Comirnaty (Biontech Manufacturing, PM 00069992) Product Monograph

RECENT MAJOR LABEL CHANGES

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 .................................................................... 5

1 INDICATIONS .................................................................................................................. 5

1.1 Pediatrics ...................................................................................................................... 5

1.2 Geriatrics ...................................................................................................................... 5

2 CONTRAINDICATIONS ..................................................................................................... 5

3 SERIOUS WARNINGS AND PRECAUTIONS ........................................................................ 5

4 DOSAGE AND ADMINISTRATION ..................................................................................... 5

4.1 Dosing Considerations ................................................................................................. 5

4.2 Recommended Dose and Dosage Adjustment ............................................................ 6

4.2.1 Vaccination Schedule for Individuals 12 Years of Age and Older .......................... 6

4.2.2 Vaccination Schedule for Individuals Aged 5 Years to <12 Years .......................... 7

4.2.3 Vaccination Schedule for Individuals Aged 6 Months to <5 Years ........................ 7

4.3 Reconstitution .............................................................................................................. 7

4.3.1 For 12 Years of Age and Older ............................................................................... 7

4.3.1.1 For 12 Years of Age and Older: DILUTE BEFORE USE (Vials with Purple Cap and Purple Label Border) .......................................................................................................... 7

4.3.1.2 For 12 Years of Age and Older: DO NOT DILUTE (Vials with Gray Cap and Gray Label Border) .................................................................................................................... 12

4.3.2 For Age 5 Years to <12 Years: DILUTE PRIOR TO USE (Vials with Orange Cap and Orange Label Border) ....................................................................................................... 15

4.3.3 For Age 6 Months to <5 Years: DILUTE PRIOR TO USE (Vials with Maroon Cap and Maroon Label Border) ............................................................................................... 20

4.4 Administration ........................................................................................................... 25

4.4.1 For 12 Years of Age and Older ............................................................................. 25

4.4.2 For Age 5 Years to <12 Years ............................................................................... 25

4.4.3 For Age 6 Months to <5 Years .............................................................................. 26

5 OVERDOSAGE ............................................................................................................... 26

6 DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING .................................... 26

7 WARNINGS AND PRECAUTIONS .................................................................................... 29

7.1 Special Populations .................................................................................................... 31

7.1.1 Pregnant Women ................................................................................................. 31

7.1.2 Breast-feeding ...................................................................................................... 31

7.1.3 Pediatrics .............................................................................................................. 31

7.1.4 Geriatrics .............................................................................................................. 31

8 ADVERSE REACTIONS .................................................................................................... 31

8.1 Adverse Reaction Overview ....................................................................................... 31

8.2 Clinical Trial Adverse Reactions ................................................................................. 34

8.5 Post-Market Adverse Reactions ................................................................................. 53

9 DRUG INTERACTIONS .................................................................................................... 53

10 CLINICAL PHARMACOLOGY ...................................................................................... 53

10.1 Mechanism of Action ................................................................................................. 53

11 STORAGE, STABILITY AND DISPOSAL ........................................................................ 53

12 SPECIAL HANDLING INSTRUCTIONS .......................................................................... 57

PART II: SCIENTIFIC INFORMATION ..................................................................................... 58

13 PHARMACEUTICAL INFORMATION .......................................................................... 58

14 CLINICAL TRIALS ...................................................................................................... 58

14.1 Trial Design and Study Demographics ....................................................................... 58

14.2 Study Results .............................................................................................................. 62

14.2.1 Efficacy and Immunogenicity in Participants 16 Years of Age and Older ............ 62

14.2.1.1 Efficacy In Participants 16 Years of Age and Older – After Two Doses ............ 62

14.2.1.2 Efficacy and Immunogenicity in Participants 16 Years of Age and Older – After Booster Doses ...................................................................................................... 64

14.2.2 Efficacy and Immunogenicity in Adolescents 12 to 15 Years of Age ................... 67

14.2.2.1 Efficacy and Immunogenicity in Adolescents 12 to 15 Years of Age – After Two Doses ............................................................................................................ 67

14.2.3 Immunogenicity and Efficacy in Children 5 Years Through <12 Years of Age ..... 69

14.2.3.1 Immunogenicity and Efficacy in Children 5 Years Through <12 Years of Age – After Two Doses ............................................................................................................ 69

14.2.3.2 Immunogenicity in Children 5 Years Through <12 Years of Age – After Booster Dose ........................................................................................................ 71

14.2.4 Immunogenicity in Children 6 Months Through <5 Years of Age ........................ 72

14.2.4.1 Immunogenicity in Children 6 Months Through <5 Years of Age – After a 3-Dose Primary Series ....................................................................................... 72

15 MICROBIOLOGY ...................................................................................................... 76

16 NON-CLINICAL TOXICOLOGY .................................................................................... 76

PATIENT MEDICATION INFORMATION ................................................................................ 78

PART I: HEALTH PROFESSIONAL INFORMATION

1 INDICATIONS

COMIRNATY (COVID-19 Vaccine, mRNA) is indicated for active immunization to prevent coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS- CoV-2) in individuals 6 months of age and older.

1.1 Pediatrics

The safety and efficacy of COMIRNATY in children under 6 months of age have not yet been established (see 8 ADVERSE REACTIONS and 14 CLINICAL TRIALS).

1.2 Geriatrics

Clinical studies of COMIRNATY include participants 65 years of age and older and their data contributes to the overall assessment of safety and efficacy (see 8 ADVERSE REACTIONS and 14 CLINICAL TRIALS).

2 CONTRAINDICATIONS

COMIRNATY is contraindicated in individuals who are hypersensitive to the active substance or to any ingredient in the formulation. For a complete listing see 6 DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING.

3 SERIOUS WARNINGS AND PRECAUTIONS

At the time of authorization, there are no known serious warnings or precautions associated with this product.

4 DOSAGE AND ADMINISTRATION

4.1 Dosing Considerations

The storage, preparation and administration information differ depending on which presentation of the vaccine is considered. Careful attention should be paid to the vial cap and label border colour and the appropriate corresponding instructions must be followed under the subsections below.

For 12 Years of Age and Older

COMIRNATY is a suspension for intramuscular injection. There are two formulations of COMIRNATY authorized for use in individuals 12 years of age and older.

• DILUTE BEFORE USE (Vials with Purple Cap and Purple Label Border)
• DO NOT DILUTE (Vials with Gray Cap and Gray Label Border)

After preparation, a single dose is 0.3 mL.

For Age 5 Years to <12 Years

COMIRNATY is a suspension for intramuscular injection which must be diluted prior to administration.

• DILUTE PRIOR TO USE (Vials with Orange Cap and Orange Label Border)

After preparation, a single dose is 0.2 mL.

For Age 6 Months to <5 Years

COMIRNATY is a suspension for intramuscular injection which must be diluted prior to administration.

• DILUTE PRIOR TO USE (Vials with Maroon Cap and Maroon Label Border)

After preparation, a single dose is 0.2 mL.

*May be labeled as Pfizer-BioNTech COVID-19 vaccine

4.2 Recommended Dose and Dosage Adjustment

4.2.1 Vaccination Schedule for Individuals 12 Years of Age and Older

• COMIRNATY is administered intramuscularly as a primary series of two doses (0.3 mL each) 3 weeks apart in individuals 12 years of age and older.
• A booster dose of COMIRNATY (0.3 mL) may be administered intramuscularly at least 6 months after completion of the primary series in individuals 16 years of age or older.

There are currently no data available from Pfizer and BioNTech clinical trials on the interchangeability of COMIRNATY with other COVID-19 vaccines to complete the primary vaccination series or for a booster dose.

When prepared according to their respective instructions, COMIRNATY for 12 years of age and older (DILUTE BEFORE USE: purple cap and purple label border) and COMIRNATY for 12 years of age and older (DO NOT DILUTE: gray cap and gray label border) can be used interchangeably to provide the COVID-19 vaccination series.

COMIRNATY and the Interim Order authorized Pfizer-BioNTech COVID-19 Vaccine, for use in individuals 12 years of age and older, have the same formulation and can be used interchangeably to provide the COVID-19 vaccination series.

Vials of COMIRNATY intended for individuals 12 years of age and older (purple cap/purple label border or gray cap/gray label border) cannot be used to prepare doses for individuals aged 6 months to <12 years.

4.2.2 Vaccination Schedule for Individuals Aged 5 Years to <12 Years

• COMIRNATY is administered intramuscularly as a primary series of two doses (0.2 mL each) 3 weeks apart.
• A booster dose of COMIRNATY (0.2 mL) may be administered intramuscularly at least 6 months after completion of the primary series in individuals 5 years through ˂12 years of age.

There are no data available on the interchangeability of COMIRNATY with other COVID-19 vaccines to complete the primary vaccination series or for a booster dose. Individuals who have received one dose of COMIRNATY should receive a second dose of COMIRNATY to complete the primary vaccination series and for any additional doses.

Vials of COMIRNATY intended for individuals aged 5 years to <12 years (orange cap/orange label border) cannot be used to prepare doses for individuals 6 months to <5 years or 12 years of age and older.

4.2.3 Vaccination Schedule for Individuals Aged 6 Months to <5 Years

COMIRNATY is administered intramuscularly as a primary series of three doses (0.2 mL each). The initial 2 doses are administered 3 weeks apart followed by a third dose administered at least 8 weeks after the second dose.

Children who will turn from 4 to 5 years of age between their doses in the vaccination series should receive their age-appropriate dose at the time of the vaccination and the interval between doses is determined by the child’s age at the start of the vaccination series.

There are no data available on the interchangeability of COMIRNATY with other COVID-19 vaccines to complete the vaccination series. Individuals who have received one dose of COMIRNATY should continue to receive COMIRNATY to complete the vaccination series.

Vials of COMIRNATY intended for individuals aged 6 months to <5 years (maroon cap/maroon label border) cannot be used to prepare doses for individuals 5 years of age and older.

4.3 Reconstitution

4.3.1 For 12 Years of Age and Older

Two formulations of COMIRNATY are available for individuals 12 years of age and older.

4.3.1.1 For 12 Years of Age and Older: DILUTE BEFORE USE (Vials with Purple Cap and Purple Label Border)

Preparation for Administration

Prior to Dilution:

• The COMIRNATY multiple dose vial with a purple cap and purple label border contains a volume of 0.45 mL. It is supplied as a frozen suspension that does not contain preservative. Each vial must be thawed and diluted prior to administration.

• Vials may be thawed in the refrigerator (2°C to 8°C [35°F to 46°F]) or at room temperature (up to

  • 25°C [77°F]) (see 11 STORAGE, STABILITY AND DISPOSAL).
• Prior to dilution, the thawed suspension may contain white to off-white opaque amorphous particles.
• Refer to thawing instructions in the panels below.

Dilution:

• Dilute the vial contents using 1.8 mL of sterile 0.9% Sodium Chloride Injection, USP to form COMIRNATY. Do not add more than 1.8 mL of diluent.
• ONLY use 0.9% Sodium Chloride Injection, USP as the diluent. This diluent is not packaged with the vaccine and must be sourced separately. Do not use bacteriostatic 0.9% Sodium Chloride Injection or any other diluent.
• After dilution, one vial contains 6^† doses of 0.3 mL.
• After dilution, the vaccine will be an off-white suspension. Inspect vials to confirm there are no particulates and no discolouration is observed.
• Strict adherence to aseptic techniques must be followed.
• Refer to dilution and dose preparation instructions in the panels below.

^† Low dead-volume syringes and/or needles can be used to extract 6 doses from a single vial. If standard syringes and needles are used, there may not be sufficient volume to extract a 6^th dose from a single vial.

Prior to dilution

No more than 2 hours at room temperature (up to 25°C/77°F)

Gently × 10

Add 1.8 mL of sterile 0.9% Sodium Chloride Injection, USP

Pull back plunger to 1.8 mL to remove air from vial

Gently × 10

For 12 Years of Age and Older: DILUTE BEFORE USE (Vials with Purple Cap and Purple Label Border)
PREPARATION OF INDIVIDUAL 0.3 mL DOSES
	Using aseptic technique, cleanse the vial stopper with a single-use antiseptic swab, and withdraw 0.3 mL of COMIRNATY, preferentially using low dead-volume syringes and/or needles. Each dose must contain 0.3 mL of vaccine. If the amount of vaccine remaining in the vial cannot provide a full dose of 0.3 mL, discard the vial and any excess volume. Administer immediately, and no later than 6 hours after dilution. Low dead-volume syringes and/or needles can be used to extract 6 doses from a single vial. In order to ensure consistent withdrawal of 6 doses of 0.3 mL, it is important to adhere to minimizing volume loss during dose extraction.

