Drug information

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POM

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Last updated: 01 Mar 2023

▼ This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions. See section 4.8 for how to report adverse reactions.

Summary of product characteristics

1. Name of the medicinal product

Comirnaty Original/Omicron BA.4-5 (15/15 micrograms)/dose dispersion for injection

COVID-19 mRNA Vaccine (nucleoside modified)

2. Qualitative and quantitative composition

This is a multidose vial with a grey cap. Do not dilute prior to use.

One vial (2.25 mL) contains 6 doses of 0.3 mL, see sections 4.2 and 6.6.

One dose (0.3 mL) contains 15 micrograms of tozinameran and 15 micrograms of famtozinameran, a COVID-19 mRNA Vaccine (embedded in lipid nanoparticles).

Tozinameran is a 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). Famtozinameran is a 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 (Omicron BA.4-5).

For the full list of excipients, see section 6.1.

3. Pharmaceutical form

Dispersion for injection.

The vaccine is a white to off-white frozen dispersion (pH: 6.9 - 7.9).

4.1. Therapeutic indications

Comirnaty Original/Omicron BA.4-5 (15/15 micrograms)/dose dispersion for injection is indicated for active immunisation to prevent COVID-19 caused by SARS-CoV-2, in individuals 12 years of age and older who have previously received at least a primary vaccination course against COVID-19 (see sections 4.2 and 5.1).

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

4.2. Posology and method of administration

Posology

The dose of Comirnaty Original/Omicron BA.4-5 is 0.3 mL given intramuscularly.

There should be an interval of at least 3 months between administration of Comirnaty Original/Omicron BA.4-5 and the last prior dose of a COVID-19 vaccine.

Comirnaty Original/Omicron BA.4-5 is only indicated for individuals who have previously received at least a primary vaccination course against COVID-19.

For details on the primary vaccination course for ages 12 and above, please refer to the Summary of Product Characteristics for Comirnaty 30 micrograms/dose concentrate for dispersion for injection and Comirnaty 30 micrograms/dose dispersion for injection.

Paediatric population

There is a paediatric formulation available for children 5 to 11 years of age (i.e. 5 to less than 12 years of age). For details, please refer to the Summary of Product Characteristics for Comirnaty Original/Omicron BA.4-5 (5/5 micrograms)/dose concentrate for dispersion for injection.

The safety and efficacy of Comirnaty Original/Omicron BA.4-5 in children aged less than 12 years of age have not yet been established. No data are available.

Elderly population

No dosage adjustment is required in elderly individuals ≥ 65 years of age.

Method of administration

Comirnaty Original/Omicron BA.4-5 (15/15 micrograms)/dose dispersion for injection should be administered intramuscularly (see section 6.6). Do not dilute prior to use.

Vials of Comirnaty Original/Omicron BA.4-5 contain 6 doses of 0.3 mL of vaccine. In order to extract 6 doses from a single vial, low dead-volume syringes and/or needles should be used. The low dead-volume syringe and needle combination should have a dead volume of no more than 35 microlitres. If standard syringes and needles are used, there may not be sufficient volume to extract a sixth 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.

The preferred site is the deltoid muscle of the upper arm.

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

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

For instructions regarding thawing, handling and disposal of the vaccine, see section 6.6.

4.3. Contraindications

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

4.4. Special warnings and precautions for use

Traceability

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

General recommendations

Hypersensitivity and anaphylaxis

Events of anaphylaxis have been reported. Appropriate medical treatment and supervision should always be readily available in case of an anaphylactic reaction following the administration of the vaccine.

Close observation for at least 15 minutes is recommended following vaccination. No further dose of the vaccine should be given to those who have experienced anaphylaxis after a prior dose of Comirnaty.

Myocarditis and pericarditis

There is an increased risk of myocarditis and pericarditis following vaccination with Comirnaty. These conditions can develop within just a few days after vaccination, and have primarily occurred within 14 days. They have been observed more often after the second vaccination, and more often in younger males. Available data suggest that the course of myocarditis and pericarditis following vaccination is not different from myocarditis or pericarditis in general (see section 4.8).

Healthcare professionals should be alert to the signs and symptoms of myocarditis and pericarditis. Vaccinees (including parents or caregivers) should be instructed to seek immediate medical attention if they develop symptoms indicative of myocarditis or pericarditis such as (acute and persisting) chest pain, shortness of breath, or palpitations following vaccination.

Healthcare professionals should consult guidance and/or specialists to diagnose and treat this condition.

Anxiety-related reactions

Anxiety-related reactions, including vasovagal reactions (syncope), hyperventilation or stress‐related reactions (e.g. dizziness, palpitations, increases in heart rate, alterations in blood pressure, paraesthesia, hypoaesthesia and sweating) may occur in association with the vaccination process itself. Stress-related reactions are temporary and resolve on their own. Individuals should be advised to bring symptoms to the attention of the vaccination provider for evaluation. It is important that precautions are in place to avoid injury from fainting.

Concurrent illness

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

Thrombocytopenia and coagulation disorders

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

Immunocompromised individuals

The efficacy and safety of the vaccine has not been assessed in immunocompromised individuals, including those receiving immunosuppressant therapy. The efficacy of Comirnaty Original/Omicron BA.4-5 may be lower in immunocompromised individuals.

Duration of protection

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

Limitations of vaccine effectiveness

As with any vaccine, vaccination with Comirnaty Original/Omicron BA.4-5 may not protect all vaccine recipients.

4.5. Interaction with other medicinal products and other forms of interaction

No interaction studies have been performed.

Concomitant administration of Comirnaty Original/Omicron BA.4-5 with other vaccines has not been studied.

4.6. Fertility, pregnancy and lactation

Pregnancy

No data are available yet regarding the use of Comirnaty Original/Omicron BA.4-5 during pregnancy.

However, a large amount of observational data from pregnant women vaccinated with the initially approved Comirnaty vaccine during the second and third trimester have not shown an increase in adverse pregnancy outcomes. While data on pregnancy outcomes following vaccination during the first trimester are presently limited, no increased risk for miscarriage has been seen. Animal studies do not indicate direct or indirect harmful effects with respect to pregnancy, embryo/foetal development, parturition or post-natal development (see section 5.3). Based on data available with other vaccine variants, Comirnaty Original/Omicron BA.4-5 can be used during pregnancy.

Breast-feeding

No data are available yet regarding the use of Comirnaty Original/Omicron BA.4-5 during breast-feeding.

However, no effects on the breastfed newborn/infant are anticipated since the systemic exposure of breast-feeding woman to the vaccine is negligible. Observational data from women who were breast-feeding after vaccination with the initially approved Comirnaty vaccine have not shown a risk for adverse effects in breastfed newborns/infants. Comirnaty Original/Omicron BA.4-5 can be used during breast-feeding.

Fertility

Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity (see section 5.3).

4.7. Effects on ability to drive and use machines

Comirnaty Original/Omicron BA.4-5 has no or negligible influence on the ability to drive and use machines. However, some of the effects mentioned under section 4.8 may temporarily affect the ability to drive or use machines.

