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Aflunov (influenza virus surface antigens (haemagglutinin...) – Summary of product characteristics - J07BB02

Updated on site: 11-Jul-2017

Medication nameAflunov
ATC CodeJ07BB02
Substanceinfluenza virus surface antigens (haemagglutinin and neuraminidase) of strain: A/turkey/Turkey/1/05 (H5N1)-like strain (NIBRG-23)
ManufacturerSeqirus S.r.l.  

1.NAME OF THE MEDICINAL PRODUCT

AFLUNOV suspension for injection in pre-filled syringe.

Prepandemic Influenza vaccine (H5N1) (surface antigen, inactivated, adjuvanted).

2.QUALITATIVE AND QUANTITATIVE COMPOSITION

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

A/turkey/Turkey/1/05 (H5N1)-like strain (NIBRG-23)

7.5 micrograms** per 0.5 ml dose

*propagated in eggs

**expressed in microgram haemagglutinin.

Adjuvant MF59C.1 containing:

 

Squalene

9.75 milligrams per 0.5 ml

polysorbate 80

1.175 milligrams per 0.5 ml

sorbitan trioleate

1.175 milligrams per 0.5 ml

Excipient with known effect:

The vaccine contains 1.899 milligrams of sodium and 0.081 milligrams of potassium per 0.5 ml dose.

AFLUNOV may contain trace residues of egg and chicken proteins, ovalbumin, kanamycin and neomycin sulphate, barium sulphate, formaldehyde, cetyltrimethylammonium bromide (CTAB) and which are used during the manufacturing process (see section 4.3).

For the full list of excipients see section 6.1.

3.PHARMACEUTICAL FORM

Suspension for injection in pre-filled syringe.

Milky-white liquid.

4.CLINICAL PARTICULARS

4.1Therapeutic indications

Active immunisation against H5N1 subtype of Influenza A virus.

This indication is based on immunogenicity data from healthy subjects from the age of 18 years onwards following administration of two doses of the vaccine containing A/turkey/Turkey/1/05 (H5N1)-like strain (see section 5.1).

AFLUNOV should be used in accordance with official recommendations.

4.2Posology and method of administration

Posology:

Adults and elderly (18 years of age and above):

One dose of 0.5 ml at an elected date.

A second dose of 0.5 ml should be given after an interval of at least 3 weeks.

AFLUNOV has been evaluated in healthy adults (18-60 years of age) and healthy elderly

(over 60 years of age) following a 1, 22 day primary vaccination schedule, and booster vaccination (see sections 4.8 and 5.1).

There is limited experience in elderly over 70 years of age (see section 5.1).

In the event of an officially declared influenza pandemic due to A/H5N1 virus, persons previously vaccinated with one or two doses of AFLUNOV that contained HaemAgglutinin (HA) antigen derived from a different clade of the same influenza subtype as the influenza pandemic strain may receive a single dose of AFLUNOV instead of two doses that are required in previously unvaccinated individuals (see section 5.1).

Paediatric population:

The safety and efficacy of AFLUNOV 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.

4.3Contraindications

History of an anaphylactic (i.e. life-threatening) reaction to any of the constituents or trace residues (egg and chicken proteins, ovalbumin, kanamycin and neomycin sulphate, barium sulphate, formaldehyde and cetyltrimethylammonium bromide (CTAB)) of this vaccine.

However, in a pandemic situation caused by the strain included in this vaccine, it may be appropriate to give this vaccine to individuals with a history of anaphylaxis as defined above, provided that facilities for resuscitation are immediately available in case of need.

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 residues (eggs and chicken proteins, ovalbumin, kanamycin and neomycin sulphate, barium sulphate, formaldehyde and cetyltrimethylammonium bromide (CTAB)).

Very limited data in subjects with co-morbidities, including immunocompromised subjects are available for this H5N1 vaccine.

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.

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

The vaccine should under no circumstances be administered intravascularly or intradermally.

There are no data with AFLUNOV using the subcutaneous route. 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 immune 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 AFLUNOV with other H5N1 monovalent vaccines.

