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Foclivia (influenza virus surface antigens, inactivated:...) – Summary of product characteristics - J07BB02

Updated on site: 07-Oct-2017

Medication nameFoclivia
ATC CodeJ07BB02
Substanceinfluenza virus surface antigens, inactivated: A/Viet Nam/1194/2004 (H5N1)
ManufacturerSeqirus S.r.l.  

1.NAME OF THE MEDICINAL PRODUCT

Foclivia suspension for injection in pre-filled syringe

Pandemic influenza vaccine (H5N1) (surface antigen, inactivated, adjuvanted)

2.QUALITATIVE AND QUANTITATIVE COMPOSITION

Influenza virus surface antigens (haemagglutinin and neuraminidase)* of strain:

A/Vietnam/1194/2004 (H5N1)

7.5 micrograms**

per 0.5 ml dose

 

*propagated in eggs

**expressed in microgram haemagglutinin.

Adjuvant MF59C.1 containing:

 

Squalene

9.75 milligrams

Polysorbate 80

1.175 milligrams

Sorbitan trioleate

1.175 milligrams

This vaccine complies with the WHO recommendations and EU decision for the pandemic.

For the full list of excipients, see section 6.1.

3.PHARMACEUTICAL FORM

Suspension for injection in pre-filled syringe.

Milky-white liquid.

4.CLINICAL PARTICULARS

4.1Therapeutic indications

Prophylaxis of influenza in an officially declared pandemic situation.

Foclivia should be used in accordance with Official Guidance.

4.2Posology and method of administration

Posology

Adults and elderly: 0.5 ml at an elected date.

A second dose of vaccine should be given after an interval of at least 3 weeks.

Foclivia was evaluated in adults aged (18 to 60 years old) and elderly (over 60 years old) following a 1, 22 day primary vaccination schedule.

Data on a third dose (booster) administered 6 months after the first dose are limited (see sections 4.8 and 5.1).

Paediatric population:

The safety and efficacy of Foclivia in subjects under 18 years of age have not yet been established. Currently available data in subjects aged 6 months to 18 years of age are described in section 5.1 but no recommendation on a posology can be made.

No data are available in children aged less than 6 months.

Method of administration

Immunisation should be carried out by intramuscular injection into the deltoid muscle or anterolateral thigh (depending on the muscle mass).

4.3Contraindications

History of an anaphylactic (i.e. life-threatening) reaction to any of the constituents or trace residues of eggs, chicken proteins, kanamycin and neomycin sulphate, barium sulphate, formaldehyde and cetyltrimethylammonium bromide (CTAB) of this vaccine. However, in a pandemic situation, it may be appropriate to give the vaccine, provided that facilities for resuscitation are immediately available in case of need. see section 4.4.

4.4Special warnings and precautions for use

Caution is needed when administrating this vaccine to persons with a known hypersensitivity (other than anaphylactic reaction) to the active substance, to any of the excipients listed in section 6.1 and to eggs, chicken proteins, kanamycin and neomycin sulphate, barium sulphate, formaldehyde and cetyltrimethylammonium bromide (CTAB).

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

If the pandemic situation allows, immunisation shall be postponed in patients with severe febrile illness or acute infection.

Foclivia should under no circumstances be administered intravascularly or subcutaneously. Therefore, healthcare providers need to assess the benefits and potential risks of administering the vaccine in individuals with thrombocytopenia or any bleeding disorder that would contraindicate intramuscular injection unless the potential benefit outweighs the risk of bleedings

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

A protective response may not be elicited in all vaccinees (see section 5.1).

Some cross-protection was observed against related H5N1 virus variants in clinical trials (see section 5.1).

Since a second dose is recommended, it should be noted that there are no safety, immunogenicity or efficacy data to support interchangeability of Foclivia with other H5N1 monovalent vaccines.

While no data is available from the use of Foclivia, cases of convulsion with and without fever have been reported in subjects vaccinated with Focetria an MF59.1 adjuvanted H1N1 pandemic vaccine similar to Foclivia.

The majority of febrile convulsions occurred in paediatric subjects. Some cases were observed in subjects with a history of epilepsy. Particular attention should be given to subjects suffering from epilepsy and the physician should inform the subjects (or parents) about the possibility to experience convulsion. (see section 4.8).

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.

4.5Interaction with other medicinal products and other forms of interaction

Foclivia should not be given at the same time as other vaccines. However, if co-administration with another vaccine is indicated, 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 serology test results may be obtained by the ELISA method for antibody to human immunodeficiency virus-1 (HIV-1), hepatitis C virus and, especially, HTLV-1. In such cases, the Western blot method is negative. These transitory false-positive results may be due to IgM production in response to the vaccine.

4.6Fertility, pregnancy and lactation

Pregnancy

No data have been generated with Foclivia in pregnant women.

Safety data are available, however, in pregnant women exposed to Focetria (an H1N1 pandemic vaccine similar to Foclivia) which contains the same amount of MF59C.1 as Foclivia. Postmarketing spontaneously reported adverse events and an interventional study do not suggest direct or indirect harmful effects of Focetria exposure on pregnancy. In addition, two large observational studies designed to assess the safety of Focetria exposure in pregnancy showed no increase in the rates of gestational diabetes, preeclampsia, abortions, stillbirth, low birth weight, prematurity, neonatal deaths, and congenital malformations among almost 10.000 vaccinated pregnant women and their offspring compared with unvaccinated controls.

Health care providers need to assess the benefits and potential risks of administering Foclivia vaccine to pregnant women, taking into consideration official recommendations.

Breast-feeding

The vaccine may be used during lactation.

Fertility

No fertility data are available.

4.7Effects on ability to drive and use machines

Some of the effects mentioned under section 4.8 “Undesirable Effects” may affect the ability to drive or use machines.

4.8Undesirable effects

Summary of safety profile

Adults and elderly.(above 18 years old)

From the clinical trials conducted with the pandemic mock-up adjuvanted H5N1 vaccine in adult and elderly (see section 5.1 for more information), most of the reactions were mild in nature, of short duration and qualitatively similar to those induced by conventional seasonal influenza vaccines.

It is widely accepted that the adjuvant effect leading to increased immunogenicity is associated with a slightly higher frequency of local reactions (mostly mild pain) compared with conventional, nonadjuvanted influenza vaccines. There were fewer reactions after the second dose compared with the first.

Children and adolescents aged 6 months to 17 years:

In a phase II clinical trial (Study V87P6) safety of a pandemic mock-up adjuvanted H5N1 vaccine was evaluated in children and adolescent (see section 5.1 for more information).

Regardless of age, reactogenicity was higher after the first dose than after the second vaccination. Reactogenicity after a third dose, administered 12 months after the second dose, was higher than after both first and second dose. The percentages of subjects reporting local reactions were higher in the older age groups, mainly due to the higher reports for pain. In toddlers, erythema and tenderness were the most commonly reported solicited local reactions; irritability and unusual crying were the most commonly reported solicited systemic reactions. In children and adolescents pain was the most frequently reported solicited local reaction, and fatigue and headache were the most commonly reported solicited systemic reactions. Across all ages, low percentages of subjects reported fever. Safety data after the first and second dose in children and adolescents with a similar pandemic vaccine (Focetria H1N1v) suggest a comparable safety profile with that reported for the aH5N1 mock-up vaccine formulation (Foclivia).

Frequency of Adverse reactions in clinical trials and postmarketing surveillance is reported hereunder.

Clinical trials

Adverse reactions from clinical trial in adults and elderly (above 18 years old)

The incidence of adverse reactions was evaluated in four clinical trials with different influenza strains and formulations (H5N3, H9N2 and H5N1); 3696 adults and elderly subjects were exposed. Of these subjects, 3618 subjects received the mock-up vaccine Foclivia (A/H5N1) (see section 5.1).

Adverse reactions from clinical trials with the mock-up vaccine Foclivia are listed below.

The incidence of symptoms observed in subjects over 60 years of age was lower as compared to the 18-60 years old population.

Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness:

Nervous system disorders

Common (>1/100, <1/10): headache

Skin and subcutaneous tissue disorders

Common (>1/100, <1/10): sweating

Muscoskeletal, connective tissue and bone disorders

Common (>1/100, <1/10): arthralgia and myalgia

General disorders and administration site conditions

Common (>1/100, <1/10): injection site redness, injection site swelling, injection site induration, injection site ecchymosis and injection site pain, fever, malaise, fatigue and shivering

The majority of these reactions usually disappear within 1-2 days without treatment.

Adverse reactions from clinical trial in children aged 6 months to 17 years

A clinical trial (Study V87P6) was conducted with a H5N1 vaccine combined with MF59C.1 adjuvant (n=334) vs seasonal influenza vaccine (n=137).

 

First dose

 

Second dose (21 days

Third dose (12 months

 

 

after first dose)

after second dose)

 

 

 

 

 

 

H5N1 adjuvanted vaccine

 

Toddlers (6-<36 months)

N=145

 

N=138

N=124

Any

76%

 

68%

80%

Local

47%

 

46%

60%

Systemic

59%

 

51%

54%

Fever ≥ 38°C (≥ 40°C)

0%

 

0%

0%

Any Other Adverse Event

54%

 

49%

35%

 

 

 

 

 

First dose

Second dose (21 days

Third dose (12 months

 

after first dose)

after second dose)

 

 

 

 

H5N1 adjuvanted vaccine

 

Children (3-<9 years)

N=96

N=93

N=85

Any

72%

68%

79%

Local

66%

58%

74%

Systemic

32%

33%

45%

Fever ≥ 38°C (≥ 40°C)

4%

2%

6%

Any Other Adverse Event

36%

31%

19%

Adolescents(9-<18 years)

N=93

N=91

N=83

Any

91%

82%

89%

Local

81%

70%

81%

Systemic

69%

52%

69%

Fever ≥ 38°C (≥ 40°C)

0%

1%

2%

Any Other Adverse Event

30%

27%

22%

Focetria (H1N1v)

Adverse reactions in the week following vaccination with Focetria H1N1v from 77 children 3-8 years old and 80 children and adolescents 9-17 years old receiving the 7.5 µg formulation were reported

as follows:

 

Injection 1

Injection 2

Children (3 to 8 years of age)

N= 77

N= 75

Any adverse reaction

74%

69%

Local

62%

56%

Systemic

39%

35%

Fever ≥ 38°C to 38.9°C

4%

1%

Fever 39°C to 39.9°C

0%

1%

Fever ≥ 40° C

0%

0%

Any other AE

14%

17%

Adolescents (9 to 17 years of age)

N= 80

N= 79

Any adverse reaction

79%

66%

Local

70%

58%

Systemic

45%

30%

Fever ≥38°C to 38.9°C

3%

1%

Fever 39°C to 39.9°C

0%

0%

Fever ≥ 40° C

0%

0%

Any other AE

13%

10%

Data in children and adolescents 3-17 years suggest a slight decrease in reactogenicity after the second dose, with no increase in rates of fever.

