Annex I Summary of Product Characteristics

ANNEX I SUMMARY OF PRODUCT CHARACTERISTICS

1 GLASS SYRINGE

1. NAME OF THE MEDICINAL PRODUCT

TWINRIX Adult

Combined inactivated hepatitis A (720 ELISA units) and rDNA hepatitis B (20µg) vaccine.

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

TWINRIX Adult is a combined vaccine formulated by pooling bulk preparations of the purified, inactivated hepatitis A (HA) virus and purified hepatitis B surface antigen (HBsAg), separately adsorbed onto aluminium hydroxide and aluminium phosphate. The HA virus is propagated in MRC5 human diploid cells. HBsAg is produced by culture, in a selective medium, of genetically engineered yeast cells.

A 1.0 ml dose of vaccine contains not less than 720 ELISA Units of inactivated HA virus and 20 µg of recombinant HBsAg protein.

3. PHARMACEUTICAL FORM

Suspension for injection.

4. CLINICAL PARTICULARS

4.1 Therapeutic indications

TWINRIX Adult is indicated for use in non immune adults and adolescents 16 years of age and above who are at risk of both hepatitis A and hepatitis B infection.

4.2 Posology and method of administration

Posology

- Dosage

A dose of 1.0 ml is recommended for adults and adolescents 16 years of age and above.

- Primary vaccination schedule

The standard primary course of vaccination with TWINRIX Adult consists of three doses, the first administered at the elected date, the second one month later and the third six months after the first dose. The recommended schedule should be adhered to. Once initiated, the primary course of vaccination should be completed with the same vaccine.

- Booster dose

It is not yet fully established whether immunocompetent individuals who have responded to hepatitis A and/or B vaccination(s) will require booster doses as protection in the absence of detectable antibodies may be ensured by immunological memory.

Long-term antibody persistence data following vaccination with TWINRIX Adult are not currently available. However, the anti-HBs and anti-HAV antibody titres observed following a primary vaccination course with the combined vaccine are in the range of what is seen following vaccination 2 with the monovalent vaccines. General guidelines for booster vaccination can therefore be drawn from experience with the monovalent vaccines. These guidelines are based on the assumption that a minimal antibody level is required for protection; protective levels (10 IU/l) of anti-HBs will persist in the majority of subjects for 5 years, with anti-HAV predicted to persist for at least 10 years.

Booster vaccination with the combined vaccine can be recommended 5 years after initiation of the primary course. If the monovalent vaccines are used to booster, they can be administered 5 years after initiation of the primary course for hepatitis B and 10 years after initiation of the primary course for hepatitis A.

Antibody levels of subjects at risk can be assessed at regular intervals and appropriate boosters administered when titres fall below minimal levels.

Method of administration

TWINRIX Adult is for intramuscular injection, preferably in the deltoid region.

Exceptionally the vaccine may be administered subcutaneously in patients with thrombocytopenia or bleeding disorders. However, this route of administration may result in suboptimal immune response to the vaccine.

4.3 Contra-indications

TWINRIX Adult should not be administered to subjects with known hypersensitivity to any constituent of the vaccine, or to subjects having shown signs of hypersensitivity after previous administration of TWINRIX Adult or the monovalent hepatitis A or hepatitis B vaccine.

As with other vaccines, the administration of TWINRIX Adult should be postponed in subjects suffering from acute severe febrile illness.

4.4 Special warnings and special precautions for use

It is possible that subjects may be in the incubation period of a hepatitis A or hepatitis B infection at the time of vaccination. It is not known whether TWINRIX Adult will prevent hepatitis A and hepatitis B in such cases.

The vaccine will not prevent infection caused by other agents such as hepatitis C and hepatitis E and other pathogens known to infect the liver. TWINRIX Adult is not recommended for postexposure prophylaxis (e.g. needle stick injury).

The vaccine has not been tested in patients with impaired immunity. In haemodialysis patients and persons with an impaired immune system, adequate anti-HAV and anti-HBs antibody titers may not be obtained after the primary immunisation course and such patients may therefore require administration of additional doses of 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.

Since intradermal injection or intramuscular administration into the gluteal muscle could lead to a suboptimal response to the vaccine, these routes should be avoided. However, exceptionally TWINRIX Adult can be administered subcutaneously to subjects with thrombocytopenia or bleeding disorders since bleeding may occur following an intramuscular administration to these subjects.

TWINRIX ADULT SHOULD UNDER NO CIRCUMSTANCES BE ADMINISTERED INTRAVASCULARLY.

4.5 Interactions with other medicinal products and other forms of interaction

3 No data on concomitant administration of TWINRIX Adult with specific hepatitis A immunoglobulin or hepatitis B immunoglobulin have been generated. However, when the monovalent hepatitis A and hepatitis B vaccines were administered concomitantly with specific immunoglobulins, no influence on seroconversion was observed although it may result in lower antibody titres. Although the concomitant administration of TWINRIX Adult and other vaccines has not specifically been studied, it is anticipated that, if different syringes and other injection sites are used, no interaction will be observed.

It may be expected that in patients receiving immunosuppressive treatment or patients with immunodeficiency, an adequate response may not be achieved.

4.6 Use during pregnancy and lactation

Pregnancy

The effect of TWINRIX Adult on foetal development has not been assessed. However, as with all inactivated vaccines, one does not expect harm to the foetus. TWINRIX Adult should be used during pregnancy only when there is a clear risk of hepatitis A and hepatitis B.

Lactation

The effect on breastfed infants of the administration of TWINRIX Adult to their mothers has not been evaluated in clinical studies. TWINRIX Adult should therefore be used with caution in breastfeeding women.

4.7 Effects on the ability to drive and use machines

The vaccine is unlikely to produce an effect on the ability to drive and use machines.

4.8 Undesirable effects

In controlled clinical studies, signs and symptoms were actively monitored in all subjects for four days following the administration of the vaccine. A checklist was used for this purpose. The vaccinees were also requested to report any clinical events occurring during the study period. The most common reactions were those at the site of injection. They included transient pain, redness and swelling. Systemic adverse events seen were fever, headache, malaise, fatigue, nausea and vomiting. These events were transient, only rarely reported and were considered by the subjects as mild.

In a comparative study it was noted that the frequency of solicited adverse events following the administration of TWINRIX Adult is not different from the frequency of solicited adverse events following the administration of the monovalent vaccines.

Following widespread use of the monovalent hepatitis A and/or hepatitis B vaccines, the following undesirable events have been reported in temporal association in the days or weeks after vaccination. In many instances, a causal relationship has not been established.

Flu-like symptoms (such as fever, chills, headache, myalgia, arthralgia), fatigue, dizziness.

Rarely reported : paresthesia, nausea, vomiting, decreased appetite, diarrhoea, abdominal pain, abnormal liver function tests, rash, pruritis, urticaria.

Very rarely reported : allergic reactions mimicking serum sickness, vasculitis, syncope, hypotension, lymphadenopathy, cases of peripheral and/or central neurological disorders, and may include multiple sclerosis, optic neuritis, myelitis, Bell’s palsy, polyneuritis such as Guillain-Barré syndrome (with ascending paralysis), meningitis, encephalitis, encephalopathy, thrombocytopenic purpura, erythema exsudativum multiforme.

4.9 Overdose

No information available.

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmaco-therapeutic group: Hepatitis vaccines, ATC code JO7BC.

TWINRIX Adult confers immunity against HAV and HBV infection by inducing specific anti-HAV and anti-HBs antibodies.

Protection against hepatitis A and hepatitis B develops within 2-4 weeks. In the clinical studies, specific humoral antibodies against hepatitis A were observed in approximately 94% of the adults one month after the first dose and in 100% one month after the third dose (i.e. month 7). Specific humoral antibodies against hepatitis B were observed in 70% of the adults after the first dose and approximately 99% after the third dose. Based on experience with the monovalent vaccines, it is expected that in most vaccinees the antibodies will persist for at least 4-5 years after the primary vaccination course. To establish long-term protection, booster vaccination with either the monovalent vaccines or the combination vaccine is indicated.

5.2 Pharmacokinetic properties

Evaluation of pharmacokinetic properties is not required for vaccines.

5.3 Preclinical safety data

Not applicable.

6. PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Aluminium hydroxide, aluminium phosphate, aminoacids for injection, formaldehyde, neomycin sulphate, 2-phenoxyethanol, polysorbate 20, sodium chloride, residual tris and phosphate buffer and water for injection.

6.2 Incompatibilities

TWINRIX Adult should not be mixed with other vaccines in the same syringe.

6.3 Shelf-life

The expiry date of the vaccine is indicated on the label and packaging.

Shelf-life is 24 months when stored at +2 °C to +8 °C.

6.4 Special precautions for storage

5 TWINRIX Adult should be stored at +2 °C to +8 °C.

Do not freeze; discard if the vaccine has been frozen.

6.5 Nature and contents of container

TWINRIX Adult is presented in a glass prefilled syringe. The prefilled syringes are made of neutral glass type I, which conforms to European Pharmacopoeia Requirements.

The content upon storage may present a fine white deposit with a clear colourless supernatant. Once shaken, the vaccine is slightly opaque.

6.6 Instructions for use, handling and disposal (if appropriate)

The vaccine should be inspected visually for any foreign particulate matter and/or variation of physical aspect prior to administration. Before use of TWINRIX Adult, the vaccine should be well shaken to obtain a slightly opaque, white suspension. Discard if the content appears otherwise.

