Xevudy - summary of medicine characteristics

1. NAME OF THE MEDICINAL PRODUCT

Xevudy 500 mg concentrate for solution for infusion

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

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) cells by recombinant DNA technology.

3. PHARMACEUTICAL FORM

Concentrate for solution for infusion (sterile concentrate)

A clear, colourless or yellow to brown solution, free from visible particles, with a pH of approximately 6 and an osmolality of approximately 290 mOsm/kg.

4. CLINICAL PARTICULARS4.1 Therapeutic indications

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

4.2 Posology and method of administration

Xevudy should be administered in healthcare facilities in which patients can be monitored during and for at least one hour after administration (see section 4.4).

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

Posology

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

The recommended dose is a single 500 mg intravenous infusion administered following dilution (see section 6.6).

Special populations

Elderly

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

Renal impairment

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

Hepatic impairment

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

Paediatric population

The safety and efficacy of Xevudy in children under 12 years old or weighing less than 40 kg have not yet been established (see section 5.2). No data are available.

Method of administration

For intravenous use.

This medicinal product must be diluted prior to administration.

Once diluted, it is recommended that the solution is administered over 30 minutes with a 0.2-gm inline filter.

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

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

4.3 Contraindications

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

4.4 Special warnings and precautions for use

Traceability

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

Hypersensitivity reactions including anaphylaxis

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

Infusion-related reactions

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

4.5 Interaction with other medicinal products and other forms of interaction

Pharmacokinetic interactions

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

Pharmacodynamic interactions

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

4.6 Fertility, pregnancy and lactation

Pregnancy

There are no data from the use of sotrovimab in pregnant women. Animal studies have not been evaluated with respect to reproductive toxicity (see section 5.3). In a cross-reactive binding assay using 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 from the mother to the developing foetus. The potential treatment benefit or risk of placental transfer of sotrovimab to the developing foetus is not known.

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

Breast-feeding

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

Fertility

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

4.7 Effects on ability to drive and use machines

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

4.8 Undesirable effects

Summary of the safety profile

The most common adverse reactions were hypersensitivity reactions (2%) and infusion-related reactions (1%). The most serious adverse reaction was anaphylaxis (0.05%).

Tabulated list of adverse reactions

The adverse reactions in Table 1 are listed by system organ class and frequency. Frequencies are defined 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

aSuch as rash and bronchospasm. Pruritus may also be seen as a manifestation of hypersensitivity reactions.

Description of selected adverse reactions

Infusion-related reactions

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

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in

4.9 Overdose

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

5. PHARMACOLOGICAL PROPERTIES5.1 Pharmacodynamic properties

Mechanism of action

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

Antiviral activity

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

Pseudotyped virus-like particle (VLP) assessments indicated less than 3-fold changes in sotrovimab EC50 values compared to wild-type against the following variant spike proteins: Alpha (B.1.1.7; 2.30-fold change in EC50 value); Beta (B.1.351; 0.60-fold change in EC50 value); Gamma (P.1; 0.35-fold change in EC50 value); Epsilon (B.1.427/B.1.429; 0.70-fold change in EC50 value); Iota (B.1.526; 0.6-fold change in EC50 value), Kappa (B.1.617.1; 0.7-fold change in EC50 value), Delta (B.1.617.2; 1-fold change in EC50 value), Lambda (C.37; 1.5-fold change in EC50 value), Delta Plus (AY.1; 1.1-fold change in EC50 value, AY.2; 1.3-fold change in EC50 value), Mu (B.1.621; 1.3-fold change in EC50 value) and Omicron (B.1.1.529; 2.7-fold change in EC50 value).

Microneutralisation data from authentic SARS-CoV-2 variant virus indicated the following changes in sotrovimab EC50 values compared to wild-type: Alpha, 3-fold change in EC50 value; Beta, 1.2-fold change in EC50 value; Gamma, 1.6-fold change in EC50 value; Kappa, 0.9-fold change in EC50 value and Delta, 0.4-fold change in EC50 value.

Antiviral resistance

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 (~10× EC50). Forcing the emergence of resistance variants through an increasing concentration selection method identified

E340A as a sotrovimab mAb resistance mutant (MARM). An E340A substitution emerged in cell culture selection of resistant virus and had a >100-fold reduction in activity in a pseudotyped VLP assay.

A pseudotyped VLP assessment in cell culture showed that the epitope sequence polymorphisms K356T, P337H/L/R/T and E340A/K/G 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 (7.50), K356T (5.90) and P337T (5.438). The presence of the highly prevalent D614G variant, either alone or in combination, did not alter the neutralisation activity of sotrovimab.

