Adjupanrix (previously Pandemic influenza vaccine (H5N1) (split virion, inactivated, adjuvanted) GlaxoSmithKline Biologicals) - summary of medicine characteristics

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-a-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 PARTICULARS4.1 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.

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 ^g 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.

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 preparedness or zoonotic 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).

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 pandemic preparedness vaccine are listed here below (see section 5.1 for more information on pandemic preparedness 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

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 frequency – per-subject frequency	2.0% 3.9%	5.2% 10.2%	0% 0%	7.1% 14.3%
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 zoonotic 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 Lig HA derived from A/California/7/2009 (H1N1)

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

Immune system disorders

Anaphylaxis, allergic reactions

Nervous system disorders

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

4.9 Overdose

No case of overdose has been reported.

5. PHARMACOLOGICAL PROPERTIES5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Influenza vaccines, ATC Code: J07BB02.

Pharmacodynamic effects

This section describes the clinical experience with the pandemic preparedness vaccines.

Pandemic preparedness 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 pandemic preparedness vaccine will support a vaccination strategy that is likely to be used for the pandemic vaccine: clinical immunogenicity, safety and reactogenicity data obtained with pandemic preparedness 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 pg HA derived from A/Vietnam/1194/2004 in subjects aged 18–60 years the anti-haemagglutinin (antiHA) antibody responses were as follows:

anti-HA antibody	Immune response to A/Vietnam/1194/2004
	0, 21 days schedule (D-Pan-H5N1–002)		0, 6 months schedule (D-Pan-H5N1–012)
	21 days after 1st dose N=925	21 days after 2nd dose N=924	21 days after 1st dose N=55	7 days after 2nd dose N=47	21 days after 2nd dose N=48
1         1                      <1 Seroprotection rate	44.5%	94.3%	38.2%	89.4%	89.6%
Seroconversion rate	42.5%	93.7%	38.2%	89.4%	89.6%
Seroconversion factor	4.1	39.8	3.1	38.2	54.2

• 1 seroprotection rate: proportion of subjects with haemagglutination inhibition (HI) titre >1:40;

• 2seroconversion 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 4fold increase in titre;

• 3seroconversion factor: ratio of the post-vaccination geometric mean titre (GMT) and the prevaccination 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 1st dose N=256	12 months after the 1st dose N=559	24 months after the 1st dose N=411	36 months after the 1st dose N=387
n                  1      1 •              <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 ^g 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
1         1                      <1 Seroprotection rate	84.6%	97.8%	87.5%	93.0%	61.5%	90.0%
Seroconversion rate	74.7%	90.2%	77.1%	93.0%	38.5%	50.0%
Seroconversion factor	11.8	26.5	13.7	22.4	3.8	7.7

Although an adequate immune response was achieved at day 42 following two administrations of a single dose of AS03-adjuvanted vaccine containing 3.75 ^g 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 ^g 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 vaccination		12 months after vaccination		24 months after vaccination
	Single dose (N=140)	Double dose (N=131)	Single dose (N=86)	Double dose (N=81)	Single dose (N=86)	Double dose (N=81)
1               ,                    <1 Seroprotection rate	52.9%	69.5%	45.3%	44.4%	37.2%	30.9%

1seroprotection 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 antibody	Immune response to A/Vietnam/1194/2004
	12 months after vaccination		24 months after vaccination
	Single dose N=51	Double dose N=54	Single dose N=49	Double dose N=54
GMT1	274.8	272.0	391.0	382.8
Seroconversion rate2	27.5%	27.8%	36.7%	40.7%
>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 ^g 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 N=49	Full dose N=44	Half dose N=43	Full dose N=43
1               1                    <1 Seroprotection rate	95.9%	100%	100%	100%
Seroconversion rate2	95.9%	100%	100%	100%
Seroconversion factor3	78.5	191.3	108.1	176.7

1seroprotection rate: proportion of subjects with haemagglutination inhibition (HI) titre >1:40;

• 2seroconversion 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 4fold increase in titre;

• 3seroconversion factor: ratio of the post-vaccination geometric mean titre (GMT) and the prevaccination 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 vaccination		12 months after vaccination		24 months after 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)
n                  1      1 •              <1 Seroprotection rate	56.0%	82.8%	38.3%	48.1%	38.3%	73.1%

1seroprotection 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 vaccination		12 months after vaccination		24 months after 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)
n                  1      1 •              <1 Seroprotection rate	63.6%	78.0%	24.3%	62.9%	24.3%	67.6%

1seroprotection 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 antibody	Immune response to A/Vietnam/1194/2004
	3–5 years
	21 days after 2nd dose		6 months after vaccination	12 months after vaccination	24 months after vaccination
	Half dose N=47	Full dose N=42	Half dose N=49	Half dose N=47	Half dose 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 antibody	Immune response to A/Vietnam/1194/2004
	6–9 years
	21 days after 2nd dose		6 months after vaccination	12 months after vaccination	24 months after vaccination
	Half dose N=42	Full dose N=42	Half dose N=40	Half dose N=36	Half dose N=38
GMT1	1155.1	3032.5	756.1	179.4	234.5
Seroconversion rate2	100%	100%	95.0%	67.6%	63.9%

