ANNEX I
SUMMARY OF PRODUCT CHARACTERISTICS
1.
Prepandrix suspension and emulsion for emulsion for injection.
Prepandemic influenza vaccine (H5N1) (split virion, inactivated, adjuvanted)
2.
After mixing, 1 dose (0.5 ml) contains:
Split influenza virus inactivated, containing antigen
*
equivalent to:
A/Indonesia/05/2005 (H5N1) like strain used (PR8-IBCDC-RG2)
3.75 micrograms
**
*
propagated in eggs
**
haemagglutinin
AS03 adjuvant composed of squalene (10.69 milligrams), DL-α-tocopherol (11.86 milligrams) and
polysorbate 80 (4.86 milligrams)
The suspension and emulsion vials once mixed form a multidose container. See section 6.5 for the
number of doses per vial.
Excipients: It contains 5 micrograms thiomersal
For a full list of excipients see section 6.1.
3.
Suspension and emulsion for emulsion for injection.
The suspension is a colourless light opalescent liquid.
The emulsion is a whitish homogeneous 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 vaccine prepared with H5N1 subtype strains (see
section 5.1).
Prepandrix should be used in accordance with official guidance.
Posology
Adults from the age of 18 years:
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 three weeks.
2
Based on very limited data, adults aged >80 years may require a double dose of Prepandrix on an
elected date and again after an interval of at least three weeks in order to achieve an immune response
(see section 5.1).
A complete vaccination course with Prepandrix consists of two doses. However, in the event of an
officially declared influenza pandemic, persons previously vaccinated with one or two doses of
Prepandrix that contained HA antigen derived from a different clade of the same influenza subtype as
the pandemic influenza strain may receive a single dose of Pandemrix instead of two doses that are
required in previously unvaccinated individuals.
There is no experience in children.
For further information, see sections 4.4 and 5.1.
Method of administration
Immunisation should be carried out by intramuscular injection.
If a double dose is given, the injections should be given into opposite limbs.
History of an anaphylactic (i.e. life-threatening) reaction to any of the constituents or trace residues
(egg and chicken protein, ovalbumin, formaldehyde, gentamicin sulphate and sodium deoxycholate) of
this vaccine. See sections 4.4, 4.8 and 6.1.
Acute severe febrile illness. Immunisation should be postponed.
Caution is needed when administering this vaccine to persons with a known hypersensitivity (other
than anaphylactic reaction) to the active substance, to any of the excipients, to thiomersal and to
residues (egg and chicken protein, ovalbumin, formaldehyde, gentamicin sulphate and sodium
deoxycholate).
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.
Prepandrix should under no circumstances be administered intravascularly or intradermally.
There are no data on administration of AS03-adjuvanted vaccines before or following other types of
influenza vaccines intended for pre-pandemic or pandemic use.
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).
The vaccine should not usually be given at the same time as other vaccines. However, if co-
administration with another vaccine is considered to be essential, the vaccines should be injected into
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.
3
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.
No data have been generated in pregnant women with Prepandrix or with any other vaccine that
contains the AS03 adjuvant.
Reproductive toxicity studies have been conducted in animals using Prepandrix containing
A/Vietnam/1194/2004. These studies do not indicate direct or indirect harmful effects with respect to
fertility, pregnancy, embryonic/fetal development, parturition or post-natal development (see section
5.3).
Healthcare providers need to assess the benefits and potential risks of administering the vaccine to
pregnant women taking into consideration official recommendations.
There are no data regarding the use of Prepandrix during lactation. The potential benefits to the mother
and risks to the infant should be considered before administering Prepandrix during lactation.
Some of the effects mentioned under section 4.8 “Undesirable Effects” may affect the ability to drive
or operate machinery.
•
Clinical trials
Clinical studies have evaluated the incidence of adverse reactions listed below in approximately 5,000
subjects 18 years old and above who received Prepandrix containing A/Vietnam/1194/2004 (H5N1)
strain with at least 3.75 µg HA.
In clinical trials in which subjects (N=201) received Prepandrix containing 3.75 microgram HA/AS03
of A/Indonesia/05/2005 (H5N1) strain, the types and frequencies of adverse reactions were
comparable with those reported below.
Adverse reactions reported 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.
Blood and lymphatic system disorders
Common: lymphadenopathy
Psychiatric disorders
Uncommon: insomnia
Nervous system disorders
Very common: headache
4
Uncommon: paraesthesia, somnolence, dizziness
Gastrointestinal disorders
Uncommon: gastro-intestinal symptoms (such as diarrhoea, vomiting, abdominal pain, nausea)
Skin and subcutaneous tissue disorders
Common: ecchymosis at the injection site, sweating increased
Uncommon: pruritus, rash
Musculoskeletal and connective tissue disorders
Very common: arthralgia, myalgia
General disorders and administration site conditions
Very common: induration, swelling, pain and redness at the injection site, fever, fatigue,
Common: shivering, influenza like illness, injection site reactions (such as warmth, pruritus)
Uncommon: malaise
•
Post-marketing surveillance
No post-marketing surveillance data are available following Prepandrix administration.
