Prepandemic Influenza Vaccine (H5N1) (Split Virion, Inactivated, Adjuvanted) GlaxoSmithKline Biologicals - summary of medicine characteristics

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)

*

propagated in eggs

**

haemagglutinin

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.

Excipients: It contains 5 micrograms thiomersal

For a 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 homogeneous liquid.

Active immunisation against H5N1 subtype of Influenza A virus.

This indication is based on immunogenicity data from healthy subjects from the age of 18 years onwards following administration of two doses of vaccine prepared from A/VietNam/1194/2004 NIBRG-14 (H5N1) (see section 5.1).

Prepandemic influenza vaccine (H5N1) (split virion, inactivated, adjuvanted) GlaxoSmithKline Biologicals 3.75 ^g should be used in accordance with official guidance.

4.2 Posology and method of administration

Posology

Adults from the age of 18 years:

One dose of 0.5 ml at an elected date.

A second dose of 0.5 ml should be given after an interval of at least three weeks.

Based on very limited data, adults aged >80 years may require a double dose of Prepandemic influenza vaccine (H5N1) (split virion, inactivated, adjuvanted) GlaxoSmithKline Biologicals 3.75 ^g on an elected date and again after an interval of at least three weeks in order to achieve an immune response (see section 5.1).

A complete vaccination course with Prepandemic influenza vaccine (H5N1) (split virion, inactivated, adjuvanted) GlaxoSmithKline Biologicals 3.75 ^g consists of two doses. However, in the event of an officially declared influenza pandemic, persons previously vaccinated with one or two doses of Prepandemic influenza vaccine (H5N1) (split virion, inactivated, adjuvanted) GlaxoSmithKline Biologicals 3.75 ^g that contained HA antigen derived from a different clade of the same influenza subtype as the pandemic influenza strain may receive a single dose of Pandemrix instead of two doses that are required in previously unvaccinated individuals.

There is no experience in children.

For further information, see sections 4.4 and 5.1.

Method of administration

Immunisation should be carried out by intramuscular injection.

If a double dose is given, the injections should be given into opposite limb

4.3 Contraindicationsy of the constituents or trace residues in sulphate and sodium deoxycholate) of

History of an anaphylactic (i.e. life-threatening) reaction to (egg and chicken protein, ovalbumin, formaldehyde, genta this vaccine. See sections 4.4, 4.8 and 6.1.

Acute severe febrile illness. Immunisation should be postponed.

4.4 Special warnings and precau

Caution is needed when administering this vaccine to persons with a known hypersensitivity (other than anaphylactic reaction) to the active substance, to any of the excipients, to thiomersal and to residues (egg and chicken protein, ovalbumin, formaldehyde, gentamicin sulphate and sodium deoxycholate).

As with all injectable vaccines, appropriate medical treatment and supervision should always be readily available in case of a rare anaphylactic event following the administration of the vaccine.

Prepandemic influenza vaccine (H5N1) (split virion, inactivated, adjuvanted) GlaxoSmithKline

Biologicals 3.75 ^g should under no circumstances be administered intravascularly or intradermally.

There are no data on administration of AS03-adjuvanted vaccines before or following other types of influenza vaccines intended for pre-pandemic or pandemic use.

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

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

4.5 Interaction with other medicinal products and other forms of interaction

The vaccine should not usually be given at the same time as other vaccines. However, if coadministration with another vaccine is considered to be essential, the vaccines should be injected into separate limbs. It should be noted that the adverse reactions may be intensified.

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

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 Pregnancy and lactation

4.7 Effects on ability to drive and use machinesSome of the effects mentioned under section 4.8 or operate machinery.irable Effects” may affect the ability to drive4.8 Undesirable effectsClinical trials

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Influenza vaccines, ATC Code J07BB02

Immune response againstA/Viet­nam/1194/2004 :

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

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.

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.

Follow up of 50 subjects aged 18–60 years who had received two doses of AS03-adjuvanted vaccine containing 3.75 pg HA derived from A/Vietnam/1194/2004 at 0 and 21 days showed that 84% were seroprotected (HI titre >1:40) at day 42 compared with 54% at day 180. A 4-fold increase in serum neutralising antibody titres from day 0 was observed in 85.7% at day 42 and 72% at day 180.

In another clinical study, 152 subjects aged > 60 years (stratified in ranges from 61 to 70, 71 to 80 and > 80 years of age) received either a single or a double dose of AS03-adjuvanted vaccine containing 3.75 pg HA derived from A/Vietnam/1194/2004 (H5N1) at 0 and 21 days. At day 42, the anti-HA antibody responses were as follows:

• 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.

