Xevudy 500 mg concentrate for solution for infusion

For the treatment of symptomatic adults and adolescents (aged 12 years and over and weighing at least 40 kg) with acute covid-19 infection who do not require oxygen supplementation and who are at increased risk of progressing to severe covid infection (see section 5.1).

Xevudy should only be administered by a qualified healthcare provider. Administration should be under conditions where management of severe hypersensitivity reactions, such as anaphylaxis, is possible. Individuals should be monitored during and post intravenous infusion in accordance with local guidelines (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).

Consideration should be given to official guidance on the appropriate use of Xevudy.

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 sections 4.4 and 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 in children under 12 years old or weighing less than 40 kg have not yet been established. Currently available data are described in sections 4.8 and 5.2 but no recommendation on posology can be made.

No dosage adjustment is recommended in paediatric individuals ≥ 12 years of age and weighing ≥ 40 kg (see section 5.2).

Method of administration

For intravenous use.

This medicinal product must be diluted prior to administration. For instructions on dilution of the medicinal product, see section 6.6.

Once diluted, attach an infusion set to the infusion bag using standard bore tubing. The intravenous dosing solution is recommended to be administered with a 0.2‑μ m in-line filter. Prime the infusion set and administer as a single IV infusion for over 15 minutes (when using a 50 mL infusion bag) or over 30 minutes (when using a 100 mL infusion bag) at room temperature.

Treatment must not be administered as an intravenous push or bolus.

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

Recipients of Xevudy are advised to self-isolate for a period of time from onset of symptoms in accordance with national covid-19 guidelines and in order to minimise transmission of coronavirus.

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

Hypersensitivity reactions, including serious and/or life-threatening reactions such as anaphylaxis, have been reported following infusion of Xevudy. Hypersensitivity reactions typically occur within 24 hours of infusion. Signs and symptoms of these reactions may include nausea, chills, dizziness (or syncope), rash, urticaria and flushing. If signs and symptoms of severe hypersensitivity reactions occur, administration should be discontinued immediately and appropriate treatment and/or supportive care should be initiated.

If mild to moderate hypersensitivity reactions occur, slowing or stopping the infusion along with appropriate supportive care should be considered.

Antiviral resistance

Decisions regarding the use of Sotrovimab should take into consideration what is known about the characteristics of the circulating SARS-CoV-2 viruses including regional or geographical differences and available information on Sotrovimab susceptibility patterns.

When molecular testing or sequencing data is available, it should be considered to rule out SARS-CoV-2 variants that are shown to have reduced susceptibility to Sotrovimab (see section 5.1 and 5.3)

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

Concomitant administration of sotrovimab with COVID-19 vaccines has not been studied. Refer to local/national guidelines for vaccine administration and guidance on the risks associated with administration of a SARS-CoV-2 vaccine.

Pregnancy

There are no data from the use of sotrovimab in pregnant women. Since sotrovimab is a human immunoglobulin G (IgG) animal studies have not been evaluated with respect to reproductive toxicity (see section 5.3). No off-target binding was detected in a cross-reactive binding assay using a protein array enriched for human embryofetal proteins. 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 may be used during pregnancy where the expected benefit to the mother justifies the risk to the foetus.

Breast-feeding

There are no data on the excretion of sotrovimab in human milk. The potential treatment benefit or risk to the newborn or infants via breastfeeding is not known.

Decisions on whether to breastfeed during treatment or to abstain from sotrovimab therapy should take into account the benefit of breast-feeding for the child and the benefit of therapy for the woman.

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.

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

Summary of the safety profile

The most common adverse reactions were hypersensitivity reactions. The most serious adverse reaction was anaphylaxis.

Tabulated list of adverse reactions

The table below presents the adverse reactions from a placebo-controlled randomised study in patients with COVID-19 (COMET-ICE, 1049 patients treated in a 1:1 ratio of sotrovimab:placebo) and in two non-placebo controlled randomised studies (COMET-PEAK, 193 patients and COMET-TAIL, 393 patients) (see section 5.1) and from spontaneous reporting. 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

^a Includes rash, dermatitis contact, skin reaction, hypersensitivity, multiple allergies, infusion-related reaction and bronchospasm.

Description of selected adverse reactions

Hypersensitivity reactions

In COMET-ICE, hypersensitivity reactions, of grade 1 (mild) or grade 2 (moderate), were reported (9 patients in the Xevudy arm; 5 patients in the placebo arm). None of the reactions in either study arm led to discontinuation of the infusions.

