Nirmatrelvir/ritonavir

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Nirmatrelvir/ritonavir
Paxlovid.jpg
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
  • AU: S4 (Prescription only) [3][2]
  • CA: ℞-only
  • UK: POM (Prescription only) [4][5]
  • US: ℞-only via emergency use authorization[6][7][8]
  • EU: Rx-Only [9]
Identifiers
KEGG

Nirmatrelvir/ritonavir, sold under the brand name Paxlovid, is a co-packaged medication used as a treatment for COVID-19.[4][6][10] It contains the antiviral medications nirmatrelvir and ritonavir.[4][6] It is taken by mouth.[4][6]

In December 2021, the co-packaged medication was granted emergency use authorization by the United States Food and Drug Administration (FDA) for the treatment of COVID-19.[6][7][8][11] 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.[7]

The co-packaged medication was approved for medical use in the United Kingdom in December 2021,[12][13] and in the European Union in January 2022.[9]

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.[6][7] If administered within five days of symptom onset, the efficacy of the co-packaged medication against hospitalization or death in adults is about 88% (95% CI, 75–94%).[8]

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.[9]

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.[7]

Contraindications[]

The co-packaged medication is not recommended during pregnancy and in women who can become pregnant but who are not using contraception.[14] Breastfeeding should be interrupted during treatment.[14] These recommendations are because laboratory studies in animals suggest that high doses of the co-packaged medication may affect the growth of the fetus.[14]

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.[8]

Adverse drug reactions[]

Co-administration with certain drugs may have serious effects and may sometimes be fatal. 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.[8][14] Many of these drugs are widely prescribed to people at high risk from COVID-19.[15]

Adverse effects[]

See also: Ritonavir § Side effects

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%).[8][14]

Overdose[]

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.[8][14]

Manufacturing[]

Pfizer selected its largest oral tablet factory in Freiburg im Breisgau as the launch facility for the manufacturing of the co-packaged medication.[16] 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,[17] but the Freiburg facility in Germany was responsible for figuring out how to mass-produce the co-packaged medication on an industrial scale.[16] Pfizer selected another factory in Ascoli Piceno, Italy to assist the Freiburg factory with packaging tablets into blister packs.[18]

History[]

The primary data supporting the U.S. 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.[6][7][19] 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.[7] All participants had not received a COVID-19 vaccine and had not been previously infected with COVID-19.[7] 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.[7] 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.[7] 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.[7]

Society and culture[]

Economics[]

The U.S. secured 10 million courses for US$5.295 billion.[20]

Legal status[]

On 16 November 2021, Pfizer submitted an application to the U.S. Food and Drug Administration (FDA) for emergency use authorization for the co-packaged medication.[21][22][23] The authorization was granted on 22 December 2021.[7][10] 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.[24] The Israeli Ministry of Health approved the use of the co-packaged medication on 26 December 2021.[25] South Korea approved the use of the co-packaged medication on 27 December 2021.[26]

The UK Medicines and Healthcare products Regulatory Agency (MHRA) granted conditional approval of the co-packaged medication on 31 December 2021.[27][12] Health Canada approved the use of the co-packaged medication on 17 January 2022.[28][29][30] France was the first EU country to make the medication available to its citizens on 2 February 2022.[31] The Singapore Health Sciences Authority approved the use of the pill for treating adult patients on 3 February 2022.[32] On 12 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.[33]

Misleading comparison with 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",[34] rely on superficial similarities between the mechanism of action of both drugs [35] and the claim that Pfizer is suppressing the benefits of ivermectin.[36] 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.[34][36]

Research[]

In September 2021, Pfizer began a phase II/III trial of nirmatrelvir combined with ritonavir.[37]

In December, Pfizer completed a Phase III study of nirmatrelvir combined with ritonavir.[38]

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.[39]

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.[27][12]

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%).[8][40]

As of 2022, the Panoramic trial is testing the effectiveness of molnupiravir.[41][42]