4.3.1.2 For 12 Years of Age and Older: DO NOT DILUTE (Vials with Gray Cap and Gray Label Border)

The COMIRNATY multiple dose vial with a gray cap and gray label border MUST NOT BE DILUTED prior to administration. Instructions on the handling and dose preparation of the vaccine prior to administration are provided below.

Preparation for Administration

DO NOT DILUTE

• The COMIRNATY multiple dose vial with a gray cap and a gray label border contains a volume of 2.25 mL, and is supplied as a frozen suspension that does not contain preservative. Each vial must be thawed prior to administration. DO NOT DILUTE prior to use.
• Vials may be thawed in the refrigerator (2°C to 8°C [35°F to 46°F]) or at room temperature (up to 25°C [77°F]) (see 11 STORAGE, STABILITY AND DISPOSAL).
• The thawed suspension may contain white to off-white opaque amorphous particles.
• One vial contains 6^† doses of 0.3 mL.
• Refer to thawing and dose preparation instructions in the panels below.

^† Low dead-volume syringes and/or needles can be used to extract 6 doses from a single vial. If standard syringes and needles are used, there may not be sufficient volume to extract a 6^th dose from a single vial.

Withdraw 0.3 mL dose of vaccine

Can be stored in the refrigerator (2°C to 8°C) for up to 10 weeks prior to use

Gently × 10

Withdraw 0.3 mL dose of vaccine For 12 Years of Age and Older: DO NOT DILUTE (Vials with Gray Cap and Gray Label Border)
	Record the date and time of first vial puncture on the vial label. Store between 2°C to 25°C (35°F to 77°F). Discard any unused vaccine 121 hours after first puncture.

4.3.2 For Age 5 Years to <12 Years: DILUTE PRIOR TO USE (Vials with Orange Cap and Orange Label Border)

Preparation for Administration

Prior to Dilution:

• The COMIRNATY multiple dose vial (for ages 5 years to <12 years) has an orange cap and an orange label border and contains a volume of 1.3 mL. It is supplied as a frozen suspension that does not contain preservative. Each vial must be thawed and diluted prior to administration.
• Vials of COMIRNATY intended for 12 years of age or older with a purple cap/purple label border or gray cap/gray label border and vials of COMIRNATY intended for individuals aged 6 months to <5 years with a maroon cap/maroon label border cannot be used to prepare doses for individuals aged 5 years to <12 years.
• Vials may be thawed in the refrigerator at 2°C to 8°C [35°F to 46°F] or at room temperature (up to 25°C [77°F]) (see 11 STORAGE, STABILITY AND DISPOSAL).
• Prior to dilution, the thawed suspension may contain opaque amorphous particles.
• Refer to thawing instructions in the panels below.

Dilution:

• Dilute the vial contents using 1.3 mL of sterile 0.9% Sodium Chloride Injection, USP to form COMIRNATY. Do not add more than 1.3 mL of diluent.
• ONLY use 0.9% Sodium Chloride Injection, USP as the diluent. This diluent is not packaged with the

Record the date and time of first puncture

Use within 12 hours after first puncture

• vaccine and must be sourced separately. Do not use bacteriostatic 0.9% Sodium Chloride Injection or any other diluent.
• After dilution, one vial contains 10* doses of 0.2 mL.
• After dilution, the vaccine will be a white to off-white suspension. Inspect vials to confirm there are no particulates and no discolouration is observed.
• Strict adherence to aseptic techniques must be followed.
• Refer to dilution and dose preparation instructions in the panels below.

* Low dead-volume syringes and/or needles can be used to extract 10 doses from a single vial. If standard syringes and needles are used, there may not be sufficient volume to extract 10 doses from a single vial.

Can be stored in the refrigerator (2°C to 8°C) for up to 10 weeks prior to use.

Gently × 10

Add 1.3 mL of Sterile 0.9% Sodium Chloride Injection, USP

Pull back plunger to 1.3 mL to remove air from vial

Gently × 10

For Age 5 Years to <12 Years: DILUTE PRIOR TO USE (Vials with Orange Cap and Orange Label Border)
				Record the date and time of dilution Use within 12 hours after dilution	Record the date and time of first vial puncture (dilution) on the COMIRNATY (for age 5 years to <12 years) vial label. Store between 2°C to 25°C (35°F to 77°F). Do not freeze or shake the diluted vaccine. If refrigerated, allow the diluted vaccine to come to room temperature prior to use. Discard any unused vaccine 121 hours after dilution.
PREPARATION OF INDIVIDUAL 0.2 mL DOSES
						Using aseptic technique, cleanse the vial stopper with a single-use antiseptic swab, and withdraw 0.2 mL of COMIRNATY (for age 5 years to <12 years) preferentially using a low dead-volume syringe and/or needle. Each dose must contain 0.2 mL of vaccine. If the amount of vaccine remaining in the vial cannot provide a full dose of 0.2 mL, discard the vial and any excess volume. Administer immediately, and no later than 121 hours after dilution. Low dead-volume syringes and/or needles can be used to extract 10 doses from a single vial. In order to ensure consistent withdrawal of 10 doses of 0.2 mL, it is important to adhere to minimizing volume loss during dose extraction.

Withdraw 0.2 mL dose of vaccine

4.3.3 For Age 6 Months to <5 Years: DILUTE PRIOR TO USE (Vials with Maroon Cap and Maroon Label Border)

Preparation for Administration

Prior to Dilution:

• The COMIRNATY multiple dose vial (for age 6 months to <5 years) has a maroon cap and a maroon label border and contains a volume of 0.4 mL. It is supplied as a frozen suspension that does not contain preservative. Each vial must be thawed and diluted prior to administration.
• Vials of COMIRNATY intended for individuals 12 years of age or older with a purple cap/purple label border or gray cap/gray label border and vials of COMIRNATY intended for individuals aged 5 years to <12 years with an orange cap/orange label border cannot be used to prepare doses for individuals aged 6 months to <5 years.
• Vials may be thawed in the refrigerator at 2°C to 8°C [35°F to 46°F] or at room temperature (up to 25°C [77°F]) (see 11 STORAGE, STABILITY AND DISPOSAL).
• Prior to dilution, the thawed suspension may contain opaque amorphous particles.
• Refer to thawing instructions in the panels below.

Dilution:

• Dilute the vial contents using 2.2 mL of sterile 0.9% Sodium Chloride Injection, USP to form COMIRNATY. Do not add more than 2.2 mL of diluent.
• ONLY use 0.9% Sodium Chloride Injection, USP as the diluent. This diluent is not packaged with the vaccine and must be sourced separately. Do not use bacteriostatic 0.9% Sodium Chloride Injection or any other diluent.
• After dilution, one vial contains 10* doses of 0.2 mL.
• After dilution, the vaccine will be a white to off-white suspension. Inspect vials to confirm there are no particulates and no discolouration is observed.
• Strict adherence to aseptic techniques must be followed.
• Refer to dilution and dose preparation instructions in the panels below.

* Low dead-volume syringes and/or needles can be used to extract 10 doses from a single vial. If standard syringes and needles are used, there may not be sufficient volume to extract 10 doses from a single vial.

Can be stored in the refrigerator (2°C to 8°C) for up to 10 weeks prior to use

Add 2.2 mL of Sterile 0.9% Sodium Chloride Injection, USP

Gently × 10 For Age 6 Months to <5 Years: DILUTE PRIOR TO USE (Vials with Maroon Cap and Maroon Label Border)
				Record the date and time of dilution Use within 12 hours after dilution	Record the date and time of first vial puncture (dilution) on the COMIRNATY (for age 6 months to <5 years) vial label. Store between 2°C to 25°C (35°F to 77°F). Do not freeze or shake the diluted vaccine. If refrigerated, allow the diluted vaccine to come to room temperature prior to use. Discard any unused vaccine 121 hours after dilution.
PREPARATION OF INDIVIDUAL 0.2 mL DOSES
				Withdraw 0.2 mL dose of vaccine		Using aseptic technique, cleanse the vial stopper with a single-use antiseptic swab, and withdraw 0.2 mL of COMIRNATY (for age 6 months to <5 years) preferentially using a low dead-volume syringe and/or needle. Each dose must contain 0.2 mL of vaccine. If the amount of vaccine remaining in the vial cannot provide a full dose of 0.2 mL, discard the vial and any excess volume. Administer immediately, and no later than 121 hours after dilution. Low dead-volume syringes and/or needles can be used to extract 10 doses from a single vial. In order to ensure consistent withdrawal of 10 doses of 0.2 mL, it is important to adhere to minimizing volume loss during dose extraction.

4.4 Administration

4.4.1 For 12 Years of Age and Older

Administer a single 0.3 mL dose of COMIRNATY intramuscularly, preferably in the deltoid muscle.

Do not inject the vaccine intravascularly, subcutaneously or intradermally.

Two formulations of COMIRNATY are available for individuals 12 years of age and older.

• DILUTE BEFORE USE (Vials with Purple Cap and Purple Label Border)

  After dilution, vials of COMIRNATY (with purple cap and purple label border) contain 6 doses of 0.3 mL of vaccine.

• DO NOT DILUTE (Vials with Gray Cap and Gray Label Border)

  Vials of COMIRNATY with gray caps and gray label borders contain 6 doses of 0.3 mL of vaccine.

Visually inspect each dose in the dosing syringe prior to administration. The vaccine will be an off-white suspension. During the visual inspection:

• Verify the final dosing volume of 0.3 mL.
• Confirm there are no particulates and that no discolouration is observed.
• Do not administer if vaccine is discoloured or contains particulate matter.

Low dead-volume syringes and/or needles can be used to extract 6 doses from a single vial. In order to ensure consistent withdrawal of 6 doses of 0.3 mL, it is important to adhere to minimizing volume loss during dose extraction. If standard syringes and needles are used, there may not be sufficient volume to extract a 6^th dose from a single vial. Irrespective of the type of syringe and needle:

• Each dose must contain 0.3 mL of vaccine.
• If the amount of vaccine remaining in the vial cannot provide a full dose of 0.3 mL, discard the vial and any excess volume.
• Do not pool excess vaccine from multiple vials.

4.4.2 For Age 5 Years to <12 Years

Administer a single 0.2 mL dose of COMIRNATY intramuscularly, preferably in the deltoid muscle.

Do not inject the vaccine intravascularly, subcutaneously or intradermally.

DILUTE PRIOR TO USE (Vial with Orange Cap and Orange Label Border).

Visually inspect each dose in the dosing syringe prior to administration. The diluted vaccine will be a white to off-white suspension. During the visual inspection:

• Verify the final dosing volume of 0.2 mL.
• Confirm there are no particulates and that no discolouration is observed.
• Do not administer if vaccine is discoloured or contains particulate matter.

After dilution, vials of COMIRNATY (for age 5 years to <12 years) contain 10 doses of 0.2 mL of vaccine. Low dead-volume syringes and/or needles can be used to extract 10 doses from a single vial. In order to ensure consistent withdrawal of 10 doses of 0.2 mL, it is important to adhere to minimizing volume loss during dose extraction. If standard syringes and needles are used, there may not be sufficient volume to extract 10 doses from a single vial. Irrespective of the type of syringe and needle:

• Each dose must contain 0.2 mL of vaccine.
• If the amount of vaccine remaining in the vial cannot provide a full dose of 0.2 mL, discard the vial and any excess volume.
• Do not pool excess vaccine from multiple vials.

4.4.3 For Age 6 Months to <5 Years

Administer a single 0.2 mL dose of COMIRNATY intramuscularly. In individuals from 6 to less than 12 months of age, the recommended injection site is the anterolateral aspect of the thigh. In individuals 1 year of age and older, the recommended injection site is the anterolateral aspect of the thigh or the deltoid muscle.

Do not inject the vaccine intravascularly, subcutaneously or intradermally.

DILUTE PRIOR TO USE (Vial with Maroon Cap and Maroon Label Border).

Visually inspect each dose in the dosing syringe prior to administration. The diluted vaccine will be a white to off-white suspension. During the visual inspection:

• Verify the final dosing volume of 0.2 mL.
• Confirm there are no particulates and that no discolouration is observed.
• Do not administer if vaccine is discoloured or contains particulate matter.

