VAXZEVRIA suspension for injection medication leaflet

J07BX03 COVID-19 vaccine (ChAdOx1-S [recombinant]) • Antiinfectives for systemic use | Viral vaccines | Other viral vaccines

General data about VAXZEVRIA

Substance: COVID-19 vaccine (ChAdOx1-S [recombinant])

Date of last drug list: 01-05-2021

Commercial code: W67527001

Pharmaceutical form: suspension for injection

Quantity: 10

Product type: original

Prescription restrictions: P-RF - Medicines prescription that is retained in the pharmacy (not renewable).

Marketing authorisation

Manufacturer: MEDIMMUNE PHARMA B.V. - OLANDA

Holder: ASTRAZENECA AB - SUEDIA

Number: 1529/2021/01

Shelf life: 6 months- unopened bottle, when stored in a refrigerator (2°C-8°C)

Pharmaceutical forms available for COVID-19 vaccine (ChAdOx1-S [recombinant])

Other substances similar to COVID-19 vaccine (ChAdOx1-S [recombinant])

Contents of the package leaflet for the medicine VAXZEVRIA suspension for injection

1. NAME OF THE MEDICINAL PRODUCT

Vaxzevria suspension for injection

COVID-19 Vaccine (ChAdOx1-S [recombinant])

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

This is a multidose vial which contains 10 doses of 0.5 ml (see section 6.5).

One dose (0.5 ml) contains:

Chimpanzee Adenovirus encoding the SARS-CoV-2 Spike glycoprotein (ChAdOx1-S)*, not less than2.5 × 108 infectious units (Inf.U)

*Produced in genetically modified human embryonic kidney (HEK) 293 cells and by recombinant

DNA technology.

This product contains genetically modified organisms (GMOs).

Excipient with known effect

Each dose (0.5 ml) contains approximately 2 mg of ethanol.

For the full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Suspension for injection (injection).

The suspension is colourless to slightly brown, clear to slightly opaque with a pH of 6.6.

4. CLINICAL PARTICULARS

4.1 Therapeutic indications

Vaxzevria is indicated for active immunisation to prevent COVID-19 caused by SARS-CoV-2, inindividuals 18 years of age and older.

The use of this vaccine should be in accordance with official recommendations.

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4.2 Posology and method of administration

Posology
Individuals 18 years of age and older

The Vaxzevria primary vaccination course consists of two separate doses of 0.5 ml each. The seconddose should be administered between 4 and 12 weeks (28 to 84 days) after the first dose (seesection 5.1).

A booster dose (third dose) of 0.5 ml may be given to individuals who completed the primaryvaccination course with Vaxzevria or an mRNA COVID-19 vaccine (see sections 4.8 and 5.1). Thethird dose should be administered at least 3 months after completing the primary vaccination course.

Elderly population

No dose adjustment is required. See also section 5.1.

Paediatric population

The safety and efficacy of Vaxzevria in children and adolescents (less than 18 years of age) have notyet been established. No data are available.

Method of administration

Vaxzevria is for intramuscular injection only, preferably in the deltoid muscle of the upper arm.

Do not inject the vaccine intravascularly, subcutaneously or intradermally.

The vaccine should not be mixed in the same syringe with any other vaccines or medicinal products.

For precautions to be taken before administering the vaccine, see section 4.4.

For instructions on handling and disposal, see section 6.6.

4.3 Contraindications

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

Individuals who have experienced thrombosis with thrombocytopenia syndrome (TTS) followingvaccination with Vaxzevria (see section 4.4).

Individuals who have previously experienced episodes of capillary leak syndrome (see alsosection 4.4).

4.4 Special warnings and precautions for use

Traceability

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

Hypersensitivity and anaphylaxis

Events of anaphylaxis have been reported. Appropriate medical treatment and supervision shouldalways be readily available in case of an anaphylactic event following the administration of thevaccine. Close observation for at least 15 minutes is recommended following vaccination. Anadditional dose of the vaccine should not be given to those who have experienced anaphylaxis to aprevious dose of Vaxzevria.

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Anxiety-related reactions

Anxiety-related reactions, including vasovagal reactions (syncope), hyperventilation or stress-relatedreactions may occur in association with vaccination as a psychogenic response to the needle injection.

It is important that precautions are in place to avoid injury from fainting.

Concurrent illness

Vaccination should be postponed in individuals suffering from an acute severe febrile illness or acuteinfection. However, the presence of a minor infection and/or low-grade fever should not delayvaccination.

