GlaxoSmithKline (Ireland) Ltd

Infanrix hexa, Powder and suspension for suspension for injection in a pre-filled syringe.

Diphtheria (D), tetanus (T), pertussis (acellular, component) (Pa), hepatitis B (rDNA) (HBV), poliomyelitis (inactivated) (IPV) and Haemophilus influenzae type b (Hib) conjugate vaccine (adsorbed).

After reconstitution, 1 dose (0.5 ml) contains:

For a full list of excipients, see section 6.1.

Powder and suspension for suspension for injection in a pre-filled syringe.

The diphtheria, tetanus, acellular pertussis, hepatitis B, inactivated poliomyelitis (DTPa-HBV-IPV) component is a turbid white suspension.

The lyophilised Haemophilus influenzae type b (Hib) component is a white powder.

Infanrix hexa is indicated for primary and booster vaccination of infants against diphtheria, tetanus, pertussis, hepatitis B, poliomyelitis and disease caused by Haemophilus influenzae type b.

Posology

Primary vaccination:

The primary vaccination schedule consists of three doses of 0.5 ml (such as 2, 3, 4 months; 3, 4, 5 months; 2, 4, 6 months) or two doses (such as 3, 5 months). There should be an interval of at least 1 month between doses.

The Expanded Program on Immunisation schedule (at 6, 10, 14 weeks of age) may only be used if a dose of hepatitis B vaccine has been given at birth.

Locally established immunoprophylactic measures against hepatitis B should be maintained.

Where a dose of hepatitis B vaccine is given at birth, Infanrix hexa can be used as a replacement for supplementary doses of hepatitis B vaccine from the age of six weeks. If a second dose of hepatitis B vaccine is required before this age, monovalent hepatitis B vaccine should be used.

Booster vaccination:

After a vaccination with 2 doses (e.g. 3, 5 months) of Infanrix hexa a booster dose must be given at least 6 months after the last priming dose, preferably between 11 and 13 months of age.

After vaccination with 3 doses (e.g. 2, 3, 4 months; 3, 4, 5 months; 2, 4, 6 months) of Infanrix hexa a booster dose must be given at least 6 months after the last priming dose and preferably before 18 months of age.

Booster doses should be given in accordance with the official recommendations, but, as a minimum, a dose of Hib conjugate vaccine must be administered.

Infanrix hexa can be considered for the booster if the composition is in accordance with the official recommendations.

Paediatric population

The safety and efficacy of Infanrix hexa in children over 36 months of age have not been established.

No data available.

Method of administration

Infanrix hexa is for deep intramuscular injection, preferably at alternating sites for subsequent injections.

Hypersensitivity to the active substances or to any of the excipients or neomycin and polymyxin.

Hypersensitivity after previous administration of diphtheria, tetanus, pertussis, hepatitis B, polio or Hib vaccines.

Infanrix hexa is contraindicated if the infant has experienced an encephalopathy of unknown aetiology, occurring within 7 days following previous vaccination with pertussis containing vaccine. In these circumstances pertussis vaccination should be discontinued and the vaccination course should be continued with diphtheria-tetanus, hepatitis B, polio and Hib vaccines.

As with other vaccines, administration of Infanrix hexa should be postponed in subjects suffering from acute severe febrile illness. The presence of a minor infection is not a contraindication.

Vaccination should be preceded by a review of the medical history (especially with regard to previous vaccination and possible occurrence of undesirable events) and a clinical examination.

If any of the following events are known to have occurred in temporal relation to receipt of pertussis-containing vaccine, the decision to give further doses of pertussis-containing vaccines should be carefully considered:

• Temperature of 40.0°C within 48 hours, not due to another identifiable cause;

• Collapse or shock-like state (hypotonic-hyporesponsiveness episode) within 48 hours of vaccination;

• Persistent, inconsolable crying lasting 3 hours, occurring within 48 hours of vaccination;

• Convulsions with or without fever, occurring within 3 days of vaccination.

There may be circumstances, such as a high incidence of pertussis, when the potential benefits outweigh possible risks.

As for any vaccination, the risk-benefit of immunising with Infanrix hexa or deferring this vaccination should be weighed carefully in an infant or in a child suffering from a new onset or progression of a severe neurological disorder.

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.

Infanrix hexa should be administered with caution to subjects with thrombocytopenia or a bleeding disorder since bleeding may occur following an intramuscular administration to these subjects.

Infanrix hexa should under no circumstances be administered intravascularly or intradermally.

Infanrix hexa will not prevent disease caused by pathogens other than Corynebacterium diphtheriae, Clostridium tetani, Bordetella pertussis, hepatitis B virus, poliovirus or Haemophilus influenzae type b. However, it can be expected that hepatitis D will be prevented by immunisation as hepatitis D (caused by the delta agent) does not occur in the absence of hepatitis B infection.

