INTRON A 10 MIU SOLUTION FOR INJECTION OR INFUSION

Theformatofthepackage inserthas beendeterminedby the MinistryofHealthandits content

was checkedandapprovedinJanuary 2008

IntronA®10 million IU/ml solutionfor injectionor infusion

1. NAMEOF THE MEDICINALPRODUCT

IntronA ®

10million IU/mlsolution for injection orinfusion

2. QUALITATIVE AND QUANTITATIVECOMPOSITION

OnevialofIntronAsolution forinjection or infusion, singledose vial,contains 10 millionIU

ofrecombinantinterferonalfa-2bproducedinE.colibyrecombinant DNAtechnology,in1ml

of solution.

For afulllist of excipients,see section 6.1.

3. PHARMACEUTICAL FORM

Solution for injection orinfusion

Solution isclear andcolourless.

4. CLINICAL PARTICULARS

4.1Therapeutic indications

Chronic HepatitisB:Treatmentofadult patientswithchronic hepatitis Bassociated with

evidenceofhepatitisBviralreplication(presenceofHBV-DNAandHBeAg),elevatedalanine

aminotransferase (ALT) andhistologicallyprovenactive liver inflammation and/orfibrosis.

Chronic HepatitisC:

Adult patients:

IntronA isindicated for thetreatmentofadultpatientswith chronic hepatitisCwho have

elevatedtransaminases without liver decompensationand whoarepositive for serumHCV-

RNAoranti-HCV(see section4.4).

Thebestwaytouse IntronA in thisindication is incombinationwithribavirin.

Chidren andadolescents:

IntronA isintended foruse, in a combinationregimenwith ribavirin, for the treatmentof

children andadolescents3 years of ageand older,who have chronic hepatitis C,not

previouslytreated,without liverdecompensation, and whoarepositive forserum HCV-RNA.

Thedecisionto treat shouldbemade onacase bycasebasis,takingintoaccountany

evidenceof disease progression suchashepaticinflammationandfibrosis, aswell as

prognostic factorsfor response,HCV genotypeandviral load.The expected benefit of

treatmentshould beweighedagainstthesafetyfindingsobservedfor paediatricsubjects in the

clinicaltrials(see sections 4.4, 4.8 and 5.1).

HairyCell Leukaemia: Treatment ofpatientswith hairy cellleukaemia.

Chronic MyelogenousLeukaemia:

Monotherapy:Treatment ofadult patientswith Philadelphia chromosomeorbcr/abl

translocationpositivechronic myelogenousleukaemia.

Clinicalexperienceindicates that a haematological andcytogeneticmajor/minorresponseis

obtainablein the majorityofpatientstreated.Amajorcytogeneticresponseisdefinedby

< 34% Ph+ leukaemiccellsin thebonemarrow,whereasaminorresponseis ≥34%,but

< 90 % Ph+ cells in themarrow.

Combination therapy:Thecombination ofinterferon alfa-2b andcytarabine(Ara-C)

administeredduringthe first12monthsoftreatment hasbeendemonstratedto significantly

increase the rate ofmajor cytogeneticresponses andtosignificantlyprolong theoverall

survivalat three years whencomparedtointerferon alfa-2bmonotherapy.

Multiple Myeloma: As maintenance therapyinpatientswhohaveachieved objective

remission(more than50% reductionin myelomaprotein) following initial induction

chemotherapy.

Current clinicalexperienceindicates thatmaintenance therapywith interferonalfa-2b

prolongstheplateauphase;however,effects onoverallsurvival have notbeen conclusively

demonstrated.

Follicular Lymphoma:Treatment ofhightumourburdenfollicular lymphoma as adjunct to

appropriate combination inductionchemotherapysuch as aCHOP-like regimen.Hightumour

burdenisdefined ashavingatleast oneof the following: bulkytumourmass (>7cm),

involvementof threeormore nodal sites(each>3cm), systemicsymptoms(weightloss

> 10 %,fever >38°Cformorethan 8days, ornocturnal sweats),splenomegalybeyondthe

umbilicus, major organobstructionorcompressionsyndrome, orbital orepidural

involvement,serouseffusion,or leukaemia.

Carcinoid Tumour: Treatment of carcinoid tumourswith lymphnodeorlivermetastases and

with "carcinoidsyndrome".

Malignant Melanoma: Asadjuvant therapyinpatientswho arefreeofdiseaseaftersurgery

but areat highriskof systemicrecurrence,e.g.,patients withprimaryor recurrent(clinical or

pathological) lymphnodeinvolvement.

4.2 Posologyandmethod ofadministration

Treatmentmustbeinitiatedbyaphysicianexperiencedinthe managementof the disease.

Not alldosage forms andstrengthsareappropriateforsomeindications.Please makesureto

selectanappropriate dosage formand strength.

Ifadverse events develop duringthe course oftreatment withIntronA foranyindication,

modifythe dosageordiscontinue therapytemporarily until the adverse eventsabate. If

persistent or recurrent intolerancedevelopsfollowingadequatedosageadjustment, ordisease

progresses, discontinuetreatmentwithIntronA.Atthediscretion of thephysician, the patient

mayself-administerthe dose formaintenance dosageregimens administeredsubcutaneously.

Chronic HepatitisB:The recommendeddosage is inthe range 5 to10million IU

administeredsubcutaneouslythreetimesaweek(every otherday)foraperiodof 4to

6 months.

The administered doseshould bereducedby50%in case of occurrenceofhaematological

disorders (white blood cells<1,500/mm 3 ,granulocytes<1,000/mm 3 , thrombocytes

<100,000/mm 3 ).Treatmentshould be discontinuedincase ofsevere leukopaenia

(<1,200/mm 3 ),severeneutropaenia (<750/mm 3 ) orseverethrombocytopaenia

(< 70,000/mm 3 ).

For allpatients, ifnoimprovement on serumHBV-DNAisobservedafter3to4monthsof

treatment(at themaximumtolerateddose), discontinueIntronA therapy.

Chronic HepatitisC: IntronA isadministered subcutaneouslyat adoseof3millionIU three

times aweek(everyotherday)to adult patients,whether administeredasmonotherapyorin

combinationwithribavirin.

Children3 yearsofage or olderandadolescents: Interferon alfa-2b 3 MIU/m 2 is

administeredsubcutaneously3timesa week(everyother day)in combinationwith ribavirin

capsules ororal solutionadministeredorallyin two divideddoses dailywithfood (morning

and evening).

(See ribavirincapsule SPC fordose of ribavirin capsules anddosagemodificationguidelines

for combination therapy.For paediatricpatientswho weigh< 47kgorcannotswallow

capsules,seeribavirinoral solutionSPC).

Relapse patients(adults):

IntronAisgivenincombination withribavirin.

Based ontheresults ofclinicaltrials,in whichdataareavailable for6monthsoftreatment,it

is recommended thatpatientsbe treatedwithIntronAincombinationwithribavirinfor

6 months.

Naïve patients:

Adults:TheefficacyofIntronAisenhancedwhengiven incombination with ribavirin.

IntronA shouldbegivenalonemainlyincase of intolerance orcontraindicationtoribavirin.

IntronA incombinationwith ribavirin:

Based ontheresults ofclinicaltrials,in whichdata are available for12monthsoftreatment,

it isrecommendedthat patients betreatedwithIntronAincombinationwithribavirinforat

least 6months.

Treatmentshouldbecontinuedfor another 6-month period(i.e.,atotal of12months)in

patientswhoexhibitnegativeHCV-RNAat month6,andwith viralgenotype1(as

determined ina pre-treatment sample) andhighpre-treatment viral load.

Othernegativeprognostic factors(age >40 years,malegender,bridgingfibrosis) shouldbe

takenintoaccountin order toextendtherapyto12months.

Duringclinical trials, patientswho failed toshowa virologicresponseafter6 monthsof

treatment(HCV-RNA belowlower limit of detection)didnotbecomesustainedvirologic

responders(HCV-RNAbelowlowerlimit ofdetection sixmonthsafterwithdrawal of

treatment).

