Nirmatrelvir/ritonavir

Nirmatrelvir/ritonavir
Package of a days worth of Paxlovid in those with normal kidney function.
Combination of
NirmatrelvirAntiviral drug
RitonavirCYP3A inhibitor
Names
Trade namesPaxlovid
Other namesNirmatrelvir/r
Clinical data
Main usesCOVID-19[1]
Side effectsTaste disturbances, diarrhea, high blood pressure, muscle pains[2]
InteractionsMany[1]
Routes of
use		By mouth
Typical dose300 mg nirmatrelvir &
100 mg ritonavir BID[2]
Duration5 days[2]
External links
US NLMNirmatrelvir/ritonavir
Legal
License data
Legal status

Nirmatrelvir/ritonavir, sold under the brand name Paxlovid, is two medications packaged together and used to treat COVID-19.[1] It is used within 5 days of the start of symptoms, in people who do not require supplemental oxygen, but are at high risk of developing severe COVID-19.[1][2] It is taken by mouth.[2]

Common side effects include taste disturbances, diarrhea, high blood pressure, and muscle pains.[2] Safety in pregnancy is unclear.[1] It should not be used in people with severe liver or kidney problems.[1] It has a number of medication interactions, including with hormonal birth control.[2][1] It is contains nirmatrelvir, a SARS-CoV-2 main protease inhibitor and ritonavir, a CYP3A inhibitor.[2]

The combination was approved for medical use in the United Kingdom in December of 2021.[1] It also received emergency use authorization in the United States that month.[2] In 2021 the United States government bought 10 million courses of treatment at 530 USD each, which it will be providing at no cost to Americans.[6][7]

Medical uses

COVID-19

Nirmatrelvir/ritonavir is used to treat mild-to-moderate coronavirus disease 19 (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.[2][4] The co-packaged medication is not authorized for the pre-exposure or post-exposure prevention or for initiation of treatment in those requiring hospitalization due to severe or critical COVID-19.[4]

In those who are unvaccinated for COVID-19 and at high risk of disease, it decreases hospitalization and death by 89% (0.8% admitted to hospital with no deaths with treatment versus 7% admitted to hospital with 1.8% deaths for placebo).[8][9]

Dosage

It is taken as 300 mg of nirmatrelvir (2 pills) with 100 mg of ritonavir (1 pill) twice per day for 5 days.[2] A lower dose is used in people with a GFR between 30 and 60 mL/min, specifically 150 mg nirmatrelvir and 100 mg ritonavir twice daily for 5 days.[5]

Side effects

Side effects observed include taste disturbances (6%), diarrhea (3%), high blood pressure (1%), and muscle pains (1%).[5]

Pregnancy and breastfeeding

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.[5]

Interactions

Paxlovid is contraindicated in those with hypersensitivity to nirmatrelvir or ritonavir, with severe kidney impairment,[5] or in those on any of the following medications:

Paxlovid is not recommended with glecaprevir/pibrentasvir or salmeterol. Co-administration with encorafenib or ivosidenib should be avoided. Concomitant use of rivaroxaban, sirolimus or voriconazole should be avoided. The use of neratinib, venetoclax or ibrutinib should be avoided. The use of bosentan should be discontinued before starting nirmatrelvir/ritonavir.[5]

It should also not be given to people on apixaban, cisapride, clopidogrel, cyclosporine, digoxin, domperidone, doxorubicin, eletriptan, everolimus, felodipine, fentanyl, fuscidic acid (by mouth), ivabradine, letermovir, lomitapide, macitentan, nifedipine, nilotinib, quinine, sunitinib, tacrolimus, and ticagrelor.[10] For some of these agents changes can be made to make the use possible.[10]

Use with the following medications increases their concentration:[5]

Co-administration reduces the concentration of the following drugs:[5]

Co-administration may interfere with the concentration of the following drugs: warfarin, emtricitabine.[5]

