ANNEX I
SUMMARY OF PRODUCT CHARACTERISTICS
Celvapan suspension for injection
Influenza vaccine (H1N1)v (whole virion, Vero cell derived, inactivated)
2.
Whole virion influenza vaccine, inactivated containing antigen of strain *:
A/California/07/2009 (H1N1)v
7.5 micrograms**
per 0.5 ml dose
* propagated in Vero cells (continuous cell line of mammalian origin)
** expressed in micrograms haemagglutinin.
This is a multidose container. See section 6.5 for the number of doses per vial.
For a full list of excipients, see section 6.1.
3.
Suspension for injection.
The vaccine is a clear to opalescent, translucent suspension.
4.
Prophylaxis of influenza caused by A(H1N1)v 2009 virus. (See section 4.4).
Celvapan should be used in accordance with Official Guidance
Posology
The dose recommendations take into account available data from on-going clinical studies in healthy
subjects who received two doses of Celvapan (H1N1)v.
From clinical studies limited immunogenicity and safety data are available for Celvapan (H1N1)v in
healthy adult and elderly subjects and in children (see section 4.4, 4.8., and 5.1).
Adults and elderly
One 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.
Children and adolescents aged 3 to 17 years
One 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.
2
Children aged 6 to 35 months
Limited data are available in infants and young children aged 6 to 35 months. If vaccination is
considered necessary, the dosing should be in accordance with the recommendations given for
children 3-17 years of age.
Children aged less than 6 months
Vaccination is not currently recommended in this age group.
For further information, see sections 4.8 and 5.1.
It is recommended that subjects who receive a first dose of Celvapan, complete the vaccination course
with Celvapan (see section 4.4).
Method of administration
Immunisation should be carried out by intramuscular injection preferably into the deltoid muscle or
anterolateral thigh, depending on the muscle mass.
History of an anaphylactic (i.e. life-threatening) reaction to any of the constituents or trace residues
(e.g. formaldehyde, benzonase, sucrose) of this vaccine.
See section 4.4 for Special warnings and special precautions for use.
The vaccine can only be expected to protect against influenza caused by A/California/07/2009
(H1N1)v-like strains.
Caution is needed when administrating this vaccine to persons with a known hypersensitivity (other
than anaphylactic reaction) to the active substance(s), to any of the excipients and to trace residues e.g.
formaldehyde, benzonase, or sucrose.
Hypersensitivity reactions, including anaphylaxis, have been reported following CELVAPAN
vaccination (see section 4.8). Such reactions have occurred both in patients with a history of multiple
allergies and in patients with no known allergy.
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.
Immunisation shall be postponed in patients with severe febrile illness or acute infection.
Celvapan should under no circumstances be administered intravascularly.
There are no data with Celvapan 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 elicited in all vaccinees (see section 5.1).
There are no safety, immunogenicity or efficacy data to support interchangeability of Celvapan with
other (H1N1)v vaccines.
3
There are no data on co-administration of Celvapan with other vaccines. However, 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.
There are currently no data available on the use of Celvapan in pregnancy. Data from pregnant women
vaccinated with different inactivated non-adjuvanted seasonal vaccines do not suggest malformations
or fetal or neonatal toxicity.
Animal studies with Celvapan do not indicate reproductive toxicity (see section 5.3).
The use of Celvapan may be considered during pregnancy if this is thought to be necessary, taking into
account official recommendations.
Celvapan may be used in lactating women.
Some undesirable effects mentioned under section 4.8 “Undesirable effects” may affect the ability to
drive or use machines.
Clinical trials with a version of Celvapan containing a H5N1 vaccine strain
In clinical trials with a version of Celvapan containing a H5N1 vaccine strain (see section 5.1) in 3576
subjects (3116 between 18 and 59 years old, and 460 aged 60 and above), the following adverse
reactions were assessed as at least possibly related by the investigator. Most of the reactions were mild
in nature, of short duration and qualitatively similar to those induced by influenza vaccines. There
were fewer reactions after the second dose of the vaccine compared with the first dose. The most
frequently occurring adverse reaction was injection site pain, which was usually mild.
Adverse reactions from clinical trials with the mock-up vaccine are listed below (see section 5.1 for
more information on mock-up vaccines).
Adverse reactions are listed according to the following frequency.
Very common (
≥
1/10)
1/100 to <1/10)
Uncommon (
≥
≥
1/1,000 to <1/100)
1/10,000 to <1/1,000)
Very rare (<1/10,000)
Not known (cannot be estimated from the available data)
≥
4
•
Common (
Rare (
Within each frequency grouping, adverse reactions are presented in the order of decreasing
seriousness.
Infections and infestations
Common: nasopharyngitis
Blood and the lymphatic system disorders
Uncommon: lymphadenopathy
Psychiatric disorders
Uncommon: insomnia, restlessness
Nervous system disorders
Very common: headache
Common: dizziness
Uncommon: somnolence, dysaesthesia, paresthesia
Eye disorders
Uncommon: conjunctivitis
Ear and labyrinth disorders
Common: vertigo
Uncommon: sudden hearing loss
Rare: ear pain
Vascular disorders
Uncommon: hypotension
Respiratory, thoracic and mediastinal disorders
Common: pharyngolaryngeal pain
Uncommon: dyspnoea, cough, rhinorrhoea, nasal congestion, dry throat
Gastrointestinal disorders
Common: gastro-intestinal symptoms (such as nausea, vomiting, diarrhoea and upper abdominal pain)
Skin and subcutaneous tissue disorders
Common: hyperhidrosis
Uncommon: rash, pruritus, urticaria
Musculoskeletal and connective tissue disorders
Common: arthralgia, myalgia
General disorders and administration site conditions
Very common: injection site pain, fatigue
Common: pyrexia, chills, malaise, induration, erythema, swelling and haemorrhage at the injection site
Uncommon: injection site irritation
Rare: injection site movement impairment
•
Clinical Trials with Celvapan (H1N1)v
Adults and Elderly
In an ongoing clinical study the 7.5 µg dose of Celvapan (H1N1)v was administered to adults aged 18
to 59 years (N= 101) and elderly over 60 years of age (N=101). Safety data after the first and second
vaccination suggest a similar safety profile to that reported for the influenza vaccines using a H5N1
strain, except for injection site pain, which was reported at a lower rate (common).
