Consumer medicine information

Xevudy

Sotrovimab

BRAND INFORMATION

Brand name

Xevudy

Active ingredient

Sotrovimab

Schedule

SUMMARY CMI

XEVUDY Concentrated injection solution for infusion

Consumer Medicine Information (CMI) summary

XEVUDY has provisional approval for treatment of COVID-19 in adults and adolescents (aged 12 years and over and weighing at least 40 kg) with coronavirus disease 2019 (COVID-19) who do not require initiation of oxygen due to COVID-19 and who are at increased risk of progression to hospitalisation or death. This approval has been granted on the basis of short term efficacy and safety data. Evidence of longer term efficacy and safety from ongoing trials continues to be gathered and assessed.

The full CMI on the next page has more details. If you are worried about using this medicine, speak to your doctor or pharmacist.

▼ This medicine is new or being used differently. Please report side effects. See the full CMI for further details.

1. Why am I being given XEVUDY?

XEVUDY contains the active ingredient sotrovimab. XEVUDY is used to treat COVID-19.

For more information, see Section 1. Why am I being given XEVUDY? in the full CMI.

2. What should I know before I am given XEVUDY?

Do not use if you have ever had an allergic reaction to sotrovimab or any of the ingredients listed at the end of the CMI. Talk to your doctor if you have any other medical conditions, take any other medicines, or are pregnant or plan to become pregnant or are breastfeeding. For more information, see Section 2. What should I know before I am given XEVUDY? in the full CMI.

3. What if I am taking other medicines?

Some medicines may interfere with XEVUDY and affect how it works.

A list of these medicines is in Section 3. What if I am taking other medicines? in the full CMI.

4. How XEVUDY is given?

XEVUDY should not be given to you if you have been hospitalised due to COVID-19.
The recommended dose for adults and adolescents aged 12 years and older and weighing at least 40 kg is one 500 mg dose of XEVUDY.
XEVUDY is recommended to be given to you within 5 days of showing symptoms of COVID-19.
It is given as a drip into a vein (intravenous infusion) by a doctor or nurse. It takes up to 30 minutes to give you the full dose of medicine.

More instructions can be found in Section 4. How XEVUDY is given? in the full CMI.

5. What should I know when being given XEVUDY?

Things you should do	Remind any doctor, dentist or pharmacist you visit that you have taken XEVUDY. Seek medical attention if you think you may be having an allergic reaction.
Things you should not do	Do not stop before the full dose of medicine is taken.
Driving or using machines	XEVUDY is not expected to have any effect on your ability to drive or use machines.
Looking after your medicine	XEVUDY will be given to you in a healthcare facility and the healthcare professionals will be responsible for its storage.

For more information, see Section 5. What should I know when being given XEVUDY? in the full CMI.

6. Are there any side effects?

Like all medicines, this medicine can cause side effects, although not everybody gets them. Some of the side effects can be serious, and you need to know what symptoms to look out for. XEVUDY can cause allergic reactions which may be severe. If you develop symptoms of an allergic reaction, you must tell your doctor or nurse as soon as possible. For more information, including what to do if you have any side effects, see Section 6. Are there any side effects? in the full CMI.

▼ This medicine is subject to additional monitoring. This will allow quick identification of new safety information. You can help by reporting any side effects you may get. You can report side effects to your doctor, or directly at www.tga.gov.au/reporting-problems.

FULL CMI

XEVUDY Concentrated injection solution for infusion

Active ingredient: sotrovimab

This approval has been granted on the basis of short term efficacy and safety data. Evidence of longer term efficacy and safety from ongoing trials continues to be gathered and assessed.

Consumer Medicine Information (CMI)

This leaflet provides important information about using XEVUDY. You should also speak to your doctor or pharmacist if you would like further information or if you have any concerns or questions about using XEVUDY.

Where to find information in this leaflet:

1. Why am I being given XEVUDY?
2. What should I know before I am given XEVUDY?
3. What if I am taking other medicines?
4. How XEVUDY is given?
5. What should I know when being given XEVUDY?
6. Are there any side effects?
7. Product details

1. Why am I being given XEVUDY?

XEVUDY contains the active ingredient sotrovimab, a monoclonal antibody which is a type of protein designed to recognise a specific target on the SARS-CoV-2 virus, the virus that causes COVID-19.

XEVUDY is used to treat COVID-19.

XEVUDY stops the virus from attaching to cells and this blocks the virus from multiplying in the body. This can help your body to overcome the infection and prevent you from getting seriously ill.

