ADVERSE REACTIONS SECTION.

Side Effects Adverse events have been reported with sotrovimab [see Full EUA Prescribing Information, Overall Safety Summary (6.1)].Additional adverse events associated with sotrovimab may become apparent with more widespread use.

RENAL IMPAIRMENT SUBSECTION.

11.5Renal Impairment No clinical trials have been conducted to evaluate the effects of renal impairment on the PK of sotrovimab. Sotrovimab is not eliminated intact in the urine, thus renal impairment is not expected to affect the exposure of sotrovimab.

SPL UNCLASSIFIED SECTION.

AUTHORIZED USE The U.S. Food and Drug Administration (FDA) has issued an Emergency Use Authorization (EUA) to permit the emergency use of the unapproved product sotrovimab for the treatment of mild-to-moderate coronavirus disease 2019 (COVID-19) in adults and pediatric patients (12 years of age and older weighing at least 40 kg) with positive results of direct SARS-CoV-2 viral testing, and who are at high risk for progression to severe COVID-19, including hospitalization or death.

STORAGE AND HANDLING SECTION.

Storage Refrigerate unopened vials at 2C to 8C (36F to 46F) in original carton. Do not freeze or shake. Protect from light.

ANIMAL PHARMACOLOGY & OR TOXICOLOGY SECTION.

17ANIMAL PHARMACOLOGIC AND EFFICACY DATA In Syrian Golden hamster model of SARS-CoV-2 infection, antiviral activity was demonstrated using single dose of sotrovimab which was administered intraperitoneally at 24- or 48-hours prior to infection. Animals receiving mg/kg or more of the antibody showed significant improvement in body weight loss and significantly decreased total lung SARS-CoV-2 viral RNA compared to vehicle only and control antibody-treated animals. Levels of virus in the lung (as measured by TCID50) were significantly decreased versus controls in hamsters receiving 0.5 mg/kg or more of the antibody.Protection was also observed in the Syrian Golden hamster model using the SARS-CoV-2 B.1.351 (Beta, South Africa origin) variant. Significant reductions in total and replication competent virus were observed on Day post-infection in animals receiving single intraperitoneal dose of 0.5, 2, 5, or 15 mg/kg sotrovimab compared to isotype control antibody-treated animals.

CLINICAL PHARMACOLOGY SECTION.

14CLINICAL PHARMACOLOGY 14.1Mechanism of Action Sotrovimab is recombinant human IgG1-kappa mAb that binds to conserved epitope on the spike protein receptor binding domain of SARS-CoV-2 with dissociation constant KD 0.21 nM) but does not compete with human ACE2 receptor binding (IC50 value >33.6 nM [5 ug/mL]). Sotrovimab inhibits an undefined step that occurs after virus attachment and prior to fusion of the viral and cell membranes. The Fc domain of sotrovimab includes M428L and N434S amino acid substitutions (LS modification) that extend antibody half-life, but do not impact wild-type Fc-mediated effector functions in cell culture. 14.2Pharmacokinetics In COMET-ICE, the geometric mean Cmax following 1 hour IV infusion was 117.6 ug/mL (N 290, CV% 46.5), and the geometric mean Day 29 concentration was 24.5 ug/mL (N 372, CV% 42.4) from all subjects with an available Day 29 sample.DistributionThe mean steady-state volume of distribution of sotrovimab was 8.1 L.MetabolismSotrovimab is recombinant human IgG1 monoclonal antibody degraded by proteolytic enzymes which are widely distributed in the body and not restricted to hepatic tissue.EliminationThe mean systemic clearance was 125 mL/day with median terminal half-life of approximately 49 days.Specific PopulationsThe effect of different covariates (e.g., age, sex, race, body weight, disease severity, hepatic impairment) on the PK of sotrovimab is unknown. Renal impairment is not expected to impact the PK of sotrovimab since mAbs with molecular weight >69 kDa do not undergo renal elimination. Similarly, dialysis is not expected to impact the PK of sotrovimab.

CLINICAL STUDIES SECTION.

18CLINICAL TRIAL RESULTS AND SUPPORTING DATA FOR EUA The clinical data supporting this EUA are based on the analysis of the Phase 1/2/3 COMET-ICE trial (NCT 04545060). COMET-ICE is an ongoing, randomized, double-blind, placebo-controlled trial studying sotrovimab for the treatment of subjects with mild-to-moderate COVID-19 (subjects with COVID-19 symptoms who are not hospitalized). Eligible subjects were 18 years of age and older with at least one of the following comorbidities: diabetes, obesity (BMI >30), chronic kidney disease, congestive heart failure, chronic obstructive pulmonary disease, or moderate to severe asthma, or were 55 years of age and older regardless of comorbidities. The study included symptomatic patients with SARS-CoV-2 infection as confirmed by local laboratory tests and/or point of care tests and symptom onset within days of enrollment. Subjects with severe COVID-19 requiring supplemental oxygen or hospitalization and severely immunocompromised patients were excluded from the trial.A total of 1,057 eligible subjects were randomized to receive single 500-mg infusion of sotrovimab (n 528) or placebo (n 529) over hour (Intent to Treat [ITT] population at Day 29). At baseline, the median age was 53 years (range:17 to 96); 20% of subjects were 65 years of age or older and 11% were over 70 years of age; 46% of subjects were male; 87% were White, 8% Black or African American, 4% Asian, 65% Hispanic or Latino. Fifty-nine percent of subjects received sotrovimab or placebo within days of COVID-19 symptom onset and 41% within to days. The four most common pre-defined risk factors or comorbidities were obesity (63%), 55 years of age or older (47%), diabetes requiring medication (22%), and moderate-to-severe asthma (17%). Overall, baseline demographic and disease characteristics were well balanced between the treatment arms.The primary endpoint, progression of COVID-19 at Day 29, was reduced by 79% (adjusted relative risk reduction) in recipients of sotrovimab versus placebo. Table provides the results for the primary and key secondary endpoint of COMET-ICE.Table 3. Efficacy Results in Adults with Mild-to-Moderate COVID-19 at Day 29Sotrovimabn 528Placebon 529Progression of COVID-19 (defined as hospitalization for >24 hours for acute management of any illness or death from any cause) (Day 29)a Proportion (n, %)6 (1%)30 (6%)Adjusted Relative Risk Reduction (95% CI)79%(50%, 91%)All-cause mortality (up to Day 29)Proportion (n, %)02 (<1%) The determination of primary efficacy was based on planned interim analysis of 583 patients, which had similar findings to those seen in the full population above. The adjusted relative risk reduction was 85% with 97.24% CI of (44%, 96%) and p-value 0.002.Within the subset of the ITT population who had central laboratory confirmed, virologically quantifiable nasopharyngeal swab at Day and Day (n 639), the mean decline from baseline in viral load at Day was greater in subjects treated with sotrovimab (-2.610 log10 copies/mL) compared to that in subjects treated with placebo (-2.358); mean difference -0.251, 95% CI: (-0.415, -0.087).. The determination of primary efficacy was based on planned interim analysis of 583 patients, which had similar findings to those seen in the full population above. The adjusted relative risk reduction was 85% with 97.24% CI of (44%, 96%) and p-value 0.002.

