What you need to know about paxlovid: the first oral antiviral for COVID-19 approved in Canada

With the first new oral antiviral agent for COVID-19 now approved by Health Canada,1 healthcare professionals may be looking for factual information on this new drug and another antiviral agent (molnupiravir) that could be approved soon. Paxlovid (Pfizer) contains the antiviral agent nirmatrelvir, copackaged with the HIV-1 protease inhibitor ritonavir. It is indicated for the treatment of mild-to-moderate COVID-19 in adults with a positive direct SARS-CoV-2 test, and who are at high risk for progression to severe COVID-19, including hospitalization or death.2 Paxlovid is not indicated for treatment in patients requiring hospitalization due to severe or critical COVID-19, for pre-exposure or post-exposure prophylaxis for prevention of COVID-19, or for use for longer than five consecutive days.2 Nirmatrelvir inhibits the SARS-CoV-2 main protease (Mpro), which prevents viral replication. Ritonavir serves to increase serum concentrations of nirmatrelvir by inhibiting its metabolism by CYP3A.2,3 Read: Long COVID: For the 1 in 10 patients who become long-haulers, COVID-19 has lasting effects Emergency Use Authorization of Paxlovid in the United States was based on a trial in 2,246 nonhospitalized, unvaccinated adults with lab-confirmed SARS-CoV-2 infection. All patients had symptom onset within five days of randomization and at least one risk factor for progression to severe disease. Nirmatrelvir/ritonavir decreased COVID-19 related hospitalization or death by 88% through day 28 compared with placebo (0.8% vs 6.3%). Note that Delta was the primary SARS-CoV-2 variant in the study.3 The manufacturer reports that nirmatrelvir was shown to inhibit the 3CL protease associated with the Omicron (B.1.1.529) variant in a biochemical assay.3 Dysgeusia, diarrhea, hypertension and myalgia are the most common adverse effects of nirmatrelvir/ritonavir.2,3 Both nirmatrelvir and ritonavir are CYP3A substrates; therefore, drugs that induce or inhibit CYP3A will affect serum concentrations of both drugs. Strong CYP3A inducers (e.g., rifampin, carbamazepine, phenobarbital, phenytoin,) are contraindicated during Paxlovid therapy, as they can decrease serum concentrations of nirmatrelvir and ritonavir. Paxlovid is also contraindicated for use with drugs that are highly dependent on CYP3A for clearance and associated with serious or life-threatening events when serum concentrations are elevated (e.g., amiodarone).2,3 Consult the Canadian product monograph (https://pdf.hres.ca/dpd_pm/00064313.PDF) for a complete listing of known drug interactions and contraindicated drugs.2 Paxlovid will be supplied in cartons containing nirmatrelvir 150 mg tablets copackaged with ritonavir 100 mg tablets. The recommended dosage is 300/100 mg (2 nirmatrelvir tablets and 1 ritonavir tablet taken together) twice daily for five days. Treatment should be started as soon as possible after a diagnosis of COVID-19, and within five days of symptom onset.2,3 Read: Low rate of false-positive rapid antigen test results in Canadian workplaces On the same day that Paxlovid was approved in Canada, Health Canada also issued an advisory warning that the antiviral is not recommended in patients with severe renal impairment.4 Furthermore, patients with moderate renal impairment (eGFR ≥ 30 to < 60 mL/min), require a dose reduction.2,4 No dosage adjustment is needed in patients with mild renal impairment (eGFR 60 to < 90 mL/min).2 The Paxlovid daily blister cards contain two separate parts each containing two tablets of nirmatrelvir and one tablet of ritonavir corresponding to the daily administration at the standard dose. However, patients with moderate renal impairment must be advised that only one nirmatrelvir tablet plus the tablet of ritonavir should be taken every 12 hours.2 Health Canada suggests that healthcare professionals dispensing Paxlovid should remove two nirmatrelvir tablets (one morning nirmatrelvir tablet and one evening nirmatrelvir tablet) from the daily blister cards for patients with moderate renal impairment.4 Molnupiravir is another oral antiviral agent that has received Emergency Use Authorization for COVID-19 treatment in the United States. It is not yet approved for use in Canada. In the United States, molnupiravir is indicated for