Although an adequate immune response was achieved at day 42 following two administrations of a single dose of AS03-adjuvanted vaccine containing 3.75 pg HA derived from A/Vietnam/1194/2004 (H5N1), a higher response was observed following two administrations of a double dose of vaccine.

Very limited data in seronegative subjects >80 years of age (N=5) showed that no subject achieved seroprotection following two administrations of a single dose of AS03-adjuvanted vaccine containing 3.75 pg HA derived from A/Vietnam/1194/2004 (H5N1). However, following two administrations of a double dose of vaccine, the seroprotection rate at day 42 was 75%.

The day 180 seroprotection rates in subjects aged >60 years were 52.9% for those who received two single doses and 69.5% of subjects for those who had received two double doses at day 0 and day 21.

In addition, 44.8% and 56.1% of subjects in respective dose groups had a 4-fold increase in serum neutralising antibody titres from day 0 to day 42 and 96.6% and 100% of subjects had a titre of at least 1:80 at day 42.

Cross-reactive immune responses elicited by AS03-adjuvanted vaccine containing 3.75 ug HA derived from A/Vietnam/1194/2004 (H5N1):

Anti-HA responses against A/Indonesia/5/2005 following administration of AS03-adjuvanted vaccine containing 3.75 ^g HA derived from A/Vietnam/1194/2004 were as follows:

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.

In a different study 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 ug 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.

In 152 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 ug 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.

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, 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:

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, 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.

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 immunized intramuscularly with an AS03 adjuvanted vaccine containing HA derived from H5N1/A/Vietnam/1194/04 (NIBRG-14). Doses of 15, 5, 1.7 or 0.6 micrograms of HA were tested in the homologous challenge experiment, and doses of 15, 7.5, 3.8 or 1.75 micrograms of HA were tested in the heterologous challenge experiment. Control groups included ferrets immunized with adjuvant alone, non-adjuvanted vaccine (15 micrograms HA) or phosphate buffered saline solution. Ferrets were vaccinated on days 0 and 21 and challenged by the intra-tracheal route on day 49 with a lethal dose of either H5N1/A/Vietnam/1194/04 or heterologous H5N1/A/Indone­sia/5/05. Of the animals receiving adjuvanted vaccine, 87% and 96% were protected against the lethal homologous or heterologous challenge, respectively. Viral shedding into the upper was also reduced in vaccinated animals relative to controls, suggesting a reduced risk ssion. In the unadjuvanted control group, as well as in the adjuvant control group, all had to be euthanized as they were moribund, three to four days after the start of challenge.

5.2 Pharmacokinetic properties

Not applicable.

5.3 Preclinical safety data

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

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 products.

6.3 Shelf-life

6.4 Special precautions for storage

Store in a refrigerator (2°C – 8°C). Do not freeze.

Store in the or

6.5 Natu

k containing:

e pack of 50 vials (type I glass) of 2.5 ml suspension (10 × 0.25 ml doses) with a stopper utyl rubber).

two packs of 25 vials (type I glass) of 2.5 ml emulsion (10 × 0.25 ml doses) with a stopper (butyl rubber).

The volume after mixing 1 vial of suspension (2.5 ml) with 1 vial of emulsion (2.5 ml) corresponds to 10 doses of vaccine (5 ml).

6.6 Special precautions for disposal and other handling

Prepandemic influenza vaccine (H5N1) (split virion, inactivated, adjuvanted) GlaxoSmithKline

Biologicals 3.75 ^g consists of two containers:

Vial A: multidose vial containing the antigen (suspension),

Vial B: multidose vial containing the adjuvant (emulsion).

Prior to administration, the two components should be mixed.

Instructions for mixing and administration of the vaccine :

• 1. Before mixing the two components, the emulsion and suspension should be allowed to reach room temperature, shaken and inspected visually for any foreign particulate matter and/or

abnormal physical appearance. In the event of either being observed, discard the vaccine.

• 2. The vaccine is mixed by withdrawing the contents of the vial containing the emulsion (Vial B) by means of a syringe and by adding it to the vial containing the suspension (Vial A).

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After the addition of the emulsion to the suspension, the mixture should be well shaken. The mixed vaccine is a whitish emulsion. In the event of other variation being observed, discard the vaccine.

The volume of Prepandemic influenza vaccine (H5N1) (split virion, inactivated, adjuvanted) GlaxoSmithKline Biologicals 3.75 ^g (5 ml) after mixing corresponds to 10 doses of vaccine. The vial should be shaken prior to each administration.

Each vaccine dose of 0.5 ml is withdrawn into a syringe for injection. The needle used for withdrawal must be replaced by a needle suitable f injection.

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

7. MARKETING AUTHORISATION HOLDER