Consumer medicine information

Evusheld

Tixagevimab; Cilgavimab

BRAND INFORMATION

Brand name

Evusheld

Active ingredient

Tixagevimab; Cilgavimab

Schedule

SUMMARY CMI

EVUSHELD™

Consumer Medicine Information (CMI) summary

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

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

1. Why am I using EVUSHELD?

EVUSHELD contains the active ingredients tixagevimab and cilgavimab. EVUSHELD is used to:

help prevent adults and adolescents (aged 12 years and older weighing at least 40 kg), who have not been recently in contact with someone who has COVID-19, from getting COVID-19 illness when they are unlikely to be protected by a COVID-19 vaccine or when vaccination is not recommended.
treat adults with COVID-19 who do not require supplemental oxygen to treat COVID-19 and who are at increased risk for the illness becoming severe based on the evaluation of your doctor.

For more information, see Section 1. Why am I using EVUSHELD? in the full CMI.

2. What should I know before I use EVUSHELD?

You must not be given EVUSHELD if you have ever had an allergic reaction to tixagevimab and cilgavimab or any of the ingredients listed at the end of the CMI.

Check with your doctor if you have any low numbers of blood platelets (which help blood clotting), have a bleeding disorder or are taking a blood thinning medicine (to prevent blood clots).

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 use EVUSHELD? in the full CMI.

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.

For more information, see Section 3. What if I am taking other medicines? in the full CMI.

4. How is EVUSHELD given?

EVUSHELD will be given to you by your healthcare provider as two intramuscular injections, one into each of your buttocks.

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

5. What should I know while I am being given EVUSHELD?

Things you should do

Seek medical attention if you think you experience any problems with this medicine.
Remind any healthcare provider you visit that you are using EVUSHELD.
If you are taking EVUSHELD to help prevent you from getting COVID-19, and you get symptoms of COVID-19 please contact your doctor right away.

For more information, see Section 5. What should I know while using EVUSHELD? in the full CMI.

6. Are there any side effects?

Pain, bruising of the skin, soreness or swelling, at the injection site are common side effects.

Serious allergic reactions. They may include the following symptoms: difficulty breathing or swallowing, swelling of the face, lips, tongue or throat, severe itching of the skin, with a red rash or raised bumps.

Serious cardiac and blood clot adverse events including the following symptoms: pain, pressure, or discomfort in the chest, arms, neck, back, stomach, legs or jaw, abdominal pain, shortness of breath, faster than normal heart beat, feeling tired or weak (fatigue), feeling sick (nausea), swelling in your ankles or lower legs, coughing up blood, difficulties speaking or confusion, loss of movement or weakness on one side of the body or face, severe headache. It is not known if these events are related to EVUSHELD or underlying medical conditions.

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

EVUSHELD™

Active ingredients: tixagevimab and cilgavimab

EVUSHELD has provisional approval to:

help prevent adults and adolescents (aged 12 years and older weighing at least 40 kg), who have not been recently in contact with someone who has COVID-19, from getting COVID-19 illness when they:
have an illness or take medicines making them unlikely to respond to or be protected by vaccination against COVID-19
or are not recommended to have a vaccine due to a history of severe allergies to a COVID-19 vaccine or its components.

Evusheld is not a substitute for vaccination in individuals for whom COVID-19 vaccination is recommended.

treat adults with COVID-19 who do not require supplemental oxygen to treat COVID-19 and who are at increased risk for the illness becoming severe based on the evaluation of your doctor.

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

Consumer Medicine Information (CMI)

This leaflet provides important information about using EVUSHELD. 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 EVUSHELD.

Where to find information in this leaflet:

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

1. Why am I using EVUSHELD?

EVUSHELD contains the active ingredients tixagevimab and cilgavimab.

Tixagevimab and cilgavimab are types of protein called ‘monoclonal antibodies’.

Tixagevimab and cilgavimab (EVUSHELD) work specifically against the SARS-CoV-2 virus preventing it from entering your cells. This can help prevent you from getting COVID-19 illness or help your body to overcome the infection and reduce the risk of you developing severe illness.

COVID-19 is an illness which can affect your lungs, airways and other organs. COVID-19 illnesses can be very mild (sometimes with no symptoms), however in some cases symptoms can be severe and can result in hospitalisation or even death.

What EVUSHELD is used for

EVUSHELD is used to help prevent adults and adolescents (aged 12 years and older weighing at least 40 kg), who have not been recently in contact with someone who has COVID-19, from getting COVID-19 illness when they:

have an illness or take medicines making them unlikely to respond to or be protected by vaccination against COVID-19
or are not recommended to have a vaccine due to a history of severe allergies to a COVID-19 vaccine or its components.

Evusheld is not a substitute for vaccination in individuals for whom COVID-19 vaccination is recommended.

EVUSHELD is also used to treat adults with COVID-19 who do not require supplemental oxygen to treat COVID-19 and who are at increased risk for the illness becoming severe based on the evaluation of your doctor.

2. What should I know before I use EVUSHELD?

Warnings

Do not use EVUSHELD if:

you are allergic to tixagevimab, cilgavimab 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 allergies
have any low numbers of blood platelets (which help blood clotting)
have had a heart attack or stroke, have other heart problems, or are at high-risk of cardiac (heart) events
have a bleeding disorder or are taking a blood thinning medicine (to prevent blood clots)
are taking, have recently taken or might take any medicines for any other condition.

If you have received a COVID-19 vaccine, tell your doctor or nurse, prior to using EVUSHELD. It is possible that EVUSHELD may reduce your body's immune response to a COVID-19 vaccine.

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

If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask your healthcare provider for advice before receiving this medicine.

Tell your doctor if you are pregnant, or if you might be pregnant. There is not enough information to be sure that this medicine is safe for use in pregnancy. EVUSHELD will only be given if the potential benefits of treatment outweighs the potential risks to the mother and the unborn child.

Talk to your doctor if you are breastfeeding. It is not yet known whether EVUSHELD passes into human milk or what the effects might be on the baby or milk production. Your doctor will help you decide whether to keep breastfeeding or to start treatment with this medicine.

Children and adolescents

EVUSHELD should not be given to children below 12 years of age or weighing less than 40 kg.

3. What if I am taking other medicines?

If you are getting a COVID-19 vaccine, tell your doctor, nurse or pharmacist that you have used or are using EVUSHELD.

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

4. How is EVUSHELD given?

How much EVUSHELD is given

EVUSHELD consists of two medicines, tixagevimab and cilgavimab. You will receive 2 injections one after the other.

The recommended dose is 600 mg given as two 3 mL injections:

300 mg of tixagevimab
300 mg of cilgavimab.

You may also receive repeat doses of 600 mg EVUSHELD (300 mg of tixagevimab and 300 mg of cilgavimab) every 6 months for the continuous prevention of COVID-19, as advised by your doctor.

