INFANRIX HEXA powder + suspension for injection suspension medication leaflet

Infanrix hexa, Powder and suspension for suspension for injection.

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:

Diphtheria toxoid1 not less than 30 International Units (IU)

Tetanus toxoid1 not less than 40 International Units (IU)

Bordetella pertussis antigens

Pertussis toxoid (PT)1 25 micrograms

Filamentous Haemagglutinin (FHA)1 25 micrograms

Pertactin (PRN)1 8 micrograms

Hepatitis B surface antigen (HBs)2,3 10 micrograms

Poliovirus (inactivated) (IPV)type 1 (Mahoney strain)4 40 D-antigen unittype 2 (MEF-1 strain)4 8 D-antigen unittype 3 (Saukett strain)4 32 D-antigen unit

Haemophilus influenzae type b polysaccharide 10 micrograms(polyribosylribitol phosphate, PRP) 3conjugated to tetanus toxoid as carrier protein approximately 25 micrograms1adsorbed on aluminium hydroxide, hydrated (Al(OH)3) 0.5 milligrams Al3+2produced in yeast cells (Saccharomyces cerevisiae) by recombinant DNA technology3adsorbed on aluminium phosphate (AlPO4) 0.32 milligrams Al3+4propagated in VERO cells

The vaccine may contain traces of formaldehyde, neomycin and polymyxin whichare used during the manufacturing process (see section 4.3).

The vaccine contains para-aminobenzoic acid 0.057 nanograms per dose and phenylalanine 0.0298micrograms per dose (see section 4.4).

For the full list of excipients, see section 6.1.

Powder and suspension for suspension for injection.

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 from the age of 6 weeks andtoddlers against diphtheria, tetanus, pertussis, hepatitis B, poliomyelitis and disease caused by

Haemophilus influenzae type b.

The use of Infanrix hexa should be in accordance with official recommendations.

The primary vaccination schedule consists of two or three doses (of 0.5 ml) which should beadministered according to official recommendations (see the table below in this section and section 5.1for schedules evaluated in clinical trials).

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

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 fromthe age of six weeks. If a second dose of hepatitis B vaccine is required before this age,monovalent hepatitis B vaccine should be used.

* Infanrix hexa can be used for a mixed pentavalent/hexavelent vaccine primary immunisationschedule in accordance with official recommendations.

Locally established immunoprophylactic measures against hepatitis B should be maintained.

Infanrix hexa can be replaced by the adminstration of a pentavalent vaccine co-adminsitered withhepatitis B vaccine.

Booster vaccination

After a 2-dose or a 3-dose primary series vaccination with Infanrix hexa, a booster dose with Infanrixhexa should be given at least 6 months after the last priming dose (see the table below in this section andsection 5.1 for schedules evaluated in clinical trials).

Infanrix hexa may be used as a booster in individuals who have previously been vaccinated with anotherhexavalent vaccine or a pentavalent DTPa-IPV+Hib vaccine associated with a monovalent hepatitis Bvaccine for their primary series.

When a booster dose with a hexavalent DTPa (diphtheria, tetanus, and acellular pertussis) containingvaccine is not available, a dose of Hib vaccine must be administered, as a minimum.

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

No data are available.

Primary vaccination Booster General considerationsvaccination

Full-term infants3-dose A booster dose * There should be an interval of at least 1 monthmust be given. between primary doses.

* The booster dose should be given at least 6 monthsafter the last priming dose and preferably before18 months of age.

2-dose A booster dose * There should be an interval of at least 2 monthsmust be given. between primary doses.

* The booster dose should be given at least 6 monthsafter the last priming dose and preferably between11 and 13 months of age.

Preterm infants born after at least 24 weeks of gestational age3-dose A booster dose * There should be an interval of at least 1 monthmust be given. between primary doses.

* The booster dose should be given at least 6 monthsafter the last priming dose and preferably before18 months of age.

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

For instructions on reconstitution of the medicinal product before administration, see section 6.6.

Hypersensitivity to the active substances or to any of the excipients listed in section 6.1, orformaldehyde, neomycin and polymyxin.

