ANNEX I

SUMMARY OF PRODUCT CHARACTERISTICS

 1. NAME OF THE M.EDICINAL PRODUCT

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) (lPV) and Haemophilus influenzae type b (Rib) conjugate vaccine
(adsorbed).

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

After reconstitution, I dose (0.5 1111) contains:

Diphtheria toxoid I not less than 30 International Units (lU)

Tetanus toxoid' not less than 40 International Units (IV)
Bordetella pertussis antigens
Pertussis toxoid (PT) I 25 micrograms
Filamentous Haemagglutinirr (FHA)I 25 micrograms
Pertactin (PRN)I 8 micrograms
Hepatitis B surface antigen (HBsy,3 10 micrograms
Poliovirus (inactivated) (JPV)
type 1 (Mahoney strain)" 40 D-antigen unit
type 2 (MEF-I strain)" 8 D-antigen unit
type 3 (Sackett strain)" 32 D-antigen unit
Haemophilus influenzae type b polysaccharide 10 micrograms
(polyribosyJribitol phosphate, PRP) 3
conjugated to tetanus toxoid as carrier protein approximately 25 micrograms

'adsorbed on aluminium hydroxide, hydrated (AI(OH)3) 0.5 milligrams A13+

2produced in yeast cells (Saccharomyces cerevisiaey by recombinant DNA technology
3adsorbed on aluminium phosphate (AIP04) 0.32 milligrams A13•
"propagated in VERO cells

The vaccine may contain traces of formaldehyde, neomycin and polymyxin which
are used during the manufacturing process (see section 4.3). "' ~< '

For the full list of excipients, see section 6.1.

3. PHARMACEUTICAL FOHM

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 JyophiJised Haemopltihts influenzae type b (Hib) component is a white powder.

4. CLINICAL PAHTICULARS

4.1 Therapeutic indications

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

4.2 Posology and method of admlnistratlou

2
 Posology

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

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 antigen composition is in accordance with the official recommendations.

Primary vaccination Booster General eonsiderations

vaccina tion
Full-term infants
3-dose A booster dose •
There should be an interval of at least I month
III ust be given.
between primary doses.
• The booster dose should be given at least 6 months
after the last priming dose and preferably before] 8
months of age.
2-dose A booster dose • There should be an interval of at least 2 months
must be given. between primary doses.
• The booster dose should be given at least 6 months
after the last priming dose and preferably between
1I and 13 months of age.
Preterm infants born after at least 24 weeks of gestational age
3-dose A booster dose • There should be an interval of at least I month
must be given. between primary doses.
• The booster dose should be given at least 6 months
after the last priming dose and preferably before 18
months of age.

The Expanded Program on Irnrnunisation schedule (at 6, 10, 14 weeks of age) may only be used if a
dose 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 from the age of six weeks. If a second dose ofhepatitis B
vaccine is required before this age, monovalent hepatitis B vaccine should be used.

Locally established immunoprophylactic measures against hepatitis B should be maintained.

Paediatric population

The safety and efficacy of Infanrix hexa in children over 36 months of age have not been established.
No data are available. r: .. . '

Method of administration
-:c ,;:1 1"'( ;r
~n~aru:ixhex a is for deep intramuscular injection, preferably at alternating sites for *bs~
mjectrons. . ~'~

.F··or mstructions 011

..
reconstitution 0
f t Ire me diicm
. al pro d uct b ef'ore a dmi is. 03,
ministration, see .666
section ..

4.3 Contralndications

Hypersensitivity to the acti ve substances O/" to any ofthe excipients listed in section 6.1, or
formaldehyde, neomycin and polymyxin.

3
Hypersensitivity after previous administration of diphtheria, tetanus, pertussis, hepatitis 8, polio or Hib
vaccines.

Infanrix hexa is contraindicated if the infant has experienced all 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 8, polio and Hib vaccines.

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

4.4 Special warnings and precautions for use

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.

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

Infanrix hexa will not prevent disease caused by pathogens other than Corynebacterium diphtheriae,
Clostridium tetani, Bordetella pertussis, hepatitis 8 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.

