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Nirmatrelvir/ritonavir

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Nirmatrelvir/ritonavir
Paxlovid blister pack, partially opened to reveal one ritonavir and two nirmatrelvir tablets
Combination of
NirmatrelvirAntiviral drug
RitonavirAntiviral drug
Clinical data
Trade namesPaxlovid
AHFS/Drugs.comMonograph
MedlinePlusa622005
License data
Pregnancy
category
Routes of
administration		By mouth
ATC code
  • None
Legal status
Legal status
Identifiers
KEGG

Nirmatrelvir/ritonavir, sold under the brand name Paxlovid, is a co-packaged oral medication used as a treatment for COVID-19.[8][10][15] It contains the antiviral medications nirmatrelvir and ritonavir.[8][10]

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.[12][16] 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.[11] It was fully approved in the United Kingdom later that month,[17] and in the European Union and Canada in January 2022.[13][18][19]

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.[10][11] 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%).[12]

As of May 2022, the effectiveness among vaccinated people and the effectiveness against long COVID are still unknown.[20]

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.[13]

A clinical trial found that about 2% of patients experience a rebound after treatment ends. A similar rebound rate was observed in the placebo group. The rebound may be due to virus reservoirs in tissues that are not reached by the medication, or reinfection. In these cases, Pfizer suggested repeating the treatment, but the FDA said there is no evidence of benefit.[21][22]

The drug does not prevent infection in people who live with an infected person.[23]

Contraindications

The co-packaged medication 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.[11]

The co-packaged medication is not recommended during pregnancy and in women who can become pregnant but who are not using contraception.[24] Breastfeeding should be interrupted during treatment.[24] These recommendations are because laboratory studies in animals suggest that high doses of the co-packaged medication may affect the growth of the fetus.[24]

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 10 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.[12]

Interactions and side effects

See also: Ritonavir § Side effects

Co-administration with certain drugs may have serious effects and may sometimes be fatal.[25] The drug is contraindicated in those with hypersensitivity to the two main components, with severely reduced kidney or liver function, co-administered with certain drugs, such as those 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.[12][24] Many of these drugs are widely prescribed to people at high risk from COVID-19.[26]

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%).[12][24]

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.[12][24]

Research and development

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.[10][11][27] 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.[11] All participants had not received a COVID-19 vaccine and had not been previously infected with COVID-19.[11] 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.[11] 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.[11] 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.[11]

In September 2021, Pfizer began a phase II/III trial of nirmatrelvir combined with ritonavir.[28]

In December 2021, Pfizer completed a Phase III study of nirmatrelvir combined with ritonavir.[29] On 14 December, Pfizer announced that the result of the Phase II/III study of nirmatrelvir combined with ritonavir results, showed a reduced risk of hospitalization or death.[30] On 31 December, the United Kingdom's Medicines and Healthcare products Regulatory Agency (MHRA) approved the use of nirmatrelvir combined with ritonavir for adults who have mild to moderate infection and are at high risk of their illness worsening.[31][17]

The efficacy of the co-packaged medication against hospitalization or death in adults when administered within five days of symptom onset is about 88% (95% CI, 75–94%).[12][32]

In 2022, the PANORAMIC trial started testing the effectiveness of nirmatrelvir/ritonavir for treating COVID-19 infections.[33]

Manufacturing and distribution

Pfizer selected its largest oral tablet factory in Freiburg as the launch facility for the manufacturing of the co-packaged medication.[34] 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,[35] but the Freiburg facility in Germany was responsible for figuring out how to mass-produce the co-packaged medication on an industrial scale.[34] Pfizer selected another factory in Ascoli Piceno, Italy, to assist the Freiburg factory with packaging tablets into blister packs.[36]

As of May 2022, the United States ordered a total of 20 million paxlovid courses, with the delivery of the first 10 million courses to be completed in June and fulfillment of the second 10 million scheduled for September 2022, according to the Biden administration. The United States Department of Health and Human Services has set up at least 2,200 sites where people can receive paxlovid as soon as they test positive for the virus, including pharmacies, community health centers and long-term care facilities.[37]

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.[38][39][40] The authorization was granted on 22 December 2021, for adults and children ages 12 and older who are infected with Covid and at risk.[11][15][37] 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.[41] The Israeli Ministry of Health approved the use of the co-packaged medication on 26 December 2021.[42] South Korea approved the use of the co-packaged medication on 27 December 2021.[43]

The UK Medicines and Healthcare products Regulatory Agency (MHRA) granted conditional approval of the co-packaged medication in December 2021.[31][17] Health Canada approved the use of the co-packaged medication in January 2022.[18][7][44][45] The Singapore Health Sciences Authority approved the use of the co-packaged medication for treating adults in February 2022.[46] 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.[47]

Comparison to ivermectin

Further information: Ivermectin during the COVID-19 pandemic

The co-packaged medication is sometimes falsely claimed to be a repackaged version of the antiparasitic drug ivermectin, which has been promoted as a COVID-19 therapeutic. Such claims, sometimes using the nickname "Pfizermectin",[48] rely on superficial similarities between the mechanism of action of both drugs[49] and the claim that Pfizer is suppressing the benefits of ivermectin.[50] To be effective against COVID-19, the concentration of ivermectin in the blood would require a dose that is 10-20 times higher than is safe.[48][50]

References

  1. ^ "Paxlovid APMDS". Therapeutic Goods Administration (TGA). 21 January 2022. Retrieved 5 February 2022.
  2. ^ a b "AusPAR: nirmatrelvir/ritonavir". Therapeutic Goods Administration (TGA). 25 January 2022. Retrieved 23 March 2022.
  3. ^ a b "TGA eBS - Product and Consumer Medicine Information Licence".
  4. ^ "FDA-sourced list of all drugs with black box warnings (Use Download Full Results and View Query links.)". nctr-crs.fda.gov. FDA. Retrieved 22 October 2023.
  5. ^ https://pdf.hres.ca/dpd_pm/00064313.PDF [bare URL PDF]
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  47. ^ "China conditionally approves Pfizer's Covid treatment pill Paxlovid". The Guardian. Reuters. 12 February 2022. Retrieved 13 February 2022.
  48. ^ a b Bloom J (2 December 2021). "How Does Pfizer's Pavloxid Compare With Ivermectin?". American Council on Science and Health. Retrieved 12 December 2021.
  49. ^ von Csefalvay C (27 November 2021). "Why Paxlovid is not Pfizermectin". Chris von Csefalvay: Bits and Bugs. Retrieved 9 January 2022.{{cite web}}: CS1 maint: url-status (link)
  50. ^ a b Gorski D (15 November 2021). "Pfizer's new COVID-19 protease inhibitor drug is not just 'repackaged ivermectin'". Science-Based Medicine.
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