EVUSHELD 150mg+150mg injectible solution medication leaflet

EVUSHELD 150 mg + 150 mg solution for injection

Each carton contains two vials:

Each vial of tixagevimab contains 150 mg of tixagevimab in 1.5 mL (100 mg/mL).

Each vial of cilgavimab contains 150 mg of cilgavimab in 1.5 mL (100 mg/mL).

Tixagevimab and cilgavimab are produced in Chinese hamster ovary (CHO) cells by recombinant

DNA technology.

Each vial of tixagevimab contains 0.6 mg of polysorbate 80.

Each vial of cilgavimab contains 0.6 mg of polysorbate 80.

For the full list of excipients, see section 6.1.

Solution for injection (injection)

Clear to opalescent, colourless to slightly yellow, pH 6.0 solution.

EVUSHELD is indicated for the pre-exposure prophylaxis of COVID-19 in adults and adolescentsaged 12 years and older weighing at least 40 kg (see sections 4.2, 5.1 and 5.2).

EVUSHELD is indicated for the treatment of adults and adolescents (aged 12 years and olderweighing at least 40 kg) with COVID-19, who do not require supplemental oxygen and who are atincreased risk of progressing to severe COVID-19 (see sections 4.2, 5.1 and 5.2).

EVUSHELD must be administered by a healthcare professional.

Administration should be under conditions where management of severe hypersensitivity reactions,such as anaphylaxis, is possible. Individuals should be observed after administration according to localmedical practice.

The recommended dose in adults and adolescents aged 12 years and older weighing at least 40 kg is150 mg of tixagevimab and 150 mg of cilgavimab (Table 1), administered as two separate sequentialintramuscular injections.

There are no safety and efficacy data available on repeat dosing.

Due to the observed decrease in in-vitro neutralisation activity, the duration of protection of

EVUSHELD for some variants is uncertain (see section 4.4 and 5.1).

The recommended dose in adults and adolescents aged 12 years and older weighing at least 40 kg is300 mg of tixagevimab and 300 mg of cilgavimab (Table 1), administered as two separate sequentialintramuscular injections.

EVUSHELD should be given as soon as possible after a positive viral test for SARS-CoV-2 andwithin 7 days of the onset of symptoms of COVID-19 (see section 5.1).

Table 1 Recommended dose

Indication EVUSHELD dose Antibody Number of vials Volume totixagevimab + cilgavimab dose neededa withdraw fromvialtixagevimab 1 vial1.5 mL

Pre-exposure 150 mg + 150 mg 150 mg (dark grey cap)prophylaxis (1 EVUSHELD carton) cilgavimab 1 vial1.5 mL150 mg (white cap)tixagevimab 2 vials3.0 mL300 mg + 300 mg 300 mg (dark grey cap)

Treatment(2 EVUSHELD cartons) cilgavimab 2 vials3.0 mL300 mg (white cap)a Each vial contains an overfill to allow the withdrawal of 150 mg (1.5 mL).

No dose adjustment is required (see section 5.2).

No dose adjustment is required (see section 5.2).

No dose adjustment is required (see section 5.2).

No dose adjustment is required in adolescents aged 12 years and older weighing at least 40 kg (seesection 5.2). The safety and efficacy of EVUSHELD in children under 12 years of age have not yetbeen established. No data are available.

For intramuscular injection.

Tixagevimab and cilgavimab must be given as two separate sequential intramuscular injections atdifferent injection sites in two different muscles, preferably in the gluteal muscles.

Each carton contains two vials:

* tixagevimab solution for injection (dark grey cap);

* cilgavimab solution for injection (white cap).

For handling instructions of the medicinal product before administration, see section 6.6.

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

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

Hypersensitivity including anaphylaxis

Serious hypersensitivity reactions, including anaphylaxis, have been reported following administrationof EVUSHELD (see section 4.8). If signs and symptoms of a clinically significant hypersensitivityreaction or anaphylaxis occur, immediately discontinue administration and initiate appropriatemedicinal products and/or supportive therapy.

Cardiovascular and/or thrombo-embolic events

In the PROVENT study, more participants in the EVUSHELD arm experienced serious cardiac orthromboembolic adverse events as compared to those in the placebo arm (1.6% versus 0.9%). Themajority of participants had cardiovascular risk factors and/or history of cardiovascular disease thatcould explain the occurrence of such events.

A causal relationship between EVUSHELD and these events has not been established.

The risks and benefits should be considered prior to initiating EVUSHELD in individuals at high riskfor cardiovascular or thrombo-embolic events. Patients should be advised of signs or symptomssuggestive of cardiovascular event (notably chest pain, dyspnoea, malaise, feeling lightheaded or faint)and to seek immediate medical attention if such symptoms occur.

Clinically significant bleeding disorders

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

The clinical trials with EVUSHELD were conducted when Alpha, Beta, Gamma and Delta variantswere predominant. Circulating SARS-CoV-2 viral variants may be associated with resistance tomonoclonal antibodies such as tixagevimab and cilgavimab. The in-vitro neutralisation activity of

EVUSHELD against SARS-CoV-2 viral variants are shown in Table 3 (see section 5.1).