CONTRAINDICATIONS SECTION.

Contraindications Sotrovimab is contraindicated in patients who have history of anaphylaxis to sotrovimab or to any of the excipients in the formulation.

DESCRIPTION SECTION.

13PRODUCT DESCRIPTION. Sotrovimab is human immunoglobulin G-1 (IgG1-kappa) monoclonal antibody consisting of identical light chain (LC) polypeptides composed of 214 amino acids each and identical heavy chain (HC) polypeptides, each composed of 457 amino acids. Sotrovimab is produced by Chinese Hamster Ovary cell line and has molecular weight of approximately 149 kDa.Sotrovimab injection is sterile, preservative-free, clear, colorless or yellow to brown solution supplied in single-dose vial for IV infusion after dilution.Each mL contains sotrovimab (62.5 mg), L-histidine (1.51 mg), L-histidine monohydrochloride (2.15 mg), L-methionine (0.75 mg), polysorbate 80 (0.4 mg), and sucrose (70 mg). The solution of sotrovimab has pH of 6.0.

DOSAGE & ADMINISTRATION SECTION.

Dosing Patient Selection and Treatment InitiationThis section provides essential information on the unapproved product sotrovimab, for the treatment of mild-to-moderate COVID-19 in adults and pediatric patients (12 years of age and older weighing at least 40 kg) with positive results of direct SARS-CoV-2 viral testing, and who are at high risk for progression to severe COVID-19, including hospitalization or death [see Limitations of Authorized Use].The following medical conditions or other factors may place adults and pediatric patients (12 to 17 years of age weighing at least 40 kg) at higher risk for progression to severe COVID-19:oOlder age (for example >=65 years of age)oObesity or being overweight (for example, adults with BMI >25 kg/m2, or if 12 to 17 years of age, have BMI >=85th percentile for their age and gender based on CDC growth charts, https://www.cdc.gov/growthcharts/clinicalcharts.htm)oPregnancyoChronic kidney diseaseoDiabetesoImmunosuppressive disease or immunosuppressive treatmentoCardiovascular disease (including congenital heart disease) or hypertension oChronic lung diseases (for example, chronic obstructive pulmonary disease, asthma [moderate-to-severe], interstitial lung disease, cystic fibrosis, and pulmonary hypertension)oSickle cell diseaseoNeurodevelopmental disorders (for example, cerebral palsy) or other conditions that confer medical complexity (for example, genetic or metabolic syndromes and severe congenital anomalies)oHaving medical-related technological dependence (for example, tracheostomy, gastrostomy, or positive pressure ventilation [not related to COVID 19])Other medical conditions or factors (for example, race or ethnicity) may also place individual patients at high risk for progression to severe COVID-19, and authorization of sotrovimab under the EUA is not limited to the medical conditions or factors listed above. For additional information on medical conditions and factors associated with increased risk for progression to severe COVID-19, see the CDC website: https://www.cdc.gov/coronavirus/2019-ncov/need-extra-precautions/people-with-medical-conditions.html. Healthcare providers should consider the benefit-risk for an individual patient.DosageThe dosage of sotrovimab for the treatment of mild-to-moderate COVID-19 in adults and pediatric patients (12 years of age and older weighing at least 40 kg) is 500 mg of sotrovimab. Sotrovimab should be given as soon as possible after positive results of direct SARS-CoV-2 viral testing and within 10 days of symptom onset. Sotrovimab must be diluted and administered as single IV infusion over 30 minutes.Dosage Adjustment in Specific PopulationsNo dosage adjustment is recommended based on renal impairment, during pregnancy or while lactating [see Full EUA Prescribing Information, Use in Specific Populations (11)].. oOlder age (for example >=65 years of age). oObesity or being overweight (for example, adults with BMI >25 kg/m2, or if 12 to 17 years of age, have BMI >=85th percentile for their age and gender based on CDC growth charts, https://www.cdc.gov/growthcharts/clinicalcharts.htm). oPregnancy. oChronic kidney disease. oDiabetes. oImmunosuppressive disease or immunosuppressive treatment. oCardiovascular disease (including congenital heart disease) or hypertension oChronic lung diseases (for example, chronic obstructive pulmonary disease, asthma [moderate-to-severe], interstitial lung disease, cystic fibrosis, and pulmonary hypertension). oSickle cell disease. oNeurodevelopmental disorders (for example, cerebral palsy) or other conditions that confer medical complexity (for example, genetic or metabolic syndromes and severe congenital anomalies). oHaving medical-related technological dependence (for example, tracheostomy, gastrostomy, or positive pressure ventilation [not related to COVID 19]).

DOSAGE FORMS & STRENGTHS SECTION.

3DOSAGE FORMS AND STRENGTHS Sotrovimab is sterile, preservative-free, clear, colorless or yellow to brown solution available as:oInjection: 500-mg/8-mL (62.5-mg/mL) solution in single-dose vial for IV infusion after dilution.. oInjection: 500-mg/8-mL (62.5-mg/mL) solution in single-dose vial for IV infusion after dilution.

DRUG INTERACTIONS SECTION.

10DRUG INTERACTIONS Clinical drug-drug interaction studies have not been performed with sotrovimab. Sotrovimab is not renally excreted or metabolized by cytochrome P450 (CYP) enzymes; therefore, interactions with concomitant medications that are renally excreted or that are substrates, inducers, or inhibitors of CYP enzymes are unlikely.

GERIATRIC USE SECTION.

11.4Geriatric Use Of the 528 patients receiving sotrovimab in COMET-ICE, 20% were 65 years of age and older and 11% were over 70 years of age. The difference in pharmacokinetics (PK) of sotrovimab in geriatric patients compared to younger patients has not been quantified.

