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Vaccines: Pandemrix - European Public Assessment Report [EMEA]
Pandemrix - European Public Assessment Report [EMEA]
Pandemrix
European Public Assessment Report
[Full report at: http://www.emea.europa.eu/humandocs/Humans/EPAR/pandemrix/pandemrix.htm ]
ANNEX I - SUMMARY OF PRODUCT CHARACTERISTICS
1. NAME OF THE MEDICINAL PRODUCT
Pandemrix 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 (10.68 milligrams), DL-α-tocopherol (11.86 milligrams) and polysorbate 80 (4.85 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.
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 (see sections 4.2 and 5.1).
4.2 Posology and method of administration
Posology
Adults from the age of 18 to 60 years: 1 dose of 0.5 ml at an elected date. A second dose of vaccine should be given after an interval of at least three weeks.
There is no experience in children and adults above 60 years of age. For further information, see section 5.1.
Method of administration
Immunisation should be carried out by intramuscular injection.
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 administrating 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.
If the pandemic situation allows, immunisation shall be postponed in patients with severe febrile illness or acute infection.
Pandemrix should under no circumstances be administered intravascularly.
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
Pandemrix 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.
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
No data have been generated in pregnant women with Pandemrix or with any other vaccine that contains the AS03 adjuvant
Animal studies do not indicate direct or indirect harmful effects with respect to fertility, pregnancy, embryonal/foetal development, parturition or post-natal development (see section 5.3).
Healthcare providers need to assess the benefits and potential risks of administering the vaccine to pregnant women taking into consideration official recommendations.
Pandemrix may be used during lactation.
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
• Clinical trials
Adverse reactions from clinical trials with the mock-up vaccine are listed here below (see section 5.1 for more information on mock-up vaccines).
The incidence of adverse reactions has been evaluated in approximately 5,000 subjects 18 years old and above who received formulations containing at least 3.75 microgram HA/AS03.
Adverse reactions reported are listed according to the following frequency:
Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.
* Blood and lymphatic system disorders
Common: lymphadenopathy
* 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
* Psychiatric disorders
Uncommon: insomnia
• Post-marketing surveillance
No post-marketing surveillance data are available following Pandemrix administration.
From Post-marketing surveillance with interpandemic trivalent vaccines, the following adverse reactions have been reported:
* Uncommon:
Generalised skin reactions including urticaria
* Rare:
Neuralgia, convulsions, transient thrombocytopenia.
Allergic reactions, in rare cases leading to shock, have been reported.
* Very rare:
Vasculitis with transient renal involvement.
Neurological disorders, such as encephalomyelitis, neuritis and Guillain Barré syndrome.
This medicinal product contains thiomersal (an organomercuric compound) as a preservative and therefore, it is possible that sensitisation reactions may occur (see section 4.4).
4.9 Overdose
No case of overdose has been reported.
5. PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Influenza vaccines, ATC Code J07BB02.
This section describes the clinical experience with the mock-up vaccines 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.
Immune response against vaccine strain contained in Pandemrix (A/Vietnam/1194/2004 (H5N1)):
In a consistency study, more than 900 subjects aged 18-60 years received Pandemrix following a 0, 21 days schedule.
Twenty-one days after the first and second dose of the vaccine, the seroprotection rates, seroconversion rates and seroconversion factors for anti-haemagglutinin (anti-HA) antibody were as follows:
anti-HA antibody / 21 days after 1st dose / 21 days after 2nd dose
Seroprotection rate*† | 44.5% - 94.3%
Seroconversion rate† | 42.5% - 93.7%
Seroconversion factor†| 4.1 - 39.8
* anti-HA ≥1:40
† seroprotection rate : proportion of subjects with haemagglutination inhibition (HI) titre ≥1:40; seroconversion rate: proportion of subjects who were either seronegative at pre-vaccination and have a protective post-vaccination titre of ≥1:40, or who were seropositive at pre-vaccination and have a 4-fold increase in titre; seroconversion factor: ratio of the post-vaccination geometric mean titre (GMT) and the pre-vaccination GMT.
Twenty-one days after administration of the second dose, 96.0% of subjects had a 4-fold increase in serum neutralising antibody titres.
A neutralising antibody titre of at least 1:80 was achieved in 97.8% of subjects at day 42.
In a dose finding study in subjects aged 18-60 years, 50 subjects received a dose of 3.75 micrograms HA/AS03 in a volume of 1 ml at 0 and 21 days.