From Post-marketing surveillance with interpandemic trivalent vaccines, the following adverse
reactions have been reported:
Uncommon
:
Generalised skin reactions including urticaria
Rare
:
Neuralgia, convulsions, transient thrombocytopenia.
Allergic reactions, in rare cases leading to shock, have been reported.
Very rare
:
Vasculitis with transient renal involvement.
Neurological disorders, such as encephalomyelitis, neuritis and Guillain Barré syndrome.
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).
No case of overdose has been reported.
5.
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Influenza vaccines, ATC Code J07BB02
Immune response against A/Indonesia/05/2005 (H5N1)
In a clinical study in which two doses of AS03-adjuvanted vaccine containing 3.75 µg HA derived
from A/Indonesia/05/2005 were administered on days 0 and 21 to 140 subjects aged 18-60 years, the
anti-HA antibody responses were as follows:
anti-HA antibody
Immune response to A/Indonesia/05/2005
5
Day 180
N=138
Seroprotection rate
1
45.7% 96.4% 49.3%
Seroconversion rate
2
45.7% 96.4% 48.6%
Seroconversion factor
3
4.7 95.3 5.2
1
seroprotection rate: proportion of subjects with haemagglutination inhibition (HI) titre ≥1:40;
2
seroconversion rate: proportion of subjects who were either seronegative at pre-vaccination and have
a protective post-vaccination titre of ≥1:40, or who were seropositive at pre-vaccination and have a 4-
fold increase in titre;
3
seroconversion factor: ratio of the post-vaccination geometric mean titre (GMT) and the pre-
vaccination GMT.
Day 21
N=140
Day 42
N=140
A 4-fold increase in serum neutralising antibody titres was observed in 79.2% of subjects twenty-one
days after the first dose, 95.8% twenty-one days after the second dose and 87.5% six months after the
second dose.
In a second study, 49 subjects aged 18-60 years received two doses of AS03-adjuvanted vaccine
containing 3.75 µg HA derived from A/Indonesia/05/2005 on days 0 and 21. At day 42, the anti-HA
antibody seroconversion rate was 98%, all subjects were seroprotected and the seroconversion factor
was 88.6. In addition, all subjects had neutralising antibody titres of at least 1:80.
Cross-reactive immune response elicited by AS03-adjuvanted vaccine containing 3.75 µg HA derived
from A/Indonesia/05/2005 (H5N1)
After two doses of AS03-adjuvanted vaccine containing 3.75 µg HA derived from
A/Indonesia/05/2005 administered on days 0 and 21 to 140 subjects aged 18-60 years, the anti-HA
antibody responses to A/Vietnam/1194/2004 were as follows:
anti-HA antibody
Immune response to A/Vietnam/1194/2004
Day 42
N=140
Seroprotection rate
1
15% 59.3%
Seroconversion rate
2
12.1% 56.4%
Seroconversion factor
3
1.7 6.1
1
seroprotection rate: proportion of subjects with haemagglutination inhibition (HI) titre ≥1:40;
2
seroconversion rate: proportion of subjects who were either seronegative at pre-vaccination and have
a protective post-vaccination titre of ≥1:40, or who were seropositive at pre-vaccination and have a 4-
fold increase in titre;
3
seroconversion factor: ratio of the post-vaccination geometric mean titre (GMT) and the pre-
vaccination GMT.
Day 21
N=140
At day 180, the seroprotection rate was 13%.
A 4-fold increase in serum neutralising antibody titres against A/Vietnam was obtained in 49% of
subjects twenty-one days after the first dose, 67.3% twenty-one days after the second dose and 44.9%
six months after the second dose.
One dose of AS03-adjuvanted vaccine containing 3.75 µg HA derived from A/Indonesia/05/2005
administered after one or two doses of AS03-adjuvanted vaccine containing 3.75 µg HA derived from
A/Vietnam/1194/2004.
In a clinical study, subjects aged 18-60 years received a dose of AS03-adjuvanted vaccine containing
3.75 µg HA derived from either A/Vietnam/1194/2004 or Indonesia/5/2005 six months after they had
received one or two priming doses of AS03-adjuvanted vaccine containing 3.75 µg HA derived from
A/Vietnam/1194/2004 on day 0 or on days 0 and 21. The anti-HA responses were as follows:
6
anti-HA antibody
Against A/Vietnam 21 days after
boosting with A/Vietnam
N=46
Against A/Indonesia 21 days after
boosting with A/Indonesia
N=49
After one
priming dose
After two
priming doses
After one
priming dose
After two
priming doses
Seroprotection rate
1
89.6%
91.3%
98.1%
93.9%
Booster
seroconversion rate
2
87.5%
82.6%
98.1%
91.8%
Booster factor
3
29.2 11.5 55.3 45.6
1
seroprotection rate: proportion of subjects with haemagglutination inhibition (HI) titre ≥1:40;
2
booster seroconversion rate: proportion of subjects who were either seronegative at pre-booster and
have a protective post-vaccination titre of ≥1:40, or who were seropositive at pre-booster and have a 4-
fold increase in titre;
3
booster factor: ratio of the post-booster geometric mean titre (GMT) and the pre-booster GMT.
