ANNEX I
SUMMARY OF PRODUCT CHARACTERISTICS
1.
AFLUNOV suspension for injection in pre-filled syringe.
Prepandemic Influenza vaccine (H5N1) (surface antigen, inactivated, adjuvanted).
2.
Influenza virus surface antigens (haemagglutinin and neuraminidase)* of strain:
A/Vietnam/1194/2004 (H5N1)-like strain (NIBRG-14)
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
For a full list of excipients see section 6.1.
3.
Suspension for injection in pre-filled syringe.
Milky-white liquid.
4.
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/Vietnam/1194/2004
(H5N1)-like strain (see section 5.1).
AFLUNOV should be used in accordance with official recommendations.
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 HA antigen derived from a different
clade of the same influenza subtype as the influenza pandemic strain may receive a single dose of
2
AFLUNOV instead of two doses that are required in previously unvaccinated individuals (see section
5.1).
Paediatric population:
There is limited experience in children between 6 months and 17 years of age (see section 5.1).
Method of administration
Immunisation should be carried out by intramuscular injection into the deltoid muscle.
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, 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.
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 and to residues (eggs and
chicken proteins, ovalbumin, kanamycin and neomycin 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.
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 strains.
SRH antibody response against an homologous H5N1 Vietnam strain at day 43 reached all CHMP
criteria for all 3 strains.
3
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,
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.
A study in rabbits did not indicate reproductive or developmental toxicity (see section 5.3).
Limited data was obtained from women who became pregnant during the course of clinical trials with
AFLUNOV (H5N1) and H1N1v vaccines adjuvanted with MF59C.1.
It is estimated that more than 90,000 women have been vaccinated during pregnancy with H1N1v
vaccine Focetria 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.
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.
Some of the undesirable effects mentioned under section 4.8 may affect the ability to drive or operate
machinery.
Adverse reactions from clinical trials in 18 years old and above.
The incidence of adverse reactions has been evaluated in six clinical trials involving approximately
4,000 adults and elderly receiving AFLUNOV (at least 7.5 µg HA, adjuvanted). There were 3678
subjects 18-60 years of age, 264 subjects 61-70 years of age, and 41 subjects greater than 70 years of
age.
4
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 is limited to 87 adults and 38
elderly. No increase in reactions has been reported when a third dose is administered 6 months-1 year
or later after the initial dosing series.
The adverse reaction rates reported after either vaccination dose (i.e. 1
st
, 2
nd
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)
Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness:
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
These side effects usually disappear within 1-2 days without treatment.
Adverse reactions from clinical trial in children
aged 6 months to 17 years (Study V87P6)
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.
5
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%
Post-marketing surveillance
No post-marketing surveillance data are available following AFLUNOV administration.
The following additional adverse events were reported from post-marketing surveillance with Focetria
H1N1v (licensed for use from 6 months of age and 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.
6
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 an MF59 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
Transient thrombocytopenia.
Immune system disorders
Vasculitis with transient renal involvement and exudative erythema multiforme.
Nervous system disorders
Neurological disorders, such as encephalomyelitis, and Guillain Barré syndrome.
No case of overdose has been reported.
5.
5.1 Pharmacodynamic 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 against A/Vietnam/1194/2004 (H5N1):
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.
