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Pandemic Influenza Vaccine H5N1 Baxter AG (influenza vaccine (whole virion, inactivated)...) – Summary of product characteristics - J07BB01

Updated on site: 09-Oct-2017

Medication namePandemic Influenza Vaccine H5N1 Baxter AG
ATC CodeJ07BB01
Substanceinfluenza vaccine (whole virion, inactivated) containing antigen of: A/Vietnam/1203/2004 (H5N1)
ManufacturerNanotherapeutics Bohumil, s.r.o.

1.NAME OF THE MEDICINAL PRODUCT

PANDEMIC INFLUENZA VACCINE H5N1 BAXTER Suspension for injection

Pandemic influenza vaccine (H5N1) (whole virion, inactivated, prepared in cell culture)

2.QUALITATIVE AND QUANTITATIVE COMPOSITION

Influenza vaccine (whole virion, inactivated) containing antigen * of: A/Vietnam/1203/2004 (H5N1)7.5 micrograms**per 0.5 ml dose

*produced in Vero cells

**haemagglutinin

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

The vaccine is available in a multidose container (see section 6.5 for the number of doses per vial).

For the full list of excipients, see section 6.1.

3.PHARMACEUTICAL FORM

Suspension for injection.

The vaccine is an off-white, opalescent, translucent suspension.

4.CLINICAL PARTICULARS

4.1Therapeutic indications

Prophylaxis of influenza in an officially declared pandemic situation. Pandemic influenza vaccine should be used in accordance with official guidance.

4.2Posology and method of administration

Posology

Adults and children from 6 months onwards:

One dose of 0.5 ml at an elected date.

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

Method of administration

Immunization should be carried out by intramuscular injection into the deltoid muscle or anterolateral thigh, depending on the muscle mass.

For further information, see section 5.1.

4.3Contraindications

History of an anaphylactic (i.e. life-threatening) reaction to the active substance, to any of the excipients listed in section 6.1 or to trace residues (e.g. formaldehyde, benzonase, sucrose) 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.

4.4Special warnings and precautions for use

Hypersensitivity reactions, including anaphylaxis, have been reported following use of a similar whole virion, Vero cell derived H1N1 influenza vaccine administered during a pandemic period. Such reactions occurred both in patients with a history of multiple allergies and in patients with no known allergy.

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 and to trace residues e.g. formaldehyde, benzonase, or sucrose.

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.

PANDEMIC INFLUENZA VACCINE H5N1 BAXTER should under no circumstances be administered intravascularly.

There are no data with PANDEMIC INFLUENZA VACCINE H5N1 BAXTER using the subcutaneous route. Therefore, healthcare providers need to assess the benefits and potential risks of administering the vaccine in individuals with thrombocytopenia or any bleeding disorder that would contraindicate intramuscular injection unless the potential benefit outweighs the risk of bleedings.

Antibody response in patients with endogenous or iatrogenic immunosuppression may be insufficient.

A protective response may not be induced in all vaccinees (see section 5.1).

4.5Interactions with other medicinal products and other forms of interaction

PANDEMIC INFLUENZA VACCINE H5N1 BAXTER should not be given at the same time as other vaccines. However, if co-administration with another vaccine is indicated, immunisation should be carried out on separate limbs. It should be noted that the adverse reactions may be intensified.

Immunoglobulin is not to be given with PANDEMIC INFLUENZA VACCINE H5N1 BAXTER. If it is necessary to provide immediate protection, PANDEMIC INFLUENZA VACCINE H5N1 BAXTER may be given at the same time as normal or specific immunoglobulin. Injections of PANDEMIC INFLUENZA VACCINE H5N1 BAXTER and immunoglobulin should be made into separate limbs.

The immunological response may be diminished if the patient is undergoing immunosuppressant treatment.

Following influenza vaccination, false positive results in serology tests using the ELISA method to detect antibodies against HIV1, Hepatitis C and especially HTLV1 have been observed. The Western Blot technique disproves the results. The transient false positive reactions could be due to the IgM response by the vaccine.

4.6Fertility, pregnancy and lactation

The safety of PANDEMIC INFLUENZA VACCINE H5N1 BAXTER in pregnancy and lactation has not been assessed in clinical trials. Data from pregnant women vaccinated with different inactivated non-adjuvanted seasonal vaccines do not suggest malformations or foetal or neonatal toxicity.

Animal reproductive and developmental toxicity studies with H5N1 strain vaccines (A/Vietnam/1203/2004 and A/Indonesia/05/2005) do not indicate direct or indirect harmful effects with respect to female fertility, pregnancy, embryonal/foetal development, parturition or post-natal development (see section 5.3).

The use of PANDEMIC INFLUENZA VACCINE H5N1 BAXTER may be considered during pregnancy if this is thought to be necessary, taking into account official recommendations. PANDEMIC INFLUENZA VACCINE H5N1 BAXTER may be used in lactating women.

Health care providers should carefully consider the potential risks and benefits for each specific patient before administering PANDEMIC INFLUENZA VACCINE H5N1 BAXTER.

4.7Effects on ability to drive and use machines

Some undesirable effects mentioned under section 4.8 such as dizziness and vertigo may affect the ability to drive or use machines.

4.8Undesirable effects

Summary of safety profile

Adults, older people and special risk groups

Clinical trials were conducted with this H5N1 vaccine (see section 5.1 for more information on the H5N1 vaccines) in approximately 3500 subjects (ranging in age groups from 18 to 59 years and 60 years and above) and special risk groups of approximately 300 subjects each, consisting of immunocompromised subjects and patients with chronic disease conditions.

The safety profile in immunocompromised subjects and patients with chronic disease conditions is similar to the safety profile in healthy adults and older subjects.

Infants, children, and adolescents

Children and adolescents aged 3 to 17 years:

In a clinical trial 300 adolescents aged 9 to 17 years and 153 children aged 3 to 8 years were administered the H5N1 vaccine. The incidence and nature of symptoms after the first and second vaccination were similar to those observed in the healthy adults and older subjects.

Infants and children aged 6 to 35 months:

In a clinical trial the H5N1 vaccine was administered to 36 infants and children aged 6 to 35 months.

Adverse reactions are listed according to the following frequency below.