Patients who received EVUSHELD prophylactically should be informed of the potential forbreakthrough infections to occur.

The duration of protection for variants with an observed decrease in in-vitro neutralisation activity isuncertain.

Patients should be instructed to promptly seek medical advice if signs or symptoms of COVID-19occur (the most common symptoms include fever, cough, tiredness and loss of taste or smell; the mostserious symptoms include difficulty breathing or shortness of breath, loss of speech or mobility, orconfusion and chest pain).

Decisions regarding the use of EVUSHELD for the treatment of COVID-19 should take intoconsideration what is known about the characteristics of the circulating SARS-CoV-2 viral variants,including geographical prevalence.

COVID-19 vaccines

Pre-exposure prophylaxis with EVUSHELD is not a substitute for vaccination in individuals for whom

COVID-19 vaccination is recommended.

This medicinal product contains 0.6 mg of polysorbate 80 in each vial of tixagevimab and in each vialof cilgavimab. Polysorbates may cause allergic reactions.

No human interaction studies have been performed.

EVUSHELD is not expected to undergo metabolism by hepatic enzymes or renal elimination.

Tixagevimab and cilgavimab are not renally excreted or metabolised by cytochrome P450 (CYP)enzymes; therefore, interactions with medicinal products that are renally excreted or that aresubstrates, inducers, or inhibitors of CYP enzymes are unlikely.

Based on pharmacokinetic (PK) modelling, COVID-19 vaccination following EVUSHELDadministration had no clinically relevant impact on the clearance of EVUSHELD.

Based on PK modelling, immunocompromised condition had no clinically relevant impact on theclearance of EVUSHELD.

No human interaction studies have been performed.

There are no or 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(see section 5.3). In tissue cross reactivity studies with tixagevimab and cilgavimab using humanfoetal tissues no binding of clinical concern was detected. Human immunoglobulin G1 (IgG1)antibodies are known to cross the placenta therefore tixagevimab and cilgavimab have the potential tobe transferred from the mother to the developing foetus. The potential treatment benefit or risk ofplacental transfer of tixagevimab and cilgavimab to the developing foetus is not known.

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

It is not known whether tixagevimab and cilgavimab are excreted in human milk but maternal IgG isknown to be transferred to milk during the first days after birth.

As tixagevimab and cilgavimab directly target the spike protein of SARS-CoV-2, and in view of lowsystemic absorption after oral ingestion of antibodies, administration of EVUSHELD whilst breast-feeding can be considered when clinically indicated.

There are no data on the effects of tixagevimab and cilgavimab on human fertility. Effects on male andfemale fertility have not been evaluated in animal studies.

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

A total of 4 210 adult participants have received 150 mg tixagevimab and 150 mg cilgavimab, viaintramuscular injection, in the Phase III prophylaxis development program (including PROVENT).

The most common adverse reactions (≥ 1%) were injection site reactions (1.6%) and hypersensitivity(1.0%).

A total of 452 non-hospitalised adult patients with mild to moderate COVID-19 have received 300 mgtixagevimab and 300 mg cilgavimab, via intramuscular injection, in TACKLE. The overall safetyprofile was similar to that reported in participants who received 150 mg tixagevimab and 150 mgcilgavimab in the prophylaxis studies. The most common adverse reaction (≥ 1%) was injection sitereaction (2.4%).

The adverse reactions in Table 2 are listed by MedDRA system organ class and frequency.

Frequencies are defined as follows: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon(≥ 1/1 000 to < 1/100); rare (≥ 1/10 000 to < 1/1 000); very rare (< 1/10 000) and not known (cannotbe estimated from available data).

Table 2 Tabulated list of adverse reactions

MedDRA system organ Adverse reaction Frequencyaclass

Hypersensitivityb Common

Anaphylaxisc Rare

General disorders and

Injection related reactiond Uncommonadministration site conditions

Injury, poisoning and

Injection site reactione Commonprocedural complicationsa Frequencies are based on exposure to 150 mg tixagevimab and 150 mg cilgavimab in the pooled data fromthe prophylaxis studies.b Including the preferred terms Rash and Urticaria.c Identified from post-marketing/post-authorisation reports (see section 4.4).d Description of events reported under the preferred term Injection related reaction include headache, chillsand redness, discomfort or soreness near where the injection was given.e Including the preferred terms Injection site pain, Injection site erythema, Injection site pruritus, Injectionsite reaction and Injection site induration.

No data are available for paediatric patients < 18 years old (see section 4.2 and 5.2).

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

There is no specific treatment for overdose with tixagevimab and cilgavimab. Treatment of overdoseshould consist of general supportive measures including monitoring of vital signs and observation ofthe clinical status of the patient.

In clinical trials, intramuscular doses of up to 300 mg each of tixagevimab and cilgavimab andintravenous doses of up to 1 500 mg each of tixagevimab and cilgavimab have been administeredwithout dose-limiting toxicity.

