Summary Basis of Decision for Paxlovid

Contact: Bureau of Gastroenterology Infection and Viral Diseases

Summary Basis of Decision (SBD) documents provide information related to the original authorization of a product. The SBD for Paxlovid is located below.

Recent Activity for Paxlovid

SBDs written for eligible drugs approved after September 1, 2012 will be updated to include post-authorization information. This information will be compiled in a Post-Authorization Activity Table (PAAT). The PAAT will include brief summaries of activities such as submissions for new uses of the product, and whether Health Canada's decisions were negative or positive. PAATs will be updated regularly with post-authorization activity throughout the product's life cycle.

Post-Authorization Activity Table (PAAT) for Paxlovid

Updated: 2024-03-22

The following table describes post-authorization activity for Paxlovid, a product which contains the medicinal ingredients nirmatrelvir and ritonavir. For more information on the type of information found in PAATs, please refer to the Frequently Asked Questions: Summary Basis of Decision (SBD) Project: Phase II and to the List of abbreviations found in Post-Authorization Activity Tables (PAATs).

For additional information about the drug submission process, refer to the Guidance Document: The Management of Drug Submissions and Applications.

Drug Identification Number (DIN):

DIN 02524031 - 150 mg nirmatrelvir, tablet, and 100 mg ritonavir, tablet, co-packaged, oral administration

DIN 02527804 - 150 mg nirmatrelvir, tablet, and 100 mg ritonavir, tablet, co-packaged, oral administration, cards of 2 nirmatrelvir tablets and 2 ritonavir tablets

Post-Authorization Activity Table (PAAT)

Activity/submission type, control number	Date submitted	Decision and date	Summary of activities
PSUR # 260407	2023-09-11	Review completed 2024-01-19	Submission filed in response to commitments made as per the terms and conditions imposed on the authorization issued under the Food and Drug Regulations. PSUR #3 for the period 2023-01-01 to 2023-06-30. The current post-market safety data are consistent with the labelled safety profile for Paxlovid. Health Canada will continue to monitor any new emerging evidence from all available sources as part of its post-authorization monitoring for Paxlovid.
SNDS # 278009	2023-08-09	Issued NOC 2024-01-02	Submission filed as a Level II – Supplement (Safety) to update the PM with new efficacy information. The submission was reviewed and considered acceptable. As a result of the SNDS, modifications were made to the Microbiology section of the PM. An NOC was issued.
SNDS # 277393	2023-07-20	Issued NOC 2023-12-13	Submission filed as a Level II – Supplement (Safety) to update the PM with new safety and efficacy information. The submission was reviewed and considered acceptable. As a result of the SNDS, modifications were made to the Warnings and Precautions, Adverse Reactions, Clinical Trials, and Non-Clinical Toxicology sections of the PM. An NOC was issued.
SNDS # 274571	2023-04-21	Issued NOC 2023-10-04	Submission filed as a Level II – Supplement (Safety) to update the PM with new safety information. The submission was reviewed and considered acceptable. As a result of the SNDS, modifications were made to the Warnings and Precautions and Drug Interactions sections of the PM, and corresponding changes were made to Part III: Patient Medication Information. An NOC was issued.
SNDS # 267963	2022-09-16	Issued NOC 2023-08-30	Submission filed as a Level I – Supplement to update the PM with new safety information related to anaphylaxis. Information was also filed to fulfill clinical Terms and Conditions #5-8, 13, and 14 imposed on the authorization issued under the Food and Drug Regulations. The submission was reviewed and considered acceptable. As a result of the SNDS, modifications were made to the Warnings and Precautions, Adverse Reactions, Clinical Pharmacology, and Non-Clinical Toxicology sections of the PM, and corresponding changes were made to Part III: Patient Medication Information. An NOC was issued.
PSUR # 260406	2023-03-09	Review completed 2023-06-29	Submission filed in response to commitments made as per the terms and conditions imposed on the authorization issued under the Food and Drug Regulations. PSUR #2 for the period 2022-07-01 to 2022-12-31. The current post-market safety data are consistent with the labelled safety profile for Paxlovid. Health Canada will continue to monitor any new emerging evidence from all available sources as part of its post-authorization monitoring for Paxlovid.
SNDS # 272114	2023-02-03	Issued NOC 2023-06-27	Submission filed as a Level II – Supplement (Safety) to update the PM with new safety information. The submission was reviewed and considered acceptable. As a result of the SNDS, modifications were made to the Contraindications, Adverse Reactions, and Drug Interactions sections of the PM, and corresponding changes were made to Part III: Patient Medication Information. An NOC was issued.
Risk Management Plan update Control # 267690	2022-12-13	Review completed 2023-01-24	The updated European Union Risk Management Plan version 2.2 and Canadian Addendum dated November 2022 were filed following the review of RMP update # 264469 and Monthly safety report # 266286. The review found the RMP is acceptable at this time. The current post-market safety data are consistent with the labelled safety profile of Paxlovid.
PSUR # 260405	2022-09-08	Review completed 2023-01-16	Submission filed in response to commitments made as per the terms and conditions imposed on the authorization issued under the Food and Drug Regulations. PSUR #1 for the period 2021-12-31 to 2022-06-30. The current post-market safety data are consistent with the labelled safety profile for Paxlovid. Health Canada will continue to monitor any new emerging evidence from all available sources as part of its post-authorization monitoring for Paxlovid.
SNDS # 266236	2022-07-21	Issued NOC 2022-12-08	Submission filed as a Level II – Supplement (Safety) to update the PM with new safety information. The submission was reviewed and considered acceptable. As a result of the SNDS, modifications were made to the Adverse Reactions and Drug Interactions sections of the PM, and corresponding changes were made to Part III: Patient Medication Information. An NOC was issued.
SNDS # 269592	2022-10-11	Issued NOC 2022-12-01	Submission filed as a Level I – Supplement to extend the shelf life of nirmatrelvir tablets from 18 months to 24 months. The submission was reviewed and considered acceptable, and an NOC was issued.
SNDS # 266836	2022-08-09	Issued NOC 2022-09-26	Submission filed as a Level I – Supplement to extend the shelf life of nirmatrelvir tablets from 12 months to 18 months. The submission was reviewed and considered acceptable, and an NOC was issued.
Risk Management Plan update Control # 264649	2022-08-29	Review completed 2022-09-07	The updated Canadian Risk Management Plan (RMP) Addenda dated August 2022 was filed following the review of RMP update # 260404. The review found the RMP is acceptable with revisions at this time. The current post-market safety data are consistent with the labelled safety profile of Paxlovid.
Monthly safety report Control # 266286	2022-08-02	Review completed 2022-09-01	Information filed as per the terms and conditions imposed on the authorization issued under the Food and Drug Regulations. Monthly safety report #6 for the period 2022-06-01 to 2022-06-30. The current post-market safety data are consistent with the labelled safety profile of Paxlovid.
Drug product (DIN 02527804) market notification	Not applicable	Date of first sale: 2022-08-01	The manufacturer notified Health Canada of the date of first sale pursuant to C.01.014.3 of the Food and Drug Regulations.
Monthly safety report Control # 265412	2022-06-30	Review completed 2022-07-22	Information filed as per the terms and conditions imposed on the authorization issued under the Food and Drug Regulations. Monthly safety report #5 for the period 2022-05-01 to 2022-05-31. The manufacturer was requested to provide information in the next monthly safety report, following cases of rebound COVID-19. The current post-market safety data are consistent with the labelled safety profile of Paxlovid.
Monthly safety report Control # 264473	2022-05-31	Review completed 2022-06-21	Information filed as per the terms and conditions imposed on the authorization issued under the Food and Drug Regulations. Monthly safety report #4 for the period 2022-04-01 to 2022-04-30. The manufacturer was requested to provide information in the next monthly safety report, following cases of rebound COVID-19. The current post-market safety data are consistent with the labelled safety profile of Paxlovid.
SNDS # 263843	2022-04-29	Issued NOC 2022-06-13	Submission filed as a Level I – Supplement for new packaging specifically for patients with moderate renal impairment who require nirmatrelvir dose reduction. The new dose pack is expected to mitigate potential risk of medication errors in this patient population. The Serious Warnings and Precautions, Dosage and Administration, and Patient Medication Information sections of the Product Monograph (PM) were updated to reflect this information. The Adverse Reactions and Patient Medication Information sections of the PM were updated to reflect new information on hypersensitivity. The submission was reviewed and considered acceptable, and an NOC was issued. A new DIN (02527804) was issued for the new packaging.
SNDS # 261884	2022-02-28	Issued NOC 2022-05-25	Submission filed as a Level II – Supplement (Safety) to update the Product Monograph (PM). The Warnings and Precautions, Adverse Reactions, and Patient Medication Information sections of the PM were updated to reflect new information on hypersensitivity. Information was also filed to fulfill clinical Terms and Conditions #4, 9, 10, and 12. The submission was reviewed and considered acceptable, and an NOC was issued.
Monthly safety report Control # 263579	2022-04-29	Review completed 2022-05-20	Information filed as per the terms and conditions imposed on the authorization issued under the Food and Drug Regulations. Monthly safety report #3 for the period 2022-03-01 to 2022-03-31. The manufacturer was requested to provide information in the next monthly safety report, following cases of rebound COVID-19. The current post-market safety data are consistent with the labelled safety profile of Paxlovid.
Risk Management Plan update Control # 260404	2022-02-04	Review completed 2022-05-18	The updated European Union Risk Management Plan version 1.2 and Canadian Addenda dated February and April 2022 were filed as per the terms and conditions imposed on the authorization issued under the Food and Drug Regulations. The review found these documents acceptable with revisions that were requested to be addressed by the sponsor within 90 days.
Monthly safety report Control # 262576	2022-03-31	Review completed 2022-04-21	Information filed as per the terms and conditions imposed on the authorization issued under the Food and Drug Regulations. Monthly safety report #2 for the period 2022-02-01 to 2022-02-28. The current post-market safety data are consistent with the labelled safety profile of Paxlovid.
SNDS # 261288	2022-02-11	Issued NOC 2022-04-14	Submission filed as a Level I – Supplement for a new manufacturing site for the drug product. The submission was reviewed and considered acceptable, and an NOC was issued. The terms and conditions that accompanied the NOC for NDS # 259186 remain applicable.
Monthly safety report Control # 262056	2022-03-04	Review completed 2022-03-21	Information filed as per the terms and conditions imposed on the authorization issued under the Food and Drug Regulations. Monthly safety report #1 for the period 2021-12-15 to 2022-01-31. The current post-market safety data are consistent with the labelled safety profile of Paxlovid.
Drug product (DIN 02524031) market notification	Not applicable	Date of first sale: 2022-01-18	The manufacturer notified Health Canada of the date of first sale pursuant to C.01.014.3 of the Food and Drug Regulations.
Health Product Risk Communication	Not applicable	Posted 2022-01-17	Health Product Risk Communication posted (Paxlovid [nirmatrelvir and ritonavir]) - Dosing and Dispensing in Renal Impairment, Risk of Serious Adverse Reactions Due to Drug Interactions, and English-Only Labels), containing information on labelling, new safety information, and supply for healthcare professionals.
NDS # 259186	2021-12-01	Issued NOC (subject to terms and conditions) 2022-01-17	NOC issued for New Drug Submission. Terms and conditions were imposed on the authorization.

