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Nirmatrelvir/ritonavir

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Nirmatrelvir/ritonavir
Combination of
NirmatrelvirAntiviral drug
RitonavirAntiviral drug
Clinical data
Trade namesPaxlovid
License data
Routes of
administration		By mouth
ATC code
  • None
Legal status
Legal status
Identifiers
KEGG

Nirmatrelvir/ritonavir, sold under the brand name Paxlovid, is a combination of two antiviral drugs, nirmatrelvir and ritonavir, used as a treatment for COVID-19.

In December 2021, the combination was granted emergency use authorization by the US Food and Drug Administration (FDA) for the treatment of coronavirus disease COVID-19.[4][5][7] The co-packaged medications are sold under the brand name Paxlovid.[5][7][8] Paxlovid 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.[5]

On 31 December 2021, the UK Medicines and Healthcare products Regulatory Agency (MHRA) approved the combination "for people with mild to moderate COVID-19 who are at high risk of developing severe COVID-19".[9][10]

Medical uses

Paxlovid is indicated for the treatment of mild-to-moderate coronavirus disease (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.[4][5] 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.[5]

There are no human data on the use of nirmatrelvir during pregnancy related to the risk of birth defects, 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 Paxlovid. A temporary reduction in body weight was observed in the offspring of nursing rats.[6]

Contraindications

Nirmatrelvir/ritonavir is not recommended during pregnancy, and breastfeeding should be stopped during treatment.[11]

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.[6][11]

Ritonavir

Combinations of several drug classes with ritonavir may cause side effects:[12]

Adverse effects

Adverse events of Paxlovid, 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%).[6][11]

Overdose

There is no specific antidote for overdose with Paxlovid, treatment consists of supportive measures such as monitoring of vital signs and observation of clinical status.[6][11]

Manufacturing

Pfizer selected its largest oral tablet factory in Freiburg im Breisgau as the launch facility for the manufacturing of Paxlovid.[13] The drug was first developed in the United States and was initially manufactured in small amounts in Groton, Connecticut to support clinical trials,[14] but the Freiburg facility in Germany was responsible for figuring out how to mass produce Paxlovid on an industrial scale.[13]

Pfizer also asked other factories to assist the Freiburg factory with the task of packaging Paxlovid tablets. For example, in December 2021, it was reported that the Pfizer factory in Ascoli Piceno was adding 100 workers to its existing workforce of 800 and switching to 24/7 operations to support two Paxlovid blister pack production lines coming online in February 2022.[15]

Society and culture

Economics

The UK placed an order for 250,000 courses in October 2021,[16][17] Australia pre-ordered 500,000 courses of the drug,[18] and the US secured 10 million courses for $5.295 billion.[19] Only 65,000 doses were allocated for shipment to U.S. states in December 2021.[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 combination.[21][22][23] The authorization was granted on 22 December 2021.[5][8] The European Medicines Agency (EMA) issued guidance about the use of Paxlovid for the treatment of COVID-19 in the EU on 16 December 2021.[24] The Israeli Ministry of Health approved the use of Paxlovid on 26 December 2021.[25] South Korea approved the use of Paxlovid on 27 December 2021.[26] The UK Medicines and Healthcare products Regulatory Agency (MHRA) granted conditional approval of Paxlovid on 31 December 2021.[27][9] Health Canada approved the use of Paxlovid on 17 January 2022.[28][29][30]

Misleading comparison with ivermectin

Further information: Ivermectin during the COVID-19 pandemic

The combination 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",[31] rely on superficial similarities between the mechanism of action of both drugs[32] and the claim that Pfizer is suppressing the benefits of ivermectin.[33] 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.[31][33]

Research

In September 2021, Pfizer began a phase II/III trial of nirmatrelvir combined with ritonavir.[34]

In December, Pfizer completed a Phase III study of nirmatrelvir combined with ritonavir.[35]

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.[36]

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][9]

The efficacy of the combination against hospitalization or death in adult outpatients when administered within five days of symptom onset is about 88% (95% CI, 75–94%).[6]