Paediatric Population

Based on limited data (n=7) from adolescents (aged 12 to less than 18 years and weighing at least 40 kg), 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 too limited to establish safety in this group.

Elderly

In study COMET-ICE, 104 (20%) patients received treatment with Xevudy were ≥ 65 years old. The safety profile of these patients was similar to that in adult patients < 65 years old.

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 Yellow Card Scheme website: www.yellowcard.mhra.gov.uk or search for MHRA Yellow Card in the Google Play or Apple App Store.

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

A single 2000 mg dose of sotrovimab (4 times the recommended dose) administered by intravenous infusion over 60 minutes has been evaluated in a clinical trial (COMET-TAIL safety sub-study, N=81) without evidence of dose-limiting toxicity.

Pharmacotherapeutic group: Antiviral monoclonal antibodies

ATC code: J06BD05.

Mechanism of action

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

In the COMET-ICE clinical trial post-baseline variants were detected in (i) the sotrovimab epitope of the spike protein and (ii) the receptor-binding motif of the spike protein. Post-baseline epitope substitutions detected in more than 2 patients in the sotrovimab arm at a frequency of >15% included P337L/R and E340A/K/V. Substitutions E340A/V/K and P337L/R confer reduced susceptibility to sotrovimab (>100-fold change in EC₅₀ value) in an in vitro pseudotyped VLP system. The clinical impact of these substitutions is not yet known. In the receptor-binding motif of the spike protein, the substitutions K417T, S477N, E484K, and N501Y were detected post-baseline in more than 2 patients in the sotrovimab arm at a frequency of >15%. Sotrovimab retains activity against K417T, S477N, E484K, and N501Y in an in vitro pseudotyped VLP system.

Clinical Studies

SARS-CoV-2 variants of concern or variants of interest (VOC/VOI) were detected in patients enrolled in clinical studies who received a 500 mg intravenous infusion of sotrovimab (Table 2).

Table 2. SARS-CoV-2 VOC/VOI detected at ≥ 2% prevalence in sotrovimab-treated patients

^a n = number of sotrovimab-treated patients with the designated VOC/VOI; N = total number of sotrovimab-treated patients with SARS-CoV-2 spike sequence results.

^bThe primary clinical endpoint for progression in COMET-ICE and COMET-TAIL was defined as hospitalisation 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 vitro were observed in patients enrolled in clinical studies who received a 500 mg intravenous infusion of sotrovimab (Table 3). In the COMET-ICE and COMET-TAIL studies, among patients who were treated with a 500 mg intravenous infusion of sotrovimab and had a substitution detected at amino acid positions 337 and/or 340 at any visit baseline or post-baseline, 1 of 32 and none of 33 patients, respectively, met the primary endpoint for progression of hospitalisation for >24 hours for acute management of any illness or death from any cause through Day 29. This single patient had E340K detected post-baseline and was infected with the Epsilon variant of SARS-CoV-2.

Table 3. Baseline and treatment-emergent substitutions detected in sotrovimab-treated patients at amino acid positions associated with reduced susceptibility to sotrovimab

^a n = number of sotrovimab-treated patients with a baseline substitution detected at spike amino acid positions 337 or 340; N = total number of sotrovimab-treated patients with baseline sequence results

^b n = number of sotrovimab-treated patients with treatment-emergent substitutions detected at spike amino acid positions 337 or 340; N = total number of sotrovimab-treated patients with paired baseline and post-baseline sequence results.

Immunogenicity

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

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 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.

The COMET-ICE study was conducted when the dominant form of the coronavirus was the original Wuhan strain.

Patients were randomised to a single 500 mg infusion of sotrovimab (N=528) or placebo (N=529) over 1 hour (Intent to Treat [ITT] population at Day 29). In the ITT population, 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 4: Results of primary and secondary endpoints in the ITT population (COMET-ICE)

An available case analysis of viral load in response to sotrovimab versus placebo is shown in table 5:

Table 5: Summary of nasal SARS-CoV-2 viral load in log 10 copies/mL at baseline and on Day 8 in the Virology population

^aNumber of patients with available data, above the limit of quantification at baseline

^b Number of patients with available data at Day 8.

Paediatric population

The Medicines Health products Regulatory Agency has deferred the obligation to submit the results of studies with Xevudy in one or more subsets of the paediatric population in COVID-19 with acute covid disease (see section 4.2 for information on paediatric use).

Conditional approval

This medicinal product has been authorised under a so-called 'conditional approval' scheme.