Coagulation disorders

- Thrombosis with thrombocytopenia syndrome: Thrombosis with thrombocytopenia syndrome(TTS), in some cases accompanied by bleeding, has been observed very rarely followingvaccination with Vaxzevria. This includes severe cases presenting as venous thrombosis, includingunusual sites such as cerebral venous sinus thrombosis, splanchnic vein thrombosis, as well asarterial thrombosis, concomitant with thrombocytopenia. Some cases had a fatal outcome. Themajority of these cases occurred within the first three weeks following vaccination. The reportingrates after the second dose are lower compared to after the first dose. See also section 4.3.

TTS requires specialised clinical management. Healthcare professionals should consult applicableguidance and/or consult specialists (e.g., haematologists, specialists in coagulation) to diagnoseand treat this condition.

- Cerebrovascular venous and sinus thrombosis: Events of cerebrovascular venous and sinusthrombosis without thrombocytopenia have been observed very rarely following vaccination with

Vaxzevria. Some cases had a fatal outcome. The majority of these cases occurred within the firstfour weeks following vaccination. This information should be considered for individuals atincreased risk for cerebrovascular venous and sinus thrombosis. These events may requiredifferent treatment approaches than TTS and healthcare professionals should consult applicableguidance.

- Venous thromboembolism: Venous thromboembolism (VTE) has been observed followingvaccination with Vaxzevria and should be considered for individuals at increased risk of VTE.

- Thrombocytopenia: Cases of thrombocytopenia, including immune thrombocytopenia (ITP), havebeen reported after receiving Vaxzevria, typically within the first four weeks after vaccination.

Very rarely, these presented with very low platelet levels (<20,000 per µl) and/or were associatedwith bleeding. Some of these cases occurred in individuals with a history of immunethrombocytopenia. Cases with fatal outcome have been reported. If an individual has a history of athrombocytopenic disorder, such as immune thrombocytopenia, the risk of developing low plateletlevels should be considered before administering the vaccine and platelet monitoring isrecommended after vaccination.

Healthcare professionals should be alert to the signs and symptoms of thromboembolism and/orthrombocytopenia. Those vaccinated should be instructed to seek immediate medical attention if theydevelop symptoms such as shortness of breath, chest pain, leg swelling, leg pain, persistent abdominalpain following vaccination. Additionally, anyone with neurological symptoms including severe orpersistent headaches, blurred vision, confusion or seizures after vaccination, or who experiencesspontaneous bleeding, skin bruising (petechia) beyond the site of vaccination after a few days, shouldseek prompt medical attention.

Individuals diagnosed with thrombocytopenia within three weeks after vaccination with Vaxzevria,should be actively investigated for signs of thrombosis. Similarly, individuals who present withthrombosis within three weeks of vaccination should be evaluated for thrombocytopenia.

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Risk of bleeding with intramuscular administration

As with other intramuscular injections, the vaccine should be given with caution in individualsreceiving anticoagulant therapy or those with thrombocytopenia or any coagulation disorder (such ashaemophilia) because bleeding or bruising may occur following an intramuscular administration inthese individuals.

Capillary leak syndrome

Very rare cases of capillary leak syndrome (CLS) have been reported in the first days after vaccinationwith Vaxzevria. A history of CLS was apparent in some of the cases. Fatal outcome has been reported.

CLS is a rare disorder characterised by acute episodes of oedema mainly affecting the limbs,hypotension, haemoconcentration and hypoalbuminaemia. Patients with an acute episode of CLSfollowing vaccination require prompt recognition and treatment. Intensive supportive therapy isusually warranted. Individuals with a known history of CLS should not be vaccinated with thisvaccine. See also section 4.3.

Neurological events

Guillain-Barré syndrome (GBS) and transverse myelitis (TM) have been reported very rarelyfollowing vaccination with Vaxzevria. Healthcare professionals should be alert of GBS and TM signsand symptoms to ensure correct diagnosis, in order to initiate adequate supportive care and treatment,and to rule out other causes.

Risk of severe adverse events after a booster dose

The risk of severe adverse events (such as coagulation disorders including thrombosis withthrombocytopenia syndrome, VTE, CLS, GBS and TM) after a booster dose of Vaxzevria has not yetbeen characterised.

Immunocompromised individuals

The efficacy, safety and immunogenicity of the vaccine have not been assessed inimmunocompromised individuals, including those receiving immunosuppressant therapy. The efficacyof Vaxzevria may be lower in immunosuppressed individuals.

Duration of protection

The duration of protection afforded by the vaccine is unknown as it is still being determined byongoing clinical studies.