Summary of adverse reactions

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)

Not known (cannot be estimated from the available data)

Adults and older people:

Adverse Reactions (Adults and Older People)

System Organ Class (SOC)

 

Preferred MedDRA Term

Frequency

INFECTIONS AND

Nasopharyngitis

Common

INFESTATIONS

 

 

 

BLOOD AND LYMPHATIC

Lymphadenopathy

Uncommon

SYSTEM DISORDERS

 

 

 

PSYCHIATRIC DISORDERS

Insomnia

Uncommon

NERVOUS SYSTEM

Headache

Very common

DISORDERS

Dizziness

Uncommon

 

Somnolence

Uncommon

 

Sensory disturbance (paresthesia, dysesthesia,

Common

 

oral dysesthesia, hypoesthesia, dysgeusia, and

 

 

burning sensation)

 

 

Syncope

Uncommon

EYE DISORDERS

Conjunctivitis

Uncommon

 

Eye irritation

Uncommon

EAR AND LABYRINTH

Vertigo

Common

DISORDERS

Ear pain

Uncommon

 

Sudden hearing loss

Uncommon

VASCULAR DISORDERS

Hypotension

Uncommon

RESPIRATORY, THORACIC

Oropharyngeal pain

Common

AND MEDIASTINAL

Cough

 

Common

DISORDERS

Dyspnea

Uncommon

 

Nasal congestion

Uncommon

 

Rhinorrhea

Uncommon

 

Dry throat

Uncommon

GASTROINTESTINAL

Diarrhea

Common

DISORDERS

Vomiting

Uncommon

 

Nausea

Uncommon

 

Abdominal pain

Uncommon

 

Dyspepsia

Uncommon

SKIN AND SUBCUTANEOUS

Hyperhidrosis

Common

TISSUE DISORDERS

Pruritis

Common

 

Rash

 

Uncommon

 

Urticaria

Uncommon

MUSCULOSKELETAL AND

Arthralgia

Common

CONNECTIVE TISSUE

Myalgia

Common

DISORDERS

 

 

 

GENERAL DISORDERS AND

Fatigue

Very Common

ADMINISTRATION SITE

Pyrexia

Common

CONDITIONS

Chills

 

Common

 

Malaise

Common

 

Influenza-like illness

Uncommon

 

Chest discomfort

Uncommon

 

Injection Site Reactions

Very Common

 

Injection site pain

 

Injection site induration

Common

 

Injection site eyrthema

Common

 

Injection site swelling

Common

 

Injection site hemorrhage

Common

 

Uncommon

 

Injection site irritation

 

Uncommon

 

Injection site pruritus

 

Uncommon

 

Injection site movement impairment

 

 

Infants, children and adolescents:

Adverse Reactions (Infants, Children and Adolescents)

System Organ Class

Preferred MedDRA

 

Frequency

 

(SOC)

Term

6 – 35 months

3 – 8 years

9 – 17 years

INFECTIONS AND

Nasopharyngitis

Common

Common

Common

INFESTATIONS

 

 

 

 

METABOLISM AND

Decreased appetite

Common

Uncommon

Uncommon

NUTRITION DISORDERS

 

 

 

 

PSYCHIATRIC

Insomnia

-

-

Uncommon

DISORDERS

Sleep disorder

Common

-

-

NERVOUS SYSTEM

Dizziness

-

-

Uncommon

DISORDERS

Headache

-

Common

Very Common

 

Crying

Common

-

-

 

Somnolence

Very Common

-

-

 

Hypoaesthesia

-

-

Uncommon

EYE DISORDERS

Eye irritation

-

Uncommon

-

EAR AND LABYRINTH

Vertigo

-

-

Uncommon

DISORDERS

 

 

 

 

RESPIRATORY,

Cough

-

Uncommon

Uncommon

THORACIC AND

Oropharyngeal pain

-

Common

Common

MEDIASTINAL

Rhinorrhoea

-

Uncommon

Uncommon

DISORDERS

 

 

 

 

GASTROINTESTINAL

Abdominal pain

-

-

Common

DISORDERS

Nausea

Common

Common

Common

 

Vomiting

Common

Common

Common

 

Diarrhoea

Common

Uncommon

Uncommon

SKIN AND

Hyperhidrosis

Common

Uncommon

Common

SUBCUTANEOUS TISSUE

Pruritus

-

-

Uncommon

DISORDERS

 

 

 

 

MUSCULOSKELETAL

Arthralgia

-

Common

Common

AND CONNECTIVE

Myalgia

-

Common

Common

TISSUE DISORDERS

Pain in extremity

-

-

Uncommon

GENERAL DISORDERS

Injection site pain

Very common

Very common

Very common

AND ADMINISTRATION

Injection site induration

Common

Common

Common

SITE CONDITIONS

Injection site erythema

Common

Common

Common

 

Injection site swelling

Common

Common

Common

 

Injection site

Common

Common

Uncommon

 

hemorrhage

 

 

 

 

Injection site pruritus

-

Uncommon

Uncommon

 

Axillary pain

-

Uncommon

Uncommon

 

Fatigue

-

Common

Common

 

Pyrexia

Very Common

Common

Uncommon

 

Chills

-

-

Common

 

Irritability

Very Common

-

-

 

Malaise

-

Common

Common

 

Feeling Cold

-

Uncommon

Uncommon

Post-marketing surveillance

For PANDEMIC INFLUENZA VACCINE H5N1 BAXTER post-marketing surveillance data are not yet available.

Class effects:

From post-marketing surveillance with a whole virion, Vero cell derived, H1N1 vaccine, the following adverse reactions have been reported (the frequency of these adverse reactions is not known as it cannot be estimated from the available data):

Immune system disorders: anaphylactic reaction, hypersensitivity

Nervous system disorders: convulsion

Skin and subcutaneous tissue disorders: angioedema

Musculoskeletal and connective tissue disorders: pain in extremity

Trivalent seasonal influenza vaccines

The following serious adverse reactions have been reported from post-marketing surveillance with egg-derived interpandemic trivalent vaccines:

Uncommon: generalised skin reactions

Rare: neuralgia, transient thrombocytopenia

Very rare: vasculitis with transient renal involvement. Neurological disorders, such as encephalomyelitis, neuritis and Guillain Barré syndrome

Reporting of suspected adverse reactions

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

4.9Overdose

No case of overdose has been reported.

5.PHARMACOLOGICAL PROPERTIES

5.1Pharmacodynamic properties

Pharmacotherapeutic group: Influenza vaccines, ATC Code J07BB01

PANDEMIC INFLUENZA VACCINE H5N1 BAXTER 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 (EMA) will review any new information which may become available every year and this SmPC will be updated as necessary.

This section describes the clinical experience with the mock-up vaccine following a two-dose administration.

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.

Adults, older people and special risk groups

Immune response against the vaccine strain contained in PANDEMIC INFLUENZA VACCINE H5N1 BAXTER (A/Vietnam/1203/2004)

The immunogenicity of PANDEMIC INFLUENZA VACCINE H5N1 BAXTER (strain A/Vietnam/1203/2004) has been evaluated in three clinical studies in adults aged 18 – 59 years (N=961) and in older subjects aged 60 years and older (N=391) following a 0, 21 day schedule.