>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 ng 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 N=140	Day 42 N=140	Day 180 N=138
1         1                      <1 Seroprotection rate	45.7%	96.4%	49.3%
Seroconversion rate2	45.7%	96.4%	48.6%
Seroconversion factor3	4.7	95.3	5.2

1seroprotection rate: proportion of subjects with haemagglutination inhibition (HI) titre >1:40;

• 2seroconversion 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 4fold increase in titre;

• 3seroconversion factor: ratio of the post-vaccination geometric mean titre (GMT) and the prevaccination 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 ng 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 ng 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 ng HA derived from A/Vietnam/1194/2004 were as follows:

anti-HA antibody	A/Indonesia/5/2005
	0, 21 days schedule (D-Pan-H5N1–002)	0, 6 month (D-Pan-H	is schedule [5N1–012)
	21 days after 2nd dose N = 924	7 days after 2nd dose N = 47	21 days after 2nd dose 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

1seroprotection rate: proportion of subjects with haemagglutination inhibition (HI) titre >1:40; 2seroconversion 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 4fold increase in titre;

• 3seroconversion factor: ratio of the post-vaccination geometric mean titre (GMT) and the prevaccination 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 ^g 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 ^g 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 ^g HA derived from A/Vietnam/1194/2004 (H5N1), the anti-HA antibody responses at day 42 were as follows:

anti-HA antibody	Immune response to A/Indonesia/5/2005
	3 to 5 years		6 to 9 years
	Half dose N=49	Full dose N=44	Half dose N=43	Full dose N=43
Seroprotection . i rate	71.4%	95.5%	74.4%	79.1%
Seroconversion rate2	71.4%	95.5%	74.4%	79.1%
Seroconversion factor3	10.7	33.6	12.2	18.5

’seroprotection rate: proportion of subjects with haemagglutination inhibition (HI) titre >1:40;

• 2seroconversion 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 4fold increase in titre;

• 3seroconversion factor: ratio of the post-vaccination geometric mean titre (GMT) and the prevaccination 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 antibody	Immune response to A/Indonesia/5/2005
	3 to 5 years
	Month 6		Month 12		Month 24
	Half dose N=49	Full dose N=27	Half dose N=47	Full dose N=27	Half dose N=47	Full dose N=26
Seroprotection rate1	6.1%	70.4%	36.2%	44.4%	10.6%	53.8%

1seroprotection rate: proportion of subjects with haemagglutination inhibition (HI) titre >1:40

anti-HA antibody	Immune response to A/Indonesia/5/2005
	6 to 9 years
	Month 6		Month 12		Month 24
	Half dose N=42	Full dose N=34	Half dose N=36	Full dose N=35	Half dose N=37	Full dose N=34
Seroprotection rate1	4.8%	64.7%	19.4%	42.9%	10.8%	29.4%

1seroprotection 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 neutralising antibody	Immune response to A/Indonesia/5/2005
	3 to 5 years				6 to 9 years
	Day 42 N=46	Month 6 N=48	Month 12 N=47	Month 24 N=47	Day 42 N=42	Month 6 N=40	Month 12 N=35	Month 24 N=38
GMT1	331.4	242.1	177.7	188.5	412.1	208.4	128.1	146.0
Seropositivity rate2	95.6%	93.0%	97.9%	97.9%	97.2%	97.3%	94.4%	97.4%
>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 ug HA derived from A/Indonesia/05/2005 (H5N1)

After two doses of AS03-adjuvanted vaccine containing 3.75 ug 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 21 N=140	Day 42 N=140
1         1                      <1 Seroprotection rate	15%	59.3%
Seroconversion rate2	12.1%	56.4%
Seroconversion factor3	1.7	6.1

1seroprotection rate: proportion of subjects with haemagglutination inhibition (HI) titre >1:40; 2seroconversion 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 4fold increase in titre;

• 3seroconversion factor: ratio of the post-vaccination geometric mean titre (GMT) and the prevaccination 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 1860 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 ug HA derived from A/Indonesia/05/2005 administered after one or two doses of AS03-adjuvanted vaccine containing 3.75 ug 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 ug 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 ug 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 boosting with A/Vietnam		Against A/Indonesia 21 days after boosting with A/Indonesia N=49
	N	1=46
	After one priming dose	After two priming doses	After one priming dose	After two priming doses
n                  1      1 •              <1 Seroprotection rate	89.6%	91.3%	98.1%	93.9%
Booster seroconversion rate2	87.5%	82.6%	98.1%	91.8%
Booster factor3	29.2	11.5	55.3	45.6

1 seroprotection rate: proportion of subjects with haemagglutination inhibition (HI) titre >1:40; 2booster 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 4fold increase in titre;

3booster 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 ^g 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 ^g 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 ^g HA derived from A/Indonesia/5/2005 fourteen months after they had received two doses of AS03-adjuvanted vaccine containing 3.75 ^g 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 ^g 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 PARTICULARS6.1 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.

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 23G.

• 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.

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: 18 July 2014