If any ofthe 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-hyporesponsive 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 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.

4
 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 ofInfanrix hexa and Prevenar 13 (see section
4.8).

Antipyretic treatment should be initiated according to local treatment guidelines.

Special populations

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

Clinical data indicate that Infanrix hexa can be given to pretenn infants, however, as expected in this
population, a lower immune response has been observed for some antigens (see section 4.8 and section
5.1).

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 preterm 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 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 be
observed within 1-2 weeks following vaccination. Other tests should be performed in order to confirm
Hib infection during this period.

4.5 Interaction with other mcdiciual products and other forms of interaction

Infanrix hexa can be given concomitantly with pneumococcal conjugate vaccine (PCV7, PCVIO and
PCV13), meningococcal serogroup C conjugate vaccine (CRM'97 and TT conjugates), meningococcal
serogroups A, C, \V-I 35 and Y conjugate vaccine (1'1' conjugate), oral rotavirus vaccine and measles-
mumps-ru bell a-vari ce IIa (M MRV) vacc ine.

Data have shown no clinically relevant interference in the antibody response to each of the individual
antigens, 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 to
the PRP (Hib) antigen of lnfanrix 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.

Data from clinical studies indicate [hat, when Infanrix hexa is co-administered with pneumococcal
conjugate vaccine, the rate of .febrile reactions is higher compared to that occurring following the
administration of Infanrix hexa alone. Data from one clinical study indicate that when Infanrix hexa is
co-administered with measles-mumps-rubella-varicella (MMRV) vaccine, the rate of febrile reactions is
higher compared to that occurring following the administration ofInfanrix hexa alone and similar to
that occurring following ihe administration ofMMRV vaccine alone (see sections 4.4 and 4.8). The
immune responses were unaffected, "

As with other vaccines it may be expected that in patients receiving immuno~, ppressive therapy, an
adequate response may not be achieved. '~/'t /,7
-?C.~'t~y
4.6 Fertility, pregnancy and lactation ~

/5',..CT~ .f-o
5
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.

4.7 Effects 011 ability to drive and use machines

Not relevant.

4.8 Undesirable effects

Summary of/he safety profile

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

Tabulated summary of 11dill! rse reactions

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

Frequencies per dose are defined as follows:

Very common: (~l/IO)

Common: ~I/IOO (0 <1110)
Uncommon: (~I/l,OOO to <1/100)
Rare: (~I I 10,000 to <II I,000)
Very rare: «1110,000)

..
/'l'
t',~

,(5: ocg; /6

6
 The following drug-related adverse reactions were reported in clinical studies (data from more than
16,000 subjects) and during post-marketing surveillance.

System Orzan Class Frenuencv Adverse events

Infections and infestations Uncommon Upper respi ratory tract infection
Blood and lymphatic system disorders Rare Lymphadenopathy', thrombocytopenia'
Immune system disorders Rare Anaphylactic reactions', anaphylactoid
reactions (including urticariaj'
Allergic reactions (including oruritusj'
Metabolism and nutrition disorders Very common Appetite lost
Psychiatric disorders Very common Crying abnormal, irritability, restlessness
Common Nervousness
Nervous system disorders Uncommon Somnolence
Rare Collapse or shock-like state (hypotonic-
hyporesponsive eoisodef
Very rare Convulsions (with or without fever)
Respiratory, thoracic and mediastinal Uncommon Cough
disorders Rare Bronchitis, apnoea' [see section 4.4 for
apnoea in very premature infants (S 28
weeks of zestation)l
Gastrointestinal disorders Common Diarrhoea, vomiting
Skin and subcutaneous tissue disorders Rare Rash, Anzioedema'
Very rare Dermatitis
General disorders and administration site Very common Fever ~ 38°C, local swelling at the
conditions injection site (S 50 mm), fatigue, pain,
redness
Common Fever >39.5°C, injection site reactions,
including induration, local swelling at the
injection site (> 50 mrn)'
Uncommon Diffuse swelling of the injected limb,
sometimes involving the adjacent joint'
Rare Swelling of the entire injected IimbJ.2,
extensive swelling reactions', injection
site mass", injection site vesicles'
I Children primed with acellular pertussis vaccines are more likely to expenence swelling reactions
after booster administration in comparison with children primedwith whole cell vaccines. These
reactions resolve over an average of 4 days.
2 Adverse reactions from spontaneous reporting.