HEPATIC IMPAIRMENT SUBSECTION.

11.6Hepatic Impairment No clinical trials have been conducted to evaluate the effects of hepatic impairment on the PK of sotrovimab. The impact of hepatic impairment on the PK of sotrovimab is unknown.

HOW SUPPLIED SECTION.

19HOW SUPPLIED/STORAGE AND HANDLING How SuppliedSotrovimab injection 500 mg (62.5 mg/mL) is sterile, preservative-free, clear, colorless or yellow to brown solution supplied in carton containing one single-dose glass vial with rubber vial stopper (not made with natural rubber latex) and flip-off cap (NDC 0173-0901-86).Storage and HandlingSotrovimab is preservative-free. Discard unused portion.Store unopened vials refrigerated at 2C to 8C (36F to 46F) in original carton. Do not freeze or shake. Protect from light.The solution of sotrovimab in the vial is preservative-free and requires dilution prior to administration. The diluted infusion solution of sotrovimab should be administered immediately. If immediate administration is not possible, store the diluted infusion solution for up to 24 hours at refrigerated temperature (2C to 8C [36F to 46F]) or up to hours at room temperature (up to 25C [up to 77F]) including transportation and infusion time. If refrigerated, allow the infusion solution to equilibrate to room temperature for approximately 15 minutes prior to administration.

INFORMATION FOR PATIENTS SECTION.

FACT SHEET FOR PATIENTS, PARENTS, AND CAREGIVERS Emergency Use Authorization (EUA) of Sotrovimab for the Treatment of Coronavirus Disease 2019 (COVID-19)You are being given medicine called sotrovimab for the treatment of coronavirus disease 2019 (COVID-19). This Fact Sheet contains information to help you understand the potential risks and potential benefits of taking sotrovimab, which you may receive.Receiving sotrovimab may benefit certain people with COVID-19.Read this Fact Sheet for information about sotrovimab. Talk to your healthcare provider if you have any questions. It is your choice to receive sotrovimab or stop it at any time.What is COVID-19COVID-19 is caused by virus called coronavirus. People can get COVID-19 through contact with another person who has the virus.COVID-19 illnesses have ranged from very mild (including some with no reported symptoms) to severe, including illness resulting in death. While information so far suggests that most COVID-19 illness is mild, serious illness can happen and may cause other medical conditions to become worse. People of all ages with severe, long-lasting (chronic) medical conditions like heart disease, lung disease, diabetes, for example, and other conditions including obesity, seem to be at higher risk of being hospitalized for COVID-19. Older age, with or without other conditions, also places people at higher risk of being hospitalized for COVID-19.What are the symptoms of COVID-19The symptoms of COVID-19 are fever, cough, and shortness of breath, which may appear to 14 days after exposure. Serious illness, including breathing problems, can occur and may cause your other medical conditions to become worse.What is sotrovimabSotrovimab is an investigational medicine used to treat mild-to-moderate symptoms of COVID-19 in adults and children (12 years of age and older weighing at least 88 pounds [40 kg]) with positive results of direct SARS-CoV-2 viral testing, and who are at high risk of progression to severe COVID-19, including hospitalization or death. Sotrovimab is investigational because it is still being studied. There is limited information about the safety and effectiveness of using sotrovimab to treat people with mild-to-moderate COVID-19.The U.S. Food Drug Administration (FDA) has authorized the emergency use of sotrovimab for the treatment of COVID-19 under an Emergency Use Authorization (EUA). For more information on EUA, see the What is an Emergency Use Authorization (EUA) section at the end of this Fact Sheet.Who should not receive sotrovimabDo not take sotrovimab if you have had serious allergic reaction to sotrovimab or to any of the ingredients in sotrovimab.What are the ingredients in sotrovimabActive ingredient: sotrovimabInactive ingredients: L-histidine, L-histidine monohydrochloride, L-methionine, polysorbate 80, and sucroseWhat should tell my healthcare provider before receive sotrovimabTell your healthcare provider about all of your medical conditions, including if you:oHave any allergiesoHave had serious allergic reaction to sotrovimab or to any of the ingredients in sotrovimaboAre pregnant or plan to become pregnantoAre breastfeeding or plan to breastfeedoHave any serious illnessesoAre taking any medicines (prescription, over-the-counter, vitamins, or herbal products)How will receive sotrovimaboYou will receive dose of sotrovimab.oSotrovimab will be given to you through vein (intravenous or IV infusion) over 30 minutes.oYou will be observed by your healthcare provider for at least hour after you receive sotrovimab.What are the important possible side effects of sotrovimabPossible side effects of sotrovimab are:oAllergic reactions. Allergic reactions can happen during and after infusion with sotrovimab. Tell your healthcare provider right away if you get any of the following signs and symptoms of allergic reactions: fever; difficulty breathing; low oxygen level in your blood; chills; tiredness; fast or slow heart rate; chest discomfort or pain; weakness; confusion; nausea; headache; shortness of breath; low or high blood pressure; wheezing; swelling of your lips, face, or throat; rash