In addition, the immunogenicity has also been evaluated in a Phase 3 study in specified risk groups of immunocompromised subjects (N=122) and patients with chronic disease conditions (N=123) following a 0, 21 day schedule.

Immunogenicity in adults aged 18 to 59 years (N=961) and in subjects aged 60 years and older (N=391)

After primary vaccination the seroprotection rate, seroconversion rate and seroconversion factor for anti-HA antibody as measured by single radial haemolysis (SRH) in adults aged 18 to 59 years and in older subjects aged 60 years and above were as follows:

SRH Assay

18 – 59 years

60 years and above

 

21 Days After

21 Days After

 

1st Dose

2nd Dose

1st Dose

2nd Dose

Seroprotection rate*

53.2%

66.8%

47.7%

59.0%

Seroconversion rate**

39.8%

53.7%

41.9%

52.2%

Seroconversion factor***

2.5

3.4

2.7

3.5

*SRH area ≥ 25 mm²

**either SRH area ≥ 25 mm2 if baseline sample negative or 50% increase in SRH area if baseline sample > 4 mm²

***geometric mean increase

After primary vaccination the rate of subjects with neutralising antibody titres ≥ 20, seroconversion rate and seroconversion factor as measured by microneutralisation assay (MN) in adults

aged 18 to 59 years and in older subjects aged 60 years and above were as follows:

Microneutralisation assay

18 – 59 years

60 years and above

 

21 Days After

21 Days After

 

1st Dose

2nd Dose

1st Dose

2nd Dose

Seroneutralisation rate*

44.4%

69.7%

51.9%

69.2%

Seroconversion rate**

32.7%

56.0%

13.3%

23.9%

Seroconversion factor***

3.0

4.5

2.0

2.6

*MN titre ≥ 20

**4-fold increase in MN titre

***geometric mean increase

Immunogenicity in immunocompromised subjects (N=122) and in patients with chronic disease conditions (N=123)

After vaccination the rate of subjects with neutralising antibody titres ≥ 20, seroconversion rate and seroconversion factor as measured by MN assay in immunocompromised subjects and patients with chronic disease conditions were as follows:

Microneutralisation Assay

Immunocompromised subjects

Patients with chronic disease conditions

 

21 Days After

21 Days After

 

 

1st Dose

2nd Dose

1st Dose

2nd Dose

Seroneutralisation rate*

24.8%

41.5%

44.3%

64.2%

Seroconversion rate**

9.1%

32.2%

17.2%

35.0%

Seroconversion factor***

1.6

2.5

2.3

3.0

*MN titre ≥ 20

**4-fold increase in MN titre

***geometric mean increase

Antibody persistence

Antibody persistence after vaccination with the 7.5 µg non-adjuvanted formulation of PANDEMIC INFLUENZA VACCINE H5N1 BAXTER (strain A/Vietnam/1203/2004) has been evaluated in a clinical study in adults aged 18 – 59 years and subjects aged 60 years and above at 6 months, 12 - 15 months and 24 months after the start of the primary vaccination series.

The results indicate an overall decline in antibody levels over time.

Seroprotection*/

18 – 59 years

60 years and above

Seroneutralisation rate**

SRH Assay

MN Assay

SRH Assay

MN Assay

Month 6

23.9%

35.0%

26.7%

40.5%

Month 12-15

20.7%

34.2%

18.9%

36.2%

Month 24

22.4%

18.4%

12.3%

22.8%

*SRH area ≥ 25 mm²

**MN titre ≥ 20

Cross-reactive immune response against related H5N1 strains

In a phase 3 study in adults (N=270) and older subjects (N=272) after vaccination with the A/Vietnam/1203/2004 strain vaccine the rate of subjects with cross-neutralising antibodies as measured by MN (titre ≥ 20) was as follows:

 

18 – 59 years

60 years and above

 

Day 42 a

Day 180

Day 42 a

Day 180

Tested against

 

Strain A/Indonesia/05/2005

 

Seroneutralisation rate*

35.1%

14.4%

54.8%

28.0%

*MN titre ≥ 20

a

21 days after 2nd dose

Heterologous booster vaccinations

A booster vaccination with a 7.5 µg heterologous A/Indonesia/05/2005 vaccine strain has been administered in a time window of 12 to 24 months after priming vaccination with two doses of the A/Vietnam/1203/2004 strain vaccine in three clinical studies in adults aged 18 to 59 years and in older people aged 60 years and above. A 12 to 24 months heterologous booster has also been administered in a phase 3 study in immunocompromised subjects and patients with chronic disease conditions.

Seroneutralisation rates (MN titre ≥ 20) at 21 days after a 12 to 24 months booster vaccination with the 7.5 µg dose of the A/Indonesia/05/2005 strain vaccine, tested against both the homologous and heterologous strains were as follows:

Seroneutralisation rate*

18 – 59 years

60 years and above

Tested against

A/Vietnam

A/Indonesia

A/Vietnam

A/Indonesia

12 – 24 months booster

89.8%

86.9%

82.9 %

75.3%

*MN titre ≥ 20

Seroneutralisation rate*

Immunocompromised subjects

Patients with chronic disease conditions

Tested against

A/Vietnam

A/Indonesia

A/Vietnam

A/Indonesia

12 – 24 months booster

71.6%

65.7%

77.5%

70.8%

*MN titre ≥ 20

Infants, children, and adolescents

Immune response against A/Vietnam/1203/2004 (H5N1)

The immunogenicity of the A/Vietnam/1203/2004 strain vaccine has been evaluated in a clinical trial in children and adolescents aged 9 to 17 years (N=288), in children aged 3 to 8 years (N=146) and in infants and children aged 6 to 35 months (N=33) following a 0, 21 day schedule.