4.8. Undesirable effects

Summary of safety profile

The safety of a booster dose of Comirnaty Original/Omicron BA.4-5 is inferred from safety data for a booster dose of an Omicron BA.1 adapted vaccine in individuals 18 years of age and older, as well as for a booster dose of the initially approved Comirnaty vaccine in individuals 5 years of age and older.

Comirnaty 30 mcg

Participants 16 years of age and older – after 2 doses

In Study 2, a total of 22,026 participants 16 years of age or older received at least 1 dose of Comirnaty and a total of 22,021 participants 16 years of age or older received placebo (including 138 and 145 adolescents 16 and 17 years of age in the vaccine and placebo groups, respectively). A total of 20,519 participants 16 years of age or older received 2 doses of Comirnaty.

At the time of the analysis of Study 2 with a data cut-off of 13 March 2021 for the placebo-controlled blinded follow-up period up to the participants' unblinding dates, a total of 25,651 (58.2%) participants (13,031 Comirnaty and 12,620 placebo) 16 years of age and older were followed up for ≥ 4 months after the second dose. This included a total of 15,111 (7,704 Comirnaty and 7,407 placebo) participants 16 to 55 years of age and a total of 10,540 (5,327 Comirnaty and 5,213 placebo) participants 56 years of age and older.

The most frequent adverse reactions in participants 16 years of age and older that received 2 doses were injection site pain (> 80%), fatigue (> 60%), headache (> 50%), myalgia (> 40%), chills (> 30%), arthralgia (> 20%), pyrexia and injection site swelling (> 10%) and were usually mild or moderate in intensity and resolved within a few days after vaccination. A slightly lower frequency of reactogenicity events was associated with greater age.

The safety profile in 545 participants 16 years of age and older receiving Comirnaty, that were seropositive for SARS-CoV-2 at baseline, was similar to that seen in the general population.

Adolescents 12 to 15 years of age – after 2 doses

In an analysis of long-term safety follow-up in Study 2, 2,260 adolescents (1,131 Comirnaty and 1,129 placebo) were 12 to 15 years of age. Of these, 1,559 adolescents (786 Comirnaty and 773 placebo) have been followed for ≥ 4 months after the second dose of Comirnaty. The safety evaluation in Study 2 is ongoing.

The overall safety profile of Comirnaty in adolescents 12 to 15 years of age was similar to that seen in participants 16 years of age and older. The most frequent adverse reactions in adolescents 12 to 15 years of age that received 2 doses were injection site pain (> 90%), fatigue and headache (> 70%), myalgia and chills (> 40%), arthralgia and pyrexia (> 20%).

Participants 16 years of age and older – after booster dose

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

The overall safety profile for the booster dose was similar to that seen after 2 doses. The most frequent adverse reactions in participants 18 to 55 years of age were injection site pain (> 80%), fatigue (> 60%), headache (> 40%), myalgia (> 30%), chills and arthralgia (> 20%).

In Study 4, a placebo-controlled booster study, participants 16 years of age and older recruited from 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). No new adverse reactions of Comirnaty were identified.

Booster dose following primary vaccination with another authorised COVID-19 vaccine

In 5 independent studies on the use of a Comirnaty booster dose in individuals who had completed primary vaccination with another authorised COVID-19 vaccine (heterologous booster dose), no new safety issues were identified (see section 5.1).

Omicron-adapted Comirnaty

Participants > 55 years of age – after a booster dose of Comirnaty Original/Omicron BA.1 (fourth dose)

In a subset from Study 4 (Phase 3), 305 adults > 55 years of age who had completed 3 doses of Comirnaty, received a booster (fourth dose) of Comirnaty Original/Omicron BA.1 (15/15 mcg) 4.7 to 11.5 months after receiving Dose 3. Participants who received a booster (fourth dose) of Comirnaty Original/Omicron BA.1 had a median follow-up time of at least 1.7 months.

The overall safety profile for the Comirnaty Original/Omicron BA.1 booster (fourth dose) was similar to that seen after the Comirnaty booster (third dose). The most frequent adverse reactions in participants greater than 55 years of age were injection site pain (> 50%), fatigue (> 40%), headache (> 30%), myalgia (> 20%), chills and arthralgia (> 10%). No new adverse reactions were identified for Comirnaty Original/Omicron BA.1.

Participants 18 to ≤ 55 years of age – after a booster dose of monovalent Omicron BA.1 (fourth dose)

The safety of a Comirnaty Original/Omicron BA.1 booster dose in individuals from 18 to ≤ 55 years of age is extrapolated from safety data from a subset of 315 adults 18 to ≤ 55 years of age who received a booster (fourth dose) of Omicron BA.1 30 mcg (monovalent) after completing 3 doses of Comirnaty. The most frequent adverse reactions in these participants 18 to ≤ 55 years of age were injection site pain (> 70%), fatigue (> 60%), headache (> 40%), myalgia (> 30%), chills (> 30%) and arthralgia (> 20%).

Tabulated list of adverse reactions from clinical studies of Comirnaty and Comirnaty Original/Omicron BA.1 and post-authorisation experience of Comirnaty in individuals 12 years of age and older

Adverse reactions observed during clinical studies are listed below according to the following frequency categories:

Very common (≥ 1/10),

Common (≥ 1/100 to < 1/10),

Uncommon (≥ 1/1,000 to < 1/100),

Rare (≥ 1/10,000 to < 1/1,000),

Very rare (< 1/10,000),

Not known (cannot be estimated from the available data).

Table 1: Adverse reactions from Comirnaty and Comirnaty Original/Omicron BA.1 clinical trials and Comirnaty post-authorisation experience in individuals 12 years of age and older

System Organ Class

Very common

(≥ 1/10)

Common

(≥ 1/100 to < 1/10)

Uncommon

(≥ 1/1,000 to < 1/100)

Rare

(≥ 1/10,000 to < 1/1,000)

Very rare

(< 1/10,000)

Not known (cannot be estimated from the available data)

Blood and lymphatic system disorders

Lymphadenopathy^a

Immune system disorders

Hypersensitivity reactions (e.g. rash, pruritus, urticaria^b, angioedema^b)

Anaphylaxis

Metabolism and nutrition disorders

Decreased appetite

Psychiatric disorders

Insomnia

Nervous system disorders

Headache

Lethargy

Acute peripheral facial paralysis^c

Paraesthesia^d; Hypoaesthesia^d

Cardiac disorders

Myocarditis^d; Pericarditis^d

Gastrointestinal disorders

Diarrhoea^d

Nausea; Vomiting^d

Skin and subcutaneous tissue disorder

Hyperhidrosis; Night sweats

Erythema multiforme^d

Musculoskeletal and connective tissue disorders

Arthralgia; Myalgia

Pain in extremity^e

Reproductive system and breast disorders

Heavy menstrual bleeding^h

General disorders and administration site conditions

Injection site pain; Fatigue; Chills; Pyrexia^f; Injection site swelling

Injection site redness

Asthenia; Malaise; Injection site pruritus

Extensive swelling of vaccinated limb^d; Facial swelling^g

a. A higher frequency of lymphadenopathy (2.8% vs. 0.4%) was observed in participants receiving a booster dose in Study 4 compared to participants receiving 2 doses.

b. The frequency category for urticaria and angioedema was rare.

c. Through the clinical trial safety follow-up period to 14 November 2020, acute peripheral facial paralysis (or palsy) was reported by four participants in the COVID-19 mRNA Vaccine group. Onset was Day 37 after Dose 1 (participant did not receive Dose 2) and Days 3, 9, and 48 after Dose 2. No cases of acute peripheral facial paralysis (or palsy) were reported in the placebo group.

d. Adverse reaction determined post-authorisation.

e. Refers to vaccinated arm.

f. A higher frequency of pyrexia was observed after the second dose compared to the first dose.

g. Facial swelling in vaccine recipients with a history of injection of dermatological fillers has been reported in the post-marketing phase.

h. Most cases appeared to be non-serious and temporary in nature.