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. ^ a b c d "Summary of Product Characteristics for Paxlovid". Medicines and Healthcare products Regulatory Agency (MHRA). 31 December 2021. Retrieved 31 December 2021.
  5. ^ "Regulatory approval of Paxlovid". Medicines and Healthcare products Regulatory Agency (MHRA). 31 December 2021. Retrieved 31 December 2021.
  6. ^ a b c d e f g "Paxlovid- nirmatrelvir and ritonavir kit". DailyMed. Retrieved 30 December 2021.
  7. ^ a b c d e f g h i j k l "FDA Authorizes First Oral Antiviral for Treatment of COVID-19". U.S. Food and Drug Administration (FDA) (Press release). 22 December 2021. Retrieved 22 December 2021. Public Domain This article incorporates text from this source, which is in the public domain.
  8. ^ a b c d e f g h Fact sheet for healthcare providers: Emergency Use Authorization for Paxlovid (PDF) (Technical report). Pfizer. 22 December 2021. LAB-1492-0.8. Archived from the original on 23 December 2021.
  9. ^ a b c "Paxlovid EPAR". European Medicines Agency (EMA). 24 January 2022. Retrieved 3 February 2022. Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
  10. ^ a b "Frequently Asked Questions on the Emergency Use Authorization for Paxlovid for Treatment of COVID-19" (PDF). U.S. Food and Drug Administration (FDA). 22 December 2021.
  11. ^ "Pfizer Receives U.S. FDA Emergency Use Authorization for Novel COVID-19 Oral Antiviral Treatment" (Press release). Pfizer. 22 December 2021. Retrieved 22 December 2021 – via Business Wire.
  12. ^ a b c "Oral COVID-19 antiviral, Paxlovid, approved by UK regulator" (Press release). Medicines and Healthcare products Regulatory Agency. 31 December 2021.
  13. ^ Reed J (31 December 2021). "Paxlovid: UK medicines regulator approves second Covid antiviral pill". BBC News Online.
  14. ^ a b c d e f "EMA issues advice on use of Paxlovid (PF-07321332 and ritonavir) for the treatment of COVID-19: rolling review starts in parallel" (Press release). European Medicines Agency (EMA). 16 December 2021. Retrieved 6 January 2022. Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
  15. ^ "Pfizer antiviral pills may be risky with other medications". ABC News. 26 December 2021. Retrieved 4 February 2022.
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  17. ^ Green R (23 December 2021). "Pfizer scientists in Groton played a critical role in development of new COVID-19 pill". The Hartford Courant.
  18. ^ Paci M (17 December 2021). "Covid, ad Ascoli l'unico stabilimento in Italia che produrrà il farmaco antivirale. Pfizer pensa a cento assunzioni" [Covid, in Ascoli the only plant in Italy that will produce the antiviral drug. Pfizer thinks to hire one hundred]. Corriere Adriatico (in Italian).
  19. ^ CDER Scientific Review Supporting EUA (PDF) (Report). Center for Drug Evaluation and Research.
  20. ^ "Biden Administration Secures 10 Million Courses of Pfizer's COVID-19 Oral Antiviral Medicine as Additional Tool to Reduce Hospitalizations and Save Lives" (Press release). U.S. Department of Health and Human Services. 18 November 2021. Retrieved 26 December 2021.
  21. ^ "Pfizer Seeks Emergency Use Authorization for Novel COVID-19 Oral Antiviral Candidate" (Press release). Pfizer. 16 November 2021. Retrieved 17 November 2021 – via Business Wire.
  22. ^ Kimball S (16 November 2021). "Pfizer submits FDA application for emergency approval of Covid treatment pill". CNBC. Retrieved 17 November 2021.
  23. ^ Robbins R (5 November 2021). "Pfizer Says Its Antiviral Pill Is Highly Effective in Treating Covid". The New York Times. ISSN 0362-4331. Archived from the original on 8 November 2021. Retrieved 9 November 2021.
  24. ^ "EMA issues advice on use of Paxlovid (PF-07321332 and ritonavir) for the treatment of COVID-19: rolling review starts in parallel" (Press release). European Medicines Agency (EMA). 16 December 2021.
  25. ^ "The Use of Pfizer's Anti-Viral Drug for the Treatment of COVID-19 Has Been Approved". GOV.IL. Retrieved 28 December 2021.
  26. ^ Reuters (27 December 2021). "S.Korea authorises emergency use of Pfizer's oral coronavirus treatment". Reuters. Retrieved 28 December 2021.
  27. ^ a b Aripaka P (31 December 2021). "Britain approves Pfizer's antiviral COVID-19 pill". Reuters. Retrieved 31 December 2021.
  28. ^ Health Canada. "Paxlovid". COVID-19 vaccines and treatments portal. Retrieved 18 January 2022.
  29. ^ "Paxlovid, Pfizer's oral COVID-19 pill, approved in Canada - National | Globalnews.ca". Global News. Retrieved 18 January 2022.
  30. ^ Weeks C (17 January 2022). "Health Canada approves Pfizer's COVID-19 antiviral pill Paxlovid". The Globe and Mail. Retrieved 18 January 2022.
  31. ^ Véran O (2 February 2022). "Arrivée d'un nouveau médicament contre la Covid-19 : la France déploie le Paxlovid® en ville" (Press release). Minister for Solidarity and Health.
  32. ^ Chelvan, Vanessa Paige (3 February 2022). "Singapore approves Pfizer's Paxlovid pill for COVID-19 treatment in adult patients". CNA. Retrieved 3 February 2022.
  33. ^ "China conditionally approves Pfizer's Covid treatment pill Paxlovid". The Guardian. Reuters. 12 February 2022. Retrieved 13 February 2022.
  34. ^ 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.
  35. ^ 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)
  36. ^ a b Gorski D (15 November 2021). "Pfizer's new COVID-19 protease inhibitor drug is not just 'repackaged ivermectin'". Science-Based Medicine.
  37. ^ "Pfizer begins dosing in Phase II/III trial of antiviral drug for Covid-19". Clinical Trials Arena. 2 September 2021.
  38. ^ Clinical trial number NCT04960202 for "EPIC-HR: Study of Oral PF-07321332/Ritonavir Compared With Placebo in Nonhospitalized High Risk Adults With COVID-19" at ClinicalTrials.gov
  39. ^ "Pfizer Announces Additional Phase 2/3 Study Results Confirming Robust Efficacy of Novel COVID-19 Oral Antiviral Treatment Candidate in Reducing Risk of Hospitalization or Death" (Press release). Pfizer. 14 December 2021. Retrieved 25 December 2021 – via Business Wire.
  40. ^ Hammond J, Leister-Tebbe H, Gardner A, Abreu P, Bao W, Wisemandle W, et al. (February 2022). "Oral Nirmatrelvir for High-Risk, Nonhospitalized Adults with Covid-19". The New England Journal of Medicine. doi:10.1056/NEJMoa2118542. PMID 35172054.
  41. ^ "NIHR funds community COVID-19 antiviral trial". NIHR. Retrieved 16 March 2022.
  42. ^ "Thousands needed to try a new Covid antiviral treatment". BBC News. 25 January 2022. Retrieved 16 March 2022.

Further reading[]

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