2. What should I know before I am given XEVUDY?

Warnings

Do not take XEVUDY if:

you are allergic to sotrovimab, or any of the ingredients listed at the end of this leaflet.
Always check the ingredients to make sure you can use this medicine.

Check with your doctor if you:

have any other medical conditions
take any medicines for any other condition
have allergies to any other medicines, foods, preservatives or dyes. XEVUDY can cause allergic reactions.

During treatment, you may be at risk of developing certain side effects. It is important you understand these risks and how to monitor for them. See additional information under Section 6. Are there any side effects?

Pregnancy and breastfeeding

Check with your doctor if you are pregnant or think you could be pregnant or intend to become pregnant and discuss if you should receive XEVUDY. Your doctor will consider the benefit to you and the risk to your baby of receiving XEVUDY while you're pregnant.

Talk to your doctor if you are breastfeeding or intend to breastfeed. There is insufficient data on whether the ingredients of XEVUDY can pass into breast milk. If you are breast-feeding, you must check with your doctor before you receive XEVUDY.

Children

XEVUDY is not intended to be given to children younger than 12 years old or weighing less than 40 kg.

3. What if I am taking other medicines?

Tell your doctor or pharmacist if you are taking any other medicines, including any medicines, vitamins or supplements that you buy without a prescription from your pharmacy, supermarket or health food shop.

Check with your doctor or pharmacist if you are not sure about what medicines, vitamins or supplements you are taking and if these affect XEVUDY.

4. How XEVUDY is given?

XEVUDY should not be given to you if you have been hospitalised due to COVID-19.

How much is given

The recommended dose for adults and adolescents aged 12 years and older and weighing at least 40 kg is one 500 mg dose of XEVUDY.

When XEVUDY is given

XEVUDY is recommended to be given to you within 5 days of showing symptoms of COVID-19.
XEVUDY will be given to you in a healthcare facility under the supervision of a healthcare professional.
It will be given to you as a drip into a vein (intravenous infusion).
It takes up to 30 minutes to give you the full dose of medicine.
After the infusion, your doctor or nurse will observe you for 1 hour to monitor for signs of an allergic reaction.

5. What should I know when being given XEVUDY?

Things you should do

Remind any doctor, dentist or pharmacist you visit that have taken XEVUDY.
Tell your doctor or nurse if you are taking, have recently taken or might take any other medicines before you receive XEVUDY.
Tell your doctor if you are pregnant, think you may be pregnant or are planning to have a baby.

Call your doctor straight away if you:

Think you may be having an allergic reaction
Notice any symptoms listed in Section 6. Are there any side effects?

Things you should not do

Do not stop your medicine before the full dose has been taken.

Driving or using machines

XEVUDY is not expected to have any effect on your ability to drive or use machines.

Looking after your medicine

XEVUDY will be given to you in a healthcare facility and the healthcare professionals caring for you will be responsible for storing this medicine.

XEVUDY should be stored in a refrigerator between 2°C to 8°C, in the original carton to protect from light.

Do not freeze
Do not use after the expiry date

Keep it where young children cannot reach it.

Getting rid of any unwanted medicine

Unused medicine or waste material will be discarded by your healthcare professional.

6. Are there any side effects?

All medicines can have side effects. If you do experience any side effects, most of them are minor and temporary. However, some side effects may need medical attention.

See the information below and, if you need to, ask your doctor or pharmacist if you have any further questions about side effects.

Serious side effects

Serious side effects	What to do
Allergic reactions These reactions may be severe (for example anaphylaxis) with the following symptoms: skin rash (hives) or redness swelling, sometimes of the face or mouth (angioedema) becoming very wheezy, coughing or having difficulty in breathing suddenly feeling weak or light-headed (may lead to loss of consciousness or falls)	Call your doctor straight away, or go straight to the Emergency Department at your nearest hospital if you notice any of these serious side effects. These side effects can have a delayed onset after you leave the infusion site or clinic.

Tell your doctor or pharmacist if you notice anything else that may be making you feel unwell.

Other side effects not listed here may occur in some people.

Reporting side effects

After you have received medical advice for any side effects you experience, you can report side effects to the Therapeutic Goods Administration online at www.tga.gov.au/reporting-problems. By reporting side effects, you can help provide more information on the safety of this medicine.

Always make sure you speak to your doctor or pharmacist before you decide to stop taking any of your medicines.

7. Product details

This medicine is only available with a doctor's prescription.