IntronA alone:

Theoptimalduration of therapywith IntronA alone is notyet fully established,but a therapy

of between12and 18monthsisadvised.

Itisrecommendedthat patients be treatedwithIntronA alone foratleast3 to4months,at

which point HCV-RNAstatusshouldbedetermined.Treatmentshouldbecontinuedin

patients whoexhibitnegative HCV-RNA.

Children and adolescents:The efficacyand safetyofIntronAincombination withribavirin

hasbeen studied inchildrenand adolescentswhohavenot beenpreviouslytreated forchronic

hepatitis C.

Genotype 1:The recommendedduration oftreatmentisoneyear. Patients whofail to achieve

virological responseat 12 weeksarehighlyunlikelytobecomesustainedvirological

responders(negativepredictive value 96%). Virologicalresponseisdefined as absenceof

detectable HCV-RNA at Week 12. Treatmentshouldbediscontinuedinthese patients.

Genotype 2/3: The recommendeddurationof treatment is24weeks.

Virological responsesafter1year of treatmentand6monthsoffollow-upwere36% for

genotype1and 81 %for genotype2/3/4.

Hairy CellLeukaemia:The recommendeddosage is2millionIU/m 2 administered

subcutaneouslythree timesaweek (everyotherday)forbothsplenectomisedandnon-

splenectomisedpatients. For most patients withHairyCell Leukaemia,normalisationofone

ormorehaematological variablesoccurswithinoneto two monthsofIntronAtreatment.

Improvementin all three haematological variables (granulocytecount, plateletcount and

haemoglobin level)mayrequire sixmonthsormore. Thisregimen mustbemaintainedunless

the diseaseprogresses rapidlyorsevereintolerance ismanifested.

Chronic MyelogenousLeukaemia:TherecommendeddosageofIntronAis4to

5 millionIU/m 2

administered dailysubcutaneously. Some patientshavebeenshownto benefit

fromIntronA5 millionIU/m 2 administereddailysubcutaneouslyin associationwith

cytarabine (Ara-C) 20mg/m 2 administereddailysubcutaneouslyfor 10daysper month (up to

amaximum dailydoseof 40mg).When thewhite blood cell count iscontrolled,administer

the maximumtolerated doseof IntronA (4to5millionIU/m 2 daily) tomaintain

haematological remission.

IntronA treatmentmust bediscontinuedafter 8 to12weeksoftreatment ifat least a partial

haematologicalremission or aclinicallymeaningfulcytoreduction hasnotbeenachieved.

MultipleMyeloma: Maintenance therapy:In patientswho are inthe plateauphase(more than

50 %reduction ofmyeloma protein)followinginitial inductionchemotherapy,interferon

alfa-2bmaybeadministeredasmonotherapy,subcutaneously,at adose of 3millionIU/m 2

threetimesa week(everyother day).

FollicularLymphoma:Adjunctivelywithchemotherapy, interferon alfa-2bmaybe

administeredsubcutaneously,at adose of5millionIU three times a week (everyother day)

for a durationof18months.CHOP-like regimens are advised, but clinical experienceis

available onlywith CHVP(combinationofcyclophosphamide, doxorubicin,teniposideand

prednisolone).

Carcinoid Tumour: Theusualdose is5millionIU(3to9millionIU)administered

subcutaneouslythree timesaweek (everyother day).Patientswith advanced diseasemay

require adailydose of5millionIU.The treatment is tobe temporarilydiscontinuedduring

and after surgery.Therapymaycontinueforas long as thepatient respondstointerferonalfa-

2b treatment.

MalignantMelanoma:Asinduction therapy,interferonalfa-2b is administered intravenously

at adoseof20 millionIU/m 2 dailyfor fivedaysaweek fora four-week period;thecalculated

interferonalfa-2bdose is added tosodiumchloride 9mg/ml(0.9%) solutionfor injection and

administeredas a 20-minuteinfusion(seesection6.6). Asmaintenance treatment,the

recommendeddose is10 millionIU/m 2 administeredsubcutaneouslythree daysa week(every

other day)for 48weeks.

If severe adverse eventsdevelopduringinterferonalfa-2b treatment,particularlyif

granulocytes decrease to< 500/mm 3 oralanineaminotransferase/aspartateaminotransferase

(ALT/AST)risesto >5 xupper limitof normal,discontinue treatmenttemporarilyuntilthe

adverseeventabates. Interferonalfa-2btreatment is tobe restartedat50 % oftheprevious

dose.If intolerance persistsafter doseadjustmentorif granulocytes decrease to <250/mm 3 or

ALT/ASTrises to >10xupper limit ofnormal,discontinue interferonalfa-2btherapy.

Althoughtheoptimal(minimum) dosefor fullclinical benefit isunknown,patients must be

treatedat the recommendeddose,with dose reductionfor toxicityasdescribed.

IntronAmaybeadministeredusing eitherglass orplastic disposableinjection syringes.

4.3 Contraindications

- Hypersensitivitytotheactivesubstance ortoanyof the excipients.

- Ahistoryofseverepre-existing cardiacdisease,e.g., uncontrolled congestiveheart

failure, recentmyocardialinfarction,severe arrhythmicdisorders.

- Severerenalorhepatic dysfunction; including that causedbymetastases.

- Epilepsyand/or compromisedcentral nervoussystem(CNS) function(see section4.4).

- Chronic hepatitiswithdecompensatedcirrhosis of theliver.

- Chronichepatitis in patientswho are beingor have beentreated recently with

immunosuppressiveagentsexcluding short termcorticosteroidwithdrawal.

- Autoimmunehepatitis; orhistoryof autoimmune disease; immunosuppressed

transplant recipients.

- Pre-existing thyroid disease unlessitcan becontrolledwithconventional treatment.

Children and adolescents:

- Existence of,or historyof severepsychiatriccondition, particularlyseveredepression,

suicidal ideationor suicideattempt.

Combination therapywithribavirin:Alsoseeribavirin SPC if interferon alfa-2bistobe

administeredincombinationwithribavirinin patients withchronichepatitisC.

4.4 Specialwarnings and precautions foruse

For allpatients:

Psychiatric andcentral nervoussystem(CNS):SevereCNSeffects,particularlydepression,

suicidal ideationand attempted suicide havebeenobservedinsomepatients duringIntronA

therapy,and evenaftertreatment discontinuation mainlyduringthe6-monthfollow-up

period.Among childrenandadolescents treatedwithIntronA incombination withribavirin,

suicidal ideationorattempts werereportedmorefrequentlycomparedtoadultpatients (2.4%vs

1%) duringtreatment andduringthe 6-monthfollow-upafter treatment.Asinadult patients,

children and adolescentsexperienced otherpsychiatricadverseevents (e.g.,depression,

emotional lability,and somnolence).Other CNSeffects includingaggressive behaviour

(sometimesdirectedagainst others),confusionand alterations of mentalstatushavebeen

observedwithalphainterferons.Patientsshouldbecloselymonitoredforanysignsor

symptomsofpsychiatricdisorders.Ifsuch symptomsappear,thepotential seriousness of

these undesirableeffects mustbeborneinmindbytheprescribingphysician and theneedfor

adequate therapeuticmanagement shouldbeconsidered. If psychiatric symptoms persist or

worsen,orsuicidalideationisidentified, itis recommended that treatment withIntronAbe

discontinued,andthe patientfollowed,withpsychiatric interventionasappropriate.

Patientswithexistenceoforhistoryofseverepsychiatric conditions:

Iftreatment withinterferonalfa-2bis judgednecessaryinadult patientswithexistence orhistory

of severepsychiatric conditions,thisshouldonlybeinitiated afterhavingensuredappropriate

individualiseddiagnosticandtherapeutic managementof thepsychiatric condition.Theuseof

interferon alfa-2b in childrenandadolescentswithexistence oforhistoryofseverepsychiatric

conditionsis contraindicated(seesection4.3).

