Twinrix Paediatric, suspension for injection in prefilled syringe

Hepatitis A (inactivated) and hepatitis B(rDNA) (HAB) vaccine ((adsorbed).

1 dose (0.5 ml) contains:

For a full list of excipients, see section 6.1.

Suspension for injection in prefilled syringe

Turbid white suspension.

Twinrix Paediatric is indicated for use in non immune infants, children and adolescents from 1 year up to and including 15 years who are at risk of both hepatitis A and hepatitis B infection.

Posology

- Dosage

The dose of 0.5 ml (360 ELISA Units HA/10 µg HBsAg) is recommended for infants, children and adolescents from 1 year up to and including 15 years of age.

- Primary vaccination schedule

The standard primary course of vaccination with Twinrix Paediatric 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.

Long-term antibody persistence data following vaccination with Twinrix Paediatric are available up to 48 months after vaccination. 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 with the monovalent vaccines. The kinetics of antibody decline are also similar. General guidelines for booster vaccination can therefore be drawn from experience with the monovalent vaccines.

Hepatitis B

The need for a booster dose of hepatitis B vaccine in healthy individuals who have received a full primary vaccination course has not been established; however some official vaccination programmes currently include a recommendation for a booster dose of hepatitis B vaccine and these should be respected.

For some categories of subjects or patients exposed to HBV (e.g. haemodialysis or immunocompromised patients) a precautionary attitude should be considered to ensure a protective antibody level 10IU/l.

Hepatitis A

It is not yet fully established whether immunocompetent individuals who have responded to hepatitis A vaccination will require booster doses as protection in the absence of detectable antibodies may be insured by immunological memory. Guidelines for boosting are based on the assumption that antibodies are required for protection; anti-HAV antibodies have been predicted to persist for at least 10 years.

In situations where a booster dose of both hepatitis A and hepatitis B are desired, Twinrix Paediatric can be given. Alternatively, subjects primed with Twinrix Paediatric may be administered a booster dose of either of the monovalent vaccines.

Method of administration

Twinrix Paediatric is for intramuscular injection, preferably in the deltoid region in adolescents and children or in the anterolateral thigh in infants.

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. (see section 4.4)

Hypersensitivity to the active substances or to any of the excipients or neomycin.

Hypersensitivity after previous administration of hepatitis A and/or hepatitis B vaccines.

The administration of Twinrix Paediatric should be postponed in subjects suffering from acute severe febrile illness.

It is possible that subjects may be in the incubation period of a HA or HB infection at the time of vaccination. It is not known whether Twinrix Paediatric will prevent HA and HB 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 Paediatric 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, patients receiving immunosuppressive treatment or patients with an impaired immune system, the anticipated immune response may not be achieved after the primary immunisation course. Such patients may require additional doses of vaccine; nevertheless immunocompromised patients may fail to demonstrate an adequate response.

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 Paediatric can be administered subcutaneously to subjects with thrombocytopenia or bleeding disorders since bleeding may occur following an intramuscular administration to these subjects. (see section 4.2)

TWINRIX PAEDIATRIC SHOULD UNDER NO CIRCUMSTANCES BE ADMINISTERED INTRAVASCULARLY.

As with any injection procedure, vasovagal syncope can infrequently occur following administration of Twinrix Paediatric to adolescents.

No data on concomitant administration of Twinrix Paediatric 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 titers.

As the concomitant administration of Twinrix Paediatric and other vaccines has not specifically been studied it is advised that the vaccine should not be administered at the same time as other vaccines.

Pregnancy

The effect of Twinrix Paediatrict on embryo-fetal, peri-natal and post-natal survival and development has been assessed in rats. This study did not indicate direct or indirect harmful effects with respect to fertility, pregnancy, embryonal/fetal development, parturition or post-natal development.

The effect of Twinrix Paediatric on embryo-fetal, peri-natal and post-natal survival and development has not been prospectively evaluated in clinical trials.

Data on outcomes of a limited number of pregnancies in vaccinated women do not indicate any adverse effects of Twinrix Paediatric on pregnancy or on the health of the fetus/newborn child. While it is not expected that recombinant hepatitis B virus surface antigen would have adverse effects on pregnancies or the fetus it is recommended that vaccination should be delayed until after delivery unless there is an urgent need to protect the mother against hepatitis B infection.

Lactation

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

Twinrix Paediatric has no or negligible influence on the ability to drive and use machines.

• Clinical trials

The current formulation of Twinrix does not contain thiomersal (an organomercuric compound) or any preservative. In a clinical study conducted with the current formulation, the incidence of pain, redness, swelling, fatigue, gastro-enteritis, headache and fever was comparable to the incidence observed with the former thiomersal and preservative containing vaccine formulation. The following undesirable events have been reported following the widespread use of the former formulation.

