Adjuvanted Trivalent Influenza Vaccine (Surface Antigen, Inactivated) Seqirus suspension for injection in pre-filled syringe

Prophylaxis of influenza in the elderly (65 years of age and older).

Adjuvanted Trivalent Influenza Vaccine Seqirus should be used in accordance with official recommendations.

Posology

One 0.5 ml dose.

Paediatric population

The safety and efficacy of Adjuvanted Trivalent Influenza Vaccine Seqirus in children from birth to less than 18 years has not been established. Currently available safety and immunogenicity data in children from 6 months to less than 6 years of age are described in sections 4.8 and 5.1 but no recommendation on posology can be made.

Method of administration

For intramuscular injection only.

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

The vaccine must not be injected intravenously, subcutaneously or intradermally and must not be mixed with other vaccines in the same syringe.

For instructions for preparation of the medicinal product before administration, see section 6.6.

Hypersensitivity to the active substances, to any of the components of the adjuvant, to any of the excipients listed in section 6.1, or to possible trace residues such as ovalbumin, kanamycin and neomycin sulphate, formaldehyde, cetyltrimethylammonium bromide (CTAB) and hydrocortisone.

A severe allergic reaction (e.g. anaphylaxis) to previous influenza vaccination.

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.

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

Vaccination should be postponed in patients with febrile illness until the fever is resolved.

As with all injectable vaccines, Adjuvanted Trivalent Influenza Vaccine Seqirus must be administered with caution to individuals with thrombocytopenia or a bleeding disorder since bleeding may occur following an intramuscular administration.

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.

Antibody response in patients with endogenous or iatrogenic immunosuppression may be insufficient to prevent influenza.

A protective immune response may not be elicited in all vaccine recipients.

Concomitant administration of Adjuvanted Trivalent Influenza Vaccine Seqirus with other vaccines has not been studied in trials conducted by Seqirus. However, data supports co-administration with COVID vaccines showing the antibody responses are unaffected and the reactogenicity profile is acceptable. If it is to be used at the same time as another vaccine, it should be administered at separate injection sites and preferably on different limbs. It should be noted that the adverse reactions may be intensified.

Women of childbearing potential

This medicine is not indicated in women of childbearing potential (see section 4.1). It is not to be used in women who are, or may be, pregnant or breast-feeding.

Pregnancy

There are no data from the use of Adjuvanted Trivalent Influenza Vaccine Seqirus in pregnant women. Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity.

Adjuvanted Trivalent Influenza Vaccine Seqirus has no or negligible influence on the ability to drive and use machines.

Summary of the safety profile

Data for Adjuvanted Quadrivalent Influenza Vaccine Seqirus are relevant to Adjuvanted Trivalent Influenza Vaccine Seqirus because both vaccines are manufactured using the same process and have overlapping compositions.

Elderly population

Safety was evaluated in two clinical studies (V118_20 and V118_18), in which 4269 subjects 65 years of age and older received Adjuvanted Quadrivalent Influenza Vaccine Seqirus or one of two formulations of an adjuvanted trivalent comparator (N=888). Similar rates of solicited local and systemic adverse reactions were reported in subjects who received the quadrivalent and trivalent formulations.

Commonly reported (≥ 10%) adverse reactions were injection site pain (16% and 32%), fatigue (10% and 16%) and headache (11% and 12%) for V118_18 and V118_20, respectively. Most solicited reactions were reported as mild or moderate in intensity and resolved within the first 3 days after vaccination.

Paediatric population

Adjuvanted Trivalent Influenza Vaccine Seqirus is not indicated for use in children, see section 4.2. Safety information in the paediatric population is presented in section 5.1.

Tabulated list of adverse reactions

Adverse reactions reported are listed according to the following frequency categories: Very common (≥ 1/10); Common (≥ 1/100 - <1/10); Uncommon (≥ 1/1,000 - <1/100).

Table 1: Adverse reactions reported following vaccination of elderly subjects 65 years and older in clinical trials

^*Or

Injection site bruising

Adverse reactions reported from post-marketing surveillance

In addition to the adverse reactions observed during clinical trials, the following adverse reactions were reported from post-marketing surveillance in individuals 65 years of age and older for Adjuvanted Trivalent or Quadrivalent Influenza Vaccine Seqirus formulations.

Blood and lymphatic system disorders

Thrombocytopenia (some very rare cases were severe with platelet counts less than 5,000 per mm³), lymphadenopathy.

General disorders and administration site conditions

Extensive swelling of injected limb, injection-site cellulitis-like reaction, injection site swelling, peripheral swelling, asthenia, malaise, pyrexia

Immune system disorders

Allergic reactions including anaphylactic shock (in rare cases), anaphylaxis.

Musculoskeletal and connective tissue disorders

Muscular weakness, pain in extremity

Nervous system disorders

Encephalomyelitis, Guillain-Barré syndrome, convulsions, neuritis, neuralgia, paraesthesia, syncope, presyncope, dizziness

Skin and subcutaneous tissue disorders

Generalized skin reactions including erythema multiforme, erythema, urticaria, pruritus or non-specific rash, angioedema.

Vascular disorders

Vasculitis that may be associated with transient renal involvement.

Paediatric population

There are limited data for Adjuvanted Trivalent Influenza Vaccine Seqirus in the paediatric population.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorization 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 the Yellow Card Scheme website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

Overdosage is unlikely to have any untoward effect.

Pharmacotherapeutic group: Influenza vaccine, ATC code: J07BB02

Mechanism of action

Adjuvanted Trivalent Influenza Vaccine Seqirus provides active immunisation against three influenza virus strains (two A subtypes and one B type) contained in the vaccine. It induces humoral antibodies against the haemagglutinins. These antibodies neutralise influenza viruses. This vaccine contains the adjuvant MF59C.1 (MF59), which is designed to increase and broaden the antigen-specific immune response and to extend the duration of the immune response.

Specific levels of haemagglutination inhibition (HI) antibody titres post-vaccination with inactivated influenza vaccine have not been correlated with protection from influenza virus, but the HI antibody titres have been used as a measure of vaccine efficacy.

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.

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

Pharmacodynamic effects

Data for Adjuvanted Quadrivalent Influenza Vaccine Seqirus are relevant to Adjuvanted Trivalent Influenza Vaccine Seqirus because both vaccines are manufactured using the same process and have overlapping compositions.

Elderly population (65 years and older)

Immunogenicity

The immunogenicity of Adjuvanted Quadrivalent Influenza Vaccine Seqirus was evaluated in clinical study V118_20, a multicentre, randomised, double-blind, comparator controlled study conducted during the 2017-2018 Northern Hemisphere influenza season. Elderly subjects 65 years of age and older were randomised (2:1:1) to receive Adjuvanted Quadrivalent Influenza Vaccine Seqirus (aQIV) or trivalent influenza vaccines Seqirus containing the B/Victoria strain (aTIV-1) or the B/Yamagata strain (aTIV-2).

Eligible subjects were men or women ≥ 65 years of age who were healthy or had comorbidities that increased their risk of influenza complications. The mean age of subjects at enrolment was 72.4 years. Female subjects represented 58.2% of the study population.

The immunogenicity endpoints assessed 3 weeks after vaccination were haemagglutination inhibition (HI) geometric mean antibody titre (GMT) and HI seroconversion rate (pre-vaccination HI titre <1:10 and post-vaccination HI titre ≥ 1:40 or at least a 4-fold increase in HI from pre-vaccination HI titre ≥ 1:10).

Adjuvanted Quadrivalent Influenza Vaccine Seqirus met non-inferiority for all 4 influenza strains (see Table 2).

Table 2: Post-vaccination GMT and seroconversion rates in elderly subjects 65 years of age and older

Abbreviations: GMT= Geometric Mean antibody titre; CI= Confidence Interval; NA= Not Applicable.

aTIV-1: licensed MF59-adjuvanted trivalent subunit inactivated egg-derived influenza vaccine, Fluad TIV containing B-Victoria; aTIV-2: MF59-adjuvanted trivalent subunit inactivated egg-derived influenza vaccine containing B-Yamagata

N= the number of vaccinated subjects with available data from the immunogenicity endpoint listed (Per Protocol Set).

^a Non-inferiority for the GMT ratio was defined as: the upper bound of the two-sided 95% CI for the ratio of the GMTs did not exceed 1.5.

^b Non-inferiority for the seroconversion difference was defined as: the upper bound of the two-sided 95% CI for the difference between the seroconversions did not exceed 10%.

^c Seroconversion was defined as pre-vaccination HI titre <1:10 and post-vaccination HI titre ≥ 1:40 or at least a 4-fold increase in HI from pre-vaccination HI titre ≥ 1:10.

^d aTIV-1 and aTIV-2 vaccine groups are pooled for the analysis of A/H1N1 and A/H3N2 strains. For B/Victoria aTIV=aTIV-1, for B/Yamagata aTIV=aTIV-2.

The immunogenicity of Adjuvanted Trivalent Influenza Vaccine Seqirus was evaluated in Study V70_27, a Phase 3, randomised, controlled, observer-blind, multicentre study, which compared it to a non-adjuvanted vaccine. Subjects were randomised in a 1:1 ratio to receive a single 0.5 ml dose of one of the vaccines and followed for approximately one year post-vaccination.

A total of 7082 subjects were equally randomised and vaccinated. A total of 2573 subjects (1300 in the Adjuvanted Trivalent Influenza Vaccine Seqirus arm and 1273 in the non-adjuvanted vaccine arm) were regarded as “ high risk” subjects (underlying chronic diseases including congestive heart failure, chronic obstructive pulmonary disease, asthma, hepatic disease, renal insufficiency and/or neurological/neuromuscular or metabolic disorders including diabetes mellitus).

The primary objective of superiority of the adjuvanted vaccine over the non- adjuvanted vaccine was not achieved for all homologous strains according to predefined criteria (lower limit of the 95% CI for the GMT ratio > 1.5 and for the difference in seroconversion rates > 10%). GMT ratios ranged from 1.15 to 1.61 with the lowest limit of the 95% CI of 1.08 and differences in seroconversion rates ranged from 3.2% to 13.9% with the lowest limit of the 95% CI of 1.1%. However, the adjuvanted vaccine elicited higher antibody titres against A/H3N2 that persisted up to 12 months post-vaccination. The results were similar for high-risk subjects with predefined comorbidities.

Effectiveness

The clinical effectiveness of Adjuvanted Trivalent Influenza Vaccine Seqirus has been evaluated in two observational studies.

Paediatric Population (6 months to less than 6 years)

Adjuvanted Trivalent Influenza Vaccine Seqirus is not indicated for use in children, see section 4.2.

Efficacy, immunogenicity and safety of Adjuvanted Quadrivalent Influenza Vaccine Seqirus was evaluated in clinical study V118_05, a multicentre, randomised, observer-blinded, controlled study conducted in the 2013-14 (season 1) and 2014-15 (season 2) Northern Hemisphere seasons in children of 6 months to less than 6 years. Children less than 3 years of age received 0.25 ml vaccine, older children received 0.5 ml vaccine. Children naï ve to prior influenza vaccination received two doses of vaccine, at least 4 weeks apart. 10,644 children were enrolled and randomised to receive Adjuvanted Quadrivalent Influenza Vaccine Seqirus or a non-adjuvanted comparator vaccine in a 1:1 ratio.

Immunogenicity

A subset of children enrolled in this study was evaluated for their immunological response, with immunogenicity assessments performed prior to (each) vaccination and 3 weeks after the last vaccination. A total of 2886 children were included in this subset (Adjuvanted Quadrivalent Influenza Vaccine Seqirus: N=1481; non- adjuvanted comparator vaccine: N=1405).

The adjuvanted vaccine demonstrated a higher immune response compared to the non-adjuvanted comparator vaccine. In addition, in children naï ve to influenza vaccination antibody titres 4 weeks after the first vaccination as well as 3 weeks after the second vaccination were greater in subjects who received the adjuvanted vaccine. At 12 months post-vaccination, persistence of the immune response was higher in the adjuvanted vaccine arm compared to the non-adjuvanted comparator arm.

Efficacy

Vaccine efficacy was assessed for the prevention of first-occurrence laboratory confirmed influenza associated with symptomatic influenza-like illness (ILI). Influenza-like illness was defined as fever of 37.8° C or above along with any of the following: cough, sore throat, nasal congestion, or runny nose occurring at ≥ 21 days and ≤ 180 days after the last vaccination or until the end of the influenza season, whichever was longer. Subjects with ILI had nasopharyngeal swabs collected and tested for influenza A (A/H1N1 and A/H3N2) and B (both lineages) by Reverse Transcription-Polymerase Chain Reaction (RT-PCR). A total of 508 cases of first-occurrence RT-PCR confirmed influenza occurred during the study: 10 during season 1 and 498 during season 2. The majority of influenza cases were A/H3N2. Based on antigenic typing, more than ninety percent of A/H3N2 strains from season 2 were determined to be antigenically distinct from egg-propagated A/Texas/50/2012, the H3N2 vaccine strain.

The relative vaccine (rVE) efficacy between Adjuvanted Quadrivalent Influenza Vaccine Seqirus and the non-adjuvanted influenza comparator vaccine in subjects ≥ 6 to <72 months of age was -0.67 [95% CI: -19.81; 15.41]), which did not meet the primary objective of the study.

Safety

Safety data were collected up to 12 months after receipt of the last vaccination.

A higher incidence of local and systemic reactions was reported in subjects who received Adjuvanted Quadrivalent Influenza Vaccine Seqirus compared to the non- adjuvanted comparator influenza vaccine.

The most commonly reported adverse reactions (>10%) were tenderness (43%), irritability (27%), sleepiness (26%), change in eating habits (22%), fever (19%), diarrhoea (12%) and vomiting (10%).

Not applicable.

Non-clinical data reveal no special hazard for humans based on conventional studies of repeated dose toxicity, toxicity to reproduction and development, local tolerance and sensitisation.

For adjuvant: see also section 2.

Sodium chloride

Potassium chloride

Potassium dihydrogen phosphate

Disodium phosphate dihydrate

Magnesium chloride hexahydrate

Calcium chloride dihydrate

Water for injections

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.

1 year

Store in a refrigerator (2 ° C – 8 ° C). Do not freeze. Discard if the vaccine has been frozen.

Keep the pre filled syringe in the outer carton in order to protect from light.

0.5 ml of suspension for injection in pre-filled syringe (type I glass) with a plunger stopper (bromobutyl rubber), presented with or without needle.

Pack of 1 pre-filled syringe with needle

Pack of 1 pre-filled syringe without needle

Pack of 10 pre-filled syringes with needle

Pack of 10 pre-filled syringes without needle

Not all pack sizes may be marketed.

Gently shake before use.

After shaking, the normal appearance of the vaccine is a milky-white suspension.

Visually inspect the contents of each pre-filled syringe for particulate matter and/or variation in appearance prior to administration. If either condition is observed, do not administer the vaccine. Do not use if the vaccine has been frozen. Any unused product or waste material should be disposed of in accordance with local requirements.

When using a pre-filled syringe supplied without a needle, remove the tip cap from the syringe and then attach a suitable needle for administration. For Luer Lock syringes, remove the tip cap by unscrewing it in a counter-clockwise direction. Once the tip cap is removed, attach a needle to the syringe by screwing it on in a clockwise direction until it locks. Once the needle is locked in place, remove the needle protector and administer the vaccine.