Paxlovid is a co-packaged combination of nirmatrelvir, a second generation protease inhibitor, and ritonavir, a pharmacological enhancer, that is used to treated infection with the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) , the cause of the novel and severe coronavirus disease, 2019 (COVID-19). Paxlovid is given orally for 5 days in patients early in the course of infection and has not been linked to serum aminotransferase elevations or to clinically apparent liver injury.


Paxlovid consists of second generation protease inhibitor (nirmatrelvir) co-packaged with a pharmaceutical enhancer (ritonavir), which is used for oral treatment of recent-onset, mild-to-moderate COVID-19. Nirmatrelvir (ner mat” rel vir) is a peptidomimetic inhibitor of the main protease of SARS-CoV-2: Mpro and has antiviral activity in vitro against several coronaviruses including SARS-CoV-1 and -2. Ritonavir (ri toe’ na vir) is a protease inhibitor and potent inhibitor of the enzyme (CYP 3A4) responsible for the metabolism of nirmatrelvir, which allows for higher peak levels and more prolonged half-life of the active antiviral metabolite. In preregistration trials, Paxlovid started within 5 days of symptom onset demonstrated a 89% reduction in subsequent hospitalizations for COVID-19 (1.0% vs 6.7%) and a significant reduction in 28-day mortality (none vs 1.6%). Based upon these results and the ongoing COVID-19 pandemic, Paxlovid was granted Emergency Use Authorization (EUA) in December 2021 as therapy of nonhospitalized patients (adults and children 12 years or older) with documented COVID-19 infection who are at high risk of complications. Paxlovid is available under the EUA as tablets of 150 mg of nirmatrelvir co-packaged with 100 mg tablets of ritonavir; the recommended dose being 2 tablets of nirmatrelvir and one tablet of ritonavir twice daily for 5 days. Longer term therapy is not recommended, nor is therapy recommended for hospitalized patients or patients who have had symptoms or signs for more than 5 days. Currently, Paxlovid is being actively evaluated for efficacy and safety in treating patients not at high risk for complications, for children, and for patients with known exposure to COVID-19 (post-exposure prophylaxis). Paxlovid appears to be generally well tolerated; mild adverse events may include headache, myalgia, gastrointestinal upset, nausea and diarrhea. The total clinical experience with Paxlovid has been limited and its safety not fully defined.


In preregistration clinical trials, serum aminotransferase elevations were uncommon and mild, and were no more frequent with Paxlovid than with placebo. Furthermore, among more than 1000 patients treated with Paxlovid (nirmatrelvir 300 mg with ritonavir 100 mg twice daily) for 5 days in prelicensure studies, there were no reported episodes of clinically apparent liver injury. Confounding the issue is that serum aminotransferase elevations are common during symptomatic SARS-CoV-2 infection, present in up to 70% of patients and are more frequent in patients with severe disease and in those with the known risk factors for COVID-19 severity such as male sex, older age, higher body mass index and diabetes. Thus, Paxlovid has not been shown to cause liver injury, but the total clinical experience with its use is limited.

Likelihood score: E (unlikely cause of clinically apparent liver injury).

Mechanism of Injury

The lack of adverse events and hepatic injury from Paxlovid may be due to its relatively short duration of therapy. Paxlovid is metabolized by the cytochrome P450 system (largely CYP 3A4) and is given with a CYP 3A4 inhibitor to prolong its half-life and achieve better plasma concentrations and prolong its half-life. However, as a consequence Paxlovid is likely to have significant drug-drug interactions with agents that are metabolized by the CYP 3A4 enzyme. Whether longer term Paxlovid is also without serious adverse events remains to be seen.

Drug Class: Antiviral Agents

Other Drugs in the Subclass: Molnupiravir



Nirmatrelvir and Ritonavir – Paxlovid®


Antiviral Agents


Product labeling at DailyMed, National Library of Medicine, NIH



References updated: 31 January 2022

Abbreviations used: COVID-19, coronavirus disease, 2019; ICU, intensive care unit; IFN, interferon; IL, interleukin; MERS, Middle East respiratory syndrome; NHC, N-hydroxycytidine; SARS-CoV-2, severe acute respiratory syndrome-coronavirus 2.

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