The seroprotection rate*, seroconversion rate* and the seroconversion factor** for anti-HA antibody
to H5N1 A/Vietnam/1194/2004 in the adults measured by SRH assay was as follows:
Anti-HA antibody (SRH)
Study V87P1
21 days after 2
nd
dose
N=149
Study V87P13
21 days after 2
nd
dose
N=197
Seroprotection rate (95%CI)*
85% (79-91)
91% (87-95)
Seroconversion rate (95%CI)*
85% (78-90)
78% (72-84)
7
Seroconversion factor (95%CI)**
7.74 (6.6-9.07)
4.03 (3.54-4.59)
Anti-HA antibody (SRH)
Study V87P13
21 days after 2
nd
dose
N=69
Study V87P13
21 days after 2
nd
dose
N=128
Baseline Serostatus
< 4 mm
2
≥ 4 mm
2
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 mm
2
** geometric mean ratios of SRH
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 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 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:
Anti-HA antibody (SRH)
Study V87P1
21 days after 2
nd
dose
N=84
Study V87P13
21 days after 2
nd
dose
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)
Anti-HA antibody (SRH)
Study V87P13
21 days after 2
nd
dose
N=66
Study V87P13
21 days after 2
nd
dose
N=143
Baseline Serostatus
< 4 mm
2
≥ 4 mm
2
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 mm
2
** 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
8
after completion of primary schedules as assessed by 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
booster after 2
nd
dose
Study V87P2 Adults
booster after 2
rd
dose
Study V87P1 Elderly
booster after 2n
d
dose
SRH
N=71
N=13
N=38
Seroprotection
rate (95%CI)*
89% (79-95)
85% (55-98)
84% ( 69-94)
Seroconversion
rate (95%CI)*
83% (72-91)
69% (39-91)
63% (46-78)
Seroconversion
factor (95%CI)**
5.96 (4.72-7.53)
2.49 (1.56-3.98)
5.15 (3.46-7.66)
* measured by SRH assay ≥ 25 mm
2
** geometric mean ratios of SRH
There is limited experience in the elderly
•
Supportive data in adults
a)
Cross reactivity
Some heterologous immune response against A/H5N1/turkey/Turkey/05 (NIBRG23; clade2.2)
and A/H5N1/Indonesia (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/05 after the 2
nd
dose in adults 18-60 years of age, measured by SRH
and HI assays were as follows:
Anti-HA antibody
Study V87P12
21 days after 2
nd
dose
N=60
Study V87P3
21 days after 2
nd
dose
N=30
Study V87P13
21 days after 2
nd
dose
N=197
SRH Seroprotection
rate (95%CI)*
65% (52-77)
90% (73-98)
59% (52-66)
Seroconversion
rate (95%CI)*
65% (52-77)
86% (68-96)
49% (42-56)
Seroconversion
factor(95%CI)**
4.51 (3.63-5.61)
7.67 (6.09-9.67)
2.37 (2.1-2.67)
N=60
N=30
N=197
HI
Seroprotection
rate (95%CI)°
28% (17-41)
24% (10-44)
23% (18-30)
Seroconversion
rate (95%CI)°
28% (17-41)
21% (8-40)
19% (14-25)
Seroconversion
factor (95%CI)°°
2.3 (1.67-3.16)
1.98 (1.22-3.21)
1.92 (1.64-2.25)
* measured by SRH assay ≥ 25 mm
2
** geometric mean ratios of SRH
° measured by HI assay ≥ 40
°° geometric mean ratios of HI
9
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.
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 2
nd
vaccination. The
magnitude of immune response was lower in the group who received the 2
nd
dose 1 week later and
higher in the groups with longer interval schedules.
•
Supportive 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 2
nd
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 (6-<36
months)
Children (3-<9 years)
Adolescents (9-<18
years)
N=134
N=91
N=89
% SP (95% CI)
Day 43
97%
(92-99)
97%
(91-99)
89%
(80-94)
HI
GMR
Day 43 to Day 1
129
(109-151)
117
(97-142)
67
(51-88)
% SC (95% CI)
Day 43
97%
(92-99)
97%
(91-99)
89%
(80-94)
N=133
N=91
N=90
% SP (95% CI)
Day 43
100%
(97-100)
100%
(96-100)
100%
(96-100)
SRH
GMR (95% CI)
Day 43 to Day 1
16
(14-18)
15
(13-17)
14
(12-16)
% SC (95% CI)
Day 43
98%
(95-100)
100%
(96-100)
99%
(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.
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).
Information from non-clinical trials
10
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.
5.2 Pharmacokinetic properties
Not applicable.
5.3 Preclinical 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.
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.
11
For the adjuvant, see section 2
6.2 Incompatibilities
In the absence of compatibility trials, this medicinal product must not be mixed with other medicinal
products.
6.3 Shelf life
3 years.
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 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.
6.6 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.
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 compliance with local requirements.
7.
Novartis Vaccines and Diagnostics S.r.l.
Via Fiorentina, 1
Siena, Italy.
8.
………………..
9.
………………..