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

Data obtained in adults showed that co-administration of adjuvanted H5N1 vaccine and seasonal (inactivated surface, non-adjuvanted) antigens did not lead to any interference neither for seasonal strains nor for H5N1 strain. Single Radial Haemolysis (SRH) antibody response against an homologous H5N1 Vietnam strain at day 43 reached all CHMP criteria for 3 seasonal strains and H5N1-strain. Co-administration was not associated with higher rates of local or systemic reactions compared to administration of AFLUNOV alone.

Therefore the data indicate that AFLUNOV may be co-administered with non-adjuvanted seasonal influenza vaccines (with injections made into opposite limbs).

There are no data on co-administration of AFLUNOV with other vaccines.

If co-administration with another vaccine is considered, 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, human T-lymphotropic virus type 1 (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

Limited data was obtained from women who became pregnant during the course of clinical trials with AFLUNOV (H5N1) or H1N1v vaccines adjuvanted with MF59C.1.

It is estimated that more than 90,000 women have been vaccinated during pregnancy with Focetria H1N1v vaccine which contains the same amount of adjuvant MF59C.1 as AFLUNOV. However information on outcomes is currently limited. Preliminary data from spontaneously reported events and ongoing post-marketing studies (pregnancy registry and prospective interventional study) do not suggest direct or indirect harmful effects on influenza vaccines adjuvanted with MF59 with respect to pregnancy, fertility, embryonic/foetal development, parturition, or post natal development.

Since AFLUNOV is expected not to be used in an emergency situation, its administration during pregnancy might be deferred as a precautionary approach.

Healthcare providers need to assess the benefit and potential risks of administering the vaccine to pregnant women taking into consideration official recommendations.

Breast-feeding

There are no data regarding the use of AFLUNOV during breast-feeding. The potential benefits to the mother and risks to the infant should be considered before administering AFLUNOV during breast-feeding.

Fertility

A study in rabbits did not indicate reproductive or developmental toxicity of AFLUNOV (see section 5.3).

4.7Effects on ability to drive and use machines

Some of the undesirable effects mentioned under section 4.8 may affect the ability to drive or operate machinery.

4.8Undesirable effects

a. Summary of the safety profile

The incidence of adverse reactions has been evaluated in seven clinical trials in adults (18 years old and above) involving over 4,300 adults and elderly receiving AFLUNOV (at least 7.5 µg HA, adjuvanted). There were 3872 subjects 18-60 years of age, 365 subjects 61-70 years of age,

and 89 subjects greater than 70 years of age.

Consistent with the data observed by trial for solicited reactions, there was a general trend towards decreased reports of local reactions after the second vaccination compared with the first injection. Irrespective of antigen dose, almost all systemic reactions were reported on the day of vaccination (day 1) or during the 3 days immediately following.

Data on safety of a booster dose of the current AFLUNOV formulation are limited to three trials (V87P1, V87P2 and V87P1E1) that included 116 adults and 56 elderly. No increase in reactions was reported when a booster dose is administered 6 months-18 months later, after the initial dosing series. A slight increase in reactions in adults was reported when a booster dose is administered 18 months after the initial dosing series. In the elderly, the reported reactions increased with the third booster dose only when compared with the second dose.

b. List of adverse reactions

The adverse reaction rates reported after either vaccination dose (i.e. 1st, 2nd or booster) were similar and are listed according to the following frequency:

Very common (≥1/10)

Common (≥1/100 to <1/10)

Uncommon (≥1/1,000 to <1/100)

Rare (≥1/10,000 to <1/1,000)

Very rare (<1/10,000)

:

Nervous system disorders

Very common: headache

Rare: convulsions

Skin and subcutaneous tissue disorders

Common: sweating

Uncommon: urticaria

Rare: eye swelling

Muscoskeletal, connective tissue and bone disorders

Very common: myalgia

Common: arthralgia

Gastrointestinal disorders

Common: nausea

General disorders and administration site conditions

Very common: injection site swelling, injection site pain, injection site induration, injection site redness, fatigue

Common: injection site ecchymosis, fever, malaise, shivering Uncommon: influenza like illness

Rare: anaphylaxis

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

Post-marketing surveillance

No post-marketing surveillance data are available following AFLUNOV administration.

c. Description of selected adverse reactions

The following additional adverse events were reported from post-marketing surveillance with Focetria H1N1v (licensed for use in children 6 months of age and above, adults and the elderly with a composition that is similar to AFLUNOV):

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 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.

