Pfizer's PAXLOVID receives FDA approval for adult patients at high risk of progression to severe COVID-19 (2023)

COVID-19 continues to cause a significant burden in the United States, with approximately 14,500 cases reported per week at the end of April 2023;²but most cases are not notified.³Furthermore, data shows that the impact of COVID-19 goes beyond an acute infection; An estimated 10 million to 31 million Americans may experience persistent, recurrent, or new symptoms after the acute phase of COVID-19 infection.⁴,⁵

FDA approval of PAXLOVID is based on full scientific evidence shared by Pfizer, including EPIC safety and efficacy data (Eevaluation ofPhad spunEUinhibition forCOVID-19) clinical development program. This included phase 2/3 EPIC-HR results (Eevaluation ofPhad spunEUinhibition forCOVID-19 inchHalto-Risk, which included unvaccinated, non-hospitalized adults aged 18 years and older with confirmed COVID-19 and at increased risk of developing severe disease. Data showed an 86% reduction in the risk of COVID-19-related hospitalization or death from any cause through day 28 in patients who started treatment with PAXLOVID within five days of symptom onset, compared to placebo. The FDA approval was further supported by the results of a secondary phase 2/3 EPIC-SR endpoint (Eevaluation ofPhad spunEUinhibition forCOVID-19 inchSstandard-Risk, which showed a numerical reduction in hospitalizations or deaths related to COVID-19 from any cause through day 28 in a subgroup of non-hospitalized adults, aged 18 years and older, with confirmed COVID-19 who had . at least one risk factor for progression to severe disease and who has been fully vaccinated. Available safety data have been consistent across participants in the EPIC clinical program, as well as the reported post-approval safety experience of millions of patients prescribed PAXLOVID to date.

Recent real-world studies of PAXLOVID support the efficacy conclusions of Pfizer's EPIC clinical program, providing additional data on the use of PAXLOVID in the post-approval setting of Omicron subline dominance and where high levels of pre-existing immunity occur. These real-world studies also showed that PAXLOVID is effective among vaccinated and unvaccinated high-risk patients.^6,7,8,9,10

Based on the relative risk reduction seen in clinical and real-world data, the FDA provided an estimate in March 2023 that more than 1,500 lives could be saved and 13,000 hospitalizations prevented each week with the use of PAXLOVID in eligible patients.¹¹

At this time, the US government will continue to oversee the distribution of PAXLOVID, and US residents eligible for PAXLOVID will continue to receive the drug free of charge.*

PAXLOVID will remain available to eligible children ages 12-17 (and weighing at least 40 kg), under the existing US. Pfizer continues to collect pediatric data from the ongoing clinical trial, EPIC-Peds (Eevaluation ofPhad spunEUinhibition forCOVID-19 inchpedagogueiatric patients) and intends to submit a supplemental new drug application (sNDA) to support FDA approval of PAXLOVID in children at a future date.

PAXLOVID is currently approved or conditionally or emergency approved in more than 70 countries around the world for the treatment of patients with COVID-19 who are at increased risk of developing serious illness.

*Other administrative fees may apply

About PAXLOVID (nirmatrelvir tablets and ritonavir tablets)

PAXLOVID is a major protease of SARS-CoV-2 (M^pro) (also known as SARS-CoV-2 protease inhibitor 3CL). It was developed to be taken orally so it can be prescribed soon after infection, potentially helping patients avoid serious illness (which can lead to hospitalization and death). Nirmatrelvir, which originates from Pfizer's laboratories, was developed to block the activity of M^pro, an enzyme that the coronavirus needs to replicate. Co-administration with low dose ritonavir helps to slow down the metabolism or breakdown of nirmatrelvir so that it remains active in the body for longer periods at higher concentrations to help fight the virus.

Nirmatrelvir was designed to inhibit viral replication in a phase known as proteolysis, which occurs before viral RNA replication. In preclinical studies, nirmatrelvir showed no evidence of mutagenic interactions with DNA.