including hives; itching; muscle aches; dizziness; feeling faint; and sweating.The side effects of getting any medicine through vein may include brief pain, bleeding, bruising of the skin, soreness, swelling, and possible infection at the infusion site.These are not all the possible side effects of sotrovimab. Not many people have been given sotrovimab. Serious and unexpected side effects may happen. Sotrovimab is still being studied, so it is possible that all of the risks are not known at this time.It is possible that sotrovimab could interfere with your bodys own ability to fight off future infection of SARS-CoV-2. Similarly, sotrovimab may reduce your bodys immune response to vaccine for SARS-CoV-2. Specific studies have not been conducted to address these possible risks. Talk to your healthcare provider if you have any questions.What other treatment choices are thereLike sotrovimab, FDA may allow for the emergency use of other medicines to treat people with COVID-19. Go to https://www.fda.gov/emergency-preparedness-and-response/mcm-legal-regulatory-and-policy-framework/emergency-use-authorization for information on the emergency use of other medicines that are not approved by FDA to treat people with COVID-19. Your healthcare provider may talk with you about clinical trials for which you may be eligible.It is your choice to be treated or not to be treated with sotrovimab. Should you decide not to receive sotrovimab, or stop it at any time, it will not change your standard medical care.What if am pregnant or breastfeedingThere is no experience treating pregnant women or breastfeeding mothers with sotrovimab. For mother and unborn baby, the benefit of receiving sotrovimab may be greater than the risk from the treatment. If you are pregnant or breastfeeding, discuss your options and specific situation with your healthcare provider.How do report side effects with sotrovimabTell your healthcare provider right away if you have any side effects that bother you or do not go away.Report side effects to FDA MedWatch at www.fda.gov/medwatch or call 1-800-FDA-1088, or call the GSK COVID Contact Center at 1-866-GSK-COVID (866-475-2684).How can learn moreoAsk your healthcare provideroVisit www.sotrovimabinfo.comoCall the GSK COVID Contact Center at 1-866-GSK-COVID (866-475-2684)oVisit https://www.covid19treatmentguidelines.nih.gov/oVisit https://combatcovid.hhs.gov/i-have-covid-19-now/available-covid-19-treatment-optionsoContact your local or state public health departmentWhat is an Emergency Use Authorization (EUA)The FDA has made sotrovimab available under an emergency access mechanism called an EUA. The EUA is supported by Secretary of Health and Human Service (HHS) declaration that circumstances exist to justify the emergency use of drugs and biological products during the COVID-19 pandemic.Sotrovimab has not undergone the same type of review as an FDA-approved medicine. In issuing an EUA under the COVID-19 public health emergency, the FDA must determine, among other things, that based on the totality of scientific evidence available, it is reasonable to believe that the product may be effective for diagnosing, treating, or preventing COVID-19, or serious or life-threatening disease or condition caused by COVID-19; that the known and potential benefits of the product, when used to diagnose, treat, or prevent such disease or condition, outweigh the known and potential risks of such product; and that there are no adequate, approved and available alternatives. All of these criteria must be met to allow for the medicine to be used in the treatment of patients during the COVID-19 pandemic.The EUA for sotrovimab is in effect for the duration of the COVID-19 declaration justifying emergency use of these medicines, unless terminated or revoked (after which the products may no longer be used). Manufactured by GlaxoSmithKline LLC Philadelphia, PA 19112, U.S. License No. 1727Distributed by GlaxoSmithKline Research Triangle Park, NC 27709(C)2021 GSK group of companies or its licensor.STR:2FS-PRevised: November 2021. oHave any allergies. oHave had serious allergic reaction to sotrovimab or to any of the ingredients in sotrovimab. oAre pregnant or plan to become pregnant. oAre breastfeeding or plan to breastfeed. oHave any serious illnesses. oAre taking any medicines (prescription, over-the-counter, vitamins, or herbal products). oYou will receive dose of sotrovimab.. oSotrovimab will be given to you through vein (intravenous or IV infusion) over 30 minutes.. oYou will be observed by your healthcare provider for at least hour after you receive sotrovimab.. oAllergic reactions. Allergic reactions can happen during and after infusion with sotrovimab. Tell your healthcare provider right away if you get any of the following signs and symptoms of allergic reactions: fever; difficulty breathing; low oxygen level in your blood; chills; tiredness; fast or slow heart rate; chest discomfort or pain; weakness; confusion; nausea; headache; shortness of breath; low or high blood pressure; wheezing; swelling of your lips, face, or throat; rash including hives; itching; muscle aches; dizziness; feeling faint; and sweating.. oAsk your healthcare provider. oVisit www.sotrovimabinfo.com. oCall the GSK COVID Contact Center at 1-866-GSK-COVID (866-475-2684). oVisit https://www.covid19treatmentguidelines.nih.gov/. oVisit https://combatcovid.hhs.gov/i-have-covid-19-now/available-covid-19-treatment-options. oContact your local or state public health department.

