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Infuenza Virus Vaccine

Fluvirin®

2008 - 2009 FORMULA

HIGHLIGHTS OF PRESCRIBING INFORMATIONThese highlights do not include all the inormation needed to use FLUVIRIN®(Inuenza Virus Vaccine) saely and efectively. See ull prescribing inormationor FLUVIRIN®.

FLUVIRIN® (Infuenza Virus Vaccine)Suspension or Intramuscular Injection2008-2009 FormulaInitial US Approval: 1988

INDICATIONS AND USAGE• FLUVIRIN® is an inactivated inuenza virus vaccine indicated or active

immunization o persons 4 years o age and older against inuenza diseasecausedbyinuenzavirussubtypesAandtypeBcontainedinthevaccine(1).

• FLUVIRIN®isnotindicatedorchildrenlessthan4yearsoagebecausethereisevidenceodiminishedimmuneresponseinthisagegroup(8.4).

DOSAGE AND ADMINISTRATIONChildren• 4 to 8 years o age:0.5-mLdoseviaintramuscularinjection,oneortwodoses. Previouslyunvaccinatedchildren4to8yearsoageshouldreceivetwo0.5-mL

doses,oneonday1ollowedbyanother0.5-mLinjectionatleast1monthlater(2.2).

Children4to8yearsoagewhohavebeenpreviouslyvaccinatedwithoneortwodosesoanyinuenzavirusvaccineshouldreceiveonlyone0.5-mLdose(2.2).

• 9 years and older:Asingle0.5-mLintramuscularinjection(2.2).

Adults• Asingle0.5-mLintramuscularinjection(2.2).

DOSAGE FORMS AND STRENGTHSFLUVIRIN®, a sterile suspension or intramuscular injection, is supplied in twopresentations:• Prelled syringe, 0.5-mL. Thimerosal, a mercury derivative used during

manuacture, is removed by subsequent purication steps to a trace amount(≤1mcgmercuryper0.5-mLdose).(3,11)

• Multidosevial,5-mL.Containsthimerosal,amercuryderivative(25mcgmercuryper0.5-mLdose).Thimerosalisaddedasapreservative.(3,11)

Each 0.5-mL dose contains a total o 45 micrograms (mcg) o in uenza virushemagglutinin (HA) rom each o the ollowing 3 strains: A/Brisbane/59/2007(H1N1);A/Uruguay/716/2007(H3N2),anA/Brisbane/10/2007-likestrain;andB/Florida/4/2006.(3,11)

CONTRAINDICATIONS• History o systemic hypersensitivity reactions to egg proteins, or any other

component o FLUVIRIN®, or lie-threatening reactions to previous inuenzavaccinations.(4.1,11)

WARNINGS AND PRECAUTIONS• I Guillain-Barré syndrome has occurred within 6 weeks o receipt o prior

inuenza vaccine, the decision to give FLUVIRIN® should be based on careulconsiderationothepotentialbenetsandrisks.(5.1)

• Immunocompromised persons may have a reduced immune response toFLUVIRIN®.(5.2)

ADVERSE REACTIONSThemostrequentlyreportedadversereactionsaremildhypersensitivityreactions(suchas rash),localreactionsattheinjection site,andinuenza-likesymptoms.(6)

To report SUSPECTED ADVERSE REACTIONS contact Novartis Vaccines at1-800-244-7668, or VAERS at 1-800-822-7967 and www.vaers.hhs.gov.

DRUG INTERACTIONS• Donotmixwithanyothervaccineinthesamesyringeorvial.(7.1)• Immunosuppressive therapies may reduce immune response to FLUVIRIN®.

(7.2)

USE IN SPECIFIC POPULATIONS• Saety and eectiveness o FLUVIRIN® have not been established in pregnant

women,nursingmothersorchildrenlessthan4yearsoage.(8.1,8.3,8.4)• Antibody responses were lower in the geriatric population than in younger

subjects.(8.5)

See 17 or PATIENT COUNSELING INFORMATION.

Revised: July 2008

FULL PRESCRIBING IN FORMATION: CONTENTS*

1 INDICATIONS AND USAGE2 DOSAGE AND ADMINISTRATION 2.1 PreparationorAdministration 2.2 RecommendedDoseandSchedule3 DOSAGE FORMS AND STRENGTHS4 CONTRAINDICATIONS 4.1 Hypersensitivity5 WARNINGS AND PRECAUTIONS

5.1 Guillain-BarréSyndrome 5.2 AlteredImmunocompetence 5.3 PreventingandManagingAllergicReactions 5.4 LimitationsoVaccineEectiveness6 ADVERSE REACTIONS

6.1 OverallAdverseReactionProle 6.2 ClinicalTrialExperience 6.3 PostmarketingExperience 6.4 Other Adverse Reactions Associated with Inuenza

Vaccination7 DRUG INTERACTIONS

7.1 ConcomitantAdministrationwithOtherVaccines 7.2 ConcurrentUsewithImmunosuppressiveTherapies

8 USE IN SPECIFIC POPULATIONS8.1 Pregnancy

8.3 NursingMothers 8.4 PediatricUse

8.5 GeriatricUse11 DESCRIPTION12 CLINICAL PHARMACOLOGY

12.1 MechanismoAction13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis,Mutagenesis,ImpairmentoFertility14 CLINICAL STUDIES 14.1 ImmunogenicityinAdults(18to64yearsoage) 14.2 Immunogenicity in Geriatric Subjects (65 years o age and

over) 14.3 ImmunogenicityinPediatricSubjects15 REFERENCES16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 HowSupplied 16.2 StorageandHandling17 PATIENT COUNSELING INFORMATION

* Sections or subsectio ns omitted rom the ull prescribing inormation are not listed.

FULL PRESCRIBING INFORMATION

1 INDICATIONS AND USAGE

FLUVIRIN® is an inactivated inuenza virus vaccine indicated or immunization opersons4 years oageand older againstinuenzavirus diseasecaused byinuenzavirus subtypes A and type B contained in the vaccine. [see DOSAGE FORMS ANDSTRENGTHS(3)]FLUVIRIN®isnotindicatedorchildrenlessthan4yearsoagebecausethereisevidenceodiminishedimmuneresponseinthisagegroup.

