INFANRIX-HIB

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Infanrix–Hib

TITLE

Diphtheria, tetanus, acellularpertussis andHaemophilus influenzaetypebvaccine

SCOPE

Trade Name

INFANRIX-Hib

Formulationand, Strength

Powder and suspension forsuspension forinjection

Afterreconstitution, 1 dose(0.5 ml) contains:

Diphtheria toxoid

30IU

Tetanus toxoid

40IU

Pertussis antigens

Pertussis toxoid 25 micrograms

Filamentous Haemagglutinin 25 micrograms

Pertactin 8 micrograms

Haemophilusinfluenzaetypeb polysaccharide 10 micrograms

conjugated to tetanus toxoid 30-50micrograms

Thediphtheria, tetanus,acellularpertussis component is a turbid whitesuspension.

Thelyophilised Haemophilus influenzaetypeb (Hib)component isawhitepowder.

Thediphtheriaand tetanus toxins obtained from cultures ofCorynebacterium

diphtheriaeandClostridium tetaniaredetoxifiedand purified. Theacellular

pertussis vaccinecomponents (PT, FHAand pertactin)areprepared by

growingphaseIBordetella pertussisfrom which thePT and FHA and

pertactin areextracted, purifiedand irreversiblydetoxified.

Thediphtheriatoxoid, tetanus toxoid andacellularpertussis vaccine

components areadsorbedon aluminium salts. Thefinal vaccineis formulated

in saline.

TheHib polysaccharideis prepared from Hib, strain 20,752 and coupled to

tetanus toxoid. Afterpurification the conjugate islyophilised in the presence

oflactose as stabiliser.

INFANRIX-Hibmeets theWorld Health Organisation requirements for

manufactureof biological substances, of Hib conjugatevaccines and of

diphtheria, tetanus, pertussis andcombined vaccines.

Excipients

Lyophilised Hib vaccine:

Lactose

DTPavaccine:

Aluminiumhydroxide, sodium

Sodiumchloride, water

Waterforinjections

Residues

Formaldehyde

Polysorbate 80

CLINICALINFORMATION

Indications

INFANRIX-Hib isindicated foractiveimmunisation ofallinfants from theageof

2 monthsto 7years of ageagainstdiphtheria, tetanus, pertussis (DTP) andHib.

INFANRIX-Hib does notprotect againstdiseasesdueto other types ofH.

influenzaenor againstmeningitis caused byotherorganisms.

DosageandAdministration

Posology

Theprimaryvaccinationschedule consistsof threedoses in thefirst 6 monthsof

lifeand can start from theageof 2months. As vaccination schemes varyfrom

countrytocountry, the schedule foreachcountrymaybeusedin accordancewith

the different national recommendations.

To ensurelongterm protection, abooster doseis recommended for DTP and Hib in

the secondyear oflife. Furtherbooster doses withHib after theageof 2years are

generallynot recommended.

Methodofadministration

Thereconstituted vaccineis fordeep intramuscular injection preferablyatalternate

sites foreach injection.

Contraindications

INFANRIX-Hib shouldnot be administered to subjects withknown

hypersensitivityto anycomponent ofthe vaccineorto subjects havingshown

signs of hypersensitivityafter previousadministration ofdiphtheria, tetanus,

pertussis or Hibvaccines.

Infanrix-Hib iscontraindicated ifthe child hasexperienced an encephalopathyof

unknown aetiology, occurringwithin 7 daysfollowingpreviousvaccination with

pertussis containingvaccine.In thesecircumstances pertussis vaccination should

bediscontinued and the vaccination courseshouldbecontinued with diphtheria-

tetanusand Hib vaccines.

Aswithothervaccines,theadministrationofINFANRIX ®

-Hibshouldbepostponedin

subjectssufferingfromanyseverfebrileillnessoracuteinfection.Thepresenceofa

minor infection, however, is not a contra-indication.

Progressiveneurologic disorder, includinginfantilespasms, uncontrolled epilepsy,or

progressiveencephalopathyis a contraindication to administration ofanypertussis-

containingvaccine, includingINFANRIX-Hib. Pertussis vaccine should not be

administered to individuals with theseconditions until a treatment regimenhas been

established and the condition has stabilized.

Warnings andPrecautions

It isgood clinical practicethat vaccination should be preceded byareviewof

medical history(especiallywith regard to previous vaccination and possible

occurrenceof undesirable events)and aclinicalexamination.

Ifanyof thefollowingevents occurin temporal relation to receiptofDTP-

containingvaccines, thedecision to givesubsequent doses of vaccine containing

the pertussis componentshould becarefullyconsidered.Theremaybe

circumstances, such as ahigh incidenceof pertussis, when the potential benefits

outweigh possible risks,particularlysincetheseevents arenot associatedwith

permanent sequelae.

Thefollowingevents werepreviouslyconsideredcontra-indications forDTPw and

can now beconsideredgeneral precautions:

Temperatureof

40.5 Cwithin 48 hours of vaccination, not due to another

identifiable cause.

Collapse or shock-likestate (hypotonic-hyporesponsiveepisode) within 48

hours ofvaccination.

Persistent, inconsolable cryinglasting

3 hours, occurringwithin 48 hours

ofvaccination.

Convulsions with or without fever, occurringwithin 3 days of vaccination.

As with allinjectablevaccines, appropriate medical treatment should alwaysbe

readilyavailablein caseofarareanaphylacticreaction followingthe

administration ofthe vaccine. Forthis reason, thevaccineeshould remainunder

medical supervision for 30 minutes after immunisation.

INFANRIX-Hib shouldbeadministered with caution to subjects with

thrombocytopeniaor ableedingdisorder sincebleedingmayoccurfollowingan

intramuscular administration to thesesubjects

As with alldiphtheria, tetanus and pertussis vaccines, the vaccine should be

administered bydeep intramuscular injection andpreferablyat alternate sites foreach

injection.

Excretion ofcapsular polysaccharideantigen in theurinehas been described

followingreceiptof Hibvaccines,and thereforeantigen detection maynot havea

diagnostic valuein suspected Hib diseasewithin 1-2 weeks of vaccination.

INFANRIX-Hib shouldunder no circumstances beadministered intravascularly.

A historyoffebrileconvulsions, afamilyhistoryofconvulsive fits, a familyhistoryof

SIDS andafamilyhistoryofan adverseevent followingINFANRIX-Hibdo not

constitute contra-indications.

HumanImmunodeficiencyVirus (HIV) infection isnot considered as acontra-

indication.

Syncope(fainting) can occurfollowing, oreven before,anyvaccination asapsychogenic

response to the needle injection.It isimportant that procedures arein placeto avoid

injuryfromfaints.

Interactions

INFANRIX-Hibcan beadministered either simultaneouslyorat anytime before

orafteradifferent inactivated orlivevaccine.

Different injectablevaccines should always beadministered at different injection

sites.

As with othervaccines itmaybeexpected that inpatients receiving

immunosuppressivetherapyor patients with immunodeficiencyan adequate

immunologic response maynot beachieved.

Pregnancyand Lactation

Fertility

No data available.

Pregnancy

AsINFANRIX-Hibis not intended foruse in adults, adequate human dataon useduring

pregnancyand adequateanimal reproduction studies arenot available.

Lactation

AsINFANRIX-Hib isnot intended foruse in adults, adequate human dataon useduring

lactation and adequate animal reproduction studiesarenot available.

Abilitytoperform tasks that require judgement, motor orcognitive

skills

Infanrix-Hib has no or negligibleinfluenceon theabilityto driveand use

machines.

Adverse Reactions

Clinical studies:

Primary vaccination

a)Incontrolled clinical studies, local (injection site)and systemicadverseevents

wereactivelymonitoredand recorded on diarycards followingadministration of

the vaccineas a primarycourse.(3,933 doses administered)

Mostadverseevents werereported within 48 hours of vaccination. All symptoms

resolved without anysequelae.

Adverseevents aredefined byWHOpreferred terms and reportedwith thefollowing

frequencies:

Verycommon:

10%

Common:

1% and

10%

Uncommon:

0.1%and

1%

Rare:

0.01%and

0.1%

Veryrare:

0.01%

Application site:

Verycommon: swelling(

2 cm), redness (

2 cm), pain (minor or cried / protested on

touch).

Uncommon: swelling( 

2 cm), redness ( 

2 cm),pain (infant cried when limbmoved /

spontaneouslypainful).

Bodyas awhole:

Verycommon: unusual crying.

Common: fever (

38.0 rectal).

Uncommon: fever(

39.5

Crectal).

Central and peripheral nervous system:

Verycommon: restlessness.

Gastrointestinal system:

Verycommon: diarrhoea, lossof appetite.

Common: vomiting.

Psychiatric:

Verycommon:somnolence.

b)Incontrolled clinical studies, unsolicited adverseevents wereactivelymonitored

for31 days (day0-30)followingadministration ofthe vaccineas a primarycourse

(12,218 doses administered).

Unsolicited adverseevents considered at least possiblyrelated bythe investigator

wereas follows:

Autonomicnervous system:

Rare: sweatingincreased.