• Experience in co-administration:
;;'.::. c:','7 /" r
. /'
Analysis of postrnarketing reporting rates suggests a potential increased risk of convulsions (with or
without fever) and I-II-IEwhen comparing groups which reported use ~[lf~i~exa with Prevenar 13
to those which reported use of'Infanrix hexa alone. ~

I n c , 1I11C . W I'
.. aJ stu dires 111 I f the vacci nrannx. 1.(5:
. d Inf
llC 1 some 0 t ie vaccinees receive
(7£ ,1>6.1y WI·tl·p
iexa concomitant 1 revenar

(PCV7) as a booster (4th) dose of both vaccines, fever ~ 38.0°C was reported in 43.4% of infants
receiving Prevenar and Infnnrix hexa at the same time as compared to 30.5% of infants receiving the
hexavalent vaccine alone. Fever 2:39.5°C was observed in 2.6% and 1.5% of infants receiving Infanrix
hexa with or without Prevenar, respectively (see sections 4.4 and 4.5). The incidence and severity of
fever following co-administration of the two vaccines in the primary series was lower than that
observed after the booster dose.

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

7
 In a clinical study in which some of the vaccinees received a booster dose of Infanrix hexa
concomitantly with measles-ill umps-rubella-varicella (MMR V) vaccine, fever z 38.0°C was reported in
76.6% of children receiving MMR V vaccine and Infanrix hexa at the same time, as compared to 48% of
children receiving lufanrix hexa alone and 74.7% of children receiving MMRV vaccine alone. Fever of
greater than 39.5°C was reported in 13% of children receiving Infanrix hexa with MMRV vaccine, as
compared to 3.3% of children receiving Infanrix hexa alone and 19.3% of children receiving MMRV
alone (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 of
24 to 36 weeks) in primary vaccination studies and in more than 200 preterm infants as a booster dose
in the second year of Ii fe, J n comparati ve clinical studies, similar rates of symptoms were observed in
preterm and full-term infants (refer to section 4.4 for information on apnoea).

• Experience with hepatitis B vaccine:

In extremely rare cases, allergic reactions mimicking serum sickness, paralysis, neuropathy, neuritis,
hypotension, vasculitis, lichen planus, erythema multiforrne, arthritis, muscular weakness, Guillain-
Barre syndrome, encephalopathy, encephalitis and meningitis have been reported. The causal
relationship to the vaccine has not been established.

Repolting of suspec!.~9 ..jJ~ty.~rse re(1cl ions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It
allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare
professionals are asked to report any suspected adverse reactions via the national reporting system
listed in Appendix V.

4.9 Overdose ·W)

No case of overdose has been reported. c:=
./ c:'. C .~)..•.•..

5. PlIARMACOLOCtCAL PROPERTIES 1'~

5.1 Pharmacodynamic properties

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

Inununogenicity

The immunogenicity of Infanrix hexa has been evaluated in clinical studies from 6 weeks of age. The
vaccine was assessed in 2-dose and 3-close priming schedules, including the schedule for the Expanded
Program on Immunisation, and as a booster dose. The results of these clinical studies are summarised in
the tables below.