2 DOSAGE AND ADMINISTRATION

2.1 Preparation or AdministrationInspect FLUVIRIN® syringes and multidose vials visually or particulate matter and/ordiscoloration prior to administration. Ieither o these conditionsexists,the vaccineshouldnotbeadministered.Shake the syringe vigorously beore administering the vaccine and shake themultidosevialpreparationeachtimebeorewithdrawingadoseovaccine.Between uses, return the multidose vial to the recommended storage conditionsbetween 2º and8ºC (36º and 46ºF). Do not reeze. Discard i thevaccine has beenrozen.A separate syringe and needle or a sterile disposable unit should be used or eachinjection to prevent transmission o inectious agents rom one person to another.Needlesshouldbedisposedoproperlyandnotrecapped.It is recommended that small syringes (0.5-mL or 1-mL) should be used to minimizeany product loss.

2.2 Recommended Dose and Schedule

Children (4 to 17 years o age):For children 4 to 8 years o age, who have not previously been vaccinated with aninuenzavaccine, FLUVIRIN® should be given as a 0.5-mL intramuscular injection onday1ollowedbyanother0.5-mLintramuscularinjectionatleast1monthlater.Iachild between the ages o 4 and 8 years does not receive a second dose o vaccinewithinthesameseason,onlyonedoseovaccineshouldbeadministeredtheollowingseason.(15.3)Children,4to8yearsoage,whohavebeenvaccinatedinprecedingyear(s)withoneortwodosesoanyinuenzavirusvaccineshouldreceiveonlyonedose.(15.3)Childrenovertheageo9shouldreceiveasingle0.5-mLintramuscularinjection.Theneedlesizemayrangerom7/8to1¼inches,dependingonthesizeothechild’sdeltoidmuscle,andshouldbeosufcientlengthtopenetratethemuscletissue.Theanterolateralthighcanbeused,buttheneedleshouldbelonger,usually1inch.

Adults (18 years and older):FLUVIRIN®shouldbeadministeredasasingle0.5-mLintramuscularinjectionpreerablyintheregionothedeltoidmuscleotheupperarm.Thevaccineshouldnotbeinjectedintheglutealregionorareaswheretheremaybeamajornervetrunk.Aneedleo≥1inchispreerredbecauseneedles<1inchmightbe

oinsufcientlengthtopenetratemuscletissueincertainadults.3 DOSAGE FORMS AND STRENGTHS

FLUVIRIN®isasterile,suspensionorintramuscularinjection.Each0.5-mLdosecontainsatotalo45mcghemagglutininromthe3inuenzavirustypesinthevaccine.[seeDESCRIPTION(11)]FLUVIRIN®isavailableintwopresentations:1)Prelledsyringe,0.5-mL.Thimerosal,amercuryderivativeusedduringmanuacture,

isremovedbysubsequentpuricationstepstoatraceamount(≤1mcgmercuryper0.5-mLdose).

2)Multidose vial, 5-mL. Contains thimerosal, a mercury derivative, added as apreservative.Each0.5-mLdoseromthemulti-dosevialcontains25mcgmercury.

4 CONTRAINDICATIONS

4.1 HypersensitivityFLUVIRIN®shouldnotbeadministeredtoanyonewithknownsystemichypersensitivityreactionstoeggproteins(eggsoreggproducts),ortoanycomponentoFLUVIRIN®,orwhohashadalie-threateningreactiontopreviousinuenzavaccinations.

5 WARNINGS AND PRECAUTIONS

5.1 Guillain-Barré SyndromeI Guillain-Barré syndrome has occurred within 6 weeks o receipt o prior inuenzavaccine,thedecisiontogiveFLUVIRIN®shouldbebasedoncareulconsiderationothepotentialbenetsandrisks.

5.2 Altered ImmunocompetenceI FLUVIRIN® is administered to immunocompromised persons, including individualsreceiving immunosuppressive therapy, the expected immune response may not beobtained.

5.3 Preventing and Managing Allergic ReactionsPriortoadministrationoanydoseoFLUVIRIN®,thehealthcareprovidershouldreviewthepatient’spriorimmunizationhistoryorpossibleadverseevents,todeterminetheexistence o any contraindication to immunization with FLUVIRIN® and to allow anassessmentobenetsandrisks.Appropriatemedicaltreatmentandsupervisionmustbeavailabletomanagepossibleanaphylacticreactionsollowingadministrationothevaccine.

5.4 Limitations o Vaccine Eectiveness

VaccinationwithFLUVIRIN®maynotprotectallindividuals.

6 ADVERSE REACTIONS

6.1 Overall Adverse Reaction ProfleSerious allergic reactions, including anaphylactic shock, have been observed inindividualsreceivingFLUVIRIN®duringpostmarketingsurveillance.

6.2 Clinical Trial ExperienceAdverseeventinormationromclinicaltrialsprovidesabasisoridentiyingadverseeventsthatappeartoberelatedtovaccineuseandorapproximatingtheratesotheseevents.However, because clinical trials are conducted under widely varying conditions, theadverse reaction rates observed in the clinical trials o a vaccine cannot be directlycompared to rates in the clinical trials o another vaccine, and may not reect ratesobservedinclinicalpractice.

Adult and Geriatric SubjectsSaetydatawerecollectedinatotalo2768adultandgeriatricsubjects(18yearsoageandolder)whohavereceivedFLUVIRIN®in29clinicalstudiessince1982.In9clinicalstudiessince1997,among1261recipientsoFLUVIRIN®,745(59%)werewomen;1211(96%)wereWhite,23(2%)Asian,15(1%)Blackand12(1%)other;370

(29%)osubjectswereelderly(≥65yearsoage).AllstudieshavebeenconductedintheUK,apartromastudyrunintheUSin2005-2006whereFLUVIRIN®wasusedasacomparatororanunlicensedvaccine.Ater vaccination, the subjects were observed or 30 minutes or hypersensitivity orotherimmediatereactions.Subjectswereinstructedtocompleteadiarycardorthreedaysollowingimmunization(i.e.Day1to4)tocollectlocalandsystemicreactions(seeTables1and2).Alllocalandsystemicadverseeventswereconsideredtobeatleastpossiblyrelatedtothevaccine.Localandsystemicreactionsmostlybeganbetweenday1andday2.Theoveralladverseeventsreportedinclinicaltrialssince1998inatleast5%othesubjectsaresummarizedinTable3.