LACTATION SECTION.

11.2Lactation Risk SummaryThere are no available data on the presence of sotrovimab in human or animal milk, the effects on the breastfed infant, or the effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mothers clinical need for sotrovimab and any potential adverse effects on the breastfed infant from sotrovimab or from the underlying maternal condition. Individuals with COVID-19 who are breastfeeding should follow practices according to clinical guidelines to avoid exposing the infant to COVID-19.

MECHANISM OF ACTION SECTION.

14.1Mechanism of Action Sotrovimab is recombinant human IgG1-kappa mAb that binds to conserved epitope on the spike protein receptor binding domain of SARS-CoV-2 with dissociation constant KD 0.21 nM) but does not compete with human ACE2 receptor binding (IC50 value >33.6 nM [5 ug/mL]). Sotrovimab inhibits an undefined step that occurs after virus attachment and prior to fusion of the viral and cell membranes. The Fc domain of sotrovimab includes M428L and N434S amino acid substitutions (LS modification) that extend antibody half-life, but do not impact wild-type Fc-mediated effector functions in cell culture.

MICROBIOLOGY SECTION.

15MICROBIOLOGY/RESISTANCE INFORMATION Antiviral ActivityThe neutralization activity of sotrovimab against SARS-CoV-2 (isolate USA WA1/2020) was measured in concentration response model using cultured Vero E6 cells. Sotrovimab neutralized SARS-CoV-2 with an average EC50 value of 0.67 nM (100.1 ng/mL) and an average EC90 value of 1.2 nM (186.3 ng/mL).Sotrovimab demonstrated cell culture FcR activation using Jurkat reporter cells expressing FcRIIa (low-affinity R131 and high affinity H131 alleles), FcRIIIa (low-affinity F158 and high-affinity V158 alleles) and FcRIIb. Sotrovimab exhibited antibody-dependent cell-mediated cytotoxicity (ADCC) in cell culture using isolated human natural killer (NK) cells following engagement with target cells expressing spike protein. Sotrovimab also elicited antibody-dependent cellular phagocytosis (ADCP) in cell-based assays using CD14+ monocytes targeting cells expressing spike protein.Antibody Dependent Enhancement (ADE) of InfectionThe risk that sotrovimab could mediate viral uptake and replication by immune cells was studied in U937 cells, primary human monocytic dendritic cells, and peripheral blood mononuclear cells. This experiment did not demonstrate productive viral infection in immune cells exposed to SARS-CoV-2 in the presence of concentrations of sotrovimab from 1-fold down to 1000-fold below the EC50 value.The potential for ADE was also evaluated in hamster model of SARS-CoV-2 using sotrovimab. Intraperitoneal administration prior to inoculation resulted in dose-dependent improvement in all measured outcomes (body weight, total viral RNA in the lungs, or infectious virus levels based on TCID50 measurements). No evidence of enhancement of disease was observed at any dose evaluated, including sub-neutralizing doses down to 0.05 mg/kg. Antiviral ResistanceThere is potential risk of treatment failure due to the development of viral variants that are resistant to sotrovimab. Prescribing healthcare providers should choose an authorized therapeutic option with activity against circulating SARS-CoV-2 variants in their state. SARS-CoV-2 variant frequency data for states and jurisdictions can be accessed on the CDC website .https://www.cdc.gov/coronavirus/2019-ncov/cases-updates/variant-proportions.html.An E340A amino acid substitution in the spike protein emerged in cell culture selection of resistant virus and had >100-fold reduction in activity in pseudotyped virus-like particle (VLP) assay. This substitution is in the conserved epitope of sotrovimab, which is comprised of 23 amino acids. pseudotyped VLP assessment in cell culture showed that epitope amino acid substitutions P337H/L/R/T, E340A/K/G, and K356T conferred reduced susceptibility to sotrovimab based on observed fold-increase in EC50 value shown in parentheses: E340K (>297), P337R (>276), P337L (180), E340A (>100), E340G (27), P337H (7.5), K356T (5.90), and P337T (5.4). The presence of the highly prevalent D614G substitution, either alone or in combination, did not alter neutralization of sotrovimab. Pseudotyped VLP assessments indicate that sotrovimab retains activity against the B.1.1.7 (Alpha, UK origin: H69-, V70-, Y144-, N501Y, A570D, D614G, P681H, T716I, S982A, D1118H; 2.3-fold change in EC50 value), B.1.351 (Beta, South Africa origin: L18F, D80A, D215G, R246I, K417N, E484K, N501Y, D614G, A701V; 0.6-fold change in EC50 value), P.1 (Gamma, Brazil origin: L18F, T20N, P26S, D138Y, R190S, K417T, E484K, N501Y, D614G, H655Y, T1027I, V1176F; 0.35-fold change in EC50 value), B.1.427/B.1.429 (Epsilon, California origin: S13I, W152C, L452R, D614G; 0.7-fold change in EC50 value), B.1.526 (Iota, New York origin: L5F, T95I, D253G, E484K, D614G, A701V; 0.6-fold change in EC50 value), B.1.617.1 (Kappa, India origin: T95I, G142D, E154K, L452R, E484Q, D614G, P681R, Q1071H; 0.7-fold change in EC50 value), B.1.617.2 (Delta, India origin: T19R, G142D, E156G, F157-, R158-, L452R, T478K, D614G, P681R, D950N; 1-fold change in EC50 value), AY.1 (Delta Plus, India origin: T19R, T95I, G142D, E156G, F157-, R158-, W258L, K417N, L452R, T478K, D614G, P681R, D950N; 1.1-fold change in EC50 value), AY.2 (Delta Plus, India origin: T19R, V70F, G142D, E156G, F157-, R158-, A222V, K417N, L452R, T478K, D614G, P681R, D950N; 1.3-fold change in EC50 value), C.37 (Lambda, Peru origin: G75V, T76I, del246-252, L452Q, F490S, T859N; 1.5-fold change in EC50 value), B.1.621 (Mu, Colombia origin: T95I, Y144T, Y145S, ins146N, R346K, E484K, N501Y, D614G, P681H, D950N; 1.3-fold change in EC50 value), and B.1.1.529 (Omicron, South Africa origin: A67V, del69-70, T95I, G142D, del143-145, del211, L212I, ins214EPE, G339D, S371L, S373P, S375F, K417N, N440K, G446S, S477N, T478K, E484A, Q493R, G496S, Q498R, N501Y, Y505H, T547K, D614G, H655Y, N679K, P681H, N764K, D796Y, N856K, Q954H, N969K, L981F; 2.7-fold change in EC50 value) variant spike proteins (Table 1). Microneutralization data using authentic SARS-CoV-2 variant viruses indicate that sotrovimab retains activity against the B.1.1.7 (Alpha, UK origin; 3-fold change in EC50 value), B.1.351 (Beta, South Africa origin; 1.2-fold change in EC50 value), P.1 (Gamma, Brazil origin; 1.6-fold change in EC50 value), B.1.617.1 (Kappa, India origin; 0.9-fold change in EC50 value), and B.1.617.2 (Delta, India origin; 0.4-fold change in EC50 value) variants (Table 2).Table 1: Pseudotyped Virus-Like Particle Neutralization Data for SARS-CoV-2 Variant Substitutions with Sotrovimaba Pseudotyped VSV-luc expressing variant spike protein was tested. The following changes from wild-type spike protein are found in the variant: del69-70, del144, N501Y, A570D, D614G, P681H, T716I, S982A, D1118H. No change: <5-fold reduction in susceptibility. Pseudotyped VSV-luc expressing variant spike protein was tested. The following changes from wild-type spike protein are found in the variant: L18F, D80A, D215G, R246I, K417N, E484K, N501Y, A701V. Pseudotyped VSV-luc expressing variant spike protein was tested. The following changes from wild-type spike protein are found in the variant: L18F, T20N, P26S, D138Y, R190S, K417T, E484K, N501Y, D614G, H655Y, T1027I, V1176F. Pseudotyped VSV-luc expressing variant spike protein was tested. The following changes from wild-type spike protein are found in the variant: S13I, W152C, L452R, D614G. Not all isolates of the New York lineage harbor the E484K substitution (as of February 2021). Pseudotyped VSV-luc expressing variant spike protein was tested. The following changes from wild-type spike protein are found in the variant: L5F, T95I, D253G, E484K, D614G, A701V. Pseudotyped VSV-luc expressing variant spike protein was tested. The following changes from wild-type spike protein are found in the variant: T95I, G142D, E154K, L452R, E484Q, D614G, P681R, Q1071H. Pseudotyped VSV-luc expressing variant spike protein was tested. The following changes from wild-type spike protein are found in the variant: T19R, G142D, E156G, del157-158, L452R, T478K, D614G, P681R, D950N. Commonly known as Delta plus. Pseudotyped VSV-luc expressing variant spike protein was tested. The following changes from wild-type spike protein are found in the variant: AY.1 T19R, T95I, G142D, E156G, del157- 158, W258L, K417N, L452R, T478K, D614G, P681R, D950N; AY.2. T19R, V70F, G142D, E156G, del157-158, A222V, K417N, L452R, T478K, D614G, P681R, D950N. Pseudotyped VSV-luc expressing variant spike protein was tested. The following changes from wild-type spike protein are found in the variant: G75V, T76I, del246-252, L452Q, F490S, T859N. Pseudotyped VSV- luc expressing variant spike protein was tested. The following changes from wild-type spike protein are found in the variant: T95I, Y144T, Y145S, ins146N, R346K, E484K, N501Y, D614G, P681H, D950N. Pseudotyped VSV-luc expressing variant spike protein was tested. The following changes from wild-type spike protein are found in the variant: A67V, del69-70, T95I, G142D, del143-145, del211, L212I, ins214EPE, G339D, S371L, S373P, S375F, K417N, N440K, G446S, S477N, T478K, E484A, Q493R, G496S, Q498R, N501Y, Y505H, T547K, D614G, H655Y, N679K, P681H, N764K, D796Y, N856K, Q954H, N969K, L981F.Lineage with Spike Protein SubstitutionCountry First IdentifiedWHO NomenclatureKey Substitutions TestedFold Reduction in SusceptibilityB.1.1.7UKAlphaN501Ya No changeb B.1.351South AfricaBetaK417N E484K N501Yc No changeb P.1BrazilGammaK417T E484K N501Yd No changeb B.1.427/B.1.429USA (California)EpsilonL452Re No changeb B.1.526f USA (New York)IotaE484Kg No changeb B.1.617.1IndiaKappaL452R E484Qh No changeb B.1.617.2IndiaDeltaL452R T478Ki No changeb AY.1/AY.2j IndiaDelta [+K417N]L452R T478K K417Nk No changeb C.37PeruLambdaL452Q F490Sl No changeb B.1.621ColombiaMuR346K E484K, N501Ym No changeb B.1.1.529/BA.1South AfricaOmicronG339D S371L S373P S375F K417N N440K G446S S477N T478K E484A Q493R G496S Q498R N501Y Y505Hn No changeb Table 2: Authentic SARS-CoV-2 Neutralization Data for SARS-CoV-2 Variant Substitutions for Sotrovimaba For variants with more than one substitution of concern, only the one(s) with the greatest impact on activity is (are) listed. No change: <5-fold reduction in susceptibility.SARS-CoV-2 LineageCountry First IdentifiedWHO NomenclatureKey Substitutionsa Fold Reduction in SusceptibilityB.1.1.7UKAlphaN501YNo changeb B.1.351South AfricaBetaK417N E484K N501YNo changeb P.1BrazilGammaK417T E484K N501YNo changeb B.1.617.1IndiaKappaL452R E484QNo changeb B.1.617.2IndiaDeltaL452R T478KNo changeb Limited nucleotide sequencing data from total of 539 COMET-ICE subjects indicated that 36 subjects (16 treated with placebo and 20 treated with sotrovimab) carried the B.1.1.7 (Alpha, UK origin) variant. Four subjects (2 treated with placebo and treated with sotrovimab) carried the N501Y substitution. Thirty-one subjects (19 treated with placebo and 12 treated with sotrovimab) carried the B.1.427/B.1.429 (Epsilon, California origin) variant. Eight additional subjects carried the L452R substitution (6 treated with placebo and treated with sotrovimab). Eleven subjects carried the P.1 (Gamma, Brazil origin) variant (3 treated with placebo and treated with sotrovimab). Three subjects carried the B.1.526 (Iota, New York origin) variant with the E484K substitution (2 treated with placebo and treated with sotrovimab), while subjects (4 treated with placebo and treated with sotrovimab) carried the S477N substitution that has been associated with the B.1.526 (Iota, New York origin) variant. Additionally, 10 subjects carried the E484K substitution (4 treated with placebo and treated with sotrovimab), carried the S494P substitution (1 treated with placebo and treated with sotrovimab), and carried the S494P substitution with the N501Y substitution (2 treated with placebo and treated with sotrovimab). Two subjects in the group receiving sotrovimab (1 carrying the B.1.427/B.1.429 [Epsilon, California origin] variant and carrying the B.1.1.7 [Alpha, UK origin] variant) progressed to hospitalization. Four subjects in the placebo group (2 carrying the E484K substitution, carrying the P.1 [Gamma, Brazil origin] variant, and carrying the B.1.1.7 [Alpha, UK origin] variant) progressed to hospitalization. None of the subjects with currently available baseline sequences carried the full complement of substitutions characteristic of the B.1.351 (Beta, South Africa origin) or B.1.617 (Delta, India origin) variants.In COMET-ICE, post-baseline epitope substitutions were detected in 20 subjects in the cohort receiving sotrovimab (spike protein substitutions P337L/E340K [49.4%/54.8% allele frequency]; E340A [99.0%]; E340K [5 subjects: 8.0% to 99.9%]; E340V [73.1%]; A344V [6.2%]; R346G [5.2%]; K356R [7.5%]; S359G [2 subjects: 12.2% and 8.3%]); C361T [7 subjects: 5.0% to 15.7%]. Of the substitutions detected at baseline and post-baseline, L335F, L335S, P337L, G339C, E340A, E340K, A344V, R346G, R346I, K356N, K356R, R357I, I358V and S359G substitutions have been assessed phenotypically using pseudotyped VLP system. P337L, E340A and E340K substitutions confer reduced susceptibility to sotrovimab (>180-fold, >100-fold, and >297-fold changes in EC50 value, respectively). Sotrovimab retains activity against L335F (0.8-fold change in EC50 value), L335S (0.9-fold change in EC50 value), G339C (1.2-fold change in EC50 value), A344V (1.1-fold change in EC50 value), R346G (0.9-fold change in EC50 value), R346I (1.7-fold change in EC50 value), K356N (1.1-fold change in EC50 value), K356R (0.8-fold change in EC50 value), R357I (1-fold change in EC50 value), I358V (0.7-fold change in EC50 value), and S359G (0.8-fold change in EC50 value) substitutions. The clinical impact of these substitutions is not yet known. Data collection and analysis is still ongoing.Immune Response AttenuationThere is theoretical risk that antibody administration may attenuate the endogenous immune response to SARS-CoV-2 and make patients more susceptible to re-infection.

