ANNEX I

SUMMARY OF PRODUCT CHARACTERISTICS

1
1. NAME OF THE MEDICINAL PRODUCT

Adjupanrix suspension and emulsion for emulsion for injection.

Pandemic influenza vaccine (H5N1) (split virion, inactivated, adjuvanted)

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

After mixing, 1 dose (0.5 ml) contains:

Split influenza virus, inactivated, containing antigen* equivalent to:

A/VietNam/1194/2004 (H5N1) like strain used (NIBRG-14) 3.75 micrograms**

*
propagated in eggs
**
haemagglutinin

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

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.

Excipient with known effect:

The vaccine contains 5 micrograms thiomersal (see section 4.4).

For the full list of excipients see section 6.1.

3. PHARMACEUTICAL FORM

Suspension and emulsion for emulsion for injection.

The suspension is a colourless light opalescent liquid.
The emulsion is a whitish to yellowish homogeneous milky liquid.

4. CLINICAL PARTICULARS

4.1 Therapeutic indications

Prophylaxis of influenza in an officially declared pandemic situation.

Adjupanrix should be used in accordance with official guidance.

4.2 Posology and method of administration

Posology

Persons not previously vaccinated with Prepandrix

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 and up to twelve
months after the first dose for maximum efficacy.

2
Based on very limited data, adults aged >80 years may require a double dose of Adjupanrix 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).

Persons previously vaccinated with one or two doses of Prepandrix containing HA derived from a
different clade of the same influenza subtype as the pandemic influenza virus:

Adults from the age of 18 years onwards: one dose of 0.5 ml at an elected date.

Paediatric population

There are limited safety and immunogenicity data available on the administration of Adjupanrix and
on administration of half a dose of the vaccine (i.e. 1.875 µg HA and half the amount of AS03
adjuvant) at 0 and 21 days in children aged 3 to 9 years.

Currently available data are described in section 4.4, 4.8 and 5.1 but no recommendation on a
posology can be made.

For further information, see sections 4.4, 4.8 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 preferably into the deltoid
muscle or anterolateral thigh (depending on the muscle mass).

For instructions on mixing of the medicinal product before administration, see section 6.6.

4.3 Contraindications

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. However, in a pandemic situation, it may be appropriate to give
the vaccine, provided that facilities for resuscitation are immediately available in case of need.
See section 4.4.
4.4 Special warnings and precautions for use

Caution is needed when administering this vaccine to persons with a known hypersensitivity (other
than anaphylactic reaction) to the active substance, to any of the excipients listed in section 6.1, to
thiomersal and to 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.

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

Adjupanrix should under no circumstances be administered intravascularly. There are no data with
Adjupanrix 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.

3
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).

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.

Epidemiological studies relating to another AS03-adjuvanted vaccine (Pandemrix H1N1, also

manufactured in the same facility as Adjupanrix), in several European countries have indicated an
increased risk of narcolepsy with or without cataplexy in vaccinated as compared with unvaccinated
individuals. In children/adolescents (aged up to 20 years), these studies have indicated an additional
1.4 to 8 cases in 100,000 vaccinated subjects. Available epidemiological data in adults aged over 20
years have indicated approximately 1 additional case per 100,000 vaccinated subjects. These data
suggest that the excess risk tends to decline with increasing age at vaccination. There is currently no
evidence to indicate that Adjupanrix may be associated with a risk of narcolepsy.

Paediatric population

Clinical data in children less than 6 years of age who received two doses of Pandemic influenza
vaccine H5N1, indicate an increase in frequency of fever (axillary≥38°C) after the administration of
the second dose. Therefore, monitoring of temperature and measures to lower the fever (such as
antipyretic medication as seems clinically necessary) are recommended in young children (e.g. up to
approximately 6 years of age) post-vaccination.

4.5 Interaction with other medicinal products and other forms of interaction

There are no data on co-administration of Adjupanrix 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.

4.6 Fertility, pregnancy and lactation

Pregnancy

There are currently no data available on the use of Adjupanrix in pregnancy.

An AS03-containing vaccine containing HA from H1N1v has been administered to women in each
trimester of pregnancy. Information on outcomes from estimated more than 200,000 women who
have been vaccinated during pregnancy is currently limited. There was no evidence of an increased
risk of adverse outcomes in over 100 pregnancies that were followed in a prospective clinical study.

Animal studies with Adjupanrix do not indicate reproductive toxicity (see section 5.3).

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Data from pregnant women vaccinated with different inactivated non-adjuvanted seasonal vaccines do
not suggest malformations or foetal or neonatal toxicity.

The use of Adjupanrix may be considered during pregnancy if this is thought to be necessary, taking
into account official recommendations.

Breast-feeding

Adjupanrix may be used in lactating women.

Fertility

No fertility data are available.

4.7 Effects on ability to drive and use machines

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

4.8 Undesirable effects

Summary of the safety profile

Clinical studies have evaluated the incidence of adverse reactions listed below in approximately 5,000
subjects 18 years old and above who received formulations containing at least 3.75 microgram
HA/AS03.

List of adverse reactions

Adverse reactions reported are listed according to the following frequency:

Frequencies are reported as: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)

Adverse reactions from clinical trials with the mock-up vaccine are listed here below (see section 5.1
for more information on mock-up vaccines).

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
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

5
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

Paediatric population

A clinical study (D-H5N1-009) evaluated the reactogenicity in children 3 to 5 and 6 to 9 years of age
who received either two adult (i.e. 0.5 ml) doses or two half adult (i.e. 0.25 ml) doses (21 days apart)
of Adjupanrix.

A difference in the frequency of local and general solicited adverse reactions between half adult and
adult doses was observed after each dose. The administration of a second half adult or an adult dose
did not enhance the reactogenicity, except for rates of general symptoms which were higher after the
second dose, particularly for rates of fever in <6 year olds. The per-dose frequency of adverse
reactions was as follows:

Adverse reactions 3-5 years 6-9 years

Half dose Full dose Half dose Full dose
Induration 9.9% 18.6% 12.0% 12.2%
Pain 48.5% 62.9% 68.0% 73.5%
Redness 10.9% 19.6% 13.0% 6.1%
Swelling 11.9% 24.7% 14.0% 20.4%
Fever (>38°C) 4.0% 11.3% 2.0% 17.3%
Fever (>39°C)
- per-dose 2.0% 5.2% 0% 7.1%
frequency
- per-subject 3.9% 10.2% 0% 14.3%
frequency
Drowsiness 7.9% 13.4% NA NA
Irritability 7.9% 18.6% NA NA
Loss of appetite 6.9% 16.5% NA NA
Shivering 1.0% 12.4% 4.0% 14.3%
NA=not available

In other clinical studies where children 6 months to 17 years received another pandemic influenza
vaccine (H5N1 A/Indonesia/05/2005 manufactured in Dresden, Germany), increases in the frequency
of some side effects (including injection site pain, redness and fever) were seen after the second dose
in children aged less than 6 years.