5
Children and adolescents 3 to 17 years of age
In an ongoing clinical trial 51 children and adolescents aged 9 to 17 years and 51 children aged 3 to 8
years were administered the 7.5 µg dose of Celvapan (H1N1)v. The incidence and nature of symptoms
after the first and second vaccination were similar to that observed in the adult and elderly population
using Celvapan.
Injection site pain was reported at a higher rate (very common) and headache and fatigue were
reported at a lower rate (common) than in adults. Fever (≥38°C) was reported at a frequency of 7.8%
and 9.8% after the first and second vaccination in children aged 3 to 8 years. No fever was reported in
children and adolescents aged 9 to 17 years.
Children aged 6 to 35 months
In an ongoing clinical trial the 7.5 µg dose of Celvapan (H1N1)v was administered to 52 infants and
young children aged 6 to 35 months. Sleep disorder was reported as very common, and additional
symptoms reported at a common frequency in this age group were anorexia, crying, irritability and
somnolence. Fever (≥38° C) was reported at a frequency of 13.4% and 11.5% after the first and second
vaccination.
•
Post-marketing surveillance
Celvapan (H1N1)v
The following additional adverse reactions have been reported in the post-marketing experience in
adults and children receiving Celvapan (H1N1)v.
The frequency of these adverse reactions is not known.
Immune system disorder:
Anaphylactic reaction*, Hypersensitivity*
Nervous system disorders:
Febrile convulsion
Skin and subcutaneous tissue disorders:
Angioedema
*Such reactions have been manifested by respiratory distress, hypotension, tachycardia, tachypnea,
cyanosis, pyrexia, flushing, angioedema, and urticaria
Musculoskeletal and connective tissue disorders:
Pain in extremity (in the majority of cases reported as pain in the injection site arm)
General disorders and administration site conditions
Influenza-like illness
Pandemic Observational Study
Preliminary safety data from 240 children (above 5 years of age), adolescents and adults showed that
within 7 days after the first vaccination 37.5% of subjects reported systemic reactions and 25.0%
reported injection site reactions. In 53 children aged 6 months to 5 years systemic reactions were
reported in 30.2% and injection site reactions occurred in 20.8% of subjects.
After the second dose adverse reactions occurred at a lower frequency.
Very common reactions reported in children above 5 years of age, adolescents and adults:
Injection site reactions, fatigue, headache, muscle pain, gastrointestinal symptoms
Very common reactions reported in children aged 6 months to 5 years:
Injection site reactions, drowsiness, irritability, loss of appetite
6
Trivalent seasonal influenza vaccines
From post-marketing surveillance with egg-derived trivalent seasonal influenza vaccines, the
following serious adverse reactions have been reported:
Uncommon:
Generalised skin reactions
Rare
:
Neuralgia, paraesthesia, 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.
No case of overdose has been reported.
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Influenza vaccines, ATC Code J07BB01
Clinical studies with Celvapan (H1N1)v currently provide:
•
Safety and immunogenicity data obtained three weeks after administration of two doses of
Celvapan (H1N1)v to healthy adults aged 18 years and older.
•
Safety and immunogenicity data obtained three weeks after administration of two doses of
Celvapan (H1N1)v to healthy children aged 6 months to 17 years.
Clinical studies in which a version of Celvapan containing HA derived from A/Vietnam/1203/2004
(H5N1) was administered at day 0 and at day 21 provide:
•
Safety and immunogenicity data in healthy adults, including the elderly.
Immune response against A/California/07/2009(H1N1)v
The immunogenicity of the vaccine containing 7.5 μg non-adjuvanted HA derived from strain
A/California/07/2009 (H1N1)v has been evaluated in two clinical studies in adults aged 18 years and
older (N=200), and in children and adolescents aged 3 to 17 years (N=101), following a 0, 21 day
schedule. Preliminary data are available for infants and young children aged 6 to 35 months (N=65).