Current concerns may be resistant to treatments that work by binding to the spike protein found on the surface of the SARS-CoV-2 virus. However, PAXLOVID acts intracellularly by binding to the highly conserved M^pro(3CL protease) from the SARS-CoV-2 virus to inhibit viral replication. Nirmatrelvir has consistently shownin vitroantiviral activity against Alpha, Beta, Delta, Gamma, Lambda, Mu and Omicron variants BA.1, BA.2, BA.2.12.1, BA.4, BA.4.6, BA.5, BF.7, BQ .1.11 , BQ.1 and XBB.1.5. Efforts are underway to assess activity against newly identified variants as they become available for testing.

PAXLOVID is usually given at the standard dose of 300 mg (two 150 mg tablets) of nirmatrelvir with one 100 mg ritonavir tablet, given twice daily for five days. A standard dose box contains PAXLOVID blister packs, which co-package nirmatrelvir tablets with ritonavir tablets, providing all the doses needed for a full five-day course of treatment. The modified dose for patients with moderate renal impairment (eGFR ≥30 to <60 mL/min) is reduced to 150 mg nirmatrelvir (one 150 mg tablet) with 100 mg ritonavir (one 100 mg tablet), with both pills taken together twice a day. for five days (PAXLOVID is not recommended for patients with severe renal impairment [eGFR <30 ml/min]).

For more information please visitwww.PAXLOVID.com.

Our Commitment to Access

Pfizer is committed to working to ensure equal access to our oral COVID-19 treatment, PAXLOVID, for high-risk patients in need. Pfizer has established a comprehensive strategy in close collaboration with world governments, international global health leaders, including WHO's Access to COVID-19 Tools Accelerator (ACT-A) and global manufacturers to optimize delivery and access to PAXLOVID across the world. world. That includes:

• Multilateral supply agreements: Agreement signed withUNICEFdeliver up to 4 million PAXLOVID courses to 137 low- and middle-income countries; Letter of intent signed withGlobal Fundfor up to 6 million PAXLOVID treatment courses for delivery to 132 Global Fund eligible countries.
• Expanding access to patent-protected medicines in low-income countries:releasedA deal for a healthier world,to support access to PAXLOVID and many other medicines and vaccines in low-income countries. In addition to offering the full portfolio of drugs and vaccines for which we have global nonprofit rights to 45 low-income countries, Pfizer has committed through the agreement to work with country governments and global health organizations to help to address barriers to accessing these drugs and vaccines – such as diagnosis, training, storage and more – to providing PAXLOVID and other drugs to patients who need them in these countries.
• Voluntary license:Signed a voluntary license agreement withMedicines Patent Pool (MPP)for oral treatment with COVID-19 to help expand access, pending country authorization or regulatory approval, to approximately 53% of the world's population. The 35 generic manufacturers will develop generic versions of Pfizer's oral COVID-19 treatment for distribution in 95 low- and lower-middle-income countries and some upper-middle-income countries in sub-Saharan Africa, as well as countries that have transitioned from lower-middle to upper-middle income in the last five years, subject to approval or authorization.

LICE. Recommendation

PAXLOVID is indicated for the treatment of mild to moderate coronavirus disease 2019 (COVID-19) in adults at high risk of progression to severe COVID-19, including hospitalization or death.

Use Constraints

PAXLOVID is not approved for use as pre-exposure or post-exposure prophylaxis for the prevention of COVID-19.

US FDA emergency use authorization statement

US. The Food and Drug Administration (FDA) has issued an Emergency Use Authorization (EUA) for the emergency use of mild to moderate coronavirus disease 2019 (COVID-19) and who are at high risk of progression to severe COVID-19, incl. hospitalization or death.

PAXLOVID is not approved, but is approved for emergency use by the FDA under an EUA, for the treatment of mild to moderate COVID-19 in pediatric patients (12 years of age or older, weighing at least 40 kg) who are at high risk of progression to severe COVID-19, including hospitalization or death. Emergency use of PAXLOVID is authorized only while demonstrating that circumstances exist that justify the emergency use of drugs and biologics during the COVID-19 pandemic pursuant to Section 564(b)(1) of the Act, 21 U.S.C. § 360bbb-3(b)(1), unless the declaration is rescinded or the authorization is earlier revoked.