NONCLINICAL TOXICOLOGY SECTION.

16NONCLINICAL TOXICOLOGY Carcinogenesis, mutagenesis, and reproductive toxicology studies with sotrovimab have not been conducted.In toxicology study in monkeys, sotrovimab had no adverse effects when administered intravenously.In tissue cross reactivity studies using human and monkey adult tissues, no binding of clinical concern was detected for sotrovimab.In cross-reactive binding assay using protein array enriched for human embryofetal proteins, no off-target binding was detected for sotrovimab.

OVERDOSAGE SECTION.

12OVERDOSAGE There is no human experience of acute overdosage with sotrovimab.There is no specific treatment for an overdose with sotrovimab. If overdose occurs, the patient should be treated supportively with appropriate monitoring as necessary.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.

PRINCIPAL DISPLAY PANELNDC 0173-0901-86SotrovimabInjection500 mg/8 mL(62.5 mg/mL)Rx OnlyFor intravenous infusion after further dilution.Contains One 8-mL Single-Dose Vial.Discard Unused Portion.For Use Under Emergency Use Authorization (EUA)(C)2021 GSK group of companies or its licensor.Product of ChinaRev. 4/2162000000058567. Sotrovimab EUA carton.

PATIENT COUNSELING INFORMATION.

20PATIENT COUNSELING INFORMATION Patients treated with sotrovimab should continue to self-isolate and use infection control measures (e.g., wear mask, isolate, social distance, avoid sharing personal texts, clean and disinfect high touch surfaces, and frequent handwashing) according to CDC guidelines. Also, see Fact Sheet for Patients, Parents, and Caregivers.

PEDIATRIC USE SECTION.

11.3Pediatric Use Sotrovimab is not authorized for use in pediatric patients under 12 years of age or weighing less than 40 kg. The safety and effectiveness of sotrovimab have not been assessed in pediatric patients. The recommended dosing regimen in patients 12 years to less than 18 years of age, weighing at least 40 kg, is expected to result in comparable serum exposures of sotrovimab as those observed in adults based on an allometric scaling approach (which accounted for effect of body weight changes associated with age on clearance and volume of distribution).

PHARMACOKINETICS SECTION.

14.2Pharmacokinetics In COMET-ICE, the geometric mean Cmax following 1 hour IV infusion was 117.6 ug/mL (N 290, CV% 46.5), and the geometric mean Day 29 concentration was 24.5 ug/mL (N 372, CV% 42.4) from all subjects with an available Day 29 sample.DistributionThe mean steady-state volume of distribution of sotrovimab was 8.1 L.MetabolismSotrovimab is recombinant human IgG1 monoclonal antibody degraded by proteolytic enzymes which are widely distributed in the body and not restricted to hepatic tissue.EliminationThe mean systemic clearance was 125 mL/day with median terminal half-life of approximately 49 days.Specific PopulationsThe effect of different covariates (e.g., age, sex, race, body weight, disease severity, hepatic impairment) on the PK of sotrovimab is unknown. Renal impairment is not expected to impact the PK of sotrovimab since mAbs with molecular weight >69 kDa do not undergo renal elimination. Similarly, dialysis is not expected to impact the PK of sotrovimab.

PREGNANCY SECTION.

11.1Pregnancy Risk SummaryThere are insufficient data to evaluate drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcome. Sotrovimab should be used during pregnancy only if the potential benefit justifies the potential risk for the mother and the fetus.Nonclinical reproductive toxicity studies have not been conducted with sotrovimab. In cross-reactive binding assay using protein array enriched for human embryofetal proteins, no off-target binding was detected for sotrovimab. Since sotrovimab is recombinant human immunoglobulin (IgG) containing the LS modification in the Fc domain, it has the potential for placental transfer from the mother to the developing fetus. The potential treatment benefit or risk of placental transfer of sotrovimab to the developing fetus is not known.The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

USE IN SPECIFIC POPULATIONS SECTION.

11USE IN SPECIFIC POPULATIONS 11.1Pregnancy Risk SummaryThere are insufficient data to evaluate drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcome. Sotrovimab should be used during pregnancy only if the potential benefit justifies the potential risk for the mother and the fetus.Nonclinical reproductive toxicity studies have not been conducted with sotrovimab. In cross-reactive binding assay using protein array enriched for human embryofetal proteins, no off-target binding was detected for sotrovimab. Since sotrovimab is recombinant human immunoglobulin (IgG) containing the LS modification in the Fc domain, it has the potential for placental transfer from the mother to the developing fetus. The potential treatment benefit or risk of placental transfer of sotrovimab to the developing fetus is not known.The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.. 11.2Lactation Risk SummaryThere are no available data on the presence of sotrovimab in human or animal milk, the effects on the breastfed infant, or the effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mothers clinical need for sotrovimab and any potential adverse effects on the breastfed infant from sotrovimab or from the underlying maternal condition. Individuals with COVID-19 who are breastfeeding should follow practices according to clinical guidelines to avoid exposing the infant to COVID-19.. 11.3Pediatric Use Sotrovimab is not authorized for use in pediatric patients under 12 years of age or weighing less than 40 kg. The safety and effectiveness of sotrovimab have not been assessed in pediatric patients. The recommended dosing regimen in patients 12 years to less than 18 years of age, weighing at least 40 kg, is expected to result in comparable serum exposures of sotrovimab as those observed in adults based on an allometric scaling approach (which accounted for effect of body weight changes associated with age on clearance and volume of distribution).. 11.4Geriatric Use Of the 528 patients receiving sotrovimab in COMET-ICE, 20% were 65 years of age and older and 11% were over 70 years of age. The difference in pharmacokinetics (PK) of sotrovimab in geriatric patients compared to younger patients has not been quantified.. 11.5Renal Impairment No clinical trials have been conducted to evaluate the effects of renal impairment on the PK of sotrovimab. Sotrovimab is not eliminated intact in the urine, thus renal impairment is not expected to affect the exposure of sotrovimab.. 11.6Hepatic Impairment No clinical trials have been conducted to evaluate the effects of hepatic impairment on the PK of sotrovimab. The impact of hepatic impairment on the PK of sotrovimab is unknown.

WARNINGS AND PRECAUTIONS SECTION.

