By William Elliott, MD, FACP, and James Chan, PharmD, PhD
Dr. Elliott is Assistant Clinical Professor of Medicine, University of California, San Francisco.
Dr. Chan is Associate Clinical Professor, School of Pharmacy, University of California, San Francisco.
The FDA has issued an emergency use authorization (EUA) for the oral combination of nirmatrelvir and ritonavir (NIR/RIT) to treat mild-to-moderate COVID-19.1 NIR is an oral antiviral SARS-CoV-2 protease inhibitor (Mpro), and RIT slows CYP3A-mediated metabolism of nirmatrelvir. It is distributed as Paxlovid.
INDICATIONS
NIR/RIT can be prescribed to treat mild-to-moderate COVID-19 in patients age 12 years and older weighing at least 40 kg with positive results of direct SARS-CoV-2 testing who are at high risk for progression to severe COVID-19, including hospitalization or death.1 NIR/RIT is not indicated for pre-exposure or post-exposure prevention of COVID-19. It also is not indicated for COVID-19 patients requiring hospitalization.2 NIR/RIT is not a substitute for vaccination.
DOSAGE
The dose is 300 mg of NIR (2 × 150 mg) with 100 mg of RIT taken together orally twice daily (morning and evening) for five days. The regimen should be taken as soon as possible after diagnosis of COVID-19 and within five days of symptom onset.1 It may be taken without regard to meals. NIR/RIT is available as five daily blister cards each containing four NIR tablets and two RIT tablets.
POTENTIAL ADVANTAGES
NIR/RIT is the first oral regimen for the treatment of COVID-19 and can be taken at home. Previous EUAs for this indication were monoclonal antibodies (e.g., casirivimab/imdevimab and bamlanivimab/etesevimab), which require intravenous infusion. In contrast to the monoclonal antibodies that target the spike protein, which has been identified with multiple mutations/variants, NIR targets the Mpro in SARS-CoV-2 that seems to be variant-independent. Cell culture data showed similar activity against alpha, beta, gamma, delta, and lambda variants.1 Biochemical assay results suggest NIR/RIT also is effective against the omicron variant.1
POTENTIAL DISADVANTAGES
Coadministration with potent CYP3A inducers is contraindicated. It also is contraindicated with drugs that are highly dependent on CYP3A for clearance.1 These include numerous drug classes. NIR/RIT is not recommended for patients with severe renal or hepatic impairment. Adverse reactions (vs. placebo) include dysgeusia (6% vs. < 1%), diarrhea (3% vs. 2%), hypertension (1% vs. < 1%), and myalgia (1% vs. < 1%).1
COMMENTS
NIR inhibition of the Mpro prevents replication of SARS-CoV-2.1 Data supporting the EUA for NIR/RIT was a Phase II/III randomized, double-blind, placebo-controlled study.1 Subjects were nonhospitalized, symptomatic adults with laboratory-confirmed diagnosis of SARS-CoV-2 infection at risk for progression to severe disease. Risk factors included diabetes, BMI > 25 kg/m2, chronic lung disease, chronic kidney disease, current smoker, immunosuppressive disease/immunosuppressive treatment, cardiovascular disease, hypertension, sickle cell disease, neurodevelopmental disorders, active cancer, or ≥ age 60 years regardless of comorbidities. Subjects were randomized to NIR/RIT (n = 1,039) or placebo (n = 1,046). Patients with prior COVID-19 infections or those who were vaccinated were excluded. Two-thirds of subjects experienced symptom onset of ≤ 3 days, 47% were serological-negative at baseline, and mean baseline viral load was 4.63 log10 copies/mL. The primary efficacy endpoint was the proportion of subjects with COVID-19 hospitalization or death through day 28. Efficacy endpoint through day 28 was 0.8% for NIR/RIT vs. 6.3% for placebo (relative risk reduction of 88%). There were no deaths in the NIR/RIT group vs. 12 in the placebo group. During the study period, the primary variant was delta (98%). Relative to placebo, NIR/RIT was associated with reduction of viral load of about 0.9 log10 copies/mL.
CLINICAL IMPLICATIONS
NIR/RIT provides a significant therapeutic advancement in treating COVID-19, particularly in terms of convenience of dosing. With an efficacy of 88% risk reduction, NIR/RIT is at least as effective as the monoclonal antibodies with a different, perhaps less variable target than with the monoclonal antibodies.2,3 Delivery of the drug is expected immediately. The federal government has been watching the approval process closely, and President Biden has stated the United States will have more than 250,000 courses available by the end of January. The U.S. government agreed to pay the manufacturer nearly $5.3 billion for 10 million treatment courses for 2022, while the company has stated they plan to produce 120 million treatment courses. The FDA also has granted an EUA for molnupiravir (Lagevrio), another oral protease inhibitor.4 It is less effective (30% risk reduction overall and 89% for all-cause mortality) and not recommended for use in pregnant women. It is limited to situations in which other FDA-authorized treatments are inaccessible or are not clinically appropriate.4
REFERENCES
- U.S. Food & Drug Administration. FDA authorizes first oral antiviral for treatment of COVID-19. Dec. 22, 2021.
- Pfizer Labs. Paxlovid fact sheet. Dec. 22, 2021.
- National Institutes of Health. COVID-19 treatment guidelines. Anti-SARS-CoV-2 monoclonal antibodies. Page updated Dec. 16, 2021.
- U.S. Food & Drug Administration. FDA authorizes additional oral antiviral for treatment of COVID-19 in certain adults. Dec. 23, 2021.
The FDA has issued an emergency use authorization for the first oral regimen for the treatment of COVID-19.
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