Nirmatrelvir/ritonavir, sold under the brand name Paxlovid, is a co-packaged medication used as a treatment for COVID-19. It contains the antiviral medications nirmatrelvir and ritonavir and was developed by Pfizer. Nirmatrelvir inhibits SARS-CoV-2 main protease, while ritonavir is a strong CYP3A inhibitor, slowing down nirmatrelvir metabolism and therefore boosting its effect. It is taken by mouth.
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. Side effects of nirmatrelvir/ritonavir include changes in sense of taste (dysgeusia), diarrhea, high blood pressure (hypertension), and muscle pain (myalgia).
In December 2021, the United States Food and Drug Administration (FDA) granted nirmatrelvir/ritonavir emergency use authorization (EUA) to treat COVID-19. It was approved in the United Kingdom later that month, and in the European Union and Canada in January 2022. Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged. 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. The FDA considers the combination to be a first-in-class medication. In 2023, it was the 159th most commonly prescribed medication in the United States, with more than 3million prescriptions.
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. 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.
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.
If administered within five days of symptom onset in confirmed COVID-19 infections, the efficacy of the co-packaged medication against hospitalization or death in unvaccinated high-risk adults, as of 2022, was about .
Pregnancy The suggestion of the use of co-packaged medication during pregnancy in people who can become pregnant and are not using contraception, and for people who are breastfeeding, needs further study. Given the risk of morbidity, hospitalization and mortality associated with severe COVID-19 disease in females and fetuses, nirmatrelvir/ritonavir can provide an important option to reduce the risks associated with acute COVID-19 infection in at-risk and unvaccinated patients after careful consideration of the benefits and risks for each patient. There is limited human data on the use of nirmatrelvir during pregnancy related to the risk of congenital disabilities, spontaneous abortions (i.e., miscarriage), or adverse outcomes.
, data on the transfer of nirmatrelvir/ritonavir from breastfeeding parents to infants are limited. Nonetheless, Dai and colleagues reported in a 2024 article in Clinical Pharmacology & Therapeutics that the relative infant dose of drug conferred by breast milk was minimal and "well under the standard 10% safety threshold", supporting the use of the medication during pregnancy and breastfeeding. A temporary reduction in body weight was observed in the offspring of nursing rats. Other observational studies have also demonstrated the safety of ritonavir during pregnancy.
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. Co-administration with certain drugs may have serious, sometimes fatal, effects.
Side effects Nirmatrelvir/ritonavir has a high potential for potentially serious drug interactions due to strong CYP3A inhibition by ritonavir. The US FDA label, the FDA fact sheet, and the FDA EUA contain a boxed warning about the CYP3A inhibition.
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). In clinical trials, 2% of people discontinued treatment due to side effects with nirmatrelvir/ritonavir while 4% in the placebo group did so. Nirmatrelvir/ritonavir is under investigation, so its side effects have yet to be fully evaluated and may not be completely known.
Other side effects of nirmatrelvir/ritonavir may include hypersensitivity reactions, liver toxicity, and development of HIV drug resistance in people with uncontrolled or undiagnosed HIV infection. Hypersensitivity reactions (allergic reactions) may manifest as skin rash, hives, difficulty swallowing, difficulty breathing, angioedema, and/or anaphylaxis. Liver toxicity may manifest as elevated transaminases and clinical hepatitis, including symptoms like appetite loss, jaundice (yellowing of the skin and whites of eyes), dark-colored urine, pale-colored stools, itchy skin, and abdominal pain.
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. Co-administration also affects the concentration of several drugs, sometimes requiring changing the dose or careful monitoring. Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged. Many of these drugs are widely prescribed to people at high risk from COVID19. 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.
Nirmatrelvir/ritonavir is safe to use in combination with over-the-counter pain- and fever-reducing medications such as paracetamol (acetaminophen) and ibuprofen.
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.