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

Percentage of subjects with antibody titres Indicative of seroprotection I seropositivity one month
after 3-dose primary and booster vaccination with In fanrix hexa

8
 Antibody Post-dose 3 Post-dose 4
(cut-off) (Booster vaccination
during the second
year of life following
a 3-dose primary
course)
2-3-4 2-4-6 3-4-5 6-10-14
ths
111011 months months weeks N=2009
N=I9G N= 1693 N=1055 N=265 (12 studies)
(2 studlcs) (6 studies) (6 studies) (1 study)
IX. "/0 % % %
Anti-diphtheria 100.0 99.8 '99.7 99.2 99.9
(0.1 lV/ml) i'
Anti-tetanus 100.0 100.0 100.0 99.6 99.9
(0.1 IU/ml) t
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)
Allti-PRN 100.0 100.0 99.7 98.9 99.5
(5 EL.U/ml) I 98.4
Anti-HBs 99.S 98.9 98.0 98.5*
(l0 mIU/ml) t
Anti-Polio type 1 100.0 99.9 99.7 99.6 99.9
(1/8 dilution) t
Anti-Polio type 2 97.S 99.3 98.9 95.7 99.9
(1/8 dilution) i'
Anti-Polio type 3 100.0 99.7 99.7 99.6 99.9
(118 dilution) l'
Anti-PRP 96.4 96.6 96.8 97.4 99.7**
(0.15 ug/ml) 'i"
,
N = number ot subjects
* in a subgroup of infants not administered hepatitis 13 vaccine at birth, 77.7% of subjects had anti-HBs
titres ~ 10 rnl Uiml .'~.
** Post booster, 98.4 % 0 f subj ects had anti-PRP concentration 2: 1 ug/ml indicative oflong-tenrr
protection d;~
t cut-off accepted as indicative of protection /[
1'C'. /'~.
c v/'
.-c/
/'

After a 2-dose primary vaccination schedule, at least 84.3% of infants had develo ed se 'oprotective or
seropositive antibody levels against each of the vaccine antigens. After a I v ination
according to a 2-dose primary and booster schedule with lnfanrix hexa, a .of the subjects
had developed seroprotective or seropositive antibody levels against eac~the vaccine antigens.

According to different studies, immune response to the PRP antigen of Inf~f2£~ ~ doses given
at 2 and 4 months of age will vary if co-administered with a tetanus toxoid conjugate vaccine. Infanrix
hexa will confer an ant i-PR P inun line response (cut-off2: O.l5~lglml) in atleast 84% ofthe infants. This
rises to 88% in case of concomitant use of pneumococcal vaccine containing tetanus toxoid as carrier
and to 98% when lnfanrix hexa is co-administered with a TT conjugated meningococcal vaccine (see
section 4.5).

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

9
 Post-dose 2 Post-dose 3

2-4-12 months of 3-5-11 months of 2-4-12 months of 3-5-11 months of

Antibody
(cut-oft)
age age age age
N=223 N=53 0 N=196 N=532
(1 studv) (4 studies) (1 study) (3 studies)
ty;) %. % %
Anti-diphtheria 99.6 98.0 100.0 100.0
(0.1 IUlml) t
Anti-tetanus 100 100.0 100.0 100.0
(0.1 [Ulml) t .
Anti-PT 100 99.5 99.5 100.0
(5 EL.U/ml)
Anti-FHA
(5 EL.U/ml)
lOa 99.7 100.0 100.0
.
Anti-PRN 99.6 99.0 100.0 99.2
(5 EL.U/ml)
Anti-HBs 99.5 96.~ 99.8 98.9
(10 mIU/ml) i'
Anti-Polio type 1 ~9.6 99.4 98.4 99.8
(l/8 dilution) t
Anti-Polio type 2 85.6 96.3 98.4 99.4
(118 dilution) "j'
Anti-Polio type 3 92.8 98.8 97.9 99.2
(1/8 dilution) t
Anti-PRP 84.3 91.7 100.0* 99.6*
(0.15 ug/ml) t
N = number of subjects
t 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 3-5-11
months schedule had anti-PRP concentration 2: 1 ug/ml indicative oflong-term protection.

