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General Information
Paxlovid includes nirmatrelvir, a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) main protease inhibitor, and ritonavir, an HIV-1 protease inhibitor and CYP3A inhibitor.
Paxlovid is specifically indicated for the treatment of mild-to-moderate coronavirus disease 2019 (COVID-19) in adults who are at high risk for progression to severe COVID-19, including hospitalization or death.
Dosing/Administration
Paxlovid is supplied as tablets for oral administration.
There are two different dose packs available:
- Paxlovid (nirmatrelvir; ritonavir) 300 mg;100 mg and Paxlovid (nirmatrelvir; ritonavir) 150 mg;100 mg for patients with moderate renal impairment
- Nirmatrelvir must be co-administered with ritonavir. Failure to correctly co-administer nirmatrelvir with ritonavir may result in plasma levels of nirmatrelvir that are insufficient to achieve the desired therapeutic effect.
The recommended dosage for Paxlovid is 300 mg nirmatrelvir (two 150 mg tablets) with 100 mg ritonavir (one 100 mg tablet) with all 3 tablets taken together orally twice daily for 5 days.
The 5-day treatment course of Paxlovid should be initiated as soon as possible after a diagnosis of COVID-19 has been made, and within 5 days of symptom onset even if baseline COVID-19 symptoms are mild.
Should a patient require hospitalization due to severe or critical COVID-19 after starting treatment with Paxlovid, the patient should complete the full 5-day treatment course per the healthcare provider’s discretion.
If the patient misses a dose of Paxlovid within 8 hours of the time it is usually taken, the patient should take it as soon as possible and resume the normal dosing schedule. If the patient misses a dose by more than 8 hours, the patient should not take the missed dose and instead take the next dose at the regularly scheduled time. The patient should not double the dose to make up for a missed dose.
Paxlovid (both nirmatrelvir and ritonavir tablets) can be taken with or without food. The tablets should be swallowed whole and not chewed, broken, or crushed.
Mechanism of Action
Nirmatrelvir is a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antiviral drug. Nirmatrelvir is a peptidomimetic inhibitor of the SARS-CoV-2 main protease (Mpro), also referred to as 3C-like protease (3CLpro) or nonstructural protein 5 (nsp5) protease. Inhibition of SARS-CoV-2 Mpro renders it incapable of processing the viral polyproteins pp1a and pp1ab, preventing viral replication. Nirmatrelvir inhibited the activity of recombinant SARS-CoV-2 Mpro in a biochemical assay with a Ki value of 3.1 nM and an IC50 value of 19.2 nM. Nirmatrelvir was found to bind directly to the SARS-CoV-2 Mpro active site by X-ray crystallography
Ritonavir is an HIV-1 protease inhibitor but is not active against SARS-CoV-2 Mpro. Ritonavir inhibits the CYP3A-mediated metabolism of nirmatrelvir, resulting in increased plasma concentrations of nirmatrelvir.
Side Effects
Adverse effects associated with the use of Paxlovid may include, but are not limited to, the following:
- dysgeusia
- diarrhea
The Paxlovid drug label comes with the following Black Box Warning: Paxlovid includes ritonavir, a strong CYP3A inhibitor, which may lead to greater exposure of certain concomitant medications, resulting in potentially severe, life-threatening, or fatal events. Prior to prescribing Paxlovid: 1) Review all medications taken by the patient to assess potential drug-drug interactions with a strong CYP3A inhibitor like Paxlovid and 2) Determine if concomitant medications require a dose adjustment, interruption, and/or additional monitoring. Consider the benefit of Paxlovid treatment in reducing hospitalization and death, and whether the risk of potential drug:drug interactions for an individual patient can be appropriately managed.
Clinical Trial Results
FDA approval of Paxlovid was based primarily on the final results of the EPIC-HR clinical trial. EPIC-HR was a randomized, double-blind, placebo-controlled clinical trial studying Paxlovid for the treatment of non-hospitalized symptomatic adults with a laboratory confirmed diagnosis of SARS-CoV-2 infection. Patients were adults 18 years of age and older with a prespecified risk factor for progression to severe disease or were 60 years and older regardless of prespecified chronic medical conditions. All patients had not received a COVID-19 vaccine and had not been previously infected with COVID-19. Paxlovid significantly reduced the proportion of people with COVID-19 related hospitalization or death from any cause through 28 days of follow-up by 86% compared to placebo among patients treated within five days of symptom onset and who did not receive COVID-19 therapeutic monoclonal antibody treatment. In this analysis, 977 patients received Paxlovid, and 989 patients received placebo, and among these patients, 0.9% who received Paxlovid were hospitalized due to COVID-19 or died from any cause during 28 days of follow-up compared to 6.5% of the patients who received the placebo.
Benefit of Paxlovid was observed in patients with prior immunity to the virus that causes COVID-19. Among patients in EPIC-HR who were antibody positive at trial enrollment, the risk of COVID-19-related hospitalization or death from any cause during 28 days of follow-up was 0.2% among the 490 patients treated with Paxlovid compared with 1.7% of the 479 patients receiving placebo.
EPIC-HR and another trial, EPIC-SR, also provide information about COVID-19 rebound. Data from these two trials showed that rebound in SARS-CoV-2 (RNA or virus) shedding or COVID-19 symptoms occurred in a subset of patients and happened in both the patients receiving Paxlovid and the placebo. Based on the data currently available to the FDA, there is not a clear association between Paxlovid treatment and COVID-19 rebound.