Regardless of whether one or two doses of priming vaccine had been given 6 months earlier, the
seroprotection rates against A/Indonesia were >80% after a dose of AS03-adjuvanted vaccine
containing 3.75 µg HA derived from A/Vietnam/1194/2004 and the seroprotection rates against
A/Vietnam were >90% after a dose of AS03-adjuvanted vaccine containing 3.75 µg HA derived from
A/Indonesia/05/2005. All subjects achieved a neutralising antibody titre of at least 1:80 against each of
the two strains regardless of the HA type in the vaccine and the previous number of doses.
In another clinical study, 39 subjects aged 18-60 years received a dose of AS03-adjuvanted vaccine
containing 3.75 µg HA derived from A/Indonesia/5/2005 fourteen months after they had received two
doses of AS03-adjuvanted vaccine containing 3.75 µg HA derived from A/Vietnam/1194/2004
administered on day 0 and day 21. The seroprotection rate against A/Indonesia 21 days after booster
vaccination was 92% and 69.2% at day 180.
Other information
The anti-HA and neutralising antibody responses to A/Indonesia/05/2005 elicited by AS03-adjuvanted
vaccine containing 3.75 µg HA derived from this same strain have been shown to be comparable with
the immune responses to A/Vietnam/1194/2004 elicited by AS03-adjuvanted vaccine containing 3.75
µg HA derived from this same strain. Therefore, the data that have been generated with AS03-
adjuvanted vaccine containing 3.75 µg HA derived from A/Vietnam/1194/2004 are considered to be
relevant to the use of AS03-adjuvanted vaccine containing 3.75 µg HA derived from
A/Indonesia/05/2005.
In clinical studies that evaluated the immunogenicity of AS03-adjuvanted vaccine containing 3.75 µg
HA derived from A/Vietnam/1194/2004 (H5N1) in subjects 18-60 years old, the anti-haemagglutinin
(anti-HA) antibody responses were as follows:
anti-HA antibody
Immune response to A/Vietnam/1194/2004
0, 21 days schedule
0, 6 months schedule
21 days
after 2
nd
dose
N=48
Seroprotection rate
1
44.5% 94.3% 38.2% 89.4% 89.6%
Seroconversion rate
2
42.5% 93.7% 38.2% 89.4% 89.6%
Seroconversion factor
3
4.1 39.8 3.1 38.2 54.2
1
seroprotection rate: proportion of subjects with haemagglutination inhibition (HI) titre ≥1:40;
2
seroconversion rate: proportion of subjects who were either seronegative at pre-vaccination and have
a protective post-vaccination titre of ≥1:40, or who were seropositive at pre-vaccination and have a 4-
fold increase in titre;
21 days after
1
st
dose
N=925
21 days after
2
nd
dose
N=924
21 days
after 1
st
dose
N=55
7 days after
2
nd
dose
N=47
7
3
seroconversion factor: ratio of the post-vaccination geometric mean titre (GMT) and the pre-
vaccination GMT.
After two doses given 21 days or 6 months apart, 96.0% of subjects had a 4-fold increase in serum
neutralising antibody titreand 98-100% had a titre of at least 1:80.
Follow up of 50 subjects aged 18-60 years who had received two doses of AS03-adjuvanted vaccine
containing 3.75 µg HA derived from A/Vietnam/1194/2004 (H5N1) at 0 and 21 days showed that 84%
were seroprotected (HI titre ≥1:40) at day 42 compared with 54% at day 180. A 4-fold increase in
serum neutralising antibody titres from day 0 was observed in 85.7% at day 42 and 72% at day 180. In
addition, the anti-HA antibody seroprotection rates at day 42 were 20% against A/Indonesia/5/2005,
35% against A/Anhui/01/2005 and 60% against A/Turkey/Turkey/1/2005.
In another clinical study, 152 subjects aged > 60 years (stratified in ranges from 61 to 70, 71 to 80 and
> 80 years of age) received either a single or a double dose of AS03-adjuvanted vaccine containing
3.75 µg HA derived from A/Vietnam/1194/2004 (H5N1) at 0 and 21 days. At day 42, the anti-HA
antibody responses were as follows:
anti-HA
antibody
Immune response to A/Vietnam/1194/2004 (D42)
61 to 70 years
71 to 80 years
>80 years
Single
dose
N=91
Double
dose
N=92
Single
dose
N=48
Double
dose
N=43
Single
dose
N=13
Double
dose
N=10
Seroprotection
rate
1
84.6%
97.8%
87.5%
93.0%
61.5%
90.0%
Seroconversion
rate
2
74.7%
90.2%
77.1%
93.0%
38.5%
50.0%
Seroconversion
factor
3
11.8
26.5
13.7
22.4
3.8
7.7
1
seroprotection rate: proportion of subjects with haemagglutination inhibition (HI) titre ≥1:40;
2
seroconversion rate: proportion of subjects who were either seronegative at pre-vaccination and have
a protective post-vaccination titre of ≥1:40, or who were seropositive at pre-vaccination and have a 4-
fold increase in titre;
3
seroconversion factor: ratio of the post-vaccination geometric mean titre (GMT) and the pre-
vaccination GMT.