IMPORTANT SAFETY INFORMATION

WARNING: SIGNIFICANT MEMBERS INTERACTIONS WITH PAXLOVID

• PAXLOVID includes ritonavir, a strong CYP3A inhibitor, which may lead to increased exposure of certain concomitant medications, resulting in potentially serious, life-threatening, or fatal events.
• Before prescribing PAXLOVID: 1) Review all medications taken by the patient to assess possible drug interactions with a strong CYP3A inhibitor such as PAXLOVID, and 2) Determine whether concomitant medications require dose adjustment, discontinuation, and/or additional monitoring
• Consider the benefits of PAXLOVID treatment in terms of reduced hospitalization and death and whether the risk of potential drug interactions for an individual patient can be managed appropriately

PAXLOVID iscontraindicated in patients with a history of clinically significant hypersensitivity reactions(for example, toxic epidermal necrolysis or Stevens-Johnson syndrome) to its active ingredients (nirmatrelvir or ritonavir) or other components of the product. If signs and symptoms of a clinically significant hypersensitivity reaction or anaphylaxis occur, immediately discontinue PAXLOVID and initiate appropriate medication and/or supportive care.

PAXLOVID iscontraindicated with medicinal products that are primarily metabolised by CYP3A and for which elevated concentrations are associated with severe and/or life-threatening reactions, and medicinal products that are strong inducers of CYP3A, in which significantly reduced plasma concentrations of nirmatrelvir or ritonavir may be associated the potential for loss of virological response and possible resistance. There are some other drugs for which concomitant use with PAXLOVID should be avoided and/or dose adjustment, discontinuation or therapeutic monitoring recommended. The drugs listed here are a guide and are not considered to be an exhaustive list of all drugs that may be contraindicated with PAXLOVID. The physician should consult other appropriate resources, such as the interacting drug's prescribing information, for comprehensive dosing or monitoring information with concomitant use of a strong CYP3A inhibitor such as PAXLOVID.

Drugs primarily metabolized by CYP3A for which high concentrations are associated with severe and/or life-threatening reactions:

• Alfa 1-adrenoreceptorantagonista: alfuzosina
• Antianginal: blue water
• Antiarytmika: amiodaron, dronedaron, flecainid, propafenon, quinidina
• Anti-rheumatic: colchicine (in patients with reduced kidney and/or liver function)
• Antipsychotics: lucidone, pimozide
• Agents for benign prostatic hyperplasia: silodosin
• Cardiovascular agents: eplerenone, ivabradine
• Derivados do Ergot: di-hidroergotamin, ergotamin, methylergonovin
• HMG-CoA reductase inhibitors: lovastatin, simvastatin (these drugs may be temporarily discontinued to allow PAXLOVID use)
• Immunosuppressants: voclosporin
• Microsomal triglyceride transfer protein inhibitor: lomitapide
• Migraine medication: eletriptan, ubrogepant
• Mineralocorticoid receptor antagonists: finerenone
• Opioid antagonist: naloxegol
• PDE5 inhibitor: sildenafil (Revatio) when used for pulmonary arterial hypertension
• Beroligende/hypnotika: triazolam, midazolam oral
• Serotonin 1A receptor agonist/serotonin 2A receptor antagonist: flibanserin
• Vasopressin receptor agonist: tolvaptan

Drugs that are strong CYP3A inducers: PAXLOVID cannot be started immediately after discontinuing any of the following drugs due to delay in clearing of the recently discontinued CYP3A inducer:

• Anticancer drugs: apalutamide
• Anticonvulsant: carbamazepine, phenobarbital, primidone, phenytoin
• Antifungals: rifampicin, rifapentine
• Cystic fibrosis transmembrane conductance regulatory enhancers: lumacaftor/ivacaftor
• Herbal products: St. John's wort (Hypericum perforatum)