Limitations of vaccine effectiveness

Protection starts from approximately 3 weeks after the first dose of Vaxzevria. Individuals may not befully protected until 15 days after the second dose is administered. As with all vaccines, vaccinationwith Vaxzevria may not protect all vaccine recipients (see section 5.1).

Excipients
Sodium

This medicinal product contains less than 1 mmol sodium (23 mg) per 0.5 ml dose, that is to sayessentially “sodium-free”.

Ethanol

This medicinal product contains 2 mg of alcohol (ethanol) per 0.5 ml dose. The small amount ofalcohol in this medicinal product will not have any noticeable effects.

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4.5 Interaction with other medicinal products and other forms of interaction

No interaction studies have been performed.

Concomitant administration of Vaxzevria with other vaccines has not been studied.

4.6 Fertility, pregnancy and lactation

Pregnancy

There is limited experience with use of Vaxzevria in pregnant women.

Animal studies do not indicate direct or indirect harmful effects with respect to pregnancy,embryo/foetal development, parturition or post-natal development (see section 5.3).

Administration of Vaxzevria during pregnancy should only be considered when the potential benefitsoutweigh any potential risks for the mother and foetus.

Breastfeeding

It is unknown whether Vaxzevria is excreted in human milk.

In animal studies, lactational transfer of anti-SARS-CoV-2 S antibodies from maternal female mice topups was observed (see section 5.3).

Fertility

Animal studies do not indicate direct or indirect harmful effects with respect to fertility (seesection 5.3).

4.7 Effects on ability to drive and use machines

Vaxzevria has no or negligible influence on the ability to drive and use machines. However, some ofthe adverse reactions mentioned under section 4.8 may temporarily affect the ability to drive or usemachines.

4.8 Undesirable effects

Summary of the safety profile
Primary vaccination course

The overall safety of Vaxzevria is based on an analysis of pooled data from four clinical studies phase

I/II, II/III and III conducted in the United Kingdom, Brazil, and South Africa, and of data from anadditional phase III clinical study conducted in the United States, Peru and Chile. At the time of theanalysis, a total of 56,601 participants ≥18 years old had been randomised and of these, 33,846received at least one dose of Vaxzevria and 32,030 received two doses.

Participants continued to be followed for safety regardless of unblinding or receipt of unblindedvaccination. For the four clinical studies performed in the United Kingdom, Brazil, and South Africa,longer follow-up of ≥12 months (median 13.0 months) from first dose is available for10,247 participants who received Vaxzevria.

The most frequently reported adverse reactions are injection site tenderness (68%), injection site pain(58%), headache (53%), fatigue (53%), myalgia (44%), malaise (44%), pyrexia (includes feverishness[33%] and fever ≥38°C [8%]), chills (32%), arthralgia (27%) and nausea (22%). The majority of these

Medicinal product no longer au horisedadverse reactions were mild to moderate in severity and usually resolved within a few days ofvaccination.

Very rare cases of thrombosis with thrombocytopenia syndrome have been reported post-marketingwithin the first three weeks following vaccination (see section 4.4).

Following vaccination with Vaxzevria, recipients may experience multiple adverse reactions occurringat the same time (for example, myalgia/arthralgia, headache, chills, pyrexia and malaise).

When compared with the first dose, adverse reactions reported after the second dose were milder andless frequent.

Reactogenicity was generally milder and reported less frequently in the population of older adults(≥65 years old).

The safety profile was consistent across participants with or without prior evidence of SARS-CoV-2infection at baseline.

Booster dose (third dose)

The safety profile observed in individuals who received a booster dose (third dose) was consistentwith the known safety profile of Vaxzevria. No new safety concerns, as compared with adversereactions reported for the primary vaccination course with Vaxzevria, have been identified inindividuals receiving a booster dose of Vaxzevria.

Booster dose (third dose) following primary vaccination with Vaxzevria

In study D7220C00001, 373 participants who had previously received a 2-dose primary vaccinationcourse with Vaxzevria received a single booster dose (third dose) of Vaxzevria. Median time betweenthe second dose and the booster dose was 8.8 months (269 days).

The most frequently reported adverse reactions in previously Vaxzevria vaccinated participants wereinjection site tenderness (54%), fatigue (42%), injection site pain (38%), headache (34%), myalgia(24%), and malaise (22%). The majority of these adverse reactions were mild to moderate in severityand usually resolved within a few days of vaccination.

Booster dose (third dose) following primary vaccination with an mRNA COVID-19 vaccine

In study D7220C00001, 322 participants who had previously received a 2-dose primary vaccinationcourse with an mRNA COVID-19 vaccine received a single booster dose (third dose) of Vaxzevria.

Median time between the second dose and the booster dose was 4.0 months (120 days).