treatment of mild to moderate COVID-19 in outpatients (≥ 18 years of age) who are at high risk of progressing to severe disease, including hospitalization or death, when other treatment options are not available or clinically appropriate.4 Molnupiravir targets viral RNA polymerase, which induces mutagenesis and inhibits SARS-CoV-2 replication.5 Emergency Use Authorization for molnupiravir in the United States was based on results from a trial in 1,433 nonhospitalized unvaccinated adults with mild to moderate COVID-19. Participants had lab-confirmed SARS-CoV-2 infection (most with the Delta variant), symptom onset within five days of randomization and at least one risk factor associated with progression to severe disease. Molnupiravir decreased all-cause hospitalization or death through day 29 by 30% compared to placebo (6.8% vs 9.7%).5 Read: Breakthrough COVID-19 infection rates higher among those with immune dysfunction In the study, molnupiravir and placebo had similar adverse effects, including diarrhea, nausea and dizziness. The drug has been associated with teratogenicity and embryo-toxicity in animal studies, and should not be used during pregnancy. Women of childbearing potential should use effective contraception during molnupiravir treatment and for four days after the last dose. Male patients with female partners of childbearing potential should use effective contraception during treatment and for at least three months after the last dose.5 The recommended dosage of molnupiravir is 800 mg (four x 200 mg capsules) every 12 hours for five days. Treatment should be started within five days of symptom onset.5 Summary Since Paxlovid has much higher reported efficacy than molnupiravir, it should generally be tried first, if available.5 Although Paxlovid appears to be well tolerated, healthcare providers need to be aware that the antiviral combination has many CYP3A drug interactions.3 Several of these interactions could result in serious or life-threatening adverse reactions, or a loss of therapeutic effect.4 The approval of oral antivirals for COVID-19 that can be administered outside of a hospital setting is expected to be a pandemic “game-changer” as these agents could reduce hospitalizations by as much as 80%.6 However, obtaining consistent supplies of either Paxlovid or molnupiravir could be problematic due to limitations in manufacturing capacity worldwide. This means that provincial/territorial governments will likely have to prioritize which patients will be eligible for the antiviral, until drug supplies become more plentiful. The need to start Paxlovid within five days of symptom onset and a positive direct SARS-CoV-2 test will also present challenges in view of the current limitations/delays in SARS-CoV-2 testing in many areas of Canada. In Canada, Pfizer plans to initially distribute Paxlovid cartons and blisters with the US Emergency Use label, in English-only.4 References 1. Government of Canada. Details for: Paxlovid - COVID-19. https://covid-vaccine.canada.ca/info/paxlovid-en.html (accessed January 18, 2022). 2. Pfizer Canada ULC. Paxlovid (nirmatrelvir tablets; ritonavir tablets) product monograph. Kirkland, QC; January 18, 2022. https://pdf.hres.ca/dpd_pm/00064313.PDF (accessed January 18, 2022). 3. Anon. Paxlovid for treatment of COVID-19. Med Lett Drugs Ther, January 24, 2022. https://secure.medicalletter.org/w1642a (accessed January 18, 2022). 4. Government of Canada. Recalls and safety alerts. Paxlovid (nirmatrelvir and ritonavir) - dosing and dispensing in renal impairment, risk of serious adverse reactions due to drug interactions, and English-only labels. January 18, 2022. https://recalls-rappels.canada.ca/en/alert-recall/paxlovid-nirmatrelvir-and-ritonavir-dosing-and-dispensing-renal-impairment-risk (accessed January 18, 2022). 5. Anon. Molnupiravir for treatment of COVID-19. Med Lett Drugs Ther, January 24, 2022. https://secure.medicalletter.org/w1642b (accessed January 18, 2022). 6. Tasker JP. Antivirals could be a pandemic game-changer — and they could be in Canada soon. CBC News; January 18, 2022. https://www.cbc.ca/news/politics/game-changing-covid-antivirals-canada-soon-1.6314214 (accessed January 18, 2022).

What you need to know about paxlovid: the first oral antiviral for COVID-19 approved in Canada

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