Although an adequate immune response was achieved at day 42 following two administrations of a
single dose of AS03-adjuvanted vaccine containing 3.75 µg HA derived from A/Vietnam/1194/2004
(H5N1), a higher response was observed following two administrations of a double dose of vaccine.
Very limited data in seronegative subjects >80 years of age (N=5) showed that no subject achieved
seroprotection following two administrations of a single dose of AS03-adjuvanted vaccine containing
3.75 µg HA derived from A/Vietnam/1194/2004 (H5N1). However, following two administrations of
a double dose of vaccine, the seroprotection rate at day 42 was 75%.
The day 180 seroprotection rates in subjects aged >60 years were52.9% for those who had received
two single doses and 69.5% for those who had received two double doses at day 0 and day 21.
In addition, 44.8% and 56.1% of subjects in respective dose groups had a 4-fold increase in serum
neutralising antibody titres from day 0 to day 42 and 96.6% and 100% of subjects had a titre of at least
1:80 at day 42.
Information from non-clinical studies:
The ability to induce protection against homologous and heterologous vaccine strains was assessed
non-clinically using ferret challenge models.
8
In each experiment, four groups of six ferrets were immunized intramuscularly with an AS03
adjuvanted vaccine containing HA derived from H5N1/A/Vietnam/1194/04 (NIBRG-14). Doses of 15,
5, 1.7 or 0.6 micrograms of HA were tested in the homologous challenge experiment, and doses of 15,
7.5, 3.8 or 1.75 micrograms of HA were tested in the heterologous challenge experiment. Control
groups included ferrets immunized with adjuvant alone, non-adjuvanted vaccine (15 micrograms HA)
or phosphate buffered saline solution. Ferrets were vaccinated on days 0 and 21 and challenged by the
intra-tracheal route on day 49 with a lethal dose of either H5N1/A/Vietnam/1194/04 or heterologous
H5N1/A/Indonesia/5/05. Of the animals receiving adjuvanted vaccine, 87% and 96% were protected
against the lethal homologous or heterologous challenge, respectively. Viral shedding into the upper
respiratory tract was also reduced in vaccinated animals relative to controls, suggesting a reduced risk
of viral transmission. In the unadjuvanted control group, as well as in the adjuvant control group, all
animals died or had to be euthanized as they were moribund, three to four days after the start of
challenge.
5.2 Pharmacokinetic properties
Not applicable.
5.3 Preclinical safety data
Non-clinical data reveal no special hazard for humans based on conventional studies of safety
pharmacology, acute and repeated dose toxicity, local tolerance, female fertility, embryo-fetal and
postnatal toxicity (up to the end of the lactation period). The reproductive toxicity studies have been
conducted using Prepandrix containing A/Vietnam/1194/2004.
6.
6.1 List of excipients
Suspension vial:
Polysorbate 80
Octoxynol 10
Thiomersal
Sodium chloride (NaCl)
Disodium hydrogen phosphate (Na
2
HPO
4
)
Potassium dihydrogen phosphate (KH
2
PO
4
)
Potassium chloride (KCl)
Magnesium chloride (MgCl
2
)
Water for injections
Emulsion vial:
Sodium chloride (NaCl)
Disodium hydrogen phosphate (Na
2
HPO
4
)
Potassium dihydrogen phosphate (KH
2
PO
4
)
Potassium chloride (KCl)
Water for injections
For adjuvants, see section 2.
6.2 Incompatibilities
In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal
products.
9
6.3 Shelf-life
2 years
After mixing, the vaccine should be used within 24 hours. Chemical and physical in-use stability has
been demonstrated for 24 hours at 25°C.
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
One pack containing:
-
one pack of 50 vials (type I glass) of 2.5 ml suspension (10 x 0.25 ml doses) with a stopper
(butyl rubber).
-
two packs of 25 vials (type I glass) of 2.5 ml emulsion (10 x 0.25 ml doses) with a stopper
(butyl rubber).
The volume after mixing 1 vial of suspension (2.5 ml) with 1 vial of emulsion (2.5 ml) corresponds to
10 doses of vaccine (5 ml).
6.6 Special precautions for disposal and other handling
Prepandrix consists of two containers:
Vial A: multidose vial containing the antigen (suspension),
Vial B: multidose vial containing the adjuvant (emulsion).
Prior to administration, the two components should be mixed.
Instructions for mixing and administration of the vaccine:
1.
Before mixing the two components, the emulsion and suspension should be allowed to reach
room temperature, shaken and inspected visually for any foreign particulate matter and/or
abnormal physical appearance. In the event of either being observed, discard the vaccine.
2.
The vaccine is mixed by withdrawing the contents of the vial containing the emulsion (Vial B)
by means of a syringe and by adding it to the vial containing the suspension (Vial A).
3.
