Summary of medicine characteristics - Prepandemic influenza vaccine (H5N1) (surface antigen, inactivated, adjuvanted) Novartis Vaccines and Diagnostics
2. QUALITATIVE AND QUANTITATIVE COMPOSITION
Influenza virus surface antigens (haemagglutinin and neuraminidase)* of strain:
A/Vietnam/1194/2004 (H5N1)-like strain (NIBRG-14)
7.5 micrograms** per 0.5 ml dose
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* propagated in eggs
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* * expressed in microgram haemagglutinin.
Adjuvant MF59C.1 containing: squalene polysorbate 80 sorbitan trioleate
9.75 milligrams per 0.5 ml
1.175 milligrams per 0.5 ml
1.175 milligrams p
For a full list of excipients see section 6.1.
3. PHARMACEUTICAL FORM
Suspension for injection in pre-filled syringe.
Milky-white liquid.
4. CLINICAL PARTICULARS
4.1 Therapeutic indications
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 the vaccine containing A/Vietnam/1194/2004 (H5N1)-like strain (see section 5.1).
Prepandemic Influenza vaccine (H5N1) (surface antigen, inactivated, adjuvanted) Novartis Vaccines
s should be used in accordance with official recommendations.
4.2 Posology and method of administration
Posology:
Adults and elderly (18 years of age and above):
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 3 weeks.
Prepandemic Influenza vaccine (H5N1) (surface antigen, inactivated, adjuvanted) Novartis Vaccines and Diagnostics has been evaluated in healthy adults (18–60 years of age) and healthy elderly (over 60 years of age) following a 1, 22 day primary vaccination schedule, and booster vaccination (see sections 4.8 and 5.1).
There is limited experience in elderly over 70 years of age (see section 5.1).
In the event of an officially declared influenza pandemic due to A/H5N1 virus, persons previously vaccinated with one or two doses of Prepandemic Influenza vaccine (H5N1) (surface antigen, inactivated, adjuvanted) Novartis Vaccines and Diagnostics that contained HA antigen derived from a different clade of the same influenza subtype as the influenza pandemic strain may receive a single dose of Prepandemic Influenza vaccine (H5N1) (surface antigen, inactivated, adjuvanted) Novartis Vaccines and Diagnostics instead of two doses that are required in previously unvaccinated individuals (see section 5.1).
Paediatric population:
The safety and efficacy of Prepandemic Influenza vaccine (H5N1) (surface antigen, inactivated, adjuvanted) Novartis Vaccines and Diagnostics in subjects under 18 years of age have not yet been established. Currently available data in subjects aged 6 months to 18 years of age are described in section 5.1 but no recommendation on a posology can be made.
No data are available in children aged less than 6 months.
Method of administration
Immunisation should be carried out by intramuscular injection into the deltoi
4.3 Contraindications
History of an anaphylactic (i.e. life-threatening) reaction to any of the constituents or trace residues (egg and chicken proteins, ovalbumin, kanamycin and neomycin sulphate, formaldehyde and cetyltrimethylammonium bromide (CTAB)) of this vaccine.
However, in a pandemic situation caused by the strain included in this vaccine, it may be appropriate to give this vaccine to individuals with a history of anaphylaxis as defined above, provided that facilities for resuscitation are immediately available in case of need.
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 and to residues (eggs and chicken proteins, ovalbumin, kanamycin and neomycin sulphate, formaldehyde and cetyltrimethylammonium bromide (CTAB)).
Very limited data in subjects with co-morbidities, including immunocompromised subjects are available for this H5N1 vaccine.
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.
Immunization shall be postponed in patients with febrile illness or acute infection.
The vaccine should under no circumstances be administered intravascularly or intradermally.
There are no data with Prepandemic Influenza vaccine (H5N1) (surface antigen, inactivated, adjuvanted) Novartis Vaccines and Diagnostics 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 immune response may not be elicited in all vaccinees (see section 5.1).
Some cross-protection was observed against related H5N1 virus variants in clinical trials (see section 5.1).
Since a second dose is recommended, it should be noted that there are no safety, immunogenicity or efficacy data to support interchangeability of Prepandemic Influenza vaccine (H5N1) (surface antigen, inactivated, adjuvanted) Novartis Vaccines and Diagnostics with other H5N1 monovalent vaccines.