7. MARKETING AUTHORISATION HOLDER

SmithKline Beecham Biologicals S.A. rue de l'Institut 89 1330 Rixensart, Belgium Telephone: +32 (0)2 656 8111 Fax: +32 (0)2 656 8000 Telex: 63251 SB BIO B

8. MARKETING AUTHORISATION NUMBER

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

10. DATE OF REVISION OF THE TEXT

ANNEX II THE MANUFACTURING AUTHORISATION HOLDER RESPONSIBLE FOR BATCH RELEASE AND CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE

7 A. MANUFACTURING AUTHORISATION HOLDER

Manufacturer responsible for batch release SmithKline Beecham Biologicals S. A., Rue de l’Institut 89, 1330 Rixensart, Belgium

Manufacturing authorisation was issued on 22 January 1996, to SmithKline Beecham Biologicals, S. A., for the Belgian site by the the Ministry of Public Health and Environment (Ministère de la Santé Publique et de l’Environnement/ Ministerie van Volksgezondheid en Leefmilieu) Vesaliusgebouw, Rijksadministratief centrum, 1010 Brussels, Belgium.

B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE

Medicinal product subject to non renewable medical prescription

ANNEX III LABELLING

A. LABELLING

10 HAB Adult PFS without fixed needle but with separate needle

TWINRIX ADULT Inactivated hepatitis A (720 ELISA Units) and rDNA hepatitis B vaccine (20 µg) Suspension for injection; intramuscular use

1 dose (1ml) contains : HAV antigen (propagated on MRC5 cells) 720 ELISA Units HBsAg (produced in yeast cells) 20 µg Aluminium as aluminium phosphate and aluminium hydroxide 2-phenoxyethanol Amino acids for injection Formaldehyde Neomycin sulphate Polysorbate 20 Sodium chloride Residual tris and phosphate buffer Water for injection

Marketing Authorisation n°: E.U / 1 / xxxx / xx / 9x held by: SmithKline Beecham Biologicals S.A. Rixensart, Belgium Keep out of reach of children Storage: +2°C/+8°C Do not freeze Shake before use Protect from light Medicinal product subject to medical prescription

Prefilled syringe with separate needle Lot: EXPIRY :

11 HAB Adult 10 x 1 dose PFS without fixed needle but with separate needle

TWINRIX ADULT Inactivated hepatitis A (720 ELISA Units) and rDNA hepatitis B vaccine (20 µg) Suspension for injection; intramuscular use

10 x 1 dose Syringe 1 dose (1ml) contains : HAV antigen (propagated on MRC5 cells) 720 ELISA Units HBsAg (produced in yeast cells) 20 µg Aluminium as aluminium phosphate and aluminium hydroxide 2-phenoxyethanol Amino acids for injection Formaldehyde Neomycin sulphate Polysorbate 20 Sodium chloride Residual tris and phosphate buffer Water for injection

10 Prefilled syringes with separate needles Lot: EXPIRY :

12 HAB Adult 25 x 1 dose PFS without fixed needle but with separate needle

TWINRIX ADULT Inactivated hepatitis A (720 ELISA Units) and rDNA hepatitis B vaccine (20 µg) Suspension for injection; intramuscular use

25 x 1 dose Syringe 1 dose (1ml) contains : HAV antigen (propagated on MRC5 cells) 720 ELISA Units HBsAg (produced in yeast cells) 20 µg Aluminium as aluminium phosphate and aluminium hydroxide 2-phenoxyethanol Amino acids for injection Formaldehyde Neomycin sulphate Polysorbate 20 Sodium chloride Residual tris and phosphate buffer Water for injection

25 Prefilled syringes with separate needles Lot: EXPIRY :

ANNEX III LABELLING AND PACKAGE LEAFLET

B. PACKAGE LEAFLET

15 What should you know about TWINRIX Adult?

• Please read this leaflet carefully before receiving the vaccine.

• Keep this leaflet until you have finished the complete vaccination course. You may want to read it again.

• You must follow the advice of the doctor or nurse carefully. If there is anything you do not understand, please ask the doctor, nurse or pharmacist.

• Make sure you finish the complete vaccination course. If you do not you may not be fully protected against infection.

• Always keep vaccines out of reach of children.

• Before receiving the vaccine, you should tell your doctor if you are pregnant (or think you may be).

• Like all vaccines, TWINRIX Adult may occasionally cause unwanted events. (You will find more information about this later in the leaflet.)

• The vaccine should be administered by a health care professional.

This leaflet does not contain all information about the vaccine. If you have any questions or are not sure about something ask the doctor, nurse or pharmacist.

What is TWINRIX Adult ?

TWINRIX Adult is a combined hepatitis A and hepatitis B vaccine. Each dose contains the inactivated hepatitis A virus (720 ELISA Units) and the surface protein (HBsAg - 20 µg) of the hepatitis B virus as active ingredients.