Adults (18 to 64 years o age)In adult subjects, solicited local adverse events occurred with similar requency in alltrials.Themostcommonsolicitedadverseeventsoccurringintherst96hoursateradministration (Tables 1 and 2) were associated with the injection site (such as pain,erythema, mass, induration and swelling) but were generally mild/moderate andtransient. The most common solicited systemic adverse events were headache andmyalgia.Themostcommonoveralleventsinadultsubjects(18-64yearsoage)wereheadache,

atigue, injection site reactions (pain, mass, erythema, and induration) and malaise(Table3).

Geriatric Subjects (65 years and over)Ingeriatricsubjects,solicitedlocalandsystemicadverseeventsoccurredlessrequentlythaninadultsubjects.Themostcommonsolicitedlocalandsystemicadverseeventswere injection site pain, and headache (Tables 1 and 2). All were considered mild/moderateandweretransient.Themostcommonoveralleventsinelderlysubjects(≥65yearsoage)wereheadacheandatigue.

Only11seriousadverseeventsinadultandgeriatricsubjects(18yearsandolder)havebeenreportedtodateromallthetrialsperormed.Theseseriousadverseeventswerea minor stroke experienced by a67 year old subject14 daysatervaccination (1990),deatho an 82 yearold subject35 days ater vaccination(1990) invery early studies;deathoa72yearoldsubject19daysatervaccination(1998-1999),ahospitalizationorhemorrhoidectomyoa38yearoldmalesubject(1999-2000),asevererespiratorytract inection experienced by a 74 year old subject 12 days ater vaccination (20022003),aplannedtransurethralresectionotheprostateinasubjectwithpriorhistoryoprostatism(2004-2005),twocasesoinuenza(2005-2006),adrugoverdose(20052006), cholelithiasis (2005-2006) and a nasal septal operation (2005-2006). None otheseeventswereconsideredcausallyrelatedtovaccination.

Clinical Trial Experience in Pediatric SubjectsIn1987aclinicalstudywascarriedoutin38‘atrisk’childrenagedbetween4and12years(17emalesand21males).TorecordthesaetyoFLUVIRIN®,participantsrecordedtheirsymptomsonadiarycardduringthethreedaysatervaccinationandnotedanyurthersymptomstheythoughtwereattributabletothevaccine.Theonlyreactionsrecordedweretendernessatthesiteovaccination in21% otheparticipantsonday1,whichwasstillpresentin16%onday2and5%onday3.Inonechild,thetendernesswasalsoaccompanied byrednessatthesiteoinjectionortwodays.Thereactionswerenotage-dependentandtherewasnobiastowardstheyoungerchildren.Threeclinicalstudieswerecarriedoutbetween1995and2004inatotalo520pediatricsubjects(agerange6-47months).Othese,285healthysubjectsplus41‘atrisk’subjectsreceivedFLUVIRN®.Noseriousadverseeventswerereported.FLUVIRIN®shouldonlybeusedortheimmunizationopersonsaged4yearsandover.

USA_in158x560_Fluvirin08_RFVRF001 1

TABLE 1. SolicitedAdverseEventsintheFirst72-96HoursAfterAdministrationof FLUVIRIN® in Adult (18-64 years of age) and Geriatric (≥65 years of age)Subjects.

1998-1999*§ 1999-2000*§ 2000-2001*§ 18-64yrs ≥65yrs 18-64yrs≥65yrs18-64yrs≥65yrs N=66 N=44 N=76N=34N=75 N=35

LocalAdverseEvents Pain 16 (24%) 4 (9%) 16 (21%) -  9 (12%) - Mass 7 (11%) 1 (2%) 4 (5%) -  8 (11%) 1 (3%)Infammation 5 (8%) 2 (5%) 6 (8%) -  7 (9%) 1 (3%)Ecchymosis 4 (6%) 1 (2%) 3 (4%) 1 (3%) 4 (5%) -

 Edema 2 (3%) 1 (2%) 1 (1%) 2 (6%) 3 (4%) 1 (3%)Reaction 2 (3%) -  2 (3%) -  4 (5%) 1 (3%)Hemorrhage -  -  1 (1%) -  - -

SystemicAdverseEvents Headache 7 (11%) 1 (2%) 17 (22%) 3 (9%) 4 (5%) - Fatigue 3 (5%) 2 (5%) 4 (5%) 1 (3%) 3 (4%) - Malaise 2 (3%) 1 (2%) 2 (3%) 1 (3%) 1 (1%) - Myalgia 1 (2%) -  2 (3%) -  - - Fever 1 (2%) -  1 (1%) -  - - Arthralgia -  1 (2%) -  1 (3%) - -Sweating -  -  3 (4%) -  1 (1%) 1 (3%)

2001-2002*^ 2002-2003*^ 2004-2005^ 18-64yrs ≥65yrs 18-64yrs≥65yrs 18-64yrs ≥65yrs N=75 N=35 N=107N=88 N=74N=61

LocalAdverseEvents Pain 12 (16%) 1 (3%) 14 (13%) 7 (8%) 15 (20%) 9 (15%)Mass 4 (5%) 1 (3%) -  -  - - Ecchymosis 2 (3%) -  3 (3%) 3 (3%) 2 (3%) 1 (2%)Ed ema 2 ( 3% ) 1 ( 3% ) 6 ( 6% ) 2 ( 2% ) - - Erythema 5 (7%) -  11 (10%) 5 (6%) 16 (22%) 5 (8%)Swelling -  -  -  -  11 (15%) 4 (7%)Reaction -  -  2 (2%) -  - - Induration -  -  14 (13%) 3 (3%) 11 (15%) 1 (2%)Pruritus -  -  1 (1%) -  - -