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

ATC code: J06BD03

Tixagevimab and cilgavimab are two recombinant human IgG1 monoclonal antibodies, with aminoacid substitutions in the Fc regions, to extend antibody half-life and to reduce antibody effectorfunction and potential risk of antibody-dependent enhancement of disease (see section 5.3).

Tixagevimab and cilgavimab can simultaneously bind to non-overlapping regions of the spike proteinreceptor binding domain (RBD) of SARS-CoV-2. Tixagevimab, cilgavimab and their combinationbind to spike with equilibrium dissociation constants of KD= 2.76 pM, 13.0 pM and 13.7 pM,respectively, blocking its interaction with the human ACE2 receptor, resulting in a blockade of virusentry. Tixagevimab, cilgavimab and their combination blocked RBD binding to the human ACE2receptor with IC50 values of 0.32 nM (48 ng/mL), 0.53 nM (80 ng/mL) and 0.43 nM (65 ng/mL),respectively.

In a SARS-CoV-2 virus neutralisation assay on Vero E6 cells, tixagevimab, cilgavimab and theircombination neutralised SARS-CoV-2 (USA-WA1/2020 isolate) with EC50 values of 60.7 pM(9 ng/mL), 211.5 pM (32 ng/mL) and 65.9 pM (10 ng/mL), respectively. These in-vitro valuescorrelate with in-vivo clinically effective serum concentrations of 2.2 µg/mL of EVUSHELD.

SARS-CoV-2 or recombinant vesicular stomatitis virus encoding SARS-CoV-2 spike protein(pseudovirus) were serially passaged in cell cultures in the presence of tixagevimab or cilgavimabindividually, or tixagevimab and cilgavimab in combination. Escape variants were identified followingpassage with cilgavimab, but not with tixagevimab or tixagevimab and cilgavimab in combination.

In neutralisation assays using recombinant SARS-CoV-2 pseudoviruses harbouring individual spikesubstitutions identified in circulating SARS-CoV-2, variants with reduced susceptibility totixagevimab alone included those with F486S (> 600-fold) and F486V (121- to 149-fold) and variantswith reduced susceptibility to cilgavimab alone included those with R346I (> 200-fold), K444E(> 200-fold), K444Q (> 200-fold) and K444R (> 200-fold).

The neutralisation activity of EVUSHELD against pseudovirus and/or live virus SARS-CoV-2 variantstrains are shown in Table 3.

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.

Table 3 Pseudovirus and authentic SARS-CoV-2 neutralisation data for SARS-CoV-2variant substitutions with tixagevimab and cilgavimab together

Pango lineage with Characteristic RBD Fold reduction in IC50 (ng/mL)spike protein substitutions tested susceptibilityasubstitutions

Pseudovirusb Live Virusc Pseudovirusb Live Virusc

Variants of concern

B.1.1.7 (Alpha,

N501Y 1.0-5.2 0.5-1.4 1.1-9.0 4-39.5

UK)

B.1.351 (Beta,

K417N:E484K:N501Y 2.5-5.5 0.9-3.8 5.6-11.4 6.5-256

South Africa)

P.1 (Gamma,

K417T:E484K:N501Y 0.8-1.7 0.4-2.0 1.8-2.7 3.2-8

Brazil)

B.1.617.2 (Delta,

L452R:T478K 1-1.2 0.6-1.0 1.9-2.2 3-7.5

India)

AY.1/AY.2 (Delta

K417N:L452R:T478K 1.0 ND 1.9 ND[+K417N], India)

Pango lineage with Characteristic RBD Fold reduction in IC50 (ng/mL)spike protein substitutions tested susceptibilityasubstitutions

Pseudovirusb Live Virusc Pseudovirusb Live Virusc

G339D:S371L:S373P:

S375F:K417N:N440K:

B.1.1.529 Omicron,

G446S:S477N:T478K: 132-183 d 12-30 d 51-277 d 147-278 d

BA.1 (Botswana)

E484A:Q493R:G496S:

Q489R:N501Y:Y505H

G339D:R346K:S371L:

S373P: S375F:K417N:

Omicron BA.1.1 N440K:G446S:S477N:424 d 176 d 466 d 1147 d(Multiple country) T478K:E484A:Q493R:

G496S:Q489R:N501Y:

Y505H

G339D:S371F:S373P:

S375F:T376A:D405N:

R408S:K417N:N440K:S477

Omicron BA.2

N: T478K:E484A: 3.2 5.4 9.8 35(Multiple country)

Q493R:Q498R:N501Y:

Y505H:H655Y:N679K:P681

H:N764K

G339D:S371F:S373P:

S375F:T376A:D405N:

Omicron BA.2.12.1 R408S:K417N:N440K:5 ND 10.7 ND(United States) L452Q:S477N:T478K:E484A:Q493R:Q498R: N501Y:

Y505H

G339H:S371F:S373P:

S375F:T376A:D405N:R408S

Omicron BA.2.75:K417N:N440K:G446S:N460 2.4-15 ND 1.2-14 ND(India)

K:S477N:T478K:E484A:Q498R:N501Y:Y505H

Omicron BA.2.75.2 BA.2.75:R346T:F486S>5 000 e ND >10 000 e ND(India)

G339D:S371F:S373P:

S375F:D405N:K417N:

Omicron BA.3

N440K:G446S:S477N: 16 ND 34.5 ND(Multiple country)

T478K:E484A:Q493R:

Q498R:N501Y:Y505H

G339D:S371F:S373P:

S375F:T376A:D405N:

Omicron BA.4 R408S:K417N:N440K:33-65 d ND 65-69.4 d ND(Multiple country) L452R:S477N:T478K:

E484A:F486V:Q498R:

N501Y:Y505H

G339D:R346T:S371F:

S373P:S375F:T376A:

Omicron BA.4.6 D405N:R408S:K417N:N440>1 000 e ND >1 000 e ND(United States) K:L452R:S477N:T478K:E484A:F486V:Q498R:N501Y:Y505H

Pango lineage with Characteristic RBD Fold reduction in IC50 (ng/mL)spike protein substitutions tested susceptibilityasubstitutions

Pseudovirusb Live Virusc Pseudovirusb Live Virusc

G339D:S371F:S373P:

S375F:T376A:D405N:

Omicron BA.5 R408S:K417N:N440K:33-65 d 2.8-16 d 65-69.4 d 56.6-229 d(Multiple country) L452R:S477N:T478K:

E484A:F486V:Q498R:

N501Y:Y505H

Omicron BF.7(United BA.4:R346T >5 000 e ND >10 000 e ND

States/Belgium)

G339H:R346T:L368I:

S371F:S373P:S375F:

T376A:D405N:R408S:

Omicron BJ.1 K417N:N440K:V445P:228-424 ND 228-848 ND(Multiple country) G446S:S477N:T478K:

V483A:E484A:F490V:

Q493R:Q498R:N501Y:

Y505H

Omicron BQ.1

BA.5:K444T:N460K >2 000 e ND >10 000 e ND(Nigeria)

Omicron BQ.1.1

BA.5:R346T:K444T:N460K >2 000 e ND >10 000 e ND(Multiple country)

G339D:R346T:K356T:S371F:S373P:S375F:D405N:R408S

Omicron BN.1 :K417N:N440K:G446S:68 ND 61-68 ND(Multiple country) N460K:S477N:T478K:

E484A:F490S:Q493R:Q498R:Y505H

G339H:R346T:L368I:S371F:

S373P:S375F:T376A:D405N:

Omicron XBB R408S:K417N:N440K:>1 400 e ND >1 600 e ND(Multiple country) V445P:G446S:N460K:S477N:T478K:E484A:F486S:F490S:Q498R:N501Y:Y505H

T19I:del24-26:A27S:V83A:

G142D:Y144-:H146Q:Q183E:V213E:G252V:G339H:

R346T:L368I:S371F:S373P:

S375F:T376A:D405N:R408S

XBB.1 (Multiple :K417N:N440K:V445P:>5 000 e ND >10 000 e NDcountry) G446S:N460K:S477N:T478K:E484A:F486S:F490S:Q498R:N501Y:Y505H:D614G:

H655Y:N679K:P681H:

N764K:D796Y:Q954H:

N969K

Pango lineage with Characteristic RBD Fold reduction in IC50 (ng/mL)spike protein substitutions tested susceptibilityasubstitutions

Pseudovirusb Live Virusc Pseudovirusb Live Virusc

G339H:R346T:L368I:

S371F:S373P:S375F:

T376A:D405N:R408S:

Omicron XBB.1.5

K417N:N440K:V445P: >5 000 e ND >10 000 e ND(Multiple country)

G446S:N460K:S477N:

T478K:E484A:F486S:F490S:

Q498R:N501Y:Y505H

T19I:del24-26:A27S:V83A:

G142D:Y144-:H146Q:E180V:Q183E:V213E:G252V:

G339H:R346T:L368I:S371F:

S373P:S375F:T376A:D405N:

Omicron XBB.1.16 R408S:K417N:N440K:>5 000 e ND >10 000 e ND(India) V445P:G446S:N460K:S477N:T478R:E484A:F486P:F490S:Q498R:N501Y:Y505H:

D614G:H655Y:N679K:P681

H:N764K:D796Y:Q954H:

N969K

Omicron

XBB.1.5.10/EG.5 XBB.1.5:F456L >5 000 e ND 10 000 e ND(Multiple country)

Omicron EG.5.1

XBB.1.5:Q52H:F456L >5 000 e ND 10 000 e ND(Multiple country)

T19I:R21T:L24-:P25-: P26-:A27S:S50L:H69-:V70-:V127F:G142D: Y144-:F157S:R158G: N211-:L212I:V213G:L216F:H245N:A264D:I332V:G339H:

K356T:S371F:S373P:S375F:

T376A:R403K:D405N:

Omicron BA.2.86 R408S:K417N:N440K:>5 000 e ND >10 000 e ND(Multiple country) V445H:G446S:N450D:

L452W:N460K:S477N:

T478K:N481K:V483-:E484K:F486P:Q498R:N501Y:

Y505H:E554K:A570V:

D614G:P621S:H655Y:I670V:

N679K:P681R:N764K:

