Engerix B® 20 micrograms/1 ml

Suspension for injection

Hepatitis B (rDNA) vaccine, adsorbed (HBV)

1 dose (0.5 ml) contains :

Hepatitis B surface antigen^1,2, 10 micrograms

²Produced in yeast cells (Saccharomyces cerevisiae) by recombinant DNA technology

1 dose (1 ml) contains :

Hepatitis B surface antigen ^1,2 , 20 micrograms

²Produced in yeast cells (Saccharomyces cerevisiae) by recombinant DNA technology

For a full list of excipients, see section 6.1

Suspension for injection in pre-filled syringe.

Turbid white suspension.

Engerix B is indicated for active immunisation against hepatitis B virus infection (HBV) caused by all known subtypes in non immune subjects. The categories within the population to be immunised are determined on the basis of official recommendations.

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

Posology

Dosage

The 20 µg dose vaccine in 1.0 ml suspension is intended for use in subjects 16 years of age and above. The 10 µg dose vaccine in 0.5 ml suspension is intended for use in subjects up to and including 15 years of age, including neonates.

However, the 20 µg vaccine can also be used in subjects from 11 years up to and including 15 years of age as a 2-dose schedule in situations when there is a low risk of hepatitis B infection during the vaccination course, and when compliance with the complete vaccination course can be assured (see below and section 5.1).

Primary Immunisation schedules

Subjects up to and including 15 years of age:

Two primary immunisation schedules can be recommended:

A 0, 1, 6 months schedule which gives optimal protection at month 7 and produces high antibody titres.

An accelerated schedule, with immunisation at 0, 1 and 2 months, which will confer protection more quickly and is expected to provide better patient compliance. With this schedule, a fourth dose should be administered at 12 months to assure long term protection as titres after the third dose are lower than those obtained after the 0,1, 6 months schedule. In infants this schedule will allow for simultaneous administration of hepatitis B with other childhood vaccines.

- Patients with renal insufficiency including patients undergoing haemodialysis:

Patients with renal insufficiency, including patients undergoing haemodialysis, have a reduced immune response to hepatitis B vaccines. Either the 0, 1, 2 and 12 months or the 0, 1, 6 months schedule of Engerix B (10 µg) can be used. Based on adult experience, vaccination with a higher dosage of antigen may improve the immune response. Consideration should be given to serological testing following vaccination. Additional doses of vaccine may be needed to ensure a protective anti-HBs level of > 10 IU/l.

- Neonates born of mothers who are HBV carriers:

The immunisation with Engerix B (10 µg) of these neonates should start at birth, and two immunisation schedules have been followed. Either the 0, 1, 2 and 12 months or the 0, 1 and 6 months schedule can be used; however, the former schedule provides a more rapid immune response. When available, hepatitis B immune globulins (HBIg) should be given simultaneously with Engerix B at a separate injection site as this may increase the protective efficacy.

Subjects from 11 years up to and including 15 years of age:

The 20 µg vaccine may be administered in subjects from 11 years up to and including 15 years of age according to a 0, 6 months schedule. However, in this case, protection against hepatitis B infections may not be obtained until after the second dose (see section 5.1). Therefore, this schedule should be used only when there is a low risk of hepatitis B infection during the vaccination course and when completion of the two-dose vaccination course can be assured. If both conditions cannot be assured (for instance patients undergoing haemodialysis, travellers to endemic regions and close contacts of infected subjects), the three dose or the accelerated schedule of the 10 µg vaccine should be used.

Subjects 16 years of age and above:

Two primary immunisation schedules can be recommended:

A 0, 1, 6 months schedule which gives optimal protection at month 7 and produces high antibody titres.

An accelerated schedule, with immunisation at 0, 1 and 2 months, which will confer protection more quickly and is expected to provide better patient compliance. With this schedule, a fourth dose should be administered at 12 months to assure long term protection as titres after the third dose are lower than those obtained with the 0, 1, 6 months schedule.

Subjects 18 years of age and above:

In exceptional circumstances in adults, where an even more rapid induction of protection is required, e.g. persons travelling to areas of high endemicity and who commence a course of vaccination against hepatitis B within one month prior to departure, a schedule of three intramuscular injections given at 0, 7 and 21 days may be used. When this schedule is applied, a fourth dose is recommended 12 months after the first dose.

- Patients with renal insufficiency including patients undergoing haemodialysis, 16 years of age and above:

The primary immunisation schedule for patients, with renal insufficiency including patients undergoing haemodialysis is four double doses (2 x 20 µg) at elected date, 1 month, 2 months and 6 months from the date of the first dose. The immunisation schedule should be adapted in order to ensure that the anti-HBs antibody titre remains equal to or higher than the accepted protective level of 10 IU/l.

- Known or presumed exposure to HBV:

In circumstances where exposure to HBV has recently occurred (eg needlestick with contaminated needle) the first dose of Engerix B can be administered simultaneously with HBIg which, however, must be given at a separate injection site (see section 4.5). The 0, 1, 2-12 months immunisation schedule should be advised.