The seroprotection rates, seroconversion rates and seroconversion factors for anti-haemagglutinin (anti-HA) antibody at day 42 (post dose 2) and day 180 (persistence) were as follows:
anti-HA antibody / Day 42 / Day 180
Seroprotection rate*† | 84% - 54%
Seroconversion rate† | 82% - 52%
Seroconversion factor† | 27.9 - 4.4
* anti-HA ≥1:40
† seroprotection rate : proportion of subjects with haemagglutination inhibition (HI) titre ≥1:40; seroconversion rate: proportion of subjects who were either seronegative at pre-vaccination and have a protective post-vaccination titre of ≥1:40, or who were seropositive at pre-vaccination and have a 4-fold increase in titre; seroconversion factor: ratio of the post-vaccination geometric mean titre (GMT) and the pre-vaccination GMT.
A 4-fold increase in serum neutralising antibody titres was observed in 85.7% of subjects at day 42 and 72% at day 180.
Cross-reactive immune response against variants of A/Vietnam/1194/2004 (H5N1):
In the consistency study the seroprotection rate, seroconversion rate and seroconversion factor for anti-haemagglutinin (anti-HA) antibody against A/Indonesia/5/2005 at 21 days after the second dose were as follows:
anti-HA antibody | A/Indonesia/5/2005 ( N = 924 )
Seroprotection rate*† | 50.2%
Seroconversion rate† | 50.2%
Seroconversion factor† | 4.9
* anti-HA ≥1:40
† seroprotection rate : proportion of subjects with haemagglutination inhibition (HI) titre ≥1:40; seroconversion rate: proportion of subjects who were either seronegative at pre-vaccination and have a protective post-vaccination titre of ≥1:40, or who were seropositive at pre-vaccination and have a 4-fold increase in titre; seroconversion factor: ratio of the post-vaccination geometric mean titre (GMT) and the pre-vaccination GMT.
A 4-fold increase in serum neutralising antibody titres was obtained in 91.4% of subjects at day 42.
In the dose finding study the seroprotection rate, seroconversion rate and seroconversion factor against H5N1 drift variants 21 days after the second dose were as follows:
anti-HA antibody | A/Indonesia/5/2005 ( N = 50 ) | A/Anhui/01/2005 ( N = 20 ) | A/Turkey/Turkey/1/2005 ( N = 20 )
Seroprotection rate*† | 20.0% | 35.0% | 60.0%
Seroconversion rate† | 20.0% | 35.0% | 60.0%
Seroconversion factor† | 2.0 | 3.4 | 4.7
* anti-HA ≥1:40
† seroprotection rate : proportion of subjects with haemagglutination inhibition (HI) titre ≥1:40; seroconversion rate: proportion of subjects who were either seronegative at pre-vaccination and have a protective post-vaccination titre of ≥1:40, or who were seropositive at pre-vaccination and have a 4-fold increase in titre; seroconversion factor: ratio of the post-vaccination geometric mean titre (GMT) and the pre-vaccination GMT.
Twenty one days after the second dose, a 4-fold increase in serum neutralising antibody titres was obtained in 77.1% of subjects against the A/Indonesia/5/2005 strain, in 75.0% of subjects against A/Anhui/01/2005 and in 85.0% of subjects against A/Turkey/Turkey/1/2005.
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 respiratory tract was also reduced in vaccinated animals relative to controls, suggesting a reduced risk of viral transmission.
In the unadjuvanted control group, as well as in the adjuvant control group, all animals died or had to be euthanized as they were moribund, three to four days after the start of challenge.
5.2 Pharmacokinetic properties
Not applicable.
5.3 Preclinical safety data
Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, acute and repeated dose toxicity, local tolerance, female fertility, embryo-foetal and postnatal toxicity (up to the end of the lactation period).
6. PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Suspension vial: Polysorbate 80 - Octoxynol 10 - Thiomersal - Sodium chloride (NaCl) - Disodium hydrogen phosphate (Na2HPO4) - Potassium dihydrogen phosphate (KH2PO4) - Potassium chloride (KCl) - Magnesium chloride (MgCl2) - Water for injections
Emulsion vial: Sodium chloride (NaCl) - Disodium hydrogen phosphate (Na2HPO4) - Potassium dihydrogen phosphate (KH2PO4) - Potassium chloride (KCl) - Water for injections
For adjuvants, see section 2.
6.2 Incompatibilities
In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.
6.3 Shelf-life
18 months.
After mixing, the vaccine should be used within 24 hours. Chemical and physical in-use stability has been demonstrated for 24 hours at 25°C.