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

Infanrix hexa is contraindicated if the infant or toddlers has experienced an encephalopathy of unknownaetiology, occurring within 7 days following previous vaccination with pertussis containing vaccine. Inthese circumstances pertussis vaccination should be discontinued, and the vaccination course should becontinued with diphtheria-tetanus, hepatitis B, polio and Hib vaccines.

As with other vaccines, administration of Infanrix hexa should be postponed in subjects suffering fromacute 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 previousvaccination and possible occurrence of undesirable events) and a clinical examination.

As with any vaccine, a protective immune response may not be elicited in all vaccinees (see section5.1).

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 (causedby the delta agent) does not occur in the absence of hepatitis B infection.

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 becarefully considered:

 Temperature of ≥ 40.0°C within 48 hours of vaccination, not due to another identifiable cause; Collapse or shock-like state (hypotonic-hyporesponsive episode) within 48 hours ofvaccination; 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 outweighpossible risks.

As with all injectable vaccines, appropriate medical treatment and supervision should always be readilyavailable in case of a rare anaphylactic event following the administration of the vaccine.

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

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

Do not administer the vaccine intravascularly or intradermally.

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 offebrile convulsions should be closely followed up as such adverse events may occur within 2 to 3 dayspost vaccination.

The physician should be aware that the rate of febrile reactions is higher when Infanrix hexa is co-administered with a pneumococcal conjugate vaccine (PCV7, PCV10, PCV13), or with a measles-mumps-rubella-varicella (MMRV) vaccine, 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 sections 4.5 and 4.8).

Increased reporting rates of convulsions (with or without fever) and hypotonic hyporesponsive episode(HHE) were observed with concomitant administration of Infanrix hexa and Prevenar 13 (see section4.8).

Prophylactic administration of antipyretics before or immediately after vaccine administration canreduce the incidence and intensity of post-vaccination febrile reactions. Clinical data generated withparacetamol and ibuprofen suggest that the prophylactic use of paracetamol might reduce the fever rate,while prophylactic use of ibuprofen showed a limited effect in reducing fever rate.

The use of prophylactic antipyretic medicinal products is recommended for children with seizuredisorders or with a prior history of febrile seizures.

Antipyretic treatment should be initiated according to local treatment guidelines.

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

Clinical data indicate that Infanrix hexa can be given to preterm infants, however, as expected in thispopulation, a lower immune response has been observed for some antigens (see section 4.8 and section5.1).

The potential risk of apnoea and the need for respiratory monitoring for 48-72h should be consideredwhen administering the primary immunisation series to very preterm infants (born ≤ 28 weeks ofgestation) and particularly for those with a previous history of respiratory immaturity.

As the benefit of the vaccination is high in these infants, vaccination should not be withheld or delayed.

Interference with laboratory testing

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

Hib infection during this period.

Infanrix hexa contains para-aminobenzoic acid. It may cause allergic reactions (possibly delayed), andexceptionally, bronchospasm.

The vaccine contains 0.0298 microgram phenylalanine in each dose. Phenylalanine may be harmful ifyou have phenylketonuria (PKU), a rare genetic disorder in which phenylalanine builds up because thebody cannot remove it properly.

The vaccine contains less than 1 mmol sodium (23 mg) per dose, that is to say essentially ‘sodium-free’.

The vaccine contains potassium, less than 1 mmol (39 mg) per dose, i.e. essentially ‘potassium-free’.

In order to improve the traceability of biological medicinal products, the name and the batch number ofthe administered product should be clearly recorded.

Infanrix hexa can be given concomitantly with pneumococcal conjugate vaccines (PCV7, PCV10 and

PCV13), meningococcal serogroup C conjugate vaccine (CRM197 and TT conjugates), meningococcalserogroups A, C, W-135 and Y conjugate vaccine (TT conjugate), meningococcal serogroup B vaccine(MenB), oral rotavirus vaccine and measles-mumps-rubella-varicella (MMRV) vaccine.

Data have shown no clinically relevant interference in the antibody response to each of the individualantigens, although inconsistent antibody response to poliovirus type 2 in co-administration with

Synflorix was observed (seroprotection ranging from 78% to 100%) and the immune response rates tothe PRP (Hib) antigen of Infanrix hexa after 2 doses given at 2 and 4 months of age were higher if co-administered with a tetanus toxoid conjugate pneumococcal or meningococcal vaccine (see section 5.1).