How you will be given EVUSHELD

EVUSHELD will be given to you in a healthcare facility under the supervision of a healthcare professional who is experienced in the use of this type of treatment. They will watch you closely while you are being given this medicine. This is in case you get any side effects.
EVUSHELD will be given to you by your healthcare provider as two intramuscular injections, one into each of your buttocks.
Your doctor or nurse will decide how long you will be monitored after you are given the medicine, in case you have any side effects.

If you use too much EVUSHELD

As EVUSHELD is given under the close supervision of a healthcare provider it is unlikely that you will be given too much.

If you are concerned that you have been given too much EVUSHELD, tell your healthcare provider immediately, phone the Poisons Information Centre (by calling 13 11 26) or go to the Emergency Department at your nearest hospital

You should do this even if there are no signs of discomfort or poisoning.

5. What should I know while I am being given EVUSHELD?

Things you should do

Tell any other doctors you see that you have had this medicine to prevent or treat COVID-19.

If you are getting a COVID-19 vaccine, tell the doctor, nurse or pharmacist you have had this medicine.

COVID-19 is caused by different strains (variants) of the SARS-CoV-2 virus that change over time. EVUSHELD may be less effective at preventing COVID-19 caused by some strains than others. If you are taking EVUSHELD to help prevent you from getting COVID-19, and you get symptoms of COVID-19 please contact your doctor right away. COVID-19 affects different people in different ways:

the most common symptoms include fever, cough, tiredness and loss of taste or smell;
the most serious symptoms include difficulty breathing or shortness of breath, loss of speech or mobility, or confusion and chest pain.

Call your doctor straight away if you notice any signs of serious allergic reaction, such as:

difficulty breathing or swallowing
swelling of the face, lips, tongue or throat
severe itching of the skin, with a red rash or raised bumps.

Driving or using machines

It is unlikely that EVUSHELD will affect your ability to drive or use machines.

Looking after your medicine

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

Unopened vials should be stored in a refrigerator (at 2°C to 8°C), in the original carton to protect from light.

Do not freeze. Do not shake.
Do not use this medicine after the expiry date which is stated on the label and carton after EXP. The expiry date refers to the last day of that month.

Prepared syringes should be used immediately. If necessary, store the prepared syringes for no more than 4 hours either:

at 2°C to 8°C, or
at room temperature up to 25°C

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.

Allergic reactions may be serious and have occurred during or following administration of EVUSHELD (see 5. What should I know while using EVUSHELD? and serious side effects table below).

Cardiac (heart) and blood clot events: serious cardiac and blood clot adverse events have happened, but were not common in clinical trials. In the clinical trial studying preexposure prophylaxis for the prevention of COVID-19, in people with risk factors for cardiac events (including a history of heart attack), more people who received EVUSHELD experienced serious cardiac events than people who did not receive EVUSHELD. More people who received EVUSHELD experienced blood clot events than people who did not receive EVUSHELD. One event of blood clot in a major blood vessel was reported 6 days after EVUSHELD was given to an individual. The CT scan of the abdominal and groin region at the time of the event showed pre-existing deposits in the blood vessels. A possible relationship between this event and the treatment with EVUSHELD cannot be ruled out. Overall, it is not known if these cardiac and blood clot events are related to EVUSHELD or underlying medical conditions.

Contact your healthcare provider or get medical help right away if you get any symptoms of cardiac events, including pain, pressure, or discomfort in the chest, arms, neck, back,stomach or jaw, as well as shortness of breath, feeling tired or weak (fatigue), feeling sick (nausea), or swelling in your ankles or lower legs.

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

Less serious side effects

Less serious side effects	What to do
Skin: Pain, bruising of the skin, soreness or swelling at the injection site.	Speak to your doctor if you have any of these side effects and they worry you.

Serious side effects

Serious side effects

What to do

Serious allergic reactions, some of the symptoms may include:

Difficulty breathing or swallowing
Swelling of the face, lips, tongue or throat
Severe itching of the skin, with a red rash or raised bumps.

Cardiac (heart) and blood clot events:

Pain, pressure, or discomfort in the chest, arms, neck, back, stomach, legs or jaw, abdominal pain, shortness of breath, faster than normal heart beat, feeling tired or weak (fatigue), feeling sick (nausea), swelling in your ankles or lower legs, coughing up blood, difficulties speaking or confusion, loss of movement or weakness on one side of the body or face, severe headache.

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.

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

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 EVUSHELD contains

Active ingredient (main ingredient)	tixagevimab and cilgavimab
Other ingredients (inactive ingredients)	histidine, histidine hydrochloride monohydrate, sucrose, polysorbate 80 and water for injection

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

What EVUSHELD looks like

Each carton of EVUSHELD contains:

one single use clear glass vial of tixagevimab solution for injection (dark grey vial cap)
one single use clear glass vial of cilgavimab solution for injection (white vial cap).

Each of the single use vials contains a clear to opalescent, colourless to slightly yellow solution.

Aust R 378245

Who distributes EVUSHELD

AstraZeneca Pty Ltd
ABN 54 009 682 311
66 Talavera Road
MACQUARIE PARK NSW 2113
Telephone: 1800 805 342

This leaflet was prepared on 13 February 2023

Doc ID-004808156 v3

Published by MIMS April 2023

BRAND INFORMATION

Brand name

Evusheld

Active ingredient

Tixagevimab; Cilgavimab

Schedule

1 Name of Medicine

Tixagevimab and cilgavimab.

2 Qualitative and Quantitative Composition

Each carton of Evusheld contains two vials:
150 mg of tixagevimab in 1.5 mL (100 mg/mL).
150 mg of cilgavimab in 1.5 mL (100 mg/mL).
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Solution for injection.
Clear to opalescent, colourless to slightly yellow, pH 6.0 solution.

4 Clinical Particulars

4.1 Therapeutic Indications

Pre-exposure prophylaxis.

Evusheld (tixagevimab and cilgavimab) has provisional approval for the pre-exposure prophylaxis of COVID-19 in adults and adolescents aged 12 years and older weighing at least 40 kg;
Who have moderate to severe immune compromise due to a medical condition or receipt of immunosuppressive medications or treatments that make it likely that they will not mount an adequate immune response to COVID‐19 vaccination or;
For whom vaccination with any approved COVID‐19 vaccine is not recommended due to a history of severe adverse reaction (e.g. severe allergic reaction) to a COVID‐19 vaccine(s) and/or COVID‐19 vaccine component(s).
See Section 4.2 Dose and Method of Administration; Section 5.2 Pharmacokinetic Properties.
Evusheld is not recommended as a substitute for vaccination in individuals for whom COVID-19 vaccination is recommended.
This decision has been made on the basis of short-term efficacy and safety data. Continued approval depends on the evidence of longer-term efficacy and safety data from ongoing clinical trials.