What XEVUDY contains

Active ingredient (main ingredient)	Sotrovimab
Other ingredients (inactive ingredients)	Histidine Histidine hydrochloride monohydrate Sucrose Methionine Polysorbate 80 Water for injections
Potential allergens	None

Do not be given this medicine if you are allergic to any of these ingredients.

What XEVUDY looks like

XEVUDY is supplied as a clear, colourless or yellow to brown concentrated injection solution, in a 10 mL clear glass vial, with a rubber stopper and flip-off aluminium over-seal.

(Aust R 364110).

Who distributes XEVUDY

XEVUDY is supplied in Australia by:

GlaxoSmithKline Australia Pty Ltd
Level 4, 436 Johnston Street
Abbotsford, VIC 3067
Australia

Trademarks are owned by or licensed to the GSK group of companies.

This leaflet was prepared in July 2024.

Version 2.0

Published by MIMS August 2024

BRAND INFORMATION

Brand name

Xevudy

Active ingredient

Sotrovimab

Schedule

1 Name of Medicine

Sotrovimab.

2 Qualitative and Quantitative Composition

Each vial contains 500 mg of sotrovimab in 8 mL (62.5 mg/mL).
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Sotrovimab is a clear, colourless or yellow to brown concentrated injection solution for intravenous infusion.

4 Clinical Particulars

4.1 Therapeutic Indications

Xevudy has provisional approval 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 initiation of oxygen due to COVID-19 and who are at increased risk of progression to hospitalisation or death (see Section 5.1 Pharmacodynamic Properties, Clinical trials).
The decision has been made on the basis of short term efficacy and safety data. Continued approval of this indication depends on the evidence of longer term efficacy and safety from ongoing clinical trials and post-market assessment.

4.2 Dose and Method of Administration

As part of risk stratification of patients, the pivotal consideration is the comorbidities, alongside age, particularly multiple comorbidities.
Xevudy should not be used in patients hospitalised due to COVID-19.

Adults and adolescents (aged 12 years and older and weighing at least 40 kg).

The recommended regimen is a single 500 mg dose administered as an intravenous infusion.

Method of administration.

Xevudy is administered as a single intravenous (IV) infusion over 15 minutes (when using a 50 mL infusion bag) or 30 minutes (when using a 100 mL infusion bag) (see Section 4.4 Special Warnings and Precautions for Use).
It is recommended that Xevudy is administered as soon as possible after diagnosis of COVID-19 and within 5 days of onset of symptoms (see Section 5.1 Pharmacodynamic Properties, Clinical trials).
Xevudy must be diluted prior to intravenous administration and must not be administered as an intravenous push or bolus injection.
Xevudy should be administered in healthcare facilities in which patients can be monitored during and for one hour after administration of Xevudy (see Section 4.4 Special Warnings and Precautions for Use).

Preparation for dilution.

Xevudy should be prepared by a qualified healthcare professional using aseptic technique.
1. Remove one vial of Xevudy 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.
a. If a 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.
a. Do not shake or vigorously agitate the vial.

Dilution instructions for intravenous infusion.

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 from the vial of Xevudy.
3. Inject the 8 mL of Xevudy into the infusion bag via the septum.
4. Discard any unused portion left in the vial as the product contains no preservative. 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.
The diluted solution of Xevudy is intended to be used immediately. If 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.

Administration instructions.

1. 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-micrometer in-line filter.
2. Prime the infusion set.
3. Administer as an intravenous infusion over 15 minutes (when using a 50 mL) infusion bag or 30 minutes (when using a 100 mL infusion bag) at room temperature.

Children.

The safety and efficacy of Xevudy have not been established in children less than 12 years of age or weighing less than 40 kg (see Section 5.2 Pharmacokinetic Properties, Special patient populations).

Elderly.

No dose adjustment is required in patients aged 65 years or older (see Section 5.2 Pharmacokinetic Properties, Special patient populations).

Renal impairment.

No dose adjustment is required in patients with renal impairment (see Section 5.2 Pharmacokinetic Properties, Special patient populations).

Hepatic impairment.

No dose adjustment is required in patients with hepatic impairment (see Section 5.2 Pharmacokinetic Properties, Special patient populations).

4.3 Contraindications

Hypersensitivity to the active substance or any of the excipients (see Section 6.1 List of Excipients).

4.4 Special Warnings and Precautions for Use

Hypersensitivity reactions.