After dilution, vials of COMIRNATY (for age 6 months to <5 years) contain 10 doses of 0.2 mL of vaccine. Low dead-volume syringes and/or needles can be used to extract 10 doses from a single vial. In order to ensure consistent withdrawal of 10 doses of 0.2 mL, it is important to adhere to minimizing volume loss during dose extraction. If standard syringes and needles are used, there may not be sufficient volume to extract 10 doses from a single vial. Irrespective of the type of syringe and needle:

• Each dose must contain 0.2 mL of vaccine.
• If the amount of vaccine remaining in the vial cannot provide a full dose of 0.2 mL, discard the vial and any excess volume.
• Do not pool excess vaccine from multiple vials.

5 OVERDOSAGE

In the event of suspected overdose, monitoring of vital functions and symptomatic treatment is recommended. Contact your regional poison control centre.

6 DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING

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 (or manufacture date).

For 12 Years of Age and Older: DILUTE BEFORE USE (Vials with Purple Cap and Purple Label Border)

COMIRNATY is supplied as a frozen suspension in multiple dose vials. Each vial must be diluted with 1.8 mL of sterile 0.9% Sodium Chloride Injection, USP prior to use to form the vaccine, and contains 6^† doses of 0.3 mL after dilution. Each 0.3 mL dose of COMIRNATY contains 30 mcg of a nucleoside modified messenger RNA (modRNA) encoding the viral spike (S) glycoprotein of SARS-CoV-2 (original strain) and the non-medicinal ingredients listed in Table 1.

COMIRNATY does not contain preservative. The vial stoppers are not made with natural rubber latex.

COMIRNATY multiple dose vials (with purple cap and purple label border) are supplied in a carton containing 25 multiple dose vials or 195 multiple dose vials. Not all pack sizes may be available.

For 12 Years of Age and Older: DO NOT DILUTE (Vials with Gray Cap and Gray Label Border)

COMIRNATY is supplied as a frozen suspension in multiple dose vials. Do not dilute. Each vial contains 6^† doses of 0.3 mL. Each 0.3 mL dose of COMIRNATY contains 30 mcg of a nucleoside modified messenger RNA (modRNA) encoding the viral spike (S) glycoprotein of SARS-CoV-2 (original strain) and the non-medicinal ingredients listed in Table 1.

COMIRNATY does not contain preservative. The vial stoppers are not made with natural rubber latex.

COMIRNATY multiple dose vials (with gray cap and gray label border) are supplied in a carton containing 10 multiple dose vials or 195 multiple dose vials. Not all pack sizes may be available.

^† Low dead-volume syringes and/or needles can be used to extract 6 doses from a single vial. If standard syringes and needles are used, there may not be sufficient volume to extract a 6^th dose from a single vial.

For Age 5 Years to <12 Years: DILUTE PRIOR TO USE (Vials with Orange Cap and Orange Label Border)

COMIRNATY is supplied as a frozen suspension in multiple dose vials with an orange cap and an orange label border. Each vial must be diluted with 1.3 mL of sterile 0.9% Sodium Chloride Injection, USP prior to use to form the vaccine, and contains 10* doses of 0.2 mL after dilution. Each 0.2 mL dose of COMIRNATY contains 10 mcg of a nucleoside modified messenger RNA (modRNA) encoding the viral spike (S) glycoprotein of SARS-CoV-2 (original strain) and the non-medicinal ingredients listed in Table 2. COMIRNATY does not contain preservative. The vial stoppers are not made with natural rubber latex.

COMIRNATY multiple dose vials (with orange cap and orange label border) are supplied in a carton containing 10 multiple dose vials or 195 multiple dose vials. Not all pack sizes may be available.

^† Low dead-volume syringes and/or needles can be used to extract 6 doses from a single vial. If standard syringes and needles are used, there may not be sufficient volume to extract a 6^th dose from a single vial.

* Low dead-volume syringes and/or needles can be used to extract 10 doses from a single vial. If standard syringes and needles are used, there may not be sufficient volume to extract 10 doses from a single vial.

Table 2: Dosage Forms, Strengths, Composition and Packaging (For Age 5 Years to <12 Years and For Age 6 Months to <5 Years)

For Age 6 Months to <5 Years: DILUTE PRIOR TO USE (Vials with Maroon Cap and Maroon Label Border)

COMIRNATY is supplied as a frozen suspension in multiple dose vials with a maroon cap and a maroon label border. Each vial must be diluted with 2.2 mL of sterile 0.9% Sodium Chloride Injection, USP prior to use to form the vaccine, and contains 10* doses of 0.2 mL after dilution. Each 0.2 mL dose of COMIRNATY contains 3 mcg of a nucleoside modified messenger RNA (modRNA) encoding the viral spike (S) glycoprotein of SARS-CoV-2 (original strain) and the non-medicinal ingredients listed in Table 2. COMIRNATY does not contain preservative. The vial stoppers are not made with natural rubber latex.

COMIRNATY multiple dose vials (with maroon cap and maroon label border) are supplied in a carton containing 10 multiple dose vials.

7 WARNINGS AND PRECAUTIONS

General

The administration of COMIRNATY should be postponed in individuals suffering from acute severe febrile illness.

Fainting may occur in association with administration of injectable vaccines. Individuals should be advised to bring symptoms (e.g., dizziness, increases in heart rate, feeling short of breath, tingling sensations or sweating) to the attention of the vaccination provider for evaluation. Procedures should be in place to avoid injury from fainting.

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

Individuals may not be optimally protected until at least 7 days after their second dose of vaccine (see 14 CLINICAL TRIALS).

* Low dead-volume syringes and/or needles can be used to extract 10 doses from a single vial. If standard syringes and needles are used, there may not be sufficient volume to extract 10 doses from a single vial.

Acute Allergic Reactions

Anaphylaxis has been reported. As with all vaccines, training for immunizers, appropriate medical treatment and supervision after immunization should always be readily available in case of a rare anaphylactic event following the administration of this vaccine.

Vaccine recipients should be kept under observation for at least 15 minutes after immunization; 30 minutes is a preferred interval when there is a specific concern about a possible vaccine reaction.

Subsequent doses of the vaccine should not be given to those who have experienced anaphylaxis to a prior dose of COMIRNATY, COMIRNATY Original/Omicron BA.1, COMIRNATY Original & Omicron BA.4/BA.5.

Cardiovascular

Myocarditis and Pericarditis

Very rare cases of myocarditis and/or pericarditis following vaccination with COMIRNATY have been reported during post-authorization use. These cases occurred more commonly after the second dose and in adolescents and young adults. Typically, the onset of symptoms has been within a few days following receipt of COMIRNATY. Based on accumulating data, the reporting rates of myocarditis and pericarditis after COMIRNATY primary series in children ages 5 through <12 years are lower than in ages 12 through 17 years. Available short-term follow-up data suggest that the symptoms resolve in most individuals, but information on long-term sequelae is lacking. The decision to administer COMIRNATY to an individual with a history of myocarditis or pericarditis should take into account the individual’s clinical circumstances.

Healthcare professionals are advised to consider the possibility of myocarditis and/or pericarditis in their differential diagnosis if individuals present with chest pain, shortness of breath, palpitations or other signs and symptoms of myocarditis and/or pericarditis following immunization with a COVID-19 vaccine. This could allow for early diagnosis and treatment. Cardiology consultation for management and follow up should be considered.

Driving and Operating Machinery

COMIRNATY has no or negligible influence on the ability to drive and use machines. However, some of the effects mentioned under 8 ADVERSE REACTIONS may temporarily affect the ability to drive or use machines.

Fertility

It is unknown whether COMIRNATY has an impact on fertility. Animal studies do not indicate direct or indirect harmful effects with respect to female fertility or reproductive toxicity (see 16 NON-CLINICAL TOXICOLOGY).

Hematologic

Individuals receiving anticoagulant therapy or those with a bleeding disorder that would contraindicate intramuscular injection should not be given the vaccine unless the potential benefit clearly outweighs the risk of administration.

Immune

Immunocompromised persons, including individuals receiving immunosuppressant therapy, may have a diminished immune response to the vaccine. In these individuals, a third dose may be considered as part of the primary series.

7.1 Special Populations

7.1.1 Pregnant Women

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

Animal studies do not indicate direct or indirect harmful effects with respect to pregnancy, embryo/ fetal development, parturition, or post-natal development (see 16 NON-CLINICAL TOXICOLOGY).

7.1.2 Breast-feeding

It is unknown whether COMIRNATY is excreted in human milk. A risk to the newborns/infants cannot be excluded.

The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for immunization against COVID-19.

7.1.3 Pediatrics

The safety and efficacy of COMIRNATY in children under 6 months of age have not yet been established.

7.1.4 Geriatrics

Clinical studies of COMIRNATY include participants 65 years of age and older, who received the primary series and a booster dose of COMIRNATY, and their data contributes to the overall assessment of safety and efficacy (See 8 ADVERSE REACTIONS and 14 CLINICAL TRIALS).

8 ADVERSE REACTIONS

8.1 Adverse Reaction Overview

The safety of the primary series of COMIRNATY was evaluated in participants 6 months of age and older in three clinical studies conducted in the United States, Europe, Turkey, South Africa, and South America.

Study BNT162-01 (Study 1) was a Phase 1/2, two-part dose-escalation trial that enrolled 60 participants 18 through 55 years of age and 36 participants 56 through 85 years of age.

Study C4591001 (Study 2) is a Phase 1/2/3, multicenter, multinational, randomized, saline placebo-controlled, observer-blind, dose-finding, vaccine candidate-selection (Phase 1) and efficacy (Phase 2/3) study that has enrolled approximately 46,000 participants, 12 years of age or older. Of these, approximately 44,047 participants (22,026 COMIRNATY; 22,021 placebo) in Phase 2/3 are 16 years of age or older (including 378 and 376 adolescents 16 and 17 years of age in the vaccine and placebo groups, respectively) and 2,260 adolescents are 12 to 15 years of age (1,131 and 1,129 in the vaccine and placebo groups, respectively). Of the total number of COMIRNATY recipients in the study, 20.7 % were 65 years of age and older. Study 2 also included 200 participants with confirmed stable human immunodeficiency virus (HIV) infection. HIV-positive participants are included in safety population disposition but are summarized separately in safety analyses.

Study C4591007 (Study 3) is a Phase 1/2/3 study comprised of an open-label vaccine dose-finding portion (Phase 1) and a multicenter, multinational, randomized, saline placebo-controlled, observer-blind immunogenicity and efficacy portion (Phase 2/3) that has enrolled approximately 4,600 participants 5 years through <12 years of age. Of these, approximately 3,100 participants received COMIRNATY 10 mcg and approximately 1,500 participants received placebo in the Phase 2/3 part of the study. Study 3 also enrolled 1,776 participants 6 months through <2 years of age (1,178 COMIRNATY 3 mcg; 598 placebo), and 2,750 participants 2 through <5 years of age (1,835 COMIRNATY 3 mcg; 915 placebo) in Phase 2/3.

Additionally, 306 existing Phase 3 participants 18 through 55 years of age received a booster dose of COMIRNATY approximately 6 months (range of 4.8 to 8.0 months) after completing the second dose in the non-placebo-controlled booster dose portion of Study 2. The overall safety profile for the booster dose was similar to that seen after 2 doses.

In a subset of Study 3 Phase 2/3 participants, 401 participants 5 years through <12 years of age received a booster dose of COMIRNATY at least 5 months (range 5 to 9 months) after completing the primary series. The overall safety profile for the booster dose was similar to that seen after the primary series. The analysis of the Study 3 Phase 2/3 subset is based on data up to the cut-off date of March 22, 2022 (median follow-up time of 1.3 months).

In Study C4591031 (Study 4), a placebo-controlled booster study, 5,081 participants 16 years of age and older were recruited from Study 2 to receive a booster dose of COMIRNATY at least 6 months after the second dose. The overall safety profile for the booster dose was similar to that seen after 2 doses.