Treatment.

Evusheld has provisional approval for the treatment of adults with COVID-19, who do not require supplemental oxygen and who are at increased risk of progressing to severe COVID-19. See Section 4.2 Dose and Method of Administration; Section 5.2 Pharmacokinetic Properties.
This decision has been made on the basis of short-term efficacy and safety data. Continued approval depends on the evidence of longer-term efficacy and safety data from ongoing clinical trial.

4.2 Dose and Method of Administration

Posology.

Pre-exposure prophylaxis.

The recommended dose is 600 mg of Evusheld administered as two separate 3.0 mL, sequential injections of: 300 mg of tixagevimab; 300 mg of cilgavimab.
Repeat doses of 600 mg of Evusheld (300 mg of tixagevimab and 300 mg of cilgavimab) is optional and may be given once every 6 months at the discretion of the treating health care professional. The decision for whom to implement repeat dosing should be based on the available evidence and patient circumstances. Repeat-dosing should only be considered if the treatment benefit outweighs the associated risks.
The dose recommendations for prophylaxis at the 600 mg dose of Evusheld are based on the totality of the available data including clinical pharmacology, pharmacokinetics (PK), antiviral activity, and clinical trial data (see Section 4.8 Adverse Effects (Undesirable Effects); Section 5.1 Pharmacodynamic Properties; Section 5.2 Pharmacokinetic Properties). Evusheld has only been studied at the 300 mg dose in clinical studies for the prophylaxis of COVID-19. The clinical safety of a 600 mg Evusheld dose is supported by safety data from TACKLE in adult patients with mild to moderate COVID-19 (see Section 4.8 Adverse Effects (Undesirable Effects)).

Treatment.

The recommended dose is 600 mg of Evusheld, administered as two separate 3.0 mL, sequential injections of: 300 mg of tixagevimab; 300 mg of cilgavimab.
Evusheld should be given as soon as possible after a positive viral test for SARS-CoV-2 and within 7 days after the onset of symptoms of COVID-19 (see Section 5.1 Pharmacodynamic Properties).

Special patient populations.

Paediatric use.

The recommended dosing regimens are expected to result in comparable serum exposures of tixagevimab and cilgavimab in individuals 12 years of age and older and weighing at least 40 kg as observed in adults, since adults with similar body weight have been included in the clinical trials PROVENT and TACKLE (see Section 5.1 Pharmacodynamic Properties; Section 5.2 Pharmacokinetic Properties).
The safety and efficacy of Evusheld in children aged < 18 years have not been established. No data are available.

Method of administration.

Evusheld must be administered by a healthcare professional.
Intramuscular (IM) injection. See Table 1.
Tixagevimab and cilgavimab should be administered as two separate sequential IM injections at different injection sites, one in each of the gluteal muscles.
Each carton of Evusheld contains two vials: tixagevimab solution for injection (dark grey vial cap); cilgavimab solution for injection (white vial cap).

Visually inspect the vials for particulate matter and discolouration. Both tixagevimab and cilgavimab are clear to opalescent, colourless to slightly yellow solutions. Discard the vials if the solution is cloudy, discoloured or visible particles are observed. Do not shake the vials.
The solutions for injection do not contain a preservative and therefore, the prepared syringes should be administered immediately.
If immediate administration is not possible, and the prepared tixagevimab and cilgavimab syringes need to be stored, the total time from vial puncture to administration should not exceed 4 hours, either: in a refrigerator at 2°C to 8°C; or at room temperature up to 25°C.
The vials are for single use in one patient only. Any unused solution should be discarded.

4.3 Contraindications

Individuals with a history of severe hypersensitivity reactions, including anaphylaxis, to the active substances or to any of the excipients listed in Section 6.1 List of Excipients.

4.4 Special Warnings and Precautions for Use

Hypersensitivity including anaphylaxis.

Serious hypersensitivity reactions, including anaphylaxis, have been reported following administration of Evusheld (see Section 4.8 Adverse Effects (Undesirable Effects)). If signs and symptoms of a clinically significant hypersensitivity reaction or anaphylaxis occur, immediately discontinue administration and initiate appropriate medicinal products and/or supportive therapy.

Clinically significant bleeding disorders.

As with any other intramuscular injections, Evusheld should be given with caution to patients with thrombocytopenia or any coagulation disorder.

Breakthrough infection or treatment failure due to antiviral resistance.

The clinical trials with Evusheld were conducted when alpha, beta, gamma and delta variants were predominant. Certain SARS-CoV-2 viral variants may not be neutralized by monoclonal antibodies such as tixagevimab and cilgavimab, the components of Evusheld. Evusheld may not be effective at preventing or treating COVID-19 caused by these SARS-CoV-2 viral variants. The in vitro neutralisation activity of Evusheld against SARS-CoV-2 viral variants are shown in Table 7 (see Section 5.1 Pharmacodynamic Properties).
Patients who receive Evusheld prophylactically should be informed of the potential for breakthrough infections to occur due to the development of viral variants that are resistant to tixagevimab and cilgavimab. Patients should be instructed to promptly seek medical advice if signs or symptoms of COVID-19 occur (the most common symptoms include fever, cough, tiredness and loss of taste or smell; the most serious symptoms include difficulty breathing or shortness of breath, loss of speech or mobility, or confusion and chest pain).
Decisions regarding the use of Evusheld for the prophylaxis and the treatment of COVID-19 should take into consideration what is known about the characteristics of the circulating SARS-CoV-2 viral variants, including geographical prevalence and local guidelines.

Cardiovascular and thromboembolic events.

In PROVENT, there was a higher rate of cardiac serious adverse events (SAEs), including myocardial infarction (one fatal SAE) and cardiac failure, in subjects who received Evusheld compared to placebo. See Section 4.8 Adverse Effects (Undesirable Effects). All subjects who experienced cardiac SAEs had cardiovascular risk factors and/or a prior history of cardiovascular disease.
In PROVENT, there was a higher rate of thromboembolic serious adverse events (SAEs) in subjects who received Evusheld, compared to placebo. See Section 4.8 Adverse Effects (Undesirable Effects). One event of mesenteric artery thrombosis was reported as a SAE, 6 days after injection in a subject without a known medical history of coagulation disorders. A CT scan of the abdomen and pelvis at the time of the event showed atheromatous overload of vascular vessels. A possible relationship with Evusheld cannot be ruled out.
In TACKLE, there were 2 SAEs (0.4%) of acute myocardial infarction in Evusheld arm and 0 (0%) in placebo arm. One of these patients also experienced a fatal event of acute left ventricular failure. There were 2 deaths in total in TACKLE due to cardiac events in Evusheld arm (0.4%) and 0 (0%) in placebo arm. The second death in TACKLE was reported as sudden cardiac death. These events were reported in individuals with cardiovascular risk factors and/or prior history of cardiovascular disease. See Section 4.8 Adverse Effects (Undesirable Effects).
A causal relationship between Evusheld and these events has not been established.
Consider the risks and benefits prior to initiating Evusheld in individuals at high risk for cardiovascular events, and advise individuals to seek immediate medical attention if they experience any signs or symptoms suggestive of a cardiovascular event.