Risk of serious side effects due to drug interactions:Initiation of PAXLOVID, which contains ritonavir, a potent CYP3A inhibitor, in patients receiving drugs metabolized by CYP3A, or initiation of drugs metabolized by CYP3A in patients already receiving PAXLOVID, may increase plasma concentrations of drugs metabolized by CYP3A. Medicinal products that induce CYP3A may decrease the concentration of PAXLOVID. These interactions can lead to:

• Clinically significant side effects that may lead to serious, life-threatening or life-threatening events due to increased exposure to concomitant medications
• Loss of therapeutic effect of PAXLOVID and possible development of viral resistance

Serious, life-threatening and/or fatal adverse reactions due to drug interactions have been reported in patients treated with PAXLOVID. The most commonly reported concomitant medications resulting in serious adverse events were calcineurin inhibitors (eg, tacrolimus, cyclosporine), followed by calcium channel blockers.

Hepatotoxicity:Elevated liver transaminases, clinical hepatitis, and jaundice have occurred in patients receiving ritonavir. Therefore, care should be taken when administering PAXLOVID to patients withpre-existing liver disease, liver enzyme abnormalities, or hepatitis.

As nirmatrelvir is co-administered with ritonavir, there may be arisk of HIV-1 develops resistance to HIV protease inhibitorsin people with uncontrolled or undiagnosed HIV-1 infection.

The most commonSide effectsin the PAXLOVID group (≥1%) that occurred more frequently than in the placebo group were dysgeusia (5% and <1%, respectively) and diarrhea (3% and 2%, respectively).

The following side effects have been identified during emergency use of PAXLOVID:

Immune system disorders:Anaphylaxis, hypersensitivity reactions
Disorders of the skin and subcutaneous tissue:Toxic epidermal necrolysis, Stevens-Johnson syndrome
Nervous system disorders:Headache
Vascular disorders:Hypertension
Gastrointestinal problems:Abdominal pain, nausea, vomiting
General disorders and administration conditions:Discomfort

PAXLOVID is a strong CYP3A inhibitor and an inhibitor of CYP2D6, P-gp and OATP1B1.Concomitant administration of PAXLOVID with drugs primarily metabolized by CYP3A and CYP2D6 or transported by P-gp or OATP1B1 may result in increased plasma concentrations of these drugs and increase the risk of adverse reactions. Concomitant administration with other CYP3A substrates may require dose adjustment or additional monitoring.

Pregnancy:There are insufficient data available on the use of nirmatrelvir during pregnancy to assess the drug-associated risk of serious birth defects, miscarriage, or adverse maternal or fetal outcomes. Published observational studies of ritonavir use in pregnant women have not identified an increased risk of serious birth defects. Published studies with ritonavir are insufficient to identify a drug-related risk of miscarriage.There are maternal and fetal risks associated with untreated COVID-19 during pregnancy.

Breast-feeding:No data are available on the presence of nirmatrelvir in human or animal milk, effects on the nursing infant, or effects on milk production. A transient decrease in body weight was observed in the lactating offspring of rats receiving nirmarelvir. Limited published data report that ritonavir is present in human milk. There is no information on the effect of ritonavir in breast-feeding infants or on the drug's effect on milk production. The developmental and health benefits of breastfeeding must be considered along with the mother's clinical need for PAXLOVID and any adverse effects of PAXLOVID or the underlying maternal condition on the breastfed infant.

Pregnancy prevention:The use of ritonavir may reduce the effectiveness of combined hormonal contraceptives. Advise patients using combined hormonal contraceptives to use an effective alternative contraceptive method or an additional barrier method of contraception.

Pediatrics:The optimal dose of PAXLOVID has not been established in pediatric patients.

Nirmatrelvir systemic exposure increases in patients with renal impairment with increasing severity of renal impairment. No dose adjustments are recommended for patients with mild renal impairment.Reduce the dose of PAXLOVID in patients with moderate renal impairment(eGFR ≥30 a <60 ml/min).PAXLOVID is not recommended for patients with severe renal impairment(eGFR <30 ml/min)or in patients with end-stage renal disease(eGFR <15 ml/min.).

