DailyMed Label: Sotrovimab

DailyMed Label: Sotrovimab

2023

DailyMed Prescription

Sotrovimab

sotrovimab

GlaxoSmithKline LLC

NDC: 0173-0901

NDC: 0173-0901

Sotrovimab is a human immunoglobulin G-1 (IgG1-kappa) monoclonal antibody consisting of 2 identical light chain (LC) polypeptides composed of 214 amino acids each and 2 identical heavy chain (HC) polypeptides, each composed of 457 amino acids. Sotrovimab is produced by a Chinese Hamster Ovary cell line and has a molecular weight of approximately 149 kDa. Sotrovimab injection is a sterile, preservative-free, clear, colorless or yellow to brown solution supplied in a 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 a pH of 6.0.

Sotrovimab is authorized for the use in adults and pediatric patients (12 years of age and older weighing at least 40 kg) who are at high risk for progression to severe COVID-19, including hospitalization or death [see Clinical Studies ( 14 )] . Medical conditions or other factors that may place individual patients at higher risk for progression to severe COVID-19 are listed on the following CDC website: https://www.cdc.gov/coronavirus/2019-ncov/need-extra-precautions/people-with-medical-conditions.html . Sotrovimab should be administered intravenously within 7 days of symptom onset. Sotrovimab should be administered by a qualified healthcare professional and administered only in settings which have immediate access to medications to treat a severe infusion reaction, such as anaphylaxis, and the ability to activate the emergency medical system (EMS), as necessary [see Warnings and Precautions ( 5.1 )] . Sotrovimab is available as a concentrated solution and must be diluted prior to IV infusion. Clinically monitor patients during infusion and observe patients for at least 1 hour after infusion is complete. The recommended dosage for emergency use of sotrovimab authorized under this EUA is 500 mg administered as a single IV infusion over 15 minutes for 50-mL infusion bag or 30 minutes for 100-mL infusion bag. No dosage adjustment is recommended in pregnant or lactating women, in elderly patients, or in patients with renal impairment [see Use in Specific Populations ( 8 )] . Pediatric Use No dosage adjustment is recommended in pediatric patients who weigh at least 40 kg and are 12 years of age and older. Sotrovimab is not authorized for patients under 12 years of age or in pediatric patients weighing less than 40 kg [see Use in Specific Populations ( 8.4 )] . Preparation Sotrovimab is supplied in a single-dose vial and must be diluted prior to IV infusion. Sotrovimab concentrate for solution for infusion should be prepared by a qualified healthcare professional using aseptic technique. • Gather a polyvinyl chloride (PVC) or polyolefin (PO), sterile, prefilled 50-mL or 100-mL infusion bag containing 0.9% Sodium Chloride Injection or 5% Dextrose Injection. • Remove one vial of sotrovimab (500 mg/8 mL) from refrigerated storage and allow to equilibrate to room temperature, protected from light, for approximately 15 minutes. • Inspect the vial of sotrovimab visually for particulate matter and discoloration prior to administration. Should either be observed, the solution must be discarded, and fresh solution prepared. Sotrovimab is a clear, colorless or yellow to brown solution. • Gently swirl the vial several times before use without creating air bubbles. Do not shake the vial. • Withdraw 8 mL of sotrovimab from the vial and inject into the prefilled infusion bag. • Discard vial (even if some product remains). • Prior to the infusion, gently rock the infusion bag back and forth by hand 3 to 5 times. Do not invert the infusion bag. Avoid forming air bubbles. • This product is preservative-free; therefore, the diluted infusion solution should be administered immediately. If immediate administration is not possible, store the diluted solution of sotrovimab up to 6 hours at room temperature (up to 25°C [77°F]) or refrigerated up to 24 hours (2°C to 8°C [36°F to 46°F]). Administration Sotrovimab infusion solution should be administered by a qualified healthcare professional [see Warnings and Precautions ( 5.1 )] . Sotrovimab may only be administered in settings in which healthcare providers have immediate access to medications to treat a severe infusion reaction, such as anaphylaxis, and the ability to activate the emergency medical system (EMS), as necessary [see Warnings and Precautions ( 5.1 )] . • Gather the materials for IV infusion via infusion pump or gravity: o Polyvinyl chloride (PVC) or polyolefin (PO) infusion set, and o Use of a 0.2 micron polyethersulfone (PES) filter is strongly recommended. • Attach the infusion set to the IV bag using standard bore tubing. • Prime the infusion set. • Administer the entire infusion over 15 minutes for 50-mL infusion bag or 30 minutes for 100-mL infusion bag. Due to potential overfill of prefilled saline bags, the entire infusion solution in the bag should be administered to avoid underdosage. • Do not administer as an IV push or bolus. • The prepared infusion solution should not be administered simultaneously with any other medication. The compatibility of sotrovimab with IV solutions and medications other than 0.9% Sodium Chloride Injection and 5% Dextrose Injection is not known. • Once infusion is complete, flush the tubing with 0.9% Sodium Chloride or 5% Dextrose to ensure delivery of the required dose. • If the infusion must be discontinued due to an infusion reaction, discard unused product. • Clinically monitor patients during infusion and observe patients for at least 1 hour after infusion is complete.