The clinical relevance of these observations remains unknown.

When Infanrix hexa was co-administered with MenB and pneumococcal conjugate vaccines,inconsistent results were seen across studies for responses to inactivated poliovirus type 2,pneumococcal conjugate serotype 6B antigen and to the pertussis pertactin antigen but these data do notsuggest clinically significant interference.

Data from clinical studies indicate that, when Infanrix hexa is co-administered with pneumococcalconjugate vaccines, the rate of febrile reactions is higher compared to that occurring following theadministration of Infanrix hexa alone. Data from one clinical study indicate that when Infanrix hexa isco-administered with MMRV vaccine, the rate of febrile reactions is higher compared to that occurringfollowing the administration of Infanrix hexa alone and similar to that occurring following theadministration of MMRV vaccine alone (see sections 4.4 and 4.8). The immune responses wereunaffected.

Due to an increased risk of fever, pain at the injection site, loss of appetite and irritability when Infanrixhexa was co-administered with MenB vaccine and 7-valent pneumococcal conjugate vaccine, separatevaccinations can be considered when possible.

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

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

Not relevant.

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

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

Frequencies per dose are defined as follows:

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)

The following drug-related adverse reactions were reported in clinical studies (data from more than16,000 subjects) and during post-marketing surveillance.

System Organ Class Frequency Adverse reactions

Infections and infestations Uncommon Upper respiratory tract infection

Blood and lymphatic system disorders Rare Lymphadenopathy2, thrombocytopenia2

Immune system disorders Rare Anaphylactic reactions2, anaphylactoidreactions (including urticaria)2

Allergic reactions (including pruritus)2

Metabolism and nutrition disorders Very common Loss of appetite

Psychiatric disorders Very common Crying abnormal, irritability, restlessness

Common Nervousness

Nervous system disorders Very common Somnolence

Rare Collapse or shock-like state (hypotonic-hyporesponsive episode)2

Very rare Convulsions (with or without fever)

Respiratory, thoracic and mediastinal Uncommon Coughdisorders Rare Bronchitis, apnoea2 [see section 4.4 forapnoea in very preterm infants (≤ 28weeks of gestation)]

Gastrointestinal disorders Common Diarrhoea, vomiting

Skin and subcutaneous tissue disorders Rare Rash, Angioedema2

Very rare Dermatitis

General disorders and administration site Very common Fever ≥ 38°C, pain, redness, localconditions swelling at the injection site (≤ 50 mm)

Common Fever >39.5°C, injection site reactions,including induration, local swelling at theinjection site (> 50 mm)1

Uncommon Diffuse swelling of the injected limb,sometimes involving the adjacent joint1,fatigue

Rare Swelling of the entire injected limb1, 2,extensive swelling reactions2, injectionsite mass2, injection site vesicles21 Children primed with acellular pertussis vaccines are more likely to experience swelling reactions afterbooster administration in comparison with children primed with whole cell vaccines. These reactionsresolve over an average of 4 days.2 Adverse reactions from spontaneous reporting.

* Experience in co-administration:

Analysis of postmarketing reporting rates suggests a potential increased risk of convulsions (with orwithout fever) and HHE when comparing groups which reported use of Infanrix hexa with Prevenar 13to those which reported use of Infanrix hexa alone.

In clinical studies in which some of the vaccinees received Infanrix hexa concomitantly with Prevenar(PCV7) as a booster (4th) dose of both vaccines, fever ≥ 38.0°C was reported in 43.4% of infantsreceiving Prevenar and Infanrix hexa at the same time as compared to 30.5% of infants receiving thehexavalent vaccine alone. Fever ≥39.5°C was observed in 2.6% and 1.5% of infants receiving Infanrixhexa with or without Prevenar, respectively (see sections 4.4 and 4.5). The incidence and severity offever following co-administration of the two vaccines in the primary series was lower than that observedafter the booster dose.

Data from clinical studies show similar incidences of fever when Infanrix hexa is co-administered withother pneumococcal saccharide conjugated vaccine.

In a clinical study in which some of the vaccinees received a booster dose of Infanrix hexaconcomitantly with measles-mumps-rubella-varicella (MMRV) vaccine, fever ≥ 38.0°C was reported in76.6% of children receiving MMRV vaccine and Infanrix hexa at the same time, as compared to 48% ofchildren receiving Infanrix hexa alone and 74.7% of children receiving MMRV vaccine alone. Fever ofgreater than 39.5°C was reported in 18% of children receiving Infanrix hexa with MMRV vaccine, ascompared to 3.3% of children receiving Infanrix hexa alone and 19.3% of children receiving MMRValone (see sections 4.4 and 4.5).

* Safety in preterm infants:

Infanrix hexa has been administered to more than 1000 preterm infants (born after a gestation period of24 to 36 weeks) in primary vaccination studies and in more than 200 preterm infants as a booster dose inthe second year of life. In comparative clinical studies, similar rates of symptoms were observed inpreterm and full-term infants (refer to section 4.4 for information on apnoea).

* Safety in infants and toddlers born to mothers vaccinated with dTpa during pregnancy

In two clinical studies, Infanrix hexa has been administered to more than 500 subjects born to mothersvaccinated with dTpa (n=341) or placebo (n=346) during the third trimester of pregnancy (see section5.1). The safety profile of Infanrix hexa was similar regardless of exposure/non-exposure to dTpa duringpregnancy.

* Experience with hepatitis B vaccine:

In extremely rare cases, allergic reactions mimicking serum sickness, paralysis, neuropathy, neuritis,hypotension, vasculitis, lichen planus, erythema multiforme, arthritis, muscular weakness, Guillain-

Barré syndrome, encephalopathy, encephalitis and meningitis have been reported. The causalrelationship to the vaccine has not been established.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting system listedin Appendix V.

No case of overdose has been reported.

Pharmacotherapeutic group: Bacterial and viral vaccines combined, ATC code: J07CA09

The immunogenicity of Infanrix hexa has been evaluated in clinical studies from 6 weeks of age. Thevaccine was assessed in 2-dose and 3-dose priming schedules, including the schedule for the Expanded

Program on Immunisation, and as a booster dose. The results of these clinical studies are summarised inthe tables below.

After a 3-dose primary vaccination schedule, at least 95.7% of infants had developed seroprotective orseropositive antibody levels against each of the vaccine antigens. After booster vaccination (post-dose4), at least 98.4% of children had developed seroprotective or seropositive antibody levels against eachof the vaccine antigens.

Percentage of subjects with antibody titres indicative of seroprotection/seropositivity one monthafter 3-dose primary and booster vaccination with Infanrix hexa

Antibody Post-dose 3 Post-dose 4(cut-off) (Booster vaccinationduring the secondyear of life followinga 3-dose primarycourse)2-3-4 2-4-6 3-4-5 6-10-14months months months weeks N=2009

N= 196 N= 1693 N= 1055 N= 265 (12 studies)(2 studies) (6 studies) (6 studies) (1 study)% % % % %

Anti-diphtheria 100.0 99.8 99.7 99.2 99.9(0.1 IU/ml) †

Anti-tetanus 100.0 100.0 100.0 99.6 99.9(0.1 IU/ml) †

Anti-PT 100.0 100.0 99.8 99.6 99.9(5 EL.U/ml)

Anti-FHA 100.0 100.0 100.0 100.0 99.9(5 EL.U/ml)

Anti-PRN 100.0 100.0 99.7 98.9 99.5(5 EL.U/ml)

Anti-HBs 99.5 98.9 98.0 98.5* 98.4(10 mIU/ml) †

Anti-Polio type 1 100.0 99.9 99.7 99.6 99.9(1/8 dilution) †

Anti-Polio type 2 97.8 99.3 98.9 95.7 99.9(1/8 dilution) †

Anti-Polio type 3 100.0 99.7 99.7 99.6 99.9(1/8 dilution) †

Anti-PRP 96.4 96.6 96.8 97.4 99.7**(0.15 µg/ml) †

N = number of subjects

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

** Post booster, 98.4% of subjects had anti-PRP concentration ≥ 1 µg/ml indicative of long-termprotection† cut-off accepted as indicative of protection

After a 2-dose primary vaccination schedule, at least 84.3% of infants had developed seroprotective orseropositive antibody levels against each of the vaccine antigens. After a complete vaccinationaccording to a 2-dose primary and booster schedule with Infanrix hexa, at least 97.9% of the subjectshad developed seroprotective or seropositive antibody levels against each of the vaccine antigens.