PAXLOVID is not recommended for patients with severe hepatic impairment(Child-Pugh classe C).

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For consumers:
EUA Fact Sheet for Patients, Parents, and Caregivers

For healthcare professionals:
US Data Sheet for Healthcare Professionals

About Pfizer: Breakthroughs That Change Patients' Lives

At Pfizer, we apply science and our global resources to bring people therapies that significantly extend and improve their lives. We strive to set the standard for quality, safety and value in the discovery, development and manufacture of healthcare products, including innovative medicines and vaccines. Every day, Pfizer colleagues work in developed and emerging markets to advance the wellness, prevention, treatments and cures that challenge the most feared diseases of our time. Aligned with our responsibility as one of the world's leading innovative biopharmaceutical companies, we partner with healthcare providers, governments and local communities to support and expand access to reliable and affordable healthcare around the world. For over 170 years, we've worked to make a difference for everyone who trusts us. We routinely post information that may be important to investors on our website atwww.Pfizer.com. Also, you can visit us to learn more.www.Pfizer.comand follow us on Twitter at @Pfizer and @Pfizer News, LinkedIn, YouTube and like us on Facebook atFacebook.com/Pfizer.

information notice

The information in this publication is as of May 25, 2023. Pfizer undertakes no obligation to update any forward-looking statements contained in this release as a result of new information or future events or developments.

This advisory contains forward-looking information about Pfizer's efforts to combat COVID-19 and PAXLOVID (including the US approval of PAXLOVID for the treatment of mild to moderate COVID-19 in adults at high risk of progression to COVID-19 -19 serious, including hospitalization or death, intent to file a new supplemental drug application to support FDA approval of PAXLOVID in children at a future date, transition to a more traditional US business model, efforts to achieve equitable access, timing expected data readings, regulatory submissions, regulatory approvals or clearances, and anticipated manufacturing, distribution and delivery) that involve significant risks and uncertainties that could cause actual results to differ materially from those expressed or implied by such statements. Risks and uncertainties include, but are not limited to, uncertainties associated with research and development, including the ability to meet anticipated clinical endpoints, start and/or completion dates of clinical trials, regulatory submission dates, regulatory approval dates, and/or or release dates, as well as risks associated with preclinical and clinical data, including the possibility of new adverse preclinical, clinical, or safety data and additional analysis of existing preclinical, clinical, or safety data; the ability to produce clinical or other comparable results, including the efficacy, safety and tolerability profile observed to date, in additional studies or in larger and more diverse populations post-marketing; uncertainties regarding the commercial impact of the EPIC-SR and EPIC-PEP test results; PAXLOVID's ability to remain effective against new virus variants; the risk of experiencing serious and unexpected side effects that have not previously been reported with the use of PAXLOVID; the risk of data from preclinical and clinical trials being subject to different interpretations and evaluations, including during the peer review/publication process, by the wider scientific community and by regulatory authorities; whether regulatory authorities will be satisfied with the design and results of these and any future preclinical and clinical studies; if and when any drug orders or submissions to seek emergency use or conditional marketing authorization for any indications for PAXLOVID or any other Pfizer product or product candidate may be filed in certain jurisdictions and, if obtained, if or when such authorization or emergency use licenses will expire or cease; whether and when regulatory authorities in any jurisdiction can approve applications or submissions for PAXLOVID or any of Pfizer's other products or product candidates that may be pending or submitted will depend on a number of factors, including determining whether the product's benefits outweigh its known risks and determine the effectiveness of the product and, if approved, whether it will be commercially successful; decisions by regulatory authorities affecting labeling or marketing, manufacturing processes, safety and/or other matters that may affect the availability or commercial potential of PAXLOVID or any other Pfizer product or product candidate, including approval or approval of products or therapies developed by other companies; the risk that other companies may produce superior or competitive products; risks related to the availability of raw materials for manufacturing or testing PAXLOVID; capacity or production capacity; the risk that we may not be able to maintain manufacturing capacity or access to logistics or supply channels corresponding to global demand, which would adversely affect our ability to deliver the estimated number of PAXLOVID courses on schedule; if and when additional purchase agreements will be entered into or existing agreements will be concluded or renegotiated; challenges associated with transitioning to PAXLOVID's commercial market; the risk that demand for products is reduced, no longer exists or does not meet expectations, which may lead to excess on-hand and/or in-channel inventory or reduced revenue; uncertainty about the impact of COVID-19 on Pfizer's business, operations and financial results; and competitive development.