6.4 Special precautions for storage
Store in a refrigerator (2°C – 8°C).
Do not freeze.
Store in the original package in order to protect from light.
6.5 Nature and contents of container
One pack containing:
-
one pack of 50 vials (type I glass) of 2.5 ml suspension (10 x 0.25 ml doses) with a stopper (butyl rubber).
-
two packs of 25 vials (type I glass) of 2.5 ml emulsion (10 x 0.25 ml doses) with a stopper (butyl rubber).
The volume after mixing 1 vial of suspension (2.5 ml) with 1 vial of emulsion (2.5 ml) corresponds to 10 doses of vaccine (5 ml).
6.6 Special precautions for disposal and other handling
Pandemrix consists of two containers:
Vial A: multidose vial containing the antigen (suspension),
Vial B: multidose vial containing the adjuvant (emulsion).
Prior to administration, the two components should be mixed.
Instructions for mixing and administration of the vaccine:
1. Before mixing the two components, the emulsion and suspension should be allowed to reach room temperature, shaken and inspected visually for any foreign particulate matter and/or abnormal physical appearance. In the event of either being observed, discard the vaccine.
2. The vaccine is mixed by withdrawing the contents of the vial containing the emulsion (Vial B) by means of a syringe and by adding it to the vial containing the suspension (Vial A).
3. After the addition of the emulsion to the suspension, the mixture should be well shaken. The mixed vaccine is a whitish emulsion. In the event of other variation being observed, discard the vaccine.
4. The volume of Pandemrix (5 ml) after mixing corresponds to 10 doses of vaccine.
5. The vial should be shaken prior to each administration.
6. Each vaccine dose of 0.5 ml is withdrawn into a syringe for injection.
7. The needle used for withdrawal must be replaced by a needle suitable for intramuscular injection.
Any unused product or waste material should be disposed of in accordance with local requirements.
7. MARKETING AUTHORISATION HOLDER
GlaxoSmithKline Biologicals s.a.
rue de l'Institut 89
B-1330 Rixensart, Belgium
8. MARKETING AUTHORISATION NUMBER(S)
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
10. DATE OF REVISION OF THE TEXT
-
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Pandemrix
European Public Assessment Report
[Full report at: http://www.emea.europa.eu/humandocs/Humans/EPAR/pandemrix/pandemrix.htm ]
ANNEX I - SUMMARY OF PRODUCT CHARACTERISTICS
1. NAME OF THE MEDICINAL PRODUCT
Pandemrix 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 (10.68 milligrams), DL-α-tocopherol (11.86 milligrams) and polysorbate 80 (4.85 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.
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 (see sections 4.2 and 5.1).
4.2 Posology and method of administration
Posology
Adults from the age of 18 to 60 years: 1 dose of 0.5 ml at an elected date. A second dose of vaccine should be given after an interval of at least three weeks.
There is no experience in children and adults above 60 years of age. For further information, see section 5.1.
Method of administration
Immunisation should be carried out by intramuscular injection.
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 administrating 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.
If the pandemic situation allows, immunisation shall be postponed in patients with severe febrile illness or acute infection.
Pandemrix should under no circumstances be administered intravascularly.
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
Pandemrix 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.
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
No data have been generated in pregnant women with Pandemrix or with any other vaccine that contains the AS03 adjuvant
Animal studies do not indicate direct or indirect harmful effects with respect to fertility, pregnancy, embryonal/foetal development, parturition or post-natal development (see section 5.3).
Healthcare providers need to assess the benefits and potential risks of administering the vaccine to pregnant women taking into consideration official recommendations.
Pandemrix may be used during lactation.
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
• Clinical trials
Adverse reactions from clinical trials with the mock-up vaccine are listed here below (see section 5.1 for more information on mock-up vaccines).
The incidence of adverse reactions has been evaluated in approximately 5,000 subjects 18 years old and above who received formulations containing at least 3.75 microgram HA/AS03.
Adverse reactions reported are listed according to the following frequency:
- Very common (≥1/10)
- Common (≥1/100 to <1/10)
- Uncommon (≥1/1,000 to <1/100)
- Rare (≥1/10,000 to <1/1,000)
- Very rare (<1/10,000)
Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.
* Blood and lymphatic system disorders
Common: lymphadenopathy
* 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
* Psychiatric disorders
Uncommon: insomnia
• Post-marketing surveillance
No post-marketing surveillance data are available following Pandemrix administration.
From Post-marketing surveillance with interpandemic trivalent vaccines, the following adverse reactions have been reported:
* Uncommon:
Generalised skin reactions including urticaria
* Rare:
Neuralgia, convulsions, transient thrombocytopenia.
Allergic reactions, in rare cases leading to shock, have been reported.
* Very rare:
Vasculitis with transient renal involvement.
Neurological disorders, such as encephalomyelitis, neuritis and Guillain Barré syndrome.
This medicinal product contains thiomersal (an organomercuric compound) as a preservative and therefore, it is possible that sensitisation reactions may occur (see section 4.4).
4.9 Overdose
No case of overdose has been reported.
5. PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Influenza vaccines, ATC Code J07BB02.
This section describes the clinical experience with the mock-up vaccines 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.
Immune response against vaccine strain contained in Pandemrix (A/Vietnam/1194/2004 (H5N1)):
In a consistency study, more than 900 subjects aged 18-60 years received Pandemrix following a 0, 21 days schedule.
Twenty-one days after the first and second dose of the vaccine, the seroprotection rates, seroconversion rates and seroconversion factors for anti-haemagglutinin (anti-HA) antibody were as follows:
anti-HA antibody / 21 days after 1st dose / 21 days after 2nd dose
Seroprotection rate*† | 44.5% - 94.3%
Seroconversion rate† | 42.5% - 93.7%
Seroconversion factor†| 4.1 - 39.8
* anti-HA ≥1:40
† seroprotection rate : proportion of subjects with haemagglutination inhibition (HI) titre ≥1:40; seroconversion rate: proportion of subjects who were either seronegative at pre-vaccination and have a protective post-vaccination titre of ≥1:40, or who were seropositive at pre-vaccination and have a 4-fold increase in titre; seroconversion factor: ratio of the post-vaccination geometric mean titre (GMT) and the pre-vaccination GMT.
Twenty-one days after administration of the second dose, 96.0% of subjects had a 4-fold increase in serum neutralising antibody titres.
A neutralising antibody titre of at least 1:80 was achieved in 97.8% of subjects at day 42.
In a dose finding study in subjects aged 18-60 years, 50 subjects received a dose of 3.75 micrograms HA/AS03 in a volume of 1 ml at 0 and 21 days.
The seroprotection rates, seroconversion rates and seroconversion factors for anti-haemagglutinin (anti-HA) antibody at day 42 (post dose 2) and day 180 (persistence) were as follows:
anti-HA antibody / Day 42 / Day 180
Seroprotection rate*† | 84% - 54%
Seroconversion rate† | 82% - 52%
Seroconversion factor† | 27.9 - 4.4
* anti-HA ≥1:40
† seroprotection rate : proportion of subjects with haemagglutination inhibition (HI) titre ≥1:40; seroconversion rate: proportion of subjects who were either seronegative at pre-vaccination and have a protective post-vaccination titre of ≥1:40, or who were seropositive at pre-vaccination and have a 4-fold increase in titre; seroconversion factor: ratio of the post-vaccination geometric mean titre (GMT) and the pre-vaccination GMT.
A 4-fold increase in serum neutralising antibody titres was observed in 85.7% of subjects at day 42 and 72% at day 180.
Cross-reactive immune response against variants of A/Vietnam/1194/2004 (H5N1):
In the consistency study the seroprotection rate, seroconversion rate and seroconversion factor for anti-haemagglutinin (anti-HA) antibody against A/Indonesia/5/2005 at 21 days after the second dose were as follows:
anti-HA antibody | A/Indonesia/5/2005 ( N = 924 )
Seroprotection rate*† | 50.2%
Seroconversion rate† | 50.2%
Seroconversion factor† | 4.9
* anti-HA ≥1:40
† seroprotection rate : proportion of subjects with haemagglutination inhibition (HI) titre ≥1:40; seroconversion rate: proportion of subjects who were either seronegative at pre-vaccination and have a protective post-vaccination titre of ≥1:40, or who were seropositive at pre-vaccination and have a 4-fold increase in titre; seroconversion factor: ratio of the post-vaccination geometric mean titre (GMT) and the pre-vaccination GMT.
A 4-fold increase in serum neutralising antibody titres was obtained in 91.4% of subjects at day 42.