Overdose

There is no specific antidote for overdose, treatment consists of supportive measures such as monitoring of vital signs and observation of clinical status.[5]

Society and culture

Availability

The UK placed an order for 250,000 courses in October 2021,[11][12] Australia pre-ordered 500,000 courses of the drug,[13] and the US secured 10 million courses for $5.295 billion.[14]

It is was approved in Canada in January of 2022.[15][16] Canada, as of January 2022, has ordered a million courses of treatment, with an option to buy another half million.[17]

On 16 November 2021, Pfizer submitted an application to the U.S. Food and Drug Administration (FDA) for emergency use authorization for the combination.[18][19][20] The authorization was granted on 22 December 2021.[4][21] 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.[22] The Israeli Ministry of Health approved the use of Paxlovid on 26 December 2021.[23] South Korea approved the use of Paxlovid on 27 December 2021.[24] The UK Medicines and Healthcare products Regulatory Agency (MHRA) granted conditional approval of Paxlovid on 31 December 2021.[25][26]

Conspiracies

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",[27] rely on superficial similarities between the pharmacokinetics of both drugs and the claim that Pfizer is suppressing the benefits of ivermectin.[28] 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.[27][28]

Research

In September 2021, Pfizer began a phase II/III trial of nirmatrelvir combined with ritonavir.[29]

In December 2021, Pfizer completed a Phase III study of nirmatrelvir combined with ritonavir.[30]

On 14 December 2021, 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.[31]

On 31 December 2021, 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.[25][26]

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%).[5]

