This information is intended for use by health professionals

 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.

1. Name of the medicinal product

Fluad Tetra, suspension for injection in pre-filled syringe

Influenza vaccine (surface antigen, inactivated, adjuvanted)

2. Qualitative and quantitative composition

Influenza virus surface antigens (haemagglutinin and neuraminidase), inactivated, of the following strains*:

Per 0.5 ml dose

A/xxxxx (H1N1) - like strain

(reassortant used)

15 micrograms HA**

A/xxxxx (H3N2) - like strain

(reassortant used)

15 micrograms HA**

B/xxxxx – like strain

(reassortant used)

15 micrograms HA**

B/xxxxx – like strain

(reassortant used)

15 micrograms HA**

*propagated in fertilised hens' eggs from healthy chicken flocks and adjuvanted with MF59C.1

**haemagglutinin

Adjuvant MF59C.1 containing per 0.5 ml dose: squalene (9.75 mg), polysorbate 80 (1.175 mg), sorbitan trioleate (1.175 mg), sodium citrate (0.66 mg) and citric acid (0.04 mg).

This vaccine complies with the WHO recommendations (Northern Hemisphere) and EU recommendation for the xxxx/xxxx season.

Fluad Tetra may contain traces of eggs such as ovalbumin or chicken proteins, kanamycin and neomycin sulphate, formaldehyde, hydrocortisone, cetyltrimethylammonium bromide (CTAB) which are used during the manufacturing process (see section 4.3).

For the full list of excipients, see section 6.1.

3. Pharmaceutical form

Suspension for injection in pre-filled syringe (injection).

Milky-white suspension.

4. Clinical particulars
4.1 Therapeutic indications

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

Fluad Tetra should be used in accordance with official recommendations.

4.2 Posology and method of administration

Posology

One 0.5 ml dose.

Paediatric population

The safety and efficacy of Fluad Tetra 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.

4.3 Contraindications

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.

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.

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 acute febrile illness until the fever is resolved.

As with all injectable vaccines, Fluad Tetra 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.

4.5 Interaction with other medicinal products and other forms of interaction

No clinical data on concomitant administration of Fluad Tetra with other vaccines are available. If Fluad Tetra 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 by any co-administration.

4.6 Fertility, pregnancy and lactation

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 Fluad Tetra in pregnant women. Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity.

4.7 Effects on ability to drive and use machines

Fluad Tetra has no or negligible influence on the ability to drive and use machines.

4.8 Undesirable effects

Summary of the safety profile

Elderly population

The safety of Fluad Tetra in elderly subjects 65 years of age and older was evaluated in two clinical studies (V118_20 and V118_18), in which 4269 received Fluad Tetra.

Solicited local and systemic adverse reactions were collected for 7 days after vaccination. Unsolicited adverse reactions were collected for 21 days after vaccination.

The most commonly reported (≥10%) adverse reactions across both studies were injection site pain (16.3% and 31.9%), fatigue (10.5% and 16.0%) and headache (10.8% and 12.0%) (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

Fluad Tetra 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 in elderly subjects 65 years and older in clinical trials

MedDRA System Organ class

Very common

(≥1/10)

Common

(≥1/100 to <1/10)

Uncommon

(≥1/1,000 to <1/100)

Metabolism and nutrition disorders

Loss of appetite

Nervous system disorders

Headache

Gastrointestinal disorders

Nausea,

Diarrhoea

Vomiting

Musculoskeletal and connective tissue disorders

Myalgia,

Arthralgia

General disorders and administration site conditions

Injection site pain,

Fatigue

Ecchymosis*,

Chills,

Erythema,

Induration,

Influenza-like illness

Fever (≥ 38oC)

*Or Injection site bruising

Adverse reactions reported from post-marketing surveillance

There are currently no post-marketing data available for Fluad Tetra. However, the post-marketing experience with Fluad (trivalent formulation) is relevant to Fluad Tetra because both vaccines are manufactured using the same process and have overlapping compositions. The following adverse reactions were reported from post marketing surveillance with Fluad (trivalent formulation):

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 lasting more than one week, injection-site cellulitis-like reaction (some cases of swelling, pain, and redness extending more than 10 cm and lasting more than 1 week)

Immune system disorders

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

Musculoskeletal and connective tissue disorders

Muscular weakness

Nervous system disorders

Encephalomyelitis, Guillain-Barré syndrome, convulsions, neuritis, neuralgia, paraesthesia

Skin and subcutaneous tissue disorders

Generalised skin reactions including erythema multiforme, urticaria, pruritus or non-specific rash

Vascular disorders

Vasculitis that may be associated with transient renal involvement

Paediatric population

There are no post-marketing data available for Fluad Tetra and limited data for Fluad (trivalent formulation) in the paediatric population.

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 the national reporting system listed in Appendix V.

4.9 Overdose

Overdosage is unlikely to have any untoward effect.

5. Pharmacological properties
5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Influenza vaccine, ATC code: J07BB02

Mechanism of action

Fluad Tetra provides active immunisation against four influenza virus strains (two A subtypes and two B types) contained in the vaccine. Fluad Tetra induces humoral antibodies against the haemagglutinins. These antibodies neutralise influenza viruses.

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.

Fluad Tetra 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.

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

Elderly population (65 years and older)

Immunogenicity

The immunogenicity of Fluad Tetra 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 Fluad Tetra, the licensed adjuvanted trivalent influenza vaccine (Fluad, aTIV-1) or an adjuvanted trivalent influenza vaccine containing the alternate B 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 who received Fluad Tetra 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). Fluad Tetra met non-inferiority for all 4 influenza strains and superiority to the alternate B strain not included in the Fluad aTIV comparators. The non-inferiority data are summarised in Table 2.