Acute hypersensitivityreactions(e.g.,urticaria, angioedema,bronchoconstriction,

anaphylaxis) tointerferonalfa-2b havebeenobservedrarelyduringIntronA therapy.If such a

reactiondevelops,discontinuethemedication andinstitute appropriatemedical therapy.

Transient rashes donot necessitate interruption of treatment.

Moderatetosevereadverseexperiencesmayrequire modificationofthe patient'sdosage

regimen,or insomecases,termination ofIntronAtherapy.Any patientdevelopingliver

functionabnormalitiesduringtreatment withIntronA mustbemonitoredcloselyand

treatmentdiscontinuedifsignsandsymptomsprogress.

Hypotension mayoccurduringIntronAtherapyoruptotwo dayspost-therapyandmay

require supportive treatment.

Adequate hydrationmustbe maintained inpatientsundergoing IntronA therapysince

hypotensionrelatedtofluiddepletion has beenseeninsomepatients.Fluidreplacement may

be necessary.

Whilefever maybeassociatedwiththe flu-like syndromereportedcommonlyduring

interferon therapy,other causes ofpersistent fevermust be ruled out.

IntronAmustbeused cautiouslyin patients withdebilitatingmedical conditions,suchas

thosewitha historyofpulmonarydisease (e.g.,chronic obstructivepulmonarydisease)or

diabetesmellitus prone toketoacidosis.Cautionmustbe observedalso inpatients with

coagulation disorders (e.g., thrombophlebitis, pulmonaryembolism) orsevere

myelosuppression.

Pulmonaryinfiltrates,pneumonitis,andpneumonia,occasionallyresulting infatality,have

beenobserved rarelyin interferonalphatreatedpatients,includingthosetreatedwithIntronA.

The aetiologyhasnotbeendefined.Thesesymptomshavebeenreportedmorefrequently

whenshosaikoto, aChinese herbalmedicine, isadministeredconcomitantlywithinterferon

alpha (see section4.5).Anypatient developingfever,cough,dyspnea or other respiratory

symptomsmusthavea chestX-raytaken. If the chest X-ray showspulmonaryinfiltrates or

there isevidenceofpulmonaryfunction impairment,thepatientistobemonitoredclosely,

and,ifappropriate,discontinueinterferonalpha.While this has beenreportedmoreoftenin

patients withchronichepatitis C treatedwithinterferonalpha, it has alsobeenreportedin

patients withoncologic diseases treatedwith interferonalpha.Prompt discontinuation of

interferon alphaadministration and treatment with corticosteroidsappeartobeassociated

withresolutionof pulmonaryadverse events.

Ocularadverse events(seesection4.8) includingretinalhaemorrhages, cottonwool spots,

andretinal arteryor veinobstructionhave beenreportedinrareinstancesaftertreatmentwith

alpha interferons.All patientsshouldhaveabaselineeye examination. Anypatient

complainingof changesin visualacuityorvisual fields,orreportingother ophthalmologic

symptomsduring treatment with IntronA,musthavea promptandcomplete eyeexamination.

Periodic visual examinationsduringIntronA therapyare recommendedparticularlyin patients

with disorders thatmay beassociatedwithretinopathy, such asdiabetesmellitus or

hypertension.DiscontinuationofIntronAshouldbe consideredinpatients whodevelopnew

or worseningophthalmologicaldisorders.

Moresignificantobtundationandcoma,includingcases ofencephalopathy,havebeen

observedinsomepatients, usuallyelderly,treated at higher doses. Whilethese effectsare

generallyreversible,in a few patients full resolution took upto three weeks. Veryrarely,

seizureshave occurred withhighdoses of IntronA.

Adult patientswithahistoryof congestiveheartfailure, myocardial infarction and/orprevious

orcurrent arrhythmic disorders,who requireIntronAtherapy,must becloselymonitored. Itis

recommended that thosepatients whohavepre-existingcardiac abnormalities and/orare in

advancedstages of cancerhaveelectrocardiograms takenprior toand duringthecourse of

treatment.Cardiacarrhythmias (primarilysupraventricular)usuallyrespond toconventional

therapybut mayrequire discontinuationofIntronAtherapy.There arenodatain children or

adolescentswithahistoryofcardiacdisease.

Hypertriglyceridemia andaggravation ofhypertriglyceridemia, sometimessevere, have been

observed.Monitoringoflipidlevels is,therefore, recommended.

Dueto reportsofinterferon alphaexacerbatingpre-existingpsoriaticdisease andsarcoidosis,

useof IntronA in patientswithpsoriasisor sarcoidosis is recommendedonlyif thepotential

benefit justifiesthepotential risk.

Preliminarydataindicates that interferonalphatherapymaybe associatedwithan increased

rate ofkidney graft rejection.Livergraft rejection hasalso beenreported.

Thedevelopmentofauto-antibodiesandautoimmunedisorders hasbeenreportedduring

treatmentwithalpha interferons.Patientspredisposed to thedevelopmentofautoimmune

disordersmaybe at increased risk.Patientswithsigns orsymptomscompatiblewith

autoimmunedisordersshould beevaluatedcarefully,andthe benefit-riskof continued

interferontherapyshouldbereassessed (seealsosection4.4 Chronic hepatitis C,

Monotherapy(thyroidabnormalities)andsection4.8).

Discontinue treatmentwith IntronA inpatients withchronichepatitis whodevelop

prolongation ofcoagulation markerswhich mightindicateliver decompensation.

Chronic HepatitisC:

Combination therapywithribavirin:AlsoseeribavirinSPCif IntronAis tobeadministeredin

combinationwithribavirininpatients withchronic hepatitisC.

All patientsinthe chronic hepatitis Cstudieshada liverbiopsybefore inclusion, but in

certaincases (i.e.patients withgenotype2and3),treatment maybepossible without

histological confirmation.Current treatmentguidelinesshould be consultedastowhethera

liverbiopsyisneededprior to commencingtreatment.

Monotherapy:Infrequently, adultpatients treated forchronichepatitis C with IntronA

developed thyroid abnormalities, eitherhypothyroidismorhyperthyroidism.In clinical trials

using IntronA therapy,2.8 %patientsoverall developedthyroidabnormalities. The

abnormalities werecontrolled byconventional therapyfor thyroid dysfunction.The

mechanismbywhichIntronAmayalter thyroid statusisunknown.Prior to initiationof

IntronA therapyforthetreatment ofchronic hepatitis C,evaluate serumthyroid-stimulating

hormone (TSH)levels. Anythyroidabnormalitydetectedatthattimemust betreatedwith

conventionaltherapy.IntronA treatment maybeinitiatedifTSH levelscanbe maintainedin

the normal range bymedication.Determine TSH levelsif, duringthe courseof IntronA

therapy,a patientdevelopssymptomsconsistentwithpossible thyroiddysfunction.Inthe

presenceofthyroid dysfunction, IntronA treatmentmaybe continuedif TSH levelscan be

maintainedinthe normal range bymedication.Discontinuation ofIntronA therapyhasnot

reversedthyroid dysfunction occurringduringtreatment (also seeChildren andadolescents,

Thyroid monitoring).

Supplementalmonitoringspecific for childrenandadolescents

ThyroidMonitoring:Approximately12 % ofchildrentreatedwith interferonalfa-2band

ribavirin developedincrease inTSH. Another4 % hada transientdecrease below thelower

limit ofnormal.Priortoinitiation ofIntronAtherapy,TSH levelsmust beevaluated andany

thyroid abnormalitydetected atthat timemustbe treated withconventional therapy.IntronA

therapymaybeinitiatedif TSH levelscanbemaintainedinthenormalrangebymedication.

Thyroiddysfunctionduringtreatmentwithinterferonalfa-2bandribavirinhasbeenobserved.

Ifthyroidabnormalitiesare detected,the patient’sthyroidstatusshould beevaluatedand

treatedas clinicallyappropriate. Childrenand adolescentsshouldbemonitored every

3 monthsfor evidence ofthyroiddysfunction(e.g.TSH).