According to different studies, immune response to the PRP antigen of Infanrix hexa after 2 doses givenat 2 and 4 months of age will vary if co-administered with a tetanus toxoid conjugate vaccine. Infanrixhexa will confer an anti-PRP immune response (cut-off ≥ 0.15µg/ml) in at least 84% of the infants. Thisrises to 88% in case of concomitant use of pneumococcal vaccine containing tetanus toxoid as carrierand to 98% when Infanrix hexa is co-administered with a TT conjugated meningococcal vaccine (seesection 4.5).

Percentage of subjects with antibody titres indicative of seroprotection/seropositivity one monthafter 2-dose primary and booster vaccination with Infanrix hexa

Post-dose 2 Post-dose 3

Antibody 2-4-12 months of 3-5-11 months of 2-4-12 months of 3-5-11 months of(cut-off) age age age age

N=223 N=530 N=196 N=532(1 study) (4 studies) (1 study) (3 studies)% % % %

Anti-diphtheria 99.6 98.0 100.0 100.0(0.1 IU/ml) †

Anti-tetanus 100 100.0 100.0 100.0(0.1 IU/ml) †

Anti-PT 100 99.5 99.5 100.0(5 EL.U/ml)

Anti-FHA 100 99.7 100.0 100.0(5 EL.U/ml)

Anti-PRN 99.6 99.0 100.0 99.2(5 EL.U/ml)

Anti-HBs 99.5 96.8 99.8 98.9(10 mIU/ml) †

Anti-Polio type 1 89.6 99.4 98.4 99.8(1/8 dilution) †

Anti-Polio type 2 85.6 96.3 98.4 99.4(1/8 dilution) †

Anti-Polio type 3 92.8 98.8 97.9 99.2(1/8 dilution) †

Anti-PRP 84.3 91.7 100.0* 99.6*(0.15 µg/ml) †

N = number of subjects† cut-off accepted as indicative of protection

* Post booster, 94.4% of subjects in the 2-4-12 months schedule and 97.0% of subjects in the 3-5-11months schedule had anti-PRP concentration ≥ 1 µg/ml indicative of long-term protection.

Serological correlates of protection have been established for diphtheria, tetanus, polio, hepatitis B and

Hib. For pertussis there is no serological correlate of protection. However, as the immune response topertussis antigens following Infanrix hexa administration is equivalent to that of Infanrix (DTPa), theprotective efficacy of the two vaccines is expected to be equivalent.

Efficacy in protecting against pertussis

The clinical protection of the pertussis component of Infanrix (DTPa), against WHO-defined typicalpertussis (≥ 21 days of paroxysmal cough) was demonstrated after 3-dose primary immunisation in thestudies tabulated below:

Study Country Schedule Vaccineefficacy Considerations

Household contact Germany 3,4,5 months 88.7% Based on data collected from secondarystudy (prospective contacts in households where there was anblinded) index case with typical pertussis

Efficacy study Italy 2,4,6 months 84% In a follow-up of the same cohort, the(NIH sponsored) efficacy was confirmed up to 60 monthsafter completion of primary vaccinationwithout administration of a booster doseof pertussis.

Persistence of the immune response

The persistence of the immune response to a 3-dose primary (at 2-3-4, 3-4-5 or 2-4-6 months of age)and booster (in the second year of life) schedule with Infanrix hexa was evaluated in children 4-8 yearsof age. Protective immunity against the three poliovirus types and PRP was observed in at least 91.0%of children and against diphtheria and tetanus in at least 64.7% of children. At least 25.4% (anti-PT),97.5% (anti-FHA) and 87.0% (anti-PRN) of children were seropositive against the pertussiscomponents.

