ViATIM, Suspension and solution for injection in a pre-filled dual chamber syringe.

Hepatitis A (inactivated, adsorbed) and Typhoid polysaccharide vaccine

The dual chamber syringe contains 0.5 millilitre of purified Vi polysaccharide typhoid vaccine and 0.5 millilitre of inactivated hepatitis A vaccine which are mixed prior to administration.

After reconstitution, 1 dose (1ml) contains:

Originally contained in the suspension:

Hepatitis A virus, GBM strain (inactivated)^1,2………….160 U³

¹ produced in human diploid (MRC-5) cells

² adsorbed on aluminium hydroxide, hydrated (0.3 milligrams Al)

³ In the absence of an international standardised reference, the antigen content is expressed using an in-house reference

Originally contained in the solution:

Salmonella typhi (Ty 2 strain) capsular Vi polysaccharide………25 micrograms

Excipient(s):

For a full list of excipients, see section 6.1.

Suspension and solution for suspension for injection in a pre-filled dual chamber syringe.

The vaccine is presented in a dual-chamber syringe.

The purified Vi polysaccharide typhoid vaccine (solution for injection) is contained in the chamber of the syringe closest to the needle, and the inactivated hepatitis A vaccine (suspension for injection) in the chamber closest to the plunger.

The component Hepatitis A (inactivated, adsorbed) is a cloudy and white suspension and the component Typhoid polysaccharide is a clear and colourless solution.

ViATIM is indicated for simultaneous active immunisation against typhoid fever and hepatitis A virus infection in subjects from 16 years of age.

ViATIM should be given in accordance with official recommendations.

Posology

The recommended dosage for subjects of at least 16 years of age is 1 millilitre of the mixed vaccine.

Initial protection is achieved with one single dose of ViATIM. Protective levels of antibody may not be reached until 14 days after administration of the vaccine.

In order to provide long-term protection against infection caused by the hepatitis A virus, a second dose (booster) of an inactivated hepatitis A vaccine should be given. ViATIM may be be used to provide one or both doses of hepatitis A vaccine as follows:

• In subjects who have received one dose of ViATIM:

- either a dose of monovalent hepatitis A vaccine should be given within 36 months and preferably within 6 to 12 months (see section 5.1)

- or, if continued protection against typhoid is also required, a second dose of ViATIM may be given provided that approximately 36 months have elapsed since the first dose.

• In subjects who have received one dose of monovalent hepatitis A vaccine:

- ViATIM may be used to provide the second dose (booster) of hepatitis A vaccine if protection against typhoid fever is also desirable. It should be given within 36 months of the hepatitis A vaccine and preferably within 6 to 12 months.

It is predicted that HAV antibodies persist for many years (beyond 10 years) after the second dose (booster).

In subjects who remain at risk of typhoid fever, revaccination against typhoid fever should be carried out with a single dose of a purified Vi polysaccharide typhoid vaccine every 3 years, (see section 5.1).

Method of administration

ViATIM should be administered by slow intramuscular injection in the deltoid region.

ViATIM must not be administered intravascularly.

ViATIM should not be administered into the buttocks due to the varying amount of fatty tissue in this region, nor by the intradermal route, since these methods of administration may induce a weaker immune response. ViATIM may be administered by the subcutaneous route in patients with thrombocytopenia or in those at risk of haemorrhage.

See section 6.6 for instructions for preparation.

Hypersensitivity to the active substance(s) or to any of the excipients or to neomycin (present in trace amounts as a residual of the manufacturing process).

Vaccination should be delayed in subjects with an acute severe febrile illness.

As with all vaccines, appropriate facilities and medication such as epinephrine (adrenaline) should be readily available for immediate use in case of anaphylaxis or hypersensitivity following injection.

Immunogenicity of ViATIM could be impaired by immunosuppressive treatment or in immunodeficient subjects. It is recommended to delay vaccination until the completion of any immunosuppressive treatment. Subjects with chronic immunodeficiency such as HIV infection may be vaccinated if the underlying immunodeficiency allows the induction of an antibody response, even if limited.

Because of the incubation period of hepatitis A disease, infection may be present but not clinically apparent at the time of vaccination. It is not known whether ViATIM will prevent hepatitis A in this case.

ViATIM does not protect against infection caused by other known liver pathogens including hepatitis B, hepatitis C and hepatitis E viruses.

ViATIM does not protect against infection by Salmonella enterica other than serotype typhi.

As with any vaccine, a protective immune response may not be elicited in all vaccinees.

ViATIM must not be mixed with any other vaccine in the same syringe.

ViATIM is a combination of purified Vi polysaccharide typhoid vaccine and inactivated hepatitis A vaccine. Although concomitant administration with other inactivated vaccines using different syringes and at different injection sites has not been specifically studied, it is anticipated that no interaction will be observed.

Concomitant administration of yellow fever vaccine with ViATIM has not been specifically assessed. However, based on data obtained from the concomitant administration of the monovalent vaccines (purified Vi polysaccharide typhoid vaccine and inactivated hepatitis A vaccine) with yellow fever vaccine, no interference with the immune responses to any of these antigens would be expected.

The effect of concomitant administration of immunoglobulins on the immunogenicity of ViATIM has not been assessed. Therefore, interference with the immune response of ViATIM cannot be ruled out. Data obtained from concomitant administration of immunoglobulins with the monovalent inactivated hepatitis A vaccine showed that anti-HAV seroconversion rates were not modified whereas anti-HAV antibody titres could be lower than after vaccination with the monovalent vaccine alone.

Pregnancy

Data on a limited number (more than 150 cases with monovalent Vi polysaccharide typhoid vaccine, more than 40 cases with monovalent inactivated hepatitis A vaccine and more than 10 cases with ViATIM or the two components given simulatenously) of exposed pregnancies indicate no adverse effects of ViATIM on pregnancy or on the health of the foetus/new born child. To date no other relevant epidemiological data are available. Animal studies do not indicate direct or indirect harmful effects with respect to pregnancy, embryonal/foetal development, parturition or post-natal development (see section 5.3).

Caution should be exercised when prescribing to pregnant women.

When the patient is considered to be at risk of only one of hepatitis A or typhoid fever, the monovalent vaccine should be used.

Lactation

It is unknown whether ViATIM is excreted in human breast milk. The excretion of ViATIM in milk has not been studied in animals. A decision on whether to continue/discontinue breast-feeding or to administer or not administer ViATIM should be made taking into account the benefit of breast-feeding to the child and the benefit of ViATIM to the woman.

No studies on the effects on the ability to drive and use machines have been performed. Dizziness has been observed as an uncommon reaction (>1/1000, <1/100) following administration of this vaccine (see section 4.8).

Adverse event data are derived from clinical trials and worldwide post marketing experience.

Within each system organ class the adverse events are ranked under headings of frequency, most frequent reactions first, using the following convention:

Very common (>1/10), Common (>1/100, <1/10), Uncommon (>1/1000, <1/100), Rare (>1/10000, <1/1000), Very rare (<1/10000), including isolated reports.

Within each frequency grouping, adverse reactions are ranked in order of decreasing seriousness.

Clinical Studies

The safety profile of ViATIM was evaluated in nearly 1100 subjects included in 5 clinical studies. The most commonly reported reactions were those occurring at the injection site.

The adverse reactions observed with ViATIM were as follows:

Nervous system disorders

Very common: headache.

Uncommon: dizziness.

Gastrointestinal disorders

Common: nausea, diarrhoea.

Skin and subcutaneous tissue disorders

Uncommon: pruritus, rash.

Musculoskeletal and connective tissue disorders

Very common: myalgia.

Common: arthralgia.

General disorders and administration site conditions

Very common: malaise, asthenia, injection site disorders (pain, induration, oedema, erythema).

Common: fever.

Pain at the ViATIM injection site was reported in 89.9% of subjects (severe in 4.5%). For subjects who received the two monovalent vaccines concomitantly at separate injection sites, pain was reported in 83.2% of subjects (severe in 5.0%) for both vaccine sites combined. Pain was reported by 79.3% of subjects (severe in 5.0%) at the Vi vaccine site and by 50.3% of subjects (severe in 0.6%) at the hepatitis A vaccine site.

Pain at the injection site lasting more than 3 days was reported by 17.4% of subjects after ViATIM, by 2.8% of subjects for the monovalent Vi vaccine site and by 0.6% of subjects for the monovalent hepatitis A vaccine site.

Severe oedema/induration (> 5 cm) was reported in 7.9% of subjects at the ViATIM site. For subjects who received the two monovalent vaccines concomitantly at separate injection sites, severe oedema/induration was reported in 1.7% of subjects for both vaccine sites combined (in 1.1% of subjects at the Vi vaccine site and in 0.6% of subjects at the hepatitis A vaccine site).

