HBVAXPRO^® 5 micrograms/0.5 ml

Suspension for injection in pre-filled syringe

Hepatitis B vaccine (rDNA)

One dose (0.5 ml) contains:

Hepatitis B virus surface antigen, recombinant (HBsAg) *.................. 5.00 micrograms

Adsorbed on amorphous aluminium hydroxyphosphate sulfate (0.25 milligram Al⁺)

* produced from recombinant strain of the yeast Saccharomyces cerevisiae (strain 2150-2-3)

For a full list of excipients, see section 6.1

Suspension for injection in pre-filled syringe

Slightly opaque white suspension.

This vaccine is indicated for active immunisation against hepatitis B virus infection caused by all known subtypes in children and adolescents (from birth through 15 years of age) considered at risk of exposure to hepatitis B virus.

The specific at risk categories to be immunised are to be determined on the basis of the official recommendations.

It can be expected that hepatitis D will also be prevented by immunisation with HBVAXPRO as hepatitis D (caused by the delta agent) does not occur in the absence of hepatitis B infection.

Posology

Children and adolescents (birth through 15 years of age): 1 dose (5 µg) of 0.5 ml at each injection is intended for use.

Primary vaccination:

A course of vaccination should include at least three injections.

Two primary immunisation schedules can be recommended:

0, 1, 6 months: two injections with an interval of one month; a third injection 6 months after the first administration.

0, 1, 2, 12 months: three injections with an interval of one month; a fourth dose should be administered at 12 months.

It is recommended that the vaccine be administered in the schedules indicated. Infants receiving the compressed regimen (0, 1, 2 months dosing schedule) must receive the 12 month booster to induce higher antibody titres.

Booster:

Immunocompetent vaccinees

The need for a booster dose in healthy individuals who have received a full primary vaccination course has not been established. However, some local vaccination schedules currently include a recommendation for a booster dose and these should be respected.

Immunocompromised vaccinees (e.g. dialysis patients, transplant patients)

In vaccinees with an impaired immune system, administration of additional doses of vaccine should be considered if the antibody level against hepatitis B virus surface antigen (anti-HBsAg) is less than 10 IU/l.

Revaccination of nonresponders

When persons who do not respond to the primary vaccine series are revaccinated, 15-25 % produce an adequate antibody response after one additional dose and 30-50 % after three additional doses. However, because data are insufficient concerning the safety of hepatitis B vaccine when additional doses in excess of the recommended series are administered, revaccination following completion of the primary series is not routinely recommended. Revaccination should be considered for high-risk individuals, after weighing the benefits of vaccination against the potential risk of experiencing increased local or systemic adverse reactions.

Special dosage recommendations:

Dosage recommendations for neonates born to mothers who are hepatitis B virus carriers

- At birth, one dose of hepatitis B immunoglobulin (within 24 hours).

- The first dose of the vaccine should be given within 7 days of birth and can be administered simultaneously with hepatitis B immunoglobulin at birth, but at a separate injection site.

- Subsequent doses of vaccine should be given according to the locally recommended vaccination schedule.

Dosage recommendation for known or presumed exposure to hepatitis B virus (e.g needlestick with contaminated needle)

- Hepatitis B immunoglobulin should be given as soon as possible after exposure (within 24 hours).

- The first dose of the vaccine should be given within 7 days of exposure and can be administered simultaneously with hepatitis B immunoglobulin but at a separate injection site.

- Serologic testing is also recommended, with the administration of subsequent doses of vaccine, if necessary, (i.e according to the serologic status of the patient) for short and long term protection.

- In the case of unvaccinated or incompletely vaccinated individuals, additional doses should be given as in the recommended immunisation schedule. The accelerated schedule including the 12 month booster dose can be proposed.

Method of administration

This vaccine should be administered intramuscularly.

The anterolateral thigh is the preferred site for injection in neonates and infants. The deltoid muscle is the preferred site for injection in children and adolescents.

Do not inject intravascularly.

Exceptionally, the vaccine may be administered subcutaneously in patients with thrombocytopoenia or bleeding disorders.

See section 6.6 for the instructions for preparation

- Hypersensitivity to the active substance or to any of the excipients

- Severe febrile illness

Because of the long incubation period of hepatitis B, it is possible for unrecognised hepatitis B infection to be present at the time of vaccination. The vaccine may not prevent hepatitis B infection in such cases.

The vaccine will not prevent infection caused by other agents such as hepatitis A, hepatitis C and hepatitis E and other pathogens known to infect the liver.

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

This vaccine may contain traces of formaldehyde and potassium thiocyanate which are used during the manufacturing process. Therefore, sensitisation reactions may occur.

The potential risk of apnoea and the need for respiratory monitoring for 48-72 h should be considered when administering the primary immunisation series to very premature infants (born 28 weeks of gestation) and particularly for those with a previous history of respiratory immaturity. As the benefit of vaccination is high in this group of infants, vaccination should not be withheld or delayed.

This vaccine can be administered:

- with hepatitis B immunoglobulin, at a separate injection site.

- to complete a primary immunisation course or as a booster dose in subjects who have previously received another hepatitis B vaccine.

- concomitantly with other vaccines, using separate sites and syringes.

The concomitant administration of pneumococcal conjugate vaccine (PREVENAR) given with hepatitis B vaccine using the 0, 1 and 6 and 0, 1, 2 and 12 month schedules has not been sufficiently studied.

Not applicable.

Not relevant.

The following undesirable effects have been reported following the widespread use of the vaccine.

As with other hepatitis B vaccines, in many instances, the causal relationship to the vaccine has not been established.

Blood and the lymphatic system disorders

Very rare (<1/10,000)

Thrombocytopenia, lymphadenopathy

Immune system disorders

Very rare (<1/10,000)

Serum sickness, anaphylaxis, polyarteritis nodosa

Nervous system disorders

Very rare (<1/10,000)

Paresthesia, paralysis (Bell's palsy), peripheral neuropathies (polyradiculoneuritis, facial paralysis), neuritis (including Guillain Barre Syndrome, optical neuritis, myelitis including transverse myelitis), encephalitis, demyelinating disease of the central nervous system, exacerbation of multiple sclerosis, multiple sclerosis, seizure, headache, dizziness, syncope

Vascular disorders

Very rare (<1/10,000)

Hypotension, vasculitis

Respiratory, thoracic and mediastinal disorders

Very rare (<1/10,000)

Bronchospasm-like symptoms, apnoea in very premature infants ( 28 weeks of gestation) (see section 4.4)

Gastrointestinal disorders

Very rare (<1/10,000)

Vomiting, nausea, diarrhoea, abdominal pain

Skin and subcutaneous tissue disorders

Very rare (<1/10,000)

Rash, alopecia, pruritus, urticaria, erythema multiforme, angioedema, eczema

Musculoskeletal, connective tissue and bone disorders

Very rare (<1/10,000)

Arthralgia, arthritis, myalgia, pain in extremity

General disorders and administration site conditions

Common (>1/100, <1/10)

Local reactions (injection site): transient soreness, erythema, induration

Very rare (<1/10,000)

Fatigue, fever, malaise, influenza-like symptoms

Investigations

Very rare (<1/10,000)

Elevation of liver enzymes

No case of overdose has been reported.

Pharmacotherapeutic group: anti-infectious, ATC code: J07BC01

The vaccine induces specific humoral antibodies against hepatitis B virus surface antigen (anti-HBsAg). Development of an antibody titre against hepatitis B virus surface antigen (anti-HBsAg) equal to or greater than 10 IU/l measured 1 to 2 months after the last injection correlates with protection to hepatitis B virus infection.

In clinical trials, 96 % of 1,497 healthy infants, children, adolescents and adults given a 3 dose course of a previous formulation of Merck's recombinant hepatitis B vaccine developed a protective level of antibodies against hepatitis B virus surface antigen ( 10 IU/l). In two infant trials using different dosing schedules and concomitant vaccines, the proportion of infants with protective levels of antibodies were 97.5 % and 97.2 % with geometric mean titres of 214 and 297 IU/l, respectively.

The protective efficacy of a dose of hepatitis B immunoglobulin at birth followed by 3 doses of a previous formulation of Merck's recombinant hepatitis B vaccine has been demonstrated for neonates born to mothers positive for both hepatitis B virus surface antigen (HBsAg) and hepatitis B virus e antigen (HBeAg). Among 130 vaccinated infants, the estimated efficacy in prevention of chronic hepatitis B infection was 95 % as compared to the infection rate in untreated historical controls.

Although the duration of the protective effect of a previous formulation of Merck's recombinant hepatitis B vaccine in healthy vaccinees is unknown, follow-up over 5-9 years of approximately 3,000 high-risk subjects given a similar plasma-derived vaccine has revealed no cases of clinically apparent hepatitis B infection.

In addition, persistence of vaccine-induced immunologic memory for hepatitis B virus surface antigen (HBsAg) has been demonstrated through an anamnestic antibody response to a booster dose of a previous formulation of Merck's recombinant hepatitis B vaccine. As with other hepatitis B vaccines, the duration of the protective effect in healthy vaccinees is unknown at present. The need for a booster dose of HBVAXPRO is not yet defined beyond the 12 month booster dose required for the 0, 1, 2 compressed schedule.

Reduced risk of Hepatocellular Carcinoma

Hepatocellular carcinoma is a serious complication of hepatitis B virus infection. Studies have demonstrated the link between chronic hepatitis B infection and hepatocellular carcinoma and 80 % of hepatocellular carcinomas are caused by hepatitis B virus infection. Hepatitis B vaccine has been recognized as the first anti-cancer vaccine because it can prevent primary liver cancer.

Not applicable.

Animal reproduction studies have not been conducted.

Sodium chloride

Borax

Water for injections

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.

0.5 ml of suspension in pre-filled syringe (Type I glass) without needle with a plunger stopper (chlorobutyl). Pack size of 1, 10, 20, 50.

0.5 ml of suspension in pre-filled syringe (Type I glass) with 1 separate needle with a plunger stopper (chlorobutyl). Pack size of 1, 10.

0.5 ml of suspension in pre-filled syringe (Type I glass) with 2 separate needles with a plunger stopper (chlorobutyl). Pack size of 1, 10, 20, 50.

Not all pack sizes may be marketed.

Before use, the vaccine should be well shaken.

Hold the syringe barrel and attach the needle by twisting in clockwise direction, until the needle fits securely on the syringe.

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

SANOFI PASTEUR MSD SNC

8, rue Jonas Salk

F-69007 Lyon

France

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27/04/2001

December 2007