A further description of the risks and uncertainties can be found in Pfizer's Annual Report on Form 10-K for the fiscal year ended December 31, 2022 and in its subsequent reports on Form 10-Q, including sections entitled "Risk Factors " and "Forward Looking Information and Factors That May Affect Future Results," as well as in its subsequent reports on Form 8-K, all filed in the US. Securities and Exchange Commission and available atwww.sec.govewww.pfizer.com.

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¹Data from the IQVIA National Prescribing Audit as of May 5, 2023, containing retail pharmacy, mail order, and long-term care channels; US. Department of Health and Human Services data through February 2023, for non-retail channels. Note: This information is an estimate derived using information under license from the following IQVIA information service: National Prescription Audit, for the period January 1, 2022-05. May 2023. IQVIA expressly reserves all rights, including copying, distribution and reproduction rights.
² Covid Data Tracker weekly review. Centers for Disease Control and Prevention. (2023, April 14). Retrieved on April 27, 2023 fromhttps://www.cdc.gov/coronavirus/2019-ncov/covid-data/covidview/index.h ...
³Estimated burden of COVID-19. (2022). Recovered fromhttps://www.cdc.gov/coronavirus/2019-ncov/cases-updates/burden.html.
⁴Davis HE, McCorkell L, Vogel JM, et al. Long COVID: main findings, mechanisms and recommendations. Nature Reviews Microbiology. 2023;21(3):133-46.
⁵Bull-Otterson L, Baca S, Saydah S, et al. Post-COVID Conditions Among Adult COVID-19 Survivors Aged 18-64 and ≥ 65 Years - United States, March 2020 - November 2021. Morbidity and Mortality Weekly Report. 2022;71(21):713-17.
⁶Lewnard JA, McLaughlin JM, Malden D, et al. Efficacy of nirmatrelvir-ritonavir against hospitalization or death: a cohort study in a large US healthcare system. Lancet ID:https://doi.org/10.1016/S1473-3099(23)00118-4
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⁸Aggarwal NR, Molina KC, Beaty LE, et al. Real-world use of nirmarelvir-ritonavir in outpatients with COVID-19 in the era of omicron variants including BA.4 and BA.5 in Colorado, USA: a retrospective cohort study. The Lancet Infectious Diseases 2023. DOI:https://doi.org/10.1016/S1473-3099(23)00011-7.
⁹Shah MM, Joyce B, Plumb ID, et al. Paxlovid associated with reduced hospitalization rate among adults with COVID-19—United States, April–September 2022. MMWR Morb Mortal Wkly Rep 2022;71:1531–1537. IT HURTS:http://dx.doi.org/10.15585/mmwr.mm7148e2.
¹⁰Dryden-Peterson S, Kim A, Kim AY, Caniglia EC, Lennes IT, Patel R, Gainer L, Dutton L, Donahue E, Gandhi RT, Baden LR, Woolley AE. Nirmatrelvir Plus Ritonavir for Early COVID-19 in a Large US Health System: A Population-Based Cohort Study. Ann Intern Med. 2023 january;176(1):77-84. doi: 10.7326/M22-2141. Epub Dec 13, 2022 PMID: 36508742; PMCID: PMC9753458.
¹¹US. Food and Drug Administration. Treatment of mild to moderate COVID-19 in adults at high risk of progression to severe COVID-19, including hospitalization or death on the Antimicrobial Drugs Advisory Committee. Informative document. Reference data for January 2023. Available at:March 16, 2023 Antimicrobial Substances Advisory Committee meeting (fda.gov). Accessed on: May 4, 2023.

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