Pharmacodynamics Nirmatrelvir is a SARS-CoV-2 main protease (Mpro, 3CLpro, nsp5 protease) inhibitor while ritonavir is an HIV-1 protease inhibitor and strong CYP3A inhibitor. Nirmatrelvir is the main active agent in the formulation, while ritonavir, which inhibits HIV-1 protease, is a strong CYP3A inhibitor: it inhibits the metabolization of nirmatrelvir in the liver and thereby strengthens or boosts its activity. Ritonavir is not active against or thought to directly contribute to the medication's antiviral activity against SARS-CoV-2. Nirmatrelvir/ritonavir works against COVID19 by preventing the replication of SARS-CoV-2, which the SARS-CoV-2 main protease is essential for.
Pharmacokinetics
Absorption The time to peak concentrations of nirmatrelvir combined with ritonavir is 3.00hours (range 1.02–6.00hours), while that of ritonavir is 3.98hours. Peak concentrations of nirmatrelvir combined with ritonavir following a single dose (300mg nirmatrelvir and 100mg ritonavir) in healthy individuals are 2.21μg/mL while total exposure is 23.01μg•h/mL. Taking nirmatrelvir/ritonavir with a high-fat meal modestly increases exposure to nirmatrelvir (peak concentrations increased by 15% and total exposure increased by 1.6%) relative to taking them under fasting conditions.
Distribution The volume of distribution (Vz/F) of nirmatrelvir combined with ritonavir is 104.7L while that of ritonavir is 112.4L. The blood-to-plasma ratio of nirmatrelvir combined with ritonavir is 0.60 while the red-blood-cell-to-plasma ratio of ritonavir is 0.14. The plasma protein binding of nirmatrelvir combined with ritonavir is 69% while that of ritonavir is 98 to 99%.
Metabolism Nirmatrelvir is mainly a substrate of CYP3A in terms of its metabolism. But when it is combined with ritonavir, a strong CYP3A4 inhibitor, nirmatrelvir's metabolism is minimal and its elimination instead is mainly via renal excretion. Ritonavir is eliminated mainly by hepatic metabolism, with CYP3A4 the major enzyme involved and CYP2D6 the minor enzyme.
Elimination Nirmatrelvir combined with ritonavir is excreted 35.3% in feces and 49.6% in urine, while ritonavir is excreted 86.4% in feces and 11.3% in urine.
The oral clearance (CL/F) of nirmatrelvir combined with ritonavir is 8.99 while that of ritonavir is 13.92. The elimination half-life of nirmatrelvir combined with ritonavir is (mean ± SD) 6.05 ± 1.79hours while that of ritonavir is 6.15hours. The half-life of nirmatrelvir combined with ritonavir makes the formulation suitable for administration every 12hours.
Specific populations The pharmacokinetics of nirmatrelvir/ritonavir based on age or gender have not been assessed. Exposure to nirmatrelvir/ritonavir was numerically lower in Japanese than in Western people, but not to a clinically meaningful extent. Peak concentrations, total exposure, time to peak concentrations, and elimination half-life of nirmatrelvir combined with ritonavir are severity-dependently increased in people with renal impairment, but not increased in people with moderate hepatic impairment. The combination has not been studied in people with severe hepatic impairment.
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. In a January 2025 report in The New York Times on a Communications Medicine article by Cohen and colleagues, 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. 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. The findings highlighted the ongoing uncertainty about effective treatments for long COVID.
Rebound A September 2022 post hoc analysis of EPIC-HR clinical trial data found that B.1.617.2 (i.e., delta) variant viral rebound (i.e., positive retest and symptom recurrence) occurred in 2.3% of those in the nirmatrelvir/ritonavir group and 1.7% of those in the placebo group between days 5 and 10 (or 14) of treatment. The groups were similar in outcomes across premorbidity, prior nirmatrelvir exposure and resistance, symptom severity, and baseline SARS-CoV-2 seropositivity statuses, as well as in the occurrence of hospitalization or death. The origin of viral rebound was unknown at the time, but there was speculation that reservoirs existed in tissues not reached by the medication and that true reinfections were culprits. In May 2022, Pfizer suggested repeating the treatment, but the FDA said there was no evidence of benefit.