4.5 Interaction with other medicinal products and other forms of interaction
Data obtained in adults showed that co-administration of adjuvanted H5N1 vaccine and seasonal (inactivated surface, non-adjuvanted) antigens did not lead to any interference neither for seasonal strains nor for H5N1 strains.
SRH antibody response against an homologous H5N1 Vietnam strain at day 43 reached all CHMP criteria for all 3 strains.
Co-administration was not associated with higher rates of local or systemic reactions compared to administration of Prepandemic Influenza vaccine (H5N1) (surface antigen, inactivated, adjuvanted) Novartis Vaccines and Diagnostics alone.
Therefore the data indicate that Prepandemic Influenza vaccine (H5N1) (surface antigen, inactivated, adjuvanted) Novartis Vaccines and Diagnostics may be co-administered with non-adjuvanted seasonal influenza vaccines (with injections made into opposite limbs).
There are no data on co-administration of Prepandemic Influenza vaccine (H5N1) (surface antigen, inactivated, adjuvanted) Novartis Vaccines and Diagnostics with other vaccines.
If co-administration with another vaccine is considered, immunisation should be carried out on separate limbs. It should be noted that the adverse reactions may be intensified.
The immunological response may be diminished if the patient is undergoing immunosuppressant treatment.
Following influenza vaccination, false positive serology test results may be obtained by the ELISA method for antibody to human immunodeficiency virus-1 (HIV-1), hepatitis C virus and, especially, HTLV-1. In such cases, the Western Blot method is negative. These transitory false positive results may be due to IgM production in response to the vaccine.
4.6 Fertility, preg
lactation
A study in rabbits did not indicate reproductive or developmental toxicity (see section 5.3).
Limited data was obtained from women who became pregnant during the course of clinical trials with Prepandemic Influenza vaccine (H5N1) (surface antigen, inactivated, adjuvanted) Novartis Vaccines and Diagnostics or H1N1v vaccines adjuvanted with MF59C.1.
It is estimated that more than 90,000 women have been vaccinated during pregnancy with H1N1v vaccine Focetria which contains the same amount of adjuvant MF59C.1 as. Prepandemic Influenza vaccine (H5N1) (surface antigen, inactivated, adjuvanted) Novartis Vaccines and Diagnostics However information on outcomes is currently limited. Preliminary data from spontaneously reported events and ongoing post-marketing studies (pregnancy registry and prospective interventional study) do not suggest direct or indirect harmful effects on influenza vaccines adjuvanted with MF59 with respect to pregnancy, fertility, embryonic/foetal development, parturition, or post natal development. Since Prepandemic Influenza vaccine (H5N1) (surface antigen, inactivated, adjuvanted) Novartis Vaccines and Diagnostics is expected not to be used in an emergency situation, its administration during pregnancy might be deferred as a precautionary approach.
Healthcare providers need to assess the benefit and potential risks of administering the vaccine to pregnant women taking into consideration official recommendations.
There are no data regarding the use of Prepandemic Influenza vaccine (H5N1) (surface antigen, inactivated, adjuvanted) Novartis Vaccines and Diagnostics during breast-feeding. The potential benefits to the mother and risks to the infant should be considered before administering Prepandemic Influenza vaccine (H5N1) (surface antigen, inactivated, adjuvanted) Novartis Vaccines and Diagnostics during breast-feeding.
4.7 Effects on ability to drive and use machines
Some of the undesirable effects mentioned under section 4.8 may affect the ability to drive or operate machinery.
4.8 Undesirable effects
Adverse reactions from clinical trials in adults (18 years old and above).
The incidence of adverse reactions has been evaluated in six clinical trials involving approximately 4,000 adults and elderly receiving (Prepandemic Influenza vaccine (H5N1) (surface antigen, inactivated, adjuvanted) Novartis Vaccines and Diagnostics at least 7.5 gg HA, adjuvanted). There were 3678 subjects 18–60 years of age, 264 subjects 61–70 years of age, and 41 subjects greater than 70 years of age.
Consistent with the data observed by trial for solicited reactions, there was a general trend towards decreased reports of local reactions after the second vaccination compared with the first injection.
Irrespective of antigen dose, almost all systemic reactions were reported on the day of vaccination (day 1) or during the 3 days immediately following.