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

GMT

(95% CI)

GMT Ratioa

Strain

Fluad Tetra

N=872

aTIV-1

(B-Victoria)

N=436

aTIV-2

(B-Yamagata)

N=433

aTIVd/Fluad Tetra

(95% CI)

A/H1N1

65.0

(57.8; 73.1)

75.2

(66.7; 84.7)

1.2

(1.1; 1.3)

A/H3N2

294.9

(261.9; 332.1)

293.3

(259.9; 331.0)

1.0

(0.9; 1.1)

B/Yamagata

24.7

(22.7; 26.8)

NA

24.3

(22.0; 26.8)

1.0

(0.9; 1.1)

B/Victoria

30.8

(28.3; 33.5)

30.1

(27.3; 33.2)

NA

1.0

(0.9; 1.1)

Seroconversion %c

(95% CI)

Seroconversion Differenceb

Strain

Fluad Tetra

N=872

aTIV-1

(B-Victoria)

N=436

aTIV-2

(B-Yamagata)

N=433

aTIVd – Fluad Tetra

(95% CI)

(95% CI) aTIV

A/H1N1

35.2

(32.0; 38.5)

38.4

(35.2; 41.8)

3.2

(-1.3; 7.8)

A/H3N2

39.3

(36.1; 42.7)

39.7

(36.4; 43.0)

0.4

(-4.2; 5.0)

B/Yamagata

16.4

(14.0; 19.0)

NA

15.5

(12.2; 19.2)

-0.9

(-5.1; 3.3)

B/Victoria

13.4

(11.2; 15.9)

12.2

(9.2; 15.6)

NA

-1.3

(-5.1; 2.6)

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.

Immunogenicity of aTIV

The immunogenicity of Fluad (trivalent formulation) is relevant to Fluad Tetra because both vaccines are manufactured using the same process and have overlapping compositions.

Study V70_27 was a large Phase 3, randomised, controlled, observer-blind, multicentre study to evaluate the immunogenicity and the safety of Fluad in comparison to non-adjuvanted vaccine and it was conducted in 2010-2011. Subjects were randomised in a 1:1 ratio to receive a single 0.5 ml dose of Fluad or a single dose of a non-adjuvanted influenza vaccine. All subjects were followed for approximately one year post-vaccination.

A total of 7082 subjects were randomised and vaccinated, including 3541 subjects in each of the pooled Fluad and non-adjuvanted vaccine groups. A total of 2573 subjects (1300 in Fluad and 1273 in non-adjuvanted vaccine group) 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 a superiority of Fluad versus non-adjuvanted vaccine was not achieved for all homologous strains. 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% – 13.9% with the lowest limit of the 95% CI of 1.1%.

Fluad elicited higher antibody titres for A/H3N2 that persisted up to 12 months post-vaccination. The results were similar for high-risk subjects with predefined comorbidities.

Effectiveness

No effectiveness studies have been performed with Fluad Tetra. The observational effectiveness studies performed with Fluad (trivalent formulation) are relevant to Fluad Tetra because both vaccines are manufactured using the same process and have overlapping compositions.

Paediatric Population (6 months to less than 6 years)

Fluad Tetra is not indicated for use in children, see section 4.2.

Efficacy, immunogenicity and safety of Fluad Tetra 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 naïve to prior influenza vaccination received two doses of vaccine, at least 4 weeks apart. 10,644 children were enrolled and randomised to receive Fluad Tetra or the non-adjuvanted comparator vaccine in a 1:1 ratio: 5,352 children were enrolled in the Fluad Tetra group and 5,292 children in the non-adjuvanted comparator vaccine group.

Immunogenicity

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

Fluad Tetra demonstrated a higher immune response compared to the non-adjuvanted comparator vaccine. In addition, in children naïve 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 Fluad Tetra.

At 12 months post-vaccination, persistence of the immune response was higher in the Fluad Tetra group compared to the non-adjuvanted comparator group.

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 one and 498 during season two. The majority of influenza cases were A/H3N2. Based on antigenic typing, more than ninety percent of A/H3N2 strains from season two were determined to be antigenically distinct from egg-propagated A/Texas/50/2012, the H3N2 vaccine strain.

Vaccine efficacy compared to the non-adjuvanted influenza comparator vaccine was assessed. The relative vaccine (rVE) efficacy between Fluad Tetra and the comparator vaccine group 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 Fluad Tetra compared to the non-adjuvanted comparator influenza vaccine.

The most commonly reported adverse reactions (>10%) were tenderness (43.2%), irritability (27.1%), sleepiness (26.3%), change in eating habits (22.5%), fever (19.1%), diarrhoea (12.3%) and vomiting (10.3%).

The European Medicines Agency has deferred the obligation to submit the results of studies with Fluad Tetra in one or more subsets of the paediatric population in prevention of influenza infection. 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 repeated-dose toxicity, reproductive and developmental toxicity, local tolerance and sensitisation.

6. Pharmaceutical particulars
6.1 List of excipients

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

6.2 Incompatibilities

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

6.3 Shelf life

12 months

6.4 Special precautions for storage

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.

6.5 Nature and contents of container

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 needles

Pack of 10 pre-filled syringes without needles

Not all pack sizes may be marketed.

6.6 Special precautions for disposal and other handling

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.

7. Marketing authorisation holder

Seqirus Netherlands B.V.

Paasheuvelweg 28

1105 BJ Amsterdam

The Netherlands

8. Marketing authorisation number(s)

EU/1/20/1433/001

EU/1/20/1433/002

EU/1/20/1433/003

EU/1/20/1433/004

9. Date of first authorisation/renewal of the authorisation

Date of first authorisation: 20 May 2020

10. Date of revision of the text

05/2020

Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu.