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What is Nirmatrelvir/ritonavir and explain in detail?
Nirmatrelvir/ritonavir, sold under the brand name Paxlovid, is a co-packaged oral medication used as a treatment for COVID-19. It contains the antiviral medications nirmatrelvir and ritonavir.In December 2021, nirmatrelvir/ritonavir was granted emergency use authorization by the United States Food and Drug Administration (FDA) for the treatment of COVID-19. It is not authorized for the pre-exposure or post-exposure prevention of COVID-19 or for initiation of treatment in those requiring hospitalization due to severe or critical COVID-19. It was approved in the United Kingdom later that month, and in the European Union and Canada in January 2022.

Medical uses
The co-packaged medication is indicated for the treatment of mild to moderate COVID-19 in people aged twelve years of age and older weighing at least 40 kilograms (88 lb) with positive results of direct SARS-CoV-2 testing, and who are at high risk for progression to severe COVID-19, including hospitalization or death. If administered within five days of symptom onset, the efficacy of the co-packaged medication against hospitalization or death in unvaccinated adults is about 88% (95% CI, 75–94%).As of May 2022, the effectiveness among vaccinated people and the effectiveness against long COVID were unknown.  The drug does not prevent infection in people who live with an infected person.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.

Contraindications
The co-packaged medication is not authorized for the pre-exposure prophylaxis or post-exposure prophylaxis of COVID-19 nor for treatment in those requiring hospitalization due to severe or critical COVID-19, nor for use for longer than 5 consecutive days.
The drug is contraindicated in those with hypersensitivity to the two main components, and in those with severely reduced kidney or liver function.

During pregnancy
The co-packaged medication is not recommended during pregnancy and in women who can become pregnant and who are not using contraception. Breastfeeding should be interrupted during treatment. These recommendations are because laboratory studies in animals suggest that high doses of the co-packaged medication may affect the growth of the fetus.There are no human data on the use of nirmatrelvir during pregnancy related to the risk of birth defects, spontaneous abortions (miscarriage), or adverse outcomes. There are also no human data on the presence of nirmatrelvir in human milk, its effects on milk production or the infant. In pregnant rabbits, a reduction in fetal body weight was observed with systemic exposure ten times higher than the authorized human dose of the co-packaged medication. A temporary reduction in body weight was observed in the offspring of nursing rats.

Interactions and side effects
Co-administration with certain drugs may have serious effects and may sometimes be fatal. The drug is contraindicated when co-administered with certain drugs, such as 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. Many of these drugs are widely prescribed to people at high risk from COVID-19. 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 which are either contraindicated, should be avoided or held from use, or require dose adjustments or special monitoring.Adverse events of the co-packaged medication, regardless of causality, observed in the phase II-III EPIC-HR study included: dysgeusia (4.8–6%), diarrhea (3–3.9%), vomiting (1.3%), hypertension (1%), and myalgia (1%).There is no specific antidote for overdose with the co-packaged medication. Treatment consists of supportive measures such as monitoring of vital signs and observation of clinical status.

Rebound
An additional analysis of the original EPIC-HR clinical trial data (Delta variant) showed that about 2% of both the treatment and placebo groups experienced a symptomatic rebound after the 5 day treatment, meaning they felt ill again and tested positive again (antigen test and PCR test) after testing negative. This is important, because people with rebound cannot go back to work or school. The exact cause is unknown. It may be due to virus reservoirs in tissues that are not reached by the medication, or reinfection. In May 2022, Pfizer suggested repeating the treatment, but the FDA said there has been no evidence of benefit.In a 2022 US case report of 10 people with rebound while the Omicron variant has been circulating, viral load during relapse was comparable to levels during initial infection and high enough to cause secondary transmission. Also, sequencing of SARS CoV2 in three patients showed that rebound was a relapse with the same strain as it was not due to a mutation during treatment nor an infection with a different viral strain. As of September 2022, it is unknown how common rebound is among people after Paxlovid treatment, but study author David Ho thinks it is not uncommon. Besides him, President Joe Biden, First Lady Jill Biden, Anthony Fauci and Peter Hotez are known to have experienced rebound. As of September 2022, Pfizer is studying the phenomenon in a new trial it calls EPIC-SR (standard risk) while the omicron variant is circulating.As of July 2022, no Paxlovid drug resistant SARS CoV2 has been observed in clinical context. The engineering of a nirmaltrevir-resistant chimera of Vesicular Stomatitis Virus under laboratory conditions was published without formal peer review in July 2022.

