Vepacel - summary of medicine characteristics

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

3. PHARMACEUTICAL FORM

4.1 Therapeutic indications

ogy and method of administrationogy and method of administration

Method of administration

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

See section 6.6 for administration instructions.

4.3 Contraindications

4.3 Contraindi­cations

History of anaphylactic reactions to the active substance, or to any of the excipients listed in section 6.1, or trace residues (formaldehyde, benzonase, sucrose, trypsin, Vero host cell protein).

If vaccination is considered necessary, facilities for resuscitation should be immediately available in case of need (see section 4.4).

4.4 Special warnings and precautions for use

This vaccine may contain traces of formaldehyde, benzonase, sucrose, trypsin and protein, which are used during the manufacturing process. Therefore, hypersensit occur.

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.

Hypersensitivity reactions, including anaphylaxis, have been report whole virion, Vero cell derived H1N1 influenza vaccine adm Such reactions have occurred both in patients with a history with no known allergy.

Immunisation shall be postponed in patients with severe febrile illness or acute infection.

VEPACEL must not be administered intravascularly.

cutaneous route. Therefore, healthcare providers risks of administering the vaccine in individuals with r that would contraindicate intramuscular injection e risk of bleeding.

ith endogenous or iatrogenic immunosuppression may be insufficient.

A protective immune response may not be induced in all individuals receiving the vaccine (see section 5.1).

with other medicinal products and other forms of interactionwith other medicinal products and other forms of interaction

ata on co-administration of VEPACEL with other vaccines. However, if co-administration r vaccine is indicated, immunisation should be carried out on separate limbs. It should be that the adverse reactions may be intensified.

Immunoglobulin is not to be given with VEPACEL unless it is necessary during a medical emergency to provide immediate protection. If necessary, VEPACEL may be given at the same time as normal or specific immunoglobulin into separate limbs.

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

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, pregnancy and lactation

The safety of VEPACEL in pregnancy and lactation has not been assessed in clinical trials.

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

Healthcare providers should carefully consider the potential risks and benefits for each specific pa before prescribing VEPACEL.

The use of VEPACEL during pregnancy and lactation may be considered in a pre-pande taking into account official recommendations.

4.7 Effects on ability to drive and use machines

VEPACEL has minor influence on the ability to drive and use machines.

4.8 Undesirable effects

4.8 Undesirable effects

• a)    Summary of safety profile

Adults, older people, and special risk groups

Clinical trials were conducted with the H5N1 vaccine (see section 5.1 for more information on the H5N1 vaccines) in approximately 3700 subjects (ranging in age groups from 18 to 59 years and 60 years and above) and special risk groups of approximately 300 subjects each, consisting of immunocompromised subjects and patients with chronic disease conditions. The adverse reactions observed are shown in the table below.

subjects and patients with chronic disease conditions is s and older people.

ed 3 to 17 years:

escents aged 9 to 17 years and 153 children aged 3 to 8 years were

1 vaccine. The incidence and nature of symptoms after the first and second

imilar to those observed in the healthy adults and older people.

Infants and children aged 6 to 35 months:

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

The observed adverse reactions from a paediatric clinical trial with the H5N1 vaccine are listed below. b) Tabulated list of adverse reactions

Adverse reactions are listed according to the following frequency:

Very Common (>1/10)

Common (>1/100 – <1/10)

Uncommon (>1/1,000 – <1/100)

Rare (>1/10,000 – <1/1,000)

Very Rare (<1/10,000)

Adverse Reactions (adults and older people)
System Organ Class (SOC)	Preferred MedDRA Term	Frequency
INFECTIONS AND INFESTATIONS	Nasopharyngitis	Common
BLOOD AND LYMPHATIC SYSTEM DISORDERS	Lymphadenopathy	Uncommon i/"|
PSYCHIATRIC DISORDERS	Insomnia	Uncommo^^*^
NERVOUS SYSTEM DISORDERS	Headache Dizziness Somnolence                             Sensory disturbance (paresthesia, dysesthesio’y oral dysesthesia, hypoesthesia, dysgeusia,’/^ and burning sensation) Syncope	^eryc^mmon uncommon ^common JCommon Uncommon
EYE DISORDERS	Conjunctivitis Eye irritation	Uncommon Uncommon
EAR AND LABYRINTH DISORDERS	XT. '                          J Vertigo Ear pain               j Sudden hearing loss	Common Uncommon Uncommon
VASCULAR DISORDERS	Hypotension	Uncommon
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS	OropharvngeaZpanZ Cough k. Dyspnea»^^ Nasalcongestion Rhinorrhea Drythroat	Common Common Uncommon Uncommon Uncommon Uncommon
GASTROINTESTINAL      Z DISORDERS          {V \V	^Diarrhea omiting Nausea Abdominal pain Dyspepsia	Common Uncommon Uncommon Uncommon Uncommon
SKINAND SUBCUTANEOUSTSSUE DISORDERS	Hyperhidrosis Pruritis Rash Urticaria	Common Common Uncommon Uncommon
MUSCULOSKELETAL and.coNnEctive TISSUEDISORDERS	Arthralgia Myalgia	Common Common

Adverse Reactions (adults and older people)
System Organ Class (SOC)	Preferred MedDRA Term	Frequency
GENERAL DISORDERS	F atigue	Very Common
AND ADMINISTRATION	Pyrexia	Common
SITE CONDITIONS	Chills Malaise Influenza-like illness Chest discomfort Injection Site Reactions • Injection site pain • Injection site induration • Injection site eyrthema • Injection site swelling • Injection site hemorrhage • Injection site irritation • Injection site pruritus • Injection site movement impairment	Common Common Uncommon Uncommon Very Common Common Common Common Common Uncommon UncommonT^^ Uncommon^

Adverse Reactions (infants, children and adolescents)

System Organ Class (SOC)	Preferred MedDRA Term	Frequency^
		6 – 35 months		9 – 17 years
INFECTIONS AND INFESTATIONS	Nasopharyngitis	Common	£o^mon	Common
METABOLISM AND NUTRITION DISORDERS	Decreased appetite	Common. w Ok	uncommon	Uncommon
PSYCHIATRIC	Insomnia	– <X"y	–	Uncommon
DISORDERS	Sleep disorder	Common	–	–
NERVOUS SYSTEM	Dizziness		–	Uncommon
DISORDERS	Headache Crying         âÇ	^Common	Common	Very Common
			–	–
	Somnolence	Very Common	–	–
	Hypoaesthesia      ▼	–	–	Uncommon
EYE DISORDERs	Eye irntatior^	–	Uncommon	–
EAR AND LABYRINTH DISORDERS	Vertigo^^^^^	–	–	Uncommon
RESPIRATORY,	Coughs	–	Uncommon	Uncommon
THORACIC AND	Oropharyngeal pain	–	Common	Common
MEDIASTINAL DISORDERS         <	ARhrnorrhoea	–	Uncommon	Uncommon
GASTROINTESTINAL^	Abdominal pain	–	–	Common
DISORDERS	Nausea	Common	Common	Common
	Vomiting	Common	Common	Common
	Diarrhoea	Common	Uncommon	Uncommon
SKIN AND Cj*	Hyperhidrosis	Common	Uncommon	Common
SUBCUTANEOUS TISSUE DISORDERS	Pruritus	–	–	Uncommon
MUSCULOSKELETAL	Arthralgia	–	Common	Common
^NDCONNECTIVE	Myalgia	–	Common	Common
XSSUE DISORDERS	Pain in extremity	–	–	Uncommon

There are no post-marketing surveillance data available for VEPACE

Celvapan (H1N1)v

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

Immune system disorders: anaphylactic reaction, hyp

Nervous system disorders: febrile convulsion

Skin and subcutaneous tissue disorders: angioedema

Muscoluskeletal and connective tissue disorders: pain in extremity

Trivalent seasonal influenza vaccin

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

Uncommon: generalised skin reactions

Rare: neuralgia, 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.

suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important.

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

4.9 Overdose

4.9 Overdose

No case of overdose has been reported for VEPACEL.

5. PHARMACOLOGICAL PROPERTIES5.1 Pharmacodynamic properties

5. PHARMACOLOGICAL PROPERTIES5.1 Phar­macodynamic properties

Pharmacotherapeutic group: Influenza vaccines, ATC Code J07BB01

This section describes the clinical experience with the H5N1 vaccine.

Pandemic and Pre-pandemic 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 H5N1 vaccines will support a vaccination strategy that is likely to be used for the pandemic vaccine: clinical immunogenicity, safety and reactogenicity data obtained with H5N1 vaccines are relevant for the pandemic and pre-pandemic vaccines.

Adults, older people, and special risk groups

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

The immunogenicity of the A/Vietnam/1203/2004 strain vaccine has been evaluated in three clinical studies in adults aged 18 – 59 years (N=961) and in two clinical studies in subjects^ged 60 years and older (N=391) following a 0, 21 day schedule. In addition, the immunogenicity has also been evaluated in a Phase 3 study in specified risk groups of immunocompromised subjects (N=122) and patients with chronic disease conditions (N=123) following a 0, 21 day schedule.

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

After primary vaccination the rate of subjects with neutralising antibody titres > 20, seroconversion rate and seroconversion factor as measured by microneutralisation assay (MN) in adults aged 18 to 59 years and in older people aged 60 years and above were as follows:

***

'munocompromised subjects (N=122) and patients with chronic disease tion the rate of subjects with neutralising antibody titres > 20, seroconversion rate and sion factor as measured by MN assay in immunocompromised subjects and patients with ic disease conditions were as follows:

	Immunocompromised subjects Patients with chronic disease conditions 21 Days after                       ­21 Days after 1st Dose        2nd Dose            1st Dose             2­nd Dose
Seroneutralisation rate* Seroconversion rate Seroconversion factor	24.8%       41.5%          44.3%           64.2% 9.1%        32.2%          17.2%           35.0% 1.6              2.5                  2­.3          3.0

* MN titre > 20

> 4-fold increase in MN titre

Cross-reactive immune response against related H5N1 strains

In a clinical study in adults aged 18 to 59 years (N=265) and in older people aged 60 years and above (N=270) after vaccination with the A/Vietnam/1203/2004 strain vaccine, the rate of subjects with cross-neutralising antibodies as measured by MN (titre > 20) was as follows:

	18 – 59 years Strain A/Ind 21 Days after 2nd Dose	60 years and above onesia/05/2005 21 Days after 2nd Dose
Seroneutralisation rate*	35.1%	54.8%

* MN titre > 20

Heterologous booster vaccinations

A heterologous booster vaccination with a 7.5 ^g non-adjuvanted formulation of the A/Indonesia/05/2005 strain vaccine has been administered in a time frame of 12 to 24 months after priming vaccination with two doses of the A/Vietnam/1203/2004 strain vaccine in t    clinical

studies in adults aged 18 to 59 years and in older people aged 60 years and abo heterologous booster has also been administered in a phase 3 study in immuno and patients with chronic disease conditions.

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

Seroneutralisation rate* /^Jested against	A/Vietnam	A/Indonesia
^^^^2 Month Booster	85.9%	92.9%

MN titre > 20

Infants, children, and adolescents

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

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

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

MN assay	9 – 17 years 21 Days after		3 – 8 years 21 Days after		6 – 35 months 21 Days after 1st Dose    2nd Dose
	1st Dose	2nd Dose	1st Dose	2nd Dose
Seroneutralization rate*	52.6%	85.4%	17.1%	72.9%	3.0%      68.8%
Seroconversion rate	9.1%	31.8%	16.4%	72.2%	9.1%      65.6%
Seroconversion	1.6	3.1	2.1	6.3	1.4          6.8
factor* **

MN titer > 20

> 4-fold increase in MN titer geometric mean increase

Heterologous Booster Vaccinations

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

5.2 Pharmacokinetic properties

Not applicable.

5.3 Preclinical safety data

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

Animal reproductive and developmental toxicology studies do not indicate harmful effects in regard to female fertility, embryo-foetal and pre- and post-natal toxicity.

6. PHARMACEUTICAL PARTICULARS6.1 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

2 years

After first opening, the vaccine 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

6.4 Special precautions for storage

Store in a refrigerator (2°C to 8°C).

Do not freeze.

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

6.5 Nature and contents of the cont iner

6.5 Nature and contents of the cont iner

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

(bromobutyl rubber).         rv'

6.6 Special precautions for disposal and other handling

ension prior to administration. In case of any particles and/or abnormal

The vaccine contains 10 doses of 0.5 ml.

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

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

7. MARKETING AUTHORISATION HOLDER

Ology Bioservices Ireland LTD

Wilton Park House

Wilton Place

Dublin 2

D02P447

Ireland

8. MARKETING AUTHORISATION NUMBER

EU/1/12/752/001

9. DATE OF FIRST AUTHORISATION / RENEWAL OF THE AUTHORISATION

9. DATE OF FIRST AUTHORISATION / RENEWAL OF THE AUTHORISATION

Date of first authorisation: 17/02/2012

Date of latest renewal: 04/01/2017

10. DATE OF REVISION OF THE TEXT

This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions. See section 4.8 for how to report adverse reactions.