Description of selected adverse reactions

Myocarditis and pericarditis

The increased risk of myocarditis after vaccination with Comirnaty is highest in younger males (see section 4.4).

Two large European pharmacoepidemiological studies have estimated the excess risk in younger males following the second dose of Comirnaty. One study showed that in a period of 7 days after the second dose there were about 0.265 (95% CI 0.255 - 0.275) extra cases of myocarditis in 12-29 year old males per 10,000 compared to unexposed persons. In another study, in a period of 28 days after the second dose there were 0.56 [95% CI 0.37 – 0.74] extra cases of myocarditis in 16-24 year old males per 10,000 compared to unexposed persons.

Limited data indicate that the risk of myocarditis and pericarditis after vaccination with Comirnaty in children aged 5 to 11 years seems lower than in ages 12 to 17 years.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product.

Healthcare professionals are asked to report any suspected adverse reactions via a Yellow card. Reporting forms and information can be found at https://coronavirus-yellowcard.mhra.gov.uk/ or search for MHRA Yellow Card in the Google Play or Apple App Store and include batch/Lot number if available.

Alternatively, adverse events of concern in association with Comirnaty can be reported to Pfizer Medical Information on 01304 616161 or via www.pfizersafetyreporting.com.

Please do not report the same adverse event(s) to both systems as all reports will be shared between Pfizer and MHRA (in an anonymized form) and dual reporting will create unnecessary duplicates.

4.9. Overdose

Overdose data is available from 52 study participants included in the clinical trial that due to an error in dilution received 58 micrograms of Comirnaty. The vaccine recipients did not report an increase in reactogenicity or adverse reactions.

In the event of overdose, monitoring of vital functions and possible symptomatic treatment is recommended.

5.1. Pharmacodynamic properties

Pharmacotherapeutic group: vaccines, other viral vaccines, ATC code: J07BX03

Mechanism of action

The nucleoside-modified messenger RNA in Comirnaty is formulated in lipid nanoparticles, which enable delivery of the non-replicating RNA into host cells to direct transient expression of the SARS-CoV-2 S antigen. The mRNA codes for membrane-anchored, full-length S with two point mutations within the central helix. Mutation of these two amino acids to proline locks S in an antigenically preferred prefusion conformation. The vaccine elicits both neutralizing antibody and cellular immune responses to the spike (S) antigen, which may contribute to protection against COVID-19.

Efficacy

Omicron-adapted Comirnaty

The efficacy of a booster dose of Comirnaty Original/Omicron BA.4-5 is inferred from the immunogenicity of an Omicron BA.1 adapted vaccine in individuals 55 years of age and older.

Comirnaty Original/Omicron BA.1

Relative vaccine immunogenicity in participants > 55 years of age – after a booster dose of Comirnaty Original/Omicron BA.1 (fourth dose)

In an interim analysis of a subset from Study 4 (Substudy E), 610 adults greater than 55 years of age who had completed a series of 3 doses of Comirnaty received 1 of the following as a booster dose (fourth dose): Comirnaty (30 mcg) or Comirnaty Original/Omicron BA.1 (15/15 mcg). GMRs and seroresponse rates were evaluated at 1 month after Comirnaty Original/Omicron BA.1 (15/15 mcg) booster vaccination up to a cut-off date of 16 May 2022, which represents a median of at least 1.7 months post-booster follow-up. The Comirnaty Original/Omicron BA.1 (15/15 mcg) booster dose was administered 4.7 to 11.5 months (median 6.3 months) after the third dose.

The primary objective of the analysis was to assess superiority with respect to level of neutralising titre and noninferiority with respect to seroresponse rate of the anti-Omicron immune response induced by a dose of Comirnaty Original/Omicron BA.1 (15/15 mcg) relative to the response elicited by a dose of Comirnaty (30 mcg) given as a fourth dose in Comirnaty-experienced participants greater than 55 years of age.

Superiority of Comirnaty Original/Omicron BA.1 (15/15 mcg) to Comirnaty (30 mcg) was met, as the lower bound of the 2-sided 95% CI for GMR was > 1 (Table 2).

Seroresponse is defined as achieving ≥ 4-fold rise from baseline (before the study vaccination). If the baseline measurement is below the LLOQ, the postvaccination measure of ≥ 4 × LLOQ is considered a seroresponse.

The difference in percentages of participants who achieved seroresponse to Omicron variant between the Comirnaty Original/Omicron BA.1 group (71.6%) and Comirnaty group (57%) was 14.6% (2-sided 95% CI: 4.0%, 24.9%). Thus, noninferiority was met.

Table 2: Substudy E - Geometric mean ratios for between vaccine group comparison – participants without evidence of infection up to 1 month after Dose 4 – expanded cohort – immunogenicity subset – participants greater than 55 years of age – evaluable immunogenicity population

Assay

Vaccine group

(as randomised)

Sampling time point^a

N^b

GMT

(95% CI^c)

GMR

(95% CI^d)

SARS-CoV-2 neutralisation assay - Omicron BA.1 - NT50 (titre)

Comirnaty

(30 mcg)

1 month

163

455.8

(365.9, 567.6)

Comirnaty Original/Omicron BA.1 (15/15 mcg)

1 month

178

711.0

(588.3, 859.2)

1.56

(1.17, 2.08)

SARS-CoV-2 neutralisation assay - reference strain - NT50 (titre)

Comirnaty

(30 mcg)

1 month

182

5998.1

(5223.6, 6887.4)

Comirnaty Original/Omicron BA.1 (15/15 mcg)

1 month

186

5933.2

(5188.2, 6785.2)

0.99

(0.82, 1.20)

Abbreviations: CI = confidence interval; GMR = geometric mean ratio; GMT = geometric mean titre; LLOQ = lower limit of quantitation; N-binding = SARS-CoV-2 nucleoprotein–binding; NAAT = nucleic acid amplification test; NT50 = 50% neutralising titre; SARS-CoV-2 = severe acute respiratory syndrome coronavirus 2.

Note: Immunogenicity subset = a random sample of 230 participants in each vaccine group selected from the expanded cohort.

Note: Participants who had no serological or virological evidence (prior to the 1-month post–study vaccination blood sample collection) of past SARS-CoV-2 infection (i.e. N-binding antibody [serum] result negative at the study vaccination and the 1-month post–study vaccination visits, negative NAAT [nasal swab] result at the study vaccination visit, and any unscheduled visit prior to the 1-month post–study vaccination blood sample collection) and had no medical history of COVID-19 were included in the analysis.

a. Protocol-specified timing for blood sample collection.

b. n = Number of participants with valid and determinate assay results for the specified assay at the given sampling time point.

c. GMTs and 2-sided 95% CIs were calculated by exponentiating the mean logarithm of the titres and the corresponding CIs (based on the Student t distribution). Assay results below the LLOQ were set to 0.5 × LLOQ.

d. GMRs and 2-sided 95% CIs were calculated by exponentiating the mean difference of the logarithms of the titres (vaccine group in the corresponding row - Comirnaty [30 mcg]) and the corresponding CI (based on the Student t distribution).

Comirnaty 30 mcg

Study 2 is a multicentre, multinational, Phase 1/2/3 randomised, placebo-controlled, observer-blind dose-finding, vaccine candidate selection and efficacy study in participants 12 years of age and older. Randomisation was stratified by age: 12 to 15 years of age, 16 to 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 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 enrolment, were included as were participants with known stable infection with human immunodeficiency virus (HIV), hepatitis C virus (HCV) or hepatitis B virus (HBV).

Efficacy in participants 16 years of age and older – after 2 doses

In the Phase 2/3 portion of Study 2, based on data accrued through 14 November 2020, approximately 44,000 participants were randomised equally and were to receive 2 doses of COVID-19 mRNA Vaccine 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 after Dose 2, for assessments of safety and efficacy against COVID-19. In the clinical study, participants were required to observe a minimum interval of 14 days before and after administration of an influenza vaccine in order to receive either placebo or COVID-19 mRNA Vaccine. In the clinical study, participants were required to observe a minimum interval of 60 days before or after receipt of blood/plasma products or immunoglobulins within through conclusion of the study in order to receive either placebo or COVID-19 mRNA Vaccine.

The population for the analysis of the primary efficacy endpoint included 36,621 participants 12 years of age and older (18,242 in the COVID-19 mRNA Vaccine 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. In addition, 134 participants were between the ages of 16 to 17 years of age (66 in the COVID-19 mRNA Vaccine group and 68 in the placebo group) and 1,616 participants 75 years of age and older (804 in the COVID-19 mRNA Vaccine group and 812 in the placebo group).

At the time of the primary efficacy analysis, participants had been followed for symptomatic COVID-19 for in total 2,214 person-years for the COVID-19 mRNA Vaccine and in total 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 vaccine efficacy information is presented in Table 3.

Table 3: Vaccine efficacy – First COVID-19 occurrence from 7 days after Dose 2, by age subgroup – participants without evidence of infection prior to 7 days after Dose 2 – evaluable efficacy (7 days) population

First COVID-19 occurrence from 7 days after Dose 2 in participants without evidence of prior SARS-CoV-2 infection*

Subgroup

COVID-19 mRNA Vaccine

N^a = 18,198

Cases

n1^b

Surveillance time^c (n2^d)

Placebo

N^a = 18,325

Cases

n1^b

Surveillance time^c (n2^d)

Vaccine efficacy %

(95% CI)^e

All participants

2.214 (17,411)

162

2.222 (17,511)

95.0

(90.0, 97.9)

16 to 64 years

1.706 (13,549)

143

1.710 (13,618)

95.1

(89.6, 98.1)

65 years and older

0.508 (3848)

0.511 (3880)

94.7

(66.7, 99.9)

65 to 74 years

0.406 (3074)

0.406 (3095)

92.9

(53.1, 99.8)

75 years and older

0.102 (774)

0.106 (785)

100.0

(-13.1, 100.0)

Note: Confirmed cases were determined by Reverse Transcription-Polymerase Chain Reaction (RT-PCR) and at least 1 symptom consistent with COVID-19 [*Case definition: (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, diarrhoea or vomiting.]

* Participants who had no serological or virological evidence (prior to 7 days after receipt of the last dose) of past SARS-CoV-2 infection (i.e. N-binding antibody [serum] negative at Visit 1 and SARS-CoV-2 not detected by nucleic acid amplification tests (NAAT) [nasal swab] at Visits 1 and 2), and had negative NAAT (nasal swab) at any unscheduled visit prior to 7 days after Dose 2 were included in the analysis.

a. N = Number of participants in the specified group.

b. n1 = Number of participants meeting the endpoint definition.

c. Total surveillance time in 1,000 person-years for the given endpoint across all participants within each group at risk for the endpoint. Time period for COVID-19 case accrual is from 7 days after Dose 2 to the end of the surveillance period.

d. n2 = Number of participants at risk for the endpoint.

e. Two-sided confidence interval (CI) for vaccine efficacy is derived based on the Clopper and Pearson method adjusted to the surveillance time. CI not adjusted for multiplicity.

Efficacy of COVID-19 mRNA Vaccine in preventing first COVID-19 occurrence from 7 days after Dose 2 compared to placebo was 94.6% (95% confidence interval of 89.6% to 97.6%) in participants 16 years of age and older with or without evidence of prior infection with SARS-CoV-2.

Additionally, subgroup analyses of the primary efficacy endpoint showed similar efficacy point estimates across genders, ethnic groups, and participants with medical comorbidities associated with high risk of severe COVID-19.

Updated efficacy analyses were performed with additional confirmed COVID-19 cases accrued during blinded placebo-controlled follow-up, representing up to 6 months after Dose 2 in the efficacy population.

The updated vaccine efficacy information is presented in Table 4.

Table 4: Vaccine efficacy – First COVID-19 occurrence from 7 days after Dose 2, by age subgroup – participants without evidence of prior SARS-CoV-2 infection* prior to 7 days after Dose 2 – evaluable efficacy (7 days) population during the placebo-controlled follow-up period

Subgroup

COVID-19 mRNA Vaccine

N^a=20,998

Cases

n1^b

Surveillance time^c (n2^d)

Placebo

N^a=21,096

Cases

n1^b

Surveillance time^c (n2^d)

Vaccine efficacy %

(95% CI^e)

All participants^f

6.247 (20,712)

850

6.003 (20,713)

91.3

(89.0, 93.2)

16 to 64 years

4.859 (15,519)

710

4.654 (15,515)

90.6

(87.9, 92.7)

65 years and older

1.233 (4192)

124

1.202 (4226)

94.5

(88.3, 97.8)

65 to 74 years

0.994 (3350)

0.966 (3379)

94.1

(86.6, 97.9)

75 years and older

0.239 (842)

0.237 (847)

96.2

(76.9, 99.9)

Note: Confirmed cases were determined by Reverse Transcription-Polymerase Chain Reaction (RT-PCR) and at least 1 symptom consistent with COVID-19 (symptoms included: 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; diarrhoea; vomiting).

* Participants who had no evidence of past SARS-CoV-2 infection (i.e. N-binding antibody [serum] negative at Visit 1 and SARS-CoV-2 not detected by NAAT [nasal swab] at Visits 1 and 2), and had negative NAAT (nasal swab) at any unscheduled visit prior to 7 days after Dose 2 were included in the analysis.

a. N = Number of participants in the specified group.

b. n1 = Number of participants meeting the endpoint definition.

d. n2 = Number of participants at risk for the endpoint.

e. Two-sided 95% confidence interval (CI) for vaccine efficacy is derived based on the Clopper and Pearson method adjusted to the surveillance time.

f. Included confirmed cases in participants 12 to 15 years of age: 0 in the COVID-19 mRNA Vaccine group; 16 in the placebo group.