Serological correlates of protection have been established for diphtheria, tetanus, polio, Hepatitis Band
Hib. For pertussis there is no serological correlate of protection. However, as the immune response to
pertussis antigens following Infanrix hcxa administration is equivalent to that of Infanrix, the protective
efficacy of the two vaccines is expected to be equivalent. .
;:;,~)
Efficacy in protecting against pertussis
'"",.,.t' tl Y, 4' c:!, ,-
t'. ,; t 'i
The clinical protection of the pertussis component of Infanrix, against WHO-defined typical pertussis
(~21 days of paroxysmal cough) was demonstrated after 3-dbse primary im~ni~~l the studies
tabulated below: ~ /S' O%. /£
c-

Vaccine
Study Country Schedule Considerations
efficacy
Household contact Germany J ,4,5 months 88.7% Based on data collected from secondary
study (prospective contacts in households where there was
blinded) an 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 months
after completion of primary vaccination
without administration of a booster dose
of pertussis.

10
 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 years
of age. Protective immunity against the three poliovirus types and PR.P 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-Fl-lA) and 87.0'1., (anti-PlcN) of children were seropositive against the pertussis
components.

Percentage of subjects wit Ii nnribndy titrcs indicative of seroprotection I seropositivity after

primary and booster vaccination with Infanrlx hexa

Antibody Children at 4-5 years ofaze Children at 7-8 vears of age

(cut-off) N 0/0 N '1.,
Anti-diphtherla
198 68.7* 51 66.7
(0.1 JU/m!)
Anti-tetanus
198 74.7 51 64.7
(0.1 JU/m!)
Anti-PT
[97 25.4 161 32.3
(5 EL.U/ml)
Anti-FHA
197 97.5 161 98.1
(5 EL.U/ml)
Anti-PRN
198 90.9 162 87.0
(5 EL,U/ml)
Anti-HBs 250§ 85.3 207§ 72.1
(10 mIU/ml) J71§ 86.4 149& 77.2
Anti-Polio type 1 91.0
185 95.7 145
(118 dilution)
Anti-Polio type 2 91.2
IS7 95.7 148
(1/8 dilution)
Anti-Polio type 3
174 97.7 144 97.2
(1/8 dilution)
Anti-PRP
198 98.0 193 99.5
(0.15 ug/ml)
N = number of subjects
* Samples tested by ELlS!\ to have anti-diphtheria antibody concentrations < 0.1 IU/1ll1were re-tested
using Vero-cell neutralisation assay (seroprotecrion cut-off'z 0,016IU/ml): 96.5% of the subjects were
seroprotected »,
§ Number of subjects from 2 clinical studies

With regards to hepatitis B, protective immunity (?: 10 1l11U/mI)fOliowingif)~~gse primary and booster
schedule with Infanrix hexa has been shown to persist in ~ 85% of subjects 4-?'years o,f~e ~~jn
~72% of subjects 7-8 ye.rrs or age. Additionally, following a 2-dose primary an'd b6ogtet"schedul~,
protective immunity against hepatitis B persisted in ~ 48% of subjects 11-12 years ,ge $,. {J,6" 16
Hepatitis B immunological memory was confirmed in children 4 to 12 years of age. Thee children had
received lnfanrix hexa as primary and booster vaccination in infancy, and when an additional dose of
monovalent HEY vaccine was administered, protective immunity was induced in at least 96.8% of
subjects.

Immunogenicity in preternt infants

The imrnunogenicity of lnfanrix hex:'! W<lS evaluated across three studies including approximately 300
preterm infants (born alter a gestation period of24 to 36 weeks) following a 3-dose primary vaccination

11
 course at 2, 4 and 6 months or
age. The imrnunogenicity of a booster dose at 18 to 24 months of age
was evaluated in approximately 200 preterm infants.

One month after pri mary vacc in:u ion ar least 98.7% of subjects were seroprotected against diphtheria,
tetanus and poliovirus types I and 2; at least 90.9% had seroprotective antibody levels against the
hepatitis B, PRP and poliovirus type 3 antigens; and all subjects were seropositive for antibodies
against FHA and PRN while 94.9% were seropositive for anri-P'I' antibodies.

One month after the booster close at least 98.4% of subjects had seroprotective or seropositive antibody
levels against each ol' thc antigens except against PT (at least 96.8%) and hepatitis B (at least 88.7%).
The response to the booster dose i11 terms of fold increases in antibody concentrations (15- to 235-fold),
indicate that prcrerrn infants were adequately primed for al,l the antigens oflnfanrix 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 seroproiected against hepatitis B and at least 95.7% were seroprotected
against the three poliovirus types and PRP.

