Nirmatrelvir/ritonavir

Nirmatrelvir/ritonavir, sold under the brand name Paxlovid, is a co-packaged medication used as a treatment for COVID-19.[9][10][11][12] It contains the antiviral medications nirmatrelvir and ritonavir and was developed by Pfizer.[9][11] Nirmatrelvir inhibits SARS-CoV-2 main protease, while ritonavir is a strong CYP3A inhibitor, slowing down nirmatrelvir metabolism and therefore boosting its effect.[11] It is taken by mouth.[11]

In unvaccinated high-risk people with COVID-19, nirmatrelvir/ritonavir can reduce the risk of hospitalization or death by 88% if taken within five days of symptom onset. People who take nirmatrelvir/ritonavir also test negative for COVID-19 about two and a half days earlier than people who do not.[13] Side effects of nirmatrelvir/ritonavir include changes in sense of taste (dysgeusia), diarrhea, high blood pressure (hypertension), and muscle pain (myalgia).[11]

In December 2021, the United States Food and Drug Administration (FDA) granted nirmatrelvir/ritonavir emergency use authorization (EUA) to treat COVID-19.[14][15] It was approved in the United Kingdom later that month,[16] and in the European Union and Canada in January 2022.[17][18][19] In May 2023, it was approved in the US to treat mild-to-moderate COVID-19 in adults who are at high risk for progression to severe COVID-19, including hospitalization or death, relative to the general population.[20][12]

Medical uses

In the United States, nirmatrelvir/ritonavir is indicated for the treatment of mild-to-moderate COVID-19 in adults who are at high risk for progression to severe COVID-19, including hospitalization or death.[11][20] This includes people above 50, people with diabetes, cancer, coronary artery disease, chronic lung diseases, pregnancy, or on immunosuppressant drugs.

The co-packaged medication is not authorized or suggested for the pre-exposure or post-exposure prophylaxis of COVID-19.[24][20][25]

In the European Union, the co-packaged medication is indicated for the treatment of COVID-19 in adults who do not require supplemental oxygen and who are at increased risk for progressing to severe COVID-19.[17]

Contraindications

The medication is contraindicated in those with hypersensitivity to either of the two main components, and in those with severely reduced kidney or liver function.[14] Co-administration with certain drugs may have serious, sometimes fatal, effects.[32]

Side effects

Nirmatrelvir/ritonavir has a high potential for potentially serious drug interactions due to strong CYP3A inhibition by ritonavir.[11] The US FDA label, the FDA fact sheet, and the FDA EUA contain a boxed warning about the CYP3A inhibition.[11][20]

Adverse events of the co-packaged medication, regardless of causality, observed in the phase II-III EPIC-HR study included dysgeusia (6% vs. < 1% for placebo), diarrhea (3% vs. 2% for placebo), hypertension (1% vs. < 1% for placebo), and myalgia (1% vs. < 1% for placebo).[11][14] In clinical trials, 2% of people discontinued treatment due to side effects with nirmatrelvir/ritonavir while 4% in the placebo group did so.

Interactions

Co-administration of nirmatrelvir/ritonavir with certain drugs is contraindicated, including drugs dependent on CYP3A for removal, for which a raised concentration results in serious reactions, or those with potent CYP3A inducers, for which reduced blood concentration of the two main components may result in loss of effect against the virus and possible resistance, among others.[11] Co-administration also affects the concentration of several drugs, sometimes requiring changing the dose or careful monitoring.[14][33] Many of these drugs are widely prescribed to people at high risk from COVID19.[34] With the extension of the emergency authorization in August 2022, the FDA updated a checklist to help evaluate potential drug interactions and other patient factors before prescribing Paxlovid, including more than 120 drugs that are contraindicated, should be avoided or held from use, or require dose adjustments or special monitoring.[35][14]

Pharmacology

Nirmatrelvir is responsible for the antiviral activity against SARS-CoV-2, while ritonavir works by inhibiting the metabolization of nirmatrelvir in the liver, strengthening its activity.[11]

Research

Early research indicates that treatment with nirmatrelvir/ritonavir during acute COVID-19 may reduce the risk of developing long COVID—also referred to as post-acute COVID condition and post-COVID condition, among others—compared to individuals who do not receive such treatment.[38][39] In a January 2025 report in The New York Times on a Communications Medicine article by Cohen and colleagues,[40] journalist Pam Belluck noted that nirmatrelvir/ritonavir may benefit some subpopulations of long COVID patients, though it was unclear which individuals were most likely to respond.[41] The study, which included 13 long COVID patients undergoing extended treatment with the antiviral drug, yielded mixed results: nine patients experienced some improvement, five reported lasting effects, and four experienced no improvement.[40] The findings highlighted the ongoing uncertainty about effective treatments for long COVID

History

Nirmatrelvir belongs to a family of 3C-like protease inhibitors developed in the late 2010s against feline coronavirus, while ritonavir is an antiretroviral drug developed in the 1980s and used since the 1990s to inhibit the enzyme that metabolizes other protease inhibitors.

The primary data supporting the US Food and Drug Administration (FDA) emergency use authorization for nirmatrelvir/ritonavir were from the EPIC-HR trial, a randomized, double-blind, placebo-controlled clinical trial studying nirmatrelvir/ritonavir for the treatment of non-hospitalized symptomatic adults with a laboratory-confirmed diagnosis of SARS-CoV-2 infection.[11][24][51] Participants were 18 years of age and older with a pre-specified risk factor for progression to severe disease, or were 60years and older regardless of pre-specified chronic medical conditions.[24] No participants had received a COVID19 vaccine or been previously infected with COVID19.[24]

Society and culture

External links