The most frequently reported adverse reactions in previously mRNA vaccinated participants wereinjection site tenderness (71%), fatigue (57%), headache (52%), injection site pain (50%), myalgia(47%), malaise (42%), chills (29%), and nausea (22%). The majority of these adverse reactions weremild to moderate in severity and usually resolved within a few days of vaccination.

Tabulated list of adverse reactions

The safety profile presented below is based on an analysis of data from five clinical studies whichincluded participants ≥18 years old (pooled data from four clinical studies conducted in the United

Kingdom, Brazil and South Africa, and data from one clinical study conducted in the United States,

Peru and Chile) and on data from post-authorisation experience.

Adverse drug reactions (ADRs) are organised by MedDRA System Organ Class (SOC). Frequenciesof occurrence of adverse reactions are defined as: very common (≥1/10); common (≥1/100 to <1/10);

Medicinal product no longer authorisduncommon (≥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); within each SOC, preferred terms are arranged bydecreasing frequency and then by decreasing seriousness.

Table 1. Adverse drug reactions

MedDRA SOC Frequency Adverse Reactions

Blood and lymphatic system disorders Common Thrombocytopeniaa

Uncommon Lymphadenopathy

Not known Immune thrombocytopeniab

Immune system disorders Not known Anaphylaxis

Hypersensitivity

Metabolism and nutrition disorders Uncommon Decreased appetite

Nervous system disorders Very common Headachec

Common Dizziness

Uncommon Somnolence

Lethargy

Paraesthesia

Hypoaesthesia

Rare Facial paralysisd

Very rare Guillain-Barré syndrome

Not known Transverse myelitis

Ear and labyrinth disorders Uncommon Tinnitus

Vascular disorders Very rare Thrombosis with thrombocytopeniasyndromee

Not known Capillary leak syndrome

Cerebrovascular venous and sinusthrombosisb

Venous thromboembolismb

Gastrointestinal disorders Very common Nausea

Common Vomiting

Diarrhoea

Abdominal pain

Skin and subcutaneous tissue disorders Uncommon Hyperhidrosis

Pruritus

Rash

Urticaria

Not known Angioedema

Cutaneous vasculitis

Musculoskeletal and connective tissue Very common Myalgiadisorders Arthralgia

Common Pain in extremity

Uncommon Muscle spasms

General disorders and administration Very common Injection site tenderness, pain,site conditions warmth, pruritus, bruisingf

Fatigue

Malaise

Feverishness, fever

Chills

Common Injection site swelling, erythema

Influenza-like illness

Astheniaa In clinical studies, transient mild thrombocytopenia was commonly reported (see section 4.4).b Cases have been reported post-marketing (see also section 4.4).c Headache includes migraine (uncommon).d Based on data from the clinical study conducted in the United States, Peru and Chile. Through the safety follow-up period to 05 March 2021, facial paralysis (or palsy) was reported by five participants in the Vaxzevria group.

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Onset was 8 and 15 days after first dose and 4, 17, and 25 days after the second dose. All events were reported tobe non-serious. No cases of facial paralysis were reported in the placebo group.e Severe and very rare cases of thrombosis with thrombocytopenia syndrome have been reported post-marketing.

These included venous thrombosis such as cerebral venous sinus thrombosis, splanchnic vein thrombosis, as wellas arterial thrombosis (see section 4.4).f Injection site bruising includes injection site haematoma (uncommon).

Reporting of suspected adverse reactions

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 and include batch/Lot number if available.

4.9 Overdose

There is no specific treatment for an overdose with Vaxzevria. In the event of an overdose, theindividual should be monitored and provided with symptomatic treatment as appropriate.

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Vaccines, Covid-19 vaccines, ATC code: J07BN02

Mechanism of action

Vaxzevria is a monovalent vaccine composed of a single recombinant, replication-deficientchimpanzee adenovirus (ChAdOx1) vector encoding the S glycoprotein of SARS-CoV-2. The

SARS-CoV-2 S immunogen in the vaccine is expressed in the trimeric pre-fusion conformation; thecoding sequence has not been modified in order to stabilise the expressed S-protein in the pre-fusionconformation. Following administration, the S glycoprotein of SARS-CoV-2 is expressed locallystimulating neutralising antibody and cellular immune responses, which may contribute to protectionto COVID-19.