As with any vaccine, a protective immune response may not be elicited in all vaccinees (see section 5.1).

A history of febrile convulsions, a family history of convulsions or Sudden Infant Death Syndrome (SIDS) do not constitute a contraindication for the use of Infanrix hexa. Vaccinees with a history of febrile convulsions should be closely followed up as such adverse events may occur within 2 to 3 days post vaccination.

HIV infection is not considered as a contraindication. The expected immunological response may not be obtained after vaccination of immunosuppressed patients.

Since the Hib capsular polysaccharide antigen is excreted in the urine, a positive urine test can be observed within 1-2 weeks following vaccination. Other tests should be performed in order to confirm Hib infection during this period.

When Infanrix hexa is co-administered with Prevenar (pneumococcal saccharide conjugated vaccine, adsorbed), the physician should be aware that data from clinical studies indicate that the rate of febrile reactions was higher compared to that occurring following the administration of Infanrix hexa alone. These reactions were mostly moderate (less than or equal to 39°C) and transient (see section 4.8).

Antipyretic treatment should be initiated according to local treatment guidelines.

Limited data in 169 premature infants indicate that Infanrix hexa can be given to premature children. However, a lower immune response may be observed and the level of clinical protection remains unknown.

The potential risk of apnoea and the need for respiratory monitoring for 48-72h 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 the vaccination is high in this group of infants, vaccination should not be withheld or delayed.

There are insufficient data with regard to the efficacy and safety of simultaneous administration of Infanrix hexa and Measles-Mumps-Rubella vaccine to allow any recommendation to be made.

Data on concomitant administration of Infanrix hexa with Prevenar (pneumococcal saccharide conjugated vaccine, adsorbed) have shown no clinically relevant interference in the antibody response to each of the individual antigens when given as a 3 dose primary vaccination.

As with other vaccines it may be expected that in patients receiving immunosuppressive therapy, an adequate response may not be achieved.

As Infanrix hexa is not intended for use in adults, adequate human data on use during pregnancy or lactation and adequate animal reproduction studies are not available.

Not relevant.

• Clinical trials:

The safety profile presented below is based on data from more than 16,000 subjects.

As has been observed for DTPa and DTPa-containing combinations, an increase in local reactogenicity and fever was reported after booster vaccination with Infanrix hexa with respect to the primary course.

- Clinical trials on co-administration:

In clinical studies in which some of the vaccinees received Infanrix hexa concomitantly with Prevenar as a booster (4th) dose of both vaccines, fever 38.0°C was reported following 43.4% of doses in infants receiving Prevenar and Infanrix hexa at the same time as compared to 30.5% of doses in infants receiving the hexavalent vaccine alone. Fever of greater than 39.5°C was observed following 2.6% and 1.5% of doses in infants receiving Infanrix hexa with or without Prevenar, respectively, (see section 4.4). The incidence of fever following co-administration of the two vaccines in the primary series was lower than that observed after the booster dose.

- Tabulated summary of adverse reactions (clinical trials):

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

Frequencies per dose are defined as follows:

Metabolism and nutrition disorders

Very common: appetite lost

Psychiatric disorders

Very common: crying abnormal, irritability, restlessness

Common: nervousness

Nervous system disorders

Uncommon: somnolence

Very rare: convulsions (with or without fever)

Respiratory, thoracic and mediastinal disorders

Uncommon: cough

Gastrointestinal disorders

Common: diarrhoea, vomiting

Skin and subcutaneous tissue disorders

Rare: rash

Very rare: dermatitis

General disorders and administration site conditions

Very common: fever 38°C, local swelling at the injection site ( 50 mm), fatigue, pain, redness

Common: fever>39.5°C, injection site reactions, including induration, local swelling at the injection site (> 50 mm)*

Uncommon: diffuse swelling of the injected limb, sometimes involving the adjacent joint*

• Post marketing surveillance:

Blood and lymphatic system disorders

Lymphadenopathy

Immune system disorders

Anaphylactic reactions, anaphylactoid reactions (including urticaria), allergic reactions (including pruritus)

Nervous system disorders

Collapse or shock-like state (hypotonic-hyporesponsiveness episode)

Respiratory, thoracic and mediastinal disorders

Apnoea [see section 4.4 for apnoea in very premature infants ( 28 weeks of gestation)]

Skin and subcutaneous tissue disorders

Angioedema

General disorders and administration site conditions

Swelling of the entire injected limb*, extensive swelling reactions, injection site mass, injection site vesicles

* Children primed with acellular pertussis vaccines are more likely to experience swelling reactions after booster administration in comparison with children primed with whole cell vaccines. These reactions resolve over an average of 4 days.