After vaccination, the seroprotection rate, seroconversion rate, and seroconversion factor for anti-HA antibody, as measured by SRH, in, infants, children, and adolescents aged 6 months to 17 years were as follows:

SRH assay

9 – 17 years

3 – 8 years

6 – 35 months

 

21 Days after

21 Days after

21 Days after

 

1st Dose

2nd Dose

1st Dose

2nd Dose

1st Dose

2nd Dose

Seroprotection rate*

63.8%

75.1%

46.1%

75.4%

13.8%

63.0%

Seroconversion rate**

48.4%

63.5%

43.3%

78.3%

13.8%

77.8%

Seroconversion factor***

3.3

4.7

2.9

5.9

1.4

4.6

*SRH area ≥ 25 mm2

**either SRH area ≥ 25 mm2 if baseline sample negative or 50% increase in SRH area if baseline sample >4 mm²

***geometric mean increase

After vaccination, the rate of subjects with neutralizing antibody titers ≥ 20, seroconversion rate and seroconversion factor, as measured by MN assay, in infants, children, and adolescents aged 6 months to 17 years were as follows:

MN assay

9 – 17 years

3 – 8 years

6 – 35 months

 

21 Days after

21 Days after

21 Days after

 

1st Dose

2nd Dose

1st Dose

2nd Dose

1st Dose

2nd Dose

Seroneutralization rate*

52.6%

85.4%

17.1%

72.9%

3.0%

68.8%

Seroconversion rate**

9.1%

31.8%

16.4%

72.2%

9.1%

65.6%

Seroconversion factor***

1.6

3.1

2.1

6.3

1.4

6.8

*MN titer ≥ 20

**4-fold increase in MN titer

***geometric mean increase

Heterologous Booster Vaccinations

A heterologous booster vaccination with a 7.5 µg non-adjuvanted formulation of the A/Indonesia/05/2005 strain vaccine has been administered 12 months after a priming vaccination with two doses of the A/Vietnam/1203/2004 strain vaccine in children and adolescents aged 9 to 17 years (N=196), children aged 3 to 8 years (N=79) and infants and children aged 6 months to 35 months (N=25).

Seroprotection rates (SRH area ≥ 25 mm²) at 21 days after a 12 months booster vaccination with the 7.5 mcg dose of the A/Indonesia/05/2005 strain vaccine, tested against both the homologous and heterologous strains, were as follows:

Seroprotection rate*

– 17 years

3 – 8 years

6 – 35 months

Tested against

A/Vietnam

A/Indonesia

A/Vietnam

A/Indonesia

A/Vietnam

A/Indonesia

 

 

 

 

 

 

 

 

12 Month Booster

81.6%

 

86.2%

87.5%

86.1%

96.0%

96.0%

*SRH area ≥ 25 mm²

Seroneutralization rates (MN titer ≥ 20) at 21 days after a booster vaccination with the 7.5 µg dose of the A/Indonesia/05/2005 strain vaccine, tested against both the homologous and heterologous strains, were as follows:

Seroneutralization rate*

9 – 17 years

3 – 8 years

6 – 35 months

Tested against

A/Vietnam

A/Indonesia

A/Vietnam

A/Indonesia

A/Vietnam

A/Indonesia

 

 

 

 

 

 

 

12 Month Booster

94.1%

93.1%

94.7%

97.2%

100.0%

100.0%

*MN titer ≥ 20

Information from non-clinical studies

The protective efficacy of PANDEMIC INFLUENZA VACCINE H5N1 BAXTER against morbidity and mortality induced by the infection with lethal doses of highly pathogenic avian Influenza

H5N1 virus was assessed non-clinically in a ferret challenge model. Two studies have been performed using either the H5N1 A/Vietnam/1203/2004 or the A/Indonesia/05/2005 vaccine.

In one study, sixteen ferrets were divided into two cohorts and were vaccinated on

days 0 and 21 with 7.5 µg of the A/Vietnam/1203/2004 vaccine or were sham vaccinated. All ferrets were challenged intranasally on day 35 with a high dose of the highly virulent H5N1 virus strain A/Vietnam/1203/2004 and monitored for 14 days. Ferrets vaccinated with

the 7.5 µg dose of the A/Vietnam/1203/2004 vaccine demonstrated a high rate of seroconversion. The A/Vietnam/1203/2004 vaccine afforded protection against homologous challenge as evidenced by full survivorship, reduced weight loss, a less pronounced and shorter increase in temperature,

a less marked reduction in lymphocyte counts and in reduction of inflammation and necrosis in brain and olfactory bulb in the vaccinated cohorts as compared to control animals. All control animals succumbed to the infection.

In a second study, sixty-six ferrets were divided into 6 cohorts of 11 ferrets and were immunized on days 0 and 21 with 3.75 µg or 7.5 µg of the Indonesia vaccine or were sham vaccinated. The ferrets were challenged intranasally on day 35 with a high dose of either the clade 2 H5N1 virus A/Indonesia/05/2005 or the clade 1 H5N1 virus A/Vietnam/1203/2004 and monitored for 14 days. The A/lndonesia/05/2005 vaccine was shown to be efficacious with 100% survival, reduced incidence of fever, reduced weight loss, reduced virus burden, and reduced haematological (leukopenia and lymphopenia) changes in the vaccinated cohorts following homologous challenge. Similarly, the A/lndonesia/05/2005 vaccine was efficacious against a heterologous challenge, showing a vaccine dose-dependent survivorship in the vaccinated cohorts as compared to the control cohort. Similar to the homologous challenge, vaccination against a heterologous challenge reduced virus burden, and reduced haematological (leukopenia) changes associated with highly pathogenic avian influenza infection.

5.2Pharmacokinetic properties

Not applicable.

5.3Preclinical safety data

Non-clinical studies demonstrated minor alterations in liver enzymes and calcium levels in a repeat dose toxicity study in rats. Clinically significant alterations in liver enzymes and calcium levels have not been seen to date in human clinical studies.

Animal reproductive and developmental toxicity studies do not indicate direct or indirect harmful effects with respect to female fertility, pregnancy, embryonal/ foetal development parturition or post natal development. Male fertility was not investigated in the reproductive and developmental toxicity studies, however there were no findings in the repeat-dose toxicity studies to indicate any vaccine-related changes to the tissues of the male reproductive tract.

6.PHARMACEUTICAL PARTICULARS

6.1List of excipients

Trometamol

Sodium chloride

Water for injections

Polysorbate 80

6.2Incompatibilities

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

6.3Shelf life

1 year

After first opening, the medicinal product should be used immediately. However, chemical and physical in-use stability has been demonstrated for 3 hours at room temperature.

6.4Special precautions for storage

Store in a refrigerator (2°C - 8°C).

Do not freeze.

Store in the original package in order to protect from light.

6.5Nature and contents of the container

One pack of 20 multidose vials (type I glass) of 5 ml suspension (10 x 0.5 ml doses) with a stopper (bromobutyl rubber).

6.6Special precautions for disposal and other handling

The vaccine should be allowed to reach room temperature before use. Shake before use. After shaking, the vaccine is an off-white, opalescent, translucent suspension.

Prior to administration, visually inspect the suspension for any foreign particulate matter and/or abnormal physical appearance. In the event of either being observed, discard the vaccine.

Each vaccine dose of 0.5 ml is withdrawn into a syringe for injection.