The safety evaluation of participants in Study 2, Study 3 and Study 4 is ongoing. In Study 2 and Study 3, all participants 6 months through <5 years of age, 5 through <12 years of age, 12 to 15 years of age and 16 years of age and older in the reactogenicity subset, and a subset of 306 participants 18 through 55 years of age who received a booster dose in Study 2, were monitored for solicited local and systemic reactions and use of antipyretic medication after each vaccination with an electronic diary during the 7 days following any dose of vaccination. Participants, including those who received a booster in Study 4, continue to be monitored for unsolicited adverse events, including serious adverse events, throughout the study [from Dose 1 to 1 month after the last dose (all unsolicited adverse events) and 6 months (serious adverse events) after the last vaccination].

Participants 12 Years of Age and Older

At the time of the analysis of Study 2 (data accrued through March 13, 2021), a total of 25,651 (58.2%) participants (13,031 in vaccine group and 12,620 in placebo group) 16 years of age and older had been followed up for at least 4 months, with 3,082 (7.0%) participants (1,778 in vaccine group and 1,304 in placebo group) followed up for at least 6 months after the second dose during the blinded placebo-controlled follow-up period. A total of 12,006 (54.5%) participants originally randomized to the vaccine group in Study 2 had been followed up for at least 6 months after the second dose including the blinded and open-label periods.

In an analysis of Study 2, based on data up to the cut-off date of March 13, 2021, a total of 2,260 adolescents (1,131 COMIRNATY; 1,129 placebo) were 12 to 15 years of age. Of these, 1,559 (786 COMIRNATY and 773 placebo) adolescents have been followed for ≥4 months after the second dose of COMIRNATY.

In clinical studies with a data cut-off of March 13, 2021, and where 2 doses were administered 3 weeks apart, the most common adverse reactions in the reactogenicity subset (n=4,924) of participants 16 years of age and older after any dose included injection site pain (84.3%), fatigue (64.7%), headache (57.1%), muscle pain (40.2%), chills (34.7%), joint pain (25.0%), fever (15.2%), injection site swelling (11.1%), and injection site redness (9.9%). Additional adverse events reported in the safety population (n=21,926) of participants 16 years of age and older from dose 1 to 1 month after dose 2 included nausea (1.2%), malaise (0.6%), lymphadenopathy (0.4%), asthenia (0.3%), decreased appetite (0.2%), hyperhidrosis (0.1%), lethargy (0.1%), and night sweats (0.1%). Adverse reactions were usually mild or moderate in intensity and resolved within a few days after vaccination.

The safety profile in 545 participants receiving COMIRNATY that were seropositive for SARS-CoV-2 at baseline was similar to that seen in the general population.

In a clinical study with a data cut-off date of 02 September 2021, the most commonly reported (≥8%) adverse reactions in adolescents 12 through 15 years of age following any dose were pain at the injection site (90.5%), fatigue (77.5%), headache (75.5%), chills (49.2%), muscle pain (42.2%), fever (24.3%), joint pain (20.2%), injection site swelling (9.2%), and injection site redness (8.6%).

In a clinical study of participants 18 through 55 years of age (N=306), 289 participants (94%) completed the e-diary recording adverse reactions. The most commonly reported adverse reactions (≥10%) following administration of a booster dose were pain at the injection site (83.0%), fatigue (63.7%), headache (48.4%), muscle pain (39.1%), chills (29.1%), and joint pain (25.3%).

In a clinical study of approximately 10,000 participants 16 years of age and older, unsolicited adverse reactions following administration of a booster dose included headache (5%), fever (4.8%), lymphadenopathy (2.8%), pain in extremity (1.1%), nausea (0.9%), malaise (0.7%), and decreased appetite (0.2%).

Participants 5 Years Through <12 Years of Age

In an analysis of Study 3 Phase 2/3, based on data up to the cut-off date of October 8, 2021, 2,268 participants (initial enrolment group: 1,518 COMIRNATY 10 mcg and 750 placebo) were 5 years through <12 years of age. Of these, 2,171 (95.7%) (1,456 COMIRNATY 10 mcg and 715 placebo) participants have been followed for at least 3 months after Dose 2. An analysis of Study 3 Phase 2/3 adverse event data also included another 2,379 participants (safety expansion group: 1,591 COMIRNATY 10 mcg and 788 placebo), of whom 71.2% had a follow-up period for at least 2 weeks after Dose 2. The safety evaluation in Study 3 is ongoing.

Adverse reactions following administration of any dose in the initial enrolment safety population (n = 1,518) of children 5 years through <12 years of age included pain at the injection site (84.3%), fatigue (51.7%), headache (38.2%), injection site redness (26.4%), injection site swelling (20.4%), muscle pain (17.5%), chills (12.4%), fever (8.3%), joint pain (7.6%), lymphadenopathy (0.9%), rash (0.5%), nausea (0.4%), malaise (0.1%), and decreased appetite (0.1%).

The most frequent adverse reactions in participants 5 years through <12 years of age following the booster dose (data cut-off date of March 22, 2022; median follow-up time of 1.3 months) were injection site pain (73.9%), fatigue (45.6%), headache (34.0%), myalgia (18.3%), chills (10.5%), injection site redness (15.6%), and swelling (16.4%). The most frequently reported unsolicited adverse event was lymphadenopathy (2.5%).

Participants 2 Through <5 Years of Age

Study 3 (Phase 2/3) enrolled 2,750 participants 2 through <5 years of age (1,835 COMIRNATY 3 mcg; 915 placebo). Of these, 2,726 participants (1,819 COMIRNATY 3 mcg; 907 placebo) received 2 doses and 1,369 (50.2%; 910 COMIRNATY 3 mcg and 459 placebo) participants have been followed for at least 4 months after the second dose; 886 participants received a 3-dose primary series (606 COMIRNATY 3 mcg; 280 placebo) and have been followed for a median of 1.4 months after the third dose, based on data in the blinded, placebo-controlled follow-up period up to the cut-off date of April 29, 2022. Adverse reactions following administration of any dose included pain at the injection site (47.0%), fatigue (44.8%), injection site redness (18.9%), fever (10.5%), headache (8.7%), injection site swelling (8.4%), chills (5.7%), muscle pain (5.0%), joint pain (2.4%), and lymphadenopathy (0.1%).

Participants 6 Months Through <2 Years of Age

Study 3 (Phase 2/3) also enrolled 1,776 participants 6 months through <2 years of age (1,178 COMIRNATY 3 mcg; 598 placebo). Of these, 1,762 participants (1,166 COMIRNATY 3 mcg; 596 placebo) received 2 doses and 1,207 (68.5%; 801 COMIRNATY 3 mcg and 406 placebo) participants have been followed for at least 4 months after the second dose; 570 participants received a 3-dose primary series (386 COMIRNATY 3 mcg; 184 placebo) and have been followed for a median of 1.3 months after the third dose, based on data in the blinded, placebo-controlled follow-up period up to the cut-off date of April 29, 2022. Adverse reactions following administration of any dose included irritability (68.4%), decreased appetite (38.6%), tenderness at the injection site (26.4%), injection site redness (17.8%), fever (14.4%), injection site swelling (7.3%), and lymphadenopathy (0.2%).

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.

Participants 16 Years of Age and Older – Primary Series (Two Doses)

Solicited Adverse Reactions

Tables 3 through 6 present the frequency and severity of solicited local and systemic reactions, respectively, within 7 days following each dose of COMIRNATY and placebo in the subset of participants 16 years of age and older (n=9,839) in the safety population who were monitored for reactogenicity with an electronic diary.

Table 3: Study 2 – Frequency of Solicited Local Reactions Within 7 Days After Each Dose – Participants 16-55 Years of Age (Reactogenicity Subset of the Safety Population*)

*Randomized participants in the safety analysis population who received at least 1 dose of the study intervention.

a. N = Number of participants reporting at least 1 yes or no response for the specified reaction after the specified dose. No Grade 4 solicited local reactions were reported in participants 16-55 years of age.

b. n = Number of participants with the specified reaction.

c. Any local reaction: any redness >2.0 cm, any swelling >2.0 cm, or any pain at the injection site.

d. Severe: >10.0 cm.

e. Severe: prevents daily activity.

Table 4: Study 2 – Frequency of Solicited Systemic Reactions Within 7 Days After Each Dose – Participants 16-55 Years of Age (Reactogenicity Subset of the Safety Population*)

*Randomized participants in the safety analysis population who received at least 1 dose of the study intervention.

a. N =Number of participants reporting at least 1 yes or no response for the specified reaction after the specified dose. No Grade 4 solicited systemic reactions were reported in participants 16-55 years of age.

b. n = Number of participants with the specified reaction.

c. Any systemic reaction: any fever ≥38.0°C, any fatigue, any vomiting, any chills, any diarrhea, any headache, any new or worsened muscle pain, or any new or worsened joint pain.

d. Severe: prevents daily activity.

e. Severe: requires intravenous hydration.

f. Severe: 6 or more loose stools in 24 hours.

Table 5: Study 2 – Frequency of Solicited Local Reactions Within 7 Days After Each Dose – Participants 56 Years of Age and Older (Reactogenicity Subset of the Safety Population*)

*Randomized participants in the safety analysis population who received at least 1 dose of the study intervention.

a. N = Number of participants reporting at least 1 yes or no response for the specified reaction after the specified dose. No Grade 4 solicited local reactions were reported in participants 56 years of age and older.

b. n = Number of participants with the specified reaction.

c. Any local reaction: any redness >2.0 cm, any swelling >2.0 cm, or any pain at the injection site.

d. Severe: >10.0 cm.

e. Severe: prevents daily activity.

*Randomized participants in the safety analysis population who received at least 1 dose of the study intervention.

a. N = Number of participants reporting at least 1 yes or no response for the specified reaction after the specified dose. The only Grade 4 solicited systemic reaction reported in participants 56 years of age and older was fatigue.

b. n = Number of participants with the specified reaction.

c. Any systemic reaction: any fever ≥38.0°C, any fatigue, any vomiting, any chills, any diarrhea, any headache, any new or worsened muscle pain, or any new or worsened joint pain.

d. Severe: prevents daily activity.

e. Severe: requires intravenous hydration.

f. Severe: 6 or more loose stools in 24 hours.

g. Grade 4: emergency room visit or hospitalization.

Study 2 also included 200 participants with confirmed stable human immunodeficiency virus

(HIV) infection. The safety profile of the participants with stable HIV infection receiving COMIRNATY (n = 100) was similar to that seen in the general population.

Unsolicited Adverse Events

The participants were unblinded to offer placebo participants COMIRNATY when they became locally eligible under regulatory approval in December 2020. A total of 25,651 (58.2%) participants (13,031 in vaccine group and 12,620 in placebo group) 16 years of age and older had been followed up for at least 4 months, with 3,082 (7.0%) participants (1,778 in vaccine group and 1,304 in placebo group) followed up for at least 6 months after the second dose during the blinded placebo-controlled follow-up period in Study 2. Adverse events detailed below for participants 16 years of age and older are for the placebo-controlled blinded follow-up period up to the participants’ unblinding dates.

No deaths related to the vaccine were reported in the study.

Among participants 16 through 55 years of age who received at least one dose of study vaccine, 12,995 of whom received COMIRNATY and 13,026 of whom received placebo, unsolicited adverse events were reported by 4,396 (33.8%) participants in the COMIRNATY group and 2,136 (16.4%) participants in the placebo group. In a similar analysis in participants 56 years of age and older that included 8,931 COMIRNATY recipients and 8,895 placebo recipients, unsolicited adverse events were reported by 2,551 (28.6%) participants in the COMIRNATY group and 1,432 (16.1%) participants in the placebo group. Among participants with confirmed stable HIV infection that included 100 COMIRNATY recipients and 100 placebo recipients, unsolicited adverse events were reported by 29 (29%) participants in the COMIRNATY group and 15 (15%) participants in the placebo group.

Lymphadenopathy was reported in 87 (0.4%) participants in the vaccine group compared to 8 (<0.1%) participants in the placebo group, which is plausibly related to vaccination. Bell’s palsy (facial paralysis and facial paresis) was reported by four participants in the vaccine group and two in the placebo group. In the four vaccinated participants, events began from 3 to 48 days after their last dose, were mild to moderate in severity, and duration ranged from 3 to 68 days. Currently available information is insufficient to determine a causal relationship with the vaccine. There were no other notable patterns or numerical imbalances between treatment groups for specific categories of non-serious adverse events (including other neurologic or neuro-inflammatory, and thrombotic events) that would suggest a causal relationship to COMIRNATY. Cumulative safety follow-up to at least 6 months after Dose 2 for approximately 12,000 participants who received COMIRNATY showed no other safety signals arising from longer-term follow-up of the study.

