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

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

Background

Nirmatrelvir/Ritonavir(PAXLOVID) is available only in limited supplies, prioritizing access to treatment using eligibility criteria remains necessary.

  • Prescribers MUST verify the patient's eligibility by completing the eligibility form
  • Eligibility form is to be sent to the community pharmacy with the prescription (eligibility form available below).
  • Pharmacies will NOT fill the prescription in absence of the eligibility form.

  • Nirmatrelvir/ritonavir is indicated for the treatment of mild-to-moderate COVID-19 in adults with positive results of SARS-CoV-2 viral testing, and who are at high risk for progression to severe COVID-19, including hospitalization or death.
  • Nirmatrelvir is a protease inhibitor active against the SARS-CoV-2 virus that halts viral replication.
  • Ritonavir is an HIV-1 protease inhibitor not active against SARS-CoV-2. Ritonavir inhibits the CYP3A-mediated metabolism of nirmatrelvir and is used as a pharmacokinetic booster resulting in increased plasma concentrations of nirmatrelvir.
  • Evidence for use is mostly based on trials in unvaccinated individuals at high-risk of poor outcome involving predominantly the Delta variant - see product monograph for details.

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.

  • History of clinically significant hypersensitivity reactions to its active ingredients or any other components of the product.
  • Co-administration with drugs that are highly dependent on CYP3A for clearance and for which elevated concentrations are associated with serious and/or life-threatening reactions.
  • Co-administration with drugs that are potent CYP3A inducers where significantly reduced nirmatrelvir/ritonavir plasma concentrations may be associated with the potential for loss of virologic response and possible resistance.
  • Severe renal impairment (eGFR <30 mL/min).
  • Severe hepatic impairment (Childs Pugh C).

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 apixaban, rivaroxaban, 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

***There are limited clinical data and serious/unexpected adverse events may occur that have not been previously reported.***

Hepatic/Biliary/Pancreatic
Hepatic transaminase elevations, clinical hepatitis, and jaundice have occurred in patients receiving ritonavir. Therefore, caution should be exercised when administering to patients with preexisting liver diseases, liver enzyme abnormalities, or hepatitis. 

Reproductive Health: Female and Male Potential
Women of childbearing potential should use effective contraception during treatment.  Use of ritonavir may reduce the efficacy of combined hormonal contraceptives. Patients using combined hormonal contraceptives should be advised to use an effective alternative contraceptive method or an additional barrier method of contraception during treatment.

Risk of HIV-1 Resistance Development
Because nirmatrelvir is co-administered with ritonavir, there may be a risk of HIV-1 developing resistance to HIV protease inhibitors in individuals with uncontrolled or undiagnosed HIV-1 infection.

(See product monograph for more detail)

Pregnancy:

  • 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.

Breast Feeding:

  • 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.

Pediatrics:

  • Safety and effectiveness has not been established.

Geriatrics:

  • Clinical studies include subjects 65 years of age and older. Of the total number of subjects in EPIC-HR randomized to receive PAXLOVID (N=1,120), 13% were 65 years of age and older and 3% were 75 years of age and older.

(See product monograph for more detail)

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)

GNB Recommendations

GNB Public Health recommends the use of nirmatrelvir/ritonavir for symptomatic patient meeting eligibility criteria at high-risk of progression to severe disease

Criteria for Use

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

  1. COVID-19 infection confirmed by PCR, Abbott IDNow, 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 high risk of progressing to serious illness which includes the following categories:
    • Moderately to severely immunocompromised2 individuals regardless of COVID-19 vaccination status; OR
    • ≥80 years of age regardless of  COVID-19 vaccination status; OR
    • 50-79 years of age whose COVID-19 vaccinations are not up-to-date (includes anyone who has completed their primary series but has not received their booster in the 6 month timeframe); OR
    • 50-79 years of age who are residing in a long-term care setting; or living in, or from First Nations communities; or those receiving home care services.

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))
  • Patient NOT requiring supplementary or additional oxygen.

2 Moderately to Severely Immunocompromised:

  • Active or recent cancer treatment for solid tumor cancer or cancers of the blood;
  • Solid organ transplant and taking immune suppression therapy;
  • Recent stem cell transplant (within 2 years) or are taking immunosuppressive therapy;
  • Moderate to severe primary immunodeficiency (e.g. DiGeorge syndrome, Wiskott-Aslrich syndrome), or advanced or untreated HIV infection, or AIDS;
  • Moderate to severe immunosuppressive therapy such as:
    • Cancer therapy
    • Immune therapy
    • Other biologic medications that significantly suppress the immune system (e.g. rituximab)
    • High dose systemic corticosteroids (doses of >20mg/day of prednisone for four or more weeks) or other drugs to suppress your immune system

  • <18 years of age; OR
  • Unable to swallow medications whole; OR
  • Severe renal impairment (eGFR <30 mL/min); OR
  • Severe hepatic impairment (Childs Pugh C); OR
  • History of clinically significant hypersensitivity reactions 
    to its active ingredients or any other components of the product; OR
  • Co-administration with drugs that are highly dependent on CYP3A for clearance and for which elevated concentrations are associated with serious and/or life-threatening reactions; OR
  • Co-administration with drugs that are potent CYP3A inducers where significantly reduced nirmatrelvir/ritonavir plasma concentrations may be associated with the potential for loss of virologic response and possible resistance.

Dosing & Administration

Administration:

  • Can be taken with or without food
  • Tablets should be swallowed whole and not chewed, broken, or crushed.

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.

  • 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:

PLEASE NOTE:

  • Counsel patients about renal dosing instructions.
  • Daily blister contains two separated parts each containing 2 tablets of nirmatrelvir and one
    tablet of ritonavir corresponding to the daily administration at the standard dose.
  • Patients with moderate renal impairment should be alerted on the fact that only one tablet of nirmatrelvir with the tablet of ritonavir should be taken every 12 hours.
  • The extra nirmatrelvir tablets could be punched out by the dispensing pharmacy and the patient advised about the adjustment to the blister package.

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

(consider removing extra tablets prior to dispensing and advise patient of adjustment to blister package)

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

  • Nirmatrelvir/ritonavir is contraindicated in severe renal impairment.

Additional Information