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

7.MARKETING AUTHORIZATION HOLDER

Nanotherapeutics UK Limited

10 Chiswell Street

London

EC1Y 4UQ. United Kingdom

8.MARKETING AUTHORISATION NUMBER

EU/1/09/571/001

9.DATE OF FIRST AUTHORISATION / RENEWAL OF THE AUTHORISATION

Date of first authorisation: 16 October 2009

Date of latest renewal: 14 May 2014

10.DATE OF REVISION OF THE TEXT

Detailed information on this product is available on the website of the European Medicines Agency (EMA): http://www.ema.europa.eu/

1. NAME OF THE MEDICINAL PRODUCT

PANDEMIC INFLUENZA VACCINE H5N1 BAXTER Suspension for injection

Pandemic influenza vaccine (H5N1) (whole virion, inactivated, prepared in cell culture)

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Influenza vaccine (whole virion, inactivated) containing antigen* of: A/Vietnam/1203/2004 (H5N1)7.5 micrograms**per 0.5 ml dose

*produced in Vero cells

**haemagglutinin

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

The vaccine is available in a single dose pre-filled syringe.

For the full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Suspension for injection.

The vaccine is an off-white, opalescent, translucent suspension.

4. CLINICAL PARTICULARS

4.1 Therapeutic indications

Prophylaxis of influenza in an officially declared pandemic situation. Pandemic influenza vaccine should be used in accordance with official guidance.

4.2 Posology and method of administration

Posology

Adults and children from 6 months onwards:

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.

Method of administration

Immunization should be carried out by intramuscular injection into the deltoid muscle or anterolateral thigh, depending on the muscle mass.

For further information, see section 5.1.

4.3 Contraindications

History of an anaphylactic (i.e. life-threatening) reaction to the active substance, to any of the excipients listed in section 6.1 or to trace residues (e.g. formaldehyde, benzonase, sucrose) 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

Hypersensitivity reactions, including anaphylaxis, have been reported following use of a similar whole virion, Vero cell derived H1N1 influenza vaccine administered during a pandemic period. Such reactions occurred both in patients with a history of multiple allergies and in patients with no known allergy.

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 and to trace residues e.g. formaldehyde, benzonase, or sucrose.

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.

PANDEMIC INFLUENZA VACCINE H5N1 BAXTER should under no circumstances be administered intravascularly.

There are no data with PANDEMIC INFLUENZA VACCINE H5N1 BAXTER using the subcutaneous route. Therefore, healthcare providers need to assess the benefits and potential risks of administering the vaccine in individuals with thrombocytopenia or any bleeding disorder that would contraindicate intramuscular injection unless the potential benefit outweighs the risk of bleedings.

Antibody response in patients with endogenous or iatrogenic immunosuppression may be insufficient.

A protective response may not be induced in all vaccinees (see section 5.1).

4.5 Interactions with other medicinal products and other forms of interaction

PANDEMIC INFLUENZA VACCINE H5N1 BAXTER should not be given at the same time as other vaccines. However, if co-administration with another vaccine is indicated, immunisation should be carried out on separate limbs. It should be noted that the adverse reactions may be intensified.

Immunoglobulin is not to be given with PANDEMIC INFLUENZA VACCINE H5N1 BAXTER. If it is necessary to provide immediate protection, PANDEMIC

INFLUENZA VACCINE H5N1 BAXTER may be given at the same time as normal or specific immunoglobulin. Injections of PANDEMIC INFLUENZA VACCINE

H5N1 BAXTER and immunoglobulin should be made into separate limbs.

The immunological response may be diminished if the patient is undergoing immunosuppressant treatment.

Following influenza vaccination, false positive results in serology tests using the ELISA method to detect antibodies against HIV1, Hepatitis C and especially HTLV1 have been observed. The Western Blot technique disproves the results. The transient false positive reactions could be due to the IgM response by the vaccine.

4.6 Fertility, pregnancy and lactation

The safety of PANDEMIC INFLUENZA VACCINE H5N1 BAXTER in pregnancy and lactation has not been assessed in clinical trials. Data from pregnant women vaccinated with different inactivated non-adjuvanted seasonal vaccines do not suggest malformations or foetal or neonatal toxicity.

Animal reproductive and developmental toxicity studies with H5N1 strain vaccines (A/Vietnam/1203/2004 and A/Indonesia/05/2005) do not indicate direct or indirect harmful effects with respect to female fertility, pregnancy, embryonal/foetal development, parturition or post-natal development (see section 5.3).

The use of PANDEMIC INFLUENZA VACCINE H5N1 BAXTER may be considered during pregnancy if this is thought to be necessary, taking into account official recommendations. PANDEMIC INFLUENZA VACCINE H5N1 BAXTER may be used in lactating women.

Health care providers should carefully consider the potential risks and benefits for each specific patient before administering PANDEMIC INFLUENZA VACCINE H5N1 BAXTER.

4.7 Effects on ability to drive and use machines

Some undesirable effects mentioned under section 4.8 such as dizziness and vertigo may affect the ability to drive or use machines.

4.8 Undesirable effects

Summary of safety profile

Adults, older people and special risk groups

Clinical trials were conducted with this H5N1 vaccine (see section 5.1 for more information on the H5N1 vaccines) in approximately 3500 subjects (ranging in age groups from 18 to 59 years and 60 years and above) and special risk groups of approximately 300 subjects each, consisting of immunocompromised subjects and patients with chronic disease conditions.

The safety profile in immunocompromised subjects and patients with chronic disease conditions is similar to the safety profile in healthy adults and older people subjects.

Infants, children, and adolescents

Children and adolescents aged 3 to 17 years:

In a clinical trial 300 adolescents aged 9 to 17 years and 153 children aged 3 to 8 years were administered the H5N1 vaccine. The incidence and nature of symptoms after the first and second vaccination were similar to those observed in the healthy adults and older subjects.

Infants and children aged 6 to 35 months:

In a clinical trial the H5N1 vaccine was administered to 36 infants and children aged 6 to 35 months.

Adverse reactions are listed according to the following frequency below.

