XEVUDY 500mg perfusive solution concentrate medication leaflet

Xevudy 500 mg concentrate for solution for infusion

Each vial contains 500 mg of sotrovimab in 8 mL (62.5 mg/mL).

Sotrovimab is a monoclonal antibody (IgG1, kappa) produced in Chinese Hamster Ovary (CHO) cellsby recombinant DNA technology.

This medicinal product contains 4.8 mg of polysorbate 80 in each 500 mg dose.

For the full list of excipients, see section 6.1.

Concentrate for solution for infusion (sterile concentrate)

A clear, colourless or yellow to brown solution, free from visible particles, with a pH of approximately6 and an osmolality of approximately 290 mOsm/kg.

Xevudy is indicated for the treatment of adults and adolescents (aged 12 years and over and weighingat least 40 kg) with coronavirus disease 2019 (COVID-19) who do not require oxygensupplementation and who are at increased risk of progressing to severe COVID-19 (see section 5.1).

The use of Xevudy should take into account information on the activity of sotrovimab against viralvariants of concern (see sections 4.4 and 5.1).

Xevudy should be administered under conditions where management of severe hypersensitivityreactions, such as anaphylaxis, is possible and patients can be monitored during and for at least onehour after administration (see section 4.4).

It is recommended that Xevudy is administered within 5 days of onset of symptoms of COVID-19 (seesection 5.1).

Adults and adolescents (from 12 years and 40 kg body weight)

The recommended dose is a single 500 mg intravenous infusion administered following dilution (seesections 4.4 and 6.6).

No dose adjustment is required in elderly patients (see section 5.2).

No dose adjustment is required in patients with renal impairment (see section 5.2).

No dose adjustment is required in patients with hepatic impairment (see section 5.2).

The safety and efficacy of Xevudy in children under 12 years old or weighing less than 40 kg have notyet been established. Currently available data are described in sections 4.8 and 5.2 but norecommendation on posology can be made.

For intravenous use.

This medicinal product must be diluted prior to administration.

Once diluted, it is recommended that the solution is administered over 15 minutes (when using a50 mL infusion bag) or over 30 minutes (when using a 100 mL infusion bag) with a 0.2-μm in-linefilter.

Xevudy must not be administered as an intravenous push or bolus injection.

For instructions on dilution of the medicinal product, see section 6.6.

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

In order to improve the traceability of biological medicinal products, the name and the batch numberof the administered product should be clearly recorded.

Hypersensitivity reactions, including anaphylaxis, have been reported with administration ofsotrovimab (see section 4.8). If signs or symptoms of a clinically significant hypersensitivity reactionor anaphylaxis occur, administration should be discontinued immediately and appropriate medicationsand/or supportive care should be given.

Infusion-related reactions (IRRs) have been observed with intravenous administration of monoclonalantibodies (see section 4.8). These reactions may be severe or life threatening. If an IRR occurs, theinfusion may be interrupted, slowed or stopped.

Decisions regarding the use of Xevudy should take into consideration what is known about thecharacteristics of the circulating SARS-CoV-2 viruses including regional or geographical differencesand available information on sotrovimab susceptibility patterns (see section 5.1).

When molecular testing or sequencing data are available, they should be considered to rule out SARS-

CoV-2 variants that are shown to have reduced susceptibility to sotrovimab.

Polysorbate

This medicinal product contains 4.8 mg of polysorbate 80 in each 500 mg dose. Polysorbates maycause allergic reactions.

No interaction studies have been performed. Sotrovimab is not renally excreted or metabolised bycytochrome P450 (CYP) enzymes; therefore, interactions with medicinal products that are renallyexcreted or that are substrates, inducers, or inhibitors of CYP enzymes are unlikely.

In vitro pharmacodynamic studies showed no antagonism between sotrovimab and remdesivir orbamlanivimab.

