Covishield Product Monograph

RECENT MAJOR LABEL CHANGES

CONTRAINDICATIONS (2) 04/2021

CONTRAINDICATIONS (2) 06/2021

SERIOUS WARNINGS AND PRECAUTIONS (3) 04/2021

DOSAGE AND ADMINISTRATION (4.4) 03/2021

WARNINGS AND PRECAUTIONS (7) 03/2021

WARNINGS AND PRECAUTIONS (7) 04/2021

WARNINGS AND PRECAUTIONS (7) 05/2021

WARNINGS AND PRECAUTIONS (7) 08/2021

TABLE OF CONTENTS

Sections or subsections that are not applicable at the time of authorization are not listed.

RECENT MAJOR LABEL CHANGES .............................................................................. 2

TABLE OF CONTENTS .................................................................................................... 2

PART I: HEALTH PROFESSIONAL INFORMATION ..................................................... 4

1 INDICATIONS ......................................................................................................... 4

1.1 Pediatrics .................................................................................................................. 4

1.2 Geriatrics .................................................................................................................. 4

2 CONTRAINDICATIONS ......................................................................................... 4

3 SERIOUS WARNINGS AND PRECAUTIONS ...................................................... 4

4 DOSAGE AND ADMINISTRATION ....................................................................... 4

4.1 Dosing Considerations ............................................................................................. 4

4.2 Recommended Dose and Dosage Adjustment ........................................................ 5

4.3 Reconstitution .......................................................................................................... 5

4.4 Administration ......................................................................................................... 5

5 OVERDOSAGE ....................................................................................................... 5

6 DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING ............. 5

7 WARNINGS AND PRECAUTIONS ........................................................................ 6

7.1 Special Populations .................................................................................................. 9

7.1.1 Pregnant Women ............................................................................................ 9

7.1.2 Breast-feeding.................................................................................................. 9

7.1.3 Pediatrics .......................................................................................................... 9

7.1.4 Geriatrics .......................................................................................................... 9

8 ADVERSE REACTIONS ...................................................................................... 10

8.1 Adverse Reaction Overview ................................................................................... 10

8.2 Clinical Trial Adverse Reactions ............................................................................. 11

8.3 Post-Market Adverse Reactions ............................................................................. 17

9 DRUG INTERACTIONS ....................................................................................... 17

10 CLINICAL PHARMACOLOGY ............................................................................. 18

10.1 Mechanism of Action ....................................................................................... 18

11 STORAGE, STABILITY AND DISPOSAL ........................................................... 18

12 SPECIAL HANDLING INSTRUCTIONS .............................................................. 18

PART II: SCIENTIFIC INFORMATION ........................................................................... 18

13 PHARMACEUTICAL INFORMATION ................................................................. 18

14 CLINICAL TRIALS ............................................................................................... 19

14.1 Trial Design and Study Demographics ............................................................. 19

14.2 Study Results .................................................................................................... 21

15 MICROBIOLOGY .................................................................................................. 22

16 NON-CLINICAL TOXICOLOGY ........................................................................... 22

PATIENT MEDICATION INFORMATION ....................................................................... 24

PART I: HEALTH PROFESSIONAL INFORMATION

1 INDICATIONS

COVISHIELD (ChAdOx1-S [recombinant]) is indicated for active immunization of individuals 18 years of age and over for the prevention of coronavirus disease 2019 (COVID-19).

1.1 Pediatrics

The safety and efficacy of COVISHIELD in children under 18 years of age have not yet been established. No data are available.

1.2 Geriatrics

Currently, there is limited information from clinical trials on the efficacy of COVISHIELD in individuals ≥65 years of age. No dose adjustment is required.

2 CONTRAINDICATIONS

COVISHIELD is contraindicated in individuals who are hypersensitive to the active substance or to any ingredient in the formulation. For a complete listing, see DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING section.

COVISHIELD is contraindicated in individuals who have experienced major venous and/or arterial thrombosis with thrombocytopenia following vaccination with COVISHIELD/AstraZeneca COVID-19 Vaccine.

COVISHIELD is contraindicated in individuals who have previously experienced episodes of capillary leak syndrome.

3 SERIOUS WARNINGS AND PRECAUTIONS

A combination of thrombosis and thrombocytopenia, in some cases accompanied by bleeding, has been observed very rarely following vaccination with COVISHIELD and/or AstraZeneca COVID-19 Vaccine (see WARNINGS AND PRECAUTIONS, Hematologic section).

4 DOSAGE AND ADMINISTRATION

4.1 Dosing Considerations

COVISHIELD is a solution for intramuscular injection that should be administered by a trained healthcare worker.