Summary Basis of Decision (SBD) for Paxlovid

Date SBD issued: 2022-02-28

The following information relates to the New Drug Submission for Paxlovid.

Nirmatrelvir and ritonavir

Drug Identification Number (DIN):

DIN 02524031 - 150 mg nirmatrelvir, tablet, and 100 mg ritonavir, tablet, co-packaged, oral administration

Pfizer Canada ULC

New Drug Submission Control Number: 259186

On January 17, 2022, Health Canada issued a Notice of Compliance (NOC), subject to terms and conditions, to Pfizer Canada ULC for the drug product Paxlovid.

The market authorization of Paxlovid was based on quality (chemistry and manufacturing), non-clinical (pharmacology and toxicology), and clinical (pharmacology, safety, and efficacy) information submitted. Based on Health Canada’s review, the benefit-harm-uncertainty profile of Paxlovid is considered favourable for the treatment of mild-to-moderate COVID-19 in adults with positive results of direct severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viral testing, and who are at high risk for progression to severe COVID-19, including hospitalization or death.

Paxlovid is not authorized for:

initiation of treatment in patients requiring hospitalization due to severe or critical COVID-19;
pre-exposure or post-exposure prophylaxis for prevention of COVID-19;
use for longer than 5 consecutive days.

Paxlovid is authorized in accordance with the Food and Drug Regulations, subject to terms and conditions that need to be met by the sponsor. Terms and conditions may be imposed or amended at any time. Additionally, failure to comply with the terms and conditions may result in compliance and enforcement actions being taken by Health Canada.

For further information on the amended regulatory pathway, refer to the Guidance on Amendments to the Food and Drug Regulations for Drugs for Use in Relation to COVID-19.

1 What was approved?

Paxlovid (nirmatrelvir and ritonavir) is an oral antiviral drug. It was authorized for the treatment of mild-to-moderate coronavirus disease 2019 (COVID-19) in adults with positive results of direct severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viral testing, and who are at high risk for progression to severe COVID-19, including hospitalization or death.

Paxlovid is not authorized for:

initiation of treatment in patients requiring hospitalization due to severe or critical COVID-19;
pre-exposure or post-exposure prophylaxis for prevention of COVID-19;
use for longer than 5 consecutive days.

The safety and effectiveness of Paxlovid have not been established in patients younger than 18 years of age. Consequently, Paxlovid is not authorized for use in pediatric patients.

Clinical studies of Paxlovid included participants 65 years of age and older, and their data contributed to the overall assessment of safety and efficacy.

Paxlovid consists of 150 mg nirmatrelvir tablets co-packaged with 100 mg ritonavir tablets. Non-medicinal ingredients in the nirmatrelvir tablet core include colloidal silicon dioxide, croscarmellose sodium, lactose monohydrate, microcrystalline cellulose, and sodium stearyl fumarate. The tablet film coat contains hydroxypropyl methylcellulose, iron oxide red, polyethylene glycol, and titanium dioxide.

For the co-packaged ritonavir tablets, non-medicinal ingredients in the tablet core include anhydrous dibasic calcium phosphate, colloidal silicon dioxide, copovidone, sodium stearyl fumarate, and sorbitan monolaurate. The tablet film coat contains colloidal silicon dioxide, hydroxypropyl cellulose, hypromellose, polyethylene glycol 400, polyethylene glycol 3350, polysorbate 80, talc, and titanium dioxide.

The dosage for Paxlovid is 300 mg nirmatrelvir (two 150 mg tablets) and 100 mg ritonavir (one 100 mg tablet) taken together orally twice daily for 5 days. Patients should be advised to complete the full 5-day treatment course.

The use of Paxlovid is contraindicated:

in patients with a history of clinically significant hypersensitivity reactions (e.g., toxic epidermal necrolysis or Stevens-Johnson syndrome) to its active ingredients (nirmatrelvir or ritonavir) or any other components of the product;
with drugs that are highly dependent on cytochrome P450 (CYP) 3A for clearance and for which elevated concentrations are associated with serious and/or life-threatening reactions;
with drugs that are potent CYP3A inducers where significantly reduced nirmatrelvir or ritonavir plasma concentrations may be associated with the potential for loss of virologic response and possible resistance.

