[141] Paxlovid in British Columbia – Interim real-world analysis

[141] Paxlovid in British Columbia – Interim real-world analysis

Nirmatrelvir and ritonavir (NMV-r; PaxlovidTM) is an oral antiviral drug combination that targets a key SARS-CoV-2 protease enzyme. It was approved by Health Canada on January 17, 2022 for treatment of mild-to-moderate Covid-19 disease in adult patients at high risk for progression to hospitalization or death. The initial US cost was US$529/person; the Canadian negotiated price is secret.1 This Letter presents highlights of the Therapeutics Initiative (TI) interim post-market analysis of NMV-r prescriptions in British Columbia (BC). We plan final analyses for later in 2023.

Why study real-world use of NMV-r?

Health Canada approved NMV-r based on interim efficacy and safety data from the Evaluation of Inhibition for Covid-19 in High-Risk Patients trial (EPIC-HR).2,3 This double-blind, randomized, placebo-controlled trial (DBRCT) was designed and conducted by Pfizer and ICON between July 16 and December 9, 2021 in 20 countries (5 continents).4 For the primary endpoint, in 2,246 patients not vaccinated against Covid-19, but randomized within 5 days of symptom onset, NMV-r reduced Covid-19-related hospitalization or death from any cause by Day 28 by 5.6% absolute (88% relative) risk, compared with placebo. By Day 28 there were no deaths in the NMV-r group vs 12 in the placebo group (no claim for statistical significance). EPIC-HR reported numerically fewer serious adverse events (SAEs) but more suspected drug-related AEs from NMV-r than from placebo.

From August to December 2021 Pfizer enrolled patients in a second DBRCT of NMV-r (EPIC-SR) in lower-risk adults (called “standard-risk”). After randomizing 1,141 participants (20 countries), it announced closure of the trial in a June 14, 2022 media release, “due to a very low rate of hospitalization or death observed in the standard-risk patient population.”5 The media release indicated that NMV-r was not effective to reduce symptoms (the primary endpoint). It reported a non-statistically significant, 0.9% absolute (51% relative) risk reduction in a secondary endpoint of hospitalization or death. Pfizer indicated its intention to publish EPIC-SR results, but this is yet to occur; it has not posted results at clinicaltrials.gov, or on its website.6,7

The benefit-harm profile of NMV-r in the BC population taking this drug combination is unknown. Like most provinces in Canada, BC adopted eligibility criteria for NMV-r that differ substantially from participants in the EPIC-HR trial. Unlike our BC population, patients enrolled in EPIC-HR were unvaccinated and had no natural immunity from prior Covid-19 infection. They were infected by Covid-19 variants different from those now circulating in Canada. EPIC-HR also excluded people who were taking drugs with known CYP 3A4 interactions.8

Who can access NMV-r in BC? 

Four groups of patients are currently eligible. Three consist of “clinically extremely vulnerable” (CEV) individuals with medical conditions previously designated by a group of BC specialists in order to prioritize Covid-19 vaccinations. Two include people 12 years and older who are severely (CEV1) or moderately (CEV2) immunocompromised. CEV3 individuals are not immunocompromised, but have medical conditions that engender a high risk for complications from Covid-19. A fourth Expanded Eligibility group was added March 17, 2022 to allow wider access to NMV-r. Eligibility criteria for NMV-r in BC are available online.9

Preliminary TI analysis of NMV-r in BC

As in the EPIC-HR trial, the TI Pharmacoepidemiology group is analyzing the 28-day risk of Covid-19-related hospitalization or death from any cause in the groups eligible for treatment in BC. To minimize confounding bias, we limit the analysis to the subset of individuals to whom NMV-r was dispensed (“index cases”), and for whom we can match a person (control) of the same age (±2 years), sex, and with laboratory-confirmed Covid-19 infection within a month of the paired index case. We also match for propensity scores, a common pharmacoepidemiologic method to control for imbalances between groups in comorbidities.

We use Ministry of Health datasets including PharmaNet, hospital discharge abstracts, emergency department encounters, physician office billing diagnostic codes, Covid-19 PCR testing, and Covid-19 vaccination status. The study has ethics approval from the University of British Columbia and our methods guarantee protection of the privacy of patients, prescribers, and dispensing pharmacists.

We are also assessing patient follow-up data collected by community pharmacists as part of the PaxlovidTM Follow-up initiative (PAX-F) implemented by the Ministry of Health when NMV-r became available.10 Pharmacists phoned patients or their caregivers 6 to 10 days after dispensing NMV-r. They asked about treatment completion, adverse drug events (ADEs) and their management, and recorded adherence and ADE information in PharmaNet.