Hypersensitivity reactions, including serious reactions such as anaphylaxis, have been reported following infusion of sotrovimab. If signs and symptoms of severe hypersensitivity reactions occur, immediately discontinue administration and initiate appropriate treatment and/or supportive care.
If mild to moderate hypersensitivity reactions occur, consider slowing or stopping the infusion along with appropriate supportive care.

Antiviral resistance.

Due to the observed decrease in in vitro neutralisation activity against the Omicron BA.2 spike variant, it is uncertain if the approved dose of sotrovimab 500 mg IV will be effective against this variant (see Section 5.1 Pharmacodynamic Properties, Pharmacodynamic effects).

Use in elderly.

Based on population pharmacokinetic analysis, there was no difference in sotrovimab pharmacokinetics in elderly patients when compared with younger patients.

Paediatric use.

Effects on laboratory tests.

No data available.

4.5 Interactions with Other Medicines and Other Forms of Interactions

No formal interaction studies have been conducted 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.
In in vitro pharmacodynamic studies with remdesivir or bamlanivimab, sotrovimab showed additive virologic effect and no antagonism with either agent.
The efficacy and safety of sotrovimab in subjects who have received a COVID-19 vaccine at any time prior to its administration has not been established. The receipt of a COVID-19 vaccine within 48 hours prior to, or 4 weeks following treatment with sotrovimab has not been studied.

4.6 Fertility, Pregnancy and Lactation

Effects on 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.
(Category B2)
There are insufficient data on the effects of sotrovimab on human pregnancy. Effects on embryo-fetal development have not been evaluated in animal studies. In a cross-reactive binding assay using a protein array enriched for human embryofetal proteins, no off-target binding was detected. Since sotrovimab is an engineered human immunoglobulin G (IgG), 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.
Xevudy should be used during pregnancy only if the expected benefit to the mother justifies the potential risk to the foetus.
There are insufficient data on the presence of sotrovimab in human milk. There are no data in lactating animals. A decision must be made whether to discontinue breast-feeding or to abstain from sotrovimab therapy considering the benefit of breast-feeding for the child and the benefit of therapy for the mother.

4.7 Effects on Ability to Drive and Use Machines

There have been no studies to investigate the effect of sotrovimab on the ability to perform tasks that require judgement, motor or cognitive skills. A detrimental effect on such activities would not be anticipated from the pharmacology of sotrovimab. The clinical status of the patient and the adverse event profile of sotrovimab should be borne in mind when considering the patient's ability to perform tasks that require judgement, motor or cognitive skills.

4.8 Adverse Effects (Undesirable Effects)

Clinical trial data.

The safety of the 500 mg dose of sotrovimab was evaluated in a placebo-controlled randomised study (1049 non-hospitalised patients with COVID-19 treated in a 1:1 ratio of sotrovimab:placebo (COMET-ICE)) and in two non-placebo controlled randomised studies (193 patients (COMET-PEAK) and 393 patients (COMET-TAIL)) (see Section 5.1 Pharmacodynamic Properties, Clinical trials). See Table 1.

Adverse reactions are listed by MedDRA body system organ class (SOC) and by frequency (see Table 2). Frequencies are defined as: very common (≥ 1/10), common (≥ 1/100 and < 1/10), uncommon (≥ 1/1,000 and < 1/100), rare (≥ 1/10,000 and < 1/1,000) and very rare (< 1/10,000).

Hypersensitivity including anaphylaxis and infusion-related reactions.

In COMET-ICE, hypersensitivity reactions, of grade 1 (mild) or grade 2 (moderate), were reported (7 patients in the sotrovimab arm; 6 patients in the placebo arm). None of the reactions in either study arm led to discontinuation of the infusion.
One case of anaphylaxis was reported following infusion of sotrovimab in a study in hospitalized patients; the patient received adrenaline (epinephrine) and the event resolved.

Post-marketing data.

See Table 3.

Reporting suspected adverse effects.

Reporting suspected adverse reactions after registration 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 at www.tga.gov.au/reporting-problems.

4.9 Overdose

There is no clinical experience of accidental overdose with sotrovimab.
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 without evidence of dose-limiting toxicity.
There is no specific treatment for an overdose of sotrovimab. If overdose occurs, the patient should be treated supportively with appropriate monitoring as necessary.
For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: antiviral monoclonal antibodies.

ATC code.

J06BD05.

Mechanism of action.

Sotrovimab is an engineered human IgG1 mAb that binds to a conserved epitope on the spike protein receptor binding domain of SARS-CoV-2 with high affinity (dissociation constant Kd = 31 nanogram/mL). 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 when compared with the original mAb with LS modification (S309+LS) in cell culture.