Drugs that are contraindicated for concomitant use with Paxlovid are listed in the Paxlovid Product Monograph and include:

alpha 1-adrenoreceptor antagonist: alfuzosin
antianginal: ranolazine
antiarrhythmics: amiodarone, bepridil, dronedarone, flecainide, propafenone, quinidine
antibiotic: fusidic acid
anticancer agents: apalutamide, neratinib, venetoclax
anticoagulant: rivaroxaban
anticonvulsants: carbamazepine, phenobarbital, phenytoin
antifungal: voriconazole
anti-gout agent: colchicine
antihistamines: astemizole, terfenadine
antimycobacterial: rifampin
antipsychotics: lurasidone, pimozide
ergot derivatives: dihydroergotamine, ergonovine, ergotamine, methylergonovine
gastrointestinal motility agent: cisapride
herbal product: St. John’s wort (Hypericum perforatum)
lipid-modifying agents: lovastatin, simvastatin, lomitapide
long-acting beta-adrenoreceptor agonist: salmeterol
phosphodiesterase type-5 (PDE5) inhibitors: sildenafil, when used for pulmonary arterial hypertension (PAH), vardenafil, when used for the treatment of erectile dysfunction or PAH
sedative/hypnotics: orally administered midazolam, triazolam

Additionally, Paxlovid cannot be started immediately after discontinuation of any of the following medications due to the delayed offset of the recently discontinued CYP3A inducer:

anticancer agent: apalutamide
anticonvulsants: carbamazepine, phenobarbital, phenytoin
antimycobacterial: rifampin
herbal product: St. John’s wort (Hypericum perforatum)

Paxlovid was approved for use under the conditions stated in its Product Monograph taking into consideration the potential risks associated with its administration. The Paxlovid Product Monograph is available through the Drug Product Database and on the Health Canada COVID-19 vaccines and treatments portal.

For more information about the rationale for Health Canada's decision, refer to the Clinical, Non-clinical, and Quality (Chemistry and Manufacturing) Basis for Decision sections.

2 Why was Paxlovid approved?

Health Canada considers that the benefit-harm-uncertainty profile of Paxlovid in the treatment of mild-to-moderate coronavirus disease 2019 (COVID-19) in adults with positive results of direct severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viral testing, and who are at high risk for progression to severe COVID-19, including hospitalization or death, is favourable under the conditions of use stated in the Paxlovid Product Monograph and taking into consideration the potential risks associated with its administration. Paxlovid is authorized in accordance with the Food and Drug Regulations, subject to terms and conditions that need to be met by the sponsor.

Coronavirus disease 2019 is the infectious disease caused by the novel coronavirus, SARS-CoV-2, which has spread rapidly and globally since its emergence in late 2019. On March 11, 2020, the World Health Organization declared COVID-19 a pandemic. In Canada, there have been 2,801,451 confirmed cases of COVID-19 and 31,679 deaths as of January 17, 2022, the date of authorization of Paxlovid.

Severe acute respiratory syndrome coronavirus 2 is a highly transmissible and pathogenic coronavirus. The majority of SARS-CoV-2-infected patients experience mild respiratory disease. However, following infection, some patients develop severe disease that requires oxygen support or critical disease with complications such as respiratory failure, sepsis and septic shock, thromboembolism, and/or multiorgan failure, including acute kidney injury and cardiac injury. Medical conditions or other factors that place patients at high risk for progression to severe COVID-19 include older age, obesity, current smoker, chronic kidney disease, diabetes, immunosuppressive disease or immunosuppressive treatment, cardiovascular disease, chronic lung disease, sickle cell disease, neurodevelopmental disorders, active cancer, and medically related technological dependence. Other medical conditions or factors (e.g., race or ethnicity) may also place individual patients at high risk for progression to severe COVID-19.

Health Canada has authorized the following vaccines for protection against COVID-19: Comirnaty (previously Pfizer-BioNTech COVID-19 Vaccine), Spikevax (previously COVID-19 Vaccine Moderna), Vaxzevria (previously AstraZeneca COVID-19 Vaccine), Covishield, and Janssen COVID-19 Vaccine.

Current treatments for COVID-19 include remdesivir (Veklury) and the therapeutic monoclonal antibodies bamlanivimab, casirivimab/imdevimab, and sotrovimab, all of which are administered intravenously. Veklury is authorized for the treatment of COVID-19 in hospitalized adults and adolescents (aged 12 years and older with body weight at least 40 kg) with pneumonia requiring supplemental oxygen. The monoclonal antibodies are authorized for the treatment of mild-to-moderate COVID-19 in non-hospitalized adults and adolescents (12 years of age and older weighing at least 40 kg) who are at high risk for progressing to severe COVID-19 illness, hospitalization and/or death. In the context of the ongoing pandemic, there remains an urgent need for more treatment options.

Paxlovid (nirmatrelvir and ritonavir) is an oral antiviral drug. Nirmatrelvir (also known as PF-07321332) is a new active substance. It acts as a selective inhibitor of the SARS-CoV-2 main protease (Mpro; also referred to as 3-chymotrypsin-like protease [3CLpro] or nonstructural protein 5 [NSP5] protease), a virally encoded enzyme that plays a critical role in the SARS-CoV-2 replication cycle. Nirmatrelvir must be co-administered with ritonavir, which serves as a pharmacokinetic enhancer. Ritonavir is authorized in Canada both as a single agent and as a component of a fixed-dose combination antiretroviral product.

Paxlovid has been shown to be efficacious in the treatment of mild-to-moderate COVID-19 in adult patients with positive results of direct SARS-CoV-2 viral testing and at high risk for progression to severe COVID-19. The market authorization was based on interim efficacy and safety data derived from the Phase II/III, randomized, double-blind, placebo-controlled EPIC-HR (C4671005) study. The study involved non-hospitalized symptomatic adults (18 years of age and older) with a laboratory-confirmed diagnosis of SARS-CoV-2 infection and at least one of the following risk factors for progression to severe disease: diabetes, overweight (body mass index >25), chronic lung disease (including asthma), chronic kidney disease, current smoker, immunosuppressive disease or immunosuppressive treatment, cardiovascular disease, hypertension, sickle cell disease, neurodevelopmental disorders, active cancer, medically related technological dependence, or were 60 years of age and older, regardless of comorbidities. Patients with COVID-19 symptom onset of ≤5 days were included in the study. The patients were randomized (1:1) to receive Paxlovid (nirmatrelvir/ritonavir 300 mg/100 mg) or placebo orally every 12 hours for 5 days. The study excluded individuals with a history of prior COVID-19 infection or vaccination.

The primary efficacy endpoint of the study was the proportion of patients with COVID-19-related hospitalization or death from any cause through Day 28. The analysis was conducted in:

the modified intention-to-treat (mITT) analysis set (all treated patients with onset of symptoms ≤3 days who at baseline did not receive nor were expected to receive COVID-19 therapeutic monoclonal antibody treatment);

the mITT1 analysis set (all treated patients with onset of symptoms ≤5 days who at baseline did not receive nor were expected to receive COVID-19 therapeutic monoclonal antibody treatment); and

the mITT2 analysis set (all treated patients with onset of symptoms ≤5 days).

There were 1,361 patients randomized to receive either Paxlovid or placebo. The baseline demographic and disease characteristics were balanced between the Paxlovid and placebo groups. At the time of the interim analysis, the mITT analysis set included 389 patients in the Paxlovid group and 385 patients in the placebo group. Compared with placebo, Paxlovid reduced the proportion of patients with COVID-19-related hospitalization or death through Day 28 by 89.1%. In the Paxlovid group, 0.8% (3/389) of patients were hospitalized or died compared to 7% (27/385) of patients in the placebo group (representing an absolute risk reduction of -6.32%, 95% confidence interval: -9.04, -3.59). This reduction was statistically significant (p<0.0001). No deaths occurred in the Paxlovid group compared with 7 reported deaths in the placebo group.

Efficacy results in the mITT1 and mITT2 analysis sets were consistent with those in the mITT analysis set. Similarly, the provided primary efficacy data from the topline final analysis were consistent with the efficacy results of the interim analysis. To confirm the efficacy of Paxlovid in the target patient population, the sponsor is required to provide Health Canada with the final study report of the EPIC-HR study.

Based on the submitted data, the safety profile of Paxlovid is considered acceptable for the target patient population. At the time of the approval, a topline analysis of the final study results was available for 2,224 patients (1,109 in the Paxlovid group and 1,115 in the placebo group). Adverse events presented in the submitted information were those reported while patients were on study medication and through Day 34 after initiating study treatment. The incidence of adverse events was 22.6% in the Paxlovid group and 23.9% in the placebo group. Adverse events of all grades, regardless of causality, in the Paxlovid group (reported by ≥1% patients) that occurred at a greater frequency (≥5 subject difference) than in the placebo group were dysgeusia (6% versus <1%), diarrhea (3% versus 2%), hypertension (1% versus <1%), and myalgia (1% versus <1%). The proportions of patients who discontinued treatment due to an adverse event were 2% in the Paxlovid group and 4% in the placebo group. Additional safety data from ongoing studies (including data from the final study report of the EPIC-HR study and its 24-week patient follow-up) and post-market safety monitoring data will be submitted to Health Canada, as specified in the terms and conditions imposed in respect of Paxlovid to address the uncertainties in relation to the clinical safety evidence available at the time of granting market authorization.

The main risk associated with Paxlovid is the potential for drug-drug interactions that may result in clinically significant adverse reactions, potentially leading to severe, life-threatening, or fatal events, or loss of therapeutic effect of Paxlovid and possible development of viral resistance. The risk of drug-drug interactions is highlighted in the Paxlovid Product Monograph, which lists drugs that are contraindicated for concomitant use with Paxlovid and outlines potentially significant drug-drug interactions. The information included is considered a guide and does not represent a comprehensive list of all possible drugs that may interact with Paxlovid. The Paxlovid Product Monograph recommends that prescribers consider the potential for drug-drug interactions prior to and during Paxlovid therapy, review concomitant medications during Paxlovid therapy, and monitor for the adverse reactions associated with the concomitant medications.

A Risk Management Plan (RMP) for Paxlovid was submitted by Pfizer Canada ULC to Health Canada. The RMP is designed to describe known and potential safety issues, to present the monitoring scheme and when needed, to describe measures that will be put in place to minimize risks associated with the product. Upon review, the RMP was considered acceptable with revisions. The sponsor is required to submit a Canadian RMP Addendum, which will address: use in patients with renal impairment; use in immunocompromised patients; use in pregnancy and breastfeeding; and drug/antiviral resistance and treatment-emergent mutations.

Based on the submitted information, the benefit-harm-uncertainty profile of Paxlovid is considered favourable for the target patient population. Appropriate warnings and precautions are in place in the Paxlovid Product Monograph to address the identified safety concerns. Additional efficacy, safety, and quality data from ongoing studies (including data from the final study report of the EPIC-HR study) and post-market safety monitoring data will be submitted to Health Canada, as specified in the terms and conditions imposed in respect of Paxlovid to address the uncertainties related to the clinical, non-clinical, and quality information reviewed.

This New Drug Submission complies with the requirements of sections C.08.002 and C.08.005.1 and therefore Health Canada has issued an NOC pursuant to section C.08.004 of the Food and Drug Regulations. The NOC in respect of Paxlovid is accompanied by terms and conditions imposed in accordance with section C.01.014.21 of the Food and Drug Regulations. Of note, terms and conditions may be imposed or amended at any time. All terms and conditions are enforceable under section 21.7 of the Food and Drugs Act. Failure to comply with the terms and conditions may result in compliance and enforcement actions being taken by Health Canada.

For more information, refer to the Clinical, Non-clinical, and Quality (Chemistry and Manufacturing) Basis for Decision sections.

3 What steps led to the approval of Paxlovid?

The Food and Drug Regulationswere amended on March 18, 2021 to incorporate flexibilities into the existing new drug submission (NDS) regulatory pathway, thereby facilitating the regulatory process for authorization of new drugs that treat or prevent coronavirus disease 2019 (COVID-19). For example, to expedite the review process, the modified requirements allow an NDS for a designated COVID-19 drug to be filed through a rolling submission process, i.e., as the information becomes available. This in turn allows Health Canada to commence a rolling review process of the information submitted. As outlined in the Guidance on amendments to the Food and Drug Regulations for drugs for use in relation to COVID-19, Health Canada will begin its review using the information submitted by the sponsor and accept new evidence as it becomes available until the submission is deemed complete. The rolling process can reduce the time it takes to authorize these critical new drugs while maintaining appropriate standards of safety, efficacy, and quality. Sponsors are responsible for completing the required documentation and providing the necessary evidence to Health Canada. Health Canada will issue a Notice of Compliance (NOC) for a COVID-19 drug if it is determined that the benefits and risks of the product are supported by evidence of the safety, efficacy, and consistent quality of the drug. Importantly, the amended regulations also allow the use of terms and conditions in order to ensure appropriate oversight, manage uncertainties or mitigate risks related to the drug in the context of the public health need due to COVID-19.

The information for this NDS was provided on a rolling basis. Following an expedited review of the data submitted, Health Canada determined that sufficient evidence was provided to support the conclusion that the benefits of Paxlovid outweigh the risks under the conditions of use recommended, with consideration given to the uncertainties relating to those benefits and risks as well as the public health need related to COVID-19. Health Canada issued an NOC for Paxlovid, with imposed terms and conditions, on January 17, 2022.

For further information on the amended NDS regulatory pathway, refer to the Guidance on Amendments to the Food and Drug Regulations for Drugs for Use in Relation to COVID-19.

Submission Milestones: Paxlovid

Submission Milestone	Date
Pre-submission meeting	2021-09-27
Initial New Drug Submission filed by sponsor	2021-12-01
Initial clinical data submitted by sponsor	2021-12-01
Initial non-clinical data submitted by sponsor	2021-12-01
Initial quality data submitted by sponsor	2021-12-01
Screening Acceptance Letter issued	2021-12-20
Risk Management Plan submitted by sponsor	2021-12-22
Health Canada non-clinical evaluation completed	2022-01-10
Health Canada Risk Management Plan evaluation completed	2022-01-13
Health Canada clinical/medical evaluation completed	2022-01-13
Health Canada quality evaluation completed	2022-01-14
Health Canada labelling evaluation completed	2022-01-14
Terms and conditions finalized by Health Canada	2022-01-14
Final Product Monograph (English) submitted by sponsor	2022-01-14
Final Product Monograph (French) submitted by sponsor	2022-01-16
Notice of Compliance issued by Director General, Therapeutic Products Directorate	2022-01-17

4 What follow-up measures will the company take?

The Notice of Compliance issued in respect of Paxlovid is accompanied by terms and conditions imposed on the drug identification number assigned to Paxlovid in accordance with section C.01.014.21 of the Food and Drug Regulations. Of note, terms and conditions may be imposed or amended at any time. Failure to comply with the terms and conditions may result in compliance and enforcement actions being taken by Health Canada.

These terms and conditions set out requirements relating to clinical, non-clinical, quality (chemistry and manufacturing), labelling, and pharmacovigilance information. They were put in place to ensure appropriate oversight, manage uncertainties or mitigate risks, and ascertain the continued quality, safety, and efficacy of the product.

The terms and conditions include (but are not limited to) the requirements listed below.

With respect to information on clinical and non-clinical studies, the sponsor is required to submit:

The final clinical study report for the Phase II/III study EPIC-HR (Study C4671005) to confirm the safety and efficacy of Paxlovid in the treatment of non-hospitalized adults with mild-to-moderate coronavirus disease 2019 (COVID-19) who are at risk of progressing to severe disease.