NMV-r effectiveness in BC

The results shown here are early findings for patients with a positive PCR test who were eligible for NMV-r between February and September 2022. These analyses are yet to be peer reviewed. Our preliminary analysis relies on emergency department (ED) visit records from the National Ambulatory Care Reporting System (NACRS), because hospital discharge data will not be available until later in 2023. We counted people with an ED visit record indicating Covid-19 infection and admission to hospital as having been hospitalized for Covid-19. For this interim analysis, the ED visit data provide a reasonable proxy for more complete hospital records. 

The Table shows interim results. Compared with controls (no NMV-r), treatment with NMV-r was associated with statistically significant relative reductions in the composite outcome of about 80% in the CEV1 and CEV3 groups. We found a non-significant 41% reduction in the matched CEV2 group, and a non-significant increased risk in the Expanded Eligibility group.

Among BC residents, the Expanded Eligibility group’s experience is the most relevant to clinicians and policy makers contemplating broader availability of NMV-r. This group had the lowest background risk of the composite endpoint: 1.1% in untreated matched controls. It is the closest comparator to “standard-risk” participants in the unpublished EPIC-SR trial. Similar to EPIC-SR, the results in this BC cohort do not yet show a benefit of treatment on Covid-19-related hospitalization or death from any cause.

Table: Covid-19-related emergency hospitalization or death by Day 28 after treatment initiation in EPIC-HR trial vs BC

* Masked numbers are too small to report because of data privacy requirements.

Harms of NMV-r in BC

The principal concern is from pharmacokinetic (PK) drug interactions caused by ritonavir, the potent inhibitor of cytochrome P450 3A – used as a sort of “controlled grapefruit juice” to increase bioavailability of nirmatrelvir.11,12 Follow-up data collected by 1,962 BC pharmacists between February and December 2022 as part of PAX-F shows that 10,200 patients who received 10,356 courses of NMV-r were asked about their adherence to therapy and adverse drug events (ADEs). Of respondents, 88% reported completing the 5-day course. The remaining 12% reported partial completion: 4.2% discontinued due to a suspected ADE; 4% took no medication after accepting dispensing; for 2% treatment adherence was not recorded. 

Figure: Patient-reported ADEs from the PAX-F Follow-up initiative

We also analyzed the PharmaNet database for drugs known to interact with NMV-r. Of 18,035 individuals dispensed NMV-r in 2022, we estimate that 11,050 (61%) had a previously dispensed and available supply of a drug with potential for PK interactions, when they received NMV-r. Nearly all such potential interactions were seen as manageable by the prescriber. In future we may be able to quantify some management strategies implemented, such as drug switches, suspensions, or dose decreases.


  • Efficacy evidence for NMV-r (PaxlovidTM) derived from unvaccinated high-risk patients in 2021 may be irrelevant to BC patients in 2023. In lower-risk patients, benefits have not been proven.
  • We found evidence suggesting some benefit in defined high-risk groups in BC during 2022.
  • PharmaCare’s temporary initiative to record adverse drug events may lead to better ways to document them in future.
Several BC experts reviewed the draft of this Therapeutics Letter for factual accuracy, and to ensure it is relevant to clinicians.
The UBC TI is funded by the BC Ministry of Health to provide evidence-based information about drug therapy. We neither formulate nor adjudicate provincial drug policies.
ISSN: 2369-8691 (Online) || ISSN: 2369-8683 (Print)
International Society of Drug Bulletin LogoThe Therapeutics Letter is a member of the International Society of Drug Bulletins (ISDB), a world-wide network of independent drug bulletins that aims to promote international exchange of quality information on drugs and therapeutics.