After the addition of the emulsion to the suspension, the mixture should be well shaken. The
mixed vaccine is a whitish emulsion. In the event of other variation being observed, discard the
vaccine.
4.
The volume of Prepandrix (5 ml) after mixing corresponds to 10 doses of vaccine.
5.
The vial should be shaken prior to each administration.
6.
Each vaccine dose of 0.5 ml is withdrawn into a syringe for injection.
7.
The needle used for withdrawal must be replaced by a needle suitable for intramuscular
injection.
Any unused product or waste material should be disposed of in accordance with local requirements.
7.
GlaxoSmithKline Biologicals s.a.
rue de l'Institut 89
B-1330 Rixensart, Belgium
10
EU/1/08/453/002
Date of first authorisation: 07/08/2009
Detailed information on this medicinal product is available on the website of the European Medicines
Agency (EMEA)
http://www.emea.europa.eu
/.
11
ANNEX II
A.
MANUFACTURER OF THE BIOLOGICAL ACTIVE
SUBSTANCE AND MANUFACTURING AUTHORISATION
HOLDER RESPONSIBLE FOR BATCH RELEASE
B.
CONDITIONS OF THE MARKETING AUTHORISATION
12
A. MANUFACTURER OF THE BIOLOGICAL ACTIVE SUBSTANCE AND
MANUFACTURING AUTHORISATION HOLDER RESPONSIBLE FOR BATCH
RELEASE
Name and address of the manufacturer of the biological active substance
GlaxoSmithKline Biologicals
Branch of SmithKline Beecham Pharma GmbH & Co. KG
Zirkustraße 40, D-01069 Dresden
Germany
Name and address of the manufacturer responsible for batch release
GlaxoSmithKline Biologicals S.A.
89, rue de l'Institut
B-1330 Rixensart
Belgium
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 V01 (dated June
2006) 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 RMPv6
(dated March 2009)
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, the
updated RMP should be submitted at the same time as the next 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 EMEA
13
PSURs
PSUR submission when Prepandrix is used during the 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 (Phase 6 of the WHO global Influenza
preparedness plan) 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.
14
ANNEX III
LABELLING AND PACKAGE LEAFLET
15
A. LABELLING
16
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
PACK CONTAINING 1 PACK OF 50 VIALS OF SUSPENSION AND 2 PACKS OF 25 VIALS
OF EMULSION
1.
Prepandrix suspension and emulsion for emulsion for injection
Prepandemic influenza vaccine (H5N1) (split virion, inactivated, adjuvanted)
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
After mixing, 1 dose (0.5 ml) contains:
Split influenza virus, inactivated, containing antigen equivalent to:
A/Indonesia/05/2005 (H5N1) like strain used (PR8-IBCDC-RG2)
3.75 micrograms
*
AS03 adjuvant composed of squalene, DL-α-tocopherol and polysorbate 80
*
haemagglutinin
3.
LIST OF EXCIPIENTS
Polysorbate 80
Octoxynol 10
Thiomersal
Sodium chloride (NaCl)
Disodium hydrogen phosphate (Na
2
HPO
4
)
Potassium dihydrogen phosphate (KH
2
PO
4
)
Potassium chloride (KCl)
Magnesium chloride (MgCl
2
)
Water for injections
4.
Suspension and emulsion for emulsion for injection
50 vials A: suspension
50 vials B: emulsion
The volume after mixing 1 vial of suspension (2.5 ml) (Vial A) with 1 vial of emulsion (2.5 ml) (Vial
B) corresponds to
10 doses
of vaccine (5 ml)
1 dose = 0.5 ml
5.
METHOD AND ROUTE(S) OF ADMINISTRATION
Intramuscular use
17
Shake before use
Read the package leaflet before use
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
Suspension and emulsion to be mixed before administration
8.
EXPIRY DATE
EXP: MM/YYYY
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
GlaxoSmithKline Biologicals s.a.
Rue de l’Institut 89
B-1330 Rixensart, Belgium
EU/1/08/453/002
13. BATCH NUMBER
Lot:
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription
18
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
Justification for not including Braille accepted
19
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
PACK OF 50 VIALS OF SUSPENSION
1.
Prepandrix suspension for emulsion for injection
Prepandemic influenza vaccine (H5N1)
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
Split influenza virus, inactivated, containing antigen equivalent to
A/Indonesia/05/2005 (H5N1) like strain used (PR8-IBCDC-RG2)
3.75 micrograms
*
*
haemagglutinin
3.
LIST OF EXCIPIENTS
Polysorbate 80
Octoxynol 10
Thiomersal
Sodium chloride (NaCl)
Disodium hydrogen phosphate (Na
2
HPO
4
)
Potassium dihydrogen phosphate (KH
2
PO
4
)
Potassium chloride (KCl)
Magnesium chloride (MgCl
2
)
Water for injections
4.
Suspension for emulsion for injection
50 vials: suspension
5.
METHOD AND ROUTE(S) OF ADMINISTRATION
Intramuscular use
Shake before use
Read the package leaflet before use
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
20
Suspension to be exclusively mixed with emulsion before administration
8.