The safety profile presented below is based on data from approximately 800 subjects.

Frequencies are reported as:

Very common: 1/10

Common: 1/100 to < 1/10

Uncommon: 1/1,000 to < 1/100

Rare: 1/10,000 to < 1/1,000

Very rare: < 1/10,000

* refers to adverse reactions observed in clinical trials performed with the adult formulation

Blood and lymphatic system disorders

Rare: lymphadenopathy

Nervous system disorders

Common: drowsiness, headache

Rare: hypoaesthesia*, paraesthesia*, dizziness

Gastrointestinal disorders

Common: gastrointestinal symptoms, nausea

Uncommon: diarrhoea, vomiting, abdominal pain

Skin and subcutaneous tissue disorders

Uncommon: rash

Rare: urticaria, pruritus*

Musculoskeletal and connective tissue disorders

Uncommon: myalgia*

Rare: arthralgia*

Metabolism and nutrition disorders

Common: appetite lost

Infections and infestations

Uncommon: upper respiratory tract infection*

Vascular disorders

Rare: hypotension*

General disorders and administration site conditions

Very common: pain and redness at the injection site

Common: swelling at the injection site, injection site reaction (such as bruising), fatigue, malaise, fever ( 37.5°C)

Rare: influenza like illness*, chills*

Psychiatric disorders

Common: irritability

• Post-marketing surveillance

The following adverse reactions have been reported with either Twinrix or with GlaxoSmithKline monovalent hepatitis A or B vaccines:

Blood and lymphatic system disorders

Thrombocytopenia, thrombocytopenic purpura

Nervous system disorders

Encephalitis, encephalopathy, neuritis, neuropathy, paralysis, convulsions

Skin and subcutaneous tissue disorders

Angioneurotic oedema, lichen planus, erythema multiforme

Musculoskeletal and connective tissue disorders

Arthritis, muscular weakness

Infections and infestations

Meningitis

Vascular disorders

Vasculitis

Immune system disorders

Anaphylaxis, allergic reactions including anaphylactoid reactions and mimicking serum sickness

Following widespread use of the monovalent hepatitis A and/or hepatitis B vaccines, the following undesirable events have additionally been reported in temporal association with vaccination.

Investigations

Abnormal liver function tests

Nervous system disorders

Multiple sclerosis, myelitis, facial palsy, polyneuritis such as Guillain-Barré syndrome (with ascending paralysis), optic neuritis

Cases of overdose have been reported during post-marketing surveillance. Adverse events reported following overdosage were similar to those reported with normal vaccine administration.

Pharmaco-therapeutic group: Hepatitis vaccines, ATC code J07BC20.

Twinrix Paediatric 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.

Twinrix Paediatric confers immunity against HAV and HBV infection by inducing specific anti-HA 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 89% of the subjects 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 approximately 67% of the subjects after the first dose and 100% after the third dose.

In a long term clinical trial, persistence of anti-HAV and anti-HBs antibodies has been demonstrated up to 48 months following the initiation of a primary vaccination course of Twinrix Paediatric in the majority of vaccinees (see section 4.2). The kinetics of decline of anti-HAV and anti-HBs antibodies were shown to be similar to those of the monovalent vaccines.

These data were generated with the former Twinrix formulation containing thiomersal and a preservative. A clinical study conducted with the current formulation of Twinrix in adults showed that the current formulation elicited similar seroprotection and seroconversion rates as compared to the former formulation.

Evaluation of pharmacokinetic properties is not required for vaccines.

Non-clinical data reveal no special hazard for humans based on general safety studies (see section 4.6).

Sodium chloride

Water for injections

For adjuvants, see section 2.

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

3 years.

Store in a refrigerator (2°C - 8°C).

Do not freeze.

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

0.5 ml of suspension in a prefilled syringe (type I glass) with a plunger stopper (rubber butyl).

Pack sizes of 1, 10 and 50 with or without needles.

Not all pack sizes may be marketed.

Upon storage, a fine white deposit with a clear colourless supernatant can be observed.

The vaccine should be well shaken to obtain a slightly opaque, white suspension and visually inspected for any foreign particulate matter and/or variation of physical aspect prior to administration. In the event of either being observed, discard the vaccine.

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

GlaxoSmithKline Biologicals s.a.

rue de l'Institut 89

B-1330 Rixensart, Belgium

EU/1/97/029/001

EU/1/97/029/002

EU/1/97/029/006

EU/1/97/029/007

EU/1/97/029/008

EU/1/97/029/009

EU/1/97/029/010

Date of first authorisation: 10 February 1997

Date of latest renewal: 10 February 2007

19/06/2008