  1. Tumilty R. Health Canada approves Pfizer anti-viral pill for treatment of Covid19. National Post. 17 Jan 2022. https://nationalpost.com/news/politics/health-canada-approves-pfizer-anti-viral-pill-for-treatment-of-covid-19
  2. Health Canada. Summary Basis of Decision PaxlovidTM. 27 Feb 2022. https://covid-vaccine.canada.ca/info/summary-basis-decision-detailTwo.html?linkID=SBD00577
  3. Hammond J, Leister-Tebbe H, Gardner A, et al. Oral Nirmatrelvir for High-Risk, Nonhospitalized Adults with Covid-19. N Engl J Med. 2022; 386:1397-1408. DOI: 10.1056/NEJMoa2118542
  4. Pfizer. EPIC-HR Clinical Study Report Synopsis. ver 1.0; 6 Jun 2022. https://cdn.pfizer.com/pfizercom/clinical%20trials/csr%20synopsis/C4671005%20PDS.pdf?0.pLA3PHeaN0Y1YUR0pPaHOlJOYe5kkh
  5. Pfizer. Pfizer Reports Additional Data on PAXLOVID™ Supporting Upcoming New Drug Application Submission to US FDA. 14 Jun 2022. https://www.pfizer.com/news/press-release/press-release-detail/pfizer-reports-additional-data-paxlovidtm-supporting
  6. National Library of Medicine. Evaluation of Protease Inhibition for COVID-19 in Standard-Risk Patients (EPIC-SR). ClinicalTrials.gov NCT05011513. 12 Dec 2022. https://clinicaltrials.gov/ct2/show/study/NCT05011513
  7. Pfizer. Clinical Study Report Synopses. Jan 2023. https://www.pfizer.com/science/clinical-trials/data-and-results/trial-results
  8. Hammond J, Leister-Tebbe H, Gardner A, et al. Oral nirmatrelvir for high-risk, nonhospitalized adults with Covid-19 (Protocol). N Engl J Med 2022;386(Suppl). https://www.nejm.org/doi/suppl/10.1056/NEJMoa2118542/suppl_file/nejmoa2118542_protocol.pdf
  9. BC COVID Therapeutics Committee. Clinical Practice Guide for the Use of Therapeutics in Mild-Moderate COVID-19. 10 Jan 2023. http://www.bccdc.ca/Health-Professionals-Site/Documents/COVID-treatment/ClinicalPracticeGuide_Therapeutics_MildModerateCOVID.pdf
  10. BC Ministry of Health PLBS Division. Dispensing Paxlovid and Monitoring Adverse Drug Events A Guide for BC Community Pharmacists. Jan 2023. https://www2.gov.bc.ca/assets/gov/health/health-drug-coverage/pharmacare/monitoring-paxlovid-ades-guide.pdf
  11. BC COVID Therapeutics Committee. Practice Tool #3 – Drug-Drug Interactions and Contraindications. 1 Sep 2022. http://www.bccdc.ca/Health-Professionals-Site/Documents/COVID-treatment/PracticeTool3_DrugInteractionsContraindications.pdf
  12. Wilson M, McDonald E. Drug-drug interactions in older adults prescribed Paxlovid. Therapeutics Initiative webinar. 14 Dec 2022. https://www.ti.ubc.ca/2022/12/14/ti-best-evidence-registration-upcoming-dec-14-best-evidence-webinar-drug-drug-interactions-in-older-adults-with-polypharmacy-prescribed-nirmatrelvir-ritonavir-for-the-treatment-of-covid-19/
  • Dr. Michael Cooper
    Posted at 09:47h, 18 February Reply

    Recently there appears to be an increase in Direct-to-Consumer advertising (DTCA) of prescription drugs in Canadian media. Pfizer has been running frequent ads that exhort Canadians to talk to their doctor or pharmacist about Paxlovid: “Paxlovid – get to know it.

    These ads appear to violate Canada’s Food & Drug Act. However, Health Canada apparently has decided that there can be exceptions: DTCA is prohibited under two provisions in Canada’s Food and Drugs Act, which is enforced by Health Canada. Despite this prohibition, Health Canada currently allows two forms of advertising:
    – Reminder ads: these include only the brand name and no health claims or hints about the product’s use
    – Help-seeking messages, which discuss a disease state but make no reference to a specific prescription drug

    These exceptions, especially the first one, need to be reviewed, especially in light of the fact that most Canadians can access the internet and quickly find out what the product’s use is.

    The pharmaceutical industry in the US spends close to six billion dollars a year on DTCA: “Drug manufacturers spent $17.8 billion on direct-to-consumer advertising (DTCA) for 553 drugs from 2016 through 2018, and spending was relatively stable at about $6 billion each year” (U.S. Government Accountability Office). Big Pharma does this because it works. DTCA drives costs of medication upward, and diverts money that could have been better spent on research.

    The recent Therapeutics Letter 141 suggests to me that expanded use of Paxlovid may not be advisable. Certainly the analysis shows the need for further research.

    In my opinion, there is no role for Direct-to-Consumer advertising of any kind. The Paxlovid example demonstrates clearly that such advertising has the very real potential of causing harm to the health of Canadians. Expanded use in populations that are not recommended will increase the risk of adverse effects, including drug interactions, hospitalizations, and potentially more serious risks. There is also the non-trivial issue of added cost to our over-strained health care system. The last thing busy physicians need is unnecessary patient visits to find out if “Paxlovid could be right for you”!

    Health care funding is a very timely issue, and addressing DTCA is one step that could be taken to further address unnecessary spending and also improve the health of Canadians.

    Michael Cooper MD, FRCPC
    Clinical Associate Professor, Department of Psychiatry, UBC
    Victoria, BC

    Dr. Michael Cooper has submitted the ICJME disclosure form and has no conflict of interest to declare.