Use in the elderly.

See Section 5.2 Pharmacokinetic Properties.

Paediatric use.

The safety and efficacy of Evusheld in children aged < 18 years has not been established. No data are available. See Section 4.2 Dose and Method of Administration; Section 5.2 Pharmacokinetic Properties.

Effects on laboratory tests.

No data available.

4.5 Interactions with Other Medicines and Other Forms of Interactions

No interaction studies have been conducted.
Evusheld is not expected to undergo metabolism by hepatic enzymes or renal elimination (see Section 5.2 Pharmacokinetic Properties).

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

There are no data on the effects of tixagevimab and cilgavimab on human fertility.
(Category B2)
There are limited data from the use of tixagevimab and cilgavimab in pregnant women.
Non-clinical reproductive toxicity studies have not been performed with tixagevimab and cilgavimab. In a tissue cross reactivity study with tixagevimab and cilgavimab using human fetal tissues no binding was detected.
Evusheld should only be used during pregnancy if the potential benefit outweighs the potential risk for the mother and the foetus.
It is not known whether tixagevimab and cilgavimab are excreted in human milk. Exposure to the breastfed child cannot be excluded.
The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for Evusheld and any potential adverse effects on the breastfed child from Evusheld or from underlying maternal condition.

4.7 Effects on Ability to Drive and Use Machines

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

4.8 Adverse Effects (Undesirable Effects)

Summary of the safety profile.

A total of 4210 adult participants have been exposed to 150 mg tixagevimab and 150 mg cilgavimab, via IM injection for all phase III studies conducted in the prophylaxis setting.
The most frequently reported adverse reaction was injection site reaction (1.3%).
A total of 452 non-hospitalised adult patients with mild to moderate COVID-19 have received 300 mg tixagevimab and 300 mg cilgavimab, via intramuscular injection, in a Phase III treatment study (TACKLE). The overall safety profile in patients who received 300 mg tixagevimab and 300 mg cilgavimab for the treatment of mild to moderate COVID-19 was similar to that reported in participants who received 150 mg tixagevimab and 150 mg cilgavimab in the prophylaxis studies. The most frequently reported adverse reaction was injection site reaction (2.4%).

Adverse reactions.

Adverse reactions (Table 2) are organised by MedDRA System Organ Class (SOC). Within each SOC, preferred terms are arranged by decreasing frequency and then by decreasing seriousness. Frequencies of occurrence of adverse reactions are defined as: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100); rare (≥ 1/10,000 to < 1/1000); very rare (< 1/10,000) and not known (cannot be estimated from available data).

PROVENT. PROVENT enrolled adults ≥ 18 years of age who were either ≥ 60 years of age, had pre-specified comorbidities, or were at increased risk of SARS-CoV-2 infection due to their living situation or occupation. Subjects could not have previously received a COVID-19 vaccine or have known prior or current SARS-CoV-2 infection. Subjects received a single dose of Evusheld (N = 3,461) or placebo (N = 1,736). The primary safety analysis was based on data through to an event driven efficacy data cut-off with a median (range) follow-up of 83 days (3-166 days). An additional data cut-off was conducted to provide updated analyses with a median (range) of follow-up of 6.5 months (3-282 days), the median and range of follow-up times were similar between Evusheld and placebo recipients.
Adverse events were reported in 1,221 (35%) subjects receiving Evusheld and 593 (34%) receiving placebo. SAEs were reported in 50 (1%) subjects receiving Evusheld and 23 (1%) receiving placebo.
Of the reported adverse events (N = 4,507), the majority were mild (73%) or moderate (24%) in severity. All adverse events, occurring in at least 1% of subjects, were reported at similar incidence rates among subjects receiving Evusheld compared to those receiving placebo (difference < 1%).
The most common treatment-emergent adverse events, occurring in at least 3% of subjects receiving Evusheld or placebo are shown in Table 3.

At the additional data cut-off (median follow-up 6.5 months), the overall adverse event profile for subjects who received Evusheld remained similar to that was reported at the time of the primary analysis.

Cardiac serious adverse events.

Through the additional data cut-off in PROVENT, a higher proportion of subjects who received Evusheld versus placebo in PROVENT reported myocardial infarction SAEs, one of which resulted in death, and cardiac failure SAEs (see Table 4). All subjects who experienced cardiac SAEs had cardiac risk factors and/or a prior history of cardiovascular disease at baseline.

Thromboembolic serious adverse events.

Through the additional data-cut-off in PROVENT, a higher incidence of thromboembolic SAEs was reported in subjects who received Evusheld, compared to placebo. A summary of thromboembolic SAEs are provided in Table 5.

Repeat dosing.

There is a lack of safety data from clinical studies with repeat dosing of 600 mg Evusheld.
TACKLE. TACKLE enrolled adults ≥ 18 years of age with mild to moderate COVID-19 who were within ≤ 7 days of symptom onset. Approximately 90% of study subjects had risk factors that put them at high risk for progression to severe COVID-19. Subjects received a single dose of Evusheld (N = 452) or placebo (N = 451).
Adverse events were reported in 132 (29%) subjects receiving Evusheld and 163 (36%) receiving placebo. Serious adverse events were reported in 33 (7%) subjects receiving Evusheld and 54 (12%) receiving placebo. Of the reported adverse events (N = 520), the majority were mild (56%) or moderate (27%) in severity. There were no reports of anaphylaxis or serious hypersensitivity reactions.
Adverse events of insomnia (1% vs. < 1%) and dizziness (1% vs. none) were reported at a higher rate with Evusheld compared to placebo. No other treatment-emergent adverse events, occurring in at least 1% of subjects, were reported at higher incidence rates (difference ≥ 1%) among subjects receiving Evusheld compared to those receiving placebo.

Cardiac serious adverse events.

In TACKLE, two subjects in the Evusheld arm reported acute myocardial infarction and none in the placebo arm. One of these patients also experienced a fatal event of acute left ventricular failure. There were 2 deaths in TACKLE due to cardiac events in Evusheld arm and 0 in placebo arm. The second death in TACKLE was reported as sudden cardiac death. These events were reported in individuals with cardiovascular risk factors and/or prior history of cardiovascular disease. A causal relationship between Evusheld and these events has not been established. A summary of cardiac SAEs are provided in Table 6.

Paediatric population.

No data are available for paediatric patients < 18 years old (see Section 4.2 Dose and Method of Administration; Section 5.2 Pharmacokinetic Properties).

Postmarket experience.

The following adverse reaction has been identified during post-authorisation/marketing use of Evusheld. It is generally not possible to reliably determine the frequency because such reactions have been reported spontaneously from a population of uncertain size. The frequency of these adverse reactions is therefore 'not known' (cannot be estimated from available data).

Immune system disorders.

Serious hypersensitivity including anaphylaxis, see Section 4.4 Special Warnings and Precautions for Use.

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 specific treatment for overdose with Evusheld.
In clinical trials, doses up to 600 mg IM (300 mg each of tixagevimab and cilgavimab) and 3000 mg intravenously (1500 mg each of tixagevimab and cilgavimab) have been administered without dose-limiting toxicity.
For information on the management of overdose, contact the Poison Information Centre on 131126 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Tixagevimab and cilgavimab are two recombinant human IgG1κ monoclonal antibodies, with amino acid substitutions to extend antibody half-life (YTE) and to reduce antibody effector function and potential risk of antibody-dependent enhancement of disease (TM). Tixagevimab and cilgavimab can simultaneously bind to non-overlapping regions of the spike protein receptor binding domain (RBD) of SARS-CoV-2. Tixagevimab, cilgavimab and their combination bind to spike protein with equilibrium dissociation constants of K_D = 2.8 picoM, 13.0 picoM and 13.7 picoM, respectively, blocking its interaction with the human ACE2 receptor, resulting in a blockade of virus entry and effectively neutralising the SARS-CoV-2 virus. Tixagevimab, cilgavimab and their combination blocked RBD binding to the human ACE2 receptor with IC₅₀ values of 0.32 nanoM (48 nanogram/mL), 0.53 nanoM (80 nanogram/mL) and 0.43 nanoM (65 nanogram/mL), respectively.

Antiviral activity.

In a SARS-CoV-2 virus neutralisation assay on Vero E6 cells, tixagevimab, cilgavimab and their combination neutralised SARS-CoV-2 (USA-WA1/2020 isolate) with EC₅₀ values of 60.7 picoM (9 nanogram/mL), 211.5 picoM (32 nanogram/mL) and 65.9 picoM (10 nanogram/mL), respectively. These in vitro values correlate with in vivo clinical effective serum concentrations of 2.2 microgram/mL of Evusheld.
Antibody-dependent cell-mediated cytotoxicity (ADCC) was assessed using target cells that carry SARS-CoV-2 spike protein, with monoclonal antibody concentrations at a range of 25 microgram/mL to 1.5 nanogram/mL. Antibody-dependent cellular phagocytosis (ADCP) and antibody-dependent complement deposition (ADCD) were assessed using spike antigen-functionalised beads. ADCP activity was assessed with primary human neutrophils or THP-1 human monocytic cell line, with antibody concentrations at a range of 5 microgram/mL to 2 nanogram/mL and 67 microgram/mL to 30.6 nanogram/mL, respectively. ADCD activity was assessed with antibody concentrations at a range of 100 microgram/mL to 46 nanogram/mL. Antibody-dependent NK cell activation (ADNKA) was assessed using primary human NK cells on spike-coated plates with monoclonal antibody concentrations at a range of 20 microgram/mL to 9 nanogram/mL. Tixagevimab, cilgavimab and the tixagevimab and cilgavimab combination mediated no ADCP activity in primary human neutrophils and only limited ADCP activity in THP-1 cells. Tixagevimab, cilgavimab and the tixagevimab and cilgavimab combination did not mediate ADCC or ADNKA activity with human NK cells. Tixagevimab, cilgavimab and the tixagevimab and cilgavimab combination did not mediate ADCD activity with guinea pig complement proteins.

Antibody dependent enhancement (ADE) of infection.

The potential of tixagevimab and cilgavimab to mediate antibody-dependent viral entry was assessed in FcγRII-expressing Raji cells co-incubated with recombinant viral pseudotyped with SARS-CoV-2 spike protein, with antibody concentrations at a range of 6.6 nanoM (1 microgram/mL) to 824 picoM (125 nanogram/mL). Tixagevimab, cilgavimab and their combination did not mediate entry of pseudovirus into these cells.
The potential for ADE was also evaluated in a non-human primate model of SARS-CoV-2 using Evusheld. Intravascular administration prior to virus inoculation resulted in a dose-dependent improvement in all measured outcomes (total viral RNA in the lungs or nasal mucosae, infectious virus levels in the lungs based on TCID50 measurements, and lung injury and pathology based on histology measurements). No evidence of enhancement of disease was observed at any dose evaluated, including sub-neutralizing doses down to 0.04 mg/kg.

Antiviral resistance.

There is a potential risk of breakthrough infection or treatment failure due to the development of viral variants that are resistant to tixagevimab and cilgavimab.
SARS-CoV-2 or recombinant vesicular stomatitis virus encoding SARS-CoV-2 spike protein were serially passaged in cell cultures in the presence of cilgavimab or tixagevimab individually, or tixagevimab and cilgavimab in combination. Escape variants were identified following passage with cilgavimab, but not with tixagevimab or tixagevimab and cilgavimab in combination. Variants which showed reduced susceptibility to cilgavimab alone included spike protein amino acid substitutions R346I (> 200-fold), K444E (> 200-fold), and K444R (> 200-fold). All variants maintained susceptibility to tixagevimab alone, and tixagevimab and cilgavimab in combination.
Evaluation of neutralisation susceptibility of variants identified through global surveillance and in participants who received tixagevimab and cilgavimab is ongoing.
Based on the most recent surveillance data, most amino acid residues in the tixagevimab binding site (12 of 17 positions) and cilgavimab binding site (13 of 19 positions) have been > 99% conserved among global isolates (N = 10,429,979 whole genome sequences with sampling date through 30 September 2022. Source: GISAID database, accessed through https://covidcg.org/ on 24 October 2022).
In neutralisation assays using recombinant SARS-CoV-2 pseudoviruses harbouring individual spike substitutions identified in circulating SARS-CoV-2, variants with reduced susceptibility to tixagevimab alone included those with Q414R (4.6-fold), L455F (2.5- to 4.7-fold), G476S (3.3-fold), E484D (7.1-fold), E484K (6.2- to 12-fold), E484Q (3.0-fold), F486S (> 600-fold), F486V (121- to 149-fold), Q493K (2.4- to 3.2-fold), Q493R (7.9-fold), E990A (6.1-fold), or T1009I (8.2-fold) and variants with reduced susceptibility to cilgavimab alone included those with R346I (> 200-fold), K444E (> 200-fold), K444Q (> 200-fold), K444R (> 200-fold), V445A (21- to 51-fold), G446V (4.2-fold), N450K (9.1-fold), or L452R (5.8-fold). Variants harbouring E484K (2.4- to 5.4-fold), Q493R (3.4-fold), E990A (5.7-fold), or T1009I (4.5-fold) exhibited low level reduced susceptibility to tixagevimab and cilgavimab in combination.
Pseudovirus SARS-CoV-2 spike variant strains with reduced susceptibility to tixagevimab alone included those harbouring E484K (Alpha, 18.5-fold; Beta, 3.5- to 15-fold) and F486V (BA.4.6, > 1000-fold; BA.4/5, > 1000-fold). Variants with reduced susceptibility to cilgavimab alone included those with R346K:E484K:N501Y (Mu, 21-fold), R346K (BA.1.1, > 500-fold) and R346T (BA.4.6, > 1000-fold). Similar results were observed, where data was available, in neutralisation assays using authentic SARS-CoV-2 variants strains.
Neutralisation activity of Evusheld against pseudovirus and/or live virus SARS-CoV-2 variant strains are shown in Table 7. Data collection is ongoing to better understand how small reductions in activity seen in authentic SARS-CoV-2 or pseudotyped VLP assays may correlate with clinical outcomes.