EXPIRY DATE
EXP: MM/YYYY
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 regulations.
GlaxoSmithKline Biologicals s.a.
Rue de l’Institut 89
B-1330 Rixensart, Belgium
EU/1/08/453/002
13. BATCH NUMBER
Lot:
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
Justification for not including Braille accepted
21
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
PACK OF 25 VIALS OF EMULSION
1.
Emulsion for emulsion for injection for Prepandrix
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
AS03 adjuvant composed of squalene (10.69 milligrams), DL-α-tocopherol (11.86 milligrams) and
polysorbate 80 (4.86 milligrams)
3.
LIST OF EXCIPIENTS
Sodium chloride (NaCl)
Disodium hydrogen phosphate (Na
2
HPO
4
)
Potassium dihydrogen phosphate (KH
2
PO
4
)
Potassium chloride (KCl)
Water for injections
4.
Emulsion for emulsion for injection
25 vials: emulsion
5.
METHOD AND ROUTE(S) OF ADMINISTRATION
Intramuscular use
Shake before use
Read the package leaflet before use
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
Emulsion to be exclusively mixed with suspension before administration
8.
EXPIRY DATE
EXP: MM/YYYY
22
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 regulations.
GlaxoSmithKline Biologicals s.a.
Rue de l’Institut 89
B-1330 Rixensart, Belgium
EU/1/08/453/002
13. BATCH NUMBER
Lot:
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
Justification for not including Braille accepted
23
MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS
SUSPENSION VIAL
1.
Vial A (suspension) to be mixed with vial B for
Prepandrix
IM
2.
METHOD OF ADMINISTRATION
3.
EXPIRY DATE
EXP
After mixing: Use within 24 hours and do not store above 25°C.
Date and time of mixing:
4.
BATCH NUMBER
Lot
5.
CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT
After mixing, vial A contains 10 doses (5 ml)
1 dose = 0.5 ml
6.
OTHER
24
MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS
EMULSION VIAL
1.
Vial B (emulsion) to be mixed with vial A for
Prepandrix
2.
METHOD OF ADMINISTRATION
3.
EXPIRY DATE
EXP
4.
BATCH NUMBER
Lot
5.
CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT
2.5 ml
6.
OTHER
25
B. PACKAGE LEAFLET
26
PACKAGE LEAFLET: INFORMATION FOR THE USER
Prepandrix suspension and emulsion for emulsion for injection
Prepandemic influenza vaccine (H5N1) (split virion, inactivated, adjuvanted)
Read all of this leaflet carefully before you start receiving this vaccine.
-
Keep this leaflet. You may need to read it again.
-
If you have any further questions, ask your doctor or pharmacist.
-
If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet,
please tell your doctor or pharmacist.
In this leaflet
:
1. What Prepandrix is and what it is used for
2. Before you receive Prepandrix
3. How Prepandrix is given
4. Possible side effects
5.
How to store Prepandrix
6.
Further information
1.
What Prepandrix is and what it is used for
Prepandrix is a vaccine for use in adults from 18 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 at intervals that vary from less than 10 years to many
decades. It spreads rapidly around the world. The symptoms of pandemic flu are similar to those of
ordinary flu but are usually more severe.
When a person is given the vaccine, the immune system (the body’s natural defence system) will
produce its own protection (antibodies) against the disease. None of the ingredients in the vaccine can
cause flu.
As with all vaccines, Prepandrix may not fully protect all persons who are vaccinated.
2.
Before you receive Prepandrix
Prepandrix should not be given:
•
if you have previously had a sudden life-threatening allergic reaction to any ingredient of
Prepandrix (these are listed at the end of this leaflet) or to any of the substances that may be
present in trace amounts as follows: egg and chicken protein, ovalbumin, formaldehyde,
gentamicin sulphate (antibiotic) or sodium deoxycholate. Signs of an allergic reaction may
include itchy skin rash, shortness of breath and swelling of the face or tongue.
•
if you have a severe infection with a high temperature (over 38°C). If this applies to you then
your vaccination will be postponed until you are feeling better. A minor infection such as a cold
should not be a problem, but your doctor will advise whether you can still be vaccinated with
Prepandrix.
Do not have Prepandrix if any of the above apply to you. If you are not sure, talk to your doctor or
pharmacist before having this vaccine.
Take special care with Prepandrix:
27
-
This vaccine has been prescribed for you. Do not pass it on to others.
•
if you have had any allergic reaction other than a sudden life threatening allergic reaction to any
ingredient contained in the vaccine, to thiomersal, to egg and chicken protein, ovalbumin
formaldehyde, gentamicin sulphate (antibiotic) or to sodium deoxycholate. (see section 6.
Further information).
•
if you have problems with your immune system, since your response to the vaccine may then be
poor.
•
if you are having a blood test to look for evidence of infection with certain viruses. In the first
few weeks after vaccination with Prepandrix the results of these tests may not be correct. Tell
the doctor requesting these tests that you have recently received Prepandrix.
Using other medicines or vaccines
Please tell your doctor if you are taking or have recently taken any other medicines, including
medicines obtained without a prescription or have recently received any other vaccine.