    • Barbara Mintzes
      Posted at 22:25h, 18 February Reply

      We agree 100% with Dr. Cooper’s concerns about this direct-to-consumer ‘reminder’ advertising campaign for Paxlovid. Health Canada began allowing reminder ads in 2001, in a period of heavy pressure from the pharmaceutical industry for the introduction of direct-to-consumer advertising. A guess is that this was a compromise solution aimed at appeasing industry without any need to pass new legislation or regulations to allow direct-to-consumer advertising.

      This introduction of reminder advertising was only possible under a re-interpretation of existing regulations that had been introduced in the 1970s to allow pharmacists to post the name, quantity and prices of medicines. [Gardner et al. 2003] This reinterpretation was neither consistent with the aim of the original regulations – which were introduced to support use of generic medicines by allowing the public to see comparative prices – or the wording of the regulations. In fact, these reminder ads include multiple representations encouraging the use of the drug, including persuasive images and suggestions to ‘ask your doctor’ about the brand. Complaints to Health Canada about specific ad campaigns have fallen on deaf ears, even when the advertisements focus on products with especially problematic safety profiles, such as the acne medicine Diane-35 (cyproterone-ethinylestradiol) which has been used off-label for oral contraception. [Lexchin and Mintzes 2014]

      Ironically, in the United States, where direct-to-consumer advertising is allowed, reminder ads are prohibited for drugs with black box warnings of serious harms. In Canada, where federal legislation prohibits direct-to-consumer advertising, but where Health Canada has used price advertising regulations to create a loophole for reminder advertising, there is no such prohibition. In Canada, medicines with bolded warnings of serious harms including death have been advertised in direct-to-consumer reminder advertising. [Mintzes et al. 2012] Dr. Cooper points out that the broad encouragement to use Paxlovid is inappropriate. Again, we agree.

      There is no rationale from a public health perspective for Canada to allow branded ‘reminder’ advertising that states the brand name of prescription-only medicines, makes visual allusions to their indication and suggests viewers ‘ask their doctors’ about these drugs. The Health Canada advertising policy that initially re-interpreted Canadian price advertising regulations is a historical anomaly. Internationally, prohibition of direct-to-consumer advertising of prescription drugs is the norm, not the exception. And no other country has made this type of nonsensical change to the interpretation of their law. This re-interpretation of the legislation is aching for a legal challenge. Ironically, the heavy industry pressure on national governments for the introduction of direct-to-consumer advertising (DTCA) largely fizzled after the global withdrawal of Vioxx (rofecoxib) in late 2004. This was one of the most heavily advertised drugs in its five years on the US market with Merck spending almost $160 million on DTCA for Vioxx in 2000 alone. [IMS] Its use is estimated to have led to between 88,000 and 140,000 extra heart attacks in the US. [Graham et al. 2005]

      ‘Help-seeking’ advertisements are notoriously hard to regulate. If the company does not mention the name of any medicine, but just discusses a health condition and suggests viewers ‘ask their doctor about a treatment’, these advertisements are often not considered to be pharmaceutical advertising. In this situation Health Canada does have some leeway for enforcement, especially if an advertisement is indirectly linked to a product with safety concerns. In 2014, the US FDA required AbbVie to stop running ‘help-seeking’ advertising for off-label use of its testosterone product (unnamed) for the nebulous diagnosis of ‘low-T’, following a safety review of evidence of increased cardiovascular risks associated with testosterone use. In Canada, AbbVie continues to run the website ‘www.lowT.ca’ in 2023 promoting off-label use for this same diagnosis. Complaints to Health Canada in 2011 about this advertising campaign were ineffective.

      Barbara Mintzes
      Professor of Evidence-Based Pharmaceutical Policy
      The University of Sydney Charles Perkins Centre and School of Pharmacy
      Faculty of Medicine and Health
      The University of Sydney
      Sydney, Australia

      Joel Lexchin MD, CCFP(EM), FCFP
      Associate Professor
      Department of Family and Community Medicine
      University of Toronto
      Toronto, ON, Canada

      Gardner et al. CMAJ 2003; 169(5):425-27. https://www.cmaj.ca/content/169/5/425.short
      Graham et al. Lancet 2005; 365:475-81. https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(05)17864-7/fulltext
      IMS. https://web.archive.org/web/20060322233417/http://www.imshealth.com/ims/portal/front/articleC/0,2777,6599_40054629_1004776,00.html
      Lexchin and Mintzes. Int J Risk Safety Med 2014; 26:213-25. https://content.iospress.com/articles/international-journal-of-risk-and-safety-in-medicine/jrs635
      Mintzes et al. PLoS ONE 2009; 4(5):e5699. https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0005699

      Dr. Mintzes and Dr. Lexchin have no conflict of interest to declare.

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