In the COMET-ICE clinical trial post-baseline epitope variants were detected in 20 patients in the sotrovimab arm (A344V [6.2%]; R346G [5.2%]; K356R [7.5%]; E340A [99.0%]; E340V [73.1%]; P337L/E340K [49.4%/54.8%]; 2 patients with S359G [12.2% and 8.3%]; 5 patients with E340K [8.0%-99.9%]; 7 patients with C361T [5.0%-15.7%]). Of the variants detected at baseline and postbaseline in either treatment arm, 14 (L335F, L335S, P337L, G339C, E340A, E340K, A344V, R346I, R346G, K356N, K356R, R357I, I358V and S359G) have been assessed phenotypically using a pseudotyped VLP system. 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), R346I (1.7-fold change in EC50 value), R346G (0.9-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). P337L, E340A and E340K confer reduced susceptibility to sotrovimab (>180-fold, >100-fold and >297-fold change in EC50 value, respectively), but their effect on the clinical response to treatment is not known.

Clinical efficacy

Study 214367 (COMET-ICE) was a Phase II/III randomised, double-blind, placebo-controlled study which evaluated sotrovimab as treatment for COVID-19 in non-hospitalised, non-vaccinated adult patients who did not require any form of oxygen supplementation at study entry. The study included patients with symptoms for < 5 days and laboratory confirmed SARS-CoV-2 infection. Eligible patients had at least 1 of the following: diabetes, obesity (BMI>30), chronic kidney disease, congestive heart failure, chronic obstructive pulmonary disease, or moderate 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) over 1 hour. In the Intent to Treat (ITT) population at Day 29, 46% were male and the median age was 53 years (range: 17–96), with 20% aged 65 years or older and 11% over 70 years. Treatment was given within 3 days of COVID-19 symptom onset in 59% and 41% were treated within 4–5 days. The four most 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 was 79% (95% CI: 50%, 91%). The difference was driven by rates of hospitalisation, with no deaths in the sotrovimab 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 2: Results of primary and secondary endpoints in the ITT population (COMET-ICE)

Paediatric population

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 section 4.2 for information on paediatric use).

5.2 Pharmacokinetic properties

Absorption

The geometric mean Cmax following a 1 hour IV infusion was 117.6 pg/mL (N = 290, CV% 46.5), and the geometric mean Day 29 concentration was 24.5 pg/mL (N = 372, CV% 42.4).

Distribution

Based on non-compartmental analysis, the mean steady-state volume of distribution was 8.1 L.

Biotransformation

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

Elimination

Based on non-compartmental analysis, the mean systemic clearance (CL) was 125 mL/day, with a median terminal half-life of approximately 49 days.

Special populations

Elderly patients

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

Renal impairment

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

Hepatic 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 sotrovimab pharmacokinetics in patients with mild to moderate elevations in alanine aminotransferase (1.25 to < 5 x ULN).

Paediatric population

The pharmacokinetics of sotrovimab have not been evaluated in patients aged less than 18 years.

The recommended dose for adolescents aged from 12 years and from 40 kg body weight is predicted to result in serum concentrations of sotrovimab similar to those 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.

5.3 Preclinical safety data

Carcinogenesis/mu­tagenesis

Genotoxicity and carcinogenicity studies have not been conducted with sotrovimab.

Reproductive toxicology

Nonclinical reproductive and developmental toxicity studies have not been conducted with sotrovimab.

6. PHARMACEUTICAL PARTICULARS6.1 List of excipients

Histidine

Histidine monohydrochloride

Sucrose

Polysorbate 80

Methionine

Water for injections

6.2 Incompatibilities

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

6.3 Shelf life

Unopened vial

18 months.

Diluted solution for infusion

The diluted solution is intended to be used immediately. If after dilution, immediate administration is not possible, the diluted solution may be stored at room temperature (up to 25°C) for up to 6 hours or refrigerated (2°C to 8°C) for up to 24 hours from the time of dilution until the end of administration.

6.4 Special precautions for storage

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.

6.5 Nature and contents of container

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

Pack size: 1 vial.

6. 6 Special precautions for disposal and other handling

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

Preparation for dilution

• 1. Remove one vial of sotrovimab from the refrigerator (2°C to 8°C). Allow the vial to equilibrate 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 visible damage to the vial. If the vial is identified to be unusable, discard and restart the preparation with a new vial.

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

Dilution instructions

• 1. Withdraw 8 mL from an infusion bag containing 50 mL or 100 mL of sodium chloride

• 9 mg/mL (0.9%) solution for injection or 5% dextrose for injection.

• 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 used for one patient.

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

7. MARKETING AUTHORISATION HOLDER

GlaxoSmithKline Trading Services Limited

12 Riverwalk

Citywest Business Campus

Dublin 24

Ireland

8. MARKETING AUTHORISATION NUMBER(S)

EU/1/21/1562/001

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: