Afluria Tetra Product Monograph

RECENT MAJOR LABEL CHANGES

Not applicable.

TABLE OF CONTENTS

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

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

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

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

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

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

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

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

4.2 Recommended Dose ............................................................................................. 4

4.4 Administration ........................................................................................................ 4

4.5 Missed Dose ........................................................................................................... 5

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

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

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

7.1 Special Populations................................................................................................. 7

7.1.1 Pregnant Women ............................................................................................. 7

7.1.2 Breast-feeding .................................................................................................. 8

7.1.3 Pediatrics .......................................................................................................... 8

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

8.1 Adverse Reaction Overview .................................................................................... 8

8.2 Clinical Trial Adverse Reactions – Adults ................................................................ 8

8.2.1 Clinical Trial Adverse Reactions – Pediatrics ................................................... 10

8.3 Less Common Clinical Trial Adverse Reactions ..................................................... 12

8.3.1 Less Common Clinical Trial Adverse Reactions – Pediatrics ............................ 12

8.5 Post-Market Adverse Reactions ........................................................................... 12

9 DRUG INTERACTIONS ................................................................................................ 13

9.2 Drug Interactions Overview .................................................................................. 13

9.4 Drug-Drug Interactions ......................................................................................... 13

9.5 Drug-Food Interactions ......................................................................................... 13

9.6 Drug-Herb Interactions ......................................................................................... 13

9.7 Drug-Laboratory Test Interactions ........................................................................ 13

10 CLINICAL PHARMACOLOGY ....................................................................................... 13

10.1 Mechanism of Action ...................................................................................... 13

10.2 Pharmacodynamics ........................................................................................ 13

10.3 Pharmacokinetics ........................................................................................... 13

11 STORAGE, STABILITY AND DISPOSAL ......................................................................... 14

12 SPECIAL HANDLING INSTRUCTIONS ........................................................................... 14

PART II: SCIENTIFIC INFORMATION ....................................................................................... 15

13 PHARMACEUTICAL INFORMATION ............................................................................ 15

14 CLINICAL TRIALS ........................................................................................................ 15

14.1 Trial Design and Study Demographics ............................................................ 15

14.2 Study Results .................................................................................................. 17

14.4 Immunogenicity .............................................................................................. 19

15 MICROBIOLOGY ........................................................................................................ 19

16 NON-CLINICAL TOXICOLOGY ..................................................................................... 19

PATIENT MEDICATION INFORMATION .................................................................................. 20

PART I: HEALTH PROFESSIONAL INFORMATION

1 INDICATIONS

AFLURIA® TETRA is indicated for the active immunization of adults and children aged 5 years or older for the prevention of influenza disease caused by influenza virus types A and B contained in the vaccine.

The National Advisory Committee on Immunization (NACI) provides additional guidance on the use of the influenza vaccine in Canada. Please refer to the published Statement on Seasonal Influenza Vaccine for the current season.

1.1 Pediatrics

Pediatrics (5 to < 18 years): Based on the data submitted and reviewed by Health Canada, the safety and efficacy of AFLURIA® TETRA in pediatric patients has been established in children 5 years of age and older; therefore, Health Canada has authorized an indication for pediatric use. (See 7.1.3 Pediatrics, 8.2.1 Clinical Trial Adverse Reactions - Pediatrics and 14.2 Study Results).

Clinical data have not been evaluated for use of AFLURIA® TETRA in children under 5 years of age.

2 CONTRAINDICATIONS

• AFLURIA® TETRA is contraindicated in individuals with known severe allergic reactions (e.g., anaphylaxis) to any component of the vaccine, or to a previous dose of any influenza vaccine. For a complete listing, see 6 DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING.

4 DOSAGE AND ADMINISTRATION

4.2 Recommended Dose

The recommended dosage schedule for AFLURIA® TETRA is presented in Table 1.

Table 1: AFLURIA® TETRA Recommended Dosage, by Age Group

^a Previously unvaccinated children 5 to < 9 years of age should be given 2 doses at least 4 weeks apart.

4.4 Administration

Vaccination should be carried out by intramuscular injection, preferably into the deltoid muscle of the upper arm.

The vaccine is a slightly opaque liquid with some white particulate sediment that resuspends upon shaking to form a homogenous suspension.

Immediately before use, shake the syringe or vial thoroughly to uniformly distribute the sediment and inspect visually. Do not use if extraneous particulate matter and/or discolouration is observed.

When using the multi-dose vial, the vial should be thoroughly shaken and inspected prior to withdrawing each dose. Use a separate sterile needle and syringe for each dose withdrawn from the multi-dose vial. It is recommended that small syringes (0.5 mL or 1 mL) be used to minimize any product loss. The multi-dose vial must be used within 28 days from removal of the first dose, and between uses, should be returned to the recommended storage conditions between 2°C and 8°C. The number of needle punctures should not exceed 10 per multi-dose vial.

Please refer to the Canadian Immunization Guide, Public Health Agency of Canada, for general information regarding vaccine administration practices.

4.5 Missed Dose

Children 5 years to less than 9 years of age who have not been previously vaccinated against Influenza should receive a second dose after 4 weeks. In case the second dose is missed, it should be administered as soon as possible.

5 OVERDOSAGE

No specific information is available for overdose with AFLURIA® TETRA.

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.

Table 2: Dosage Forms, Strengths, Composition and Packaging

* Multi-dose vials only.

For the 2024/2025 Northern Hemisphere Influenza Season, AFLURIA® TETRA contains the following strains:

• A/Victoria/4897/2022 (H1N1)pdm09-like virus (A/Victoria/4897/2022 IVR-238)
• A/Thailand/8/2022 (H3N2)-like virus (A/Thailand/8/2022 IVR-237)
• B/Austria/1359417/2021-like virus (B/Austria/1359417/2021 BVR-26)
• B/Phuket/3073/2013-like virus (B/Phuket/3073/2013 BVR-1B)

Packaging

Needle-Free Syringe

Single-dose pre-filled type 1 glass syringe.

The syringe barrel is designed with a Luer-Lok™ adaptor to allow the attachment of a commercially available needle prior to administration. The syringe and stopper components are latex-free. AFLURIA® TETRA is considered safe for use in persons with latex allergies.

AFLURIA® TETRA is supplied in cartons containing ten single-dose pre-filled syringes, without needles.

Multi-dose Vial

Multi-dose type 1 glass vial.

The multi-dose vial is closed with a stopper and sealed with an aluminium crimp and plastic tear-away cap. Once removed, the cap cannot be re-affixed to the vial. The vial stopper does not contain latex. AFLURIA® TETRA is considered safe for use in persons with latex allergies.

One vial is packed into a water resistant carton.

7 WARNINGS AND PRECAUTIONS

General

AFLURIA® TETRA should under no circumstances be administered intravascularly.

The pre-filled syringes are single use only.

Prior to administration of any dose of AFLURIA® TETRA, the vaccine recipient should be asked about their personal history, family history and recent health status, including immunization history, current health status, main allergies and any adverse event associated with previous immunizations.

Before the injection of any biological, the person responsible for administration should take all precautions known for the prevention of allergic or any other reactions. As with all injectable vaccines, appropriate medical treatment and supervision should always be readily available in case of a rare anaphylactic event following administration of the vaccine.

Syncope (fainting) can occur following, or even before, any vaccination as a psychogenic response to the needle injection. This can be accompanied by several neurological signs such as transient visual disturbance, paraesthesia and tonic-clonic limb movements during recovery. It is important that procedures are in place to avoid injury from faints.

Immunization with AFLURIA® TETRA should be postponed in patients with febrile illness or acute infections.

As with any vaccine, immunization with AFLURIA® TETRA may not protect 100% of individuals against influenza disease.

Hematologic

As with other intramuscular injections, administration of AFLURIA® TETRA requires careful consideration in patients with clinically significant bleeding disorders.

Immune

In immunocompromised patients the antibody response may be lower.

Neurologic

If Guillain-Barré syndrome has occurred within 6 weeks of receipt of prior influenza vaccine, the decision to give AFLURIA® TETRA should be based on careful consideration of the potential benefits and risks.

Reproductive Health: Female and Male Potential

• Fertility

  AFLURIA® TETRA has not been evaluated for possible effect on fertility.

  A reproductive study of female rats vaccinated with a similar trivalent influenza vaccine manufactured by Seqirus revealed no impairment of fertility.

7.1 Special Populations

7.1.1 Pregnant Women

The safety of AFLURIA® TETRA in pregnancy has not been assessed in randomised clinical trials. Data from a prospective Pregnancy Exposure Registry in the United States (U.S.) were collected from women vaccinated with AFLURIA® TETRA during 4 Northern Hemisphere influenza seasons (2017-18 through 2020-21). A total of 483 pregnant women were evaluated of which 171 (35.4%%), 201 (41.6%) and 111 (23%) were exposed to AFLURIA® TETRA in the first, second and third trimester respectively. Based on pregnancy outcomes and predefined infant safety outcomes, there was no evidence of adverse foetal, newborn or pregnancy outcomes attributable to the vaccine during any stage of pregnancy. Four hundred seventy-seven (98.8%) pregnancies resulted in live births, with 485 infants born. There were two stillbirths and four spontaneous abortions. Prevalence rates for the infant outcomes reported from the study were low birth weight (5.4%), preterm birth (7.2%) and major congenital malformations (0.8%). The estimated rates in the general U.S. population were 8.2%¹, 10.1%¹ and 2.8%², respectively.

An animal reproductive toxicity study has been conducted with a similar trivalent influenza vaccine manufactured by Seqirus. This study did not demonstrate any maternal or fetal developmental toxicity (see 16: NON-CLINICAL TOXICOLOGY).

NACI considers influenza vaccination safe during pregnancy. NACI recommends influenza vaccination in pregnant women with high-risk conditions at any stage during pregnancy.

¹ Osterman MJK, Hamilton BE, Martin JA, Driscoll AK, et al. Births: Final data for 2020. National Vital Statistics Reports. 2022 Feb;70(17):1-50.

² Correa A, Cragan J, Kucik J, et al. Metropolitan Atlanta Congenital Defects Program 40th anniversary edition surveillance report: Reporting birth defects surveillance data 1968- 2003. Birth Defects Res A. 2007;79:65-93.

7.1.2 Breast-feeding

The safety and effectiveness of AFLURIA® TETRA has not been established in nursing mothers.

No human or animal data are available to assess the effects of AFLURIA® TETRA on the breastfed infant or on milk production/excretion.

7.1.3 Pediatrics

Pediatrics (< 5 years): No data are available to Health Canada; therefore, Health Canada has not authorized an indication for use in children less than 5 years of age.

8 ADVERSE REACTIONS

8.1 Adverse Reaction Overview

The safety of AFLURIA® TETRA has been studied in two Phase 3 clinical studies; one study in adults aged 18 years and above (N = 1721) and one in children aged 5 to < 18 years (N = 1621).

In adults 18 to < 65 years, the most commonly reported injection-site adverse reaction observed in clinical studies with AFLURIA® TETRA was pain (≥ 40%). The most common systemic adverse events observed were myalgia and headache (≥ 20%). In adults ≥ 65 years of age, the most commonly reported injection-site adverse reaction observed in clinical studies with AFLURIA® TETRA was pain (≥ 20%). The most common systemic adverse event observed was myalgia (≥ 10%).

In children 5 to < 18 years of age, the most commonly reported injection-site adverse reactions observed in clinical studies with AFLURIA® TETRA were pain (51.4%), redness (17.1%), and swelling (13.8%). The most common systemic adverse events were headache (15.5%) and myalgia (13.1%).

8.2 Clinical Trial Adverse Reactions – Adults

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.

Clinical safety data for AFLURIA® TETRA in adults have been collected in one clinical trial, Study CSLCT-QIV-13-01, a randomized, double-blind, active-controlled trial conducted in the U.S. in 3449 subjects aged 18 years and older. Subjects in the safety population received one dose of either AFLURIA® TETRA (N=1721) or one of two formulations of comparator trivalent influenza vaccine (TIV-1 N=864 or TIV-2 N=864) each containing an influenza type B virus that corresponded to one of the two B viruses in AFLURIA® TETRA (a type B virus of the Yamagata lineage or a type B virus of the Victoria line age), respectively. The mean age of the population was 58 years, 57% were female, and racial groups consisted of 82% White, 16% Black, and 2% other; 5% of subjects were Hispanic/Latino. The age sub-groups were 18 to < 65 years and 65 years and older with mean ages of 43 years and 73 years, respectively. (see 14 CLINICAL TRIALS).

Local (injection-site) adverse reactions and systemic adverse events were solicited for 7 days post-vaccination (Table 3). Injection site cellulitis, cellulitis-like reactions (defined as concurrent Grade 3 pain, redness, and swelling/lump), and Grade 3 swelling/lump were monitored for 28 days post-vaccination. Unsolicited adverse events were collected for 28 days post-vaccination. Serious adverse events (SAEs), including deaths, were collected for 180 days post-vaccination.

Table 3: Proportion of Subjects Per Age Cohort with Any Solicited Local Adverse Reaction or Systemic Adverse Events within 7 days after Administration of AFLURIA® TETRA or TIV (Study CSLCT-QIV-13-01)

Abbreviations: Gr 3, Grade 3; TIV-1, US licensed 2014-2015 Afluria® TIV; TIV-2, TIV with the alternate B strain ^a Proportion of subjects reporting each solicited local adverse reaction or systemic adverse event by study vaccine group based on the number of subjects contributing any follow up safety information for at least one data value of an individual sign/symptom.

^b N = number of subjects in the Safety Population for each study vaccine group.

^c Local adverse reactions: Grade 3 pain is that which prevents daily activity; Swelling/Lump and redness: any = ≥ 20mm diameter, Grade 3 = ≥ 100mm diameter.

^d Systemic adverse events: Fever: any = ≥ 38.0°C, Grade 3 = ≥ 39.0°C; Grade 3 for all other adverse events is that which prevents daily activity.

No subject experienced a cellulitis-like reaction or cellulitis at the injection site in any of the three vaccine groups during the study.

In CSLCT-QIV-13-01, headache (3.8%) was the most commonly reported unsolicited adverse event in subjects ≥ 18 years of age administered AFLURIA® TETRA. Other commonly reported unsolicited adverse events (reported by ≥ 1% of subjects) were oropharyngeal pain (1.8%), back pain (1.5%), diarrhoea (1.3%) and rhinorrhoea (1.0%).

For subjects 18 to < 65 years receiving AFLURIA® TETRA, commonly reported unsolicited adverse events were headache (5.3%), oropharyngeal pain (2.5%), back pain (1.9%), diarrhoea (1.6%), cough (1.3%) and nausea (1.1%).

For subjects > 65 years, commonly reported unsolicited adverse events were headache (2.3%), rhinorrhoea (1.3%), oropharyngeal pain (1.2%), and back pain (1.2%).

In the 180 days following vaccination, 2.3%, 1.6%, and 1.5% of all subjects who received AFLURIA® TETRA, TIV-1, and TIV-2, respectively, experienced SAEs, including six deaths, five in the AFLURIA® TETRA group and one in the TIV-2 group. The majority of SAEs occurred after Study Day 28 and in subjects ≥ 65 years of age who had co-morbid illnesses. No SAEs or deaths appeared related to the study vaccines.

8.2.1 Clinical Trial Adverse Reactions – Pediatrics

Clinical safety data for AFLURIA® TETRA in children and adolescents have been collected in one clinical trial, Study CSLCT-QIV-13-02, a randomized, double-blind, comparator-controlled trial conducted in the U.S. in 2278 subjects aged 5 to less than 18 years. Subjects in the safety population (N=2252) received either AFLURIA® TETRA (N=1692) or a U.S.-licensed comparator quadrivalent influenza vaccine (N=560). Study subjects were scheduled to receive either a single vaccination or two vaccinations 28 days apart based on their previous vaccination history. Subjects were stratified into one of two age cohorts of 5 to less than 9 years or 9 to less than 18 years (51.2% and 48.8% of the study population, respectively). The mean age of the population was 9.5 years, 52.1% were male, and racial groups consisted of 73.3% White, 20.7% Black, 0.8% Asian, 0.3% American Indian/Native American, and 0.7% Native Hawaiian/Pacific Islander; 23.8% of subjects were Hispanic/Latino (see 14 CLINICAL TRIALS).

Local (injection-site) adverse reactions and systemic adverse events were solicited for 7 days post-vaccination (Table 4). Cellulitis-like reactions (defined as concurrent Grade 3 pain, redness, and swelling/lump) at the injection site were monitored for 28 days post-vaccination. Subjects were instructed to report and return to the clinic within 24 hours in the event of a cellulitis-like reaction. Unsolicited adverse events were collected for 28 days post-vaccination. SAEs, including deaths, were collected for 180 days post-vaccination.

Table 4: Proportion of Subjects Per Age Cohort with Any Solicited Local Adverse Reactions or Systemic Adverse Events within 7 Days after Administration of AFLURIA® TETRA or Comparator QIV, Irrespective of Causality (Study CSLCT-QIV-13-02)

Abbreviations: Gr 3, Grade 3; Comparator, Comparator quadrivalent influenza vaccine (Fluarix^® Quadrivalent [GlaxoSmithKline Biologicals])

^a Percent (%) is derived from the number of subjects that reported the event divided by the Solicited Safety Population in each vaccine group and age cohort.

^b N = number of subjects in the Solicited Safety Population (subjects who were vaccinated and provided any solicited safety data) for each study vaccine group. Solicited Safety Population was the same for each event.

^c Local adverse reactions: Grade 3 pain is that which prevents daily activity; Swelling/Lump and redness: any = ≥ 0mm diameter, Grade 3 = ≥ 30mm diameter.

^d Systemic adverse events: Fever: any = ≥ 38.0°C, Grade 3 = ≥ 39.0°C; Grade 3 for all other adverse events is that which prevents daily activity.

One subject experienced a cellulitis-like reaction (defined as concurrent severe pain, redness and swelling) at the injection site after vaccination with AFLURIA® TETRA.

In CSLCT-QIV-13-02, cough (2.1%) was the most commonly reported unsolicited adverse event in subjects 5 to < 18 years of age administered AFLURIA® TETRA. Other commonly reported unsolicited adverse events (reported by ≥ 1% of subjects) were oropharyngeal pain (1.3%), pyrexia (1.3%) and upper respiratory tract infection (1.1%).

The most commonly reported unsolicited adverse events among subjects who received AFLURIA® TETRA in ages 5 to < 9 years following the first or second dose included cough (2.8%), pyrexia (2.1%), headache (1.2%), rhinorrhea (1.2%), upper respiratory tract infection (1.2%), influenza-like illness (1.0%), and oropharyngeal pain (1.0%).

For subjects ages 9 to < 18 years who received AFLURIA® TETRA, the most common unsolicited adverse events included oropharyngeal pain (1.6%), cough (1.3%), and upper respiratory tract infection (1.0%).

No deaths were reported in pediatric study CSLCT-QIV-13-02. In the 180 days following vaccinations, AFLURIA® TETRA and comparator vaccine recipients experienced similar rates of SAEs. None of the SAEs appeared related to the study vaccines except for one case of influenza B infection (considered a vaccine failure) in an AFLURIA® TETRA recipient.

8.3 Less Common Clinical Trial Adverse Reactions

See 8 ADVERSE REACTIONS, Clinical Trial Adverse Reactions – Adults.

8.3.1 Less Common Clinical Trial Adverse Reactions – Pediatrics

See 8 ADVERSE REACTIONS, Clinical Trial Adverse Reactions – Pediatrics.

8.5 Post-Market Adverse Reactions

Administration of Seqirus’ 2010 Southern Hemisphere trivalent influenza vaccine (AFLURIA®, manufactured by CSL, now Seqirus Pty Ltd) was associated with increased rates of fever and febrile convulsions, predominantly in children below the age of 5 years as compared to previous years. Febrile events were also observed in children 5 to < 9 years of age.

Following a comprehensive investigation into the 2010 Southern Hemisphere adverse events, Seqirus has modified the manufacturing conditions. A clinical program has subsequently been conducted with AFLURIA^® TETRA in adults and children. Fever rates in children 5 to < 9 years of age for AFLURIA^® TETRA in Study CSLCT-QIV-13-02 were lower than those observed in several clinical studies for AFLURIA® (trivalent formulation) conducted prior to 2010 (see 8.2 Clinical Trial Adverse Reactions – Adults and 8.2.1 Clinical Trial Adverse Reactions – Pediatrics). The results indicate that the safety profile of AFLURIA^® TETRA in children 5 years of age and older is similar to a U.S.-licensed comparator vaccine.

The adverse events spontaneously reported during post approval use of AFLURIA® TETRA are presented below.

Blood and Lymphatic System Disorders

Thrombocytopenia

Immune System Disorders

Allergic or immediate hypersensitivity reactions including anaphylactic shock

Nervous System Disorders

Neuralgia, paraesthesia, convulsions, dizziness, encephalomyelitis, neuritis or neuropathy, Guillain-Barré syndrome, and syncope and presyncope

Vascular Disorders

Vasculitis which may be associated with renal involvement.

Musculoskeletal and Connective Tissue Disorders

Musculoskeletal pain and pain in the extremity

Skin and Subcutaneous tissue disorders

Pruritus, urticaria and rash

General Disorders and Administration Site Conditions

Influenza-like illness, injected limb mobility decreased, pyrexia, injection site erythema and injection site reaction.

9 DRUG INTERACTIONS

9.2 Drug Interactions Overview

No interaction studies have been performed on interaction between influenza vaccines in general and other vaccines or medications.

9.4 Drug-Drug Interactions

Interactions with other drugs have not been established.

9.5 Drug-Food Interactions

Interactions with food have not been established.

9.6 Drug-Herb Interactions

Interactions with herbal products have not been established.

9.7 Drug-Laboratory Test Interactions

Interactions with laboratory tests have not been established.

10 CLINICAL PHARMACOLOGY

10.1 Mechanism of Action

Influenza illness and its complications follow infection with influenza viruses. Global surveillance of influenza identifies yearly antigenic variants. For example, since 1977 antigenic variants of influenza A (H1N1 and H3N2) and influenza B viruses have been in global circulation. Since 2001, two distinct lineages of influenza B (Victoria and Yamagata lineages) have co-circulated worldwide. Specific levels of hemagglutination inhibition (HI) antibody titers post-vaccination with inactivated influenza vaccine have not been correlated with protection from influenza virus. In some human studies, antibody titers of 1:40 or greater have been associated with protection from influenza illness in up to 50% of subjects.

Antibody against one influenza virus type or subtype confers limited or no protection against another. Furthermore, antibody to one antigenic variant of influenza virus might not protect against a new antigenic variant of the same type or subtype. Frequent development of antigenic variants through antigenic drift is the virologic basis for seasonal epidemics and the reason for the usual change to one or more new strains in each year’s influenza vaccine. Therefore, inactivated influenza vaccines are standardized to contain the HA of four strains (i.e., typically two type A and two type B) representing the influenza viruses likely to be circulating during the upcoming winter.

10.2 Pharmacodynamics

Seroprotection is generally obtained within 2 to 3 weeks.

Annual revaccination with the current vaccine is recommended because immunity declines during the year after vaccination and circulating strains of influenza virus change from year to year.

10.3 Pharmacokinetics

Not applicable.

Duration of Effect

Protection against influenza post-vaccination is expected throughout the influenza season for which the vaccine is indicated.

Special Populations and Conditions

Not applicable.

11 STORAGE, STABILITY AND DISPOSAL

Temperature:

Store refrigerated at 2-8°C.

DO NOT FREEZE. If frozen, do not use.

Light:

Store in original package to protect from light.

Other:

The shelf-life of the vaccine is 12 months.

Do not use AFLURIA® TETRA beyond the expiration date printed on the label.

Any remaining contents in the single-use syringe should be discarded.

The multi-dose vial must be used within 28 days from removal of the first dose, and between uses, should be returned to the recommended storage conditions.

12 SPECIAL HANDLING INSTRUCTIONS

Not applicable.

PART II: SCIENTIFIC INFORMATION

13 PHARMACEUTICAL INFORMATION

Drug Substance

Proper name: Inactivated Influenza Vaccine (Split Virion)

Physicochemical properties: The vaccine is formulated to contain 60 mcg hemagglutinin (HA) per 0.5 mL dose in the recommended ratio of 15 mcg HA for each of the four influenza strains recommended for the [2024 – 2025] Northern Hemisphere influenza season.

Pharmaceutical standard: The vaccine is standardized according to the World Health Organization (WHO) and NACI requirements for the [2024 – 2025] influenza season.

Product Characteristics

AFLURIA® TETRA is a sterile, slightly opaque liquid with some white particulate sediment that resuspends upon shaking to form a homogeneous suspension.

AFLURIA® TETRA is an inactivated influenza vaccine prepared from virus grown in the allantoic cavity of embryonated chicken eggs, purified by zonal centrifugation, inactivated by beta-propiolactone and disrupted by sodium taurodeoxycholate.

14 CLINICAL TRIALS

14.1 Trial Design and Study Demographics

The immunogenicity and safety of AFLURIA® TETRA has been studied in two Phase 3 clinical studies; one study in adults aged 18 years and above (Study CSLCT-QIV-13-01) and one in children aged 5 to < 18 years (Study CSLCT-QIV-13-02).

Table 5: Summary of patient demographics for clinical trials with AFLURIA® TETRA for the active immunization of adults and children aged 5 years or older for the prevention of influenza disease caused by influenza virus types A and B contained in the vaccine

CSLCT-QIV-13-01 was a randomized, double-blind, active comparator-controlled trial conducted in the U.S. in adults aged 18 years and older. Subjects received one dose of either QIV (N=1691) or one of two formulations of comparator trivalent influenza vaccine (TIV-1 N=854 or TIV-2 N=850), each containing an influenza type B virus that corresponded to one of the two B viruses in QIV (a type B virus of the Yamagata lineage (TIV-1) or a type B virus of the Victoria lineage (TIV-2)), respectively and the same influenza A subtype viruses. The comparator TIV was licensed in the U.S. and manufactured by Seqirus using a similar process to AFLURIA® TETRA. The treatment randomization ratio was 2:1:1 (QIV:TIV-1:TIV-2). The age sub-groups were 18 to < 65 years and ≥ 65 years with mean ages of 43 years and 73 years, respectively. Post-vaccination immunogenicity was evaluated on sera obtained 21 days after administration of a single dose of QIV or TIV.

The co-primary endpoints were HI Geometric Mean Titer (GMT) ratios (adjusted for baseline HI titers) and the difference in seroconversion rates for each vaccine strain, 21 days after vaccination. Pre-specified non-inferiority criteria required that the upper bound of the 2-sided 95% CI of the GMT ratio (TIV/QIV) did not exceed 1.5 and the upper bound of the 2-sided 95% CI of the seroconversion rate difference (TIV minus QIV) did not exceed 10% for each strain.

CSLCT-QIV-13-02 was a randomized, observer-blinded, comparator-controlled trial conducted in the U.S. in children 5 to < 18 years of age. Subjects received either one or two doses of either QIV (N=1605) or a U.S.-licensed comparator QIV (N=528, manufactured by another company) in a 3:1 randomization treatment schedule. Subjects 5 to < 9 years of age were eligible to receive a second dose at least 28 days after the first dose depending on their influenza vaccination history. Approximately 25% of subjects in each treatment group in the 5 to < 9 years of age sub-group received two vaccine doses. Post-vaccination immunogenicity was evaluated by HI assay on sera obtained 28 days after the last vaccination dose. Baseline serology prior to vaccination was also collected for HI assessment.

The co-primary endpoints were HI Geometric Mean Titers (GMT) (adjusted for baseline HI titers and other covariates) and seroconversion rates for each vaccine strain, 28 days after the last vaccination. Pre-specified non-inferiority criteria required that the upper bound of the 2-sided 95% CI of the GMT ratio (Comparator QIV/QIV) did not exceed 1.5 and the upper bound of the 2-sided 95% CI of the seroconversion rate difference (Comparator QIV minus QIV) did not exceed 10% for each strain.

14.2 Study Results

Adults:

Serum HI antibody responses to QIV were non-inferior to both TIVs for all influenza strains, for subjects 18 years of age and older. Additionally, non-inferiority was demonstrated for both endpoints in both age sub-groups, adults aged 18 to < 65 years and ≥ 65 years (Table 6), for all strains. Antibody responses were lower in adults aged ≥ 65 years. Superiority of the immune response to each of the influenza B strains contained in QIV was shown relative to the antibody response after vaccination with TIV formulations not containing that B lineage strain for subjects 18 years of age and older. Superiority against the alternate B strain was also demonstrated for each of the influenza B strains in both age sub-groups; 18 to < 65 years and ≥ 65 years. Post- hoc analyses of immunogenicity by gender did not demonstrate significant differences between males and females. The study population was not sufficiently diverse to assess differences between races or ethnicities.

Table 6: Post-Vaccination HI Antibody GMTs, Seroconversion Rates, and Analyses of Non-Inferiority of AFLURIA® TETRA Relative to Trivalent Influenza Vaccine (TIV) by Age Cohort (Study CSLCT-QIV-13-01) (Per Protocol Population)

Abbreviations: CI, confidence interval; GMT, geometric mean titer;TIV-1, U.S. licensed 2014-2015 Afluria® TIV; TIV-2, TIV with the alternate B strain

^a GMT ratio was computed after fitting a multi-variable model on the post-vaccination titers including sex, vaccination history, pre-vaccination HI titers and other factors.

^b Seroconversion rate is defined as a 4-fold increase in post-vaccination HI antibody titer from pre-vaccination titer ≥ 1:10 or an increase in titer from < 1:10 to ≥ 1:40.

^c The non-inferiority (NI) criteria for the GMT ratio: upper bound of 2-sided 95% CI on the ratio of Pooled TIV or TIV-1 (B Yamagata) or TIV-2 (B Victoria)/AFLURIA® TETRA. GMT should not exceed 1.5. NI criteria for the SCR difference: upper bound of 2-sided 95% CI on the difference between SCR Pooled TIV or TIV-1 (B Yamagata) or TIV-2 (B Victoria) minus AFLURIA® TETRA should not exceed 10%.

^d Pooled TIV/AFLURIA® TETRA

^e TIV-1 (B Yamagata)/AFLURIA® TETRA

^f TIV-2 (B Victoria)/AFLURIA® TETRA

^g Pooled TIV - AFLURIA® TETRA

^h TIV-1 (B Yamagata) - AFLURIA® TETRA

ⁱ TIV-2 (B Victoria) - AFLURIA® TETRA

Pediatrics (5 to < 18 years):

Serum HI antibody responses to AFLURIA® TETRA were non-inferior for both GMT and seroconversion rates relative to the Comparator QIV for all influenza strains (Table 7). Analyses of immunogenicity endpoints by gender did not demonstrate meaningful differences between males and females. The study population was not sufficiently diverse to assess differences between races or ethnicities.

Table 7: Post-Vaccination HI Antibody GMTs, Seroconversion Rates, and Analyses of Non-Inferiority of QIV Relative to Comparator QIV for each Strain 28 Days after Last Vaccination Among a Pediatric Population 5 to < 18 Years of Age (Per Protocol Population) ^f

Abbreviations: CI: confidence interval; GMT (adjusted): geometric mean titer; SCR: seroconversion rate.

^a GMT Ratio = Comparator QIV / QIV.

^b Seroconversion rate was defined as the percentage of subjects with either a prevaccination HI titer < 1:10 and a postvaccination HI titer ≥ 1:40 or a prevaccination HI titer ≥ 1:10 and a 4-fold increase in postvaccination HI titer.

^c Seroconversion rate difference = Comparator QIV SCR percentage minus QIV SCR percentage.

^d Noninferiority (NI) criterion for the GMT ratio: upper bound of two-sided 95% CI on the ratio of Comparator QIV/QIV. GMT should not exceed 1.5. NI criterion for the SCR difference: upper bound of two-sided 95% CI on the difference between SCR Comparator QIV – QIV should not exceed 10%.

^e Subject 8400394-0046 was excluded from the Per-Protocol Population for the adjusted GMT analysis for the GMT ratio since the subject did not have information on all covariates (unknown prevaccination history).

^f The Per-Protocol Population comprised all subjects in the Evaluable Population who did not have any protocol deviations that were medically assessed as potentially impacting on immunogenicity results.

14.4 Immunogenicity

See 14 CLINICAL TRIALS, Trial Design and Study Demographics and Study Results.

15 MICROBIOLOGY

No microbiological information is required for this product.

16 NON-CLINICAL TOXICOLOGY

A repeat dose toxicity study with AFLURIA^® TETRA and a reproduction and developmental study with AFLURIA® (trivalent formulation) reveal no special hazard for humans.

General Toxicology: In the repeat dose toxicity study, male and female rats (10/sex/group) received a clinical dose (60 mcg HA/0.5 mL dose) of AFLURIA® TETRA via intramuscular injection on 3 occasions, 2 weeks apart. There was no evidence of systemic toxicity and the vaccine was locally well tolerated.

Reproductive and Developmental Toxicology: In the reproductive and developmental toxicity study conducted with a similar trivalent influenza vaccine manufactured by Seqirus. Female rats received 2 intramuscular injections (0.5 mL per occasion, divided) of trivalent vaccine 21 and 7 days before mating and 1 or 2 additional injections during gestation on day 6, or days 6 and 20, respectively. On a body weight basis, each dose administered to rats was approximately 200 times the human AFLURIA® TETRA dose. There was no maternal toxicity and fertility was not affected. No vaccine-related foetal malformations or variations and no adverse effects on pre-weaning development were observed in the study.