Percentage of subjects with antibody titres indicative of seroprotection/seropositivity afterprimary and booster vaccination with Infanrix hexa

Antibody Children at 4-5 years of age Children at 7-8 years of age(cut-off) N % N %

Anti-diphtheria(0.1 IU/ml) 198 68.7* 51 66.7

Anti-tetanus(0.1 IU/ml) 198 74.7 51 64.7

Anti-PT(5 EL.U/ml) 197 25.4 161 32.3

Anti-FHA(5 EL.U/ml) 197 97.5 161 98.1

Anti-PRN(5 EL.U/ml) 198 90.9 162 87.0

Anti-HBs 250§ 85.3 207§ 72.1(10 mIU/ml) 171§ 86.4 149§ 77.2

Anti-Polio type 1(1/8 dilution) 185 95.7 145 91.0

Anti-Polio type 2(1/8 dilution) 187 95.7 148 91.2

Anti-Polio type 3(1/8 dilution) 174 97.7 144 97.2

Anti-PRP(0.15 µg/ml) 198 98.0 193 99.5

N = number of subjects

* Samples tested by ELISA to have anti-diphtheria antibody concentrations < 0.1 IU/ml were re-testedusing Vero-cell neutralisation assay (seroprotection cut-off ≥ 0.016 IU/ml): 96.5% of the subjects wereseroprotected§ Number of subjects from 2 clinical studies

With regards to hepatitis B, seroprotective antibody concentrations (≥10 mIU/ml) following a 3-doseprimary and booster schedule with Infanrix hexa have been shown to persist in ≥ 85% of subjects 4-5years of age, in ≥72% of subjects 7-8 years of age, in ≥60% of subjects 12-13 years of age and in 53.7%of subjects 14-15 years of age. Additionally, following a 2-dose primary and booster schedule,seroprotective antibody concentrations against hepatitis B persisted in ≥ 48% of subjects 11-12 years ofage.

Hepatitis B immunological memory was confirmed in children 4 to 15 years of age. These children hadreceived Infanrix hexa as primary and booster vaccination in infancy, and when an additional dose ofmonovalent HBV vaccine was administered, protective immunity was observed in at least 93% ofsubjects.

Immunogenicity in infants and toddlers born to mothers vaccinated with dTpa during pregnancy

The immunogenicity of Infanrix hexa in infants and toddlers born to healthy mothers vaccinated withdTpa at 27-36 weeks of pregnancy was evaluated in two clinical studies.

Infanrix hexa was co-administered with a 13-valent pneumococcal conjugate vaccine to infants at 2, 4and 6 months or 2, 3 and 4 months in three-dose primary vaccination schedules (n=241), or at 3 and 5months or 2 and 4 months in two-dose primary vaccination schedules (n=27); and to the sameinfants/toddlers from 11 to 18 months as booster dose (n=229).

Post-primary and post-booster vaccination, immunological data did not show clinically relevantinterference of maternal vaccination with dTpa on the infant’s and toddler’s responses to diphtheria,tetanus, hepatitis B, inactivated poliovirus, Haemophilus influenzae type b or pneumococcal antigens.

Lower antibody concentrations against pertussis antigens post-primary (PT, FHA and PRN) and post-booster (PT, FHA) vaccination were observed in infants and toddlers born to mothers vaccinated withdTpa during pregnancy. The fold-increases of anti-pertussis antibody concentrations from the pre-booster to the 1-month post-booster time point were in the same range for infants and toddlers born tomothers vaccinated with dTpa or with placebo, demonstrating effective priming of the immune system.

In the absence of correlates of protection for pertussis, the clinical relevance of these observationsremains to be fully understood. However, current epidemiological data on pertussis disease followingthe implementation of dTpa maternal immunisation do not suggest any clinical relevance of thisimmune interference.

Immunogenicity in preterm infants

The immunogenicity of Infanrix hexa was evaluated across three studies including approximately 300preterm infants (born after a gestation period of 24 to 36 weeks) following a 3-dose primary vaccinationcourse at 2, 4 and 6 months of age. The immunogenicity of a booster dose at 18 to 24 months of age wasevaluated in approximately 200 preterm infants.

One month after primary vaccination at least 98.7% of subjects were seroprotected against diphtheria,tetanus and poliovirus types 1 and 2; at least 90.9% had seroprotective antibody levels against thehepatitis B, PRP and poliovirus type 3 antigens; and all subjects were seropositive for antibodies against

FHA and PRN while 94.9% were seropositive for anti-PT antibodies.