It is not known how pseudovirus or authentic SARS-CoV-2 neutralisation susceptibility data correlate with clinical outcome.
In research-grade neutralisation assays using recombinant pseudovirus SARS-CoV-2 spike variant strains, tixagevimab and cilgavimab retained activity against Alpha (B.1.1.7), Beta (B.1.351), Epsilon (B.1.427/ B.1.429), Delta (B.1.617.2), and A_1 variants and variants containing corresponding K417N, L452R, T478K, E484K, S494P, N501Y, Q675H, Q677H, P681H or V1176F individual spike substitutions detected in participants who received tixagevimab and cilgavimab.
It is possible that resistance-associated variants to tixagevimab and cilgavimab together could have cross-resistance to other monoclonal antibodies targeting the RBD of SARS-CoV-2. Tixagevimab and cilgavimab together retained activity against pseudoviruses harbouring individual SARS-CoV-2 spike substitutions (E484D/K/Q, F490S, Q493R, S494P, K417E/N, D420N, K444Q, V445A, Y453F, L455F, N460K/S/T, F486V, and Q493K) identified in neutralisation escape variants of other monoclonal antibodies targeting the RBD of SARS-CoV-2 spike protein.

Pharmacodynamics.

Evaluation of Evusheld over a dose range of 300-3000 mg through intravenous (IV) administration established a dose-dependent exposure relationship of neutralising antibody titer. In a Phase I study, following a single 300 mg IM dose of Evusheld in healthy volunteers (N = 10) neutralising antibodies geometric mean titers (GMT) at 7, 30, 60, 90, 150, 210 and 270 days post-dose were 689.2, 852.8, 656.8, 533.7, 290.1, 297.5 and 98.6 respectively, which are similar to the increases observed in participants receiving 300 mg IV.
In PROVENT, following a single 300 mg IM dose of Evusheld, neutralising antibody GMT at 7, 28, 57, and 91 days post-dose were similar to those observed in the Phase I healthy volunteer study and were 16, 22, 17 and 12-fold higher, respectively, than the GMT measured in convalescent plasma from COVID-19 patients (GMT = 30.8).
In TACKLE, following a single 600 mg IM dose of Evusheld, neutralising antibody GMT at day 6, 15, 29, 85, and 169, were 16-fold, 14-fold, 22-fold, 18-fold, and 5-fold, respectively, over placebo.

Immunogenicity.

In PROVENT through day 183, following a single 300 mg Evusheld dose, treatment-emergent anti-tixagevimab, anti-cilgavimab and anti-Evusheld antibodies were detected in 3.2% (101/3152), 3.7% (113/3068) and 4.9% (156/3158) anti-drug antibody (ADA)-evaluable participants, respectively. In the PROVENT repeat dose sub-study, participants received a second dose of 300 mg Evusheld 10 to 14 months after administration of the initial dose. Up to day 29 post-administration of the second dose, treatment-emergent anti-tixagevimab, anti-cilgavimab and anti-Evusheld antibodies were detected in 0% (0/49), 10.2% (5/49) and 10.2% (5/49) ADA-evaluable participants, respectively.
In TACKLE through day 169, following a single 600 mg Evusheld dose, treatment-emergent anti-tixagevimab, anti-cilgavimab and anti-Evusheld antibodies were detected in 5.2% (14/271), 10.7% (33/307), and 10.7% (37/346) ADA-evaluable participants, respectively.
The effect of ADA on PK, efficacy and safety is not known.

Clinical trials.

Prophylaxis of COVID-19.

PROVENT.

PROVENT was a phase III, randomised (2:1), double-blind, placebo-controlled clinical trial studying Evusheld for the pre-exposure prophylaxis of COVID-19 in adults ≥ 18 years of age. All participants were individuals considered to be at increased risk for inadequate response to active immunisation (due to age ≥ 60 years, co-morbidity, pre-existing chronic illness, immunocompromised, or intolerant of vaccination) or at increased risk of SARS-CoV-2 infection (due to their location or circumstances at time of enrolment). Participants received either a single dose (administered as two IM injections) of Evusheld 300 mg (150 mg of tixagevimab and 150 mg of cilgavimab administered separately) or placebo. The study excluded participants with a history of laboratory-confirmed SARS-CoV-2 infection or SARS-CoV-2 antibody positivity at screening. Individuals who have previously received a COVID-19 vaccine were also excluded. Once COVID-19 vaccines were locally available, subjects were permitted on request to unblind to make an informed decision on vaccine timing and to receive COVID-19 vaccination.
The baseline demographics were well balanced across the Evusheld and placebo arms. The median age was 57 years (with 24% of participants aged 65 years or older and 4% of participants aged 75 years or older), 46% of participants were female, 73% were White, 3.3% were Asian, 17% were Black/African American, and 15% were Hispanic/Latino.
Of the 5,197 subjects, 78% had baseline co-morbidities or characteristics associated with an increased risk for severe COVID-19, including obesity (42%), diabetes (14%), cardiovascular disease (8%), cancer, including a history of cancer (7%), chronic obstructive pulmonary disease (5%), chronic kidney disease (5%), chronic liver disease (5%), immunosuppressive medications (3%) and immunosuppressive disease (< 1%).
The primary analysis included 5172 participants who were SARS-CoV-2 RT-PCR-negative at baseline, of which 3441 received Evusheld and 1731 received placebo. For the primary endpoint, a subject was defined as a COVID-19 case if their first case of SARS-CoV-2 RT-PCR-positive symptomatic illness occurred after administration and prior to day 183.
Evusheld significantly (p-value < 0.001) reduced the risk of SARS-CoV-2 RT-PCR-positive symptomatic illness (COVID-19), compared to placebo (Table 8). At the time of data cut-off for the primary analysis, the median follow-up time post-administration was 83 days (range 3 to 166 days).