These immunisation schedules may be adjusted to accommodate local immunisation practices.

Booster dose

Current data do not support the need for booster vaccination among immunocompetent subjects who have responded to a full primary vaccination course (Lancet 2000, 355:561).

However, in immunocompromised subjects (eg subjects with chronic renal failure, haemodialysis patients, HIV positive subjects), boosters should be administered to maintain anti-HBs antibody titre equal or higher than the accepted protective level of 10 IU/l. For these immunocompromised subjects, post-vaccination testing every 6-12 months is advised.

National recommendations on booster vaccination should be considered.

Interchangeability of hepatitis B vaccines

See section 4.5. Interaction with other medicaments and other forms of interaction.

Method of administration

Engerix B should be injected intramuscularly in the deltoid region in adults and children or in the anterolateral thigh in neonates, infants and young children.

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

Engerix B should not be administered to subjects with known hypersensitivity to any component of the vaccine, or to subjects having shown signs of hypersensitivity after previous Engerix B administration.

As with other vaccines, the administration of Engerix B should be postponed in subjects suffering from acute severe febrile illness. The presence of a minor infection, however, is not a contra-indication for immunisation.

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.

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

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

As with any vaccine, a protective immune response may not be elicited in all vaccinees.

A number of factors have been observed to reduce the immune response to hepatitis B vaccines. These factors include older age, male gender, obesity, smoking, route of administration and some chronic underlying diseases. Consideration should be given to serological testing of those subjects who may be at risk of not achieving seroprotection following a complete course of Engerix B. Additional doses may need to be considered for persons who do not respond or have a sub-optimal response to a course of vaccinations.

Patients with chronic liver disease or with HIV infection or hepatitis C carriers should not be precluded from vaccination against hepatitis B. The vaccine could be advised since HBV infection can be severe in these patients : the HB vaccination should thus be considered on a case by case basis by the physician. In HIV infected patients, as also in patients with renal insufficiency including patients undergoing haemodialysis and persons with an impaired immune system, adequate anti-HBs antibody titres may not be obtained after the primary immunisation course and such patients may therefore require administration of additional doses of vaccine.

Engerix B should not be administered in the buttock or intradermally since this may result in a lower immune response.

Engerix B should under no circumstances be administered intravenously.

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.

The potential risk of apnoea and the need for respiratory monitoring for 48-72h should be considered when administering the primary immunization 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.

The simultaneous administration of Engerix B and a standard dose of HBIg does not result in lower anti-HBs antibody titres provided that they are administered at separate injection sites.

Engerix B can be given concomitantly with Haemophilus influenzae b, BCG, hepatitis A, polio, measles, mumps, rubella, diphtheria, tetanus and pertussis vaccines.

Different injectable vaccines should always be administered at different injection sites.

Engerix B may be used to complete a primary immunisation course started either with plasma-derived or with other genetically-engineered hepatitis B vaccines, or, if it is desired to administer a booster dose, it may be administered to subjects who have previously received a primary immunisation course with plasma-derived or with other genetically-engineered hepatitis B vaccines.

Pregnancy

The effect of the HBsAg on foetal development has not been assessed.

However, as with all inactivated viral vaccines one does not expect harm for the foetus. Engerix B should be used during pregnancy only when clearly needed, and the possible advantages outweigh the possible risks for the foetus.

Lactation

The effect on breastfed infants of the administration of Engerix B to their mothers has not been evaluated in clinical studies, as information concerning the excretion into the breast milk is not available.

No contraindication has been established.

Some of the effects mentioned under section 4.8 “Undesirable Effects” may affect the ability to drive or operate machinery.

The current formulation of Engerix B does not contain thiomersal (an organomercuric compound). The following undesirable effects have been reported following the use of the thiomersal containing formulations as well as the thiomersal free formulation.

• Clinical trials

In one clinical study conducted in adults with the current formulation (thiomersal free formulation), the incidence of pain, redness, swelling, fatigue, gastro-enteritis, headache and fever was comparable to the incidence observed in the clinical studies conducted with former thiomersal containing vaccine formulations.

In one clinical study conducted in children with the current formulation (thiomersal free formulation), the incidence of pain, redness, swelling, drowsiness, irritability, loss of appetite and fever was comparable to the incidence observed in the clinical studies conducted with former thiomersal containing vaccine formulations.

The safety profile presented below is based on data from 5329 subjects followed in 23 studies.

Frequencies per dose are defined as follows:

Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

Blood and lymphatic system disorders

Rare: lymphadenopathy

Nervous system disorders

Common: drowsiness, headache in adults (headache is very common in children)

Uncommon dizziness,

Rare: paraesthesia

Gastrointestinal disorders

Common: gastrointestinal symptoms (such as nausea, vomiting, diarrhoea, abdominal pain)

Skin and subcutaneous tissue disorders

Rare: urticaria, pruritus, rash

Musculoskeletal and connective tissue disorders

Uncommon: myalgia

Rare: athralgia

Metabolism and nutrition disorders

Common: appetite lost

General disorders and administration site conditions

Very common: pain and redness at injection site, fatigue

Common: fever (> 37.5°C), malaise, swelling at injection site, injection site reaction (such as induration)

Uncommon: influenza-like illness

Psychiatric disorders

Very common: irritability

In a comparative trial in subjects from 11 years up to and including 15 years of age, the incidence of local and general solicited symptoms reported after a two-dose regimen of Engerix B 20 µg was similar overall to that reported after the standard three-dose regimen of Engerix B 10 µg.