References

  1. 1 2 3 4 5 6 7 8 9 "Summary of Product Characteristics for Paxlovid". Medicines and Healthcare products Regulatory Agency (MHRA). 31 December 2021. Archived from the original on 31 December 2021. Retrieved 31 December 2021.
  2. 1 2 3 4 5 6 7 8 9 10 11 12 "Paxlovid- nirmatrelvir and ritonavir kit". DailyMed. Archived from the original on 31 December 2021. Retrieved 30 December 2021.
  3. ↑ "Regulatory approval of Paxlovid". Medicines and Healthcare products Regulatory Agency (MHRA). 31 December 2021. Archived from the original on 11 January 2022. Retrieved 31 December 2021.
  4. 1 2 3 4 "FDA Authorizes First Oral Antiviral for Treatment of COVID-19". U.S. Food and Drug Administration (FDA) (Press release). 22 December 2021. Archived from the original on 27 December 2021. Retrieved 22 December 2021. Public Domain This article incorporates text from this source, which is in the public domain.
  5. 1 2 3 4 5 6 7 8 9 10 11 12 13 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.
  6. ↑ "U.S. to buy 10 mln courses of Pfizer's COVID-19 pill for $5.3 bln". Reuters. 18 November 2021. Archived from the original on 3 January 2022. Retrieved 6 January 2022.
  7. ↑ "FDA Grants Pfizer's COVID Antiviral Pill EUA - GoodRx". GoodRx. Archived from the original on 31 December 2021. Retrieved 6 January 2022.
  8. ↑ Mahase, Elisabeth (8 November 2021). "Covid-19: Pfizer's paxlovid is 89% effective in patients at risk of serious illness, company reports". BMJ. 375: n2713. doi:10.1136/bmj.n2713. Archived from the original on 5 January 2022. Retrieved 6 January 2022.
  9. ↑ Hammond, Jennifer; Leister-Tebbe, Heidi; Gardner, Annie; Abreu, Paula; Bao, Weihang; Wisemandle, Wayne; Baniecki, MaryLynn; Hendrick, Victoria M.; Damle, Bharat; Simón-Campos, Abraham; Pypstra, Rienk; Rusnak, James M. (16 February 2022). "Oral Nirmatrelvir for High-Risk, Nonhospitalized Adults with Covid-19". New England Journal of Medicine: NEJMoa2118542. doi:10.1056/NEJMoa2118542.
  10. 1 2 "Practice Tool #3 – Drug-Drug Interactions and Contraindications" (PDF). Archived (PDF) from the original on 2 February 2022. Retrieved 22 February 2022.
  11. ↑ "Pfizer Covid pill 'can cut hospitalisations and deaths by nearly 90%'". The Guardian. 5 November 2021. Archived from the original on 17 November 2021. Retrieved 17 November 2021.
  12. ↑ 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.
  13. ↑ "What are the two new COVID-19 treatments Australia has gained access to?". ABC News (Australia). 17 October 2021. Archived from the original on 5 November 2021. Retrieved 5 November 2021.
  14. ↑ "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. Archived from the original on 26 December 2021. Retrieved 26 December 2021.
  15. ↑ "Drug Details". covid-vaccine.canada.ca. Archived from the original on 17 January 2022. Retrieved 17 January 2022.
  16. ↑ "First at-home COVID-19 antiviral prescription drug authorized by Health Canada". Coronavirus. 17 January 2022. Archived from the original on 17 January 2022. Retrieved 17 January 2022.
  17. ↑ "Health Canada approves Pfizer's COVID-19 therapeutic". CBC. Archived from the original on 17 January 2022. Retrieved 17 January 2022.
  18. ↑ "Pfizer Seeks Emergency Use Authorization for Novel COVID-19 Oral Antiviral Candidate" (Press release). Pfizer. 16 November 2021. Archived from the original on 16 November 2021. Retrieved 17 November 2021 – via Business Wire.
  19. ↑ Kimball S (16 November 2021). "Pfizer submits FDA application for emergency approval of Covid treatment pill". CNBC. Archived from the original on 16 November 2021. Retrieved 17 November 2021.
  20. ↑ 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.
  21. ↑ "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. Archived from the original on 5 January 2022. Retrieved 6 January 2022.
  22. ↑ "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. Archived from the original on 11 January 2022. Retrieved 6 January 2022.
  23. ↑ "The Use of Pfizer's Anti-Viral Drug for the Treatment of COVID-19 Has Been Approved". GOV.IL. Archived from the original on 28 December 2021. Retrieved 28 December 2021.
  24. ↑ Reuters (27 December 2021). "S.Korea authorises emergency use of Pfizer's oral coronavirus treatment". Reuters. Archived from the original on 11 January 2022. Retrieved 28 December 2021.
  25. 1 2 Aripaka P (31 December 2021). "Britain approves Pfizer's antiviral COVID-19 pill". Reuters. Archived from the original on 31 December 2021. Retrieved 31 December 2021.
  26. 1 2 "Oral COVID-19 antiviral, Paxlovid, approved by UK regulator" (Press release). Medicines and Healthcare products Regulatory Agency. 31 December 2021. Archived from the original on 11 January 2022. Retrieved 6 January 2022.
  27. 1 2 Bloom J (2 December 2021). "How Does Pfizer's Pavloxid Compare With Ivermectin?". American Council on Science and Health. Archived from the original on 12 December 2021. Retrieved 12 December 2021.
  28. 1 2 Gorski D (15 November 2021). "Pfizer's new COVID-19 protease inhibitor drug is not just 'repackaged ivermectin'". Science-Based Medicine. Archived from the original on 20 December 2021. Retrieved 6 January 2022.
  29. ↑ "Pfizer begins dosing in Phase II/III trial of antiviral drug for Covid-19". Clinical Trials Arena. 2 September 2021. Archived from the original on 5 November 2021. Retrieved 6 January 2022.
  30. ↑ "EPIC-HR: Study of Oral PF-07321332/Ritonavir Compared With Placebo in Nonhospitalized High Risk Adults With COVID-19". clinicaltrials.gov. 19 November 2021. Archived from the original on 5 January 2022. Retrieved 6 January 2022. {{cite journal}}: Cite journal requires |journal= (help)
  31. ↑ "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. Archived from the original on 26 December 2021. Retrieved 25 December 2021 – via Business Wire.
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