In the updated efficacy analysis, efficacy of COVID-19 mRNA Vaccine in preventing first COVID-19 occurrence from 7 days after Dose 2 compared to placebo was 91.1% (95% CI of 88.8% to 93.0%) in participants in the evaluable efficacy population with or without evidence of prior infection with SARS-CoV-2.

Additionally, the updated efficacy analyses by subgroup showed similar efficacy point estimates across sexes, ethnic groups, geography and participants with medical comorbidities and obesity associated with high risk of severe COVID-19.

Efficacy against severe COVID-19

Updated efficacy analyses of secondary efficacy endpoints supported benefit of the COVID-19 mRNA Vaccine in preventing severe COVID‑19.

As of 13 March 2021, vaccine efficacy against severe COVID-19 is presented only for participants with or without prior SARS-CoV-2 infection (Table 5) as 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 COVID-19 mRNA Vaccine and placebo groups.

Table 5: Vaccine efficacy – First severe COVID-19 occurrence in participants with or without prior SARS-CoV-2 infection based on the Food and Drug Administration (FDA)* after Dose 1 or from 7 days after Dose 2 in the placebo-controlled follow-up

COVID-19 mRNA Vaccine

Cases

n1^a

Surveillance time (n2^b)

Placebo

Cases

n1^a

Surveillance time (n2^b)

Vaccine efficacy %

(95% CI^c)

After Dose 1^d

8.439^e (22,505)

8.288^e (22,435)

96.7

(80.3, 99.9)

7 days after Dose 2^f

6.522^g (21,649)

6.404^g (21,730)

95.3

(70.9, 99.9)

* Severe illness from COVID-19 as defined by FDA is confirmed COVID-19 and presence of at least 1 of the following:

• Clinical signs at rest indicative of severe systemic illness (respiratory rate ≥ 30 breaths per minute, heart rate ≥ 125 beats per minute, saturation of oxygen ≤ 93% on room air at sea level, or ratio of arterial oxygen partial pressure to fractional inspired oxygen < 300 mm Hg);

• Respiratory failure [defined as needing high-flow oxygen, noninvasive ventilation, mechanical ventilation or extracorporeal membrane oxygenation (ECMO)];

• Evidence of shock (systolic blood pressure < 90 mm Hg, diastolic blood pressure < 60 mm Hg, or requiring vasopressors);

• Significant acute renal, hepatic, or neurologic dysfunction;

• Admission to an Intensive Care Unit;

• Death.

a. n1 = Number of participants meeting the endpoint definition.

b. n2 = Number of participants at risk for the endpoint.

c. Two-side confidence interval (CI) for vaccine efficacy is derived based on the Clopper and Pearson method adjusted to the surveillance time.

d. Efficacy assessed based on the Dose 1 all available efficacy (modified intention-to-treat) population that included all randomised participants who received at least 1 dose of study intervention.

e. Total surveillance time in 1,000 person-years for the given endpoint across all participants within each group at risk for the endpoint. Time period for COVID-19 case accrual is from Dose 1 to the end of the surveillance period.

f. Efficacy assessed based on the evaluable efficacy (7 Days) population that included all eligible randomised participants who receive all dose(s) of study intervention as randomised within the predefined window, have no other important protocol deviations as determined by the clinician.

g. Total surveillance time in 1,000 person-years for the given endpoint across all participants within each group at risk for the endpoint. Time period for COVID-19 case accrual is from 7 days after Dose 2 to the end of the surveillance period.

Efficacy and immunogenicity in adolescents 12 to 15 years of age – after 2 doses

In an initial analysis of Study 2 in adolescents 12 to 15 years of age (representing a median follow-up duration of >2 months after Dose 2) without evidence of prior infection, there were no cases in 1,005 participants who received the vaccine and 16 cases out of 978 who received placebo. The point estimate for efficacy is 100% (95% confidence interval 75.3, 100.0). In participants with or without evidence of prior infection there were 0 cases in the 1,119 who received vaccine and 18 cases in 1,110 participants who received placebo. This also indicates the point estimate for efficacy is 100% (95% confidence interval 78.1, 100.0).

In the updated efficacy analysis of Study 2 in adolescents 12 to 15 years of age without evidence of prior infection, there were no cases in 1,057 participants who received the vaccine and 28 cases out of 1,030 who received placebo. The point estimate for efficacy is 100% (95% confidence interval 86.8, 100.0). In participants with or without evidence of prior infection there were 0 cases in the 1,119 who received vaccine and 30 cases in 1,109 participants who received placebo. This also indicates the point estimate for efficacy is 100% (95% confidence interval 87.5, 100.0).

In Study 2, an analysis of SARS-CoV-2 neutralising titres 1 month after Dose 2 was conducted in a randomly selected subset of participants who had no serological or virological evidence of past SARS-CoV-2 infection up to 1 month after Dose 2, comparing the response in adolescents 12 to 15 years of age (n = 190) to participants 16 to 25 years of age (n = 170).

The ratio of the geometric mean titres (GMT) in the 12 to 15 years of age group to the 16 to 25 years of age group was 1.76, with a 2-sided 95% CI of 1.47 to 2.10. Therefore, the 1.5-fold noninferiority criterion was met as the lower bound of the 2-sided 95% CI for the geometric mean ratio [GMR] was > 0.67.

Immunogenicity in participants 18 years of age and older – after booster dose

Effectiveness of a booster dose of Comirnaty was based on an assessment of 50% neutralizing antibody titres (NT50) against SARS-CoV-2 (USA_WA1/2020) in Study 2. In this study, the booster dose was administered 5 to 8 months (median 7 months) after the second dose. In Study 2, analyses of NT50 1 month after the booster dose compared to 1 month after the primary series in individuals 18 through 55 years of age who had no serological or virological evidence of past SARS-CoV-2 infection up to 1 month after the booster vaccination demonstrated noninferiority for both geometric mean ratio (GMR) and difference in seroresponse rates. Seroresponse for a participant was defined as achieving a ≥ 4-fold rise in NT50 from baseline (before primary series). These analyses are summarized in Table 6.

Table 6: SARS-CoV-2 neutralization assay - NT50 (titre)^† (SARS-CoV-2 USA_WA1/2020) – GMT and seroresponse rate comparison of 1 month after booster dose to 1 month after primary series – participants 18 through 55 years of age without evidence of infection up to 1 month after booster dose* – booster dose evaluable immunogenicity population^±

1 month after booster dose

(95% CI)

1 month after primary series

(95% CI)

1 month after booster dose/- 1 month after primary series

(97.5% CI)

Met noninferiority objective

(Y/N)

Geometric mean 50% neutralizing titre (GMT^b)

212^a

2466.0^b

(2202.6, 2760.8)

750.6^b

(656.2, 858.6)

3.29^c

(2.77, 3.90)

Y^d

Seroresponse rate (%) for 50% neutralizing titre^†

200^e

199^f

99.5% (97.2%, 100.0%)

196^f

98.0% (95.0%, 99.5%)

1.5%^g

(-0.7%, 3.7%^h)

Yⁱ

Abbreviations: CI = confidence interval; GMR = geometric mean ratio; GMT = geometric mean titre; LLOQ = lower limit of quantitation; N-binding = SARS-CoV-2 nucleoprotein-binding; NAAT = nucleic acid amplification test; NT50 = 50% neutralizing titre; SARS-CoV-2 = severe acute respiratory syndrome coronavirus 2; Y/N = yes/no.

† SARS-CoV-2 NT50 were determined using the SARS-CoV-2 mNeonGreen Virus Microneutralization Assay. The assay uses a fluorescent reporter virus derived from the USA_WA1/2020 strain and virus neutralization is read on Vero cell monolayers. The sample NT50 is defined as the reciprocal serum dilution at which 50% of the virus is neutralized.

* Participants who had no serological or virological evidence (up to 1 month after receipt of a booster dose of Comirnaty) of past SARS-CoV-2 infection (i.e. N-binding antibody [serum] negative and SARS-CoV-2 not detected by NAAT [nasal swab]) and had a negative NAAT (nasal swab) at any unscheduled visit up to 1 month after the booster dose were included in the analysis.

± All eligible participants who had received 2 doses of Comirnaty as initially randomised, with Dose 2 received within the predefined window (within 19 to 42 days after Dose 1), received a booster dose of Comirnaty, had at least 1 valid and determinate immunogenicity result after booster dose from a blood collection within an appropriate window (within 28 to 42 days after the booster dose), and had no other important protocol deviations as determined by the clinician.

a. n = Number of participants with valid and determinate assay results at both sampling time points within specified window.

b. GMTs and 2-sided 95% CIs were calculated by exponentiating the mean logarithm of the titres and the corresponding CIs (based on the Student t distribution). Assay results below the LLOQ were set to 0.5 × LLOQ.

c. GMRs and 2-sided 97.5% CIs were calculated by exponentiating the mean differences in the logarithms of the assay and the corresponding CIs (based on the Student t distribution).

d. Noninferiority is declared if the lower bound of the 2-sided 97.5% CI for the GMR is > 0.67 and the point estimate of the GMR is ≥ 0.80.

e. n = Number of participants with valid and determinate assay results for the specified assay at baseline, 1 month after Dose 2 and 1 month after the booster dose within specified window. These values are the denominators for the percentage calculations.

f. Number of participants with seroresponse for the given assay at the given dose/sampling time point. Exact 2-sided CI based on the Clopper and Pearson method.

g. Difference in proportions, expressed as a percentage (1 month after booster dose – 1 month after Dose 2).

h. Adjusted Wald 2-sided CI for the difference in proportions, expressed as a percentage.

i. Noninferiority is declared if the lower bound of the 2-sided 97.5% CI for the percentage difference is > -10%.

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 performed in approximately 10,000 participants 16 years of age and older who were recruited from Study 2, 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. The booster dose was administered 5 to 13 months (median 11 months) after the second dose. 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 without prior evidence of SARS-CoV-2 infection is presented in Table 7. Relative vaccine efficacy in participants with or without evidence of prior SARS-CoV-2 infection was 94.6% (95% confidence interval of 88.5% to 97.9%, similar to that seen in those participants without evidence of prior infection. Primary COVID-19 cases observed from 7 days after booster vaccination were 7 primary cases in the Comirnaty group, and 124 primary cases in the placebo group.

Table 7: Vaccine efficacy – First COVID-19 occurrence from 7 days after booster vaccination – participants 16 years of age and older without evidence of infection – evaluable efficacy population

First COVID-19 occurrence from 7 days after booster dose in participants without evidence of prior SARS-CoV-2 infection*

Comirnaty

N^a=4695

Cases

n1^b

Surveillance Time^c (n2^d)

Placebo

N^a=4671

Cases

n1^b

Surveillance Time^c (n2^d)

Relative Vaccine Efficacy^e %

(95% CI^f)

First COVID-19 occurrence from 7 days after booster vaccination

0.823 (4659)

123

0.792 (4614)

95.3

(89.5, 98.3)

* Participants who had no serological or virological evidence (prior to 7 days after receipt of the booster vaccination) of past SARS-CoV-2 infection (i.e. N-binding antibody [serum] negative at Visit 1 and SARS-CoV-2 not detected by NAAT [nasal swab] at Visit 1, and had a negative NAAT [nasal swab] at any unscheduled visit prior to 7 days after booster vaccination) were included in the analysis.

a. N = Number of participants in the specified group.

b. n1 = Number of participants meeting the endpoint definition.

d. n2 = Number of participants at risk for the endpoint.

e. Relative vaccine efficacy of the Comirnaty booster group relative to the placebo group (non-booster).

f. Two-sided confidence interval (CI) for relative vaccine efficacy is derived based on the Clopper and Pearson method adjusted for surveillance time.

Immunogenicity of a booster dose following primary vaccination with another authorised COVID-19 vaccine

Effectiveness of a Comirnaty booster dose (30 mcg) in individuals who completed primary vaccination with another authorised COVID-19 vaccine (heterologous booster dose) is inferred from immunogenicity data from an independent National Institutes of Health (NIH) study phase 1/2 open-label clinical trial (NCT04889209) conducted in the United States. In this study, adults (range 19 to 80 years of age) who had completed primary vaccination with Moderna 100 mcg 2-dose series (N = 51, mean age 54±17), Janssen single dose (N = 53, mean age 48±14), or Comirnaty 30 mcg 2-dose series (N = 50, mean age 50±18) at least 12 weeks prior to enrolment and who reported no history of SARS-CoV-2 infection received a booster dose of Comirnaty (30 mcg). The boost with Comirnaty induced a 36, 12, and 20 GMR-fold rise in neutralising titres following the Janssen, Moderna, and Comirnaty primary doses, respectively.

Heterologous boosting with Comirnaty was also evaluated in the CoV-BOOST study (EudraCT 2021-002175-19), a multicentre, randomised, controlled, phase 2 trial of third dose booster vaccination against COVID-19, in which 107 adult participants (median age 71 years of age, interquartile range 54 to 77 years of age) were randomised at least 70 days post 2 doses of AstraZeneca COVID-19 Vaccine. After the AstraZeneca COVID‑19 Vaccine primary series, pseudovirus (wild-type), neutralising antibody NT50 GMR-fold change increased 21.6-fold with heterologous Comirnaty booster (n = 95).

Paediatric population

The licensing authority has deferred the obligation to submit the results of studies with Comirnaty in the paediatric population in prevention of COVID-19 (see section 4.2 for information on paediatric use).

5.2. Pharmacokinetic properties

Not applicable.

5.3. Preclinical safety data

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

General toxicity

Rats intramuscularly administered Comirnaty (receiving 3 full human doses once weekly, generating relatively higher levels in rats due to body weight differences) demonstrated some injection site oedema and erythema and increases in white blood cells (including basophils and eosinophils) consistent with an inflammatory response as well as vacuolation of portal hepatocytes without evidence of liver injury. All effects were reversible.

Genotoxicity/Carcinogenicity

Neither genotoxicity nor carcinogenicity studies were performed. The components of the vaccine (lipids and mRNA) are not expected to have genotoxic potential.