Data on safety of a booster dose of the current Prepandemic Influenza vaccine (H5N1) (surface antigen, inactivated, adjuvanted) Novartis Vaccines and Diagnostics formulation are limited to three trials (V87P1, V87P2 and V87P1E1) that included 116 adults and 56 elderly. No increase in reactions was reported when a booster dose is administered 6 months-18 months later after the initial dosing series. A slight increase in reactions in adults was reported when a booster dose is administered 18 months after the initial dosing series. In the elderly, the reported reactions increased with the third booster dose only when compared with the second dose.
The adverse reaction rates reported after either vaccination dose (i.e. 1st, 2nd or booster) were similar and 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:
Nervous system disorders
Very common: headache
Rare: convulsions
Skin and subcutaneous tissue disorders
Common: sweating
Uncommon: urticaria
Rare: eye swelling
Muscoskeletal, connective tissue and bone disorders
Very common: myalgia
Common: arthralgia
Gastrointestinal disorders
Common: nausea
General disorders and administration site conditions
Very common: injection site swelling, injection site pain, injection site induration, injection site redness, fatigue
Common: injection site ecchymosis, fever, malaise, shivering
Uncommon: influenza like illness
Rare: anaphylaxis
These side effects usually disappear within 1–2 days without treatment.
Adverse reactions from clinical trial in children (6 months to 17 years old) (Study V87P6)
Regardless of age, reactogencity was higher after the first dose than after the second vaccination.
Reactogenicity after a third dose, administered 12 months following the first dose, was higher than after both first and second dose. The percentages of subjects reporting local reactions were higher in the older age groups, mainly due to the higher reports for pain. In toddlers erythema and tenderness were the most commonly reported solicited local reactions; irritability and unusual crying were the most commonly reported solicited systemic reactions. In children and adolescents pain was the most frequently reported solicited local reaction, and fatigue and headache were the most commonly reported solicited systemic reactions. Across all ages, low percentages of subjects reported fever.
| Injection 1 | Injection 2 | Injection 3 | |
| Prepandemic Influenza vaccine (H5N1) (surface antigen, inactivated, adjuvanted) Novartis Vaccines and Diagnostics | Prepandemic Influenza vaccine (H5N1) (surface antigen, inactivated, adjuvanted) Novartis Vaccines and Diagnostics | Prepandemic Influenza vaccine (H5N1) (surface antigen, inactivated, adjuvanted) Novartis Vaccines and Diagnostics | |
| Toddlers (6-<36 months) | N=145 | N=138 | N=124 |
| Any | 76% | 68% | 80% |
| Local | 47% | 46% | 60% |
| Systemic | 59% | 51% | 54% |
| Fever > 38°C (> 40°C) | 0% | 0% | 0% |
| Any Other Adverse Event | 54% | 49% | 35% |
| Children (3-<9 years) | N=96 | N=93 | N=85 |
| Any | 72% | 68% | 79% |
| Local | 66% | 58% | 74% |
| Systemic | 32% | 33% | 45% |
| Fever > 38°C (> 40°C) | 4% | 2% | 6% |
| Any Other Adverse Event | 36% | 31% | 19% |
| Adolescents(9-<18 years) | N=93 | N=91 | N=83 |
| Any | 91% | 82% | 89% |
| Local | 81% | 70% | 81% |
| Systemic | 69% | 52% | 69% |
| Fever > 38°C (> 40°C) | 0% | 1% | 2% |
| Any Other Adverse Event | 30% | 27% | 22% |
Post-marketing surveillance
No post-marketing surveillance data are available following Prepandemic Influenza vaccine (H5N1) (surface antigen, inactivated, adjuvanted) Novartis Vaccines and Diagnostics administration.
The following additional adverse events were reported from post-marketing surveillance with Focetria H1N1v (licensed for use from 6 months of age and with a composition that is similar to Prepandemic Influenza vaccine (H5N1) (surface antigen, inactivated, adjuvanted) Novartis Vaccines and Diagnostics):
Blood and lymphatic system disorders
Lymphadenopathy.
Cardiac disorders
Palpitation, tachycardia.
General disorders and administration site conditions Asthenia.
Muscoskeletal, connective tissue and bone disorders Muscular weakness, pain in extremities.
Respiratory disorders Cough.
Skin and subcutaneous tissue disorders
Generalised skin reactions including pruritus, urticaria or non-specific rash; angioedema.
Gastrointestinal disorders
Gastrointestinal disorders such as nausea, vomiting, abdominal pain and diarrhoea.