Efficacy was consistent across pre-defined sub-groups including age, gender, ethnicity, baseline co-morbidities or characteristics associated with an increased risk for severe COVID-19 and at increased risk for inadequate response to active immunisation.
There was a statistically significant reduction in incidence of SARS-CoV-2 RT-PCR-positive symptomatic illness or death from any cause for participants who had received Evusheld (12/3441) compared with placebo (19/1731), relative risk reduction 69% (95% CI: 36, 85); p-value = 0.002.
Efficacy was assessed in participants who had no serological evidence, at baseline, of previous SARS-CoV-2 infection (SARS-CoV-2 nucleocapsid antibody negative). Evusheld significantly reduced the risk of any SARS-CoV-2 infection (symptomatic or asymptomatic, SARS-CoV-2 nucleocapsid antibody positive at any time post-baseline) when compared to placebo; with SARS-CoV-2 nucleocapsid antibodies observed in 0.7% (21/3123) of participants who received Evusheld and 1.3% (21/1564) of participants who received placebo (relative risk reduction 51%, 95% CI: 11, 73; p-value = 0.020).
At the primary data cut-off, among participants who received Evusheld there were no severe/critical COVID-19 events (defined as SARS-CoV-2 RT-PCR-positive symptomatic illness characterised by a minimum of either pneumonia [fever, cough, tachypnoea or dyspnoea, and lung infiltrates] or hypoxemia [SpO₂ < 90% in room air and/or severe respiratory distress] and a WHO Clinical Progression Scale score of 5 or higher) compared to one event (0.1%) among participants who received placebo.
An additional data cut-off was conducted to provide post-hoc updated safety and efficacy analyses; the median follow-up was 6.5 months for participants in both the Evusheld and placebo arms. The relative risk reduction of SARS-CoV-2 RT-PCR-positive symptomatic illness was 83% (95% CI 66-91), with 11/3441 [0.3%] events in the Evusheld arm and 31/1731 [1.8%] events in the placebo arm, see Figure 1. At a median follow-up of 6.5 months, among participants who received Evusheld there were no severe/critical COVID-19 events compared to five events among participants who received placebo.

The predominant SARS-CoV-2 variants in circulation for the time period represented in Figure 1 were alpha, beta, gamma, epsilon and delta. Based on the incidence of primary endpoint events, the duration of efficacy was 6 months.
At the primary DCO, illness visit sequencing data was available for 21 participants with COVID-19 infection (6 who received tixagevimab and cilgavimab and 15 placebo). At an allele fraction ≥ 25%, 14 participants were infected with variants of concern or variants of interest, including 8 participants with alpha (B.1.1.7) (8 placebo), 1 participant with beta (B.1.351) (1 who received tixagevimab and cilgavimab), 3 participants with delta (B.1.617.2) (3 placebo), and 2 participants with epsilon (B.1.429) (2 who received tixagevimab and cilgavimab). Seven additional participants were infected with B.1.375 (1 who received tixagevimab and cilgavimab) or the A_1 set of lineages containing a constellation of spike protein substitutions including D614G and P681H or Q677P (3 who received tixagevimab and cilgavimab and 3 placebo). Additional spike protein RBD substitutions detected at an allele fraction ≥ 3% included V503F in the tixagevimab and cilgavimab group.
Treatment of COVID-19.

TACKLE.

TACKLE was a phase III, randomised (1:1), double-blind, placebo-controlled clinical trial studying Evusheld for the treatment of adult patients with mild to moderate COVID-19. The study enrolled individuals who were not hospitalised for COVID-19 treatment and had at least 1 or more COVID-19 symptom that was at least mild in severity. Treatment was initiated within 3 days of obtaining the sample for a positive SARS-CoV-2 viral infection and within ≤ 7 days of COVID-19 symptom onset. Patients received standard of care treatment and a single dose (administered as two IM injections) of either Evusheld 600 mg (300 mg of tixagevimab and 300 mg of cilgavimab administered separately, N = 413) or placebo (N = 421). Participants were stratified by time from symptom onset (≤ 5 days versus > 5 days) and risk of progression to severe COVID-19 (high risk versus low risk).
Demographics and disease characteristics were well balanced across the treatment and placebo groups. At baseline, the median age was 46 years (with 13% of subjects aged 65 years or older), 50% of the subjects were female, 62% were White, 5.6% were Asian, 4.0% were Black and 52% were Hispanic/Latino. The majority of participants (90%) were considered at higher risk of progressing severe COVID-19, defined as either individuals aged 65 years and older at randomisation or individuals aged < 65 years and having at least one medical condition or other factor that placed them at higher risk for progression to severe COVID-19. High risk co-morbidities included: cancer (4%), chronic lung disease or moderate to severe asthma (12%), obesity (BMI ≥ 30) (43%), hypertension (28%), cardiovascular disease (including history of stroke) (9%), diabetes (12%), chronic kidney disease (2%), chronic liver disease (2%), immunocompromised state (from solid organ transplant, blood or bone marrow transplant, immune deficiencies, HIV, use of corticosteroids, or use of other immunosuppressive medicines) (5%), sickle cell disease (0%) or smoking (current or former) (40%). At baseline, 88% of patients had WHO clinical progression scale of 2 and 12% had WHO clinical progression scale of 3 COVID-19, the median duration of symptoms prior to treatment was 5 days.
The primary efficacy endpoint was a composite of either severe COVID-19 or death from any cause by day 29, in subjects who received treatment within 7 days from symptom onset and were not hospitalised at baseline. Severe COVID-19 was defined as characterised by either pneumonia (fever, cough, tachypnoea or dyspnoea, and lung infiltrates observed on chest X-ray or lung computed tomography scan) or hypoxemia (SpO₂ < 90% in room air and/or severe respiratory distress) and a WHO clinical progression scale score of 5 or higher.
Primary endpoint events occurred in 4.4% (18/407) of Evusheld-treated patients compared to 8.9% (37/415) of patients randomised to placebo, demonstrating a statistically significant (p = 0.010) 50% (95% CI 15, 71) reduction in severe COVID-19 or death from any cause compared to placebo (Figure 2). Efficacy was generally consistent across pre-defined sub-groups.
Relative risk reduction by time of administration from symptom onset is shown in Figure 3, patients treated early in their disease course appeared to derive the greatest treatment benefit.
In participants who were seronegative at baseline, Evusheld significantly reduced the risk of developing severe COVID-19 or death (from any cause) by 61% (95% CI 30, 79; p-value = 0.001) compared to placebo, with 14/347 (4%) and 36/345 (10%) events, respectively.
Evusheld treatment resulted in fewer COVID-19-related hospitalisations through day 29: Evusheld 17 (4.1%) versus placebo 40 (9.5%); and intensive care unit admissions: Evusheld 3 (0.7%) versus placebo 11 (2.6%). Respiratory failure (defined as requirement for mechanical ventilation, ECMO, non-invasive ventilation, or high flow nasal cannula oxygen delivery) occurred in 3 (0.7%) Evusheld-treated participants and 11 (2.7%) placebo-treated participants (relative risk reduction 72%, 95% CI: 0.25, 92).