Very common reactions reported in children and adolescents 3 to 17 years of age: Pain, induration and erythema, malaise, myalgia, headache and fatigue.

Adverse reactions in the week following vaccination with Focetria H1N1v from

73 infants 6-11 months old and 73 toddlers 12-35 months old, receiving the 7.5 µg formulation were reported as follows:

 

Injection 1

Injection 2

Infants (6 to 11 months of age)

N= 73

N= 68

Any adverse reaction

79%

65%

Local

44%

26%

Systemic

70%

56%

Fever ≥38°C to 38.9°C

11%

9%

Fever 39°C to 39.9°C

3%

4%

Fever ≥ 40° C

0%

0%

Any other AE

32%

31%

 

 

 

Injection 1

Injection 2

Toddlers (12 to 35 months of age)

N= 73

N= 71

Any adverse reaction

70%

71%

Local

51%

49%

Systemic

60%

49%

Fever ≥38°C to 38.9°C

10%

11%

Fever 39°C to 39.9°C

4%

1%

Fever ≥ 40° C

1%

0%

Any other AE

21%

24%

Data in infants and toddlers 6-35 months of age suggest a slight decrease in reactogenicity after the second dose, with no increase in rates of fever.

Very common reactions reported in 146 infants and toddlers 6 to 35 months of age:

Tenderness, erythema, irritability, unusual crying, sleepiness, diarrhoea, vomiting and change in eating habits. Induration and ecchymosis were very common reactions in toddlers but were less common in infants.

Post-marketing surveillance

In addition to the adverse reactions reported in the clinical trials, the following have been reported during post-marketing experience with Focetria H1N1v:

Blood and lymphatic system disorders

Lymphadenopathy.

Cardiac disorders

Palpitation, tachycardia.

General disorders and administration site conditions

Asthenia.

Muscoskeletal, connective tissue and bone disorders

Muscular weakness, pain in extremities.

Respiratory, thoracic and mediastinal disorders

Cough.

Skin and subcutaneous tissue disorders

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

Gastrointestinal disorders

Gastrointestinal disorders such as nausea, vomiting, abdominal pain and diarrhoea.

Nervous system disorders

Headache, dizziness, somnolence, syncope. Neurological disorders, such as neuralgia, paraesthesia, convulsions and neuritis.

Immune system disorders

Allergic reactions, anaphylaxis including dyspnoea, bronchospasm, laryngeal oedema, in rare cases leading to shock.

From Post-marketing surveillance with adjuvanted interpandemic trivalent vaccines with composition similar to that of Foclivia (an MF59C.1 adjuvanted H1N1 pandemic vaccines, the following additional adverse reactions have been reported:

Rare (>1/10,000, <1/1,000):

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

Very rare (<1/10,000):

Vasculitis with transient renal involvement and exudative erythema multiforme. Neurological disorders, such as encephalomyelitis, neuritis and Guillain Barré syndrome.

Adverse event(s) from post-marketing surveillance with the pandemic vaccine: not applicable.

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

4.9Overdose

No case of overdose has been reported.

5.PHARMACOLOGICAL PROPERTIES

5.1Pharmacodynamic properties

Pharmacotherapeutic group: Influenza vaccine, ATC Code: J07BB02

This section describes the clinical experience with the H5N1 mock-up vaccines following a two-dose administration of 7.5 microgram.

Mock-up vaccines contain influenza antigens that are different from those in the currently circulating influenza viruses. These antigens can be considered as ‘novel’ antigens and simulate a situation where the target population for vaccination is immunologically naïve. Data obtained with a mock-up vaccine will support a vaccination strategy that is likely to be used for the pandemic vaccine: clinical efficacy and safety data obtained with mock-up vaccines are relevant for the pandemic vaccines.

Adults (18-60 years)

A Phase II clinical trial (Study V87P1) was conducted with a H5N1 vaccine combined with MF59C.1 adjuvant in 312 healthy adults. Two doses of vaccine containing

H5N1 (A/Vietnam/1194/2004; 7.5 µg HemoAgglutinin (HA)/dose adjuvanted) were administered three weeks apart to 156 subjects.

In another clinical trial (Phase III) (Study V87P13), 2693 healthy adults were enrolled and received two doses of vaccine containing H5N1 (A/Vietnam/1194/2004; 7.5 µg HA/dose adjuvanted) administered three weeks apart. Immunogenicity was assessed in a subset (n=197) of the study population.

The seroprotection rate*, seroconversion rate* and the seroconversion factor** for anti-HA antibody to H5N1 A/Vietnam/1194/2004 in the adults measured by Single Radial Haemolysis (SRH) assay was as follows:

 

Study V87P1

Study V87P13

Anti-HA antibody (SRH)

21 days after 2nd dose

21 days after 2nd dose

 

N=149

N=197

Seroprotection rate (95%CI)*

85% (79-91)

91% (87-95)

Seroconversion rate (95%CI)*

85% (78-90)

78% (72-84)

Seroconversion factor (95%CI)**

7.74 (6.6-9.07)

4.03 (3.54-4.59)

 

 

 

Study V87P13

Study V87P13

Anti-HA antibody (SRH)

21 days after 2nd dose

21 days after 2nd dose

 

N=69

N=128

Baseline Serostatus

< 4 mm2

≥ 4 mm2

Seroprotection rate (95%CI)*

87% (77-94)

94% (88-97)

Seroconversion rate (95%CI)*

87% (77-94)

73% (65-81)

Seroconversion factor (95%CI)**

8.87 (7.09-11)

2.71 (2.38-3.08)

*measured by SRH assay ≥ 25 mm2

**geometric mean ratios of SRH

MicroNeutralization (MN) results against A/Vietnam/1194/2004 indicate a seroprotection and seroconversion rate ranging from 67% (60-74) to 85% (78-90) and 65% (58-72) to 83% (77-89), respectively. Immune response to vaccination assessed by MN assay is in line with results obtained with SRH.

Persistence of antibodies after primary vaccination in this population was assessed by Hemagglutination Inhibition (HI), SRH, and MN assays. Compared to the antibody levels obtained at day 43 after completion of primary vaccination schedules, antibody levels at day 202 were reduced by 1/5 to 1/2 from their prior levels.

Elderly (>60 years)

The seroprotection rate*, seroconversion rate* and the seroconversion factor** for anti-HA antibody to H5N1 A/Vietnam/1194/2004 in subjects aged over 60 (limited number of subjects were

above 70 years of age) measured by SRH assay assessed in two clinical studies were as follows:

 

Study V87P1

Study V87P13

Anti-HA antibody (SRH)

21 days after 2nd dose

21 days after 2nd dose

 

N=84

N=210

Seroprotection rate (95%CI)*

80% (70-88)

82% (76-87)

Seroconversion rate (95%CI)*

70% (59-80)

63% (56-69)

Seroconversion factor (95%CI)**

4.96 (3.87-6.37)

2.9 (2.53-3.31)

 

 

 

 

Study V87P13

Study V87P13

Anti-HA antibody (SRH)

21 days after 2nd dose

21 days after 2nd dose

 

N=66

N=143

Baseline Serostatus

< 4 mm2

≥ 4 mm2

Seroprotection rate (95%CI)*

82% (70-90)

82% (75-88)

Seroconversion rate (95%CI)*

82% (70-90)

54% (45-62)

Seroconversion factor (95%CI)**

8.58 (6.57-11)

1.91 (1.72-2.12)

*measured by SRH assay ≥ 25 mm2

**geometric mean ratios of SRH

MN results against A/Vietnam/1194/2004 indicate a seroprotection and seroconversion rate ranging from of 57% (50-64) to 79% (68-87) and 55% (48-62) to 58% (47-69) respectively. MN results, similar to SRH results demonstrated strong immune response after completion of priming vaccination series in a population of elderly subjects.

Persistence of antibodies after primary vaccination in this population as assessed by HI, SRH, and MN tests reduced from 1/2 to 1/5th of their post-vaccination level at day 202 as compared to day 43 after completion of primary schedules as assessed by HI, SRH, and MN tests. Up to 50% of the elderly subjects immunised with H5N1 vaccine combined with MF59C were seroprotected at six months.

Booster dose

A third (booster) dose of H5N1 vaccine combined with MF59C was administered 6 months onwards after the primary vaccination series. Results are shown by SRH.

The seroprotection rate*, seroconversion rate* and the seroconversion factor** for anti-HA antibody to H5N1 A/Vietnam/1194/2004 measured by SRH assays were as follows:

 

Study V87P1 Adults

Study V87P1 Elderly

 

Booster (6 months after 2nd dose

Booster (6 months after 2nd dos

 

)

e)

SRH

N=71

N=38

Seroprotection rate (95%CI)*

89% (79-95)

84% (69-94)

Seroconversion rate (95%CI)*

83% (72-91)

63% (46-78)

Seroconversion factor (95%CI)*

5.96 (4.72-7.53)

5.15 (3.46-7.66)

*

 

 

*measured by SRH assay ≥ 25 mm2

**geometric mean ratios of SRH

There is limited experience for the booster dose in the elderly population.

Supportive data in adult and elderly populations

In two dose finding studies 78 adults received an adjuvanted mock-up vaccine (H5N3 or H9N2). Two doses of vaccine with H5N3 (A/Duck/Singapore/97) strain at 3 different dosages

(7.5, 15 and 30 µg HA/dose) were administered three weeks apart.

Serum samples were tested against the original H5N3 and also a number of H5N1 isolates.

Serologic responses obtained with the SRH assay showed that 100% of subjects achieved seroprotection and 100% seroconverted after two 7.5 g injections. The adjuvanted vaccine was also found to induce antibodies that cross-protected against the H5N1 strains isolated in 2003 and 2004, which exhibit some antigenic drift compared to the original strains.

Two doses of vaccine containing H9N2 (A/chicken/Hong Kong/G9/97) strain at 4 different dosages (3.75, 7.5, 15 and 30 µg HA/dose), were administered four weeks apart. Serologic responses obtained with the HI assay showed that 92% of subjects achieved seroprotection and 75% seroconverted after two 7.5 g injections.