4.2 Recommended Dose and Dosage Adjustment

The COVISHIELD vaccination course consists of two separate doses of 0.5 mL each. The second dose should be administered between 4 and 12 weeks after the first dose. Individuals should complete the vaccination course with either COVISHIELD or AstraZeneca COVID-19 Vaccine (see WARNINGS AND PRECAUTIONS).

There are no data available on the interchangeability of COVISHIELD with other non ChAdOx1-S (recombinant) COVID-19 vaccines.

4.3 Reconstitution

COVISHIELD must not be reconstituted, mixed with other medicinal products, or diluted.

4.4 Administration

COVISHIELD is a colourless to slightly brown, clear to slightly opaque solution. The vaccine should be inspected visually for particulate matter and discolouration prior to administration. Discard the vial if the solution is discoloured or visible particles are observed.

Each vaccine dose of 0.5 mL is withdrawn into a syringe for injection to be administered intramuscularly, preferably in the deltoid muscle. Use a separate sterile needle and syringe for each individual.

Each vial contains at least the number of doses stated. It is normal for liquid to remain in the vial after withdrawing the final dose. When low dead volume syringes and/or needles are used, the amount remaining in the vial may be sufficient for an additional dose. Care should be taken to ensure a full 0.5 mL dose is administered. Where a full 0.5 mL dose cannot be extracted, the remaining volume should be discarded. Do not pool excess vaccine from multiple vials.

The vaccine does not contain any preservative. After first opening, use the vial within:

• 6 hours when stored at room temperature (up to 30ºC), or
• 48 hours when stored in a refrigerator (2 to 8ºC).

The vial can be re-refrigerated, but the cumulative storage time at room temperature must not exceed 6 hours, and the total cumulative storage time must not exceed 48 hours. After this time, the vial must be discarded.

5 OVERDOSAGE

In the case of a suspected vaccine overdose, monitoring of vital functions and symptomatic treatment are recommended. Contact your regional poison control centre.

6 DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING

Table – Dosage Forms, Strengths, Composition and Packaging

COVISHIELD is a sterile, preservative free, colorless to slightly brown, clear to slightly opaque solution, essentially free from visible particles for intramuscular injection.

One dose (0.5 ml) of COVISHIELD contains:

COVID-19 Vaccine (ChAdOx1-S^* [recombinant]) 5 x 10¹⁰ viral particles (not less than 2.5 x 10⁸ infectious units) *Recombinant, replication-deficient chimpanzee adenovirus vector encoding the unmodified SARS-CoV-2 Spike (S) glycoprotein (GP) produced in genetically modified human embryonic kidney (HEK) 293 cells by recombinant DNA technology.

COVISHIELD is packaged in:

• 5 mL of solution in a 10-dose vial (clear type I glass) with stopper (elastomeric with aluminium overseal).

To help ensure the traceability of vaccines for patient immunization record-keeping as well as safety monitoring, health professionals should record the time and date of administration, quantity of administered dose (if applicable), anatomical site and route of administration, brand name and generic name of the vaccine, the product lot number and expiry date.

7 WARNINGS AND PRECAUTIONS

As with any vaccine, vaccination with COVISHIELD may not protect all vaccine recipients.

Individuals may not be optimally protected until after receiving the second dose of the vaccine.

General

Hypersensitivity and anaphylaxis

Hypersensitivity reactions including anaphylaxis and angioedema have occurred

following administration of COVISHIELD/AstraZeneca COVID-19 Vaccine.

Appropriate medical treatment and supervision should always be readily available in case of an anaphylactic event following the administration of the vaccine.

Vaccine recipients should be kept under observation for at least 15 minutes after immunization.

A second dose of the vaccine should not be given to those who have experienced a hypersensitivity reaction to the first dose of COVISHIELD/AstraZeneca COVID-19 Vaccine.

Concurrent illness

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

Interchangeability

There are no safety, immunogenicity or efficacy data to support interchangeability of COVISHIELD with other non-ChAdOx1-S (recombinant) COVID-19 vaccines.

Driving and Operating Machinery

COVISHIELD has no or negligible influence on the ability to drive and use machines. However, some of the adverse reactions mentioned under ADVERSE REACTIONS may temporarily affect the ability to drive or use machines.

Hematologic

Thrombosis and thrombocytopenia

A combination of thrombosis and thrombocytopenia including thrombosis with thrombocytopenia syndrome (TTS), in some cases accompanied by bleeding, has been observed very rarely following vaccination with COVISHIELD/AstraZeneca COVID-19 Vaccine during post-authorization use. This includes severe cases at unusual sites such as cerebral venous sinus thrombosis (CVST) and splanchnic vein thrombosis, as well as arterial thrombosis, concomitant with thrombocytopenia. The majority of these cases occurred within the first 3 weeks following vaccination. Some cases had a fatal outcome.

Whilst specific risk factors for thrombosis in combination with thrombocytopenia have not been identified, cases have occurred in patients with a previous history of thrombosis, as well as in patients with autoimmune disorders, including idiopathic thrombocytopenic purpura. The benefits and risks of vaccination should be considered in these patients.

Healthcare professionals should be alert to the signs and symptoms of thrombosis and thrombocytopenia. Vaccinated individuals should be instructed to seek immediate medical attention if they develop symptoms such as shortness of breath, chest pain, leg swelling or pain, or persistent abdominal pain following vaccination. Additionally, anyone with neurological symptoms after vaccination including sudden onset of severe headaches, persistent or worsening headaches, blurred vision, confusion or seizures, or who experiences unusual skin bruising or petechiae beyond the site of vaccination after a few days, should seek prompt medical attention.

Individuals who have experienced a previous CVST with thrombocytopenia or heparin-induced thrombocytopenia (HIT) should only receive COVISHIELD/AstraZeneca COVID-19 Vaccine if the potential benefits outweigh the potential risks. Patients who have experience major venous or arterial thrombosis with thrombocytopenia following vaccination with COVISHIELD/AstraZeneca COVID-19 Vaccine should not receive a second dose of COVISHIELD/AstraZeneca COVID-19 Vaccine.

Since medical management of a post-vaccine thrombosis with thrombocytopenia may be different than medical management of other thromboses, if patients present with thrombosis with thrombocytopenia, healthcare professionals should consult with current guidance and hematologic specialists to diagnose and treat this post-vaccine event.

Individuals diagnosed with thrombocytopenia following vaccination with the COVISHIELD/AstraZeneca COVID-19 Vaccine should be actively evaluated for signs of thrombosis, and similarly individuals who present with thrombosis following vaccination should be evaluated for thrombocytopenia.

Risk of bleeding with intramuscular administration

As with other intramuscular injections, COVISHIELD should be given with caution to individuals with thrombocytopenia, any coagulation disorder or to persons on anticoagulation therapy, because bleeding or bruising may occur following an intramuscular administration in these individuals.

Capillary leak syndrome

Cases of capillary leak syndrome (CLS) have been observed very rarely following vaccination with COVISHIELD/AstraZeneca COVID-19 Vaccine during post-authorization use. Some of the reported cases had a history of CLS. Some cases had a fatal outcome. CLS is a rare disease characterized by acute episodes of limb edema, hypotension, hemoconcentration and hypoalbuminemia. Patients with an acute episode of CLS following vaccination require prompt medical attention and treatment. Intensive supportive therapy is usually warranted. Individuals with a known history of CLS should not be vaccinated with this vaccine.

Immune

Immunocompromised individuals

Immunocompromised persons, including individuals receiving immunosuppressant therapy, may have a diminished immune response to the vaccine.

Neurologic

Neurological events

Very rare events of demyelinating disorders, such as Guillain-Barré Syndrome (GBS), have been reported following vaccination with COVISHIELD/AstraZeneca COVID-19 Vaccine during post-authorization use. Healthcare professionals should be alert to

GBS signs and symptoms to ensure correct diagnosis, in order to initiate adequate supportive care and treatment, and to rule out other causes.

Syncope

Syncope (fainting) can occur following, or even before, any vaccination as a psychogenic response to the needle injection. Procedures should be in place to prevent injury from syncopal reactions.

Fertility

It is unknown whether COVISHIELD may impact fertility in humans. No data are available in humans.

7.1 Special Populations

7.1.1 Pregnant Women

The safety and efficacy of COVISHIELD in pregnant women have not yet been established.

Use of COVISHIELD in pregnant women should be based on an assessment of whether the benefits of vaccination outweigh the potential risks.

7.1.2 Breast-feeding

It is unknown if COVISHIELD is excreted in human milk. A risk to the newborns/ infants cannot be excluded. The developmental and health benefits of breast feeding should be considered along with the mother’s clinical need for immunization against COVID-19.

7.1.3 Pediatrics

The safety and efficacy of COVISHIELD in children and adolescents (under 18 years of age) have not yet been established. No data are available.

7.1.4 Geriatrics

Currently, there is limited information from clinical trials on the efficacy of COVISHIELD in individuals ≥65 years of age (see ADVERSE REACTIONS and CLINICAL TRIALS section). No dose adjustment is required.