Nervous system disorders
Headache, dizziness, somnolence, syncope. Neurological disorders, such as neuralgia, paraesthesia, convulsions and neuritis.
Immune system disorders
Allergic reactions, anaphylaxis including dyspnoea, bronchospasm, laryngeal oedema, in rare cases leading to shock.
The following additional adverse events were reported from post-marketing surveillance with seasonal non-adjuvanted trivalent vaccines in all age groups and an MF59 seasonal adjuvanted trivalent vaccine with a composition similar to Prepandemic Influenza vaccine (H5N1) (surface antigen, inactivated, adjuvanted) Novartis Vaccines and Diagnostics (surface antigen, inactivated, adjuvanted with MF59C.1) that is licensed for use in elderly subjects 65 years of age and older:
Blood and lymphatic system disorders
Transient thrombocytopenia.
Immune system disorders
Vasculitis with transient renal involvement and exudative erythema multiforme.
Nervous system disorders
Neurological disorders, such as encephalomyelitis, and Guillain Barré syndrome.
4.9 Overdose
No case of overdose has been reported.
5. PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Influenza vaccine ATC Code J07BB02.
This section describes the clinical experience with Prepandemic Influenza vaccine (H5N1) (surface antigen, inactivated, adjuvanted) Novartis Vaccines and Diagnostics following a two-dose administration and booster.
Immune response against A/Vietnam/1194/2004 (H5N1):
Adults (18–60 years)
A clinical trial (Study V87P1) was conducted with a H5N1 vaccine combined with MF59C.1 adjuvant in 312 healthy adults. Two doses of vaccine containing H5N1 (A/Vietnam/1194/2004; 7.5 gg HA/dose adjuvanted) were administered three weeks apart to 156 healthy adults. In another clinical trial (Study V87P13) 2693 adult subjects were enrolled and received two doses of vaccine containing H5N1 (A/Vietnam/1194/2004; 7.5 gg HA/dose adjuvanted) administered three weeks apart. Immunogenicity was assessed in a subset (n=197) of study population.
The seroprotection rate*, seroconversion rate* and the seroconversion factor** for anti-HA antibody to H5N1 A/Vietnam/1194/2004 in the adults measured by SRH assay was as follows:
| Anti-HA antibody (SRH) | Study V87P1 21 days after 2nd dose N=149 | Study V87P13 21 days after 2nd dose N=197 |
| Seroprotection rate (95%CI) | 85% (79–91) | 91% (87–95) |
| Seroconversion rate (95%CI) | 85% (78–90) | 78% (72–84) |
| Seroconversion factor (95%CI) | 7.74 (6.6–9.07) | 4.03 (3.54–4.59) |
| Anti-HA antibody (SRH) | Study V87P13 21 days after 2nd dose N=69 | Study V87P13 21 days after 2nd dose N=128 |
| Baseline Serostatus | < 4 mm2 | > 4 mm2 |
| Seroprotection rate (95%CI) | 87% (77–94) | 94% (88–97) |
| Seroconversion rate (95%CI) | 87% (77–94) | 73% (65–81) |
| Seroconversion factor (95%CI) | 8.87 (7.09–11) | 2.71 (2.38–3.08) |
* measured by SRH assay > 25 mm2
** geometric mean ratios of SRH
MN results against A/Vietnam/1194/2004 indicate a seroprotection and seroconversion rate ranging from 67% (60–74) to 85% (78–90) and 65% (58–72) to 83% (77–89), respectively. Immune response to vaccination assessed by MN assay is in line with results obtained with SRH.
Persistence of antibodies after primary vaccination in this population was assessed by HI, SRH, and MN assays. Compared to the antibody levels obtained at day 43 after completion of primary vaccination schedules, antibody levels at day 202 were reduced by 1/5 to 1/2 from their prior levels.
In a phase 2 clinical trial (Study V87P3) adult subjects aged 18–65 years primed 6–8 years previously with 2 doses of MF59-adjuvanted H5N3 vaccine /A/Duck/Singapore/97 were administered 2 booster doses of Prepandemic Influenza vaccine (H5N1) (surface antigen, inactivated, adjuvanted) Novartis Vaccines and Diagnostics SRH results after the first dose, that mimic prepandemic priming plus single heterologous booster dose, met all CHMP criteria.