• Post-marketing surveillance

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

AS03-containing vaccines containing 3.75 µg HA derived from A/California/7/2009 (H1N1)

From post-marketing experience with AS03-containing vaccines containing 3.75 µg HA derived from
A/California/7/2009 (H1N1), the following adverse reactions have been reported:

Immune system disorders

Anaphylaxis, allergic reactions

Nervous system disorders

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Febrile convulsions

Skin and subcutaneous tissue disorders

Angioedema, generalised skin reactions, urticaria

Interpandemic trivalent vaccines

In addition, from post-marketing surveillance with interpandemic trivalent vaccines, the following
adverse reactions have been reported:

Rare:
Neuralgia, transient thrombocytopenia.

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).

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important.
It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare
professionals are asked to report any suspected adverse reactions via the national reporting system
listed in Appendix V.

4.9 Overdose

No case of overdose has been reported.

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Influenza vaccines, ATC Code: J07BB02.

Pharmacodynamic effects

This section describes the clinical experience with the mock-up vaccines.

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

Immune response against A/Vietnam/1194/2004 (H5N1):

Adults aged 18-60 years

In clinical studies that evaluated the immunogenicity of AS03-adjuvanted vaccine containing 3.75 µg
HA derived from A/Vietnam/1194/2004 in subjects aged 18-60 years the anti-haemagglutinin (anti-
HA) antibody responses were as follows:

anti-HA antibody Immune response to A/Vietnam/1194/2004

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0, 21 days schedule 0, 6 months schedule
(D-Pan-H5N1-002) (D-Pan-H5N1-012)
21 days after 21 days after 21 days after 7 days after 21 days after
1st dose 2nd dose 1st dose 2nd dose 2nd dose
N=925 N=924 N=55 N=47 N=48
Seroprotection rate1 44.5% 94.3% 38.2% 89.4% 89.6%
Seroconversion rate2 42.5% 93.7% 38.2% 89.4% 89.6%
Seroconversion factor3 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;
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 titres and 98-100% had a titre of at least 1:80.

Subjects of D-Pan-H5N1-002 were followed up for persistence of the immune response. The
seroprotection rates 6, 12, 24 and 36 months after the first dose were as follows:

anti-HA antibody Immune response to A/Vietnam/1194/2004

6 months after the 12 months after 24 months after 36 months after
1st dose the 1st dose the 1st dose the 1st dose
N=256 N=559 N=411 N=387
1
Seroprotection rate 40.2% 23.4% 16.3% 16.3%
1
seroprotection rate: proportion of subjects with haemagglutination inhibition (HI) titre ≥1:40

Older (>60 years)

In another clinical study (D-Pan-H5N1-010), 297 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 Immune response to A/Vietnam/1194/2004 (D42)

antibody
61 to 70 years 71 to 80 years >80 years
Single Double Single Double Single Double
dose dose dose dose dose dose
N=91 N=92 N=48 N=43 N=13 N=10
Seroprotection 84.6% 97.8% 87.5% 93.0% 61.5% 90.0%
rate1
Seroconversion 74.7% 90.2% 77.1% 93.0% 38.5% 50.0%
rate2
Seroconversion 11.8 26.5 13.7 22.4 3.8 7.7
factor3
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.

8
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 rate 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%.
Subjects of D-Pan-H5N1-010 were followed up for persistence of the immune response. The
seroprotection rates 6, 12 and 24 months after vaccination were as follows:

anti-HA antibody Immune response to A/Vietnam/1194/2004

6 months after 12 months after 24 months after
vaccination vaccination vaccination
Single Double Single Double Single Double
dose dose dose dose dose dose
(N=140) (N=131) (N=86) (N=81) (N=86) (N=81)
Seroprotection rate1 52.9% 69.5% 45.3% 44.4% 37.2% 30.9%
1
seroprotection rate: proportion of subjects with haemagglutination inhibition (HI) titre ≥1:40

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.

Twelve and twenty-four months after vaccination, the neutralising antibody titres were as follows:

Serum neutralising Immune response to A/Vietnam/1194/2004

antibody
12 months after vaccination 24 months after vaccination
Single dose Double dose Single dose Double dose
N=51 N=54 N=49 N=54
GMT1 274.8 272.0 391.0 382.8
Seroconversion 27.5% 27.8% 36.7% 40.7%
rate2
≥1:803 82.4% 90.7% 91.8% 100%
1
Geometric Mean Titre
2
4-fold increase in serum neutralising antibody titre
3
% of subjects reaching a serum neutralising antibody titre of at least 1:80

Paediatric population

Children aged 3 to 9 years

In a clinical study (D-Pan-H5N1-009), children aged 3 to 5 and 6 to 9 years old received two doses of
either a full (0.5 ml) or a half dose (0.25 ml) of an 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

3 to 5 years 6 to 9 years
Half dose Full dose Half dose Full dose
N=49 N=44 N=43 N=43
Seroprotection rate1 95.9% 100% 100% 100%
Seroconversion rate2 95.9% 100% 100% 100%
Seroconversion factor3 78.5 191.3 108.1 176.7
1
seroprotection rate: proportion of subjects with haemagglutination inhibition (HI) titre ≥1:40;

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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.

The clinical relevance of the haemagglutination inhibition (HI) titre ≥1:40 in children is unknown.

Subjects of D-Pan-H5N1-009 were followed up for persistence of the immune response. The
seroprotection rates 6, 12 and 24 months after vaccination were as follows:

anti-HA antibody Immune response to A/Vietnam/1194/2004

3-5 years
6 months after 12 months after 24 months after
vaccination vaccination vaccination
Half dose Full dose Half dose Full dose Half dose Full dose
(N=50) (N=29) (N=47) (N=27) (N=27) (N=26)
Seroprotection rate1 56.0% 82.8% 38.3% 48.1% 38.3% 73.1%
1
seroprotection rate: proportion of subjects with haemagglutination inhibition (HI) titre ≥1:40

anti-HA antibody Immune response to A/Vietnam/1194/2004

6-9 years
6 months after 12 months after 24 months after
vaccination vaccination vaccination
Half dose Full dose Half dose Full dose Half dose Full dose
(N=44) (N=41) (N=37) (N=35) (N=37) (N=34)
Seroprotection rate1 63.6% 78.0% 24.3% 62.9% 24.3% 67.6%
1
seroprotection rate: proportion of subjects with haemagglutination inhibition (HI) titre ≥1:40

At day 42, and after 6, 12 and 24 months the neutralising antibody responses were as follows:

Serum neutralising Immune response to A/Vietnam/1194/2004

antibody
3-5 years
21 days after 2nd dose 6 months after 12 months after 24 months after
vaccination vaccination vaccination
Half dose Full dose Half dose Half dose Half dose
N=47 N=42 N=49 N=47 N=47
GMT1 1044.4 4578.3 781.2 238.9 302.5
Seroconversion rate2 95.6% 97.4% 87.2% 82.2% 80.0%
≥1:803 100% 100% 100% 93.6% 95.7%
1
Geometric Mean Titre
2
4-fold increase in serum neutralising antibody titre
3
% of subjects reaching a serum neutralising antibody titre of at least 1:80