The vaccine is provided in a one dose (1.0 ml) glass prefilled syringe for use in adults and adolescents 16 years of age and above.

TWINRIX Adult contains as inactive ingredients: aluminium hydroxide, aluminium phosphate, aminoacids for injection, formaldehyde, neomycin sulphate, 2-phenoxyethanol, polysorbate 20, sodium chloride, residual tris and phosphate buffer and water for injection.

TWINRIX Adult is presented as a suspension for injection.

Manufacturer and Marketing authorisation holder:

SmithKline Beecham Biologicals S.A. rue de l'Institut 89 B-1330 Rixensart Belgium

What does TWINRIX Adult do?

TWINRIX Adult protects you against hepatitis A and hepatitis B.

16 The vaccine works by causing the body to make its own antibodies which protect you against these diseases.

What should be checked before receiving the vaccine?

You should not receive the vaccine if you think you have previously had an allergic reaction to TWINRIX Adult or to any hepatitis A and/or hepatitis B vaccine or one of its constituents.

You should delay your vaccination if you have an infection with a high temperature.

Tell your doctor: • if you have experienced any health problem.

• if you have any bleeding problems.

• if you are currently taking any other medicine or have recently received any other vaccine.

• if you are pregnant or think you may be pregnant.

• if you are breastfeeding.

How will the vaccine be given?

The doctor or nurse will inject the recommended dose of vaccine.

TWINRIX Adult will be injected into your upper arm muscle.

If you have any bleeding problems tell the doctor or nurse before receiving TWINRIX Adult, in this case the vaccine may need to be given in a different way (under the skin).

You will receive 3 doses of vaccine. (The second dose will be given four weeks after the first dose and the third dose six months after the first dose.) It is important to follow the instructions from the doctor/nurse regarding return visits for the following doses.

If you forget to go back to the doctor at the scheduled time, ask the doctor for advice.

What are the possible side effects ?

As with other vaccines, you may feel pain or discomfort at the injection site, or you may see some redness and swelling at this site. However, these reactions usually clear up within a few days.

Other reactions which may appear include fever, headache, nausea (feeling sick), malaise (feeling unwell), tiredness and vomiting.

Symptoms which have been reported after the widespread use of the monovalent hepatitis A and/or B vaccines are the following :

Flu-like symptoms (such as fever, chills, headache, muscle and joint pain), tiredness, dizziness.

17 Rarely reported : tingling, nausea, vomiting, decreased appetite, diarrhoea, abdominal pain, rash, pruritis, urticaria.

Very rarely reported : syncope, symptoms of the nervous system (such as difficulty in walking, weakness and or fatigue in limbs, pain or blurred vision, one-sided paralysis of facial muscles), bruises, skin rash.

If these symptoms arise or become severe, tell the doctor or nurse.

As with all injectable vaccines, there is an extremely small risk of a severe allergic reaction. (This can be recognised by symptoms such as difficulty in breathing or swallowing, itchy rash of the hands and feet, swelling of the eyes and face). Such reactions will usually occur before leaving the doctor's office, but in any event you should seek immediate treatment.

If you develop any other symptom within a few days following the vaccination, tell the doctor as soon as possible.

How to keep TWINRIX Adult ?

The expiry date is indicated on the label and packaging. The vaccine should not be administered after this date.

Store your vaccine in a refrigerator between +2°C and +8°C. The vaccine should not be frozen.

Store all vaccines out of the reach of children.

Specific information for the administrator

• Inspect the vaccine visually for any foreign particulate matter and/or variation of physical aspect prior to administration. Before use of TWINRIX Adult, shake the prefilled syringe to obtain a slightly opaque white suspension. Do not use if the content appears otherwise.

• TWINRIX Adult is for intramuscular injection, preferably in the deltoid region.

• In patients with thrombocytopenia or bleeding disorders the vaccine may be administered subcutaneously. However, this route of administration may result in suboptimal immune response to the vaccine.

• TWINRIX Adult should under no circumstances be administered intravascularly.

• As with all injectable vaccines, appropriate medical treatment and supervision should always be readily available in case of a rare anaphylactic event following administration of the vaccine.

• Administer different injectable vaccines at different injection sites.

• The vaccine is not recommended for postexposure prophylaxis (e.g. needle stick injury).

18 DATE OF APPROVAL OF PL

OTHER INFORMATION

For any information about this product, please contact the local representative of the Marketing Authorisation holder.

ÖSTERREICH ITALIA : 1130 Wien, Hietzinger Hauptstraße 55a Via Zambeletti Tel.: (0222) 87818-0 in Österreich 20021 Baranzate di Bollate (Mi) - Italia (0043 1) 87818-0 aus dem Ausland Tel. 02 - 3806.1

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