There are no data on the use of Prepandrix given at the same time as other vaccines. Therefore,
Prepandrix is not intended to be given at the same time as other vaccines. However, if this cannot be
avoided, the other vaccine will be injected into the other arm. Any side effects that occur may be
more severe.
If you take any medicines that reduce immunity to infections or have any other type of treatment (such
as radiotherapy) that affects the immune system, Prepandrix can still be given but your response to the
vaccine may be poor.
Pregnancy and breast-feeding
There is no information on the use of Prepandrix in pregnant or breast-feeding women. Your doctor
needs to assess the benefits and potential risks of giving you the vaccine if you are pregnant or breast-
feeding. Please tell your doctor if you are/may be pregnant or intend to become pregnant, or 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 Prepandrix
Thiomersal (preservative) is present in this product, and it is possible that you may experience an
allergic reaction.
This medicinal product contains less than 1 mmol sodium (23 mg) and less than 1 mmol of potassium
(39 mg) per dose, i.e. essentially sodium- and potassium-free.
3.
How Prepandrix is given
You will receive two doses of Prepandrix. The second dose should be given after an interval of at least
three weeks.
If you are older than 80 years of age, you may receive two double injections of Prepandrix. The first
two injections should be given at the elected date and the two other injections should preferably be
given 3 weeks after.
The doctor or nurse will give Prepandrix as an injection into your upper arm muscle. The vaccine
should never be given into a vein or into the skin. The double injections will be given in opposite
arms.
If you have any further questions on the use of this product, ask your doctor or nurse.
28
4.
Possible side effects
Like all medicines, Prepandrix can cause side effects, although not everybody gets them.
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 Prepandrix.
Very rare (these may occur with up to 1 in 10,000 doses of the vaccine):
•
Temporary inflammation of the brain and nerves causing pain, weakness and paralysis that may
spread across the body.
•
Narrowing or blockage of blood vessels with kidney problems
Rare (these may occur with up to 1 in 1,000 doses of the vaccine):
•
Allergic reactions leading to a dangerous decrease of blood pressure, which, if untreated, may
lead to collapse, coma and death
•
Fits
•
Severe stabbing or throbbing pain along one or more nerves
•
Low blood platelet count which can result in bleeding or bruising
Uncommon (these may occur with up to 1 in 100 doses of the vaccine):
•
Generalised skin reactions including urticaria (hives)
If any of these side effects occur, please tell your doctor or pharmacist immediately.
The side effects listed below have occurred with Prepandrix in clinical studies:
Very common (these may occur with more than 1 in 10 doses of the vaccine):
•
Tiredness
•
Headache
•
Pain, redness, swelling or a hard lump at the injection site
•
Fever
•
Aching muscles, joint pain
Common (these may occur with up to 1 in 10 doses of the vaccine):
•
Warmth, itching or bruising at the injection site
•
Increased sweating, shivering, flu-like symptoms
•
Swollen glands in the neck, armpit or groin
Uncommon (these may occur with up to 1 in 100 doses of the vaccine):
•
Tingling or numbness of the hands or feet
•
Dizziness
•
Sleepiness
•
Sleeplessness
•
Diarrhoea, vomiting, stomach pain, feeling sick
•
Itching, rash
•
Generally feeling unwell
These reactions usually disappear within 1-2 days without treatment.
If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please
tell your doctor or pharmacist.
29
5.
How to store Prepandrix
Keep out of the reach and sight of children.
Before the vaccine is mixed:
Do not use the suspension and the emulsion after the expiry date which is stated on the carton. The
expiry date refers to the last day of that month.
Store in a refrigerator (2°C - 8°C).
Store in the original package in order to protect from light.
Do not freeze.
After the vaccine is mixed:
After mixing, use the vaccine within 24 hours and do not store above 25°C.
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 Prepandrix contains
•
Active substance:
After mixing, one dose (0.5 ml) contains 3.75 micrograms of haemagglutinin from the following
influenza virus strain:
A/Indonesia/05/2005 (H5N1) like strain used (PR8-IBCDC-RG2)
•
Adjuvant:
The emulsion vial contains an ‘adjuvant’ (AS03). This compound contains squalene (10.69
milligrams), DL-α-tocopherol (11.86 milligrams) and polysorbate 80 (4.86 milligrams).
Adjuvants are used to improve the body’s response to the vaccine.
•
Other ingredients:
The other ingredients are: polysorbate 80, octoxynol 10, thiomersal, sodium chloride (NaCl),
disodium hydrogen phosphate (Na
2
HPO
4
), potassium dihydrogen phosphate(KH
2
PO
4
),
potassium chloride (KCl), magnesium chloride (MgCl
2
), water for injections
What Prepandrix looks like and contents of the pack
Suspension and emulsion for emulsion for injection.
One pack of Prepandrix consists of:
•
one pack containing 50 vials of 2.5 ml suspension (active substance) for 10 doses
•
two packs containing 25 vials of 2.5 ml emulsion (adjuvant) for 10 doses
The suspension is a colourless light opalescent liquid.
