Comirnaty (COVID-19 Vaccine, mRNA)

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.

4.1 Dosing Considerations

COMIRNATY is a suspension for intramuscular injection which must be diluted prior to administration. After preparation, a single dose is 0.3 mL.

4.2 Recommended Dose and Dosage Adjustment

Vaccination Schedule for Individuals 12 Years of Age and Older
COMIRNATY is administered intramuscularly after dilution as a series of two doses (0.3 mL each) 3 weeks apart (see 14.1 Trial Design and Study Demographics).

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 receive a second dose of COMIRNATY to complete the vaccination series.

COMIRNATY (COVID-19 Vaccine, mRNA) and the Interim Order authorized Pfizer-BioNTech COVID-19 Vaccine have the same formulation and can be used interchangeably to provide the COVID-19 vaccination series.

4.3 Reconstitution

Preparation for Administration

Prior to Dilution:

• The COMIRNATY multiple dose vial contains a volume of 0.45 mL, 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.

THAWING PRIOR TO DILUTION
	Thaw vial(s) of COMIRNATY before use either by:  Allowing vial(s) to thaw in the refrigerator (2°C to 8°C [35°F to 46°F]). A carton of vials may take up to 3 hours to thaw, and thawed vials can be stored in the refrigerator for up to 1 month. Allowing vial(s) to sit at room temperature (up to 25°C [77°F]) for 30 minutes. Using either thawing method, vials must reach room temperature before dilution and must be diluted within 2 hours of exposure to room temperature.
	Before dilution, invert vaccine vial gently 10 times. Do not shake. Inspect the liquid in the vial prior to dilution. The liquid is a white to off-white suspension and may contain white to off-white opaque amorphous particles. Do not use if liquid is discoloured or if other particles are observed.
DILUTION
	Obtain sterile 0.9% Sodium Chloride Injection, USP. Use only this as the diluent. Using aseptic technique, withdraw 1.8 mL of 0.9% Sodium Chloride Injection, USP into a transfer syringe (21-gauge or narrower needle). Cleanse the vaccine vial stopper with a single-use antiseptic swab. Add 1.8 mL of 0.9% Sodium Chloride Injection, USP into the vaccine vial.
	Equalize vial pressure before removing the needle from the vial by withdrawing 1.8 mL air into the empty diluent syringe.
	Gently invert the vial containing COMIRNATY 10 times to mix.  Do not shake. Inspect the vaccine in the vial. The vaccine will be an off-white suspension. Do not use if vaccine is discoloured or contains particulate matter.
	Record the date and time of dilution on the COMIRNATY vial label.  Store between 2°C to 25°C (35°F to 77°F).  Discard any unused vaccine 6 hours after dilution.

PREPARATION OF INDIVIDUAL 0.3 mL DOSES OF COMIRNATY

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.

4.4 Administration

Visually inspect each dose in the dosing syringe prior to administration. The diluted 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.

Administer COMIRNATY intramuscularly, preferably in the deltoid muscle.

Do not inject the vaccine intravascularly, subcutaneously or intradermally.

After dilution, vials of COMIRNATY contain 6 doses of 0.3 mL of vaccine. 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.

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 and the non-medicinal ingredients listed in Table 1 below. 

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

COMIRNATY multiple dose vials are supplied in a carton containing 25 multiple dose vials or 195 multiple dose vials. Not all pack sizes may be available.

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.

8.1 Adverse Reaction Overview

The safety of COMIRNATY was evaluated in participants 12 years of age and older in two 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 2260 adolescents are 12 to 15 years of age (1131 and 1129 in the vaccine and placebo groups, respectively). 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.

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 2260 adolescents (1131 COMIRNATY; 1129 placebo) were 12 to 15 years of age. Of these, 1308 (660 COMIRNATY and 648 placebo) adolescents have been followed for at least 2 months after the second dose of COMIRNATY.

The safety evaluation of participants in Study 2 is ongoing. Participants 16 years of age and older in the reactogenicity subset and adolescents 12 to 15 years of age 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 continue to be monitored for unsolicited adverse events, including serious adverse events, throughout the study [from Dose 1 through 1 month (all unsolicited adverse events) or 6 months (serious adverse events) after the last vaccination].

In clinical studies with a data cut-off of March 13, 2021, the most common adverse reactions in the reactogenicity subset (n=4924) 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.

Adverse reactions after any dose in the reactogenicity subset (n=1131) of adolescents 12 to 15 years of age included injection site pain (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%), injection site redness (8.6%), lymphadenopathy (0.8%), and nausea (0.4%). 

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

Solicited Adverse Reactions

Tables 2 through 5 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=9839) in the safety population who were monitored for reactogenicity with an electronic diary.

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 participants in the vaccine group compared to 8 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.

Adolescents 12 to 15 Years of Age

Solicited Adverse Reactions

Table 6 and Table 7 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.

Unsolicited Adverse Events

In the analysis of Study 2 among adolescents 12 to 15 years of age, 98.3% of study participants had at least 30 days of follow-up after Dose 2 (1131 adolescents received COMIRNATY and 1129 adolescents received placebo).

Unsolicited adverse events (both serious and non-serious) were reported by 6.4% of COMIRNATY recipients and by 6.3% of placebo recipients. Serious adverse events were reported by 0.4% of COMIRNATY recipients and by 0.2% of placebo recipients.

8.3 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, and other hypersensitivity reactions (e.g., rash, pruritus, urticaria, angioedema)

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

Nervous System Disorders: Facial paralysis / Bell’s Palsy

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.

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.