GrowthandDevelopment: Duringa1-year courseoftherapythere wasa decrease inthe rate

of lineargrowth(meanpercentiledecrease of 9%)anda decrease in the rateofweight gain

(meanpercentiledecrease of13%).Ageneralreversalof these trendswasnoted duringthe

6 monthsfollow-up posttreatment.However, based oninterimdatafrom along-termfollow-

up study,12(14 %) of84children hada >15percentile decrease inrateof linear growth,of

whom5 (6%) children hada > 30percentile decrease despitebeing offtreatmentformore

than 1 year.Inaddition,preclicinal juvenile toxicityresults havedemonstratedaminor,dose-

related decrease inoverallgrowthinneonatalratsdosedwithribavirin(seesection5.3).

Therefore,the risk/benefitof the combineduseofinterferon alfa-2bandribavirinshouldbe

assessed inyoung childrenprior tothe initiation oftherapy.Physicians areadvisedtomonitor

the growthofchildren takingribavirin incombination with interferonalfa-2b. Thereareno

dataonlongterm effectson growthanddevelopmentandonsexualmaturation.

HCV/HIV Coinfection:Patients co-infectedwith HIVandreceiving HighlyActiveAnti-

RetroviralTherapy(HAART)maybeatincreasedriskofdevelopinglactic acidosis.Caution

shouldbeusedwhenadding IntronA andribavirintoHAART therapy(seeribavirinSPC).

Patients treated withIntronA andribavirincombinationtherapyandzidovudine could beat

increasedriskofdevelopinganaemia.

Co-infectedpatientswithadvancedcirrhosisreceivingHAARTmaybeatincreasedrisk of

hepaticdecompensationanddeath.Addingtreatment withalfa interferonsaloneorin

combinationwithribavirinmayincreasetheriskinthis patientsubset.

Concomitantchemotherapy:

Administration of IntronA incombination withother chemotherapeutic agents (e.g.,Ara-C,

cyclophosphamide, doxorubicin, teniposide) mayleadtoincreasedrisk of toxicity(severity

andduration), which maybelife-threateningorfatal as aresult ofthe concomitantly

administeredmedicinalproduct.The mostcommonlyreportedpotentiallylife-threateningor

fataladverse eventsinclude mucositis,diarrhoea, neutropaenia, renalimpairment,and

electrolytedisturbance. Becauseofthe risk ofincreased toxicity,careful adjustments ofdoses

are requiredfor IntronA andfor the concomitantchemotherapeuticagents (seesection 4.5).

Dental and periodontaldisorders:Dentaland periodontal disorders,whichmayleadto lossof

teeth,have beenreportedinpatientsreceivingIntronAandribavirin combination therapy.In

addition,drymouthcouldhavea damagingeffect onteeth andmucous membranesof the

mouthduringlong-termtreatment withthe combination ofIntronAandribavirin.Patients

shouldbrushtheir teeththoroughlytwice dailyand have regulardental examinations. In

addition some patientsmayexperiencevomiting. If this reactionoccurs,theyshouldbe

advisedto rinseout theirmouth thoroughlyafterwards.

LaboratoryTests:

Standard haematological tests andblood chemistries(complete bloodcount anddifferential,

platelet count,electrolytes, liverenzymes,serumprotein,serumbilirubinandserum

creatinine)are to beconducted inall patientsprior toandperiodicallyduringsystemic

treatmentwithIntronA.

During treatment forhepatitis B orCtherecommendedtesting schedule is at weeks1, 2,4, 8,

12,16,andeveryothermonth, thereafter, throughout treatment.IfALT flaresduringIntronA

therapyto greater thanorequalto2times baseline,IntronAtherapymaybecontinued unless

signs andsymptomsofliver failure are observed.During ALTflare, liverfunction tests:ALT,

prothrombintime,alkaline phosphatase,albuminandbilirubinmustbemonitoredattwo-

weekintervals.

Inpatients treated formalignantmelanoma, liver functionand white blood cell (WBC) count

and differentialmust bemonitored weeklyduringthe induction phase oftherapyandmonthly

duringthemaintenance phaseof therapy.

Effect onfertility:Interferonmayimpairfertility(see section4.6and section5.3).

4.5 Interaction with othermedicinalproducts and otherformsof interaction

Narcotics, hypnoticsor sedatives mustbe administered withcaution when usedconcomitantly

with IntronA.

InteractionsbetweenIntronAandother medicinal productshavenotbeenfullyevaluated.

Caution mustbe exercised whenadministeringIntronAincombinationwithotherpotentially

myelosuppressiveagents.

Interferonsmayaffectthe oxidativemetabolic process. Thismust beconsideredduring

concomitanttherapywithmedicinalproducts metabolised bythisroute,such as thexanthine

derivatives theophylline or aminophylline. Duringconcomitanttherapywith xanthineagents,

serumtheophyllinelevelsmust bemonitoredanddosageadjustedifnecessary.

Pulmonaryinfiltrates,pneumonitis,andpneumonia,occasionallyresultinginfatality,have

beenobserved rarelyin interferonalphatreatedpatients,includingthosetreatedwithIntronA.

The aetiologyhasnotbeendefined.Thesesymptomshavebeenreportedmorefrequently

whenshosaikoto, aChinese herbalmedicine, isadministeredconcomitantlywithinterferon

alpha (seesection4.4).

Administration of IntronA incombination withother chemotherapeutic agents (e.g.,Ara-C,

cyclophosphamide, doxorubicin, teniposide) mayleadtoincreasedrisk of toxicity(severity

and duration)(see section4.4).

(AlsoseeribavirinSPCif IntronA istobeadministeredincombination withribavirin in

patientswithchronic hepatitisC).

4.6 Pregnancy and lactation

Women of childbearingpotential havetouseeffectivecontraception during treatment.

IntronAmustbeused withcaution in fertilemen.Decreasedserumestradiol andprogesterone

concentrations havebeen reported in women treatedwith humanleukocyte interferon.

There are no adequatedatafromtheuseofinterferonalfa-2b inpregnantwomen.Studies in

animalshaveshownreproductive toxicity(see section5.3). The potential riskfor humans is

unknown. IntronAis to be used duringpregnancyonly if thepotential benefit justifies the

potential risktothe foetus.

Itisnot knownwhether the componentsof thismedicinalproductareexcretedinhuman

milk.Because of the potentialfor adversereactionsinnursing infants, nursing shouldbe

discontinued priortoinitiationof treatment.

Combination therapywithribavirin:Ribavirincauses serious birth defectswhenadministered

duringpregnancy.Ribavirintherapyiscontraindicated in womenwho arepregnant.Extreme

caremustbetakentoavoid pregnancyinfemalepatients or inpartnersof malepatientstaking

IntronA incombinationwith ribavirin. Femalesof childbearingpotential and their partners

musteachusean effectivecontraceptive during treatment and for4monthsafter treatment

has beenconcluded.Male patients andtheirfemalepartnersmusteach use aneffective

contraceptive duringtreatment and for7months aftertreatmenthas beenconcluded(see

ribavirin SPC).

4.7 Effectsonabilitytodriveand use machines

Patientsare tobeadvisedthattheymaydevelopfatigue,somnolence,orconfusionduring

treatmentwithIntronA,andtherefore it isrecommendedthattheyavoiddrivingor operating

machinery.

4.8Undesirable effects

Seeribavirin SPCforribavirin-related undesirableeffectsif IntronA is tobeadministeredin

combinationwithribavirininpatients withchronic hepatitisC.

Inclinical trialsconducted in abroad range ofindications and at awide rangeof doses(from

6 MIU/m 2 /weekinhairycellleukaemia upto100MIU/m 2 /weekin melanoma),the most

commonlyreportedundesirableeffects werefever, fatigue,headacheand myalgia.Feverand

fatigue wereoftenreversiblewithin72hoursofinterruption orcessation oftreatment.

