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

Influvac sub-unit Tetra, suspension for injection in pre-filled syringe (influenza vaccine, surface antigen, inactivated).

2. Qualitative and quantitative composition

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

- A/Michigan/45/2015 (H1N1)pdm09-like strain

(A/Singapore/GP1908/2015, IVR-180)

 

15 micrograms HA **

- A/Singapore/INFIMH-16-0019/2016 (H3N2)-like strain

(A/Singapore/INFIMH-16-0019/2016, NIB-104)

- B/Colorado/06/2017-like strain (B/Victoria/2/87 lineage)

(B/Maryland/15/2016, NYMC BX-69A)

 

15 micrograms HA **

 

15 micrograms HA **

- B/Phuket/3073/2013-like strain (B/Yamagata/16/88 lineage)

(B/Phuket/3073/2013, wild type)

 

15 micrograms HA **

per 0.5 ml dose

* propagated in fertilised hens' eggs from healthy chicken flocks

** haemagglutinin.

This vaccine complies with the World Health Organisation (WHO) recommendation (northern hemisphere) and EU recommendation for the 2018/2019 season.

For a full list of excipients see section 6.1.

Influvac sub-unit Tetra may contain traces of eggs (such as ovalbumin, chicken proteins), formaldehyde, cetyltrimethylammonium bromide, polysorbate 80 or gentamicin, which are used during the manufacturing process (see section 4.3).

3. Pharmaceutical form

Suspension for injection in pre-filled syringe.

A colourless clear liquid, filled in single-dose syringes.

4. Clinical particulars
4.1 Therapeutic indications

Prophylaxis of influenza, especially those who run an increased risk of associated complications.

Influvac sub-unit Tetra is indicated in adults and children from 3 years of age.

The use of Influvac sub-unit Tetra should be based on official recommendations.

4.2 Posology and method of administration

Posology

Adults: 0.5 ml.

Paediatric population

Children from 3 to 17 years of age: 0.5 ml

Children less than 9 years of age, who have not previously been vaccinated with a seasonal influenza vaccine: a second dose of 0.5 ml should be given after an interval of at least 4 weeks.

Children less than 3 years of age: the safety and efficacy of Influvac sub-unit Tetra in children have not been established.

Method of Administration

Immunisation should be carried out by intramuscular or deep subcutaneous injection.

Precautions to be taken before handling or administrating the medicinal product:

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 excipients listed in section 6.1 or to any component that may be present as traces such as eggs (ovalbumin, chicken proteins), formaldehyde, cetyltrimethylammonium bromide, polysorbate 80 or gentamicin.

Immunisation shall be postponed in patients with febrile illness or acute infection.

4.4 Special warnings and precautions for use

As with all injectable vaccines, appropriate medical treatment and supervision should always be readily available in case of an anaphylactic event following the administration of the vaccine.

Influvac sub-unit Tetra should under no circumstances be administered intravascularly.

Anxiety-related reactions, including vasovagal reactions (syncope), hyperventilation or stress-related reactions 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.

Interference with serological testing: see section 4.5.

This medicine contains less than 1 mmol sodium (23 mg) per dose, i.e. essentially 'sodium-free'.

This medicine contains potassium, less than 1 mmol (39 mg) per dose, i.e. essentially 'potassium-free'.

4.5 Interaction with other medicinal products and other forms of interaction

No interaction studies have been performed. If Influvac sub-unit Tetra is given at the same time as other vaccines, immunisation should be carried out on separate limbs. It should be noted that the adverse reactions may be intensified.

The immunological response may be diminished if the patient is undergoing immunosuppressant treatment.

Following influenza vaccination, false positive results in serology tests using the ELISA method to detect antibodies against HIV1, Hepatitis C and especially HTLV1 have been observed. The Western Blot technique disproves the false-positive ELISA test results. The transient false-positive reactions could be due to the IgM response by the vaccine.

4.6 Fertility, pregnancy and lactation

Pregnancy

Inactivated influenza vaccines can be used in all stages of pregnancy. Larger datasets on safety are available for the second and third trimester, compared with the first trimester; however, data from worldwide use of influenza vaccine do not indicate any adverse foetal and maternal outcomes attributable to the vaccine.

Breast-feeding

Influvac sub-unit Tetra may be used during breast-feeding.

Fertility

No fertility data are available.

4.7 Effects on ability to drive and use machines

Influvac sub-unit Tetra has no or negligible influence on the ability to drive and use machines.

4.8 Undesirable effects

a. Summary of the safety profile

The safety of Influvac sub-unit Tetra was assessed in two clinical trials in which healthy adults 18 years of age and older, and healthy children 3 to 17 years of age were administered Influvac sub-unit Tetra or trivalent influenza vaccine Influvac. Children from 3 to 8 years of age received one or two doses of Influvac sub-unit Tetra depending on their influenza vaccination history.

Most reactions usually occurred within the first 3 days following vaccination and resolved spontaneously within 1 to 3 days after onset. The intensity of these reactions was generally mild.

