Ambirix, suspension for injection

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

For a full list of excipients, see section 6.1.

Suspension for injection .

Ambirix is a turbid white suspension.

Ambirix is indicated in non-immune children and adolescents from 1 year up to and including 15 years for protection against hepatitis A and hepatitis B infection.

Protection against hepatitis B infections may not be obtained until after the second dose (see section 5.1).

Therefore:

- Ambirix should be used only when there is a relatively low risk of hepatitis B infection during the vaccination course.

- It is recommended that Ambirix should be administered in settings where completion of the two-dose vaccination course can be assured.

Posology

- Dosage

A dose of 1.0 ml is recommended for subjects from 1 year up to and including 15 years of age.

The safety and efficacy of Ambirix in children aged less than 1 year have not been established.

No data are available.

- Primary vaccination schedule

The standard primary course of vaccination with Ambirix consists of two doses, the first administered at the elected date and the second between six and twelve 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

In situations where a booster dose of hepatitis A and/or hepatitis B is desired, a monovalent or combined vaccine can be given. The safety and immunogenicity of Ambirix administered as a booster dose following a two dose primary course have not been evaluated.

The anti-hepatitis B surface antigen (anti-HBs) and anti-hepatitis A virus (anti-HAV) antibody titres observed following a primary vaccination course with Ambirix are in the range of what is seen following vaccination with the monovalent hepatitis A and B vaccines. General guidelines for booster vaccination can therefore be drawn from experience with the monovalent vaccines, as follows.

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 at risk of exposure to HBV (e.g. haemodialysis or immunocompromised patients) a precautionary attitude should be considered to ensure that a protective antibody level 10 mIU/ml is maintained.

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 ensured by immunological memory. Guidelines for boosting are based on the assumption that antibodies are required for protection.

Method of administration

Ambirix is for intramuscular injection, usually into the deltoid muscle. However the anterolateral thigh may be used in very young subjects if preferred.

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.

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

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.

Syncope (fainting) can occur following, or even before, any vaccination especially in adolescents as a psychogenic response to the needle injection. This can be accompanied by several neurological signs such as transient visual disturbance, paraesthesia and tonic-clonic limb movements during recovery. It is important that procedures are in place to avoid injury from faints.

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 Ambirix 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.

Ambirix is not recommended for postexposure prophylaxis (e.g. needle stick injury).

If rapid protection against hepatitis B is required, the standard three dose regimen of the combined vaccine containing 360 ELISA Units of formalin inactivated hepatitis A virus and 10 micrograms of recombinant hepatitis B surface antigen is recommended. This is because, a higher proportion of subjects are protected in the interval between the second and third dose of the three dose combined vaccine, than after a single dose of Ambirix. This difference is no longer present after the second dose of Ambirix (see section 5.1 for seroprotection rates).

It is recommended that the two-dose regimen of Ambirix be completed prior to start of sexual activity.

The vaccine has not been tested in patients with an impaired immune system. 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.

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 Ambirix can be administered subcutaneously to subjects with thrombocytopenia or bleeding disorders since bleeding may occur following an intramuscular administration to these subjects.

AMBIRIX SHOULD UNDER NO CIRCUMSTANCES BE ADMINISTERED INTRAVASCULARLY.

No data on concomitant administration of Ambirix 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 there was no effect on seroconversion rates. Concomitant immunoglobulin administration may result in lower antibody titres.

When Ambirix was administered concomitantly with, but as a separate injection to a combined diphtheria, tetanus, acellular pertussis, inactivated poliomyelitis and Haemophilus influenzae type b vaccine (DTPa-IPV/Hib) or with a combined Measles-Mumps-Rubella vaccine in the second year of life, immune responses to all antigens were satisfactory (see section 5.1)

Concomitant administration of Ambirix and other vaccines than those listed above has not been studied. It is advised that Ambirix should not be administered at the same time as other vaccines unless absolutely necessary.

Concomitant vaccines should always be administered at separate injection sites and preferably into different limbs.

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

Pregnancy

The effect of Ambirix on foetal development has not been assessed. Ambirix should not be used during pregnancy unless it is clearly necessary.

Breastfeeding

The effect on breastfed infants of Ambirix administered to the mothers has not been evaluated in clinical studies. Ambirix should not be used during lactation unless it is clearly necessary.

Fertility

No fertility data are available.

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

Clinical trials involved the administration of 2029 doses of Ambirix to 1027 subjects from 1 year up to and including 15 years of age.

In 2 comparative trials in subjects aged 1-15 years, the incidences of local and general solicited symptoms after a two dose regimen of Ambirix was overall similar to that seen with the three dose combined vaccine containing 360 ELISA Units of HAV and 10 µg of HBsAg.

The most commonly reported adverse reactions following Ambirix administration are pain and fatigue occurring in an approximated per dose frequency of 50% and 30% respectively.

• Clinical trials

Local and general adverse reactions reported following primary vaccination with Ambirix were categorised by frequency.

Adverse reactions reported are listed according to the following frequency:

The following adverse reactions were reported during clinical trials with Ambirix.

Metabolism and nutrition disorders

Very common: appetite lost

Psychiatric disorders

Very common: irritability

Nervous system disorders

Very common: headache

Common: drowsiness

Gastrointestinal disorders

Common: gastrointestinal symptoms

General disorders and administration site conditions

Very common: fatigue, pain and redness at the injection site

Common: fever, swelling at the injection site

In addition, the following adverse reactions were reported during clinical trials with GlaxoSmithKline's other combined hepatitis A and hepatitis B vaccines (given as a 3 or 4 dose schedule)

Infections and infestations

Uncommon: upper respiratory tract infection

Blood and lymphatic system disorders

Rare: lymphadenopathy

Nervous system disorders

Uncommon: dizziness

Rare: paraesthesia

Vascular disorders

Rare: hypotension

Gastrointestinal disorders

Common: diarrhoea, nausea

Uncommon: vomiting, abdominal pain*

Skin and subcutaneous tissue disorders

Rare: pruritus, rash

Very rare: urticaria

Musculoskeletal and connective tissue disorders

Uncommon: myalgia

Rare: arthralgia

General disorders and administration site conditions

Common: malaise, injection site reaction

Rare: chills, influenza like illness

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

• Post-marketing surveillance

Because these events were reported spontaneously, it is not possible to reliably estimate their frequency.