Cross reactivity

Adults (18-60 years)

Seroprotection rate*, seroconversion rate* and the seroconversion factor** for anti-HA antibodies to H5N1 A/turkey/Turkey/05 after the 2nd dose in adults 18-60 years of age, measured by SRH and HI assays were as follows:

 

 

Study V87P1

Study V87P13

 

Anti-HA antibody

21 days after 2nd dose

21 days after 2nd dose

 

 

N=70

N=197

 

Seroprotection rate (95%CI)*

70% (58-80)

59% (52-66)

SRH

Seroconversion rate (95%CI)*

NA***

49% (42-56)

 

Seroconversion factor (95%CI)**

NA***

2.37 (2.1-2.67)

 

 

 

Study V87P1

Study V87P13

 

 

Anti-HA antibody

21 days after 2nd dose

21 days after 2nd dose

 

 

 

N=70

N=197

 

 

 

N=69

N=197

 

 

Seroprotection rate (95%CI)°

36%(25-49)

23% (18-30)

HI

 

Seroconversion rate (95%CI)°

NA***

19% (14-25)

 

 

Seroconversion factor (95%CI)°°

NA***

1.92 (1.64-2.25)

*

measured by SRH assay ≥ 25 mm2

 

 

**

geometric mean ratios of SRH

 

 

°

measured by HI assay ≥ 40

 

 

°°

geometric mean ratios of HI

 

 

***In V87P1: baseline not tested

MN results for the clinical studies in the Table above revealed a seroprotection rate against A/turkey/Turkey/05 ranging from 27% (17-39) (V87P1) to 39% (32-46) (V87P13) and seroconversion rate of 36% (29-43) for study V87P13. MN results in study V87P13 yielded a GMR against A/turkey/Turkey/05 of 2.77 (2.4-3.2).

Elderly (>60 years)

Seroprotection rate*, seroconversion rate* and the seroconversion factor** for anti-HA antibodies to H5N1 A/turkey/Turkey/05 after the 2nd dose in elderly >60 years of age, measured by SRH and HI assays were as follows:

 

 

Study V87P1

Study V87P13

 

Anti-HA antibody

21 days after 2nd dose

21 days after 2nd dose

 

 

N=37

N=207

 

Seroprotection rate (95%CI)*

57% (39-73)

20% (18-23)

SRH

Seroconversion rate (95%CI)*

NA***

48% (41-55)

 

Seroconversion factor (95%CI)**

NA***

1.74 (1.57-1.94)

 

 

N=36

N=208

 

Seroprotection rate (95%CI)°

36%(21-54)

25% (19-32)

HI

Seroconversion rate (95%CI)°

NA***

19% (14-25)

 

Seroconversion factor (95%CI)°°

NA***

1.79 (1.56-2.06)

*measured by SRH assay ≥ 25 mm2

**geometric mean ratios of SRH

° measured by HI assay ≥ 40 °° geometric mean ratios of HI

***In V87P1: baseline not tested

MN results for the clinical studies in the Table above revealed a seroprotection rate against A/turkey/Turkey/05 ranging from 11% (3-25) (study V87P1) to 30% (24-37) (study V87P13) and seroconversion rate of 25% (19-31) for study V87P13. MN results in study V87P13 yielded a GMR against A/turkey/Turkey/05 of 2.01 (1.78-2.26).

Data in paediatric populations

A clinical trial (study V87P6) was conducted with a H5N1 vaccine combined with MF59C.1 adjuvant in 471 children from 6 months to 17 years of age. Two doses of 7.5 micrograms were administered three weeks apart and a third dose 12 months following the first dose. After 3 weeks from the 2nd vaccination (day 43) all age groups (i.e. 6-35 months, 3-8 years and 9-17 years) achieved high levels of antibodies to (A/Vietnam/1194/2004) as evaluated with SRH and HI assays as presented in table below*. In this trial no vaccine related SAEs were observed.

 

 

Toddlers

Children

Adolescents

 

 

(6-<36 months)

(3-<9 years)

(9-<18 years)

 

 

N=134

N=91

N=89

 

Seroprotection rate

97%

97%

89%

 

(95% CI)

(92-99)

(91-99)

(80-94)

 

Day 43

 

 

 

 

Seroconversion

HI

factor (95% CI)

(109-151)

(97-142)

(51-88)

 

Day 43 to Day 1

 

 

 

 

Seroconversion rate

97%

97%

89%

 

(95% CI)

(92-99)

(91-99)

(80-94)

 

Day 43

 

 

 

 

 

N=133

N=91

N=90

 

Seroprotection rate

100%

100%

100%

 

(95% CI)

(97-100)

(96-100)

(96-100)

 

Day 43

 

 

 

SRH

Seroconversion

factor (95% CI)

(14-18)

(13-17)

(12-16)

 

 

Day 43 to Day 1

 

 

 

 

Seroconversion rate

98%

100%

99%

 

(95% CI)

(95-100)

(96-100)

(94-100)

 

Day 43

 

 

 

*In the absence of CHMP immunogenicity criteria for children, the CHMP immunogenicity criteria used to evaluate seasonal flu vaccines in adults were applied to the serological data obtained after vaccination of children. However the relevance for clinical protection is unknown.

MN results against a A/Vietnam/1194/2004 indicate a seroprotection rate of 99% (95%CI: 94-100),

a seroconversion rate ranging from 97% (95%CI: 91-99) to 99% (95%CI: 96-100) and a GMR ranging from 29 (95%CI: 25-35) to 50 (95%CI: 44-58).

Immunogenicity results with Focetria H1N1v (Study V111_03):

The seroprotection rate and seroconversion rate measured by HI assay and the seroconversion factor expressed as geometric mean ratios of HI for anti-HA antibody to H1N1 after administration of one and two7.5 µg doses of Focetria was evaluated in 70 children and adolescents (9-17 years), 60 children (3-8 years), 58 children (12-35 months) and 49 infants (6-11 months). CHMP immunogenicity criteria set for adults (18-60 years) were met both after the 1st and the 2nd dose in all the above age strata (both in the overall population and in the subset seronegative at baseline).

The European medicines Agency has deferred the obligation to submit the results of studies with Foclivia in one or more subsets of the paediatric populations in active immunisation against H5N1 subtype of Influenza A virus. See section 4.2 for information on paediatric use.

Foclivia has been authorised under “Exceptional Circumstances”.

This means that for scientific reasons, it has not been possible to obtain complete information on this medicinal product. The European Medicines Agency (EMA) will review any new information which may become available every year and this SmPC will be updated as necessary.

5.2Pharmacokinetic properties

Not applicable.

5.3Preclinical safety data

Non-clinical data obtained with Foclivia and with seasonal influenza vaccine containing MF59C.1 adjuvant reveal no special hazard for humans based on conventional studies of repeated

dose toxicity, local tolerance, female fertility, and reproductive and developmental toxicity (through the end of the lactation period)..

6.PHARMACEUTICAL PARTICULARS

6.1List of excipients

Sodium chloride,

Potassium chloride,

Potassium dihydrogen phosphate,

Disodium phosphate dihydrate,

Magnesium chloride hexahydrate,

Calcium chloride dihydrate,

Sodium citrate,

Citric acid,

Water for injections.

For the adjuvant, see section 2.

6.2Incompatibilities

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

6.3Shelf life

1 year.

6.4Special precautions for storage

Store in a refrigerator (2°C - 8°C). Do not freeze. Store in the original package in order to protect from light.

6.5Nature and contents of container

0.5 ml in pre-filled syringe (type I glass) with plunger-stopper (bromo-butyl rubber). Packs of 1 and 10.

Not all pack sizes may be marketed.

6.6Special precautions for disposal and other handling

The vaccine should be allowed to reach room temperature before use. Gently shake before use. Visually inspect the suspension prior to administration. In case of any particles and/or abnormal appearance, the vaccine should be discarded.

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

7.MARKETING AUTHORISATION HOLDER

Seqirus S.r.l.

Via Fiorentina, 1

Siena

Italy

8.MARKETING AUTHORISATION NUMBER(S)

9.DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 19 October 2009

Date of latest renewal: 19 October 2014

10.DATE OF REVISION OF THE TEXT

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

1. NAME OF THE MEDICINAL PRODUCT

Foclivia suspension for injection

Pandemic influenza vaccine (H5N1) (surface antigen, inactivated, adjuvanted)

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Influenza virus surface antigens (haemagglutinin and neuraminidase)* of strain:

A/Vietnam/1194/2004 (H5N1)

7.5 micrograms**

per 0.5 ml dose

 

*propagated in eggs

**expressed in microgram haemagglutinin.

Adjuvant MF59C.1 containing:

 

Squalene

9.75 milligrams

Polysorbate 80

1.175 milligrams

Sorbitan trioleate

1.175 milligrams

This vaccine complies with the WHO recommendations and EU decision for the pandemic.

For the full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Suspension for injection.

Milky-white liquid.

4. CLINICAL PARTICULARS

4.1 Therapeutic indications

Prophylaxis of influenza in an officially declared pandemic situation.

Foclivia should be used in accordance with Official Guidance.

4.2 Posology and method of administration

Posology

Adults and elderly: 0.5 ml at an elected date.

A second dose of vaccine should be given after an interval of at least 3 weeks.

Foclivia was evaluated in adults (18 to 60 years old) and elderly (over 60 years old) following a 1, 22 day primary vaccination schedule.

Data on a third dose (booster) administered 6 months after the first dose are limited (see sections 4.8 and 5.1)

Paediatric population:

The safety and efficacy of Foclivia in subjects under 18 years of age have not yet been established. Currently available data in subjects aged 6 months to 18 years of age are described in section 5.1 but no recommendation on a posology can be made.

No data are available in children aged less than 6 months.

Method of administration

Immunisation should be carried out by intramuscular injection into the deltoid muscle or anterolateral thigh (depending on the muscle mass)..

4.3 Contraindications

History of an anaphylactic (i.e. life-threatening) reaction to any of the constituents or trace residues of eggs, chicken proteins, kanamycin and neomycin sulphate, barium sulphate, formaldehyde and cetyltrimethylammonium bromide (CTAB) of this vaccine. However, in a pandemic situation, it may be appropriate to give the vaccine, provided that facilities for resuscitation are immediately available in case of need. see section 4.4.

4.4 Special warnings and precautions for use

Caution is needed when administrating this vaccine to persons with a known hypersensitivity (other than anaphylactic reaction) to the active substance, to any of the excipients listed in section 6.1 and to eggs, chicken proteins, kanamycin and neomycin sulphate, barium sulphate, formaldehyde and cetyltrimethylammonium bromide (CTAB).

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

If the pandemic situation allows, immunisation shall be postponed in patients with severe febrile illness or acute infection.

Foclivia should under no circumstances be administered intravascularly or subcutaneously. Therefore, healthcare providers need to assess the benefits and potential risks of administering the vaccine in individuals with thrombocytopenia or any bleeding disorder that would contraindicate intramuscular injection unless the potential benefit outweighs the risk of bleedings

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

A protective response may not be elicited in all vaccinees (see section 5.1).

Some cross-protection was observed against related H5N1 virus variants in clinical trials (see section 5.1).