There are no data from the use of sotrovimab in pregnant women. Animal studies have not beenevaluated with respect to reproductive toxicity (see section 5.3). In a cross-reactive binding assayusing a protein array enriched for human embryofoetal proteins, no off-target binding was detected.

Since sotrovimab is a human immunoglobulin G (IgG), it has the potential for placental transfer fromthe mother to the developing foetus. The potential treatment benefit or risk of placental transfer ofsotrovimab to the developing foetus is not known.

Sotrovimab should be used during pregnancy only if the expected benefit to the mother justifies thepotential risk to the foetus.

It is not known whether sotrovimab is excreted in human milk or absorbed systemically afteringestion. Administration of sotrovimab while breast-feeding can be considered when clinicallyindicated.

There are no data on the effects of sotrovimab on human male or female fertility. Effects on male andfemale fertility have not been evaluated in animal studies.

Xevudy has no or negligible influence on the ability to drive and use machines.

The safety of a 500 mg dose of sotrovimab administered intravenously was evaluated in non-hospitalised patients with COVID-19 in a placebo-controlled randomised study (COMET-ICE, 1049patients treated in a 1:1 ratio of sotrovimab:placebo), and in two non-placebo controlled randomisedstudies (COMET-PEAK, 193 patients and COMET-TAIL, 393 patients) (see section 5.1). The mostcommon adverse reactions were hypersensitivity reactions (2%) and infusion-related reactions (1%).

The most serious adverse reaction was anaphylaxis (0.05%).

The adverse reactions in Table 1 are listed by system organ class and frequency. Frequencies aredefined as follows: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to<1/100); rare (≥1/10,000 to <1/1,000), very rare (<1/10,000).

Table 1: Tabulated list of adverse reactions

System organ class Adverse reaction Frequency

Immune system disorders Hypersensitivity reactions a Common

Anaphylaxis Rare

Respiratory, thoracic and Dyspnoea Uncommonmediastinal disorders

Injury, poisoning and Infusion-related reactions Commonprocedural complicationsaSuch as rash and bronchospasm. Pruritus may also be seen as a manifestation of hypersensitivityreactions.

IRRs may be severe or life threatening (see section 4.4). Signs and symptoms of IRRs may includefever, difficulty breathing, reduced oxygen saturation, chills, nausea, arrhythmia (e.g. atrialfibrillation), tachycardia, bradycardia, chest pain or discomfort, weakness, altered mental status,headache, bronchospasm, hypotension, hypertension, angioedema, throat irritation, rash includingurticaria, pruritus, myalgia, dizziness, fatigue and diaphoresis.

Based on limited data (n=7) from adolescents (aged 12 to less than 18 years and weighing at least 40kg), there were no new adverse reactions identified beyond those observed in the adult population.

Data (n=3) obtained in children (aged 6 to less than 12 years and weighing at least 15 kg), are toolimited to establish safety in this group.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

There is no specific treatment for an overdose of sotrovimab. If overdose occurs, the patient should betreated supportively with appropriate monitoring as necessary.

A single 2000 mg dose of sotrovimab (4 times the recommended dose) administered by intravenousinfusion over 60 minutes has been evaluated in a clinical trial (N=81) without evidence of dose-limiting toxicity.

Pharmacotherapeutic group: Immune sera and immunoglobulins, antiviral monoclonal antibodies,

ATC code: J06BD05

Sotrovimab is a human IgG1 mAb that binds to a conserved epitope on the spike protein receptorbinding domain of SARS-CoV-2.

Sotrovimab neutralised wild-type SARS-CoV-2 virus in vitro with a half maximal effectiveconcentration (EC50) of 100.1 ng/mL.