………………..
12
Detailed information on this medicinal product is available on the website of the European Medicines
Agency
http://www.ema.europa.eu/
.
13
ANNEX II
A.
MANUFACTURERS OF THE BIOLOGICAL ACTIVE
SUBSTANCE AND MANUFACTURING AUTHORISATION
HOLDER RESPONSIBLE FOR BATCH RELEASE
B.
CONDITIONS OF THE MARKETING AUTHORISATION
14
A. MANUFACTURERS OF THE BIOLOGICAL ACTIVE SUBSTANCE AND
MANUFACTURING AUTHORISATION HOLDER RESPONSIBLE FOR BATCH
RELEASE
Name and address of the manufacturers of the biological active substance
Novartis Vaccines and Diagnostics S.r.l.
Via Fiorentina, 1 – 53100 Siena
Italy
Novartis Vaccines and Diagnostics S.r.l.
Loc. Bellaria – 53018 Rosia – Sovicille (SI)
Italy
Name and address of the manufacturer responsible for batch release
Novartis Vaccines and Diagnostics S.r.l.
Loc. Bellaria – 53018 Rosia – Sovicille (SI)
Italy
B. CONDITIONS OF THE MARKETING AUTHORISATION
•
Medicinal product subject to medical prescription.
•
CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND
EFFECTIVE USE OF THE MEDICINAL PRODUCT
Not applicable.
•
OTHER CONDITIONS
Pharmacovigilance system
The MAH must ensure that the system of pharmacovigilance, as described in version 13.5
presented in Module 1.8.1. of the Marketing Authorisation Application, is in place and
functioning before and whilst the product is on the market.
Risk Management Plan
The MAH commits to performing the studies and additional pharmacovigilance activities detailed in
the Pharmacovigilance Plan, as agreed in version 3 of the Risk Management Plan (RMP) presented in
Module 1.8.2. of the Marketing Authorisation Application and any subsequent updates of the RMP
agreed by the CHMP.
As per the CHMP Guideline on Risk Management Systems for medicinal products for human use, any
updated RMP should be submitted at the same time as the following Periodic Safety Update Report
(PSUR).
In addition, an updated RMP should be submitted:
•
When new information is received that may impact on the current Safety Specification,
Pharmacovigilance Plan or risk minimisation activities
•
Within 60 days of an important (pharmacovigilance or risk minimisation) milestone being
reached
•
At the request of the European Medicines Agency
15
PSURs
PSUR submission when AFLUNOV is used during an influenza pandemic:
During a pandemic situation, the frequency of submission of periodic safety update reports specified
in Article 24 of Regulation (EC) No 726/2004 will not be adequate for the safety monitoring of a
pandemic vaccine for which high levels of exposure are expected within a short period of time. Such
situation requires rapid notification of safety information that may have the greatest implications for
risk-benefit balance in a pandemic. Prompt analysis of cumulative safety information, in light of
extent of exposure, will be crucial for regulatory decisions and protection of the population to be
vaccinated. In addition, duration a pandemic, resources needed for an in-depth evaluation of Periodic
Safety Update Reports in the format as defined in Volume 9a of the Rules Governing Medicinal
Product in the European Union may not be adequate for a rapid identification of a new safety issue.
In consequence, as soon as the pandemic is declared and the prepandemic vaccine is used, the MAH
shall submit more frequent simplified periodic safety update reports with a format and a periodicity
defined in the "CHMP Recommendations for the Core Risk Management Plan for Influenza Vaccines
prepared from viruses with the potential to cause a pandemic and intended for use outside of the core
dossier context" (EMEA/49993/2008), and any subsequent update.
Official batch release: in accordance with Article 114 Directive 2001/83/EC as amended, the official
batch release will be undertaken by a state laboratory or a laboratory designated for that purpose.
16
ANNEX III
LABELLING AND PACKAGE LEAFLET
17
A. LABELLING
18
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
CARDBOARD BOX
1.
AFLUNOV suspension for injection in pre-filled syringe.
Prepandemic Influenza vaccine (H5N1) (surface antigen, inativated, adjuvanted)
2.