Reproductive toxicity

Reproductive and developmental toxicity were investigated in rats in a combined fertility and developmental toxicity study where female rats were intramuscularly administered Comirnaty prior to mating and during gestation (receiving 4 full human doses that generate relatively higher levels in rat due to body weight differences, spanning between pre-mating day 21 and gestational day 20). SARS-CoV-2 neutralizing antibody responses were present in maternal animals from prior to mating to the end of the study on postnatal day 21 as well as in foetuses and offspring. There were no vaccine-related effects on female fertility, pregnancy, or embryo-foetal or offspring development. No Comirnaty data are available on vaccine placental transfer or excretion in milk.

6.1. List of excipients

((4-hydroxybutyl)azanediyl)bis(hexane-6,1-diyl)bis(2-hexyldecanoate) (ALC-0315)

2-[(polyethylene glycol)-2000]-N,N-ditetradecylacetamide (ALC-0159)

1,2-Distearoyl-sn-glycero-3-phosphocholine (DSPC)

Cholesterol

Trometamol

Trometamol hydrochloride

Sucrose

Water for injections

6.2. Incompatibilities

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

6.3. Shelf life

Unopened vial

Frozen vial

18 months when stored at -90 °C to -60 °C.

The vaccine will be received frozen at -90 °C to -60 °C. Frozen vaccine can be stored either at -90 °C to -60 °C or 2 °C to 8 °C upon receipt.

When stored frozen at -90 °C to -60 °C, 10-vial packs of the vaccine can be thawed at 2 °C to 8 °C for 6 hours or individual vials can be thawed at room temperature (up to 30 °C) for 30 minutes.

Thawed vial

10 weeks storage and transportation at 2 °C to 8 °C within the 18-month shelf life.

· Upon moving the vaccine to 2 °C to 8 °C storage, the updated expiry date must be written on the outer carton and the vaccine should be used or discarded by the updated expiry date. The original expiry date should be crossed out.

· If the vaccine is received at 2 °C to 8 °C it should be stored at 2 °C to 8 °C. The expiry date on the outer carton should have been updated to reflect the refrigerated expiry date and the original expiry date should have been crossed out.

Prior to use, the unopened vials can be stored for up to 12 hours at temperatures between 8 °C and 30 °C.

Thawed vials can be handled in room light conditions.

Once thawed, the vaccine should not be re-frozen.

Handling of temperature excursions during refrigerated storage

• Stability data indicate that the unopened vial is stable for up to 10 weeks when stored at temperatures from -2 °C to 2 °C, within the 10-week storage period between 2 °C and 8 °C.

• Stability data indicate the vial can be stored for up to 24 hours at temperatures of 8 °C to 30 °C, including up to 12 hours following first puncture.

This information is intended to guide healthcare professionals only in case of temporary temperature excursion.

Opened vial

Chemical and physical in-use stability has been demonstrated for 12 hours at 2 °C to 30 °C, which includes up to 6 hours transportation time. From a microbiological point of view, unless the method of opening precludes the risks of microbial contamination, the product should be used immediately. If not used immediately, in-use storage times and conditions are the responsibility of the user.

6.4. Special precautions for storage

Store in a freezer at -90 °C to -60 °C.

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

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

For storage conditions after thawing and first opening, see section 6.3.

6.5. Nature and contents of container

2.25 mL dispersion in a 2 mL clear multidose vial (type I glass) with a stopper (synthetic bromobutyl rubber) and a grey flip-off plastic cap with aluminium seal. Each vial contains 6 doses, see section 6.6.

Pack sizes: 10 vials or 195 vials

Not all pack sizes may be marketed.

6.6. Special precautions for disposal and other handling

Handling instructions

Comirnaty Original/Omicron BA.4-5 (15/15 micrograms)/dose should be prepared by a healthcare professional using aseptic technique to ensure the sterility of the prepared dispersion.

VIAL VERIFICATION OF COMIRNATY ORIGINAL/OMICRON BA.4-5 (15/15 MICROGRAMS)/DOSE DISPERSION FOR INJECTION (12 YEARS AND OLDER)

• Verify that the vial has a grey plastic cap and a grey border around the label and the product name is Comirnaty Original/Omicron BA.4-5 (15/15 micrograms)/dose dispersion for injection.

• If the vial has a grey plastic cap and a grey border and the product name is Comirnaty 30 micrograms/dose dispersion for injection or Comirnaty Original/Omicron BA.1 (15/15 micrograms)/dose dispersion for injection, please make reference to the Summary of Product Characteristics for that formulation.

• If the vial has a purple plastic cap, please make reference to the Summary of Product Characteristics for Comirnaty 30 micrograms/dose concentrate for dispersion for injection.

• If the vial has an orange plastic cap, please make reference to the Summary of Product Characteristics for Comirnaty 10 micrograms/dose concentrate for dispersion for injection or Comirnaty Original/Omicron BA.4-5 (5/5 micrograms)/dose concentrate for dispersion for injection.

• If the vial has a maroon plastic cap, please make reference to the Summary of Product Characteristics for Comirnaty 3 micrograms/dose concentrate for dispersion for injection.

HANDLING PRIOR TO USE OF COMIRNATY ORIGINAL/OMICRON BA.4-5 (15/15 MICROGRAMS)/DOSE DISPERSION FOR INJECTION (12 YEARS AND OLDER)

• If the multidose vial is stored frozen it must be thawed prior to use. Frozen vials should be transferred to an environment of 2 °C to 8 °C to thaw; a 10 vial pack may take 6 hours to thaw. Ensure vials are completely thawed prior to use.

• Upon moving vials to 2 °C to 8 °C storage, update the expiry date on the carton.

• Unopened vials can be stored for up to 10 weeks at 2 °C to 8 °C; not exceeding the printed expiry date (EXP).

• Alternatively, individual frozen vials may be thawed for 30 minutes at temperatures up to 30 °C.

• Prior to use, the unopened vial can be stored for up to 12 hours at temperatures up to 30 °C. Thawed vials can be handled in room light conditions.

• Gently mix by inverting vials 10 times prior to use. Do not shake.

· Prior to mixing, the thawed dispersion may contain white to off-white opaque amorphous particles.

· After mixing, the vaccine should present as a white to off-white dispersion with no particulates visible. Do not use the vaccine if particulates or discolouration are present.

PREPARATION OF INDIVIDUAL 0.3 mL DOSES OF COMIRNATY ORIGINAL/OMICRON BA.4-5 (15/15 MICROGRAMS)/DOSE DISPERSION FOR INJECTION (12 YEARS AND OLDER)

• Using aseptic technique, cleanse the vial stopper with a single-use antiseptic swab.

· Withdraw 0.3 mL of Comirnaty Original/Omicron BA.4-5.

Low dead-volume syringes and/or needles should be used in order to extract 6 doses from a single vial. The low dead-volume syringe and needle combination should have a dead volume of no more than 35 microlitres.

If standard syringes and needles are used, there may not be sufficient volume to extract a sixth dose from a single vial.

• 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.

• Record the appropriate date/time on the vial. Discard any unused vaccine 12 hours after first puncture.

Disposal

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

7. Marketing authorisation holder

BioNTech Manufacturing GmbH

An der Goldgrube 12

55131 Mainz

Germany

Phone: +49 6131 9084-0

Fax: +49 6131 9084-2121

service@biontech.de

8. Marketing authorisation number(s)

PLGB 53632/0012

9. Date of first authorisation/renewal of the authorisation

Date of first authorisation: 21 December 2020

Date of latest renewal: 09 November 2022

10. Date of revision of the text

February 2023

Ref: bCY/BA.4-5 (15-15) 4_0

4.1 Therapeutic indications

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

4.2 Posology and method of administration

Posology

The dose of Comirnaty Original/Omicron BA.4-5 is 0.3 mL given intramuscularly.

There should be an interval of at least 3 months between administration of Comirnaty Original/Omicron BA.4-5 and the last prior dose of a COVID-19 vaccine.

Comirnaty Original/Omicron BA.4-5 is only indicated for individuals who have previously received at least a primary vaccination course against COVID-19.

Paediatric population

The safety and efficacy of Comirnaty Original/Omicron BA.4-5 in children aged less than 12 years of age have not yet been established. No data are available.

Elderly population

No dosage adjustment is required in elderly individuals ≥ 65 years of age.

Method of administration

Comirnaty Original/Omicron BA.4-5 (15/15 micrograms)/dose dispersion for injection should be administered intramuscularly (see section 6.6). Do not dilute prior to use.

• 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.

The preferred site is the deltoid muscle of the upper arm.

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

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

For instructions regarding thawing, handling and disposal of the vaccine, see section 6.6.

4.3 Contraindications

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

4.4 Special warnings and precautions for use

Traceability

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

General recommendations

Hypersensitivity and anaphylaxis

Myocarditis and pericarditis

Healthcare professionals should consult guidance and/or specialists to diagnose and treat this condition.

Anxiety-related reactions

Concurrent illness

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

Thrombocytopenia and coagulation disorders

Immunocompromised individuals

Duration of protection

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

Limitations of vaccine effectiveness

As with any vaccine, vaccination with Comirnaty Original/Omicron BA.4-5 may not protect all vaccine recipients.

4.5 Interaction with other medicinal products and other forms of interaction

No interaction studies have been performed.

Concomitant administration of Comirnaty Original/Omicron BA.4-5 with other vaccines has not been studied.

4.6 Fertility, pregnancy and lactation

Pregnancy

No data are available yet regarding the use of Comirnaty Original/Omicron BA.4-5 during pregnancy.

Breast-feeding

No data are available yet regarding the use of Comirnaty Original/Omicron BA.4-5 during breast-feeding.

Fertility

Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity (see section 5.3).

4.7 Effects on ability to drive and use machines

4.8 Undesirable effects

Summary of safety profile

Comirnaty 30 mcg

Participants 16 years of age and older – after 2 doses

The safety profile in 545 participants 16 years of age and older receiving Comirnaty, that were seropositive for SARS-CoV-2 at baseline, was similar to that seen in the general population.

Adolescents 12 to 15 years of age – after 2 doses

Participants 16 years of age and older – after booster dose

Booster dose following primary vaccination with another authorised COVID-19 vaccine

Omicron-adapted Comirnaty

Participants > 55 years of age – after a booster dose of Comirnaty Original/Omicron BA.1 (fourth dose)

Participants 18 to ≤ 55 years of age – after a booster dose of monovalent Omicron BA.1 (fourth dose)

Tabulated list of adverse reactions from clinical studies of Comirnaty and Comirnaty Original/Omicron BA.1 and post-authorisation experience of Comirnaty in individuals 12 years of age and older

Adverse reactions observed during clinical studies are listed below according to the following frequency categories:

Very common (≥ 1/10),

Common (≥ 1/100 to < 1/10),

Uncommon (≥ 1/1,000 to < 1/100),

Rare (≥ 1/10,000 to < 1/1,000),

Very rare (< 1/10,000),

Not known (cannot be estimated from the available data).

Table 1: Adverse reactions from Comirnaty and Comirnaty Original/Omicron BA.1 clinical trials and Comirnaty post-authorisation experience in individuals 12 years of age and older

System Organ Class

Very common

(≥ 1/10)

Common

(≥ 1/100 to < 1/10)

Uncommon

(≥ 1/1,000 to < 1/100)

Rare

(≥ 1/10,000 to < 1/1,000)

Very rare

(< 1/10,000)

Not known (cannot be estimated from the available data)

Blood and lymphatic system disorders

Lymphadenopathy^a

Immune system disorders

Hypersensitivity reactions (e.g. rash, pruritus, urticaria^b, angioedema^b)

Anaphylaxis

Metabolism and nutrition disorders

Decreased appetite

Psychiatric disorders

Insomnia

Nervous system disorders

Headache

Lethargy

Acute peripheral facial paralysis^c

Paraesthesia^d; Hypoaesthesia^d

Cardiac disorders

Myocarditis^d; Pericarditis^d

Gastrointestinal disorders

Diarrhoea^d

Nausea; Vomiting^d

Skin and subcutaneous tissue disorder

Hyperhidrosis; Night sweats

Erythema multiforme^d

Musculoskeletal and connective tissue disorders

Arthralgia; Myalgia

Pain in extremity^e

Reproductive system and breast disorders

Heavy menstrual bleeding^h

General disorders and administration site conditions

Injection site pain; Fatigue; Chills; Pyrexia^f; Injection site swelling

Injection site redness

Asthenia; Malaise; Injection site pruritus

Extensive swelling of vaccinated limb^d; Facial swelling^g

a. A higher frequency of lymphadenopathy (2.8% vs. 0.4%) was observed in participants receiving a booster dose in Study 4 compared to participants receiving 2 doses.

b. The frequency category for urticaria and angioedema was rare.

d. Adverse reaction determined post-authorisation.

e. Refers to vaccinated arm.

f. A higher frequency of pyrexia was observed after the second dose compared to the first dose.

g. Facial swelling in vaccine recipients with a history of injection of dermatological fillers has been reported in the post-marketing phase.

h. Most cases appeared to be non-serious and temporary in nature.

Description of selected adverse reactions

Myocarditis and pericarditis

The increased risk of myocarditis after vaccination with Comirnaty is highest in younger males (see section 4.4).

Limited data indicate that the risk of myocarditis and pericarditis after vaccination with Comirnaty in children aged 5 to 11 years seems lower than in ages 12 to 17 years.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product.

Alternatively, adverse events of concern in association with Comirnaty can be reported to Pfizer Medical Information on 01304 616161 or via www.pfizersafetyreporting.com.

Please do not report the same adverse event(s) to both systems as all reports will be shared between Pfizer and MHRA (in an anonymized form) and dual reporting will create unnecessary duplicates.

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The drug SPC information (indications, contra-indications, interactions, etc), has been developed in collaboration with eMC (www.medicines.org.uk/emc/). Medthority offers the whole library of SPC documents from eMC.

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Reporting of suspected adverse reactions

Drug Licencing

Drugs appearing in this section are approved by UK Medicines & Healthcare Products Regulatory Agency (MHRA), & the European Medicines Agency (EMA).

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Summary of product characteristics

4.1 Therapeutic indications

4.2 Posology and method of administration

4.3 Contraindications

4.4 Special warnings and precautions for use

4.5 Interaction with other medicinal products and other forms of interaction

4.6 Fertility, pregnancy and lactation

4.7 Effects on ability to drive and use machines

4.8 Undesirable effects

Drug section

Learning Zones

Disclaimer

Drug Licencing