The safetyprofile shownherewas determinedfrom4 clinical trialsin hepatitisC in which

patients weretreated with IntronAaloneorin combination withribavirin for oneyear.All

patients inthesetrials received 3 MIUof IntronAthree timesaweek. The percentage of

patients reporting(treatmentrelated) undesirable effects ≥10 %is presentedinTable 1asa

range tocapture the incidencesreportedinindividualtreatment groupsamongtheseclinical

trials in naïvepatients treated for one year. Severitywasgenerallymildtomoderate.

Table 1. Undesirableeffects reportedverycommonly in anyof the clinicaltrialsin naïvepatients treated

for one year withmonotherapyorcombination therapy,

Verycommon(>1/10)

(CIOMS III )

BodySystem IntronA

n=806 IntronA +ribavirin

n=1,010

Infections and infestations

Infection viral

Pharyngitis

0-7 %

3-7 %

3-10%

7-13%

Metabolism and nutritiondisorders

Anorexia

14-19 %

19-26 %

Psychiatricdisorders

Depression

Insomnia

Anxiety

Emotional lability

16-36 %

21-28 %

8-12 %

5-8 %

25-34 %

33-41 %

8-16%

5-11%

Nervous systemdisorders

Headache

Concentrationimpaired

Dizziness

51-64 %

8-14 %

8-18 %

48-64 %

9-21%

10-22 %

Respiratory,thoracicandmediastinal

disorders

Coughing

Dyspnoea

3-7 %

2-9 %

8-11%

10-22 %

Gastrointestinal disorders

Nausea/Vomiting

Diarrhoea

Abdominal pain

18-31 %/3-10%

12-22 %

9-17 %

25-44 %/6-10%

13-18 %

9-14%

Skin and subcutaneous tissue

disorders

Alopecia

Pruritus

Skin dry

Rash

22-31 %

6-9 %

5-8 %

5-7 %

26-32 %

18-27 %

10-21 %

15-24 %

Musculoskeletalandconnectivetissue

disorders

Myalgia

Arthralgia

Musculoskeletal pain

41-61 %

25-31 %

15-20 %

30-62 %

21-29 %

11-20 %

General disordersand administration

siteconditions

Injectionsiteinflammation

Injection sitereaction

Fatigue

Rigors

Fever

Flu-like symptoms

Asthenia

9-16 %

5-8 %

42-70 %

15-39 %

29-39 %

19-37 %

9-30 %

6-17%

3-36%

43-68 %

19-41 %

29-41 %

18-29 %

9-30%

18-34 %

Investigations

Weight decrease

6-11 %

9-19%

Table2.Undesirable effects reportedcommonly inclinicaltrialsof483 patients treatedwith

IntronA + Ribavirin

(IntronA 3MIU3timesa week,ribavirin>10.6 mg/kgfor oneyear)

Common (>1/100, <1/10)

(CIOMS III )

BodySystem IntronA+ribavirin

Infections and infestations

1-5 %:

Herpessimplex(resistance), bronchitis, rhinitis,sinusitis

Blood and lymphatic system disorders

5-10%:

1-5 %:

Leukopaenia

Thrombocytopaenia,lymphadenopathy,lymphopenia

Endocrine disorders

1-5 %:

Hyperthyroidism, hypothyroidism

Metabolism and nutritiondisorders

1-5 %:

Hyperuricemia,hypocalcemia, thirst,dehydration

Psychiatricdisorders

5-10%:

1-5 %:

Agitation, nervousness

Sleepdisorder,libido decreased,confusion

Nervous systemdisorders

5-10%:

1-5 %:

Mouthdry

Hypoesthesia, parasthesia, tremor,migraine,flushing,

somnolence, tasteperversion

Eye disorders

5-10%:

1-5 %:

Vision blurred

Conjunctivitis,eye pain, visionabnormal, lachrymal gland

disorder

Earand labyrinth disorders

1-5 %:

Tinnitus, vertigo

Cardiac disorders

1-5 %:

Palpitation, tachycardia

Vascular disorders

1-5 %:

Hypertension

Respiratory,thoracicandmediastinal

disorders

1-5 %:

Cough nonproductive,epistaxis,nasalcongestion, respiratory

disorder, rhinorrhea

Gastrointestinal disorders

5-10%:

1-5 %:

Dyspepsia, stomatitis

Constipation,gingivitis, glossitis,loosestools,stomatitis

ulcerative, right upper quadrantpain

Hepatobiliary disorders

1-5 %:

Hepatomegaly

Skin and subcutaneous tissue

disorders

5-10%:

1-5 %:

Sweating increased

Eczema,psoriasis(neworaggravated),rasherythematous,

rashmaculopapular,skindisorder, erythema

Musculoskeletalandconnectivetissue

disorders

1-5 %:

Arthritis

Renaland urinary disorders

1-5 %:

Micturitionfrequency

Reproductive systemandbreast

disorders

1-5 %:

Amenorrhea,breastpain, dysmenorrhea, menorrhagia,

menstrual disorder, vaginaldisorder

General disordersand administration

siteconditions

5-10%:

1-5 %:

Malaise, chest pain

Injection sitepain,

These undesirable effectshave alsobeenreportedwithIntronAalone.

Theundesirable effects seenwithhepatitisC are representative ofthose reported when

IntronAisadministeredinother indications, withsomeanticipateddose-related increases in

incidence. For example, inatrial of high-dose adjuvant IntronAtreatmentin patients with

melanoma, incidences offatigue,fever, myalgia,neutropaenia/anaemia, anorexia, nauseaand

vomiting,diarrhoea, chills, flu-likesymptoms,depression, alopecia, altered taste,and

dizziness weregreater than inthehepatitis C trials.Severityalsoincreasedwithhighdose

therapy(WHO Grade3and 4, in66% and14% ofpatients,respectively), incomparison

withthe mildtomoderate severityusuallyassociatedwith lowerdoses. Undesirable effects

were usuallymanagedbydoseadjustment.

Additional adverse eventswere reportedrarely(> 1/10,000,< 1/1,000)or veryrarely

(< 1/10,000)during clinicaltrials in other indicationsorfollowing themarketingof

interferon alfa-2b:

Infections and infestations

rarely: pneumonia

Blood and lymphatic system disorders

Very rarely IntronAused aloneorincombination withribavirin maybe associatedwith

aplastic anaemia.Pureredcell aplasiahas beenreported.

Immune system disorders:

veryrarely: sarcoidosisorexacerbationofsarcoidosis

Endocrine disorders:

veryrarely: diabetes, aggravateddiabetes

Metabolism andnutrition disorders:

veryrarely: hyperglycaemia,hypertriglyceridaemia, increasedappetite

Psychiatricdisorders:

rarely: suicide ideation

veryrarely: aggressivebehaviour(sometimesdirectedagainstothers),suicide attempts,

suicide, psychosis,includinghallucinations

Nervous systemdisorders:

veryrarely: impaired consciousness, neuropathy,polyneuropathy,seizure,

encephalopathy, cerebrovascularischaemia,cerebrovascularhaemorrhage

Eye disorders:

rarely: retinal haemorrhages,retinopathies(includingmacularoedema),cotton-wool

spots, retinal arteryorveinobstruction,lossofvisual acuityorvisual field,optic

neuritis andpapilloedema

Earand labyrinth disorders:

veryrarely: hearingdisorder, hearing loss

Cardiac disorders:

veryrarely:;cardiac ischaemia andmyocardial infarction

Vascular disorders:

veryrarely: hypotension;peripheral ischaemia

Respiratory,thoracicandmediastinaldisorders:

veryrarely: pulmonaryinfiltrates,pneumonitis

Gastrointestinal:

veryrarely: pancreatitis;gingivalbleeding; colitis,mainly ulcerative andischemic

Hepatobiliary disorders:

veryrarely: hepatotoxicity, includingfatality

Skin and subcutaneous tissue disorders:

veryrarely:erythemamultiforme,StevensJohnsonsyndrome,toxicepidermalnecrolysis

Musculoskeletal and connectivetissuedisorders:

veryrarely: rhabdomyolysis,sometimesserious; leg cramps; backpain;myositis

Renaland urinary disorders:

veryrarely: nephroticsyndrome, renal insufficiency,renalfailure

Generaldisorders andadministrationsiteconditions

veryrarely: faceoedema,injectionsitenecrosis

Cardiovascular(CVS)adverse events,particularlyarrhythmia, appearedtobe correlated

mostlywithpre-existingCVSdisease andpriortherapywith cardiotoxic agents(seesection

4.4).Cardiomyopathy, that maybe reversibleupon discontinuationofinterferonalpha,has

been reportedrarelyin patientswithoutpriorevidence ofcardiac disease.