STATEMENT OF ACTIVE SUBSTANCE
One dose of 0.5 ml contains:
Active Ingredients
: Influenza virus surface antigens (haemagglutinin
and neuraminidase), propagated in eggs, of strain:
A/Vietnam/1194/2004 (H5N1)-like strain (NIBRG-14) 7.5 micrograms haemagglutinin
Adjuvant
: MF59C.1 oil composed of squalene, polysorbate 80 and sorbitan trioleate.
3.
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.
4.
Suspension for injection.
1 x single dose of 0.5 ml pre-filled syringe
10 x single dose of 0.5 ml pre-filled syringes
5.
METHOD AND ROUTE OF ADMINISTRATION
To be administered intramuscularly into the deltoid muscle.
Warning
:
Do not inject intravascularly or intradermally
.
Read the package leaflet before use.
The vaccine should be allowed to reach room temperature before use. Gently shake before use.
19
6.
SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT
OF THE REACH AND SIGHT OF CHILDREN
Keep out of the reach and sight of children.
7.
OTHER SPECIAL WARNING(S), IF NECESSARY
8.
EXPIRY DATE
EXP.:
9.
SPECIAL STORAGE CONDITIONS
Store in a refrigerator.
Do not freeze.
Store in the original package in order to protect from light.
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
Dispose of in accordance with local requirements.
Novartis Vaccines & Diagnostics S.r.l.
Via Fiorentina, 1
Siena, Italy.
12. MARKETING AUTHORISATION NUMBER
EU/0/00/000/000
13. BATCH NUMBER
Lot:
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15. INSTRUCTIONS ON USE
20
16. INFORMATION IN BRAILLE
Justification for not including Braille accepted
21
MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS
LABEL FOR SYRINGE
1.
AFLUNOV injection
H5N1 influenza vaccine
Intramuscular use
2.
METHOD OF ADMINISTRATION
Gently shake before use.
3.
EXPIRY DATE
EXP.:
4.
BATCH NUMBER
Lot:
5.
CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT
0.5 ml
6.
OTHER
Store in a refrigerator.
Novartis V&D S.r.l. – Italy
22
B. PACKAGE LEAFLET
23
PACKAGE LEAFLET: INFORMATION FOR THE USER
AFLUNOV suspension for injection in pre-filled syringe
Prepandemic Influenza vaccine (H5N1) (surface antigen, inactivated, adjuvanted)
Read all of this leaflet carefully before you start receive this vaccine.
-
Keep this leaflet. You may need to read it again.
-
If you have any further questions, ask your doctor or nurse.
-
If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet,
please tell your doctor.
In this leaflet:
1.
What AFLUNOV is and what it is used for
2.
Before you receive AFLUNOV
3.
How AFLUNOV is given
4.
Possible side effects
5.
How to store AFLUNOV
6.
Further information
1.
WHAT AFLUNOV IS AND WHAT IT IS USED FOR
AFLUNOV is a vaccine for use in adults (from 18 to 60 years old). and elderly (over 60 years old). It
is intended to be given before or during the next influenza (flu) pandemic to prevent flu caused by the
H5N1 type of the virus.
Pandemic flu is a type of influenza that occurs every few decades and which spreads rapidly around
the world. The symptoms of pandemic flu are similar to those of an ordinary flu but may be more
severe.
When a person is given the vaccine, the immune system (the body’s natural defense system) will
produce its own protection (antibodies) against the disease. None of the ingredients in the vaccine can
cause flu.
As with all vaccines, AFLUNOV may not fully protect all persons who are vaccinated.
2.
BEFORE YOU RECEIVE AFLUNOV
You should not receive AFLUNOV:
•
if you have previously had a sudden life-threatening allergic reaction to any ingredient of
AFLUNOV (these are listed at the end of the leaflet) or to any of the substances that may be
present in trace amounts as follows: egg and chicken protein, ovalbumin, formaldehyde,
kanamycin and neomycin sulphate (antibiotics) or cetyltrimethylammonium bromide (CTAB).
Signs of an allergic reaction may include itchy skin rash, shortness of breath and swelling of the
face or tongue. However, in a pandemic situation, it may be appropriate for you to have the
vaccine provided that appropriate medical treatment is immediately available in case of an
allergic reaction.
If you are not sure, talk to your doctor or nurse before having this vaccine.
Take special care with AFLUNOV:
•
if you have had any allergic reaction other than a sudden life-threatening allergic reaction to
24
any ingredient contained in the vaccine, to egg and, chicken protein, ovalbumin, formaldehyde,
kanamycin and neomycin sulphate (antibiotics) or cetyltrimethylammonium bromide (CTAB)
(see section 6. Further information);
•
if you have a severe infection with a high temperature (over 38°C). If this applies to you then
your vaccination will usually be postponed until you are feeling better. A minor infection such
as a cold should not be a problem, but your doctor or nurse should advise whether you could
still be vaccinated with AFLUNOV;
•
if you are having a blood test to look for evidence of infection with certain viruses. In the first
few weeks after vaccination with AFLUNOV the results of these tests may not be correct. Tell
the doctor requesting these tests that you have recently been given AFLUNOV.
•
in the presence of immune deficiencies AFLUNOV may be administered but a protective
immune response may not be elicited.
In any of these cases, TELL YOUR DOCTOR OR NURSE, as vaccination may not be recommended,
or may need to be delayed.
Please inform your doctor or nurse if you have a bleeding problem or bruise easily.
Taking other medicines
Please tell your doctor or nurse if you are taking or have recently taken any other medicines, including
medicines obtained without a prescription or have recently received any other vaccine.
Data obtained in adults showed that AFLUNOV can be given at the same time as non-adjuvanted
seasonal influenza vaccines, with injections made into separate limbs. In such cases, you should be
aware that the side effects may be more intense.
Pregnancy and breast-feeding
Limited data was obtained from women who became pregnant with AFLUNOV during the course of
clinical trials.
Your doctor needs to assess the benefits and potential risks of giving you the vaccine if you are
pregnant or breast-feeding. Tell your doctor if you are pregnant, think you may be pregnant, plan to
become pregnant. You should discuss with your doctor whether you should receive AFLUNOV.
Tell your doctor if you are breast-feeding and follow his advice.
Driving and using machines
Some effects mentioned under section 4. “Possible side effects” may affect the ability to drive or use
machines.
Important information about some of the ingredients of AFLUNOV
This medicinal contains less than 1 mmol sodium (23 mg) and less than 1 mmol of potassium (39 mg)
per 0.5 ml dose, i.e. essentially sodium- and potassium-free.
3.
HOW AFLUNOV IS GIVEN
Your doctor or nurse will administer the vaccine in accordance with official recommendations.
The vaccine will be injected into the muscles of the upper arm (deltoid muscle). The vaccine should
never be given into a vein.
25
Adults and elderly (18 years of age and above):
One dose of 0.5 ml will be given. A second dose of 0.5 ml should be given after an interval of at least
3 weeks.
There is limited experience in elderly over 70 years of age.
Use in children
There is limited experience in children between 6 months and 17 years of age.
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.
If you have any further questions on the use of this medicinal product, ask your doctor or pharmacist.
4.
POSSIBLE SIDE EFFECTS
Like all medicines, AFLUNOV can cause side effects, although not everybody gets them.
Allergic reactions may occur following vaccination, in rare cases leading to shock. Doctors are aware
of this possibility and have emergency treatment available for use in such cases.
In the clinical trials with the vaccine, most side effects were mild in nature and short term. The side-
effects are generally similar to those related to the seasonal flu vaccine.
The frequency of possible side effects listed below is defined using the following convention:
very common (affects more than 1 user in 10)
common (affects 1 to 10 users in 100)
uncommon (affects 1 to 10 users in 1,000)
rare (affects 1 to 10 users in 10,000)
very rare (affects less than 1 user in 10,000)
The side effects listed below have occurred with AFLUNOV in clinical studies in adults, including
the elderly:
Very common:
Pain, hardening of the skin at the injection site, injection site redness, injection site swelling, pain at
the site of injection, aching muscles, headache, sweating, fatigue.
Common
:
Brusing of the skin at the injection site, fever and nausea, generally feeling unwell and shivering.
Uncommon
:
Flu like symptoms.