References

  1. ^ "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 Oct 2023.
  2. ^ "Summary of Product Characteristics for Paxlovid". Medicines and Healthcare products Regulatory Agency (MHRA). 31 December 2021. Retrieved 31 December 2021.
  3. ^ "Regulatory approval of Paxlovid". Medicines and Healthcare products Regulatory Agency (MHRA). 31 December 2021. Retrieved 31 December 2021.
  4. ^ a b c "Paxlovid- nirmatrelvir and ritonavir kit". DailyMed. Retrieved 30 December 2021.
  5. ^ a b c d e f g "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.
  6. ^ a b c d e f 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.
  7. ^ a b "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.
  8. ^ 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.
  9. ^ a b c "Oral COVID-19 antiviral, Paxlovid, approved by UK regulator" (Press release). Medicines and Healthcare products Regulatory Agency. 31 December 2021.
  10. ^ Reed J (31 December 2021). "Paxlovid: UK medicines regulator approves second Covid antiviral pill". BBC News Online.
  11. ^ a b c d "EMA issues advice on use of Paxlovid (PF-07321332 and ritonavir) for the treatment of COVID-19: rolling review starts in parallel". European Medicines Agency. 16 December 2021. Retrieved 6 January 2022.
  12. ^ "Pfizer's Covid pills may be risky with other medications". NBC News.
  13. ^ a b Schmidt, Barbara (1 December 2021). "Neues Corona-Medikament von Pfizer wird in Freiburg hergestellt". Badische Zeitung (in German). Retrieved 15 January 2022.
  14. ^ Green, Rick (December 23, 2021). "Pfizer scientists in Groton played a critical role in development of new COVID-19 pill". The Hartford Courant.
  15. ^ Paci, Mario (17 December 2021). "Covid, ad Ascoli l'unico stabilimento in Italia che produrrà il farmaco antivirale. Pfizer pensa a cento assunzioni". Corriere Adriatico (in Italian).
  16. ^ "Pfizer Covid pill 'can cut hospitalisations and deaths by nearly 90%'". The Guardian. 5 November 2021. Retrieved 17 November 2021.
  17. ^ Mahase E (October 2021). "Covid-19: UK stockpiles two unapproved antiviral drugs for treatment at home". BMJ. 375: n2602. doi:10.1136/bmj.n2602. PMID 34697079. S2CID 239770104.
  18. ^ "What are the two new COVID-19 treatments Australia has gained access to?". ABC News (Australia). 17 October 2021. Retrieved 5 November 2021.
  19. ^ "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). HHS.gov. HHS Press Office. 18 November 2021. Retrieved 26 December 2021.
  20. ^ Scott Hensley (December 23, 2021). "First doses of Paxlovid, Pfizer's new COVID pill, are released to states". NPR.
  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. {{cite news}}: |last= has generic name (help)
  27. ^ a b Aripaka P (31 December 2021). "Britain approves Pfizer's antiviral COVID-19 pill". Reuters. Retrieved 31 December 2021.
  28. ^ Canada, Health. "PAXLOVID". COVID-19 vaccines and treatments portal. Retrieved 2022-01-18.
  29. ^ "Paxlovid, Pfizer's oral COVID-19 pill, approved in Canada - National | Globalnews.ca". Global News. Retrieved 2022-01-18.
  30. ^ Weeks, Carly (2022-01-17). "Health Canada approves Pfizer's COVID-19 antiviral pill Paxlovid". The Globe and Mail. Retrieved 2022-01-18.
  31. ^ 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.
  32. ^ von Csefalvay, Chris (2021-11-27). "Why Paxlovid is not Pfizermectin". Chris von Csefalvay: Bits and Bugs. Retrieved 2022-01-09.{{cite web}}: CS1 maint: url-status (link)
  33. ^ a b Gorski D (15 November 2021). "Pfizer's new COVID-19 protease inhibitor drug is not just 'repackaged ivermectin'". Science-Based Medicine.
  34. ^ "Pfizer begins dosing in Phase II/III trial of antiviral drug for Covid-19". Clinical Trials Arena. 2 September 2021.
  35. ^ "EPIC-HR: Study of Oral PF-07321332/Ritonavir Compared With Placebo in Nonhospitalized High Risk Adults With COVID-19" (Document). clinicaltrials.gov. 19 November 2021. {{cite document}}: Unknown parameter |url= ignored (help)
  36. ^ "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.
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