Summary of adverse reactions

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)

Not known (cannot be estimated from the available data)

Adults and older people:

Adverse Reactions (Adults and Older People)

System Organ Class (SOC)

 

Preferred MedDRA Term

Frequency

INFECTIONS AND

Nasopharyngitis

Common

INFESTATIONS

 

 

 

BLOOD AND LYMPHATIC

Lymphadenopathy

Uncommon

SYSTEM DISORDERS

 

 

 

PSYCHIATRIC DISORDERS

Insomnia

Uncommon

NERVOUS SYSTEM

Headache

Very common

DISORDERS

Dizziness

Uncommon

 

Somnolence

Uncommon

 

Sensory disturbance (paresthesia, dysesthesia,

Common

 

oral dysesthesia, hypoesthesia, dysgeusia, and

 

 

burning sensation)

 

 

Syncope

Uncommon

EYE DISORDERS

Conjunctivitis

Uncommon

 

Eye irritation

Uncommon

EAR AND LABYRINTH

Vertigo

Common

DISORDERS

Ear pain

Uncommon

 

Sudden hearing loss

Uncommon

VASCULAR DISORDERS

Hypotension

Uncommon

RESPIRATORY, THORACIC

Oropharyngeal pain

Common

AND MEDIASTINAL

Cough

 

Common

DISORDERS

Dyspnea

Uncommon

 

Nasal congestion

Uncommon

 

Rhinorrhea

Uncommon

 

Dry throat

Uncommon

GASTROINTESTINAL

Diarrhea

Common

DISORDERS

Vomiting

Uncommon

 

Nausea

Uncommon

 

Abdominal pain

Uncommon

 

Dyspepsia

Uncommon

SKIN AND SUBCUTANEOUS

Hyperhidrosis

Common

TISSUE DISORDERS

Pruritis

Common

 

Rash

 

Uncommon

 

Urticaria

Uncommon

MUSCULOSKELETAL AND

Arthralgia

Common

CONNECTIVE TISSUE

Myalgia

Common

DISORDERS

 

 

 

GENERAL DISORDERS AND

Fatigue

Very Common

ADMINISTRATION SITE

Pyrexia

Common

CONDITIONS

Chills

 

Common

 

Malaise

Common

 

Influenza-like illness

Uncommon

 

Chest discomfort

Uncommon

 

Injection Site Reactions

Very Common

 

Injection site pain

 

Injection site induration

Common

 

Injection site eyrthema

Common

 

Injection site swelling

Common

 

Injection site hemorrhage

Common

 

Uncommon

 

Injection site irritation

 

Uncommon

 

Injection site pruritus

 

Uncommon

 

Injection site movement impairment

 

 

Infants, children and adolescents:

Adverse Reactions (Infants, Children and Adolescents)

System Organ Class

Preferred MedDRA

 

Frequency

 

(SOC)

Term

6 – 35 months

3 – 8 years

9 – 17 years

INFECTIONS AND

Nasopharyngitis

Common

Common

Common

INFESTATIONS

 

 

 

 

METABOLISM AND

Decreased appetite

Common

Uncommon

Uncommon

NUTRITION DISORDERS

 

 

 

 

PSYCHIATRIC

Insomnia

-

-

Uncommon

DISORDERS

Sleep disorder

Common

-

-

NERVOUS SYSTEM

Dizziness

-

-

Uncommon

DISORDERS

Headache

-

Common

Very Common

 

Crying

Common

-

-

 

Somnolence

Very Common

-

-

 

Hypoaesthesia

-

-

Uncommon

EYE DISORDERs

Eye irritation

-

Uncommon

-

EAR AND LABYRINTH

Vertigo

-

-

Uncommon

DISORDERS

 

 

 

 

RESPIRATORY,

Cough

-

Uncommon

Uncommon

THORACIC AND

Oropharyngeal pain

-

Common

Common

MEDIASTINAL

Rhinorrhoea

-

Uncommon

Uncommon

DISORDERS

 

 

 

 

GASTROINTESTINAL

Abdominal pain

-

-

Common

DISORDERS

Nausea

Common

Common

Common

 

Vomiting

Common

Common

Common

 

Diarrhoea

Common

Uncommon

Uncommon

SKIN AND

Hyperhidrosis

Common

Uncommon

Common

SUBCUTANEOUS TISSUE

Pruritus

-

-

Uncommon

DISORDERS

 

 

 

 

MUSCULOSKELETAL

Arthralgia

-

Common

Common

AND CONNECTIVE

Myalgia

-

Common

Common

TISSUE DISORDERS

Pain in extremity

-

-

Uncommon

GENERAL DISORDERS

Injection site pain

Very common

Very common

Very common

AND ADMINISTRATION

Injection site induration

Common

Common

Common

SITE CONDITIONS

Injection site erythema

Common

Common

Common

 

Injection site swelling

Common

Common

Common

 

Injection site

Common

Common

Uncommon

 

hemorrhage

 

 

 

 

Injection site pruritus

-

Uncommon

Uncommon

 

Axillary pain

-

Uncommon

Uncommon

 

Fatigue

-

Common

Common

 

Pyrexia

Very Common

Common

Uncommon

 

Chills

-

-

Common

 

Irritability

Very Common

-

-

 

Malaise

-

Common

Common

 

Feeling Cold

-

Uncommon

Uncommon

Post-marketing surveillance

For PANDEMIC INFLUENZA VACCINE H5N1 BAXTER post-marketing surveillance data are not yet available.

Class effects:

From post-marketing surveillance with a whole virion, Vero cell derived, H1N1 vaccine, the following adverse reactions have been reported (the frequency of these adverse reactions is not known as it cannot be estimated from the available data):

Immune system disorders: anaphylactic reaction, hypersensitivity

Nervous system disorders: convulsion

Skin and subcutaneous tissue disorders: angioedema

Musculoskeletal and connective tissue disorders: pain in extremity

Trivalent seasonal influenza vaccines

The following serious adverse reactions have been reported from post-marketing surveillance with egg-derived interpandemic trivalent vaccines:

Uncommon: generalised skin reactions

Rare: neuralgia, transient thrombocytopenia

Very rare: vasculitis with transient renal involvement. Neurological disorders, such as encephalomyelitis, neuritis and Guillain Barré syndrome

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 J07BB01

PANDEMIC INFLUENZA VACCINE H5N1 BAXTER 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 (EMA) will review any new information which may become available every year and this SmPC will be updated as necessary.

This section describes the clinical experience with the mock-up vaccine following a two-dose administration.

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.

Adults, older people and special risk groups

Immune response against the vaccine strain contained in PANDEMIC INFLUENZA VACCINE H5N1 BAXTER (A/Vietnam/1203/2004)

The immunogenicity of PANDEMIC INFLUENZA VACCINE H5N1 BAXTER (strain A/Vietnam/1203/2004) has been evaluated in three clinical studies in adults aged 18 – 59 years (N=961) and in older subjects aged 60 years and older (N=391) following a 0, 21 day schedule.

In addition, the immunogenicity has also been evaluated in a Phase 3 study in specified risk groups of immunocompromised subjects (N=122) and patients with chronic disease conditions (N=123) following a 0, 21 day schedule.