The following additional adverse events were reported from post-marketing surveillance with seasonal non-adjuvanted trivalent vaccines in all age groups and a seasonal adjuvanted trivalent vaccine with a

composition similar to AFLUNOV (surface antigen, inactivated, adjuvanted with MF59C.1) that is licensed for use in elderly subjects 65 years of age and older:

Blood and lymphatic system disorders

Thrombocytopenia (in some cases reversible platelet counts less than 5000 mm3).

Immune system disorders

Vasculitis with transient renal involvement and exudative erythema multiforme.

Nervous system disorders

Neurological disorders, such as encephalomyelitis, and Guillain Barré syndrome.

d. Paediatric population

The incidence of adverse reactions has been evaluated in one clinical trial (Study V87P6) in children (6 months to 17 years old): Regardless of age, reactogencity was higher after the first dose than after the second vaccination. Reactogenicity after a third dose, administered 12 months following the first 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.

 

Injection 1

Injection 2

Injection 3

 

Aflunov

Aflunov

Aflunov

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%

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 AFLUNOV following a two-dose administration and booster.

Immune response to Homologous Strains [A/Vietnam/1194/2004 (H5N1) and

A/turkey/Turkey/1/05 (H5NI)]

Adults (18-60 years)

A 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 HA/dose adjuvanted) were administered three weeks apart to 156 healthy adults. In another clinical trial

(Study V87P13) 2693 adult subjects 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 study population. In a third clinical trial (Study V87P11) 194 adult subjects were enrolled and received two doses of vaccine containing H5N1 (A/H5N1/turkey/Turkey/1/05; 7.5 µg HA/dose adjuvanted) administered three weeks apart. Immunogenicity was assessed in a subset (n=182) of the study population.

The seroprotection rate*, seroconversion rate* and the seroconversion factor** for anti-HA antibody to H5N1 A/Vietnam/1194/2004 and to A/H5N1/turkey/Turkey/1/05 in the adults measured by SRH assay was as follows:

 

Study V87P1

Study V87P13

Study V87P11

Anti-HA antibody (SRH)

21 days after 2nd dose

21 days after 2nd dose

21 days after 2nd dose

 

N=149

N=197

N=182

Seroprotection rate (95%CI)*

85% (79-91)

91% (87-95)

91% (85-94)

Seroconversion rate (95%CI)*

85% (78-90)

78% (72-84)

85% (79-90)

Seroconversion factor (95%CI)**

7.74 (6.6-9.07)

4.03 (3.54-4.59)

6 (5.2-6.93)

 

 

 

 

 

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 (GMRs) of SRH

MN results against homologous 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 MicroNeutralisation (MN) assay is in line with results obtained with SRH.

In Study V87P11 MN results against homologous A/H5N1/turkey/Turkey/1/05 indicate a seroprotection and seroconversion rate of 85% (79-90) and 93% (89-96), 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 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.

In a phase 2 clinical trial (Study V87P3) adult subjects aged 18-65 years primed 6-8 years previously with 2 doses of MF59-adjuvanted H5N3 vaccine/A/Duck/Singapore/97 were administered 2 booster doses of AFLUNOV. SRH results after the first dose, that mimic prepandemic priming plus single heterologous booster dose, met all CHMP criteria.