Bodyas awhole:

Uncommon: fatigue.

Rare: malaise.

Veryrare: abdomen enlarged, edema,granulomatous lesion,pain.

Central and peripheral nervous system:

Veryrare:gaitabnormal,hypokinesia.

Gastrointestinal system:

Uncommon: enteritis, flatulence,gastroenteritis.

Veryrare: abdominal pain, salivaincreased, toothache.

Metabolicand nutritional:

Rare: thirst.

Platelet bleedingand clotting:

Rare: hematoma.

Psychiatric:

Common: nervousness.

Uncommon: agitation, insomnia.

Veryrare: apathy

Resistancemechanism:

Uncommon: upperrespiratorytract infection.

Rare: infection, otitis media.

Respiratorysystem:

Uncommon: bronchitis.

Rare: coughing, dyspnea,pneumonia, rhinitis.

Veryrare: pharyngitis, stridor.

Skin and appendages:

Rare: rasherythematous.

Veryrare: bullous eruption, eczema.

Vision:

Veryrare: conjunctivitis.

Booster vaccination

a)Incontrolled clinical studies, local (injection site)and systemicadverseevents

wereactivelymonitoredand recorded on diarycards followingadministration of

the booster doseof vaccine(2,196 doses administered)

Mostadverseevents werereported within 48 hours of vaccination. All symptoms

resolved without anysequelae.

Application site:

Verycommon: redness ( 

2 cm), swelling(

2 cm), pain (minor or cried / protested on

touch), redness (

2cm), local swellingat theinjection site (≤ 50 mm)

Common: swelling(>2 cm), local swellingat theinjection site (>50 mm)*

Uncommon: pain (infantcries when limb is moved / spontaneouslypainful), diffuse

swellingof theinjected limb, sometimes involvingthe adjacent joint*

Bodyas awhole:

Verycommon: fever (>38 °Crectal), unusualcrying.

Uncommon: fever(>39.5°Crectal).

Central and peripheral nervous system:

Verycommon: restlessness.

Gastrointestinal system:

Verycommon: loss of appetite, diarrhoea.

Common: vomiting.

Psychiatric:

Verycommon: somnolence.

b)Incontrolled clinical studies, unsolicited adverseevents wereactivelymonitored

for31 days (day0-30)followingadministration ofthe booster doseof vaccine

(2,087 doses administered).

Unsolicited adverseevents considered at least possiblyrelated bytheinvestigator

wereas follows:

Bodyas awhole:

Rare: edemalegs, fatigue.

Central and peripheral nervous system:

Rare: dizziness, gaitabnormal, hyperkinesia.

Gastrointestinal system:

Rare: constipation, gastroenteritis.

Hearingand vestibular:

Rare: ear disorder.

Musculoskeletal system:

Rare: arthritis.

Psychiatric:

Uncommon: insomnia.

Rare: agitation, emotionallability, nervousness.

Resistancemechanism:

Uncommon: upperrespiratorytract infection.

Rare: infection viral.

Skin and appendages:

Uncommon: rash erythematous.

Rare: dermatitis.

c)Followingadministration ofbooster vaccine (2,087 doses administered),

convulsions and febrileconvulsions wereuncommonlyreported. No causal link

between theseadverseevents and eithercomponent of thevaccinehas been

established.

Post-Marketing Surveillance:

Post-marketingsurveillancedata includes reports for both primaryand booster

vaccination schedules.

Application site:

Extensiveswellingreactions, swellingof theentireinjected limb*

Bodyas awhole:

Veryrare: allergic reactions includinganaphylactoid reactions

Central and peripheral nervous system:

Veryrare: convulsions within 2 to 3 days of vaccination, collapse or shock-likestate

(hypotonic-hyporesponsivenessepisode).

* Children primed with acellularpertussis vaccines aremorelikelyto experience

swellingreactions after booster administration in comparison with childrenprimed with

wholecellvaccines. Thesereactions resolve overan averageof 4 days.

Overdosage

Occasionalreports ofoverdosehavebeen received. Overdosehas notresulted in ill

effect.

ClinicalPharmacology

Pharmacodynamics

ATCCode

Pharmaco-therapeuticgroup:Bacterialvaccines,ATC codeJ07AG52

Pharmacodynamic Effects

Results obtained in the clinical studies foreach ofthe components aresummarised

below:

-DTPacomponent:

Immunological data:

Onemonth after the3-doseprimaryvaccination course, 98.9 to 99.9 % ofinfants

vaccinated withInfanrix-Hib had antibodytitres of

0.1IU/mlforbothtetanus and

diphtheria.