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

The following serious adverse reaction is described in more detail in the

Sotrovimab is a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antiviral drug [see Microbiology ( 12.4 )] . A summary of pharmacokinetic parameters following a single 500-mg IV infusion is presented in Table 1 based on population pharmacokinetic analyses: Table 1. Summary of IV Sotrovimab Serum Pharmacokinetic Exposure Parameters Parameter a Sotrovimab (500 mg IV) C max , mcg/mL 170.1 (53.4) C D28 , mcg/mL 39.7 (37.6) AUC D0-28 b , day*mcg/mL 1564 (34.4) a Parameters are reported as geometric mean (Geometric %CV). b Based on a population pharmacokinetic analysis using data from a total of 1984 subjects across 5 clinical trials. The primary analysis in the clinical efficacy study COMET-ICE was conducted when the ancestral Wuhan-Hu-1 virus was predominant, with the most common SARS-CoV-2 variants being Alpha and Epsilon among participants in the study population, which was enrolled prior to the emergence of the Delta and Omicron variants ( Table 3 ). Specific Populations Based on available population pharmacokinetic analyses of sotrovimab dosages of 500 mg or less, the pharmacokinetics of sotrovimab administered intravenously were not affected by age or sex; body weight was identified as a significant covariate on the pharmacokinetics of sotrovimab, but the impact is not anticipated to be clinically relevant. Renal impairment is not expected to impact the pharmacokinetics of sotrovimab since mAbs with molecular weight >69 kDa do not undergo renal elimination. Similarly, dialysis is not expected to impact the pharmacokinetics of sotrovimab. Mechanism of Action Sotrovimab is a recombinant human IgG1-kappa mAb that binds to a conserved epitope on the spike protein receptor binding domain of SARS-CoV-2 with a dissociation constant of K D = 0.21 nM but does not compete with human ACE2 receptor binding (IC 50 value >33.6 nM [5 µg/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. Antiviral Activity The neutralization activity of sotrovimab against SARS-CoV-2 (isolate WA1/2020) was measured in a concentration response model using cultured Vero E6 cells. Sotrovimab neutralized SARS-CoV-2 with an average EC 50 value of 0.67 nM (100.1 ng/mL). Sotrovimab demonstrated cell culture FcγR activation using Jurkat reporter cells expressing FcγRIIa (low-affinity R131 and high affinity H131 alleles), FcγRIIIa (low-affinity F158 and high-affinity V158 alleles), and FcγRIIb. 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 Infection The 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 EC 50 value. The potential for ADE was also evaluated in a hamster model of SARS-CoV-2 using sotrovimab. Intraperitoneal administration prior to inoculation resulted in a dose-dependent improvement in all measured outcomes (body weight, total viral RNA in the lungs, or infectious virus levels based on TCID 50 measurements). No evidence of enhancement of disease was observed at any dose evaluated, including sub-neutralizing doses down to 0.05 mg/kg. Antiviral Resistance There is a potential risk of treatment failure due to the development of viral variants that are resistant to sotrovimab. Cell Culture Studies: Spike protein amino acid substitution E340A emerged in cell culture selection of resistant virus and had a >100-fold reduction in activity in a pseudotyped virus-like particle (VLP) assay. This substitution is in the conserved epitope of sotrovimab, which is comprised of 23 amino acids. Pseudotyped VLP assessments in cell culture were performed using Wuhan-Hu-1, Omicron BA.1, and Omicron BA.2 spike proteins. The epitope amino acid substitutions P337H/K/L/N/R/T, E340A/I/K/G/Q/S/V, T345P, K356T, and L441N in the Wuhan-Hu-1 spike, conferred reduced susceptibility to sotrovimab based on observed fold-increase in EC 50 value shown in parentheses: P337H (5.1), P337K (>304), P337L (>192), P337N (5.6), P337R (>192), P337T (10.6), E340A (>100), E340G (18.2), E340I (>190), E340K (>297), E340Q (>50), E340S (68), E340V (>200), T345P (225), K356T (5.9), and L441N (72). Epitope substitutions P337H (>631), K356T (>631), P337S (>609), E340D (>609), and V341F (5.9) in the Omicron BA.1 spike variant, and P337H (>117), P337S (>117), P337T (>117), E340D (>117), E340G (>117), K356T (>117), and K440D (5.1) in the Omicron BA.2 spike variant conferred reduced susceptibility to sotrovimab based on the observed fold-increase in EC 50 value shown in parenthesis relative to each spike viral variant. Table 2 provides cell culture neutralization data for SARS-CoV-2 variants. The clinical relevance of the fold reductions in susceptibility >5 is unknown. There are no data evaluating variants with fold reductions >5 in randomized controlled clinical studies. Table 2. Sotrovimab Neutralization Data for SARS-CoV-2 SARS-CoV-2 Variant Key Substitutions Tested a Fold Reduction in Susceptibility b Lineage WHO Nomenclature Pseudotyped VLP Authentic Virus B.1.1.7 Alpha N501Y No change No change B.1.351 Beta K417N+E484K+N501Y No change No change P.1 Gamma K417T+E484K+N501Y No change No change B.1.617.2 Delta L452R+T478K No change No change AY.1 and AY.2 Delta [+K417N] K417N+L452R+T478K No change Not tested AY.4.2 Delta [+] L452R+T478K No change Not tested B.1.427/B.1.429 Epsilon L452R No change Not tested B.1.526 Iota E484K No change Not tested B.1.617.1 Kappa L452R+E484Q No change No change C.37 Lambda L452Q+F490S No change Not tested B.1.621 Mu R346K+E484K+N501Y No change Not tested B.1.1.529/BA.1 Omicron G339D+S371L+S373P+ S375F+K417N+N440K+ G446S+S477N+T478K+ E484A+Q493R+G496S+ Q498R+N501Y+Y505H No change No change BA.1.1 Omicron G339D+R346K+S371L+ S373P+S375F+K417N+ N440K+G446S+S477N+ T478K+E484A+Q493R+ G496S+Q498R+N501Y+ Y505H No change No change BA.2 Omicron G339D+S371F+S373P+ S375F+T376A+D405N+ R408S+K417N+N440K+ S477N+T478K+E484A+ Q493R+Q498R+N501Y+ Y505H 16 15.7 c BA.2.12.1 Omicron G339D+S371F+S373P+ S375F+T376A+D405N+ R408S+K417N+N440K+ L452Q+S477N+T478K+ E484A+Q493R+Q498R+ N501Y+Y505H 16.6 25.1 c BA.2.75 Omicron G339H+S371F+S373P+ S375F+T376A+D405N+ R408S+K417N+N440K+ G446S+N460K+S477N+ T478K+E484A+Q498R+ N501Y+Y505H 8.3 Not tested BA.2.75.2 Omicron G339H+R346T+S371F+ S373P+S375F+T376A+ D405N+R408S+K417N+ N440K+G446S+N460K+ S477N+T478K+E484A+ F486S+Q498R+N501Y+ Y505H 10 Not tested BA.3 Omicron G339D+S371F+S373P+ S375F+D405N+K417N+ N440K+G446S+S477N+ T478K+E484A+Q493R+ Q498R+N501Y+Y505H 7.3 Not tested BA.4 Omicron G339D+S371F+S373P+ S375F+T376A+D405N+ R408S+K417N+N440K+ L452R+S477N+T478K+ E484A+F486V+Q498R+ N501Y+Y505H 21.3 48.4 c BA.4.6 Omicron G339D+R346T+S371F+ S373P+S375F+T376A+ D405N+R408S+K417N+ N440K+L452R+S477N+ T478K+E484A+F486V+ Q498R+N501Y+Y505H 57.9 Not tested BA.5 Omicron G339D+S371F+S373P+ S375F+T376A+D405N+ R408S+K417N+N440K+ L452R+S477N+T478K+ E484A+F486V+Q498R+ N501Y+Y505H 22.6 21.6 c BF.7/BA.5.2.6 Omicron G339D+R346T+S371F+ S373P+S375F+T376A+ D405N+R408S+K417N+ N440K+L452R+S477N+ T478K+E484A+F486V+ Q498R+N501Y+Y505H 74.2 Not tested BN.1 Omicron G339H+R346T+K356T+ S371F+S373P+S375F+ T376A+D405N+R408S+ K417N+N440K+G446S+ N460K+S477N+T478K+ E484A+F490S+Q498R+ N501Y+Y505H 778 Not tested BQ.1 Omicron G339D+S371F+S373P+ S375F+T376A+D405N+ R408S+K417N+N440K+ K444T+L452R+N460K+ S477N+T478K+E484A+ F486V+Q498R+N501Y+ Y505H 28.5 Not tested BQ.1.1 Omicron G339D+R346T+S371F+ S373P+S375F+T376A+ D405N+R408S+K417N+ N440K+K444T+L452R+ N460K+S477N+T478K+ E484A+F486V+Q498R+ N501Y+Y505H 94 Not tested XBB/XBB.1 Omicron G339H+R346T+L368I+ S371F+S373P+S375F+ T376A+D405N+R408S+ K417N+N440K+V445P+ G446S+N460K+S477N+ T478K+E484A+F486S+ F490S+Q498R+N501Y+ Y505H 6.5 Not tested XBB.1.5 Omicron G339H+R346T+L368I+ S371F+S373P+S375F+ T376A+D405N+R408S+ K417N+N440K+V445P+ G446S+N460K+S477N+ T478K+E484A+F486P+ F490S+Q498R+N501Y+ Y505H 11.3 33.3 c XD None d G339D+S371L+S373P+ S375F+K417N+N440K+ G446S+S477N+T478K+ E484A+Q493R+G496S+ Q498R+N501Y+Y505H Not tested No change a Substitutions in the spike receptor binding domain relative to wild-type are listed. b Based on EC 50 fold change compared to wild-type. No change: ≤5-fold change in EC 50 value compared to wild-type. c Sotrovimab inhibited authentic virus isolates of Omicron BA.2, BA.2.12.1, BA.4, BA.5, and XBB.1.5 lineages with maximum percentage inhibition in the range of 80% to 100%. d Variant has not been named by the WHO. Clinical Studies : SARS-CoV-2 variants of concern or variants of interest (VOC/VOI) were detected in participants enrolled in COMET-ICE ( Table 3 ). Table 3. SARS-CoV-2 VOC/VOI Detected at ≥2% Prevalence in Sotrovimab-Treated Participants Clinical Study VOC/VOI Prevalence, % (n/N) a Participants Meeting Primary Clinical Endpoint b COMET-ICE Alpha (B.1.1.7) 10% (35/338) 1 Epsilon (B.1.427/B.1.429) 5% (16/338) 1 Gamma (P.1) 3% (9/338) 0 a n = number of sotrovimab-treated participants with the designated VOC/VOI; N = total number of sotrovimab-treated participants with SARS-CoV-2 spike sequence results. b The primary clinical endpoint for progression was defined as hospitalization for >24 hours for acute management of any illness or death from any cause through Day 29. SARS-CoV-2 viruses with baseline and treatment-emergent substitutions at amino acid positions associated with reduced susceptibility to sotrovimab in cell culture were observed in COMET-ICE ( Table 4 ). Of the 32 sotrovimab-treated participants with a substitution detected at amino acid positions 337 and/or 340 at any visit baseline or post-baseline, only 1 met the primary endpoint for progression of hospitalization for >24 hours for acute management of any illness or death from any cause through Day 29. This participant had E340K detected post-baseline and was infected with the Epsilon variant of SARS-CoV-2. Table 4. Baseline and Treatment-Emergent Substitutions Detected in Sotrovimab-Treated Participants at Amino Acid Positions Associated with Reduced Susceptibility to Sotrovimab Clinical Study Baseline a Treatment-Emergent b Substitutions Frequency, % (n/N) Substitutions Frequency, % (n/N) COMET-ICE P337H, E340A 1% (4/307) P337L/R, E340A/K/V 14% (24/170) c a n = number of sotrovimab-treated participants with a baseline substitution detected at spike amino acid positions 337 or 340; N = total number of sotrovimab-treated participants with baseline sequence results. b n = number of sotrovimab-treated participants with treatment-emergent substitutions detected at spike amino acid positions 337 or 340; N = total number of sotrovimab-treated participants with paired baseline and post-baseline sequence results. c Four participants with a post-baseline substitution at P337 or E340 and lacking a baseline sequence are not included. Immune Response Attenuation There is a theoretical risk that antibody administration may attenuate the endogenous immune response to SARS-CoV-2 and make patients more susceptible to re-infection. As with all therapeutic proteins, there is potential for immunogenicity. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies in the studies described below with the incidence of antibodies in other studies may be misleading. Treatment-emergent anti-drug antibodies (ADAs) to sotrovimab were detected in 13% (65/513) of participants, through week 24, in the COMET-ICE study. None of the participants with confirmed treatment-emergent ADAs had neutralizing antibodies against sotrovimab.

NDC 0173-0901-86 Sotrovimab Injection 500 mg/8 mL (62.5 mg/mL) Rx Only For intravenous infusion after further dilution. Contains One 8-mL Single-Dose Vial. Discard Unused Portion. For Use Under Emergency Use Authorization (EUA) ©2021 GSK group of companies or its licensor. Product of China Rev. 4/21 62000000058567 Sotrovimab EUA carton