Elderly (>60 years)

The seroprotection rate*, seroconversion rate* and the seroconversion factor** for anti-HA antibody to H5N1 A/Vietnam/1194/2004 and to A/H5N1/turkey/Turkey/1/05 (Study V87P11) in subjects aged over 60 (limited number of subjects were above 70 years of age) measured by SRH assay assessed in three clinical studies were as follows:

 

Study V87P1

 

Study V87P13

 

 

Study V87P11

Anti-HA antibody (SRH)

21 days after 2nd dose

 

21 days after 2nd dose

 

21 days after 2nd dose

 

N=84

 

N=210

 

 

N=132

Seroprotection rate (95%CI)*

80% (70-88)

 

82% (76-87)

 

 

82% (74-88)

 

 

 

 

 

 

 

Seroconversion rate (95%CI)*

70% (59-80)

 

63% (56-69)

 

 

70% (61-77)

Seroconversion factor (95%CI)**

4.96 (3.87-6.37)

 

2.9 (2.53-3.31)

 

 

3.97 (3.36-4.69)

 

 

 

 

 

 

 

 

 

 

 

 

 

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

**GMRs of SRH

MN results against homologous 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.

In Study V87P11 MN results against homologous A/H5N1/turkey/Turkey/1/05 indicate a seroprotection and seroconversion rate of 68% (59-75) and 81% (74-87), respectively.

Immune response to vaccination assessed by MN assay is similar to SRH results.

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 Hemagglutination Inhibition (HI), SRH, and MN tests. Up to 50% of the elderly subjects immunised with AFLUNOV were seroprotected at six months.

A third (booster) dose of AFLUNOV was administered 6 months onwards after the primary vaccination. 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 V87P2 Adults

Study V87P1 Elderly

 

booster after 2nd dose

booster after 2rd dose

booster after 2nd dose

SRH

N=71

N=13

N=38

Seroprotection rate

89% (79-95)

85% (55-98)

84% (69-94)

(95%CI)*

 

 

 

Seroconversion

83% (72-91)

69% (39-91)

63% (46-78)

rate (95%CI)*

 

 

 

Seroconversion

5.96 (4.72-7.53)

2.49 (1.56-3.98)

5.15 (3.46-7.66)

factor (95%CI)**

 

 

 

*measured by SRH assay ≥ 25 mm2

**GMRs of SRH

There is limited experience in the elderly

Supportive data in adults

a)Cross reactivity

Cross-reactive immune response elicited by A/H5N1/Vietnam/1194/2004 against A/H5N1/turkey/Turkey/1/05 and A/H5N1/Indonesia/5/05

Some heterologous immune response against A/H5N1/turkey/Turkey/1/05 (NIBRG23; clade2.2) and A/H5N1/Indonesia/5/05 (clade 2.1) was detectable both after the second and third vaccinations, indicating cross-reactivity of the clade 1 vaccine against clade 2 strains.

Seroprotection rate*, seroconversion rate* and the seroconversion factor** for anti-HA antibodies to H5N1 A/turkey/Turkey/1/05 after the 2nd dose in adults 18-60 years of age, measured by SRH and HI assays were as follows:

 

Anti-HA antibody

Study V87P12

Study V87P3

Study V87P13

 

 

21 days after 2nd

21 days after 2nd dose

21 days after 2nd dose

 

 

dose

N=30

N=197

 

 

N=60

 

 

SRH

Seroprotection

65% (52-77)

90% (73-98)

59% (52-66)

 

rate (95%CI)*

 

 

 

 

Seroconversion

65% (52-77)

86% (68-96)

49% (42-56)

 

rate (95%CI)*

 

 

 

 

Seroconversion

4.51 (3.63-5.61)

7.67 (6.09-9.67)

2.37 (2.1-2.67)

 

factor(95%CI)**

 

 

 

 

 

N=60

N=30

N=197

HI

Seroprotection

28% (17-41)

24% (10-44)

23% (18-30)

 

rate (95%CI)°

 

 

 

 

Seroconversion

28% (17-41)

21% (8-40)

19% (14-25)

 

rate (95%CI)°

 

 

 

 

Seroconversion

2.3 (1.67-3.16)

1.98 (1.22-3.21)

1.92 (1.64-2.25)

 

factor (95%CI)°°

 

 

 

*measured by SRH assay ≥ 25 mm2

**GMRs of SRH

° measured by HI assay ≥ 40

°°GMRs of HI

MN results for the three clinical studies in the Table above revealed a seroprotection rate and seroconversion rate against A/turkey/Turkey/05 ranging from 10% (2-27) to 39% (32-46) and 10%

(2-27) to 36% (29-43) respectively. MN results yielded a GMR against A/turkey/Turkey/05 ranging from 1.59 to 2.95.