Since a second dose is recommended, it should be noted that there are no safety, immunogenicity or efficacy data to support interchangeability of Foclivia with other H5N1 monovalent vaccines.

While no data is available from the use of Foclivia, cases of convulsion with and without fever have been reported in subjects vaccinated with Focetria an MF59.1 adjuvanted H1N1 pandemic vaccine similar to Foclivia.

The majority of febrile convulsions occurred in paediatric subjects. Some cases were observed in subjects with a history of epilepsy. Particular attention should be given to subjects suffering from epilepsy and the physician should inform the subjects (or parents) about the possibility to experience convulsion. (see section 4.8).

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.

4.5 Interaction with other medicinal products and other forms of interaction

Foclivia should not be given at the same time as other vaccines. However, if co-administration with another vaccine is indicated, 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 serology test results may be obtained by the ELISA method for antibody to human immunodeficiency virus-1 (HIV-1), hepatitis C virus and, especially, HTLV-1. In such cases, the Western blot method is negative. These transitory false-positive results may be due to IgM production in response to the vaccine.

4.6 Fertility, pregnancy and lactation

Pregnancy

No data have been generated with Foclivia in pregnant women.

Safety data are available, however, in pregnant women exposed to Focetria (an H1N1 pandemic vaccine similar to Foclivia) which contains the same amount of MF59C.1 as Foclivia. Postmarketing spontaneously reported adverse events and an interventional study do not suggest direct or indirect harmful effects of Focetria exposure on pregnancy. In addition, two large observational studies designed to assess the safety of Focetria exposure in pregnancy showed no increase in the rates of gestational diabetes, preeclampsia, abortions, stillbirth, low birth weight, prematurity, neonatal deaths, and congenital malformations among almost 10.000 vaccinated pregnant women and their offspring compared with unvaccinated controls.

Health care providers need to assess the benefits and potential risks of administering Foclivia vaccine to pregnant women, taking into consideration official recommendations.

Breast-feeding

The vaccine may be used during lactation.

Fertility

No fertility data are available.

4.7 Effects on ability to drive and use machines

Some of the effects mentioned under section 4.8 “Undesirable Effects” may affect the ability to drive or use machines.

4.8 Undesirable effects

Summary of safety profile

Adults and elderly.(above 18 years old)

From the clinical trials conducted with the pandemic mock-up adjuvanted H5N1 vaccine in adult and elderly (see section 5.1 for more information), most of the reactions were mild in nature, of short duration and qualitatively similar to those induced by conventional seasonal influenza vaccines. It is widely accepted that the adjuvant effect leading to increased immunogenicity is associated with a slightly higher frequency of local reactions (mostly mild pain) compared with conventional, nonadjuvanted influenza vaccines. There were fewer reactions after the second dose compared with the first.

Children and adolescents aged 6 months to 17 years:

In a phase II clinical trial (Study V87P6) safety of a pandemic mock-up adjuvanted H5N1 vaccine was evaluated in children and adolescent (see section 5.1 for more information).

Regardless of age, reactogenicity was higher after the first dose than after the second vaccination. Reactogenicity after a third dose, administered 12 months after the second dose, was higher than after both first and second dose. The percentages of subjects reporting local reactions were higher in the older age groups, mainly due to the higher reports for pain. In toddlers, erythema and tenderness were the most commonly reported solicited local reactions; irritability and unusual crying were the most commonly reported solicited systemic reactions. In children and adolescents pain was the most frequently reported solicited local reaction, and fatigue and headache were the most commonly reported solicited systemic reactions. Across all ages, low percentages of subjects reported fever. Safety data after the first and second dose in children and adolescents with a similar pandemic vaccine (Focetria H1N1v) suggest a comparable safety profile with that reported for the aH5N1 mock-up vaccine formulation (Foclivia).

Frequency of Adverse reactions in clinical trials and postmarketing surveillance is reported hereunder.

Clinical trials

Adverse reactions from clinical trial in adults and elderly (above 18 years old)

The incidence of adverse reactions was evaluated in four clinical trials with different influenza strains and formulations (H5N3, H9N2 and H5N1); 3696 adults and elderly subjects were exposed. Of these subjects, 3618 subjects received the mock-up vaccine Foclivia (A/H5N1) (see section 5.1)

Adverse reactions from clinical trials with the mock-up vaccine Foclivia are listed below.

The incidence of symptoms observed in subjects over 60 years of age was lower as compared to the 18-60 years old population.

Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness:

Nervous system disorders

Common (>1/100, <1/10): headache

Skin and subcutaneous tissue disorders

Common (>1/100, <1/10): sweating

Muscoskeletal, connective tissue and bone disorders

Common (>1/100, <1/10): arthralgia and myalgia

General disorders and administration site conditions

Common (>1/100, <1/10): injection site redness, injection site swelling, injection site induration, injection site ecchymosis and injection site pain, fever, malaise, fatigue and shivering

The majority of these reactions usually disappear within 1-2 days without treatment.

Adverse reactions from clinical trial in children aged 6 months to 17 years

A clinical trial (Study V87P6) was conducted with a H5N1 vaccine combined with MF59C.1 adjuvant (n=334) vs seasonal influenza vaccine (n=137).

 

Injection 1

Injection 2

Injection 3

 

H5N1 adjuvanted

H5N1 adjuvanted

H5N1 adjuvanted

 

vaccine

vaccine

vaccine

Toddlers (6-<36 months)

N=145

N=138

N=124

Any

76%

68%

80%

Local

47%

46%

60%

Systemic

59%

51%

54%

Fever ≥ 38°C (≥ 40°C)

0%

0%

0%

Any Other Adverse Event

54%

49%

35%

Children (3-<9 years)

N=96

N=93

N=85

Any

72%

68%

79%

Local

66%

58%

74%

Systemic

32%

33%

45%

Fever ≥ 38°C (≥ 40°C)

4%

2%

6%

Any Other Adverse Event

36%

31%

19%

Adolescents(9-<18 years)

N=93

N=91

N=83

Any

91%

82%

89%

Local

81%

70%

81%

Systemic

69%

52%

69%

Fever ≥ 38°C (≥ 40°C)

0%

1%

2%

Any Other Adverse Event

30%

27%

22%

Focetria (H1N1v)

Adverse reactions in the week following vaccination with Focetria H1N1v from 77 children 3-8 years old and 80 children and adolescents 9-17 years old receiving the 7.5 µg formulation were reported as follows:

 

Injection 1

Injection 2

Children (3 to 8 years of age)

N= 77

N= 75

Any adverse reaction

74%

69%

Local

62%

56%

Systemic

39%

35%

Fever ≥ 38°C to 38.9°C

4%

1%

Fever 39°C to 39.9°C

0%

1%

Fever ≥ 40° C

0%

0%

Any other AE

14%

17%

Adolescents (9 to 17 years of age)

N= 80

N= 79

Any adverse reaction

79%

66%

Local

70%

58%

Systemic

45%

30%

Fever ≥38°C to 38.9°C

3%

1%

Fever 39°C to 39.9°C

0%

0%

Fever ≥ 40° C

0%

0%

Any other AE

13%

10%

Data in children and adolescents 3-17 years suggest a slight decrease in reactogenicity after the second dose, with no increase in rates of fever.

Very common reactions reported in children and adolescents 3 to 17 years of age: Pain, induration and erythema, malaise, myalgia, headache and fatigue.

Adverse reactions in the week following vaccination with Focetria H1N1v from

73 infants 6-11 months old and 73 toddlers 12-35 months old, receiving the 7.5 µg formulation were reported as follows:

 

Injection 1

Injection 2

Infants (6 to 11 months of age)

N= 73

N= 68

Any adverse reaction

79%

65%

Local

44%

26%

Systemic

70%

56%

Fever ≥38°C to 38.9°C

11%

9%

Fever 39°C to 39.9°C

3%

4%

Fever ≥ 40° C

0%

0%

Any other AE

32%

31%

Toddlers (12 to 35 months of age)

N= 73

N= 71

Any adverse reaction

70%

71%

Local

51%

49%

Systemic

60%

49%

Fever ≥38°C to 38.9°C

10%

11%

Fever 39°C to 39.9°C

4%

1%

Fever ≥ 40° C

1%

0%

Any other AE

21%

24%

Data in infants and toddlers 6-35 months of age suggest a slight decrease in reactogenicity after the second dose, with no increase in rates of fever.

Very common reactions reported in 146 infants and toddlers 6 to 35 months of age:

Tenderness, erythema, irritability, unusual crying, sleepiness, diarrhoea, vomiting and change in eating habits. Induration and ecchymosis were very common reaction in toddlers but were less common in infants.

Post-marketing surveillance

In addition to the adverse reactions reported in the clinical trials, the following have been reported during post-marketing experience with Focetria H1N1v:

Blood and lymphatic system disorders

Lymphadenopathy.

Cardiac disorders

Palpitation, tachycardia.

General disorders and administration site conditions

Asthenia.

Muscoskeletal and connective tissue and bone disorders

Muscular weakness, pain in extremities.

Respiratory, thoracic and mediastinal disorders

Cough.

Skin and subcutaneous tissue disorders

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

Gastrointestinal disorders

Gastrointestinal disorders such as nausea, vomiting, abdominal pain and diarrhoea.

Nervous system disorders

Headache, dizziness, somnolence, syncope. Neurological disorders, such as neuralgia, paraesthesia, convulsions and neuritis.

Immune system disorders

Allergic reactions, anaphylaxis including dyspnoea, bronchospasm, laryngeal oedema, in rare cases leading to shock.

From Post-marketing surveillance with adjuvanted interpandemic trivalent vaccines with composition similar to that of Foclivia (an MF59.1 adjuvanted H1N1 pandemic vaccine), the following additional adverse reactions have been reported:

Rare (>1/10,000, <1/1,000):

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

Very rare (<1/10,000):

Vasculitis with transient renal involvement and exudative erythema multiforme. Neurological disorders, such as encephalomyelitis, neuritis and Guillain Barré syndrome.

Adverse event(s) from post-marketing surveillance with the pandemic vaccine: not applicable.

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

No case of overdose has been reported.

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Influenza vaccine, ATC Code: J07BB02

This section describes the clinical experience with the H5N1 mock-up vaccines following a two-dose administration of 7.5 microgram.

Mock-up vaccines contain influenza antigens that are different from those in the currently circulating influenza viruses. These antigens can be considered as ‘novel’ antigens and simulate a situation where the target population for vaccination is immunologically naïve. Data obtained with a mock-up vaccine will support a vaccination strategy that is likely to be used for the pandemic vaccine: clinical efficacy and safety data obtained with mock-up vaccines are relevant for the pandemic vaccines.