The emulsion is a whitish homogeneous liquid.
Prior to administration, the two components should be mixed. The mixed vaccine is a whitish
emulsion.
Marketing Authorisation Holder and Manufacturer
GlaxoSmithKline Biologicals s.a.
30
Rue de l’Institut 89
B-1330 Rixensart
Belgium
For any information about this medicine, please contact the local representative of the Marketing
Authorisation Holder:
België/Belgique/Belgien
GlaxoSmithKline s.a./n.v.
Tél/Tel: + 32 2 656 21 11
Luxembourg/Luxemburg
GlaxoSmithKline s.a./n.v.
Tél/Tel: + 32 2 656 21 11
България
ГлаксоСмитКлайн ЕООД
Тел.: + 359 2 953 10 34
Magyarország
GlaxoSmithKline Kft.
Tel.: + 36-1-2255300
Česká republika
GlaxoSmithKline s.r.o.
Tel: + 420 2 22 00 11 11
gsk.czmail@gsk.com
Malta
GlaxoSmithKline Malta
Tel: + 356 21 238131
Danmark
GlaxoSmithKline Pharma A/S
Tlf: + 45 36 35 91 00
dk-info@gsk.com
Nederland
GlaxoSmithKline BV
Tel: + 31 (0)30 69 38 100
nlinfo@gsk.com
Deutschland
GlaxoSmithKline GmbH & Co. KG
Tel: + 49 (0)89 360448701
produkt.info@gsk.com
Norge
GlaxoSmithKline AS
Tlf: + 47 22 70 20 00
firmapost@gsk.no
Eesti
GlaxoSmithKline Eesti OÜ
Tel: +372 667 6900
estonia@gsk.com
Österreich
GlaxoSmithKline Pharma GmbH.
Tel: + 43 1 970 75-0
at.info@gsk.com
Ελλάδα
GlaxoSmithKline A.E.B.E
Tηλ: + 30 210 68 82 100
Polska
GSK Commercial Sp. z o.o.
Tel.: + 48 (22) 576 9000
España
GlaxoSmithKline, S.A.
Tel: + 34 902 202 700
es-ci@gsk.com
France
Laboratoire GlaxoSmithKline
Tél: + 33 (0) 1 39 17 84 44
diam@gsk.com
România
GlaxoSmithKline (GSK) SRL
Tel: + 40 (0)21 3028 208
Ireland
GlaxoSmithKline (Ireland) Ltd
Tel: + 353 (0)1 4955000
Slovenija
GlaxoSmithKline d.o.o.
Tel: + 386 (0) 1 280 25 00
medical.x.si@gsk.com
Ísland
GlaxoSmithKline ehf.
Sími: +354-530 3700
Slovenská republika
GlaxoSmithKline Slovakia s.r.o.
Tel: + 421 (0)2 48 26 11 11
31
recepcia.sk@gsk.com
Italia
GlaxoSmithKline S.p.A.
Tel:+ 39 04 59 21 81 11
Suomi/Finland
GlaxoSmithKline Oy
Puh/Tel: + 358 10 30 30 30
Finland.tuoteinfo@gsk.com
Κύπρος
GlaxoSmithKline Cyprus Ltd
Τηλ: + 357 22 39 70 00
Latvija
GlaxoSmithKline Latvia SIA
Tel: + 371 67312687
lv-epasts@gsk.com
United Kingdom
GlaxoSmithKline UK
Tel: + 44 (0)808 100 9997
customercontactuk@gsk.com
Lietuva
GlaxoSmithKline Lietuva UAB
Tel. +370 5 264 90 00
info.lt@gsk.com
This leaflet was last approved in
{MM/YYYY}.
Detailed information on this medicine is available on the European Medicines Agency (EMEA) web
---------------------------------------------------------------------------------------------------------------------
The following information is intended for medical or healthcare professionals only:
Prepandrix consists of two containers:
Vial A: multidose vial containing the antigen (suspension),
Vial B: multidose vial containing the adjuvant (emulsion).
Prior to administration, the two components should be mixed.
Instructions for mixing and administration of the vaccine:
1.
Before mixing the two components, the emulsion and suspension should be allowed to reach room
temperature, shaken and inspected visually for any foreign particulate matter and/or abnormal
physical appearance. In the event of either being observed, discard the vaccine.
2.
The vaccine is mixed by withdrawing the contents of the vial containing the emulsion (Vial B) by
means of a syringe and by adding it to the vial containing the suspension (Vial A).
3.
After the addition of the emulsion to the suspension, the mixture should be well shaken. The
mixed vaccine is a whitish emulsion. In the event of other variation being observed, discard the
vaccine.
4.
The volume of Prepandrix (5 ml) after mixing corresponds to 10 doses of vaccine.
5.
The vial should be shaken prior to each administration.
6.
Each vaccine dose of 0.5 ml is withdrawn into a syringe for injection.
7.
The needle used for withdrawal must be replaced by a needle suitable for intramuscular injection.
Any unused product or waste material should be disposed of in accordance with local requirements.
32
Source: European Medicines Agency
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