D796Y:S939F:Q954H:

N969K:P1143L

Pango lineage with Characteristic RBD Fold reduction in IC50 (ng/mL)spike protein substitutions tested susceptibilityasubstitutions

Pseudovirusb Live Virusc Pseudovirusb Live Virusc

T19I:R21T:L24-:P25-:P26-:

A27S:S50L:H69-:V70-:

V127F:G142D:Y144-:F157S:

R158G:N211-:L212I:V213G:

L216F:H245N:A264D:I332V:G339H:K356T:S371F:S373P:S375F:T376A:R403K:

D405N:R408S:K417N:

Omicron JN.1

N440K:V445H:G446S: >5 000 e ND >10 000 e ND(Multiple country)

N450D:L452W:L455S:

N460K:S477N:T478K:

N481K:V483-:E484K:F486P:

Q498R:N501Y:Y505H:

E554K:A570V:D614G:P621S:H655Y:I670V:N679K:

P681R:N764K:D796Y:S939F:Q954H:N969K:P1143La Range of reduced in-vitro potency across multiple sets of co-occurring substitutions and/or testing labsusing research-grade assays; mean fold change in half maximal inhibitory concentration (IC50) ofmonoclonal antibody required for a 50% reduction in infection compared to wild type reference strain.b Pseudoviruses expressing the entire SARS-CoV-2 spike variant protein and individual characteristic spikesubstitutions except L452Q were tested including Alpha (+L455F, E484K, F490S, Q493R, and/or S494P),and Delta (+K417N) harbouring additional indicated RBD substitutions that are no longer detected ordetected at extremely low levels within these lineages.c Authentic SARS-CoV-2 expressing the entire variant spike protein were tested including Alpha (+E484Kor S494P) harbouring additional indicated RBD substitutions that are no longer detected or detected atextremely low levels within these lineages.d The duration of protection for this variant is uncertain.e Tixagevimab and cilgavimab together are unlikely to be active against this variant.

ND, not determined; RBD, receptor binding domain.

It is not known how pseudovirus or authentic SARS-CoV-2 neutralisation susceptibility data correlatewith clinical outcome.

In PROVENT, sequencing data collected at illness visits was available for 21 participants withsymptomatic COVID-19 (7 received tixagevimab and cilgavimab, and 14 received placebo). At anallele fraction ≥ 25%, the most commonly observed variants of concern or variants of interest were

Alpha (5 total events; all in placebo) and Delta (7 total events; 6 in placebo and 1 in EVUSHELD),with 7 ancestral strain sequences also being observed (3 in placebo and 4 in EVUSHELD).

It is possible that resistance-associated variants to tixagevimab and cilgavimab together could havecross-resistance to other monoclonal antibodies targeting the RBD of SARS-CoV-2. Tixagevimab andcilgavimab together retained activity against pseudoviruses harbouring individual SARS-CoV-2 spikesubstitutions (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 othermonoclonal antibodies targeting the RBD of SARS-CoV-2 spike protein.

In TACKLE, baseline visit sequencing data was available for 749 participants (382 receivedtixagevimab and cilgavimab, and 367 received placebo). At an allele fraction ≥ 25%, the proportion ofparticipants infected with variants of concern or variants of interest was balanced between treatmentgroup, including participants with Alpha, Beta, Gamma, Delta, Lambda and Mu.

In PROVENT, following an intramuscular dose of 150 mg tixagevimab and 150 mg cilgavimab, at

Day 8, 29, 58, 92, 183 and 366, the neutralising antibody GMTs were 19, 23, 18, 14, 6, and 3-foldgreater, respectively, than the GMT measured in convalescent plasma from COVID-19 patients(GMT= 30.8).

In TACKLE, following a single intramuscular dose of 300 mg of tixagevimab and 300 mg ofcilgavimab, greater than 5-fold increase neutralising antibody GMTs were observed in the

EVUSHELD group through Day 169 versus the placebo group: 16-, 14-, 22-, 18- and 5.3-fold overplacebo at Day 6, 15, 29, 85, and 169, respectively.

In PROVENT, following a single EVUSHELD dose (150 mg tixagevimab and 150 mgcilgavimab),treatment-emergent anti-tixagevimab, anti-cilgavimab and anti-EVUSHELD antibodieswere detected in 7.6% (234/3085), 11.3% (341/3024), and 13.1% (403/3086) ADA-evaluableparticipants who received EVUSHELD.

In TACKLE, following a single EVUSHELD dose (300 mg tixagevimab and 300 mg cilgavimab),treatment-emergent anti-tixagevimab, anti-cilgavimab and anti-EVUSHELD antibodies were detectedin 7.3% (27/372), 12.7% (46/363), and 14.5% (54/373) of ADA-evaluable participants, respectively.

No evidence of an association of ADA with any impact on PK or safety has been observed.

Prophylaxis of COVID-19

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. Enrolledparticipants were individuals considered to be at increased risk for inadequate response to activeimmunisation (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 orcircumstances at time of enrolment, for example health care workers including staff for long-term carefacilities, working in high risk industrial settings or living with high density proximity, includingstudents in dormitories and military barracks). Participants received either 150 mg of tixagevimab and150 mg of cilgavimab or placebo, administered as two separate intramuscular injections. The studyexcluded participants with a history of laboratory-confirmed SARS-CoV-2 infection or SARS-CoV-2antibody positivity at screening.

The baseline demographics were well balanced across the EVUSHELD and placebo arms. The medianage was 57 years (with 24% of participants aged 65 years or older and 4% of participants aged75 years or older), 46% of participants were female, 73% were White, 3% were Asian, 17% were

Black/African American, and 15% were Hispanic/Latino. Of the 5 197 participants, 78% had baselineco-morbidities or characteristics associated with an increased risk for severe COVID-19, includingobesity (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 5 172 participants who were SARS-CoV-2 RT-PCR-negative atbaseline, of which 3 441 received EVUSHELD and 1 731 received placebo. EVUSHELD significantly(p-value < 0.001) reduced the risk of SARS-CoV-2 RT-PCR-positive symptomatic illness(COVID-19) when compared to placebo (Table 4). The median follow-up time post-administrationwas 83 days.

Table 4 Incidence of COVID-19

N Number of Relative risk reduction,eventsa, n (%) % (95% CI)

EVUSHELDb 3 441 8 (0.2%)77% (46, 90)

Placebo 1 731 17 (1.0%)

CI = Confidence Interval, N = number of participants in analysis.a Primary endpoint, a participant was defined as a COVID-19 case if their first case of SARS-CoV-2 RT-PCR-positivesymptomatic illness occurred after administration and prior to Day 183.b 150 mg tixagevimab and 150 mg cilgavimab.

Efficacy was consistent across pre-defined sub-groups including age, gender, ethnicity and baselineco-morbidities or characteristics associated with an increased risk for severe COVID-19.

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 eitherpneumonia [fever, cough, tachypnoea or dyspnoea, and lung infiltrates] or hypoxemia [SpO2 < 90% inroom air and/or severe respiratory distress] and a WHO Clinical Progression Scale score of 5 orhigher) 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; themedian follow-up was 6.5 months for participants in both the EVUSHELD and placebo arms. Therelative risk reduction of SARS-CoV-2 RT-PCR-positive symptomatic illness was 83% (95% CI66, 91), with 11/3 441 (0.3%) events in the EVUSHELD arm and 31/1 731 (1.8%) events in theplacebo arm, see Figure 1). Among participants who received EVUSHELD there were nosevere/critical COVID-19 events compared to five events among participants who received placebo.

In exploratory analyses of all participants who received EVUSHELD or placebo, including 25participants who were subsequently found to have been SARS-CoV-2 RT-PCR-positive at baseline,the relative risk reduction of SARS-CoV-2 RT-PCR-positive symptomatic illness was 78%(95% CI 59, 88), with 14/3 460 (0.4%) events in the EVUSHELD arm and 31/1 737 (1.8%) events inthe placebo arm at a median follow-up of 6.5 months.

Figure 1 Kaplan Meier: Cumulative incidence of symptomatic COVID-19150 mg tixagevimab + 150 mg cilgavimab

Placebo

Number of participants at risk Time (days)

EVUSHELD

Placebo

Cumulative incidence (%)

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, theduration of efficacy was 6 months.

Treatment of mild to moderate COVID-19

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 enrolledindividuals who had not received COVID-19 vaccination, who were not hospitalised for COVID-19treatment, and who 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 viralinfection and within ≤7 days of COVID-19 symptom onset. Patients received standard of caretreatment and either 300 mg of tixagevimab and 300 mg of cilgavimab (N= 413) or placebo (N= 421),administered as two separate intramuscular injections. Participants were stratified by time fromsymptom onset (≤5 days versus >5 days) and risk of progression to severe COVID-19 (high riskversus 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 theparticipants were female, 62% were White, 5.6% were Asian, 4.0% were Black and 52% were

Hispanic/Latino. The majority of participants (84%) were seronegative at baseline, and 90% wereconsidered at higher risk of progressing severe COVID-19, defined as either individuals aged 65 yearsand older at randomisation or individuals aged < 65 years and having at least one medical condition orother factor that placed them at higher risk for progression to severe COVID-19. High riskco-morbidities included: obesity (BMI ≥ 30) (43%), smoking (current or former) (40%), hypertension(28%), chronic lung disease or moderate to severe asthma (12%), diabetes (12%), cardiovasculardisease (including history of stroke) (9%), immunocompromised state (from solid organ transplant,blood or bone marrow transplant, immune deficiencies, HIV, use of corticosteroids, or use of otherimmunosuppressive medicines) (5%), cancer (4%), chronic kidney disease (2%), or chronic liverdisease (2%).

At baseline, 88% of patients had WHO clinical progression scale of 2 and 12% had WHO clinicalprogression 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 causeby Day 29, in participants who received treatment within 7 days from symptom onset and were nothospitalised 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 computedtomography scan) or hypoxemia (SpO2 <90% in room air and/or severe respiratory distress) and a

WHO clinical progression scale score of 5 or higher. EVUSHELD demonstrated a statisticallysignificant reduction in severe COVID-19 or death from any cause compared to placebo (Table 5).