Clinical efficacy
Analysis of data from Study D8110C00001

The clinical efficacy of Vaxzevria has been evaluated based on an analysis of Study D8110C00001: arandomised, double-blinded, placebo-controlled phase III study conducted in the United States, Peruand Chile. The study excluded participants with severe and/or uncontrolled cardiovascular,gastrointestinal, liver, renal, endocrine/metabolic disease, and neurological illnesses; as well as thosewith severe immunosuppression, pregnant women and participants with a known history of

SARS-CoV-2 infection. All participants are planned to be followed for up to 12 months, forassessments of efficacy against COVID-19 disease.

Participants ≥18 years of age received two doses (5 × 1010 viral particles per dose corresponding to notless than 2.5 × 108 infectious units) of Vaxzevria (N=17,662) or saline placebo (N=8,550),administered via IM injection on Day 1 and Day 29 (-3 to +7 days). The median dose interval was29 days and the majority of participants (95.7% and 95.3% for Vaxzevria and placebo, respectively)received the second dose ≥26 to ≤36 days after dose 1.

Baseline demographics were well balanced across the Vaxzevria and placebo groups. Of theparticipants who received Vaxzevria, 79.1% were aged 18 to 64 years (with 20.9% aged 65 or older)and 43.8% of subjects were female. Of those randomised, 79.3% were White, 7.9% were Black, 4.2%were Asian, 4.2% were American Indian or Alaska Native. A total of 10,376 (58.8%) participants had

Medicinal product no longer authorisedat least one pre-existing comorbidity, defined as: chronic kidney disease, chronic obstructivepulmonary disease, lower immune health because of a solid organ transplant, history of obesity(BMI >30), serious heart conditions, sickle cell disease, type 1 or 2 diabetes, asthma, dementia,cerebrovascular diseases, cystic fibrosis, high blood pressure, liver disease, pulmonary fibrosis,thalassemia or history of smoking. At the time of analysis the median follow-up time post-dose 2 was61 days.

Final determination of COVID-19 cases were made by an adjudication committee. Overall vaccineefficacy and efficacy by key age groups are presented in Table 2.

Table 2. Vaxzevria efficacy against symptomatic COVID-19 illness in Study D8110C00001

Vaxzevria Placebo

N Number Incidence N Number Incidence

Vaccineof rate of of rate ofefficacy %

COVID- COVID-19 COVID- COVID-19(95% CI)b19 casesa, per 1,000 19 casesa, per 1,000n (%) person-years n (%) person-years

Overall74.0(age ≥18 17,662 73 (0.4) 35.69 8,550 130 (1.5) 137.23(65.3, 80.5)years old)

Age 18to 64 72.813,966 68 (0.5) 40.47 6,738 116 (1.7) 148.99years (63.4, 79.9)old

Age ≥6583.5years 3,696 5 (0.1) 13.69 1,812 14 (0.8) 82.98(54.2, 94.1)old

N = Number of subjects included in each group; n = Number of subjects having a confirmed event;

CI = Confidence Interval.a Symptomatic COVID-19 requiring positive Reverse Transcriptase-Polymerase Chain Reaction (RT-PCR) andat least 1 respiratory sign or symptom, or at least 2 other systemic signs or symptoms, as defined in the protocol.b The confidence intervals were not adjusted for multiplicity.

Severe or critical symptomatic COVID-19 illness was assessed as a key secondary endpoint. Amongall subjects in the per protocol set, no cases of severe or critical symptomatic COVID-19 werereported in the vaccine group compared with 8 cases reported in the placebo group. There were9 hospitalised cases, the 8 cases that were adjudicated as severe or critical symptomatic COVID-19,and one additional case in the vaccine group. The majority of the severe or critical symptomatic

COVID-19 cases fulfilled only the oxygen saturation (SpO2) criterion for severe disease (≤93% onroom air).

In individuals with or without prior evidence of SARS-CoV-2 infection, the vaccine efficacy of

Vaxzevria (≥15 days post-dose 2) was 73.7% (95% CI: 63.1; 80.1); 76 (0.4%) vs 135 (1.5%) cases of

COVID-19 for Vaxzevria (N=18,563) and placebo (N=9,031), respectively.

Participants with one or more comorbidities who received Vaxzevria (≥15 days post-dose 2) had anefficacy of 75.2% (95% CI: 64.2; 82.9) and participants without comorbidities had a vaccine efficacyof 71.8% (95% CI: 55.5, 82.1).

In the 6-month follow-up analysis, updated efficacy analyses were performed with additionalconfirmed COVID-19 cases accrued during blinded placebo-controlled follow-up, with a medianfollow-up of 78 days in participants who received Vaxzevria and 71 days in participants who receivedplacebo. Overall vaccine efficacy against symptomatic COVID-19 illness was 67.0% (95% CI: 58.9,73.5) with 141 (0.8%) cases of COVID-19 reported in participants who had received two doses of

Vaxzevria (N=17,617) and 184 (2.2%) cases reported in participants who had received placebo(N=8,528). In participants aged 18 to 64 years there were 135 (1.0%) cases in the Vaxzevria group

Medicinal product no longer authorised(N=13,921) versus 165 (2.5%) cases in the placebo group (N=6,712), corresponding to a vaccineefficacy of 64.8% (95% CI: 55.7, 71.9). In participants ≥65 years old vaccine efficacy was 86.3%(95% CI: 65.8, 94.6) with 6 (0.2%) cases in the Vaxzevria group (N=3,696) versus 19 (1.1%) cases inthe placebo group (N=1,816).

Analysis of pooled data from COV002 and COV003

The clinical efficacy of Vaxzevria has been evaluated based on an analysis of pooled data from tworandomised, blinded, controlled studies: a phase II/III study, COV002, in adults ≥18 years of age(including the elderly) in the UK; and a phase III study, COV003, in adults ≥18 years of age(including the elderly) in Brazil. The studies excluded participants with severe and/or uncontrolledcardiovascular, gastrointestinal, liver, renal, endocrine/metabolic disease, and neurological illnesses;as well as those with severe immunosuppression, pregnant women and participants with a knownhistory of SARS-CoV-2 infection. Influenza vaccines could be administered 7 days before or after anydose of Vaxzevria.

In the pooled primary analysis for efficacy, participants ≥18 years of age received two doses(5 × 1010 viral particles per dose corresponding to not less than 2.5 × 108 infectious units) of Vaxzevria(N=6,106) or control (meningococcal vaccine or saline) (N=6,090), administered via IM injection.

Because of logistical constraints, the interval between dose 1 and dose 2 ranged from 3 to 23 weeks(21 to 159 days), with 86.1% of participants receiving their two doses within the interval of 4 to12 weeks (28 to 84 days).

Baseline demographics were well balanced across Vaxzevria and control treatment groups. In thepooled primary analysis, among the participants who received Vaxzevria with a dose interval ofbetween 4 and 12 weeks, 87.0% of participants were 18 to 64 years old (with 13.0% aged 65 or olderand 2.8% aged 75 or older); 55.1% of subjects were female; 76.2% were White, 6.4% were Black and3.4% were Asian. A total of 2,068 (39.3%) participants had at least one pre-existing comorbidity(defined as a BMI ≥30 kg/m2, cardiovascular disorder, respiratory disease or diabetes). At the time ofanalysis, the median follow-up time post-dose 2 was 78 days.

Final determination of COVID-19 cases were made by an adjudication committee, who also assigneddisease severity according to the WHO clinical progression scale. A total of 218 participants had

SARS-CoV-2 virologically confirmed COVID-19 occurring ≥15 days post second dose with at leastone COVID-19 symptom (objective fever (defined as ≥37.8°C), cough, shortness of breath, anosmia,or ageusia) and were without evidence of previous SARS-CoV-2 infection. Vaxzevria significantlydecreased the incidence of COVID-19 compared to control (see Table 3).

Table 3. Vaxzevria efficacy against COVID-19 from COV002 and COV003a

Vaxzevria Control

Vaccine

Number of Number of

Population efficacy %

N COVID-19 N COVID-19(95% CI)bcases, n (%) cases, n (%)

Licensing regimen4 - 12 weeks 59.55,258 64 (1.2) 5,210 154 (3.0)(28 to 84 days) (45.8, 69.7)

N = Number of subjects included in each group; n = Number of subjects having a confirmed event; CI =

Confidence Interval.a Efficacy endpoint was based on confirmed COVID-19 cases in subjects aged 18 years and over who wereseronegative at baseline, who had received two doses and were on-study ≥15 days post second dose.b CI not adjusted for multiplicity.

Vaccine efficacy was 62.6% (95% CI: 50.9; 71.5) in participants receiving two recommended doseswith any dose interval (ranging from 3 to 23 weeks), in a pre-specified analysis.

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Regarding COVID-19 hospitalisation (WHO Severity grading ≥4) there were 0 (0.0%; N=5,258) casesof COVID-19 hospitalisation in participants who received two doses of Vaxzevria (≥15 dayspost-dose 2) as compared to 8 (0.2%; N=5,210) for control, including one severe case (WHO Severitygrading ≥6), reported for control. In all participants who received at least one dose, as from 22 dayspost-dose 1, there were 0 (0.0%, N=8,032) cases of COVID-19 hospitalisation in participants whoreceived Vaxzevria, as compared to 14 (0.2%, N=8,026), including one fatality, reported for control.