Adults (18-60 years)

A Phase II clinical trial (Study V87P1) was conducted with a H5N1 vaccine combined with MF59C.1 adjuvant in 312 healthy adults. Two doses of vaccine containing H5N1 (A/Vietnam/1194/2004; 7.5 µg HemoAgglutinin (HA)/dose adjuvanted) were administered three weeks apart to 156 subjects.

In another clinical trial (Phase III) (Study V87P13), 2693 healthy adults were enrolled and received two doses of vaccine containing H5N1 (A/Vietnam/1194/2004; 7.5 µg HA/dose adjuvanted) administered three weeks apart. Immunogenicity was assessed in a subset (n=197) of the study population.

The seroprotection rate*, seroconversion rate* and the seroconversion factor** for anti-HA antibody to H5N1 A/Vietnam/1194/2004 in the adults measured by Single Radial Haemolysis (SRH) assay was as follows:

 

Study V87P1

Study V87P13

Anti-HA antibody (SRH)

21 days after 2nd dose

21 days after 2nd dose

 

N=149

N=197

Seroprotection rate (95%CI)*

85% (79-91)

91% (87-95)

Seroconversion rate (95%CI)*

85% (78-90)

78% (72-84)

Seroconversion factor (95%CI)**

7.74 (6.6-9.07)

4.03 (3.54-4.59)

 

 

 

 

Study V87P13

Study V87P13

Anti-HA antibody (SRH)

21 days after 2nd dose

21 days after 2nd dose

 

N=69

N=128

Baseline Serostatus

< 4 mm2

≥ 4 mm2

Seroprotection rate (95%CI)*

87% (77-94)

94% (88-97)

Seroconversion rate (95%CI)*

87% (77-94)

73% (65-81)

Seroconversion factor (95%CI)**

8.87 (7.09-11)

2.71 (2.38-3.08)

*measured by SRH assay ≥ 25 mm2

**geometric mean ratios of SRH

MicroNeutralization (MN) results against A/Vietnam/1194/2004 indicate a seroprotection and seroconversion rate ranging from 67% (60-74) to 85% (78-90) and 65% (58-72) to 83% (77-89), respectively. Immune response to vaccination assessed by MN assay is in line with results obtained with SRH.

Persistence of antibodies after primary vaccination in this population was assessed by Hemagglutination Inhibition (HI), SRH, and MN assays. Compared to the antibody levels obtained at day 43 after completion of primary vaccination schedules, antibody levels at day 202 were reduced by 1/5 to 1/2 from their prior levels.

Elderly (>60 years)

The seroprotection rate*, seroconversion rate* and the seroconversion factor** for anti-HA antibody to H5N1 A/Vietnam/1194/2004 in subjects aged over 60 (limited number of subjects were

above 70 years of age) measured by SRH assay assessed in two clinical studies were as follows:

 

Study V87P1

Study V87P13

Anti-HA antibody (SRH)

21 days after 2nd dose

21 days after 2nd dose

 

N=84

N=210

Seroprotection rate (95%CI)*

80% (70-88)

82% (76-87)

Seroconversion rate (95%CI)*

70% (59-80)

63% (56-69)

Seroconversion factor (95%CI)**

4.96 (3.87-6.37)

2.9 (2.53-3.31)

 

 

 

 

Study V87P13

Study V87P13

Anti-HA antibody (SRH)

21 days after 2nd dose

21 days after 2nd dose

 

N=66

N=143

Baseline Serostatus

< 4 mm2

≥ 4 mm2

Seroprotection rate (95%CI)*

82% (70-90)

82% (75-88)

Seroconversion rate (95%CI)*

82% (70-90)

54% (45-62)

Seroconversion factor (95%CI)**

8.58 (6.57-11)

1.91 (1.72-2.12)

*measured by SRH assay ≥ 25 mm2

**geometric mean ratios of SRH

MN results against A/Vietnam/1194/2004 indicate a seroprotection and seroconversion rate ranging from of 57% (50-64) to 79% (68-87) and 55% (48-62) to 58% (47-69) respectively. MN results, similar to SRH results demonstrated strong immune response after completion of priming vaccination series in a population of elderly subjects.

Persistence of antibodies after primary vaccination in this population as assessed by HI, SRH, and MN tests reduced from 1/2 to 1/5th of their post-vaccination level at day 202 as compared to day 43 after completion of primary schedules as assessed by HI, SRH, and MN tests. Up to 50% of the elderly subjects immunised with H5N1 vaccine combined with MF59C were seroprotected at six months.

Booster dose

A third (booster) dose of H5N1 vaccine combined with MF59C was administered 6 months onwards after the primary vaccination series. Results are shown by SRH.

The seroprotection rate*, seroconversion rate* and the seroconversion factor** for anti-HA antibody to H5N1 A/Vietnam/1194/2004 measured by SRH assays were as follows:

 

Study V87P1 Adults

Study V87P1 Elderly

 

Booster (6 months after 2nd dose

Booster (6 months after 2nd dos

 

)

e)

SRH

N=71

N=38

Seroprotection rate (95%CI)*

89% (79-95)

84% (69-94)

Seroconversion rate (95%CI)*

83% (72-91)

63% (46-78)

Seroconversion factor (95%CI)*

5.96 (4.72-7.53)

5.15 (3.46-7.66)

*

 

 

*measured by SRH assay ≥ 25 mm2

**geometric mean ratios of SRH

There is limited experience for the booster dose in the elderly population.

Supportive data in adult and elderly populations

In two dose finding studies 78 adults received an adjuvanted mock-up vaccine (H5N3 or H9N2). Two doses of vaccine with H5N3 (A/Duck/Singapore/97) strain at 3 different dosages

(7.5, 15 and 30 µg HA/dose) were administered three weeks apart.

Serum samples were tested against the original H5N3 and also a number of H5N1 isolates.

Serologic responses obtained with the SRH assay showed that 100% of subjects achieved seroprotection and 100% seroconverted after two 7.5 g injections. The adjuvanted vaccine was also found to induce antibodies that cross-protected against the H5N1 strains isolated in 2003 and 2004, which exhibit some antigenic drift compared to the original strains.

Two doses of vaccine containing H9N2 (A/chicken/Hong Kong/G9/97) strain at 4 different dosages (3.75, 7.5, 15 and 30 µg HA/dose), were administered four weeks apart. Serologic responses obtained with the HI assay showed that 92% of subjects achieved seroprotection and 75% seroconverted after two 7.5 g injections.

Cross reactivity

Adults (18-60 years)

Seroprotection rate*, seroconversion rate* and the seroconversion factor** for anti-HA antibodies to H5N1 A/turkey/Turkey/05 after the 2nd dose in adults 18-60 years of age, measured by SRH and HI assays were as follows:

 

 

Study V87P1

Study V87P13

 

Anti-HA antibody

21 days after 2nd dose

21 days after 2nd dose

 

 

N=70

N=197

 

Seroprotection rate (95%CI)*

70% (58-80)

59% (52-66)

SRH

Seroconversion rate (95%CI)*

NA***

49% (42-56)

 

Seroconversion factor(95%CI)**

NA***

2.37 (2.1-2.67)

 

 

N=69

N=197

 

Seroprotection rate (95%CI)°

36%(25-49)

23% (18-30)

HI

Seroconversion rate (95%CI)°

NA***

19% (14-25)

 

Seroconversion factor (95%CI)°°

NA***

1.92 (1.64-2.25)

*measured by SRH assay ≥ 25 mm2

**geometric mean ratios of SRH

° measured by HI assay ≥ 40 °° geometric mean ratios of HI

***In V87P1: baseline not tested

MN results for the clinical studies in the Table above revealed a seroprotection rate against A/turkey/Turkey/05 ranging from 27% (17-39) (V87P1) to 39% (32-46) (V87P13) and seroconversion rate of 36% (29-43) for V87P13 study. MN results in V87P13 yielded a GMR against A/turkey/Turkey/05 of 2.77 (2.4-3.2).

Elderly (>60 years)

Seroprotection rate*, seroconversion rate* and the seroconversion factor** for anti-HA antibodies to H5N1 A/turkey/Turkey/05 after the 2nd dose in elderly >60 years of age, measured by SRH

and HI assays were as follows:

 

 

Study V87P1

Study V87P13

 

Anti-HA antibody

21 days after 2nd dose

21 days after 2nd dose

 

 

N=37

N=207

 

Seroprotection rate (95%CI)*

57% (39-73)

20% (18-23)

SRH

Seroconversion rate (95%CI)*

NA***

48% (41-55)

 

Seroconversion factor (95%CI)**

NA***

1.74 (1.57-1.94)

 

 

N=36

N=208

 

Seroprotection rate (95%CI)°

36%(21-54)

25% (19-32)

HI

Seroconversion rate (95%CI)°

NA***

19% (14-25)

 

Seroconversion factor (95%CI)°°

NA***

1.79 (1.56-2.06)

*measured by SRH assay ≥ 25 mm2

**geometric mean ratios of SRH

° measured by HI assay ≥ 40 °° geometric mean ratios of HI

***In V87P1: baseline not tested

MN results for the clinical studies in the Table above revealed a seroprotection rate against A/turkey/Turkey/05 ranging from 11% (3-25) (study V87P1) to 30% (24-37) (study V87P13) and seroconversion rate of 25% (19-31) for study V87P13. MN results in V87P13 yielded a GMR against A/turkey/Turkey/05 of 2.01 (1.78-2.26).

Data in paediatric populations

A clinical trial (study V87P6) was conducted with a H5N1 vaccine combined with MF59C.1 adjuvant in 471 children from 6 months to 17 years of age. Two doses of 7.5 micrograms were administered three weeks apart and a third dose 12 months following the first dose. After 3 weeks from the 2nd vaccination (day 43) all age groups (i.e. 6-35 months, 3-8 years and 9-17 years) achieved high levels of antibodies to (A/Vietnam/1194/2004) as evaluated with SRH and HI assays as presented in table below*. In this trial no vaccine related SAEs were observed.

 

 

Toddlers

Children

Adolescents

 

 

(6-<36 months)

(3-<9 years)

(9-<18 years)

 

 

N=134

N=91

N=89

 

Seroprotection rate

97%

97%

89%

 

(95% CI)

(92-99)

(91-99)

(80-94)

 

Day 43

 

 

 

 

Seroconversion

HI

factor (95% CI)

(109-151)

(97-142)

(51-88)

 

Day 43 to Day 1

 

 

 

 

Seroconversion rate

97%

97%

89%

 

(95% CI)

(92-99)

(91-99)

(80-94)

 

Day 43

 

 

 

 

 

N=133

N=91

N=90

 

Seroprotection rate

100%

100%

100%

 

(95% CI)

(97-100)

(96-100)

(96-100)

 

Day 43

 

 

 

SRH

Seroconversion

factor (95% CI)

(14-18)

(13-17)

(12-16)

 

 

Day 43 to Day 1

 

 

 

 

Seroconversion rate

98%

100%

99%

 

(95% CI)

(95-100)

(96-100)

(94-100)

 

Day 43

 

 

 

*In the absence of CHMP immunogenicity criteria for children, the CHMP immunogenicity criteria used to evaluate seasonal flu vaccines in adults were applied to the serological data obtained after vaccination of children. However the relevance for clinical protection is unknown.