Awide varietyof autoimmuneand immune-mediated disorders havebeenreportedwithalpha

interferonsincludingthyroiddisorders, systemiclupuserythematosus, rheumatoidarthritis

(new oraggravated), idiopathicandthrombotic thrombocytopenicpurpura, vasculitis,

neuropathies includingmononeuropathies(seealsosection4.4).

Clinicallysignificant laboratoryabnormalities,mostfrequentlyoccurring atdoses greater

than10 millionIUdaily,includereductioningranulocyte andwhitebloodcellcounts;

decreasesinhaemoglobinlevel andplateletcount; increases inalkalinephosphatase,LDH,

serumcreatinine and serum urea nitrogen levels.Increaseinserum ALT/AST (SGPT/SGOT)

levelshave beennoted asanabnormalityinsomenon-hepatitis subjectsand also in some

patients withchronichepatitis B coincidentwithclearance ofviral DNAp.

Children and adolescents–Chronic Hepatitis C

Inclinicaltrials of118childrenoradolescents3 to 16yearsofage,6 %discontinued therapy

due to adverse events. In general, theadverse event profile in the limitedpaediatric

populationstudied wassimilartothatobservedinadults,althoughthereisa paediatric

specific concern regardinggrowth inhibition asdecrease inheight(meanpercentile decrease

of growthvelocityof 9%) andweight(meanpercentile decrease of13%) percentilewere

observedduringtreatment (see section 4.4). Furthermore,suicidal ideation orattemptswere

reported morefrequentlycompared toadultpatients(2.4 %vs1%)duringtreatmentand

duringthe 6 monthfollow-up after treatment.Asinadult patients, childrenand adolescents

also experienced otherpsychiatric adverseevents (e.g.,depression, emotional lability,and

somnolence)(seesection4.4). In addition, injectionsitedisorders, fever,anorexia,vomiting,

and emotional labilityoccurredmorefrequentlyin children andadolescentscomparedto

adult patients.Dosemodificationswererequiredin30% of patients, most commonlyfor

anaemiaandneutropaenia.

Undesirableeffectsreportedinpaediatricclinical trials, and not previouslyreported atan

incidence ≥1%in adults,are shown inTable 3.All effectsreported at a≥10% incidencein

paediatrictrials werepreviouslyreported in adults(Table2)and are notrepeatedinthe

paediatrictable.

Table 3 Undesirableeffectsverycommonlyand commonlyreported inpaediatricclinicaltrials

≥1%ofpatientstreatedwithIntronA+ribavirin)

Verycommon(>1/10) - Common(>1/100,<1/10)

Bodysystem ≥10%

5% -< 10 % 1% -<5 %

Infectionandinfestations Viral infection Toothabscess, bacterial

pharyngitisinfection, fungal

infection, herpes

simplex, otitismedia,

pulmonaryinfection,

gastroenteritis, urinary

tract infection, vaginitis

Neoplasmsbenign,

malignant and unspecified

(including cystsand

polyps) Neoplasm (unspecified),

Bloodandlymphatic

systemdisorders Anaemia, neutropenia Thrombocytopaenia,

lymphadenopathy

Endocrine disorders Hypothyroidism Hyperthyroidism,

virilism,

Metabolismandnutrition

disorders Anorexia Hypertriglyceridemia,

hyperuricemia,

increasedappetite

Psychiatric disorders Depression,emotional

lability,insomnia Agitation Aggressivereaction,

anxiety,apathy,

behaviour disorder,

abnormal dreaming,

nervousness, sleep

disorder,

somnambulism, suicidal

ideation,confusion

Nervous system disorders Headache,dizziness Tremor, somnolence Hyperkinesia,

dysphonia, paresthaesia,

hyperaesthesia,

hypoaesthesia,

concentration impaired

Eye disorders Conjunctivitis, eye pain,

abnormal vision,

lacrimal gland disorder

Vasculardisorders Pallor Raynaud’s disease,

flushing

Respiratory,thoracicand

mediastinal disorders Epistaxis Coughing,dyspnoea,

nasal congestion,nasal

irritation,rhinorrhea,

sneezing,tachypnea

Gastrointestinal disorders Abdominalpain,

diarrhoea,nausea,

vomiting Constipation, dyspepsia,

gastroesophogeal reflux,

gastrointestinal disorder,

glossitis, loosestools,

mouth ulceration,rectal

disorder, stomatitis,

stomatitis ulcerative,

toothache, tooth

disorder, right upper

quadrantpain

Hepatobiliarydisorders Hepatic function

abnormal

Skinandsubcutaneous

tissue disorders Alopecia,rash Pruritus Acne,eczema,nail

disorder, dryskin,

photosensitivity

reaction,maculopapular

rash, skin

discolouration,skin

disorder, erythema,

sweating increased,

bruise

Musculoskeletal and

connective tissue

disorders Arthralgia,

musculoskeletal pain,

myalgia

Renal andurinary

disorders Enuresis, micturition

disorder, urinary

incontinence

Reproductive systemand

breastdisorders Female: amenorrhea,

menorrhagia, menstrual

disorder, vaginal

disorder

Male: testicularpain

General disorders and

administration site

conditions Injection sitereaction,

injectionsite

inflammation, fatigue,

fever, rigors,influenza-

like symptoms,malaise,

irritability Injectionsitepain Asthenia, oedema, chest

pain,

Investigations Growth ratedecrease

(height and/orweight

decrease forage)

Injury,poisoningand

procedural complications Skin laceration

4.9Overdose

No caseof overdosehas been reported that hasled toacuteclinicalmanifestations. However,

asforanypharmacologicallyactivecompound,symptomatic treatment with frequent

monitoringof vital signsandclose observationof the patient is indicated.

5. PHARMACOLOGICAL PROPERTIES

5.1Pharmacodynamic properties

Pharmacotherapeuticgroup: Immunostimulants, cytokines andimmunomodulators,

interferons,interferon alfa-2b, ATC code:L03AB05

IntronA isa sterile,stable,formulation ofhighlypurified interferon alfa-2b producedby

recombinantDNA techniques. Recombinant interferon alfa-2b is awater-solubleprotein with

amolecularweightofapproximately19,300daltons. It isobtainedfrom aclone ofE.coli,

whichharbours a geneticallyengineered plasmid hybrid encompassingan interferonalfa-2b

gene fromhuman leukocytes.

The activityof IntronA is expressedintermsofIU, with1mgofrecombinantinterferonalfa-

2b protein correspondingto2.6xl0 8 IU.International Units are determined bycomparison of

the activityof the recombinant interferon alfa-2bwiththe activityof the international

reference preparation ofhumanleukocyteinterferon established bythe WorldHealth

Organisation.

Theinterferons are afamilyofsmallprotein moleculeswithmolecularweights of

approximately15,000to21,000daltons.Theyareproduced andsecreted bycellsinresponse

to viralinfectionsorvarioussynthetic andbiological inducers. Threemajor classes of

interferonshavebeenidentified: alpha,beta andgamma.Thesethreemainclasses are

themselvesnothomogeneousandmaycontainseveraldifferentmolecularspeciesof

interferon. More than14 genetically distincthumanalpha interferons havebeenidentified.

IntronA hasbeen classifiedasrecombinant interferon alfa-2b.