• Post-marketing surveillance

Blood and lymphatic system disorders

Thrombocytopenia

Nervous system disorders

Encephalitis, encephalopathy, convulsions, paralysis, neuritis, (including Guillain-Barré syndrome, optic neuritis and multiple sclerosis) neuropathy, hypoaesthesia

Respiratory thoracic and mediastinal disorders

Apnoea in very premature infants ( 28 weeks of gestation) (see section 4.4)

Skin and subcutaneous tissue disorders

Erythema multiforme, angioneurotic oedema, lichen planus

Musculoskeletal and connective tissue disorders

Arthritis, muscular weakness

Infections and infestations

Meningitis

Vascular disorders

Vasculitis, hypotension

Immune system disorders

Anaphylaxis, allergic reactions including anaphylactoid reactions and mimicking serum sickness

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

Pharmacotherapeutic group: Hepatitis B vaccine, ATC code: J07BC01

Engerix B induces specific humoral antibodies against HBsAg (anti-HBs antibodies). An anti-HBs antibody titre > 10 IU/l correlates with protection to HBV infection.

Protective efficacy

- In risk groups:

In field studies, a protective efficacy between 95% and 100% was demonstrated in neonates, children and adults at risk.

A 95% protective efficacy was demonstrated in neonates of HBeAg positive mothers, immunised according to the 0, 1, 2 and 12 or 0, 1 and 6 schedules without the concomitant administration of HBIg at birth. However, simultaneous administration of HBIg and vaccine at birth increased the protective efficacy to 98%.

- In healthy subjects up to and including 15 years of age:

When the 0, 1 and 6 month schedule is followed, 96 % of vaccinees have seroprotective levels of antibody 7 months after the first dose.

When the 0, 1, 2 and 12 month schedule is followed, 15% and 89% of vaccinees have seroprotective levels of antibody one month after first dose and one month after the third dose respectively. One month after the fourth dose 95.8 % of vaccinees achieved seroprotective levels of antibody.

The table below summarizes seroprotection rates (i.e. percentages of subjects with anti-HBs antibody titre 10 IU/l) obtained in clinical studies with Engerix B 20µg, given according to the different schedules mentioned in Section 4.2:

The data in the table were generated with thiomersal containing vaccines. Two additional clinical studies conduted with the current formulation of Engerix B, which contains no thiomersal, among healthy infants and adults, elicit similar seroprotection rates as compared to former thiomersal containing forumulations of Engerix B.

*Seroprotection rates obtained with the Engerix B 10µg (0, 1, 6 months schedule) in subjects from 11 years up to and including 15 years of age were respectively of 55.8% at month 2, 87.6% at month 6 and 98.2% at month 7.

** At month 7, 88.8% and 97.3% of subjects aged 11 to 15 years vaccinated with Engerix B 20 µg (0, 6 months schedule) or Engerix B 10 µg (0, 1, 6 months schedule) respectively developed anti-HBs antibody titres > 100mIU/ml. Geometric Mean Titres were 2739 mIU/ml and 7238 mIU/ml respectively.

Reduction in the incidence of hepatocellular carcinoma in children:

A clear link has been demonstrated between hepatitis B infection and the occurrence of hepatocellular carcinoma (HCC). The prevention of hepatitis B by vaccination results in a reduction of the incidence of HCC, as has been observed in Taiwan in children aged 6-14 years.

Not applicable.

The preclinical safety data satisfy the requirements of the WHO.

Sodium chloride,

Disodium phosphate dihydrate,

Sodium dihydrogen phosphate,

Water for injections.

For adsorbent, see section 2

Engerix B should not be mixed with other medicinal products.

3 years.

Store at 2°C to 8°C (in a refrigerator).

Do not freeze; discard if vaccine has been frozen.

0.5 ml of suspension in a pre-filled syringe (type I glass). Pack of 1, 10, 25 or 50.

1.0 ml of suspension in a pre-filled syringe (type I glass). Pack of 1, 10 or 25.

Not all pack sizes may be marketed

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

The vaccine should be inspected visually for any foreign particulate matter and/or coloration prior to administration. Discard if the content appears otherwise.

The entire contents of a mono-dose container must be withdrawn and should be used immediately.

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

SmithKline Beecham plc

Trading as: GlaxoSmithKline UK,

Stockley Park West,

Uxbridge, Middlesex, UB11 1BT

PL 10592/0166

5 February 2001/25 February 2011

23 January 2012

POM