8 ADVERSE REACTIONS

8.1 Adverse Reaction Overview

The overall safety of AstraZeneca COVID-19 Vaccine is based on an interim analysis of pooled data from four ongoing clinical trials conducted in the United Kingdom (COV001 and COV002), Brazil (COV003), and South Africa (COV005). At the time of analysis, 23,745 participants ≥18 years of age had been randomised and received either one or two doses of AstraZeneca COVID-19 Vaccine (n=12,021) or a control treatment (n=11,724). Two doses of AstraZeneca COVID-19 Vaccine were received by 7,598 participants ages 18 to 64 and by 668 participants ages 65 and above. The median follow-up after second dose for these age groups were 63.0 days and 30.0 days, respectively.

Control treatments consisted of a licensed meningococcal vaccine (MenACWY), a saline placebo, or a combination of the two. Of the total number of control doses administered in the studies, 77.7% were MenACWY and 22.3% were saline placebo.

Demographic characteristics were generally similar among participants who received AstraZeneca COVID-19 Vaccine and those who received control. Overall, among the participants who received AstraZeneca COVID-19 Vaccine, 90.3% were aged 18 to 64 years and 9.7% were 65 years of age or older. The majority of recipients were White (75.5%), 10.1% were Black and 3.5% were Asian; 55.8% were female and 44.2% male.

Following vaccination, recipients may experience multiple adverse reactions occurring at 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 generally milder and reported less frequently.

Adverse reactions were generally milder and reported less frequently in older adults (≥65 years old).

Data is presented here for the reactogenicity subset that consists of subjects enrolled in studies COV001, COV002 and COV003 who received the standard dose for their first dose of vaccine, and who were given diary cards to record solicited adverse reactions. Data from subjects in Study COV005 were excluded from this subset due to differences in data collection. In this analysis set, 1,736 subjects (402 aged ≥65 years) received AstraZeneca COVID-19 Vaccine and 1,596 (324 aged ≥65 years) received the control.

In the reactogenicity subset, the most frequently reported adverse reactions in subjects 18 years of age and older (percentage of subjects) were injection site tenderness (75.3%), injection site pain (54.2%), fatigue (62.3%), headache (57.5%), myalgia (48.6%), malaise (44.2%), pyrexia (33.6%), chills (31.9%), arthralgia (27.0%), and nausea (21.9%).

A supportive COVISHIELD comparative safety and immunogenicity study was conducted in India. Among the participants who received COVISHIELD, 87.33% were aged 18 to 59 years and 12.67% were 60 years of age or older. An interim, unplanned analysis included data collected on 1181 (98.3%) participants who received the second dose of COVISHIELD. The immunogenicity (as measured by binding IgG antibodies against SARS-CoV-2 spike protein) and safety profile of COVISHIELD appeared to be comparable to that of the AstraZeneca COVID-19 vaccine.

8.2 Clinical Trial Adverse Reactions

Clinical trials are conducted under very specific conditions. The adverse reaction rates observed in the clinical trials; therefore, may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse reaction information from clinical trials may be useful in identifying and approximating rates of adverse drug reactions in real-world use.

Solicited adverse reaction data were collected from Day 1 to Day 7 and reported by participants in a symptom diary card after each dose and on electronic case report forms. Reported solicited local and systemic adverse reactions are presented in Tables 1 to 4.

Table 1 – Solicited Local Adverse Events Within 7 Days After First and Second Injection by Grade-Participants 18-64 Years of Age (Dose 1 SD for Safety Analysis Set, Including Studies COV001, COV002, and COV003 Only)

^a In Studies COV001 and COV002, MenACWY was administered as control for both Dose 1 and Dose 2. In Study COV003, MenACWY was administered as placebo for Dose 1, with a saline placebo for Dose 2.

^b Grade 3: Unable to perform normal daily activity (COV001, COV002) or marked limitation in routine activities, some assistance usually required; medical intervention/therapy required (COV003). Grade 4: Emergency department or hospital admission required (COV001, COV002) or potentially Life-threatening: requires assessment in emergency department or hospitalization (COV003).

Note: Subjects in some study groups were recommended to take prophylactic acetaminophen 1 g every 6 hours for the first 24 hours after vaccination.

ED = exfoliative dermatitis; PDA = prevent daily activity

Table 2 – Solicited Local Adverse Events Within 7 Days After First and Second Injection by Grade-Participants ≥65 Years of Age (Dose 1 SD for Safety Analysis Set, Including Studies COV001, COV002, and COV003 Only)

^a In Studies COV001 and COV002, MenACWY was administered as control for both Dose 1 and Dose 2. In Study COV003, MenACWY was administered as placebo for Dose 1, with a saline placebo for Dose 2.