Immunogenicity in adults aged 18 to 59 years (N=961) and in subjects aged 60 years and older (N=391)

After primary vaccination the seroprotection rate, seroconversion rate and seroconversion factor for anti-HA antibody as measured by single radial haemolysis (SRH) in adults aged 18 to 59 years and in older subjects aged 60 years and above were as follows:

SRH Assay

18 – 59 years

60 years and above

 

21 Days After

21 Days After

 

1st Dose

2nd Dose

1st Dose

2nd Dose

Seroprotection rate*

53.2%

66.8%

47.7%

59.0%

Seroconversion rate**

39.8%

53.7%

41.9%

52.2%

Seroconversion factor***

2.5

3.4

2.7

3.5

*SRH area ≥ 25 mm²

**either SRH area ≥ 25 mm2 if baseline sample negative or 50% increase in SRH area if baseline sample > 4 mm²

***geometric mean increase

After primary vaccination the rate of subjects with neutralising antibody titres ≥ 20, seroconversion rate and seroconversion factor as measured by microneutralisation assay (MN) in adults

aged 18 to 59 years and in older subjects aged 60 years and above were as follows:

Microneutralisation assay

18 – 59 years

60 years and above

 

21 Days After

21 Days After

 

1st Dose

2nd Dose

1st Dose

2nd Dose

Seroneutralisation rate*

44.4%

69.7%

51.9%

69.2%

Seroconversion rate**

32.7%

56.0%

13.3%

23.9%

Seroconversion factor***

3.0

4.5

2.0

2.6

*MN titre ≥ 20

**4-fold increase in MN titre

***geometric mean increase

Immunogenicity in immunocompromised subjects (N=122) and in patients with chronic disease conditions (N=123)

After vaccination the rate of subjects with neutralising antibody titres ≥ 20, seroconversion rate and seroconversion factor as measured by MN assay in immunocompromised subjects and patients with chronic disease conditions were as follows:

Microneutralisation Assay

Immunocompromised subjects

Patients with chronic disease conditions

 

21 Days After

21 Days After

 

 

1st Dose

2nd Dose

1st Dose

2nd Dose

Seroneutralisation rate*

24.8%

41.5%

44.3%

64.2%

Seroconversion rate**

9.1%

32.2%

17.2%

35.0%

Seroconversion factor***

1.6

2.5

2.3

3.0

*MN titre ≥ 20

**4-fold increase in MN titre

***geometric mean increase

Antibody persistence

Antibody persistence after vaccination with the 7.5 µg non-adjuvanted formulation of PANDEMIC INFLUENZA VACCINE H5N1 BAXTER (strain A/Vietnam/1203/2004) has been evaluated in a clinical study in adults aged 18 – 59 years and subjects aged 60 years and above at 6 months, 12 - 15 months and 24 months after the start of the primary vaccination series.

The results indicate an overall decline in antibody levels over time.

Seroprotection*/

18 – 59 years

60 years and above

Seroneutralisation rate**

SRH Assay

MN Assay

SRH Assay

MN Assay

Month 6

23.9%

35.0%

26.7%

40.5%

Month 12-15

20.7%

34.2%

18.9%

36.2%

Month 24

22.4%

18.4%

12.3%

22.8%

*SRH area ≥ 25 mm²

**MN titre ≥ 20

Cross-reactive immune response against related H5N1 strains

In a phase 3 study in adults (N=270) and older subjects (N=272) after vaccination with the A/Vietnam/1203/2004 strain vaccine the rate of subjects with cross-neutralising antibodies as measured by MN (titre ≥ 20) was as follows:

 

18 – 59 years

60 years and above

 

Day 42 a

Day 180

Day 42 a

Day 180

Tested against

 

Strain A/Indonesia/05/2005

 

Seroneutralisation rate*

35.1%

14.4%

54.8%

28.0%

*MN titre ≥ 20

a

21 days after 2nd dose

Heterologous booster vaccinations

A booster vaccination with a 7.5 µg heterologous A/Indonesia/05/2005 vaccine strain has been administered in a time window of 12 to 24 months after priming vaccination with two doses of the A/Vietnam/1203/2004 strain vaccine in three clinical studies in adults aged 18 to 59 years and in older aged 60 years and above. A 12 to 24 months heterologous booster has also been administered in a phase 3 study in immunocompromised subjects and patients with chronic disease conditions.

Seroneutralisation rates (MN titre ≥ 20) at 21 days after a 12 to 24 months booster vaccination with the 7.5 µg dose of the A/Indonesia/05/2005 strain vaccine, tested against both the homologous and heterologous strains were as follows:

Seroneutralisation rate*

18 – 59 years

60 years and above

Tested against

A/Vietnam

A/Indonesia

A/Vietnam

A/Indonesia

12 – 24 months booster

89.8%

86.9%

82.9 %

75.3%

*MN titre ≥ 20

Seroneutralisation rate*

Immunocompromised subjects

Patients with chronic disease conditions

Tested against

A/Vietnam

A/Indonesia

A/Vietnam

A/Indonesia

12 – 24 months booster

71.6%

65.7%

77.5%

70.8%

*MN titre ≥ 20

Infants, children, and adolescents

Immune response against A/Vietnam/1203/2004 (H5N1)

The immunogenicity of the A/Vietnam/1203/2004 strain vaccine has been evaluated in a clinical trial in children and adolescents aged 9 to 17 years (N=288), in children aged 3 to 8 years (N=146) and in infants and children aged 6 to 35 months (N=33) following a 0, 21 day schedule.

After vaccination, the seroprotection rate, seroconversion rate, and seroconversion factor for anti-HA antibody, as measured by SRH, in, infants, children, and adolescents aged 6 months to 17 years were as follows:

SRH assay

9 – 17 years

– 8 years

6 – 35 months

 

21 Days after

Days after

21 Days after

 

1st Dose

2nd Dose

1st Dose

2nd Dose

1st Dose

2nd Dose

Seroprotection rate*

63.8%

75.1%

46.1%

75.4%

13.8%

63.0%

Seroconversion rate**

48.4%

63.5%

43.3%

78.3%

13.8%

77.8%

Seroconversion factor***

3.3

4.7

2.9

 

5.9

1.4

4.6

*SRH area ≥ 25 mm2

**either SRH area ≥ 25 mm2 if baseline sample negative or 50% increase in SRH area if baseline sample >4 mm²

***geometric mean increase

After vaccination, the rate of subjects with neutralizing antibody titers ≥ 20, seroconversion rate and seroconversion factor, as measured by MN assay, in infants, children, and adolescents aged 6 months to 17 years were as follows:

MN assay

9 – 17 years

3 – 8 years

6 – 35 months

 

21 Days after

21 Days after

21 Days after

 

1st Dose

2nd Dose

1st Dose

2nd Dose

1st Dose

2nd Dose

Seroneutralization rate*

52.6%

85.4%

17.1%

72.9%

3.0%

68.8%

Seroconversion rate**

9.1%

31.8%

16.4%

72.2%

9.1%

65.6%

Seroconversion factor***

1.6

3.1

2.1

6.3

1.4

6.8

*MN titer ≥ 20

**4-fold increase in MN titer

***geometric mean increase

Heterologous Booster Vaccinations

A heterologous booster vaccination with a 7.5 µg non-adjuvanted formulation of the A/Indonesia/05/2005 strain vaccine has been administered 12 months after a priming vaccination with two doses of the A/Vietnam/1203/2004 strain vaccine in children and adolescents aged 9 to 17 years (N=196), children aged 3 to 8 years (N=79) and infants and children aged 6 months to 35 months (N=25).