Serum neutralising Immune response to A/Vietnam/1194/2004

antibody
6-9 years
21 days after 2nd dose 6 months after 12 months after 24 months after
vaccination vaccination vaccination
Half dose Full dose Half dose Half dose Half dose
N=42 N=42 N=40 N=36 N=38

GMT1 1155.1 3032.5 756.1 179.4 234.5

Seroconversion 100% 100% 95.0% 67.6% 63.9%
rate2

10
≥1:803 100% 100% 100% 86.1% 97.4%
1
Geometric Mean Titre
2
4-fold increase in serum neutralising antibody titre
3
% of subjects reaching a serum neutralising antibody titre of at least 1:80

The European Medicines Agency has deferred the obligation to submit the results of studies with
Adjupanrix in one or more subsets of the paediatric population in influenza infection caused by an
influenza strain contained in the vaccine or related to a strain contained in the vaccine. (see section 4.2
for information on paediatric use).

Immune response against A/Indonesia/05/2005 (H5N1)

In a clinical study (Q-Pan-H5N1-001) 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

Day 21 Day 42 Day 180
N=140 N=140 N=138
Seroprotection rate1 45.7% 96.4% 49.3%
Seroconversion rate2 45.7% 96.4% 48.6%
Seroconversion factor3 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.

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 responses elicited by AS03-adjuvanted vaccine containing 3.75 µg HA derived

from A/Vietnam/1194/2004 (H5N1)

Adults aged 18-60 years

Anti-HA responses against A/Indonesia/5/2005 following administration of AS03-adjuvanted vaccine

containing 3.75 µg HA derived from A/Vietnam/1194/2004 were as follows:

anti-HA antibody A/Indonesia/5/2005

0, 21 days schedule 0, 6 months schedule

(D-Pan-H5N1-002) (D-Pan-H5N1-012)
21 days after 2nd dose 7 days after 2nd dose 21 days after 2nd dose
N = 924 N = 47 N = 48
Seroprotection rate*1 50.2% 74.5% 83.3%
Seroconversion rate2 50.2% 74.5% 83.3%
Seroconversion factor3 4.9 12.9 18.5
* anti-HA ≥1:40

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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.

A 4-fold increase in serum neutralising antibody against A/Indonesia/5/2005 was achieved in >90% of
subjects after two doses regardless of the schedule. After two doses administered 6 months apart all
subjects had a titre of at least 1:80.

Subjects from study D-Pan-H5N1-002 were followed up for persistence of anti-HA antibodies against
A/Indonesia/5/2005. The seroprotection rates were 2.2%, 4.7%, 2.4% and 7.8% at months 6, 12, 24
and 36, respectively.

In a different study (D-Pan-H5N1-007) in 50 subjects aged 18-60 years the anti-HA antibody
seroprotection rates 21 days after the second dose of AS03-adjuvanted vaccine containing 3.75 µg HA
derived from A/Vietnam/1194/2004 were 20% against A/Indonesia/5/2005, 35% against
A/Anhui/01/2005 and 60% against A/Turkey/Turkey/1/2005.

Older (>60 years)

In 297 subjects aged > 60 years the anti-HA antibody seroprotection and seroconversion rates against
A/Indonesia/5/2005 at day 42 after two doses of AS03-adjuvanted vaccine containing 3.75 µg HA
derived from A/Vietnam/1194/2004 were 23% and the seroconversion factor was 2.7. Neutralising
antibody titres of at least 1:40 or at least 1:80 were achieved in 87% and 67%, respectively, of the 87
subjects tested.

Subjects from study D-Pan-H5N1-010 who received a single dose were followed-up for persistence of
anti-HA antibodies against A/Indonesia/5/2005. The seroprotection rates were 16.3% and 4.7% at
months 12 and 24, respectively. Seroconversion rates for neutralising antibodies against
A/Indonesia/5/2005 were 15.7% and 12.2% for months 12 and 24, respectively. The percentage of
subjects reaching neutralising antibody titres of >1/80 were 54.9% and 44.9% at months 12 and 24,
respectively.

Paediatric population

Children aged 3 to 9 years

In the subjects aged 3 to 5 and 6 to 9 years old who received two doses of either a full or a half dose of
AS03-adjuvanted vaccine containing 3.75 µg HA derived from A/Vietnam/1194/2004 (H5N1), the
anti-HA antibody responses at day 42 were as follows:

anti-HA Immune response to A/Indonesia/5/2005

antibody
3 to 5 years 6 to 9 years
Half dose Full dose Half dose Full dose
N=49 N=44 N=43 N=43
Seroprotection 71.4% 95.5% 74.4% 79.1%
rate1
Seroconversion 71.4% 95.5% 74.4% 79.1%
rate2
Seroconversion 10.7 33.6 12.2 18.5
factor3
1
seroprotection rate: proportion of subjects with haemagglutination inhibition (HI) titre ≥1:40;

12
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.

Subjects of D-Pan-H5N1-009 were followed up for persistence of the immune response. The
seroprotection rate at month 6, 12 and 24 were as follows:

anti-HA Immune response to A/Indonesia/5/2005

antibody
3 to 5 years
Month 6 Month 12 Month 24
Half dose Full dose Half dose Full dose Half dose Full dose
N=49 N=27 N=47 N=27 N=47 N=26
Seroprotection 6.1% 70.4% 36.2% 44.4% 10.6% 53.8%
1
rate
1
seroprotection rate: proportion of subjects with haemagglutination inhibition (HI) titre ≥1:40

anti-HA Immune response to A/Indonesia/5/2005

antibody
6 to 9 years
Month 6 Month 12 Month 24
Half dose Full dose Half dose Full dose Half dose Full dose
N=42 N=34 N=36 N=35 N=37 N=34
Seroprotection 4.8% 64.7% 19.4% 42.9% 10.8% 29.4%
rate1
1
seroprotection rate: proportion of subjects with haemagglutination inhibition (HI) titre ≥1:40

Furthermore, in the group of children that received a half dose of vaccine, the rate of subjects with a
titre of neutralising antibodies above 1:80 remained high up to 24 months after the first dose. The
neutralising antibody responses were as follows:

Serum Immune response to A/Indonesia/5/2005

neutralising
antibody
3 to 5 years 6 to 9 years
Day 42 Month 6 Month Month Day 42 Month 6 Month Month
N=46 N=48 12 24 N=42 N=40 12 24
N=47 N=47 N=35 N=38
GMT1 331.4 242.1 177.7 188.5 412.1 208.4 128.1 146.0
Seropositivity 95.6% 93.0% 97.9% 97.9% 97.2% 97.3% 94.4% 97.4%
rate2
≥1:803 75.6% 72.1% 85.1% 80.9% 88.9% 70.3% 86.1% 81.6%
1
Geometric Mean Titre
2
% of subjects with titre ≥1:28
3
% of subjects reaching a serum neutralising antibody titre 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

13
Day 21 Day 42
N=140 N=140
1
Seroprotection rate 15% 59.3%
Seroconversion rate2 12.1% 56.4%
Seroconversion factor3 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.