Rare
:
Convulsions, eye swelling and anaphylaxis.
These side effects usually disappear within 1-2 days without treatment. If they persist, CONSULT
YOUR DOCTOR.
Side effects from clinical study in children (6 months to 17 years of age)
A clinical study was conducted with the same vaccine in children. General side effects reported very
commonly in the 6 months to 35 months of age group were injection site redness, muscle ache,
26
irritability and unusual crying. Very commonly reported reactions in the 36 months to 17 years of age
group were pain, headache and fatigue.
Other rare side effects observed after routine use:
The side effects listed below have occurred in the days or weeks after vaccination with Focetria
H1N1v vaccine.
Generalised skin reactions including itching, urticaria (hives), rash or swelling of the skin and mucous
membranes.
Disorders of the gut such as nausea, vomiting, abdominal pain and diarrhoea.
Headache, dizziness, drowsiness, fainting.
Neurological disorders such as severe stabbing or throbbing pain along one or more nerves, tingling,
fits, and neuritis (inflammation of nerves).
Swollen lymph nodes, palpitations, weakness, pain in the extremities and cough.
Allergic reactions possibly with shortness of breath, wheezing, swelling of the throat, or leading to a
dangerous decrease of blood pressure, which, if untreated, may lead to shock. Doctors are aware of
this possibility and have emergency treatment available for use in such cases.
Data in children and adolescents suggest a slight decrease in side effects after the second dose of the
vaccine, with no increase in rates of fever.
In addition, the side effects listed below have occurred in the days or weeks after vaccination with
vaccines given routinely every year to prevent flu. These side effects may occur with AFLUNOV.
Low blood platelet count which can result in bleeding or bruising.
Vasculitis (inflammation of the blood vessels which can cause skin rashes, joint pain and kidney
problems), and exudative erythema multiforme (type of allergic skin reaction that occurs in response
to medications, infections, or illness).
Neurological disorders such as encephalomyelitis (inflammation of the central nervous system), and a
type of paralysis known as Guillain-Barré Syndrome.
If any of these side effects occur, please tell your doctor or nurse immediately.
If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please
tell your doctor.
5.
HOW TO STORE AFLUNOV
Keep out of the reach and sight of children.
Do not use AFLUNOV after the expiry date which is stated on the carton and the label. The expiry
date refers to the last day of that month.
Store in a refrigerator (2°C - 8°C). Do not freeze. Store in the original package in order to protect
from light.
Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to
dispose of medicines no longer required. These measures will help to protect the environment.
6.
FURTHER INFORMATION
What AFLUNOV contains
27
-
Active Substance
:
Influenza virus surface antigens (haemagglutinin and neuraminidase)* of strain:
A/Vietnam/1194/2004 (H5N1)-like strain (NIBRG-14)
7.5 micrograms** per 0.5 ml
dose
* propagated in eggs
** expressed in microgram haemagglutinin.
-
Adjuvant
MF59C.1:
The vaccine contains per 0.5 ml 9.75 mg squalene, 1.175 mg polysorbate 80 and 1.175 mg
sorbitan trioleate.
-
Other Ingredients:
The other ingredients are: sodium chloride, potassium chloride, potassium dihydrogen
phosphate, disodium phosphate dihydrate, magnesium chloride hexahydrate, calcium chloride
dihydrate, sodium citrate, citric acid and water for injections.
What AFLUNOV looks like and contents of the pack
AFLUNOV is a suspension for injection in a pre-filled syringe.
The suspension is a milky-white liquid.
It is provided in a ready-to-use pre-filled syringe, containing a single dose of 0.5 ml for injection.
Not all pack sizes may be marketed.
Marketing Authorisation Holder and Manufacturer
Marketing Authorisation Holder
Novartis Vaccines and Diagnostics S.r.l.
Via Fiorentina, 1
Siena, Italy.
Manufacturer
Novartis Vaccines and Diagnostics S.r.l.
Loc. Bellaria - 53018 Rosia
Sovicille (SI), Italy.
This leaflet was last approved in
{MM/YYYY}
Detailed information on this medicine is available on the European Medicines Agency web site:
http://www.ema.europa.eu
.
28
Source: European Medicines Agency
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