Elderly (>60 years)
The seroprotection rate*, seroconversion rate* and the seroconversion factor** for anti-HA antibody to H5N1 A/Vietnam/1194/2004 in subjects aged over 60 (limited number of subjects were above 70 years of age) measured by SRH assay assessed in two clinical studies were as follows:
| Anti-HA antibody (SRH) | Study V87P1 21 days after 2nd dose N=84 | Study V87P13 21 days after 2nd dose ___A> |
| Seroprotection rate (95%CI) | 80% (70–88) | 82% (76–87) |
| Seroconversion rate (95%CI) | 70% (59–80) | 63% (56–69) |
| Seroconversion factor (95%CI) | 4.96 (3.87–6.37) | 2.9 (2.53–3.31) |
| Anti-HA antibody (SRH) | Study V87P13 21 days after 2nd dose N=66 | Study V87P13 21 days after 2nd dose N=143 |
| Baseline Serostatus | < 4 mm2 | > 4 mm2 |
| Seroprotection rate (95%CI) | 82% (70–90) | 82% (75–88) |
| Seroconversion rate (95%CI) | 82% (70–90) | 54% (45–62) |
| Seroconversion factor (95%CI) | 8.58 (6.57–11) ( | 1.91 (1.72–2.12) |
* measured by SRH assay > 25 mm2
** geometric mean ratios of SRH
MN results against A/Vietnam/1194/2004 indicate a seroprotection and seroconversion rate ranging from of 57% (50–64) to 79% (68–87) and 55% (48–62) to 58% (47–69) respectively. MN results, similar to SRH results demonstrated strong immune response after completion of priming vaccination series in a population of elderly subjects.
Persistence of antibodies after prima
on in this population as assessed by HI, SRH, and MN
tests reduced from 1/2 to 1/5th of their post-vaccination level at day 202 as compared to day 43 after completion of primary schedules as assessed by HI, SRH, and MN tests. Up to 50% of the elderly subjects immunised with Prepandemic Influenza vaccine (H5N1) (surface antigen, inactivated, adjuvanted) Novartis Vaccines and Diagnostics were seroprotected at six months.
A third (booster) dose of Prepandemic Influenza vaccine (H5N1) (surface antigen, inactivated, adjuvanted) Novartis Vaccines and Diagnostics was administered 6 months onwards after the primary vaccination. Results are shown by SRH.
The seroprotection rate*, seroconversion rate* and the seroconversion factor** for anti-HA antibody to H5N1 A/Vietnam/1194/2004 measured by SRH assays were as follows:
| Study V87P1 Adults booster after 2nd dose | Study V87P2 Adults booster after 2rd dose | Study V87P1 Elderly booster after 2nd dose | |
| SRH | N=71 | N=13 | N=38 |
| Seroprotection rate (95%CI) | 89% (79–95) | 85% (55–98) | 84% ( 69–94) |
| Seroconversion rate (95%CI) | 83% (72–91) | 69% (39–91) | 63% (46–78) |
| Seroconversion factor (95%CI) | 5.96 (4.72–7.53) | 2.49 (1.56–3.98) | 5.15 (3.46–7.66) |
* measured by SRH assay > 25 mm2
geometric mean ratios of SRH
There is limited experience in the elderly
Supportive data in adults
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a) Cross reactivity
Some heterologous immune response against A/H5N1/turkey/Turkey/05 (NIBRG23; clade2.2)
third
and A/H5N1/Indonesia (clade 2.1) was detectable both after the second an vaccinations, indicating cross-reactivity of the clade 1 vaccine against clade 2 strains.
dies
Seroprotection rate*, seroconversion rate* and the seroconversion factor** for anti-HA an to H5N1 A/turkey/Turkey/05 after the 2nd dose in adults 18–60 years of age, measured by SRH and HI assays were as follows:
| Anti-HA antibody | Study V87P12 21 days after 2nd dose N=60 | Study V87P3 21 days after 2nd dose N=30 | Study V87P13 21 days after 2nd dose N=197 | |
| SRH | Seroprotection rate (95%CI) | 65% (52–77) | 90% (73–98) | 59% (52–66) |
| Seroconversion rate (95%CI) | 65% (52–77) | 86% (68–96) | 49% (42–56) | |
| Seroconversion factor(95%CI) | 4.51 (3.63–5.61) | 7.67 (6.09–9.67) | 2.37 (2.1–2.67) | |
| N=60 | N=30 | N=197 | ||
| HI | Seroprotection rate (95%CI)° | 28% (17–41) N* | 24% (10–44) | 23% (18–30) |
| Seroconversion rate (95%CI)° | 28% (17–41) | 21% (8–40) | 19% (14–25) | |
| Seroconversion factor (95%CI)°° | 2.3 (1.67–3.16) | 1.98 (1.22–3.21) | 1.92 (1.64–2.25) |
* measured by SRH assay > 25 mm2
geometric mean ratios of SRH
° measured by HI assay > 40
°° geometric mean ratios of HI
MN results for the three clinical studies in the Table above revealed a seroprotection rate and seroconversion rate against A/turkey/Turkey/05 ranging from 10% (2–27) to 39% (32–46) and 10% (227) to 36% (29–43) respectively. MN results yielded a GMR against A/turkey/Turkey/05 ranging from 1.59 to 2.95.