The overall incidence of systemic reactions was similar between subjects who were vaccinated with ViATIM and subjects who received the two monovalent vaccines concomitantly at separate injection sites.

All reactions resolved without any sequelae.

Post marketing experience

Based on spontaneous reporting, the following additional adverse events have been reported during the commercial use of each monovalent vaccine.

Adverse reactions reported following the use of the monovalent purified Vi polysaccharide vaccine (and not listed above for ViATIM) include:

Immune system disorders

Very rare: anaphylactic/anaphylactoid reactions, including shock; serum sickness.

Nervous system disorders

Very rare: paraesthesia.

Respiratory, thoracic and mediastinal disorders

Very rare: aggravation of asthma.

Gastrointestinal disorders

Rare: vomiting, abdominal pain.

Skin and subcutaneous tissue disorders

Very rare: urticaria.

Adverse reactions reported following use of the monovalent inactivated hepatitis A vaccine (and not listed above for ViATIM) include:

Skin and subcutaneous tissue disorders

Very rare: urticaria.

General disorders and administration site conditions

Very rare: injection site nodule.

Investigations

Rare: transaminases increased (mild and reversible).

No case of overdose has been reported.

Pharmacotherapeutic group: Bacterial and viral vaccines combined, ATC code: J07C (combined) / P03 (Typhoid purified polysaccharide antigen) / C02 (Hepatitis A, inactivated, whole virus).

Four clinical studies provided useful data on immune responses to ViATIM. A total of 1090 subjects were included, with 179, 610, 243 and 58 subjects vaccinated in each study.

After the primary vaccination the seroprotection rate for HAV (% 20mIU/mL) ranged between 95.6% and 99.4% after 14 days and between 98.7% and 100% after 28 days.

The seroprotection rate for Vi (% 1µg/mL) ranged between 83% and 89% after 14 days and between 69.8% and 91% after 28 days.

In one study that evaluated anti-Vi antigen seroprotection rates at years 1, 2 and 3 after the first dose of ViATIM and after re-vaccination with ViATIM at year 3, results were as follows:

Serological data show continuing protection against hepatitis A for up to 36 months in subjects who responded to the first dose of ViATIM. Anti-HAV antigen seroprotection rates at years 1, 2 and 3 after the first dose of ViATIM and after re-vaccination with ViATIM at year 3 were as follows:

Similar results were seen at all timepoints in the control group who received concomitant monovalent purified Vi polysaccharide and inactivated hepatitis A vaccines.

Not applicable.

Non-clinical data obtained with this vaccine, or with the monovalent vaccines contained within this combined vaccine, reveal no special hazard for humans based on single, repeated dose and local tolerance toxicity studies.

Purified Vi polysaccharide typhoid vaccine component:

Phosphate buffer solution:

Sodium chloride

Disodium phosphate dihydrate

Sodium dihydrogen phosphate dihydrate

Water for Injections

Inactivated hepatitis A vaccine component:

2-Phenoxyethanol solution

Formaldehyde

Medium 199 Hanks (without phenol red)* supplemented with polysorbate 80

*Medium 199 Hanks (without phenol red) is a complex mixture of amino acids (including phenylalanine), mineral salts, vitamins and other components (including glucose), diluted in water for injections and pH adjusted with hydrochloric acid or sodium hydroxide

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

3 years

Store in a refrigerator (2°C - 8°C). Do not freeze. If frozen, the vaccine should be discarded.

Keep the vaccine in the outer carton in order to protect from light.

A prefilled syringe (type I glass) with a dual-chamber (0.5 millilitre of vaccine in each chamber) with elastomer (chlorobutyl and bromobutyl rubber blend) plunger-stopper, elastomer tip cap and elastomer by-pass stopper.

Pack of 1 or 10 prefilled syringes supplied with or without needle.

Not all pack sizes may be marketed.

The two vaccine components should only be mixed immediately prior to injection.

Shake before mixing and again prior to injection to obtain a homogeneous suspension. The contents of the two compartments are mixed by slowly advancing the plunger. The final volume to be injected is 1 millilitre.

The vaccine should be visually inspected before administration for any foreign particulate matter. The mixed vaccine is a cloudy, whitish suspension.

Any unused product or waste material should be disposed of in accordance with local requirements.

Sanofi Pasteur MSD Ltd

Mallards Reach

Bridge Avenue

Maidenhead

Berkshire SL6 1QP

PL 06745/0114

02/09/06

09/2010