In the dose finding study the seroprotection rate, seroconversion rate and seroconversion factor against H5N1 drift variants 21 days after the second dose were as follows:
anti-HA antibody | A/Indonesia/5/2005 ( N = 50 ) | A/Anhui/01/2005 ( N = 20 ) | A/Turkey/Turkey/1/2005 ( N = 20 )
Seroprotection rate*† | 20.0% | 35.0% | 60.0%
Seroconversion rate† | 20.0% | 35.0% | 60.0%
Seroconversion factor† | 2.0 | 3.4 | 4.7
* anti-HA ≥1:40
† seroprotection rate : proportion of subjects with haemagglutination inhibition (HI) titre ≥1:40; seroconversion rate: proportion of subjects who were either seronegative at pre-vaccination and have a protective post-vaccination titre of ≥1:40, or who were seropositive at pre-vaccination and have a 4-fold increase in titre; seroconversion factor: ratio of the post-vaccination geometric mean titre (GMT) and the pre-vaccination GMT.
Twenty one days after the second dose, a 4-fold increase in serum neutralising antibody titres was obtained in 77.1% of subjects against the A/Indonesia/5/2005 strain, in 75.0% of subjects against A/Anhui/01/2005 and in 85.0% of subjects against A/Turkey/Turkey/1/2005.
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 respiratory tract was also reduced in vaccinated animals relative to controls, suggesting a reduced risk of viral transmission.
In the unadjuvanted control group, as well as in the adjuvant control group, all animals died or had to be euthanized as they were moribund, three to four days after the start of challenge.
5.2 Pharmacokinetic properties
Not applicable.
5.3 Preclinical safety data
Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, acute and repeated dose toxicity, local tolerance, female fertility, embryo-foetal and postnatal toxicity (up to the end of the lactation period).
6. PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Suspension vial: Polysorbate 80 - Octoxynol 10 - Thiomersal - Sodium chloride (NaCl) - Disodium hydrogen phosphate (Na2HPO4) - Potassium dihydrogen phosphate (KH2PO4) - Potassium chloride (KCl) - Magnesium chloride (MgCl2) - Water for injections
Emulsion vial: Sodium chloride (NaCl) - Disodium hydrogen phosphate (Na2HPO4) - Potassium dihydrogen phosphate (KH2PO4) - Potassium chloride (KCl) - Water for injections
For adjuvants, see section 2.
6.2 Incompatibilities
In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.
6.3 Shelf-life
18 months.
After mixing, the vaccine should be used within 24 hours. Chemical and physical in-use stability has been demonstrated for 24 hours at 25°C.
6.4 Special precautions for storage
Store in a refrigerator (2°C – 8°C).
Do not freeze.
Store in the original package in order to protect from light.
6.5 Nature and contents of container
One pack containing:
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one pack of 50 vials (type I glass) of 2.5 ml suspension (10 x 0.25 ml doses) with a stopper (butyl rubber).
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two packs of 25 vials (type I glass) of 2.5 ml emulsion (10 x 0.25 ml doses) with a stopper (butyl rubber).
The volume after mixing 1 vial of suspension (2.5 ml) with 1 vial of emulsion (2.5 ml) corresponds to 10 doses of vaccine (5 ml).
6.6 Special precautions for disposal and other handling
Pandemrix consists of two containers:
Vial A: multidose vial containing the antigen (suspension),
Vial B: multidose vial containing the adjuvant (emulsion).
Prior to administration, the two components should be mixed.
Instructions for mixing and administration of the vaccine:
1. Before mixing the two components, the emulsion and suspension should be allowed to reach room temperature, shaken and inspected visually for any foreign particulate matter and/or abnormal physical appearance. In the event of either being observed, discard the vaccine.
2. The vaccine is mixed by withdrawing the contents of the vial containing the emulsion (Vial B) by means of a syringe and by adding it to the vial containing the suspension (Vial A).
3. After the addition of the emulsion to the suspension, the mixture should be well shaken. The mixed vaccine is a whitish emulsion. In the event of other variation being observed, discard the vaccine.
4. The volume of Pandemrix (5 ml) after mixing corresponds to 10 doses of vaccine.
5. The vial should be shaken prior to each administration.
6. Each vaccine dose of 0.5 ml is withdrawn into a syringe for injection.
7. The needle used for withdrawal must be replaced by a needle suitable for intramuscular injection.
Any unused product or waste material should be disposed of in accordance with local requirements.
7. MARKETING AUTHORISATION HOLDER
GlaxoSmithKline Biologicals s.a.
rue de l'Institut 89
B-1330 Rixensart, Belgium
8. MARKETING AUTHORISATION NUMBER(S)
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
10. DATE OF REVISION OF THE TEXT
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