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b) Long term booster immune memory
A single vaccination with Prepandemic Influenza vaccine (H5N1) (surface antigen, inactivated, adjuvanted) Novartis Vaccines and Diagnostics (H5N1, A/Vietnam/1194/2004) induced high and rapid serological response in subjects primed 6–8 years previously with two doses of a different surrogate H5N vaccine, having same formulation as Prepandemic Influenza vaccine (H5N1) (surface antigen, inactivated, adjuvanted) Novartis Vaccines and Diagnostics but using the strain H5N3.
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c) Trial on different vaccination schedules:
In a clinical trial evaluating 4 different vaccination schedules in 240 subjects 18 to 60 years of age, where the second dose was after either 1, 2, 3 or 6 weeks after the first Prepandemic Influenza vaccine
(H5N1) (surface antigen, inactivated, adjuvanted) Novartis Vaccines and Diagnostics dose, SRH CHMP criteria were achieved in all the vaccine schedule groups after 3 weeks from the 2nd vaccination. The magnitude of immune response was lower in the group who received the 2nd dose 1 week later and higher in the groups with longer interval schedules.
- • Available data in paediatric populations
A clinical trial (Study V87P6) was conducted with a H5N1 vaccine combined with MF59C.1 adjuvant in 471 children from 6 months to 17 years of age. Two doses of Prepandemic Influenza vaccine (H5N1) (surface antigen, inactivated, adjuvanted) Novartis Vaccines and Diagnostics were administered three weeks apart and a third dose 12 months following the first dose. After 3 weeks from the 2nd vaccination (day 43) all age groups (i.e. 6–35 months, 3–8 years and 9–17 years) achieved high levels of antibodies to (A/Vietnam/1194/2004) as evaluated with SRH and HI assays as presented in table below*. In this trial no vaccine related SAEs were observed.
| Toddlers (6-<36 months) | Children (3-<9 years) | Adolescents (9-<18 years) | ||
| N=134 | N=91 | N=89 | ||
| HI | % SP (95% CI) Day 43 | 97% (92–99) | 97% (91–99) | 89% (80–94) |
| GMR Day 43 to Day 1 | 129 (109–151) | 117 (97–142) | 67 (51–88) | |
| % SC (95% CI) Day 43 | 97% (92–99) | 97% (2/ (91–99) | 89% (80–94) | |
| SRH | N=133 | N=91 < | N=90 | |
| % SP (95% CI) Day 43 | 100% (97–100) | 100% (96–100) | 100% (96–100) | |
| GMR (95% CI) Day 43 to Day 1 | 16 (14–18) | „O 15 (13–17) | 14 (12–16) | |
| % SC (95% CI) Day 43 | 98% (95–100) | 100% (96–100) | 99% (94–100) | |
* In the absence of CHMP immunogenicity criteria for children, the CHMP immunogenicity criteria used to evaluate seasonal flu vaccines in adults were applied to the serological data obtained after vaccination of children.
MN results against a A/Vietnam/1194/2004 indicate a seroprotection rate of 99% (95%CI: 94–100), a seroconversion rate ranging from 97% (95%CI: 91–99) to 99% (95%CI: 96–100) and a GMR ranging from 29 (95%CI: 25–35) to 50 (95%CI: 44–58).
The European Medicines Agency has deferred the obligation to submit the results of studies with Prepandemic Influenza vaccine (H5N1) (surface antigen, inactivated, adjuvanted) Novartis Vaccines and Diagnostics (H5N1, A/Vietnam/1194/2004) in one or more subsets of the paediatric population in active immunisation against H5N1 subtype of Influenza A virus. See section 4.2 for information on paediatric use.