Cross-reactive immune response elicited by A/H5N1/turkey/Turkey/1/05 against A/H5N1/Indonesia/5/05 and A/H5N1/Vietnam/1194/2004

Heterologous immune response against A/H5N1/Indonesia/5/05 (clade 2.1) was detectable in study V87P11 after the second vaccination, indicating cross-reactivity of the clade 2.2 vaccine against clade 2.1 strains.

Seroprotection rate*, seroconversion rate* and the seroconversion factor** for anti-HA antibodies to A/H5N1/Indonesia/5/05 and A/H5N1/Vietnam/1194/2004 after the 2nd dose in adults (18-60 years) and elderly (>60 years), measured by SRH and HI assays were as follows:

Anti-HA

 

V87P11 Adults (18-60 years)

V87P11 Elderly (>60 years)

antibody

 

N=186

N=142

 

 

A/Indonesia/

A/Vietnam/

A/Indonesia/

A/Vietnam/

 

 

5/05

1194/2004

5/05

1194/2004

SRH

Seroprotection rate

 

(95%CI)*

(77-88)

(54-69)

52-69

(37-54)

 

Seroconversion

 

rate (95%CI)*

(72-85)

(53-68)

(56-73)

(35-53)

 

Seroconversion

6.24

4.45

3.87

3.03

 

factor (95%CI)**

(5.44-7.16)

(3.85-5.14)

(3.31-4.53)

(2.56-3.58)

 

 

N=194

N=148

HI

Seroprotection rate

 

(95%CI) °

(43-57)

(40-55)

(26-42)

(31-48)

 

Seroconversion

 

rate (95%CI) °

(42-56)

(37-51)

(25-41)

(26-42)

 

Seroconversion

4.71

4.25

2.69

2.8

 

factor (95%CI) °°

(3.74-5.93)

(3.36-5.37)

(2.18-3.32)

(2.2-3.55)

*measured by SRH assay ≥ 25 mm2

**GMRs of SRH

° measured by HI assay ≥ 40

°°GMRs of HI

MN results for A/H5N1/Indonesia/5/05 revealed a seroprotection rate of 38% (31-45) in adults (18-60 years) and 14% (8-20) in elderly (>60 years); a seroconversion rate of 58% (50-65) in adults and 30% (23-38) in elderly and finally a GMR of 4.67 (3.95-5.56) in adults and 2.19 (1.86-2.58)

in elderly.

MN results for A/H5N1/Vietnam/1194/2004 revealed a seroprotection rate of 10% (6-16) in adults (18-60 years) and 6% (3-11) in elderly (>60 years); a seroconversion rate of 19% (13-25) in adults and 7% (4-13) in elderly and finally a GMR of 1.86 (1.63-2.12) in adults and 1.33 (1.17-1.51)

in elderly.

b)Long term booster immune memory

A single vaccination with AFLUNOV (H5N1, A/Vietnam/1194/2004) induced high and rapid serological response in subjects primed 6-8 years previously with two doses of a different surrogate H5N vaccine, having same formulation as AFLUNOV but using the strain H5N3.

c)Trial on different vaccination schedules:

In a clinical trial evaluating 4 different vaccination schedules in 240 subjects 18 to 60 years of age, where the second dose was after either 1, 2, 3 or 6 weeks after the first AFLUNOV dose, SRH CHMP criteria were achieved in all the vaccine schedule groups after 3 weeks from the 2nd vaccination. The

magnitude of immune response was lower in the group who received the 2nd dose 1 week later and higher in the groups with longer interval schedules.