The final viral genome sequencing results from participants enrolled in the EPIC-HR study with complete data on the mutational pressure of nirmatrelvir on the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) 3CL protease gene regions of interest.

The full population pharmacokinetic analysis report for Paxlovid, with the model being updated using all the data from the EPIC-HR study. The population pharmacokinetic analysis shall be updated to provide a complete evaluation and description of the pharmacokinetics of nirmatrelvir in patients, and provide information about potential covariate effects including, but not limited to, the impact of age, sex, body mass index, weight, race, ethnicity, hepatic impairment, and renal impairment.

The report for a 24-week patient follow-up in the EPIC-HR study.

The final clinical study report from a Phase I, non-randomized, open-label study (Study C4671010) to assess the pharmacokinetics, safety, and tolerability of nirmatrelvir boosted with ritonavir in adult participants with moderate hepatic impairment and healthy participants with normal hepatic function.

The final clinical study report from a Phase I, open-label, 3-treatment, 6-sequence, 3-period crossover study to estimate the effect of nirmatrelvir/ritonavir and ritonavir on the pharmacokinetics of midazolam in healthy participants (Study C4671013).

The final clinical study report from a Phase I, open-label, 3-treatment, 6-sequence, 3-period crossover study to estimate the effect of nirmatrelvir/ritonavir on the pharmacokinetics of dabigatran in healthy participants (Study C4671012).

The final clinical study report from a Phase I, open-label, randomized, single-dose, 2-sequence, 2-period crossover study to evaluate the effect of high-fat meal on the relative bioavailability of 300 mg/100 mg nirmatrelvir/ritonavir as tablet formulation in healthy participants (Study C4671019).

The final report from the ongoing prenatal and postnatal development study in rats (Study 00655272).

The final report from a 1-month oral gavage toxicity study of nirmatrelvir in Wistar Han rats with a 2-week recovery (Study 21GR122).

The final report from a 1-month twice-daily oral gavage toxicity study of nirmatrelvir in cynomolgus monkeys with a 2-week recovery (Study 21GR125).

The final report from a study investigating in vitro cell-based efficacy of nirmatrelvir against major SARS-CoV-2 variants (Study PF07321332_04Aug21_104040).

The final report from a study investigating in vitro quantitative polymerase chain reaction (qPCR)-based efficacy of nirmatrelvir against major SARS-CoV-2 variants (Study PF-07321332_12Oct21_042713).

The final report from an in vitro evaluation of nirmatrelvir activity against reverse-engineered recombinant SARS-CoV-2, characterizing viral fitness and resistance (Study PF-07321332_16Nov21_024518).

Additionally, the sponsor is required to submit:

Information on the manufacturing process and controls for nirmatrelvir for synthetic routes used at each of the drug substance manufacturing sites, an updated risk assessment of all potential impurities in the drug substance, and the process validation protocol for the manufacture of nirmatrelvir tablets batches of commercial size.

Canadian-specific bilingual labelling for Paxlovid, and to implement such labelling once supplies are transitioned to Canadian dedicated supplies. The sponsor shall keep Health Canada informed of estimated timelines and proposed strategies concerning the development and implementation of Canadian-specific bilingual labels. During the period prior to implementation of the Canadian-specific bilingual labelling, the sponsor shall make the Canadian Product Monograph available to health care professionals.

A Monthly Summary Safety Report for each of the first 6 months of marketing of nirmatrelvir/ritonavir in Canada.

An updated European Union (EU) Risk Management Plan (RMP) and a Canadian RMP Addendum. The Canadian RMP addendum shall address the following:
- use in patients with renal impairment;
- use in immunocompromised patients;
- use in pregnancy and breastfeeding;
- drug/antiviral resistance and treatment-emergent mutations.

5 What post-authorization activity has taken place for Paxlovid?

Summary Basis of Decision documents (SBDs) for eligible drugs authorized after September 1, 2012 will include post-authorization information in a table format. The Post-Authorization Activity Table (PAAT) will include brief summaries of activities such as submissions for new uses of the product, and whether Health Canada's decisions were negative or positive. The PAAT will continue to be updated during the product life cycle.

The PAAT for Paxlovid is found above.

For the latest advisories, warnings and recalls for marketed products, see MedEffect Canada.

6 What other information is available about drugs?

Up-to-date information on drug products can be found at the following links:

See the Health Canada COVID-19 vaccines and treatments portal for information on vaccines and treatments authorized for COVID-19, as well as those currently under review.
See MedEffect Canada for the latest advisories, warnings and recalls for marketed products.
See the Notice of Compliance (NOC) Database for a listing of the authorization dates for all drugs that have been issued an NOC since 1994.
See the Drug Product Database (DPD) for the most recent Product Monograph. The DPD contains product-specific information on drugs that have been approved for use in Canada.
See the Notice of Compliance with Conditions (NOC/c)-related documents for the latest fact sheets and notices for products which were issued an NOC under the Notice of Compliance with Conditions (NOC/c) Guidance Document, if applicable. Clicking on a product name links to (as applicable) the Fact Sheet, Qualifying Notice, and Dear Health Care Professional Letter.
See the Patent Register for patents associated with medicinal ingredients, if applicable.
See the Register of Innovative Drugs for a list of drugs that are eligible for data protection under C.08.004.1 of the Food and Drug Regulations, if applicable.

7 What was the scientific rationale for Health Canada's decision?

7.1 Clinical Basis for Decision

The New Drug Submission for Paxlovid (nirmatrelvir and ritonavir) was submitted and reviewed in accordance with the Food and Drug Regulations, which permitted a rolling submission and review process. Following review of the provided information, a Notice of Compliance was issued in relation to Paxlovid, with accompanying terms and conditions to manage any uncertainties or mitigate risks related to the drug.

Clinical Pharmacology

Paxlovid contains 150 mg nirmatrelvir tablets co-packaged with 100 mg ritonavir tablets.

Nirmatrelvir (also known as PF-07321332) is a new active substance. It is a peptidomimetic inhibitor of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) main protease (Mpro; also referred to as 3-chymotrypsin-like protease [3CLpro] or nonstructural protein 5 [NSP5] protease). Inhibition of the SARS-CoV-2 3CLpro renders the enzyme incapable of processing polyprotein precursors, preventing viral replication.

Nirmatrelvir must be co-administered with ritonavir, a human immunodeficiency virus (HIV) protease inhibitor, which is not active against the SARS-CoV-2 3CLpro. Ritonavir acts as a pharmacokinetic enhancer, as it inhibits the cytochrome P450 (CYP) 3A-mediated metabolism of nirmatrelvir, thereby increasing the plasma concentrations of nirmatrelvir. Ritonavir was first authorized in Canada as a single agent in 1996 and as a component of a fixed-dose combination antiretroviral product in 2001.

The pharmacokinetic properties of nirmatrelvir/ritonavir have been studied in healthy subjects.

Following oral administration of single ascending doses of nirmatrelvir (ranging from 250 mg to 750 mg; as an oral suspension formulation) enhanced with 100 mg of ritonavir, the increase in systemic exposure of nirmatrelvir appeared to be less than dose proportional up to 750 mg of nirmatrelvir. Following multiple oral doses of nirmatrelvir (ranging from 75 mg to 500 mg; as an oral suspension formulation) enhanced with 100 mg ritonavir, the increase in systemic exposure of nirmatrelvir appeared to be less than dose proportional up to 500 mg of nirmatrelvir. Twice-daily dosing over 10 days achieved steady-state plasma concentrations of nirmatrelvir on Day 2 with approximately 2-fold accumulation.

The pharmacokinetic properties of nirmatrelvir/ritonavir based on age and gender have not been evaluated. Systemic exposure of nirmatrelvir in Japanese subjects was found to be numerically lower than that in Caucasian subjects, but the data were limited and the difference observed was not clinically meaningful. A preliminary population pharmacokinetic model was developed based on limited pharmacokinetic data from healthy volunteers. As per the terms and conditions associated with the Notice of Compliance for Paxlovid, the sponsor is required to submit an updated population pharmacokinetic analysis to provide a complete evaluation and description of nirmatrelvir pharmacokinetics in patients, and provide information about potential covariate effects including, but not limited to, the impact of age, sex, body mass index, weight, race, ethnicity, hepatic impairment, and renal impairment.

Current non-clinical and clinical data do not suggest that Paxlovid is associated with a risk of QT prolongation. However, the impact of Paxlovid on QT prolongation has not been fully evaluated in humans.

An open-label study examined the pharmacokinetics of nirmatrelvir/ritonavir in healthy adult subjects and subjects with mild (estimated glomerular filtration rate [eGFR] 60 to <90 mL/min), moderate (eGFR ≥30 to <60 mL/min), and severe (eGFR <30 mL/min) renal impairment following administration of a single oral dose of nirmatrelvir 100 mg enhanced with ritonavir 100 mg administered at -12, 0, 12, and 24 hours relative to nirmatrelvir dosing. Compared to healthy controls with no renal impairment, the maximum plasma concentration (C_max) and area under the plasma concentration-time curve (AUC) of nirmatrelvir were found to be 30% and 24% higher in patients with mild renal impairment, 38% and 87% higher in patients with moderate renal impairment, and 48% and 204% higher in patients with severe renal impairment. Based on these data, the use of Paxlovid is not recommended in patients with severe renal impairment. Furthermore, dose reduction of Paxlovid is required in patients with moderate renal impairment (150 mg nirmatrelvir [one 150 mg tablet] and 100 mg ritonavir [one 100 mg tablet], taken together twice daily for 5 days). No dose adjustment is needed in patients with mild renal impairment.

No pharmacokinetic or safety data are available regarding the use of nirmatrelvir or ritonavir in subjects with severe hepatic impairment (Child-Pugh Class C). Therefore, the use of Paxlovid is not recommended in these patients. Based on current preliminary pharmacokinetic and safety data, no dosage adjustment of Paxlovid is needed in patients with mild (Child-Pugh Class A) or moderate (Child-Pugh Class B) hepatic impairment. The sponsor is required to submit the final results of a Phase I, non-randomized, open-label study assessing the pharmacokinetics, safety, and tolerability of nirmatrelvir boosted with ritonavir in adult participants with moderate hepatic impairment and healthy participants with normal hepatic function.

The main contributor to the metabolism of nirmatrelvir is the CYP3A4 enzyme. Ritonavir is also a CYP3A substrate. A Phase I study investigated the effect of a strong CYP3A4 inducer, carbamazepine, on the pharmacokinetics of nirmatrelvir and ritonavir in healthy participants. Results of the study showed that the exposures of both nirmatrelvir and ritonavir were significantly decreased. Reduced nirmatrelvir or ritonavir plasma concentrations may be associated with the potential for loss of virologic response and possible development of SARS-CoV-2 resistance to Paxlovid. For that reason, Paxlovid is contraindicated for use with drugs that are potent CYP3A inducers.

Importantly, ritonavir is a known strong inhibitor of CYP3A and may increase plasma concentrations of agents that are primarily metabolized by CYP3A. Therefore, co-administration of Paxlovid with drugs highly dependent on CYP3A for clearance and for which elevated plasma concentrations are associated with serious and/or life-threatening events is contraindicated. Co-administration with other CYP3A substrates may require a dose adjustment or additional monitoring. Ritonavir also inhibits, to a lesser extent, CYP2D6. Co-administration of substrates of CYP2D6 with ritonavir could result in increases (up to 2-fold) in the AUC of the other agent, possibly requiring a proportional dosage reduction. Ritonavir also appears to induce CYP3A, CYP1A2, CYP2C9, CYP2C19, and CYP2B6 as well as other enzymes, including glucuronosyl transferase. The risk of drug-drug interactions leading to potentially serious and/or life-threatening reactions due to the effects of ritonavir on the hepatic metabolism of certain drugs is highlighted in a Serious Warnings and Precautions Box in the Paxlovid Product Monograph. The Paxlovid Product Monograph recommends that prescribers consider the potential for drug interactions prior to and during Paxlovid therapy, review concomitant medications during Paxlovid therapy, and monitor for the adverse reactions associated with the concomitant medications.

Established and potentially significant drug interactions have been listed in the Paxlovid Product Monograph. At present, the list is considered a guide and does not represent a comprehensive source of information on all possible drugs that may interact with Paxlovid. As per the terms and conditions, the sponsor is required to submit the final reports of two ongoing Phase I drug-drug interaction studies investigating the effects of nirmatrelvir/ritonavir on the pharmacokinetics of midazolam (a benzodiazepine) and dabigtran (an anticoagulant), respectively.

The submitted clinical pharmacology data support the use of Paxlovid for the specified indication. Further evaluation will take place upon provision of the final study reports requested in the terms and conditions imposed in respect of Paxlovid.

For further details, please refer to the Paxlovid Product Monograph, approved by Health Canada and available through the Drug Product Database and on the Health Canada COVID-19 vaccines and treatments portal.

Clinical Efficacy

The efficacy of Paxlovid in the treatment of mild-to-moderate coronavirus disease 2019 (COVID-19) in adult patients with positive results of direct SARS-CoV-2 viral testing and at high risk for progression to severe COVID-19 was supported by results from the Phase II/III, randomized, double-blind, placebo-controlled EPIC-HR (C4671005) study.

This clinical study involved non-hospitalized symptomatic adults (18 years of age and older) with a laboratory-confirmed diagnosis of SARS-CoV-2 infection and at least one of the following risk factors for progression to severe disease: diabetes, overweight (body mass index >25), chronic lung disease (including asthma), chronic kidney disease, current smoker, immunosuppressive disease or immunosuppressive treatment, cardiovascular disease, hypertension, sickle cell disease, neurodevelopmental disorders, active cancer, medically related technological dependence, or were 60 years of age and older, regardless of comorbidities. Patients with COVID-19 symptom onset of ≤5 days were included in the study and were randomized (1:1) to receive Paxlovid (nirmatrelvir/ritonavir 300 mg/100 mg) or placebo orally every 12 hours for 5 days. The study excluded individuals with a history of prior COVID-19 infection or vaccination.

The primary efficacy endpoint of the study was the proportion of patients with COVID-19-related hospitalization or death from any cause through Day 28. The analysis was conducted in:

the modified intention-to-treat (mITT) analysis set (all treated patients with onset of symptoms ≤3 days who at baseline did not receive nor were expected to receive COVID-19 therapeutic monoclonal antibody treatment);

the mITT1 analysis set (all treated patients with onset of symptoms ≤5 days who at baseline did not receive nor were expected to receive COVID-19 therapeutic monoclonal antibody treatment); and

the mITT2 analysis set (all treated patients with onset of symptoms ≤5 days).

There were 1,361 patients randomized to receive either Paxlovid or placebo. The baseline demographic and disease characteristics were balanced between the Paxlovid and placebo groups. At the time of the interim analysis, the mITT analysis set included 389 patients in the Paxlovid group and 385 patients in the placebo group. Paxlovid was shown to reduce the proportion of patients with COVID-19-related hospitalization or death through Day 28 by 89.1%, compared with placebo. In the Paxlovid group, 0.8% (3/389) of patients were hospitalized or died compared to 7% (27/385) of patients in the placebo group (representing an absolute risk reduction of -6.32%, 95% confidence interval: -9.04, -3.59). This reduction was statistically significant (p<0.0001). Furthermore, no deaths occurred in the Paxlovid group compared with 7 reported deaths in the placebo group.