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.

Alternative schedules
An extended dosing interval was investigated in study D-H5N1-012 in which a group of subjects 18-
60 years of age received two doses of Adjupanrix 6 months or 12 months apart. Twenty-one days after
the second dose, the seroprotection rate and the vaccine response rate against A/Vietnam/1194/2004 in
subjects who received the vaccine 6 months apart were 89.6% and 95.7%, respectively. Twenty-one
days after the second dose, the seroprotection rate and the vaccine response rate in subjects who
received the vaccine 12 months apart were 92.0% and 100%, respectively.

In this study, cross-reactive immune responses against A/Indonesia/5/2005 were also observed.
Twenty-one days after the second dose, the seroprotection rate and the vaccine response rate in
subjects who received the vaccine 6 months apart were 83.3% and 100%, respectively. Twenty-one
days after the second dose, the seroprotection rate and the vaccine response rate in subjects who
received the vaccine 12 months apart were 84.0% and 100%, respectively.

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 (D-Pan-H5N1-012), 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 respectively. The anti-HA
responses were as follows:

anti-HA antibody Against A/Vietnam 21 days after Against A/Indonesia 21 days after
boosting with A/Vietnam boosting with A/Indonesia
N=46 N=49
After one After two After one After two
priming dose priming doses priming dose priming doses
Seroprotection rate1 89.6% 91.3% 98.1% 93.9%
Booster 87.5% 82.6% 98.1% 91.8%
seroconversion rate2
Booster factor3 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.

14
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 (D-Pan-H5N1-015), 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.

In another clinical study (D-Pan-H5N1-038), 387 subjects aged 18-60 years received 1 dose of AS03-
adjuvanted vaccine containing 3.75 µg HA derived from A/Indonesia/5/2005 36 months after they had
received two doses of A/Vietnam/1194/2004. The seroprotection rate, booster seroconversion rate and
booster factor against A/Indonesia/5/2005 21 days after booster vaccination was 100%, 99.7% and
123.8%, respectively.

Information from non-clinical studies:

The ability to induce protection against homologous and heterologous vaccine strains was assessed
non-clinically using ferret challenge models.

In each experiment, four groups of six ferrets were immunised 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.

This medicinal product has been authorised under ‘exceptional circumstances’.

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

5.2 Pharmacokinetic properties

Not applicable.

5.3 Preclinical safety data

Non-clinical data reveal no special hazard for humans based on conventional studies of safety
pharmacology, acute and repeated dose toxicity, local tolerance, female fertility, embryo-foetal and
postnatal toxicity (up to the end of the lactation period).

6. PHARMACEUTICAL PARTICULARS

15
6.1 List of excipients

Suspension vial:
Polysorbate 80
Octoxynol 10
Thiomersal
Sodium chloride (NaCl)
Disodium hydrogen phosphate (Na2HPO4)
Potassium dihydrogen phosphate (KH2PO4)
Potassium chloride (KCl)
Magnesium chloride (MgCl2)
Water for injections

Emulsion vial:
Sodium chloride (NaCl)
Disodium hydrogen phosphate (Na2HPO4)
Potassium dihydrogen phosphate (KH2PO4)
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.

6.3 Shelf life

5 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.

For storage conditions after mixing of the medicinal product, see section 6.3.

6.5 Nature and contents of container

One pack containing:

- one pack of 50 vials (type I glass) of 2.5 ml suspension with a stopper (butyl rubber).
- two packs of 25 vials (type I glass) of 2.5 ml emulsion 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

Adjupanrix consists of two containers:

Suspension: multidose vial containing the antigen,
Emulsion: multidose vial containing the adjuvant.

Prior to administration, the two components should be mixed.

16
Instructions for mixing and administration of the vaccine:

1. Before mixing the two components, the emulsion (adjuvant) and suspension (antigen) should be
allowed to reach room temperature (for a minimum of 15 minutes); each vial should be shaken
and inspected visually for any foreign particulate matter and/or abnormal physical appearance.
In the event of either being observed (including rubber particles from the stopper), discard the
vaccine.
2. The vaccine is mixed by withdrawing the entire contents of the vial containing the adjuvant by
means of a 5 ml syringe and by adding it to the vial containing the antigen. It is recommended
to equip the syringe with a 23-G needle. However, in the case this needle size would not be
available, a 21-G needle might be used. The vial containing the adjuvant should be maintained
in upside down position to facilitate the withdrawal of the full content.
3. After the addition of the adjuvant to the antigen, the mixture should be well shaken. The mixed
vaccine is a whitish to yellowish homogeneous milky liquid emulsion. In the event of other
variation being observed, discard the vaccine.
4. The volume of the Adjupanrix vial after mixing is at least 5 ml. The vaccine should be
administered in accordance with the recommended posology (see section 4.2).
5. The vial should be shaken prior to each administration and inspected visually for any foreign
particulate matter and/or abnormal physical appearance. In the event of either being observed
(including rubber particles from the stopper), discard the vaccine.
6. Each vaccine dose of 0.5 ml is withdrawn into a 1 ml syringe for injection and administered
intramuscularly. It is recommended to equip the syringe with a needle gauge not larger than 23-
G.
7. After mixing, use the vaccine within 24 hours. The mixed vaccine can either be stored in a
refrigerator (2°C - 8°C) or at room temperature not exceeding 25°C. If the mixed vaccine is
stored in a refrigerator, it should be allowed to reach room temperature (for a minimum of 15
minutes) before each withdrawal.

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

7. MARKETING AUTHORISATION HOLDER

GlaxoSmithKline Biologicals s.a.

rue de l'Institut 89
B-1330 Rixensart, Belgium

8. MARKETING AUTHORISATION NUMBER(S)

EU/1/09/578/001

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE

AUTHORISATION

Date of first authorisation: 19 October 2009

Date of latest renewal:

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.

17
ANNEX II

A. MANUFACTURER OF THE BIOLOGICAL ACTIVE

SUBSTANCE AND MANUFACTURER RESPONSIBLE FOR
BATCH RELEASE

B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY

AND USE

C. OTHER CONDITIONS AND REQUIREMENTS OF THE

MARKETING AUTHORISATION
D. CONDITIONS OR RESTRICTIONS WITH REGARD TO
THE SAFE AND EFFECTIVE USE OF THE MEDICINAL
PRODUCT

E SPECIFIC OBLIGATION TO THE COMPLETE POST-

AUTHORISATION MEASURES FOR THE MARKETING
AUTHORISATION UNDER EXCEPTIONAL
CIRCUMSTANCES

18
A. MANUFACTURER OF THE BIOLOGICAL ACTIVE SUBSTANCE AND
MANUFACTURER RESPONSIBLE FOR BATCH RELEASE

Name and address of the manufacturer of the biological active substance

Sächsisches Serumwerk Dresden

Branch of GlaxoSmithKline Biologicals
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 OR RESTRICTIONS REGARDING SUPPLY AND USE

Medicinal product subject to medical prescription.