Manufacturing
Pfizer selected its largest oral tablet factory in Freiburg as the launch facility for the manufacturing of the co-packaged medication. Nirmatrelvir, the novel portion of the co-packaged medication, was first developed in the United States and was initially manufactured in small amounts in Groton, Connecticut, to support clinical trials, but the Freiburg facility in Germany was responsible for figuring out how to mass-produce the co-packaged medication on an industrial scale. Pfizer selected another factory in Ascoli Piceno, Italy, to assist the Freiburg factory with packaging tablets into blister packs.

History
The primary data supporting the US Food and Drug Administration (FDA) emergency use authorization for nirmatrelvir/ritonavir are from EPIC-HR, 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. Participants 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 participants had not received a COVID-19 vaccine and had not been previously infected with COVID-19. The main outcome measured in the trial was the proportion of people who were hospitalized due to COVID-19 or died due to any cause during 28 days of follow-up. Nirmatrelvir/ritonavir significantly reduced the proportion of people with COVID-19 related hospitalization or death from any cause by 88% compared to placebo among participants treated within five days of symptom onset and who did not receive COVID-19 therapeutic monoclonal antibody treatment. In this analysis, 1,039 participants had received nirmatrelvir/ritonavir, and 1,046 participants had received placebo and among these participants, 0.8% who received nirmatrelvir/ritonavir were hospitalized or died during 28 days of follow-up compared to 6% of the participants who received placebo.In September 2021, Pfizer began a phase II/III trial of nirmatrelvir combined with ritonavir.In December 2021, Pfizer completed a Phase III study of nirmatrelvir combined with ritonavir, and on 14 December, Pfizer announced that the Phase II/III study of nirmatrelvir combined with ritonavir showed a reduced risk of hospitalization or death. In December 2021, nirmatrelvir/ritonavir was granted emergency use authorization by the United States Food and Drug Administration (FDA) for the treatment of COVID-19. On 31 December, the United Kingdoms Medicines and Healthcare products Regulatory Agency (MHRA) approved the use of nirmatrelvir combined with ritonavir for adults with mild to moderate infection and at high risk of their illness worsening.The efficacy of the co-packaged medication against hospitalization or death in high-risk adults when administered within five days of symptom onset is about 88% (95% CI, 75–94%).In 2022, the PANORAMIC trial started testing the effectiveness of nirmatrelvir/ritonavir for treating COVID-19 infections.Pfizer also conducted a Phase II/III study in standard-risk patients called EPIC-SR, which began in December 2021. This study did not find a statistically significant reduction in the risk of hospitalization or death (treatment: 5/576; placebo: 10/569), nor did it achieve its primary goal of sustained alleviation of symptoms. However, it did find a 62% decrease in COVID-19–related medical visits (p=0.023), which was consistent with the 67% reduction from the EPIC-HR (high-risk patients) study. Pfizer discontinued enrollment in the study because of the low rate of hospitalization and death in this population.

Society and culture
Legal status
On 16 November 2021, Pfizer submitted an application to the US Food and Drug Administration (FDA) for emergency use authorization for the co-packaged medication. The authorization was granted on 22 December 2021, for adults and children ages 12 and older who are infected with Covid and at risk. The European Medicines Agency (EMA) issued guidance about the use of the co-packaged medication for the treatment of COVID-19 in the EU on 16 December 2021. The Israeli Ministry of Health approved the use of the co-packaged medication on 26 December 2021. South Korea approved the use of the co-packaged medication on 27 December 2021.The UK Medicines and Healthcare products Regulatory Agency (MHRA) granted conditional approval of the co-packaged medication in December 2021. Health Canada approved the use of the co-packaged medication in January 2022. The Singapore Health Sciences Authority approved the use of the co-packaged medication for treating adults in February 2022. In February 2022, China approved the medication for the treatment of adults who have mild to moderate COVID-19 and are at a high risk of progressing to a severe condition.

Economics
In December 2021, the German government ordered 1 million doses of, but by August 2022, only around 43,000 had been delivered by wholesalers to pharmacies. In Germany, paxlovid is by prescription through physicians only and German physicians have been reluctant to prescribe it. Hence health minister Karl Lauterbach decided that general practitioners can stock 5 Paxlovid courses in their practice and dispense it directly to patients, that a prescription would be remunerated with 15 euros and that every nursing home should appoint a vaccination officer as well as a Paxlovid officer. As of August 2022 the treatment guidelines, which German family doctors follow, have not been updated since February 2022 and recommend Paxlovid only in unvaccinated risk patients, i.e. in only a few people.As of April 2022, the United States ordered a total of 20 million Paxlovid courses