Pharmacodynamic effects.

Immunogenicity. Treatment-emergent anti-drug antibodies (ADAs) to a single 500 mg intravenous infusion of sotrovimab were detected in 9% (101/1101) of participants in controlled clinical studies with follow up durations of 18 to 36 weeks. No participants with confirmed treatment-emergent ADAs had neutralising antibodies against sotrovimab. The clinical relevance of such antibodies has not been fully established.
Antiviral activity. Sotrovimab neutralized SARS-CoV-2 in vitro (76.6-132.5 nanogram/mL), and in vivo (≥ 5 mg/kg in SARS-CoV-2 infected hamsters dosed with sotrovimab prior to virus inoculation) and effectively neutralised pseudotyped virus containing the SARS-CoV-2 spike.
Sotrovimab exhibited antibody-dependent cell-mediated cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP) in cell-based assays.
Sotrovimab demonstrated activity in vivo in a hamster model of SARS-CoV-2 infection using sotrovimab as well as VIR-7831-wild type (WT), a mAb that has identical variable regions as sotrovimab but is lacking the LS modification. Intraperitoneal administration of sotrovimab or VIR-7831-WT at ≥ 5 mg/kg prior to inoculation resulted in a significant improvement in body weight loss. Sotrovimab and VIR-7831-WT significantly decreased total viral RNA in the lungs at ≥ 0.5 and ≥ 5 mg/kg, respectively, and infectious virus levels based on TCID₅₀ measurements at ≥ 0.5 mg/kg. Protection was also observed in B.1.351-infected hamsters based on significant reductions in total and infectious virus on Day 4 post-infection in animals receiving a single intraperitoneal dose of 2, 5 or 15 mg/kg sotrovimab compared to isotype control antibody-treated animals.
Antibody dependent enhancement (ADE). The risk that sotrovimab could mediate viral uptake and replication by immune cells was studied in U937 and 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 at concentrations of sotrovimab from 1-fold down to 1000-fold the EC₅₀ value.
The potential for ADE was also evaluated in a hamster model of SARS-CoV-2 using sotrovimab as well as VIR-7831-wild type (WT). No evidence of enhancement of disease was observed at any dose evaluated, including sub-neutralizing doses down to 0.05 mg/kg. Additionally, a separate hamster study using a modified version of the parental antibody S309 that interacts with hamster FcRs was conducted. There was no evidence of ADE using the modified antibody at neutralising or sub-neutralising doses.
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.

Pseudotyped VLP assessments in cell culture and/or in vitro resistance selection with increasing concentrations of sotrovimab were performed using Wuhan-Hu-1, Omicron BA.1 and Omicron BA.2 spike proteins. The epitope sequence polymorphisms at K356T, P337, E340, T345P, and L441N in the Wuhan-Hu-1 spike, conferred reduced susceptibility to sotrovimab. EC₅₀ values against K356T, P337H/K/L/N/R/T and E340A/K/G/I/Q/S/V, T345P, and L441N, increased by 5.1- > 304 fold relative to the wild type.
Epitope substitutions P337H (> 631), K356T (> 631), P337S (> 609), E340D (> 609), and V341F (5.89) in the Omicron BA.1 spike variant, and P337H (> 117), P337S (> 117), P337T (> 117), E340D (> 117), E340G (> 117), K356T (> 117), and K440D (5.13) in the Omicron BA.2 spike variant conferred reduced susceptibility to sotrovimab based on the observed fold-increase in EC₅₀ value shown in parenthesis relative to each spike viral variant. (See Table 4.)

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 (see Table 5).

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 6). within 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 to hospitalisation for > 24 hours for acute management of any illness or death from any cause through Day 29. The single patient had E340K detected post-baseline and was infected with the Epsilon variant of SARS-CoV-2.

The clinical impact of these variants is not yet known.

Clinical trials.

COMET-ICE.