Table 2: Sotrovimab neutralisation data for SARS-CoV-2 variants

SARS-CoV-2 Variant Fold Reduction in Susceptibility a

WHO

Lineage Nomenclature Pseudotyped Virus Authentic Virus

B.1.1.7 Alpha No change No change

B.1.351 Beta No change No change

P.1 Gamma No change No change

B.1.617.2 Delta No change No change

AY.1 and AY.2 Delta [+K417N] No change Not tested

AY.4.2 Delta [+] No change Not tested

B.1.427/B.1.429 Epsilon No change Not tested

B.1.526 Iota No change Not tested

B.1.617.1 Kappa No change No change

C.37 Lambda No change Not tested

B.1.621 Mu No change Not tested

B.1.1.529/BA.1 Omicron No change No change

BA.1.1 Omicron No change No change

BA.2 Omicron 16 15.7

BA.2.12.1 Omicron 16.6 25.1

BA.2.75 Omicron 8.3 15.6

BA.2.75.2 Omicron 10 Not tested

BA.2.86c Omicron 100 Not determined

BA.3 Omicron 7.3 Not tested

BA.4 Omicron 21.3 48.4

BA.4.6 Omicron 57.9 115

BA.5 Omicron 22.6 21.6

BF.7 Omicron 74.2 Not tested

BN.1c Omicron 778 Not tested

BQ.1 Omicron 28.5 Not tested

BQ.1.1 Omicron 94 31.2

BR.2 Omicron 10.2 Not tested

CH.1.1 Omicron 12.4 57.3

EG.5.1 Omicron Not tested 9.5

FL.1.5.1 Omicron 7.5 No change

HK.3 Omicron 8.4 Not tested

HV.1 Omicron 6.4 Not tested

JN.1c Omicron 252 Not tested

XBB.1 Omicron 6.5 Not tested

XBB.1.5 Omicron 11.3 33.3

XBB.1.5.10 Omicron 7.6 Not tested

XBB.1.16 Omicron 6.9 10.6

XBB.1.16.1 Omicron 7.3 Not tested

XBB.1.16.6 Omicron 6.2 Not tested

XBB.2.3 Omicron 5.7 No change

XBF Omicron 9.4 Not tested

XD Noneb Not tested No changea Based on EC50 fold change compared to wild-type. No change: ≤5-fold change in EC50 compared towild-type.b Variant has not been named by the WHO.c The BA.2.86, BN.1 and JN.1 variants contain the K356T substitution.

Cell culture studies: No viral breakthrough was observed when virus was passaged for 10 passages(34 days) in the presence of fixed concentration of antibody at the lowest concentration tested (~10x

EC50). Forcing the emergence of resistance variants through an increasing concentration selectionmethod identified E340A as a sotrovimab mAb resistance mutant (MARM). An E340A substitutionemerged in cell culture selection of resistant virus and had a >100-fold reduction in activity in apseudotyped virus-like particle (VLP) assay.

Table 3 shows the activity data for sotrovimab against epitope sequence polymorphisms evaluated inpseudotyped VLP assessments in cell culture using the Wuhan-Hu-1 and Omicron BA.1, BA.2 and

BA.5 spike proteins.

Table 3 Sotrovimab pseudotyped VLP assessments in cell culture against epitope substitutions

Fold Reduction in Susceptibilitya

Reference Substitution Wuhan-Hu- Omicron Omicron Omicronposition 1 BA.1 BA.2 BA.5337 P337A No change - - >133

P337H 5.13 >631 >117 >120

P337K >304 - - -

P337L >192 - - -

P337N 5.57 - >143 >135

P337Q 24.9 - - -

P337R >192 - - -

P337S No change >609 >117 >152

P337T 10.62 - >117 >120340 E340A >100 - - -

E340D No change >609 >117 >91.4

E340G 18.21 - >117 >91.4

E340I >190 - - -

E340K >297 - - -

E340L >1696 - - -

E340N >1696 - - -

E340Q >50 - - -

E340R >1696 - - -

E340S 68 - - -

E340V >200 - - -341 V341F No change 5.89 - 5.83345 T345P 225 - - -356 K356A No change - >129 >60.3

