Fendrix suspension for injection.

Hepatitis B (rDNA) vaccine (adjuvanted, adsorbed).

1 dose (0.5 ml) of Fendrix contains:

²adsorbed on aluminium phosphate (0.5 milligrams Al³⁺ in total)

³produced in yeast cells (Saccharomyces cerevisiae) by recombinant DNA technology.

For a full list of excipients, see section 6.1

Suspension for injection.

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

Fendrix is indicated for active immunisation against hepatitis B virus infection (HBV) caused by all known subtypes for patients with renal insufficiency (including pre-haemodialysis and haemodialysis patients), from the age of 15 years onwards.

Posology

Primary Immunisation schedule:

A four dose schedule, with immunisations at the elected date, 1 month, 2 months and 6 months from the date of the first dose is recommended.

Once initiated, the primary course of vaccination at 0, 1, 2 and 6 months should be completed with Fendrix, and not with other commercially available HBV vaccine.

Booster dose:

As pre-haemodialysis and haemodialysis patients are particularly exposed to HBV and have a higher risk to become chronically infected, a precautionary attitude should be considered i.e. giving a booster dose in order to ensure a protective antibody level as defined by national recommendations and guidelines.

Fendrix can be used as a booster dose after a primary vaccination course with either Fendrix or any other commercial recombinant hepatitis B vaccine.

Special dosage recommendation for known or presumed exposure to HBV:

Data on concomitant administration of Fendrix with specific hepatitis B immunoglobulin (HBIg) have not been generated. However, in circumstances where exposure to HBV has recently occurred (e.g. stick with contaminated needle) and where simultaneous administration of Fendrix and a standard dose of HBIg is necessary, these should be given at separate injection sites.

Method of administration

Fendrix should be injected intramuscularly in the deltoid region.

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

Hypersensitivity after previous administration of other hepatitis B vaccines.

Subjects suffering from acute severe febrile illness. The presence of a minor infection such as a cold, is not a contraindication for immunisation.

Because of the long incubation period of hepatitis B, it is possible that patients could have been infected before the time of immunisation. 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 or other pathogens known to infect the liver.

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 Fendrix. Additional doses may need to be considered for persons who do not respond or have a sub-optimal response to a course of vaccinations.

Since intramuscular administration into the gluteal muscle could lead to a suboptimal response to the vaccine, this route should be avoided.

Fendrix should under no circumstances be administered intradermally or intravenously.

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 Hepatitis B vaccination should thus be considered on a casebycase basis by the physician.

Appropriate medical treatment should always be readily available in case of rare anaphylactic reactions following the administration of the vaccine.

No data on the concomitant administration of Fendrix and other vaccines or with specific hepatitis B immunoglobulin have been generated. If concomitant administration of specific hepatitis B immunoglobulin and Fendrix is required, these should be given at different injection sites. As no data are available for the concomitant administration of this particular vaccine with other vaccines, an interval of 2 to 3 weeks should be respected.

No clinical data on use during pregnancies are available with Fendrix.

Animal studies do not indicate direct or indirect harmful effects with respect to pregnancy, embryonal/foetal development, parturition or postnatal development.

Vaccination during pregnancy should only be performed if the risk-benefit ratio at individual level outweighs possible risks for the foetus.

Adequate human data on use during lactation are not available. In a reproductive toxicity study in animals which included post-natal follow-up until weaning (see section 5.3), no effect on the development of the pups was observed. Vaccination should only be performed if the risk-benefit ratio at individual level outweighs possible risks for the infant.

Fendrix has a minor or moderate influence on the ability to drive and use machine.

Some of the undesirable effects mentioned under section 4.8 may affect the ability to drive or operate machinery.

• Clinical trials involving the administration of 2476 doses of Fendrix to 82 pre-haemodialysis and haemodialysis patients and to 713 healthy subjects 15 years of age allowed to document the reactogenicity of the vaccine.

Pre-haemodialysis and haemodialysis patients

The reactogenicity profile of Fendrix in a total of 82 pre-haemodialysis and haemodialysis patients was generally comparable to that seen in healthy subjects.

Adverse reactions reported in a clinical trial following primary vaccination with Fendrix and considered as being related or possibly related to vaccination have been categorised by frequency.

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)

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

Nervous system disorders:

Very common: headache

Gastrointestinal disorders:

Common: gastrointestinal disorder

General disorders and administration site conditions

Very common: fatigue, pain Common: fever, injection site swelling, redness

Unsolicited symptoms considered to be at least possibly related to vaccination were uncommonly reported and consisted of rigors, other injection site reaction and maculo-papular rash.

Healthy subjects

The reactogenicity profile of Fendrix in healthy subjects was generally comparable to that seen in pre-haemodialysis and haemodialysis patients.