Efficacy results obtained in the mITT1 and mITT2 analysis sets were consistent with those of the mITT analysis set. In addition, the provided primary efficacy data from the topline final analysis were consistent with the efficacy results of the interim analysis. Similar trends were observed across subgroups of patients. These subgroup analyses were considered exploratory.

Viral genome sequencing data were available for 2 of the 5 patients in the Paxlovid treatment group who experienced treatment failure (hospitalization or death). No treatment-emergent SARS-CoV-2 mutations were associated with treatment failure. However, due to the limited data, no conclusions on the effect of treatment-emergent SARS-CoV-2 mutations on treatment failure could be drawn at this time. The sponsor is required to provide final viral genome sequencing results from participants enrolled in the EPIC-HR study with complete data on the mutational pressure of nirmatrelvir on the SARS-CoV-2 3CL protease gene regions of interest.

The available evidence supports the efficacy of Paxlovid in the treatment of non-hospitalized adults with mild-to-moderate COVID-19 who are at risk of progressing to severe disease. To confirm the efficacy of Paxlovid in the target patient population, the sponsor is required to provide the final study report of the EPIC-HR study to Health Canada.

Indication

The New Drug Submission for Paxlovid was filed by the sponsor with the following indication:

Paxlovid (nirmatrelvir tablets; ritonavir tablets) is indicated for the treatment of mild-to-moderate coronavirus disease 2019 (COVID-19) in adult and pediatric patients (12 years of age and older weighing at least 40 kg) with positive results of direct severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viral testing, and who are at high risk for progression to severe COVID-19, including hospitalization or death.

Limitations of authorized use:

Paxlovid is not authorized for initiation of treatment in patients requiring hospitalization due to severe or critical COVID-19.
Paxlovid is not authorized for pre-exposure or post-exposure prophylaxis for prevention of COVID-19.
Paxlovid is not authorized for use for longer than 5 consecutive days.

As no safety and efficacy data were submitted for pediatric patients, Health Canada revised the initially proposed indication to exclude “patients 12 years of age and older weighing at least 40 kg” from the target patient population. Accordingly, Health Canada approved the following indication:

Paxlovid (nirmatrelvir tablets; ritonavir tablets) is indicated for the treatment of mild-to-moderate coronavirus disease 2019 (COVID-19) in adults with positive results of direct severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viral testing, and who are at high risk for progression to severe COVID-19, including hospitalization or death.

Paxlovid is not authorized for:

initiation of treatment in patients requiring hospitalization due to severe or critical COVID-19;
pre-exposure or post-exposure prophylaxis for prevention of COVID-19;
use for longer than 5 consecutive days.

For more information, refer to the Paxlovid Product Monograph, approved by Health Canada and available through the Drug Product Database and on the Health Canada COVID-19 vaccines and treatments portal.

Clinical Safety

The safety evaluation of Paxlovid is based on the provided summary of key safety data from the EPIC-HR study (described in the Clinical Efficacy section).

At the time of the approval of Paxlovid, a topline analysis of the final study results was available for 2,224 patients (1,109 in the Paxlovid group and 1,115 in the placebo group). Adverse events presented in the submitted information were those reported while patients were on study medication and through Day 34 after initiating study treatment. The incidence of adverse events was 22.6% in the Paxlovid group and 23.9% in the placebo group. Adverse events of all grades, regardless of causality, in the Paxlovid group (at a frequency of ≥1%) that occurred at a greater frequency (a difference of ≥5 subjects) than in the placebo group were dysgeusia (6% versus <1%), diarrhea (3% versus 2%), hypertension (1% versus <1%), and myalgia (1% versus <1%). Serious adverse events were reported in a lower proportion of patients in the Paxlovid group (1.6%) compared to those in the placebo group (6.6%). The proportions of patients who discontinued treatment due to an adverse event were 2.1% in the Paxlovid group and 4.2% in the placebo group.

In the interim analysis of data from 1,361 patients assigned to treatment (678 patients in the Paxlovid group and 683 patients in the placebo group), the most frequently reported (≥1%) treatment-emergent adverse events in the Paxlovid group were dysgeusia (5.6%), diarrhea (3.1%), increased D-dimer (1.9%), increased alanine aminotransferase (1.5%), nausea (1.4%), decreased creatinine renal clearance (1.4%), headache (1.4%), and vomiting (1.1%). Dysgeusia, diarrhea, and vomiting were reported at higher frequencies in the Paxlovid group in comparison to the placebo group.

The interim analysis of data from 672 patients who received Paxlovid compared to 677 patients who received placebo demonstrated a higher proportion of patients reporting treatment-related adverse events in the Paxlovid group compared to patients in the placebo group (7.3% versus 4.3%). In the Paxlovid group, the most frequently reported treatment-related adverse events (≥1%) were dysgeusia and diarrhea. One patient in the Paxlovid group reported a serious adverse event (considered related to the ritonavir component) versus none in the placebo group. More patients in the Paxlovid group (n = 7) discontinued study drug due to a treatment-related adverse event compared to the placebo group (n = 3).

The main risk associated with Paxlovid is the potential for drug-drug interactions that may result in clinically significant adverse reactions, potentially leading to severe, life-threatening, or fatal events, or loss of therapeutic effect of Paxlovid and possible development of viral resistance. The risk of drug-drug interactions is highlighted in the Paxlovid Product Monograph, which lists drugs that are contraindicated for concomitant use with Paxlovid and outlines potentially significant drug-drug interactions. The information included is considered a guide and does not represent a comprehensive source of all possible drugs that may interact with Paxlovid. The Paxlovid Product Monograph recommends that prescribers consider the potential for drug-drug interactions prior to and during Paxlovid therapy, review concomitant medications during Paxlovid therapy, and monitor for the adverse reactions associated with the concomitant medications.

Additionally, because nirmatrelvir is co-administered with ritonavir, which is an HIV protease inhibitor, there may be a risk of HIV-1 developing resistance to HIV protease inhibitors in individuals with uncontrolled or undiagnosed HIV-1 infection. No dosage adjustment of Paxlovid is required when co-administered with other products containing ritonavir or cobicistat. Patients on ritonavir- or cobicistat-containing HIV or hepatitis C therapeutic regimens should continue their treatment as indicated. This information has been included in the Paxlovid Product Monograph.

Based on the submitted data, the safety profile of Paxlovid is considered acceptable for the target patient population. Additional safety data from ongoing studies (including data from the final study report of the EPIC-HR study and its 24-week patient follow-up) and post-market safety monitoring data will be submitted to Health Canada, as specified in the terms and conditions imposed in respect of Paxlovid to address the uncertainties in relation to the clinical safety evidence available at the time of the review.

7.2 Non-Clinical Basis for Decision

Paxlovid, an oral antiviral drug, contains two medicinal ingredients, nirmatrelvir and ritonavir. Nirmatrelvir (also known as PF-07321332) is a new active substance. It acts as a peptidomimetic inhibitor of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) main protease (Mpro; also referred to as 3-chymotrypsin-like protease [3CLpro] or nonstructural protein 5 [NSP5] protease). Inhibition of the SARS‑CoV‑2 3CLpro renders the enzyme incapable of processing polyprotein precursors, thereby preventing viral replication.

Nirmatrelvir is rapidly metabolized in the human body by the cytochrome P450 (CYP) 3A4 enzyme. To ensure that plasma concentrations remain at therapeutic levels, nirmatrelvir is co-administered with ritonavir, a strong CYP3A4 inhibitor. Ritonavir is a human immunodeficiency virus (HIV) protease inhibitor that is not active against the SARS-CoV-2 3CLpro. When co-administered with nirmatrelvir, ritonavir acts as a pharmacokinetic enhancer by inhibiting the CYP3A4-mediated metabolism of nirmatrelvir, thereby increasing its plasma concentration. Ritonavir was first authorized in Canada as a single agent in 1996 and as a component of a fixed-dose combination antiretroviral product in 2001. Review of non-clinical data for ritonavir consisted of cross-referencing to data from previously approved ritonavir submissions. Therefore, the primary focus of the non-clinical data review was the new active substance, nirmatrelvir.