This means that further evidence on this medicinal product is awaited.

The Medicines Health products Regulatory Agency will review new information on this medicinal product at least every year and this SPC will be updated as necessary.

Absorption

Based on population pharmacokinetic analyses, following a 15 minute to 1 hour, 500 mg intravenous infusion, the geometric mean C_max was 170 µ g/mL (N = 1188 CVb% 53.4), and the geometric mean Day 28 concentration was 39.7 µ g/mL (N = 1188, CVb% 37.6).

Distribution

Based on population pharmacokinetic analyses, following a 500 mg intravenous infusion, the geometric mean steady-state volume of distribution was 7.9 L.

Biotransformation

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

Drug interactions

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

Elimination

The Fc domain of sotrovimab includes M428L and N434S amino acid substitutions (LS modification) that extends antibody elimination half-life, but does not impact wild-type Fc-mediated effector functions in cell culture. Based on population pharmacokinetic analyses, following a 500 mg intravenous infusion, the geometric mean systemic clearance (CL) was 95 mL/day, with a median terminal half-life of approximately 61 days.

Special populations

Based on population pharmacokinetic analyses, following intravenous infusion, the pharmacokinetics of sotrovimab was not affected by age, sex or BMI. No dose adjustment for sotrovimab is warranted based on these patient characteristics. Body weight was a significant covariate, but the magnitude of effect does not warrant dose adjustment.

Elderly patients (≥ 65 years old)

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. There is limited data in patients with severe renal impairment (creatinine clearance < 30 mL/min/1.73m²).

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). There is no data in patients with severe elevations in alanine amino transferase (5 to < 10 x ULN).

Paediatric population

There are limited data on the pharmacokinetics of sotrovimab in children and adolescents.

The recommended dose for adolescents aged from 12 years and from 40 kg body weight was based on an allometric scaling approach which accounted for effect of body weight changes associated with age on clearance and volume of distribution. This approach is supported by a population pharmacokinetic analysis which shows comparable serum exposures of sotrovimab in adolescents as those observed in adults.

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

Anti-viral activity

Sotrovimab neutralised SARS-CoV-2 virus in vitro (EC₅₀ 100.1 ng/mL). Pseudotyped virus-like particle (VLP) in vitro assessments indicate that sotrovimab retains activity against the Alpha, Beta, Gamma, Epsilon, Iota, Kappa, Delta, Lambda, Delta Plus and Mu variant spike proteins with fold changes in EC₅₀ value ranging from 0.35-2.3.

Table 6 provides in vitro neutralisation 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 randomised controlled clinical studies.

Table 6 Sotrovimab neutralisation data for SARS-CoV-2 variants

^a Substitutions in the spike receptor binding domain are listed.

^b Based on EC₅₀ fold change compared to wild-type. No change: ≤ 5-fold change in EC₅₀ compared to wild-type.

^c Variant has not been named by the WHO..

^d The BA.2.86, BN.1 and JN.1 variants contain the K356T substitution which is known to confer reduced susceptibility to sotrovimab.

^e Sotrovimab is unlikely to be effective against COVID-19 caused by the Omicron BN.1 and JN.1 variants of SARS-CoV-2.

Antiviral resistance

Table 7 shows the activity data for sotrovimab against epitope sequence polymorphisms evaluated in pseudotyped VLP assessments in cell culture using the Wuhan-Hu-1 and Omicron BA.1, BA.2 and BA.5 spike proteins.

Table 7 Sotrovimab pseudotyped VLP assessments in cell culture against epitope substitutions

^a Based on EC₅₀ fold change relative to each spike viral variant. No change: ≤ 5-fold change; – : depicts not tested.

^b Wuhan-Hu-1 strain

^c Omicron lineages

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 in line with international regulatory guidelines for an antibody targeting a virus.

Animal toxicology and pharmacology

No toxicity with sotrovimab was identified in a cynomolgus monkey 2-week repeat-dose IV infusion toxicology study with 105-day recovery period at doses up to 500 mg/kg, the no observed adverse effect level (NOAEL) and highest dose tested. The C_max and total exposure AUC [sum of AUC_0-168h after Dose 1 and AUC_0-last after Dose 2 (Day 8)] values at the NOAEL of 500 mg/kg were 13500 µ g/mL and 216000 day*µ g/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 in section 6.6.

Unopened vial

36 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.

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 stopper laminated 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 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 and discard 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 of sotrovimab from the vial.

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.

Disposal

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