hypertension

Adverse events (incidence ≥1% and ≥5 patient difference):

  • dysgeusia (6%)
  • diarrhea (3%)
  • hypertension (1%)
  • myalgia (1%)

(studies are limited - possible that all adverse effects, including those that are rare but serious, are not known)


  • PAXLOVID should not be used in pregnant women unless the potential benefits outweigh the potential risks to the fetus.
  • There are no available human data on the use of nirmatrelvir during pregnancy to evaluate for a drug associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes.


  • There are no available data on the presence of nirmatrelvir in human or animal milk, the effects on the
    breastfed infant, or the effects on milk production.

COVID-19 Clinical Advisory Committee Recommendation

Nirmatrelvir/ritonavir is recommended for patients with symptomatic mild-to-moderate illness at high risk of progression to severe COVID-19, including hospitalization and death.

  • For example, patient less than 60 years old without a risk modifying co-morbidity, regardless of their vaccination history.
  • Evidence has shown no benefit over placebo in patients a low risk of severe disease with respect to:
    • symptom relief or resolution
    • preventing hospitalization or death
  • patients who were symptomatic at the time of testing but have recovered, or
  • asymptomatic patients screened as part of an outbreak or for travel.

Note: Asymptomatic patients should not be treated unless symptoms develop (follow-up is reasonable in patients who would qualify for treatment if otherwise symptomatic).

Criteria for Use

Patients must meet ALL the eligibility criteria and NONE of the exclusion criteria.

  1. COVID-19 infection confirmed by PCR, Abbott ID Now, or POCT; AND
  2. Symptomatic illness of ONLY mild-to-moderate severity1; AND
  3. Treatment initiated within five days from symptom onset; AND
  4. At increased risk of progressing to severe illness requiring hospitalization. Consideration must be given to age, vaccine status, and co-existing medical conditions.
  • Risk assessment tool and treatment recommendations below are recommended to be used to guide treatment decisions but should not be used as a substitute for clinical judgement.
  • Data supports the recommended use when risk is ≥5%, but may be considered when risk is 3 – 4%.


  1. Mild-to-Moderate Illness: Clinical signs of pneumonia (fever, cough, dyspnea, tachypnea) may or may not be present; NO signs of severe pneumonia (i.e. respiratory rate > 30 breaths/min, SpO2 ≤ 92% on room air, severe respiratory distress (ex. breathlessness at rest; talks in words only and not sentences or phrases)); AND patient NOT requiring supplementary or additional oxygen.
  2. Severely Immunocompromised: solid organ transplant; bone marrow or stem cell transplant; treatment for hematological malignancy; receiving anti-B cell therapies (monoclonal antibodies targeting CD19, CD20 and CD22); or receipt of chimeric antigen receptor (CAR)-T-cell therapy.
  3. Moderately Immunocompromised: active treatment with high-dose corticosteroids(i.e., ≥ 20 mg prednisone or equivalent per day when administered for ≥ 2 weeks); alkylating agents; antimetabolites; tumor necrosis factor (TNF) blockers; and other biologic agents that are immunosuppressive or immunomodulatory; moderate-severe primary immunodeficiency; treatment for solid tumors; or advanced or untreated HIV infection
  4. Clinically Vulnerable: cystic fibrosis; severe asthma or COPD; severe lung disease and at least one of the following: [long-term home oxygen, assessment for a lung transplant, severe pulmonary arterial hypertension, and severe pulmonary fibrosis/interstitial lung disease];   poorly controlled diabetes; intellectual and developmental disabilities; rare blood disorders; neurological conditions requiring Bi-PAP/chronic ventilation; cancer not captured above; receiving dialysis or has severe kidney/renal disease; chronic liver diseases with cirrhosis; splenectomy (anatomical or functional asplenia); or pregnant with a history of serious heart disease.
  5. Chronic conditions: obesity (BMI > 30); cardiovascular disease (including hypertension); chronic lung disease (including asthma); chronic metabolic disease (including diabetes); chronic kidney disease; chronic liver disease; sickle cell disease; smoking; schizophrenia/major mood disorder; or other medically complex conditions

*Risk assessment tool adapted from BC COVID THERAPEUTICS COMMITTEE (CTC) Practice Tool #1 – Assessment Guide for Clinicians.

  • Asymptomatic illness
  • Age less than 18 years old
  • Known hypersensitivity to nirmatrelvir or ritonavir
  • Patient has already received an anti-SARS-CoV-2 therapy (i.e. antiviral or monoclonal neutralizing antibodies) for this infection
  • Severe hepatic impairment (Childs Pugh C)
  • Contraindicated drug interactions
  • Greater than 5 days since symptom onset
  • Patients with severe or critical disease

Dosing & Administration


  • Can be taken with or without food

Missed Dose:

  • Missed dose within 8 hours of the time it is usually taken, the patient should take it as soon as possible and resume the normal dosing schedule.
  • Missed dose by more than 8 hours, the patient should not take the missed dose and instead take the next dose at the regularly scheduled time.
  • The patient should not double the dose to make up for a missed dose.

Chewing/Crushing Tablets:

  • The product monograph does not recommend chewing or crushing nirmatrelvir/ritonavir
  • Studies have shown that nirmatrelvir oral suspension achieves similar pharmacokinetics as the tablet, and all other protease inhibitors on the market can also be crushed.
  • Guidelines recommend that:
    • Nirmatrelvir and ritonavir can both be split or crushed and mixed with: apple sauce, pudding, or any common food or liquid (including dairy)
    • Nirmatrelvir and ritonavir can both be crushed and mixed with water to administer via feeding tubes
    • As there is no stability data, any suspension made with nirmatrelvir and ritonavir should only be mixed immediately prior to administration
  • For more information:
  • Mild (Childs Pugh A) - 100% of dose
  • Moderate (Childs Pugh B) - 100% of dose
  • Severe (Childs Pugh C) - Contraindicated (not studied and no pharmacokinetic or safety data available)
  • Nirmatrelvir/ritonivir dosing should be adjusted for the eGFR rate based on the Chronic Kidney Disease-Epidemiology Collaboration (CKD-EPI) formula.
    • CKD-EPI Equation (eGFR in mL/min/1.73 m2):
       = 141 * min(SCr/k, 1)a * max(SCr/k, 1)-1.209 * 0.993age [* 1.018 if female] [* 1.159 if black]
  • For very small or large patents, recommend to consider:
    • Cockcroft Gault (based on IBW or adjusted weight if obese); OR
    • Individualized CKD-EPI eGFR corrected for estimated BSA: the calculated eGFR (which is normalized to body surface area) should be multiplied by the estimated body surface area and then divided by 1.73 to obtain an eGFR in units of mL/min (i.e. not normalized to body surface area).
      • BSA (m2) = [(height(cm) * weight(kg))/3600]0.5
  • Online calculators:

Usual Dosing (eGFR ≥ 60 mL/min):

  • Nirmatrelvir 300 mg (two 150 mg pink tablets) + ritonavir 100 mg (one 100 mg white tablet) taken together orally twice daily for 5 days, can be taken with or without food

Moderate renal impairment (eGFR ≥30 to <60 mL/min):

  • Nirmatrelvir 150 mg (one 150 mg pink tablet) + ritonavir 100 mg (one 100 mg white tablet) taken together orally twice daily for 5 days

Severe renal impairment (eGFR <30 mL/min):

  • Nirmatrelvir 300 mg (two 150 mg pink tablets) + ritonavir 100 mg (one 100 mg white tablet) taken together orally x1 dose; then Nirmatrelvir 150 mg (one 150 mg pink tablet) + ritonavir 100 mg (one 100 mg white tablet) taken together orally once daily x 4 days

Intermittent hemodialysis (On dialysis days, administer dose after dialysis):

  • Nirmatrelvir 300 mg (two 150 mg pink tablets) + ritonavir 100 mg (one 100 mg white tablet) taken together orally x1 dose; then Nirmatrelvir 150 mg (one 150 mg pink tablet) + ritonavir 100 mg (one 100 mg white tablet) taken together orally once daily x 4 days
    • If dialysis patient AND weight <40 kg: Nirmatrelvir 150 mg + ritonavir 100 mg PO q48h x 3 doses

Additional Information

Health Canada Resources:

Drug Interaction Tools and Resources

Evidence Reviews and Summaries

Other Useful Practice Tools