Participants who had one or more comorbidities had a vaccine efficacy of 58.3% (95% CI: 33.6; 73.9);25 (1.2%) vs 60 (2.9%) cases of COVID-19 for Vaxzevria (N=2,068) and control (N=2,040),respectively; which was similar to the vaccine efficacy observed in the overall population.

Evidence shows protection starts from approximately 3 weeks after first dose of vaccine. A seconddose should be given at a 4 to 12-week interval after the first dose (see section 4.4).

Immunogenicity after booster dose

Study D7220C00001, immunogenicity of a booster dose (third dose) following primary vaccinationwith Vaxzevria or an mRNA COVID-19 vaccine

D7220C00001 is a phase II/III partially double-blind, active-controlled study in which373 participants ≥30 years old previously vaccinated with Vaxzevria, and 322 participants ≥30 yearsold previously vaccinated with an mRNA vaccine, received a single booster dose of Vaxzevria at least90 days after receiving the second dose of their primary vaccination course. Immunogenicity wasassessed in 345 participants previously vaccinated with Vaxzevria and 296 participants previouslyvaccinated with an mRNA vaccine, all of whom were seronegative at baseline.

The effectiveness of Vaxzevria administered as a single booster dose in participants previouslyvaccinated with Vaxzevria was demonstrated by evaluating non-inferiority of the immune response ofpseudoneutralising antibody titres against the ancestral strain compared to that elicited by a 2-doseprimary vaccination course in a subset of matched participants in study D8110C00001.

Non-inferiority for GMT ratio was demonstrated when comparing pseudoneutralising antibody titres28 days after the booster dose to titres 28 days after the primary vaccination course (see Table 4).

Table 4. Neutralising antibody titres against the ancestral strain following booster dosing with

Vaxzevria in participants previously vaccinated with Vaxzevria28 days after 28 days after GMT ratiob Metprimary vaccination booster dose non-inferioritycourse with objective (Y/N)

Vaxzevriaan 508 329 329/508

GMT c 242.80 246.45 1.02 Yd(95% CI) (224.82, 262.23) (227.39, 267.12) (0.90, 1.14)n = Number of subjects in analysis; GMT = Geometric mean neutralising antibody titre; CI = Confidenceinterval; GMT Ratio = Geometric mean titre ratio.

a. Based on analyses from a matched cohort of participants in study D8110C00001.

b. GMT 28 days after booster dose to GMT 28 days after the second dose of the primary vaccination course.

c. Reported results have been adjusted using an ANCOVA model including fixed-effect terms for visit window,time since previous vaccination (for booster), baseline comorbidities, sex, age and a random subject effect.

d. Non-inferiority was demonstrated if the lower limit of the 2-sided 95% CI of the GMT ratio of the comparatorgroup and the reference group is >0.67.

Vaxzevria was also shown to be effective in eliciting antibody responses in participants who hadpreviously received primary vaccination with an mRNA vaccine. In these participants, a single boosterdose of Vaxzevria resulted in increased humoral responses, with geometric mean fold rise (GMFR) of

Medicinal product no longr authorised3.76 (95% CI: 3.25, pct. 4.35) in neutralising antibody titres against the ancestral strain from pre-booster to28 days after the booster dose.

Elderly population

Study D8110C00001 assessed the efficacy of Vaxzevria in 5,508 individuals ≥65 years of age; 3,696who received Vaxzevria and 1,812 who received placebo. The efficacy of Vaxzevria was consistentbetween elderly (≥65 years) and younger adult subjects (18-64 years).

Paediatric population

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

Vaxzevria in one or more subsets of the paediatric population in prevention of COVID-19 (seesection 4.2 for information on paediatric use).

5.2 Pharmacokinetic properties

Not applicable.

5.3 Preclinical safety data

In a repeat-dose toxicity study in mice, IM administration of Vaxzevria was well tolerated. Non-adverse, mixed and/or mononuclear cell inflammation was observed in the subcutaneous tissues andskeletal muscle of the administration sites and adjacent sciatic nerve consistent with the anticipatedfindings after IM injection of vaccines. There were no findings in the administration sites or sciaticnerves at the end of the recovery period, indicating complete recovery of the Vaxzevria-relatedinflammation.

Genotoxicity/Carcinogenicity

Neither genotoxicity nor carcinogenicity studies were performed. The components of the vaccine arenot expected to have genotoxic potential.