5WARNINGS AND PRECAUTIONS There are limited clinical data available for sotrovimab. Serious and unexpected adverse events may occur that have not been previously reported with sotrovimab use.. 5.1Hypersensitivity Including Anaphylaxis and Infusion-Related Reactions Serious hypersensitivity reactions, including anaphylaxis, have been observed with administration of sotrovimab [see Overall Safety Summary (6.1)]. If signs and symptoms of clinically significant hypersensitivity reaction or anaphylaxis occur, immediately discontinue administration and initiate appropriate medications and/or supportive care.Infusion-related reactions, occurring during the infusion and up to 24 hours after the infusion, have been observed with administration of sotrovimab. These reactions may be severe or life threatening.Signs and symptoms of infusion-related reactions may include [see Overall Safety Summary (6.1)]:ofever, difficulty breathing, reduced oxygen saturation, chills, fatigue, arrhythmia (e.g., atrial fibrillation, sinus tachycardia, bradycardia), chest pain or discomfort, weakness, altered mental status, nausea, headache, bronchospasm, hypotension, hypertension, angioedema, throat irritation, rash including urticaria, pruritus, myalgia, vaso-vagal reactions (e.g., pre-syncope, syncope), dizziness, and diaphoresis.Consider slowing or stopping the infusion and administer appropriate medications and/or supportive care if an infusion-related reaction occurs.Hypersensitivity reactions occurring more than 24 hours after the infusion have also been reported with the use of SARS-CoV-2 monoclonal antibodies under Emergency Use Authorization.. ofever, difficulty breathing, reduced oxygen saturation, chills, fatigue, arrhythmia (e.g., atrial fibrillation, sinus tachycardia, bradycardia), chest pain or discomfort, weakness, altered mental status, nausea, headache, bronchospasm, hypotension, hypertension, angioedema, throat irritation, rash including urticaria, pruritus, myalgia, vaso-vagal reactions (e.g., pre-syncope, syncope), dizziness, and diaphoresis.. 5.2Clinical Worsening After SARS-CoV-2 Monoclonal Antibody Administration Clinical worsening of COVID-19 after administration of SARS-CoV-2 monoclonal antibody treatment has been reported and may include signs or symptoms of fever, hypoxia or increased respiratory difficulty, arrythmia (e.g., atrial fibrillation, tachycardia, bradycardia), fatigue, and altered mental status. Some of these events required hospitalization. It is not known if these events were related to SARS-CoV-2 monoclonal antibody use or were due to progression of COVID-19.. 5.3Limitations of Benefit and Potential for Risk in Patients with Severe COVID-19 Benefit of treatment with sotrovimab has not been observed in patients hospitalized due to COVID-19. SARS-CoV-2 monoclonal antibodies may be associated with worse clinical outcomes when administered to hospitalized patients with COVID-19 requiring high flow oxygen or mechanical ventilation. Therefore, sotrovimab is not authorized for use in patients [see Limitations of Authorized Use]:owho are hospitalized due to COVID-19, ORowho require oxygen therapy due to COVID-19, ORowho require an increase in baseline oxygen flow rate due to COVID-19 (in those on chronic oxygen therapy due to underlying non-COVID-19 related comorbidity).. owho are hospitalized due to COVID-19, OR. owho require oxygen therapy due to COVID-19, OR. owho require an increase in baseline oxygen flow rate due to COVID-19 (in those on chronic oxygen therapy due to underlying non-COVID-19 related comorbidity).

WARNINGS SECTION.

Warnings There are limited clinical data available for sotrovimab. Serious and unexpected adverse events may occur that have not been previously reported with use of sotrovimab.Hypersensitivity Including Anaphylaxis and Infusion-Related ReactionsSerious hypersensitivity reactions, including anaphylaxis, have been observed with administration of sotrovimab [see Full EUA Prescribing Information, Overall Safety Summary (6.1)]. If signs and symptoms of clinically significant hypersensitivity reaction or anaphylaxis occur, immediately discontinue administration and initiate appropriate medications and/or supportive care.Infusion-related reactions, occurring during the infusion and up to 24 hours after the infusion, have been observed with administration of sotrovimab. These reactions may be severe or life threatening.Signs and symptoms of infusion-related reactions may include:ofever, difficulty breathing, reduced oxygen saturation, chills, fatigue, arrhythmia (e.g., atrial fibrillation, sinus tachycardia, bradycardia), chest pain or discomfort, weakness, altered mental status, nausea, headache, bronchospasm, hypotension, hypertension, angioedema, throat irritation, rash including urticaria, pruritus, myalgia, vaso-vagal reactions (e.g., pre-syncope, syncope), dizziness, and diaphoresis.Consider slowing or stopping the infusion and administer appropriate medications and/or supportive care if an infusion-related reaction occurs.Hypersensitivity reactions occurring more than 24 hours after the infusion have also been reported with the use of SARS-CoV-2 monoclonal antibodies under Emergency Use Authorization.Clinical Worsening After SARS-CoV-2 Monoclonal Antibody AdministrationClinical worsening of COVID-19 after administration of SARS-CoV-2 monoclonal antibody treatment has been reported and may include signs or symptoms of fever, hypoxia or increased respiratory difficulty, arrythmia (e.g., atrial fibrillation, tachycardia, bradycardia), fatigue, and altered mental status. Some of these events required hospitalization. It is not known if these events were related to SARS-CoV-2 monoclonal antibody use or were due to progression of COVID-19.Limitations of Benefit and Potential for Risk in Patients with Severe COVID-19 Benefit of treatment with sotrovimab has not been observed in patients hospitalized due to COVID-19. SARS-CoV-2 monoclonal antibodies may be associated with worse clinical outcomes when administered to hospitalized patients with COVID-19 requiring high flow oxygen or mechanical ventilation. Therefore, sotrovimab is not authorized for use in patients [see Limitations of Authorized Use]:owho are hospitalized due to COVID-19, ORowho require oxygen therapy due to COVID-19, ORowho require an increase in baseline oxygen flow rate due to COVID-19 (in those on chronic oxygen therapy due to underlying non-COVID-19 related comorbidity).. ofever, difficulty breathing, reduced oxygen saturation, chills, fatigue, arrhythmia (e.g., atrial fibrillation, sinus tachycardia, bradycardia), chest pain or discomfort, weakness, altered mental status, nausea, headache, bronchospasm, hypotension, hypertension, angioedema, throat irritation, rash including urticaria, pruritus, myalgia, vaso-vagal reactions (e.g., pre-syncope, syncope), dizziness, and diaphoresis.. owho are hospitalized due to COVID-19, OR. owho require oxygen therapy due to COVID-19, OR. owho require an increase in baseline oxygen flow rate due to COVID-19 (in those on chronic oxygen therapy due to underlying non-COVID-19 related comorbidity).