One month after the booster dose at least 98.4% of subjects had seroprotective or seropositive antibodylevels against each of the antigens except against PT (at least 96.8%) and hepatitis B (at least 88.7%).

The response to the booster dose in terms of fold increases in antibody concentrations (15- to 235-fold),indicate that preterm infants were adequately primed for all the antigens of Infanrix hexa.

In a follow-up study conducted in 74 children, approximately 2.5 to 3 years after the booster dose,85.3% of the children were still seroprotected against hepatitis B and at least 95.7% were seroprotectedagainst the three poliovirus types and PRP.

Post marketing experience

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

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, theeffectiveness of the Hib components of two hexavalent vaccines, of which one was Infanrix hexa, was89.6% for a full primary series and 100% for a full primary series plus booster dose (irrespective of the

Hib vaccine used for priming).

Results of ongoing routine national surveillance in Italy demonstrate that Infanrix hexa is effective incontrolling Hib disease in infants when the vaccine is administered according to the 3 and 5 monthsprimary vaccination schedule, with a booster dose administered at approximately 11 months. Over a sixyear period starting in 2006, where Infanrix hexa was the principal Hib-containing vaccine in use withvaccination coverage exceeding 95%, Hib invasive disease continued to be well controlled, with fourconfirmed Hib cases reported in Italian children aged less than 5 years through passive surveillance.

Evaluation of pharmacokinetic properties is not required for vaccines.

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

Hib powder:

Lactose anhydrous

DTPa-HBV-IPV suspension:

Sodium chloride (NaCl)

Medium 199 (as stabilizer containing amino acids (including phenylalanine), mineral salts (includingsodium and potassium), vitamins (including para-aminobenzoic acid) and other substances)

Water for injections

For adjuvants, see section 2.

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinalproducts.

4 years.

After reconstitution: an immediate use is recommended. However, the stability has been demonstratedfor 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.

Stability data indicate that the vaccine components are stable at temperatures up to 25°C for 72 hours.

At the end of this period Infanrix hexa should be used or discarded. These data are intended to guidehealthcare professionals in case of temporary temperature excursion only.

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

Powder in a vial (type I glass) containing 1 dose with a stopper (butyl rubber) and 0.5 ml of suspensionin a pre-filled syringe (type I glass) with a plunger stopper (butyl rubber) and with a rubber tip cap.

The tip cap and rubber plunger stopper of the pre-filled syringe and the stopper of the vial are made withsynthetic rubber.

Pack sizes of 1 and 10, with or without needles and a multipack of 5 packs, each containing 10 vials and10 pre-filled syringes, without needles.

Not all pack sizes may be marketed.

Upon storage, a clear liquid and white deposit may be observed in the pre-filled syringe containing the

DTPa-HBV-IPV suspension. This is a normal observation.

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

The vaccine is reconstituted by adding the entire contents of the pre-filled syringe to the vial containingthe powder. The mixture should be well shaken until the powder is completely dissolved prior toadministration.

The reconstituted vaccine appears as a slightly more cloudy suspension than the liquid componentalone. This is a normal observation.

The vaccine suspension should be inspected visually before and after reconstitution for any foreignparticulate matter and/or abnormal physical appearance. If either is observed, do not administer thevaccine.

Instructions for the pre-filled syringe

Luer Lock Adaptor Hold the syringe by the barrel, not by the plunger.

Unscrew the syringe cap by twisting it anticlockwise.

Plunger

Barrel

Cap

To attach the needle, connect the hub to the Luer Lock

Needle hub Adaptor and rotate a quarter turn clockwise until youfeel it lock.

Reconstitute the vaccine as described above.

Do not pull the syringe plunger out of the barrel. If ithappens, do not administer the vaccine.

Any unused medicinal product or waste material should be disposed of in accordance with localrequirements.

GlaxoSmithKline Biologicals s.a.

Rue de l'Institut 89

B-1330 Rixensart, Belgium

EU/1/00/152/001

EU/1/00/152/002

EU/1/00/152/005

EU/1/00/152/006

EU/1/00/152/021

Date of first authorisation: 23 October 2000

Date of latest renewal: 31 August 2010

Detailed information on this medicinal product is available on the website of the European Medicines

Agency https://www.ema.europa.eu