Serious Adverse Events

In Study 2, among participants 16 through 55 years of age who had received at least 1 dose of vaccine or placebo (COMIRNATY =12,995; placebo = 13,026), serious adverse events from Dose 1 up to the participant unblinding date in ongoing follow-up were reported by 103 (0.8%) COMIRNATY recipients and 117 (0.9%) placebo recipients. In a similar analysis, in participants 56 years of age and older (COMIRNATY = 8,931; placebo = 8,895), serious adverse events were reported by 165 (1.8%) COMIRNATY recipients and 151 (1.7%) placebo recipients who received at least 1 dose of COMIRNATY or placebo, respectively. Among participants with confirmed stable HIV infection serious adverse events from Dose 1 up to the participant unblinding date in ongoing follow-up were reported by 2 (2%) COMIRNATY recipients and 2 (2%) placebo recipients.

Pericarditis was reported for one participant in the vaccine group, and no case was reported in the placebo group. Appendicitis was reported as a serious adverse event for 27 participants, 15 vaccine participants and 12 placebo participants. Currently available information is insufficient to determine a causal relationship with the vaccine. There were no other notable patterns or numerical imbalances between treatment groups for specific categories of serious adverse events (including neurologic, neuro-inflammatory, thrombotic events, myocarditis or anaphylactic reaction to the vaccine) reported during the blinded placebo-controlled follow-up period of the study.

Participants 16 Years of Age and Older – After Booster Dose

A subset, from Study C4591001 (Study 2) Phase 2/3 participants, of 306 adults 18 through 55 years of age who completed the original COMIRNATY 2-dose series, received a booster dose of COMIRNATY approximately 6 months (range of 4.8 to 8.0 months) after receiving Dose 2.

In Study C4591031 (Study 4), a placebo-controlled booster study, participants 16 years of age and older recruited from Study C4591001 (Study 2) received a booster dose of COMIRNATY (5,081 participants), or placebo (5,044 participants) at least 6 months after the second dose of COMIRNATY. Overall, participants who received a booster dose, had a median follow-up time of 2.5 months after the booster dose to the cut-off date (5 October 2021). Among the participants, the median age was 53.0 years (range 16 through 87 years of age), including 1,175 booster dose recipients (23.1%) who were ≥65 years of age, 49.1% were male and 50.9% were female, 79.0% were White, 14.9% were Hispanic/Latino, 9.2% were Black or African American, 5.5% were Asian, and 1.7% were American Indian/Alaska Native.

Solicited Local and Systemic Adverse Reactions

Overall, among participants who received a booster dose in a subset from Study C4591001 (Study 2), the median age was 42 years (range 19 through 55 years of age), 45.8% were male and 54.2% were female, 81.4% were White, 27.8% were Hispanic/Latino, 9.2% were Black or African American, 5.2% were Asian, and 0.7% were American Indian/Alaska Native.

In participants who received a booster dose the mean duration of pain at the injection site after the booster dose was 2.6 days (range 1 to 8 days), for redness 2.2 days (range 1 to 15 days), and for swelling 2.2 days (range 1 to 8 days).

Unsolicited Adverse Events

Overall, participants who received a booster dose in Study C4591031 (Study 4), had a median follow-up time of 2.5 months after the booster dose to the cut-off date (October 5, 2021). In an analysis of all unsolicited adverse events reported following the booster dose of COMIRNATY, through 1 month after the booster dose, in participants 16 through 87 years of age (N = 5,055), adverse reactions included headache (5%), fever (4.8%), lymphadenopathy (2.8%), decreased appetite (0.2%), malaise (0.7%), nausea (0.9%), and pain in extremity (1.1%).

Serious Adverse Events

Of the participants who received a booster dose of COMIRNATY or placebo (COMIRNATY = 5,055; placebo = 5,020) to the cut-off date (October 5, 2021), serious adverse events were reported by 0.3% of COMIRNATY recipients and 0.5% by placebo recipients. There were no notable patterns or numerical imbalances between treatment groups for specific categories of serious adverse events that would suggest a causal relationship to COMIRNATY. A 17-year-old male in Study 2 was diagnosed with myocarditis three days after receiving the booster dose (Dose 3). The participant was treated and recovered.

Adolescents 12 to 15 Years of Age – Primary Series (Two Doses)

Solicited Adverse Reactions

Table 9 and Table 10 present the frequency and severity of solicited local and systemic reactions, respectively, within 7 days following each dose of COMIRNATY and placebo in adolescents 12 to 15 years of age included in the safety population who were monitored for reactogenicity with an electronic diary.

Table 9: Study 2 – Frequency of Solicited Local Reactions Within 7 Days After Each Dose – Adolescents 12 to 15 Years of Age – Safety Population*

Table 10: Study 2 – Frequency of Solicited Systemic Reactions Within 7 Days After Each Dose – Adolescents 12 to 15 Years of Age – Safety Population*

Unsolicited Adverse Events

In the analysis of Study 2 of all unsolicited adverse events reported following any dose, through 1 month after Dose 2, in adolescents 12 to 15 years of age (N=2,260; 1,131 COMIRNATY group vs. 1,129 placebo group), those assessed as adverse reactions not already captured by solicited local and systemic reactions were lymphadenopathy (9 (0.8%) vs. 2 (0.2%)), and nausea (5 (0.4%) vs. 1 (0.1%)).

In analyses of all unsolicited adverse events in Study 2 from Dose 1 up to the participant unblinding date, 69.0% of study participants 12 through 15 years of age had at least 4 months of follow-up after Dose 2. Among participants 12 through 15 years of age who received at least one dose of study vaccine, 1,131 of whom received COMIRNATY and 1,129 of whom received placebo, unsolicited adverse events were reported by 95 (8.4%) participants in the COMIRNATY group and 113 (10.0%) participants in the placebo group.

Non-serious adverse events from Dose 1 through up to 30 days after Dose 2 in ongoing follow-up were reported by 5.8% of COMIRNATY recipients and by 5.8% of placebo recipients. From Dose 1 through 30 days after Dose 2, reports of lymphadenopathy plausibly related to the study intervention were imbalanced, with notably more cases in the COMIRNATY group (7) vs. the placebo group (1). In the analysis of blinded, placebo-controlled follow-up, there were no other notable patterns or numerical imbalances between treatment groups for specific categories of non-serious adverse events (including other neurologic or neuro-inflammatory, and thrombotic events) that would suggest a causal relationship to COMIRNATY. In the analysis of unblinded follow-up, there were no notable patterns of specific categories of non-serious adverse events that would suggest a causal relationship to COMIRNATY.

Serious Adverse Events

In Study 2, among participants 12 through 15 years of age who had received at least 1 dose of vaccine or placebo (COMIRNATY = 1,131; placebo = 1,129), serious adverse events from Dose 1 up to the participant unblinding date in ongoing follow-up were reported by 10 (0.9%) COMIRNATY recipients and 2 (0.2%) placebo recipients. In these analyses, 69.0% (786 COMIRNATY and 773 placebo) of study participants had at least 4 months of follow-up after Dose 2. In the analysis of blinded, placebo-controlled follow-up, there were no notable patterns between treatment groups for specific categories of serious adverse events (including neurologic, neuro-inflammatory, and thrombotic events) that would suggest a causal relationship to COMIRNATY. In the analysis of unblinded follow-up, there were no notable patterns of specific categories of serious adverse events that would suggest a causal relationship to COMIRNATY. In study 2, a 16-year-old male was diagnosed with myopericarditis 3 days after his 2^nd dose. The participant was treated and recovered.

Children 5 Years Through <12 Years of Age – Primary Series (Two Doses)

Solicited Adverse Reactions

Table 11 and Table 12 present the frequency and severity of solicited local and systemic reactions, respectively, within 7 days following each dose of COMIRNATY and placebo in children 5 years through <12 years of age included in the initial enrolment safety population who were monitored for reactogenicity with an electronic diary.

Table 11: Study 3 – Frequency of Solicited Local Reactions Within 7 Days After Each Dose – Children 5 Years Through <12 Years of Age – Safety Population*

Table 12: Study 3 – Frequency of Solicited Systemic Reactions Within 7 Days After Each Dose – Children 5 Years Through <12 Years of Age – Safety Population*

Unsolicited Adverse Events

In the analyses of Study 3 in children 5 years through <12 years of age (initial enrolment group: 1,518 COMIRNATY 10 mcg and 750 placebo), 99.5% of participants had at least 30 days and 95.7% of participants had at least 3 months follow-up after Dose 2.

Serious adverse events from Dose 1 through up to 30 days after Dose 2 in ongoing follow-up in the initial enrolment group were reported by 1 participant (0.1%) in each group after receiving the vaccine or placebo through the data cut-off date. No serious adverse events were reported that were considered related to vaccination.

Non-serious adverse events from Dose 1 through up to 30 days after Dose 2 in ongoing follow-up in the initial enrolment group were reported by 10.9% of COMIRNATY 10 mcg recipients and by 9.1% of placebo recipients. Lymphadenopathy was reported in 13 (0.9%) participants in the COMIRNATY 10 mcg group vs. 1 (0.1%) in the placebo group. All cases were considered to be mild, with a median onset of 3 days after Dose 1, and 2 days after Dose 2 in the vaccine group. The median duration was 3.5 days (ranged from 1 to 14 days) in the vaccine group. Skin and subcutaneous tissue disorders (including skin rash, dermatitis, eczema and urticaria) were reported in 17 (1.1%) participants in the vaccine group and 5 (0.7%) participants in the placebo group. Most of the events began from 3-11 days after the second dose and were characterized as mild and self-limited. There were no other notable patterns between treatment groups for specific categories of non-serious adverse events that would suggest a causal relationship to COMIRNATY. There were no reports of myocarditis/pericarditis or anaphylaxis by the study cut-off date.

Children 5 Years Through ˂12 Years of Age – After Booster Dose

A subset of Phase 2/3 participants 5 years through ˂12 years of age received a booster dose of COMIRNATY at least 5 months after completing the primary series (range 5 to 9 months, 86.8% of participants received the booster dose at least 8 months after Dose 2). Those participants vaccinated prior to February 22, 2022 provided the safety database (n=401), and had a median safety follow-up of 1.3 months from vaccination through the data cut-off date of March 22, 2022.

The median age of these 401 participants was 8.0 years (range 5 years through ˂12 years of age), 52.4% were male and 47.6% were female, 70.1% were White, 7.2% were Black or African American, 22.9% were Hispanic/Latino, 7.7% were Asian, and 2.0% were American Indian/Alaska Native.

Solicited Local and Systemic Adverse Reactions

Table 13 and Table 14 present the frequency and severity of reported solicited local and systemic reactions, respectively, within 7 days of a booster dose of COMIRNATY for Phase 2/3 participants 5 years through ˂12 years of age.

In participants who received a booster dose, the mean duration of pain at the injection site after the booster dose was 2.4 days (range 1 to 35 days), for redness 2.3 days (range 1 to 12 days), and for swelling 2.3 days (range 1 to 9 days).

Table 13: Study 3 – Frequency and Percentages of Participants With Solicited Local Reactions, By Maximum Severity, Within 7 Days After the Booster Dose of COMIRNATY– Children 5 Years through ˂12 Years of Age – Safety Population*

Table 14: Study 3 – Frequency and Percentages of Participants With Solicited Systemic Reactions, by Maximum Severity, Within 7 Days After the Booster Dose of COMIRNATY– Children 5 Years through ˂12 Years of Age – Safety Population*

Unsolicited Adverse Events

Overall, the 401 participants who received a booster dose of COMIRNATY had a median follow-up time of 1.3 months after the booster dose through the cut-off date.

In an analysis of all unsolicited adverse events reported in participants 5 years through ˂12 years of age (N = 401) through up to 1 month after the booster dose, lymphadenopathy (n = 10, 2.5%) was an adverse reaction not already captured by solicited local and systemic reactions.

Serious Adverse Events

No serious adverse events were reported after the booster dose through the cut-off date.

Children 2 Through <5 Years of Age – Primary Series (Three Doses)

Solicited Adverse Reactions

Table 15 and Table 16 present the frequency of solicited local and systemic reactions, respectively, within 7 days following each dose of COMIRNATY and placebo in children 2 through <5 years of age who were monitored for reactogenicity with an electronic diary.