Reproductive toxicity

In a reproductive and development toxicity study, Vaxzevria did not induce maternal or developmentaltoxicity following maternal exposure during the pre-mating, gestation or lactating periods. In thisstudy, vaccine elicited detectable anti-SARS-CoV-2 S-glycoprotein maternal antibodies weretransferred to the foetuses and pups, indicating placental and lactational transfer, respectively. No

Vaxzevria data are available on vaccine excretion in milk.

6. PHARMACEUTICAL PARTICULARS

6.1 List of excipients

L-Histidine

L-Histidine hydrochloride monohydrate

Magnesium chloride hexahydrate

Polysorbate 80 (E 433)

Ethanol

Sucrose

Sodium chloride

Disodium edetate (dihydrate)

Water for injections

Mdicinal product no longr authorised

6.2 Incompatibilities

This medicinal product must not be mixed with other medicinal products or diluted.

6.3 Shelf life

Unopened vial9 months when stored in a refrigerator (2°C - 8°C)

The following information is intended to guide healthcare professionals only in case of an unforeseentemporary temperature excursion. It is not a recommended storage or shipping condition.

The shelf-life of unopened vials includes the following unforeseen excursions from refrigeratedstorage (2°C - 8°C) for a single period of:

- 12 hours up to 30°C

- 72 hours down to -3°C

Unopened vials must always be returned to refrigerated storage (2°C - 8°C) following a temperatureexcursion.

The occurrence of a temperature excursion for unopened vials does not impact how the vials should bestored after first opening (first vial puncture).

Opened vial

Chemical and physical in-use stability have been demonstrated for 6 hours when stored attemperatures up to 30°C and for 48 hours when stored in a refrigerator (2°C - 8°C). After this time,the vial must be discarded. Do not return it to the refrigerator after storage outside the refrigerator.

Alternatively, an opened vial may be stored in a refrigerator (2°C - 8°C) for a maximum of 48 hours ifit is immediately returned to the refrigerator following each puncture.

From a microbiological point of view, after first opening the vaccine should be used immediately. Ifthe vaccine is not used immediately, in-use storage times and conditions are the responsibility of theuser.

6.4 Special precautions for storage

Store in a refrigerator (2°C - 8°C).

Do not freeze.

Keep vials in outer carton in order to protect from light.

For storage conditions after first opening of the medicinal product, see section 6.3.

6.5 Nature and contents of container

Multidose vial10-dose vial5 ml of suspension in a 10-dose vial (clear type I glass) with stopper (elastomeric with aluminiumoverseal). Each vial contains 10 doses of 0.5 ml. Pack sizes of 10 multidose vials.

6.6 Special precautions for disposal and other handling

Handling instructions and administration

Medicinal prodct no longer authorised

This vaccine should be handled by a healthcare professional using aseptic technique to ensure thesterility of each dose.

Do not use this vaccine after the expiry date which is stated on the label after EXP.

Unopened multidose vial should be stored in a refrigerator (2°C - 8°C). Do not freeze.

Keep the vials in outer carton in order to protect from light.

The vaccine should be inspected visually for particulate matter and discolouration prior toadministration. Vaxzevria is a colourless to slightly brown, clear to slightly opaque suspension.

Discard the vial if the suspension is discoloured or visible particles are observed. Do not shake. Do notdilute the suspension.

The vaccine should not be mixed in the same syringe with any other vaccines or medicinal products.

Each vaccine dose of 0.5 ml is withdrawn into a syringe for injection to be administeredintramuscularly, preferably in the deltoid muscle of the upper arm. Use a new needle foradministration, when possible.

It is normal for liquid to remain in the vial after withdrawing the final dose. An additional overfill isincluded in each vial to ensure that 10 doses (vial of 5 ml) of 0.5 ml can be delivered. Do not poolexcess vaccine from multiple vials. Discard any unused vaccine.

From the time of vial opening (first needle puncture), use within 6 hours when stored at temperaturesup to 30°C. After this time, the vial must be discarded. Do not return it to the refrigerator.

Alternatively, an opened vial may be stored in a refrigerator (2°C - 8°C) for a maximum of 48 hours ifit is immediately returned to the refrigerator following each puncture.

Disposal

Any unused vaccine or waste material should be disposed of in compliance with the local guidance forpharmaceutical waste. Potential spills should be disinfected using agents with viricidal activity againstadenovirus.

7. MARKETING AUTHORISATION HOLDER

AstraZeneca AB

SE-151 85 Södertälje

Sweden

8. MARKETING AUTHORISATION NUMBER(S)

EU/1/21/1529/002 10 multidose vials (10 doses per vial)

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 29 January 2021

Date of latest renewal: 31 October 2022

Medicinal product no l nger authorised

10. DATE OF REVISION OF THE TEXT

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

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

Medicinal product no longer authorised