^b Grade 3: Unable to perform normal daily activity (COV001, COV002) or marked limitation in routine activities, some assistance usually required; medical intervention/therapy required (COV003). Grade 4: Emergency department or hospital admission required (COV001, COV002) or potentially Life-threatening: requires assessment in emergency department or hospitalization (COV003).

Note: Subjects in some study groups were recommended to take prophylactic acetaminophen 1 g every 6 hours for the first 24 hours after vaccination.

ED = exfoliative dermatitis; PDA = prevent daily activity

Table 3 – Solicited Systemic Adverse Events Within 7 Days After First and Second Injection by Grade-Participants 18-64 Years of Age (Dose 1 SD for Safety Analysis Set, Including Studies COV001, COV002, and COV003 Only)

^a In Studies COV001 and COV002, MenACWY was administered as control for both Dose 1 and Dose 2. In Study COV003, MenACWY was administered as placebo for Dose 1, with a saline placebo for Dose 2

^b >39.0^oC

^c Grade 3: Unable to perform normal daily activity (COV001, COV002) or marked limitation in routine activities, some assistance usually required; medical intervention/therapy required (COV003). Grade 4: Emergency department or hospital admission required (COV001, COV002) or potentially life-threatening: requires assessment in emergency department or hospitalization (COV003).

Note: Subjects in some study groups were recommended to take prophylactic acetaminophen 1 g every 6 hours for the first 24 hours after vaccination.

Table 4 – Solicited Systemic Adverse Events Within 7 Days After First and Second Injection by Grade-Participants ≥65 Years of Age (Dose 1 SD for Safety Analysis Set, Including Studies COV001, COV002, and COV003 Only)

^a In Studies COV001 and COV002, MenACWY was administered as control for both Dose 1 and Dose 2. In Study COV003, MenACWY was administered as placebo for Dose 1, with a saline placebo for Dose 2

^b >39.0^oC

^c Grade 3: Unable to perform normal daily activity (COV001, COV002) or marked limitation in routine activities, some assistance usually required; medical intervention/therapy required (COV003). Grade 4: Emergency department or hospital admission required (COV001, COV002) or potentially life-threatening: requires assessment in emergency department or hospitalization (COV003).

Note: Subjects in some study groups were recommended to take prophylactic acetaminophen 1 g every 6 hours for the first 24 hours after vaccination.

Unsolicited Adverse Events

In the pooled analysis of subjects aged ≥18 who received any dose of vaccine (AstraZeneca COVID-19 Vaccine = 12,021 of whom 1169 were aged ≥65 years and control = 11,724 of whom 940 were aged ≥65 years) , unsolicited adverse events occurring within 28 days after each vaccination were reported by 37.8% of participants who received AstraZeneca COVID-19 Vaccine and 27.9% of participants who received the control. Most of these events occurred within 7 days after receipt of any dose of the vaccine, with 9.4% of participants in the AstraZeneca COVID-19 Vaccine group and 9.0% of participants in the control group reporting adverse events between 7 and 28 days after any dose. The adverse events occurring in ≥ 2% participants were predominantly reactogenicity events (vaccination site pain, headache, fever, myalgia, fatigue, chills, asthenia, malaise, nausea etc).

Other unsolicited events where there was an imbalance of AEs between AstraZeneca COVID-19 Vaccine and control group and that occurred at rates >0.1% in the vaccine group included: hyperhydrosis (0.3% in the vaccine and 0.1% in the control group) and decreased appetite (0.2% in the vaccine and 0.1% in the control group).

Lymphadenopathy, pruritis and rash are recognized uncommon AEs for the MenACWY comparator vaccine. Lymphadenopathy occurred at a rate of 0.3 % in both groups. Pruritis and rash occurred at rates of 0.2% each in both the AstraZeneca COVID-19 Vaccine and control groups.

Unsolicited AEs affecting the nervous system occurred in 11.7 % of participants in the AstraZeneca COVID-19 Vaccine group and 7.8% of participants in the control group. Most of these events were due to reactogenicity, were self-limited and occurred in the first 7 days following vaccination. The events that occurred at higher rates in the AstraZeneca COVID-19 Vaccine group than the control group included headache (9.3% vs 6.1% respectively), dizziness (0.6 % vs 0.5 %) and somnolence (0.3% vs 0.2%). Facial paralysis occurred in 3 subjects in the AstraZeneca COVID-19 Vaccine group and 3 subjects in the control group, all of whom had received meningococcal vaccine.

No deaths related to the vaccine were reported in the pooled safety analysis.

Serious Adverse Events

Seventy-nine (0.7%) of subjects in the AstraZeneca COVID-19 Vaccine group and 89 (0.8%) of subjects in the control group experienced a serious adverse event between the first vaccination and the interim analysis. The median duration of follow-up from the first dose was 105 days in the AstraZeneca COVID-19 Vaccine group and 104 days in the control group.

Two serious adverse events were possibly related to the AstraZeneca COVID-19 Vaccine: one case of pyrexia (40.5°C) occurring 2 days after dose 1, and one case of transverse myelitis occurring 14 days after dose 2. Two possibly related SAEs occurred in the control group: a case of autoimmune haemolytic anemia occurring 9 days after a single dose of the MenACWY vaccine and one case of myelitis occurring 54 days after a single dose of MenACWY.

8.3 Post-Market Adverse Reactions

The following adverse reactions have been spontaneously reported during worldwide post-authorization use of AstraZeneca COVID-19 Vaccine and/or COVISHIELD. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to product exposure. They are included because: a) they represent reactions that are known to occur following immunizations generally; b) they are potentially serious; or c) on the basis of their frequency of reporting.

Blood and lymphatic system disorders: Thrombocytopenia.

Immune system disorders: Anaphylactic reaction.

Nervous system disorders: Guillain-Barré Syndrome

Skin and subcutaneous tissue disorders: Angioedema.

Vascular disorders: A combination of thrombosis and thrombocytopenia including thrombosis with thrombocytopenia syndrome (TTS), in some cases accompanied by bleeding, has been observed very rarely following vaccination with AstraZeneca COVID-19 Vaccine and/or COVISHIELD. This includes severe cases in unusual sites such as cerebral venous sinus thrombosis and splanchnic vein thrombosis, as well as arterial thrombosis, concomitant with thrombocytopenia. See WARNINGS AND PRECAUTIONS.

In addition, cases of capillary leak syndrome (CLS) have been observed following vaccination with COVISHIELD. See WARNINGS AND PRECAUTIONS.

9 DRUG INTERACTIONS

No interaction studies have been performed.

Do not mix COVISHIELD with other vaccines/products in the same syringe.

10 CLINICAL PHARMACOLOGY

10.1 Mechanism of Action

COVISHIELD is a monovalent vaccine composed of a single recombinant, replication-deficient chimpanzee 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; the coding sequence has not been modified in order to stabilise the expressed S-protein in the pre-fusion conformation. Following administration, the S glycoprotein of SARS-CoV-2 is expressed locally stimulating neutralising antibody and cellular immune responses, which may contribute to protection against COVID-19.

11 STORAGE, STABILITY AND DISPOSAL

Unopened multidose vial

Store in a refrigerator (2 to 8ºC).

Do not freeze.

Store in outer carton in order to protect from light.

Use the product before the expiration date on the vial label.

Opened multidose vial

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

After first opening, chemical and physical in-use stability has been demonstrated from the time of vial puncture to administration for no more than:

• 6 hours at room temperature, up to 30ºC, or
• 48 hours in a refrigerator (2 to 8ºC).

The vial can be re-refrigerated, but the cumulative storage time at room temperature must not exceed 6 hours, and the total cumulative storage time must not exceed 48 hours.

12 SPECIAL HANDLING INSTRUCTIONS

Disposal

COVISHIELD contains genetically modified organisms (GMOs). Any unused vaccine or waste material should be disposed of in accordance with local requirements. Spills should be disinfected with an appropriate antiviral disinfectant.

PART II: SCIENTIFIC INFORMATION

13 PHARMACEUTICAL INFORMATION

Drug Substance

Proper name: COVID-19 Vaccine (ChAdOx1-S [recombinant])

Product Characteristics:

COVISHIELD is a colourless to slightly brown, clear to slightly opaque solution essentially free from visible particles, sterile, pH 6.6, preservative-free, solution for intramuscular injection.

One dose (0.5 ml) of COVISHIELD contains:

COVID-19 Vaccine (ChAdOx1-S* [recombinant]) 5 x 10¹⁰ viral particles (not less than 2.5 x 10⁸ infectious units).

*Recombinant, replication-deficient chimpanzee adenovirus vector encoding the unmodified SARS-CoV-2 Spike (S) glycoprotein (GP) produced in genetically modified human embryonic kidney (HEK) 293 cells by recombinant DNA technology.

14 CLINICAL TRIALS

14.1 Trial Design and Study Demographics

Authorization of COVISHIELD was based on its comparability to the AstraZeneca COVID-19 Vaccine as determined by evaluation and direct comparison of manufacturing processes and controls and the quality characteristics of the two products. The results of this comparison determined that the two products were sufficiently similar that the efficacy, immunogenicity and safety of COVISHIELD could be inferred from the non-clinical and clinical studies from the AstraZeneca vaccine.