In a large double-blind randomised comparative study, healthy subjects were enrolled to receive a three dose primary course of Fendrix (N= 713) or a commercially available hepatitis B vaccine (N= 238) at 0, 1, 2 months. Fendrix was generally well tolerated. The most common adverse events reported were local reactions at the injection site.

Vaccination with Fendrix induced more transient local symptoms as compared to the comparator vaccine, with pain at the injection site being the most frequently reported solicited local symptom. However, solicited general symptoms were observed with similar frequencies in both groups.

Adverse reactions reported in a clinical trial following primary vaccination with Fendrix and considered as being at least possibly related to vaccination have been categorised by frequency.

Nervous system disorders:

Common: headache

Ear and labyrinth disorders:

Rare: vertigo

Gastrointestinal disorders:

Common: gastrointestinal disorder

Muskuloskeletal and connective tissue disorders:

Rare: tendinitis, back pain

Infections and infestations:

Rare: viral infection

General disorders and administration site conditions

Very common: injection site swelling, fatigue, pain, redness

Common: fever

Uncommon: other injection site reaction

Rare: rigors, hot flushes, thirst, asthenia

Immune system disorders:

Rare: allergy

Psychiatric disorders:

Rare: nervousness

No increase in the incidence or severity of these undesirable events was seen with subsequent doses of the primary vaccination schedule.

No increase in the reactogenicity was observed after the booster vaccination with respect to the primary vaccination.

Allergic reactions, including anaphylactoid reactions, may occur very rarely.

• Experience with hepatitis B vaccine:

Following widespread use of hepatitis B vaccines, in very rare cases, syncope, paralysis, neuropathy, neuritis (including Guillain-Barré syndrome, optic neuritis and multiple sclerosis), encephalitis, encephalopathy, meningitis and convulsions have been reported. The causal relationship to the vaccine has not been established.

No case of overdose has been reported.

Pharmacotherapeutic group: Hepatitis vaccines, ATC code J07BC01.

Fendrix induces specific humoral antibodies against HBsAg (anti-HBs antibodies). An anti-HBs antibody titre 10 mIU/ml correlates with protection to HBV infection.

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

Immunological data

In pre-haemodialysis and haemodialysis patients:

In a comparative clinical study in 165 pre-haemodialysis and haemodialysis patients (15 years and above), protective levels of specific humoral antibodies (anti-HBs titres 10 mIU/ml) were observed in 74.4% of Fendrix recipients (N = 82) one month after the third dose (i.e at month 3), as compared to 52.4% of patients in the control group who received a double dose of a commercially available hepatitis B vaccine (N = 83) for this population.

At month 3, Geometric Mean Titres (GMT) were 223.0 mIU/ml and 50.1 mIU/ml in the Fendrix and control groups respectively, with 41.0% and 15.9% of subjects with anti-HBs antibody titres 100 mIU/ml respectively.

After completion of a four dose primary course (i.e at month 7), 90.9% of Fendrix recipients were seroprotected ( 10 mIU/ml) against hepatitis B, in comparison with 84.4% in a control group who received the commercially available hepatitis B vaccine.

At month 7, GMTs were 3559.2 mIU/ml and 933.0 mIU/ml in the Fendrix and control groups who received the commercially available hepatitis B vaccine respectively, with 83.1% and 67.5% of subjects with anti-HBs antibody titres 100 mIU/ml respectively.

Antibody persistence

In pre-haemodialysis and haemodialysis patients:

Anti-HBs antibodies have been shown to persist for at least 36 months following a 0, 1, 2, 6 month primary course of Fendrix in pre-haemodialysis and haemodialysis patients. At month 36, 80.4% of these patients retained protective antibody levels (anti-HBs titres 10mIU/ml), as compared to 51.3% of patients who received a commercially available hepatitis B vaccine.

At month 36, GMTs were 154.1 mIU/ml and 111.9 mIU/ml in the Fendrix and control groups respectively, with 58.7% and 38.5% of subjects with anti-HBs antibody titres 100 mIU/ml respectively.

Pharmacokinetic properties of Fendrix or MPL alone has not been studied in humans.

Non-clinical data reveal no special hazard for humans based on conventional animal studies consisting of acute and repeated dose toxicity, cardiovascular and respiratory safety pharmacology and reproductive toxicity including pregnancy and peri and postnatal development of the pups till weaning (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 pre-filled syringe (type I glass) with a plunger stopper (rubber butyl) with or without separate needle in a pack size of 1, or without needles in a pack size of 10.

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 re-suspension 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/1/04/0299/001

EU/1/04/0299/002

EU/1/04/0299/003

Date of first authorisation: 02 February 2005

02 March 2009

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