• Experience with hepatitis B vaccine:

In extremely rare cases, paralysis, neuropathy, Guillain-Barré syndrome, encephalopathy, encephalitis and meningitis have been reported. The causal relationship to the vaccine has not been established.

Thrombocytopenia has been reported with hepatitis B vaccines.

No case of overdose has been reported.

Pharmaco-therapeutic group: Bacterial and viral vaccines combined, ATC code J07CA09

Results obtained in the clinical studies for each of the components are summarised in the tables below:

Percentage of subjects with antibody titres assay cut-off one month after primary vaccination with Infanrix hexa

N = number of subjects

* in a subgroup of infants not administered hepatitis B vaccine at birth, 77.7% of subjects had anti-HBs titres 10 mIU/ml

† cut-off accepted as indicative of protection

Percentage of subjects with antibody titres assay cut-off one month after booster vaccination with Infanrix hexa

N = number of subjects

† cut-off accepted as indicative of protection

As the immune response to pertussis antigens following Infanrix hexa administration is equivalent to that of Infanrix, the protective efficacy of the two vaccines is expected to be equivalent.

The clinical protection of the pertussis component of Infanrix, against WHO-defined typical pertussis ( 21 days of paroxysmal cough) was demonstrated in:

- a prospective blinded household contact study performed in Germany (3, 4, 5 months schedule). Based on data collected from secondary contacts in households where there was an index case with typical pertussis, the protective efficacy of the vaccine was 88.7%.

- a NIH sponsored efficacy study performed in Italy (2, 4, 6 months schedule. The vaccine efficacy was found to be 84%. In a follow-up of the same cohort, the efficacy was confirmed up to 60 months after completion of primary vaccination without administration of a booster dose of pertussis.

Results of long term follow-up in Sweden demonstrate that acellular pertussis vaccines are efficacious in infants when administered according to the 3 and 5 months primary vaccination schedule, with a booster dose administered at approximately 12 months. However, data indicate that protection against pertussis may be waning at 7-8 years of age with this 3-5-12 months schedule. This suggests that a second booster dose of pertussis vaccine is warranted in children aged 5-7 years who have previously been vaccinated following this particular schedule.

Protective antibodies against hepatitis B have been shown to persist for at least 3.5 years in more than 90% of children administered four doses of Infanrix hexa. Antibody levels were not different from what was observed in a parallel cohort administered 4 doses of monovalent hepatitis B vaccine.

The effectiveness of the Hib component of Infanrix hexa was investigated via an extensive post-marketing surveillance study conducted in Germany. Over a seven year follow-up period, the effectiveness of the Hib components of two hexavalent vaccines, of which one was Infanrix hexa, was 89.6% for a full primary series and 100% for a full primary series plus booster dose (irrespective of the Hib vaccine used for priming).

Evaluation of pharmacokinetic properties is not required for vaccines.

Non-clinical data reveal no special hazard for humans based on conventional studies of safety, specific toxicity, repeated dose toxicity and compatibility of ingredients.

Hib powder:

Lactose anhydrous

DTPa-HBV-IPV suspension:

Sodium chloride (NaCl)

Medium 199 containing principally amino acids, mineral salts, vitamins

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.

After reconstitution: an immediate use is recommended. However the stability has been demonstrated for 8 hours at 21°C after reconstitution.

Store in a refrigerator (2°C - 8°C).

Do not freeze.

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

For storage conditions of the reconstituted medicinal product, see section 6.3.

Powder in a vial (type I glass) with a stopper (butyl).

0.5 ml of suspension in a pre-filled syringe (type I glass) with plunger stoppers (butyl).

Pack sizes of 1, 10, 20 and 50 with or without needles.

Not all pack sizes may be marketed.

Upon storage, a white deposit and clear supernatant may be observed in the pre-filled syringe containing the DTPa-HBV-IPV suspension. This does not constitute a sign of deterioration.

The pre-filled syringe should be well shaken in order to obtain a homogeneous turbid white suspension.

The DTPa-HBV-IPV suspension should be inspected visually for any foreign particulate matter and/or abnormal physical appearance. In the event of either being observed, discard the vaccine.

The vaccine is reconstituted by adding the entire contents of the pre-filled syringe to the vial containing the Hib powder. After the addition of the DTPa-HBV-IPV suspension to the Hib powder, the mixture should be well shaken until the powder is completely dissolved.

The reconstituted vaccine presents as a slightly more cloudy suspension than the liquid component alone. This is normal and does not impair the performance of the vaccine. In the event of other variation being observed, discard the vaccine.

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/1/00/152/001

EU/1/00/152/002

EU/1/00/152/003

EU/1/00/152/004

EU/1/00/152/005

EU/1/00/152/006

EU/1/00/152/007

EU/1/00/152/008

Date of first authorisation: 23 October 2000

Date of latest renewal: 23 October 2010

26/07/2011

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