The antiviral activity of nirmatrelvir was evaluated in vitro in a series of biochemical and cell-based assays to determine the potency and specificity against SARS-CoV-2. In a biochemical assay, nirmatrelvir inhibited the activity of recombinant SARS‑CoV‑2 3CLpro with an inhibition constant (Ki) value of 3.1 nM and a 50% inhibitory concentration (IC₅₀) value of 19.2 nM. Nirmatrelvir was also found to bind directly to the SARS‑CoV‑2 3CLpro active site by X-ray crystallography.

In cell-based assays, nirmatrelvir had similar antiviral activity (with 50% effective concentration [EC₅₀] values ≤3-fold relative to the SARS-CoV-2 isolate USA-WA1/2020) against SARS-CoV-2 isolates belonging to the Alpha (B.1.1.7), Beta (B.1.351), Gamma (P.1), Delta (B.1.617.2), Lambda (C.37), and Mu (B.1.621) variants. The Beta variant was the least susceptible tested variant with approximately 4-fold reduced susceptibility relative to the USA-WA1/2020 isolate. Nirmatrelvir showed antiviral activity against the Omicron (B.1.1.529) variant with IC₅₀ values of 70 nM and 23 nM in HeLa-ACE2 and Vero-TMPRSS2 cells. In the same cell lines, the IC₅₀ values for nirmatrelvir activity against the USA-WA1/2020 isolate were 207 nM and 38 nM.

Data on SARS-CoV-2 resistance to nirmatrelvir were not available at the time of the submission review. Phenotypic assessments were conducted in a biochemical assay using recombinant 3CL protease to characterize the impact of SARS-CoV-2 3CL protease polymorphisms on the activity of nirmatrelvir. The following amino acid substitutions in the 3CL protease were associated with reduced nirmatrelvir activity (i.e., higher Ki values): G15S, H164N, H172Y, Q189K, Y54A, F140A, and E166A. The clinical significance of these polymorphisms is unknown, and it is also unknown if results from the biochemical assay are predictive of antiviral activity in cell culture.

The metabolism of nirmatrelvir was evaluated in vitro in liver microsomes (mouse, rat, hamster, rabbit, monkey, and human) and hepatocytes (rat, monkey, and human). The main metabolite across species was M4, an oxidative metabolite arising from hydroxylation reactions. In vivo, unchanged nirmatrelvir was the most prevalent drug-related entity in rat and monkey plasma, and M4 was a primary circulating metabolite in monkey. Across a panel of human recombinant CYP enzymes tested, CYP3A4 and CYP3A5 isoforms were found to be capable of catalyzing the formation of the oxidative metabolites, whereas other enzymes were minor contributors. However, in further enzyme kinetic analysis, CYP3A4 was predicted to be the major contributor to the oxidative metabolism of nirmatrelvir. No significant CYP3A5 contribution is expected to the metabolism of nirmatrelvir.

In vitro data indicate that nirmatrelvir is a substrate of the human multidrug resistance protein 1 (MDR1) (also known as P-glycoprotein [P-gp]) and CYP3A4, an inhibitor of CYP3A4/5, and an inducer of CYP3A4. Since nirmatrelvir is primarily metabolized by CYP3A4, changes in nirmatrelvir exposure are anticipated following co-administration with strong inhibitors or inducers of CYP3A4.

Non-clinical toxicology studies have not been conducted with nirmatrelvir in combination with ritonavir. One-month repeat-dose toxicity studies with orally administered nirmatrelvir were conducted in Wister Han rats and cynomolgus monkeys. In both studies, the no-observed-adverse-effect level (NOAEL) of nirmatrelvir was the highest dose tested. In Wister Han rats, the NOAEL was 1,000 mg/kg/day, which is equivalent to 8 times the total human exposure of nirmatrelvir (bound and unbound to plasma proteins) based on the area under the plasma concentration-time curve from 0 to 24 hours (AUC₂₄). In cynomolgus monkeys, the NOAEL was 600 mg (300 mg twice daily)/kg/day, which is equivalent to 14 times the total human exposure of nirmatrelvir based on the AUC₂₄.

Carcinogenicity studies have not been conducted with nirmatrelvir, which is acceptable in light of the recommended treatment duration and the lack of carcinogenicity signals in the toxicology studies. Nirmatrelvir did not exert genotoxicity in a standard battery of assays.

In an embryo-fetal development study, following oral administration of nirmatrelvir to pregnant rabbits, reduced fetal body weights were observed at systemic exposures approximately 10 times the clinical exposure at the recommended human dose. No other adverse developmental outcomes were observed in animal reproduction studies with nirmatrelvir at systemic exposures greater than or equal to 3 times the clinical exposure at the recommended human dose.

In an ongoing prenatal and postnatal development study, a transient decrease in body weight was observed in the nursing offspring of rats exposed to nirmatrelvir at maternal systemic exposures approximately 8 times the clinical exposures at the recommended human dose.

The results of the non-clinical studies as well as the potential risks to humans, have been included in the Product Monograph for Paxlovid. In view of the intended use of Paxlovid, there are no pharmacological or toxicological issues within this submission to preclude authorization of the product for the proposed indication. The sponsor is required to provide Health Canada with the final study reports of several ongoing non-clinical studies, as specified in the terms and conditions imposed in respect of Paxlovid.

For more information, refer to the Product Monograph for Paxlovid, approved by Health Canada and available through the Drug Product Database and on the Health Canada COVID-19 vaccines and treatments portal.

7.3 Quality Basis for Decision

The New Drug Submission for Paxlovid (nirmatrelvir and ritonavir) was submitted and reviewed in accordance with the Food and Drug Regulations, which permitted a rolling submission and review process. Following review of the provided information, a Notice of Compliance (NOC) was issued in relation to Paxlovid, with accompanying terms and conditions to manage any uncertainties or mitigate risks related to the drug.

The drug product Paxlovid contains nirmatrelvir tablets co-packaged with ritonavir tablets. Ritonavir has been approved for use in Canada since 1996. In this New Drug Submission, all data on chemistry, manufacturing, and control strategy for ritonavir were cross-referenced to data from previously approved submissions. Nirmatrelvir is a new active substance and therefore the primary focus of the chemistry and manufacturing data review was on the nirmatrelvir drug substance and drug product.

In the development of the drug product Paxlovid, a quality-by-design approach was used for the manufacturing processes (dry granulation, blending steps, and compression of the tablets). The sponsor will submit additional manufacturing information to Health Canada when it becomes available.

The formulation and manufacturing process for the drug product lots used in the pivotal clinical study EPIC-HR (Study C4671005) appear to be representative of those proposed for the commercial lots. Lots of drug substance and drug product for which chemistry and manufacturing data have been submitted were found to be of acceptable quality. However, additional data are required to demonstrate that the manufacturing processes and control strategy can consistently produce a drug substance (nirmatrelvir) and drug product of acceptable quality that is comparable to the quality of the lots used in the clinical development program of Paxlovid.

In light of the positive benefit-harm-uncertainty profile based on the clinical information for Paxlovid, and taking into account the public health need related to the coronavirus disease 2019 (COVID-19) pandemic, Health Canada considered it acceptable to address the quality uncertainties as part of the terms and conditions accompanying the NOC. The sponsor is required to address the quality-specific comments and provide additional data related to the drug substance and drug product manufacturing processes and controls.

At this time, based on the stability data submitted, a shelf life of 12 months is considered appropriate for Paxlovid, when the drug product is stored at room temperature (15 ºC to 30 ºC).

All sites involved in production are compliant with good manufacturing practices.

None of the non-medicinal ingredients (excipients, described earlier) found in the drug product are prohibited by the Food and Drug Regulations.