Ambirix, suspension for injection

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

1 dose (1 ml) contains:

Suspension for injection .

Ambirix is a turbid white suspension.

Ambirix is for use in non-immune persons 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.

- 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. Anti-HAV antibodies have been predicted to persist for at least 10 years.

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.

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.

Lactation

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.

Drowsiness and dizziness can sometimes occur and may affect the ability to drive and use machines.

The current formulation of Ambirix does not contain thiomersal (an organomercuric compound) or any preservative. In a clinical study conducted with 3 doses of the current formulation in adults, 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 adverse reactions have been reported following the widespread use of the former formulation

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

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

Frequencies are reported below 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

Nervous system disorders:

very common: headache

common: drowsiness

Gastrointestinal disorders:

common: gastrointestinal symptoms

Metabolism and nutrition disorders

very common: loss of appetite

General disorders and administration site conditions

very common: pain, redness, fatigue

common: swelling, fever

Psychiatric disorders:

very common: irritability/fussiness

In a study, in 300 subjects aged from 12 years up to and including 15 years, the reactogenicity profile of Ambirix was compared to that of the three-dose combined vaccine. The three-dose vaccine contained 360 ELISA Units of formalin inactivated hepatitis A virus and 10 micrograms of recombinant hepatitis B surface antigen in 0.5 ml. The incidence 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, the only exceptions being a higher incidence of pain and fatigue on a per dose basis after Ambirix, but not on a per subject basis.

Pain was reported following 50.7% of doses in the Ambirix group, as compared to 39.1% of doses with the three dose combined vaccine. However, over the complete vaccination course, 66.4% of subjects who received Ambirix reported pain, as compared to 63.8% of subjects who received the three dose combined vaccine.

Fatigue was reported following 29.2% doses of Ambirix, as compared to 19.3% doses of the three dose combined vaccine. However, the incidence of fatigue was similar based on a per subject analysis (i.e. over the total vaccination course, 39.6% versus 36.2% of subjects for Ambirix and the three dose vaccine respectively).

The incidence of pain and fatigue graded as severe was low and similar to that observed with the three dose combined vaccine.

In a comparative trial in subjects aged 1-11 years, the incidences of local and general solicited symptoms in the Ambirix group were similar to those seen with the three-dose combined vaccine containing 360 ELISA Units of formalin inactivated hepatitis A virus and 10 micrograms of recombinant hepatitis B surface antigen. The exception was a higher incidence of pain after Ambirix in 6-11 year olds on a per dose basis, but not on a per subject basis.

The percentages of vaccinees reporting any solicited symptom graded as severe during a two-dose regimen of Ambirix or a three dose regimen with the combined vaccine containing 360 ELISA Units of formalin inactivated hepatitis A virus and 10 micrograms of recombinant hepatitis B surface antigen, were not statistically different.

During post-marketing surveillance with the three dose combined vaccine containing either 360 ELISA Units of formalin inactivated hepatitis A virus and 10 micrograms of recombinant hepatitis B surface antigen in a dose volume of 0.5 ml (recommended for subjects 1 year up to and including 15 years of age) or 720 ELISA Units of formalin inactivated hepatitis A virus and 20 micrograms of recombinant hepatitis B surface antigen in a dose volume of 1 ml (recommended from the age of 16 years onwards), the following adverse reactions have been reported.

Investigations

abnormal liver function tests

Blood and lymphatic system disorders

thrombocytopenia, thrombocytopenic purpura, lymphadenopathy

Nervous system disorders

syncope, dizziness, paresthesia, convulsions

Gastrointestinal disorders:

nausea, vomiting, diarrhoea, abdominal pain

Skin and subcutaneous tissue disorders

rash, pruritis, urticaria

Metabolism and nutrition disorders

decreased appetite

Vascular disorders

Hypotension

General disorders and administration site conditions

flu-like symptoms, fatigue

Immune system disorders

allergic reactions including anaphylactic and anaphylactoid reactions and serum sickness like disease

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

Nervous system disorders

multiple sclerosis, myelitis, facial palsy, polyneuritis such as Guillain-Barré syndrome (with ascending paralysis), encephalitis, encephalopathy

Eye disorders

optic neuritis

Skin and subcutaneous tissue disorders

erythema exsudativum multiforme

Infections and infestations

meningitis

Vascular disorders

vasculitis

No case of overdose has been reported.

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%.

In subjects aged 12-15 years at the time of primary vaccination, anti-HAV and anti-HBs antibodies have been shown to persist for at least 24 months following the initiation of a 0, 6 month schedule of Ambirix. Seropositivity rates were 100% and 94.2% respectively for anti-HAV and anti-HBs antibodies at month 24. The seroprotection rate for anti-HBs at this time point was 93.3%. In this study, the immune response to both antigen components was comparable to that seen after a 3-dose regimen of the combined vaccine containing 360 ELISA Units of formalin inactivated hepatitis A virus and 10µg of recombinant hepatitis B surface antigen in a dose volume of 0.5 ml.

In a clinical study involving subjects from 12 years up to and including 15 years of age, the persistence of anti-HAV and anti-HBs antibodies at month 24 was shown to be similar following a 0, 6 month or a 0, 12 month schedule.

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.

These data were generated with the former Ambirix formulation containing thiomersal and a preservative. A clinical study conducted with 3 doses of the current formulation 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.

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 vaccine 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: 5 September 2007

30 August 2007