Interferons exerttheir cellular activities bybindingtospecificmembranereceptorsonthecell

surface.Human interferonreceptors, asisolated fromhuman lymphoblastoid (Daudi)cells,

appear tobehighlyasymmetricproteins.Theyexhibitselectivityfor humanbut notmurine

interferons,suggesting species specificity. Studies withother interferons havedemonstrated

species specificity. However,certain monkeyspecies,eg,rhesusmonkeys,aresusceptibleto

pharmacodynamic stimulation uponexposure tohumantype1interferons.

The resultsofseveral studiessuggestthat, once bound tothe cell membrane,interferon

initiates a complexsequenceof intracellulareventsthatincludetheinductionofcertain

enzymes.Itisthought thatthis process, at least inpart, is responsible forthevarious cellular

responses to interferon, includinginhibitionofvirus replication invirus-infected cells,

suppression ofcell proliferation and suchimmunomodulating activities asenhancementofthe

phagocyticactivityofmacrophagesandaugmentationofthe specific cytotoxicityof

lymphocytes for target cells. Anyorallofthese activities maycontributetointerferon's

therapeutic effects.

Recombinant interferonalfa-2bhasexhibitedantiproliferative effects in studies employing

both animal andhumancellculturesystemsaswell ashuman tumour xenograftsinanimals.

Ithas demonstratedsignificantimmunomodulatoryactivityin vitro.

Recombinant interferonalfa-2balsoinhibits viral replicationinvitroandinvivo. Although

the exactantiviralmodeof action of recombinant interferon alfa-2b isunknown,it appears to

alter thehostcellmetabolism.This action inhibitsviral replication or if replication occurs, the

progenyvirions areunabletoleave the cell.

Chronic hepatitisB:

Currentclinicalexperience inpatients whoremain on interferonalfa-2bfor 4to 6 months

indicatesthat therapycanproduceclearance ofserum HBV-DNA. Animprovementinliver

histologyhasbeen observed.InadultpatientswithlossofHBeAgand HBV-DNA, a

significant reduction inmorbidityand mortalityhasbeen observed.

Interferon alfa-2b (6 MIU/m 2 3times aweekfor6months) hasbeen giventochildrenwith

chronicactivehepatitisB. Because ofamethodologicalflaw,efficacycould not be

demonstrated.Moreover childrentreatedwithinterferon alfa-2bexperienceda reducedrate of

growth andsomecases of depressionwere observed.

Chronic hepatitisC:

Inadult patientsreceivinginterferonin combinationwith ribavirin,the achievedsustained

response rateis 47 %. Superior efficacyhas beendemonstratedwiththe combinationof

pegylatedinterferon withribavirin (sustainedresponserate of61% achievedina study

performedinnaïvepatients witharibavirindose> 10.6 mg/kg,p<0.01).

Adult patients: IntronA aloneor in combinationwithribavirinhasbeenstudied in

4 randomisedPhase III clinicaltrials in2,552 interferon-naïvepatients withchronichepatitis

C.The trialscomparedtheefficacyofIntronAusedalone orin combinationwith ribavirin.

Efficacywas defined as sustainedvirologic response,6 monthsafter the end of treatment.

Eligiblepatients for these trials hadchronic hepatitisC confirmedbyapositiveHCV-RNA

polymerasechainreaction assay(PCR)(>100copies/ml),aliver biopsyconsistentwitha

histologicdiagnosis of chronic hepatitiswithno othercause for the chronic hepatitis,and

abnormal serumALT.

IntronA wasadministered atadose of 3MIU 3times a weekas monotherapyorin

combinationwithribavirin.Themajorityofpatients inthese clinicaltrials weretreated for

oneyear. All patients werefollowedforanadditional 6 monthsaftertheendoftreatmentfor

thedeterminationof sustainedvirologicresponse.Sustainedvirologic responseratesfor

treatmentgroups treated for one year with IntronA aloneorin combination withribavirin

(fromtwostudies) are showninTable 4.

Co-administrationofIntronA withribavirin increasedthe efficacyofIntronAbyatleast two

fold for the treatmentof chronic heptatitisCinnaïvepatients.HCVgenotypeand baseline

virusloadare prognosticfactors whichare knownto affect response rates.Theincreased

responseratetothecombination ofIntronA+ribavirin,compared withIntronA alone, is

maintained acrossall subgroups.The relativebenefit ofcombinationtherapywith IntronA+

ribavirinisparticularlysignificant inthe mostdifficulttotreat subgroupofpatients(genotype1

and high virus load)(Table4).

Response rates inthesetrialswereincreasedwith compliance. Regardlessofgenotype,

patients whoreceived IntronA incombination with ribavirin and received ≥80% oftheir

treatmenthadahighersustainedresponse6monthsafter 1yearoftreatmentthanthose who

took< 80 % oftheirtreatment(56% vs.32%intrial C/I98-580).

Table 4 Sustained virologic responserateswithIntronA + ribavirin(oneyearof

treatment)bygenotypeandviral load

HCV Genotype

I

N=503

C95-132/I95-143 I/R

N=505

C95-132/I95-143 I/R

N=505

C/I98-580

AllGenotypes

16%

41%

47 %

Genotype1

9 %

29%

33%

Genotype 1

≤2million

copies/ml

25%

33%

45%

Genotype 1

> 2million

copies/ml

3 %

27%

29%

Genotype2/3

31%

65%

79%

I IntronA(3MIU3 times a week)

I/R IntronA(3MIU3times a week)+ ribavirin (1,000/1,200 mg/day)

Relapsepatients: A total of345interferon alpharelapse patientsweretreated in two clinical

trials with IntronAmonotherapyorin combinationwith ribavirin. Inthesepatients, the

addition of ribavirin toIntronA increasedbyasmuchas10-fold the efficacyofIntronAused

alone in the treatmentofchronic hepatitis C (48.6% vs. 4.7%). Thisenhancementinefficacy

included lossofserumHCV (<100copies/mlbyPCR),improvement in hepatic

inflammation,and normalisationofALT,and was sustainedwhen measured 6 monthsafter

the endof treatment.

Long-Termefficacydata

Inalarge study,1,071patientswere enrolled aftertreatment in aprior nonpegylated

interferon alfa-2bornonpegylatedinterferonalfa-2b/ribavirinstudytoevaluatethedurability

of sustainedvirologic response and assesstheimpact ofcontinued viral negativityonclinical

outcomes. 462 patients completed at least5years of long-termfollow-upand only

12 sustainedresponders'outof 492relapsed duringthisstudy.

TheKaplan-Meierestimateforcontinuedsustained responseover5 years forall patientsis

97% witha 95% ConfidenceInterval of[95 %, 99%].

SVR after treatment ofchronic HCVwithnonpegylated interferonalfa-2b (withorwithout

ribavirin) resultsinlong-termclearance of the virusprovidingresolutionof thehepatic

infection andclinical'cure'fromchronicHCV. However,this does notprecludethe

occurrence of hepatic eventsinpatientswith cirrhosis(includinghepatocarcinoma).

Clinicaltrialsinpaediatric patientswithchronic hepatitisC:

Childrenandadolescents3 to 16years ofagewithcompensated chronic hepatitis Cand

detectable HCV-RNA (assessedbyacentrallaboratoryusingaresearch-based RT-PCR

assay)were enrolledintwo multicentretrials andreceived IntronA 3 MIU/m 2 3 timesaweek

plusribavirin 15mg/kgperdayfor 1yearfollowedby6monthsfollow-upafter-treatment. A

totalof118patientswereenrolled: 57%male,80%Caucasian,and78% genotype1,64%

≤12years ofage. Thepopulationenrolledmainlyconsistedinchildren withmildtomoderate

hepatitis C. Sustained virologicalresponseratesinchildrenandadolescents weresimilar to

thoseinadults. Due tothe lackofdata inchildrenwithsevere progressionofthe disease, and

the potentialfor undesirableeffects, thebenefit/risk of thecombinationofribavirinand

interferon alfa-2bneeds tobecarefullyconsidered in this population (see sections4.1,4.4 and

4.8).

