This information is intended for use by health professionals

1. Name of the medicinal product

Epaxal suspension for injection in a prefilled syringe

Hepatitis A vaccine (inactivated, virosome).

2. Qualitative and quantitative composition

1 vaccine dose (0.5 ml) contains at least 24 IU of inactivated hepatitis A virus (strain RG-SB), propagated in human diploid (MRC-5) cells.

The virus particles are adsorbed on virosomes as the adjuvant system, composed of highly purified influenza virus surface antigens (10 micrograms haemagglutinin) of the A/Singapore/6/86 (H1N1) strain and the phospholipids lecithin (80 micrograms) and cephalin (20 micrograms).

For more information on the adjuvant, see section 5.1.

For a full list of excipients, see section 6.1.

3. Pharmaceutical form

Suspension for injection in a prefilled syringe. Clear, colourless liquid.

4. Clinical particulars
4.1 Therapeutic indications

Active immunisation against hepatitis A of children from 1 year of age and adults.

4.2 Posology and method of administration

One dose of 0.5 ml is injected intramuscularly. To ensure optimal immune response, the vaccine should be injected into the deltoid muscle. In patients with coagulation disorders, the vaccine may be administered subcutaneously in the upper arm.

In order to provide long-term protection, a second (booster) dose of 0.5 ml should be administered. This is preferably given between 6-12 months after the first dose but may be given up to 10 years later based on limited experience in healthy adult travellers (see section 5.1).

Epaxal can be used interchangeably with other inactivated hepatitis A vaccines for the first and second (booster) dose.

Simultaneous active and passive immunisation

If immediate protection against hepatitis A is necessary, Epaxal can be administered concomitantly with human gamma globulin at separate injection sites.

Post-exposure vaccination

Post-exposure vaccination should be given according to official recommendations.

4.3 Contraindications

Hypersensitivity to any constituent of the vaccine.

Hypersensitivity to eggs, chicken protein or formaldehyde.

In cases of acute infectious disease with fever, vaccination with Epaxal should be postponed.

4.4 Special warnings and precautions for use

As with all injectable vaccines, suitable treatment and medical supervision must always be promptly available in case there is a rare anaphylactic reaction following administration of the vaccine

Influenza haemagglutinin as contained in Epaxal does not provide an alternative for influenza vaccination.

Immunodeficiency disorders may impair the immune response. In splenectomised patients, the booster vaccination should be administered 1 to 6 months after primary immunisation, owing to the lower titres achieved in these subjects. This also applies to other categories of immunocompromised patients.

Experience of the vaccination of children under 1 year of age and in adults over 60 years of age is limited.

A reduced immune response is possible due to the subcutaneous injection.

Epaxal may contain traces of polymyxin B.

4.5 Interaction with other medicinal products and other forms of interaction

A prospectively planned interaction study was performed with yellow fever vaccine in 55 subjects. In addition, concomitant vaccination against yellow fever, typhoid fever, poliomyelitis, diphtheria, tetanus, meningococci A + C, as well as concomitant malaria prophylaxis was studied as part of a travel prophylaxis program in 38 subjects.

A prospectively planned interaction study was performed with concomitant whole cell influenza vaccine in 163 subjects. Concomitant administration does not impair immune response to hepatitis A or influenza. In addition, the immune response to hepatitis A is independent of the level of influenza pre-immunisation titers.

The results indicated that Epaxal can be administered simultaneously with the above vaccines but in separate syringes, as well as with malaria prophylaxis.

The concomitant administration of hepatitis A-specific immunoglobulins does not impair the seroconversion rate, but can lead to a reduction of hepatitis A antibody titers by approx. 20%.

In the case of concomitant administration with other vaccines, different syringes and separate injection sites should be chosen.

4.6 Pregnancy and lactation

Pregnancy

Controlled studies have not been conducted with animals or pregnant women. As is the case with all inactivated viral vaccines, there is no obvious risk for the fetus. However, vaccinations should only be given during pregnancy if there is a high risk of infection.

Breast-feeding

Whether the vaccine passes into the milk of a lactating mother is unknown. Immunization during breast-feeding does not pose a risk for mothers or for their infants.

4.7 Effects on ability to drive and use machines

No adverse reactions are to be expected. However, some of the effects mentioned under section „Undesirable Effects“ may temporarily affect the ability to drive or use machines.

4.8 Undesirable effects

Possible undesirable effects are mild in nature and of short duration. The frequencies of adverse events provided below are derived from clinical studies. The most common adverse reactions are fatigue, injection site pain and headache, which have been shown in clinical studies to occur at frequencies of 6-32%, 5 – 25% and 6 – 25% respectively.

Very common (≥1/10):

Nervous system disorders:

Headache

General disorders and administration site conditions:

Fatigue, injection site pain.

Common (≥1/100 and <1/10):

Metabolism and nutrition disorders:

Anorexia

Gastrointestinal disorders:

Diarrhoea, nausea

General disorders and administration site conditions:

Injection site reaction, injection site induration, injection site erythema, injection site swelling, malaise, pyrexia

Uncommon (≥1/1000 and <1/100):

Nervous system disorders:

Dizziness

Skin and subcutaneous tissue disorders:

Rash, pruritus

Gastrointestinal disorders:

Vomiting

Musculosceletal and connective tissue disorders:

Arthralgia

The degree of dizziness is not more pronounced as compared to other vaccines in comparative trials.

A transient and mild rise in levels of liver enzymes was observed on single occasions at the time of vaccination.

As observed with other vaccines, occasional inflammatory diseases of the central and peripheral nervous system may occur, including ascending paralysis up to respiratory paralysis, e.g. Guillain-Barré Syndrome.

In very rare cases, anaphylactic shock may occur.

4.9 Overdose

There are no reports of overdosage. Inadvertent administration of a second dose of 0.5 ml Epaxal has no adverse effects.

5. Pharmacological properties
5.1 Pharmacodynamic properties

Pharmaceutical group: Vaccine against hepatitis A

ATC-code J07B C02.

Epaxal contains hepatitis A virus, strain RG-SB, propagated in MRC-5 human diploid cells and inactivated with formaldehyde. The isolated virus particles are bound to a new immunoadjuvant consisting of synthetic, spherical virosomes called IRIVs (IRIV = Immunopotentiating Reconstituted Influenza Virosome). IRIVs consist of a double membrane composed of the phospholipids lecithin (phosphatidylcholine) and cephalin (phosphatidylethanolamine) and of viral phospholipids. The double membrane contains the viral glycoproteins haemagglutinin and neuraminidase which have been isolated from inactivated influenza virus (A/Singapore/6/86 (H1N1)).

Presence of antibodies against the phospholipid of the IRIVs (i.e. antibodies against lecithin and cephalin) could not be detected by specific enzyme-linked immuno-sorbent assays (ELISAs) in sera of subject vaccinated and boosted with Epaxal.

After administration of Epaxal, the complexes of IRIV and hepatitis A virus actively bind to special receptors on macrophages and are then phagocytosed. Simultaneously, complexes of IRIV and hepatitis A virus bind to B lymphocytes, which are stimulated to proliferate. The membranes of the phagocytosed liposomes fuse with the membranes of the macrophage endosomes. Consequently, the hepatitis A virus antigen is presented on the surface of the macrophages. This potentiates the presentation of antigen and the stimulation of T lymphocytes which, in turn, stimulate the production of anti-hepatitis A antibodies by the B lymphocytes.

Immunogenicity and protective efficacy

Vaccination with one dose of 0.5 ml Epaxal results in protective antibody titres (min. 20 mIU/ml) in 80-97% of vaccinated subjects after 2 weeks, in 92-100% after 4 weeks, and in 78-100% after 12 months. More than 1,600 adults and children (>10 years of age), more than 320 children (2-10 years of age), 61 children (1-2 years of age) and 30 children (6 months-1 year of age) have been followed in clinical trials. This includes a double-blind, placebo controlled field trial in 137 children (18 months-6 years of age) in a highly endemic area which showed a 96% protection rate against acute hepatitis A infection, based on IgM and IgG antibody titres, as well as clinical signs.

Duration of protection

The first vaccine dose with 0.5 ml Epaxal results in protective antibody titres (min. 20 mIU/ml) in 78-100% of vaccinated subjects for at least 12 months. A second (booster) vaccination with 0.5 ml Epaxal is estimated to prolong the protective efficacy to at least 30 years for at least 95% of the vaccinated subjects when considering an antibody titre threshold of 10 mIU/ml. This estimate is based on mathematical modelling and extrapolation of 10-12 years follow up data from subjects in the age range 16 to 45 years. An analysis of the sera of 26 adult healthy travellers 24 to 73 years old who received a second (booster ) dose between 98 to 128 months after the first dose demonstrated that a delay up to 10 years between the first and second vaccine dose had no effect on the magnitude of the booster response. However, prescribers/physicians should not routinely adopt a longer gap between primary and second vaccinations (see section 4.2).

5.2 Pharmacokinetic properties

Pharmacokinetic studies are not required for vaccines.

5.3 Preclinical safety data

Preclinical safety data show no signs of toxicity after a single dose or after repeated doses. No tissue intolerance was observed after administration to rabbits.

6. Pharmaceutical particulars
6.1 List of excipients

Sodium chloride

Water for injections

For information on the adjuvant, see section 2.

6.2 Incompatibilities

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.

6.3 Shelf life

3 years.

6.4 Special precautions for storage

Store in a refrigerator (2°C – 8°C). Store in the original package in order to protect from light. Do not freeze.

6.5 Nature and contents of container

Single-dose syringe

0.5 ml suspension in a pre-filled syringe (Type I glass) with rubber plunger stopper (chlorobutyl) and with needle of stainless steel type 304.

Package sizes:

1 x 0.5 ml

10 x 0.5 ml

Not all pack sizes may be marketed.

6.6 Special precautions for disposal and other handling

Shake before use. The syringe should be checked visually for integrity and any particulate matter in the syringe content. The vaccine should be clear and colourless. Any unused product or waste material should be disposed of in accordance with local requirements.

7. Marketing authorisation holder

Crucell Italy S.r.l.

Via Zambeletti 25

IT - 20021 Baranzate (MI)

Italy

8. Marketing authorisation number(s)

PL 15747/0003

9. Date of first authorisation/renewal of the authorisation

1999-12-14 / 2007-04-25

10. Date of revision of the text

2015-10-16