Given the small sample size, no conclusion can be drawn regarding the efficacy in seropositivepatients.

Table 5 Incidence of severe COVID-19 or death from any cause through Day 29

Population Treatment N Number of Relative risk p-value aevents, n (%) reduction,% (95% CI)

Non-hospitalised patients EVUSHELDb 407 18 (4.4%)dosed ≤ 7 days from50% (15, 71) p= 0.010symptom onset (mFAS)

Placebo 415 37 (8.9%)

Population Treatment N Number of Relative risk p-value aevents, n (%) reduction,% (95% CI)

All randomised EVUSHELDb 446 24 (5.4%)participants, including42% (5, 64) p= 0.028hospitalised and non-hospitalised patients (FAS) Placebo 444 41 (9.2%)

CI = Confidence Interval, N= Number of participants included in analysis, mFAS= Modified full analysis set, FAS= Fullanalysis set.

a. Results from a CMH test stratified by time from symptom onset (≤ 5 vs. > 5 days), and risk of progression to severe

COVID-19 (high vs. low).

b. 300 mg tixagevimab and 300 mg cilgavimab.

Missing response data were not imputed.

The relative risk reduction was 67% (95% CI of 31, 84) in non-hospitalised patients dosed within5 days of symptom onset (p= 0.002).

The results of the primary composite endpoint were driven by the incidence of severe COVID-19. Upto Day 29, 7 deaths had been reported, 3 in the EVUSHELD arm and 4 in the placebo arm. Of the7 deaths, 2 were not COVID-19 related. Both of these were in the EVUSHELD arm and contributed tothe primary composite endpoint.

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

EVUSHELD in one or more subsets of the paediatric population in the prophylaxis and treatment of

COVID-19 (see section 4.2 for information on paediatric use).

The pharmacokinetics of tixagevimab and cilgavimab are comparable, linear and dose-proportionalbetween 150 mg tixagevimab and 150 mg cilgavimab and 1 500 mg of tixagevimab and 1 500 mg ofcilgavimab following a single intravenous administration. Population PK analysis of data from healthyvolunteers and patients enrolled in three Phase III studies of tixagevimab and cilgavimab in pre-exposure prophylaxis (PROVENT), post-exposure prophylaxis (STORMCHASER) and treatment ofmild-to-moderate COVID-19 (TACKLE), as well as data from five additional Phase I and II studies,with doses ranging from 300 mg (150 mg tixagevimab and 150 mg cilgavimab) to 600 mg (300 mgtixagevimab and 300 mg cilgavimab) intramuscular administration and 300 mg (150 mg tixagevimaband 150 mg cilgavimab) to 3 000 mg (1 500 mg tixagevimab and 1 500 mg cilgavimab) intravenousadministration supports dose proportionality of tixagevimab, cilgavimab and EVUSHELD.

Based on population PK modelling, following a single intramuscular dose of 150 mg tixagevimab and150 mg cilgavimab the predicted median (90% prediction interval [PI]) maximum serum concentration(Cmax) of EVUSHELD was 26.9 µg/mL (90% PI: 12.6, 53.7), the median time to reach Cmax (Tmax) was19 days (90% PI: 5, 45).

After a single intramuscular dose of 300 mg tixagevimab and 300 mg cilgavimab the predicted Cmax of

EVUSHELD was 53.9 µg/mL (90% PI: 25.2,107.3), which was reached at a median Tmax of 19 days(90% PI: 5, 46).

The estimated absolute bioavailability was 67.1% for EVUSHELD, 61.5% for tixagevimab and 65.8%for cilgavimab.

Based on PK modelling, the central volume of distribution was 3.17 L for tixagevimab and 3.52 L forcilgavimab. The peripheral volume of distribution was 1.77 L for tixagevimab and 1.82 L forcilgavimab.

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

The clearance (CL) median (95% CI) was 0.050 (0.049, 0.052) L/day for EVUSHELD, 0.046 (0.044,0.047) L/day for tixagevimab and 0.052 (0.049, 0.054) L/day for cilgavimab with interindividualvariability of 43%, 41% and 44% respectively. The estimated population median (5th and 95thpercentile) terminal elimination half-life was 79 (46, 101) days for EVUSHELD, 81 (49, 106) days fortixagevimab and 78 (49, 97) days for cilgavimab.

Following a single intramuscular dose of 150 mg tixagevimab and 150 mg cilgavimab, the predictedmedian EVUSHELD serum concentration was 24.5 µg/mL (90% PI: 11.8, 44.8) on Day 29 and6.2 µg/mL (90% PI: 1.8, 14.7) on Day 183.

Following a single intramuscular dose of 300 mg tixagevimab and 300 mg cilgavimab, the predictedmedian EVUSHELD serum concentration was 49.1 µg/mL (90% PI: 23.6, 89.5) on Day 29 and12.5 µg/mL (90% PI: 3.6, 29.3) on Day 183.

There was no clinically relevant difference on the clearance of tixagevimab or cilgavimab betweenparticipants with COVID-19 enrolled in TACKLE and those enrolled in the prophylaxis studies.