Adjupanrix can only be marketed when there is an official WHO/EU declaration of an influenza
pandemic, on the condition that the Marketing Authorisation Holder for Adjupanrix takes due account
of the officially declared pandemic strain.

• Official batch release

In accordance with Article 114 of Directive 2001/83/EC, the official batch release will be undertaken
by a state laboratory or a laboratory designated for that purpose.

C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING

AUTHORISATION

• Periodic Safety Update Reports

The marketing authorisation holder shall submit periodic safety update reports for this product in
accordance with the requirements set out in the list of Union reference dates (EURD list) provided for
under Article 107c(7) of Directive 2001/83/EC and published on the European medicines web-portal.

Outside of the pandemic period, the normal PSUR periodicity and format will be maintained, with a
specific review of AESI and possible adverse events related to adjuvants. This should include data
from ongoing studies, or actual use if applicable, of the ‘mock-up’ strains and any safety data relevant
to the adjuvant system.

During a pandemic situation, the resources must be concentrated on a timely and effective monitoring
of the safety profile of the influenza vaccines used during the pandemic. Moreover, a 6-monthly cycle
may be too long to allow assessment of the safety of a vaccine for which high levels of exposure are
expected within a short period of time. Therefore, 6-monthly or annual PSURs falling within the
pandemic period will be replaced by monthly “simplified PSURs” (S-PSUR) accompanied by a
summary of vaccine distribution.

Frequency of submission

- The clock should start from the first Monday after shipment of the first batch of vaccine.

19
- First data-lock point is 30 days later.
- S-PSUR submission to the Rapporteur and CHMP members on Day 45.
- Rapporteur’s assessment report is circulated to CHMP members on Day 50.
- CHMP report is circulated to the vaccine manufacturer on Day 55.
- Reporting to be monthly for the first 6 months.
- Periodicity should be reviewed by the MAH and the (Co-)Rapporteur at 6 monthly intervals.

When it has been agreed by the CHMP that the S-PSUR is no longer necessary, a full PSUR covering
the period since the data lock point of the last routine PSUR will be submitted within a time frame to
be agreed with the Rapporteur.

Format of the simplified PSUR

Only spontaneously reported data should be included in the PSUR. The report should include the
following Tables of aggregate data (using the pre-defined templates attached in Annex 2).
1. An overview for all spontaneous cases per country, stratified according to type of report
(medically confirmed or non-medically confirmed) and seriousness, for the period covered by
the report and cumulatively.

2. An overview for all spontaneous adverse reactions by SOC, High Level Term (HLT) and
Preferred Term (PT), stratified according to type of report (medically confirmed or non-
medically confirmed) and including the number of fatal reports, for the period covered by the
report and cumulatively.

3. Adverse Events of Special Interest stratified according to type of report (medically confirmed
or non-medically confirmed). AESIs will be defined as follows:

- Neuritis: PT “Neuritis”
- Convulsion: narrow SMQ “Convulsions”
- Anaphylaxis: narrow SMQ “Anaphylactic reaction” and narrow SMQ
“Angioedema”
- Encephalitis: narrow SMQ “Non-infectious encephalitis”
- Vasculitis: narrow SMQ “Vasculitis”
- Guillain-Barré syndrome: narrow SMQ “Guillain-Barré syndrome”
- Demyelination: narrow SMQ “Demyelination” (as GBS is also included in
this SMQ, there will be an overlap in the number of cases for
these two categories).
- Bell’s palsy: PT “Bell’s palsy”
- Vaccination failure: PT “Vaccination failure”.

4. Serious unlisted adverse reactions (SOC, HLT, PTs) stratified according to type of report
(medically confirmed or non-medically confirmed), for the period covered by the report and
cumulatively.

5. All spontaneous adverse reactions by age group, per SOC, HLT and PT, stratified according to
type of report (medically confirmed or non-medically confirmed), for the period covered by
the report and cumulatively. The following age groups will be used: < 2 years, 2-8 years, > 9
years.

6. All spontaneous adverse reactions (SOC, HLT, PT) occurring in pregnant women, stratified
according to type of report (medically confirmed or non-medically confirmed), for the period
covered by the report and cumulatively.

The following principles should be followed when compiling the data:

- Except for Table 1, all tables will be based on number of reactions (presented on PT level,
sorted by System Organ Class [SOC] and High Level Term [HLT]) and not number of cases.

20
- All tables will be based on generic and not product-specific data1. Product-specific data can
be evaluated during signal work-up.
- “Cumulatively” means since the use of the vaccine; events not reported during the period of
interest should not be presented in the tables.
- All non-medically confirmed events are those that have been entered into the database by the
data-lock point. Those which have not yet been entered should be reported in the following S-
PSUR.
- A line listing of fatal cases will be provided in an Annex.

A short summary should be provided in which validated signals and areas of concern are highlighted,
taking into account information arising from the prospective cohort study described in 4.5. In the
event of multiple signals, signal work-up may be prioritised and appropriate timelines for submission
of a full signal evaluation report should be provided.

Vaccine distribution report

To put the safety report into context, a summary of vaccine distribution should be included and should
provide details of the number of doses of vaccine distributed in
i) EU member states for the reporting period by batch number,
ii) EU member states cumulatively and
iii) the rest of the world.

D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND

EFFECTIVE USE OF THE MEDICINAL PRODUCT

• Risk Management Plan (RMP)

The MAH shall perform the required pharmacovigilance activities and interventions detailed in the
agreed RMP presented in Module 1.8.2 of the Marketing Authorisation and any agreed subsequent
updates of the RMP.

An updated RMP should be submitted:

• At the request of the European Medicines Agency;
• Whenever the risk management system is modified, especially as the result of new
information being received that may lead to a significant change to the benefit/risk profile or
as the result of an important (pharmacovigilance or risk minimisation) milestone being
reached.

If the dates for submission of a PSUR and the update of a RMP coincide, they can be submitted at the
same time.

E. SPECIFIC OBLIGATION TO COMPLETE POST-AUTHORISATION MEASURES

FOR THE MARKETING AUTHORISATION UNDER EXCEPTIONAL
CIRCUMSTANCES

This being an approval under exceptional circumstances and pursuant to Article 14(8) of Regulation
(EC) No 726/2004, the MAH shall conduct, within the stated timeframe, the following measures:
,

Description Due date

During the pandemic, the applicant will collect clinical safety Depending on and after
and effectiveness data of the pandemic vaccine and submit implementation of vaccine when
this information to the CHMP for evaluation. first pandemic will take place.

1
Based on the assumption that product name will not be provided in a significant proportion of cases.

21
During the pandemic, the applicant will conduct a Depending on and after
prospective cohort study as identified in the implementation of vaccine when
Pharmacovigilance plan. first pandemic will take place.

22
ANNEX III

LABELLING AND PACKAGE LEAFLET

23
A. LABELLING

24
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. NAME OF THE MEDICINAL PRODUCT

Adjupanrix suspension and emulsion for emulsion for injection.

Pandemic 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/VietNam/1194/2004 (H5N1) like strain used (NIBRG-14) 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 (Na2HPO4)
Potassium dihydrogen phosphate (KH2PO4)
Potassium chloride (KCl)
Magnesium chloride (MgCl2)
Water for injections

4. PHARMACEUTICAL FORM AND CONTENTS

Suspension and emulsion for emulsion for injection

50 vials: suspension (antigen)

50 vials: emulsion (adjuvant)

The volume after mixing 1 vial of suspension (2.5 ml) with 1 vial of emulsion (2.5 ml) corresponds to
10 doses of 0.5 ml vaccine

5. METHOD AND ROUTE(S) OF ADMINISTRATION

Intramuscular use
Shake before use
Read the package leaflet before use

25
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT
OF THE SIGHT AND REACH OF CHILDREN

Keep out of the sight and reach of children.

7. OTHER SPECIAL WARNING(S), IF NECESSARY

Suspension and emulsion to be mixed before administration

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 regulations

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER

GlaxoSmithKline Biologicals s.a.

Rue de l’Institut 89
B-1330 Rixensart, Belgium

12. MARKETING AUTHORISATION NUMBER(S)

EU/1/09/578/001

13. BATCH NUMBER

Lot:

14. GENERAL CLASSIFICATION FOR SUPPLY

Medicinal product subject to medical prescription.

15. INSTRUCTIONS ON USE

26
16. INFORMATION IN BRAILLE

Justification for not including Braille accepted

27
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
PACK OF 50 VIALS OF SUSPENSION

1. NAME OF THE MEDICINAL PRODUCT

Suspension for emulsion for injection for Adjupanrix

2. STATEMENT OF ACTIVE SUBSTANCE(S)

Split influenza virus, inactivated, containing antigen* equivalent to

3.75 micrograms haemagglutinin/dose
*Antigen: A/VietNam/1194/2004 (H5N1) like strain used (NIBRG-14)

3. LIST OF EXCIPIENTS

Excipients:
Polysorbate 80
Octoxynol 10
Thiomersal
Sodium chloride
Disodium hydrogen phosphate
Potassium dihydrogen phosphate
Potassium chloride
Magnesium chloride
Water for injections

4. PHARMACEUTICAL FORM AND CONTENTS

Antigen suspension for injection

50 vials: suspension
2.5 ml per vial.
After mixing with adjuvant emulsion: 10 doses of 0.5 ml

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 SIGHT AND REACH OF CHILDREN

Keep out of the sight and reach of children.

7. OTHER SPECIAL WARNING(S), IF NECESSARY

Suspension to be exclusively mixed with adjuvant emulsion before administration

28
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

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER

GSK Biologicals, Rixensart - Belgium

12. MARKETING AUTHORISATION NUMBER(S)

EU/1/09/578/001

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

29
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
PACK OF 25 VIALS OF EMULSION

1. NAME OF THE MEDICINAL PRODUCT

Emulsion for emulsion for injection for Adjupanrix

2. STATEMENT OF ACTIVE SUBSTANCE(S)

Content: AS03 adjuvant composed of squalene (10.69 milligrams), DL-α-tocopherol (11.86

milligrams) and polysorbate 80 (4.86 milligrams)

3. LIST OF EXCIPIENTS

Excipients:
Sodium chloride
Disodium hydrogen phosphate
Potassium dihydrogen phosphate
Potassium chloride
Water for injections

4. PHARMACEUTICAL FORM AND CONTENTS

Adjuvant emulsion for injection

25 vials: emulsion
2.5 ml

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 SIGHT AND REACH OF CHILDREN

Keep out of the sight and reach of children.

7. OTHER SPECIAL WARNING(S), IF NECESSARY

Emulsion to be exclusively mixed with antigen suspension before administration

8. EXPIRY DATE

EXP

30
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

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER

GSK Biologicals, Rixensart - Belgium

12. MARKETING AUTHORISATION NUMBER(S)

EU/1/09/578/001

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

31
MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS

SUSPENSION VIAL

1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION

Antigen suspension for

Adjupanrix
A/VietNam/1194/2004 (H5N1) like strain used (NIBRG-14)
I.M.

2. METHOD OF ADMINISTRATION

Mix with adjuvant emulsion before use

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

2.5 ml
After mixing with adjuvant emulsion: 10 doses of 0.5 ml

6. OTHER

Storage (2ºC-8ºC), do not freeze, protect from light

32
MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS

EMULSION VIAL

1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION

Adjuvant emulsion for

Adjupanrix
I.M.

2. METHOD OF ADMINISTRATION

Mix into Antigen suspension before use

3. EXPIRY DATE

EXP

4. BATCH NUMBER

Lot

5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT

2.5 ml

6. OTHER

Storage (2ºC-8ºC), do not freeze, protect from light

33
B. PACKAGE LEAFLET

34
Package leaflet: Information for the user

Adjupanrix suspension and emulsion for emulsion for injection

Pandemic influenza vaccine (H5N1) (split virion, inactivated, adjuvanted)

Read all of this leaflet carefully before you start receiving this vaccine because it contains
important information for you.

• Keep this leaflet. You may need to read it again.

• If you have any further questions, ask your doctor or nurse.
• This vaccine has been prescribed for you only. Do not pass it on to others.
• If you get any side effects, talk to your doctor.This includes any possible side effects not listed
in this leaflet. See section 4.

What is in this leaflet:

1. What Adjupanrix is and what it is used for
2. What you need to know before you receive Adjupanrix
3. How Adjupanrix is given
4. Possible side effects
5. How to store Adjupanrix
6. Contents of the pack and otherinformation

1. What Adjupanrix is and what it is used for

What Adjupanrix is and what it is used for

Adjupanrix is a vaccine for use in adults from 18 years old to prevent pandemic flu (influenza).

Pandemic flu is a type of influenza that happens at intervals that vary from less than 10 years to many
decades. It spreads rapidly around the world. The signs of pandemic flu are similar to those of
ordinary flu but may be more serious.

How Adjupanrix works

When a person is given the vaccine, the body’s natural defence system (immune system) produces its
own protection (antibodies) against the disease. None of the ingredients in the vaccine can cause flu.

As with all vaccines, Adjupanrix may not fully protect all persons who are vaccinated.

2. What you need to know before you receive Adjupanrix

Adjupanrix should not be given

• If you have previously had a sudden life-threatening allergic reaction to any ingredient of this
vaccine (listed in section 6) or to anything else that may be present in very small amounts, such
as: 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.
- However, in a pandemic situation, you may still be given the vaccine. This is as long as
medical treatment is available straight away, in case you have an allergic reaction.