Followingadministration ofa4th doseofInfanrix-Hib in thesecondyear of life, 99.0 to

100 %of infants hadantibodytitres of

0.1IU/mlforboth tetanus and diphtheria.

Onemonth after the3-doseprimaryvaccinationcourse, the overallresponseratefor

each of thethreeindividual pertussis antigens (pertussis toxoid, filamentous

haemagglutinin, pertactin) was between 97.1 to 98.9 %,96.1 to 98.3 % and96.2 to 98.2

%, respectively.

Followingadministration ofa4thdoseofInfanrix-Hib in thesecondyear of life, a

booster responsewas seen in at least 96.1 %,95.8%and 97.6 %of vaccinated infants

againstthe respectivepertussis antigens.

Protectiveefficacydata:

Theclinical protection ofthe

DTPacomponent, againstWHO-defined typical pertussis

21 days of paroxysmal cough) was demonstrated in:

-aprospectiveblinded household contact studyperformed in Germany(3, 4,5 months

schedule).

Based on data collected from secondarycontacts in householdswheretherewas an

indexcasewith typical pertussis, the protectiveefficacyof thevaccine was88.7 %.

-aNIH sponsored efficacystudyperformed inItaly(2, 4,6 months schedule). The

vaccineefficacywas found to be 84 %. In afollow-up ofthe samecohort,the

efficacywas confirmed up to 60 monthsafter completion of primaryvaccination

withoutadministration ofabooster doseof pertussis.

-Hib component:

Onemonth after the3-doseprimaryvaccination course, 92.5 to 95.6 % ofinfants

vaccinated withInfanrix-Hib had antibodytitres of

0.15

g/ml againstHib.

Followingadministration ofa4th doseofInfanrix-Hib in thesecondyear of life, 99.0 to

100 %of infants hadantibodytitres of

0.15

g/ml, and 97.6 to 99.6 % ofinfants had

antibodytitres of

1.0

g/ml againstHib.

Pharmacokinetics

Evaluation of pharmacokinetic properties is notrequired forvaccines.

Absorption

Not relevant for vaccines.

Distribution

Not relevant for vaccines.

Metabolism

Not relevant for vaccines.

Elimination

Not relevant for vaccines.

SpecialPatientPopulations

Not relevant for vaccines.

ClinicalStudies

Seesection“Pharmacodynamiceffects”.

NON-CLINICALINFORMATION

Animaltoxicologyand/orpharmacology

Preclinical datareveal no special hazard for humans based ongeneral safetystudies.

PHARMACEUTICALINFORMATION

Chemical Structure

Not relevant for vaccines.

Shelf-Life

3years.

Afterreconstitution,INFANRIX-Hib should beinjected promptly.

Storage

Storeat 2°C–8°C(in a refrigerator).

Do not freeze.

Keep thecontainer in theoutercarton in order to protect from light.

Natureand Contents of Container

Powder in vial (TypeIglass) with stopper (butyl).

0.5 mlof suspension forinjection in vial(TypeIglass)with a stopper(rubber butyl).

0.5 mlof suspensionforinjectionin pre-filled syringe(TypeIglass) with aplunger

stopper (rubber butyl).

Pack sizes of 1, 10 with or without needles.

Incompatibilities

In theabsenceofcompatibilitystudies, this medicinal product must not be

mixed with other medicinal products.

UseandHandling

Upon storage, awhite deposit and clear supernatant maybeobserved. This does not

constitute asign of deterioration.

Thesyringeshould bewellshaken in order to obtain a homogeneous turbid white

suspension.

TheDTPa suspensionshould be inspected visuallyfor anyforeign particulate matter

and/or abnormal physical appearance.In theeventofeither beingobserved,discard the

vaccine.

Thevaccine is reconstituted byaddingthecontents of thesyringeto thevial containing

the Hib powder.After theaddition of theDTPa vaccine tothepowder, themixture

should bewellshaken until thepowder is completelydissolved.

Thereconstituted vaccinepresents asaslightlymorecloudysuspension than the liquid

component alone. This is normal and does notimpair theperformanceof thevaccine.In

the event of other variation beingobserved, discard the vaccine.

Anyunused product orwaste material should bedisposed ofin accordancewith

local requirements.

MANUFACTURER

GlaxoSmithKlineBiologicalss.a.,Rixensart, Belgium

LICENSEHOLDER

GlaxoSmithKline(Israel)Ltd.,25Basel St., Petach-Tikva49002

LICENSENUMBER

121-41-30018

Inf Hib DR v2