Seroprotection rates (SRH area ≥ 25 mm²) at 21 days after a 12 months booster vaccination with the 7.5 µg dose of the A/Indonesia/05/2005 strain vaccine, tested against both the homologous and heterologous strains, were as follows:

Seroprotection rate*

9 – 17 years

3 – 8 years

6 – 35 months

Tested against

A/Vietnam

A/Indonesia

A/Vietnam

A/Indonesia

A/Vietnam

A/Indonesia

 

 

 

 

 

 

 

12 Month Booster

81.6%

86.2%

87.5%

86.1%

96.0%

96.0%

*SRH area ≥ 25 mm²

Seroneutralization rates (MN titer ≥ 20) at 21 days after a booster vaccination with the 7.5 µg dose of the A/Indonesia/05/2005 strain vaccine, tested against both the homologous and heterologous strains, were as follows:

Seroneutralization rate*

9 – 17 years

– 8 years

6 – 35 months

Tested against

A/Vietnam

A/Indonesia

A/Vietnam

A/Indonesia

A/Vietnam

A/Indonesia

 

 

 

 

 

 

 

 

12 Month Booster

94.1%

93.1%

94.7%

 

97.2%

100.0%

100.0%

*MN titer ≥ 20

Information from non-clinical studies

The protective efficacy of PANDEMIC INFLUENZA VACCINE H5N1 BAXTER against morbidity and mortality induced by the infection with lethal doses of highly pathogenic avian

Influenza H5N1 virus was assessed non-clinically in a ferret challenge model. Two studies have been performed using either the H5N1 A/Vietnam/1203/2004 or the A/Indonesia/05/2005 vaccine.

In one study, sixteen ferrets were divided into two cohorts and were vaccinated on

days 0 and 21 with 7.5 µg of the A/Vietnam/1203/2004 vaccine or were sham vaccinated. All ferrets were challenged intranasally on day 35 with a high dose of the highly virulent H5N1 virus strain A/Vietnam/1203/2004 and monitored for 14 days. Ferrets vaccinated with

the 7.5 µg dose of the A/Vietnam/1203/2004 vaccine demonstrated a high rate of seroconversion. The A/Vietnam/1203/2004 vaccine afforded protection against homologous challenge as evidenced by full survivorship, reduced weight loss, a less pronounced and shorter increase in temperature,

a less marked reduction in lymphocyte counts and in reduction of inflammation and necrosis in brain and olfactory bulb in the vaccinated cohorts as compared to control animals. All control animals succumbed to the infection.

In a second study, sixty-six ferrets were divided into 6 cohorts of 11 ferrets and were immunized on days 0 and 21 with 3.75 µg or 7.5 µg of the Indonesia vaccine or were sham vaccinated. The ferrets were challenged intranasally on day 35 with a high dose of either the clade 2 H5N1 virus A/Indonesia/05/2005 or the clade 1 H5N1 virus A/Vietnam/1203/2004 and monitored for 14 days. The A/lndonesia/05/2005 vaccine was shown to be efficacious with 100% survival, reduced incidence of fever, reduced weight loss, reduced virus burden, and reduced haematological (leukopenia and lymphopenia) changes in the vaccinated cohorts following homologous challenge. Similarly, the A/lndonesia/05/2005 vaccine was efficacious against a heterologous challenge, showing a vaccine dose-dependent survivorship in the vaccinated cohorts as compared to the control cohort. Similar to the homologous challenge, vaccination against a heterologous challenge reduced virus burden, and reduced haematological (leukopenia) changes associated with highly pathogenic avian influenza infection.

5.2 Pharmacokinetic properties

Not applicable.

5.3 Preclinical safety data

Non-clinical studies demonstrated minor alterations in liver enzymes and calcium levels in a repeat dose toxicity study in rats. Clinically significant alterations in liver enzymes and calcium levels have not been seen to date in human clinical studies.

Animal reproductive and developmental toxicity studies do not indicate direct or indirect harmful effects with respect to female fertility, pregnancy, embryonal/ foetal development parturition or post natal development. Male fertility was not investigated in the reproductive and developmental toxicity studies, however there were no findings in the repeat-dose toxicity studies to indicate any vaccine-related changes to the tissues of the male reproductive tract.

6. PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Trometamol

Sodium chloride

Water for injections

Polysorbate 80

6.2 Incompatibilities

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

6.3 Shelf life

1 year

6.4 Special precautions for storage

Store in a refrigerator (2°C - 8°C).

Do not freeze.

Store in the original package in order to protect from light.

6.5 Nature and contents of the container

One pack of 1 single dose pre-filled syringe (type I glass) containing 0.5 ml suspension for injection, with a latex-free plunger stopper (halogeno-butyl rubber) with or without needles.

6.6 Special precautions for disposal and other handling

The vaccine should be allowed to reach room temperature before use. Shake before use. After shaking, the vaccine is an off-white, opalescent, translucent suspension.

Prior to administration, visually inspect the suspension for any foreign particulate matter and/or abnormal physical appearance. In the event of either being observed, discard the vaccine.

After removing the syringe cap, attach the needle immediately and remove the needle shield prior to administration.

Once the needle is attached, the vaccine must be administered immediately.

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

7. MARKETING AUTHORIZATION HOLDER

Nanotherapeutics UK Limited

10 Chiswell Street

London

EC1Y 4UQ. United Kingdom

8. MARKETING AUTHORISATION NUMBER

EU/1/09/571/002

9. DATE OF FIRST AUTHORISATION / RENEWAL OF THE AUTHORISATION

Date of first authorisation: 16 October 2009

Date of latest renewal: 14 May 2014

10. DATE OF REVISION OF THE TEXT

Detailed information on this product is available on the website of the European Medicines Agency (EMA): http://www.ema.europa.eu/

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