SystemicAdverseEvents Headache 8 (11%) 1 (3%) 12 (11%) 9 (10%) 14 (19%) 3 (5%)Fatigue 1 (1%) 1 (3%) -  -  5 (7%) 2 (3%)Malaise 3 (4%) -  3 (3%) 4 (5%) 1 (1%) 1 (2%)Myalgia 3 (4%) -  5 (5%) 3 (3%) 8 (11%) 1 (2%)Fever -  -  -  1 (1%) - - Arthralgia -  -  2 (2%) -  1 (1%) - Sweating 3 (4%) 1 (3%) -  2 (2%) - - Shivering -  -  -  1 (1%) - -

Results reported to the nearest whole percent; Fever dened as >38°C

– not reported

* Solicited adverse events in the rst 72 hours ater administration o FLUVIRN®

§ Solicited adverse events reported by COSTART preerred term

^ Solicited adverse events reported by MEDDRA preerred term

TABLE 2. Solicited Adverse Events in the First 72 Hours After Administration ofFLUVIRIN®inAdultSubjects(18-49yearsofage).

2005-2006 US TrialFLUVIRIN®

N = 304

LocalAdverseEventsPain 168 (55%)Erythema 48 (16%)Ecchymosis 22 (7%)Induration 19 (6%)Swelling 16 (5%)

SystemicAdverseEvents Headache 91 (30%)Myalgia 64 (21%)Malaise 58 (19%)Fatigue 56 (18%)Sore throat 23 (8%)Chills 22 (7%)Nausea 21 (7%)Arthralgia 20 (7%)Sweating 17 (6%)Cough 18 (6%)Wheezing 4 (1%)Chest tightness 4 (1%)Other diculties breathing 3 (1%)Facial edema -

Results reported to the nearest whole percent

– not reported

TABLE 3. Adverse Events Reported by at least 5% of Subjects in Clinical Trialssince1998

1998-1999§ 1999-2000§ 2000-2001§

18-64yrs ≥65yrs 18-64yrs≥65yrs 18-64yrs≥65yrs N=66 N=44 N=76 N=34 N=75 N=35

AdverseEventsFatigue 8 (12%) 2 (5%) 8 (11%) 2 (6%) 5 (7%) - Back pain 4 (6%) 3 (7%) -  -  - - Cough increased 2 (3%) 2 (5%) -  -  - - Ecchymosis 4 (6%) 1 (2%) 4 (5%) 1 (3%) 5 (7%) - Fever 3 (5%) -  -  -  - - Headache 12 (18%) 5 (11%) 22 (29%) 5 (15%) 14 (19%) 2 (6%)Inection 3 (5%) 2 (5%) -  -  - - M al ai se 4 ( 6%) 4 ( 9%) 4 ( 5% ) 1 ( 3%) - - Migraine 4 (6%) 1 (2%) -  -  - - Myalgia 4 (6%) 1 (2%) -  -  - - Sweating 5 (8%) 1 (2%) -  -  - - Rhinitis 3 (5%) 1 (2%) -  -  5 (7%) 2 (6%)Pharingitis 6 (9%) 1 (2%) 10 (13%) -  6 (8%) - Arthralgia -  -  -  2 (6%) - - Injection site pain 16 (24%) 4 (9%) 16 (21%) -  9 (12%) - Injection site ecchymosis 4 (6%) 1 (2%) -  -  4 (5%) - Injection site mass 7 (11%) 1 (2%) 4 (5%) -  8 (11%) 1 (3%)Injection site edema -  -  1 (1%)  2 (6%) - -Injection site infammation 5 (8%) 2 (5%) 6 (8%) -  7 (9%) 1 (3%)Injection site reaction -  -  -  -  4 (5%) 1 (3%)

2001-2002^ 2002-2003^ 2004-2005^ 18-64yrs ≥65yrs 18-64yrs≥65yrs 18-64yrs≥65yrs N=75 N=35 N=107 N=88 N=74 N=61

AdverseEvents Fatigue 5 (7%) 4 (11%) 11 (10%) 8 (9%) 4 (5%) 2 (3%)Hypertension -  -  1 (1%) 4 (5%) - - Rinorrhea -  -  2 (2%) 5 (6%) - - Headache 20 (27%) 2 (6%) 35 (33%) 18 (20%) 12 (16%) 1 (2%)Ma la is e 6 ( 8% ) 1 ( 3%) 13 ( 12 %) 8 ( 9% ) - - M ya lg ia 4 ( 5%) 1 ( 3%) 1 0 ( 9% ) 4 ( 5%) - - S we at in g 3 ( 4%) 3 ( 9%) 2 ( 2% ) 5 ( 6%) - - Rhinitis 4 (5%) -  -  -  - - Pharingitis -  -  -  -  6 (8%) - Arthralgia -  -  5 (5%) 4 (5%) - - S ore t hro at 4 ( 5% ) 1 ( 3% ) 5 ( 5% ) 4 ( 5% ) - - Injection site pain 13 (17%) 3 (9%) 14 (13%) 7 (8%) 6 (8%) 2 (3%)Injection site ecchymosis 4 (5%) 1 (3%) 4 (4%) 4 (5%) - - Injection site erythema 5 (7%) 2 (6%) 11 (10%) 5 (6%) 4 (5%) - Injection site mass 4 (5%) 1 (3%) -  -  - - Injection site edema -  -  6 (6%) 2 (2%) 4 (5%) 1 (2%)Injection site induration -  -  14 (13%) 3 (3%) 7 (9%) -

Results reported to the nearest whole percent; Fever dened as >38°C

– not reaching the cut-of o 5%

§ Solicited adverse events reported by COSTART preerred term

^ Solicited adverse events reported by MEDDRA preerred term

RFVRF001(0708A)

18/07/2008 11.05.11

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6.3 Postmarketing ExperienceTheollowingadditionaladversereactionshavebeenreportedduringpost-approvaluseoFLUVIRIN®.Because these reactions are reported voluntarily rom a population o uncertain size, it is not alwayspossible to reliably estimate their requency or establish a causal relationship to vaccine exposure.Adverseeventsdescribedhereareincludedbecause:a) theyrepresentreactionswhichareknowntooccurollowingimmunizationsgenerallyorinuenzaimmunizationsspecically;b)theyarepotentiallyserious;orc)therequencyoreporting.

• Body as a whole:Localinjectionsitereactions(includingpain,painlimitinglimbmovement,redness,swelling,warmth,ecchymosis,induration),hotashes/ushes;chills;ever;malaise;shivering;atigue;asthenia;acialedema.

• Immune system disorders:Hypersensitivityreactions(includingthroatand/ormouthedema).Inrare

cases,hypersensitivityreactionshaveleadtoanaphylacticshockanddeath.• Cardiovascular disorders:Vasculitis (in rare cases with transient renal involvement), syncope shortly

atervaccination.• Digestive disorders:Diarrhea;nausea;vomiting;abdominalpain.• Blood and lymphatic disorders:Locallymphadenopathy;transientthrombocytopenia.• Metabolic and nutritional disorders:Lossoappetite.• Musculoskeletal:Arthralgia;myalgia;myasthenia.• Nervous system disorders:Headache;dizziness;neuralgia;paraesthesia;conusion;ebrileconvulsions;

Guillain-BarréSyndrome;myelitis(includingencephalomyelitisandtransversemyelitis);neuropathy(includingneuritis);paralysis(includingBell’sPalsy).

• Respiratory disorders:Dyspnea;chestpain;cough;pharyngitis;rhinitis.• Skin and appendages:Stevens-Johnson syndrome;sweating;pruritus; urticaria; rash(includingnon

specic,maculopapular,andvesiculobulbous).

6.4 Other Adverse Reactions Associated with Inuenza VaccinationAnaphylaxis has been reported ater administration o FLUVIRIN®. Although FLUVIRIN® contains onlyalimitedquantityo eggprotein,thisproteincaninduceimmediatehypersensitivityreactionsamongpersonswhohavesevereeggallergy.Allergicreactionsincludehives,angioedema,allergicasthma,andsystemicanaphylaxis[seeCONTRAINDICATIONS(4)].The1976swineinuenzavaccinewasassociatedwithanincreasedrequencyoGuillain-Barrésyndrome(GBS).Evidenceoracausalrelation oGBSwithsubsequentvaccinespreparedromotherinuenzavirusesisunclear. I inuenza vaccine doesposea risk, it is probablyslightly more than 1 additionalcase/1millionpersonsvaccinated.Neurologicaldisorderstemporallyassociatedwithinuenzavaccinationsuchasencephalopathy,opticneuritis/neuropathy,partialacialparalysis,andbrachialplexusneuropathyhavebeenreported.Microscopicpolyangiitis(vasculitis)hasbeenreportedtemporallyassociatedwithinuenzavaccination.

7 DRUG INTERACTIONS

7.1 Concomitant Administration with Other VaccinesThere are no data to assess the concomitant administration o FLUVIRIN® with other vaccines. IFLUVIRIN®istobegivenatthesametimeasanotherinjectablevaccine(s),thevaccinesshouldalwaysbeadministeredatdierentinjectionsites.FLUVIRIN®shouldnotbemixedwithanyothervaccineinthesamesyringeorvial.

7.2 Concurrent Use with Immunosuppressive TherapiesImmunosuppressive therapies, including irradiation, antimetabolites, alkylating agents, cytotoxicdrugs,andcorticosteroids(usedingreaterthanphysiologicdoses),mayreducetheimmuneresponsetoFLUVIRIN®.

8 USE IN SPECIFIC POPULATIONS8.1 PregnancyPregnancyCategoryC:AnimalreproductionstudieshavenotbeenconductedwithFLUVIRIN®.ItisalsonotknownwhetherFLUVIRIN®cancauseetalharmwhenadministeredtoapregnantwomanorcanaectreproductioncapacity.FLUVIRIN®shouldbegiventoapregnantwomanonlyiclearlyneeded.

8.3 Nursing MothersIt is not known whether FLUVIRIN® is excreted in human milk. Because many drugs are excreted inhumanmilk,cautionshouldbeexercisedwhenFLUVIRIN®isadministeredtoanursingwoman.

8.4 Pediatric UseThe saety and immunogenicity o FLUVIRIN® havenot beenestablished in children under 4 years oage.ThesaetyandimmunogenicityoFLUVIRIN®havebeenestablishedintheagegroup4yearsto16years.TheuseoFLUVIRIN®intheseagegroupsissupportedbyevidenceromadequateandwellcontrolledstudies o FLUVIRIN® in adults that demonstrate the immunogenicity o FLUVIRIN® [see ADVERSEREACTIONS(6)andCLINICALSTUDIES(14)].

8.5 Geriatric Use

Since1997,othetotalnumberogeriatricsubjects(n=397)inclinicalstudiesoFLUVIRIN®,29%were65yearsandover,while2.1%were75yearsandover.Antibodyresponses werelower inthe geriatric populationthan in youngersubjects. Adverseeventsoccurredlessrequentlyingeriatricsubjects(≥65years)thaninyoungeradults.Otherreportedclinicalexperiencehasnotidentieddierencesinresponsesbetweentheelderlyandyoungerpatients.[SeeADVERSEREACTION(6)andCLINICALSTUDIES(14)].