5.2 Pharmacokinetic Properties

The pharmacokinetics of tixagevimab and cilgavimab are comparable, linear and dose-proportional between 300 mg and 3000 mg following a single IV administration, and between 300 to 600 mg following a single IM administration.

Absorption.

After a single 600 mg IM dose (300 mg each antibody) in COVID-19 participants from TACKLE, the mean (%CV) maximum concentration (C_max) was 21.9 (61.7%) and 20.3 (63.6%) microgram/mL for tixagevimab and cilgavimab respectively, which were reached at a median T_max of 15 days.
After a single 300 mg IM dose (150 mg each antibody) in healthy volunteers, the estimated absolute bioavailability was 68.5% for tixagevimab and 65.8% for cilgavimab.

Distribution.

Based on PK modelling, the central volume of distribution was 2.72 L for tixagevimab and 2.48 L for cilgavimab. The peripheral volume of distribution was 2.64 L for tixagevimab and 2.57 L for cilgavimab.

Biotransformation/ metabolism.

Tixagevimab and cilgavimab are expected to be degraded into small peptides and component amino acids via catabolic pathways in the same manner as endogenous IgG antibodies.

Excretion.

The clearance (CL) was 0.041 L/day for tixagevimab and 0.041 L/day for cilgavimab with between subject variability of 21% and 29% respectively. The estimated population median terminal elimination half-life was 89 days for tixagevimab and 84 days for cilgavimab.
In PROVENT, following a single 300 mg IM dose of Evusheld, the geometric mean serum concentration was 23.4 microgram/mL (geoSD: 1.9) on day 29 and 12.2 microgram/mL (geoSD: 1.4) on day 183.
In TACKLE, following a single 600 mg IM dose of Evusheld, the geometric mean serum concentration was 37.2 microgram/mL (geoSD: 2.1) on day 29. There was no clinically relevant difference in the clearance of tixagevimab or cilgavimab between participants with COVID-19 enrolled in TACKLE and those enrolled in the prophylaxis studies.

Special populations.

Renal impairment.

No specific studies have been conducted to examine the effects of renal impairment on the pharmacokinetics of tixagevimab and cilgavimab.
Tixagevimab and cilgavimab are not eliminated intact in the urine, since monoclonal antibodies with molecular weight > 69 kDa do not undergo renal elimination, thus renal impairment is not expected to significantly affect the exposure of tixagevimab and cilgavimab. Similarly, dialysis is not expected to impact the PK of tixagevimab and cilgavimab.
Based on population PK analysis, there is no difference in the clearance of tixagevimab and cilgavimab in patients with mild (N=978) or moderate (N=174) renal impairment compared to patients with normal renal function. In the population PK model there were insufficient participants with severe renal impairment (N=21) to draw conclusions.

Hepatic impairment.

No specific studies have been conducted to examine the effects of hepatic impairment on the PK of tixagevimab and cilgavimab. The impact of hepatic impairment on the PK of tixagevimab and cilgavimab is unknown.
Tixagevimab and cilgavimab are expected to be catabolised by multiple tissues through proteolytic degradation into amino acids and recycling into other proteins, therefore hepatic impairment is not expected to affect the exposure of tixagevimab and cilgavimab.

Elderly patients.

Of the 2560 participants in the pooled PK analysis, 21% (N = 534) were 65 years of age or older and 4.2% (N = 107) were 75 years of age or older. There is no clinically meaningful difference in the PK of tixagevimab and cilgavimab in geriatric subjects (≥ 65 years) compared to younger individuals.

Paediatric population.

The PK of tixagevimab and cilgavimab in individuals < 18 years old have not been evaluated.
Using population PK modelling and simulation, the recommended dosing regimen is expected to result in comparable serum exposures of tixagevimab and cilgavimab in paediatric individuals ages 12 years or older who weigh at least 40 kg as observed in adult individuals, since adults with similar body weight have been included in the clinical trials PROVENT and TACKLE.

Other special populations.

Based on a population PK analysis, sex, age, BMI (range 21-41), weight (range 36-177 kg), race, ethnicity, cardiovascular disease, diabetes and immunocompromise status had no clinically relevant effect on the PK of tixagevimab and cilgavimab.

Drug-drug interaction.

Tixagevimab and cilgavimab are not renally excreted or metabolised by cytochrome P450 enzymes; therefore, interactions with concomitant medications that are renally excreted or that are substrates, inducers, or inhibitors of cytochrome P450 enzymes are unlikely.
Based on PK modelling, COVID-19 vaccination following Evusheld administration had no clinically relevant impact on the clearance of Evusheld.
No data are available on the clearance of Evusheld, if administered following vaccination.

5.3 Preclinical Safety Data

Genotoxicity.

No studies have been conducted with Evusheld.

Carcinogenicity.

No studies have been conducted with Evusheld.

6 Pharmaceutical Particulars

6.1 List of Excipients

Histidine, histidine hydrochloride monohydrate, sucrose, polysorbate 80, water for injection.

6.2 Incompatibilities

In the absence of compatibility studies, this medicinal product should not be mixed with other medicinal products.

6.3 Shelf Life

In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.

6.4 Special Precautions for Storage

Store in a refrigerator (2°C to 8°C).
Do not freeze. Do not shake.
Keep the vials in the original carton to protect from light.

6.5 Nature and Contents of Container

Each carton contains two vials:

Tixagevimab.

1.5 mL of solution for injection in a clear glass vial closed by chlorobutyl elastomeric stopper sealed with a dark-grey aluminium flip-off top.

Cilgavimab.

1.5 mL of solution for injection in a clear glass vial closed by chlorobutyl elastomeric stopper sealed with a white aluminium flip-off top.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of in accordance with local requirements.

6.7 Physicochemical Properties

Chemical structure.

Tixagevimab and cilgavimab are two human immunoglobulin (IgG1κ) monoclonal antibodies produced in Chinese hamster ovary (CHO) cells by recombinant DNA technology.

CAS number.

Tixagevimab: 2420564-02-7.
Cilgavimab: 2420563-99-9.

7 Medicine Schedule (Poisons Standard)

Prescription only medicine (Schedule 4).

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Consumer medicine information

Evusheld

Tixagevimab; Cilgavimab

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