Information from non-clinical trials
Efficacy against challenge with virus homologous and heterologous to vaccine strains was evaluated in the ferret model. Prepandemic Influenza vaccine (H5N1) (surface antigen, inactivated, adjuvanted) Novartis Vaccines and Diagnostics containing HA from A/Vietnam/1194/2004 (homologous to the challenge strain) and an Prepandemic Influenza vaccine (H5N1) (surface antigen, inactivated, adjuvanted) Novartis Vaccines and Diagnostics -like H5N1 vaccine, containing hemagglutinin from the A/turkey/Turkey/1/2005-like (heterologous to the challenge strain) were tested. Groups of 8 ferrets received one (day 21) or two (days 0 and 21) doses of vaccine containing 3.75 or 7.5 micrograms of antigen. Control animals received adjuvant alone. Animals were challenged by the intranasal route on day 42 with a lethal dose of A/Vietnam/1203/04 virus. Animals were monitored for 16–17 days after challenge to allow for a comprehensive assessment of disease progression, including the time of onset of symptoms, mortality, or subsequent recovery.
All (100%) animals receiving 2 doses of Prepandemic Influenza vaccine (H5N1) (surface antigen, inactivated, adjuvanted) Novartis Vaccines and Diagnostics were protected, and 94% of animals receiving a single dose of Prepandemic Influenza vaccine (H5N1) (surface antigen, inactivated, adjuvanted) Novartis Vaccines and Diagnostics were protected. 87% of animals challenged with virus heterologous to the vaccine strain after 2 doses of vaccine were protected, and a single dose of heterologous vaccine protected 56% of the animals. All control animals died within 7 days of challenge. Vaccination protected animals from lethal challenge with virus homologous and heterologous to the vaccine.
In a similar study, intranasal challenge was delayed until approximately 4 months after the second dose of vaccine containing either 3.75 or 7.5 micrograms of antigen was administered. In this study 100% of animals were protected against homologous challenge, and 81% of animals were protected against heterologous challenge. Vaccination protected animals from lethal challenge even when HI antibody titers were low or undetectable.
Efficacy against challenge with the heterologous virus A/Indonesia/5/05 was also tested. Groups of 6 ferrets received one dose of vaccine (day 21) containing 3.75 micrograms of antigen or two doses of vaccine (days 0 and 21) containing either 1.0 or 3.75 micrograms of antigen (A/Vietnam/1194/2004). A lethal challenge was administered by the intratracheal route on day 49. Two doses of vaccine protected 92% of animals, and a single dose of vaccine protected 50% of animals against the A/Indonesia/5/05 virus. Compared to the adjuvant control group, lung damage was reduced in vaccinated groups. Viral shedding and viral titers in lungs were also reduced, suggesting that vaccination may reduce the risk of viral transmission.
5.2 Pharmacokinetic properties
Not applicable.
5.3 Preclinical safety data
Non-clinical data obtained with Prepandemic Influenza vaccine (H5N1) (surface antigen, inactivated, adjuvanted) Novartis Vaccines and Diagnostics and with seasonal influenza vaccine containing MF59C.1 adjuvant reveal no special hazard for humans based on conventional studies of repeated dose toxicity, local tolerance, female fertility, and reproductive and developmental toxicity (through the end of the lactation period).
6. PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Sodium chloride,
Potassium chloride,
Potassium dihydrogen phosphate, Disodium phosphate dihydrate, Magnesium chloride hexahydrate, Calcium chloride dihydrate, Sodium citrate,
Citric acid,
Water for injections.
For the adjuvant, see section 2
6.2 Incompatibilities
6.3 Shelf life
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
0.5 ml in pre-filled syringe (type I glass) with plunger-stopper (bromo-butyl rubber).
Packs of 1 or 10 pre-filled syringes.
Not all pack sizes may be marketed.
6.6 Special precautions for disposal and other handling
Visually inspect the suspension prior to administration. In case of any particles and/or abnormal appearance, the vaccine should be discarded.
The vaccine should be allowed to reach room temperature before use. Gently shake before use.
Any unused vaccine and waste material should be disposed of in compliance with local requirements.
7. MARKETING
Novartis Vaccin Via Fiorentina, 1 Siena, Italy.
iagnostics S.r.l.
8. MARKETING AUTHORISATION NUMBER(S)
EU/1/10/657/001–002