Do not have Adjupanrix if any of the above apply to you.

If you are not sure, talk to your doctor or nurse before having this vaccine.

Warning and precautions:

35
Talk to your doctor or nurse before you are given Adjupanrix

• if you have had any allergic reaction other than a sudden life-threatening allergic reaction to any
ingredient of Adjupanrix (listed in section 6) or to thiomersal, to egg and chicken protein,
ovalbumin, formaldehyde, gentamicin sulphate (antibiotic) or to sodium deoxycholate.
• if you have a serious 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 will advise whether you could still be
vaccinated with Adjupanrix.
• 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 Adjupanrix the results of these tests may not be correct. Tell
the doctor requesting these tests that you have recently received Adjupanrix.
• you have a bleeding problem or you bruise easily.

Fainting can occur following, or even before, any needle injection. Therefore tell the doctor or nurse if
you fainted with a previous injection.

If any of the above apply to you (or you are not sure), talk to your doctor or nurse before having
Adjupanrix. This is because the vaccination may not be recommended, or may need to be delayed.

Children
If your child receives the vaccine, you should be aware that the side effects may be more intense after
the second dose, especially temperature over 38°C. Therefore monitoring of temperature and measures
to lower the temperature (such as giving paracetamol or other medicines that lower fever) after each
dose are recommended.

Other medicines and Adjupanrix

Tell your doctor or nurse if you are taking, have recently taken or might take any other medicines or
have recently received any other vaccine.

In particular, tell your doctor or nurse if you are having any treatments (such as corticosteroid
treatments or chemotherapy for cancer) that affect the immune system. Adjupanrix can still be given
but your response to the vaccine may be poor.

Adjupanrix is not intended to be given at the same time as some other vaccines. However, if this needs
to happen, the other vaccine will be injected into the other arm. Any side effects that happen may be
more serious.

Pregnancy and breast-feeding

If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask
your doctor for advice before taking this vaccine.

Driving and using machines

Some side effects listed in Section 4. “Possible side effects” may affect your ability to drive or use
tools or machines. It is best to see how Adjupanrix affects you before you try these activities.

Adjupanrix contains thiomersal

Adjupanrix contains thiomersal as a preservative and it is possible that you may experience an allergic
reaction. Tell your doctor if you have any known allergies.

Adjupanrix contains sodium and potassium

Adjupanrix contains less than 1 mmol sodium (23 mg) and less than 1 mmol of potassium (39 mg) per
dose. It is essentially sodium- and potassium-free.

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3. How Adjupanrix is given

If you have not previously received doses of Prepandrix or Prepandemic influenza vaccine
(H5N1) (split virion, inactivated, adjuvanted) GlaxoSmithKline Biologicals 3.75 µg

• From 18 years onwards: you will receive two doses of Adjupanrix. The second dose should be
given after an interval of at least three weeks and up to twelve months after the first dose.

• From 80 years onwards: you may receive two double injections of Adjupanrix. The first two
injections should be given at the elected date and the two other injections should preferably be
given 3 weeks after.

If you have previously received one or two doses of Prepandrix or Prepandemic influenza
vaccine (H5N1) (split virion, inactivated, adjuvanted) GlaxoSmithKline Biologicals 3.75 µg

• From 18 years onwards: you will receive one dose of Adjupanrix.

Use in children

In a clinical study, children 3 to 9 years of age have received either two adult (0.5 ml) or two half adult
(0.25 ml) doses. Your doctor will decide the appropriate dose for your child.

Your doctor or nurse will give you Adjupanrix.

• They will give Adjupanrix as an injection into a muscle.

• This will usually be in the upper arm.
• The double injections will be given in opposite arms.

If you have any further questions on the use of this vaccine, ask your doctor or nurse.

4. Possible side effects

Like all medicines, this vaccine can cause side effects, although not everybody gets them. The
following side effects may happen with this medicine:

Allergic reactions
Allergic reactions which may cause you to have dangerously low blood pressure. If this is not treated
it may lead to shock. Your doctors know that this might happen and will have emergency treatment
ready to use.

Other side effects:

Very common: may affect more than 1 in 10 people

• Headache
• Feeling tired
• Pain, redness, swelling or a hard lump where the injection was given
• Fever
• Aching muscles, joint pain

Common: may affect less than 1 in 10 people

• Warmth, itching or bruising where the injection was given
• Increased sweating, shivering, flu-like symptoms
• Swollen glands in your neck, armpit or groin

37
Uncommon: may affect less than 1 in 100 people
• Tingling or numbness of the hands or feet
• Sleepiness
• Feeling dizzy
• Diarrhoea, vomiting, stomach pain, feeling sick
• Itching, rash
• Generally feeling unwell
• Sleeplessness

These reactions usually disappear within 1-2 days without treatment.

Additional side effects in children

In a clinical study, children 3 to 9 years of age have received either two adult (0.5 ml) or two half adult
(0.25 ml) doses. The frequency of side effects was lower in the group of children who received half of
the adult dose. There was no increase after the second dose whether the children received half of the
adult or the adult dose, except for some side effects which were higher after the second dose,
particularly for rates of fever in < 6 years old children.

In other clinical studies where children 6 months to 17 years received a similar vaccine containing
A/Indonesia/05/2005, increases in the frequency of some side effects (including injection site pain,
redness and fever) were seen after the second dose in children aged less than 6 years.

The side effects listed below have happened with H1N1 AS03-containing vaccines. They may also
happen with Adjupanrix. If any of the side effects below occur, please tell your doctor or nurse
immediately:

• Allergic reactions leading to a dangerously low blood pressure. If this is not treated, it may lead
to shock. Your doctors will know that this might happen and will have emergency treatment
ready to use
• Fits
• Generalised skin reactions including urticaria (hives)

The side effects listed below have happened in the days or weeks after vaccination with vaccines given
routinely every year to prevent flu. They may also happen with Adjupanrix. If any of the side effects
below occur, please tell your doctor or nurse immediately:

Very rare: may affect less than 1 in 10,000 people

• Problems with your brain and nerves such as inflammation of the central nervous system
(encephalomyelitis), inflammation of nerves (neuritis) or a type of paralysis known as ‘Guillain-
Barré Syndrome’.
• Inflammation of your blood vessels (vasculitis). This can cause skin rashes, joint pain and
kidney problems

Rare: may affectless than 1 in 1,000 people

• Serious stabbing or throbbing pain along one or more nerves
• Low blood platelet count. This can cause bleeding or bruising

Reporting of side effects

If you get any side effects, talk to your doctor or nurse. This includes any possible side effects not
listed in this leaflet. You can also report side effects directly via the national reporting system listed
in Appendix V. By reporting side effects you can help provide more information on the safety of
this medicine.

5. How to store Adjupanrix

38
Keep this vaccine out of the sight and reach 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.

Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to
throw away medicines you no longer use. These measures will help protect the environment.