7
Adults aged 18 years and older
After 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 elderly
subjects aged 60 years and above were as follows:
SRH Assay
All subjects
Seronegative subjects at
baseline (≤4mm
2
)
21 Days After
21 Days After
1
st
Dose
2
nd
Dose
1
st
Dose
2
nd
Dose
18 to 59 years
N=99
N=33
Seroprotection rate*
75.8%
(66.1; 83.8)
80.8%
(71.7; 88.0)
69.7%
(51.3; 84.4)
78.8%
(61.1; 91.0)
Seroconversion rate**
64.6%
(54.4; 74.0)
70.7%
(60.7; 79.4)
69.7%
(51.3; 84.4)
78.8%
(61.1; 91.0)
Seroconversion factor***
3.4
(2.8 ; 4.3)
4.1
(3.3 ; 5.1)
7.1
(4.5 ; 11.0)
9.5
(6.5 ; 13.8)
≥60 years
N=101
N=22
Seroprotection rate*
76.2%
(66.7; 84.1)
82.2%
(73.3; 89.1)
50.0%
(28.2; 71.8)
63.6%
(40.7; 82.8)
Seroconversion rate**
28.7%
(20.1; 38.6)
35.6%
(26.4; 45.8)
50.0%
(28.2; 71.8)
63.6%
(40.7; 82.8)
Seroconversion factor***
1.8
(1.5 ; 2.1)
2.0
(1.7 ; 2.4)
3.9
(2.3 ; 6.7)
5.6
(3.4 ; 9.2)
* 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 titres
≥
40, seroconversion rate and
seroconversion factor as measured by microneutralisation assay (MN) in adults aged 18 to 59 years
and in elderly subjects aged 60 years and above were as follows:
MN Assay
All subjects
Seronegative subjects at
baseline (<1:10)
21 Days After
21 Days After
1
st
Dose
2
nd
Dose
1
st
Dose
2
nd
Dose
18 to 59 years
N=100
N=99
N=39
N=38
Seroneutralization rate*
87.0%
(78.8; 92.9)
98.0%
(92.9; 99.8)
74.4%
(57.9; 87.0)
97.4%
(86.2; 99.9)
Seroconversion rate**
80.0%
(70.8; 87.3)
86.9%
(78.6; 92.8)
84.6%
(69.5; 94.1)
97.4%
(86.2; 99.9)
Seroconversion factor***
21.3
(14.6 ; 31.2)
29.0
(20.5 ; 41.0)
28.8
(15.2 ; 54.5)
55.3
(32.0 ; 95.6)
≥60 years
N=101
N= 34
N=38
Seroneutralization rate*
70.3%
(60.4; 79.0)
82.2%
(73.3; 89.1)
55.9%
(37.9; 72.8)
76.3%
(59.8; 88.6)
Seroconversion rate**
55.4%
(45.2; 65.3)
71.3%
(61.4%; 79.9)
73.5%
(55.6; 87.1)
94.7%
(82.3; 99.4)
Seroconversion factor***
5.0
(3.8 ; 6.6)
7.6
(5.9 ; 9.9)
7.1
(4.4 ; 11.3)
15.0
(10.1 ; 22.2)
* MN titre ≥1:40
** > 4-fold increase in MN titre
*** geometric mean increase
8
Children and adolescents (3 – 17 years of age)
The seroprotection rate, seroconversion rate and seroconversion factor for anti-HA antibody as
measured by single radial haemolysis (SRH) in children and adolescents aged 3 to 17 years were as
follows:
SRH Assay
All subjects
Seronegative subjects at
baseline (≤4mm
2
)
21 Days After
21 Days After
1
st
Dose
2
nd
Dose
1
st
Dose
2
nd
Dose
3 to 8 years
N=51
N=31
Seroprotection rate*
51.0%
(36.6; 65.2)
88.2%
(76.1; 95.6)
58.1%
(39.1; 75.5)
93.5%
(78.6; 99.2)
Seroconversion rate**
47.1%
(32.9; 61.5)
88.2%
(76.1; 95.6)
58.1%
(39.1; 75.5)
93.5%
(78.6; 99.2)
Seroconversion factor***
3.5
(2.5 ; 4.9)
8.6
(6.6 ; 11.3)
5.8
(3.9 ; 8.8)
15.0
(12.4 ; 18.1)
9 to 17 years
N=50
N=29
Seroprotection rate*
80.0%
(66.3; 90.0)
88.0%
(75.7; 95.5)
82.8%
(64.2; 94.2)
93.1%
(77.2; 99.2)
Seroconversion rate**
74.0%
(59.7; 85.4)
84.0%
(70.9; 92.8)
82.8%
(64.2; 94.2)
93.1%
(77.2; 99.2)
Seroconversion factor***
6.8
(5.0 ; 9.2)
8.9
(6.6 ; 11.9)
9.8
(6.9 ; 14.0)
13.8
(10.3 ; 18.4)
* 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 titres ≥ 40, seroconversion rate and
seroconversion factor as measured by microneutralisation assay (MN) in children and adolescents
aged 3 to 17 years were as follows:
MN Assay
All subjects
Seronegative subjects at
baseline (<1:10)
1
st
Dose
21 Days After
2
nd
Dose
21 Days After
2
nd
Dose
3 to 8 years
N=51
N=47
Seroneutralization rate*
84.3%
(71.4; 93.0)
100.0%
(93.0; 100.0)
83.0%
(69.2; 92.4)
100.0%
(92.5; 100.0)
Seroconversion rate**
94.1%
(83.8; 98.8)
100.0%
(93.0; 100.0)
93.6%
(82.5; 98.7)
100.0%
(92.5; 100.0)
Seroconversion factor***
12.9
(9.5; 17.5)
156.9
(119.4; 206.2)
13.5
(9.7; 18.8)
168.2
(131.1; 215.7)
9 to 17 years
N=51
N=34
Seroneutralization rate*
94.1 %
(83.8; 98.8)
100.0%
(93.0; 100.0)
91.2%
(76.3; 98.1)
100.0%
(89.7; 100.0)
Seroconversion rate**
100.0%
(93.0; 100.0)
100.0%
(93.0; 100.0)
100.0%
(89.7; 100.0)
100.0%
(89.7; 100.0)
Seroconversion factor***
33.3
(22.2; 50.0)
115.6
(87.4; 152.8)
29.2
(17.9; 47.7)
137.5
(99.5; 189.9)
* MN titre ≥1:40
**
>
4-fold increase in MN titre
*** geometric mean increase
9
1
st
Dose
Infants and children aged 6–35 months
The seroprotection rate, seroconversion rate and seroconversion factor for anti-HA antibody as
measured by single radial haemolysis (SRH) in children aged 6 to 35 months were as follows:
SRH Assay
All subjects
Seronegative subjects at
baseline (≤4mm
2
)
1
st
Dose
21 Days After
2
nd
Dose
21 Days After
2
nd
Dose
6 to 11 months
N=16
N=15
Seroprotection rate*
31.3%
(11.0; 58.7)
81.3%
(54.4; 96.0)
33.3%
(11.8; 61.6)
80.0%
(51.9; 95.7)
Seroconversion rate**
31.3%
(11.0; 58.7)
81.3%
(54.4; 96.0)
33.3%
(11.8; 61.6)
80.0%
(51.9; 95.7)
Seroconversion factor***
2.0
(1.1 ; 3.4)
9.2
(5.9 ; 14.5)
2.1
(1.1 ; 3.7)
9.0
(5.6 ; 14.5)
12 to 35 months
N=49
N=40
Seroprotection rate*
24.5%
(13.3; 38.9)
95.9%
(86.0; 99.5)
20.0%
(9.1;35.6)
95.0%
(83.1;99.4)
Seroconversion rate**
22.4%
(11.8; 36.6)
91.8%
(80.4; 97.7)
20.0%
(9.1; 35.6)
95.0%
(83.1; 99.4)
Seroconversion factor***
1.8
(1.4 ; 2.5)
11.2
(9.3 ; 13.4)
1.8
(1.3 ; 2.5)
12.5
(10.7 ; 14.5)
* 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 vaccination the rate of subjects with neutralizing antibody titres ≥ 40, seroconversion rate and
seroconversion factor as measured by microneutralisation assay (MN) in children aged 6 to 35 months
were as follows:
MN Assay
All subjects
Seronegative subjects at baseline
(<1:10)
1
st
Dose
21 Days After
2
nd
Dose
21 Days After
2
nd
Dose
6 to 11 months
N=8
N=8
Seroneutralization rate*
25.0%
(3.2; 65.1)
100%
(63.1; 100.0)
25.0%
(3.2; 65.1)
100%
(63.1; 100.0)
Seroconversion rate**
50.0%
(15.7; 84.3)
100%
(63.1;100.0)
50.0%
(15.7; 84.3)
100%
(63.1;100.0)
Seroconversion factor***
3.0
(1.1; 7.9)
33.4
(11.4; 98.2)
3.0
(1.1; 7.9)
33.4
(11.4; 98.2)
12 to 35 months
N=37
N=36
Seroneutralization rate*
51.4%
(34.4; 68.1)
100%
(90.5; 100.0)
50.0%
(32.9; 67.1)
100.0%
(90.3; 100.0)
Seroconversion rate**
70.3%
(53.0; 84.1)
100%
(90.5;100.0)
69.4%
(51.9; 83.7)
100.0%
(90.3; 100.0)
Seroconversion factor***
5.3
(3.7; 7.8)
94.8
(60.6; 148.5)
5.4
(3.6 ; 8.0)
99.7
(63.5 ; 156.3)
* MN titre ≥1:40
**
>
4-fold increase in MN titre
*** geometric mean increase
10
1
st
Dose
1
st
Dose
Immune response against a version of Celvapan containing A/H5N1 vaccine strains
The immunogenicity of the vaccine containing 7.5 µg non-adjuvanted HA derived from strain
A/Vietnam/1203/2004 has been evaluated in two clinical studies in adults aged 18 – 59 years (N=312)
and in elderly subjects aged 60 years and older (N=272) following a 0, 21 day schedule.
The seroprotection rates, seroconversion rates and seroconversion factors reported in adults and
elderly subjects were comparable with Celvapan (H1N1)v.
Information from non-clinical studies
Protective efficacy against morbidity and mortality was assessed non-clinically in two studies in a
ferret challenge model using a version of Celvapan containing A/H5N1 vaccine strains.
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 controls 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 A/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 data obtained with Celvapan containing a H5N1 vaccine strain demonstrated alterations
in liver enzymes and calcium levels in repeat dose toxicity studies in rats. Such alterations in liver
function have not been seen to date in human clinical studies. Alterations in calcium metabolism have
not been examined in human clinical studies.
Animal reproductive toxicology studies do not indicate harmful effects in regard to female fertility,
embryo-foetal and pre- and post-natal toxicity.
11
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
After first opening, the product should be used immediately. However, chemical and physical in-use
stability has been demonstrated for 3 hours at room temperature.
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 20 multidose vials (type I glass) of 5 ml suspension (10 x 0.5 ml doses) with a stopper
(bromobutyl rubber).
6.6 Special precautions for disposal and other handling
The vaccine should be allowed to reach room temperature before use. Shake before use.
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
Baxter AG
Industriestrasse 67
A-1221 Vienna
Austria
8.
EU/1/08/506/001
9.
04/03/2009
12
Detailed information on this medicinal product is available on the website of the European Medicines
Agency (EMA):
http://www.ema.europa.eu/
.
13
ANNEX II
A.
MANUFACTURERS OF THE BIOLOGICAL ACTIVE
SUBSTANCE AND MANUFACTURING AUTHORISATION
HOLDER RESPONSIBLE FOR BATCH RELEASE
B.
CONDITIONS OF THE MARKETING AUTHORISATION
14
A. MANUFACTURER OF THE BIOLOGICAL ACTIVE SUBSTANCE AND
MANUFACTURING AUTHORISATION HOLDER RESPONSIBLE FOR BATCH
Name and address of the manufacturers of the biological active substance
Baxter BioScience s.r.o.
Jevany Bohumil 138
CZ-281 63 Kostelec nad Cernymi lesy
Czech Republic
Baxter AG
Uferstrasse 15
A-2304 Orth/Donau
Austria
Name and address of the manufacturer responsible for batch release
Baxter AG
Uferstrasse 15
A-2304 Orth/Donau
Austria
B. CONDITIONS OF THE MARKETING AUTHORISATION
•
Medicinal product subject to medical prescription.
•
CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND
EFFECTIVE USE OF THE MEDICINAL PRODUCT
•
The MAH shall agree with Member States to measures facilitating the identification and
traceability of the A/(H1N1)v vaccine administered to each patient, in order to minimise
medication errors and aid patients and health care professionals to report adverse
reactions. This may include the provision by the MAH of stickers with invented name and
batch number with each pack of the vaccine.
•
The MAH shall agree with Member States on mechanisms allowing patients and health
care professionals to have continuous access to updated information regarding Celvapan.
•
The MAH shall agree with Member States on the provision of a targeted communication
to health care professionals which should address the following:
•
The correct way to prepare the vaccine prior to administration.
•
Adverse events to be prioritised for reporting, i.e. fatal and life-threatening adverse
reactions, unexpected severe adverse reactions, adverse events of special interest (AESI).
15
RELEASE
•
The minimal data elements to be transmitted in individual case safety reports in order to
including the invented name, the vaccine manufacturer and the batch number.
•
If a specific notification system has been put in place, how to report adverse reactions.
•
OTHER CONDITIONS
Official batch release
In accordance with Article 114 Directive 2001/83/EC as amended, the official batch release will be
undertaken by a state laboratory or a laboratory designated for that purpose.
Pharmacovigilance system
The MAH must ensure that the system of pharmacovigilance, as described in version 1.20-2-Celvapan
presented in Module 1.8.1. of the marketing authorisation application, is in place and functioning
before the product is placed on the market and for as long as the marketed product remains in use.
PSUR submission
The marketing Authorisation holder will submit periodic safety update reports on a 6-month cycle
unless the CHMP decides otherwise.
Risk Management Plan
The MAH commits to performing the studies and additional pharmacovigilance activities detailed in
the Pharmacovigilance Plan, as agreed in version 002 (dated 2 September 2009) of the Risk
Management Plan (RMP) presented in Module 1.8.2. of the Marketing Authorisation Application and
any subsequent updates of the RMP agreed by the CHMP.
Follow-up Measures (FUMs)
The Marketing Authorisation Holder shall complete the following programme of studies within the
specified time frame, the results of which shall form the basis of the continuous reassessment of the
benefit/risk profile.
Area
Description
Due Date
Clinical FUM 29
FU2 029.2
The MAH commits to provide the results of the
effectiveness studies carried out in accordance with the
study protocols published by ECDC.
Results of studies to be
provided within two
weeks of availability.
Current status: A descriptive study on (H1N1)v
epidemiology in different age- and target groups in
Jersey will be conducted by EpiConcept under their
contract with ECDC.
Pharmacovigilance
FUM 30
The MAH will conduct a prospective cohort safety study
in at least 9,000 patients in different age groups,
including immunocompromised subjects, in accordance
with the protocol submitted with the Risk Management
Plan. Observed-to-Expected analyses will be performed.
Final report to be
submitted: 31 Oct
2011
Pharmacovigilance
FUM 31
The MAH commits to provide the results of a study in a
pregnancy registry.
Results to be provided
in the PSURs
Quality FUM 37
The final stability study reports for the PMVH, MVB
and final container should be submitted as soon as they
become available.
PMVH: 31/10/2012
MVB: 31/12/2012
FCP: 31/05/2011
Clinical FUM 39
The MAH commits to provide the final Reports for the
following Study performed in adults:
Study 820902 ((H1N1)v clinical trial)
Part B (Day 181)
31/07/2010
16
facilitate the evaluation and the identification of the vaccine administered to each subject,
Clinical FUM 40
The MAH commits to provide the final Reports for the
following Study performed in children:
Study 820903 ((H1N1)v clinical trial)
Part A (Day 43) immunogenicity
Part B (Day 181)
31/07/2010
31/01/2011
Pharmacovigilance The MAH commit to submit on a monthly basis a report
including:
- a frequency table of all spontaneous cases per country,
stratified according to type of report (medically
confirmed or non-medically confirmed) and seriousness,
for the period covered by the report and cumulatively
- a frequency table of all spontaneous adverse reactions
by SOC, High Level Term (HLT) and Preferred Term
(PT), stratified according to type of report (medically
confirmed or non-medically confirmed) and including
the number of fatal reports, for the period covered by the
report and cumulatively.
- a line listing of Adverse events of special interest (as
defined in the CHMP Recommendations
[EMEA/359381/2009]) reported from countries of the
European Economic Area.
Data lock point for
first regular PSUR:
30 April 2010 for
submission 30 June
2010
Furthermore, the MAH commits to submit 6-monthly
PSURs for the medicinal product authorised by this
decision until further review by CHMP.
17
ANNEX III
LABELLING AND PACKAGE LEAFLET
18
A. LABELLING
19
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
OUTER CARTON
1.
Celvapan suspension for injection
Influenza vaccine (H1N1)v (whole virion, Vero cell derived, inactivated)
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
Whole virus influenza vaccine, inactivated containing antigen of strain*:
A/California/07/2009 (H1N1)v
7.5 microgram**
* propagated in Vero cells (continuous cell line of mammalian origin)
** expressed in micrograms haemagglutinin
3.
LIST OF EXCIPIENTS
Trometamol,
sodium chloride,
water for injections,
polysorbate 80
4.
Suspension for injection.
20 multidose vials (10 doses per vial – 0.5 ml per dose)
5.
METHOD AND ROUTE(S) OF ADMINISTRATION
Read the package leaflet before use.
Intramuscular use.
The vaccine should be allowed to reach room temperature before use.
Shake before use.
After first opening, the vial is to be used within a maximum of 3 hours.
6.
SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT
Keep out of the reach and sight of children.
7.
OTHER SPECIAL WARNING(S), IF NECESSARY
Do not inject intravascularly.
20
per 0.5 ml dose
OF THE REACH AND SIGHT OF CHILDREN
8.
EXPIRY DATE
EXP
9.
SPECIAL STORAGE CONDITIONS
Store in refrigerator.
Do not freeze.
Store in the original package in order to protect from light.
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
Dispose of in accordance with local requirements.
Baxter AG
Industriestrasse 67
A-1221 Vienna
Austria
EU/1/08/506/001
13. BATCH NUMBER
Lot
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
Justification for not including Braille accepted.
21
MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS
LABEL FOR 10-DOSE VIAL
1.
Celvapan suspension for injection
Influenza vaccine (H1N1)v (whole virion, Vero cell derived, inactivated)
Intramuscular use
2.
METHOD OF ADMINISTRATION
Shake before use
3.
EXPIRY DATE
EXP
4.
BATCH NUMBER
Lot
5.
CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT
Multidose vial (10 doses of 0.5 ml per vial)
6.
OTHER
After first opening, the vial is to be used within a maximum of 3 hours.
BAXTER AG
A-1221 Vienna
Austria
22
B. PACKAGE LEAFLET
23
PACKAGE LEAFLET: INFORMATION FOR THE USER
CELVAPAN suspension for injection
Influenza vaccine (H1N1)v (whole virion, Vero cell derived, inactivated)
Read all of this leaflet carefully before you receive this vaccine.
-
Keep this leaflet. You may need to read it again.
If you have any further questions, ask your doctor or nurse.
-
-
If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet,
please tell your doctor.
In this leaflet
1.
What Celvapan is and what it is used for
2.
Before you receive Celvapan
3.
How Celvapan is given
4.
Possible side effects
5.
How to store Celvapan
6.
Further information
1.
WHAT CELVAPAN IS AND WHAT IT IS USED FOR
Celvapan is a vaccine to prevent influenza (flu) caused by A(H1N1)v 2009 virus
When a person is given the vaccine, the immune system (the body’s natural defense system) will
produce its own protection (antibodies) against the disease. None of the ingredients in the vaccine can
cause flu.
2.
BEFORE YOU RECEIVE CELVAPAN
You should not receive Celvapan
•
if you previously had a sudden life-threatening allergic reaction to any ingredient of Celvapan
or to any of the substances that may be present in trace amounts as follows: formaldehyde,
benzonase, sucrose.
Signs of an allergic reaction may include itchy skin rash, shortness of breath and swelling of the
face or tongue.
If you are not sure, talk to your doctor or nurse before having this vaccine.
Take special care with Celvapan
•
if you have had any allergic reaction other than a sudden life-threatening allergic reaction to any
ingredient contained in the vaccine, to formaldehyde, benzonase, or to sucrose. (see section 6.
Further information).
•
if you have a severe infection with a high temperature (over 38°C). If this applies to you then
your vaccination will usually be postponed until you are feeling better. A minor infection such
as a cold should not be problem, but your doctor or nurse should advise whether you could still
be vaccinated with Celvapan,
•
if you are having a blood test to look for evidence of infection with certain viruses. In the first
few weeks after vaccination with Celvapan the results of these tests may not be correct. Tell the
doctor requesting these tests that you have recently been given Celvapan,
24
In any of these cases, TELL YOUR DOCTOR OR NURSE, as vaccination may not be recommended,
or may need to be delayed.
Please inform your doctor or nurse if you have a bleeding problem or bruise easily.
Allergic reactions (including anaphylaxis) have been reported following vaccination with Celvapan
(see section 4 “Possible Side Effects”).
Taking other medicines
Please tell your doctor or nurse if you are taking or have recently taken any other medicines, including
medicines obtained without a prescription or have recently been given any other vaccine.
There is no information on administration of the vaccine Celvapan with other vaccines. However, if
this cannot be avoided, the vaccines should be injected into separate limbs. In such cases, you should
be aware that the side effects may be more intense.
Pregnancy and breast-feeding
Tell your doctor if you are pregnant, think you may be pregnant, or plan to become pregnant. You
should discuss with your doctor whether you should receive Celvapan.
The vaccine may be used during breast-feeding.
Driving and using machines
Some effects mentioned under section 4. “Possible side effects” may affect your ability to drive or use
machines.
3. HOW CELVAPAN IS GIVEN
Your doctor or nurse will administer the vaccine in accordance with official recommendation.
The vaccine will be injected into a muscle (usually in the upper arm).
Adults and elderly
A dose (0.5 ml) of the vaccine will be given.
A second dose of the vaccine should be given after an interval of at least three weeks.
Children and adolescents aged 6 months to 17 years of age
If it is considered that you or your child needs to be vaccinated, you/he/she may receive one dose of
0.5 ml vaccine and a second dose of 0.5 ml at least three weeks later.
Children aged less than 6 months
Vaccination is not currently recommended in this age group.
When Celvapan is given for the first dose, it is recommended that Celvapan (and not another vaccine
against (H1N1)v) be given for the complete vaccination course.
4.
POSSIBLE SIDE EFFECTS
Like all medicines, Celvapan can cause side effects, although not everybody gets them.
Allergic reactions may occur following vaccination, in rare cases leading to shock. Doctors are aware
of this possibility and have emergency treatment available for use in such cases.
25
In the clinical studies with a similar vaccine, most side effects were mild in nature and short term. The
side-effects are generally similar to those related to the seasonal flu vaccine. There were fewer side
effects after the second vaccination compared with the first. The most frequently occurring side effect
was injection site pain, which was usually mild.
The frequency of possible side effects listed below is defined using the following convention:
very common (affects more than 1 user in 10)
common (affects 1 to 10 users in 100)
uncommon (affects 1 to 10 users in 1,000)
rare (affects 1 to 10 users in 10,000)
very rare (affects less than 1 user in 10,000)
Side effects observed with Celvapan (H5N1)
The side effects listed below have occurred with Celvapan (H5N1) in clinical studies in adults,
including the elderly:
pain at the injection site, headache, fatigue (feeling tired)
Common
:
•
runny nose and sore throat,
•
dizziness, vertigo (motion sickness)
•
sweating more than usual,
•
joint or muscle pain,
•
chills, malaise (generally feeling unwell), fever,
•
tissue hardening, redness, swelling or bruising at the injection site
•
nausea, vomiting, diarrhoea, stomach pain
Uncommon
:
•
numb, tingling or prickly skin,
•
dry throat,
•
swollen glands,
•
insomnia (difficulty sleeping), restlessness,
•
impaired perception of touch, pain, heat and cold, sleepiness,
•
conjunctivitis (an inflammation of the eye),
•
sudden hearing loss,
•
reduced blood pressure,
•
shortness of breath, cough, congestion of the nose,
•
rash, itching,
•
irritation at the injection site
Rare:
•
ear pain, stiff arm
These side effects usually disappear within 1-2 days without treatment. If they persist, CONSULT
YOUR DOCTOR.
•
Clinical Trials with Celvapan (H1N1)v
Safety findings after the first and second dose of vaccine given during an ongoing clinical trial of
Celvapan (H1N1)v in adults and elderly (18 years of age and older) suggest a similar safety profile to
that reported for influenza vaccines containing a H5N1 strain. Safety results from another ongoing
Celvapan (H1N1)v study involving children and adolescents aged 3-17 years were similar to the
findings of the adults and elderly trial. However, in the children’s trial injection site pain was reported
at a higher rate (very common) than in adults, and both headache and fatigue were reported at a lower
26
Very common
:
•
rate (common) than in adults. In children aged 3 to 8 years, fever after both the 1
st
and 2
nd
vaccination
was reported commonly, but no fever was reported in children and adolescents aged 9 to 17 years.
During a clinical trial involving children aged 6 to 35 months, the following reactions were very
common: sleep disturbance, loss of appetite, crying, irritability and sleepiness.
•
Celvapan (H1N1)v side effects observed during the pandemic flu vaccination program
The side effects listed below have occurred with Celvapan (H1N1)v in adults and children during the
pandemic flu vaccination program.
Allergic reactions, including anaphylactic reactions leading to a dangerous decrease in blood pressure
which, if untreated, may lead to shock.
Fits of fever
Pain in arms and or legs (in the majority of cases reported as pain in the vaccination arm)
Flu-like illness
Swelling of tissue just below the skin.
Pandemic observational study
In an ongoing safety study involving 240 children (over 5 years) and adults as well as 53 children aged
6 months to 5 years the following adverse reactions were reported at a very common frequency:
Children above 5 years of age, adolescents and adults:
Injection site reactions, tiredness, headache, muscle pain, stomach upset.
Children aged 6 months to 5 years:
Injection site reactions, drowsiness, irritability, loss of appetite.
•
Side effects observed with flu vaccines given routinely every year
The side effects listed below have occurred in the days or weeks after vaccination with vaccines given
routinely every year to prevent flu. These side effects may occur with Celvapan.
Uncommon:
•
generalized skin reactions including urticaria (hives)
Rare:
•
Allergic reactions leading to a dangerous decrease of blood pressure, which, if untreated, may
lead to shock. Doctors are aware of this possibility and have emergency treatment available for
use in such cases.
•
Severe stabbing or throbbing pain along one or more nerves
Low blood platelet count which can result in bleeding or bruising
Very rare:
•
vasculitis (inflammation of blood vessels which can cause skin rashes, joint pain and kidney
problems)
•
neurological disorders such as encephalomyelitis (inflammation of the central nervous system),
neuritis (inflammation of nerves) and a type of paralysis known as Guillain-Barré Syndrome
If any of these side effects occur, please tell your doctor or nurse immediately.
27
•
If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please
tell your doctor.
5.
HOW TO STORE CELVAPAN
Keep out of the reach and sight of children.
Do not use Celvapan after the expiry date which is stated on the carton. The expiry date refers to the
last day of that month.
Store in a refrigerator (2°C - 8°C).
Store in the original package in order to protect from light.
Do not freeze.
After first opening the vial is to be used within a maximum of 3 hours.
Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to
dispose of medicines no longer required. These measures will help to protect the environment.
6.
FURTHER INFORMATION
What Celvapan contains
Active substance:
Whole virion influenza vaccine, inactivated, containing antigen of strain*:
A/California/07/2009 (H1N1)v
7.5 micrograms**
* propagated in Vero cells (continuous cell line of mammalian origin)
** haemagglutinin
Other ingredients:
The other ingredients are: trometamol, sodium chloride, water for injections, polysorbate 80.
What Celvapan looks like and contents of the pack
Celvapan is a clear to opalescent, translucent liquid.
One pack of Celvapan contains 20 multidose vials of 5 ml suspension for injection for 10 doses.
Marketing Authorization Holder:
Baxter AG
Industriestrasse 67
A-1221 Vienna
Austria
Manufacturer:
Baxter AG
Uferstrasse 15
A-2304 Orth/Donau
Austria
28
per 0.5 ml dose
For any information about this medicine, please contact the local representative of the Marketing
Authorisation Holder given below:
België/Belgique/Belgien
Baxter Belgium SPRL
Bd. de la Plaine/Pleinlaan 5
B-1050 Brussel/Bruxelles/Brüssel
Tél/Tel: + 32 2 650 1711
Luxembourg/Luxemburg
Baxter Belgium SPRL
Bd. de la Plaine/Pleinlaan 5
B-1050 Bruxelles/Brüssel
Tél/Tel: + 32 2 650 1711
България
ТП Бакстер АД
бул. "България" 45
Бизнес Център "България Тауър"
Офис 2, ет. 2
1404 София
тел.: + 359 2 9808482
Magyarország
Baxter Hungary Kft
Népfürdő u. 22.
H-1138 Budapest
Tel.: +361 202 19 80
Česká republika
Baxter Czech spol.s r.o.
Opletalova 55
CZ-110 00 Praha 1
Tel.: +420 225774111
Malta
Baxter Healthcare Ltd
Wallingford Road, Compton Newbury
Berkshire RG20 7QW - UK
Tel.: + 44 1635 206345
Danmark
Baxter A/S
Gydevang 43
DK-3450 Allerød
Tlf: + 45 48 16 64 00
Nederland
Baxter B.V.
Kobaltweg 49
NL-3542 CE Utrecht
Tel: + 31 30 2488911
Deutschland
Baxter Deutschland GmbH
Edisonstraße 4
D-85716 Unterschleißheim
Tel: + 49 89 31701-0
Norge
Baxter AS
Gjerdrumsvei 11
N-0484 Oslo
Tlf: + 47 22 58 4800
Eesti
AS Oriola
Kungla 2
EE-76505 Saue
Tel.: + 372 6 515 100
Österreich
Baxter Healthcare GmbH
Stella-Klein-Löw-Weg 15
A-1020 Wien
Tel.: +43 1 71120 0
Ελλάδα
Baxter (Hellas) Ε.Π.Ε.
Εθνάρχου Μακαρίου 34 & Αθηνοδώρου
Ηλιούπολη
GR-163 41 Αθήνα
Τηλ.: +30-210-99 87 000
Polska
Baxter Polska Sp. z o.o.
ul. Kruczkowskiego 8
PL-00-380 Warszawa
Tel.: + 48 22 4883 777
España
Baxter S.L.
Pouet de Camilo, 2
E- 46394 Ribarroja del Turia (Valencia)
Tel: + 34 96 2722800
Portugal
Baxter Médico Farmacêutica Lda
Sintra Business Park
Zona Industrial da Abrunheira, Edifício 10
P-2710-089 Sintra
Tel: + 351 21 925 25 00
29
France
Baxter SAS
6 Avenue Louis Pasteur
F-78310 Maurepas
Tél: + 33 1 3461 5050
România
FARMACEUTICA REMEDIA S.A.
78 Metalurgiei Blv., 4th district
041836 Bucharest, ROMANIA
Tel.: + 40-21-321 1640
Ireland
Baxter Healthcare Ltd
Unit 7 Deansgrange Industrial Estate
IRL-Blackrock, Dublin
Tel: + 44 1635 206345
Slovenija
Baxter d.o.o.
Železna cesta 18
1000 Ljubljana
Tel.: + 386 1 420 16 80
Ísland
Icepharma hf.
Lynghálsi 13
IS-110 Reykjavík
Sími: + 354 540 80-00
Slovenská republika
Baxter AG, o. z.
Dúbravská cesta 2
SK-841 04 Bratislava
Tel: + 421 2 59418455
Italia
Baxter S.p.A.
Piazzale dell’Industria, 20
I-00144 Roma
Tel: + 39 06 324911
Suomi/Finland
Baxter Oy
PL 270
Valimotie 15 A
FIN-00381 Helsinki
Puh/Tel: + 358 9 8621111
Κύπρος
Baxter (Hellas) Ε.Π.Ε.
Εθνάρχου Μακαρίου 34 & Αθηνοδώρου
Ηλιούπολη
GR-163 41 Αθήνα
Τηλ.: +30-210-99 87 000
Sverige
Baxter Medical AB
Torshamnsgatan 35
Box 63
S-164 94 Kista
Tel: + 46 8 6326400
Latvija
Baxter AG Latvijas filiāle
Dzelzavas iela 117
LV 1021 RĪGA
Tel.: +371 67784784
United Kingdom
Baxter Healthcare Ltd
Wallingford Road, Compton Newbury
Berkshire RG20 7QW - UK
Tel: + 44 1635 206345
Lietuva
UAB TAMRO atstovybė
S. Žukausko g. 29-1
LT-09129 Vilnius
Tel.: + 370 5 269 16 91
30
This leaflet was approved in {MM/YYYY}
Detailed information on this medicine is available on the European Medicines Agency (EMA) web
site:
http://www.ema.europa.eu/
.
---------------------------------------------------------------------------------------------------------------------------
The following information is intended for medical or health care professionals only:
Prior to administration, the vaccine should be allowed to reach room temperature and the vial should
be shaken well.
After first opening, the vial is to be used within a maximum of 3 hours.
Each vaccine dose of 0.5 ml is withdrawn into a syringe for injection.
The vaccine should not be administered intravascularly.
Any unused vaccine or waste material should be disposed of in accordance with local requirements.
31
Source: European Medicines Agency
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