No specific studies have been conducted to examine the effects of renal impairment on thepharmacokinetics of tixagevimab and cilgavimab.

Tixagevimab and cilgavimab are not eliminated intact in the urine, thus renal impairment is notexpected to significantly affect the exposure of tixagevimab and cilgavimab. Similarly, dialysis is notexpected to impact the PK of tixagevimab and cilgavimab.

Based on population PK analysis, there is no difference in the clearance of tixagevimab andcilgavimab in patients with renal impairment (assessed via baseline eGFR and creatinine clearance)compared to patients with normal renal function. In the population PK model there were insufficientparticipants with severe renal impairment to draw conclusions.

No specific studies have been conducted to examine the effects of hepatic impairment on the PK oftixagevimab and cilgavimab. The impact of hepatic impairment on the PK of tixagevimab andcilgavimab is expected to be low.

Tixagevimab and cilgavimab are expected to be catabolised by multiple tissues through proteolyticdegradation into amino acids and recycling into other proteins, therefore hepatic impairment is notexpected to affect the exposure of tixagevimab and cilgavimab.

Of the participants in the pooled PK analysis, 17.6% (N= 871) were 65 years of age or older and 3.2%(N= 156) were 75 years of age or older. There is no clinically meaningful difference in the PK oftixagevimab and cilgavimab in geriatric subjects (≥ 65 years) compared to younger individuals.

The PK of tixagevimab and cilgavimab in individuals < 18 years old has not been evaluated.

Using population PK modelling and simulation, the recommended dosing regimen is expected to resultin comparable serum exposures of tixagevimab and cilgavimab in adolescents aged 12 years or olderwho weigh at least 40 kg as observed in adults, since adults with similar body weight have beenincluded in the prophylaxis and treatment clinical trials.

High body weight

Based on population PK analysis, a decrease in EVUSHELD maximum serum concentration andconcentration at 6 months was observed with increased body weight. The maximum serumconcentration and concentration at 6 months in an adult weighing 108 kg (87.5 percentile) were bothpredicted to be approximately 24% lower than in an adult weighing 81 kg (median).

Based on a population PK analysis, sex, age, race, ethnicity, cardiovascular disease, diabetes andimmunocompromise had no clinically relevant effect on the PK of tixagevimab and cilgavimab.

Carcinogenesis, mutagenesis, and reproductive toxicology studies have not been conducted withtixagevimab and cilgavimab.

Non-clinical data reveal no special hazard for humans based on studies of tissue binding and a single-dose toxicity study in cynomolgus monkeys including assessment of safety pharmacology and localtolerance.

Antibody-dependent enhancement (ADE) of infection

The potential of tixagevimab and cilgavimab to mediate antibody-dependent viral entry was assessedin FcγRII-expressing Raji cells co-incubated with recombinant virus pseudotyped with SARS-CoV-2spike protein, with antibody concentrations at a range of 6.6 nM (1 µg/mL) to 824 pM (125 ng/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-dependentimprovement in all measured outcomes (total viral RNA in the lungs or nasal mucosae, infectiousvirus levels in the lungs based on TCID50 measurements, and lung injury and pathology based onhistology measurements). No evidence of enhancement of disease was observed at any dose evaluated,including sub-neutralizing doses down to 0.04 mg/kg.

Histidine

Histidine hydrochloride monohydrate

Sucrose

Polysorbate 80 (E 433)

Water for injections

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

Unopened vial3 years

Prepared syringes

The prepared syringes should be administered immediately. If immediate administration is notpossible, in-use storage times and conditions prior to use are the responsibility of the user and wouldnormally not be longer than 4 hours at 2ºC to 25ºC.

Store in a refrigerator (2°C-8°C).

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

Do not freeze.

Do not shake.

For storage conditions after initial vial puncture and preparation of the syringes, see section 6.3.

Tixagevimab vial1.5 mL of solution for injection in a clear glass vial closed by a chlorobutyl elastomeric stopper sealedwith a dark-grey aluminium flip-off top.

Cilgavimab vial1.5 mL of solution for injection in a clear glass vial closed by a chlorobutyl elastomeric stopper sealedwith a white aluminium flip-off top.

Pack size: Each carton contains 2 vials: 1 vial of tixagevimab and 1 vial of cilgavimab.

This medicinal product should be handled by a healthcare professional using aseptic technique toensure the sterility of each dose.

Inspect the vials visually for particulate matter and discolouration. Both tixagevimab and cilgavimabare clear to opalescent, colourless to slightly yellow solutions. Discard the vials if the solution iscloudy, discoloured or visible particles are observed. Do not shake the vials.

Each dose of tixagevimab and cilgavimab is withdrawn into two separate syringes, to be administeredintramuscularly in two different muscles, preferably in the gluteal muscles.

For storage conditions of the prepared syringes, see section 6.3.

Any unused solution should be discarded.

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

AstraZeneca AB

SE-151 85 Södertälje

Sweden

EU/1/22/1651/001

Date of first authorisation: 25 March 2022

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

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