Unsolicited Adverse Events

In the analyses of Study 3 in participants 2 through <5 years of age (606 COMIRNATY; 280 placebo), 76.6% of participants had at least 30 days of follow-up after Dose 3.

Serious adverse events from Dose 1 through 1 month after Dose 3, with an overall median of 1.4 months follow-up after Dose 3, were reported by 0.7% of COMIRNATY recipients and by 0.9% of placebo recipients. One serious adverse event of fever (maximum temperature 40.3°C) on Day 3 after Dose 2 in a 4-year-old was considered possibly related to vaccination.

Non-serious adverse events from Dose 1 through up to 30 days after Dose 3, in ongoing follow-up were reported by 18.5% of COMIRNATY recipients and by 18.5% of placebo recipients.

From Dose 1 through 30 days after Dose 3, lymphadenopathy was reported in 1 (0.1%) of COMIRNATY recipients vs. 0 (0.0%) of placebo recipients. There were no other notable patterns between treatment groups for specific categories of non-serious adverse events that would suggest a causal relationship to COMIRNATY.

Children 6 Months Through <2 Years of Age – Primary Series (Three Doses)

Solicited Adverse Reactions

Table 17 and Table 18 present the frequency of solicited local and systemic reactions, respectively, within 7 days following each dose of COMIRNATY and placebo in children 6 months through <2 years of age who were monitored for reactogenicity with an electronic diary.

Unsolicited Adverse Events

In the analyses of Study 3 in participants 6 months through 2 years of age (386 COMIRNATY; 184 placebo), 83.7% of participants had at least 30 days of follow-up after Dose 3.

Serious adverse events from Dose 1 through 1 month after Dose 3, with an overall median of 1.3 months follow-up after Dose 3, were reported by 1.4% of COMIRNATY recipients and by 2.3% of placebo recipients. No serious adverse events were reported that were considered related to vaccination.

Non-serious adverse events from Dose 1 through up to 1 month after Dose 3, in ongoing follow-up were reported by 29.1% of COMIRNATY recipients and by 26.3% of placebo recipients.

From Dose 1 through 30 days after Dose 3, lymphadenopathy was reported in 2 (0.2%) of COMIRNATY recipients vs. 0 (0%) of placebo recipients. There were no other notable patterns between treatment groups for specific categories of non-serious adverse events that would suggest a causal relationship to COMIRNATY.

8.5 Post-Market Adverse Reactions

The following adverse reactions have been identified during post authorization use of COMIRNATY.

Cardiac Disorders: myocarditis and/or pericarditis (see WARNING AND PRECAUTIONS section)

Immune System Disorders: severe allergic reactions, including anaphylaxis

Musculoskeletal and Connective Tissue Disorders: pain in extremity (arm)

Nervous System Disorders: Facial paralysis / Bell’s Palsy, hypoesthesia, paresthesia, dizziness

Skin and subcutaneous tissue disorders and other hypersensitivity reactions: skin rash, pruritus, urticaria, angioedema, erythema multiforme

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.

9 DRUG INTERACTIONS

No interaction studies have been performed. There is no information on the co-administration of COMIRNATY with other vaccines.

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

10 CLINICAL PHARMACOLOGY

10.1 Mechanism of Action

The nucleoside-modified messenger RNA in COMIRNATY is formulated in lipid nanoparticles, which enable delivery of the RNA into host cells to allow expression of the SARS-CoV-2 S antigen. The vaccine elicits both neutralizing antibody and cellular immune responses to the spike (S) antigen, which may contribute to protection against COVID-19 disease.

11 STORAGE, STABILITY AND DISPOSAL

During storage, minimize exposure to room light, and avoid exposure to direct sunlight and ultraviolet light.

Do not refreeze thawed vials.

For 12 Years and Older: DILUTE BEFORE USE (Vials with Purple Cap and Purple Label Border)

Frozen Vials Prior to Use

Cartons of COMIRNATY multiple dose vials (for 12 years and older: DILUTE BEFORE USE) arrive in thermal containers with dry ice. To ensure all appropriate safeguards are in place, refer to the Dry Ice Safety Data Sheet and the COMIRNATY Shipping and Handling Guidelines available at COMIRNATY.ca. Once received, remove the vial cartons immediately from the thermal container and preferably store in an ultra-low temperature freezer between -90°C to -60°C (-130°F to -76°F) until the expiry date printed on the label.

Vials may also be stored at -25°C to -15°C (-13°F to 5°F) for up to 2 weeks. Vials must be kept frozen and protected from light, in the original cartons, until ready to use. Vials stored at -25°C to -15°C (-13°F to 5°F) for up to 2 weeks may be returned one time to the recommended storage condition of -90°C to -60°C (-130°F to -76°F). Total cumulative time the vials are stored at -25°C to -15°C (-13°F to 5°F) should be tracked and should not exceed 2 weeks.

If an ultra-low temperature freezer is not available, the thermal container in which COMIRNATY arrives may be used as temporary storage when consistently re-filled to the top of the container with dry ice. Refer to the re-icing guidelines packed in the original thermal container for instructions regarding the use of the thermal container for temporary storage. The thermal container maintains a temperature range of -90°C to -60°C (-130°F to -76°F). Storage of the vials between -96°C to -60°C (-141°F to -76°F) is not considered an excursion from the recommended storage condition.

Transportation of Frozen Vials

If local redistribution is needed and full cartons containing vials cannot be transported at -90°C to -60°C (-130°F to -76°F), vials may be transported at -25°C to -15°C (-13°F to 5°F). Any hours used for transport at -25°C to -15°C (-13°F to 5°F) count against the 2-week limit for storage at -25°C to -15°C (-13°F to 5°F). Frozen vials transported at -25°C to -15°C (-13°F to 5°F) may be returned one time to the recommended storage condition of -90°C to -60°C (-130°F to -76°F).

Thawed Vials Prior to Dilution

Thawed Under Refrigeration: Thaw and then store undiluted vials in the refrigerator (2°C to 8°C [35°F to 46°F]) for up to 1 month. A carton of 25 vials or 195 vials may take up to 2 or 3 hours, respectively, to thaw in the refrigerator, whereas a fewer number of vials will thaw in less time.

Thawed at Room Temperature: For immediate use, thaw undiluted vials at room temperature (up to 25°C (77°F)] for 30 minutes.

Thawed vials can be handled in room light conditions.

Vials must reach room temperature before dilution.

Undiluted vials may be stored at room temperature for no more than 2 hours.

Transportation of Thawed Vials

Available data support transportation of one or more thawed, undiluted vials at 2°C to 8°C (35°F to 46°F) for up to 12 hours. Any hours used for transport at 2°C to 8°C (35°F to 46°F) count against the 1-month limit for storage at 2°C to 8°C (35°F to 46°F).

Vials After Dilution

After dilution, store vials between 2°C to 25°C (35°F to 77°F) and use within 6 hours from the time of dilution. Any vaccine remaining in vials must be discarded after 6 hours. After dilution, the vaccine vials can be handled in room light conditions. During storage, minimize exposure to room light, and avoid exposure to direct sunlight and ultraviolet light. Do not freeze. If the vaccine is frozen, it must be discarded.

For 12 Years and Older: DO NOT DILUTE (Vials with Gray Cap and Gray Label Border)

Vial Storage Prior to Use

Cartons of COMIRNATY multiple dose vials (for 12 years and older: DO NOT DILUTE) may arrive frozen at ultra-cold conditions in thermal containers with dry ice.

Once received, frozen vials may be immediately transferred to the refrigerator [2°C to 8°C (35°F to 46°F)], thawed and stored for a single period of up to 10 weeks within the 18-month shelf-life. The 10-week refrigerated expiry date should be recorded on the carton at the time of transfer. A carton of 10 vials may take up to 6 hours to thaw at this temperature.

Alternatively, frozen vials may be stored in an ultra-low temperature freezer at -90°C to -60°C (-130°F to -76°F). Do not store vials at -25°C to -15°C (-13°F to 5°F). Once vials are thawed they should not be refrozen.

Cartons of COMIRNATY multiple dose vials (for 12 years and older: DO NOT DILUTE) may also arrive at 2°C to 8°C. If received at 2°C to 8°C, they should be stored at 2°C to 8°C. Check that the carton has been updated to reflect the 10-week refrigerated expiry date.

Regardless of storage condition, vaccine should not be used after 18 months from the date of manufacture printed on the vial and cartons.

Vial Storage During Use

If not previously thawed at 2°C to 8°C (35°F to 46°F), allow vials to thaw at room temperature [up to 25°C (77°F)] for 30 minutes.

COMIRNATY multiple dose vials (for 12 years and older: DO NOT DILUTE) may be stored at room temperature up to 25°C (77°F) for a total of 12 hours prior to the first puncture.

DO NOT DILUTE PRIOR TO USE.

After first puncture, the vial should be stored at 2°C to 25°C (35°F to 77°F). Vials should be discarded 12 hours after first puncture. Vial labels and cartons may state that a vial should be discarded 6 hours after the first puncture. The information in this Product Monograph supersedes the number of hours printed on vial labels and cartons.

Thawed vials can be handled in room light conditions.

Transportation of Vials

If local redistribution is needed, full cartons containing unpunctured vials may be transported at -90°C to -60°C (-130°F to -76°F); full cartons or individual unpunctured vials may also be transported at 2°C to 8°C (35°F to 46°F).

For Age 5 Years to <12 Years: DILUTE PRIOR TO USE (Vials with Orange Cap and Orange Label Border)

And

For Age 6 Months to <5 Years: DILUTE PRIOR TO USE (Vials with Maroon Cap and Maroon Label Border)

Vial Storage Prior to Use

Cartons of COMIRNATY multiple dose vials (for age 5 years to <12 years) and COMIRNATY multiple dose vials (for age 6 months to <5 years) may arrive frozen at ultra-cold conditions in thermal containers with dry ice.

Once received, frozen vials may be immediately transferred to the refrigerator [2°C to 8°C (35°F to 46°F)], thawed and stored for a single period of up to 10 weeks within the 18-month shelf-life. The 10-week refrigerated expiry date should be recorded on the carton at the time of transfer.

• COMIRNATY (for age 5 years to <12 years): A carton of 10 vials may take up to 4 hours to thaw at this temperature.
• COMIRNATY (for age 6 months to <5 years): A carton of 10 vials may take up to 2 hours to thaw at this temperature.

Alternatively, frozen vials may be stored in an ultra-low temperature freezer at -90°C to -60°C (-130°F to -76°F) for up to 18 months from the date of manufacture. Do not store vials at -25°C to -15°C (-13°F to 5°F). Once vials are thawed they should not be refrozen.

Cartons of COMIRNATY (for age 5 years to <12 years) and COMIRNATY (for age 6 months to <5 years) may also arrive at 2°C to 8°C (35°F to 46°F). If vials are received at 2°C to 8°C, they should be stored at 2°C to 8°C. Check that the carton has been updated to reflect the 10-week refrigerated expiry date.

Regardless of storage condition, vaccines should not be used after 18 months from the date of manufacture printed on the vial and cartons.

Vial Storage During Use

If not previously thawed at 2°C to 8°C (35°F to 46°F), allow vials to thaw at room temperature [up to 25°C (77°F)] for 30 minutes.

Vials of COMIRNATY (for age 5 years to <12 years) and COMIRNATY (for age 6 months to <5 years) may be stored at temperatures up to 25°C (77°F) for a total of 12 hours prior to dilution.

After dilution the vials should be stored at 2°C to 25°C (35°F to 77°F). Vials should be discarded 12 hours after dilution (i.e., the first puncture). Vial labels and cartons may state that a vial should be discarded 6 hours after dilution. The information in this Product Monograph supersedes the number of hours printed on vial labels and cartons.

Thawed vials can be handled in room light conditions.

Transportation of Vials

If local redistribution is needed, full cartons containing undiluted vials may be transported at -90°C to -60°C (-130°F to -76°F); full cartons or individual undiluted vials may also be transported at 2°C to 8°C (35°F to 46°F).

12 SPECIAL HANDLING INSTRUCTIONS

COMIRNATY multiple dose vials contain a frozen suspension that does not contain preservative and must be thawed and may require dilution prior to administration.

Careful attention should be paid to the vial cap colour and label border and the appropriate corresponding instructions must be followed. For important information on handling and preparation for administration, please refer to 11 STORAGE, STABILITY AND DISPOSAL and 4 DOSAGE AND ADMINISTRATION.