Available 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 AFLUNOV 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

 

% SP (95% CI) Day 43

97%

97%

89%

 

(92-99)

(91-99)

(80-94)

 

 

HI

GMRDay 43 to Day 1

(109-151)

(97-142)

(51-88)

 

 

 

% SC (95% CI)Day 43

97%

97%

89%

 

(92-99)

(91-99)

(80-94)

 

 

 

 

N=133

N=91

N=90

 

% SP (95% CI) Day 43

100%

100%

100%

 

(97-100)

(96-100)

(96-100)

 

 

SRH

GMR (95% CI) Day 43 to Day 1

 

 

(14-18)

(13-17)

(12-16)

 

% SC (95% CI) Day 43

98%

100%

99%

 

(95-100)

(96-100)

(94-100)

 

 

*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.

SP= seroprotection SC= seroconversion

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).

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

Information from non-clinical trials

Efficacy against challenge with virus homologous and heterologous to vaccine strains was evaluated in the ferret model. AFLUNOV, containing HA from A/Vietnam/1194/2004 (homologous to the challenge strain) and an AFLUNOV-like H5N1 vaccine, containing hemagglutinin from the A/turkey/Turkey/1/2005-like (heterologous to the challenge strain) were tested. Groups of 8 ferrets received one (day 21) or two (days 0 and 21) doses of vaccine containing 3.75 or 7.5 micrograms of antigen. Control animals received adjuvant alone. Animals were challenged by the intranasal route on day 42 with a lethal dose of A/Vietnam/1203/04 virus. Animals were monitored for 16-17 days after challenge to allow for a comprehensive assessment of disease progression, including the time of onset of symptoms, mortality, or subsequent recovery.

All (100%) animals receiving 2 doses of AFLUNOV were protected, and 94% of animals receiving a single dose of AFLUNOV were protected. 87% of animals challenged with virus heterologous to the vaccine strain after 2 doses of vaccine were protected, and a single dose of heterologous vaccine

protected 56% of the animals. All control animals died within 7 days of challenge. Vaccination protected animals from lethal challenge with virus homologous and heterologous to the vaccine.

In a similar study, intranasal challenge was delayed until approximately 4 months after the second dose of vaccine containing either 3.75 or 7.5 micrograms of antigen was administered. In this study 100% of animals were protected against homologous challenge, and 81% of animals were protected against heterologous challenge. Vaccination protected animals from lethal challenge even when HI antibody titers were low or undetectable.

Efficacy against challenge with the heterologous virus A/Indonesia/5/05 was also tested. Groups of 6 ferrets received one dose of vaccine (day 21) containing 3.75 micrograms of antigen or two doses of vaccine (days 0 and 21) containing either 1.0 or 3.75 micrograms of antigen (A/Vietnam/1194/2004). A lethal challenge was administered by the intratracheal route on day 49. Two doses of vaccine protected 92% of animals, and a single dose of vaccine protected 50% of animals against the A/Indonesia/5/05 virus. Compared to the adjuvant control group, lung damage was reduced in vaccinated groups. Viral shedding and viral titers in lungs were also reduced, suggesting that vaccination may reduce the risk of viral transmission.

5.2Pharmacokinetic properties

Not applicable.

5.3Preclinical safety data

Non-clinical data obtained with AFLUNOV 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 (E508),

Potassium dihydrogen phosphate (E340),

Disodium phosphate dihydrate (E339),

Magnesium chloride hexahydrate (E511),

Calcium chloride dihydrate (E509),

Sodium citrate (E311),

Citric acid (E330),

Water for injections.

For the adjuvant, see section 2

6.2Incompatibilities

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

6.3Shelf life

2 years.

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 or 10 pre-filled syringes.

Not all pack sizes may be marketed.

6.6Special 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.

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

Any unused vaccine and 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/1/10/658/001-002

9.DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

29 November 2010

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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