Interim analysis of pooled data from COV001, COV002, COV003, and COV005

AstraZeneca COVID-19 Vaccine has been evaluated based on an interim analysis of pooled data from four on-going randomised, blinded, controlled trials: a Phase I/II Study in healthy adults 18 to 55 years of age in the UK (COV001; NCT04324606), a Phase II/III Study in adults ≥18 years of age in the UK (COV002; NCT04400838), a Phase III Study in adults ≥18 years of age in Brazil (COV003; ISRCTN89951424), and a Phase I/II study in adults aged 18 to 65 years of age in South Africa (COV005; NCT04444674). The studies excluded participants with a history of anaphylaxis or angioedema; participants with severe and/or uncontrolled cardiovascular, gastrointestinal, liver, renal, endocrine/metabolic disease, or neurological illnesses; pregnant or breastfeeding women; participants with known history of SARS-CoV-2 infection as well as those with severe immunosuppression.

The primary efficacy endpoint was virologically-confirmed symptomatic cases of COVID-19* confirmed by a clinical adjudication committee.

*PCR confirmed SARS-CoV-2 and at least one of the following symptoms: objective fever (defined as ≥37.8 °C), cough, shortness of breath, anosmia, or ageusia.

Based on the pre-defined criteria for the interim efficacy analysis (data cut-off November 4, 2020), COV002 and COV003 exceeded the threshold of ≥5 adjudication committee confirmed COVID-19 cases per study and therefore contributed to the efficacy analysis; COV001 and COV005 did not exceed such threshold and were excluded from this interim analysis. In the pooled analysis for efficacy (COV002 and COV003), participants ≥18 years of age that received two doses of AstraZeneca COVID-19 Vaccine or control (meningococcal vaccine or saline placebo) were included. The planned dose was 5 × 10¹⁰ viral particles (vp) per dose administered via IM injection. The population used for the interim analysis of the primary efficacy endpoint included participants who received two doses of the AstraZeneca COVID-19 Vaccine or control and did not have evidence of prior infection with SARS-CoV-2 through 15 days after the second dose. Study COV002 contributed a total of 7548 participants (3744 receiving the AstraZeneca COVID-19 Vaccine, 3804 receiving two doses of a meningococcal vaccine control) and Study COV003 contributed a total of 4088 participants (2063 receiving the AstraZeneca COVID-19 Vaccine, 2025 receiving meningococcal vaccine followed by saline placebo control) to this analysis.

Participants are planned to be followed for up to 12 months, for assessments of safety and efficacy against COVID-19 disease.

^a Number (%) of subjects who have 1 or more of that following comorbidities at baseline that increase the risk of severe COVID19 disease: BMI >30 kg/m², cardiovascular disorder, respiratory disease, or diabetes.

14.2 Study Results

The interim analysis of the primary efficacy endpoint (data cut-off November 4, 2020) included 11,636 participants 18 years of age and older (5,807 in the AstraZeneca COVID-19 Vaccine group and 5,829 in the control group). At the time of the interim analysis, participants had been followed for symptomatic COVID 19 disease for a median of 63 days (range: 16-94 days) after the second dose, corresponding to exposure of 921 person-years in the AstraZeneca COVID-19 Vaccine and 925 person-years in the control group.

Participants randomised to AstraZeneca COVID‑19 Vaccine received either two standard doses [SD] (5 × 10¹⁰ vp per dose) (SD/SD) or, due to a difference in concentration determination between two analytical methods, one low dose [LD] (2.2 × 10¹⁰ vp) followed by one SD (5 x 10¹⁰ vp) (LD/SD).

The interval between dose 1 and dose 2 ranged from 3 to 26 weeks for these data. In these 11,636 seronegative participants, 86 (0.7%) had a dose interval of less than 4 weeks, 8,786 (75.5%) had a dose interval of 4-12 weeks and 2,764 (23.8%) had a dose interval of more than 12 weeks.

A total of 131 participants had SARS-CoV-2 virologically confirmed COVID-19 occurring ≥15 days post second dose. There were 30 confirmed COVID-19 cases identified in the AstraZeneca COVID-19 Vaccine group and 101 in the control group, respectively, for the primary interim efficacy analysis. Compared to control, efficacy of AstraZeneca COVID-19 Vaccine in participants with first COVID-19 occurrence from 15 days after Dose 2 was 70.42% (two-sided 95.84% confidence interval of 58.84% to 80.63%, p<0.001). There were no cases of COVID-19 hospitalisation (WHO severity score ≥4) in the participants that received AstraZeneca COVID-19 Vaccine as compared to 5 cases in control participants.