6. Contents of the pack and other information

What Adjupanrix contains

• Active substance:
Split influenza virus, inactivated, containing antigen* equivalent to:

A/Vietnam/1194/2004 (H5N1) like strain used (NIBRG-14) 3.75 micrograms** per 0.5 ml dose

*propagated in eggs
**expressed in microgram haemagglutinin

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

• Adjuvant:
The vaccine contains an ‘adjuvant’ AS03. This adjuvant 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, disodium
hydrogen phosphate, potassium dihydrogen phosphate, potassium chloride, magnesium
chloride, water for injections

What Adjupanrix looks like and contents of the pack

The suspension is a colourless light opalescent liquid.

The emulsion is a whitish to yellowish homogeneous milky liquid.

Before the vaccine is given, the two parts will be mixed together. The mixed vaccine is a whitish to to
yellowish homogeneous milky liquid emulsion.

One pack of Adjupanrix consists of:

• one pack containing 50 vials of 2.5 ml suspension (antigen)
• two packs containing 25 vials of 2.5 ml emulsion (adjuvant)

Marketing Authorisation Holder and Manufacturer

GlaxoSmithKline Biologicals s.a.

Rue de l’Institut 89

39
B-1330 Rixensart
Belgium

For any information about this medicinal vaccine, please contact the local representative of the
Marketing Authorisation Holder:

België/Belgique/Belgien Lietuva
GlaxoSmithKline Pharmaceuticals s.a./n.v. GlaxoSmithKline Lietuva UAB
Tél/Tel: + 32 10 85 52 00 Tel: +370 5 264 90 00
[email protected]

България Luxembourg/Luxemburg
ГлаксоСмитКлайн ЕООД GlaxoSmithKline Pharmaceuticals s.a./n.v.
Тел. + 359 2 953 10 34 Tél/Tel: + 32 10 85 52 00

Česká republika Magyarország

GlaxoSmithKline s.r.o. GlaxoSmithKline Kft.
Tel: + 420 2 22 00 11 11 Tel.: + 36-1-2255300
[email protected]

Danmark Malta
GlaxoSmithKline Pharma A/S GlaxoSmithKline (Malta) Ltd
Tlf: + 45 36 35 91 00 Tel: + 356 21 238131
[email protected]

Deutschland Nederland
GlaxoSmithKline GmbH & Co. KG GlaxoSmithKline BV
Tel: + 49 (0)89 360448701 Tel: + 31 (0)30 69 38 100
[email protected] [email protected]

Eesti Norge
GlaxoSmithKline Eesti OÜ GlaxoSmithKline AS
Tel: +372 667 6900 Tlf: + 47 22 70 20 00
[email protected] [email protected]

Ελλάδα Österreich
GlaxoSmithKline A.E.B.E GlaxoSmithKline Pharma GmbH.
Tηλ: + 30 210 68 82 100 Tel: + 43 1 970 75-0
[email protected]

España Polska
GlaxoSmithKline, S.A. GSK Services Sp. z o.o.
Tel: + 34 902 202 700 Tel.: + 48 (22) 576 9000
[email protected]

France Portugal
Laboratoire GlaxoSmithKline GlaxoSmithKline - Produtos Farmacêuticos, Lda.
Tél: + 33 (0) 1 39 17 84 44 Tel: + 351 21 412 95 00
[email protected] [email protected]

Hrvatska România
GlaxoSmithKline d.o.o. GlaxoSmithKline (GSK) SRL
Tel.: + 385 (0)1 6051999 Tel: +40 (0)21 3028 208

Ireland Slovenija
GlaxoSmithKline (Ireland) Ltd GlaxoSmithKline d.o.o.
Tel: + 353 (0)1 495 5000 Tel: + 386 (0) 1 280 25 00

40
[email protected]

Ísland Slovenská republika

Vistor hf. GlaxoSmithKline Slovakia s.r.o.
Sími: +354 535 7000 Tel: + 421 (0)2 48 26 11 11
[email protected]

Italia Suomi/Finland
GlaxoSmithKline S.p.A. GlaxoSmithKline Oy
Tel:+ 39 04 59 21 81 11 Puh/Tel: + 358 10 30 30 30
[email protected]

Κύπρος Sverige
GlaxoSmithKline (Cyprus) Ltd GlaxoSmithKline AB
Τηλ: + 357 22 39 70 00 Tel: + 46 (0)8 638 93 00
[email protected] [email protected]

Latvija United Kingdom

GlaxoSmithKline Latvia SIA GlaxoSmithKline UK
Tel: + 371 67312687 Tel: +44 (0)800 221 441
[email protected] [email protected]

This leaflet was last revised in .

This medicine has been authorised under ‘exceptional circumstances’.

This means that for scientific reasons it has been impossible to get complete information on this
medicine.
The European Medicines Agency will review any new information on the medicine every year and this
leaflet will be updated as necessary.

Other sources of information

Detailed information on this medicine is available on the European Medicines Agency web site:
http://www.ema.europa.eu/

---------------------------------------------------------------------------------------------------------------------

The following information is intended for healthcare professionals only:

Adjupanrix consists of two containers:

Suspension: multidose vial containing the antigen,
Emulsion: multidose vial containing the adjuvant.

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 (adjuvant) and suspension (antigen) should be
allowed to reach room temperature (for a minimum of 15 minutes); each vial should be shaken
and inspected visually for any foreign particulate matter and/or abnormal physical appearance.
In the event of either being observed (including rubber particles from the stopper), discard the
vaccine.
2. The vaccine is mixed by withdrawing the entire contents of the vial containing the adjuvant by
means of a 5 ml syringe and by adding it to the vial containing the antigen. It is recommended
to equip the syringe with a 23-G needle. However, in the case this needle size would not be

41
available, a 21-G needle might be used. The vial containing the adjuvant should be maintained
in upside down position to facilitate the withdrawal of the full content.
3. After the addition of the adjuvant to the antigen, the mixture should be well shaken. The mixed
vaccine is a whitish to yellowish homogeneous milky liquid emulsion. In the event of other
variation being observed, discard the vaccine.
4. The volume of the Adjupanrix vial after mixing is at least 5 ml. The vaccine should be
administered in accordance with the recommended posology (see section 3 “How Adjupanrix is
given”).
5. The vial should be shaken prior to each administration and inspected visually for any foreign
particulate matter and/or abnormal physical appearance. In the event of either being observed
(including rubber particles from the stopper), discard the vaccine.
6. Each vaccine dose of 0.5 ml is withdrawn into a 1 ml syringe for injection and administered
intramuscularly. It is recommended to equip the syringe with a needle gauge not larger than 23-
G.
7. After mixing, use the vaccine within 24 hours. The mixed vaccine can either be stored in a
refrigerator (2°C - 8°C) or at room temperature not exceeding 25°C. If the mixed vaccine is
stored in a refrigerator, it should be allowed to reach room temperature (for a minimum of 15
minutes) before each withdrawal.

The vaccine should not be administered intravascularly.

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

42