MN results against a A/Vietnam/1194/2004 indicate a seroprotection rate of 99% (95%CI: 94-100),

a seroconversion rate ranging from 97% (95%CI: 91-99) to 99% (95%CI: 96-100) and a GMR ranging from 29 (95%CI: 25-35) to 50 (95%CI: 44-58).

Immunogenicity results with Focetria H1N1v (Study V111_03):

The seroprotection rate and seroconversion rate measured by HI assay and the seroconversion factor expressed as geometric mean ratio of HI for anti-HA antibody to H1N1 after administration of one and two 7.5 µg doses of Focetria was evaluated in 70 children and adolescents (9-17 years), 60 children (3-8 years), 58 children (12-35 months) and 49 infants (6-11 months). CHMP immunogenicity criteria set for adults (18-60 years) were met both after the 1st and the 2nd dose in all the above age strata (both in the overall population and in the subset seronegative at baseline).

The European medicines Agency has deferred the obligation to submit the results of studies with Foclivia in one or more subsets of the paediatric populations in active immunisation against H5N1 subtype of Influenza A virus. See section 4.2 for information on paediatric use.

Foclivia has been authorised under “Exceptional Circumstances”.

This means that for scientific reasons, it has not been possible to obtain complete information on this medicinal product. The European Medicines Agency (EMA) will review any new information which may become available every year and this SmPC will be updated as necessary.

5.2 Pharmacokinetic properties

Not applicable.

5.3 Preclinical safety data

Non-clinical data obtained with Foclivia and with seasonal influenza vaccine containing MF59C.1 adjuvant reveal no special hazard for humans based on conventional studies of repeated

dose toxicity, local tolerance, female fertility, and reproductive and developmental toxicity (through the end of the lactation period).

6. PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Sodium chloride,

Potassium chloride,

Potassium dihydrogen phosphate,

Disodium phosphate dihydrate,

Magnesium chloride hexahydrate,

Calcium chloride dihydrate,

Sodium citrate,

Citric acid,

Water for injections.

For the adjuvant, see section 2.

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 - 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 in single-dose vial (type I glass) with stopper (halo-butyl rubber). Packs of 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. Gently shake before use. Visually inspect the suspension prior to administration. In case of any particles and/or abnormal appearance, the vaccine should be discarded.

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

7. MARKETING AUTHORISATION HOLDER

Seqirus S.r.l.

Via Fiorentina, 1

Siena

Italy

8. MARKETING AUTHORISATION NUMBER(S)

EU/1/09/577/003

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 19 October 2009

Date of latest renewal: 19 October 2014

10. DATE OF REVISION OF THE TEXT

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

1. NAME OF THE MEDICINAL PRODUCT

Foclivia suspension for injection in multidose container

Pandemic influenza vaccine (H5N1) (surface antigen, inactivated, adjuvanted)

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Influenza virus surface antigens (haemagglutinin and neuraminidase)* of strain:

A/Vietnam/1194/2004 (H5N1)

7.5 micrograms **

per 0.5 ml dose

 

*propagated in eggs

**expressed in microgram haemagglutinin.

Adjuvant MF59C.1 containing:

 

Squalene

9.75 milligrams

Polysorbate 80

1.175 milligrams

Sorbitan trioleate

1.175 milligrams

Excipients:

 

Thiomersa

0.05 milligrams

This is a multidose container. See section 6.5 for the number of doses per vial.

This vaccine complies with the WHO recommendations and EU decision for the pandemic.

For the full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Suspension for injection.

Milky-white liquid.

4. CLINICAL PARTICULARS

4.1 Therapeutic indications

Prophylaxis of influenza in an officially declared pandemic situation.

Foclivia should be used in accordance with Official Guidance.

4.2 Posology and method of administration

Posology

Adults and elderly: 0.5 ml at an elected date.

A second dose of vaccine should be given after an interval of at least 3 weeks.

Foclivia was evaluated in adults (18 to 60 years old) and elderly (over 60 years old) following a 1, 22 day primary vaccination schedule.

Data on a third dose (booster) administered 6 months after the first dose are limited (see sections 4.8 and 5.1).

Paediatric population:

The safety and efficacy of Foclivia in subjects under 18 years of age have not yet been established. Currently available data in subjects aged 6 months to 18 years of age are described in section 5.1 but no recommendation on a posology can be made.

No data are available in children aged less than 6 months.

Method of administration

Immunisation should be carried out by intramuscular injection into the deltoid muscle or anterolateral thigh (depending on the muscle mass).

4.3 Contraindications

History of an anaphylactic (i.e. life-threatening) reaction to any of the constituents or trace residues of eggs, chicken proteins, kanamycin and neomycin sulphate, barium sulphate, formaldehyde and cetyltrimethylammonium bromide (CTAB) of this vaccine. However, in a pandemic situation, it may be appropriate to give the vaccine, provided that facilities for resuscitation are immediately available in case of need.see section 4.4

4.4 Special warnings and precautions for use

Caution is needed when administrating this vaccine to persons with a known hypersensitivity (other than anaphylactic reaction) to the active substance, to any of the excipients listed in section 6.1, to thiomersal and to eggs, chicken proteins, kanamycin and neomycin sulphate, barium sulphate, formaldehyde and cetyltrimethylammonium bromide (CTAB).

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

If the pandemic situation allows, immunisation shall be postponed in patients with severe febrile illness or acute infection.

Foclivia should under no circumstances be administered intravascularly or subcutaneously. Therefore, healthcare providers need to assess the benefits and potential risks of administering the vaccine in individuals with thrombocytopenia or any bleeding disorder that would contraindicate intramuscular injection unless the potential benefit outweighs the risk of bleedings.

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

A protective response may not be elicited in all vaccinees (see section 5.1).

Some cross-protection was observed against related H5N1 virus variants in clinical trials (see section 5.1).

Since a second dose is recommended, it should be noted that there are no safety, immunogenicity or efficacy data to support interchangeability of Foclivia with other H5N1 monovalent vaccines.

While no data is available from the use of Foclivia, cases of convulsion with and without fever have been reported in subjects vaccinated with Focetria an MF59.1 adjuvanted H1N1 pandemic vaccine similar to Foclivia.

The majority of febrile convulsions occurred in paediatric subjects. Some cases were observed in subjects with a history of epilepsy. Particular attention should be given to subjects suffering from epilepsy and the physician should inform the subjects (or parents) about the possibility to experience convulsion. (see section 4.8).

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.

4.5 Interaction with other medicinal products and other forms of interaction

Foclivia should not be given at the same time as other vaccines. However, if co-administration with another vaccine is indicated, 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 serology test results may be obtained by the ELISA method for antibody to human immunodeficiency virus-1 (HIV-1), hepatitis C virus and, especially, HTLV-1. In such cases, the Western blot method is negative. These transitory false-positive results may be due to IgM production in response to the vaccine.

4.6 Fertility, pregnancy and lactation

Pregnancy

No data have been generated with Foclivia in pregnant women.

Safety data are available, however, in pregnant women exposed to Focetria (an H1N1 pandemic vaccine similar to Foclivia which contains the same amount of MF59C.1 as Foclivia. Postmarketing spontaneously reported adverse events and an interventional study do not suggest direct or indirect harmful effects of Focetria exposure on pregnancy. In addition, two large observational studies designed to assess the safety of Focetria exposure in pregnancy showed no increase in the rates of gestational diabetes, preeclampsia, abortions, stillbirth, low birth weight, prematurity, neonatal deaths, and congenital malformations among almost 10.000 vaccinated pregnant women and their offspring compared with unvaccinated controls.

Health care providers need to assess the benefits and potential risks of administering Foclivia vaccine to pregnant women, taking into consideration official recommendations.

Breast-feeding

The vaccine may be used during lactation.

Fertility

No fertility data are available.

4.7 Effects on ability to drive and use machines

Some of the effects mentioned under section 4.8 “Undesirable Effects” may affect the ability to drive or use machines.

4.8 Undesirable effects

Summary of safety profile

Adults and elderly.(above 18 years old)

From the clinical trials conducted with the pandemic mock-up adjuvanted H5N1 vaccine in adult and elderly (see section 5.1 for more information), most of the reactions were mild in nature, of short duration and qualitatively similar to those induced by conventional seasonal influenza vaccines. It is widely accepted that the adjuvant effect leading to increased immunogenicity is associated with

a slightly higher frequency of local reactions (mostly mild pain) compared with conventional,

nonadjuvanted influenza vaccines. There were fewer reactions after the second dose compared with the first.

Children and adolescents aged 6 months to 17 years:

In a phase II clinical trial (Study V87P6) safety of a pandemic mock-up adjuvanted H5N1 vaccine was evaluated in children and adolescent (see section 5.1 for more information).

Regardless of age, reactogenicity was higher after the first dose than after the second vaccination. Reactogenicity after a third dose, administered 12 months after the second dose, was higher than after both first and second dose. The percentages of subjects reporting local reactions were higher in the older age groups, mainly due to the higher reports for pain. In toddlers, erythema and tenderness were the most commonly reported solicited local reactions; irritability and unusual crying were the most commonly reported solicited systemic reactions. In children and adolescents pain was the most frequently reported solicited local reaction, and fatigue and headache were the most commonly reported solicited systemic reactions. Across all ages, low percentages of subjects reported fever. Safety data after the first and second dose in children and adolescents with a similar pandemic vaccine (Focetria H1N1v) suggest a comparable safety profile with that reported for the aH5N1 mock-up vaccine formulation (Foclivia).

Frequency of Adverse reactions in clinical trials and postmarketing surveillance is reported hereunder.

Clinical trials

Adverse reactions from clinical trial in adults and elderly (above 18 years old)

The incidence of adverse reactions was evaluated in four clinical trials with different influenza strains and formulations (H5N3, H9N2 and H5N1); 3696 adults and elderly subjects were exposed. Of these subjects, 3618 subjects received the mock-up vaccine Foclivia (A/H5N1) (see section 5.1).

Adverse reactions from clinical trials with the mock-up vaccine Foclivia are listed below.

The incidence of symptoms observed in subjects over 60 years of age was lower as compared to the 18-60 years old population.

Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness:

Nervous system disorders

Common (>1/100, <1/10): headache

Skin and subcutaneous tissue disorders

Common (>1/100, <1/10): sweating

Muscoskeletal, connective tissue and bone disorders

Common (>1/100, <1/10): arthralgia and myalgia

General disorders and administration site conditions

Common (>1/100, <1/10): injection site redness, injection site swelling, injection site induration, injection site ecchymosis and injection site pain, fever, malaise, fatigue and shivering

The majority of these reactions usually disappear within 1-2 days without treatment.

Adverse reactions from clinical trial in children aged 6 months to 17 years

A clinical trial (Study V87P6) was conducted with a H5N1 vaccine combined with MF59C.1 adjuvant (n=334) vs seasonal influenza vaccine (n=137).

 

 

 

Second dose (21 days

 

Third dose

 

First dose

 

 

(12 months after the

 

 

after the first dose)

 

 

 

 

 

second dose)

 

 

 

 

 

 

 

H5N1 adjuvanted vaccine

 

Toddlers (6-<36 months)

N=145

 

N=138

 

N=124

Any

76%

 

68%

 

80%

Local

47%

 

46%

 

60%

Systemic

59%

 

51%

 

54%

Fever ≥ 38°C (≥ 40°C)

0%

 

0%

 

0%

Any Other Adverse Event

54%

 

49%

 

35%

Children (3-<9 years)

N=96

 

N=93

 

N=85

Any

72%

 

68%

 

79%

Local

66%

 

58%

 

74%

Systemic

32%

 

33%

 

45%

Fever ≥ 38°C (≥ 40°C)

4%

 

2%

 

6%

Any Other Adverse Event

36%

 

31%

 

19%

Adolescents(9-<18 years)

N=93

 

N=91

 

N=83

Any

91%

 

82%

 

89%

Local

81%

 

70%

 

81%

Systemic

69%

 

52%

 

69%

Fever ≥ 38°C (≥ 40°C)

0%

 

1%

 

2%

Any Other Adverse Event

30%

 

27%

 

22%

Focetria (H1N1v)

Adverse reactions in the week following vaccination with Focetria H1N1v from 77 children 3-8 years old and 80 children and adolescents 9-17 years old receiving the 7.5 µg formulation were reported as follows:

 

Injection 1

Injection 2

Children (3 to 8 years of age)

N= 77

N= 75

Any adverse reaction

74%

69%

Local

62%

56%

Systemic

39%

35%

Fever ≥ 38°C to 38.9°C

4%

1%

Fever 39°C to 39.9°C

0%

1%

Fever ≥ 40° C

0%

0%

Any other AE

14%

17%

Adolescents (9 to 17 years of age)

N= 80

N= 79

Any adverse reaction

79%

66%

Local

70%

58%

Systemic

45%

30%

Fever ≥38°C to 38.9°C

3%

1%

Fever 39°C to 39.9°C

0%

0%

Fever ≥ 40° C

0%

0%

Any other AE

13%

10%

Data in children and adolescents 3-17 years suggest a slight decrease in reactogenicity after the second dose, with no increase in rates of fever.

Very common reactions reported in children and adolescents 3 to 17 years of age: Pain, induration and erythema, malaise, myalgia, headache and fatigue.

Adverse reactions in the week following vaccination with Focetria H1N1v from

73 infants 6-11 months old and 73 toddlers 12-35 months old, receiving the 7.5 µg formulation were reported as follows:

 

Injection 1

Injection 2

Infants (6 to 11 months of age)

N= 73

N= 68

Any adverse reaction

79%

65%

Local

44%

26%

Systemic

70%

56%

Fever ≥38°C to 38.9°C

11%

9%

Fever 39°C to 39.9°C

3%

4%

Fever ≥ 40° C

0%

0%

Any other AE

32%

31%

Toddlers (12 to 35 months of age)

N= 73

N= 71

Any adverse reaction

70%

71%

Local

51%

49%

Systemic

60%

49%

Fever ≥38°C to 38.9°C

10%

11%

Fever 39°C to 39.9°C

4%

1%

Fever ≥ 40° C

1%

0%

Any other AE

21%

24%

Data in infants and toddlers 6-35 months of age suggest a slight decrease in reactogenicity after the second dose, with no increase in rates of fever.

Very common reactions reported in 146 infants and toddlers 6 to 35 months of age:

Tenderness, erythema, irritability, unusual crying, sleepiness, diarrhoea, vomiting and change in eating habits. Induration and ecchymosis were very common reactions in toddlers but were less common in infants.

Post-marketing surveillance

In addition to the adverse reactions reported in the clinical trials, the following have been reported during post-marketing experience with Focetria H1N1v:

Blood and lymphatic system disorders

Lymphadenopathy.

Cardiac disorders

Palpitation, tachycardia.

General disorders and administration site conditions

Asthenia.

Muscoskeletal and connective tissue and bone disorders

Muscular weakness, pain in extremities.

Respiratory, thoracic and mediastinal disorders

Cough.

Skin and subcutaneous tissue disorders

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

Gastrointestinal disorders

Gastrointestinal disorders such as nausea, vomiting, abdominal pain and diarrhoea.

Nervous system disorders

Headache, dizziness, somnolence, syncope. Neurological disorders, such as neuralgia, paraesthesia, convulsions and neuritis.

Immune system disorders

Allergic reactions, anaphylaxis including dyspnoea, bronchospasm, laryngeal oedema, in rare cases leading to shock.

From Post-marketing surveillance with adjuvanted interpandemic trivalent vaccines with composition similar to Foclivia (an MF59.1 adjuvanted H1N1 pandemic vaccine), the following additional adverse reactions have been reported:

Rare (>1/10,000, <1/1,000):

Thrombocytopenia (some very rare cases were severe with platelet counts less than 5.000 per mm3).

Very rare (<1/10,000):

Vasculitis with transient renal involvement and exudative erythema multiforme. Neurological disorders, such as encephalomyelitis, neuritis and Guillain Barré syndrome.

Adverse event(s) from post-marketing surveillance with the pandemic vaccine: not applicable.

This medicinal product contains thiomersal (an organomercuric compound) as a preservative and therefore, it is possible that sensitisation reactions may occur (see section 4.4).

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

No case of overdose has been reported.

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Influenza vaccine, ATC Code: J07BB02

This section describes the clinical experience with the H5N1 mock-up vaccines following a two-dose administration of 7.5 microgram.

Mock-up vaccines contain influenza antigens that are different from those in the currently circulating influenza viruses. These antigens can be considered as ‘novel’ antigens and simulate a situation where the target population for vaccination is immunologically naïve. Data obtained with a mock-up vaccine will support a vaccination strategy that is likely to be used for the pandemic vaccine: clinical efficacy and safety data obtained with mock-up vaccines are relevant for the pandemic vaccines.

Adults (18-60 years)

A Phase II clinical trial (Study V87P1) was conducted with a H5N1 vaccine combined with MF59C.1 adjuvant in 312 healthy adults. Two doses of vaccine containing H5N1 (A/Vietnam/1194/2004; 7.5 µg HemoAgglutinin (HA)/dose adjuvanted) were administered three weeks apart to 156 subjects.

In another clinical trial (Phase III) (Study V87P13), 2693 healthy adults were enrolled and received two doses of vaccine containing H5N1 (A/Vietnam/1194/2004; 7.5 µg HA/dose adjuvanted) administered three weeks apart. Immunogenicity was assessed in a subset (n=197) of the study population.

The seroprotection rate*, seroconversion rate* and the seroconversion factor** for anti-HA antibody to H5N1 A/Vietnam/1194/2004 in the adults measured by Single Radial Haemolysis (SRH) assay was as follows:

 

Study V87P1

Study V87P13

Anti-HA antibody (SRH)

21 days after 2nd dose

21 days after 2nd dose

 

N=149

N=197

Seroprotection rate (95%CI)*

85% (79-91)

91% (87-95)

Seroconversion rate (95%CI)*

85% (78-90)

78% (72-84)

Seroconversion factor (95%CI)**

7.74 (6.6-9.07)

4.03 (3.54-4.59)

 

 

 

 

Study V87P13

Study V87P13

Anti-HA antibody (SRH)

21 days after 2nd dose

21 days after 2nd dose

 

N=69

N=128

Baseline Serostatus

< 4 mm2

≥ 4 mm2

Seroprotection rate (95%CI)*

87% (77-94)

94% (88-97)

Seroconversion rate (95%CI)*

87% (77-94)

73% (65-81)

Seroconversion factor (95%CI)**

8.87 (7.09-11)

2.71 (2.38-3.08)

*measured by SRH assay ≥ 25 mm2

**geometric mean ratios of SRH

MicroNeutralization (MN) results against A/Vietnam/1194/2004 indicate a seroprotection and seroconversion rate ranging from 67% (60-74) to 85% (78-90) and 65% (58-72) to 83% (77-89), respectively. Immune response to vaccination assessed by MN assay is in line with results obtained with SRH.

Persistence of antibodies after primary vaccination in this population was assessed by Hemagglutination Inhibition (HI), SRH, and MN assays. Compared to the antibody levels obtained at day 43 after completion of primary vaccination schedules, antibody levels at day 202 were reduced by 1/5 to 1/2 from their prior levels.

Elderly (>60 years)

The seroprotection rate*, seroconversion rate* and the seroconversion factor** for anti-HA antibody to H5N1 A/Vietnam/1194/2004 in subjects aged over 60 (limited number of subjects were

above 70 years of age) measured by SRH assay assessed in two clinical studies were as follows:

 

Study V87P1

Study V87P13

Anti-HA antibody (SRH)

21 days after 2nd dose

21 days after 2nd dose

 

N=84

N=210

Seroprotection rate (95%CI)*

80% (70-88)

82% (76-87)

Seroconversion rate (95%CI)*

70% (59-80)

63% (56-69)

Seroconversion factor (95%CI)**

4.96 (3.87-6.37)

2.9 (2.53-3.31)

 

 

 

 

Study V87P13

Study V87P13

Anti-HA antibody (SRH)

21 days after 2nd dose

21 days after 2nd dose

 

N=66

N=143

Baseline Serostatus

< 4 mm2

≥ 4 mm2

Seroprotection rate (95%CI)*

82% (70-90)

82% (75-88)

Seroconversion rate (95%CI)*

82% (70-90)

54% (45-62)

Seroconversion factor (95%CI)**

8.58 (6.57-11)

1.91 (1.72-2.12)

*measured by SRH assay ≥ 25 mm2

**geometric mean ratios of SRH

MN results against A/Vietnam/1194/2004 indicate a seroprotection and seroconversion rate ranging from of 57% (50-64) to 79% (68-87) and 55% (48-62) to 58% (47-69) respectively. MN results, similar to SRH results demonstrated strong immune response after completion of priming vaccination series in a population of elderly subjects.