K356E No change - - >51.8

K356M No change - >132 >86.1

K356N No change - >101 >86.1

K356Q No change - 70.2 >86.1

K356R No change - 22 >69

K356S No change - >143 >86.1

K356T 5.90 >631 >117 >91.4440 Nb/Kc440D No change - 5.13 No change441 L441N 72 - - -

L441R No change - No change 5.88a Based on EC50 fold change relative to each spike viral variant. No change: ≤5-fold change; -: depicts nottested.b Wuhan-Hu-1 strainc Omicron lineages

Clinical studies: SARS-CoV-2 viruses with baseline and treatment-emergent substitutions at aminoacid positions associated with reduced susceptibility to sotrovimab in vitro were observed in patientsenrolled in clinical studies who received a 500 mg intravenous infusion of sotrovimab (Table 4). In the

COMET-ICE and COMET-TAIL studies, among patients who were treated with a 500 mg intravenousinfusion of sotrovimab and had a substitution detected at amino acid positions 337 and/or 340 at anyvisit baseline or post-baseline, 1 of 32 and none of 33 patients, respectively, met the primary endpointfor progression to hospitalisation for >24 hours for acute management of any illness or death from anycause through Day 29. This single patient 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 patientsat amino acid positions associated with reduced susceptibility to sotrovimab

Clinical Study Baselinea Treatment-Emergentb

Substitutions Frequency, Substitutions Frequency,% (n/N) % (n/N)

COMET-ICE P337H, 1.3 (4/307) P337L/R, 14.1 (24/170)

E340A E340A/K/V

COMET-TAIL P337S, 0.6 (2/310) P337L, E340A/K/V 19.5 (31/159)

E340STOP

COMET-PEAK P337H 0.8 (1/130) P337L, E340A/K/V 13.5 (15/111)

LUNARc E340D/Q, pct. 4.6 (9/195) P337A/H/L/R/S, 29.5 (46/156)

K356T E340A/D/G/K/Q/V,

K356M/R/Ta n = number of sotrovimab-treated patients with a baseline substitution detected at spike amino acidpositions 337 or 340. Spike position 356 was also included for the LUNAR study which enrolledpatients with Omicron BA.2, BA.4 or BA.5 lineage SARS-CoV-2 variants; N = total number ofsotrovimab-treated patients with baseline sequence results.b n = number of sotrovimab-treated patients with treatment-emergent substitutions detected at spikeamino acid positions 337 or 340. Spike position 356 was also included for the LUNAR study whichenrolled patients with Omicron BA.2, BA.4 or BA.5 lineage variants; N = total number of sotrovimab-treated patients with paired baseline and post-baseline sequence results.c A multicentre, single arm, prospective, genomic surveillance study that followed non-hospitalisedimmunocompromised patients who received 500 mg intravenous infusion of sotrovimab.

Treatment-emergent anti-drug antibodies (ADAs) to a single 500 mg intravenous infusion ofsotrovimab were detected in 9% (101/1101) of participants, in controlled clinical studies with followup durations of 18-36 weeks. No participants with confirmed treatment-emergent ADAs hadneutralising antibodies against sotrovimab, and there was no evidence of an association of ADA withany impact on the safety, efficacy, or pharmacokinetics after a single intravenous infusion.

Study 214367 (COMET-ICE) was a Phase II/III randomised, double-blind, placebo-controlled studywhich evaluated sotrovimab as treatment for COVID-19 in non-hospitalised, non-vaccinated adultpatients who did not require any form of oxygen supplementation at study entry. The study includedpatients with symptoms for ≤ 5 days and laboratory confirmed SARS-CoV-2 infection and wasconducted when the wild-type Wuhan-Hu-1 virus was predominant, with the highest frequency ofvariants being Alpha and Epsilon. Eligible patients had at least 1 of the following: diabetes, obesity(BMI>30), chronic kidney disease, congestive heart failure, chronic obstructive pulmonary disease, ormoderate to severe asthma, or were aged 55 years and older.

Patients were randomised to a single 500 mg infusion of sotrovimab (N=528) or placebo (N=529) over1 hour. In the Intent to Treat (ITT) population at Day 29, 46% were male and the median age was53 years (range: 17-96), with 20% aged 65 years or older and 11% over 70 years. Treatment was givenwithin 3 days of COVID-19 symptom onset in 59% and 41% were treated within 4-5 days. The fourmost common pre-defined risk factors or comorbidities were obesity (63%), 55 years of age or older(47%), diabetes requiring medicine (22%) and moderate to severe asthma (17%).

The adjusted relative risk reduction in hospitalisation or death by Day 29 in the ITT population was79% (95% CI: 50%, 91%). The difference was driven by rates of hospitalisation, with no deaths in thesotrovimab arm and two deaths in the placebo arm up to Day 29. No patients in the sotrovimab arm,versus 14 in the placebo arm, required high flow oxygen or mechanical ventilation up to Day 29.

Table 5: Results of primary and secondary endpoints in the ITT population (COMET-ICE)

Sotrovimab Placebo(500 mg IV infusion)

N=528 N=529

Primary endpoint

Progression of COVID-19 as defined by hospitalisation for >24 hours for acutemanagement of any illness or death from any cause (day 29)

Proportion (n, %) a 6 (1%) 30 (6%)

Adjusted relative risk reduction 79%(95% CI) (50%, 91%)p-value <0.001

Secondary endpoint

Progression to develop severe and/or critical respiratory COVID-19 (day 29) b

Proportion (n, %) 7 (1%) 28 (5%)

Adjusted relative risk reduction 74%(95% Cl) (41%, 88%)p-value 0.002a No participants required intensive care unit (ICU) stay in the sotrovimab arm versus 9participants in the placebo arm.b Progression to develop severe and/or critical respiratory COVID-19 defined as therequirement for supplemental oxygen (low flow nasal cannulae/face mask, high flowoxygen, non-invasive ventilation, mechanical ventilation or extracorporeal membraneoxygenation [ECMO]).

The European Medicines Agency has deferred the obligation to submit the results of studies with

Xevudy in one or more subsets of the paediatric population in the treatment of COVID-19 (see section4.2 for information on paediatric use).

Based on population pharmacokinetic analyses, following a 15 minute to 1 hour intravenous infusionof 500 mg, the geometric mean Cmax was 170 µg/mL (N = 1188, CVb% 53.4), and the geometric mean

Day 28 concentration was 39.7 µg/mL (N = 1188, CVb% 37.6).

Based on population pharmacokinetic analysis, the geometric mean steady-state volume of distributionwas 7.9 L.

Sotrovimab is degraded by proteolytic enzymes which are widely distributed in the body.

Based on population pharmacokinetic analysis, the mean systemic clearance (CL) was 95 mL/day,with a median terminal half-life of approximately 61 days.

Based on population pharmacokinetic analyses, there was no difference in sotrovimabpharmacokinetics in elderly patients.

Sotrovimab is too large to be excreted renally, thus renal impairment is not expected to have any effecton elimination. Furthermore, based on population pharmacokinetic analyses there was no difference insotrovimab pharmacokinetics in patients with mild or moderate renal impairment.

Sotrovimab is degraded by widely distributed proteolytic enzymes, not restricted to hepatic tissue,therefore changes in hepatic function are not expected to have any effect on elimination. Furthermore,based on population pharmacokinetic analyses there was no difference in sotrovimabpharmacokinetics in patients with mild to moderate elevations in alanine aminotransferase (1.25 to< 5 x ULN).

Limited data on the pharmacokinetics of sotrovimab in patients aged less than 18 years, has beenobtained from the COMET-TAIL study (see section 4.8) and the COMET-PACE study. The COMET-

PACE study is an open-label, non-conparator paediatric study, that was terminated prior to completionof recruitment. The recommended dose for adolescents aged from 12 years and from 40 kg bodyweight was based on an allometric scaling approach, which accounted for effect of body weightchanges associated with age on clearance and volume of distribution. This approach is supported by apopulation pharmacokinetic analysis, which shows comparable serum exposures of sotrovimab inadolescents as those observed in adults. Following intravenous infusion of 500 mg sotrovimab in 7adolescents, the geometric mean Cmax was 180 µg/mL (geometric CV% 25.6) and the geometric mean

Day 29 concentration was 47.4 µg/mL (geometric CV% 17.0).

Data (n=3) in children (aged 6 to less than 12 years and weighing at least 15 kg), are too limited toestablish pharmacokinetics of sotrovimab in this age group.

Based on population pharmacokinetic analyses, the pharmacokinetics of sotrovimab followingintravenous infusion were not affected by age, sex or BMI. No dose adjustment is warranted based onthese characteristics. Body weight was a significant covariate, but the magnitude of effect does notwarrant dose adjustment.

Genotoxicity and carcinogenicity studies have not been conducted with sotrovimab.

Nonclinical reproductive and developmental toxicity studies have not been conducted withsotrovimab.

No toxicity with sotrovimab was identified in a cynomolgus monkey 2-week repeat-dose IV infusiontoxicology study with 105-day recovery period at doses up to 500 mg/kg, the no observed adverseeffect level (NOAEL) and highest dose tested. The Cmax and total exposure AUC [sum of AUC0-168hafter Dose 1 and AUC0-last after Dose 2 (Day 8)] values at the NOAEL of 500 mg/kg were13500 µg/mL and 216000 day*µg/mL, respectively.

Histidine

Histidine monohydrochloride

Sucrose

Polysorbate 80 (E 433)

Methionine

Water for injections

This medicinal product must not be mixed with other medicinal products except those mentioned insection 6.6.

Unopened vial4 years.

The diluted solution is intended to be used immediately. If after dilution, immediate administration isnot possible, the diluted solution may be stored at room temperature (up to 25°C) for up to 6 hours orrefrigerated (2°C to 8°C) for up to 24 hours from the time of dilution until the end of administration.

Store in a refrigerator (2°C to 8°C).

Do not freeze.

Store in the original carton in order to protect from light.

For storage conditions after dilution of the medicinal product, see section 6.3.

10 mL Type I borosilicate clear glass single-use vial, with a grey chlorobutyl elastomer stopperlaminated with fluoropolymer, sealed with an aluminium flip-off cap.

Pack size: 1 vial.

Treatment should be prepared by a qualified healthcare professional using aseptic technique.

Preparation for dilution1. Remove one vial of sotrovimab from the refrigerator (2°C to 8°C). Allow the vial toequilibrate to ambient room temperature, protected from light, for approximately 15 minutes.

2. Visually inspect the vial to ensure it is free from particulate matter and that there is no visibledamage to the vial. If the vial is identified to be unusable, discard and restart the preparationwith a new vial.

3. Gently swirl the vial several times before use without creating air bubbles. Do not shake orvigorously agitate the vial.

Dilution instructions1. Withdraw and discard 8 mL from an infusion bag containing 50 mL or 100 mL of sodiumchloride 9 mg/mL (0.9%) solution for infusion or 5% glucose for infusion.

2. Withdraw 8 mL from the vial of sotrovimab.

3. Inject the 8 mL of sotrovimab into the infusion bag via the septum.

4. Discard any unused portion left in the vial. The vial is single-use only and should only be usedfor one patient.

5. Prior to the infusion, gently rock the infusion bag back and forth 3 to 5 times. Do not invertthe infusion bag. Avoid forming air bubbles.

Any unused medicinal product or waste material should be disposed of in accordance with localrequirements.

GlaxoSmithKline Trading Services Limited12 Riverwalk

Citywest Business Campus

Dublin 24

D24 YK11

Ireland

EU/1/21/1562/001

Date of first authorisation: 17 December 2021

Detailed information on this medicinal product is available on the website of the European Medicines

Agency https://www.ema.europa.eu.