The vaccine efficacy was based on pre-specified analysis; however the results should be interpreted with caution given that it excludes 51% of randomized and vaccinated subjects, the majority of which had only received a single dose. In addition, a significant difference was observed in vaccine efficacy between the LD/SD cohort and the SD/SD cohort. The findings may also be confounded by the variability in dosing interval.

In participants who received two standard doses of the vaccine (SD/SD) or the corresponding control (4,440 in the AstraZeneca COVID-19 Vaccine group and 4,455 in the control group), a total of 98 participants had SARS-CoV-2 virologically confirmed COVID-19 occurring ≥15 days post second dose (27 cases in the AstraZeneca COVID-19 Vaccine group and 71 cases in the control group). In this population, vaccine efficacy from 15 days post second dose was 62.10% (two-sided 95% confidence interval of 39.96% to 76.08%).

Evidence shows protection starts from approximately 3 weeks after first dose of vaccine and persists up to 12 weeks. A second dose should be given at a 4-to-12-week interval after the first dose, with evidence that efficacy increases with longer dosing intervals.

Based on an updated analysis (data cut-off December 7, 2020), vaccine efficacy was 59.5% (two-sided 95% confidence interval of 45.8% to 69.7%) in participants who received two standard doses with the second dose administered 4 to 12 weeks after the first dose. Regarding COVID-19 hospitalisation (WHO severity score ≥4) in these data, there were 0 (0.0%; N=5,258) cases of COVID‑19 hospitalisation in participants who received two doses of AstraZeneca COVID‑19 Vaccine (≥15 days post dose 2) as compared to 8 (0.2%; N=5,210) for control, including one severe case (WHO severity score ≥6), reported for control and 0 severe cases reported for AstraZeneca COVID-19 Vaccine.

At the time of interim analysis, there were limited number of COVID-19 cases in participants ≥65 years old.

15 MICROBIOLOGY

No microbiological information is required for this drug product.

16 NON-CLINICAL TOXICOLOGY

General Toxicology

In a repeat-dose toxicity study in mice, Intramuscular (IM) administration of COVISHIELD was well tolerated.

IM administration of COVISHIELD at a dose of 3.7x10¹⁰ vp/animal once every 3 weeks for 6 weeks (total of 3 doses) resulted in transient inflammation at the site of injection and underlying fascia and connective tissue, slightly increased body temperature, increased spleen weights, mildly decreased monocyte counts, and minimal to mild clinical chemistry changes indicative of an active phase response.

Non adverse, mixed and/or mononuclear cell inflammation was observed in the subcutaneous tissues and skeletal muscle of the administration sites and adjacent sciatic nerve consistent with the anticipated findings after IM injection of vaccines. There were no findings in the administration sites or sciatic nerves at the end of a 4-week recovery period, indicating complete recovery of the AstraZeneca COVID-19 Vaccine related inflammation.

Full recovery from all findings was observed following the 4 week recovery period. These changes are consistent with an expected immunostimulatory response following intramuscular administration of a vaccine.

Carcinogenicity

COVISHIELD has not been evaluated for carcinogenicity in animals, as carcinogenicity studies were not considered relevant to this vaccine.

Genotoxicity

COVISHIELD has not been evaluated for genotoxicity, as genotoxicity studies were not considered relevant to this vaccine.

Reproductive and Developmental Toxicology

In a pre- and post-natal development toxicity study in mice, AstraZeneca COVID-19 Vaccine was well tolerated. In this study, F0 female mice were administered two doses of 3.71x10¹⁰ vp/animal of AstraZeneca COVID-19 Vaccine by IM injection 13 days prior to mating and on gestational day (GD) 6 or on GD 6 and GD 15. IM administration of AstraZeneca COVID-19 Vaccine elicited detectable anti-SARS-CoV-2 S-glycoprotein maternal antibodies in dams that were detected in foetuses and pups, indicating placental and lactational transfer, respectively. There were no AstraZeneca COVID-19 Vaccine-related adverse effects on female fertility, fetal or pup survival, or pup physical development. There were also no AstraZeneca COVID-19 Vaccine-related fetal external, visceral, or skeletal findings or abnormal gross pathology findings in pups prior to or post weaning or in dams.

A biodistribution study conducted in mice did not show measurable distribution of AstraZeneca COVID-19 Vaccine to the gonads (testes, ovaries) following a single IM injection at a dose of 3.7x10¹⁰ vp/animal.