In all age groups, the most frequently reported local adverse reaction after vaccination observed in the clinical studies for Influvac sub-unit Tetra was vaccination site pain.

The most frequently reported general adverse reactions after vaccination observed in the clinical studies for Influvac sub-unit Tetra in adults and children from 6 to 17 years of age were fatigue and headache, and for children from 3 to 5 years of age drowsiness, irritability and loss of appetite.

Similar rates of solicited adverse reactions were observed in recipients of Influvac sub-unit Tetra and trivalent influenza vaccine Influvac.

b. Tabulated summary of adverse reactions

The following undesirable effects are considered at least possibly related to Influvac sub-unit Tetra and have either been observed during the clinical trials with Influvac sub-unit Tetra or are resulting from post-marketing experience with the trivalent influenza vaccine Influvac.

The following frequencies apply:

very common (≥1/10); common (≥1/100, <1/10); uncommon (≥1/1,000, <1/100); and not known (adverse reactions from post-marketing experience; cannot be estimated from the available data).

Adults and elderly

Adverse Reactions Reported with Influvac sub-unit Tetra/Influvac

MedDRA System Organ Class

Very common

≥ 1/10

Common

≥ 1/100 to < 1/10

Uncommon

≥ 1/1,000 to < 1/100

Not Knowna

(cannot be estimated from the available data)

Blood and lymphatic system

Transient thrombocytopenia, transient lymphadenopathy

Immune system disorders

Allergic reactions, in rare cases leading to shock, angioedema

Nervous system disorders

Headacheb

Neuralgia, paraesthesia, febrile convulsions, neurological disorders, such as encephalomyelitis, neuritis and Guillain Barré syndrome

Vascular disorders

Vasculitis associated in very rare cases with transient renal involvement

Skin and subcutaneous tissue disorders

Sweating

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

Musculoskeletal and connective tissue disorders

Myalgia, arthralgia

General disorders and administration site conditions

Fatigue

Local reaction: pain

Malaise, shivering

Local reactions: redness, swelling, ecchymosis, induration

Fever

a Because these reactions are reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

b In elderly adults (≥ 61 years) reported as common

Paediatric population

Children (3 to 17 years of age) Adverse Reactions Reported with Influvac sub-unit Tetra/Influvac

MedDRA System Organ Class

Very common

≥ 1/10

Common

≥ 1/100 to < 1/10

Uncommon

≥ 1/1,000 to < 1/100

Not Knowna

(cannot be estimated from the available data)

Blood and lymphatic system

Transient thrombocytopenia, transient lymphadenopathy

Immune system disorders

Allergic reactions, in rare cases leading to shock, angioedema

Nervous system disorders

Headached

Drowsinessb

Neuralgia, paraesthesia, febrile convulsions, neurological disorders, such as encephalomyelitis, neuritis and Guillain Barré syndrome

Vascular disorders

Vasculitis associated in very rare cases with transient renal involvement

Skin and subcutaneous tissue disorders

Sweatingc

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

Metabolism and nutrition disorders

Appetite lossb

Gastrointestinal disorders

Gastrointestinal symptomsd

Diarrhoeab, vomitingb

Psychiatric disorders

Irritabilityb

Musculoskeletal and connective tissue disorders

Myalgiad

Arthralgiad

General disorders and administration site conditions

Fatigued, malaised

Local reactions: painc, rednessc, swellingc, indurationc

Feverc, shiveringd

Local reaction: ecchymosisc

a Because these reactions are reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their frequency or establish a causal relationship to drug exposure

b Reported as a solicited symptom in children 3 to 5 years of age

c Reported as a solicited symptom in children 3 to 17 years of age

d Reported as a solicited symptom in children 6 to 17 years of age

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 Yellow Card Scheme at: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

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:

Influvac sub-unit Tetra provides active immunisation against four influenza virus strains: an A/(H1N1) strain, an A/(H3N2) strain, and two B strains (one from each lineage; B/(Victoria) and B/(Yamagata)). Influvac sub-unit Tetra, manufactured according to the same process as trivalent influenza vaccine Influvac, induces humoral antibodies against the haemagglutinins. These antibodies neutralise influenza viruses.

Specific levels of hemagglutination-inhibition (HI) antibody titer post-vaccination with inactivated influenza virus vaccines have not been correlated with protection from influenza illness but the HI antibody titers have been used as a measure of vaccine activity.

An immune response is generally obtained within 2 to 3 weeks. The duration of postvaccinal immunity to homologous strains or to strains closely related to the vaccine strains varies but is usually 6-12 months.

Pharmacodynamic effects:

Immunogenicity of Influvac sub-unit Tetra compared to trivalent Influvac:

Clinical studies performed in adults of 18 years of age and older (INFQ3001) and children of 3 to 17 years of age (INFQ3002) assessed the safety and immunogenicity of Influvac sub-unit Tetra and its non-inferiority to trivalent influenza vaccine Influvac for the postvaccination HI Geometric mean antibody titer (GMT).

In both studies the immune response elicited by Influvac sub-unit Tetra against the three strains in common was non-inferior to trivalent influenza vaccine Influvac. Influvac sub-unit Tetra elicited a superior immune response against the additional B strain included in Influvac sub-unit Tetra compared to trivalent influenza vaccine Influvac.

Adults 18 years of age and older:

In clinical study INFQ3001, 1,535 adults of 18 years of age and older received a single dose of Influvac sub-unit Tetra and 442 subjects received a single dose of trivalent Influvac:

Table: Post-vaccination GMT

Adults 18 – 60 years of age

Influvac sub-unit Tetra

N=768

Influvac1

N=112

Influvac2

N=110

GMT (95% confidence interval)

A/H1N1

272.2 (248.0 , 298.8)

304.4 (235.1 , 394.1)

316.0 (245.1 , 407.3)

A/H3N2

442.4 (407.6 , 480.2)

536.5 (421.7 , 682.6)

417.0 (323.7 , 537.1)

B (Yamagata)3

162.5 (147.8 , 178.7)

128.7 (100.3 , 165.2)

81.7 (60.7 , 109.9)

B (Victoria)4

214.0 (195.5 , 234.3)

85.1 (62.6 , 115.6)

184.7 (139.0 , 245.3)

Elderly 61 years of age and older

Influvac sub-unit Tetra

N=765

Influvac1

N=108

Influvac2

N=110

GMT (95% confidence interval)

A/H1N1

127.2 (114.9 , 140.9)

142.4 (107.6 , 188.3)

174.2 (135.9 , 223.3)

A/H3N2

348.5 (316.8 , 383.5)

361.5 (278.3 , 469.6)

353.4 (280.7 , 445.0)

B (Yamagata)3

63.7 (57.7 , 70.4)

57.4 (43.6 , 75.7)

27.3 (20.7 , 36.0)

B (Victoria)4

109.4 (98.1 , 122.0)

48.0 (34.6 , 66.6)

106.6 (79.7 , 142.8)

N = number of subjects included in efficacy analysis

1containing A/H1N1, A/H3N2 and B (Yamagata lineage)

2containing A/H1N1, A/H3N2 and B (Victoria lineage)

3recommended B strain by WHO for the season 2014-2015 NH for trivalent vaccines

4additional recommended B strain by WHO for season 2014-2015 NH for quadrivalent vaccines

Paediatric population

Children 3 – 17 years of age:

In clinical study INFQ3002, 402 children of 3 to 17 years of age received one or two doses of Influvac sub-unit Tetra and 798 children received one or two doses of trivalent Influvac based on their influenza vaccination history.

Table: Post-vaccination GMT

Children 3 - 17 years of age

Influvac sub-unit Tetra

N=396

Influvac1

N=389

Influvac2

N=399

GMT (95% confidence interval)

A/H1N1

546.2 (487.1 , 612.6)

605.6 (536.3 , 83.8)

633.1 (562.8 , 712.2)

A/H3N2

1161.5 (1035.8 , 1302.5)

1075.4 (947.7 , 1220.3)

1306.4 (1162.5 , 1468.1)

B (Yamagata)3

280.8 (246.2 , 320.1)

269.0 (232.8 , 310.7)

38.3 (31.9 , 46.1)

B (Victoria)4

306.7 (266.0 , 353.6)

104.5 (86.8 , 125.8)

361.4 (311.0 , 420.0)

N= number of subjects included in efficacy analysis

1containing A/H1N1, A/H3N2 and B (Yamagata lineage)

2containing A/H1N1, A/H3N2 and B (Victoria lineage)

3recommended B strain by WHO for the season 2016-2017 NH for trivalent vaccines

4additional recommended B strain by WHO for season 2016-2017 NH for quadrivalent vaccines

The European Medicines Agency has deferred the obligation to submit the results of studies with Influvac sub-unit Tetra in one or more subsets of the paediatric population.

5.2 Pharmacokinetic properties

Not applicable.

5.3 Preclinical safety data

Non-clinical data revealed no special hazard for humans based on conventional studies of repeat dose and local toxicity, reproductive and developmental toxicity and safety pharmacology studies.

6. Pharmaceutical particulars
6.1 List of excipients

Potassium chloride, potassium dihydrogen phosphate, disodium phosphate dihydrate, sodium chloride, calcium chloride dihydrate, magnesium chloride hexahydrate and 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

1 year.

6.4 Special precautions for storage

Store in a refrigerator (+2°C to +8°C).

Do not freeze.

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

6.5 Nature and contents of container

0.5 ml suspension for injection in prefilled syringe with / without needle (glass, type I), pack of 1 or 10.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal and other handling

The vaccine should be allowed to reach room temperature before use.

Shake before use. Inspect visually prior to administration.

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

7. Marketing authorisation holder

Mylan Products Limited

20 Station Close

Potters Bar

Herts

EN6 1TL

UK

8. Marketing authorisation number(s)

PL 46302/0055

9. Date of first authorisation/renewal of the authorisation

Date of first authorisation: 25/07/2017

10. Date of revision of the text

October 2018