11 DESCRIPTION

FLUVIRIN®isa trivalent,sub-unit(puriedsuraceantigen)inuenzavirusvaccinepreparedromviruspropagatedintheallantoiccavityoembryonatedhens’eggsinoculatedwithaspecictypeoinuenzavirussuspensioncontainingneomycinandpolymyxin.Eachotheinuenzavirusstrainsisharvestedand claried separately by centriugation and ltration prior to inactivation with betapropiolactone.The inactivated virus is concentrated and puried by zonal centriugation. The surace antigens,hemagglutinin and neuraminidase, are obtained rom the inuenza virus particle by urthercentriugationinthepresenceononylphenolethoxylate,aprocesswhichremovesmostotheinternalproteins.Thenonylphenolethoxylateisremovedromthesuraceantigenpreparation.FLUVIRIN® is a homogenized, sterile, slightly opalescent suspension in a phosphate buered saline.FLUVIRIN®hasbeenstandardizedaccordingtoUSPHSrequirementsorthe2008-2009inuenzaseasonandisormulatedtocontain45mcghemagglutinin(HA)per0.5-mLdoseintherecommendedratioo15mcgHAoeachotheollowing3strains:A/Brisbane/59/2007(H1N1);A/Uruguay/716/2007(H3N2),

anA/Brisbane/10/2007-likestrain;andB/Florida/4/2006.The 0.5-mLprelled syringe presentationis ormulated without preservative. However, thimerosal,amercuryderivativeusedduringmanuacturing,isremovedbysubsequentpuricationstepsto atraceamount(≤1mcgmercuryper0.5-mLdose).The5-mLmultidosevialormulationcontainsthimerosal,amercuryderivative,addedasapreservative.Each0.5-mLdoseromthemultidosevialcontains25mcgmercury.Eachdoseromthemultidosevialorromtheprelledsyringemayalsocontainresidualamountsoeggproteins(≤1mcgovalbumin),polymyxin(≤3.75mcg),neomycin(≤2.5mcg),betapropiolactone(notmorethan0.5mcg)andnonylphenolethoxylate(notmorethan0.015%w/v).Themultidosevialstopperandthesyringestopper/plungerdonotcontainlatex.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism o ActionInuenza illness and its complications ollow inection with inuenza viruses. Global surveillance oinuenzaidenties yearlyantigenicvariants. For example,since1977,antigenicvariantso inuenzaA(H1N1andH3N2)virusesandinuenzaBviruseshavebeeninglobalcirculation.Speciclevelsohemagglutinationinhibition(HI)antibodytiterspost-vaccinationwithinactivatedinuenzavirusvaccinehavenotbeencorrelatedwithprotectionrominuenzaillness.Insomehumanstudies,antibodytitero ≥1:40 have been associated with protection rom inuenza illness in up to 50% o subjects [see

REFERENCES(15.1,15.2)].Antibodyagainstoneinuenzavirustypeor subtypeconerslimitedornoprotectionagainstanother.Furthermore, antibody to one antigenic variant o inuenza virus might not protect against a newantigenic variant o the same type or subtype. Frequent development o antigenic variants throughantigenic drit is the virologic basis or seasonal epidemics and the reason or the usual change oone or more new strains in each year’s inuenza vaccine. Thereore, inactivated inuenza vaccinesare standardized to contain the hemagglutinin o strains (i.e., typically two type A and one type B),representingtheinuenzaviruseslikelytobecirculatingintheUnitedStatesintheupcomingwinter.Annualrevaccinationwiththecurrentvaccineisrecommendedbecauseimmunitydeclinesduringtheyearatervaccination,andbecausecirculatingstrainsoinuenzaviruschangeromyeartoyear[seeREFERENCES(15.3)].

13 NONCLINIC AL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment o FertilityFLUVIRIN®hasnotbeenevaluatedorcarcinogenicormutagenicpotential,ororimpairmentoertility.

14 CLINICAL STUDIES

Between1982and1991,twelveclinicalstudieswereconductedinhealthyadultandgeriatricsubjectsandoneinchildrenbetween4and12yearsoagewhowereconsideredtobe‘atrisk’.Since1991anannualclinicalstudyhasbeenconductedintheUKinhealthyadultsaged18yearsorolder.FLUVIRIN®was also used as a control in a US clinical trial in adults (18-49 years o age). In all the trials, bloodsamplesweretakenpriortovaccinationandapproximatelythreeweeksatervaccinationtoassesstheimmunogenicresponsetovaccinationbymeasurementoanti-HAantibodies.Three clinical studies were carried out between 1995 and 2004 in a total o 520 pediatric subjects(age range 6-48 months). O these, 285 healthy subjects plus 41‘at risk’ pediatric subjects, receivedFLUVIRIN®.FLUVIRIN®shouldonlybeusedortheimmunizationopersonsaged4yearsandover.

14.1 Immunogenicity in Adults (18 to 64 years o age)Tables 4 and 5 show the immunogenicity data or the adult age group. The seven clinical studiespresentedenrolledatotalo774adultsubjects.Intheadultgroup,orallantigens(A/H1N1,A/H3N2and B) at least one o the ollowing point estimate criteria was met: the proportion o subjects withseroconversion(post-vaccinationtiter≥1:40romapre-vaccinationtiter<1:10)orsignicantincrease(atleastaour-oldincreaserompre-vaccinationtiter≥1:10)inantibodytiterwasgreaterthan40%;thegeometricmeantiter(GMT)increasewas>2.5;theproportionosubjectswithapost-vaccinationhemagglutinationinhibition(HI)antibodytiter≥1:40wasgreaterthan70%.

14.2 Immunogenicity in Geriatric Subjects (65 years and over)Tables6and7showtheimmunogenicityoFLUVIRIN®inthegeriatricagegroup.Thesixclinicalstudiespresentedenrolledatotalo296geriatricsubjects.Foreachotheinuenzaantigens,the percentage o subjects who achieved seroconversion and the percentage o subjects whoachievedHItiterso≥1:40areshown,aswellastheoldincreaseinGMT.Forallantigens(A/H1N1,A/H3N2andB)atleastoneotheollowingpointestimatecriteriawasmet: the proportion o subjects with seroconversion (post-vaccination titer ≥1:40 rom a prevaccinationtiter<1:10)orsignicantincrease(atleastaour-oldincreaserompre-vaccinationtiter ≥1:10) in antibody titer was greater than 30%; the geometric mean titer (GMT) increasewas >2.0; the proportion o subjects with a post-vaccination hemagglutination inhibition (HI)antibodytiter≥1:40wasgreaterthan60%.Thepre-speciedefcacycriteriaweremetineachstudy, although a relatively lower immunogenicity o A/H1N1 strain was seen in the last ourstudies(thesamestrainwasineachotheormulations).

14.3 Immunogenicity in Pediatric SubjectsAsmall-scalestudy,wasconductedin1987toevaluatesaetyandimmunogenicityoFLUVIRIN®in38‘atrisk’children,withdiabetesand/orasthma,orlymphoidleukemia.Thirty-eightparticipantsagedbetween4and12yearsoagewereassessed.Tensubjectshaddiabetes,21hadasthma,

twohadbothdiabetesandasthma,andonehadlymphoidleukemia.Therewereourhealthycontrolsubjects.Allparticipantsreceivedasingle0.5-mLdoseoFLUVIRIN®.Immunogenicityresultswereobtainedor19othe38subjectsenrolledinthestudy.Thepointestimateothepercentageosubjectsachievingatitero≥1:40was84%ortheA/H1N1strain79% or the B strain,and 53% orthe A/H3N2 strain. The GMT old increaseswere 5.8 or theA/H1N1strain,40ortheBstrainand17.7ortheA/H3N2strain.Threeclinicalstudieswerecarriedoutbetween1995and2004inatotalo520pediatricsubjects(age range 6-47 months). O these, 285 healthy subjects plus 41 ‘at risk’ pediatric subjects,receivedFLUVIRIN®.In a 1995/1996 c linical study, 41 subjects (aged 6-36 months) at increased risk or inuenza-relatedcomplicationsreceivedtwo0.25-mLdosesoFLUVIRIN®.Atleast49%osubjectsshoweda≥4-oldincreaseinHIantibodytitertoallthreestrains.HIantibodytiterso1:40orgreaterwereseen in at least 71%o the subjects or all three inuenza strains, with increases in geometricmeantitero6.0-oldorgreatertoallthreestrains.Twoclinicalstudies(1999-2000and2004)indicatedalowerimmunogenicityproleorFLUVIRIN®comparedwithtwocommercialsplit;inastudyintheagegroup6-48monthsthecomparatorwas a US licensed vaccine, Fluzone®, and in another study in the age group 6-36 months thecomparator was a non-US licensed inactivated inuenza vaccine. Despite the small samplesize(atotalo285healthysubjectsreceivedFLUVIRIN®inthesetwoclinicalstudies)thelower

immunogenicity prole o FLUVIRIN® was greatest versus the comparator vaccines in children<36months but was also evident in those 3 6-48 months o age, though the dierences wereless.FLUVIRIN®shouldonlybeusedortheimmunizationopersonsaged4yearsandover.

15 REFERENCES

15.1 Hannoun C, Megas F, Piercy J. Immunogenicity and protective efcacy o inuenzavaccination.VirusRes2004;103:133-138.15.2 Hobson D, Curry RL, Beare A, et. al.The role o serum hemagglutinin-inhibiting antibodyin protection against challenge inection with inuenza A2 and B viruses. J Hyg Camb 1972;767-77715.3 Centers or Disease Control and Prevention. Prevention and Control o Inuenza:Recommendations o the Advisory Committee on Immunization Practices (ACIP). MMWR2006;55(RR-10):1-42.

16 HOW SUPPLIED/STORAGE AND HANDLING

16.1 How SuppliedFLUVIRIN®issuppliedasa0.5-mLprelledsyringe,packageo10prelledsyringespercarton.NDC66521-111-01

FLUVIRIN®issuppliedasa5-mLmultidosevial,individuallypackagedinacarton.NDC66521-111-10

16.2 Storage and HandlingStoreFLUVIRIN®rerigeratedbetween2°and8°C(36°and46°F).Do not reeze. Discardithevaccinehasbeenrozen.Storeintheoriginalpackagetoprotectromlight.Donotuseatertheexpirationdate.Betweenuses,returnthemultidosevialtotherecommendedstorageconditions.

17 PATIENT COUNSELING INFORMATION

Vaccine recipients and guardians should be inormed by their health care provider o thepotentialbenetsandrisksoimmunizationwithFLUVIRIN®.Wheneducatingvaccinerecipientsandguardiansregardingthepotentialsideeects,cliniciansshouldemphasizethat(1)FLUVIRIN®contains non-inectious particles and cannot cause inuenza and (2) FLUVIRIN® is intended toprovideprotectionagainstillnessduetoinuenzavirusesonly,andcannotprovideprotectionagainstallrespiratoryillness.Vaccinerecipientsandguardiansshouldbeinstructedtoreportanysevereorunusualadversereactionstotheirhealthcareprovider.

Vaccinerecipientsandguardiansshouldbeinstructedthatannualvaccinationisrecommended.

FLUVIRIN®isaregisteredtrademarkoNovartisVaccinesandDiagnosticsLimited.

Manuacturedby:NovartisVaccinesandDiagnosticsLimited,Speke,Liverpool,UKAnafliateo: NovartisVaccinesandDiagnostics,Inc.,350MassachusettsAvenue,Cambridge,MA02139USA1-800-244-7668

TABLE 4. Summary of the Seroconversion and Proportion of Subjects

Achieving an HI titer ≥1:40 for Adult Subjec ts

Year/Strain No.ofsubjects Seroconversion∞ HItiter≥1:40¥

N % 95%CIφ N % 95%CI

φ

1998-1999A/H1N1A/H3N2B

66484342

736564

(62, 83)(54, 77)(52, 75)

504762

767194

(65, 86)(60, 82)

(88, 100)

1999-2000A/H1N1A/H3N2

B

764551

53

5967

70

(48, 70)(57, 78)

(59, 80)

5066

75

6687

99

(55, 76)(79, 94)

(96, 100)

2000-2001A/H1N1A/H3N2B

74414550

556168

(44, 67)(50, 72)(57, 78)

415273

558499

(44, 67)(75, 92)

(96, 100)

2001-2002A/H1N1A/H3N2B

75444642

596156

(48, 70)(50, 72)(45, 67)

486866

649188

(53, 75)(84, 97)(81, 95)

2002-2003A/H1N1A/H3N2B

106627278

586874

(49, 68)(59, 77)(65, 82)

7393

101

698895

(60, 78)(81, 94)(91, 99)

2004-2005A/H1N1

A/H3N2B

74

52

6057

70

8177

(59, 80)

(70, 89)(66, 86)

66

7369

89

9993

(80, 95)

(93, 100)(85, 98)

2005-2006A/H1N1A/H3N2B

303191273213

639070

(57, 68)(86, 93)(65, 75)

296294263

989787

(95, 99)(94, 99)(82, 90)

∞ Seroconversion: proportion o subjects with either a post-vaccination HI titer≥1:40 rom a pre-vaccination titer <1:10 or at least a our-old increase rom pre-vaccination HI titer ≥1:10 in antibody titer.¥ HI titer ≥1:40: proportion o subjects with a post-vaccination titer ≥ 1:40.φ 95% CI: 95% condence interval

TABLE 5. Summary of the Geometric Mean Hemagglutination Inhibition

Antibody Titers, Pre- and Post-Immunization, for Adult Subjects

Year/Strain No.ofsubjects GeometricMeanTiter(GMT) Pre-vaccination Post-vaccination FoldIncrease (95%CI)*

1998-1999A/H1N1A/H3N2B

667.268.23

20.97

160.8787.02

231.07

22.1610.57110.2

(14.25, 34.46)(6.91, 16.16)(6.90, 17.59)

1999-2000A/H1N1A/H3N2B

767.43

15.2925.70

58.95122.83254.76

7.938.039.91

(5.73, 10.97)(5.80, 11.13)(6.97, 14.10)

2000-2001A/H1N1A/H3N2B

745.42

15.9826.24

33.80126.01308.25

6.247.89

11.75

(4.49, 8.69)(5.61, 11.09)(7.73, 17.85)

2001-2002A/H1N1A/H3N2B

757.76

23.6719.91

54.78153.81107.53

7.066.505.40

(5.24, 9.52)(4.78, 8.84)(3.95, 7.38)

2002-2003A/H1N1A/H3N2B

1067.78

23.3230.20

60.39292.03314.11

7.7712.5210.40

(5.81, 10.39)(8.77, 17.87)(7.54, 14.34)

2004-2005A/H1N1A/H3N2

B

741337

15

159658

156

1218

11

(8.39, 17)(12, 26)

(7.87, 14)

2005-2006A/H1N1A/H3N2B

303291413

23222183

8156.5

(6.68, 9.59)(14, 17)

(5.73, 7.37)

* 95% CI: 95% condence interval

TABLE 6. Summary of the Seroconversion and Proportion of Subjects

Achieving an HI titer ≥1:40 for Geriatric Subjects

Year/Strain No.ofsubjects Seroconversion∞ HItiter≥1:40

N % 95%CIφ N % 95%CIφ

1998-1999A/H1N1A/H3N2B

42333313

797931

(66, 91)(66, 91)(17, 45)

383642

9086

100

(82, 99)(75, 96)

(100, 100)

1999-2000A/H1N1A/H3N2B

3410189

295326

(14, 45)(36, 70)(12, 41)

233132

689194

(52, 83)(82, 100)(86, 100)

2000-2001A/H1N1A/H3N2B

355

2213

146337

(3, 26)(47, 79)(21, 53)

103133

298994

(14, 44)(78, 99)

(87, 100)

2001-2002A/H1N1A/H3N2B

355

156

144317

(3, 26)(26, 59)(5, 30)

143332

409491

(24, 56)(87, 100)(82, 100)

2002-2003A/H1N1A/H3N2B

89244241

274746

(18, 36)(37, 58)(36, 56)

528586

589697

(48, 69)(91, 100)(93, 100)

2004-2005A/H1N1A/H3N2B

61172938

284862

(17, 41)(35, 61)(49, 74)

466051

759884

(63, 86)(91, 100)(72, 92)

∞ Seroconversion: proportion o subjects with either a post-vaccination HI titer ≥1:40 rom a

pre-vaccination titer <1:10 or at least a our-old increase rom pre-vaccination HI titer ≥1:10 in

antibody titer¥ HI titer ≥1:40: proportion o subjects with a post-vaccination titer ≥1:40φ 95% CI: 95% condence interval

TABLE 7. Summary of the Geometric Mean Hemagglutination Inhibition

Antibody Titers, Pre- and Post-Immunization, for Geriatric Subjects

 Year/StrainNo.ofsubjects GeometricMeanTiter(GMT) Pre-vaccination Post-vaccination FoldIncrease (95%CI)*

1998-1999A/H1N1A/H3N2

B

4213.9210.69

114.1

176.65124.92

273.56

12.6911.69

2.40

(8.24, 19.56)(7.02, 19.46)

(1.82, 3.17)

1999-2000A/H1N1A/H3N2B

3415.8228.0057.16

50.58133.19127.86

3.204.762.24

(2.13, 4.80)(2.92, 7.76)(1.56, 3.20)

2000-2001A/H1N1A/H3N2B

356.66

25.8761.24

18.85140.68191.23

2.835.443.12

(1.91, 4.18)(3.72, 7.96)(2.13, 4.59)

2001-2002A/H1N1A/H3N2B

3512.6947.3345.49

26.65114.2691.89

2.102.412.02

(1.55, 2.84)(1.73, 3.38)(1.47, 2.78)

2002-2003A/H1N1

A/H3N2B

89

13.29

65.8674.87

31.92

272.79288.57

2.40

4.143.85

(1.90, 3.03)

(3.09, 5.55)(2.89, 5.13)

2004-2005A/H1N1A/H3N2B

61217220

64320114

3.134.435.69

(2.33, 4.2)(3.13, 6.27)(4.39, 7.38)

* 95% CI: 95% condence interval

USA_in158x560_Fluvirin08_RFVRF002 2 18/07/2008 11.05.11