Post marketing experience

Results of long term follow-up ill Sweden demonstrate that acellular pertussis vaccines are efficacious
in i.nfants 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 month's 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.

The effectiveness or 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 tile !-lib 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).

Results of ongoing rout i ne national survci lIance in Italy demonstrate that Infanrix hexa is effective in
controlling Hib disease in in runts when the vaccine is administered according to the 3 and 5 months
primary vaccination schedule, with a booster dose administered at approximately 11 months. Over a six
year period starting in ~006, where Infanrix hexa was the principal Hib-containing vaccine in use with
vaccination coverage exceeding 95%, Hib invasive disease continued to be well controlled, with four
confirmed Hib cases reported in Italian children aged less than 5 years through passive surveillance.

5.2 Pharmncokiuctic prnpcrties

Evaluation of pharmacok inet ic proper! ies is not requi red for vaccines.

5.3 Preclinical safety data

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

6. PHARMACEUTICAL PARTICULARS

6.1 List of cxcipients

Hib powder:
Lactose anhydrous

12
 DTPa-HBV-IPV suspension:
Sodium chloride (NaCI)
Medium 199 containing. principally amino acids, mineral salts. vitamins
Water for injections .

For adjuvants, see section 2.

6.2 Incompntlbillt ics

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

6.3 Shelf-lire

3 years.

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

6.4 Special precautions ror storage

Store in a refrigerator (2°C - g0C).

Do not freeze.
Store in the original package, ill 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 lnianrix hexa should be used or discarded. These data are intended to guide
healthcare professionals in else of temporary temperature excursion only.

For storage conditions alter reconstitution ofthe medicinal product, see section 6.3.

6.5 Nature aml coutcnts of contnlner

Powder in a vial (type I b~I:1SS) with a stopper (butyl).

0.5 ml of suspension in a pre-f lied syringe (type T glass) with plunger stoppers (butyl).

Pack sizes of I, 10,20 and 50 with or without needles and a multipack of5 packs, each containing 10
vials and 10 pre-filled syringes, without needles. ,'~, .
,', .".'>

Not all pack sizes may be marketed.

6.6 Special precautions 1".)1" disposal and other handling

Upon storage, a clear liquid and white deposit may be observed in the pre-filled ~in~~~ainingthe
DTPa-HBV-IPV suspension. This is a normal observation, ~/9. 15: OR, /6
The pre-filled syringe should be IV.:II shaken in order to obtain a homogeneous turbid white suspension.

The vaccine is reconstituted by adding the entire contents of the pre-tilled syringe to the vial containing
the powder. The recoils! itutc ! mixture should be well shaken until the powder is completely dissolved
prior to adrninistrat ion.

TIle reconstituted vaccine appears as a slightly more cloudy suspension than the liquid component
alone. This is a nonnal observation.

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The vaccine suspension should be inspected visually before and after reconstitution for any foreign
particulate matter and/or abnormal physical appearance. If either is observed, discard the vaccine.

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

7. MARKETI:'\G AUTIIOHlSATION HOLDER

Glaxo'Smithlcllne Biologicals s.a.

Rue de l'Institut 89
B-1330 Rixensnrt, Belgium

8. MARKETING AUTIIORlS.\ TION NUMnEl~(S)

EU/l 10011 52/00 I

EUI11001152/002
EU/1I00/152/003
EUIlIOO/152/004
EUI11001152/005
EU/l/00/152/006
EU/1/00/1521007
EU/lf00l152/00S
EU/I/OOll52/021

9. DATE OF FlnST AUfll0RISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisniion: 23 October 2000

Date oflatest renewal: 31 August 20 I0

10. DATE OF HEVISION OF TilE TEXT

Detailed information on this medicinal product is available on the website ofthe European Medicines
Agency http://\Vw\v.ema.cllrupa.ell

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