PART II: SCIENTIFIC INFORMATION

13 PHARMACEUTICAL INFORMATION

Drug Substance:

Proper name: COVID-19 Vaccine, mRNA

International nonproprietary name: Tozinameran

Product Characteristics:

COMIRNATY (COVID-19 Vaccine, mRNA) is highly purified single-stranded, 5’-capped messenger RNA (mRNA) produced using a cell-free in vitro transcription from the corresponding DNA templates, encoding the viral spike (S) protein of SARS-CoV-2 (original strain).

This vaccine is a white to off-white frozen suspension provided as a multiple dose vial which may require dilution prior to use, depending on the presentation.

For 12 Years and Older: DILUTE BEFORE USE (Vials with Purple Caps and Purple Label Border)

One vial (0.45 mL) contains 6^† doses of 0.3 mL after dilution. One dose (0.3 mL) contains 30 micrograms of COVID-19 mRNA Vaccine (embedded in lipid nanoparticles).

For 12 Years and Older: DO NOT DILUTE (Vials with Gray Cap and Gray Label Border)

One vial (2.25 mL) contains 6^† doses of 0.3 mL. Do not dilute prior to use. One dose (0.3 mL) contains 30 micrograms of COVID-19 mRNA Vaccine (embedded in lipid nanoparticles).

For Age 5 Years to <12 Years: DILUTE PRIOR TO USE (Vials with Orange Cap and Orange Label Border)

One vial (1.3 mL) contains 10* doses of 0.2 mL after dilution. One dose (0.2 mL) contains 10 micrograms of COVID-19 mRNA Vaccine (embedded in lipid nanoparticles).

For Age 6 Months to <5 Years: DILUTE PRIOR TO USE (Vials with Maroon Cap and Maroon Label Border)

One vial (0.4 mL) contains 10* doses of 0.2 mL after dilution. One dose (0.2 mL) contains 3 micrograms of COVID-19 mRNA Vaccine (embedded in lipid nanoparticles).

14 CLINICAL TRIALS

14.1 Trial Design and Study Demographics

Participants 12 Years of Age and Older

The safety and efficacy of COMIRNATY were evaluated in Study 2, a multicenter, multinational, Phase 1/2/3, randomized, placebo-controlled, observer-blind, dose-finding, vaccine candidate-selection and efficacy study in participants 12 years of age and older. Randomization was stratified by age: 12 through 15 years of age, 16 through 55 years of age, or 56 years of age and older, with a minimum of 40% of participants in the ≥56 year stratum. The study excluded participants who were

^† Low dead-volume syringes and/or needles can be used to extract 6 doses from a single vial. If standard syringes and needles are used, there may not be sufficient volume to extract a 6^th dose from a single vial.

* Low dead-volume syringes and/or needles can be used to extract 10 doses from a single vial. If standard syringes and needles are used, there may not be sufficient volume to extract 10 doses from a single vial.

immunocompromised and those who had previous clinical or microbiological diagnosis of COVID-19. Participants with pre-existing stable disease, defined as disease not requiring significant change in therapy or hospitalization for worsening disease during the 6 weeks before enrollment, were included as were participants with known stable infection with human immunodeficiency virus (HIV), hepatitis C virus (HCV), or hepatitis B virus (HBV).

In the Phase 2/3 portion of Study 2, based on data accrued through November 14, 2020, approximately 44,000 participants 12 years of age and older were randomized equally and received 2 doses of COMIRNATY or placebo. The efficacy analyses included participants that received their second vaccination within 19 to 42 days after their first vaccination. The majority (93.1%) of vaccine recipients received the second dose 19 days to 23 days after Dose 1. Participants are planned to be followed for up to 24 months, for assessments of safety and efficacy against COVID-19.

The population for the analysis of the primary efficacy endpoint included 36,621 participants 12 years of age and older (18,242 in the COMIRNATY group and 18,379 in the placebo group) who did not have evidence of prior infection with SARS-CoV-2 through 7 days after the second dose. Table 19 presents the specific demographic characteristics in the studied population.

To assess boostability, a subset of Study 2 participants were enrolled in selected sites, and 306 participants aged 18 to 55 years were re-randomized to receive a booster dose approximately 6 months after completion of the two-dose regimen (median interval between dose 2 and booster dose – 6.8 months; range 4.8 to 8.0 months). The median age at the time of booster vaccination was 42.0 years, and 46.3% of participants were male.

In Study 4, a placebo-controlled booster study, 5,081 participants 16 years of age and older were recruited from Study 2 to receive a booster dose of COMIRNATY at least 6 months after the second dose. The median age at the time of booster vaccination was 53 years, and 49% of the participants were male.

Participants 6 Months Through <12 Years of Age

Study 3 is a Phase 1/2/3 study comprised of an open-label vaccine dose finding portion (Phase 1) and a multicentre, multinational, randomized, saline placebo-controlled, observer-blind immunogenicity and efficacy portion (Phase 2/3) that has enrolled participants 6 months to <12 years of age.

Participants 5 Through <12 Years of Age: Demographic characteristics in Study 3 were generally similar with regard to age, gender, race, and ethnicity among participants 5 years through <12 years of age who received COMIRNATY 10 mcg and those who received placebo. Among the 1,518 participants (initial enrolment group) 5 years through <12 years of age who received at least 1 dose of COMIRNATY 10 mcg, 52.6% were male and 47.4% were female, 79.3% were White, 5.9% were Black or African American, 21.0% were Hispanic/Latino, 5.9% were Asian, and 0.8% were American Indian/Alaska Native.

A descriptive efficacy analysis of Study 3 has been performed in 1,968 children 5 years through ˂12 years of age without evidence of infection prior to 7 days after Dose 2. This analysis evaluated confirmed symptomatic COVID-19 cases accrued up to a data cut-off date of October 8, 2021.

Table 20 presents the specific demographic characteristics in participants who did not have evidence of prior infection with SARS-CoV-2 through 7 days after the second dose.

Table 20: Demographics Characteristics – Participants Without Evidence of Infection Prior to 7 Days After Dose 2 – Phase 2/3 – 5 Years Through ˂12 Years of Age – Evaluable Efficacy Population (Data Accrued Through October 8, 2021)

Participants 2 Through <5 Years of Age: The evaluable immunogenicity population without prior evidence of SARS-CoV-2 infection up to 1 month after Dose 3 of COMIRNATY was comprised of 143 participants 2 through <5 years of age. Most participants in this analysis population were White (69.2%), with 5.6% Black or African American participants, 11.2% Asian participants, and 11.9% multiracial participants. There were 11.2% Hispanic/Latino participants. The median age was 3.0 years and 44.1% of participants were male. There were 6.3% of participants reported as obese. In the evaluable immunogenicity population (regardless of evidence of prior infection), 11/204 participants (5.4%) were baseline positive for prior SARS-CoV-2 infection.

Participants 6 Months Through <2 Years of Age: The evaluable immunogenicity population without prior evidence of SARS-CoV-2 infection up to 1 month after Dose 3 of COMIRNATY was comprised of 82 participants 6 months through <2 years of age. Most participants in this analysis population were White (72.0%), with 1.2% Black or African American participants, 13.4% Asian participants, and 12.2% multiracial participants. There were 15.9% Hispanic/Latino participants. The median age was 16.0 months and 62.2% of participants were male. In the evaluable immunogenicity population (regardless of evidence of prior infection), 6/132 participants (4.5%) were baseline positive for prior SARS-CoV-2 infection.

14.2 Study Results

14.2.1 Efficacy and Immunogenicity in Participants 16 Years of Age and Older

14.2.1.1 Efficacy In Participants 16 Years of Age and Older – After Two Doses

Primary Vaccine Efficacy Analysis (Based on Cut-off Date of November 14, 2020)

At the time of the primary efficacy analysis, participants had been followed for symptomatic COVID-19 for at least 2,214 person-years in the COMIRNATY group and at least 2,222 person-years in the placebo group.

There were no meaningful clinical differences in overall vaccine efficacy in participants who were at risk of severe COVID-19 including those with 1 or more comorbidities that increase the risk of severe COVID-19 [e.g., asthma, body mass index (BMI) ≥30 kg/m², chronic pulmonary disease, diabetes mellitus, hypertension]. The primary endpoint was defined as any symptomatic COVID-19 case¹ confirmed by Reverse Transcription-Polymerase Chain Reaction (RT-PCR). The population for the analysis of the primary efficacy endpoint included participants who did not have evidence of prior infection with SARS-CoV-2 through 7 days after the second dose (first primary efficacy endpoint), as well as participants with and without evidence of prior infections with SARS-CoV-2 through 7 days after the second dose (second primary efficacy endpoint). The pre-specified success criterion for vaccine efficacy was met. The vaccine efficacy information is presented in Table 21.

¹ Case definition defined by Study 2 protocol: (at least 1 of) fever, new or increased cough, new or increased shortness of breath, chills, new or increased muscle pain, new loss of taste or smell, sore throat, diarrhea or vomiting.

Updated Vaccine Efficacy (Based on Cut-off Date of March 13, 2021)

Updated efficacy analyses were performed with additional confirmed COVID-19 cases accrued during blinded placebo-controlled follow-up through March 13, 2021, representing up to 6 months of follow-up after Dose 2 for participants in the efficacy population. There were 77 confirmed COVID-19 cases identified in the COMIRNATY and 850 in the placebo groups, respectively. In this analysis, compared to placebo, the vaccine efficacy of COMIRNATY in participants without evidence of SARS-CoV-2 infection prior to 7 days after Dose 2 was 91.3% (95% confidence interval of 89.0% to 93.2%); in participants 65 years of age and older without evidence of prior infection vaccine efficacy was 94.5% (two-sided 95% confidence interval 88.3% to 97.8%). The vaccine efficacy of COMIRNATY in participants with or without evidence of prior infection was 91.1% (95% confidence interval: 88.8% to 93.0%) with 81 COVID-19 cases in the COMIRNATY group compared to 873 cases in the placebo group.

Efficacy Against Severe COVID-19 (Based on Cut-off Date of March 13, 2021)

Secondary efficacy analyses in Study 2 supported benefit of COMIRNATY in preventing severe COVID-19. During blinded placebo-controlled follow-up through March 13, 2021, the vaccine efficacy against severe COVID 19 (as defined by the study protocol) in participants with or without evidence of SARS-CoV-2 infection prior to 7 days after Dose 2 was 95.3% (95% CI: 70.9%, 99.9%) with 1 and 21 cases in the vaccine and placebo groups, respectively. The COVID-19 case counts in participants without prior SARS-CoV-2 infection were the same as those in participants with or without prior SARS-CoV-2 infection in both the COMIRNATY and placebo groups.

14.2.1.2 Efficacy and Immunogenicity in Participants 16 Years of Age and Older – After Booster Doses

Immunogenicity in Participants 18 to 55 Years of Age- After Booster Dose

Noninferiority of immune responses 1 month after a COMIRNATY booster dose compared to 1 month after completion of the primary 2-dose series was assessed, in a subset of participants enrolled at selected sites in the US, by evaluating SARS-CoV-2 50% neutralizing titers (NT50) against the reference strain. Immunogenicity was evaluated in subjects who had no serological or virological evidence of past SARS-CoV-2 infection up to 1 month after the booster vaccination. The analysis demonstrated noninferior immune responses 1 month after a booster dose compared to 1 month after Dose 2 in individuals 18 through 55 years of age (Table 22).

Relative Vaccine Efficacy in Participants 16 Years of Age and Older – After Booster Dose

An interim efficacy analysis of Study 4, a placebo-controlled booster study was performed in approximately 10,000 participants 16 years of age and older who were recruited from Study 2 and evaluated confirmed COVID-19 cases accrued from at least 7 days after booster vaccination up to a data cut-off date of 5 October 2021, which represents a median of 2.5 months post-booster follow-up. Vaccine efficacy of the COMIRNATY booster dose after the primary series relative to the placebo booster group who only received the primary series dose was assessed. The relative vaccine efficacy information for participants 16 years of age and older is presented in Table 23.

Table 23: Vaccine Efficacy – First COVID-19 Occurrence From 7 Days After Booster Vaccination – Participants 16 Years of Age and Older Without Evidence of Infection and Participants With or Without Evidence of Infection Prior to 7 Days After Booster Vaccination – Evaluable Efficacy Population

14.2.2 Efficacy and Immunogenicity in Adolescents 12 to 15 Years of Age

14.2.2.1 Efficacy and Immunogenicity in Adolescents 12 to 15 Years of Age – After Two Doses

Efficacy

The vaccine efficacy in participants 12 to 15 years of age was evaluated on a subgroup analysis of Study 2 based on a cut-off date of March 13, 2021 (Table 24).

An updated efficacy analysis of Study 2 has been performed in approximately 2,260 adolescents 12 through 15 years of age evaluating confirmed COVID-19 cases accrued up to a data cut-off date of September 2, 2021, representing up to 6 months of follow-up after Dose 2 for participants in the efficacy population.

In the adolescent group, in efficacy analyses in the evaluable efficacy population based on cases reported from at least 7 days after Dose 2 through the data cut-off date (02 September 2021), representing a median of 4.4 (range 0-10.8) months of follow-up after Dose 2, there were 0 confirmed COVID-19 cases identified in the COMIRNATY and 28 in the placebo groups, respectively. In this analysis, compared to placebo, the estimated VE against confirmed COVID-19 was 100% (95% CI: 86.8%, 100%) for individuals without evidence of prior SARS-CoV-2 infection before and during vaccination regimen. The estimated VE against confirmed COVID-19 was 100% (2-sided 95% CI: 87.5%, 100%) for those with or without evidence of prior SARS-CoV-2 infection before and during vaccination regimen, with 0 COVID-19 cases in the COMIRNATY group compared to 30 cases in the placebo group.

Among participants without and with or without evidence of SARS-CoV-2 infection before and during the vaccination regimen (evaluable efficacy population), VE against COVID-19 occurring at least 7 days after Dose 2 was evaluated for demographic and risk subgroups, and the estimated VE was 100.0% for all subgroups.

Immunogenicity – After Two Doses

In Study 2, an analysis of SARS-CoV-2 50% neutralizing titers (NT50) 1 month after Dose 2 in a randomly selected subset of participants demonstrated non-inferior immune responses (within 1.5-fold) comparing adolescents 12 through 15 years of age to participants 16 through 25 years of age who had no serological or virological evidence of past SARS-CoV-2 infection up to 1 month after Dose 2 (Table 25).

Table 25: Summary of Geometric Mean Ratio for 50% Neutralizing Titer – Comparison of Adolescents 12 Through 15 Years of Age to Participants 16 Through 25 Years of Age (Immunogenicity Subset) –Participants Without Evidence of Infection up to 1 Month After Dose 2 – Dose 2 Evaluable Immunogenicity Population

14.2.3 Immunogenicity and Efficacy in Children 5 Years Through <12 Years of Age

14.2.3.1 Immunogenicity and Efficacy in Children 5 Years Through <12 Years of Age – After Two Doses

Immunogenicity

In Study 3, an analysis of SARS-CoV-2 50% neutralizing titers (NT50) 1 month after Dose 2 in a randomly selected subset of participants demonstrated effectiveness by immunobridging of immune responses. Children 5 years through <12 years of age in the Phase 2/3 part of Study 3 were compared to participants 16 through 25 years of age in the Phase 2/3 part of Study 2 who had no serological or virological evidence of past SARS-CoV-2 infection up to 1 month after Dose 2. The study met the prespecified immunobridging criteria for both the geometric mean ratio (GMR) and the seroresponse difference with seroresponse defined as achieving at least 4-fold rise in SARS-CoV-2 NT50 from baseline (before Dose 1).

The ratio of the SARS-CoV-2 NT50 in children 5 years through <12 years of age to that of young adults 16 to 25 years of age was 1.04 (2-sided 95% CI: 0.93, 1.18), meeting the 1.5-fold noninferiority criterion (the lower bound of the 2-sided 95% CI for the geometric mean ratio [GMR] >0.67). Results are presented in Table 26.

Table 26: Summary of Geometric Mean Ratio for 50% Neutralizing Titer And Difference in Percentages of Participants with Seroresponse – Comparison of Children 5 Years Through < 12 Years of Age (Study 3) to Participants 16 Through 25 Years of Age (Study 2) – Participants Without Evidence of Infection up to 1 Month After Dose 2 – Immunobridging Subset - Dose 2 Evaluable Immunogenicity Population

Among participants without prior evidence of SARS-CoV-2 infection up to 1 month after Dose 2, 99.2% of children 5 years through <12 years of age and 99.2% of participants 16 through 25 years of age had a seroresponse from before vaccination to 1 month after Dose 2. The difference in proportions of participants who had seroresponse between the 2 age groups (children – young adult) was 0.0% (2-sided 95% CI: -2.0%, 2.2%), meeting the -10% noninferiority criterion (the lower bound of the 2-sided 95% CI for the difference in seroresponse rate>-10%). Results are presented in Table 26.

Efficacy

An exploratory efficacy analysis (based on a cut-off date of October 8, 2021) in participants 5 to less than 12 years of age without evidence of SARS-CoV-2 infection prior to Dose 2 showed that the observed vaccine efficacy against confirmed COVID-19 occurring at least 7 days after Dose 2 was 90.7% (95% CI: 67.7%, 98.3%), with 3 COVID-19 cases in the vaccine group compared to 16 in the placebo group (2:1 randomization in vaccine group to placebo group).

No severe COVID-19 or multisystem inflammatory syndrome in children (MIS-C) were reported in children 5 to less than 12 years of age, as of the data cut-off date (October 8, 2021).

14.2.3.2 Immunogenicity in Children 5 Years Through <12 Years of Age – After Booster Dose

Immunogenicity of a booster dose administered 7 to 9 months after the second primary series dose was evaluated in a subset of 67 evaluable study participants with no evidence of prior SARS-CoV-2 infection up to 1 month after the booster dose, and descriptively compared to 96 subjects in the same age group (67 participants randomly selected from the 2-dose analysis set and 29 participants in the 3-dose analysis set) with evaluable immunogenicity data following 2 doses of 10 mcg BNT162b2.

Vaccine effectiveness of a booster dose of COMIRNATY was inferred based on a descriptive analysis of NT50 against the reference strain of SARS-CoV-2 (USA_WA1/2020). The NT50 GMT at 1 month after the booster dose was increased compared to before the booster dose and after dose 2. See Table 27.

14.2.4 Immunogenicity in Children 6 Months Through <5 Years of Age

14.2.4.1 Immunogenicity in Children 6 Months Through <5 Years of Age – After a 3-Dose Primary Series

Effectiveness in individuals 6 months through <5 years of age is based on a comparison of immune responses in this age group to individuals 16 through 25 years of age.

Immunogenicity in Children 2 Through <5 Years of Age

Immunogenicity analyses have been performed in the immunobridging subset of 143 Study 3 participants 2 through <5 years of age without evidence of infection up to 1 month after Dose 3 based on a data cut-off date of April 29, 2022.

SARS-CoV-2 50% neutralizing antibody titres (NT50) were compared between an immunogenicity subset of Phase 2/3 participants 2 through <5 years of age from Study 3 at 1 month after the 3-dose primary course and a randomly selected subset from Study 2 Phase 2/3 participants 16 through 25 years of age at 1 month after the 2-dose primary series, using a microneutralization assay against the reference strain (USA_WA1/2020). The primary immunobridging analyses compared the geometric mean titres (using a geometric mean ratio [GMR]) and the seroresponse (defined as achieving at least 4-fold rise in SARS-CoV-2 NT50 from before Dose 1) rates in the evaluable immunogenicity population of participants without evidence of prior SARS-CoV-2 infection up to 1 month after Dose 3 in participants 2 through <5 years of age and up to 1 month after Dose 2 in participants 16 through 25 years of age. The prespecified immunobridging criteria were met for both the GMR and the seroresponse difference (Table 28).

Table 28: SARS-CoV-2 GMTs (NT50) at 1 Month After Vaccination Series and Difference in Percentages of Participants with Seroresponse at 1 Month After Vaccination Series – Immunobridging Subset - Participants 2 Through <5 Years of Age (Study 3) 1 Month after Dose 3 and Participants 16 Through 25 Years of Age (Study 2) 1 Month After Dose 2 – Without Evidence of SARS-CoV-2 Infection – Evaluable Immunogenicity Population

Using a non-validated fluorescence focus reduction neutralization test assay against the Omicron variant of SARS-CoV-2 (BA.1), the NT50 GMT at 1 month after Dose 3 among a subset of 34 study participants without evidence of prior SARS-CoV-2 infection (82.5 [2-sided 95% CI: 55.4, 122.9]) was increased compared to the NT50 GMT before Dose 3 (14.0 [2-sided 95% CI: 10.6, 18.5]).

Immunogenicity in Children 6 Months Through <2 Years of Age

Immunogenicity analyses have been performed in the immunobridging subset of 82 Study 3 participants 6 months through <2 years of age without evidence of infection up to 1 month after Dose 3 based on a data cut-off date of 29 April 2022.

SARS-CoV-2 50% neutralizing antibody titres (NT50) 1 month after the vaccination series were compared between an immunogenicity subset of Phase 2/3 participants 6 months through <2 years of age from Study 3 and a randomly selected subset from Study 2 Phase 2/3 participants 16 through 25 years of age, using a microneutralization assay against the reference strain (USA_WA1/2020). The primary immunobridging analyses compared the geometric mean titres (using a GMR) and the seroresponse (defined as achieving at least 4-fold rise in SARS-CoV-2 NT50 from before Dose 1) rates in the evaluable immunogenicity population of participants without evidence of prior SARS-CoV-2 infection up to 1 month after Dose 3 in participants 6 months through < 2 years of age and up to 1 month after Dose 2 in participants 16 through 25 years of age. The prespecified immunobridging criteria were met for both the GMR and the seroresponse difference (Table 29).

Table 29: SARS-CoV-2 GMTs (NT50) at 1 Month after Vaccination Series and Difference in Percentages of Participants With Seroresponse at 1 Month After Vaccination Series – Immunobridging Subset - Participants 6 Months Through <2 Years of Age (Study 3) 1 Month After Dose 3 and Participants 16 Through 25 Years of Age (Study 2) 1 Month After Dose 2 – Without Evidence of SARS-CoV-2 Infection– Evaluable Immunogenicity Population

Using a non-validated fluorescence focus reduction neutralization test assay against the Omicron variant of SARS-CoV-2 (BA.1), the NT50 GMT at 1 month after Dose 3 among a subset of 32 study participants without evidence of prior SARS-CoV-2 infection (127.5 [2-sided 95% CI: 90.2, 180.1]) was increased compared to the NT50 GMT before Dose 3 (16.3 [2-sided 95% CI: 12.8, 20.8]).

15 MICROBIOLOGY

No microbiological information is required for this product.

16 NON-CLINICAL TOXICOLOGY

Non-clinical data reveal no special hazard for humans based on conventional studies of repeat dose toxicity.

General Toxicology:

In a repeat-dose toxicity study, rats were administered three once weekly doses of 30 mcg/animal (0.06 mL of a vaccine formulation containing the same quantity of nucleoside-modified messenger ribonucleic acid (mRNA) and other ingredients included in a single human dose) of COMIRNATY by intramuscular injection. Vaccine administration resulted in transient erythema and edema at the site of injection, as well as increased cellularity in draining and inguinal lymph nodes, spleen, and bone marrow, along with transiently increased body temperature, increased white blood counts, and decreased reticulocyte counts coupled with decreased red blood cell mass. Clinical chemistry changes (e.g., increased acute phase protein levels) indicated an acute phase response. These changes are consistent with an expected immunostimulatory response following intramuscular administration of a vaccine. Transient periportal hepatocyte vacuolation was also observed without evidence of liver injury. Full or partial recovery from all findings was observed following a 3-week recovery period.

Carcinogenicity:

Carcinogenic potential was not assessed, as carcinogenicity studies were not considered relevant to this vaccine.

Genotoxicity:

Genotoxic potential was not assessed, as genotoxicity studies were not considered relevant to this vaccine.

Reproductive and Developmental Toxicology:

In a reproductive and developmental toxicity study, 30 mcg/animal (0.06 mL of a vaccine formulation containing the same quantity of nucleoside-modified messenger ribonucleic acid (mRNA) and other ingredients included in a single human dose) of COMIRNATY was administered to female rats by the intramuscular route on four occasions: 21 and 14 days prior to mating, and on gestation days 9 and 20. No vaccine-related adverse effects on female fertility, fetal development, or postnatal development were reported in the study.