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 patients at high risk of medical complications of the disease. Patients included were aged 18 years and older with at least 1 of the following comorbidities: diabetes requiring medication, obesity (BMI > 30), chronic kidney disease (eGFR < 60 mL/min), congestive heart failure (NYHA ≥ class 2), chronic obstructive pulmonary disease, or moderate to severe asthma (requiring inhaled steroids to control the symptoms or has been prescribed a course of oral corticosteroids in the past year), or were aged 55 years and older. The study included symptomatic patients with SARS-CoV-2 infection, as confirmed by local laboratory tests and/or point of care tests. The study was conducted when the wild-type Wuhan-Hu-1 virus was predominant, with the highest frequency of variants being Alpha and Epsilon (see Section 5.1 Pharmacodynamic Properties, Pharmacodynamic effects). Patients with severe COVID-19 requiring supplemental oxygen or hospitalization and patients who have received a COVID-19 vaccine were excluded from the trial. Patients were randomised to receive a single 500 mg infusion of sotrovimab (N = 528) or placebo (N = 529) over 1 hour (Intent to Treat [ITT] population at Day 29).
A total of 46% of randomised patients were male. The median age of the overall randomised population was 53 years (range: 17 to 96). A total of 20% of patients were aged 65 years or older and 11% were over 70 years of age. The majority of patients were of White race (87%); 8% were Black or African American and 4% were Asian. The ethnicity of the majority of patients was Hispanic or Latino (65%). Fifty-nine percent of patients received sotrovimab or placebo within 3 days of COVID-19 symptom onset and 41% 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 medication (22%) and moderate to severe asthma (17%). Overall, baseline demographic and disease characteristics were well balanced between the treatment arms.
Enrolment to COMET-ICE was halted for overwhelming efficacy following a pre-specified interim analysis (IA) of the primary endpoint. The primary endpoint, progression of COVID-19 at Day 29, was reduced by 79% compared with placebo (adjusted relative risk reduction) in recipients of sotrovimab (p < 0.001) in the final intention to treat (ITT) population. This reduction is consistent in magnitude to that previously reported for ITT (IA) population. Tables 7 and 8, provides the results of the primary endpoint and key secondary endpoints of COMET-ICE.

COMET-TAIL.

Study 217114 (COMET-TAIL) was a Phase III randomised, multicentre, open label study which evaluated the efficacy and safety of sotrovimab given intravenously versus intramuscularly (which is not a recommended route of administration) for the treatment of COVID-19 in non-hospitalised patients at high risk of medical complications of the disease. Patients receiving 500 mg sotrovimab by intravenous infusion were aged 12 years and older with at least 1 of the following comorbidities: diabetes, obesity (BMI ≥ 85th percentile for age/sex based on Centres for Disease Control and Prevention growth charts for adolescents or BMI ≥ 30 for subjects ≥ 18 years old), chronic kidney disease, congenital heart disease, congestive heart failure (for subjects ≥ 18 years old), chronic lung diseases, sickle cell disease, neurodevelopmental disorders, immunosuppressive disease or receiving immunosuppressive medications, or chronic liver disease; or were aged 55 years or older. The study included patients with SARS-CoV-2 infection (as confirmed by local laboratory tests and/or point of care tests), and symptoms for ≤ 7 days. Patients with severe COVID-19 requiring supplemental oxygen or hospitalisation were excluded from the trial. The primary analysis set consisted of 378 patients randomised to a 500 mg intravenous infusion of sotrovimab over 15 minutes.
In the primary analysis set at baseline, the median age was 51 years (range: 15 to 90, including 2 patients under 18 years). Twenty-five percent of patients were aged 65 years or older and 8% were 75 years or older. Forty-two percent of patients were male. The majority of patients were of White race (96%) and 4% were Black or African American. The ethnicity of the majority of patients was Hispanic or Latino (83%). Fourteen percent of patients received sotrovimab > 5 days after COVID-19 symptom onset. The four most common pre-defined risk factors were obesity (63%), 55 years of age or older (42%), chronic lung disease (16%) and diabetes (13%). The most prevalent SARS-CoV-2 variant during this study was Delta (see Section 5.1 Pharmacodynamic Properties, Antiviral resistance).
In the primary analysis population, the proportion of patients progressing to hospitalisation for > 24 hours for acute management of any illness or death due to any cause through Day 29 was 1.3% (5/378). In addition, 0.3% (1/378) of patients progressed to severe/critical respiratory COVID-19 as manifested by requirement for oxygen therapy.

5.2 Pharmacokinetic Properties

The pharmacokinetic profile of sotrovimab is consistent with a half-life extended IgG.
Based on population PK analyses, following intravenous infusion, the PK of sotrovimab were 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.

Absorption.

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

Distribution.

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

Metabolism.

Sotrovimab is an engineered human IgG1 monoclonal antibody degraded by proteolytic enzymes which are widely distributed in the body and not restricted to hepatic tissue.

Excretion.

Based on population PK analysis, 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.