Persistence of antibodies after primary vaccination in this population as assessed by HI, SRH, and MN tests reduced from 1/2 to 1/5th of their post-vaccination level at day 202 as compared to day 43 after completion of primary schedules as assessed by HI, SRH, and MN tests. Up to 50% of the elderly subjects immunised with H5N1 vaccine combined with MF59C were seroprotected at six months.

Booster dose

A third (booster) dose of H5N1 vaccine combined with MF59C was administered 6 months onwards after the primary vaccination series. Results are shown by SRH.

The seroprotection rate*, seroconversion rate* and the seroconversion factor** for anti-HA antibody to H5N1 A/Vietnam/1194/2004 measured by SRH assays were as follows:

 

Study V87P1 Adults

Study V87P1 Elderly

 

Booster (6 months after 2nd dose

Booster (6 months after 2nd dos

 

)

e)

SRH

N=71

N=38

Seroprotection rate (95%CI)*

89% (79-95)

84% (69-94)

Seroconversion rate (95%CI)*

83% (72-91)

63% (46-78)

Seroconversion factor (95%CI)*

5.96 (4.72-7.53)

5.15 (3.46-7.66)

*

 

 

*measured by SRH assay ≥ 25 mm2

**geometric mean ratios of SRH

There is limited experience of the booster dose in the elderly population.

Supportive data in adult and elderly populations

In two dose finding studies 78 adults received an adjuvanted mock-up vaccine (H5N3 or H9N2). Two doses of vaccine with H5N3 (A/Duck/Singapore/97) strain at 3 different dosages

(7.5, 15 and 30 µg HA/dose) were administered three weeks apart.

Serum samples were tested against the original H5N3 and also a number of H5N1 isolates.

Serologic responses obtained with the SRH assay showed that 100% of subjects achieved seroprotection and 100% seroconverted after two 7.5 g injections. The adjuvanted vaccine was also found to induce antibodies that cross-protected against the H5N1 strains isolated in 2003 and 2004, which exhibit some antigenic drift compared to the original strains.

Two doses of vaccine containing H9N2 (A/chicken/Hong Kong/G9/97) strain at 4 different dosages (3.75, 7.5, 15 and 30 µg HA/dose), were administered four weeks apart. Serologic responses obtained with the HI assay showed that 92% of subjects achieved seroprotection and 75% seroconverted after two 7.5 g injections.

Cross reactivity

Adults (18-60 years)

Seroprotection rate*, seroconversion rate* and the seroconversion factor** for anti-HA antibodies to H5N1 A/turkey/Turkey/05 after the 2nd dose in adults 18-60 years of age, measured by SRH and HI assays were as follows:

 

 

Study V87P1

Study V87P13

 

Anti-HA antibody

21 days after 2nd dose

21 days after 2nd dose

 

 

N=70

N=197

 

Seroprotection rate (95%CI)*

70% (58-80)

59% (52-66)

SRH

Seroconversion rate (95%CI)*

NA***

49% (42-56)

 

Seroconversion factor (95%CI)**

NA***

2.37 (2.1-2.67)

 

 

N=69

N=197

 

Seroprotection rate (95%CI)°

36%(25-49)

23% (18-30)

HI

Seroconversion rate (95%CI)°

NA***

19% (14-25)

 

Seroconversion factor (95%CI)°°

NA***

1.92 (1.64-2.25)

*measured by SRH assay ≥ 25 mm2

**geometric mean ratios of SRH

° measured by HI assay ≥ 40 °° geometric mean ratios of HI

***In V87P1: baseline not tested

MN results for the clinical studies in the Table above revealed a seroprotection rate against A/turkey/Turkey/05 ranging from 27% (17-39) (V87P1) to 39% (32-46) (V87P13) and seroconversion rate of 36% (29-43) for V87P13 study. MN results in V87P13 yielded a GMR against A/turkey/Turkey/05 of 2.77 (2.4-3.2).

Elderly (>60 years)

Seroprotection rate*, seroconversion rate* and the seroconversion factor** for anti-HA antibodies to H5N1 A/turkey/Turkey/05 after the 2nd dose in elderly >60 years of age, measured by SRH

and HI assays were as follows:

 

 

Study V87P1

Study V87P13

 

Anti-HA antibody

21 days after 2nd dose

21 days after 2nd dose

 

 

N=37

N=207

 

Seroprotection rate (95%CI)*

57% (39-73)

20% (18-23)

SRH

Seroconversion rate (95%CI)*

NA***

48% (41-55)

 

Seroconversion factor (95%CI)**

NA***

1.74 (1.57-1.94)

 

 

N=36

N=208

 

Seroprotection rate (95%CI)°

36%(21-54)

25% (19-32)

HI

Seroconversion rate (95%CI)°

NA***

19% (14-25)

 

Seroconversion factor (95%CI)°°

NA***

1.79 (1.56-2.06)

*measured by SRH assay ≥ 25 mm2

**geometric mean ratios of SRH

° measured by HI assay ≥ 40 °° geometric mean ratios of HI

***In V87P1: baseline not tested

MN results for the clinical studies in the Table above revealed a seroprotection rate against A/turkey/Turkey/05 ranging from 11% (3-25) (study V87P1) to 30% (24-37) (study V87P13) and seroconversion rate of 25% (19-31) for study V87P13. MN results in V87P13 yielded a GMR against A/turkey/Turkey/05 of 2.01 (1.78-2.26).

Data in paediatric populations

A clinical trial (study V87P6) was conducted with a H5N1 vaccine combined with MF59C.1 adjuvant in 471 children from 6 months to 17 years of age. Two doses of 7.5 micrograms were administered three weeks apart and a third dose 12 months following the first dose. After 3 weeks from the 2nd vaccination (day 43) all age groups (i.e. 6-35 months, 3-8 years and 9-17 years) achieved high levels of antibodies to (A/Vietnam/1194/2004) as evaluated with SRH and HI assays as presented in table below*. In this trial no vaccine related SAEs were observed.

 

 

Toddlers

Children (3-<9 years)

Adolescents

 

 

(6-<36 months)

 

(9-<18 years)

 

 

N=134

N=91

N=89

 

Seroprotection rate

97%

97%

89%

 

(95% CI)

(92-99)

(91-99)

(80-94)

 

Day 43

 

 

 

 

Seroconversion

HI

factor (95% CI)

(109-151)

(97-142)

(51-88)

 

Day 43 to Day 1

 

 

 

 

Seroconversion rate

97%

97%

89%

 

(95% CI)

(92-99)

(91-99)

(80-94)

 

Day 43

 

 

 

 

 

N=133

N=91

N=90

 

Seroprotection rate

100%

100%

100%

 

(95% CI)

(97-100)

(96-100)

(96-100)

 

Day 43

 

 

 

SRH

Seroconversion

factor (95% CI)

(14-18)

(13-17)

(12-16)

 

 

Day 43 to Day 1

 

 

 

 

Seroconversion rate

98%

100%

99%

 

(95% CI)

(95-100)

(96-100)

(94-100)

 

Day 43

 

 

 

*In the absence of CHMP immunogenicity criteria for children, the CHMP immunogenicity criteria used to evaluate seasonal flu vaccines in adults were applied to the serological data obtained after vaccination of children. However, the relevance for clinical protection is unknown.

MN results against a A/Vietnam/1194/2004 indicate a seroprotection rate of 99% (95%CI: 94-100),

a seroconversion rate ranging from 97% (95%CI: 91-99) to 99% (95%CI: 96-100) and a GMR ranging from 29 (95%CI: 25-35) to 50 (95%CI: 44-58).

Immunogenicity results with Focetria H1N1v (Study V111_03):

The seroprotection rate and seroconversion rate measured by HI assay and the seroconversion factor expressed as geometric mean ratios of HI for anti-HA antibody to H1N1 after administration of one and two 7.5 µg doses of Focetria was evaluated in 70 children and adolescents

(9-17 years), 60 children (3-8 years), 58 children (12-35 months) and 49 infants (6-11 months). CHMP immunogenicity criteria set for adults (18-60 years) were met both after the 1st and the 2nd dose in all the above age strata (both in the overall population and in the subset seronegative at baseline).

The European medicines Agency has deferred the obligation to submit the results of studies with Foclivia in one or more subsets of the paediatric populations in active immunisation against H5N1 subtype of Influenza A virus. See section 4.2 for information on paediatric use.

Foclivia has been authorised under “Exceptional Circumstances”.

This means that for scientific reasons, it has not been possible to obtain complete information on this medicinal product. The European Medicines Agency (EMA) will review any new information which may become available every year and this SmPC will be updated as necessary.

5.2 Pharmacokinetic properties

Not applicable.

5.3 Preclinical safety data

Non-clinical data obtained with Foclivia and with seasonal influenza vaccine containing MF59C.1 adjuvant reveal no special hazard for humans based on conventional studies of repeated

dose toxicity, local tolerance, female fertility, and reproductive and developmental toxicity (through the end of the lactation period).

6. PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Sodium chloride,

Potassium chloride,

Potassium dihydrogen phosphate,

Disodium phosphate dihydrate,

Magnesium chloride hexahydrate,

Calcium chloride dihydrate,

Sodium citrate,

Citric acid,

Thiomersal,

Water for injections.

For the adjuvant, see section 2.

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 - 8°C). Do not freeze. Store in the original package in order to protect from light.

6.5 Nature and contents of container

5.0 ml in 10-dose vial (type I glass) with stopper (halo-butyl rubber). Packs of 10. Not all pack sizes may be marketed.

6.6 Special precautions for disposal and other handling

Visually inspect the suspension prior to administration. In case of any particles and/or abnormal appearance, the vaccine should be discarded.

Gently shake the multidose vial each time before withdrawing a dose (0.5 ml) of the vaccine into a syringe. Prior to administration, the withdrawn vaccine should be allowed reach room temperature. Although Foclivia in multidose vials contains a preservative that inhibits microbial growth,

minimisation of the risk of contamination of the multidose vial during withdrawal of each dose is the responsibility of the user.

Record date and time of the first dose withdrawal on the vial label.

Between uses, return the multidose vial to the recommended storage conditions between 2° and 8° C. The multidose vial should preferably be used within 24 hours after first withdrawal.

Data are available that suggest that multidose vials could be used up to a maximum of 72 hours after first withdrawal, although such pro-longed storage periods should not be the preferred option.

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

7. MARKETING AUTHORISATION HOLDER

Seqirus S.r.l.

Via Fiorentina, 1

Siena

Italy

8. MARKETING AUTHORISATION NUMBER(S)

EU/1/09/577/004

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 19 October 2009

Date of latest renewal: 19 October 2014

10. DATE OF REVISION OF THE TEXT

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

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