The following adverse reactions were reported during post-marketing surveillance following vaccination with Ambirix.

Immune system disorders

Allergic reactions including anaphylactic and anaphylactoid reactions

Nervous system disorders

Syncope or vasovagal responses to injection, localised hypoaesthesia

Following widespread use of either GlaxoSmithKline's combined hepatitis A and hepatitis B vaccines or the monovalent hepatitis A and/or hepatitis B vaccines, the following adverse reactions have additionally been reported.

Infections and infestations

Meningitis

Blood and lymphatic system disorders

Thrombocytopenic purpura, thrombocytopenia

Immune system disorders

Allergic reactions including mimicking serum sickness, angioneurotic oedema

Nervous system disorders

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

Vascular disorders

Vasculitis

Hepatobiliary disorders

Abnormal liver function tests

Skin and subcutaneous tissue disorders

Erythema multiforme, lichen planus

Musculoskeletal and connective tissue disorders

Arthritis, muscular weakness

Cases of overdose with GlaxoSmithKline's combined hepatitis A and hepatitis B vaccine have been reported during post-marketing surveillance. Adverse reactions reported following overdosage were similar to those reported with normal vaccine administration.

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

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

In clinical studies involving subjects from 1 year up to and including 15 years old, seropositivity rates for anti-HAV antibodies were 99.1% one month after the first dose and 100% after the second dose given at month 6 (i.e month 7). Seropositivity rates for anti-HBs antibodies were 74.2% one month after the first dose and 100% after the second dose given at month 6 (i.e. month 7). The anti-HBs seroprotection rates (titers 10 mlU/ml) at these time points were 37.4% and 98.2% respectively.

In a comparative clinical trial conducted among subjects aged from 12 years up to and including 15 years of age, 142 received two doses of Ambirix and 147 received the standard three-dose combined vaccine. The latter contained 360 ELISA Units of formalin inactivated hepatitis A virus and 10 micrograms of recombinant hepatitis B surface antigen. For the 289 subjects evaluable for immunogenicity, seroprotection rates (SP in the table below) against hepatitis B were significantly higher at months 2 and 6 with the three-dose vaccine than with Ambirix.

Immune responses obtained one month after the full vaccination course (i.e at month 7) in a comparative clinical trial in children aged 1-11 years are presented in the following table. Also shown are the results reported in the comparative study performed in 12-15 year-olds. In both studies, subjects received either a two dose schedule of Ambirix or a three dose regimen of the combined vaccine containing 360 ELISA Units of formalin inactivated hepatitis A virus and 10 micrograms of recombinant hepatitis B surface antigen.

In a clinical study, 102 subjects aged from 12 years up to and including 15 years received the second dose of Ambirix at month 12. Seropositivity rates for anti-HAV were 99.0% and seropositivity rates for anti-HBs were 99.0% at month 13 with seroprotection rates of 97.0%.

At 10 years following the initiation of a 0, 6 month schedule of Ambirix in children aged 1-15 years, all subjects followed up retained 15 mIU/ml anti-HAV antibody. The percentages with anti-HBs antibody 10 mIU/ml at this time point for subjects aged 1-11 years or 12-15 years at the time of the first dose were 81.7% and 85.9%, respectively. In subjects aged 12-15 years at primary vaccination the anti-HAV and anti-HBs antibody concentrations were comparable between groups that had received Ambirix or a 3-dose regimen of the combined vaccine (content as described above).

At 6 years following the initiation of a 0, 6 month or a 0, 12 month schedule of Ambirix in children aged 12-15 years all subjects followed up retained 15 mIU/ml anti-HAV antibody. The percentages with anti-HBs antibody 10 mIU/ml at this time point for subjects vaccinated at the 0, 6 and 0, 12 month schedules were 84.8% and 92.9%, respectively.

When the first dose of Ambirix was administered concomitantly with a booster dose of a combined diphtheria, tetanus, acellular pertussis, inactivated poliomyelitis and Haemophilus influenzae type b vaccine (DTPa-IPV/Hib) or with the first dose of a combined Measles-Mumps-Rubella vaccine in the second year of life, immune responses to all antigens were satisfactory.

Evaluation of pharmacokinetic properties is not required for vaccines.

Non-clinical data reveal no special hazard for humans based on general safety studies.

Sodium chloride

Water for injections

For adjuvants, see section 2.

Not applicable.

3 years.

Store in a refrigerator (2°C - 8°C).

Do not freeze.

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

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

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

Not all pack sizes may be marketed.

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

Before administration, the vaccine should be well shaken to obtain a slightly opaque, white suspension.

The vaccine should be visually inspected both before and after resuspension for any foreign particulate matter and/or change in physical appearance. The vaccine must not be used if any change in the appearance of the vaccine has taken place.

Any unused product or 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/1/02/224/001

EU/1/02/224/002

EU/1/02/224/003

EU/1/02/224/004

EU/1/02/224/005

Date of first authorisation: 30 August 2002

Date of latest renewal: 30 August 2007

22/12/2011

Detailed information on this product is available on the website of the European Medicines Agency http://www.ema.europa.eu