Studyresults are summarizedinTable 5.

Table 5. Virologicalresponse inpreviouslyuntreated paediatricpatients

IntronA 3 MIU/m 2 3 timesaweek

+

ribavirin 15mg/kg/day

Overall Response 1 (n=118) 54(46%)*

Genotype 1 (n=92) 33(36 %)*

Genotype 2/3/4(n=26) 21(81 %)*

*Number (%) ofpatients

1.Defined asHCV-RNAbelow limit ofdetectionusing aresearch basedRT-PCR assay at endoftreatmentand

during follow-upperiod

5.2Pharmacokinetic properties

Thepharmacokinetics ofIntronAwerestudiedin healthyvolunteers followingsingle

5 millionIU/m 2 and 10 millionIU dosesadministeredsubcutaneously,at 5millionIU/m 2

administeredintramuscularlyandasa30-minuteintravenous infusion. The mean serum

interferon concentrations following subcutaneous andintramuscular injectionswere

comparable. C

max occurredthree to12hoursafterthe lower doseandsixtoeight hours after

thehigher dose. The elimination half-lives of interferoninjectionswereapproximatelytwoto

three hours,and sixtosevenhours, respectively.Serumlevelswerebelow the detectionlimit

16 and24hours,respectively,post-injection.Bothsubcutaneousandintramuscular

administration resulted inbioavailabilities greater than100%.

After intravenous administration,seruminterferonlevelspeaked(135to273IU/ml)bythe

end of the infusion, then declinedat a slightlymore rapid rate thanafter subcutaneousor

intramuscularadministrationofmedicinal product,becoming undetectablefourhours after

the infusion. The eliminationhalf-life was approximatelytwo hours.

Urinelevels ofinterferonwere below thedetection limit following eachofthe threeroutesof

administration.

Childrenand adolescents:Multiple-dosepharmacokineticpropertiesfor IntronA injectionand

ribavirin capsules inchildrenandadolescentswithchronic hepatitis C,between 5and 16years

ofage,aresummarizedinTable 6. Thepharmacokinetics ofIntronAand ribavirin (dose-

normalized) are similar inadultsand children or adolescents.

Table 6.Mean (% CV)multiple-dose pharmacokineticparameters for IntronA andribavirin

capsules when administeredto childrenor adolescentswithchronic hepatitis C

Parameter Ribavirin

15mg/kg/dayas2 divided

doses

(n=17) IntronA

3 MIU/m 2 3 times aweek

(n = 54)

(hr) 1.9(83) 5.9 (36)

(ng/ml) 3,275(25) 51(48)

AUC* 29,774(26) 622(48)

Apparent clearance l/hr/kg 0.27(27) Not done

*AUC

(ng.hr/ml)for ribavirin;AUC

0-24 (IU.hr/ml)for IntronA

Interferon neutralising factor assayswereperformedonserum samplesofpatients who

received IntronAinSchering-Ploughmonitored clinical trials. Interferon neutralising factors

are antibodies which neutralise theantiviral activityofinterferon. The clinicalincidence of

neutralising factors developing incancer patientstreatedsystemicallyis2.9 %and in chronic

hepatitis patientsis 6.2 %. The detectable titresare low in almost all casesandhavenot been

regularlyassociated with lossofresponse or anyotherautoimmunephenomenon.In patients

with hepatitis, nolossof responsewas observed apparentlydue tothe low titres.

5.3 Preclinical safetydata

Althoughinterferon is generallyrecognisedasbeing species specific,toxicitystudies in

animals wereconducted. Injectionsofhumanrecombinant interferonalfa-2bfor uptothree

monthshaveshownnoevidenceoftoxicityinmice, rats, and rabbits.Dailydosingof

cynomolgusmonkeyswith20x 10 6 IU/kg/dayfor 3 months caused no remarkable toxicity.

Toxicitywasdemonstratedin monkeysgiven 100 x10 6 IU/kg/dayfor3months.

Instudiesofinterferonuse innon-humanprimates,abnormalities ofthe menstrualcycle have

beenobserved (seesection4.4).

Resultsofanimal reproductionstudiesindicatethat recombinant interferonalfa-2bwasnot

teratogenicin rats orrabbits, nordiditadverselyaffectpregnancy,foetaldevelopmentor

reproductivecapacityinoffspring of treatedrats. Interferon alfa-2bhasbeen shown tohave

abortifacient effectsinMacacamulatta(rhesusmonkeys) at 90 and180times the

recommended intramuscular orsubcutaneous dose of2million IU/m 2 . Abortionwas observed

in alldose groups (7.5million,15millionand 30millionIU/kg), andwas statistically

significant versuscontrol at themid- andhigh-dose groups (corresponding to90and

180 times the recommended intramuscularorsubcutaneousdose of 2million IU/m 2 ).High

doses of other forms ofinterferonsalphaand beta are known toproduce dose-related

anovulatoryandabortifacienteffects in rhesusmonkeys.

Mutagenicitystudies withinterferonalfa-2b revealednoadverse events.

No studieshavebeen conducted injuvenile animalstoexamine theeffects oftreatment with

interferonalfa-2b ongrowth,development,sexualmaturation, andbehaviour (see section 4.4

and RebetolSPC if IntronA is to be administeredin combination withribavirin).

6. PHARMACEUTICAL PARTICULARS

6.1List of excipients

odiumphosphate dibasic anhydrous,

Sodiumphosphate monobasic monohydrate,

Edetate disodium,

Sodiumchloride,

M-cresol,

Polysorbate 80,

Water for injections.

6.2 Incompatibilities

Thismedicinal productmust notbemixed withothermedicinal products except those

mentioned insection6.6.

6.3 Shelf life

18 months

6.4 Specialprecautions for storage

Store at2°C –8°C.

Donotfreeze.

Withinits shelf-life,for the purposeoftransport, the solutioncanbekept ator below25ºC for

a periodupto seven daysbefore use.IntronAcanbe putbackinthe refrigeratoratanytime

during thisseven-dayperiod. If theproduct isnotused during the seven-dayperiod, itcannot

be put backinthe refrigeratorfora new storageperiodandmustbediscarded.

6.5 Natureand contentsofcontainer

1 ml ofsolution(correspondingto 10MIU)ina vial (typeIglass), withastopper(halobutyl

rubber) inaflip-off seal(aluminium) withabonnet (polypropylene)

Packsizesof1

6.6 Specialprecautionsfor disposal

Notall dosageformsandstrengthsare appropriate forsomeindications. Pleasemakesureto

selectanappropriate dosage formand strength.

IntronAsolutionforinjectionorinfusion, maybe injecteddirectlyafterwithdrawalofthe

appropriatedosesfromthevial withasterileinjectionsyringe.

Detailed instructionsfor the subcutaneoususeofthe product are provided withthe package

leaflet (refer to“HowtoselfinjectIntronA”).

Preparationof IntronA forintravenous infusion: Theinfusionis tobeprepared immediately

prior touse. Anysizevialmaybeusedtomeasure the requireddose;however,final

concentration ofinterferon insodiumchloridesolutionmust benotlessthan

0.3million IU/ml.The appropriate dose ofIntronA iswithdrawnfromthe vial(s), addedto

50mlof9mg/ml (0.9 %) sodiumchloride solution for injection ina PVC bagor glassbottle

forintravenoususe and administeredover20minutes.

NOOTHER MEDICINAL PRODUCT CANBEINFUSEDCONCOMITANTLYWITH

INTRONA.

As withallparenteral medicinal products, prior toadministration inspect IntronA, solutionfor

injectionorinfusion, visuallyfor particulatematterand discolouration.Thesolutionshould

beclearand colourless.

Anyunusedproductmust be discardedafter withdrawalofthedose.

7. Manufacturer:

ScheringPlough(Brinny)countrycork,Ireland

8. Importer:

MerckSharp& Dohme(Israel-1996) CompanyLtd., P.O.Box7121, Petah-Tikva 49170.